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1.  Childhood Cancer Survivor Study participants’ perceptions and knowledge of health insurance coverage: implications for the Affordable Care Act 
Introduction
Childhood cancer survivors face long-term health consequences, and comprehensive health insurance is critical. However, childhood cancer survivors may face barriers in accessing medical services due to being uninsured or underinsured. Little is known about the quality of survivors’ health insurance coverage, and improving health insurance within the context of changes mandated by the 2010 Affordable Care Act requires understanding survivors’ coverage. The current study explored adult childhood cancer survivors’ quality of health insurance coverage.
Methods
From 9/09 to 2/10, we conducted in-depth, semi-structured qualitative interviews with 39 adult participants from the Childhood Cancer Survivor Study, a cohort of 5-year survivors of cancers diagnosed before age 21. Interviews were recorded and transcribed; content analyses were conducted by two coders (kappa00.88) using NVivo 8.
Results
Most insured survivors reported satisfaction with the quality of their coverage; however, they expressed low expectations. Almost half reported annual out-of-pocket costs exceeding $2,000, yet most felt fortunate to simply have coverage. One third of insured survivors had difficulty obtaining coverage, and many had difficulties understanding how to utilize it. Most uninsured survivors minimized their need for care. Worry about future health care costs seemed inevitable among insured and uninsured survivors. Almost all participants lacked knowledge about existing health insurance-related laws.
Conclusions and implications for cancer survivors
Insured survivors had low coverage expectations, and uninsured survivors avoided care. Childhood cancer survivors will likely benefit from assistance in how to access and utilize the new health care reform provisions (e.g., Medicaid expansion, expansion of parents’ insurance, and mandatory primary care coverage).
doi:10.1007/s11764-012-0225-y
PMCID: PMC4706983  PMID: 22592507
Childhood cancer; Childhood Cancer Survivor Study; Health insurance; Affordable Care Act
2.  Lifestyle, distress and pregnancy outcomes in the Childhood Cancer Survivor Study cohort 
OBJECTIVE
To evaluate associations between prepregnancy lifestyle factors, psychological distress and adverse pregnancy outcomes among female survivors of childhood cancer.
STUDY DESIGN
We examined pregnancies of 1,192 female participants from the Childhood Cancer Survivor Study. Generalized linear models, adjusted for age at diagnosis, age at pregnancy, parity, and education were used to calculate the odds ratio (OR) and confidence interval (CI) for associations between prepregnancy inactivity, overweight or obese status, smoking status, risky drinking, psychological distress and pregnancy outcomes. Interactions between lifestyle factors, psychological distress, type of cancer and cancer treatment were assessed in multivariable models.
RESULTS
The median age of study participants at the beginning of pregnancy was 28 years (range: 14–45). Among 1,858 reported pregnancies, there were 1,300 singleton live births (310 were preterm), 21 stillbirths, 397 miscarriages, and 140 medical abortions. Prepregnancy physical inactivity, risky drinking, distress and depression were not associated with any pregnancy outcomes. Compared to those who had never smoked, survivors with > 5 pack-years smoking history had a higher risk for miscarriage among those treated with > 2.5 Gy uterine radiation (OR: 53.9; 95% CI: 2.2, 1,326.1) than among those treated with ≤ 2.5 Gy uterine radiation (OR: 1.9; 95% CI: 1.2, 3.0). There was a significant interaction between smoking and uterine radiation (Pinteraction = 0.01).
CONCLUSION
While most lifestyle factors and psychological distress were not predictive of adverse pregnancy outcomes, the risk for miscarriage was significantly increased among survivors exposed to > 2.5 Gy uterine radiation who had a history of smoking.
doi:10.1016/j.ajog.2014.07.036
PMCID: PMC4275351  PMID: 25068563
pregnancy; childhood cancer survivors; uterine radiation; smoking; lifestyle
3.  An Outbreak of Wild Poliovirus in the Republic of Congo, 2010–2011 
Background
The Republic of Congo has had no cases of wild poliovirus type 1 (WPV1) since 2000. In October 2010, a neurologist noted an abnormal number of cases of acute flaccid paralysis (AFP) among adults, which were later confirmed to be caused by WPV1.
Methods
Those presenting with AFP underwent clinical history, physical examination, and clinical specimen collection to determine if they had polio. AFP cases were classified as laboratory-confirmed, clinical, or nonpolio AFP. Epidemiologic features of the outbreak were analyzed.
