Tumor response and toxicity with multiple infusions of high dose 131I-MIBG for refractory neuroblastoma

BACKGROUND: (131)I Metaiodobenzylguanidine ((131)I-MIBG) is an effective targeted radiotherapeutic for neuroblastoma with response rates greater than 30% in refractory disease. Toxicity is mainly limited to myelosuppression. The aim of this study was to determine the response rate and hematologic toxicity of multiple infusions of (131)I-MIBG. PROCEDURE: Patients received two to four infusions of (131)I-MIBG at activity levels of 3-19 mCi/kg per infusion. Criteria for subsequent infusions were neutrophil recovery without stem cell support and lack of disease progression after the first infusion. RESULTS: Sixty-two infusions were administered to 28 patients, with 24 patients receiving two infusions, two patients receiving three infusions, and two patients receiving four infusions. All patients were heavily pre-treated, including 16 with prior myeloablative therapy. Eleven patients (39%) had overall disease response to multiple therapies, including eight patients with measurable responses to each of two or three infusions, and three with a partial response (PR) after the first infusion and stable disease after the second. The main toxicity was myelosuppression, with 78% and 82% of patients requiring platelet transfusion support after the first and second infusion, respectively, while only 50% had grade 4 neutropenia, usually transient. Thirteen patients did not recover platelet transfusion independence after their final MIBG infusion; stem cell support was given in ten patients. CONCLUSIONS: Multiple therapies with (131)I-MIBG achieved increasing responses, but hematologic toxicity, especially to platelets, was dose limiting. More effective therapy might be given using consecutive doses in rapid succession with early stem cell support.     

Expectation of pregnancy outcome among mature women

OBJECTIVE: Increasing numbers of mature women are achieving pregnancy largely through assisted reproductive technology (ART). Our objective was to investigate women over 45 years of age to determine the impact of pregnancy complications on newborn outcome. STUDY DESIGN: A study of women older than 45 years at their estimated date of confinement (EDC) was compared with a control group under 36 years at their EDC, matched by parity and plurality. All study patients and controls received uniform obstetric management through a single maternal fetal practice. The primary outcome was gestational age at birth stratified by plurality; secondary outcomes included birth weight, NICU days, composite neonatal morbidity, and a variety of obstetric complications. Wilcoxon signed rank and McNemar's tests were used as appropriate; logistic regression was used to calculate odds ratios (ORs) and CIs. Statistical significance was assumed for P < .05. RESULTS: Fifty study and control patients were identified over a 5-year period. Study patients were older than controls, but the difference in "gamete" age was not significant. There was significantly more assisted reproduction (donor egg) and preeclampsia among study patients. Importantly, gestational age at birth and birth weights stratified by plurality were not different (86% power to detect 2-week gestational age difference, alpha 0.05). Hospital days, NICU days, and composite neonatal morbidity were not different between study patients and controls. CONCLUSION: When controlled for parity and plurality, mature women over 45 years conceiving largely through ART with donor eggs can expect newborn outcomes similar to younger women cared for in the same setting of a high-risk maternal-fetal practice.     

Incidence of Churg-Strauss syndrome in asthma drug users: a population-based perspective

OBJECTIVE: To estimate the incidence of Churg-Strauss syndrome (CSS) among a large population of asthma drug users. METHODS: A retrospective study was conducted among patients who had been dispensed asthma drugs at 3 managed care organizations. Adults who received >or =3 dispensings of an asthma drug during any consecutive 12-month period between January 1, 1995 and June 30, 2000 were identified. Information on patient age, gender, enrollment status, asthma drugs dispensed, and inpatient and outpatient diagnoses and procedures was obtained from automated databases. Chart reviews were performed on persons identified by combinations of diagnostic and billing codes indicative of CSS. A rheumatologist reviewed abstracted information on all subjects; those who met >or =2 American College of Rheumatology criteria for CSS were reviewed by 2 clinical experts. Each clinical expert independently rated the cases; disagreements were resolved by consensus. Cases classified as having "probable/definite" CSS were included in these analyses. The incidence of CSS was estimated overall and according to patient gender, age, and calendar year. RESULTS: From a population of 184,667 asthma drug users contributing 606,184 person-years of exposure, 21 incident cases of CSS were identified (overall incidence of 34.6 per million person-years; 95% confidence interval 21.4 to 53.0). Incidence rates did not differ by gender and age group. The incidence rates for 1995, 1996, 1997, 1998, 1999, and the first 6 months of 2000 were 0, 22, 52, 75, 14, and 14 per million person-years respectively. CONCLUSIONS: Results from this population-based study suggest a somewhat lower incidence of CSS in asthma drug users than previously reported and provides important information as to the risk of developing CSS from a population-based perspective.     

