Michael Væth

Studies of the Mortality of Atomic Bomb Survivors.Report 12, Part I. Cancer: 1950–1990

This continues the series of periodic general reports on cancer mortality in the cohort of A-bomb survivors followed by the Radiation Effects Research Foundation. The follow-up is extended by the 5 years 1986-1990, and analysis includes an additional 10,500 survivors with recently estimated radiation doses. Together these extensions add about 550,000 person-years of follow-up. The cohort analyzed consists of 86,572 subjects, of which about 60% have dose estimates of at least 0.005 Sv. During 1950-1990 there have been 3086 and 4741 cancer deaths for the less than and greater than 0.005 Sv groups, respectively. It is estimated that among these there have been approximately 420 excess cancer deaths during 1950-1990, of which about 85 were due to leukemia. For cancers other than leukemia (solid cancers), about 25% of the excess deaths in 1950-1990 occurred during the last 5 years; for those exposed as children this figure is nearly 50%. For leukemia only about 3% of the excess deaths in 1950-1990 occurred in the last 5 years. Whereas most of the excess for leukemia occurred in the first 15 years after exposure, for solid cancers the pattern of excess risk is apparently more like a life-long elevation of the natural age-specific cancer risk. Taking advantage of the lengthening follow-up, increased attention is given to clarifying temporal patterns of the excess cancer risk. Emphasis is placed on describing these patterns in terms of absolute excess risk, as well as relative risk. For example: (a) although it is becoming clearer that the excess relative risk for those exposed as children has declined over the follow-up, the excess absolute risk has increased rapidly with time; and (b) although the excess relative risk at a given age depends substantially on sex and age at exposure, the age-specific excess absolute risk depends little on these factors. The primary estimates of excess risk are now given as specific to sex and age at exposure, and these include projections of dose-specific lifetime risks for this cohort. The excess lifetime risk per sievert for solid cancers for those exposed at age 30 is estimated at 0.10 and 0.14 for males and females, respectively. Those exposed at age 50 have about one-third these risks. Projection of lifetime risks for those exposed at age 10 is more uncertain. Under a reasonable set of assumptions, estimates for this group range from about 1.0-1.8 times the estimates for those exposed at age 30. The excess life-time risk for leukemia at 1 Sv for those exposed at either 10 or 30 years is estimated as about 0.015 and 0.008 for males and females, respectively. Those exposed at age 50 have about two-thirds that risk. Excess risks for solid cancer appear quite linear up to about 3 Sv, but for leukemia apparent nonlinearity in dose results in risks at 0.1 Sv estimated at about 1/20 of those for 1.0 Sv. Site-specific risk estimates are given, but it is urged that great care be taken in interpreting these, because most of their variation can be explained simply by imprecision in the estimates.

Risk of aggressive periodontitis in adolescent carriers of the JP2 clone of Aggregatibacter (Actinobacillus) actinomycetemcomitans in Morocco: a prospective longitudinal cohort study.

BACKGROUND Periodontitis is a loss of supporting connective tissue and alveolar bone around teeth, and if it occurs in an aggressive form it can lead to tooth loss before the age of 20 years. Although the cause of periodontitis in general remains elusive, a particular clone (JP2) of the gram-negative rod Aggregatibacter (Actinobacillus) actinomycetemcomitans is considered a possible aetiological agent of the aggressive form in adolescents living in or originating from north and west Africa, where the disease is highly prevalent. We did a population-based longitudinal study of adolescents to assess the role of the JP2 clone in the initiation of aggressive periodontitis. METHODS A total of 700 adolescents from public schools in Rabat, Morocco, were enrolled in the study. We used PCR to detect A actinomycetemcomitans in plaque samples (taken from molar and incisor sites) and to differentiate between the JP2 clone and other non-JP2 genotypes of the bacterium. 18 individuals were found to already have periodontitis and were excluded. The 682 periodontally healthy adolescents (mean age 12.5 years; SD 1.0) were classified according to their A actinomycetemcomitans carrier status at baseline. After 2 years, 428 (62.8%) individuals returned for re-examination, which included recording of periodontal attachment loss measured from the cemento-enamel junction to the bottom of the periodontal pockets of all teeth present. FINDINGS Individuals who carried the JP2 clone of A actinomycetemcomitans alone (relative risk 18.0; 95% CI 7.8-41.2, p<0.0001) or together with non-JP2 clones of A actinomycetemcomitans (12.4; 5.2-29.9, p<0.0001) had a significantly increased risk of periodontal attachment loss. A much less pronounced disease risk was found in those carrying non-JP2 clones only (3.0; 1.3-7.1, p=0.012). INTERPRETATION The JP2 clone of A actinomycetemcomitans is likely to be an important aetiological agent in initiation of periodontal attachment loss in children and adolescents. Co-occurrence of non-JP2 clones of A actinomycetemcomitans reduces the risk of development of periodontitis, suggesting competition for the ecological niche between the JP2 and non-JP2 clones of this species.

