The Effect of Atorvastatin on Vascular Function and Structure in Young Adult Survivors of Childhood Cancer: A Randomized, Placebo-Controlled Pilot Clinical Trial.

Purpose: Many adult survivors of childhood cancer are at high-risk of developing cardiovascular disease. Cancer therapy may cause damage to the vascular endothelium, thereby initiating atherosclerosis. Atorvastatin has been shown to improve endothelial function independent of reducing cholesterol, as well as reduce/slow arterial stiffness and thickening, yet has never been studied in childhood cancer survivors (CCS). Methods: Twenty-seven young adult (age 26.8 ± 6.2 years) survivors of childhood acute lymphoblastic leukemia or Non-Hodgkin's lymphoma were randomly assigned (1:1) 40 mg/day of atorvastatin or placebo for 6 months. Brachial artery flow-mediated dilation (FMD), small artery reactive hyperemia index (RHI), arterial stiffness, and carotid artery elasticity/thickness were assessed. Results: Fifteen participants completed the trial. No significant treatment effect for any vascular outcomes was observed at 6 months; however, a significant decrease in peak FMD (-3.0 [95% confidence interval [CI]: -5.3, -0.7]) and a trending significant decrease in RHI (-0.3 [95% CI: -0.62, 0.01]) was observed in the placebo group, resulting in a trend toward a treatment effects (p < 0.10). No effect on arterial stiffness, carotid arterial elasticity, or thickness was observed. Conclusion: Six months of atorvastatin treatment did not improve endothelial function or arterial stiffness in young adult CCS. While a trend toward an improvement in endothelial function was present, findings should be interpreted with caution owing to the small number of evaluable participants and subsequent lack of sufficient power. Further research in a larger sample size is needed to fully elucidate the effects of atorvastatin on vascular function. Trial registered at clinicaltrials.gov as NCT01733953.

Immune Dysfunction After Completion of Childhood Leukemia Therapy.

BACKGROUND: Children with leukemia suffer immune dysfunction from their malignancy and chemotherapy. The immune system components most affected, the degree to which immune suppression occurs, and the duration of immunodeficiency are incompletely characterized. This study measures immunologic parameters following completion of therapy. METHODS: This is a prospective, single institution cohort study. Eligible children with acute myelogenous or acute lymphoblastic leukemia diagnosed between 1 and 21 years of age were enrolled at therapy completion. Immune parameters were assessed at the end of therapy and 6 months later: complete blood counts, immunoglobulin levels, quantitative lymphocyte subsets, mitogen-induced lymphocyte proliferation, natural killer cell function, and vaccine titers. RESULTS: Twenty patients were evaluated; 13 (65%) were female, 15 had acute lymphoblastic leukemia (75%). Mean age at diagnosis was 7.9 years. At end of therapy, all patients had some degree of immune dysfunction. At 6 months posttherapy, persistent abnormalities included: leukopenia (25%), neutropenia (15%), lymphopenia (5%), hypogammaglobulinemia (25%), one or more subtherapeutic vaccine titers (100%), abnormal lymphocyte subset levels (20%), decreased (15%), or absent (10%) natural killer cell function and abnormal lymphocyte proliferative responses (25%). CONCLUSIONS: All patients had multiple abnormalities at end of therapy, and all patients had some degree of persistent immune dysfunction at 6 months after completion of therapy. Clinical implications of these laboratory abnormalities are currently unknown; longer term evaluations are ongoing. We demonstrate that survivors of childhood cancer have lasting quantitative and functional immunologic defects and may remain at risk for infectious complications after completion of therapy.

Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Children's Oncology Group Report.

