Päivi M. Lähteenmäki

Scholastic Achievements of Childhood Leukemia Patients: A Nationwide, Register-Based Study

PURPOSE Studies concerning the scholastic achievement of survivors of childhood leukemia have yielded controversial results. We studied the school marks of childhood leukemia survivors in a register-based study. PATIENTS AND METHODS Three hundred seventy-one patients with a diagnosis of leukemia before the age of 16 years who were born between 1974 and 1986 and alive on their 16th birthday were identified from the Finnish Cancer Registry. Five matched controls were sought for each patient from the Population Register Center of Finland. Information on the ninth-grade school report was obtained from Statistics Finland. The overall mark average and the marks (scale 4 to 10) for mother tongue, foreign language, mathematics, and physical education were compared between the patients and controls. RESULTS The ninth-grade school report was obtained by 97.6% of the patients and 98.5% of the controls. The patients whose treatment included cranial irradiation had a lower overall mark average (mean difference, -0.24; 95% CI, -0.33 to -0.15) and lower marks for all assessed school subjects compared with their controls. Of the patients treated with chemotherapy alone, only the females with leukemia diagnosed before 7 years of age had lower school marks than their controls. The biggest difference was observed in the marks for foreign language among the irradiated females diagnosed at a young age (mean difference, -1.0; 95% CI, -1.25 to -0.74). CONCLUSION Leukemia treatment that includes cranial irradiation impairs scholastic achievement. It is noteworthy that treatment of leukemia with chemotherapy alone impairs school performance only in females diagnosed before school age.

Probability of parenthood after early onset cancer: a population-based study.

We evaluated in a population‐based setting the postdiagnosis parenthood among survivors compared with the fertility patterns of siblings. Cancer patients aged 0–34 years at diagnosis were identified from the Finnish Cancer Registry (N = 25,784), and their siblings (N = 44,611) by registry linkage. Further linkage identified the offspring of the patient and sibling cohorts. The relative probabilities of parenthood for first and second births separately were estimated for male and female survivors in different diagnostic age‐groups and subsites using a Cox proportional hazards model, with age as the time variable and adjusting for the birth cohort of parents. In addition, estimates were calculated for 5 diagnostic eras in all subsites combined. Compared to siblings, both female and male cancer survivors were less likely to parent at least 1 child (RR 0.46, 95% CI 0.44–0.48 and RR 0.57, 95% CI 0.54–0.60, respectively). The relative probability of parenthood was especially low in male childhood cancer survivors and female young adult cancer survivors. However, cancer patients were only slightly less likely than siblings to parent a second child, with RR 0.91, 95% CI 0.86–0.97 and RR 0.95, 95% CI 0.89–1.01 for females and males, respectively. The relative probability of parenthood increased over calendar time among young adult cancer patients. The relative probability of parenthood following early onset cancer was overall significantly reduced by ∼50%. Parenting a second child, however, was not reduced among pediatric and adolescent survivors, and only slightly reduced among early adulthood cancer survivors compared to siblings.

Effects of a home-based exercise program on metabolic risk factors and fitness in long-term survivors of childhood acute lymphoblastic leukemia†

Long‐term survivors of childhood acute lymphoblastic leukemia (ALL) have increased risk of cardiovascular disease (CVD). The prevalence of insulin resistance and other cardiometabolic risk factors is increased in ALL survivors, and insufficient physical activity (PA) and low cardiopulmonary fitness are common. The purpose of this study was to evaluate the effects of a simple, inexpensive home‐based exercise program on cardiometabolic risk factors and fitness in long‐term ALL survivors.

Cardiovascular morbidity in long-term survivors of early-onset cancer: A population-based study

Improvements in cancer therapy have resulted in an expanding population of early‐onset cancer survivors. In contrast to childhood and adolescent cancer survivors, there is still a lack of data concerning late morbidities among young adult (YA) cancer survivors. Thus, our aim was to investigate cardiac and vascular morbidity among early‐onset cancer survivors with a special interest in YA cancer survivors. In a population‐based setting, we explored the risk of cardiovascular disease in early‐onset cancer survivors compared to healthy siblings. Patients diagnosed with cancer below 35 years of age since 1975 were identified from the Finnish Cancer Registry, and 5‐year survivors were included in our study (N = 13,860). Information on cardiovascular morbidity was collected from the national hospital discharge registry. Compared to siblings, cancer survivors aged 0–19 and 20–34 at diagnosis had significantly elevated hazard ratios (HRs) for the studied outcomes: HR 13.5 (95% CI 8.9–20.4) and 3.6 (95% CI 2.8–4.6) for cardiomyopathy/cardiac insufficiency; HR 3.4 (95% CI 2.3–5.1) and 1.7 (95% CI 1.4–2.0) for atherosclerosis/brain vascular thrombosis; HR 3.3 (95% CI 1.7–6.5) and 1.8 (95% CI 1.5–2.1) for myocardial infarction/cardiac ischemia and HR 1.7 (95% CI 1.2–2.6) and 1.4 (95% CI 1.2–1.7) for cardiac arrhythmia. In both groups, depending on the outcome, the HR for adverse events was highest among lymphoma, brain tumor, leukemia and testicular malignancy survivors. Our results regarding late effects of childhood cancer survivors confirmed previous findings. Additionally, our study provides novel information concerning the YA cancer survivor population. Hence, our data may help in planning the risk‐based long‐term follow‐up of early‐onset cancer survivors.

