Catherine Rechnitzer

Radiotherapy at a young age reduces uterine volume of childhood cancer survivors

Background.  In contrast to chemotherapy, previous irradiation of the uterus carries an increased risk of an adverse pregnancy outcome. Conflicting results exist as regards the ability of the uterus to increase in volume following radiotherapy‐induced damage. We measured uterine volume in a cohort of childhood cancer survivors, and assessed uterine response to a high‐dose estrogen replacement regimen.

Lifelong Cancer Incidence in 47 697 Patients Treated for Childhood Cancer in the Nordic Countries

BACKGROUND The pattern of cancer in long-term survivors from childhood cancer has not been investigated comprehensively. METHODS We obtained a cohort of 47,697 children and adolescents aged 0-19 years with cancer as defined by the country-wide cancer registries of Denmark, Finland, Iceland, Norway, and Sweden during 1943-2005. Cohort members were followed through age 79 years for subsequent primary cancers notified to the registries, and the age-specific risk pattern of the survivors was compared with that of the national populations using country and sex standardized incidence ratios (SIRs). We used a multiplicative Poisson regression model to estimate relative risk of cancer for attained age, with adjustment for calendar period and age at diagnosis of primary cancer. We also calculated excess absolute risk (EAR) attributable to status as childhood cancer survivor and determined the cumulative incidence of second primary cancer as a function of attained age for three subcohorts defined by period of treatment for childhood cancer. RESULTS A total of 1180 asynchronous second primary cancers were observed in 1088 persons, yielding an overall SIR of 3.3 (95% confidence interval = 3.1 to 3.5). The relative risk was statistically significantly increased in all age groups, even for cohort members approaching 70 years of age. The EAR for second primary cancer among survivors increased gradually from one additional case per 1000 person-years of observation in early life to six additional cases per 1000 person-years in the age group 60-69 years. For children treated in the prechemotherapy era (1943-1959), the cumulative risk for a second primary cancer reached 18%, 34%, and 48% at ages 60, 70, and 80 years, respectively. The age-specific incidence rates were highest for cohort members treated in the era of intensive, multiple-agent chemotherapy (1975-2005). CONCLUSION Survivors of childhood cancer have a persistent excess risk for a second primary cancer throughout their lives, accompanied by continuous changes in the risk of cancers at specific sites.

A systematic review of studies on psychosocial late effects of childhood cancer: Structures of society and methodological pitfalls may challenge the conclusions

High survival rates after childhood cancer raise attention to possible psychosocial late effects. We focus on predictors of psychosocial outcomes based on diagnosis, treatment, demography, somatic disease, and methodological problems. Overall, survivors evaluate their health‐related quality of life to be normal or even better than controls, although virtually all diagnostic subgroups report psychosocial impairment. Central nervous system tumor survivors have significant psychosocial problems. Negative outcomes were associated with cranial radiation therapy, female gender, and young age at diagnosis. Significant methodological problems hamper current knowledge. Systematic registration of psychosocial and somatic problems at diagnosis and prospectively through protocols is needed. Pediatr Blood Cancer 2011;56:532–543.

Clinical and biochemical correlates of successful semen collection for cryopreservation from 12–18-year-old patients: a single-center study of 86 adolescents

BACKGROUND Cryopreservation of semen should be offered to adults before gonadotoxic treatment. However, the experience with semen collection in adolescents is still limited. The objective of this study was to evaluate potential correlates of successful semen sampling in adolescents. METHODS A total of 86 boys (aged 12.2-17.9 years), referred for cryopreservation of semen prior to gonadotoxic treatment were included. Age, testicular volume, diagnosis and reproductive hormones were evaluated as correlates of successful semen collection. RESULTS Median sperm concentration was 9.6 (range 0-284) million/ml. Of the 86 included boys, 76 (88.4%) had spermatozoa in their ejaculate. Of the 76 patients for whom a semen sample was obtained, 71 (93.4%) had motile spermatozoa eligible for cryopreservation. Of the 86 boys, 74 produced a semen sample by masturbation, whereas semen samples were obtained from 12 patients by penile vibration or electroejaculation. The youngest patient with an ejaculate containing motile spermatozoa was 12.2 years old, and the smallest testicular volumes in boys associated with motile spermatozoa in the ejaculate were 6-7 ml. Testicular volume correlated with sperm concentration (R = 0.283, P = 0.046), and the percentage of motile spermatozoa (R = 0.410, P = 0.003). Chronological age, but not reproductive hormones, also correlated with sperm concentration (R = 0.25, P = 0.049). CONCLUSIONS Semen was successfully collected and cryopreserved in 71 out of 86 boys and adolescents. Testicular volume, but not age or reproductive hormone levels, was indicative of successful semen collection. Regardless of their age, adolescent boys with testicular volumes of more than 5 ml should be offered semen banking prior to gonadotoxic treatment or other procedures that could potentially damage future fertility.