Results
From 19 September 2010 to 22 January 2011, 445 cases of WPV1 were reported in the Republic of Congo; 390 cases were from Pointe Noire. Overall, 331 cases were among adults; 378 cases were clinically confirmed, and 64 cases were laboratory confirmed. The case-fatality ratio (CFR) was 43%. Epidemiologic characteristics differed among polio cases reported in Pointe Noire and cases reported in the rest of the Republic of Congo, including age distribution and CFR. The outbreak stopped after multiple vaccination rounds with oral poliovirus vaccine, which targeted the entire population.
Conclusions
This outbreak underscores the need to maintain high vaccination coverage to prevent outbreaks, the need to maintain timely high-quality surveillance to rapidly identify and respond to any potential cases before an outbreak escalates, and the need to perform ongoing risk assessments of immunity gaps in polio-free countries.
doi:10.1093/cid/cis714
PMCID: PMC4663667  PMID: 22911642
4.  Life Satisfaction in Adult Survivors of Childhood Brain Tumors 
Adult survivors of childhood brain tumors experience multiple, significant, life-long deficits as a consequence of their malignancy and therapy. Current survivorship literature documents the substantial impact such impairments have on survivors’ physical health and quality of life. Psychosocial reports detail educational, cognitive, and emotional limitations characterizing survivors as especially fragile, often incompetent, and unreliable in evaluating their circumstances. Anecdotal data suggests some survivors report life experiences similar to those of healthy controls. The aim of our investigation was to determine whether life satisfaction in adult survivors of childhood brain tumors differs from that of healthy controls and to identify potential predictors of life satisfaction in survivors. This cross-sectional study compared 78 brain tumor survivors with population–based matched controls. Chi-square tests, t-tests, and linear regression models were used to investigate patterns of life satisfaction and identify potential correlates. Results indicated life satisfaction of adult survivors of childhood brain tumors was similar to that of healthy controls. Survivors’ general health expectations emerged as the primary correlate of life satisfaction. Understanding life satisfaction as an important variable will optimize the design of strategies to enhance participation in follow-up care, reduce suffering, and optimize quality of life in this vulnerable population.
doi:10.1177/1043454214534532
PMCID: PMC4280831  PMID: 25027187
pediatric brain tumors; survivorship; life satisfaction; quality of life
5.  Progress toward Global Interruption of Wild Poliovirus Transmission, 2010–2013 and Tackling the Challenges to Complete Eradication 
The Journal of infectious diseases  2014;210(0 1):S5-15.
Despite substantial progress, global polio eradication has remained elusive. Indigenous wild poliovirus (WPV) transmission in four endemic countries (Afghanistan, India, Nigeria, and Pakistan) persisted into 2010 and outbreaks from imported WPV continued. By 2013, most outbreaks in the interim were promptly controlled. The number of polio-affected districts globally has declined by74% (from 481 in 2009 to 126 in 2013), including a 79% decrease in the number of affected districts in endemic countries (from 304 to 63). India is now polio-free. The challenges to success in the remaining polio-endemic countries include 1) threats to the security of vaccinators in each country and a ban on polio vaccination in areas of Afghanistan and Pakistan; 2) a risk of decreased government commitment; and 3) remaining surveillance gaps. Coordinated efforts under the International Health Regulations and efforts to mitigate the challenges provide a clear opportunity to soon secure global eradication.
doi:10.1093/infdis/jiu456
PMCID: PMC4615678  PMID: 25316873
Poliovirus; polio; poliomyelitis; surveillance; outbreak control; eradication; international health regulations
6.  Social context, diversity and risk among women who inject drugs in Vietnam: descriptive findings from a cross-sectional survey 
Background
Women who inject drugs (WWID) are neglected globally in research and programming yet may be likelier than males to practise sexual and injecting risks and be infected with HIV and more stigmatised but seek fewer services. Little is known about characteristics, practices and nexus between drugs and sex work of WWID in Vietnam, where unsafe injecting has driven HIV transmission, and commercial sex and inconsistent condom use are prevalent. This was the first quantitative investigation of Vietnamese WWID recruited as injecting drug users. This article summarises descriptive findings.
Findings
A cross-sectional survey was conducted among WWID in Hanoi (n = 203) and Ho Chi Minh City (HCMC) (n = 200) recruited using respondent-driven sampling. Characteristics varied within and between sites. Twenty-two percent in Hanoi and 47.5 % in HCMC had never sold sex. Almost all commenced with smoking heroin, some as children. Most injected frequently, usually alone, although 8 % (Hanoi) and 18 % (HCMC) shared equipment in the previous month. Some had sex—and sold it—as children; most had multiple partners. Condom use was high with clients but very low with intimate partners, often injecting drug users. HIV knowledge was uneven, and large minorities were not tested recently (or ever) for HIV. Nearly all perceived intense gender-related stigma, especially for drug use.
