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1.  Surveillance for Breast Cancer in Women Treated with Chest Radiation for a Childhood, Adolescent or Young Adult Cancer: A Report from the Children's Oncology Group 
Annals of internal medicine  2010;152(7):444-W154.
Background
Women treated with therapeutic chest radiation may develop breast cancer.
Purpose
Summarize breast cancer risk and breast cancer surveillance in women following chest radiation for a pediatric or young adult cancer.
Data Sources
Studies from MEDLINE, EMBASE, Cochrane Library, and CINAHL (1966 through December 2008).
Study Selection
Articles selected to answer any of 3 questions: 1) What is the incidence and excess risk of breast cancer in women following chest radiation for a pediatric or young adult cancer? 2) For these women, are the clinical characteristics of the breast cancer and the outcomes following therapy different than for women with sporadic breast cancer in the general population? 3) What are the potential benefits and harms associated with breast cancer surveillance among women exposed to chest radiation?
Data Extraction
Three investigators independently extracted data and assessed study quality.
Data Synthesis
Standardized incidence ratios ranged from 13.3 to 55.5; cumulative incidence of breast cancer by 40–45 years of age ranged from 13–20%. Risk of breast cancer increased linearly with chest radiation dose. Available limited evidence suggests that the characteristics of the breast cancers in these women and the outcomes following diagnosis are similar to those in the general population; these breast cancers can be detected by mammography, though sensitivity is limited.
Limitations
Limitations include study heterogeneity, design and small sample size.
Conclusions
Women treated with chest radiation have a substantially elevated risk of breast cancer at a young age, which does not appear to plateau. Among this high risk population, there appears to be a benefit associated with early detection. Further research is required to better define the harms and benefits of lifelong surveillance.
doi:10.1059/0003-4819-152-7-201004060-00009
PMCID: PMC2857928  PMID: 20368650
2.  Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(36):4496-4503.
Purpose
Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality.
Methods
Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fisher's exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death.
Results
The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2).
Conclusion
The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.
doi:10.1200/JCO.2013.52.2268
PMCID: PMC3871511  PMID: 24248696
3.  Association Between the Prevalence of Symptoms and Health-Related Quality of Life in Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(33):4242-4251.
Purpose
We investigated the association between prevalence of symptoms and health-related quality of life (HRQOL) in adult survivors of childhood cancer enrolled in the St Jude Lifetime Cohort study.
Methods
Eligibility criteria include childhood malignancy treated at St Jude, survival ≥ 10 years from diagnosis, and current age ≥ 18 years. Study participants were 1,667 survivors (response rate = 65%). Symptoms were self-reported by using a comprehensive health questionnaire and categorized into 12 classes: cardiac; pulmonary; motor/movement; pain in head; pain in back/neck; pain involving sites other than head, neck, and back; sensation abnormalities; disfigurement; learning/memory; anxiety; depression; and somatization. HRQOL was measured by using physical/mental component summary (PCS/MCS) and six domain scores of the Medical Outcomes Study 36-Item Short-Form Health Survey. Multivariable regression analysis was performed to investigate associations between symptom classes and HRQOL. Cumulative prevalence of symptom classes in relation to time from diagnosis was estimated.
Results
Pain involving sites other than head, neck and back, and disfigurement represented the most frequent symptom classes, endorsed by 58.7% and 56.3% of survivors, respectively. Approximately 87% of survivors reported multiple symptom classes. Greater symptom prevalence was associated with poorer HRQOL. In multivariable analysis, symptom classes explained up to 60% of the variance in PCS and 56% of the variance in MCS; demographic and clinical variables explained up to 15% of the variance in PCS and 10% of the variance in MCS. Longer time since diagnosis was associated with higher cumulative prevalence in all symptom classes.
Conclusion
A large proportion of survivors suffered from many symptom classes, which was associated with HRQOL impairment.
doi:10.1200/JCO.2012.47.8867
PMCID: PMC3821013  PMID: 24127449
4.  Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer 
Journal of Clinical Oncology  2013;31(29):3673-3680.
Purpose
To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer.
Patients and Methods
Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models.
Results
Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all Ptrend < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7).
Conclusion
Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.
doi:10.1200/JCO.2013.49.3205
PMCID: PMC3804290  PMID: 24002505
5.  Telomere Content and Risk of Second Malignant Neoplasm in Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
PURPOSE
Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine if less telomere content was associated with treatment-related second malignant neoplasms (SMNs) in childhood cancer survivors.
