Dysfunction In Childhood Cancer Survivors Research Articles

Sexual health in adult survivors of childhood cancer: A Project REACH study.

Sexual dysfunction is a significant complication of treatment for many adult-onset cancers. However, comparatively less is known about sexual dysfunction in adult childhood cancer survivors (CCSs). Research has been limited by the exclusion of specific cancers (e.g., central nervous system [CNS] tumors) and the lack of validated measures, which makes it difficult to understand the nature and prevalence of sexual dysfunction in CCSs. A total of 249 adult CCSs (aged 18-65 years) enrolled in Project REACH, a prospective cohort study, and completed measures of physical and mental health, including sexual dysfunction. Participants scoring ≤19 on the Female Sexual Function Index 6 or ≤21 on the International Index of Erectile Function 5 were classified as experiencing sexual dysfunction. Analyses examined the relationships between sexual dysfunction and demographic, disease, treatment, and health variables. A total of 78 participants (32%) experienced clinically significant sexual dysfunction. In univariate analysis, sexual dysfunction was significantly associated with CNS tumor diagnosis (odds ratio [OR],2.56) and surgery (OR,1.96) as well as with health variables such as fatigue (OR,3.00), poor sleep (OR,2.84), pain (OR,2.04), depression (OR,2.64), poor physical health (OR,2.45), and poor mental health (OR,2.21). Adjusted analyses found that CNS tumor diagnosis (p=.001) and health variables (p=.025) contribute significantly to sexual dysfunction in CCSs. Approximately one third of adult CCSs report clinically significant sexual dysfunction, which underscores a significant screening and treatment need. However, because available measures were developed for survivors of adult cancers, research to create a sexual health measure specifically for adult CCSs is necessary to better identify the sexual health concerns of this vulnerable population.

The Value of IgM Memory B-Cells in the Assessment of Splenic Function in Childhood Cancer Survivors at Risk for Splenic Dysfunction: A DCCSS-LATER Study.

Childhood cancer survivors (CCS) who received radiotherapy involving the spleen or total body irradiation (TBI) might be at risk for splenic dysfunction. A comprehensive screening test for examining splenic dysfunction is lacking. We investigated whether IgM memory B-cells could be used to assess splenic dysfunction in CCS who received a splenectomy, radiotherapy involving the spleen, or TBI. All CCS were enrolled from the DCCSS-LATER cohort. We analyzed differences in IgM memory B-cells and Howell-Jolly bodies (HJB) in CCS who had a splenectomy (n = 9), received radiotherapy involving the spleen (n = 36), or TBI (n = 15). IgM memory B-cells < 9 cells/µL was defined as abnormal. We observed a higher median number of IgM memory B-cells in CCS who received radiotherapy involving the spleen (31 cells/µL, p=0.06) or TBI (55 cells/µL, p = 0.03) compared to CCS who received splenectomy (20 cells/µL). However, only two CCS had IgM memory B-cells below the lower limit of normal. No difference in IgM memory B-cells was observed between CCS with HJB present and absent (35 cells/µL vs. 44 cells/µL). Although the number of IgM memory B-cells differed between splenectomized CCS and CCS who received radiotherapy involving the spleen or TBI, only two CCS showed abnormal values. Therefore, this assessment cannot be used to screen for splenic dysfunction.

Extensive Cardiac Function Analyses Using Contemporary Echocardiography in Childhood Cancer Survivors: A DCCSS LATER Study.

