William Henry, Duke of Gloucester (1689-1700), son of Queen Anne (1665-1714), could have ruled Great Britain.

Hope for continuation of the Stuart dynasty in Britain ended with the death, from pneumonia in 1700, of the 11-year-old son of Princess Anne and Prince George, William Henry Duke of Gloucester. Considered by some to have been physically and mentally unfit to reign, careful examination of primary source materials shows him to have been a bright and interesting boy with mild hydrocephalus. Had he lived, he could have ruled.

Integrative assessment of multiple pesticides as risk factors for non-Hodgkin's lymphoma among men.

BACKGROUND: An increased rate of non-Hodgkin's lymphoma (NHL) has been repeatedly observed among farmers, but identification of specific exposures that explain this observation has proven difficult. METHODS: During the 1980s, the National Cancer Institute conducted three case-control studies of NHL in the midwestern United States. These pooled data were used to examine pesticide exposures in farming as risk factors for NHL in men. The large sample size (n = 3417) allowed analysis of 47 pesticides simultaneously, controlling for potential confounding by other pesticides in the model, and adjusting the estimates based on a prespecified variance to make them more stable. RESULTS: Reported use of several individual pesticides was associated with increased NHL incidence, including organophosphate insecticides coumaphos, diazinon, and fonofos, insecticides chlordane, dieldrin, and copper acetoarsenite, and herbicides atrazine, glyphosate, and sodium chlorate. A subanalysis of these "potentially carcinogenic" pesticides suggested a positive trend of risk with exposure to increasing numbers. CONCLUSION: Consideration of multiple exposures is important in accurately estimating specific effects and in evaluating realistic exposure scenarios.

Increased lymphocyte replicative index following 2,4-dichlorophenoxyacetic acid herbicide exposure.

OBJECTIVE: Evaluate peripheral blood lymphocyte proliferation (replicative index:RI) and micronuclei frequency (MF) among 2,4-D herbicide applicators. METHODS: Twelve applicators spraying only 2,4-D provided a blood and urine specimen upon enrollment, several urine samples during the spraying season, and a blood specimen at the study's end. Nine controls provided blood and urine specimens upon enrollment and at the study's end. Gas chromatography/tandem mass spectroscopy determined urinary 2,4-D levels and standard in-vitro assays determined RI and MF scores. Applicator RI and MF were compared before and after spraying and with controls. RESULTS: Applicators contributed 45 urine specimens with concentrations ranging from 1.0 to 1700 (microg 2,4-D/g creatinine/L urine) that logarithmically (In) increased as spraying time increased. Applicator RI increased after spraying (p = 0.016), independent of tobacco and alcohol use, and demonstrated a weak dose-response with increasing urinary 2,4-D levels (p = 0.15). Among 2,4-D applicators, pre-exposure complete blood counts and lymphocyte immunophenotypes were not significantly different from post-exposure measurements. CONCLUSION: Urinary 2,4-D concentration, an exposure biomarker, may be associated with lymphocyte replicative index, a cell proliferation biomarker.

Very long survival in pediatric cancer between 1944 and 1993.

OBJECTIVE: To identify factors associated with very long survival among all cancer cases diagnosed at age 19 years or younger registered by the Cancer Data Service at the University of Kansas Medical Center in Kansas City, Kansas, U.S.A. in the 40-year period between 1944 and 1983, with follow-up to 1993. METHODS: There were 2720 pediatric patients with 2750 cancers who were studied. Forty-four types of cancer were grouped into 11 diagnostic categories. Diagnosis years spanned four eras: 1944-1953, 1954-1963, 1964-1973, and 1974-1983. Cases were compared using specific characteristics and were divided into short-term and long-term survivors with the division generously set at seven years. The proportions of the long-term survivors were compared by specific characteristics. RESULTS: Among the diagnostic categories, leukemias were the most common (29.8%), followed by CNS tumors (15.2%), and Hodgkin's disease (9.0%). Male to female ratio was 4:3; average age at diagnosis was 8.83 +/- 6.08 years. Long-term survivors totaled 1148 (41.7%). Prognosis was better in cases diagnosed in earlier stages and in later eras. Proportion of long-term survivors increased from 18.7% in era I to 52.6% in era IV. Improvement of survival was statistically significant in most diagnostic categories. CONCLUSIONS: This study shows continuing improvement of survival during four consecutive eras for childhood and adolescent cancer. Early diagnosis was associated with better survival. Unstaged cases decreased over time reflecting progress in diagnostic techniques. Many patients died before seven years after diagnosis. Those who survived more than seven years had excellent survival. Pediatricians can expect to participate in the care of these patients long after the original dianosis and treatment.

