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Biomedical subjects

N Breslow

Publications and source records attributed to N Breslow.

At least 19 recordsLinked to original sources
PubMed2001

Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: a report from the National Wilms Tumor Study Group.

PURPOSE: This review characterized cases of secondary acute myelogenous leukemia (AML) occurring after treatment of renal neoplasms on protocols of the National Wilms Tumor Study Group (NWTSG) between October 1969 and December 1991. PATIENTS AND METHODS: The NWTSG database was reviewed for cases of secondary AML and for WT1 status of the affected patients. Referring institutions were contacted by a confidential letter requesting pathology reports, results of immunophenotyping, cytogenetic, and molecular analyses, and details concerning treatment of AML. RESULTS: Of the 5,278 patients treated during the study period, 43 had second malignant neoplasms, and 7 of these 43 had AML. At the time of diagnosis of Wilms tumor, the median age of the seven patients (4 boys) was 3.2 years. Five of the seven renal neoplasms had favorable histologic characteristics. The most common French-American-British morphology was M5. One patient had bilateral tumors, and two were treated for recurrent Wilms tumor. All patients received chemotherapy regimens that included doxorubicin (6) or etoposide (1), and six were treated with infradiaphragmatic irradiation. The median latency period from initial diagnosis of the renal neoplasm to development of secondary AML was 3 years (range, 1.2-4 yrs). One patient had the translocation t(9:11)(p22;q23); WT1 status was not noted for any of the seven patients. CONCLUSIONS: The development of secondary AML in this subset of patients after treatment of renal neoplasms may reflect the interaction of the effects of treatment and possible genetic predisposition toward cancer.

Abnormalities, Multiple↗
PubMed2000

What does a single determination of malaria parasite density mean? A longitudinal survey in Mali.

Temporal variations of blood parasite density were evaluated in a longitudinal study of young, asymptomatic men in a village with endemic malaria in Mali (West Africa). Our main intention was to challenge the value of a single measure of parasite density for the diagnosis of malaria, and to define the level of endemicity in any given area. Parasitaemia and body temperature were recorded three times a day in the wet season (in 39 subjects on 12 days) and in the dry season (in 41 subjects on 13 days). Two thousand nine hundred and fifty seven blood smears (98.5% of the expected number) were examined for malaria parasites. We often found 100-fold or greater variations in parasite density within a 6-hour period during individual follow-up. All infected subjects had frequent negative smears. Although fever was most likely to occur in subjects with a maximum parasite density exceeding 10000 parasites/mm3 (P = 0.009), there was no clear relationship between the timing of these two events. Examples of individual profiles for parasite density and fever are presented. These variations (probably due to a 'sequestration-release' mechanism, which remains to be elucidated) lead us to expect a substantial impact on measurements of endemicity when only a single sample is taken. In this study, the percentage of infected individuals varied between 28.9% and 57.9% during the dry season and between 27.5% and 70.7% during the wet season. The highest rates were observed at midday, and there were significant differences between days. Thus, high parasite density sometimes associated with fever can no longer be considered as the gold standard in the diagnosis of malaria. Other approaches, such as decision-making processes involving clinical, biological and ecological variables must be developed, especially in highly endemic areas where Plasmodium infection is the rule rather than the exception and the possible causes of fever are numerous.

Adult↗
PubMed2000

Characteristics and outcome of children with Beckwith-Wiedemann syndrome and Wilms' tumor: a report from the National Wilms Tumor Study Group.