Childhood cancer survivors (CCS) are at risk for cardiotoxicity. We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by risk factors. This cross-sectional Dutch Childhood Cancer Survivor Study evaluated echocardiograms of 1,397≥5-year CCS and 277 siblings. Of CCS, n=1,254 received cardiotoxic (anthracyclines/mitoxantrone/radiotherapy involving the heart region [RTheart]) and n=143 received potentially cardiotoxic (cyclophosphamide, ifosfamide, or vincristine) therapy. We assessed demographic, treatment-related, and traditional cardiovascular risk factors for cardiac dysfunction using multivariable logistic regression. CCS were a median of 26.7 years after diagnosis; 49% were women. Abnormal left ventricular ejection fraction (LVEF) (defined as<52% in men,<54% in women) occurred most commonly in CCS treated with anthracyclines and RTheart combined (38%). Age/sex-specific abnormal global longitudinal strain (GLS) occurred most commonly in CCS treated with RTheart, either with (41%) or without (38%) anthracyclines. Of CCS with normal LVEF, 20.2% showed abnormal GLS. Diastolic dysfunctiongrade ≥II was rare. Abnormal LVEF was mainly associated with female sex, anthracycline dose, and only in women, RTheart dose. Abnormal GLS was associated with female sex, RTheart dose, diastolic blood pressure, and only in women, anthracycline dose. Cyclophosphamide, ifosfamide, and vincristine were not associated with LVEF or GLS. Compared with siblings, CCS showed higher risk of abnormal LVEF (OR: 2.9; 95% CI: 1.4-6.6) and GLS (OR: 2.1; 95% CI: 1.2-3.7), independent of (potentially) cardiotoxic treatment-related and cardiovascular risk factors. Abnormal LVEF and GLS constitute complementary measures of systolic dysfunction among long-termCCS. Their diagnostic value may differ according to cardiotoxic exposures. Also, CCS have residual, unexplained riskof cardiac dysfunction. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors, a DCOG LATERstudy; NTR7481).

Current Status and Issues on Cancer Therapy-Related Cardiac Dysfunctionin Survivors of Childhood Cancer

Current Status and Issues on Cancer Therapy-Related Cardiac Dysfunctionin Survivors of Childhood Cancer

Osteoporosis in Childhood Cancer Survivors: Physiopathology, Prevention, Therapy and Future Perspectives.

Simple SummaryAnti-cancer treatments induced an increase in the childhood cancer survival rate. However, they are responsible for several long-term side effects in childhood cancer survivors, including osteoporosis. Cancer itself, a sedentary lifestyle, and an unhealthy diet might adversely affect bone health. Early identification and adequate management of bone fragility in childhood cancer survivors could be useful to prevent osteoporosis onset and consequently fragility fractures.The improvement of chemotherapy, radiotherapy, and surgical interventions, together with hematopoietic stem cell transplantation, increased childhood cancer survival rate in the last decades, reaching 80% in Europe. Nevertheless, anti-cancer treatments are mainly responsible for the onset of long-term side effects in childhood cancer survivors (CCS), including alterations of the endocrine system function and activity. In particular, the most frequent dysfunction in CCS is a metabolic bone disorder characterized by low bone mineral density (BMD) with increased skeletal fragility. BMD loss is also a consequence of a sedentary lifestyle, malnutrition, and cancer itself could affect BMD, thus inducing osteopenia and osteoporosis. In this paper, we provide an overview of possible causes of bone impairment in CCS in order to propose management strategies for early identification and treatment of skeletal fragility in this population.

The Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 kidney analysis examined long-term glomerular dysfunction in childhood cancer survivors

This investigation aimed to evaluate glomerular dysfunction among childhood cancer survivors in comparison with matched controls from the general population. In the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 kidney analysis, a nationwide cross-sectional cohort study, 1024 survivors five or more years after diagnosis, aged 18 or more years at study, treated between 1963-2001 with nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide or hematopoietic stem cell transplantation participated. In addition, 500 age- and sex-matched controls from Lifelines, a prospective population-based cohort study in the Netherlands, participated. At a median age of 32.0 years (interquartile range 26.6-37.4), the glomerular filtration rate was under 60 ml/min/1.73m2 in 3.7% of survivors and in none of the controls. Ten survivors had kidney failure. Chronic kidney disease according to age-thresholds (glomerular filtration rate respectively under 75 for age under 40, under 60 for ages 40-65, and under 40 for age over 65) was 6.6% in survivors vs. 0.2% in controls. Albuminuria (albumin-to-creatinine ratio over3 mg/mmol) was found in 16.2% of survivors and 1.2% of controls. Risk factors for chronic kidney disease, based on multivariable analyses, were nephrectomy (odds ratio 3.7 (95% Confidence interval 2.1-6.4)), abdominal radiotherapy (1.8 (1.1-2.9)), ifosfamide (2.9 (1.9-4.4)) and cisplatin over 500 mg/m2 (7.2 (3.4-15.2)). For albuminuria, risk factors were total body irradiation (2.3 (1.2-4.4)), abdominal radiotherapy over 30 Gy (2.6 (1.4- 5.0)) and ifosfamide (1.6 (1.0-2.4)). Hypertension and follow-up 30 or more years increased the risk for glomerular dysfunction. Thus, lifetime monitoring of glomerular function in survivors exposed to these identified high risk factors is warranted.

