Long-term adverse outcomes in survivors of childhood bone sarcoma: the British Childhood Cancer Survivor Study.

BACKGROUND: With improved survival, more bone sarcoma survivors are approaching middle age making it crucial to investigate the late effects of their cancer and its treatment. We investigated the long-term risks of adverse outcomes among 5-year bone sarcoma survivors within the British Childhood Cancer Survivor Study. METHODS: Cause-specific mortality and risk of subsequent primary neoplasms (SPNs) were investigated for 664 bone sarcoma survivors. Use of health services, health and marital status, alcohol and smoking habits, and educational qualifications were investigated for survivors who completed a questionnaire. RESULTS: Survivors were seven times more likely to experience all-cause mortality than expected, and there were substantial differences in risk depending on tumour type. Beyond 25 years follow-up the risk of dying from all-causes was comparable to the general population. This is in contrast to dying before 25 years where the risk was 12.7-fold that expected. Survivors were also four times more likely to develop a SPN than expected, where the excess was restricted to 5-24 years post diagnosis. Increased health-care usage and poor health status were also found. Nonetheless, for some psychosocial outcomes survivors were better off than expected. CONCLUSIONS: Up to 25 years after 5-year survival, bone sarcoma survivors are at substantial risk of death and SPNs, but this is greatly reduced thereafter. As 95% of all excess deaths before 25 years follow-up were due to recurrences and SPNs, increased monitoring of survivors could prevent mortality. Furthermore, bone and breast SPNs should be a particular concern. Since there are variations in the magnitude of excess risk depending on the specific adverse outcome under investigation and whether the survivors were initially diagnosed with osteosarcoma or Ewing sarcoma, risks need to be assessed in relation to these factors. These findings should provide useful evidence for risk stratification and updating clinical follow-up guidelines.

Educational attainment among adult survivors of childhood cancer in Great Britain: a population-based cohort study.

BACKGROUND: Previous studies of educational attainment among childhood cancer survivors were small, had contradictory findings, and were not population based. This study investigated educational attainment in a large population-based cohort of survivors of all types of childhood cancer in Great Britain. METHODS: Four levels of educational attainment among 10,183 cancer survivors--degree, teaching qualification, advanced (A') levels, and ordinary (O') levels--were compared with expected levels in the general population. A questionnaire was used to obtain educational attainment data for survivors, and comparable information for the general population was available from the General Household Survey. Factors associated with level of educational attainment achieved by cancer survivors were identified using multivariable logistic regression together with likelihood ratio tests. Logistic regression adjusting for age and sex was used for comparisons with the general population. All statistical tests were two-sided. RESULTS: Childhood cancer survivors had lower educational attainment than the general population (degree: odds ratio [OR] = 0.77, 99% confidence interval [CI] = 0.68 to 0.87; teaching qualification: OR = 0.85, 99% CI = 0.77 to 0.94; A'level: OR = 0.85, 99% CI = 0.78 to 0.93; O'level: OR = 0.81, 99% CI = 0.74 to 0.90; P < .001, all levels). Statistically significant deficits were restricted to central nervous system (CNS) neoplasm and leukemia survivors. For leukemia, only those treated with radiotherapy were considered. Odds ratios for achievement by irradiated CNS tumor survivors were 50%-74% of those for cranially irradiated leukemia or nonirradiated CNS tumor survivors. Survivors at greater risk of poorer educational outcomes included those treated with cranial irradiation, diagnosed with a CNS tumor, older at questionnaire completion, younger at diagnosis, diagnosed with epilepsy, and who were female. CONCLUSIONS: Specific groups of childhood cancer survivors achieve lower-than-expected educational attainment. Detailed educational support and implementation of regular cognitive assessment may be indicated for some groups to maximize long-term function.

The British Childhood Cancer Survivor Study: Objectives, methods, population structure, response rates and initial descriptive information.

BACKGROUND: In Britain 75% of individuals diagnosed with childhood cancer survive at least 5 years. The British Childhood Cancer Survivor Study was established to determine the risks of adverse health and social outcomes among survivors. To be eligible individuals were diagnosed with childhood cancer in Britain between 1940 and 1991 and survived at least 5 years. The entire cohort of 17,981 form the basis of population-based studies of late mortality and the risks/causes of second malignant neoplasms using national registration systems. METHODS: A postal questionnaire was sent to survivors who were alive and aged at least 16 years via their primary care physician. RESULTS: Of the 14,836 survivors eligible to receive a questionnaire, 10,483 (71%) returned it completed. Of the 13,211 who were mailed a questionnaire by their primary care physician 10,483 (79%) returned it completed. Outline treatment information concerning initial radiotherapy, chemotherapy and surgery is available. CONCLUSIONS: This is the largest available population-based cohort of childhood cancer survivors to have included investigation of a wide spectrum of adverse outcomes (the risk of which might be increased as a result of childhood cancer or its treatment). The study should provide useful information for counselling survivors, planning long-term clinical follow-up and evaluating the long-term risks likely to be associated with proposed treatment strategies.

