Showing papers by "Steven E. Lipshultz published in 2002"

Long-Term Enalapril Therapy for Left Ventricular Dysfunction in Doxorubicin-Treated Survivors of Childhood Cancer

Abstract: PURPOSE: A common late effect of doxorubicin therapy for childhood cancer is reduced left-ventricular (LV) wall thickness resulting in elevated LV afterload and depressed LV function. Many children are given angiotensin-converting enzyme inhibitors, which have been studied primarily in adults. We document the long-term effects of angiotensin-converting enzyme inhibitors in doxorubicin-treated survivors of childhood cancer. PATIENTS AND METHODS: In this retrospective study, we reviewed records of 18 children who had regular echocardiographic examinations during enalapril therapy (mean age at cancer diagnosis, 8 years; mean time between completion of doxorubicin therapy and start of enalapril, 7 years; median follow-up since the start of enalapril, 10 years). RESULTS: Over the first 6 years of enalapril therapy, there was progressive improvement toward normal values in LV dimension, afterload, fractional shortening, and mass, but all these parameters deteriorated between 6 and 10 years. LV wall thickness de...

Doxorubicin Administration by Continuous Infusion Is Not Cardioprotective: The Dana-Farber 91-01 Acute Lymphoblastic Leukemia Protocol

Abstract: PURPOSE: Acute doxorubicin-induced cardiotoxicity can be prevented in adults by continuous infusion of the drug, but mechanisms of cardiotoxicity are different in children. We compared cardiac outcomes in children receiving bolus or continuous infusion of doxorubicin. PATIENTS AND METHODS: In a randomized study, children with high-risk acute lymphoblastic leukemia received doxorubicin 360 mg/m2 in 30-mg/m2 doses every 3 weeks either by bolus (within 1 hour, n = 57) or by continuous infusion (over 48 hours, n = 64). Echocardiograms obtained before doxorubicin and at longest follow-up times were centrally remeasured, and z scores of cardiac measurements were calculated based on a healthy population. RESULTS: The groups were similar in age, sex distribution, doxorubicin dose, and duration of follow-up. Before treatment, measures of left ventricular (LV) structure and function did not reveal dilated cardiomyopathy and were not statistically different between bolus and continuous-infusion groups. The follow-up...

Parameter estimation in longitudinal studies with outcome-dependent follow-up

Abstract: In many observational studies, individuals are measured repeatedly over time, although not necessarily at a set of prespecified occasions. Instead, individuals may be measured at irregular intervals, with those having a history of poorer health outcomes being measured with somewhat greater frequency and regularity; i.e., those individuals with poorer health outcomes may have more frequent follow-up measurements and the intervals between their repeated measurements may be shorter. In this article, we consider estimation of regression parameters in models for longitudinal data where the follow-up times are not fixed by design but can depend on previous outcomes. In particular, we focus on general linear models for longitudinal data where the repeated measures are assumed to have a multivariate Gaussian distribution. We consider assumptions regarding the follow-up time process that result in the likelihood function separating into two components: one for the follow-up time process, the other for the outcome process. The practical implication of this separation is that the former process can be ignored when making likelihood-based inferences about the latter; i.e., maximum likelihood (ML) estimation of the regression parameters relating the mean of the longitudinal outcomes to covariates does not require that a model for the distribution of follow-up times be specified. As a result, standard statistical software, e.g., SAS PROC MIXED (Littell et al., 1996, SAS System for Mixed Models), can be used to analyze the data. However, we also demonstrate that misspecification of the model for the covariance among the repeated measures will, in general, result in regression parameter estimates that are biased. Furthermore, results of a simulation study indicate that the potential bias due to misspecification of the covariance can be quite considerable in this setting. Finally, we illustrate these results using data from a longitudinal observational study (Lipshultz et al., 1995, New England Journal of Medicine 332, 1738-1743) that explored the cardiotoxic effects of doxorubicin chemotherapy for the treatment of acute lymphoblastic leukemia in children.