Conclusion
This ground-breaking study challenges assumptions about characteristics and risks based on anecdotal evidence and studies among men. Most WWID were vulnerable to sexual HIV transmission from intimate partners. Interventions should incorporate broader sociocultural context to protect this highly stigmatised population.
doi:10.1186/s12954-015-0067-9
PMCID: PMC4608123  PMID: 26472467
PWID; Women; Vietnam; Gender; HIV; Risk; Cross-sectional survey
7.  Late Cardiotoxicity in Aging Adult Survivors of Childhood Cancer 
Progress in pediatric cardiology  2014;36(1-2):19-26.
The survival rate for childhood cancer is steadily improving, and the current estimate for the prevalence of childhood cancer survivors in the United States is 420,000. With this encouraging trend and the aging of this population, there is an ever-increasing responsibility to identify adult survivors of childhood cancer with adverse health outcomes related to cancer treatment across the span of their lives. To accomplish this, large cohort studies have been developed to follow survivors longitudinally. Compared to siblings, survivors have a higher cumulative incidence of morbidity and mortality, and this gap in incidence only widens with age. One of the most significant late toxicities in survivors is late onset cardiotoxicity, largely due to anthracycline and chest-directed radiation exposure. Survivors also have an increased prevalence of traditional cardiovascular risk factors as they age, which potentiates the risk for major cardiac events. Prevention is essential. Minimizing anthracycline dose exposure in pediatric cancer patients is a primary method of cardioprotection. Dexrazoxane and enalapril have also been studied as primary (pre-exposure) and secondary (post-exposure) cardioprotecant agents, respectively. Additionally, the Children’s Oncology Group has published exposure-driven, risk-based screening guidelines for long-term follow-up, which may be a cost-effective way to identify subclinical cardiac disease before progression to clinical presentation. Ongoing research is needed to determine the most effective diagnostic modality for screening (e.g. echocardiography), and the most effective intervention strategies to improve long-term outcomes.
doi:10.1016/j.ppedcard.2014.09.003
PMCID: PMC4580976  PMID: 26412958
Anthracycline; cardiomyopathy; cardioprotection; intervention; screening
8.  Non-cancer Related Mortality Risks in Adult Survivors of Pediatric Malignancies: The Childhood Cancer Survivor Study 
Purpose
We sought to identify factors, other than cancer-related treatment and presence/severity of chronic health conditions, which may be associated with late mortality risk among adult survivors of pediatric malignancies.
Methods
Using the Childhood Cancer Survivor Study cohort and a case-control design, 445 participants who died from causes other than cancer recurrence/progression or non-health related events were compared with 7162 surviving participants matched for primary diagnosis, age at baseline questionnaire, time from diagnosis to baseline questionnaire, and time at-risk. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for overall/cause-specific mortality. Independent measures included number/severity of chronic conditions, medical care, health-related behaviors, and health perceptions/concerns.
Results
Adjusting for education, income, chemotherapy/radiation exposures, and number/severity of chronic health conditions, an increased risk for all-cause mortality was associated with exercising fewer than 3 days/week (OR=1.72, CI:1.27 – 2.34), being underweight (OR=2.58, CI:1.55 – 4.28), increased medical-care utilization (p<0.001), and self-reported fair to poor health (p<0.001). Physical activity was associated with a higher risk of death among males (OR=3.26, CI: 1.90 – 5.61) reporting no exercise compared to those who exercised ≥3 times per week. Ever consuming alcohol was associated with a reduced risk of all-cause (OR=0.61, CI: 0.41–0.89) and other non-external causes of death (OR=0.40, CI: 0.20–0.79). Concerns/worries about future health (OR=1.54, CI: 1.10–2.71) were associated with increased all-cause mortality.
Conclusions
Factors independent of cancer treatment and chronic health conditions modify the risk of death among adult survivors of pediatric cancer.
Implications for Cancer Survivors
Continued cohort observation may inform interventions to reduce mortality.
doi:10.1007/s11764-014-0353-7
PMCID: PMC4127349  PMID: 24719269
mortality risk; childhood cancer; surveillance; cancer survivorship
9.  Comprehensive Echocardiographic Detection of Treatment-related Cardiac Dysfunction in Adult Survivors of Childhood Cancer: Results from the St. Jude Lifetime Cohort Study 
Background
Treatment-related cardiac death is the primary non-cancer cause of mortality in adult survivors of childhood malignancies. Early detection of cardiac dysfunction using modern echocardiographic techniques may identify a high risk subset of survivors for early intervention.