Long-Term Tubular Dysfunction in Childhood Cancer Survivors; DCCSS-LATER 2 Renal Study.

Simple SummaryWe studied survivors of childhood cancer who received cancer treatment that might affect the kidneys and compared them to controls from the general population. We investigated if there was a difference in the occurrence of tubular dysfunction. The tubules are the part of the kidney responsible for reabsorption of needed substances to the blood and the removal of wastes. After around 25 years since their cancer diagnosis, we found that in general there were no differences between survivors and controls, but survivors more often had losses of small proteins in the urine. Yet, some survivors of childhood cancer were found to have an increased risk of tubular dysfunction. Namely, survivors treated with the chemotherapeutic agents ifosfamide, cisplatin or carboplatin. Therefore, these patients should be monitored during their follow-up.The aim of this nationwide cross-sectional cohort study was to determine the prevalence of and risk factors for tubular dysfunction in childhood cancer survivors (CCS). In the DCCSS-LATER 2 Renal study, 1024 CCS (≥5 years after diagnosis), aged ≥ 18 years at study, treated between 1963 and 2001 with potentially nephrotoxic therapy (i.e., nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide, or hematopoietic stem cell transplantation) participated, and 500 age- and sex-matched participants from Lifelines acted as controls. Tubular electrolyte loss was defined as low serum levels (magnesium < 0.7 mmol/L, phosphate < 0.7 mmol/L and potassium < 3.6 mmol/L) with increased renal excretion or supplementation. A α1-microglobulin:creatinine ratio > 1.7 mg/mmol was considered as low-molecular weight proteinuria (LMWP). Multivariable risk analyses were performed. After median 25.5 years follow-up, overall prevalence of electrolyte losses in CCS (magnesium 5.6%, potassium 4.5%, phosphate 5.5%) was not higher compared to controls. LMWP was more prevalent (CCS 20.1% versus controls 0.4%). LMWP and magnesium loss were associated with glomerular dysfunction. Ifosfamide was associated with potassium loss, phosphate loss (with cumulative dose > 42 g/m2) and LMWP. Cisplatin was associated with magnesium loss and a cumulative dose > 500 mg/m2 with potassium and phosphate loss. Carboplatin cumulative dose > 2800 mg/m2 was associated with potassium loss. In conclusion, long-term tubular dysfunction is infrequent. Yet, ifosfamide, cisplatin and carboplatin are risk factors.

Left ventricular function in pediatric all survivors using speckle-tracking echocardiography and its relation to N-terminal brain natriuretic peptide

The aim of the present research is to investigate cardiac abnormalities using plasma N-terminal pro brain natriuretic peptide (NT-proBNP) and speckle-tracking echocardiography in asymptomatic pediatric acute lymphoblastic leukemia (ALL) survivors who received cardiotoxic drugs during their treatment. The Institutional Review Board (IRB) of the Menoufia Faculty of Medicine approved the study. Research work was performed in accordance with the Declaration of Helsinki. 40 pediatric ALL survivors and 25 healthy children were enrolled. Complete blood cell count, renal function tests and liver function tests, iron &amp; lipid profile, fasting blood sugar and plasma NT-proBNP level in addition to conventional and speckle-tracking Echocardiography were done. NT-proBNP was highly more significant in survivors than controls. Cardiac parameters as LV global longitudinal systolic peak strain (GLPS) of the three apical views, the GLPS of apical four chamber view (GLPS-A4C), the GLPS of apical two chamber view (GLPSA2C), the GLPS of apical long axis view (GLPS-LAX), and the “NT-proBNP levels were significantly higher in survivors when compared to controls”. NT-proBNP and 2-D speckle tracking echo show promise in detecting cardiac dysfunction in childhood cancer survivors beyond what is detected by conventional echocardiography. So, it should be added to the follow-up studies of CCS.