EXPERIMENTAL DESIGN
Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at time of sample collection, years of follow up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content (TC) as a continuous variable to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma.
RESULTS
There was an inverse relationship between TC and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single copy gene ratio (95% CI, 0.09–1.02, p=0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR 0.04, 95% CI, 0.00–0.55, p=0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma.
CONCLUSIONS
A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.
doi:10.1158/1078-0432.CCR-13-2076
PMCID: PMC3944671  PMID: 24277454
telomere; second malignant neoplasm; risk; childhood cancer
6.  Measured versus Self-reported Physical Function in Adult Survivors of Childhood Cancer 
Introduction/Purpose
Childhood cancer survivors (CCS) experience late effects that interfere with physical function. Limitations in physical function can impact CCS abilities to actively participate in daily activities. The purpose of this investigation was to evaluate the concordance between self-reported physical performance and clinically evaluated physical performance among adult CCS.
Methods
CCS 18+ years of age and 10+ years from diagnosis who are participants in the St. Jude Lifetime Cohort study responded to the physical function section of the Medical Outcome Survey Short Form (SF36). Measured physical performance was evaluated with the physical performance test (PPT), and the six minute walk test (6MW).
Results
1778 individuals (50.8% female) with a median time since diagnosis of 24.9 years (range 10.9-48.2) and a median age of 32.4 years (range 19.1-48.2) completed testing. Limitations in physical performance were self-reported by 14.1% of participants. The accuracy of self-report physical performance was 0.87 when the SF-36 was compared to the 6MW or PPT. Reporting inaccuracies most often involved reporting a physical performance limitation. Poor accuracy was associated with previous diagnosis of a bone or central nervous system tumor, lymphoma, older age, and large body size.
Conclusion
These results suggest that self-report, using the physical performance sub-scale of the SF-36 correctly identifies CCS who do not have physical performance limitations. In contrast, this same measure is less able to identify individuals who have performance limitations.
doi:10.1249/MSS.0b013e3182a65c73
PMCID: PMC4128913  PMID: 23899895
Self-report; physical function; childhood cancer; physical performance limitation; cancer survivorship
7.  Suicide Ideation and Associated Mortality in Adult Survivors of Childhood Cancer 
Cancer  2013;120(2):271-277.
Background
Adult survivors of childhood cancer are at-risk for suicide ideation, though longitudinal patterns and rates of recurrent suicide ideation are unknown. We investigated the prevalence of late report (i.e. post-initial assessment) and recurrent suicide ideation in adult survivors of childhood cancer, identified predictors of suicide ideation, and examined associations among suicide ideation and mortality.
Methods
Participants included 9,128 adult survivors of childhood cancer and 3,082 sibling controls enrolled in the Childhood Cancer Survivor Study who completed a survey question assessing suicide ideation on one or more occasions between 1994 and 2010. Suicide ideation was assessed using the Brief Symptom Inventory-18. Mortality data was ascertained from the National Death Index.
Results
Survivors were more likely to report late (Odds Ratio (OR) =1.9; 95% Confidence Interval (CI) =1.5–2.5) and recurrent suicide ideation (OR=2.6, 95% CI=1.8–3.8) compared to siblings. Poor physical health status was associated with increased risk of suicide ideation in survivors (late report: OR=1.9, 95% CI=1.3–2.7; recurrent: OR=1.9, 95% CI=1.2–2.9). Suicide ideation was associated with increased risk for all-cause mortality (Hazard Ratio (HR) =1.3, 95% CI=1.03–1.6) and death by external causes (HR=2.4, 95% CI=1.4–4.1).
Conclusion
Adult survivors of childhood cancer are at-risk for late report and recurrent suicide ideation, which is associated with increased risk of mortality. Routine screening for psychological distress in adult survivors appears warranted, especially for survivors who develop chronic physical health conditions.
doi:10.1002/cncr.28385
PMCID: PMC3947253  PMID: 24122148
childhood cancer; survivorship; suicide; mortality; late effects
8.  Lack of Specificity of Plasma Concentrations of Inhibin B and Follicle-Stimulating Hormone for Identification of Azoospermic Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(10):1324-1328.
Purpose
Many male survivors of childhood cancer are at risk for azoospermia. Although both the levels of follicle-stimulating hormone (FSH) and inhibin B are correlated with sperm concentration, their ability to predict azoospermia in survivors of childhood cancer remains uncertain.
