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Biomedical subjects

W D Dupont

Publications and source records attributed to W D Dupont.

At least 19 recordsLinked to original sources
PubMed1999

Estrogen replacement therapy in women with a history of proliferative breast disease.

BACKGROUND: Little information is available regarding the invasive breast carcinoma risk associated with estrogen replacement therapy (ERT) in women with histories of histologically defined breast lesions. METHODS: A retrospective cohort study of a consecutive series of women who underwent breast biopsies that proved to be benign between 1952-1978 was conducted. Follow-up data were obtained for 9494 women (87.6% of women eligible for follow-up). To investigate the effect of ERT on invasive breast carcinoma risk, the analysis was restricted to women with premenopausal breast disease whose follow-up extended through menopause and who did not develop premenopausal breast carcinoma. Relative risks were calculated with respect to women who took ERT but whose benign breast biopsies had neither atypical hyperplasia (AH), complex fibroadenoma (CFA), nor proliferative disease without atypia (PDWA). RESULTS: During 190,845 woman-years of follow-up there were 444 confirmed cases of invasive breast carcinoma in the entire cohort. Women with a history of AH had relative risks of invasive breast carcinoma of 2.87 (95% confidence interval [95% CI], 1.3-6.3) and 2.53 (95% CI, 1.0-6.3) if they did or did not take ERT, respectively. For women with a history of CFA these risks were 1.57 (95% CI, 0.72-3.4) and 1.46 (95% CI, 0.53-4.0), respectively, whereas for women with a history of PDWA they were 1.37 (95% CI, 0.88-2.1) and 1.13 (95% CI, 0.69-1.9), respectively. CONCLUSIONS: ERT does not significantly elevate the risk of invasive breast carcinoma in women with previous histologically defined benign breast disease. Therefore, ERT is not contraindicated in these women.

Adult↗
PubMed1999

Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group.

OBJECTIVES: The objective was to compare the clinical and physiologic characteristics of febrile septic patients with hypothermic septic patients; and to examine plasma levels of cytokines tumor necrosis factor alpha (TNF-alpha and interleukin 6 (IL-6) and the lipid mediators thromboxane B2 (TxB2) and prostacyclin in hypothermic septic patients in comparison with febrile patients. Most importantly, we wanted to report the effect of ibuprofen treatment on vital signs, organ failure, and mortality in hypothermic sepsis. SETTING: The study was performed in the intensive care units (ICUs) of seven clinical centers in the United States and Canada. PATIENTS: Four hundred fifty-five patients admitted to the ICU who met defined criteria for severe sepsis and were suspected of having a serious infection. INTERVENTION: Ibuprofen at a dose of 10 mg/kg (maximum 800 mg) was administered intravenously over 30 to 60 mins every 6 hrs for eight doses vs. placebo (glycine buffer vehicle). MEASUREMENTS AND MAIN RESULTS: Forty-four (10%) septic patients met criteria for hypothermia and 409 were febrile. The mortality rate was significantly higher in hypothermic patients, 70% vs. 35% for febrile patients. At study entry, urinary metabolites of TxB2, prostacyclin, and serum levels of TNF-alpha and IL-6 were significantly elevated in hypothermic patients compared with febrile patients. In hypothermic patients treated with ibuprofen, there was a trend toward an increased number of days free of major organ system failures and a significant reduction in the 30-day mortality rate from 90% (18/20 placebo-treated patients) to 54% (13/24 ibuprofen-treated patients). CONCLUSIONS: Hypothermic sepsis has an incidence of approximately 10% and an untreated mortality twice that of severe sepsis presenting with fever. When compared with febrile patients, the hypothermic group has an amplified response with respect to cytokines TNF-alpha and IL-6 and lipid mediators TxB2 and prostacyclin. Treatment with ibuprofen may decrease mortality in this select group of septic patients.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Association of cytochrome P450 1B1 (CYP1B1) polymorphism with steroid receptor status in breast cancer.