Allowing for Random Errors in Radiation Dose Estimates for the Atomic Bomb Survivor Data

The presence of random errors in the individual radiation dose estimates for the A-bomb survivors causes underestimation of radiation effects in dose-response analyses, and also distorts the shape of dose-response curves. Statistical methods are presented which will adjust for these biases, provided that a valid statistical model for the dose estimation errors is used. Emphasis is on clarifying some rather subtle statistical issues. For most of this development the distinction between radiation dose and exposure is not critical. The proposed methods involve downward adjustment of dose estimates, but this does not imply that the dosimetry system is faulty. Rather, this is a part of the dose-response analysis required to remove biases in the risk estimates. The primary focus of this report is on linear dose-response models, but methods for linear-quadratic models are also considered briefly. Some plausible models for the dose estimation errors are considered, which have typical errors in a range of 30-40% of the true values, and sensitivity analysis of the resulting bias corrections is provided. It is found that for these error models the resulting estimates of excess cancer risk based on linear models are about 6-17% greater than estimates that make no allowance for dose estimation errors. This increase in risk estimates is reduced to about 4-11% if, as has often been done recently, survivors with dose estimates above 4 Gy are eliminated from the analysis.

The influence of psychosocial factors on the duration of breastfeeding

Aim: A study was undertaken to examine to what extent psychosocial factors are related to the length of breastfeeding. Methods: A cohort of Danish mothers giving birth to a single child was followed up for four months. Information on mother and baby including psychosocial variables was obtained from a self-report questionnaire. Breastfeeding status was subsequently monitored by a health visitor. Results: A total of 471 (88%) mothers participated, 98.7 % initiated breastfeeding and after four months 277 (59%) were still exclusive breastfeeding; 99 mothers, 51% of those who stopped, stopped within the first five weeks. In Cox regression analyses the duration of breastfeeding showed a positive association with mothers schooling ( p=0.002), her intention to breastfeed ( p=0.001), previous experience with breastfeeding ( p<0.001), self-efficacy with respect to breastfeeding ( p<0.001), her confidence in breastfeeding ( p=0.012) and knowledge about breastfeeding ( p=0.001). The effect of the mothers knowledge depended on the parity of the child. Among primiparous mothers high knowledge was associated with long duration of breastfeeding, but this association was not found among the multiparous. Conclusions: To help the mothers who would like to breastfeed their baby, we must improve our ability to identify mothers at risk of early cessation. Mothers schooling, her intention, self-efficacy and earlier breastfeeding experience can be used as early predictors. An intervention should aim at improving the self-efficacy and resources of these mothers, with a focus on practical knowledge. The first five weeks, when the largest proportion of the cessations occurred, require special attention.

Cardiovascular death and manic-depressive psychosis

In order to study if tricyclic antidepressant drugs (TCA) in therapeutic doses increase the risk of death due to cardiovascular causes, the relative mortality from cardiovascular diseases was studied in two large groups of first hospitalized manic-depressive patients, one from the TCA era, the other from the period just before the introduction of TCA. Both groups were selected from the Danish Psychiatric Central Register and followed for an average of 4.5 years. Among 2662 manic-depressive men hospitalized between 1969 and 1976, the relative cardiovascular mortality was 1.53 compared to the general population. Among 1133 such cases admitted between 1950 and 1956, the rate was 1.87. Our findings do not support the hypothesis that TCA contribute to the cardiovascular mortality in manic-depressives and even support suggestions that TCA treatment may lower the risk of death by cardiovascular disease, suicide, and other non-cancer causes.

Cerebral palsy among children born after in vitro fertilization : The role of preterm delivery-a population-based, cohort study

OBJECTIVE. Our aim was to assess the incidence of cerebral palsy among children conceived with in vitro fertilization and children conceived without in vitro fertilization. METHODS. A population-based, cohort study, including all live-born singletons and twins born in Denmark between January 1, 1995, and December 31, 2000, was performed. Children conceived with in vitro fertilization (9255 children) were identified through the In Vitro Fertilization Register; children conceived without in vitro fertilization (394713) were identified through the Danish Medical Birth Register. Cerebral palsy diagnoses were obtained from the National Register of Hospital Discharges. The main outcome measure was the incidence of cerebral palsy in the in vitro fertilization and non-in vitro fertilization groups. RESULTS. Children born after in vitro fertilization had an increased risk of cerebral palsy; these results were largely unchanged after adjustment for maternal age, gender, parity, small-for-gestational age status, and educational level. The independent effect of in vitro fertilization vanished after additional adjustment for multiplicity or preterm delivery. When both multiplicity and preterm delivery were included in the multivariate models, preterm delivery remained associated strongly with the risk of cerebral palsy. CONCLUSIONS. The large proportions of preterm deliveries with in vitro fertilization, primarily for twins but also for singletons, pose an increased risk of cerebral palsy.