Evaluation of kidney dysfunction in childhood cancer survivors

BackgroundThe major increase in the survival rate among children with cancer is due to improvement in the diagnosis and treatment. Despite this increase, childhood cancer survivors (CCS) are at high risk of developing late complications such as nephrotoxicity due to chemotherapy. So, we aimed to detect early subclinical kidney dysfunction among CCS.MethodsThis cross-sectional study was implemented on 52 survivors of childhood cancer recruited from Pediatric Oncology Unit, Menoufia University. Laboratory evaluations for each participant, including complete blood count, serum urea, creatinine, urinary protein, urinary calcium, uric acid, and serum cystatin C and urinary Neutrophil Gelatinase Associated Lipocalin (UrNGAL) by ELISA were obtained.ResultsEstimated GFR was decreased in 23.1% of cases, with elevated serum cystatin C, UrNGAL and UrNGAL/Cr. There was a significant increase of Uprotein/Cr, UCa/Cr, UACR (p = 0.02), UrNGAL and UrNGAL/Cr (P < 0.001) in patients with tubular dysfunction compared without tubular dysfunction. There was a significant difference between two groups regarding cisplatin (P = 0.03) and high-dose methotrexate chemotherapy (p = 0.04). The AUCs for detecting kidney tubular dysfunction by UrNGAL and UrNGAL/Cr were 0.807 and 0.747.ConclusionA significant tubular dysfunction among childhood cancer survivors receiving chemotherapy as cisplatin and high-dose methotrexate.ImpactDetection of kidney dysfunction mainly tubular in childhood cancer survivors after finishing chemotherapy.Urinary NGAL is a good predictor for detection of tubular dysfunction in childhood cancer survivors after finishing chemotherapy.

Cardiovascular Health Status And Genetic Risk In Survivors of Childhood Neuroblastoma and Nephroblastoma Treated With Doxorubicin: Protocol of the Pharmacogenetic Part of the LESS-Anthra Cross-Sectional Cohort Study.

BackgroundIn childhood cancer survivors (survival of 5 years or more after diagnosis), cardiac toxicity is the most common nonmalignant cause of death attributed to treatment-related consequences. Identifying patients at risk of developing late cardiac toxicity is therefore crucial to improving treatment outcomes. The use of genetic markers has been proposed, together with clinical risk factors, to predict individual risk of cardiac toxicity from cancer therapies, such as doxorubicin.ObjectiveThe primary aim of this study is to evaluate the value of multimarker genetic testing for RARG rs2229774, UGT1A6 rs17863783, and SLC28A3 rs7853758 for predicting doxorubicin-induced cardiotoxicity. The secondary aim is to replicate previously described associations of candidate genetic markers with doxorubicin-induced cardiotoxicity. Moreover, we will evaluate the prevalence of cardiovascular dysfunction in childhood cancer survivors after neuroblastoma or nephroblastoma.MethodsThis is the pharmacogenetic substudy of the research project Structural Optimization for Children With Cancer After Anthracycline Therapy (LESS-Anthra). We invited 2158 survivors of childhood neuroblastoma or nephroblastoma treated with doxorubicin according to the trial protocols of SIOP 9/GPOH, SIOP 93-01/GPOH, SIOP 2001/GPOH, NB 90, NB 97, or NB 2004 to participate in this prospective cross-sectional cohort study. The study participants underwent a cardiological examination and were asked to provide a blood or saliva sample for genotyping. The study participants' health statuses and cardiovascular diagnoses were recorded using a questionnaire completed by the cardiologist. Digital echocardiographic data were centrally evaluated to determine the contractile function parameters. Medical data on the tumor diagnosis and treatment protocol were taken from the study documentation. Survivors were screened for variants of several candidate genes by TaqMan genotyping.ResultsThis study includes 657 survivors treated with doxorubicin for childhood cancer, the largest German cohort assembled to date to investigate cardiovascular late effects. Data analyses are yet to be completed.ConclusionsThis study will define the genetic risk related to 3 marker genes proposed in a pharmacogenetic guideline for risk assessment. Moreover, the results of this study will show the prevalence of cardiovascular dysfunction in survivors of pediatric neuroblastoma or nephroblastoma who were treated with doxorubicin. The results will help to improve primary treatment and follow-up care, thus reducing cardiovascular late effects in the growing population of childhood cancer survivors.Trial RegistrationGerman Clinical Trials Register DRKS00015084; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015084International Registered Report Identifier (IRRID)DERR1-10.2196/27898