Objective
To determine the prevalence of cardiac dysfunction in adult survivors of childhood malignancies using state of the art echocardiographic evaluation of cardiac function including strain imaging
Methods
Echocardiographic assessment included three dimensional (3D) left ventricular ejection fraction (LVEF), global longitudinal and circumferential myocardial strain and diastolic function, graded per American Society of Echocardiography (ASE) guidelines on 1,820 adult (median age 31 [range 18-65] years) survivors of childhood cancer (median time from diagnosis 23 years [range10-48] years) exposed to either anthracycline chemotherapy (N=1,050), chest-directed radiotherapy (RT, N=306), or both therapies (N=464).
Results
Only 5.8% of survivors had an abnormal 3D LVEF (<50%). However, 32.1% of survivors with a normal 3D LVEF had evidence for cardiac dysfunction by either global longitudinal strain (28.0%), ASE graded diastolic assessment (8.7%), or both. Abnormal global longitudinal strain was associated with chest-directed RT (1-19.9 Gy, Rate Ratio (RR) 1.38, 95% Confidence Interval (CI) 1.14-1.66; 20-29.9 Gy, RR 1.65, 95% CI 1.31-2.08; >30 Gy, RR 2.39, 95% CI 1.79-3.18) and anthracycline dose >300 mg/m2 (RR 1.72, 95% CI 1.31-2.26). Survivors with metabolic syndrome were twice as likely to have abnormal global longitudinal strain (Rate Ratio [RR] 1.94, 95% CI 1.66-2.28) as well as abnormal diastolic function (RR 1.68, 95% CI 1.39-2.03), but not abnormal 3D LVEF (RR 1.07, 95% CI 0.74-1.53).
Conclusions and Relevance
Abnormal global longitudinal strain and abnormal diastolic function are more prevalent than reduced 3D LVEF and are associated with treatment exposure. They may identify a subset of survivors at higher risk for poor clinical cardiac outcome who may benefit from early medical intervention.
doi:10.1016/j.jacc.2015.04.013
PMCID: PMC4539123  PMID: 26065990
Childhood Cancer; Survivor; Late effects; Cardiotoxicity; Screening
10.  Decline in physical activity level in the Childhood Cancer Survivor Study cohort 
Background
We aimed to identify demographic and health-related predictors of declining physical activity levels over a four year period among participants in the Childhood Cancer Survivor Study.
Methods
Analyses included 7287 ≥5 year childhood cancer survivors and 2107 siblings who completed multiple follow-up questionnaires. Participants were classified as active if they met the Centers for Disease Control and Prevention guidelines for physical activity. Generalized linear models were used to compare participants whose physical activity levels declined from active to inactive over the study to those who remained active. Additionally, selected chronic conditions (CTCAE v4.03 Grade 3 and 4) were evaluated as risk factors in an analysis limited to survivors only.
Results
The median age at last follow-up among survivors and siblings was 36 (range: 21–58) and 38 (range: 21–62) years, respectively. The rate of decline did not accelerate over time among survivors when compared with siblings. Factors that predicted declining activity included BMI ≥30kg/m2 (RR=1.32, 95%CI=1.19–1.46, p<0.01), not completing high school (RR=1.31, 95%CI=1.08–1.60, p<0.01), and female sex (RR=1.33, 95%CI=1.22–1.44, p<0.01). Declining physical activity levels were associated with the presence of chronic musculoskeletal conditions (p=0.034), but not with the presence of cardiac (p=0.10), respiratory (p=0.92) or neurological conditions (p=0.21).
Conclusions
Interventions designed to maximize physical activity should target female, obese, and less educated survivors. Survivors with chronic musculoskeletal conditions should be monitored, counseled and/or referred for physical therapy.
Impact
Clinicians should be aware of low activity levels among sub-populations of childhood cancer survivors which may heighten their risk for chronic illness.
doi:10.1158/1055-9965.EPI-14-0213
PMCID: PMC4119523  PMID: 24842624
children; cancer; survivor; physical; activity
11.  Estimating the risk for late effects of therapy in children newly diagnosed with standard risk acute lymphoblastic leukemia using an historical cohort: A report from the Childhood Cancer Survivor Study 
The Lancet. Oncology  2014;15(8):841-851.
Summary
Background
Pediatric acute lymphoblastic leukemia (ALL) therapy has evolved such that the risk for late effects in ALL survivors treated on contemporary protocols is likely different from that observed in survivors treated in prior eras. We estimated the risk for late effects in children with standard-risk ALL treated in the current era using data from similarly treated members of the Childhood Cancer Survivor Study (CCSS) cohort.
Methods
The CCSS is a multi-centre North American study of five-year survivors of childhood cancer diagnosed between 1970 and1986. Cohort members were eligible for this analysis if they were aged 1·0–9·9 years at the time of ALL diagnosis and received therapy consistent with contemporary standard-risk ALL protocols. Outcomes were compared to a sibling cohort (n=2788) and the general United States population.