Treatment of Childhood Acute Lymphoblastic Leukemia: Results of Dana-Farber ALL Consortium Protocol 87-01

Abstract: PURPOSE: To improve efficacy and reduce toxic- ity of treatment for children with acute lymphoblas- tic leukemia. PATIENTS AND METHODS: Patients from all risk groups, including infants and those with T-cell disease, were treated between 1987 and 1991. Standard-risk (SR) patients did not receive cranial irradiation, whereas high-risk (HR) and very high-risk (VHR) patients participated in a randomized comparison of 18 Gy of cranial irradiation conventionally fractionated versus two fractions per day (hyperfractionated). RESULTS: At a median follow-up of 9.2 years, the 9-year event-free survival (EFS ± SE) was 75% ± 2% for all 369 patients, 77% ± 4% for the 142 SR patients, and 73% ± 3% for the 227 HR/VHR patients (P = .37 comparing SR and HR/VHR). The CNS, with or without concomitant bone marrow involvement, was the first site of relapse in 19 (13%) of the 142 SR patients: 16 (20%) of 79 SR boys and three (5%) of 63 SR girls. This high incidence of relapses necessitated a recall of SR boys for additional th...

Myocardial and Pericardial Disease in HIV.

Abstract: Cardiovascular complications are frequently encountered in the HIV-infected population. Cardiac care providers should implement appropriate preventive, screening, and therapeutic strategies to maximize survival and quality of life in this increasingly treatable, chronic disease. All HIV-infected individuals should undergo periodic cardiac evaluation, including echocardiography, in order to identify subclinical cardiac dysfunction. Left ventricular (LV) dysfunction can result from, or be exacerbated by, a variety of treatable infectious, endocrine, nutritional, and immunologic disorders. Aggressive diagnosis and treatment of these conditions may lead to improvement or even normalization of myocardial function. Endomyocardial biopsy should be considered to direct etiology-specific therapy. Standard measures for the prevention and treatment of congestive heart failure are recommended for HIV-infected patients. Afterload reduction with angiotensin-converting enzyme inhibitors may be indicated for patients with elevated afterload and preclinical LV dysfunction diagnosed by echocardiogram. However, judicious drug selection and titration are necessary in this cohort of patients with frequent autonomic dysfunction, at risk for a number of potentially lethal drug interactions. Carnitine, selenium, and multivitamin supplementation should be considered, especially in those with wasting or diarrhea syndromes. Monthly intravenous immunoglobulin (IVIG) infusions have been demonstrated to preserve LV parameters in HIV-infected children; ventricular recovery has been documented in some children with recalcitrant HIV-related cardiomyopathy following IVIG infusion. We support the use of immunomodulatory therapy in the pediatric population, and look forward to further study into the efficacy and broader application of this approach. Highly active antiretroviral therapy (HAART) may be associated with dyslipidemia and the metabolic syndrome. This should be treated with dietary and possibly with pharmacologic interventions. Drug interactions need to be considered when instituting pharmacologic therapies. Pericardial effusions are often seen in patients with advanced HIV infection. Asymptomatic effusions are most often nonspecific in nature, related to the proinflammatory milieu found in advanced AIDS. Nonspecific effusions are a marker of advanced disease and do not require exhaustive etiologic evaluation. In contrast, large or symptomatic effusions are often associated with infection or malignancy, and warrant thorough investigation and etiology-specific treatment.

A weighted estimating equation for linear regression with missing covariate data.