Genetic disease in offspring of long-term survivors of childhood and adolescent cancer.

Numerous case series have addressed the concern that cancer therapy may damage germ cells, leading to clinical disease in offspring of survivors. None has documented an increased risk. However, the methodological problems of small series make it difficult to draw firm conclusions regarding the potential of cancer treatments to damage the health of future offspring. We conducted a large interview study of adult survivors of childhood cancer treated before 1976. Genetic disease occurred in 3.4% of 2,198 offspring of survivors, compared with 3.1% of 4,544 offspring of controls (P=.33; not significant); there were no statistically significant differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. A comparison of survivors treated with potentially mutagenic therapy with survivors not so treated showed no association with sporadic genetic disease (P=.49). The present study provides reassurance that cancer treatment using older protocols does not carry a large risk for genetic disease in offspring conceived many years after treatment. With 80% power to detect an increase as small as 40% in the rate of genetic disease in offspring, this study did not do so. However, we cannot rule out the possibility that new therapeutic agents or specific combinations of agents at high doses may damage germ cells.

Tobacco and non-Hodgkin's lymphoma: combined analysis of three case-control studies (United States).

The role of tobacco in the etiology of non-Hodgkin's lymphoma (NHL) was evaluated in a combined analysis of data from three population-based case-control studies conducted in four midwestern states of the United States: Nebraska, Iowa, Minnesota, and Kansas. Interviews were obtained from 1,177 cases (993 men, 184 women) and 3,625 controls (2,918 men, 707 women) or, if deceased, from their next-of-kin. Overall, there was no association between NHL and tobacco use (odds ratio [OR] = 1.0, 95 percent confidence interval [CI] = 0.8-1.1) or cigarette smoking (OR = 1.0, CI = 0.8-1.1). A slight negative association evident in analyses by intensity and duration of smoking was not present when interviews from proxy respondents were eliminated. There was a suggestion of a positive association between smoking and NHL among women (OR = 1.3, CI = 0.9-1.9), although there was no clear exposure-response relationship. This large case-control analysis provides no evidence that smoking is linked to the development of NHL among men. The possible role of smoking in the etiology of NHL among women needs further evaluation.

Effect of age on survival in acute leukemia. 1950-1990.

BACKGROUND: Four decades ago, survival of patients with acute leukemia was brief at any age. Since 1950, survival of children has increased remarkably but has changed little for the elderly. The nature and magnitude of this age difference in survival are not understood. METHODS: Median survival was determined in 2364 Kansas residents diagnosed with acute leukemia from 1947 until 1990. Of this number, 1032 had acute lymphocytic leukemia and 1227 had acute myelocytic leukemia diagnosed between 1950 and 1989. These patients were stratified by age and decade of diagnosis. Survival was computed by life-table analysis with significance determined by log-rank, Wilcoxon, and Fisher exact tests. RESULTS: During the 40 years of the study, highly significant increases occurred in median survivals for all groups with either acute lymphocytic leukemia or acute myelocytic leukemia occurring in patients younger than 60 years of age (P < 0.0001 for some age groups), but no significant increases for those 61 to 80 years of age and those 81 years of age and older. Viewed in another dimension, for each decade from the 1960s to the present in acute lymphocytic leukemia and from the 1970s to the present in acute myelocytic leukemia, age at diagnosis was inversely correlated with median survival in a highly significant manner (P < 0.001). CONCLUSIONS: Increasing age is inversely related to survival in patients with acute leukemia. The lack of significant improvement in median survival in the last 40 years for those older than 60 years of age stands in stark contrast to the remarkable improvement for younger patients. Acute leukemia in older patients demands new and probably different therapeutic strategies.

Role of the herbicide atrazine in the development of non-Hodgkin's lymphoma.

Atrazine is the most commonly used herbicide in the United States and is a wide-spread groundwater contaminant in the Midwest. The role of atrazine in the development of human non-Hodgkin's lymphoma (NHL) was investigated in three case-referent studies conducted in four midwestern states in the United States. A total of 993 white men with NHL and 2918 population-based referents were interviewed concerning their agricultural practices. When the results of the three studies were combined, atrazine use was associated with an odds ratio of 1.4 [95% confidence interval (95% CI) 1.1-1.8, 130 cases, 249 referents) for NHL. However, adjustments for the use of 2,4-dichlorophenoxyacetic acid and organophosphate insecticides reduced the apparent association between NHL and atrazine in all but one state and reduced the associations for the long-term and frequent users in Nebraska. Detailed analyses suggested that there was little or no increase in the risk of NHL attributable to the agricultural use of atrazine.

