Photosensitizing antihypertensive drug use and risk of cutaneous squamous cell carcinoma.

BACKGROUND: Many antihypertensive drugs (ADs) are photosensitizing, heightening reactivity of the skin to sunlight. Photosensitizing ADs have been associated with lip cancer, but whether they impact the risk of cutaneous squamous cell carcinoma (cSCC) is unknown. OBJECTIVES: To examine the association between AD use and cSCC risk among a cohort of non-Hispanic white individuals with hypertension enrolled in a comprehensive integrated healthcare delivery system in northern California (n = 28 357). METHODS: Electronic pharmacy data were used to determine exposure to ADs, which were classified as photosensitizing, nonphotosensitizing or unknown, based on published literature. We identified patients who developed a cSCC during follow-up (n = 3010). We used Cox modelling to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Covariates included age, sex, smoking, comorbidities, history of cSCC and actinic keratosis, survey year, healthcare utilization, length of health plan membership and history of photosensitizing AD use. RESULTS: Compared with nonuse of ADs, risk of cSCC was increased with ever having used photosensitizing ADs (aHR = 1·17, 95% CI 1·07-1·28) and ever having used ADs of unknown photosensitizing potential (aHR = 1·11, 95% CI 1·02-1·20), whereas no association was seen with ever having used nonphotosensitizing ADs (aHR = 0·99; 95% CI 0·91-1·07). Additionally, there was a modest increased risk with an increased number of prescriptions for photosensitizing ADs (aHR = 1·12, 95% CI 1·02-1·24; aHR = 1·19, 95% CI 1·06-1·34; aHR = 1·41, 95% CI 1·20-1·67 for one to seven, eight to 15 and ≥ 16 fills, respectively). CONCLUSIONS: These findings provide moderate support for an increased cSCC risk among individuals treated with photosensitizing ADs.

Hydrochlorothiazide use is strongly associated with risk of lip cancer.

BACKGROUND: The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. OBJECTIVES: To study the association between use of hydrochlorothiazide and squamous cell carcinoma of the lip. METHODS: We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined potential confounders obtained from demographic, prescription and patient registries. RESULTS: Ever-use of hydrochlorothiazide was associated with an adjusted OR for SCC lip cancer of 2.1 (95% confidence interval (CI): 1.7-2.6), increasing to 3.9 (95%CI: 3.0-4.9) for high use (≥25 000 mg). There was a clear dose-response effect (P < 0.001), with the highest cumulative dose category of hydrochlorothiazide (≥100 000 mg) presenting an OR of 7.7 (95%CI: 5.7-10.5). No association with lip cancer was seen with use of other diuretics or nondiuretic antihypertensives. Assuming causality, we estimated that 11% of the SCC lip cancer cases could be attributed to hydrochlorothiazide use. CONCLUSIONS: Hydrochlorothiazide use is strongly associated with an increased risk of lip cancer.

Feasibility of collecting tumor samples of breast cancer patients diagnosed up to 50 years ago in the Child Health and Development Studies.

Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.

Histological classification of gastric adenocarcinoma for epidemiological research: concordance between pathologists.

Epidemiology of gastric adenocarcinoma suggests that intestinal-type and diffuse-type cancers develop through distinct causal pathways. To examine the differences in risk factors and molecular changes between the histological types, reliable data on histological typing are essential. We evaluated the concordance between two pathologists in assessment of 95 gastric adenocarcinomas for Laurén classification and tumor grade. Two pathologists, each blinded to the other's assessment, reviewed H&E-stained slides of gastric tumor. The responses of the two pathologists for histological type were considered as concordant if they fell on one of the three categories (intestinal type, diffuse type, or other). Tumor grade was classified into three categories (well, moderately, or poorly differentiated). The pathologists agreed on the classification of histological type for 71 of 92 (77%) tumors. Kappa coefficient was 0.59 (95% confidence interval, 0.44-0.73). Concordance for tumor grade was 87%, with a kappa coefficient of 0.72 (95% confidence interval, 0.57-0.87). Both observed concordance and kappa coefficient for histological type and tumor grade were similar across three calendar periods of study. Interobserver agreement was virtually identical between tumors with biopsy specimens only and those with surgical specimens. Although the level of disagreement for histological type observed in this study is comparable with that in other studies, the resulting misclassification would lead to the reduction in observed differences in prevalence and odds ratio estimates between two histological types.