Patients and Methods
Semen analysis was performed and serum levels of FSH and inhibin B were measured in 275 adult male survivors of childhood cancer who had received gonadotoxic therapy. Receiver operating characteristic (ROC) analysis was performed to determine the optimal inhibin B and FSH values for identifying patients with azoospermia. The patient sample was divided into a learning set and a validation set. Sensitivity, specificity, and positive and negative predictive value were calculated.
Results
Inhibin B was dichotomized as ≤ 31 ng/L or more than 31 ng/L and FSH was dichotomized as ≤ 11.5 mIU/mL or more than 11.5 mIU/mL based on results of the ROC analysis. Using these values, the specificity of the serum level of inhibin B for identifying azoospermic survivors was 45.0%, and the positive predictive value was 52.1%. The specificity for FSH was 74.1%, and the positive predictive value was 65.1%.
Conclusion
Neither serum inhibin B nor FSH is a suitable surrogate for determination of sperm concentration in a semen sample. Young men and their physicians should be aware of the limitations of these measures for assessment of fertility potential.
doi:10.1200/JCO.2012.43.7038
PMCID: PMC3607671  PMID: 23423746
9.  The Cyclophosphamide Equivalent Dose as an Approach for Quantifying Alkylating Agent Exposure. A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2013;61(1):53-67.
BACKGROUND
Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.
METHODS
We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS)outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike’s Information Criterion (AIC).
RESULTS
The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure.
CONCLUSION
The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure.
doi:10.1002/pbc.24679
PMCID: PMC3933293  PMID: 23940101
late effects of cancer treatment; chemotherapy; long term survival; cyclophosphamide; alkylating agent; alkylating agent dose score
10.  Increased Tricuspid Regurgitant Jet Velocity by Doppler Echocardiography in Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(6):774-781.
Purpose
To determine the prevalence of pulmonary hypertension, a late effect of cancer therapy not previously identified in aging survivors of childhood cancer, and associations with chest-directed radiation therapy (RT) and measures of current cardiac function, lung function, and exercise capacity.
Patients and Methods
Cross-sectional evaluation of 498 survivors at a median age of 38.0 years (range, 20.0 to 59.0 years) and a median of 27.3 years (range, 12.2 to 46.0 years) from primary cancer diagnosis was performed. Abnormal tricuspid regurgitant jet velocity (TRV) was defined as more than 2.8 m/s by Doppler echocardiography.
Results
Increased TRV was identified in 25.2% of survivors who received chest-directed RT and 30.8% of those who received more than 30 Gy. In multivariable models, increased TRV was associated with increasing dose of RT (1 to 19.9 Gy: odds ratio [OR], 2.09; 95% CI, 0.63 to 6.96; 20 to 29.9 Gy: OR, 3.46; 95% CI, 1.59 to 7.54; ≥ 30 Gy: OR, 4.54; 95% CI, 1.77 to 11.64 compared with no RT; P for trend < .001), body mass index more than 40 kg/m2 (OR, 3.89; 95% CI, 1.46 to 10.39), and aortic valve regurgitation (OR, 5.85; 95% CI, 2.05 to 16.74). Survivors with a TRV more than 2.8 m/s had increased odds (OR, 5.20; 95% CI, 2.5 to 11.0) of severe functional limitation on a 6-minute walk compared with survivors with a TRV ≤ 2.8 m/s.
Conclusion
A substantial number of adult survivors of childhood cancer who received chest-directed RT have an increased TRV and may have pulmonary hypertension as a result of both direct lung injury and cardiac dysfunction. Longitudinal follow-up and confirmation by cardiac catheterization are warranted.
doi:10.1200/JCO.2012.43.0702
PMCID: PMC3574270  PMID: 23295810
11.  Neurocognitive Outcomes Decades After Treatment for Childhood Acute Lymphoblastic Leukemia: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(35):4407-4415.
Purpose
To determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL).
Patients and Methods
Survivors of childhood ALL treated at St Jude Children's Research Hospital who were still alive at 10 or more years after diagnosis and were age ≥ 18 years were recruited for neurocognitive testing. In all, 1,014 survivors were eligible, 738 (72.8%) agreed to participate, and 567 (76.8%) of these were evaluated. Mean age was 33 years; mean time since diagnosis was 26 years. Medical record abstraction was performed for data on doses of cranial radiation therapy (CRT) and cumulative chemotherapy. Multivariable modeling was conducted and glmulti package was used to select the best model with minimum Akaike information criterion.