Factors affecting rheumatoid arthritis patients' decisions to participate in clinical trials

OBJECTIVE: To delineate the personal, psychosocial, and disease-related factors that may influence rheumatoid arthritis (RA) patients' decisions to participate in clinical trials. METHODS: A total of 191 patients with RA were asked to participate in this survey. The questionnaire collected information on demographics, RA disease-related factors, and the importance of several factors that might influence patients' willingness to participate in clinical trials. Patients were then asked if they would consider participating in a hypothetical study. RESULTS: Participants were 88% female with a mean age of 40.5 years. The ethnic composition was 57% Hispanic, 25% Caucasian, 12% Asian, and 6% African American, with 71% having a family income < $20,000/year. Factors that patients considered important for participation in a clinical study included: the opportunity to help others, the possibility of improved health, early access to new therapy, the availability of free treatments, unknown side effects of the study drug, and the need to stop current therapy. There were strong correlations between the rank order importance weights between Hispanics and Caucasians, suggesting fundamental similarities in preferences. The most important factor was the opportunity to help others. In general, the more important factors were associated with preferences for trial participation. CONCLUSION: This questionnaire identified factors that may affect RA patients' willingness to participate in a study. Patient participation in trials is driven by diverse factors that include altruism and the opportunity for healthcare and improved health. Consideration of these factors may facilitate the inclusion of more diverse patient populations into trials and enhance the applicability of trial results.     

Unifying the spatial population dynamics and molecular evolution of epidemic rabies virus

Infectious disease emergence is under the simultaneous influence of both genetic and ecological factors. Yet, we lack a general framework for linking ecological dynamics of infectious disease with underlying molecular and evolutionary change. As a model, we illustrate the linkage between ecological and evolutionary dynamics in rabies virus during its epidemic expansion into eastern and southern Ontario. We characterized the phylogeographic relationships among 83 isolates of fox rabies virus variant using nucleotide sequences from the glycoprotein-encoding glycoprotein gene. The fox rabies virus variant descended as an irregular wave with two arms invading from northern Ontario into southern Ontario over the 1980s and 1990s. Correlations between genetic and geographic distance suggest an isolation by distance population structure for the virus. The divergence among viral lineages since the most recent common ancestor correlates with position along the advancing wave front with more divergent lineages near the origin of the epidemic. Based on divergence from the most recent common ancestor, the regional population can be partitioned into two subpopulations, each corresponding to an arm of the advancing wave. Subpopulation A (southern Ontario) showed reduced isolation by distance relative to subpopulation B (eastern Ontario). The temporal dynamics of subpopulation A suggests that the subregional viral population may have undergone several smaller waves that reduced isolation by distance. The use of integrated approaches, such as the geographical analysis of sequence variants, coupled with information on spatial dynamics will become indispensable aids in understanding patterns of disease emergence.     

A data integration methodology for systems biology

Different experimental technologies measure different aspects of a system and to differing depth and breadth. High-throughput assays have inherently high false-positive and false-negative rates. Moreover, each technology includes systematic biases of a different nature. These differences make network reconstruction from multiple data sets difficult and error-prone. Additionally, because of the rapid rate of progress in biotechnology, there is usually no curated exemplar data set from which one might estimate data integration parameters. To address these concerns, we have developed data integration methods that can handle multiple data sets differing in statistical power, type, size, and network coverage without requiring a curated training data set. Our methodology is general in purpose and may be applied to integrate data from any existing and future technologies. Here we outline our methods and then demonstrate their performance by applying them to simulated data sets. The results show that these methods select true-positive data elements much more accurately than classical approaches. In an accompanying companion paper, we demonstrate the applicability of our approach to biological data. We have integrated our methodology into a free open source software package named POINTILLIST.     

Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using a multimedia training video and CD-ROM we developed after a two-step validation process. We hypothesized that use of CD-ROM interactive training will lead to reliable and valid performance of the neurologic examination by both pediatric neurologists and nonpediatric neurologists. All examiners were asked to take one of six interobserver variability tests found on the CD-ROM on two occasions. In the first interobserver variability evaluation, 89% (531 of 594) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the two items that had a 60% correct rate, the correct response rate rose to 93% (114 of 123). In the second interobserver variability evaluation, 88% (493 of 560) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the four items that had a 70% correct rate, the correct response rate rose to 96% (104 of 108). Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children. It provides an effective means to evaluate interobserver variability, offers a route for feedback, and creates an opportunity to reevaluate variability, both immediately and at periodic intervals.     

Diagnosis of hypertension and high blood pressure levels negatively affect cognitive function in older adults

bdBackground: Hypertension is associated with diminished performance on tests of cognitive function. The degree to which those diagnosed with hypertension have controlled blood pressure (BP) levels may be a critical determinant of cognitive outcomes. Persons with hypertension and poorly controlled BP are likely to display the worst performance on cognitive tests.Purpose: The purpose is to examine potential interactive relations of hypertension diagnostic status and current BP levels to cognitive function.Methods: Participants were 101 healthy older adults (ages 53–84, 62% male, 90% White, 29% diagnosed with hypertension) who engaged in biomedical and neuropsychological assessment.Results: After statistical adjustment for age and education, persons with high BP performed more poorly than those with normal BP on the Visual Reproductions—Immediate and Delayed Recall and the Grooved Pegboard tests. Diagnosed hypertension was related to poorer performance on the Grooved Pegboard tests. An interaction of diagnosed hypertension and BP level revealed that those diagnosed with hypertension and also having poorly controlled BP levels performed least well on the Grooved Pegboard tests and the Trail Making Test-Part A.Conclusion: Irrespective of prior diagnostic status, individuals with high BP displayed compromised performance on tests of nonverbal memory, motor speed, and manual dexterity. However, as compared to the other groups, those diagnosed with hypertension and also having poorly controlled BP elevation were most vulnerable to difficulties on tests of perceptuo-motor speed, motor speed, and manual dexterity. These findings suggest the need for increased attention to preventative efforts with respect to BP assessment and control in older adults to help preserve cognitive function. Karl J. Maier is now in the Department of Psychology at Salisbury University. This work was supported by National Institutes of Health Grant R29 AG15112, and K24 AG00930; a VA Merit Grant, Bristol Myers Squibb Medical Imaging, Inc., the Department of Veterans Affairs Baltimore Geriatric Research Education and Clinical Center; and the Geriatrics and Gerontology Education and Research Program of the University of Maryland, Baltimore. We thank Denise Cooper, Karen Gibbs, Layne Goble, Joseph Snow, and Carol Tankard for their assistance with data collection.     

An updated review of the long-term neurological effects of galactosemia

Classical galactosemia is an autosomal recessive condition in which there is near total absence of the activity of galactose-1-phosphate uridyltransferase. Patients with this condition have substantial motor, cognitive, and psychiatric impairments despite dietary treatment. A characteristic pattern of biochemical abnormalities is observed in patients with this disorder. Galactose-1-phosphate, the substrate of galactose-1-phosphate uridyltransferase, accumulates within cells, and surplus galactose is reduced to galactitol or oxidized to galactonate. Using sophisticated mass spectrometry, these compounds as well as free galactose can be measured in plasma and in urine. It is clear that initiation of dietary restriction of galactose in the newborn period produces reversal of hepatic, renal, brain, and immune dysfunction, along with reduction of the accumulated galactose metabolites. However, the neurologist should be aware that chronic and progressive neurologic impairments occur even in patients spared these neonatal symptoms. The purpose of this review is to summarize current information about neurologic complications of galactosemia and what is known, and still unknown, about its pathophysiology.