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1.  Developing Interventions for Cancer-Related Cognitive Dysfunction in Childhood Cancer Survivors 
Survivors of childhood cancer frequently experience cancer-related cognitive dysfunction, commonly months to years after treatment for pediatric brain tumors, acute lymphoblastic leukemia (ALL), or tumors involving the head and neck. Risk factors for cancer-related cognitive dysfunction include young age at diagnosis, treatment with cranial irradiation, use of parenteral or intrathecal methotrexate, female sex, and pre-existing comorbidities. Limiting use and reducing doses and volume of cranial irradiation while intensifying chemotherapy have improved survival and reduced the severity of cognitive dysfunction, especially in leukemia. Nonetheless, problems in core functional domains of attention, processing speed, working memory and visual-motor integration continue to compromise quality of life and performance. We review the epidemiology, pathophysiology and assessment of cancer-related cognitive dysfunction, the impact of treatment changes for prevention, and the broad strategies for educational and pharmacological interventions to remediate established cognitive dysfunction following childhood cancer. The increased years of life saved after childhood cancer warrants continued study toward the prevention and remediation of cancer-related cognitive dysfunction, using uniform assessments anchored in functional outcomes.
PMCID: PMC4155432  PMID: 25080574
2.  Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2014;32(7):647-653.
The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed.
Patients and Methods
By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease.
By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10−7). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m2) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09).
Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) –induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.
PMCID: PMC3927733  PMID: 24470002
3.  Pediatric Genitourinary Tumors 
Current opinion in oncology  2009;21(3):278-283.
Purpose of review
We will review the 2007/2008 literature on pediatric genitourinary tumors.
Recent findings
Newly identified constitutional epigenetic defects in Wilms tumor (WT) genes extends the understanding of WT risks in children lacking syndromic features, and adds to the complexity of the pathogenesis of these tumor suppressor genes. Pediatric renal cell carcinoma (RCC) has distinct molecular characteristics and clinical associations from the adult counterpart. The pathway from PAX3-FKHR translocation to the development of rhabdomyosarcoma (RMS) tumors has been further elucidated.
Therapeutic strategies continue to be driven by developments in molecular diagnostics in pediatric GU tumors.
PMCID: PMC4086793  PMID: 19295433
genitourinary; childhood cancer; Wilms' tumor; rhabdomyosarcoma; germ cell tumor; testicle
4.  Toxicity and Efficacy of the Acetylcholinesterase (AChe) Inhibitor Donepezil in Childhood Brain Tumor Survivors: A Pilot Study 
Pediatric blood & cancer  2012;59(3):540-547.
Neurocognitive deficits are a recognized late effect of curative brain tumor therapy. We evaluated the feasibility, tolerance, and impact of a pilot pharmacologic intervention with the acetylcholinesterase (AChe) inhibitor, donepezil, in pediatric brain tumor (BT) survivors at risk for neurocognitive dysfunction.
A single institution open-label pilot study was conducted in childhood BT survivors: ≥ 1 year from cancer treatment; and who received > 23.5 Gy cranial radiation therapy (RT). Toxicity, adherence and neurocognitive outcomes were evaluated at baseline and serially during 24 weeks of donepezil, and following a 12-week washout period off drug.
From a pool of subjects, 13 were successfully contacted and screened, and 11 met all eligibility criteria to initiate donepezil at a median of 4.7 (1.9–11.9) years from RT. Seventy-two percent of patients completed the 24-week drug study visit. Despite transient gastrointestinal toxicity (vomiting and diarrhea) in 30% of patients there was no weight loss on donepezil. Significant improvement in performance was noted at 24 weeks on the Dellis-Kaplan Executive Function (D-KEF) Tower test (p<=0.001), the Wide Range Assessment of Memory and Learning, 2nd Edition (WRAML-2) Visual memory (p= 0.007), and the Number/Letter task (p= 0.018).
Donepezil was well tolerated among childhood BT survivors who had received substantial prior therapy. Based on improved executive function and memory performance in this pilot trial, a randomized placebo controlled trial of this pharmacologic agent is warranted to fully evaluate its efficacy in remediating neurocognitive dysfunction.
PMCID: PMC3345166  PMID: 22238217
childhood brain tumor; survivors; AChe inhibitor; donepezil; executive function
5.  Decline in physical activity level in the Childhood Cancer Survivor Study cohort 
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.
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.
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).
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.
Clinicians should be aware of low activity levels among sub-populations of childhood cancer survivors which may heighten their risk for chronic illness.
PMCID: PMC4119523  PMID: 24842624
children; cancer; survivor; physical; activity
6.  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
7.  Potential Role of Community-Based Healthcare System Data in Research on Survivors of Adolescent and Young Adult Cancer 
We sought to examine issues of generalizability in research on adolescent and young adult (AYA) cancer survivorship that relies on using community-based healthcare delivery system data.