Hematopoietic cell transplantation (HCT) is an important curative treatment for children with high-risk hematologic malignancies, solid tumors, and, increasingly, nonmalignant diseases. Given improvements in care, there are a growing number of long-term survivors of pediatric HCT. Compared with childhood cancer survivors who did not undergo transplantation, HCT survivors have a substantially increased burden of serious chronic conditions and impairments involving virtually every organ system and overall quality of life. This likely reflects the joint contributions of pretransplantation treatment exposures and organ dysfunction, the transplantation conditioning regimen, and any post-transplantation graft-versus-host disease (GVHD). In response, the Children's Oncology Group (COG) has created long-term follow-up guidelines (www.survivorshipguidelines.org) for survivors of childhood, adolescent, and young adult cancer, including those who were treated with HCT. Guideline task forces, consisting of HCT specialists, other pediatric oncologists, radiation oncologists, organ-specific subspecialists, nurses, social workers, other health care professionals, and patient advocates systematically reviewed the literature with regards to late effects after childhood cancer and HCT since 2002, with the most recent review completed in 2013. For the most recent review cycle, over 800 articles from the medical literature relevant to childhood cancer and HCT survivorship were reviewed, including 586 original research articles. Provided herein is an organ system-based overview that emphasizes the most relevant COG recommendations (with accompanying evidence grade) for the long-term follow-up care of childhood HCT survivors (regardless of current age) based on a rigorous review of the available evidence. These recommendations cover both autologous and allogeneic HCT survivors, those who underwent transplantation for nonmalignant diseases, and those with a history of chronic GVHD.

Physical activity and cardiovascular risk factors in childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCS) are at high risk of developing treatment-related late effects, including cardiovascular disease and diabetes. Late effects can be exacerbated by low physical activity (PA) levels. Relationships between PA and cardiovascular risk factors during childhood have not been well described in CCS. PROCEDURE: PA and cardiovascular risk factors were measured cross-sectionally in 319 CCS and 208 sibling controls aged 9-18 years. Comparisons between CCS and controls and associations of outcomes with PA (dichotomized at 60 min/day or treated as continuous) were performed with linear regression. RESULTS: Among CCS, the high PA group had lower percent fat mass (24.4% vs. 29.8%, P < 0.0001), abdominal subcutaneous fat (67.9 vs. 97.3 cm3 , P = 0.0004), and abdominal visceral fat (20.0 vs. 24.9 cm3 , P = 0.007) and greater lean body mass (41.3 vs. 39.5 kg, P = 0.009) than the low PA group. Comparing CCS to controls, differences in waist circumference (Pinteraction = 0.04), percent fat mass (Pinteraction = 0.04), and abdominal subcutaneous (Pinteraction = 0.02) and visceral (Pinteraction = 0.004) fat between low and high PA groups were greater in CCS than controls, possibly due to greater overall adiposity in CCS. CONCLUSIONS: High PA in CCS resulted in an improved cardiovascular profile, consisting primarily of lower fat mass and greater lean mass, similar to that observed in controls. This suggests interventions directed to increase PA in CCS may reduce the risk of future cardiovascular disease. Pediatr Blood Cancer 2015;62:305-310. © 2014 Wiley Periodicals, Inc.

Bilateral ovarian B-lineage lymphoblastic lymphoma with MLL gene rearrangement: a novel case in infancy.

Mixed-lineage leukemia (MLL) gene rearrangements have rarely been reported in pediatric lymphoma despite their high prevalence in pediatric leukemia. We present a case of an infant with bilateral ovarian B-lineage lymphoblastic lymphoma with MLL gene rearrangement. We also briefly summarize the clinicopathologic significance of MLL gene rearrangements, and review the reported cases of pediatric ovarian lymphoma with and without MLL rearrangement.

Infections among long-term survivors of childhood and adolescent cancer: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Little is known about infections among adult survivors of childhood cancer. The authors report the occurrence of infections and risk factors for infections in a large cohort of survivors of childhood cancer. METHODS: The Childhood Cancer Survivor Study cohort was used to compare incidence rates of infections among 12,360 5-year survivors of childhood cancer with the rates of 4023 siblings. Infection-related mortality of survivors was compared with that of the US population. Demographic and treatment variables were analyzed using Poisson regression to determine the rate ratios (RRs) and corresponding 95% confidence intervals (CIs) for associations with infectious complications. RESULTS: Compared with the US population, survivors were at an increased risk of death from infectious causes (standardized mortality ratio [SMR], 4.2; 95% CI, 3.2-5.4), with the greatest risk observed among females (SMR, 3.2; 95% CI, 1.5-6.9) and among those who had been exposed to total body irradiation (SMR, 7.8; 95% CI, 1.8-33.0). Survivors also reported higher rates than siblings of overall infectious complications (RR, 1.3; 95% CI, 1.2-1.4) and higher rates of all categories of infection. CONCLUSIONS: Survivors of childhood cancer remain at elevated risk for developing infectious-related complications, and they have a higher risk of infection-related mortality years after therapy. Further investigation is needed to provide insight into the mechanisms for the observed excess risks.

