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1.  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.
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.
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%.
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.
PMCID: PMC3607671  PMID: 23423746
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.
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.
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.
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).
The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.
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.
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.
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.
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.
A large proportion of survivors suffered from many symptom classes, which was associated with HRQOL impairment.
PMCID: PMC3821013  PMID: 24127449
4.  Eating Behavior and BMI in Adolescent Survivors of Brain Tumor and Acute Lymphoblastic Leukemia 
Elevated BMI has been reported in pediatric cancer survivors. It is unclear whether this is related to altered energy intake (via disordered eating), decreased energy expenditure (via limited exercise), or treatment-related direct/indirect changes. The aims of this study are to describe the occurrence of overweight and obesity, exercise frequency, and the extent of disordered eating patterns in this sample of survivors, and to examine relationships among BMI, eating patterns, exercise frequency and demographic and disease and treatment-related variables to identify those survivors most at risk for overweight/obesity.
This cross-sectional study recruited 98 cancer survivors (50 ALL, 48 Brain Tumor), aged 12-17 years and >12 months post-treatment from a large pediatric oncology hospital. Survivors completed health behavior measures assessing disordered eating patterns and physical activity. Clinical variables were obtained through medical record review. Univariate analyses were conducted to make comparisons on health behaviors by diagnosis, gender, treatment history, and BMI category.
Fifty-two percent of ALL survivors and 41.7% of BT survivors were classified as overweight/obese. Overweight/obesity status was associated with higher Cognitive Restraint (OR=1.0, 95%CI:1.0-1.1). Only 12% of ALL survivors and 8.3% of BT survivors met CDC guidelines for physical activity. Males reported more physical activity (t(96)=2.2, p<.05).
Overweight/obese survivors may attempt to purposefully restrict their food intake and rely less on physiological cues to regulate consumption. Survivors should be screened at follow-up for weight-related concerns.
PMCID: PMC4089040  PMID: 24451908
BMI; disordered eating; physical activity; health behaviors
5.  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.
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.
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).
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.
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.
PMCID: PMC3933293  PMID: 23940101
late effects of cancer treatment; chemotherapy; long term survival; cyclophosphamide; alkylating agent; alkylating agent dose score
6.  Risk Factors for Non-Initiation of the Human Papillomavirus (HPV) Vaccine among Adolescent Survivors of Childhood Cancer 
Effective vaccination is now available to prevent human papillomavirus (HPV), the most common sexually transmitted infection and cause of cervical cancer. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and identify factors associated with HPV vaccine initiation and completion. Mothers of daughters aged 9–17 years with/without a history of childhood cancer (n = 235, Mage= 13.2 years, SD= 2.69; n = 70, Mage= 13.3 years, SD=2.47, respectively) completed surveys querying HPV vaccination initiation and completion along with socio-demographic, medical, HPV knowledge and communication, and health belief factors, which may relate to vaccination outcomes. Multivariate logistic regression was utilized to identify factors which associate with HPV vaccination initiation and completion. Among cancer survivors, 32.6% initiated and 17.9% completed the 3-dose vaccine series, whereas 34.3% and 20.0% of controls initiated and completed, respectively. Univariate analyses indicated no differences between cancer/no cancer groups on considered risk factors. Among all participants, multivariate logistic regression analyses found vaccine initiation associated with older age of daughter and physician recommendation, while increased perceived barriers associated with a decreased likelihood of initiation (all Ps < .05). Among those having initiated, risk factors for non-completion included being non-white, increased perceived severity of HPV, and increased perceived barriers to vaccination (all Ps < .05). A minority of adolescents surviving childhood cancer have completed vaccination despite their increased risk for HPV-related complication. These results inform the prioritization of strategies to be included in vaccine promotion efforts.
PMCID: PMC4264381  PMID: 23983087
7.  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.
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.
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.
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.
PMCID: PMC3574270  PMID: 23295810
8.  Neurocognitive Function and CNS Integrity in Adult Survivors of Childhood Hodgkin Lymphoma  
Journal of Clinical Oncology  2012;30(29):3618-3624.
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.
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.
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.
PMCID: PMC3462045  PMID: 22949149
9.  Clinical Ascertainment of Health Outcomes among Adults Treated for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study 
Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic clinical assessment to determine the prevalence of chronic health conditions.