Cardiovascular Function and Exercise Capacity in Childhood Cancer Survivors.

Introduction: Childhood cancer survivors (CCS) might be at high risk of additional chronic diseases due to cardiotoxic side effects. The aim of this study was to analyze long-term side effects of cancer therapy on vascular structure/function, cardiac biomarkers and on physical activity. Methods: In total, 68 asymptomatic patients aged 16–30 years with childhood cancer (diagnosed 10.6 ± 3.9 years ago) were examined from 2015–2020. (Central) blood pressure and pulse wave velocity were registered via the oscillometric method, while carotid intima-media thickness (cIMT) was measured non-invasively by ultrasound. cIMT values of patients were compared to healthy controls (n = 68; aged 22.3 ± 3.5 years). Patients’ exercise capacity was recorded. The plasma N-terminal pro-brain natriuretic protein (NTproBNP) and troponin levels were measured as cardiac biomarkers. CCS were categorized in groups with low, moderate and high anthracyclines. Results: No differences were found in cIMT between patients and controls as well as between patients with various anthracycline dosage. Patients with high dose anthracyclines showed a significant lower performance versus patients with moderate dose anthracyclines (84.4% of predicted VO2peak; p = 0.017). A total of 11.6% of CCS had abnormal NTproBNP values which correlated with received anthracycline dosage (p = 0.024; r = 0.343). Conclusion: NTproBNP levels and exercise capacity might be early markers for cardiovascular dysfunction in CCS and should be included in a follow-up protocol, while cIMT and troponin seem not to be adequate parameters.

To study asymptomatic cardiac dysfunction in childhood cancer survivors exposed to Adriamycin

To study asymptomatic cardiac dysfunction in childhood cancer survivors exposed to Adriamycin

Endothelial Dysfunction in Childhood Cancer Survivors: A Narrative Review.

Assessment of endothelial dysfunction in cancer survivors may have a role in the early identification of non-communicable diseases and cardiovascular late effects. Oncological therapies may impair endothelial function. Therefore, in patients such as childhood cancer survivors who could benefit from early cardioprotective pharmacological interventions, it is essential to monitor endothelial function, even if the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, as well as invasive and non-invasive tools with and without pharmacological stimuli have been studied. Human clinical studies that have examined lifestyle or cancer treatment protocols have yielded evidence showing the involvement of lipid and lipoprotein levels, glycemic control, blood pressure, adiposity, inflammation, and oxidative stress markers on the state of endothelial health and its role as an early indicator of cardiometabolic risk. However, with regards to pharmacological interventions, cautious interpretation of the result attained whilst monitoring the endothelial function is warranted due to methodological limitations and substantial heterogeneity of the results reported in the published studies. In this narrative review, an overview of evidence from human clinical trials examining the effects of cancer therapies on endothelial disease is provided together with a discussion of endothelial function assessment using the different non-invasive techniques available for researchers and clinicians, in recent years.

A prospective survey study of lower urinary tract dysfunction in childhood cancer survivors after vincristine and/or doxorubicin chemotherapy.