Hospital contact for mental disorders in survivors of childhood cancer and their siblings in Denmark: a population-based cohort study

BACKGROUND Survivors of childhood cancer are known to be at risk for long-term physical and mental effects. However, little is known about how cancers can affect mental health in the siblings of these patients. We aimed to assess the long-term risks of mental disorders in survivors of childhood cancer and their siblings. METHODS Hospital contact for mental disorders was assessed in a population-based cohort of 7085 Danish children treated for cancer by contemporary protocols between 1975 and 2010 and in their 13 105 siblings by use of data from the Danish Psychiatric Central Research Registry. Hazard ratios (HRs) for first hospital contact were calculated using a Cox proportional hazards model. We compared these sibling and survivor cohorts with two population-based cohorts who were not childhood cancer survivors or siblings of survivors. FINDINGS Survivors of childhood cancer were at increased risk of hospital contact for mental disorders, with HRs of 1·50 (95% CI 1·32-1·69) for males and 1·26 (1·10-1·44) for females. Children younger than 10 years at diagnosis had the highest risk, and increased risks were seen in survivors of CNS tumours, haematological malignancies, and solid tumours. Survivors had higher risk of neurodevelopmental, emotional, and behavioural disorders than population-based comparisons and siblings, and male survivors had higher risk for unipolar depression. Overall, siblings had no excess risk for mental disorders. However, our data suggest that siblings who were young at the time of cancer diagnosis of the survivor were at increased risk for mental disorders, whereas those older than 15 years at diagnosis were at a lower risk than the general population. INTERPRETATION Childhood cancer survivors should be followed up for mental late effects, especially those diagnosed in young age. Further, clinicians should also be aware that siblings who were young at the time of cancer diagnosis might be at increased risk for mental health disorders.

MMSET Is Highly Expressed and Associated with Aggressiveness in Neuroblastoma

MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis.

Germline minisatellite mutations in survivors of childhood and young adult cancer treated with radiation

Purpose: To investigate minisatellite germline mutation rates in survivors of childhood and young adult cancer who received radiotherapy. Materials and methods: DNA samples from 100 families, where one parent was a cancer survivor, were analysed for mutations at eight hypervariable minisatellite loci (B6.7, CEB1, CEB15, CEB25, CEB36, MS1, MS31, MS32) by Southern hybridisation. Results: No significant difference was observed between the paternal mutation rate of 5.6% in exposed fathers with a mean preconceptional testicular dose of 1.23 Gy (56 mutations in 998 informative alleles) and that of 5.8% in unexposed fathers (17 in 295 informative alleles). Subgrouping the exposed fathers into dose groups of <0.10 Gy, 0.10–0.99 Gy, 1.00–1.99 Gy, ≥2.00 Gy revealed no significant differences in paternal mutation rate in comparison with the unexposed fathers. Maternal mutation rates of 1.6% in cancer survivor mothers with a mean preconceptional ovarian dose of 0.58 Gy (five mutations in 304 informative alleles) and 2.1% in unexposed mothers (21 in 987 informative alleles) were not significantly different. There were no differences in minisatellite mutation rates associated with treatment with chemotherapeutic agents. Conclusions: This study provides evidence that preconception radiotherapy for childhood or early adulthood cancer does not increase the germline minisatellite mutation rate.

