David C. Landy

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions A Scientific Statement From the American Heart Association

Cancer is diagnosed in >12 000 children and adolescents in the United States each year.1 Progress in cancer therapeutics over the past 40 years has remarkably improved survival rates for most childhood malignancies. For all pediatric cancers, 5-year survival increased from 58% for children diagnosed between 1975 and 1977 to 82% for those diagnosed between 1999 and 2006.2 In the United States, this success translates into >325 000 survivors of childhood cancer, of whom 24% are now >30 years from diagnosis.3 During this same period, the incidence of many histological subtypes of childhood cancer has increased, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, and soft-tissue and germ-cell tumors.3 Consequently, the number of childhood cancer survivors is expected to increase as a result of the rising pediatric cancer incidence and improved long-term survival rates.3 The increasing number of survivors soon revealed acute and delayed modality-specific toxicities and their impact on quality of life and early mortality. In their seminal 1974 publication, Meadows and D’Angio4 described the wide array of potential late effects of successful therapy for childhood cancer. In the past 2 decades, the Childhood Cancer Survivor Study has also improved our understanding of the long-term mortality and morbidity in this high-risk population. Among young adult survivors of childhood cancer diagnosed between 1970 and 1986, at least 1 of 6 domains of health status (general health, mental health, functional status, activity limitations, cancer-related pain, and cancer-related anxiety) declined moderately to severely in 44%.5 The cumulative incidence of a chronic health condition 30 years after cancer diagnosis is now 73%, with a cumulative incidence of 42% for severe, disabling, or life-threatening conditions or death attributable to a chronic condition.6 Also by 30 years after cancer diagnosis, the cumulative mortality rate from causes …

Anthracycline-Associated Cardiotoxicity in Survivors of Childhood Cancer

Anthracycline chemotherapeutic agents are widely used to treat childhood cancers, helping to create an increasing population of childhood cancer survivors. Cardiac complications can occur years after exposure to anthracyclines and are a leading cause of noncancerous morbidity and mortality in this population. The mechanism of its cardiotoxicity is not completely known, although oxidative stress is believed to play a significant role. This pathway and other nonoxidative mechanisms are reviewed. Several risk factors such as age, dose, female gender, and concomitant radiation therapy are known, but the relative risks of many comorbidities such as diabetes and hypertension are not well studied. No standard, evidence-based guidelines for appropriate screening methods to detect cardiotoxicity exist. Periodic imaging with echocardiography or radionuclide angiography is appropriately recommended for long-term survivors but is of limited use during therapy. Biomarkers such as cardiac troponins and brain natriuretic peptides may aid in detecting cardiotoxicity. Studies investigating the use of agents such as angiotensin-converting enzyme (ACE)-inhibitors and beta-blockers to treat anthracycline cardiotoxicity have shown promise, but more data are needed. Structural analogs such as epirubicin were developed to minimize cardiotoxicity but have not sufficiently reduced it. Liposome-encapsulated anthracyclines have shown a considerable decrease of cardiotoxicity in adults without sacrificing efficacy, but the data related to children are sparse. The only agent proven to be cardioprotective is the iron chelator, dexrazoxane. Studies have shown that dexrazoxane is safe and significantly reduces the incidence of cardiotoxicity. Dexrazoxane should be considered for pediatric oncology protocols using anthracyclines that include longitudinal assessment.

The Pediatric Cardiomyopathy Registry and Heart Failure: Key Results from the First 15 Years

Cardiomyopathy is a serious disorder of the heart muscle and, although rare, is a common cause of heart failure in children and the most common cause for heart transplantation in children older than 1 year of age. Funded by the National Heart Lung and Blood Institute since 1994, the Pediatric Cardiomyopathy Registry (PCMR) has followed more than 3500 North American children with cardiomyopathy. Early analyses determined estimates for the incidence of pediatric cardiomyopathy (1.13 cases per 100,000 children per year), risk factors for cardiomyopathy (age <1 year, male sex, black race, and living in New England as opposed to the central southwestern states), the prevalence of heart failure at diagnosis (6%-84% depending on cause), and 10-year survival (29%-94% depending on cause). More recent analyses explored cause-specific functional status, survival and transplant outcomes, and risk factors in greater detail. For many topics these analyses are based on the largest and best-documented samples of children with disease such as the muscular dystrophies, mitochondrial disorders, and Noonan syndrome. Data from the PCMR continue to provide valuable information that guides clinical management and the use of life-saving therapies, such as cardiac transplantation and approaches to treating heart failure, and prepares children, their families, and their caregivers to deal with this serious condition.