Two chemotherapeutic agents used widely in pediatric oncology are vincristine (VCR) and doxorubicin (DOX), which may cause neuropathy and myopathy, respectively. The study hypothesis is that neurotoxic effects of VCR and/or myotoxic effects of DOX affect bladder physiology and manifest clinically as lower urinary tract dysfunction (LUTD). Based on a priori power analysis, 161 children divided evenly by gender were recruited. Children aged 5-10years completed the dysfunctional voiding scoring system (DVSS) survey. The study cohort comprised cancer survivors treated with VCR and/or DOX. Healthy controls were recruited from well-child clinic visits. Exclusion criteria included pelvic-based malignancy, pelvic irradiation, pre-existing LUTD, neurologic abnormalities, and treatment with cyclophosphamide/ifosfamide. DVSS scores and presence of LUTD, defined as DVSS scores above gender-specific thresholds (males ≥9, females ≥6), were compared across cohorts. Median DVSS scores were higher in the study cohort (6 vs. 4, p=.003). Moreover, children in the study cohort were more likely to exceed threshold scores for LUTD (38.8% vs. 21%, p=.014; OR 1.8). Subanalysis by gender revealed female cancer survivors are more likely to report LUTD than controls (57.5% vs. 30%, p=.013, OR 1.9). This did not hold true for males (20% vs. 12.2%, p=.339). Childhood cancer survivors who received VCR and/or DOX reported higher rates of LUTD than controls. Female cancer survivors appear more likely to suffer from LUTD than males. Further study with a positive control cohort of cancer survivors who received non-VCR, non-DOX chemotherapy is underway to elucidate the contribution of a cancer diagnosis to LUTD.

Subclinical Cardiac Dysfunction in Childhood Cancer Survivors on 10-Years Follow-Up Correlates With Cumulative Anthracycline Dose and Is Best Detected by Cardiopulmonary Exercise Testing, Circulating Serum Biomarker, Speckle Tracking Echocardiography, and Tissue Doppler Imaging.

Background: Survivors of childhood cancer are at risk for anthracycline- and/or radiotherapy-induced cardiotoxicity.Aims: The aim of this study was to assess clinical, laboratory, and imaging parameters of subclinical cardiovascular disease in childhood cancer survivors.Methods: Patients underwent cardiopulmonary exercise test (CPET), laboratory testing, transthoracic echocardiography (TTE) with tissue doppler imaging (TDI) and speckle tracking. A subset of patients also underwent cardiovascular magnetic resonance imaging (CMR). Findings were correlated to cumulative anthracycline and exposure to mediastinal irradiation during cancer treatment. In a subgroup analysis, TTE and CMR findings were compared to data from 40 gender- and age-matched patients with childhood onset hypertrophic cardiomyopathy (HCM).Results: Cardiac evaluation was performed in 79 patients (43 males) at 11.2 ± 4.5 years after cancer treatment. Oncologic diagnosis at a median age of 12.0 years was Hodgkin lymphoma in 20, sarcoma in 17, acute leukemia in 24, relapse leukemia in 10, and others in 8 patients. Cumulative anthracycline dose exceeded 300 mg/m2 in 28 patients. Twenty six patients also received mediastinal irradiation. Decreased peak respiratory oxygen uptake in % predicted on CPET, increased levels of N-terminal pro-brain natriuretic peptide (NTproBNP), increased global longitudinal strain on TTE speckle tracking, and diastolic dysfunction on TDI were the most prominent findings on detailed cardiology follow-up. In contrast to HCM patients, childhood cancer survivors did not show left ventricular hypertrophy (LVPWd z-score median 0.9 vs. 2.8, p < 0.001), hyperdynamic systolic function on TTE (Ejection fraction 62 ± 7 vs. 72 ± 12%, p = 0.001), or fibrotic myocardial changes on CMR (Late gadolinium positive 0/13 vs. 13/36, p = 0.001; extracellular volume fraction 22 ± 2 vs. 28 ± 3, p < 0.001) at time of follow-up. There was no correlation between chest radiation exposure and abnormal cardiac findings. Cumulative anthracycline dose was the only significant independent predictor on multivariate analysis for any cardiovascular abnormality on follow-up (p = 0.036).Conclusion: Increasing cumulative anthracycline dose during cancer treatment correlates with subclinical cardiac dysfunction in childhood cancer survivors best detected by elevated cardiac serum biomarkers, decreased exercise capacity on CPET, and abnormalities on echocardiographic speckle tracking and TDI.