A study of soft tissue sarcomas after childhood cancer in Britain.

Among 16 541 3-year survivors of childhood cancer in Britain, 39 soft tissue sarcomas (STSs) occurred and 1.1 sarcomas were expected, yielding a standardised incidence ratio (SIR) of 16.1. When retinoblastomas were excluded from the cohort, the SIR for STSs was 15.9, and the cumulative risk of developing a soft tissue tumour after childhood cancer within 20 years of 3-year survival was 0.23%. In the case-control study, there was a significant excess of STSs in those patients exposed to both radiotherapy (RT) and chemotherapy, which was five times that observed among those not exposed (P=0.02). On the basis of individual radiation dosimetry, there was evidence of a strong dose-response effect with a significant increase in the risk of STS with increasing dose of RT (P<0.001). This effect remained significant in a multivariate model. The adjusted risk in patients exposed to RT doses of over 3000 cGy was over 50 times the risk in the unexposed. There was evidence of a dose-response effect with exposure to alkylating agents, the risk increasing substantially with increasing cumulative dose (P=0.05). This effect remained after adjusting for the effect of radiation exposure.

Offspring sex ratio and gonadal irradiation in the British Childhood Cancer Survivor Study.

We investigated offspring sex ratio among 6232 offspring born to 3218 survivors of childhood cancer in relation to therapeutic irradiation, and pooled our data with those from two other large-scale studies giving a total of 9685 offspring. Exposure to high-dose gonadal irradiation was not associated with a significant alteration in offspring sex ratio compared to low doses (men: P=0.58, women: P=0.66). There was also no evidence that the ratio varied with time since cancer diagnosis when comparing survivors treated with radiotherapy vs those without (men: P=0.51; women: P=0.46). This, the largest study to date, finds no evidence that exposure to radiation affects the offspring sex ratio among survivors of childhood cancer.

Long-term population-based risks of second malignant neoplasms after childhood cancer in Britain.

In a population-based, retrospective cohort study of 16 541 3-year survivors of childhood cancer treated in Britain up to the end of 1987, 278 second malignant neoplasms (SMNs) were identified against 39.4 expected giving a standardised incidence ratio (SIR) of 6.2. The overall cumulative risk of an SMN by 25 years from 3-year survival from childhood cancer was 4.2%. Analysis of the cohort of nonretinoblastoma childhood cancers combined revealed a significant decline in SIR of SMN with increasing duration of follow-up. There was a greater risk of developing a SMN, particularly secondary acute myeloid leukaemia, in those diagnosed with childhood cancer from 1980 onwards. However, on multivariate modeling, this was not an independent risk factor. There was significant heterogeneity (P<0.001) in SIR of SMN across different treatment groups, the greatest risk observed in the group exposed to both radiotherapy and chemotherapy. The risks of SMN observed were comparable with those in other population-based studies. While the decline in SIR with duration of follow-up and the small excess numbers of cancers observed over later decades after diagnosis are reassuring, the high excess risk, particularly of leukaemia, associated with recent more intense therapy is of concern.

Plasma levels of IGF-1, IGF-2, and IGFBP-3 in white and African-American men at increased risk of prostate cancer.

OBJECTIVES: To further investigate the relationship between the plasma levels of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), insulin-like growth factor binding protein-3 (IGFBP-3), growth hormone, testosterone, and demographic factors, particularly race, within a group of men at increased risk of prostate cancer development. METHODS: Enzyme-linked immunosorbent assays or an immunosorbent assay was used to quantitate the plasma levels of IGF-1, IGF-2, IGFBP-3, growth hormone, and testosterone. The study group consisted of 169 men (85 African-American, 84 white) aged 35 to 69 years, with no personal history of prostate cancer, but having at least one first-degree relative diagnosed with the disease, unless they were African-American. The relationships between the plasma levels and the categorical covariates were assessed using the nonparametric Wilcoxon test and between the continuous variables using Spearman's correlation coefficient. RESULTS: The mean plasma levels of IGFBP-3 were significantly lower in African-American (2657 ng/mL) than in white (2965 ng/mL) men (P = 0.0062). The plasma levels of IGF-2 were also lower in the African-American (503.5 ng/mL) than in the white (549.1 ng/mL) men (P = 0.0084). Overall, the IGF-1 plasma levels correlated positively with the IGF-2, IGFBP-3, and growth hormone levels and the IGF-2 plasma levels correlated negatively with the testosterone levels. CONCLUSIONS: Our results demonstrate that lower plasma levels of IGFBP-3 and IGF-2 are associated with race in a population of men at increased risk of developing prostate cancer. The ability of these markers to predict earlier disease onset is currently under investigation.