A key enzyme involved in the production of potentially carcinogenic estrogen metabolites and the activation of environmental carcinogens is cytochrome P450 1B1 (CYP1B1), the predominant member of the CYP1 family expressed in normal breast tissue and breast cancer. Because of the preeminent role of CYP1B1 in mammary estrogen/carcinogen metabolism, we examined the CYP1B1 gene to determine whether genetic differences could account for interindividual differences in breast cancer risk. We focused on exon 3, because it encodes the catalytically important heme binding domain of the enzyme, and discovered three polymorphisms of which two are associated with amino acid substitutions in codons 432 (Val-->Leu) and 453 (Asn-->Ser), designated as m1 and m2, respectively. Approximately 40% of Caucasian women have the m1 Val allele compared with nearly 70% of African-American women (P < 0.0001). The allele frequency also differs significantly in m2, with the rare Ser allele being present in 17.4% of Caucasians but only in 3.4% of African Americans (P < 0.0003). To determine whether the polymorphic CYP1B1 alleles hold implications as potential breast cancer risk factors, we compared the CYP1B1 genotypes in 164 Caucasian and 59 African-American breast cancer cases with those in age-, race-, and frequency-matched controls. Odds ratio calculations failed to show a significant association between any of the genotypes and breast cancer. Because CYP1B1 is known to be involved in mammary estrogen metabolism, we investigated whether the estrogen receptor status is influenced by the CYP1B1 genotypes. Caucasian patients with the m1 Val/Val genotype have a significantly higher percentage of estrogen receptor-positive (P = 0.02) and progesterone receptor-positive breast cancers (P = 0.003). There was no correlation with the m2 genotypes. These data suggest that the CYP1B1 polymorphisms in exon 3 are not associated with increased breast cancer risk but that the m1 polymorphism may be functionally important for steroid receptor expression in breast cancer of Caucasian patients.

Aryl Hydrocarbon Hydroxylases↗
PubMed1998

Breast cancer and CYPIA1, GSTM1, and GSTT1 polymorphisms: evidence of a lack of association in Caucasians and African Americans.

Genetically based differences in carcinogen metabolism have been related to polymorphisms of the cytochrome P450IA1 gene (CYPIA1) and the null genotypes of glutathione S-transferase classes mu and theta (GSTM1 and GSTT1). By PCR we examined the genotypes of CYPIA1, GSTM1, and GSTT1 in relation to breast cancer risk in Caucasian and African-American women. The study included 164 Caucasian and 59 African-American women with primary invasive breast cancer and age-matched female controls. Enzyme polymorphisms included in this study were the null deletions of GSTM1 and GSTT1 and the m1 (MspI), m2 (codon 462: isoleucine-->valine), m3 (MspI-AA), and m4 (codon 461: threonine-->asparagine) polymorphisms of CYPIA1. Contrary to previous reports by other investigators, none of the enzyme genotypes, individually or combined, appear to associate with an increased risk for breast cancer in Caucasian or African-American women. We also report that the recently described m4 allele occurs at a lower frequency in African-Americans than Caucasians and is not linked with breast cancer in either race. Thus, it is unlikely that polymorphisms of GSTM1, GSTT1, or CYPIA1 represent susceptibility factors for breast cancer in Caucasians or African-Americans.

Alleles↗
PubMed1998

Power and sample size calculations for studies involving linear regression.

This article presents methods for sample size and power calculations for studies involving linear regression. These approaches are applicable to clinical trials designed to detect a regression slope of a given magnitude or to studies that test whether the slopes or intercepts of two independent regression lines differ by a given amount. The investigator may either specify the values of the independent (x) variable(s) of the regression line(s) or determine them observationally when the study is performed. In the latter case, the investigator must estimate the standard deviation(s) of the independent variable(s). This study gives examples using this method for both experimental and observational study designs. Cohen's method of power calculations for multiple linear regression models is also discussed and contrasted with the methods of this study. We have posted a computer program to perform these and other sample size calculations on the Internet (see http://www.mc.vanderbilt.edu/prevmed/psintro+ ++.htm). This program can determine the sample size needed to detect a specified alternative hypothesis with the required power, the power with which a specific alternative hypothesis can be detected with a given sample size, or the specific alternative hypotheses that can be detected with a given power and sample size. Context-specific help messages available on request make the use of this software largely self-explanatory.

Bacterial Vaccines↗
PubMed1998

Monoclonality in fibroadenomas with complex histology and phyllodal features.

Fibroadenoma is a common cause of benign breast masses in young women. These women have a slightly increased risk of subsequent breast cancer, particularly if their tumors have complex histologic patterns. We assessed monoclonality in fibroadenomas and correlated the results with histologic analysis. We performed a clonal analysis of 52 fibroadenomas from 43 patients using X-chromosome inactivation studies. The cases included fibroadenomas with complex and simple histology. Areas examined were predominantly stroma but epithelium was also present. DNA was isolated from paraffin-embedded tissue and was subjected to polymerase chain reaction amplification of the human androgen receptor gene with and without predigestion of the DNA with Hha 1. If a monoclonal process was identified, the epithelial and stromal components were subsequently microdissected and reanalyzed. 36/43 (83.7%) women were heterozygous. We studied 45 tumors in these 36 informative women. 1/20 (5% complex fibroadenomas and 1/25 (4%) simple fibroadenomas were monoclonal. The epithelial component of both monoclonal fibroadenomas was polyclonal. The one monoclonal simple fibroadenoma was also the only one with mixed features to contain a phyllodes component. In this case, monoclonality was found in the stroma of both the fibroadenoma and phyllodes regions. Monoclonality has been previously associated with phyllodes phenotype, but not with fibroadenomas, except for 3 fibroadenomas that recurred as phyllodes tumor. We report that monoclonality may also be seen occasionally in complex fibroadenomas, and was found in a tumors with mixed fibroadenoma/phyllodes features without clinical recurrence for 4 years.