Findings
556/5980 cohort members treated for ALL met the inclusion criteria. After a median follow up of 18·4 years (range 0·0–33·0) from cohort entry, 28/556 (5%) had died (standardized mortality ratio, 3·5; 95% CI, 2·3–5·0). Sixteen deaths were due to causes other than ALL recurrence. Among 556 survivors, six (1%) developed a subsequent malignant neoplasm (standardized incidence ratio, 2·6; 95% CI, 1·0–5·7). 107 subjects in each group would need to be followed for one year in order to observe one extra chronic health condition in the ALL group compared to the sibling group (95% CI, 81–193). 415 subjects in each group would need to be followed for one year to observe one extra severe, life-threatening or fatal condition in the ALL group (95% CI, 376–939) Survivors did not differ from siblings in their educational attainment, rate of marriage or independent living.
Interpretation
Overall, the expected prevalence of adverse long-term outcomes among children treated for standard risk ALL on contemporary protocols is low, but regular care from a knowledgeable primary care practitioner is warranted.
Funding
National Cancer Institute, Cancer Center Support, American Lebanese-Syrian Associated Charities, Cancer Research Switzerland.
doi:10.1016/S1470-2045(14)70265-7
PMCID: PMC4142216  PMID: 24954778
12.  Evaluation of amifostine for protection against cisplatin-induced serious hearing loss in children treated for average-risk or high-risk medulloblastoma 
Neuro-Oncology  2014;16(6):848-855.
Background
The purpose of this study was to evaluate amifostine for protection from cisplatin-induced serious hearing loss in patients with average-risk medulloblastoma by extending a previous analysis to a much larger sample size. In addition, this study aimed to assess amifostine with serious hearing loss in patients with high-risk medulloblastoma treated with cisplatin.
Methods
Newly diagnosed medulloblastoma patients (n = 379; ages 3–21 years), enrolled on one of 2 sequential St. Jude clinical protocols that included 4 courses of 75 mg/m2 cisplatin, were compared for hearing loss by whether or not they received 600 mg/m2 of amifostine immediately before and 3 hours into each cisplatin infusion. Amifostine administration was not randomized. The last audiological evaluation between 5.5 and 24.5 months following protocol treatment initiation was graded using the Chang Ototoxicity Scale. A grade of ≥2b (loss requiring a hearing aid or deafness) was considered a serious event.
Results
Among average-risk patients (n = 263), amifostine was associated with protection from serious hearing loss (adjusted OR, 0.30; 95% CI, 0.14–0.64). For high-risk patients (n = 116), however, there was not sufficient evidence to conclude that amifostine prevented serious hearing loss (OR, 0.89; 95% CI, 0.31–2.54).
Conclusions
Although patients in this study were not randomly assigned to amifostine treatment, we found evidence in favor of amifostine administration for protection against cisplatin-induced serious hearing loss in average-risk but not in high-risk, medulloblastoma patients.
doi:10.1093/neuonc/not241
PMCID: PMC4022215  PMID: 24414535
audiology; brain neoplasms; late effects; ototoxicity; platinum drugs
13.  Efficacy and Cost-effectiveness of the Children’s Oncology Group Long-Term Follow-Up Screening Guidelines for Childhood Cancer Survivors at Risk of Treatment-related Heart Failure 
Annals of internal medicine  2014;160(10):672-683.
Background
Childhood cancer survivors treated with anthracyclines are at high risk for asymptomatic left ventricular dysfunction (ALVD), subsequent heart failure (HF), and death. The consensus-based Children’s Oncology Group (COG) Long-Term Follow-Up Guidelines recommend lifetime echocardiographic screening for ALVD.
Objective
To evaluate the efficacy and cost-effectiveness of the COG Guidelines and to identify more cost-effective screening strategies.
Design
Simulation of life-histories using Markov health states.
Data Sources
Childhood Cancer Survivor Study; published literature.
Target Population
Childhood cancer survivors.
Time Horizon
Lifetime.
Perspective
Societal.
Intervention
Echocardiographic screening, followed by angiotensin-converting enzyme (ACE) inhibitor and beta-blocker therapies after ALVD diagnosis.
Measurements
Quality-adjusted life years (QALYs), costs, incremental cost-effectiveness ratios (ICERs) in dollars per QALY, and the cumulative incidence of HF.
Results of Base-Case Analysis
The COG Guidelines versus no screening have an ICER of $61,500, extend life expectancy by 6 months and QALYs by 1.6 months, and reduce the cumulative incidence of HF by 18% at 30 years after cancer diagnosis. However, less-frequent screenings are more cost-effective than the Guidelines, and maintain 80% of the health benefits.