Cardiovascular Status of Childhood Cancer Survivors Exposed and Unexposed to Cardiotoxic Therapy

PURPOSE To determine whether cardiovascular abnormalities in childhood cancer survivors are restricted to patients exposed to cardiotoxic anthracyclines and cardiac irradiation and how risk factors for atherosclerotic disease and systemic inflammation contribute to global cardiovascular status. METHODS We assessed echocardiographic characteristics and atherosclerotic disease risk in 201 survivors of childhood cancer with and without exposure to cardiotoxic treatments at a median of 11 years after diagnosis (range, 3 to 32 years) and in 76 sibling controls. RESULTS The 156 exposed survivors had below normal left ventricular (LV) mass, wall thickness, contractility, and fractional shortening and above normal LV afterload. The 45 unexposed survivors also had below normal LV mass overall, and females had below normal LV wall thickness. Exposed and unexposed survivors, compared with siblings, had higher levels of N-terminal pro-brain natriuretic peptide (81.7 and 69.0 pg/mL, respectively, v 39.4 pg/mL), higher mean fasting serum levels of non-high-density lipoprotein cholesterol (126.5 and 121.1 mg/dL, respectively, v 109.8 mg/dL), higher insulin levels (10.4 and 10.5 μU/mL, respectively, v 8.2 μU/mL), and higher levels of high-sensitivity C-reactive protein (2.7 and 3.1 mg/L, respectively, v 0.9 mg/L; P < .001 for all comparisons). Age-adjusted, predicted-to-ideal 30-year risk of myocardial infarction, stroke, or coronary death was also higher for exposed and unexposed survivors compared with siblings (2.16 and 2.12, respectively, v 1.70; P < .01 for both comparisons). CONCLUSION Childhood cancer survivors not receiving cardiotoxic treatments nevertheless have cardiovascular abnormalities, systemic inflammation, and an increased risk of atherosclerotic disease. Survivorship guidelines should address cardiovascular concerns, including the risk of atherosclerotic disease and systemic inflammation, in exposed and unexposed survivors.

How disease advocacy organizations participate in clinical research: a survey of genetic organizations.

Purpose:Disease advocacy organizations may assist in the conduct of research in a variety of ways. We sought to characterize how disease advocacy organizations participate in clinical research and perceive their contributions.Methods:Postal and electronic surveys administered to leaders of disease advocacy organizations for genetic conditions identified through the Genetic Alliance’s Disease InfoSearch.Results:Of the 201 disease advocacy organizations approached, 124 (62%) responded. In the past 2 years, 91% of these organizations had assisted in participant recruitment, 75% collected data, 60% provided a researcher with financial support, and 56% assisted with study design. Forty-five percent of these organizations also supported a research registry or biobank. Few disease advocacy organization leaders (12%) reported regrets about research studies they had supported. Most (68%) felt their involvement in clinical research had increased the amount of research on their condition and that researchers should consult organizations like theirs in deciding how to recruit participants (58%) and in selecting research topics (56%).Conclusion:In addition to providing financial support, disease advocacy organizations participate directly in multiple aspects of research, ranging from study design and patient recruitment to data collection and analysis. Leaders of these organizations feel strongly that scientists and research sponsors should engage them as partners in the conduct of clinical research.Genet Med 2012:14(2):223–228

Dietary Quality, Caloric Intake, and Adiposity of Childhood Cancer Survivors and Their Siblings: An Analysis from the Cardiac Risk Factors in Childhood Cancer Survivors Study

Childhood cancer survivors are at increased risk of cardiovascular disease, in part because of adiposity. Whether survivors have healthy diets and whether dietary quality is associated with adiposity among survivors are not known. Survivors and siblings from the Cardiac Risk Factors in Childhood Cancer Survivors Study completed 3-day food records that were used to estimate daily caloric intake relative to recommended and dietary quality using the Healthy Eating Index-2005 (HEI). Medical records were reviewed for cancer therapies. Body composition was measured by dual-energy x-ray absorptiometry. Of 91 childhood cancer survivors and 30 sibling controls, there were no marked differences in mean daily caloric intakes (98% vs. 100% of recommended) or HEI total scores (55.5 vs. 53.3), respectively, with both groups scoring worst for the consumption of dark green vegetables and whole grains. Survivors exposed to cranial irradiation had lower total HEI scores (−6.4, P = 0.01). Among survivors, better dietary quality, as reflected by the total HEI score, was associated with decreasing percent body fat (β = −0.19, P = 0.04). Survivors consume diets similar to their siblings although these diets are only moderately adherent to current guidelines. Decreased dietary quality is associated with higher body fat and receipt of cranial irradiation in survivors.

Aggregating traditional cardiovascular disease risk factors to assess the cardiometabolic health of childhood cancer survivors: an analysis from the Cardiac Risk Factors in Childhood Cancer Survivors Study.

