Search PubMed⌕ Search

Biomedical subjects

W D Dupont

Publications and source records attributed to W D Dupont.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1995

Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer.

BACKGROUND: In breast cancer patients, about two thirds of the tumors are estrogen receptor (ER)-positive and one third are ER-negative. The molecular mechanisms leading to the ER-negative phenotype are poorly understood. Nearly all ER-negative and about 40% of ER-positive cancers are resistant to endocrine therapy. PURPOSE: In this study, we examined the entire coding region of the ER gene in ER-positive and ER-negative primary breast tumors to determine whether deletions/insertions or point mutations might account for the ER-negative phenotype. METHODS: We amplified exons 1 through 8 of the ER gene in 118 ER-positive and 70 ER-negative primary breast tumors and searched for mutations by single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and DNA sequencing. RESULTS: Both ER-negative and ER-positive tumors contained neutral polymorphisms in codons 10 [TCT-->TCC (Ser)], 87 [GCG-->GCC (Ala)], 243 [CGC-->CGT (Arg)], 325 [CCC-->CCG (Pro)], and 594 [ACA-->ACG (Thr)]. There was no correlation of any of the polymorphic alleles with the ER phenotype or other clinicopathologic parameters including tumor type, size, grade, or stage. However, the polymorphism in codon 325 showed a strong association with a family history of breast cancer (P = .0005). This association was observed both in premenopausal and postmenopausal patients. Despite extensive searching in exons 1 through 8, we found no deletions/insertions and only two missense mutations in codons 69 [AAC (Asn)-->AAG (Lys)] and 396 [ATG (Met)-->GTG (Val)] of the same ER-negative tumor. Thus, only 1% of the primary breast cancers had point mutations in the ER gene. CONCLUSIONS: In the majority of primary breast cancers, the ER-negative phenotype is not the result of mutations in the coding region of the ER gene, but is due to deficient ER expression at the transcriptional or post-transcriptional level. IMPLICATIONS: The correlation reported previously, as well as our current findings, suggest that further investigations are warranted to understand the possible linkage of the ER gene locus to hereditary breast cancer.

Base Sequence↗
PubMed1994

Long-term risk of breast cancer in women with fibroadenoma.

BACKGROUND: Fibroadenomas are benign breast tumors that are commonly diagnosed in young women and are associated with a slight increase in the risk of breast cancer. These lesions vary considerably in their histologic characteristics. We assessed the correlation between the histologic features of fibroadenomas and the risk of subsequent breast cancer. METHODS: We conducted a retrospective cohort study of a consecutive series of patients with fibroadenoma diagnosed between 1950 and 1968. Follow-up data were obtained for 1835 patients (90 percent of those eligible). Fibroadenomas with cysts, sclerosing adenosis, epithelial calcifications, or papillary apocrine changes were classified as complex. The rate of subsequent breast cancer among the patients was compared with the rates in two control groups, women listed in the Connecticut Tumor Registry and women chosen from among the patients' sisters-in-law. RESULTS: The risk of invasive breast cancer was 2.17 times higher among the patients with fibroadenoma than among the controls (95 percent confidence interval, 1.5 to 3.2). The relative risk increased to 3.10 among patients with complex fibroadenomas (95 percent confidence interval, 1.9 to 5.1) and remained elevated for decades after diagnosis. Patients with benign proliferative disease in the parenchyma adjacent to the fibroadenoma had a relative risk of 3.88 (95 percent confidence interval, 2.1 to 7.3). Patients with a family history of breast cancer in whom complex fibroadenoma was diagnosed had a relative risk of 3.72, as compared with controls with a family history (95 percent confidence interval, 1.4 to 10). Two thirds of the patients had noncomplex fibroadenomas and no family history of breast cancer and did not have an increased risk. CONCLUSIONS: Fibroadenoma is a long-term risk factor for breast cancer. The risk is increased in women with complex fibroadenomas, proliferative disease, or a family history of breast cancer.

Adult↗
PubMed1994

Histologic grading of breast carcinoma. A reproducibility study.