Results of Sensitivity Analysis
The ICER was most sensitive to the magnitude of ALVD treatment efficacy; higher treatment efficacy resulted in lower ICER.
Limitation
Lifetime non-HF mortality and the cumulative incidence of HF more than 20 years after diagnosis were extrapolated; the efficacy of ACE inhibitor and beta-blocker therapy in childhood cancer survivors with ALVD is undetermined (or unknown).
Conclusion
The COG Guidelines could reduce the risk of HF in survivors at less than $100,000/QALY. Less-frequent screening achieves most of the benefits and would be more cost-effective than the COG Guidelines.
Primary Funding Source
Lance Armstrong Foundation, National Cancer Institute.
doi:10.7326/M13-2498
PMCID: PMC4073480  PMID: 24842414
14.  Feasibility and Efficacy of a Computer-Based Intervention Aimed at Preventing Reading Decoding Deficits Among Children Undergoing Active Treatment for Medulloblastoma: Results of a Randomized Trial 
Journal of Pediatric Psychology  2013;39(4):450-458.
Objective To investigate the feasibility of a computer-based reading intervention completed by patients diagnosed with a brain tumor. Methods Patients were randomized to the intervention (n = 43) or standard of care group (n = 38). The intervention consisted of 30 sessions using Fast ForWord® exercises in a game-like format. Change in reading decoding scores over time since diagnosis was examined. Gender, race, parent education, parent marital status, and age at diagnosis were examined as covariates. Results 17 patients (39.5%) were able to complete the target goal of 30 intervention sessions. Females had significantly greater training time than males (p = .022). Age at diagnosis was associated with average training time/session for females (r = .485, p = .041). No significant differences were found in reading scores between the randomized groups. Conclusions The study was well accepted by families and adherence by patients undergoing radiation therapy for medulloblastoma was moderate. Suggestions for improved methodology are discussed.
doi:10.1093/jpepsy/jst095
PMCID: PMC3994317  PMID: 24369366
academic functioning; cancer and oncology; children; cognitive assessment; intervention outcome; longitudinal research; neuropsychology
15.  Regional Brain Glucose Metabolism and Neurocognitive Function in Adult Survivors of Childhood Cancer Treated with Cranial Radiation 
The objective of this study was to examine associations between regional brain metabolism, as measured by 18F-FDG PET, and neurocognitive outcomes in adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation.
Method
Thirty-eight adult survivors of ALL were randomly selected from a large cohort treated with cranial radiation therapy (19 with 18 Gy and 19 with 24 Gy of exposure). At a mean age of 26.4 (range, 22.3–37.4) years, and 23.5 (range, 20.4–32.8) years since diagnosis, patients underwent comprehensive neurocognitive evaluations and brain 18F-FDG PET imaging during a resting condition. 18F-FDG PET images were analyzed stereotactically, and pixel values were normalized to global activity. Predefined region-of-interest and voxel-based correlation analyses were performed.
Results
Compared with national norms, survivors demonstrated lower vocabulary (P < 0.001), reading (P < 0.001), mathematics (P < 0.001), working memory (P < 0.001), oral naming speed (P < 0.001), and cognitive flexibility (P < 0.001). Metabolic activity was higher in basal gangliar structures for those treated with 24 Gy of cranial radiation therapy (P = 0.04). Metabolic activity was positively correlated with oral naming speed in both lateral frontal lobes (ρ = 0.48 and 0.47 for right and left frontal regions, respectively, P < 0.01) and negatively correlated with cognitive flexibility in the sections of the basal ganglia (P < 0.01 for both caudate and putamen).
Conclusion
Neurocognitive impairment in long-term survivors of ALL treated with cranial radiation appears to be associated with increased metabolic activity in frontal cerebral cortical and subcortical regions in the basal ganglia, suggesting decreased efficiency of the frontostriatal brain circuit.
doi:10.2967/jnumed.114.142950
PMCID: PMC4366940  PMID: 25315244
18F-FDG PET; childhood cancer survivor; neurocognitive function
16.  Aging and Risk of Severe, Disabling, Life-Threatening, and Fatal Events in the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2014;32(12):1218-1227.
Purpose
The first generation of childhood cancer survivors is now aging into their fourth and fifth decades of life, yet health risks across the aging spectrum are not well established.
Methods
Analyses included 14,359 5-year survivors from the Childhood Cancer Survivor Study, who were first diagnosed when they were younger than 21 years old and who received follow-up for a median of 24.5 years after diagnosis (range, 5.0 to 39.3 years) along with 4,301 of their siblings. Among the survivors, 5,604 were at least 35 years old (range, 35 to 62 years) at last follow-up. Severe, disabling, life-threatening, and fatal health conditions more than 5 years from diagnosis were classified using the Common Terminology Criteria for Adverse Events, grades 3 to 5 (National Cancer Institute).