Breast Neoplasms↗
PubMed1997

The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group.

BACKGROUND: In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases, but the pathophysiologic role of these prostaglandins is unclear. In animal models, inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival. In pilot studies of patients with sepsis, treatment with ibuprofen led to improvements in gas exchange and airway mechanics. METHODS: From October 1989 to March 1995, we conducted a randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (10 mg per kilogram of body weight [maximal dose, 800 mg], given every six hours for eight doses) in 455 patients who had sepsis, defined as fever, tachycardia, tachypnea, and acute failure of at least one organ system. RESULTS: In the ibuprofen group, but not the placebo group, there were significant declines in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis. With ibuprofen therapy there was no increased incidence of renal dysfunction, gastrointestinal bleeding, or other adverse events. However, treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days (mortality, 37 percent with ibuprofen vs 40 percent with placebo). CONCLUSIONS: In patients with sepsis, treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever, tachycardia, oxygen consumption, and lactic acidosis, but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival.

Acidosis, Lactic↗
PubMed1997

Loss of heterozygosity and microsatellite instability in breast hyperplasia. No obligate correlation of these genetic alterations with subsequent malignancy.

Loss of heterozygosity and microsatellite instability have been often reported in breast cancer and seldom in proliferative breast disease (PBD). DNA samples from microdissected PBD lesions, including papillomas (25 lesions), from 8 women were analyzed by polymerase chain reaction for loss of heterozygosity and microsatellite instability at 10 loci including INT-2 oncogene locus, D17S796 (the p53 gene region), and D17S579 (in the region of the BRCA-1 gene). In a patient, five loci with microsatellite instability and two loci with loss of heterozygosity were identified in one papilloma with florid hyperplasia and atypia, and 10 other PBD lesions were negative for genetic alteration (GA) and atypia. Three loci with microsatellite instability were identified in another PBD lesion without atypia, whereas another lesion from this second patient had minimal atypia without GAs. These two patients have been well for more than 20 years. No other patient, including a woman developing cancer, had GAs. We detected GAs in PBD (25% of women, 8% of lesions). Incomplete correlation between GAs and anatomic atypia was suggested. It seems evident that several GAs in PBD lesions may not indicate clinically meaningful premalignancy for remaining breast.

Adolescent↗
PubMed1996

Subsequent breast carcinoma risk after biopsy with atypia in a breast papilloma.

BACKGROUND: Risk of breast cancer after biopsy demonstrating a papilloma has long been variously interpreted on the basis of histologic pattern of multiplicity of papillomas. METHODS: A nested case control study was performed on women with surgical breast biopsies evidencing papillomas; cases who subsequently developed invasive carcinoma were compared with controls who did not. Presence of atypical hyperplasia (AH) within the papilloma as well as areas of AH in the surrounding parenchyma were evaluated in both cases and controls. The entire cohort (not tested) was separately evaluated for all variables except for atypia within papillomas. RESULTS: The relative risk of invasive carcinoma for women with papillomas containing AH was > 4x that of papillomas without AH within or surrounding the papilloma. This risk may be greater with added atypical hyperplasia outside the papilloma and most strikingly, most of the subsequent invasive carcinomas developed in the same breast and probably near the site of the original papilloma. However, ordinary patterns of epithelial hyperplasia lacking specific features of AH within the papilloma do not add to the risk of subsequent carcinoma development over papillomas without hyperplasia. CONCLUSIONS: This study indicates that women having papillomas with AH have a similar or greater cancer risk than others with specifically defined patterns of atypical hyperplasia within the breast parenchyma (4-5x relative risk). Most importantly, this risk is largely local in the region of the original papilloma.

Adult↗
PubMed1996

Understanding the relationship between relative and absolute risk.

BACKGROUND: Relative risks are the most common statistics used to quantify the risk of mortal or morbid outcomes associated with different patient groups and therapeutic interventions. However, absolute risks are of greater value of both patient and physician in making clinical decisions. METHODS: The relationship between relative and absolute risks is explained using graphical aids. A program to estimate absolute risks from relative risks is available on the internet (see ftp://ftp.vanderbilt.edu/pub/biostat/absrisk+ ++.txt). This program uses a competing hazards model of morbidity and mortality to derive these estimates. RESULTS: When a patient's absolute risk is low, it can be approximated by multiplying her relative risk by the absolute risk in the reference population. This approximation fails for higher absolute risks. The relationship between relative and absolute risk can vary dramatically for different diseases. This is illustrated by breast cancer morbidity and cardiovascular mortality in American women. The accuracy of absolute risk estimates will be affected by the accuracy of relative risk estimates, by the appropriateness of the reference groups used to calculate relative risks, by the stability of cross-sectional, age-specific morbidity and mortality rates over time, by the influence of individual risk factors on multiple causes of mortality, and by the extent to which relative risks may vary over time. CONCLUSIONS: Valid absolute risk estimates are valuable when making treatment decisions. They can often be obtained over time intervals of 10 to 20 years when the corresponding relative risk estimates have been accurately determined.