The risk and outcome of cerebral oedema developing during diabetic ketoacidosis.

BACKGROUND: Cerebral oedema is a major cause of morbidity and mortality in children with insulin dependent diabetes. AIMS: To determine the risk and outcome of cerebral oedema complicating diabetic ketoacidosis (DKA). METHODS: All cases of cerebral oedema in England, Scotland, and Wales were reported through the British Paediatric Surveillance Unit between October 1995 and September 1998. All episodes of DKA were reported by 225 paediatricians identified as involved in the care of children with diabetes through a separate reporting system between March 1996 and February 1998. Further information about presentation, management, and outcome was requested about the cases of cerebral oedema. The risk of cerebral oedema was investigated in relation to age, sex, seasonality, and whether diabetes was newly or previously diagnosed. RESULTS: A total of 34 cases of cerebral oedema and 2940 episodes of DKA were identified. The calculated risk of developing cerebral oedema was 6.8 per 1000 episodes of DKA. This was higher in new (11.9 per 1000 episodes) as opposed to established (3.8 per 1000) diabetes. There was no sex or age difference. Cerebral oedema was associated with a significant mortality (24%) and morbidity (35% of survivors). CONCLUSIONS: This first large population based study of cerebral oedema complicating DKA has produced risk estimates which are more reliable and less susceptible to bias than those from previous studies. Our study indicates that cerebral oedema remains an important complication of DKA during childhood and is associated with significant morbidity and mortality. Little is known of the aetiology of cerebral oedema in this condition and we are currently undertaking a case control study to address this issue.

Racial differences in insulin-like growth factor binding protein-3 in men at increased risk of prostate cancer.

OBJECTIVES: To determine the overall plasma levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) in a group of men at higher risk of prostate cancer development and to investigate the relationships between demographics and these levels, particularly with regard to race. METHODS: An enzyme-linked immunosorbant assay was used to quantitate plasma levels of IGF-1 and IGFBP-3. The study group consisted of 105 men (63 African American [AA], 42 white), aged 35 to 69 years, with no personal history of prostate cancer, but having at least one first-degree relative diagnosed with the disease, unless they were AA. Differences in plasma levels and categorical covariates were assessed using the nonparametric Wilcoxon test. Associations between plasma levels and the continuous variables were quantified using the nonparametric Spearman correlation coefficient. RESULTS: The mean plasma level of IGF-1 was not significantly different between AA (162.3 ng/mL) and white (172.1 ng/mL) men (P = 0.415). However, the mean plasma level of IGFBP-3 was lower in AA (2789 ng/mL) than in white (3216 ng/mL) men, and this decrease was highly significant (P = 0.0045). No correlation between IGFBP-3 plasma level and age was detected in the group as a whole, but an inverse relationship between IGF-1 plasma level and age was evident (P = 0.0079). CONCLUSIONS: Our results demonstrate that IGFBP-3 plasma levels are lower in AA men than in white men. Since IGFBP-3 can control IGF-1 bioavailability, the lowered IGFBP-3 could explain in part the increased risk of prostate cancer in AA men.

Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer.

BACKGROUND: Individuals who had cancer in childhood are at higher risk of developing bone cancer than any other type of second primary cancer. PURPOSE: Using the population-based National Registry of Childhood Tumours in Britain, we investigated the incidence and etiology of second primary bone cancer after childhood cancer in a cohort study and in a case-control study. METHODS: A cohort study of 13,175 3-year survivors of childhood cancer diagnosed in Britain between 1940 and 1983 revealed 55 subsequent bone cancers. A largely nested case-control study comprised 59 case subjects developing second primary bone cancer, and 220 control subjects were selected and matched for sex, type of first cancer, age at first cancer, and interval between diagnosis of first cancer and subsequent bone cancer. Outcome measures were the incidence of bone cancer after childhood cancer, the cumulative dose of radiation received at the site of the second cancer in the case subject and at the corresponding anatomic site in the matched control subjects, and the cumulative dose of alkylating agents and vinca alkaloids received by case and control subjects. RESULTS: The percentage of 3-year survivors developing bone cancer within 20 years did not exceed 0.9%, except following heritable retinoblastoma (7.2%), Ewing's sarcoma (5.4%), and other malignant bone tumors (2.4%). The risk of bone cancer increased substantially with increased cumulative dose of radiation to the bone (P< .001, linear trend). At the highest levels of exposure, however, the risk appeared to decline somewhat (P=.065, nonlinearity). Exposure to less than 10 Gy was at worst, associated with only a small increased relative risk (RR) of bone cancer (RR= 0.7; 95% confidence interval = 0.2-2.2). The risk of bone cancer increased linearly (P= .04, one-tailed test) with increased cumulative dose of alkylating agents. IMPLICATIONS: This population-based study provides grounds for reassurance of the majority of survivors in that their risk of developing bone cancer within 20 years of 3-year survival did not exceed 0.9%. The higher risks found for bone cancer following the other specific rare types of childhood cancer provide a rational basis for surveillance. The RRs reported for bone cancer after specified levels of exposure to radiation should help in making decisions concerning future treatment protocols.