Effect of Childhood Acute Lymphoblastic Leukemia Therapy on Spermatogonia Populations and Future Fertility

CONTEXT Isolation of spermatogonial stem cells before potentially sterilizing cancer therapy, followed by transplantation of these cells into the testis after such treatment, may be an effective approach to prevent infertility among prepubertal boys suffering from acute lymphoblastic leukemia (ALL). A key clinical consideration in this context is the timing of biopsy, if collection of spermatogonia could be delayed from diagnosis to the later phase of leukemia treatment, better patient selection could be offered. OBJECTIVE The objective of the study was to examine the routine testicular biopsy material collected to detect testicular leukemia to evaluate if treatment for leukemia affects numbers and maturation of the spermatogonia during the prepubertal period. DESIGN AND PARTICIPANTS The study involved 28 testicular biopsies from 23 prepubertal boys treated for ALL. OUTCOME MEASURE Samples were stained immunohistochemically to evaluate the expression of the spermatogonial markers MAGE 4A, OCT4, CD9, and AP2gamma, and of the Sertoli cell marker WT-1. To relate these findings to gonadal function after sexual maturation, the surviving patients were evaluated as adults. RESULTS Several MAGE 4A-, CD9-, or OCT4-positive spermatogonia were detected in testicular biopsies after standard risk therapy without cyclophosphamide, whereas their numbers were significantly reduced in six patients receiving high-risk ALL therapy involving cyclophosphamide. No significant alteration in spermatogonial numbers was associated with testicular leukemia. All patients not treated with cyclophosphamide recovered normal testicular function, with normal sperm quality and endocrine function. CONCLUSION Treatment for childhood leukemia without high-dose cyclophosphamide seldom depletes the spermatogonial stem cell pool totally.

The use of next generation sequencing technology to study the effect of radiation therapy on mitochondrial DNA mutation

The human mitochondrial genome has an exclusively maternal mode of inheritance. Mitochondrial DNA (mtDNA) is particularly vulnerable to environmental insults due in part to an underdeveloped DNA repair system, limited to base excision and homologous recombination repair. Radiation exposure to the ovaries may cause mtDNA mutations in oocytes, which may in turn be transmitted to offspring. We hypothesized that the children of female cancer survivors who received radiation therapy may have an increased rate of mtDNA heteroplasmy mutations, which conceivably could increase their risk of developing cancer and other diseases. We evaluated 44 DNA blood samples from 17 Danish and 1 Finnish families (18 mothers and 26 children). All mothers had been treated for cancer as children and radiation doses to their ovaries were determined based on medical records and computational models. DNA samples were sequenced for the entire mitochondrial genome using the Illumina GAII system. Mothers age at sample collection was positively correlated with mtDNA heteroplasmy mutations. There was evidence of heteroplasmy inheritance in that 9 of the 18 families had at least one child who inherited at least one heteroplasmy site from his or her mother. No significant difference in single nucleotide polymorphisms between mother and offspring, however, was observed. Radiation therapy dose to ovaries also was not significantly associated with the heteroplasmy mutation rate among mothers and children. No evidence was found that radiotherapy for pediatric cancer is associated with the mitochondrial genome mutation rate in female cancer survivors and their children.

Fetal Growth, Preterm Birth, Neonatal Stress and Risk for CNS Tumors in Children: A Nordic Population- and Register-Based Case-Control Study