Individuals aged 15 to 39 diagnosed with cancer between 1992 and 2006 were identified using data from community-based healthcare systems in California and Seattle. Loss to follow-up was defined as the first disenrollment (the end) of membership in the healthcare systems after cancer. Censoring occurred at death or study end (2009). We used Kaplan–Meier analysis to quantify follow-up, and multiple Cox regression to examine the association of follow-up loss with demographic and cancer characteristics.
Of 6828 eligible AYAs, most (93%) were aged between 20 and 39 years at diagnosis; 62% were female and 39% were non-White. Solid tumors accounted for 81% of diagnoses. The majority (89%) of patients continued to be members of the healthcare systems and available for follow-up 1 year after diagnosis. Approximately 60% remained enrolled 5 years after diagnosis. Loss to follow-up was associated with younger age at diagnosis, male gender, and African American or Hispanic race/ethnicity.
Data from community-based healthcare delivery systems offer an efficient way to identify large and diverse samples of AYA-onset cancer survivors. Differential loss to follow-up can threaten the generalizability of results from these studies and should be assessed quantitatively. Healthcare system data offer an alternative to studies requiring direct contact with participants.
PMCID: PMC3684133  PMID: 23781401
survivorship; epidemiologic methods; healthcare research; bias
8.  The peabody picture vocabulary test as a pre-screening tool for global cognitive functioning in childhood brain tumor survivors 
Journal of neuro-oncology  2011;104(2):559-563.
Minimal acceptable global intelligence is often a determinant for entry into studies utilizing children’s self-reported health-related quality of life (HRQL) or symptoms’ appraisal. However, most measures of cognitive functioning are lengthy and require a trained psychologist for administration. We used the Peabody Picture Vocabulary Test (third edition; PPVT-III) to assess adequacy of verbal comprehension and language flexibility before entry into a pilot pharmacologic intervention trial in pediatric BT survivors who were >1 year from treatment, and received >23.4 gray as part of therapy. Participation included the ability to complete self-reported measures of HRQL. Among thirteen BT survivors who were screened, twelve proceeded to the full intervention trial and then underwent a detailed baseline neurocognitive assessment including the Wechsler Abbreviated Scale of Intelligence (WASI), administered by a neuropsychologist. Correlation of PPVT-III with WASI was 0.90 for full scale IQ (P < 0.0001), 0.89 for verbal IQ (P = 0.0001) and 0.75 for performance IQ (P = 0.0004) The PPVT-III is easy to administer by trained clinical staff and is a reliable clinic-based screening tool for research studies. While it is not designed to replace in depth neuropsychological evaluation of potential areas of cognitive dysfunction, it provides an estimation of minimal global cognitive functioning for entry into studies that rely on self-report in childhood BT survivors and other cancer survivors who have received central nervous system-directed therapy.
PMCID: PMC3681605  PMID: 21225316
Childhood brain tumor survivor; Intelligence; Screening; PPVT-III
9.  Impact of Insurance Type on Survivor-Focused and General Preventive Health Care Utilization in Adult Survivors of Childhood Cancer: The Childhood Cancer Survivor Study (CCSS) 
Cancer  2010;117(9):1966-1975.
Lack of health insurance is a key barrier to accessing care for chronic conditions and cancer screening. We examined the influence of insurance type (private, public, none) on survivor-focused and general preventive health care in adult survivors of childhood cancer.
The Childhood Cancer Survivor Study is a retrospective cohort study of childhood cancer survivors diagnosed between 1970–1986. Among 8425 adult survivors, the Relative Risk (RR), 95% confidence interval (CI) of receiving survivor-focused and general preventive health care were estimated for uninsured (n=1390) and publicly insured (n=640), comparing to privately insured (n=6395).
Uninsured survivors were less likely than privately insured to report a cancer-related (adjusted RR=0.83, 95% CI, 0.75–0.91) or a cancer center visit (adjusted RR=0.83, 95% CI, 0.71–0.98). Uninsured survivors had lower levels of utilization in all measures of care in comparison with privately insured. In contrast, publicly insured survivors were more likely to report a cancer-related (adjusted RR=1.22, 95% CI, 1.11–1.35) or a cancer center visit (adjusted RR=1.41, 95% CI, 1.18–1.70) than privately insured. While having a similar utilization level of general health examinations, publicly insured survivors were less likely to report Papanicolaou smear or dental examinations.
Among this large, socioeconomically diverse cohort, publicly insured survivors utilize survivor-focused health care at rates at least as high as survivors with private insurance. Uninsured survivors have lower utilization to both survivor-focused and general preventive health care.
PMCID: PMC3433164  PMID: 21509774
Childhood Cancer Survivors; Health Insurance; Health Care Access; Survivorship; Delivery of Health Care

Results 1-9 (9)