Impact of treatment exposures on cardiovascular risk and insulin resistance in childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCS) are more insulin resistant and have higher levels of several cardiovascular risk factors even while still children. This study examines specific treatment exposures associated with cardiovascular risk factors and insulin resistance. METHODS: CCS of ages 9 to 18 years at study entry and in remission 5 years or more from diagnosis (n = 319) and 208 sibling controls were recruited into this cross-sectional study that included physiologic assessment of insulin resistance (hyperinsulinemic euglycemic clamp) and assessment of cardiovascular risk factors. Regression and recursive tree modeling were used to ascertain treatment combinations associated with insulin resistance and cardiovascular risk. RESULTS: Mean current age of CCS was 14.5 years and 54% were male (siblings 13.6 years, 54% male). Diagnoses included leukemia (35%), brain tumors (36%), solid tumors (33%), or lymphoma (6%). Among CCS, analysis of individual chemotherapy agents failed to find associations with cardiovascular risk factors or insulin resistance. Compared with siblings, insulin resistance was significantly higher in CCS who received platinum plus cranial radiotherapy (CRT, 92% brain tumors) and in those who received steroids but no platinum (majority leukemia). Insulin resistance did not differ between CCS who received surgery alone versus siblings. Within survivor comparisons failed to elucidate treatment combinations that increased insulin resistance compared with those who received surgery only. CONCLUSIONS: Exposure to platinum, CRT, or steroids is associated with insulin resistance and cardiovascular risk factors and should be taken into consideration in the development of screening recommendations for cardiovascular risk. IMPACT: Earlier identification of CCS who may benefit from targeted prevention efforts may reduce their future risk of cardiovascular disease.

Ofatumumab for refractory opsoclonus-myoclonus syndrome following treatment of neuroblastoma.

Opsoclonus-myoclonus syndrome (OMS) may be associated with ANNA-1 (anti-Hu) autoantibodies. The standard treatment with IVIG, steroids, and anti-CD20 monoclonal antibody may fail, and optimal therapy is unknown. A patient developed OMS with high-titer ANNA-1 following recovery from neuroblastoma. She failed standard therapy and had only transient response to rituximab. Treatment with the humanized anti-CD20 monoclonal antibody ofatumumab combined with methotrexate resulted in transient neurologic improvement and decrease of ANNA-1. This suggests that ofatumumab combined with methotrexate should further be considered OMS patients, particularly in refractory disease.

Blunted response to a growth hormone stimulation test is associated with unfavorable cardiovascular risk factor profile in childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCS) are at risk for growth hormone (GH) deficiency. CCS are also at increased risk for early mortality from cardiovascular (CV) disease, but the association between GH levels and CV risk remains poorly understood. The goal of this study was to examine the cross-sectional association between stimulated GH levels and CV risk factors in CCS younger than 18 years. PROCEDURE: A total of 276 CCS (147 males, 14.4 ± 2.6 years) ≥5 years after cancer diagnosis, and 208 sibling controls (112 males, 13.6 ± 2.4 years) participated in this cross-sectional study, which included anthropometry, body composition, and metabolic studies. Blunted response (BR) was defined as peak GH level <7 µg/L after clonidine and arginine. Insulin sensitivity (M(lbm) ) was measured by euglycemic hyperinsulinemic clamp. Statistical analyses used linear and logistic regression accounting for sibling clustering, adjusted for age, sex, Tanner stage, and adiposity. RESULTS: Thirty-four (12%) CCS showed BR to GH stimulation. BR CCS were shorter and had a lower IGF-1 than controls; only 6 of 34 received cranial radiation therapy. CCS with normal stimulated GH response were similar to controls for CV risk factors. Conversely, BR CCS had greater adiposity, higher lipids, and lower M(lbm) than controls. Differences in lipids and M(lbm) between BR CCS and controls remained significant after adjustment for BMI or visceral fat. CONCLUSIONS: BR to GH stimulation is prevalent in CCS youth and is associated with an unfavorable CV risk factor profile. Further studies are needed to establish the mechanisms of these associations.