Body size, age at shaving initiation, and prostate cancer in a large, multiracial cohort.

BACKGROUND: The purpose of this study was to examine the potential relationship between body size, self-reported age at initiation of shaving, and subsequent risk of prostate cancer in a large, racially diverse cohort of men followed for up to 32 years. METHODS: The study population included 70,712 male subscribers to the Kaiser Permanente Medical Care Program who had received a multiphasic health checkup between 1964-1973. This general health checkup consisted of a number of laboratory tests and physical measurements, as well as a self-completed health questionnaire that included a request for men to record the age when they began shaving. Subjects were followed for the development of prostate cancer, using the local tumor registry. Cox regression was used to estimate relative risks (RR) and 95% confidence intervals (CI). RESULTS: Altogether, 2, 079 men in the study cohort were diagnosed with prostate cancer. There was a very strong positive association between prostate cancer risk and birth cohort. After adjusting for race, age, and birth year, there was no association between height, weight, body mass index, or several other anthropometric measures and prostate cancer risk in the full cohort. There was a suggestion of a very weak positive association between height and prostate cancer risk among white men. There also was no overall association between age at shaving initiation and prostate cancer risk, although nonwhite men who started shaving at a young age (

Cimetidine use and risk of breast, prostate, and other cancers.

Purpose - The study was conducted to examine whether use of cimetidine is associated with the risk of cancer, with special attention to cancers of the breast and prostate because cimetidine increases estradiol levels and interferes with androgen binding. Methods - Individuals who received a prescription of cimetidine were identified from two computerized pharmacy databases of medications dispensed at Northern California Kaiser Permanente between 1982 and 1987. Users of ranitidine, a histamine-2 receptor antagonist that does not appear to influence estrogen levels or androgen binding, and non-users of either cimetidine or ranitidine, were also identified from these databases. Study subjects were followed through December 1995 for new diagnoses of cancer. Cox regression was used to estimate relative risks of cancer associated with use of cimetidine and ranitidine. Non-users of cimetidine and ranitidine were the referent group for all analyses. Result - While there were very modest increases and decreases in risk for some cancer sites among cimetidine users, most were within the limits of chance given no true association. Furthermore, similar risks of these cancers were also observed among ranitidine users. Conclusions - Although our results do not support an association between cancer risk and cimetidine use, it is one of the most widely prescribed drugs in the US and may now be purchased over-the-counter. The potential effect of cimetidine on risk of cancer, especially those that are hormone-related, should continue to be monitored, preferably in larger study populations. Copyright (c) 2000 John Wiley & Sons, Ltd.

Barbiturates and lung cancer: a re-evaluation.

BACKGROUND: Barbiturates, particularly phenobarbital, have been shown to be a tumour promoter in animal experiments and were found to be associated with increased risk of lung cancer in our cohort follow-up study to screen pharmaceuticals for possible carcinogenic effects. Sixteen more years of follow-up have accumulated permitting a more detailed evaluation of this association. METHODS: In all, 10,213 subscribers of the Kaiser Permanente Medical Care Program who received barbiturates between 1969 and 1973 from its San Francisco pharmacy were followed up through 1992 and their incidence of lung cancer at biennial intervals was compared with what was expected based on the experience of the entire pharmacy cohort (143,594). Smoking-habit data were available on about half of the barbiturate users and were used to adjust for cigarette smoking in both the observed/expected analysis and in Cox proportional hazards analysis. RESULTS: The initially elevated standard morbidity ratio of 1.55 (95% CI: 1.25-1.91) with 3-7 years of follow-up gradually decreased and stabilized at about 1.3 after 11-15 years of follow-up. This trend for diminishing relative risk over time was more pronounced among the never smokers but their initial excess risk was not statistically significant due to small numbers. A dose-response trend was observed, based on the number of prescriptions dispensed. Analytical control for cigarette smoking reduced but did not eliminate either the association or the dose-response trend. Most of the barbiturate-associated cases in never smokers were women and the predominant histological type was adenocarcinoma. CONCLUSIONS: These findings from up to 23 years of follow-up are not conclusive because of the continuing small number of never smokers who developed lung cancer. However, they strengthen and refine previous observations of a barbiturate-lung cancer association, which is probably not fully explained by confounding by cigarette smoking. The diminution of excess risk over time is consistent with a tumour promoter effect. Findings among the never smokers suggest that this possible effect may be greatest on adenocarcinomas in women.