Following systematic exposure-based medical assessments of a large cohort of adult survivors of childhood cancer, determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures.
Design, Setting, and Participants
Presence of health outcomes was ascertained among 1713 adult (median age 32 years, range 18-60) survivors of childhood cancer (median time from diagnosis 25 years, range 10-47) enrolled in the St. Jude Lifetime Cohort Study since 10/1/2007 and followed through 10/31/2012.
Main Outcome Measures
Age-specific cumulative prevalence of adverse outcomes by organ system and sex-adjusted attributable fraction percentages with 95% confidence intervals were calculated.
Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary [65.2%(95% CI, 60.4-69.8%)], auditory [62.1%(95% CI, 55.8-68.2%)], endocrine-reproductive [62.0%(95% CI, 59.5-64.6%)], cardiac [56.4(95% CI, 53.5-59.2%)] and neurocognitive [48.0%(95%CI, 44.9-51.0%)] function, whereas abnormalities impacting hepatic [13.0%(95% CI, 10.8-15.3%)], skeletal [9.6%(95% CI, 8.0-11.5%)], renal [5.0%(95% CI, 4.0-6.3%)] and hematopoietic [3.0%(95% CI: 2.1-3.9%)] function were less common. Attributable fractions were highest for endocrine-reproductive disorders [88.4%(95% CI, 80.1-93.3%)] to 100%, but considerably lower for conditions highly prevalent in the general population such as hypertension [9.3%(95%CI, −16.3-29.2%)], dyslipidemia [15.5%(95% CI, 10.2-20.5%)], and obesity [42.1%(95% CI, 34.4-48.9%)]. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at 50 years of age was 21.6%(95% CI, 19.3-23.9%) for cardiomyopathy, 83.5%(95% CI, 80.2-86.8%) for heart valve disorder, 76.8%(95% CI, 73.6-80.0%) for pituitary dysfunction, 81.3%(95% CI, 77.6-85.0%) for pulmonary dysfunction, 86.5%(95% CI, 82.3-90.7%) for hearing loss, 40.9%(95% CI, 32.0-49.8%) for breast cancer, 31.1%(95% CI, 27.3-34.9%) for Leydig cell failure, and 31.9%(95% CI, 28.0-35.8%) for primary ovarian failure. At age 45 years, the estimated cumulative prevalence of any chronic health condition is 95.2% (95% CI 94.8-98.6%) and 80% (95% CI 73.0-86.6%) for a serious, life-threatening or disabling chronic condition.
Conclusion and Relevance
Systematic risk-based medical assessments of adults treated for childhood cancer identified a substantial number of previously undiagnosed problems that are typically prevalent in an older population underscoring the need for ongoing health monitoring and intervention of this population.
PMCID: PMC3771083  PMID: 23757085
Childhood cancer; late effects; long-term follow-up; health screening
10.  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.
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.
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.
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.
PMCID: PMC3671529  PMID: 22802310
11.  Relevance of Historical Therapeutic Approaches to the Contemporary Treatment of Pediatric Solid Tumors 
Pediatric blood & cancer  2013;60(7):10.1002/pbc.24487.
Children with solid tumors, most of which are malignant, have an excellent prognosis when treated on contemporary regimens. These regimens, which incorporate chemotherapeutic agents and treatment modalities used for many decades, have evolved to improve relapse-free survival and reduce long-term toxicity. This review discusses the evolution of the treatment regimens employed for management of the most common solid tumors, emphasizing the similarities between contemporary and historical regimens. These similarities allow the use of historical patient cohorts to identify the late effects of successful therapy and to evaluate remedial interventions for these adverse effects.
PMCID: PMC3810072  PMID: 23418018
Childhood cancer therapy; late effects; long-term follow-up
12.  RELAPSE AFTER TREATMENT OF PEDIATRIC HODGKIN LYMPHOMA: Outcome and Role of Surveillance After End of Therapy 
Pediatric blood & cancer  2013;60(9):1458-1463.
The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additional therapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well-defined.
We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history, physical examination, laboratory tests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse.
Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse and timing (whether detected at a routine visit or an extra visit) did not impact survival.
