Relationships among attention function, exercise, and body mass index: a comparison between young breast cancer survivors and acquaintance controls.

OBJECTIVE: Although regular physical activity is associated with lower all-cause and disease-specific mortality among breast cancer survivors (BCS), most BCS do not meet its recommended guidelines. Attention function, a domain of cognition, is essential for daily tasks such as exercising, a form of planned physical activity. We tested the hypotheses that lower self-reported attention function in BCS would be associated with less exercise and higher body mass index (BMI) by comparing a group of 505 young BCS (45 years or younger at diagnosis and 3-8 years post-treatment) with 466 acquaintance controls (AC). METHODS: The groups were compared on self-reported physical and psychological outcomes. Mplus software was used to perform confirmatory structural equation modeling with a robust maximum likelihood estimator to evaluate hypothesized relationships among variables. The criteria for good model fit were having root mean square error of approximation (RMSEA) < 0.06, comparative fit index (CFI) > 0.95, and standardized root mean square residual (SRMR) < 0.08. Modification indices were used to better fit the model. RESULTS: The final model demonstrated good fit, with RMSEA = 0.05, CFI = 0.98, and SRMR = 0.03. After controlling for demographics, parameter estimates revealed that, compared with AC, young BCS reported worse attention function (p < 0.001), more depressive symptoms (p < 0.001), and more fatigue (p < 0.001). Controlling for fatigue, depression, and anxiety, better attention function was associated with a greater likelihood of exercise in the past 3 months (p = 0.039), which in turn was associated with a lower BMI (p < 0.001). CONCLUSIONS: The significant association between attention function and physical activity, if confirmed in a longitudinal study, will provide new targets for interventions aimed at improving physical activity and decreasing BMI among BCS.

A Pilot Study of Circulating Endothelial and Hematopoietic Progenitor Cells in Children With Sarcomas.

Utilizing a multiparametric flow cytometry protocol, we assessed various cell types implicated in tumor angiogenesis that were found circulating in the peripheral blood of children with sarcomas (cases) based on their cell surface antigen expression. Circulating endothelial cells (CECs), endothelial colony-forming cells (ECFCs), and the ratio of 2 distinct populations of circulating hematopoietic stem and progenitor cells (CHSPCs), the proangiogenic CHSPCs (pCHSPCs) and nonangiogenic CHSPCs (nCHSPCs) were enumerated. Multiparametric flow cytometry was analyzed in cases at baseline and at 4 additional timepoints until the end of treatment and levels compared with each other and with healthy controls. At all timepoints, cases had significantly lower levels of CECs, but elevated ECFCs and a pCHSPC:nCHSPC ratio compared with controls (all P-values <0.05). There was no significant difference in any of the cell types analyzed based on tumor histology, stage (localized vs. metastatic), or tumor size. After treatment, only the CECs among the complete responders were significantly lower at end of therapy (P<0.01) compared with nonresponders, whereas the ECFCs among all cases significantly increased (P<0.05) compared with baseline. No decline in the pCHSPC:nCHSPC ratio was observed despite tumor response. On the basis of these results, a validation of CECs as prognostic biomarker is now warranted.

Human proangiogenic circulating hematopoietic stem and progenitor cells promote tumor growth in an orthotopic melanoma xenograft model.

We previously identified a distinct population of human circulating hematopoietic stem and progenitor cells (CHSPCs; CD14(-)glyA(-)CD34(+)AC133(+/-)CD45(dim)CD31(+) cells) in the peripheral blood (PB) and bone marrow, and their frequency in the PB can correlate with disease state. The proangiogenic subset (pCHSPC) play a role in regulating tumor progression, for we previously demonstrated a statistically significant increase in C32 melanoma growth in NOD.Cg-Prkdc (scid) (NOD/SCID) injected with human pCHSPCs (p < 0.001). We now provide further evidence that pCHSPCs possess proangiogenic properties. In vitro bio-plex cytokine analyses and tube forming assays indicate that pCHSPCs secrete a proangiogenic profile and promote vessel formation respectively. We also developed a humanized bone marrow-melanoma orthotopic model to explore in vivo the biological significance of the pCHSPC population. Growth of melanoma xenografts increased more rapidly at 3-4 weeks post-tumor implantation in mice previously transplanted with human CD34(+) cells compared to control mice. Increases in pCHSPCs in PB correlated with increases in tumor growth. Additionally, to determine if we could prevent the appearance of pCHSPCs in the PB, mice with humanized bone marrow-melanoma xenografts were administered Interferon α-2b, which is used clinically for treatment of melanoma. The mobilization of the pCHSPCs was decreased in the mice with the humanized bone marrow-melanoma xenografts. Taken together, these data indicate that pCHSPCs play a functional role in tumor growth. The novel in vivo model described here can be utilized to further validate pCHSPCs as a biomarker of tumor progression. The model can also be used to screen and optimize anticancer/anti-angiogenic therapies in a humanized system.

Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial.

BACKGROUND: Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. METHODS: Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. FINDINGS: Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). INTERPRETATION: Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. FUNDING: Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

Psychometric Testing of Attitudes Toward Physical Activity Scale for Adolescent and Young Adult Survivors of Pediatric Cancer.

Purpose: Adolescent and young adult (AYA) survivors of pediatric cancer experience chronic health problems following treatment, many of which could be prevented through healthy lifestyle choices. This report describes the development of the AYA Cancer Survivor Attitude (AYA-CSA) Scale, an attitudinal scale that is associated with physical activity in AYA survivors of pediatric cancer. Methods: AYA survivors (n = 100) completed a survey to evaluate their attitudes toward engagement in physical activity. Internal consistency was calculated using Cronbach's alpha. Construct validity was assessed by exploratory factor analysis, correlation with physical activity intention and physical activity behavior, and prediction of physical activity, after adjusting for past physical activity, survivor age, gender, and family income. Results: Data demonstrated a single 6-item scale with excellent internal consistency (α = 0.82). Construct validity was supported by significant correlations with physical activity intention (r = 0.553, p < 0.001) and physical activity behavior (r = 0.489, p < 0.001). After controlling for past physical activity and demographic covariates, survivor age, attitude toward physical activity, and intention were significant predictors of physical activity, and the overall model (F(6, 77) = 7.722, p < 0.001) predicted 39.5% of the variability in physical activity. Conclusion: The AYA-CSA scale demonstrates good reliability and construct validity, most important of which was the ability to predict actual physical activity in AYA survivors of pediatric cancer. This reliable and valid measure is an important tool in the design of behavioral interventions to improve physical activity engagement in AYA survivors.

Endocrine and Metabolic Disorders in Survivors of Childhood Cancers and Health-Related Quality of Life and Physical Activity.

CONTEXT: Childhood cancer survivors experience chronic health conditions that impact health-related quality of life (HRQOL) and participation in optimal physical activity. OBJECTIVE: The study aimed to determine independent effects of endocrine and metabolic disorders on HRQOL and physical activity. DESIGN, SETTING, AND PATIENTS: Retrospective cohort with longitudinal follow-up of survivors of childhood cancer enrolled in the North American Childhood Cancer Survivor Study. MAIN OUTCOME MEASURES: Medical Outcomes Short Form-36 estimated HRQOL, and participation in physical activity was dichotomized as meeting or not meeting recommendations from the Centers for Disease Control and Prevention. Log binomial regression evaluated the association of each endocrine/metabolic disorder with HRQOL scales and physical activity. RESULTS: Of 7287 survivors, with a median age of 32 years (range, 18 to 54 years) at their last follow-up survey, 4884 (67%) reported one or more endocrine/metabolic disorders. Survivors with either disorder were significantly more likely to be male, older, have received radiation treatment, and have experienced other chronic health conditions. After controlling for covariates, survivors with any endocrine/metabolic disorder were more likely to report poor physical function risk ratio (RR, 1.25; 95% CI, 1.05 to 1.48), increased bodily pain (RR, 1.27; 95% CI, 1.12 to 1.44), poor general health (RR, 1.49; 95% CI, 1.32 to 1.68), and lower vitality (RR, 1.21; 95% CI, 1.09 to 1.34) compared with survivors without. The likelihood of meeting recommended physical activity was lower among survivors with growth disorders (RR, 0.90; 95% CI, 0.83 to 0.97), osteoporosis (RR, 0.87; 95% CI, 0.76 to 0.99), and overweight/obesity (RR, 0.92; 95% CI, 0.88 to 0.96). CONCLUSION: Endocrine and metabolic disorders are independently associated with poor HRQOL and suboptimal physical activity among childhood cancer survivors.