Barbiturates, smoking, and bladder cancer risk.

Phenobarbital treatment has been observed to be negatively associated with bladder cancer risk in a few studies. It has been suggested that phenobarbital may induce drug-metabolizing enzymes that detoxify the bladder carcinogens found in cigarette smoke. We examined the relationship of barbiturate use to bladder cancer risk and the potential modifying effect of cigarette smoking in a large cohort of Kaiser Permanente Medical Care Program members with computerized pharmacy prescriptions and smoking information. Newly diagnosed bladder cancers were identified among individuals in the study cohort by linkage with data from cancer registries. The overall standardized incidence ratio associated with barbiturate use was 0.71 [95% confidence interval (CI), 0.51-0.99]. Among current smokers, former smokers, and never smokers, the standardized incidence ratios were 0.56 (95% CI, 0.23-1.16), 0.68 (95% CI, 0.27-1.40), and 1.04 (95% CI, 0.48-1.98), respectively. Although our estimates were imprecise, the finding of an inverse association between barbiturate treatment and bladder cancer risk only among current and former cigarette smokers is consistent with the hypothesis that treatment with these medications induces drug-metabolizing enzymes that deactivate bladder carcinogens found in cigarette smoke.

Risk of recurrence after ductal carcinoma in situ of the breast.

A cohort study was conducted to estimate the risk of breast cancer recurrence among women diagnosed with ductal carcinoma in situ (DCIS) and to identify tumor or patient characteristics that influence that risk. A population-based cancer registry was used to identify a cohort of 709 female residents of western Washington who were diagnosed with DCIS between January 1980 and June 1992 and were treated with breast-conserving surgery. Information about breast cancer recurrences, treatment, and several patient characteristics and exposures was obtained from postal questionnaires. Recurrences were confirmed using information from the cancer registry or hospital pathology reports. Approximately 15% of women experienced a recurrence within the first 5 years after diagnosis [95% confidence interval (CI), 12-18%]; 31% had a recurrence within 10 years (95% CI, 24-38%). There was a suggestion that risk was slightly elevated for women with larger tumors (> or =1.5 cm) and tumors of comedo subtype. Relative risks (RRs) were elevated for women who were premenopausal at diagnosis of DCIS (RR = 2.3; 95% CI, 1.1-5.0). Women in the upper decile of body mass index were at twice the risk of a recurrence as those women in the lower four deciles (RR = 2.3; 95% CI, 1.1-4.8). There was also a suggestion that women who used menopausal hormones for at least 2 years after their diagnosis of DCIS were at increased risk of recurrence compared to nonusers of menopausal hormones (RR = 1.8; 95% CI, 0.7-5.0). Our results suggest that the risk of recurrence may be related to some tumor characteristics as well as the hormonal milieu of the patient at or after her diagnosis of DCIS. However, larger studies are needed to more clearly document predictors of disease recurrence after DCIS.

Risk factors for incident and recurrent condylomata acuminata among men. A population-based study.