PURPOSE: Children with Beckwith-Wiedemann syndrome (BWS) are at increased risk for developing Wilms' tumor (WT). We reviewed the National Wilms Tumor Study Group (NWTSG) records to assess clinical characteristics and outcome of patients with WT and BWS. METHODS: In the NWTSG, treating clinicians were asked to report, for each enrolled patient, whether the patient had BWS. Between 1980 and 1995, 4,669 patients were treated on two consecutive NWTSG protocols (NWTS 3 and NWTS 4). We retrospectively reviewed the clinical characteristics and treatment outcomes of BWS patients compared with patients with WT without BWS. RESULTS: Fifty-three children enrolled onto NWTS 3 and 4 were reported to have BWS. BWS patients were more likely to present with lower-stage tumors (P =.0001), with more than half (27 of 53) presenting with stage I disease. The overall treatment outcomes for the BWS patients were nearly identical to those without BWS, with overall survival at 4 years from diagnosis at 89% and 90%, respectively. Overall, 21% of the patients with BWS had bilateral disease, either at diagnosis (nine of 53) or as metachronous contralateral recurrence (two of 53). BWS patients enrolled onto NWTS 4 had smaller tumors than those enrolled onto NWTS 3 (P =.02), a trend not seen in the non-BWS patients. CONCLUSION: Like children without BWS, children with BWS and WT have an excellent prognosis with modern treatment regimens. There is a high risk of bilateral disease, and increasingly smaller tumors are being detected. This suggests that a national trial assessing the role of ultrasound screening followed by nephron-sparing surgery for some patients may be appropriate.

Beckwith-Wiedemann Syndrome↗
PubMed1999

Generalized linear mixed models for meta-analysis.

We examine two strategies for meta-analysis of a series of 2 x 2 tables with the odds ratio modelled as a linear combination of study level covariates and random effects representing between-study variation. Penalized quasi-likelihood (PQL), an approximate inference technique for generalized linear mixed models, and a linear model fitted by weighted least squares to the observed log-odds ratios are used to estimate regression coefficients and dispersion parameters. Simulation results demonstrate that both methods perform adequate approximate inference under many conditions, but that neither method works well in the presence of highly sparse data. Under certain conditions with small cell frequencies the PQL method provides better inference.

Humans↗
PubMed1998

Approximate hierarchical modelling of discrete data in epidemiology.

Hierarchical models are used in epidemiology to estimate and analyse multiple, related relative risks. Examples include meta-analyses of series of 2 x 2 tables and mapping of spatially correlated disease rates. Empirical transform and penalized quasilikelihood procedures, both of which may be implemented using standard programs for mixed model analysis, provide satisfactory approximate inferences for these problems when cell frequencies are large. Simulation studies show that, in certain situations involving small cell frequencies, penalized quasilikelihood provides satisfactory estimates of variance components and regression coefficients whereas the empirical transform approach does not.

BCG Vaccine↗
PubMed1998

Constitutional WT1 mutations in Wilms' tumor patients.

PURPOSE: Patients with Wilms' tumors (WT) who carry constitutional mutations in the WT1 gene have been described in case reports and small case series. We sought to determine the frequency of constitutional WT1 mutations in a larger cohort, and to identify clinical manifestations associated with the risk for carrying a WT1 mutation. METHODS: We collected clinical data and blood samples from 201 patients with a history of WT. Southern blot analysis, single-strand conformation polymorphism (SSCP) analysis, and direct DNA sequencing were performed on DNA isolated from peripheral-blood lymphocytes from each patient. Odds ratios (ORs) for the carriage of a germline mutation of the WT1 gene were calculated for patients who had specific clinical risk factors compared with those who did not. RESULTS: Of 201 patients with WT in the cohort, eight patients were carriers of mutations in the WT1 gene. Six of the eight mutations were protein-truncating nonsense mutations. None of 56 patients with isolated unilateral WT was a carrier. The OR of carrying a WT1 mutation was elevated for patients with genitourinary anomalies (OR19.3; P < .002). Seven of 28 boys with WT with cryptorchidism carried WT1 mutations. No increased risk was observed for patients with nephrogenic rests, bilateral tumors, history of secondary cancers, or family history of WT. CONCLUSION: Germline WT1 mutations in patients with WT are associated with genitourinary anomalies, especially cryptorchidism and/or hypospadias. Patients with WT and no genitourinary anomalies are at low risk for carrying a WT1 mutation. Constitutional WT1 mutations that encode truncated WT1 proteins may predispose to the development of cryptorchidism, hypospadias, and WTs.