Results
Impairment rates across neurocognitive domains ranged from 28.6% to 58.9%, and those treated with chemotherapy only demonstrated increased impairment in all domains (all P values < .006). In survivors who received no CRT, dexamethasone was associated with impaired attention (relative risk [RR], 2.12; 95% CI, 1.11 to 4.03) and executive function (RR, 2.42; 95% CI, 1.20 to 4.91). The impact of CRT was dependent on young age at diagnosis for intelligence, academic, and memory functions. Risk for executive function problems increased with survival time in a CRT dose-dependent fashion. In all survivors, self-reported behavior problems increased by 5% (RR, 1.05; 95% CI, 1.01 to 1.09) with each year from diagnosis. Impairment was associated with reduced educational attainment and unemployment.
Conclusion
This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature.
doi:10.1200/JCO.2012.48.2315
PMCID: PMC3842908  PMID: 24190124
12.  A General Semiparametric Hazards Regression Model: Efficient Estimation and Structure Selection 
Statistics in medicine  2013;32(28):4980-4994.
We consider a general semiparametric hazards regression model that encompasses Cox’s proportional hazards model and the accelerated failure time model for survival analysis. To overcome the nonexistence of the maximum likelihood, we derive a kernel-smoothed profile likelihood function, and prove that the resulting estimates of the regression parameters are consistent and achieve semiparametric efficiency. In addition, we develop penalized structure selection techniques to determine which covariates constitute the accelerate failure time model and which covariates constitute the proportional hazards model. The proposed method is able to estimate the model structure consistently and model parameters efficiently. Furthermore, variance estimation is straightforward. The proposed estimation performs well in simulation studies and is applied to the analysis of a real data set. Copyright
doi:10.1002/sim.5885
PMCID: PMC3913752  PMID: 23824784
Accelerated failure time model; Cox’s proportional hazards model; Efficiency; Kernel-smoothed profile likelihood function; Model selection; Penalized likelihood
13.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
Purpose
We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
Patients and Methods
We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
Results
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
Conclusion
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
doi:10.1200/JCO.2012.41.8996
PMCID: PMC3530689  PMID: 23169509
14.  Dexamethasone Exposure and Memory Function in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the SJLIFE Cohort 
Pediatric blood & cancer  2013;60(11):1778-1784.
Background
Dexamethasone is used in acute lymphoblastic leukemia (ALL) treatment, though long-term impact on central nervous system (CNS) function is unclear. As glucocorticoids influence hippocampal function, we investigated memory networks in survivors of childhood ALL treated with dexamethasone or prednisone.
Procedure
Neurocognitive assessment and functional magnetic resonance imaging (fMRI) were conducted in 38 adult survivors randomly recruited from cohorts treated on one of two standard treatment protocols, which differed primarily in the glucocorticoid administered during continuation therapy (dexamethasone [n=18] vs. prednisone [n=20]). Groups did not differ in age at diagnosis, age at evaluation, or cumulative intravenous or intrathecal methotrexate exposure.
Results
Survivors treated with dexamethasone demonstrated lower performance on multiple memory-dependent measures, including story memory (p=0.01) and word recognition (p=0.04), compared to survivors treated with only prednisone. Dexamethasone treatment was associated with decreased fMRI activity in the left retrosplenial brain region (effect size =1.3), though the small sample size limited statistical significance (p=0.08). Story memory was associated with altered activation in left inferior frontal-temporal brain regions (p=0.007).
Conclusions
Results from this pilot study suggest that adult survivors of ALL treated with dexamethasone are at increased risk for memory deficits and altered neural activity in specific brain regions and networks associated with memory function.
doi:10.1002/pbc.24644
PMCID: PMC3928631  PMID: 23775832
Leukemia; fMRI; memory; survivors; glucocorticoid; retrosplenium
15.  Neurocognitive Function and CNS Integrity in Adult Survivors of Childhood Hodgkin Lymphoma  
Journal of Clinical Oncology  2012;30(29):3618-3624.
Purpose
Long-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL.
Patients and Methods
In all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (≥ 30 Gy) thoracic radiation (n = 38) or lower-dose (< 30 Gy) thoracic radiation combined with anthracycline (n = 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations.
Results
Compared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P = .004), short-term memory (P = .001), long-term memory (P = .006), working memory (P < .001), naming speed (P < .001), and cognitive fluency (P = .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/E′; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [E′]; P = .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DLcocorr; P = .04), and leukoencephalopathy (P = .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P = .001). Working memory impairment was associated with E/E′, although impaired sustained attention and naming speed were associated with DLcocorr. Neurocognitive performance was associated with academic and vocational functioning.
