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Background: The aim of this study is to evaluate how cumulative burden of clinically relevant, self‐reported outcomes in childhood cancer survivors (CCSs) compares to a sibling control group and to explore how the burden corresponds to levels of care proposed by existing risk stratifications. Methods: The authors invited 5925 5‐year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS LATER) cohort and their 1066 siblings to complete a questionnaire on health outcomes. Health outcomes were validated by self‐reported medication use or medical record review. Missing data on clinically relevant outcomes in CCSs for whom no questionnaire data were available were imputed with predictive mean matching. We calculated the mean cumulative count (MCC) for clinically relevant outcomes. Furthermore, we calculated 30‐year MCC for groups of CCSs based on primary cancer diagnosis and treatment, ranked 30‐year MCC, and compared the ranking to levels of care according to existing risk stratifications. Results: At median 18.5 years after 5‐year survival, 46% of CCSs had at least one clinically relevant outcome. CCSs experienced 2.8 times more health conditions than siblings (30‐year MCC = 0.79; 95% confidence interval [CI], 0.74–0.85 vs. 30‐year MCC = 0.29; 95% CI, 0.25–0.34). CCSs' burden of clinically relevant outcomes consisted mainly of endocrine and vascular conditions and varied by primary cancer type. The ranking of the 30‐year MCC often did not correspond with levels of care in existing risk stratifications. Conclusions: CCSs experience a high cumulative burden of clinically relevant outcomes that was not completely reflected by current risk stratifications. Choices for survivorship care should extend beyond primary tumor and treatment parameters, and should consider also including CCSs' current morbidity. Survivors of childhood cancer experience a high cumulative burden of clinically relevant outcomes. Choices for survivorship care should extend beyond primary tumor and treatment parameters and should also consider including the current morbidity of childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors are at risk for developing long‐term adverse health outcomes. To identify the risk of and risk factors for specific health outcomes, well‐established cohorts are needed with detailed information on childhood cancer diagnosis, treatment, and health outcomes. We describe the design, methodology, characteristics, and data availability of the Dutch Childhood Cancer Survivor Study LATER cohort (1963–2001) part 1; questionnaire and linkage studies. Methods: The LATER cohort includes 5‐year childhood cancer survivors, diagnosed in the period 1963–2001, and before the age of 18 in any of the seven former pediatric oncology centers in the Netherlands. Information on health outcomes from survivors and invited siblings of survivors was collected by questionnaires and linkages to medical registries. Results: In total, 6165 survivors were included in the LATER cohort. Extensive data on diagnosis and treatment have been collected. Information on a variety of health outcomes has been ascertained by the LATER questionnaire study and linkages with several registries for subsequent tumors, health care use, and hospitalizations. Conclusion: Research with data of the LATER cohort will provide new insights into risks of and risk factors for long‐term health outcomes. This can enhance risk stratification for childhood cancer survivors and inform surveillance guidelines and development of interventions to prevent (the impact of) long‐term adverse health outcomes. The data collected will be a solid baseline foundation for future follow‐up studies. [ABSTRACT FROM AUTHOR]