Adolescent↗
PubMed1997

Seasonality and malaria in a west African village: does high parasite density predict fever incidence?

In this cohort study, the authors studied the effect of blood malaria parasite density on fever incidence in children in an endemic area with 9 days' follow-up of 1- to 12-year-old children during two time periods: the end of the dry season (May 1993: n = 783) and the end of the rainy season (October 1993: n = 841) in Bougoula, West Africa (region of Sikasso, Mali). The cumulative incidence of fever (temperature > 38.0 degrees C) was 2.0% in the dry season and 8.2% in the rainy season (p < 0.0001). In the rainy season, the risk of fever was increased in children of ages 1-3 years (relative risk (RR) = 2.5, 95% confidence interval (CI) 1.6-4.1); in those with an initial parasitemia > 15,000/microliter (RR = 2.7, 95% CI 1.4-5.4); in children with an enlarged spleen (RR = 2.0, 95% CI 1.2-3.3); or in those with anemia (hematocrit < 30%: RR = 1.8, 95% CI 1.1-2.9). In the dry season, anemia was the only predictor of fever incidence. In the rainy season, the best predictors of fever were, in order, age (< 4 years), enlarged spleen, and high parasite density. Even in the higher risk groups, the cumulative incidence was < 20%. The authors conclude that most children with high parasite density do not develop fever subsequently. The association between parasite density and fever varies according to age and season. Since even high levels of parasite density do not reliably predict fever incidence, parasite density should be considered as just one of a group of indicators that increase the probability of a fever of malarial origin.

Africa, Western↗
PubMed1997

Seasonality, malaria, and impact of prophylaxis in a West African village I. Effect of anemia in pregnancy.

The importance of malaria as a cause of anemia in pregnancy in endemic areas remains controversial. The prevalence of anemia in pregnant women following the dry (May) and the rainy (November) seasons was compared in two successive years in Bougoula village (region of Sikasso, Mali). Phase I (1992) was observational and included 172 pregnant women and 208 controls. In Phase II (1993, 174 pregnant women and 206 controls), malaria prophylaxis with proguanil (200 mg/day) and chloroquine (300 mg/week) was offered to pregnant women. A strong seasonal variation in the prevalence of moderate to severe anemia in pregnant women (hematocrit < 30%) occurred in Phase I (dry season = 8.7%, rainy season = 41.2%). This variation was present only in women of parity lower than five, and paralleled variation in parasitemia. In Phase II, the seasonal variation of anemia was suppressed in women under malaria prophylaxis (presence of antimalarial metabolites in urine), and the overall prevalence of moderate to severe anemia in pregnancy decreased by 55.5% (22.8-74.3%). We conclude that malaria is the major cause of anemia in pregnancy in this region. A high priority should be given to prevention of malaria in pregnancy.

Adolescent↗
PubMed1997

Seasonality, malaria, and impact of prophylaxis in a West African village. II. Effect on birthweight.

The impact of malaria on low birthweight was investigated in Bougoula village (Sikasso region, Mali). In two successive years, pregnant women were followed until delivery. Phase I (1992) was observational, with 135 complete observations. Phase II (1993) included 126 participants, who were offered malaria prophylaxis with proguanil (200 mg/day) and chloroquine (300 mg/week). The results show that 1) infants of first and second pregnancies had lower birth weights (-382.7 +/- 62.6 g; P < 0.0001) compared with higher rank pregnancies; 2) strong seasonal variation in birthweight was observed in Phase I, with an annual cycle, a nadir in January, and an amplitude of 372.4 g (P = 0.0002); 3) parasitemia measured during pregnancy was associated with lower birthweight in infants from first and second pregnancies, but not from higher parity mothers; and 4) malaria prophylaxis taken for 20 weeks or more in Phase II suppressed the seasonal variation of birthweight and the effect of low parity (+423.4 +/- 118.8 g; P = 0.0004). We conclude that malaria in pregnancy has an important negative impact on birthweight in first and second pregnancies. Prophylaxis with proguanil and chloroquine is an effective prophylaxis when taken for 20 weeks or more.