Adult BMI change and risk of Breast Cancer: National Health and Nutrition Examination Survey (NHANES) 2005-2010.

OBJECTIVE: Breast cancer is the second leading cause of cancer mortality among women in the developed world. This study assessed the association between occurrence of breast cancer and body mass index (BMI) change from age 25 to age closest to breast cancer diagnosis while exploring the modifying effects of demographic variables. METHODS: The National Health and Nutrition Examination Survey data were used. Women included were ≥50 years, not pregnant and without a diagnosis of any cancer but breast. The total sample included 2895 women (172 with breast cancer and 2723 controls with no breast cancer diagnosis). Multivariate logistic regression was used to estimate the OR and 95 % CIs and interaction evaluated by including an interaction term in the model. RESULTS: Women whose BMI increased from normal or overweight to obese compared to those who remained at a normal BMI were found to have a 2 times higher odds (OR = 2.1; 95 % CI 1.11-3.79) of developing breast cancer. No significant association was observed for women who increased to overweight. However, a more pronounced association was observed in non-Hispanic black women (OR = 6.6; 95 % CI 1.68-25.86) and a significant association observed when they increased from normal to overweight (OR = 4.2; 95 % CI 1.02-17.75). CONCLUSIONS: Becoming obese after age 25 is associated with increased risk of breast cancer in women over 50 years old, with non-Hispanic black women being at greatest risk.

Evaluation of Physician and Nurse Dyad Training Procedures to Deliver a Palliative and End-of-Life Communication Intervention to Parents of Children with a Brain Tumor.

When a child's prognosis is poor, physicians and nurses (MDs/RNs) often struggle with initiating discussions about palliative and end-of-life care (PC/EOL) early in the course of illness trajectory. We describe evaluation of training procedures used to prepare MD/RN dyads to deliver an intervention entitled: Communication Plan: Early Through End of Life (COMPLETE) intervention. Our training was delivered to 5 pediatric neuro-oncologists and 8 pediatric nurses by a team of expert consultants (i.e., in medical ethics, communication, and PC/EOL) and parent advisors. Although half of the group received training in a 1-day program and half in a 2-day program, content for all participants included 4 modules: family assessment, goal-directed treatment planning, anticipatory guidance, and staff communication and follow-up. Evaluations included dichotomous ratings and qualitative comments on content, reflection, and skills practice for each module. Positive aspects of our training included parent advisers' insights, emphasis on hope and non-abandonment messages, written materials to facilitate PC/EOL communication, and an MD/RN dyad approach. Lessons learned and challenges related to our training procedures will be described. Overall, the MDs and RNs reported that our PC/EOL communication-training procedures were helpful and useful. Future investigators should carefully plan training procedures for PC/EOL communication interventions.

Pituitary hormone dysfunction after proton beam radiation therapy in children with brain tumors.