BACKGROUND: A concern with the histologic grading of breast cancer is that tumor grading is a subjective evaluation that may have problems with reproducibility. METHODS: A single slide from 10 invasive breast cancers was submitted to 25 pathologists who practice in six separate groups. Pathologists graded the tumors using a modified Bloom-Richardson (B-R) scheme, and the results were compared. RESULTS: In 8 of the 10 cases, there was greater than 87% agreement by the pathologists as to the final combined B-R grade, with complete agreement in 2 cases. Only one case had any discrepant opinions that ranged from low to high grade, and this involved only 3 of the 25 pathologists. With respect to B-R score, the pathologists tended to score the tumors as either one of two adjacent scores. Due to this clustering, the B-R scheme appears reproducible into five groups: very low and very high grade tumors and B-R score "5,6," "6,7," and "7,8" tumors. This clustering was especially noticeable in two cases with split decisions, in which the discrepancy in final combined grade was largely due to the tumors being given B-R scores that straddled and were then condensed into two B-R grades. A consensus from each pathology group tended to merge with the majority opinion of all 25 pathologists and was correct for outliers. CONCLUSIONS: This study indicates that reproducibility of grading breast cancers can be achieved when a histologic grading scheme with specified guidelines is used. Pathologists must be aware of the limits of reproducibility, with appropriate guidelines being followed to help optimize agreement, and there should be an awareness of how pathologists group in their evaluations. Also, it may be advisable to better correlate or link reproducibility data with prognostic data in the design of grading schemes.

Breast Neoplasms↗
PubMed1994

Heterogeneous expression of nm23 gene product in noninvasive breast carcinoma.

BACKGROUND: The two major types of noninvasive breast carcinoma, ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), are quite different in their histopathologic appearance and clinical implications. LCIS is only a marker of an increased risk of later development of invasive carcinoma, whereas most DCIS lesions are at least nonobligate precursors of invasive carcinoma. DCIS is a heterogeneous group of lesions composed of several distinct subtypes, with only the comedo subtype having immediate malignant potential. The authors' purpose was to analyze noninvasive carcinomas for the presence of a gene product (nm23) indicative of a favorable prognosis in invasive carcinomas to determine differences (1) among the different types of CIS and (2) in CIS with and without an accompanying invasive component. METHODS: Immunohistochemical methods were used to detect nm23 gene product in archival material from two groups of patients: Group 1 consisted of 54 cases of purely noninvasive carcinoma, and Group 2 consisted of 55 examples of noninvasive carcinoma associated with an invasive component. RESULTS: Among the cases of CIS with no invasion, LCIS and comedo DCIS expressed more nm23 than noncomedo DCIS (P < or = 0.03). There were no differences among these CIS subtypes in the group with invasion. Comparing subtypes of CIS in the groups with or without invasion, only comedo DCIS was significantly different, with greater expression in the CIS group with no invasion compared with comedo DCIS associated with an invasive component (P = 0.04). CONCLUSIONS: These results support the special nature of LCIS and the heterogeneous nature of DCIS. The in situ component attending an invasive component may be different from anatomically similar lesion without associated invasion. The absence of nm23 in comedo DCIS may be indicative of invasive capacity.

Adult↗
PubMed1994

p53 gene mutations and steroid receptor status in breast cancer. Clinicopathologic correlations and prognostic assessment.

BACKGROUND: There is increasing evidence linking development and progression of cancer to an accumulation of mutations at the genomic level. The most frequently mutated gene known to date in sporadic breast cancer appears to be the tumor suppressor gene p53. This study was designed to determine the frequency of p53 gene mutations in primary breast cancer, to correlate the presence of p53 mutations with established clinicopathologic parameters, including the estrogen receptor (ER) and progesterone receptor (PR) status, and to assess the prognostic significance of p53 mutations regarding patient survival. METHODS: We examined the p53 gene in genomic DNA samples from 192 primary breast cancers. Using denaturant gradient gel electrophoresis, the authors analyzed exons 5-9 in all tumors for mutations and performed DNA sequencing in 20 tumors to identify the exact nature of the p53 mutations. RESULTS: p53 gene alterations were identified in 43 of the 192 tumors (22%), the majority localized in exons 5 and 6. DNA sequencing showed mostly missense mutations resulting from G or C substitutions. p53 mutations were found more often in tumors of younger women (P = 0.002), Afro-American women (P = 0.05), and in tumors lacking ER (P = 0.03), PR (P = 0.04), or both (P = 0.06). There were no significant correlations with family history, tumor size, histologic grade or type, nodal status, or disease stage. The overall survival rates showed no significant difference between patients with mutant and wild-type p53 tumors. The same was true when the comparison was limited to node-negative patients or patients with ER-positive or ER-negative tumors. Finally, there was no significant difference in survival between patients with tumors harboring mutations in exons 5 and 6 versus exons 7-9. CONCLUSIONS: The results of this and other studies demonstrate a consistent relationship between ER-positive tumors and wild-type p53 on one hand and ER-negative cancers and p53 mutations on the other. Our data do not support a significant prognostic role for p53 mutations in predicting survival.

Base Sequence↗