BACKGROUND AND OBJECTIVES: The rapid increase in the number of physician office visits for condylomata acuminata and the association of human papillomavirus and cancer has prompted renewed interest in the epidemiology of this sexually-transmitted disease. Few epidemiologic studies have examined what risk factors are associated with condylomata acuminata in men. GOAL: To determine what factors may predispose a man to the occurrence of condylomata acuminata. STUDY DESIGN: A population-based case-control study was conducted among male members of a health maintenance organization. Patients were men 18 years or older who were seen for condyloma at one of four primary care clinics of Group Health Cooperative of Puget Sound between April 1, 1987 and September 30, 1991. Control subjects were frequency matched to the patients on clinic site, race, and age. In-person interviews were used to ascertain exposure histories from both patients and control subjects. RESULTS: Recurrent condyloma was reported by about one third of our patients. Patients with multiple partners were strongly associated with developing the disease. Several factors were either more strongly or only associated with recurrent disease. Other behavioral measures, such as recreational drug use, were also related the occurrence of condyloma. CONCLUSION: These results confirm the sexual-transmitted mechanism of condyloma in men. Exposure to multiple partners was associated with elevated risk of both recurrent and incident disease. Other cofactors may be involved in the etiology of condyloma.

Risk factors for incident and recurrent condylomata acuminata among women. A population-based study.

BACKGROUND: Condylomata acuminata is one of the most common sexually transmitted diseases (STDs) diagnosed in the United States, yet relatively little research has been conducted on the determinants of this disease in well-defined populations. GOAL: To determine the exposures that predispose a woman to the development of condylomata acuminata or genital warts. STUDY DESIGN: A population-based case-control study was conducted among enrollees of Group Health Cooperative of Puget Sound. Patients (94 women with incident and 55 women with recurrent condyloma) were diagnosed between April 1, 1987 and September 30, 1991. Control subjects were 133 women without a history of genital warts. An in-person interview was conducted to collect information on subject characteristics, exposures, and on all episodes of genital warts. RESULTS: Women with five or more partners within the 5 years before reference date were over seven times more likely to have incident condyloma (relative risk [RR], 7.5; 95% confidence interval [CI], 3.1-18.1) and over 12 times more likely to have recurrent condyloma (RR, 12.8; 95% CI, 4.2-38.9) compared with women with only one sexual partner during this time period. An increased risk of incident condyloma was also associated with a history of any STD (RR, 2.6; 95% CI, 1.1-5.8), a history of oral herpes (RR, 2.2; 95% CI, 1.1-4.4), and a history of allergies (RR, 2.0 95% CI, 1.0-3.8). Our data did not support a strong association between risk of condyloma and smoking or recent use of oral contraceptives. CONCLUSION: Our results suggest that risk of condyloma is primarily related to sexual behavior. We did not observe a strong association between risk of condyloma and many of the exposures considered to be potential cofactors for anogenital cancers associated with other types of human papillomaviruses.

Risk of contralateral breast cancer among women with carcinoma in situ of the breast.

BACKGROUND: Information is limited on the risk of contralateral breast cancer after a diagnosis of breast carcinoma in situ (BCIS). METHODS: In western Washington, between 1974 and 1993, 1929 women with a first primary ductal carcinoma in situ (DCIS) and 282 women with a first primary lobular carcinoma in situ (LCIS) were followed for contralateral breast cancer. Rates of contralateral invasive breast cancer and BCIS were compared with population rates of first primary breast cancer using Poisson regression to adjust for age and calendar year. RESULTS: The rate of contralateral invasive disease after BCIS was approximately twice the population rate for women with DCIS and three times the population rate for women with LCIS; relative rates decreased somewhat with increasing time since diagnosis of LCIS, but were fairly stable after DCIS. The relative rate of contralateral DCIS after BCIS was substantially higher than for contralateral invasive disease, but dropped dramatically after the first year after the initial BCIS, especially among women with LCIS. Contralateral BCIS usually was of the same histologic type as the initial BCIS; histologic concordance of BCIS was 71% for women with an initial LCIS and 78% for women with DCIS. CONCLUSIONS: Data suggest that the rate of contralateral invasive breast cancer is elevated for at least 5 years after a diagnosis of BCIS compared with the rate of first primary breast cancer in the population, and that the rate is only slightly higher for women with LCIS than for women with DCIS. The markedly elevated rate of contralateral DCIS may result in large part from increased medical surveillance of women diagnosed with BCIS, especially during the first year after the initial diagnosis.