Abstract: Linear regression is one of the most popular statistical techniques. In linear regression analysis, missing covariate data occur often. A recent approach to analyse such data is a weighted estimating equation. With weighted estimating equations, the contribution to the estimating equation from a complete observation is weighted by the inverse 'probability of being observed'. In this paper, we propose a weighted estimating equation in which we wrongly assume that the missing covariates are multivariate normal, but still produces consistent estimates as long as the probability of being observed is correctly modelled. In simulations, these weighted estimating equations appear to be highly efficient when compared to the most efficient weighted estimating equation as proposed by Robins et al. and Lipsitz et al. However, these weighted estimating equations, in which we wrongly assume that the missing covariates are multivariate normal, are much less computationally intensive than the weighted estimating equations given by Lipsitz et al. We compare the weighted estimating equations proposed in this paper to the efficient weighted estimating equations via an example and a simulation study. We only consider missing data which are missing at random; non-ignorably missing data are not addressed in this paper.

Evaluation of coxsackievirus infection in children with human immunodeficiency virus type 1-associated cardiomyopathy

Abstract: Coxsackievirus group B infects 10 million US citizens annually, with most infections occurring among children <5 years old. Coxsackievirus serotypes B2, B3, and B4 are endemic in the United States, whereas serotypes B1 and B5 occur in epidemic patterns [1]. Although only 10% of enterovirus infections result in clinical illness, at least 5% of patients may experience cardiac infection, and an unknown proportion will develop myocarditis. The prevalence of myocarditis in the general population at autopsy is 1%–4% [2]. Coxsackieviruses are present in 40%– 50% of hearts with myocarditis or dilated cardiomyopathy, with coxsackievirus B3 being the most common [3]. A higher proportion of patients with chronic myocarditis or dilated cardiomyopathy than patients with heart diseases of other infectious etiologies have antibodies to coxsackievirus B [2, 3]. Cardiac impairment with dysrhythmias and hemodynamic abnormalities occurs frequently in children with human immunodeficiency virus (HIV) type 1 infection [4–6]. Children infected with HIV-1 provide a better opportunity to identify a causal role of coxsackieviruses with HIV-1–associated cardiomyopathy than do adults, since there may be fewer confounding factors affecting cardiac function in children. A matched case-control study was done among 24 HIV-1–infected children with cardiac impairment and 24 HIV-1–infected control subjects without cardiac impairment, to identify differences in coxsackieviruses infection rates and associated immune response as possible risk factors for cardiac impairment.

Treatment o f C hildhood A cute L ymphoblastic L eukemia: Results o f D ana-Farber A LL C onsortium P rotocol 8 7-01

Abstract: Purpose: To improve efficacy and reduce toxicity of treatment for children with acute lymphoblastic leukemia. Patients and Methods: Patients from all risk groups, including infants and those with T-cell disease, were treated between 1987 and 1991. Standard-risk (SR) patients did not receive cranial irradiation, whereas high-risk (HR) and very high-risk (VHR) patients participated in a randomized comparison of 18 Gy of cranial irradiation conventionally fractionated versus two fractions per day (hyperfractionated). Results: At a median follow-up of 9.2 years, the 9-year event-free survival (EFS SE) was 75% 2% for all 369 patients, 77% 4% for the 142 SR patients, and 73% 3% for the 227 HR/VHR patients (P .37 comparing SR and HR/VHR). The CNS, with or without concomitant bone marrow involvement, was the first site of relapse in 19 (13%) of the 142 SR patients: 16 (20%) of 79 SR boys and three (5%) of 63 SR girls. This high incidence of relapses necessitated a recall of SR boys for additional therapy. CNS relapse occurred in only two (1%) of 227 HR and VHR patients. There were no outcome differences found among randomized treatment groups. Nine-year overall survival was 84% 2% for the entire population, 93% 2% for SR children, and 79% 3% for HR and VHR children (P < .01 comparing SR and HR/VHR). Conclusion: A high overall survival outcome was obtained for SR patients despite the high risk of CNS relapse for SR boys, which was presumed to be associated with eliminating cranial radiation without intensifying systemic or intrathecal chemotherapy. For HR/ VHR patients, inability to salvage after relapse (nearly all of which were in the bone marrow) remains a significant clinical problem. J Clin Oncol 20:237-246. © 2001 by American Society of Clinical Oncology.