Studies have shown higher survival rates for patients with Hodgkin lymphoma (HL) treated within clinical trials compared to patients treated outside clinical trials. However, endpoints are often limited to overall survival (OS). In this retrospective cohort study, we investigated the effect of trial participation on OS, the incidence of relapse, second cancer, and cardiovascular disease (CVD). The study population consisted of patients with HL, aged between 14 and 51 years at diagnosis, who started their treatment between 1962 and 2002 at three Dutch cancer centres. Patients were either included in the EORTC Lymphoma Group trials (H1–H9) or treated according to standard guidelines at the time. After adjusting for differences in baseline characteristics, trial participation was associated with longer OS (median OS: 29.4 years [95%CI: 27.0–31.6] for treatment inside trials versus 27.4 years [95%CI: 26.0–28.5] for treatment outside trials, p =.046), a lower incidence of relapse (HR = 0.79, 95%CI: 0.63–0.98, p =.036) and a higher incidence of CVD (HR = 1.49, 95%CI: 1.23–1.79, p <.001). The trial effect for CVD was present only for patients treated before 1983. No evidence of differences in the incidence of second cancer was found. Consequently, essential results from clinical trials should be implemented into standard practice without undue delay. [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit BC treatment options. It is unknown how treatment adaptations affect BC and CVD outcomes. Methods: The authors compared 195 BC patients treated with chest/axillary radiotherapy for HL (BC‐HL) with 5988 age‐ and calendar year‐matched patients with first primary BC (BC‐1). Analyses included cumulative incidence functions and Cox regression models, accounting for tumor characteristics and BC treatment. Results: Compared to BC‐1 patients, BC‐HL patients received anthracycline‐containing chemotherapy (23.7% vs. 43.8%, p <.001) and breast‐conserving surgery followed by radiotherapy (7.1% vs. 57.7%, p <.001) less often. BC treatment considerations were reported for 71% of BC‐HL patients. BC‐HL patients had a significantly higher risk of 15‐year overall mortality than BC‐1 patients (61% vs. 23%). Furthermore, risks of BC‐specific mortality and nonfatal BC events were significantly increased among BC‐HL patients, also when accounting for tumor and treatment characteristics (2.2‐ to 4.5‐fold). BC‐HL patients with a screen‐detected BC had a significantly reduced (61%) BC‐specific mortality. One‐third of BC‐HL patients had CVD at BC‐diagnosis, compared to <0.1% of BC‐1 patients. Fifteen‐year CVD‐specific mortality and CVD incidence were significantly higher in BC‐HL patients than in BC‐1 patients (15.2% vs. 0.4% and 40.4% vs. 6.8%, respectively), which was due to HL treatment rather than BC treatment. Conclusions: BC‐HL patients experience a higher burden of CVD and worse BC outcomes than BC‐1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. Lay summary: Patients with breast cancer after Hodgkin lymphoma (BC‐HL) may have limited options for BC treatment, due to earlier HL treatment and an associated increased risk of cardiovascular disease (CVD).BC treatment considerations were reported for 71% of BC‐HL patients.We examined whether BC‐HL patients have a higher risk of CVD or BC events (recurrences/metastases) compared to patients with breast cancer that had no earlier tumors (BC‐1).We observed a higher burden of CVD and worse BC outcomes in HL patients compared to BC‐1 patients.Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. Hodgkin lymphoma survivors with radiation‐induced breast cancer experience a higher burden of cardiovascular disease and worse breast cancer outcomes than first primary breast cancer patients. Clinicians should be aware of increased cardiovascular disease risk when selecting breast cancer treatment for Hodgkin lymphoma survivors. [ABSTRACT FROM AUTHOR]

Summary: Chronotype is frequently assessed in human observational studies using various morningness–eveningness questionnaires. An alternative single‐item chronotype question has been proposed for its reduced administration time and its accessibility to all types of populations. We investigated whether this single‐item chronotype is associated with dim light melatonin onset, the "gold standard" for estimating the endogenous circadian phase. We used data from a randomised trial in 166 (non‐)Hodgkin lymphoma survivors with cancer‐related fatigue. All participants completed a questionnaire, including a single‐item chronotype question. A subsample of 47 participants also provided saliva samples before sleep onset for melatonin measurement. Using multiple linear regression, we examined whether chronotype based on a single question was associated with dim light melatonin onset. The subsample of 47 participants had a mean age of 44.6 years. The mean (SD) dim light melatonin onset was at 8:42 (1:19) p.m. and the most common chronotype was more evening than morning person (29.2%). A gradual increase in dim light melatonin onset with later chronotype (i.e. evening preference) was observed, with a mean ranging from 7:45 p.m. in definite morning persons to 9:16 p.m. in definite evening persons. Our study shows that single‐item chronotype is associated with dim light melatonin onset as a marker of the endogenous circadian phase of fatigued lymphoma survivors. This type of chronotype assessment can therefore be a useful alternative for more extensive morningness–eveningness questionnaires. [ABSTRACT FROM AUTHOR]