Oral contraceptive use and risk of breast cancer in middle-aged women.

The authors used data from a population-based, case-control study of breast cancer conducted among women residing in King County, Washington State, who were 50-64 years of age in 1988-1990, to examine the relation of oral contraceptive use to the risk of breast cancer. There were no clear differences between cases and controls with respect to the total duration of oral contraceptive use, time since last use, or age at first or last use. While a small increase in risk was noted in women who had first used oral contraceptives within 20 years of the interview reference date, within that period there was no trend in risk observed with decreasing amounts of time since the last use of these agents. Overall, this study supports the absence of any strong association between oral contraceptive use and breast cancer risk during middle age in the cohort of women who first used these drugs.

Use of human papillomavirus type 6 capsids to detect antibodies in people with genital warts.

Human papillomavirus (HPV) type 6 capsids were produced by recombinant vaccinia viruses and used in a capture ELISA to screen 901 human sera from three studies of genital HPVs. The highest seroprevalence was observed among subjects with recurrent genital warts. In a population-based case-control study of genital warts, 26 (58%) of 45 women with recurrent genital warts were seropositive compared with 19 (19%) of 101 control women with no history of genital warts (odds ratio, 6.5; 95% confidence interval, 3.0, 14.1). Among a cohort of pregnant women, 7 (88%) of 8 with recurrent warts were seropositive compared with 24 (30%) of 79 pregnant women with no such history. A significant association between seropositivity to HPV-6 capsids and the detection of HPV-6/11 DNA from genital specimens by polymerase chain reaction was also observed. Men with genital warts were less likely to be seropositive than were women with genital warts, and a positive association between the number of sex partners and seropositivity was observed among only the female university students.

Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women.

OBJECTIVE: To determine the risk of breast cancer in relation to the use of combined estrogen and progestin hormone replacement therapy (HRT). DESIGN: A population-based case-control study. SETTING: The general female population of King County in western Washington State. PARTICIPANTS: Middle-aged (50 to 64 years) women, including 537 patients with incident primary breast cancer diagnosed between January 1, 1988, and June 30, 1990, who were ascertained through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry and 492 randomly selected control women without a history of breast cancer. MAIN OUTCOME MEASURE: Breast cancer risk in relation to use of menopausal hormones. RESULTS: Menopausal hormones of some type had been used by 57.6% of breast cancer cases and 61.0% of comparison women. The women who had ever taken combined estrogen-progestin HRT, representing 21.5% of cases and 21.3% of controls, were not at increased risk of breast cancer (relative odds [RO] = 0.9; 95% confidence interval [CI], 0.7 to 1.3). Compared with nonusers of menopausal hormones, those who used estrogen-progestin HRT for 8 or more years had, if anything, a reduced risk of breast cancer (RO = 0.4; 95% CI, 0.2 to 1.0). CONCLUSIONS: On the whole, the use of estrogen with progestin HRT does not appear to be associated with an increased risk of breast cancer in middle-aged women. Nonetheless, since the use of combined estrogen-progestin HRT has only recently become prevalent, future investigations must assess whether breast cancer incidence is altered many years after estrogen-progestin HRT has been initiated, particularly among long-term users.

Occupation and breast cancer risk in middle-aged women.

The authors analyzed data from a population-based case-control study of breast cancer in middle-aged women residing in King County, Washington, to examine the relation between occupation and breast cancer risk. A total of 537 cases and 492 controls completed in-person interviews. Subjects provided job titles and years of employment for their three main occupations since age 18. While there were case-control differences in the frequency with which certain jobs were reported, all were within the limits of chance, given no true association. Also, few additional increases in risk were associated with long-term employment. Relative risk (RR) estimates were elevated for women working in precision textile and apparel jobs (six cases and one control, RR = 5.2). To a lesser extent, RR estimates were also elevated for receptionists, cosmetologists, and the category of painters/sculptors/printmakers. A slight increase in risk was associated with several occupations, including nursing and teaching.