Conclusion
These results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.
doi:10.1200/JCO.2012.42.6841
PMCID: PMC3462045  PMID: 22949149
16.  Screening Adult Survivors of Childhood Cancer for Cardiomyopathy: Comparison of Echocardiography and Cardiac Magnetic Resonance Imaging 
Journal of Clinical Oncology  2012;30(23):2876-2884.
Purpose
To compare two-dimensional (2D) echocardiography, the current method of screening for treatment-related cardiomyopathy recommended by the Children's Oncology Group Guidelines, to cardiac magnetic resonance (CMR) imaging, the reference standard for left ventricular (LV) function.
Patients and Methods
Cross-sectional, contemporaneous evaluation of LV structure and function by 2D and three-dimensional (3D) echocardiography and CMR imaging in 114 adult survivors of childhood cancer currently median age 39 years (range, 22 to 53 years) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy.
Results
In this survivor population, 14% (n = 16) had an ejection fraction (EF) less than 50% by CMR. Survivors previously undiagnosed with cardiotoxicity (n = 108) had a high prevalence of EF (32%) and cardiac mass (48%) that were more than two standard deviations below the mean of normative CMR data. 2D echocardiography overestimated the mean EF of this population by 5%. Compared with CMR, 2D echocardiography (biplane method) had a sensitivity of 25% and a false-negative rate of 75% for detection of EF less than 50%, although 3D echocardiography had 53% and 47%, respectively. Twelve survivors (11%) had an EF less than 50% by CMR but were misclassified as ≥ 50% (range, 50% to 68%) by 2D echocardiography (biplane method). Detection of cardiomyopathy was improved (sensitivity, 75%) by using a higher 2D echocardiography cutoff (EF < 60%) to detect an EF less than 50% by the reference standard CMR.
Conclusion
CMR identified a high prevalence of cardiomyopathy among adult survivors previously undiagnosed with cardiac disease. 2D echocardiography demonstrated limited screening performance. In this high-risk population, survivors with an EF 50% to 59% by 2D echocardiography should be considered for comprehensive cardiac assessment, which may include CMR.
doi:10.1200/JCO.2011.40.3584
PMCID: PMC3671529  PMID: 22802310
17.  Scarring, Disfigurement, and Quality of Life in Long-Term Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2012;30(20):2466-2474.
Purpose
Childhood cancer survivors are at increased risk for adverse outcomes and chronic medical conditions. Treatment-related scarring, disfigurement, and persistent hair loss, in addition to their long-term impact on psychological distress or health-related quality of life (HRQOL), have received little attention.
Patients and Methods
Self-reported scarring/disfigurement and persistent hair loss were examined in 14,358 survivors and 4,023 siblings from the Childhood Cancer Survivor Study. Multivariable models were used to examine associations with demographic and cancer treatment. The impact of disfigurement and hair loss on HRQOL (ie, Medical Outcomes Short Form–36) and emotional distress (ie, Brief Symptom Inventory–18) was examined.
Results
Survivors reported a significantly higher rate of scarring/disfigurement compared with siblings for head/neck (25.1% v 8.4%), arms/legs (18.2% v 10.2%), and chest/abdomen (38.1% v 9.1%), as well as hair loss (14.0% v 6.3%). In age-, sex-, and race-adjusted models, cranial radiation exposure ≥ 36 Gy increased risk for head/neck disfigurement (relative risk [RR], 2.42; 95% CI, 2.22 to 2.65) and hair loss (RR, 4.24; 95% CI, 3.63 to 4.95). Adjusting for cranial radiation, age, sex, race, education, and marital status, survivor hair loss increased risk of anxiety (RR, 1.60; 95% CI, 1.23 to 2.07), whereas head/neck disfigurement increased risk of depression (RR, 1.19; 95% CI, 1.01 to 1.41). Limitations due to emotional symptoms were associated with head/neck disfigurement (RR, 1.24; 95% CI, 1.10 to 1.41), arm/leg disfigurement (RR, 1.19; 95% CI, 1.05 to 1.35), and hair loss (RR, 1.26; 95% CI, 1.09 to 1.47).
Conclusion
Survivors of childhood cancer are at increased risk for disfigurement and persistent hair loss, which is associated with future emotional distress and reduced quality of life. Future studies are needed to better identify and manage functional outcomes in these patients.
doi:10.1200/JCO.2011.39.3611
PMCID: PMC3397782  PMID: 22614987
18.  SECONDARY GASTROINTESTINAL MALIGNANCIES IN CHILDHOOD CANCER SURVIVORS: A COHORT STUDY 
Annals of internal medicine  2012;156(11):757-260.