OBJECTIVE: To characterize endocrine dysfunction in pediatric patients with brain tumors who received proton beam (PB) radiation therapy and to compare those treated with PB radiotherapy only versus combined conventional and PB irradiation. METHODS: A retrospective review of medical records of patients ≤18 years of age who received PB radiation therapy for a brain tumor between 2000 and 2008 was performed. Variables analyzed included patient demographics, tumor type, therapeutic modalities, radiation doses, and types and timing of endocrine dysfunction. RESULTS: Thirty-eight patients were identified, of whom 31 (19 boys and 12 girls; mean age, 11.9 ± 3.3 years) had undergone endocrine evaluation. Of these patients, 19 received PB radiotherapy only and 12 received conventional plus PB irradiation. Before irradiation, a cranial surgical procedure was performed in 28 study subjects, and 22 received chemotherapy. The mean duration of follow-up after radiation therapy was 1.8 ± 0.8 years. Nine patients (47%) in the PB only group and 4 (33%) in the conventional plus PB group developed endocrine dysfunction (no significant difference) after cranial irradiation. Children with endocrine sequelae treated with PB irradiation alone received fewer cobalt gray equivalents than those treated with conventional plus PB irradiation (5,384 ± 268 versus 5,775 ± 226, respectively; P<.02), and pituitary hormone deficiencies were detected later during follow-up in those who received PB radiotherapy only versus conventional plus PB irradiation (1.17 ± 0.4 years versus 0.33 ± 0.11 year, respectively; P<.01). CONCLUSION: A high rate of endocrine sequelae was seen in our study. Children with brain tumors treated with conventional plus PB irradiation developed endocrine dysfunction faster and received a higher radiation dose than those receiving PB radiotherapy only. Prior surgical treatment and chemotherapy were additional risk factors. Large prospective studies are needed to evaluate further the incidence of endocrine sequelae after PB irradiation in children.

Polychromatic flow cytometry identifies novel subsets of circulating cells with angiogenic potential in pediatric solid tumors.

BACKGROUND: Pediatric solid tumors depend upon angiogenesis for their growth and metastases. A new polychromatic flow cytometry (PFC) protocol has revealed circulating cells of hematopoietic and endothelial lineages from the peripheral blood (PB) of healthy individuals, and has defined the different cell types involved in the growth of tumor vasculature that are critical in angiogenesis. METHODS: PB was collected from both healthy children and children with different malignant solid tumors and the mononuclear cells (MNCs) were subsequently isolated. PFC was applied and the MNCs were evaluated for proangiogenic and nonangiogenic circulating progenitor cells (CPCs), endothelial colony forming cells (ECFCs), and mature endothelial cells using the markers CD45, CD31, AC133, CD34, CD14, CD235a, CD41a, and a viability marker. RESULTS: ECFCs and CPCs were significantly elevated in patients at day 21 compared to controls. The ratio of proangiogenic to nonangiogenic CPCs was significantly elevated compared to controls at baseline and returned to healthy baseline levels following treatment. CONCLUSIONS: We describe the successful identification of these hematopoietic and endothelial progenitor cells in both healthy children and children with solid tumors. In addition, this is a potential discovery of novel predictive biomarkers for future clinical trials.

A novel intensive induction therapy for high-risk neuroblastoma utilizing sequential peripheral blood stem cell collection and infusion as hematopoietic support.

OBJECTIVE: To determine the feasibility, toxicities, and the response rate (RR) of a dose intensive, submyeloablative, induction chemotherapy protocol termed EPiC (etoposide, carboplatin, and intensive cyclophosphamide) utilizing sequential peripheral blood stem cell (PBSC) collection and infusion as hematopoietic support in children with newly diagnosed Stage 4 neuroblastoma. PATIENTS AND METHODS: Twenty-five children (age >1 year) with Stage 4 neuroblastoma were enrolled. First and third cycles consisted of cyclophosphamide (4 gm/m2) and carboplatin (400 mg/m2). Second and fourth cycles consisted of carboplatin (1 gm/m2), and etoposide (450 mg/m2). PBSC were collected following Cycles 1, 2, and 3 and reinfused in each subsequent cycle. Following EPiC and surgical resection of the primary tumor, patients proceeded to various consolidation therapies. RR was scored using the International Neuroblastoma Response Criteria. RESULTS: Using PBSC infusion following EPiC chemotherapy resulted in a dose intensity averaging 85% of intended dose intensity; and in early neutrophil but not platelet recovery. PBSC were adequately collected in all, but one patient. The protocol had minimal non-hematological toxicities. There was one toxic death. The overall RR was 78%, which included PR (partial response) and VGPR (very good partial response). The 5-year event-free survival and overall survival were 44% and 54%, respectively at a median follow-up of 58.6 months. CONCLUSION: EPiC is a feasible, well-tolerated, sub-myeloablative, induction chemotherapy protocol for children with high-risk neuroblastoma. RR is equivalent to prior published studies, however, with minimal toxicities. Sequential PBSC collection and infusion is feasible even in very young children.