Adult↗
PubMed1996

Focal versus diffuse anaplasia in Wilms tumor--new definitions with prognostic significance: a report from the National Wilms Tumor Study Group.

Anaplasia, defined by the presence of extreme nuclear and mitotic atypia, is a potent marker of adverse prognosis in Wilms tumor (WT). Anaplastic WT cells apparently have increased resistance to therapy rather than increased aggressiveness. The distribution of anaplasia should therefore have critical prognostic relevance. The original definitions for focal anaplasia (FA) and diffuse anaplasia (DA) were based on quantitative rather than topographical criteria and lacked prognostic significance. A new definition was developed based on the distribution of anaplastic changes within the tumor: FA applies only to tumors with anaplasia confined to one or a few discrete loci within the primary tumor, with no anaplasia or marked nuclear atypia elsewhere. This revised definition was evaluated in 165 cases with anaplastic WT entered on the third and fourth National Wilms Tumor Study. Only three relapses and one death occurred among 39 cases with FA, regardless of tumor stage, a result comparable to that for nonanaplastic WT. Eight children with metastases at diagnosis and FA in the primary tumor were alive and free of relapse; 22 of 23 children with stage IV DA WT died of tumor. This new definition reinforces the importance of carefully documenting the exact site from which each tumor section is obtained.

Anaplasia↗
PubMed1996

A comparison of three statistical models for IDDM associations with HLA.

The association between HLA-DQ haplotypes and insulin-dependent diabetes mellitus (IDDM) was studied in 48 children from 44 families ascertained from the high incidence area around Umeå, Sweden. Numerous hypotheses have been proposed to explain associations between HLA and IDDM, but comparisons of statistical models based on these hypotheses have not been attempted. The aim of the present study was to compare the goodness-of-fit and predictive abilities among different statistical models. A likelihood-based analysis rather than a conventional analysis based on contingency tables was therefore adopted. We first used parental haplotype information in a conditional likelihood analysis (1) and then compared this analysis with that of an unaffected control group which used information on geographically matched controls. Under the analysis conditional on parental haplotype, a statistical model motivated by the hypothesis that the entire DQ heterodimer is involved in IDDM pathogenesis fit the data significantly better and had greater predictive ability than either a model motivated by the explanation that an IDDM gene is linked to DQB1 or that the DQB1 chain itself is involved in IDDM pathogenesis, or a model arising from the hypothesis that single amino acids at codon 57 of DQB1 and codon 52 of DQA1, respectively, confer susceptibility. Under the case-control analysis, the identity of the best-fitting or more predictive statistical model was not as clear, although both approaches to analyzing risk suggested that the single-amino-acids model had significantly poorer fit compared to the remaining two models.

Diabetes Mellitus, Type 1↗
PubMed1995

Epidemiologic features of Wilms tumor.

The elucidation of factors involved in the development of Wilms tumor represents a remarkable and fruitful marriage between epidemiology, clinical practice, histopathology, and molecular biology. Many fascinating research problems remain to be solved, and it is to be expected that the study of Wilms tumor will continue to yield valuable insights, not only in relation to Wilms tumor itself but also into tissue development and processes involved in malignant transformation in general.

Female↗
PubMed1994

Loss of heterozygosity for chromosomes 16q and 1p in Wilms' tumors predicts an adverse outcome.

We have prospectively analyzed Wilms' tumors from 232 patients registered on the National Wilms' Tumor Study for loss of heterozygosity (LOH) on chromosomes 11p, 16q, and 1p. These chromosomal aberrations were found in 70 (33%), 35 (17%), and 21 (12%) of the informative cases, respectively. LOH for two of these regions occurred in only 25 cases, and only one tumor harbored LOH at all three sites. There was no statistically significant association between LOH at any of the three regions and either the stage or histological classification of the tumor. Patients with tumor-specific LOH for chromosome 16q had relapse rates 3.3 times higher (P = 0.01) and mortality rates 12 times higher (P < 0.01) than patients without LOH for chromosome 16q. These differences remained when adjusted for histology or for stage. Patients with LOH for chromosome 1p had relapse and mortality rates three times higher than those for patients without LOH for chromosome 1p, but these results were not statistically significant. In contrast, LOH for chromosome 11p had no effect on measures of outcome. These molecular markers may serve to further stratify Wilms' tumor patients into biologically favorable and unfavorable subgroups, allowing continued use of the clinical trial mechanism in the study of Wilms' tumor.