Dissociation of Pubertal Development Abnormality and Gonadal Dysfunction in Childhood Cancer Survivors

Purpose: To determine the relationship between pubertal development and postpubertal gonadal function in childhood cancer survivors. Methods: Childhood cancer survivors (≥10 years of age) who received follow-up care in a pediatric oncology group in an academic medical center during the period from January 1, 1985, to July 1, 2010 were included in this case series. Their pubertal development and gonadal function were evaluated. Results: The cohort consists of 39 males (age 10-21 years) and 35 females (age 10-29 years) with a variety of cancer diagnosis and treatments. The average age at diagnosis was ∼7.5 years. The average age at the time of the study was 16 and 16.7 years in males and females, respectively, representing a mean follow-up interval of ∼9 years. Despite the fact that 60% of survivors received cyclophosphamide equivalents and 16.2% received cranial radiation or brain tumor resection, the majority of survivors (68%) presented with both normal puberty and normal gonadal functions at the time of follow-up. In 27% of survivors, puberty development did not predict gonadal function in early adulthood: 20% of survivors had normal puberty, but abnormal gonadal function; 7% of survivors had abnormal puberty, but gonadal function remained normal as young adults. Conclusions: Most childhood cancer survivors had normal puberty and gonadal function despite a variety of cancer treatment modalities. However, normal puberty did not predict normal gonadal function later in life in many survivors. Therefore, close follow-up with gonadal function in adolescent and early adulthood years is essential.

Adherence to Surveillance for Second Malignant Neoplasms and Cardiac Dysfunction in Childhood Cancer Survivors: A Childhood Cancer Survivor Study.

To evaluate childhood cancer survivors' adherence to surveillance protocols for late effects of treatment and to determine the factors affecting adherence. Between 2014 and 2016, 11,337 survivors and 2,146 siblings in the Childhood Cancer Survivor Study completed a survey ascertaining adherence to Children's Oncology Group (COG) guidelines for survivors at high risk for second malignant neoplasms or cardiac dysfunction and to the American Cancer Society (ACS) cancer screening guidelines for average-risk populations. Adherence rates and factors affecting adherence were analyzed. Median age at diagnosis was 7 years (range, 0-20.9 years), and median time from diagnosis was 29 years (range, 15-47 years). Among high-risk survivors, adherence to COG breast, colorectal, skin, and cardiac surveillance was 12.6% (95% CI, 10.0% to 15.3%), 37.0% (34.1% to 39.9%), 22.3% (21.2% to 23.4%), and 41.4% (40.1% to 42.7%), respectively. Among average-risk survivors, adherence to ACS breast, cervical, and colorectal screening was 57.1% (53.2% to 61.0%), 83.6% (82.7% to 84.5%), and 68.5% (64.7% to 72.2%), respectively. Twenty-seven percent of survivors and 20.0% of primary care providers (PCPs) had a survivorship care plan (SCP). For high-risk survivors, SCP possession was associated with increased adherence to COG breast (22.3% v. 8.1%; prevalence ratio [PR], 2.52; CI, 1.59 to 4.01), skin (34.8% v 23.0%; PR, 1.16; CI, 1.01 to 1.33), and cardiac (67.0% v 33.1%; PR, 1.73; CI, 1.55 to 1.92) surveillance. For high-risk survivors, PCP possession of a SCP was associated only with increased adherence to COG skin cancer surveillance (36.9% v 23.2%; PR, 1.24; CI, 1.08 to 1.43). Guideline adherence is suboptimal. Although survivor SCP possession is associated with better adherence, few survivors and PCPs have one. New strategies to improve adherence are needed.