In pediatric Hodgkin lymphoma, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted.
PMCID: PMC4313350  PMID: 23677874
pediatric; childhood; Hodgkin lymphoma; relapse; surveillance; outcome
13.  Measured versus Self-reported Physical Function in Adult Survivors of Childhood Cancer 
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.
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).
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.
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.
PMCID: PMC4128913  PMID: 23899895
Self-report; physical function; childhood cancer; physical performance limitation; cancer survivorship
14.  Intervention to Reduce Secondhand Smoke Exposure Among Children with Cancer: A Controlled Trial 
Psycho-oncology  2012;22(5):1104-1111.
This randomized controlled trial tested the efficacy of parent-based behavioral counseling for reducing secondhand smoke exposure (SHSe) among children with cancer. It also examined predictors of smoking and SHSe outcomes.
Participants were 135 parents or guardians of non-smoking children with cancer, <18 yrs, at least 30 days post-diagnosis, living with at least one adult smoker. Parents were randomized to either a standard care control group or an intervention consisting of six counseling sessions delivered over three months. Parent-reported smoking and child SHSe levels were obtained at baseline, 3, 6, 9, and 12 months. Children provided urine samples for cotinine analyses.
Reductions in parent-reported smoking and exposure were observed in both the intervention and control conditions. There was a significantly greater reduction in parent-reported smoking and child SHSe at 3 months for the intervention group compared to the control group. Child SHSe was significantly lower at 12 months relative to baseline in both groups. Children’s cotinine levels did not show significant change over time in either group. Exposure outcomes were influenced by the number of smokers at home, smoking status of the parent participating in the trial, and the child’s environment (home vs. hospital) the day before the assessment.
Children’s SHSe can be reduced by advising parents to protect their child from SHSe, combined with routine reporting of their child’s exposure and cotinine testing, when delivered in the context of the pediatric cancer setting. More intensive interventions may be required to achieve greater reductions in SHSe.
PMCID: PMC3491144  PMID: 22684982
cancer; oncology; secondhand smoke exposure; intervention; cotinine
15.  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.
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.
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.
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.
PMCID: PMC3842908  PMID: 24190124
16.  Impact of Survivorship-Based Research on Defining Clinical Care Guidelines 
The growing number of individuals living 5 or more years from cancer diagnosis underscores the importance of providing guidance about potential late treatment effects to clinicians caring for long-term cancer survivors. Late treatment effects are commonly experienced by cancer survivors, increase in prevalence with aging, produce substantial morbidity, and predispose to early mortality. Findings from survivorship research permit providers to anticipate health risks among predisposed survivors and facilitate their access to interventions to prevent, detect, or rehabilitate cancer-related morbidity. This manuscript reviews the impact that survivorship research has made in defining clinical care guidelines and the challenges that remain in developing and translating research findings into health screening recommendations that can optimize the quality and duration of survival after cancer.
PMCID: PMC3191890  PMID: 21980016
cancer survivor; late effects; long-term follow-up; guidelines
17.  Recommendations for Breast Cancer Surveillance for Female Childhood, Adolescent and Young Adult Cancer Survivors Treated with Chest Radiation: A Report from the International Late Effects of Childhood Cancer Guideline Harmonization Group 
The Lancet. Oncology  2013;14(13):e621-e629.
Female childhood, adolescent and young adult (CAYA) cancer survivors treated with radiation to fields that include breast tissue (chest radiation) have an increased risk of breast cancer. Clinical practice guidelines are essential to ensure that these survivors receive optimum care, and thereby reduce the detrimental consequences of cancer treatment. However, surveillance recommendations vary among the existing long-term follow-up guidelines. This guideline provides international harmonized breast cancer surveillance recommendations for female CAYA cancer survivors treated with chest radiation prior to age 30 years. We applied evidence-based methods to develop the international harmonized recommendations. The recommendations were formulated by an international multidisciplinary guideline panel and categorized according to a 4-level colour grading schema adapted from existing level of evidence criteria. The harmonized breast cancer surveillance recommendations are based on a transparent process and are intended to be scientifically rigorous, positively influence health outcomes, and facilitate care for CAYA cancer survivors.