Background: Cancer‐related fatigue is a debilitating late effect after treatment for childhood cancer. The prevalence of fatigue in childhood cancer survivors (CCSs) and associated factors for fatigue has varied widely in previous studies. Two important aspects of cancer‐related fatigue, its severity and chronicity, are often not assessed. This study investigated the prevalence of, and risk factors for, severe chronic fatigue (CF) in a national cohort of Dutch CCSs. Methods: In this study, 2810 CCSs (5‐year survivors of all childhood malignancies diagnosed between 1963 and 2001 with a current age of 12‐65 years) and 1040 sibling controls were included. CF was assessed with the Short Fatigue Questionnaire and was defined as a score ≥ 18 and persistence of fatigue for ≥6 months. Cancer‐ and treatment‐related characteristics, current health problems, and demographic and lifestyle variables were assessed as potential risk factors for CF via multivariable logistic regression analyses. Results: In adult CCSs and sibling controls (≥18 years old), the prevalence of CF was 26.1% and 14.1%, respectively (P <.001). In adolescent CCSs and sibling controls (<18 years old), the prevalence of CF was 10.9% and 3.2%, respectively. Female gender (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.73‐2.62), unemployment (OR, 2.18; 95% CI, 1.67‐2.85), having 1 or more health problems (OR for 1‐2, 1.48; 95% CI, 1.18‐1.87; OR for >2, 2.20; 95% CI, 1.50‐3.21), and a central nervous system diagnosis (OR, 1.74; 95% CI, 1.17‐2.60) were significantly associated with CF in adult CCSs. Conclusions: This study shows that CCSs, regardless of their cancer diagnosis, report CF more often than sibling controls. This study provides new evidence for the prevalence of fatigue in CCSs. One in 4 childhood cancer survivors reports chronic fatigue. Current health problems increase the risk of reporting chronic fatigue. [ABSTRACT FROM AUTHOR]

Background: Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia. Aims: We evaluated the clinicopathological characteristics and risk factors for developing (advanced) neoplasia (AN) in HL survivors. Methods: In all, 101 HL survivors (median age 51 years, median age of HL diagnosis 25 years) underwent colonoscopy and 350 neoplasia and 44 AN (classified as advanced adenomas/serrated lesions or colorectal cancer), mostly right‐sided, were detected, as published previously. An average‐risk asymptomatic cohort who underwent screening colonoscopy were controls (median age 60 years). Clinicopathological characteristics of AN were evaluated in both groups. Mismatch repair (MMR) status was assessed using immunohistochemistry (MLH1/MSH2/MSH6/PMS2). Logistic regression analysis was performed to evaluate the risk factors for AN in HL survivors, including age at HL diagnosis and interval between HL and colonoscopy. Results: In 101 colonoscopies in HL survivors, AN was primarily classified based on polyp size ≥10 mm, whereas (high‐grade)dysplasia was more often seen in AN in controls. An interval between HL diagnosis and colonoscopy >26 years was associated with more AN compared with an interval of <26 years, with an odds ratio for AN of 3.8 (95% confidence interval 1.4–9.1) (p < 0.01). All 39 AN that were assessed were MMR proficient. Conclusions: Colorectal neoplasia in HL survivors differ from average‐risk controls; classification AN was primarily based on polyp size (≥10 mm) in HL survivors. Longer follow‐up between HL diagnosis and colonoscopy was associated with a higher prevalence of AN in HL survivors. [ABSTRACT FROM AUTHOR]

Epidemiologic studies conducted to quantify the impact of radiation dose d on an outcome typically model the hazard ratio (HR) for association using a linear term, HR(d)=1+βd, via a linear excess relative risk (ERR) model, based on biological considerations. To study associations of risk of a second cancer with radiation treatment for a first cancer, several nested case‐control designs to estimate β have been proposed that use refined doses received by different locations in the organ of interest. Here we first evaluated the small sample bias in maximum likelihood estimates of β for the linear ERR model using location‐specific radiation doses in simulations. As we found substantial upward bias for studies of realistic sample sizes (more than 50% relative bias for studies with 75 cases), we also proposed and investigated several approaches to correct this bias. We studied first and second order jackknife bias corrections and we derived a modified set of score functions under retrospective case‐control sampling, from which we directly obtained bias‐corrected estimates. In simulations based on doses from a study of stomach cancer among testicular cancer survivors and synthetically generated data, neither the first nor second order jackknife bias correction performed well. Estimates based on the modified score equations corrected the bias much better, albeit not completely, and were numerically much more stable. [ABSTRACT FROM AUTHOR]