Modifiable risk factors associated with bone deficits in childhood cancer survivors.

BACKGROUND: To determine the prevalence and severity of bone deficits in a cohort of childhood cancer survivors (CCS) compared to a healthy sibling control group, and the modifiable factors associated with bone deficits in CCS. METHODS: Cross-sectional study of bone health in 319 CCS and 208 healthy sibling controls. Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). Generalized estimating equations were used to compare measures between CCS and controls. Among CCS, multivariable logistic regression was used to evaluate odds ratios for BMD Z-score ≤ -1. RESULTS: All subjects were younger than 18 years of age. Average time since treatment was 10.1 years (range 4.3 - 17.8 years). CCS were 3.3 times more likely to have whole body BMD Z-score ≤ -1 than controls (95% CI: 1.4-7.8; p = 0.007) and 1.7 times more likely to have lumbar spine BMD Z-score ≤ -1 than controls (95% CI: 1.0-2.7; p = 0.03). Among CCS, hypogonadism, lower lean body mass, higher daily television/computer screen time, lower physical activity, and higher inflammatory marker IL-6, increased the odds of having a BMD Z-score ≤ -1. CONCLUSIONS: CCS, less than 18 years of age, have bone deficits compared to a healthy control group. Sedentary lifestyle and inflammation may play a role in bone deficits in CCS. Counseling CCS and their caretakers on decreasing television/computer screen time and increasing activity may improve bone health.

Cardiovascular risk and insulin resistance in childhood cancer survivors.

OBJECTIVE: Increased cardiovascular (CV) risk has been reported in adults who are childhood cancer survivors (CCS). We sought to determine the emergence of CV risk factors in CCS while still children. STUDY DESIGN: CCS in remission ≥5 years from cancer diagnosis (n=319, age=14.5 years) and their siblings (control subjects, n=208, age=13.6 years) participated in this cross-sectional study of CV risk, which included physiologic assessment of insulin sensitivity/resistance (hyperinsulinemic euglycemic clamp). Adjusted comparisons between CCS major diagnoses (leukemia [n=110], central nervous system tumors [n=82], solid tumors [n=127]) and control subjects were performed with linear regression for CV risk factors and insulin sensitivity. RESULTS: Despite no significant differences in weight and body mass index, CCS had greater adiposity (waist [73.1 versus 71.1 cm, P=.02]; percent fat [28.1 versus 25.9%, P=.007]), lower lean body mass (38.4 versus 39.9 kg, P=.01) than control subjects. After adjustment for adiposity, CCS had higher total cholesterol level (154.7 versus 148.3 mg/dL, P=.004), low-density lipoprotein cholesterol level (89.4 versus 83.7 mg/dL, P=.002), and triglyceride level (91.8 versus 84 mg/dL, P=.03) and were less insulin sensitive (insulin stimulated glucose uptake, measure of insulin resistance, adjusted for lean body mass 12.1 versus 13.4 mg/kg/min, P=.002) than control subjects. CONCLUSIONS: CCS have greater CV risk than healthy children. Because CV risk factors track from childhood to adulthood, early development of altered body composition and decreased insulin sensitivity in CCS may contribute significantly to their risk of early CV morbidity and mortality.

Is there an association between bicuspid aortic valve and neuroblastoma?

An association has been reported between neuroblastoma and congenital heart disease, frequently bicuspid aortic valve [Holzer and Franklin. Arch Dis Child 2002;87:61-64; George et al. J Pediatr 2004;144:444-448; Friedman et al. Pediatr Cardiol 1998;19:480-481; Monte et al. Am J Pediatr Hematol Oncol 1985;7:109-116]. To evaluate this in a large patient group with neuroblastoma, we examined echocardiograms of patients with neuroblastoma from 1987 to January 2007 to determine if there was a higher incidence of bicuspid aortic valves compared to the general population without neuroblastoma. We found that only 0.7% of neuroblastoma patients had the congenital heart defect of bicuspid aortic valves compared with 1-2% in the general population [Braverman et al. Curr Prob Cardiol 2005;30:470-522]. Our data show that neuroblastoma is not associated with bicuspid aortic valves.