Background: The peak incidence of central nervous system (CNS) tumors in childhood indicates that intrauterine or neonatal characteristics are potential risk factors or symptoms of early onset of disease. Methods: We conducted a registry-based case-control study nested in the childhood populations of Denmark, Finland, Sweden, and Norway on the association between indicators of fetal growth and neonatal stress and childhood CNS tumor risk diagnosed during the period 1985-2006. Each of the 3,443 cases was matched individually on date of birth, sex, and country to five controls sampled randomly from population registries. Information on birth characteristics was obtained from national birth registries. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) by conditional logistic regression analyses. Results: We observed a U-shaped relation between risk for CNS tumors and birthweight, at >4.5 kg (OR, 1.27; 95% CI, 1.03-1.55) and <2.0 kg (OR, 1.50; 95% CI, 1.13-1.99), the latter being attenuated after adjustment for gestational age. Moreover, small-for-gestational age (OR, 1.28; 95% CI, 0.98-1.66) and large-for-gestational age (OR, 1.26; 95% CI, 1.02-1.55) were both associated with CNS tumors. The OR for preterm births was increased per 1-week decrease in gestational age (OR, 1.58; 95% CI, 1.04-2.44). Increased ORs were also observed for head circumference >38 cm (1.80; 95% CI, 1.18-2.74), 5-minute Apgar score <7 (1.44; 95% CI, 0.98-2.12), and breech presentation (1.33; 95% CI, 1.04-1.69). The observed associations varied little by histologic subgroup. Conclusions: This study supports intrauterine or neonatal onset of childhood CNS tumors. The findings provide insight into the natural history of childhood CNS tumors indicating an early onset or, alternatively, potentially harmful exposures in the neonatal period that might be preventable. Cancer Epidemiol Biomarkers Prev; 19(4); 1042–52. ©2010 AACR.

Incidence of Childhood Central Nervous System Tumors in the Nordic Countries

The incidence rates of childhood central nervous system (CNS) tumors in the Nordic countries remain among the highest in the world. Large geographical and temporal variations in the incidence rates of CNS tumors have been reported. Increasing incidence rates would be a public health concern, as they might indicate increased exposure to environmental risk factors.

Low serum inhibin B concentrations in male survivors of childhood malignancy

The aim of this study was to assess the value of serum inhibin B in detecting male gonadal dysfunction in childhood cancer survivors. 27 male postpubertal (Tanners pubertal stage G5 or P6) and 12 pubertal (> or = G2) patients were drawn from the endocrine follow-up protocol of childhood cancer patients at the Paediatric Clinic of Turku University Hospital, Turku, Finland. The average time (mean +/- S.D.) between the diagnosis and this study was 11.7 +/- 4.5 years in the postpubertal and 7.0 +/- 3.9 years in the pubertal group. Serum samples for the determination of follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, testosterone, and inhibin A and B dimers were collected. The demographic factors, pubertal stage and testicular size of the patient were measured at the same routine outpatient visit. Serum inhibin concentrations were correlated to testicular volume and gonadotrophin concentrations. Strong correlations were observed between testicular size (r = 0.80, P < 0.001) or FSH (r = -0.58, P = 0.002) and inhibin B concentration in the postpubertal group. Inhibin A was not detectable (< 2 pg/ml). Testicular volume measurement was accurately documented in 21 postpubertal subjects. Patients with small testicles (< 10 ml) had inhibin B concentrations under 42 pg/ml and those whose testicular size was over 13 ml had inhibin B concentrations exceeding 100 pg/ml. In all 12 pubertal survivors, serum inhibin B levels were > or = 94 pg/ml, except in one case of testicular cancer where inhibin B was 8.1 pg/ml and the FSH concentration was elevated. Inhibin B seems to be an indicator of male gonadal function in postpubertal childhood cancer survivors and could be used in the estimation of gonadal function of male survivors earlier than testicular volume or semen analyses would be routinely possible. However, the correct cut-off level of serum inhibin B, as well as the details of inhibin B physiology during puberty, remain to be determined before semen analysis can be replaced by the measurement of inhibin B.

Late mortality among 5-year survivors of early onset cancer: A population-based register study

To date, only few studies have been published documenting late mortality among early onset cancer survivors, especially regarding young adulthood (YA) malignancies. Our nation‐wide population‐based registry study provides information concerning cause‐specific long‐term mortality among 16,769 5‐year survivors of early onset cancer (aged 0–34 years at diagnosis), with follow‐up for death extending from 1971 through 2012. A sibling cohort and population data were used as reference. The overall standardized mortality ratio (SMR) of cancer patients was 4.6‐fold, (95% CI 4.4–4.8). Highest SMRs were found for malignancies (12.8, 95% CI 12.3–13.3), infectious (4.8, 95%CI 2.9–6.7) and cardiovascular diseases (1.9, 95% CI 1.7–2.1). Malignancies and cardiovascular diseases accounted for the largest number of deaths. Childhood and YA cancer survivors with the same primary cancer site had a similarly elevated overall SMR with the exception of markedly higher SMRs after childhood Hodgkin lymphoma. The highest cumulative non‐malignancy‐related mortality was due to cardiovascular disease with a steady rise throughout the follow‐up, but strongly dependent on the primary cancer site and age at diagnosis. In childhood cancer survivors, the cumulative cardiovascular mortality did not reduce over time. However, overall and malignancy‐related mortality showed a declining tendency towards the most recent periods after both, childhood and YA cancer. Our findings on non‐malignancy‐related mortality stress the need to set up long‐term individual follow‐up with a focus on cardiovascular late effects for early onset cancer survivors, especially for YA cancer survivors still lacking those.