Results
The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6%; 95% CI, 51.5 to 55.6; v 19.8%; 95% CI, 17.0 to 22.7) by age 50 years. When comparing survivors with siblings, hazard ratios (HR) were significantly increased within the age group of 5 to 19 years (HR, 6.8; 95% CI, 5.5 to 8.3), age group of 20 to 34 years (HR, 3.8; 95% CI, 3.2 to 4.5), and the ≥ 35 years group (HR, 5.0; 95% CI, 4.1 to 6.1), with the HR significantly higher among those ≥ 35 years versus those 20 to 34 years old (P = .03). Among survivors who reached age 35 years without a previous grade 3 or 4 condition, 25.9% experienced a subsequent grade 3 to 5 condition within 10 years, compared with 6.0% of siblings (P < .001).
Conclusion
Elevated risk for morbidity and mortality among survivors increases further beyond the fourth decade of life, which affects the future clinical demands of this population relative to ongoing surveillance and interventions.
doi:10.1200/JCO.2013.51.1055
PMCID: PMC3986385  PMID: 24638000
17.  Advancing Survivors’ Knowledge (ASK) about skin cancer study: study protocol for a randomized controlled trial 
Trials  2015;16:109.
Background
Advances in treatment have increased childhood cancer 5-year survival rates to greater than 80%. However, children previously treated with radiation are at significantly increased risk of developing subsequent neoplasms, the most common of which are skin cancers. The National Cancer Institute and Children’s Oncology Group have issued recommendations for survivors treated with radiation to perform monthly skin self-examinations and receive a physician skin examination at least annually, as early detection has demonstrated markedly improved outcomes in the diagnosis and treatment of skin cancers. The goal of the present study is to increase rates of skin self-examinations and clinical skin examinations among adult survivors of childhood cancer treated with radiation.
Methods/Design
This randomized controlled trial uses a 3-group comparative effectiveness design comparing: (1) Patient Activation and Education (PAE) including text messaging, print and web-based tutorials over 12 months; (2) PAE plus physician activation (PAE + MD) adding physician activation/educational materials about survivors’ increased skin cancer risk and conducting full-body skin exams; and (3) PAE plus physician activation, plus teledermoscopy (PAE + MD + TD) adding participant receipt of a dermatoscope intended to empower them to photograph suspect moles or lesions for review by the study dermatologist.
Discussion
The current study addresses barriers to screening in this population by providing educational and motivational information for both survivors and physicians regarding the value of periodic skin examinations. It also utilizes innovative mobile health technology to encourage and motivate (that is activate) survivors to conduct skin self-examinations, request physician exams, and obtain treatment when worrisome lesions are found. Finally, as a comparative effectiveness trial, this study isolates the effects of adding specific components to the patient activation intervention to test the most effective intervention for enhancing skin examination vigilance among this high-risk group.
Trial registration
Clinicaltrials.gov: NCT02046811; Registration date: 22 January 2014.
doi:10.1186/s13063-015-0637-x
PMCID: PMC4392639  PMID: 25873142
Skin cancer; Early detection; Melanoma; Childhood cancer; Survivor; Dermoscopy; Skin self-examination; Health communication
18.  Management and outcome of focal low-grade brainstem tumors in pediatric patients: the St. Jude experience 
Object
Whereas diffuse intrinsic pontine gliomas generally have a short symptom duration and more cranial nerve involvement, focal brainstem gliomas are commonly low grade, with fewer cranial neuropathies. Although these phenotypic distinctions are not absolute predictors of outcome, they do demonstrate correlation in most cases. Because there is a limited literature on focal brainstem gliomas in pediatric patients, the objective of this paper was to report the management and outcome of these tumors.
Methods
The authors reviewed the records of all children diagnosed with radiographically confirmed low-grade focal brainstem gliomas from 1986 to 2010. Each patient underwent biopsy or resection for tissue diagnosis. Eventfree survival (EFS) and overall survival were evaluated. Univariate analysis was conducted to identify demographic and treatment variables that may affect EFS.
Results
Fifty-two patients (20 girls, 32 boys) with follow-up data were identified. Median follow-up was 10.0 years, and the median age at diagnosis was 6.5 years (range 1–17 years). The tumor locations were midbrain (n = 22, 42%), pons (n = 15, 29%), and medulla (n = 15, 29%). Surgical extirpation was the primary treatment in 25 patients (48%). The 5- and 10-year EFS and overall survival were 59%/98% and 52%/90%, respectively. An event or treatment failure occurred in 24 patients (46%), including 5 deaths. Median time to treatment failure was 3.4 years. Disease progression in the other 19 patients transpired within 25.1 months of diagnosis. Thirteen of these patients received radiation, including 11 within 2 months of primary treatment failure. Although children with intrinsic tumors had slightly better EFS at 5 years compared with those with exophytic tumors (p = 0.054), this difference was not significant at 10 years (p = 0.147). No other variables were predictive of EFS.