White versus gray matter function as seen on neuropsychological testing following bone marrow transplant for acute leukemia in childhood.

Current theory suggests that neurocognitive late effects of treatments for childhood cancer such as difficulties with attention, processing speed and visual-motor ability are the result of white matter damage. Neuroimaging studies have produced a variety of white matter findings. However, although white matter is thought to be differentially affected, previous studies have not demonstrated a discrepancy between white and gray matter function. The present study included 36 children treated for childhood leukemia with hematopoietic stem cell transplant (HCT). Their performance on neurocognitive measures traditionally thought to measure white matter was compared to performance on measures thought to measure gray matter function. Composite white and gray matter standard scores were created based on neuropsychological measures that individuals with known white or gray matter damage perform poorly. As predicted, composite white matter scores (mean = 98.1) were significantly lower (t = 2.26, p = 0.03) than composite gray matter scores (mean = 102.5). Additionally, as gray matter performance increased, the difference between gray and white matter scores increased (R = 0.353, p = 0.035). Overall, the results of this study support the current theory that white matter damage is responsible for the more subtle neurocognitive late effects resulting from treatment for childhood leukemia.

Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age.

BACKGROUND: Hematopoeitic cell transplantation (HCT) in childhood has been associated with late complications including endocrine, neurocognitive, and cardiopulmonary abnormalities. Little is known about the complications of transplantation in infants. PROCEDURE: Eligible subjects underwent HCT for acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) at less than 3 years of age. Seventeen out of 33 eligible patients were evaluated, transplanted between 1981-2000. Eleven patients had AML, 11 were female. Preparative regimen included total body irradiation (TBI) for eleven. Age at HCT ranged from 0.58 to 2.97 years, and survival 3.25 to 22.33 years. Patients underwent physical and laboratory evaluation, dual-energy X-ray absorptiometry (DXA) scan, bone age X-ray, neuropsychological, and quality of life (QOL) evaluation. RESULTS: Identified abnormalities included: growth hormone deficiency (59%), hypothyroidism (35%), osteochondromas (24%), decreased bone mineral density (24%), and dyslipidemias (59%). Two patients developed a second malignancy. Neuropsychological testing revealed average intelligence quotient (IQ) with attention deficits and other weaknesses for most patients. There were no overall differences between QOL in these children when compared to population norms. CONCLUSIONS: Of the survivors evaluated, typical late effects seen after radiation exposure are common, yet most subjects were doing well without major ongoing medical issues. Dyslipidemias affect more than half of patients and may be associated with metabolic syndrome, placing patients at increased risk for early cardiovascular disease. Even in this group of patients where the majority was exposed to TBI at a very young age, most are functioning at an average or above-average level.

Nonmelanoma skin cancer in survivors of childhood and adolescent cancer: a report from the childhood cancer survivor study.

PURPOSE: Nonmelanoma skin cancer (NMSC) has become the most common type of cancer in many populations throughout the world. Ultraviolet and ionizing radiation are known risk factors. Because NMSCs are rarely lethal and most cancer registries do not routinely report data regarding these cancers, they have received little attention in studies evaluating long-term effects of cancer therapy. This article reports on the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer. PATIENTS AND METHODS: The Childhood Cancer Survivor Study (CCSS) is a cohort study of 5-year survivors of childhood and adolescent cancer from 25 participating institutions in North America. NMSC patients were defined by a history of basal cell or squamous cell carcinoma of the skin after primary malignancy treatment. Demographic and treatment data were collected and analyzed. RESULTS: Among the 13,132 eligible CCSS participants, 213 have reported NMSC; 99 patients (46%) have had multiple occurrences. Median age of occurrence was 31 years (range, 7 to 46 years). Location of NMSC included head and neck (43%), back (24%), chest (22%), abdomen and pelvis (5%), extremity (3%), and unknown (4%). Ninety percent of patients had previously received radiation therapy (RT); 90% of tumors occurred within the RT field. RT was associated with a 6.3-fold increase in risk (95% CI, 3.5- to 11.3-fold). CONCLUSION: Long-term survivors of childhood and adolescent cancer who were treated with RT are at highest risk for developing NMSC. Educational efforts need to be directed to this population to facilitate early diagnosis of NMSC and reduction in sun exposure.