The heritability of G2 chromosomal radiosensitivity and its association with cancer in Danish cancer survivors and their offspring.

Purpose: To investigate the relationship between chromosomal radiosensitivity and early-onset cancer under the age of 35 years and to examine the heritability of chromosomal radiosensitivity. Materials and methods: Peripheral blood lymphocytes were cultured for 72 hours prior to being irradiated with 0.5 Gy, 300 kV X-rays. Colcemid was added to cultures 30 min post-irradiation. Cultures were harvested 90 min post-irradiation and analysed for chromatid gaps and breaks. Heritability was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR) software and by segregation analysis. Results: Elevated radiosensitivity was seen for seven out of 29 (24.1%) cancer survivors, three out of 29 (10.3%) partners and 10 out of 53 (20.8%) offspring. Although the proportion of individuals displaying enhanced radiosensitivity was twice as high in both the cancer survivor and offspring groups than the partner controls, neither reached statistical significance. Heritability analysis of the radiosensitive phenotype suggested 57.9–78.0% of the variance could be attributed to genetic factors. Conclusion: An association between G2 chromosomal radiosensitivity and childhood and young adult cancer is suggested but was not statistically significant. In contrast, there is strong evidence for heritability of the radiosensitive phenotype. The cancer survivors included a broad range of malignancies and future studies should focus on specific cancers with known or likely faults in deoxyribonucleic acid (DNA) damage recognition and repair mechanisms.

A 10-year follow up of reproductive function in women treated for childhood cancer

Previously, this study group found that female childhood cancer survivors could be at risk of early cessation of fertility. The aim of the present study was to evaluate reproductive function in the same group of survivors 10 years after the initial study. Of the original cohort of 100, 71 were re-examined. Thirty-six survivors reported regular menstrual cycles. When they were compared with 210 controls, they differed significantly in antral follicle count (AFC) (median 15 versus 18, P=0.047) but not in anti-Müllerian hormone (AMH) (median 13.0 versus 17.8 pmol/l). Survivors cured with minimal gonadotoxic treatment had significantly higher AMH and AFC compared with survivors cured with either potentially gonadotoxic treatment or treatment including alkylating chemotherapy and ovarian irradiation (20.0, 5.8 and <3 pmol/l, P<0.001; and 15, 9 and 2, P=0.03, respectively). Thirty-eight survivors had achieved at least one live birth. Complicated second-trimester abortions (n=4) were observed primarily in survivors cured with radiotherapy affecting pelvic organs. In conclusion, childhood cancer survivors have signs of diminished ovarian reserve. However, if the ovarian function is preserved in the early to mid-twenties, it is likely to persist until the mid-thirties, giving a good chance of childbearing.

A pilot study examining germline minisatellite mutations in the offspring of Danish childhood and adolescent cancer survivors treated with radiotherapy

Purpose:To investigate germline mutation rate at eight minisatellite loci in 24 Danish families, where one parent is the survivor of childhood or adolescent cancer treated with radiotherapy. Materials and methods:Parents and offspring were profiled for eight hypervariable minisatellite loci (B6.7, CEB1, CEB15, CEB25, CEB36, MS1, MS31, MS32) by Southern blotting. Results:Seven paternal mutations were observed for 130 informative alleles in 18 offspring from 11 radiation-exposed fathers (mean preconceptional dose for offspring 0.29 Gy, range <0.01 – 1.2 Gy), compared to six mutations for 146 informative alleles in 21 offspring from 13 unexposed fathers. No statistically significant difference between the total paternal mutation rates was observed (5.4% for exposed fathers and 4.1% for unexposed fathers). Three maternal mutations were observed for 148 informative alleles in 21 offspring from 13 radiation-exposed mothers (mean preconceptional dose for offspring 0.71 Gy, range <0.01 – 9.2 Gy), compared to one mutation for 130 informative alleles in 18 offspring from 11 unexposed mothers. Again, no statistically significant difference was observed between the total maternal mutation rates (2.0% for exposed mothers and 0.8% for unexposed mothers). Conclusions:The data from this pilot study demonstrate no statistically significant increase in germline minisatellite mutation rate associated with radiotherapy for childhood and adolescent cancer.