Breast cancer care in old age: what we know, don't know, and do.

In this review of current pertinent literature from the fields of cancer epidemiology, oncology, health services research, and geriatrics, we describe the epidemiology and unique features of breast cancer and its victims in old age. In addition, we review the current evidence regarding treatment efficacy (i.e., beneficial under ideal circumstances) and effectiveness (i.e., beneficial under usual circumstances) in relation to primary tumor management and the use of adjuvant therapy in early stage disease and outline the challenges associated with studying breast cancer care in older women (> or = 65 years of age). Comorbidity, impaired functional status, lack of social support, and differences in host physiology are among the many factors that influence treatment efficacy and effectiveness, making extrapolation of study findings from younger to older women questionable. Indeed, with the exception of studies of adjuvant tamoxifen therapy, none of the clinical trials supporting the 1990 National Institutes of Health Consensus Development Conference on Treatment of Early-Stage Breast Cancer guidelines have included women over the age of 70 years. Because (a) breast cancer is becoming increasingly common in old age and (b) health-related quality of life is frequently more important to older women than is risk of recurrence or death, all three aspects (surgical management of the primary tumor, postoperative irradiation, and axillary lymph node dissection) of recommended primary treatment deserve fresh scrutiny. The value of adjuvant chemotherapy has yet to be defined. Substantial variations in breast cancer diagnosis, treatment, and care exist, and these differences become greater with increasing age of the patient. However, evidence regarding the reasons for these variations and their relationships with subsequent outcomes is lacking. Challenges for investigators in studies of older women include recruitment into studies, collection of reliable data from interviews or surveys, measurement of disease severity and comorbidity, and selection of relevant outcomes. Given current uncertainty about optimal treatment, clinicians can best serve older patients with early stage breast cancer by involving them in decision-making, taking into account available efficacy data, and individualizing care on the basis of such factors as comorbidity, social support, functional status, and patient preferences for outcomes. Future studies of treatment efficacy in older women should examine the roles of radiation therapy and axillary lymph node dissection that follow breast-conserving therapy and should focus on quality of life in addition to recurrence and mortality. Less aggressive treatments, tamoxifen therapy, and adjuvant chemotherapy should also be evaluated.

Meningiomas are not significantly associated with breast cancer.

We studied 283 meningiomas seen at the University of Kansas, Kansas City, from 1948 through 1984, identifying all additional nonmeningeal malignancies and primary brain tumors in these patients and calculating the expected number of additional tumors by the use of a person-year method from age and sex-matched cancer incidence data. We determined expected numbers of total neoplasms in our meningioma population as well as the expected numbers in each major organ system for the sexes independently and together. We then calculated standard morbidity ratios and 95% confidence intervals for each tumor type. The number of breast cancers did not reach statistical significance. We found a significantly increased number of second primary brain tumors in women (standard morbidity ratio, 8.0; 95% confidence interval, 2.2 to 20.4) and an increased number of thyroid cancers in both sexes (standard morbidity ratio, 7.5; 95% confidence interval, 1.5 to 21.9).

Early menopause in long-term survivors of cancer during adolescence.

OBJECTIVE: We attempted to investigate the risk of early menopause after treatment for cancer during childhood or adolescence. STUDY DESIGN: We interviewed 1067 women in whom cancer was diagnosed before age 20, who were at least 5-year survivors, and who were still menstruating at age 21. Self-reported menopause status in survivors was compared with that in 1599 control women. RESULTS: Cancer survivors, with disease diagnosed between ages 13 and 19, had a risk of menopause four times greater than that of controls during the ages 21 to 25; the risk relative to controls declined thereafter. Significantly increased relative risks of menopause during the early 20s occurred after treatment with either radiotherapy alone (relative risk 3.7) or alkylating agents alone (relative risk 9.2). During ages 21 to 25 the risk of menopause increased 27-fold for women treated with both radiation below the diaphragm and alkylating agent chemotherapy. By age 31, 42% of these women had reached menopause compared with 5% for controls. CONCLUSION: Treatment for cancer during adolescence carries a substantial risk for early menopause among women still menstruating at age 21. Increasing use of radiation and chemotherapy, together with the continued trend toward delayed childbearing, suggests that these women should be made aware of their smaller window of fertility so that they can plan their families accordingly.

Smoking habits in survivors of childhood and adolescent cancer.