PMCID: PMC4257601  PMID: 24275135
18.  Long-Term Outcome and Risk Factors for Uncontrolled Seizures After a First Seizure in Children With Hematological Malignancies 
Journal of child neurology  2013;29(6):774-781.
Long-term outcomes of seizures that develop during treatment of childhood hematological malignancies have not been described. We analyzed seizure outcome in 62 children with leukemia or lymphoma treated at our institution. There was a median follow-up of 6.5 years since first seizure. Seizure etiology included intrathecal or systemic methotrexate in 24, leucoencephalopathy in 11, brain hemorrhage or thrombosis in 11, meningitis in 4, and no identifiable cause in 12. Seizures remained uncontrolled in 18, and risk factors for poor control included female sex (P = .02), no seizure control with first antiseizure drug (P = .08), and longer interval between cancer diagnosis and seizure onset (P = .09). Poor seizure control after initial antiseizure drug also predicted recurrent seizure after drug withdrawal (P = .04). In conclusion, seizures are controlled with medications in a majority of patients with hematological cancer. After a period without seizures, antiseizure drug withdrawal in appropriately selected patient has a high success rate.
PMCID: PMC4207712  PMID: 23666043
leukemia; lymphoma; seizures; outcome; hematological malignancy; methotrexate
19.  Prospective Medical Assessment of Adults Surviving Childhood Cancer: Study Design, Cohort Characteristics, and Feasibility of the St. Jude Lifetime Cohort Study 
Pediatric blood & cancer  2010;56(5):825-836.
To facilitate prospective medical assessment of adults surviving pediatric malignancies and advance knowledge about long-term childhood cancer survivor health, St. Jude Children’s Research Hospital (SJCRH) is establishing a lifetime cohort of survivors.
Eligibility criteria for inclusion in the St. Jude Lifetime Cohort (SJLIFE) study include: 1) diagnosis of childhood malignancy treated at SJCRH; 2) survival ≥ 10 years from diagnosis; and 3) current age ≥ 18 years. Three levels of participation are offered: 1) comprehensive evaluation on SJCRH campus; 2) limited home evaluation; or 3) completion of health surveys only. A systematic recruitment structure based upon blocks of 50 patients initially focused on leukemia and lymphoma survivors and patients eligible for pilot studies.
As of 01/01/2010, 1625 (42%) of 3900 eligible ≥ 10 year survivors have been contacted. Among the first 1000 potentially eligible survivors selected for recruitment, 971 were subsequently confirmed to fulfill eligibility criteria. To date, 898/971 (92.5%) have been successfully contacted of whom 825 (91.8%) have agreed to participate. Among participants, 88.6% agreed to comprehensive medical evaluation, 0.4% limited local evaluation, and 11.0% survey only. Anticipated minimum overall participation rate for medical evaluation is 75.3% (731/971). Comparison of those contacted who agreed versus declined to participate revealed a greater proportion of males who declined participation (p = 0.001).
Early results of the SJLIFE study support its feasibility to recruit aging childhood cancer survivors to research investigations evaluating late health outcomes by medical assessments.
PMCID: PMC3088729  PMID: 21370418
Childhood cancer; late effects; long-term follow-up
20.  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.
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.
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.
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).
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.
PMCID: PMC3928631  PMID: 23775832
Leukemia; fMRI; memory; survivors; glucocorticoid; retrosplenium
21.  Abdominal Aortic Calcification in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia: Results from the St. Jude Lifetime Cohort Study 
Pediatric blood & cancer  2012;59(7):1307-1309.
Abdominal aortic calcification (AAC), metabolic syndrome, and low bone mineral density (BMD) are risk factors for atherosclerotic disease and cardiovascular morbidity. We evaluated AAC in 662 adult survivors of childhood ALL (median age 31 years). AAC was present in 10% of subjects, metabolic syndrome in 36%, and low BMD in 29%. The adjusted odds ratio (OR) for AAC among women with metabolic syndrome was 2.3 (95% CL=1.0, 4.3). The OR for AAC in men with low BMD was 3.1 (95% CL=1.3, 7.3). A substantial proportion of adult survivors of childhood ALL have AAC and/or metabolic syndrome, suggestive of early atherosclerotic disease.