BACKGROUND Childhood cancer survivors are at increased risk of cardiovascular disease (CVD), which may be associated with traditional CVD risk factors. We used CVD risk aggregation instruments to describe survivor cardiometabolic health and compared their results with sibling controls. METHODS Traditional CVD risk factors measured in 110 survivors and 31 sibling controls between 15 and 39 years old were aggregated using Pathobiological Determinants of Atherosclerosis in Youth (PDAY) scores and the Framingham Risk Calculator (FRC) and expressed as ratios. The PDAY odds ratio represents the increased odds of currently having an advanced coronary artery lesion, and the FRC risk ratio represents the increased risk of having a myocardial infarction, stroke, or coronary death in the next 30 years. Ratios are relative to an individual of similar age and sex without CVD risk factors. RESULTS The median PDAY odds ratio for survivors was 2.2 (interquartile range 1.3-3.3), with 17% >4. The median FRC risk ratio was 1.7 (interquartile range 1.0-2.0), with 12% >4. Survivors and siblings had similar mean PDAY odds ratios (2.33 vs 2.29, P = .86) and FRC risk ratios (1.72 vs 1.53, P = .24). Cancer type and treatments were not associated with cardiometabolic health. There was a suggested association for physical inactivity with PDAY odds ratios (r = 0.17, P = .10) and FRC risk ratios (r = 0.19, P = .12). CONCLUSIONS Cardiometabolic health is poor in childhood cancer survivors but not different than that of their siblings, highlighting the importance of managing traditional CVD risk factors and considering novel exposures in survivors.

Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis

INTRODUCTION Reduced dopaminergic activity in the pre-frontal cortex may partially explain the negative symptoms of schizophrenia. Animal models have shown that adding an alpha-2 adrenergic receptor antagonist to a D2 antagonist can efflux dopamine into the frontal cortex increasing dopaminergic activity. Trials of alpha-2 antagonist add-on therapy in humans have been limited by small sample sizes. Therefore, a meta-analysis was conducted to determine if adding an alpha-2 antagonist to a D2 antagonist improves schizophrenia treatment by reducing negative symptoms. METHODS Randomized, placebo-controlled trials of the addition of an alpha-2 antagonist to a D2 antagonist were identified through a PubMed search. Treatment effects were measured using schizophrenia rating scales and meta-analyzed as standardized mean differences using random effects models. RESULTS Eight unique studies were identified, each including 18 to 41 patients and lasting four to eight weeks. The overall effect size of add-on alpha-2 therapy across the eight trials was an improvement of 0.16 (95% C.I., -.30 to 0.62) for positive symptoms, 0.84 (95% C.I., .17 to 1.51) for negative symptoms, 0.28 (95% C.I., -.08 to 0.64) for general symptoms, and .80 (95% C.I., .15 to 1.46) for symptoms overall. Negative symptom improvements were independent of improvements in depressive symptoms, measured using the Hamilton depression rating scale, for 3 of the 5 studies. CONCLUSIONS Add-on agents with alpha-2 antagonist activity appear to improve the efficacy of D2 antagonists for the treatment of schizophrenia by reducing negative symptoms. These results support conducting a more definitive confirmatory clinical trial.

Aggregate Risk of Cardiovascular Disease Among Adolescents Perinatally Infected With the Human Immunodeficiency Virus

Background— Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. Methods and Results— Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. Conclusions— A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.

Local administration of β-blockers for infantile hemangiomas: a systematic review and meta-analysis.

BackgroundInfantile hemangiomas (IHs) are a common pediatric lesion. Orally administered &bgr;-blockers have been reported as effective in treating these lesions. However, oral administration is also associated with systemic adverse effects. Treatment with locally administered &bgr;-blockers may provide acceptable efficacy with lower incidence of adverse effects. This may offer a better first-line treatment. MethodsPubMed was searched through March 2014 for studies reporting patient-level response of 5 or more patients treated with intralesional propranolol, topical timolol, or topical propranolol for cutaneous IHs. Rates of response to treatment, defined as clinically significant regression, were combined using random-effects meta-analysis. ResultsNinety-four articles were identified. Seventeen articles met the study criteria. These studies primarily focused on superficial IHs. Response rates for topical propranolol and topical timolol were not significantly different, 76% [95% confidence interval (CI), 62%–86%] and 83% (95% CI, 65%–93%), respectively (P = 0.45). Prospectively conducted studies reported lower response rates compared to retrospective studies for both topical propranolol (P = 0.06) and topical timolol (P < 0.01). When only prospectively conducted studies were included, response rates for topical propranolol and topical timolol were not significantly different, 72% (95% CI, 57%–83%) and 72% (95% CI, 53%–86%), respectively (P = 0.98). Significant adverse effects were rare. Only 1 case of sleep disturbance was reported across 554 patients from all studies. ConclusionsTopically administered &bgr;-blockers are an effective treatment for superficial IHs that pose few adverse effects and should be considered for primary treatment.