Aged↗
PubMed1996

Diagnosis and therapy of acute respiratory distress syndrome in adults: an international survey.

In an attempt to identify the range of opinions influencing the diagnosis and therapy of patients with the adult respiratory distress syndrome (ARDS), a postal survey was mailed to 3,164 physician members of the American Thoracic Society Critical Care Assembly. The questionnaire asked opinions regarding the factors important in the diagnosis of ARDS and its treatment. Thirty-one percent of physicians surveyed responded within 4 weeks, the vast majority of which were board certified or eligible in Internal Medicine, Pulmonary Disease, and/or Critical Care Medicine. A known predisposing cause, measure of oxygenation efficiency, and a chest radiograph depicting pulmonary edema were reported to be the most important criteria for a clinical and research diagnosis of ARDS. Lung compliance and bronchoalveolar lavage neutrophil or protein content were reportedly less important. The initial treatment of patients with ARDS was reported to be most commonly accomplished using volume-cycled ventilation in the assist/control mode. Nearly half the responders reported using lower tidal volumes (5 to 9 mL/kg) than the traditionally recommended 10 to 15 mL/kg. Most respondents indicated they have intentionally allowed CO2 retention. On average, oxygen toxicity was thought to begin at an FIO2 between 0.5 and 0.6. It was reported that modest levels of positive end-expiratory pressure (PEEP) were used in incremental fashion as FiO2 requirements increased. Perceived indications for insertion of pulmonary artery catheters and compensation of the effects of PEEP on the pulmonary artery occlusion pressure varied widely among the responders. We conclude that reported practice patterns regarding the care of ARDS patients vary widely even within a relatively homogenous group of critical care practitioners.

Adult↗
PubMed1996

Papillary apocrine change of the breast: associations with atypical hyperplasia and risk of breast cancer.

Micropapillary patterns of apocrine change in human female breasts are common histological findings. They have been identified as cancer associated and implicated as an indicator of cancer risk in a predictive manner. This study has stratified papillary apocrine change (PAC) into categories of increasing complexity using a combination of cytological and histological pattern rules. Cases (2,876) were identified in a review of 10,357 benign breast biopsies. Of 5966 women, 1613 and PAC and were followed for a median of 20 years after biopsy for the development of invasive carcinoma of the breast. There was a slight association with cancer risk elevation, but most of this disappeared when women with concurrent, specifically identified patterns of atypical hyperplasia (AH) were excluded from the groups with PAC. The resultant relative risk was only 1.2 after women with AH were excluded. Only 1% of the reviewed biopsies demonstrated highly complex patterns of PAC, and 20% of these had coexistent lesions of AH. Women with highly complex patterns of PAC without AH did experience a relative risk of 2.4 (95% confidence interval = 0.77-7.04) but without statistical significance. More than one-half of all PAC patterns occurred without concurrent foci of lesions of proliferative disease that are associated with a slight elevation of breast cancer risk (at least 1.5 times); when present without proliferative disease, there was no suggestion of later breast cancer risk for PAC.

Adult↗
PubMed1995

Continued local recurrence of carcinoma 15-25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy.

BACKGROUND: The stratification of ductal carcinoma in situ (DCIS) of the human breast into prognostically relevant categories by size and histologic pattern is a current concern. Few studies have been able to follow women after the identification of any type of DCIS when they have had biopsy only. METHODS: This is an extension of a follow-up study of a group of 28 women with small, noncomedo ductal carcinomas in situ that were excised by biopsy only, published in 1982. All these women have now been successfully followed for an average of almost 30 years. RESULTS: The overall risk of development of invasive carcinoma for these women over almost 30 years is nine times that of the general population (95% confidence interval, 4.7-17). This is similar to the 11-fold elevation in relative risk that was determined after about 15 years of follow-up. All invasive carcinomas have developed in the same area in the same breast. There were two women in whom invasive carcinoma developed between 20 and 30 years after initial biopsy. One other woman had an extensive noncomedo DCIS that was identified 25 years after her initial biopsy, but had no evidence of invasive disease. CONCLUSIONS: The natural history of small, noncomedo DCIS can last over at least 2 decades, with invasive carcinoma developing at the same site in which DCIS was previously discovered in a significant percentage of women (broadly, between 25%-50%). This is quite different from the natural history of comedo DCIS or any type of DCIS treated purposefully by surgery alone.

Aged↗