PMCID: PMC3386469  PMID: 22431278
adverse late effects; bone mineral density; cancer; cardiovascular disease; epidemiology; metabolic syndrome
22.  Oral and dental late effects in survivors of childhood cancer: a Children’s Oncology Group report 
Multi-modality therapy has resulted in improved survival for childhood malignancies. The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers provide practitioners with exposure- and risk-based recommendations for the surveillance and management of asymptomatic survivors who are at least 2 years from completion of therapy. This review outlines the pathophysiology and risks for oral and dental late effects in pediatric cancer survivors and the rationale for oral and dental screening recommended by the Children’s Oncology Group.
An English literature search for oral and dental complications of childhood cancer treatment was undertaken via MEDLINE and encompassed January 1975 to January 2013. Proposed guideline content based on the literature review was approved by a multi-disciplinary panel of survivorship experts and scored according to a modified version of the National Comprehensive Cancer Network “Categories of Consensus” system.
The Children’s Oncology Group oral-dental pan el selected 85 relevant citations. Childhood cancer therapy may impact tooth development, salivary function, craniofacial development, and temporomandibular joint function placing some childhood cancer survivors at an increased risk for poor oral and dental health. Addition ally, head and neck radiation and hematopoietic stem cell transplantation increase the risk of subsequent ma lignant neoplasms in the oral cavity. Survivors require routine dental care to evaluate for potential side effects and initiate early treatment.
Certain childhood cancer survivors are at an increased risk for poor oral and dental health. Early identification of oral and dental morbidity and early interventions can optimize health and quality of life.
PMCID: PMC4118932  PMID: 24781353
Pediatric cancer; Oral dental health; Survivorship; Late effects
23.  Predictors of Risk-based Medical Follow-up: A Report from the Childhood Cancer Survivor Study1 
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.
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.
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.
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.
PMCID: PMC3737257  PMID: 23568405
pediatric cancer; survivorship; late effects; communication
24.  Slower Processing Speed after Treatment for Pediatric Brain Tumor and ALL 
Psycho-oncology  2013;22(9):1979-1986.
ALL and brain tumor (BT) survivors are at risk for post-treatment IQ declines. The extent to which lower scores represent global cognitive decline versus domain-specific impairment remains unclear. This study examined discrepancies between processing speed and Estimated IQ (EIQ) scores and identified clinical characteristics associated with score discrepancies in a sample of pediatric cancer survivors.
Survivors (50 ALL, 50 BT) ages 12–17 completed cognitive testing. The Wechsler Abbreviated Scale of Intelligence provided an untimed measure of general reasoning ability (EIQ). The age-appropriate Wechsler Intelligence Scale provided a Processing Speed Index (PSI) score. Scores were examined and compared.
Survivors’ PSI scores were lower than their EIQ scores (BT t(45)=6.3, p<0.001; ALL t(49)=6.9, p<0.001). For BT survivors, lower PSI scores were associated with history of craniospinal irradiation, t(44)=3.3, p<0.01. For ALL survivors, lower PSI scores were associated with male gender, grade retention, and time since diagnosis, F(3,46)=10.1, p<0.001. Clinically significant EIQ-PSI score discrepancies were identified in 41.3% of BT and 14.0% of ALL survivors.
Many pediatric BT and ALL survivors exhibit slower processing speed than expected for age while general reasoning ability remains largely intact. Risk factors associated with larger EIQ-PSI discrepancies include: BT diagnosis, craniospinal irradiation (BT only), male gender and younger age at diagnosis (ALL only). Grade retention was frequent and associated with lower EIQ scores (both groups) and PSI scores (ALL only). Describing post-treatment cognitive declines using global measures of intellectual ability may underestimate dysfunction or fail to isolate specific underlying deficits contributing to impairment.
PMCID: PMC3740073  PMID: 23447439
pediatric hematology/oncology; processing speed; intelligence; late effects of cancer treatment
25.  Incidental Detection of Late Subsequent Intracranial Neoplasms with Magnetic Resonance Imaging Among Adult Survivors of Childhood Cancer 
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.
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.
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.
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.
PMCID: PMC4119575  PMID: 24488818
Survivors of Childhood Cancer; Cranial Radiation Therapy; Subsequent Intracranial Neoplasms; Meningiomas

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