C.M. Ronckers

RE: A further plea for adherence to the principles underlying science in general and the epidemiologic enterprise in particular

nisms that could lead to changes in incidence. Here I try to meet this latter need. I have adduced very substantial quantities of data to support the hypothesis that mammalian (including human) sex ratios (proportions male) at birth are partially controlled by the hormone levels of both parents around the time of conception. Baron-Cohen hypothesized that one cause of autism is high maternal intrauterine concentrations of testosterone. If both hypotheses were correct, then sibs of autistic probands should contain an excess of brothers. I reported evidence for such an inference at a statistically significant level, and this finding has itself been confirmed. So there is good evidence for BaronCohen’s hypothesis that one cause of autism is high maternal intrauterine testosterone concentration. There is good reason to suppose that over the past few decades, there has been an increase in women’s testosterone levels. Such an increase would be expected to have been associated with the rise in rates of diabetes, and of obesity in women. Thus, it seems reasonable to propose that the reported increase in rates of autism is at least partially real and due to increasing maternal intrauterine testosterone levels.

Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy

Purpose Childhood cancer survivors (CCSs) are at increased risk for subsequent malignant neoplasms (SMNs). We evaluated the long-term risk of SMNs in a well-characterized cohort of 5-year CCSs, with a particular focus on individual chemotherapeutic agents and solid cancer risk. Methods The Dutch Childhood Cancer Oncology Group-Long-Term Effects After Childhood Cancer cohort includes 6,165 5-year CCSs diagnosed between 1963 and 2001 in the Netherlands. SMNs were identified by linkages with the Netherlands Cancer Registry, the Dutch Pathology Registry, and medical chart review. We calculated standardized incidence ratios, excess absolute risks, and cumulative incidences. Multivariable Cox proportional hazard regression analyses were used to evaluate treatment-associated risks for breast cancer, sarcoma, and all solid cancers. Results After a median follow-up of 20.7 years (range, 5.0 to 49.8 years) since first diagnosis, 291 SMNs were ascertained in 261 CCSs (standardized incidence ratio, 5.2; 95% CI, 4.6 to 5.8; excess absolute risk, 20.3/10,000 person-years). Cumulative SMN incidence at 25 years after first diagnosis was 3.9% (95% CI, 3.4% to 4.6%) and did not change noticeably among CCSs treated in the 1990s compared with those treated earlier. We found dose-dependent doxorubicin-related increased risks of all solid cancers ( Ptrend < .001) and breast cancer ( Ptrend < .001). The doxorubicin-breast cancer dose response was stronger in survivors of Li-Fraumeni syndrome-associated childhood cancers (leukemia, CNS, and non-Ewing sarcoma) versus survivors of other cancers ( Pdifference = .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner ( Ptrend = .01). Conclusion The results strongly suggest that doxorubicin exposure in CCSs increases the risk of subsequent solid cancers and breast cancer, whereas cyclophosphamide exposure increases the risk of subsequent sarcomas. These results may inform future childhood cancer treatment protocols and SMN surveillance guidelines for CCSs.