Background
Childhood cancer survivors develop gastrointestinal malignancies more frequently and at a younger age than the general population, but risk factors for their development have not been well characterized.
Objective
To determine the risk and associated risk factors for gastrointestinal subsequent malignant neoplasms (SMN) in childhood cancer survivors.
Design
Retrospective cohort study.
Setting
The Childhood Cancer Survivor Study, a multi-center study of childhood cancer survivors diagnosed between 1970 and 1986.
Patients
14,358 survivors of a malignancy diagnosed at < 21 years who had survived for 5 or more years from initial diagnosis.
Measurements
Standardized incidence ratios (SIR) for gastrointestinal SMN were calculated using age-specific population data. Multivariate Cox regression models identified associations between risk factors and gastrointestinal SMN development.
Results
At median follow-up of 22.8 years (range: 5.5-30.2), 45 gastrointestinal malignancies were identified. Gastrointestinal SMN risk was 4.6-fold higher in childhood cancer survivors than the general population (95% confidence interval [CI]: 3.5-6.1). Colorectal cancer SIR was 4.2 (95% CI: 2.8-6.3). The highest gastrointestinal SMN risk was associated with abdominal radiation (SIR=11.2, 95% CI: 7.6-16.4). However, survivors not exposed to radiation had a significantly increased risk (SIR=2.4, 95% CI-1.4-3.9). In addition to abdominal radiation, high dose procarbazine (RR=3.2, 95% CI 1.1-9.4) and platinum drugs (RR 7.6, 95% CI: 2.3-25.5) independently increased the gastrointestinal SMN risk.
Limitations
This cohort has not yet attained an age at which gastrointestinal malignancy risk is greatest.
Conclusions
Childhood cancer survivors, particularly those exposed to abdominal radiation, are at increased risk for gastrointestinal SMN. These findings suggest that surveillance of at-risk childhood cancer survivors should commence at a younger age than recommended for the general population.
doi:10.1059/0003-4819-156-11-201206050-00002
PMCID: PMC3554254  PMID: 22665813
19.  Predictors of Risk-based Medical Follow-up: A Report from the Childhood Cancer Survivor Study1 
Purpose
To conduct an intervention study designed to assess the effectiveness of using a newsletter to increase medical follow-up in pediatric cancer survivors at risk of selected treatment complications.
Methods
Survivors participating in the Childhood Cancer Survivor Study who were at least 25 years of age and at risk of cardiovascular disease, breast cancer, or osteoporosis related to previous cancer treatment were randomly assigned to receive a newsletter featuring brief health risk information or a newsletter including an insert providing more comprehensive health risk information. A follow-up survey distributed 24 months after the newsletter intervention assessed predictors of medical follow-up.
Results
Overall there were no differences found among the groups in terms of access to a treatment summary, medical follow-up, discussion of childhood cancer health risks, and medical screening for the targeted health behaviors. One exception, indicating borderline significance was that women at risk for osteoporosis who received the newsletter insert were more likely to have discussed their risk with a doctor than those who only received the brief information (10.1% vs. 4.0% p=0.05). Discussion of breast cancer (OR=2.14; 95% CI=1.73–2.65), heart disease (OR=5.54; 95% CI=4.67–6.57) and osteoporosis (OR=7.87; 95% CI=6.34–9.78) risk with physician significantly predicted report of undergoing screening for targeted behavior in previous 2 years as did physician access to treatment summary.
Conclusions
More detailed content in a newsletter had minimal effect on recommended screening. However, survivor’s discussion of cancer-related risks with one’s doctor significantly influenced participation in health screening. These results highlight the integral role of communication in health behavior.
doi:10.1007/s11764-013-0280-z
PMCID: PMC3737257  PMID: 23568405
pediatric cancer; survivorship; late effects; communication
20.  Incidental Detection of Late Subsequent Intracranial Neoplasms with Magnetic Resonance Imaging Among Adult Survivors of Childhood Cancer 
Purpose
Survivors of childhood cancer are at increased risk of developing subsequent neoplasms. In long term survivors of childhood malignancies treated with and without cranial radiation therapy (CRT), undergoing unenhanced magnetic resonance imaging (MRI) of the brain, we estimated detection of intracranial neoplasms.