Pregnancy outcomes related to gestational weight gain in women defined by their body mass index, parity, height, and smoking status

BACKGROUND Recommendations for gestational weight gain (GWG) account for a womans prepregnancy body mass index (BMI), but other factors may be important. OBJECTIVES The objectives were to investigate whether, within BMI categories, the GWG with the lowest risks to mother and infant varied with parity and to describe these risks in short (<160 cm), young (<20 y), and smoking women. DESIGN Of 27,030 primiparous and 31,407 multiparous women with term births within the Danish National Birth Cohort, self-reported GWG was divided into 6 categories (<5, 5-9, 10-15, 16-19, 20-24, and > or =25 kg). Population-based registers provided information about birth outcomes. GWG-specific absolute adjusted risks for emergency cesarean delivery, birth of a small-for-gestational-age (SGA) or large-for-gestational-age (LGA) infant, and postpartum (6 mo) weight retention (PPWR) were compared across different types of women. RESULTS The risk of SGA decreased with increasing GWG in both parity groups, but SGA risk <10% was reached at 2-3 GWG categories lower in multiparae than in primiparae. An excess risk of LGA was present only in obese primiparae and multiparae, but the PPWR risk increased with increasing GWG irrespective of BMI and parity. Young primiparae had better outcomes than other primiparae. Short women had a higher risk of emergency cesarean delivery that varied minimally with GWG. Smokers had a higher SGA risk and had a PPWR risk similar to that of nonsmokers. CONCLUSIONS The tradeoff in risk between mother and infant is reached at lower GWG in multiparae than in primiparae; therefore, a lower GWG may be needed among multiparae. Differential guidelines seem unnecessary for short or young women or smokers.

Excess mortality of bipolar and unipolar manic-depressive patients

To compare mortality in bipolar and unipolar manic-depressive patients, 2168 manic-depressive first admissions reported to the Danish Psychiatric Central Register were divided into a bipolar group (19%), i.e., patients with at least one admission for mania during an average observation period of six years, and a unipolar group. When compared with the general population, the total group had an increased mortality by suicide and accidents in both sexes and by non-violent causes in men. The bipolar group had a higher non-violent mortality than the unipolar group, but the violent mortality was not different. Statistical problems introduced by patients switching from the unipolar to the bipolar group during the period of observation are discussed.

Why actuarial estimates should be used in reporting late normal-tissue effects of cancer treatment ... now!

Cancer is a life-threatening disease, and the prime measure of treatment success has logically been patient survival. Treatment-related morbidity, the back-side of the coin, has often been regarded as the unavoidable price that the patient had to pay for being alive. In radiation oncology, it has been clear since the very early years that this price in some cases may become unacceptable. More recently, the experience with large doses per fraction and with dose-escalation in split-course treatment schedules has emphasized the need for careful recording and analysis of treatment toxicity and has further stimulated research into rational design of clinical trials aiming for sufficient statistical resolution on tumor outcome and treatment toxicity ( 1) . This development is amplified by several current socioeconomic trends. These include a stronger emphasis on the patient’s rights for complete information and for autonomy, as well as an increasing demand from the society to evaluate the cost, in all senses of the word, and effectiveness of medical procedures. All of this means that treatment-related morbidity is getting increasing attention. An excellent paper that will further enforce this tendency is the comprehensive study by Eifel and colleagues, which is reported in this issue of the Journal (6). These authors document the time evolution of late complications in patients with FIG0 Stage IB carcinoma of the uterine cervix treated with radiotherapy. A substantial number of patients have been followed for more than 20 years, and it is convincingly shown how new radiation-related complications continue to occur during this long follow-up period. Unfortunately, it is clear from the medical literature that the quality of the study by Eifel and colleagues is far from being typical and there is still a long way to go in clinical research in radiation complications. It seems relevant to take this opportunity to revisit a few of the methodological problems involved in assessing late radia

Effect of cancer chemotherapeutic drugs on radiation-induced lung damage in mice

The effect of adriamycin (ADM), bleomycin (BLM), cyclophosphamide (CTX), 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin C (MM-C) and cis-diamminedichloroplatinum(II) (cis-DDP) on the radiation-induced lung damage in mice was assessed by the ventilation rate (VR) and the lethality. Single drug doses were administered 15 min before graded single doses of irradiation and at different intervals from 28 days before to 28 days after fixed radiation doses. ADM, BLM and CTX administered 15 min before irradiation enhanced the radiation response with dose effect factors (DEF) of 1.46, 1.56 and 2.35, respectively. The effect of MM-C presented a complex picture. The drug had no effect at administration 15 min before 14-20 Gy, but enhanced the radiation response if given 15 min before 6-12 Gy (DEF = 1.57). The radiation-modifying effect of ADM, BLM, CTX and MM-C was most pronounced when the drugs were given 15 min before irradiation. The effect of ADM was present when administered from 7 days before to 7 days after irradiation. BLM and CTX enhanced the radiation response at administration from 24 h before to 3 days after irradiation, and the effect of MM-C was observed when the drug was given from 24 h before to 24 h after irradiation. 5-FU, MTX and cis-DDP had no effect on the radiation response at any of the investigated intervals.