Conclusions
Surgery suffices in many children with low-grade focal brainstem gliomas. Radiation treatment is often reserved for disease progression but offers comparable disease control following biopsy. In the authors’ experience, combining an assessment of clinical course, imaging, and tumor biopsy yields a reasonable model for managing children with focal brainstem tumors.
doi:10.3171/2012.11.PEDS12317
PMCID: PMC4349190  PMID: 23289916
focal brainstem glioma; low grade; radiation treatment; outcomes; oncology; event-free survival
19.  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
20.  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
21.  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
22.  HIV risks vary according to type of sex work in a cross-sectional survey from Nagaland, India 
BMC Women's Health  2014;14:133.
Background
Human immunodeficiency virus (HIV) infection is a significant problem among female sex workers (FSWs) in Nagaland, India. Place of solicitation and sex vary considerably in this context. The aim of this study was to investigate the relationship between categories of sex work and HIV risks.
Methods
In 2009 a survey was undertaken among 417 FSWs in Dimapur, Nagaland using an interviewer-administered questionnaire and blood and urine samples. Using this data, we constructed a typology of sex work by combining usual place of solicitation and place of sex, and examined variations in demographics, sex work patterns, sexually transmitted infections (STIs) and HIV prevalence across typology categories. Binary logistic regression analyses were done to examine the association between category of sex work and HIV, STIs, and condom use.
Results
By combining place of solicitation with place of sex, seven distinct categories of sex work emerged. The largest category were women who usually solicited in a public place and had sex in a rented room or lodge (31.7%, n = 132). One-tenth of participants were HIV positive (10.3%) and 35.4% had at least one STI (reactive syphilis serology, gonorrhoea or chlamydia). FSWs who both solicited and entertained in a rented room or lodge (OR = 13.3; 95% CI 2.2, 81.5) and those who solicited by phone and had sex in a rented room or lodge (OR = 6.3; 95% CI 1.0, 38.0) were more likely to be HIV positive compared to home-based FSWs. Women who both solicited and entertained in public (OR = 6.7; 95% CI 1.6, 28.0) and who solicited in public and entertained in a rented room or lodge (OR = 2.5; 95% CI 1.1, 6.0) were more likely to test positive for an STI compared to home-based FSWs.
Conclusion
The results indicate that different categories of sex work are associated with different HIV and STI risk profiles. Local contextual understanding of the different types of sex work and the associated levels of risk assist NGOs to target their interventions more effectively and efficiently in order to reduce STI and HIV prevalence among FSWs and their clients.
doi:10.1186/s12905-014-0133-6
PMCID: PMC4240872  PMID: 25388946
HIV; Sex work; STI; India; Typology
23.  Injecting drug use in Manipur and Nagaland, Northeast India: injecting and sexual risk behaviours across age groups 
Background
There is an HIV epidemic among people who inject drugs (PWID) in Manipur and Nagaland, Northeast India. Approximately one-third of PWID across these two states are aged below 25 years, yet until now there has been no systematic investigation of the differences between the younger and older PWID. We sought to profile differences in drug use and sexual practices across age groups and to examine whether age is associated with injecting and sexual risk behaviours.
Methods
We used combined cross-sectional survey data collected in 2009 from two surveys involving a total of 3,362 (male) PWID in eight districts of Manipur and Nagaland. All data were collected using interviewer-administered questionnaires.
Results
Compared to PWID aged 35 years or older, PWID aged 18 to 24 years were more likely share needles/syringes in both Manipur (OR =1.8) and Nagaland (OR =1.6). Compared to PWID aged 35 years or older, PWID aged 18 to 24 years were almost two times as likely to draw up drug solution from a common container at their last injection in Manipur (OR =1.8). In Nagaland, PWID aged 18 to 24 years were more likely to use condoms consistently with both casual (OR =3.1) and paid (OR =17.7) female sexual partners compared to PWID aged 35 years or older.
Conclusion
Risky injecting practices were more common among younger PWID in both Manipur and Nagaland, while unprotected sex was more common among older PWID in Nagaland. There is a clear need to focus public health messages across different age groups.
doi:10.1186/1477-7517-11-27
PMCID: PMC4210540  PMID: 25312004
Injecting drug use; HIV; Youth
24.  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
25.  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

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