Diagnostic tools for early detection of cardiac dysfunction in childhood cancer survivors: Methodological aspects of the Dutch late effects after childhood cancer (LATER) cardiology study

Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and electrocardiographic measurements, and/or biomarkers will allow for improved recognition of patients with cardiac dysfunction before heart failure develops, and may also identify patients at lower risk for heart failure. To describe the methodology of the Dutch LATER cardiology study (LATER CARD). The LATER CARD study is a cross-sectional study in long-term CCS treated with (potentially) cardiotoxic cancer therapies and sibling controls. We will evaluate 1) the prevalence and associated (treatment related) risk factors of subclinical cardiac dysfunction in CCS compared to sibling controls and 2) the diagnostic value of echocardiography including myocardial strain and diastolic function parameters, blood biomarkers for cardiomyocyte apoptosis, oxidative stress, cardiac remodeling and inflammation and ECG or combinations of them in the surveillance for cancer therapy-related cardiac dysfunction. From 2017 to 2020 we expect to include 1900 CCS and 500 siblings. The LATER CARD study will provide knowledge on different surveillance modalities for detection of cardiac dysfunction in long-term CCS at risk for heart failure. The results of the study will enable us to improve long-term follow-up surveillance guidelines for CCS at risk for heart failure.

Targeted Proteomics to Identify Early Diagnostic Biomarkers for Anthracycline-Induced Cardiomyopathy in Long-Term Survivors of Childhood Cancer

Introduction Plasma biomarkers may aid in the early diagnosis of anthracycline-induced cardiomyopathy in long-term childhood cancer survivors (CCS) and may provide insights into the underlying mechanisms involved. Natriuretic peptides and troponins are of limited value to diagnose left ventricular dysfunction in CCS >1 year after anthracycline treatment. To improve cardiomyopathy surveillance in long-term CCS, we aim to identify new plasma biomarkers for the early diagnosis of anthracycline-induced cardiomyopathy. Methods Five-year CCS treated with anthracyclines and ≥18 years at time of the study were identified from the ongoing Dutch Childhood Oncology Late Effects After Childhood Cancer (DCOG-LATER) study. Genetic cardiomyopathy cases were identified from a dilated cardiomyopathy cohort in the Amsterdam UMC (figure 1). Levels of 184 plasma proteins (from 32 different biological processes) were compared between three groups of 30 patients: anthracycline-induced cardiomyopathy cases (left ventricular ejection fraction (LVEF) Results The results will be available in August 2019 and will be presented during the congress. Conclusion Targeted proteomics in CCS treated with anthracyclines may identify new biomarkers for the early diagnosis of anthracycline-induced cardiomyopathy in CCS and may provide additional insights into the pathophysiology of anthracycline cardiomyopathy.

Dysautonomia in Childhood Cancer Survivors: A Widely Underestimated Risk.

Survival rate of childhood cancers is now reaching 80% overall. However, early or late complications related to surgery, chemotherapy, and radiotherapy remain at a high rate and greatly increase the risk of late mortality. The objective of this study is to assess the autonomic nervous system (ANS) activity, measured through heart rate variability indices in childhood cancer survivors compared with healthy controls. This prospective study included 51 long-term childhood cancer survivors diagnosed before 15 years of age between 1987 and 1992 and controlled for age and sex with healthy volunteers. We observed a significant increase in spontaneous heart rate (beats per minute) (67 ± 10 vs. 60 ± 10, p = 0.001), and all the studied parameters showed a significantly altered ANS activity in cases compared with healthy controls. In both groups, the main cofactors of dysautonomia (tobacco, drugs, cannabis, estro-progestative pills, alcohol, limited physical activity) were analyzed without any significant difference. The effect of cancer treatments received was not analyzed due to the small number of participants. The results showed a significant ANS dysfunction in childhood cancer survivors compared with healthy controls and suggested the value of autonomic screening to underscore and possibly quantify the effect of the cancer treatments in a larger cohort. This evaluation could lead to the recommendation to increase physical activity, the most efficient way known to improve ANS activity, as already shown in other pathologies (breast cancer).