Cancer in the offspring of survivors of childhood leukaemia and non-Hodgkin lymphomas.

Understanding the extent to which childhood leukaemia and non-Hodgkin lymphomas are heritable is important to the survivors of these diseases, their families and clinicians who provide genetic counselling. Such understanding is also relevant to the possibility raised by Gardner et al. (1990, Br. Med. J., 300, 423-429) that paternal preconception irradiation may be an aetiological factor in these diseases. No malignant neoplasm was diagnosed among 382 offspring of survivors of childhood leukaemia and non-Hodgkin lymphoma followed up for a median period of 5.8 years, the largest available cohort of such offspring. These data indicate that it is unlikely that the risk of a malignant neoplasm occurring in the offspring exceeds eight times that expected in the general population. Similarly, the risk of leukaemia and non-Hodgkin lymphoma among offspring is unlikely to exceed 21 times that expected. The proportion of survivors of childhood leukaemia and non-Hodgkin lymphoma with the heritable form of these diseases is unlikely to exceed 5%, assuming an autosomal dominant pattern of transmission, with penetrance of at least 70% and that all heritable cases develop by age 15 years. The best (i.e. at present most likely) estimates of these risks are of course much lower. There was no evidence of an excess of congenital abnormalities among the offspring and the sex ratio was similar to that expected from the general population.

Weightlessness and gravitational physiology.

Physiologic responses to the weightless environment have been documented in Skylab astronauts. Significant changes in cardiovascular responses, calcium metabolism, fluid distribution, and red blood cell mass are described. Although the data are limited and the sample size small, several hypotheses can be formulated. Future studies in a space laboratory setting offer the potential for understanding the effects of weightlessness on human physiology and the implications to medicine.

The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: III. Dosimeter design, construction, and implantation.

To detect the passage of cosmic ray particles through the heads of the pocket mice during the Apollo XVII flight, a "monitor" (dosimeter) composed of plastics was prepared and implanted under the scalp. The monitor was mounted on a platform, the undersurface of which fitted the contour of the skull. Numerous tests were run to assure that the presence of the monitor assembly beneath the scalp would be compatible with the well-being of the mice and that the capacity of the monitor to detect the traversal of cosmic ray particles would be preserved over the several weeks during which it would remain under the scalp.

The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: I. Project BIOCORE (M212), a biological cosmic ray experiment: procedures, summary, and conclusions.

The primary objective of the experiment was to determine whether a specific portion of the high Z-high energy (HZE)* galactic cosmic ray particle spectrum, especially particles with Z greater than or equal to 6, can produce microscopically visible injury of brain and eye tissues. Pocket mice (Perognathus longimembris), obtained from the California desert, were selected as the biological target. Five of these mice were flown on Apollo XVII. Not only the brain and eyes but also many other tissues of these animals were studied for evidence of cosmic ray particle damage. The lack of prior experimental evidence as to the character of the potential injury induced by HZE particles required reliance on the physical characteristics of particle radiation in ascertaining the probable nature of the injruy. These characteristics and the key aspects of the experiment are summarized in this paper. Subsequent articles in this special supplement give details of the biological, engineering, and dosimetric aspects of BIOCORE together with the results.

The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: VI. launch, flight, and recovery.

The final phase to fly five pocket mice in the Apollo XVII command module was carried out at the NASA Kennedy Space Center. Upon completion of the 13-d space flight, the package was removed from the spacecraft and, after having been purged with an oxygen-helium gas mixture, was flown to American Samo. Four of the five mice were recovered alive from the package. Analysis of the mouse that died during the flight revealed several factors that could have contributed to its death, the chief of which was massive hemorrhage in its middle ear cavities.