Landelijke richtlijnen voor follow-up van overlevenden van kinderkanker

SamenvattingMembers of the Late Effects Taskforce of the Dutch Childhood Oncology Group (dcog) and of the Haematology-Oncology Section of the Dutch Paediatric Association are involved in the development of guidelines for the follow-up of childhood cancer survivors. The recommendations of these guidelines are based on the best available clinical evidence, current guidelines and clinical experience of late effects specialists. The guidelines will lead to a uniform and standardised post-treatment care and long-term follow-up of childhood cancer survivors in the Netherlands. The information in the guidelines will be of importance for care providers in paediatrics, general medicine, internal medicine, gynaecology/obstetrics as well as for other specialists and particularly for childhood cancer survivors themselves. The information will lead to an increased awareness for all Dutch care providers who are responsible for the health problems of childhood cancer survivors. The development of guidelines for childhood cancer survivors is an important part of a new Dutch project: Late Effects Registry (later). Within this new national project patient and treatment data as well as follow-up data on childhood cancer survivors in the Netherlands will be registered. The project later aims at: to coordinate and to evaluate care of the survivors, and to stimulate new research in the field of late effects of childhood cancer.SamenvattingVanuit de skion (Stichting Kinderoncologie Nederland) en de sectie Kinderoncologie-Hematologie van de Nederlandse Vereniging voor Kindergeneeskunde worden in Nederland richtlijnen opgesteld voor de follow-up van overlevenden van kinderkanker meer dan vijf jaar na diagnose. De aanbevelingen in deze richtlijnen voor follow-up zijn gebaseerd op het beschikbare bewijs, bestaande richtlijnen en het klinische inzicht van experts op het gebied van de late effecten. Deze richtlijnen zullen leiden tot een uniforme en gestandaardiseerde langetermijnzorg voor overlevenden na kinderkanker in Nederland. De informatie van de richtlijnen is belangrijk voor zorgverleners in het veld van kindergeneeskunde, huisartsgeneeskunde, interne geneeskunde, gynaecologie/obstetrie en andere specialisten en ook voor de overlevenden van kinderkanker. De informatie zal bijdragen aan een algemene bewustwording van de Nederlandse zorgverleners voor de gezondheidsproblemen van kinderen en jongvolwassenen die genezen zijn van kinderkanker. De richtlijnontwikkeling voor de follow-up van overlevenden van kinderkanker vormt een belangrijk onderdeel van het nieuwe landelijke project Lange Termijn Effecten Registratie: later. Binnen dit landelijke project zullen patiëntengegevens, gegevens over de oorspronkelijke behandeling en follow-upgegevens van alle overlevenden van kinderkanker in Nederland geregistreerd worden. Het doel van deze registratie is om de patiëntenzorg in Nederland te coördineren, te evalueren en nieuw wetenschappelijk onderzoek te stimuleren.

Validity of self-reported data on pregnancies for childhood cancer survivors: a comparison with data from a nationwide population-based registry

STUDY QUESTIONnTo what degree do records registered in the Netherlands Perinatal Registry (PRN) agree with self-report in a study questionnaire on pregnancy outcomes in childhood cancer survivors (CCSs)?nnnSUMMARY ANSWERnThis study suggests that self-reported pregnancy outcomes of CCSs agree well with registry data and that outcomes reported by CCSs agree better with registry data than do those of controls.nnnWHAT IS KNOWN ALREADYnMany studies have shown that childhood cancer treatment may affect fertility outcomes in female CCSs; however, these conclusions were often based on questionnaire data, and it remains unclear whether self-report agrees well with more objective sources of information.nnnSTUDY DESIGN, SIZE, DURATIONnIn an nationwide cohort study on fertility (inclusion period January 2008 and April 2011, trial number: NTR2922), 1420 CCSs and 354 sibling controls were invited to complete a questionnaire regarding socio-demographic characteristics and reproductive history. In total, 879 CCSs (62%) and 287 controls (81%) returned the questionnaire.nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnThe current validation study compared the agreement between pregnancy outcomes as registered in the PRN and self-reported outcomes in the study questionnaire. A total of 589 pregnancies were reported in CCSs, and 300 pregnancies in sibling controls, of which 524 could be linked to the PRN.nnnMAIN RESULTS AND THE ROLE OF CHANCEnA high intra-class correlation coefficient (ICC) was found for birthweight (BW) (0.94 and 0.87 for CCSs and controls, respectively). The self-reported BWs tended to be higher than reported in the PRN. For gestational age (GA), the ICC was high for CCSs (0.88), but moderate for controls (0.49). CCSs overestimated GA more often than controls. The Kappa values for method of conception and for method of delivery were moderate to good. Multilevel analyses on the mean difference with regard to BW and GA showed no differences associated with time since pregnancy or educational level.nnnLIMITATIONS, REASONS FOR CAUTIONnNot all pregnancies reported could be linked to the registry data. In addition, the completeness of the PRN could not be assessed precisely, because there is no information on the number of missing records. Finally, for some outcomes there were high proportions of missing values in the PRN registry.nnnWIDER IMPLICATIONS OF THE FINDINGSnOur study suggests that questionnaires are a reliable method of data collection, and that for most variables, self-report agrees well with registry data.nnnSTUDY FUNDING/COMPETING INTERESTnThis work was supported by the Dutch Cancer Society (grant no. VU 2006-3622) and by Foundation Children Cancer Free. None of the authors report a conflict of interest.nnnTRIAL REGISTRATION NUMBERnNTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review

INTRODUCTIONnThe variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment.nnnMETHODSnA systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment.nnnRESULTSnTwenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (nu202f=u202f6); BMD (nu202f=u202f6); gonadal impairment (nu202f=u202f2); hearing impairment (nu202f=u202f12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (nu202f<u202f200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26u202f=u202f15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report.nnnCONCLUSIONnGenetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.