Methods
To investigate neurocognitive outcomes, 219 survivors of childhood cancer underwent unenhanced screening MRI of the brain. 164 of the survivors had been treated for acute lymphoblastic leukemia (ALL) (125 received CRT), and 55 for Hodgkin lymphoma (HL) (none received CRT). MRI examinations were reviewed and systematically coded by a single neuroradiologist. Demographic and treatment characteristics were compared for survivors with and without subsequent neoplasms.
Results
Nineteen of the 219 survivors (8.7%) had a total of 31 subsequent intracranial neoplasms identified by neuroimaging at a median time of 25 years (range 12-46 years) from diagnosis. All neoplasms occurred after CRT, except for a single vestibular schwannoma within the cervical radiation field in a HL survivor. The prevalence of subsequent neoplasms after CRT exposure was 14.4% (18 of 125). By noncontrast MRI, intracranial neoplasms were most suggestive of meningiomas. Most patients presented with no specific, localizing neurological complaints. In addition to the schwannoma, six tumors were resected based on results of MRI screening, all of which were meningiomas on histologic review.
Conclusion
Unenhanced brain MRI of long-term survivors of childhood cancer detected a substantial number of intracranial neoplasms. Screening for early detection of intracranial neoplasms among aging survivors of childhood cancer who received CRT should be evaluated.
Implications for Cancer Survivors
The high prevalence of incidentally detected subsequent intracranial neoplasms after CRT in long-term survivors of childhood cancer and the minimal symptoms reported by those with intracranial tumors in our study indicate that brain MRI screening of long-term survivors who received CRT may be warranted. Prospective studies of such screening are needed.
doi:10.1007/s11764-014-0344-8
PMCID: PMC4119575  PMID: 24488818
Survivors of Childhood Cancer; Cranial Radiation Therapy; Subsequent Intracranial Neoplasms; Meningiomas
21.  Congenital Anomalies in the Children of Cancer Survivors: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;30(3):239-245.
Purpose
Children with cancer receive mutagenic treatments, which raises concern about the potential transmissibility of germline damage to their offspring. This question has been inadequately studied to date because of a lack of detailed individual treatment exposure assessment such as gonadal radiation doses.
Methods
Within the Childhood Cancer Survivor Study, we performed a retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female childhood cancer survivors. We quantified chemotherapy with alkylating agents and radiotherapy doses to the testes and ovaries and related these exposures to risk of congenital anomalies using logistic regression.
Results
One hundred twenty-nine children had at least one anomaly (prevalence = 2.7%). For children whose mothers were exposed to radiation or alkylating agents versus neither, the prevalence of anomalies was 3.0% versus 3.5% (P = .51); corresponding figures were 1.9% versus 1.7% (P = .79) for the children of male survivors. Neither ovarian radiation dose (mean, 1.19 Gy; odds ratio [OR] = 0.59; 95% CI, 0.20 to 1.75 for 2.50+ Gy) nor testicular radiation dose (mean, 0.48 Gy; OR = 1.01; 95% CI, 0.36 to 2.83 for 0.50+ Gy) was related to risk of congenital anomalies. Treatment with alkylating agents also was not significantly associated with anomalies in the children of male or female survivors.
Conclusion
Our findings offer strong evidence that the children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parent's exposure to mutagenic cancer treatments. This information is important for counseling cancer survivors planning to have children.
doi:10.1200/JCO.2011.37.2938
PMCID: PMC3269950  PMID: 22162566
22.  Risk Factors for Obesity in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;30(3):246-255.
Purpose
Many Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood.
Patients and Methods
We evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index ≥ 30 kg/m2) among 9,284 adult (> 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM).
Results
Independent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P = .03), abnormal Short Form–36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P < .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P = .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P = .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P = .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P = .04) reduced the risk of obesity. Results of SEM (N = 8,244; comparative fit index = 0.999; Tucker Lewis index = 0.999; root mean square error of approximation = 0.014; weighted root mean square residual = 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity.
Conclusion
Treatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.
doi:10.1200/JCO.2010.34.4267
PMCID: PMC3269951  PMID: 22184380
23.  Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort 
The lancet oncology  2013;14(9):10.1016/S1470-2045(13)70251-1.
Background
Prior studies have documented decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. This study investigates infertility and time to pregnancy among female childhood cancer survivors, and analyzes treatment characteristics associated with infertility and subsequent pregnancy.