Because of their increased risk for second cancers, childhood cancer survivors are people who really should not smoke, but available evidence suggests that they do. We studied the smoking habits of long-term childhood cancer survivors in data collected from 1289 adult survivors of childhood cancer and 1930 of their sibling controls. Survivors were diagnosed with cancer between 1945 and 1974 when they were less than 20 years old. Using matched analyses that controlled for the influence of family, survivors were 8% less likely than controls to be current smokers, 13% less likely to be ever-smokers, but 12% less likely to have quit smoking; these differences were not statistically significant. In a logistic regression analysis there was a significant difference by year of diagnosis for current smoking rate ratios (RR); survivors were less likely to be current smokers if diagnosed in recent years (RR = 0.76; 95% confidence intervals = 0.58-0.98, between 1965-74) and quite similar to controls if diagnosed in earlier years (RR = 1.05 between 1945 and 1954). In our group of long-term cancer survivors, the reduction in current smoking came about because survivors were more inclined never to start smoking than controls. Once addicted to tobacco, they were less likely to quit. While the fact that survivors are less likely to start smoking is encouraging, the persistence of smoking habits strongly suggests the need for continuing efforts to prevent smoking in this most vulnerable group.

Biology of cancer and aging.

The greatest risk factor for cancer is aging. Human cancer incidence increases exponentially with advancing age. Cancer growth rate and potential for metastatic spread may be influenced by age-specific change in host response. Because cancer and aging are, thus, inextricably linked, the American Cancer Society should encourage submission of research proposals that address the mechanisms of aging and how aging alters cancer development.

Gender influences subsite of origin of laryngeal carcinoma.

The relationship of gender to laryngeal cancer is not well understood. We analyzed 688 laryngeal cancers diagnosed in Kansas from 1980 through 1989 for sex differences in subsite distribution (glottis, supraglottis, subglottis, and laryngeal cartilage) as well as survival, histologic grade, and age at diagnosis. The ratio of glottic to supraglottic tumors was 22.12:1 in men and 0.56:1 in women, a highly significant difference. Survival in glottic tumors was significantly better than in supraglottic tumors, but survival was not significantly better for women than it was for men. Glottic tumors were significantly more likely than were supraglottic tumors to be of low-grade malignancy for all subjects and for male subjects alone, but not for female subjects alone. Women were younger at time of diagnosis than were men, but not significantly so. Gender is an important factor in the genesis of laryngeal cancer.

Survival in acute non-lymphocytic leukaemia following breast cancer.

Acute non-lymphocytic leukaemia (ANLL) occurs with increased frequency in women with previously diagnosed breast cancer. Adjuvant radiotherapy and chemotherapy are related to this increase. We studied the interrelationships among age at breast cancer diagnosis, interval to ANLL diagnosis, and survival in 54 women of whom 11 were from Kansas and 43 were from two other published series. Median age at breast cancer diagnosis was 50.5 years, median interval to ANLL diagnosis was 4.8 years, and median survival after ANLL diagnosis was 2.2 months. Increasing age was associated with a decrease of the interval to ANLL diagnosis just short of statistical significance (P = 0.0591). There was no association of survival with either age or the interval to ANLL diagnosis. With an increase in the use of adjuvant therapy in breast cancer there is a need to identify women at greatest risk of subsequently developing ANLL, at present not possible.

Analysis of bladder carcinoma by subsite. Cystoscopic location may have prognostic value.

Nine hundred fourteen cases of carcinoma of the urinary bladder registered from 1977 to 1988 with the Kansas state tumor registry were evaluated by subsite for differences in grade, histology, sex, age at diagnosis, and survival. Only initial occurrences of carcinoma were included. Carcinoma of the lateral walls accounted for 37.1%; the posterior wall, 17.9%; the trigone, 12.6%; the neck, 11.1%; the ureteric orifices, 9.8%; the dome, 7.7%; and the anterior wall, 3.8%. Malignant neoplasms occurring in the neck of the bladder had a significantly poorer prognosis by survival analysis (P less than 0.05). Malignancies of the dome were found to present as higher grade lesions (P = 0.00003), and carcinoma of the ureteric orifices and lateral walls tended to be of lower grade (P = 0.02 and P = 0.05, respectively). Carcinomas of the anterior wall and dome occurred in a more elderly population (mean ages, 75.6 and 73.9 years, respectively), and carcinomas of the trigone and ureteric orifices occurred in a younger group (mean ages, 68.3 and 67.5 years, respectively). On histologic evaluation the trigone gave rise to more squamous cell carcinoma than expected (P = 0.001, 325% of expected). No distribution difference was noted among subsites with respect to sex. These data show significant differences among subsites of the urinary bladder with regard to survival, grade, histology, and age at diagnosis.