Background: We aimed to develop dose-response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies.Methods and Results: A case-control study was performed within a cohort of breast cancer survivors treated during 1980-2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9-13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) -2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7-21.7) compared to <10% exposed to ≥20 Gy. For cases who received radiotherapy, median cumulative anthracycline dose was 247 mg/m2 (IQR 240-319). A dose-dependent increase was observed after anthracycline without trastuzumab (ERR = 1.5% per mg/m2 , 95% CI 0.5-4.1). After anthracycline and trastuzumab, the rate ratio was 34.9 (95% CI 11.1-110.1) compared to no chemotherapy.Conclusions: In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies. [ABSTRACT FROM AUTHOR]

Aims: Anthracyclines increase heart failure (HF) risk, but the long-term prevalence of myocardial dysfunction in young breast cancer (BC) survivors is unknown. Early measures of left ventricular myocardial dysfunction are needed to identify BC patients at risk of symptomatic HF.Methods and Results: Within an established cohort, we studied markers for myocardial dysfunction among 569 women, who were 5-7 years (n = 277) or 10-12 years (n = 292) after BC treatment at ages 40-50 years. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were assessed by echocardiography. N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured in serum. Associations between patient-related and treatment-related risk factors and myocardial dysfunction were evaluated using linear and logistic regression. Median ages at BC diagnosis and cardiac assessment were 46.7 and 55.5 years, respectively. Anthracycline-treated patients (n = 313), compared to the no-anthracycline group (n = 256), more often had decreased LVEF (10% vs. 4%), impaired GLS (34% vs. 27%) and elevated NT-proBNP (23% vs. 8%). GLS and LVEF declined in a linear fashion with increasing cumulative anthracycline dose (GLS: +0.23 and LVEF: -0.40 per cycle of 60 mg/m2 ; P < 0.001) and GLS was worse for patients with left breast irradiation. The risk of NT-proBNP >125 ng/L was highest for patients who received 241-300 mg/m2 anthracycline dose compared to the no-anthracycline group (odds ratio: 3.30, 95% confidence interval: 1.83-5.96).Conclusion: Impaired GLS and increased NT-proBNP levels are present in a substantial proportion of young BC survivors treated with anthracyclines. Whether this will lead to future cardiac disease needs to be evaluated by longitudinal assessment. [ABSTRACT FROM AUTHOR]

The recent UK HL guideline also discusses the advantages and disadvantages of omitting radiotherapy in selected cases.[5] Of note, the omission of radiotherapy may come at a price. In addition, modern radiotherapy regimens include conformal radiotherapy techniques, radiotherapy in deep inspiration, and, if available, proton therapy. [Extracted from the article]

Background: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors.Methods: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis.Results: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P < .001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P < .001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P = .08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P < .001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P < .001).Conclusions: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered. [ABSTRACT FROM AUTHOR]

This article presents a study which investigated the association of plasminogen-activator inhibitor 1 (PAI-1) gene polymorphism with survival and chemotherapy-related vascular toxicity in testicular cancer (TC). The study included 324 non-seminomatous TC patients treated with platinum-based chemotherapy. Details of the methodology and key findings of the study are described.

Background: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era.Methods: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis.Results: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m2 platinum dose administered (Ptrend  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure.Conclusions: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality. [ABSTRACT FROM AUTHOR]

Objective: To study the impact of premenopausal risk-reducing salpingo-oophorectomy (RRSO), compared with postmenopausal RRSO, on urinary incontinence (UI) ≥10 years later., Design: Cross-sectional study, nested in a nationwide cohort., Setting: Multicentre in the Netherlands., Population: 750 women (68% BRCA1/2 pathogenic variant carriers) who underwent either premenopausal RRSO (≤45 years, n = 496) or postmenopausal RRSO (≥54 years, n = 254). All participants were ≥55 years at the time of the study., Methods: Urinary incontinence was assessed by the urinary distress inventory-6 (UDI-6); a score ≥33.3 indicated symptomatic UI. The incontinence impact questionnaire short form (IIQ-SF) was used to assess the impact on women's health-related quality of life (HR-QoL). Differences between groups were analysed using regression analyses adjusting for current age and other confounders., Main Outcome Measures: Differences in UDI-6 scores and IIQ-SF scores between women with a premenopausal and a postmenopausal RRSO., Results: Women in the premenopausal RRSO group had slightly higher UDI-6 scores compared with women in the postmenopausal RRSO group (P = 0.053), and their risk of symptomatic UI was non-significantly increased (odds ratio [OR] 2.1, 95% confidence interval [95% CI] 0.93-4.78). A premenopausal RRSO was associated with a higher risk of stress UI (OR 3.5, 95% CI 1.2-10.0) but not with urge UI. The proportions of women with a significant impact of UI on HR-QoL were similar in the premenopausal and postmenopausal RRSO groups (10.4% and 13.0%, respectively; P = 0.46)., Conclusions: More than 15 years after premenopausal RRSO, there were no significant differences in overall symptomatic UI between women with a premenopausal and those with a postmenopausal RRSO., (© 2023 John Wiley & Sons Ltd.)