Methods
The Childhood Cancer Survivor Study (CCSS) is a cohort study including five-year cancer survivors from 26 institutions who were <21 years old at the time of diagnosis between January 1, 1970, and December 31, 1986, and a sibling control group. CCSS females ages 18–39 years reporting they had ever been sexually active (3,531 survivors and 1,366 female controls) were studied. Self-reported infertility, medical treatment for infertility, the time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analyzed.
Findings
Survivors had an increased risk of clinical infertility (>1 year of attempts at conception without success) compared to siblings which was most pronounced at early reproductive ages (≤24 years Relative Risk (RR)=2·92, 95% Confidence Interval (CI) 1·18–7·20; 25–29 years RR=1·61, 95% CI 1·05–2·48; 30–39 years RR=1·37, 95% CI 1·11–1·69). Despite being equally likely to seek treatment for infertility, survivors were less likely to be prescribed medication for treatment of infertility (RR=0·57, 95% CI 0·46–0·70). Increasing doses of uterine radiation and alkylating agent chemotherapy were most strongly associated with infertility. Although survivors had an increased time to pregnancy interval (p=0·032), 64·2% (292/455) with infertility achieved a pregnancy.
Interpretation
A more comprehensive understanding of infertility after cancer is critical for counseling and decision-making regarding future attempts at conception as well as fertility preservation.
doi:10.1016/S1470-2045(13)70251-1
PMCID: PMC3845882  PMID: 23856401
24.  ARID5B and IKZF1 variants, selected demographic factors, and childhood acute lymphoblastic leukemia: A report from the Children’s Oncology Group 
Leukemia research  2013;37(8):936-942.
Interactions between common germline variants in ARID5B and IKZF1 and other known childhood acute lymphoblastic leukemia (ALL) risk factors were queried using biospecimens and data from 770 ALL cases and 384 controls. Case-control comparisons revealed dosedependent associations between ARID5B rs10821936, ARID5B rs10994982, and IKZF1 rs11978267 and childhood ALL overall, and B lineage and B lineage hyperdiploid ALL examined separately (all allelic odds ratios≥1.33, Ptrend≤0.001). No heterogeneity was observed between ORs for males and females (all Pinteraction≥0.48). Likewise, no significant genotype-birth weight interactions were detected (all Pinteraction≥0.12) among cases. These results indicate similar ALL risk across strata of known risk factors.
doi:10.1016/j.leukres.2013.04.022
PMCID: PMC3731070  PMID: 23692655
acute lymphoblastic leukemia; children; genetic susceptibility; gene-environment interaction
25.  Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of childhood: Results from the St. Jude Lifetime Cohort Study 
Objective
To ascertain prevalence of peripheral sensory and motor neuropathy; to evaluate impairments in relation to function.
Design
St. Jude Lifetime Cohort Study, a clinical follow-up study designed to evaluate adverse late effects in adult survivors of childhood cancer.
Setting
St. Jude Children’s Research Hospital (SJCRH).
Participants
Eligibility required treatment for an extracranial solid malignancy between 1962 and 2002, age ≥18 years, ≥10 years post-diagnosis, no history of cranial radiation. 531 survivors were included in the evaluation: median age 32 years, median time from diagnosis 25 years.
Interventions
Not applicable.
Main Outcome Measures
Primary exposure measures were cumulative doses of vinca-alkaloid and platinum-based chemotherapies. Survivors with scores ≥ 1 on the sensory subscale of the modified Total Neuropathy Score were classified with prevalent sensory impairment. Those with sex-specific Z-scores of ≤−1.3 for dorsiflexion strength were classified with prevalent motor impairment. Participants completed the 6-minute walk test (endurance), the timed up and go test (mobility), and the sensory organization test (balance).
Results
The prevalence of sensory and motor impairment was 20% and 17.5%, respectively. Vinca-alkaloid exposure was associated with an increased risk of motor impairment (adjusted odds ratio (OR)=1.66, 95% Confidence Interval (CI): 1.04–2.64) without evidence for a dose response. Platinum exposure was associated with increased risk of sensory impairment (adjusted OR= 1.62, 95% CI: 0.97–2.72) without evidence of a dose response. Sensory impairment was associated with poor endurance (OR=1.99, 95% CI: 0.99–4.00) and mobility (OR=1.65, 95% CI: 0.96–2.83).
Conclusion
Vincristine and cisplatin exposure may increase risk for long-term motor and sensory impairment, respectively. Survivors with sensory impairment are at increased risk for functional performance limitations.
doi:10.1016/j.apmr.2013.03.009
PMCID: PMC3929944  PMID: 23537607
Peripheral nervous system diseases; vincristine; cisplatin; neoplasm

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