Chromosome Deletion↗
PubMed1993

Epidemiology of Wilms tumor.

Wilms tumor affects approximately one child per 10,000 worldwide before the age of 15 years. Incidence rates appear to be slightly elevated for U.S. and African Blacks in comparison to Whites, but are only half as great among Asians. Several case-control studies have suggested that paternal occupational or maternal hormonal exposures during pregnancy may increase the risk of Wilms tumor, but small numbers of subjects and inconsistencies in the patterns of exposures do not permit firm conclusions to be drawn. It is unlikely that such environmental exposures play a major role in the etiology of Wilms tumor. The median age-at-onset of Wilms tumor is 38 months in the U.S. National Wilms Tumor Study series, with cases in girls occurring on average 6 months later than in boys. Patients with bilateral tumors, aniridia, cryptorchism/hypospadias, Beck-with-Wiedemann syndrome, or intralobar nephrogenic rests tend to be diagnosed much younger than average (median 17-27 months). Those with familial disease or multicentric tumors have intermediate age-at-onset distributions, while those with perilobar nephrogenic rests are diagnosed at older ages. The epidemiologic features suggest that somatic mosaicism, rather than a germline mutation, may be responsible for some of the bilateral and multicentric cases.

Africa↗
PubMed1993

Position paper: imaging methods for primary renal tumors of childhood: costs versus benefits.

The patterns of disease distribution at diagnosis and during follow-up were cataloged for the primary renal tumors of childhood. These data, derived from more than 1,500 patients, were used to define the most rewarding and cost-effective imaging methods required for patient management. The basic information needed prior to surgery includes whether there is a functioning kidney on the opposite side, and whether there are lung metastases or inferior vena cava thrombi. Simple X-ray examinations and ultrasonography (US) will provide the necessary data. Postoperatively, when the histology is known, examination of the brain (MRI or CT scan) is needed for patients with the rhabdoid tumor and clear cell sarcoma of the kidney (CCSK) who are prone to develop brain lesions; and the skeletal system (bone scan, X-ray skeletal survey) for CCSK and for renal cell carcinoma patients who tend to develop bone metastases. Continuing examination of the lung (chest films) is required for all histologies except perhaps for mesoblastic nephroma, which seldom metastasizes. The opposite kidney needs follow-up (US) for 5 or more years to exclude metachronous involvement if nephrogenic rests are present in either kidney. Sophisticated imaging studies, which cost five times or more than simple X-ray examinations or US, are not warranted routinely, and should be reserved for those cases where simpler, less expensive studies do not suffice for reaching patient management decisions.

Bone Neoplasms↗
PubMed1993

Health practices and disability: some evidence from Alameda County.

With greater longevity people are increasingly concerned about how to avoid disability during their longer lives. Policy decisions concerning ways to extend health as well as life have become part of the nation's health agenda. Opportunity to examine that issue has arisen in the Alameda County Human Population Laboratory. Earlier studies there established seven health practices as risk factors for higher mortality: excessive alcohol consumption, smoking cigarettes, being obese, sleeping fewer or more than 7-8 hours, having very little physical activity, eating between meals, and not eating breakfast. Observation now reveals that, taking into account age, gender, physical health status, and social network index in 1965, the occurrence of disability was only about one-half as great among the cohort survivors in 1974 who reported good health practices in 1965 as among those with poor health practices; those with an intermediate level of health practices experienced about two-thirds the relative disability risk of those with poor health practices. Essentially similar relationships prevailed for the 1982/1983 survivors of the original (1965) cohort who, upon requestioning, had been found to be without disability in 1974.

Adult↗