Objective: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO., Design: A cross-sectional study with prospective follow-up, nested in a nationwide cohort., Setting: Multicentre in the Netherlands., Population or Sample: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n = 436) or a postmenopausal RRSO ≥ age 54 (n = 205). All participants were older than 55 years at recruitment., Methods: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression., Main Outcome Measures: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO., Results: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1-3.1) and multitasking (OR 1.9, 95% CI 1.1-3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60-70 years)., Conclusions: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition., (© 2023 John Wiley & Sons Ltd.)

Background Heart failure is one of the most important late effects after treatment for cancer in childhood. The goals of this study were to evaluate the risk of heart failure, temporal changes by treatment periods, and the risk factors for heart failure in childhood cancer survivors ( CCS ). Methods and Results The DCOG-LATER (Dutch Childhood Oncology Group-Long-Term Effects After Childhood Cancer) cohort includes 6,165 5-year CCS diagnosed between 1963 and 2002. Details on prior cancer diagnosis and treatment were collected for this nationwide cohort. Cause-specific cumulative incidences and risk factors of heart failure were obtained. Cardiac follow-up was complete for 5,845 CCS (94.8%). After a median follow-up of 19.8 years and at a median attained age of 27.3 years, 116 survivors developed symptomatic heart failure. The cumulative incidence of developing heart failure 40 years after childhood cancer diagnosis was 4.4% (3.4%-5.5%) among all CCS. The cumulative incidence of heart failure grade ≥3 among survivors treated in the more recent treatment periods was higher compared with survivors treated earlier (Gray test, P=0.05). Mortality due to heart failure decreased in the more recent treatment periods (Gray test, P=0.02). In multivariable analysis, survivors treated with a higher dose of mitoxantrone or cyclophosphamide had a higher risk of heart failure than survivors who were exposed to lower doses. Conclusions CCS treated with mitoxantrone, cyclophosphamide, anthracyclines, or radiotherapy involving the heart are at a high risk for severe, life-threatening or fatal heart failure at a young age. Although mortality decreased, the incidence of severe or life-threatening heart failure increased with more recent treatment periods.

Clinical morphology has proven to be a strong tool in the delineation of many syndromes and a helpful instrument in molecular studies. Numerous studies have been performed investigating the prevalence of minor anomalies in various disorders; all concluding that minor anomalies can well be utilized as indicators of altered embryonic differentiation. However, for adequate evaluation, normal values for phenotypic abnormalities are essential. So far, only few studies on the frequency of phenotypic abnormalities in the normal population have been done having one thing in common: all were performed in newborn infants. We studied morphological characteristics in a group of 1,007 school children, representative for the Dutch population, through a body surface examination using detailed definitions for all morphological findings. The region of study and distribution of children over various school types was chosen in such a way that it represented the general Dutch population. The median age of the studied children was 11 years (range 8-14 years), sex ratio (M:F) was 0.93. Nine hundred twenty-three children were of Caucasian descent, 84 others of mixed ethnic backgrounds. The reliability of the examinations was tested by independent scoring of 111 children by two observers, showing a kappa score of 0.85. Normal values for the morphological findings are presented together with their age-adjusted classification. These normal values provide a valuable source for validation of classifications of phenotypic abnormalities, especially those that are depending on frequency, that is, minor anomalies and common variants. Furthermore, they will allow a proper evaluation of patterns of phenotypic abnormalities found in patient groups with specific disorders.