Diet and genital warts: a case-control study.

BACKGROUND AND OBJECTIVES: Clinical observations support a substantial role for impaired immunity in the development of human papillomavirus (HPV) infections. Intake of vitamins, especially vitamins A and C, and alcohol consumption have been reported to influence immune response. GOAL OF THE STUDY: To examine the relationship between nutritional risk factors, including alcohol consumption, and the risk of genital warts. STUDY DESIGN: A case-control study was conducted among enrollees at four clinics of Group Health Cooperative in western Washington state. A total of 188 cases diagnosed with condyloma from April 1, 1987 to September 30, 1991 and 245 controls completed a semi-quantitative food frequency questionnaire. RESULTS: After adjustment for socioeconomic indicators, total energy intake, smoking and sexual behavior, a weekly consumption of two to four alcoholic drinks was associated with an almost doubled risk of genital warts (OR = 1.9, 95% confidence interval [CI] = 1.0-3.6). Consuming five or more alcoholic drinks per week was even more related to the risk of genital warts (OR = 2.4, 95% CI = 1.2-5.1). The risks tended to increase with the number of alcoholic drinks (P = 0.006). Vitamin A and C intakes as measured by a food frequency questionnaire did not alter the risk of condyloma. CONCLUSION: Moderately high consumption of alcohol is associated with increased risk of condyloma. Further biological and epidemiological studies are needed to explain this association.

Influenza in the elderly: report of an outbreak and a review of vaccine effectiveness reports.

An outbreak of influenza A in nursing home residents is reported and other studies of influenza vaccine effectiveness in elderly populations are reviewed. The outbreak occurred in a Los Angeles nursing home between February and March 1983. Of the 87 residents, 46 (53%) were affected with influenza-like illness. Attack rates were similar between immunized and unimmunized residents (52% versus 58%), and yielded a vaccine effectiveness estimate of 10%. No additional protection could be demonstrated in residents who received vaccine for two consecutive years. Seven persons died (mortality rate of 8.1%); the mortality rate was greater in the unimmunized (15.8%) than in the immunized (6.2%). Because this study and other field studies of influenza vaccine are limited in precision and power, a statistical summary of the various studies was constructed. Summarizing the studies of institutionalized elderly (in hospitals and nursing and retirement homes) yielded an estimate of 74% for the average vaccine effectiveness in mortality reduction, and an estimate of 33% for the average effectiveness in preventing clinical illness. For the non-institutionalized elderly, the corresponding estimates were 47% for mortality, and 5% for clinical illness. Despite the obvious limitations of such summaries, it seems reasonable to conclude that influenza vaccines have on the average been of clear benefit in the institutionalized elderly, while the benefits in the non-institutionalized elderly have been less dramatic and may warrant further investigation.

Clinical effectiveness of rubella vaccine in a college population.

An outbreak of rash-like illness compatible with rubella occurred among the student population of a large university in Los Angeles between November 1, 1981 and January 31, 1982. A case-control study was conducted in order to estimate the effectiveness of rubella vaccine in preventing clinical rubella in this university population. Immunization and disease histories were obtained from parents and physicians for 39 cases and 86 controls. For those students with a clear documentation of immunization history, only one of 16 cases (6%) had evidence of prior rubella immunization, compared with 40 of 56 controls (71%). This yielded an estimated vaccine effectiveness of 97% (95% confidence limits of 82% to 100%). The level of protection observed for students immunized with rubella vaccine in our study population was high and comparable to that reported in other recent studies. This supports the notion that the current large reservoir of young adult susceptibles is primarily attributable to past failures to vaccinate school-age children, rather than vaccine failures.