Peripheral blood eosinophilia in association with sarcoidosis.

OBJECTIVES: To review retrospectively our experience with peripheral blood eosinophilia (PBE) in sarcoidosis and to analyze histologically lung biopsy specimens for the presence of lung tissue eosinophils. PATIENTS AND METHODS: We reviewed 140 cases of sarcoidosis diagnosed between May 1975 and January 1998. Ninety-five patients (66.3% women; 70.5% African American; mean age, 35.9 years) met the inclusion criteria. Transbronchial biopsy specimens from 82 patients were divided into 4 morphologic compartments: parenchyma, bronchial wall, parenchymal granulomas, and bronchial wall granulomas. Within compartments, up to 10 high-power fields were scored semiquantitatively for eosinophils, from 0 (none) to 4+ (numerous). RESULTS: Thirty-nine patients (41%) had PBE. Four had PBE greater than 10%. The highest eosinophil count (21%) occurred in 1 patient. Sixty-five (79%) of 82 patients had no or few (1+) eosinophils in lung tissue; 17 patients had eosinophils scored as 2+ or higher. There was no correlation between peripheral blood eosinophil count and presence of eosinophils in transbronchial biopsy specimens. Eosinophils were least conspicuous in parenchyma but evenly distributed in bronchial wall and parenchymal and bronchial wall granulomas. CONCLUSIONS: Peripheral blood eosinophilia occurs frequently in sarcoidosis. However, there appears to be no association between peripheral blood eosinophil count and presence of lung tissue eosinophils. Whether eosinophils participate in the pathogenesis of sarcoidosis requires further study.

Case-mix adjustment using objective measures of severity: the case for laboratory data.

OBJECTIVE: We evaluate the use of routinely gathered laboratory data to subclassify surgical and nonsurgical major diagnostic categories into groups homogeneous with respect to length of stay (LOS). DATA SOURCES AND STUDY SETTING: The source of data is the Combined Patient Experience database (COPE), created by merging data from computerized sources at the University of California San Francisco (UCSF) Medical Center and Stanford University Medical Center for a total sample size of 73,117 patient admissions. STUDY DESIGN: The study is cross-sectional and retrospective. All data were extracted from COPE consecutive admissions; the unit of analysis is an admission. The outcome variable LOS proxies hospital resource utilization for an inpatient stay. Nine (candidate) predictor variables were derived from seven lab tests (WBC, Na, K, C02, BUN, ALB, HCT) by recording the whole-stay minimum or maximum test result. DATA COLLECTION/EXTRACTION METHODS: Patient groups were formed by first assigning to major diagnostic categories (MDCs) all 73,117 admissions. Each MDC was then partitioned into medical and surgical subgroups (sub-MDCs). The 13 sub-MDCs selected for study define a study population of 32,599 patients that represents approximately 45 percent of inpatients. Within each of the 13 sub-MDCs, patients were randomly assigned to one of two data sets in a ratio of 2:1. The first set was used to create, the second to validate, three different LOS predictors. Predictive accuracies of individual DRG classes were compared with those of two alternative classification schemes, one formed by recursive partitioning (the sub-MDC) using only lab test results, the other by partitioning with both lab test results and individual DRGs. PRINCIPAL FINDINGS: For the eight largest sub-MDCs (81 percent of study population), individual DRGs explained 23 percent of the within sub-MDC variance in LOS, laboratory data classes explained 31 percent, and classes derived by considering individual DRGs and laboratory data explained 37 percent. (Each result is a weighted average R2. The average number of LOS classes into which the eight largest sub-MDCs were partitioned were 20, 10, and 10, respectively. Within six of the eight, partitioning on the basis of laboratory data alone explained more within sub-MDC variance than did partitioning into individual DRGs. CONCLUSIONS: Routine lab test data improve the accuracy of LOS prediction over that possible using DRG classes. We note that the improvements do not result from overfitting the data, since the numbers of LOS classes we use to predict LOS are considerably fewer than the numbers of individual DRGs.

Heterogeneity for allelic loss in human breast cancer.

BACKGROUND: Loss of heterozygosity (LOH) at specific chromosomal regions in the tumor cells implicates the presence of tumor suppressor genes. However, it is also possible for an LOH to be randomly acquired and irrelevant to tumor development. PURPOSE: To determine whether a particular LOH in human breast carcinomas represents a loss of tumor suppressor gene or merely a random loss, we analyzed untreated primary breast cancers for LOH. METHODS: Ninety-eight primary human breast cancers from previously untreated patients were analyzed for LOH at 12 chromosomal regions including five randomly selected regions and seven regions previously reported in other cancer types and/or breast cancers. RESULTS: The baseline incidence of LOH was five out of 124 tests (4%) using randomly selected probes on chromosomes 1p, 2p, 4p, 11q, and Xq. Incidences of LOH significantly greater than background were seen in the following chromosomal regions: 22q (10 of 26 cases, 38%); 18p (five of 24 cases, 21%); 17p (30 of 59 cases, 51%); 13q (five of 14 cases, 36%); 3p (13 of 28 cases, 46%); and 1q (18 of 70 cases, 26%). In contrast to previous reports, the incidence of LOH was not significantly different from background for 11p15. In all cases, results were the same for metastatic lymph nodes and primary tumors, suggesting that the losses occurred early in the malignant progression. In cases with LOH at more than one locus, the same DNA sample often varied in degree of signal reduction for the missing alleles. CONCLUSION: These observations indicate the presence of both intertumor and intratumor heterogeneity for LOH.

In vivo measurement of breast cancer growth rate.

S-phase cells of 66 primary breast cancers were labeled in vivo by preoperative infusion of the thymidine analogue bromodeoxyuridine. A monoclonal antibody specific for DNA-incorporated bromodeoxyuridine was used to identify positive cells and compute a labeling index on histologic sections. The labeling index (the percentage of cells in S-phase) ranged from 0.1% to 23.9%; it correlated positively with poorly differentiated cancer, higher mitotic counts on routine histologic examination, and tumor size; and it correlated inversely with estrogen and progesterone receptors. The labeling index did not correlate with nodal involvement or ploidy. Of the 15 patients with a labeling index greater than 12%, three died and one had systemic disease after a median follow-up of 19 months. No other patients had recurrences. There were no clinical complications of bromodeoxyuridine infusion.

Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer.

Loss of heterozygosity (LOH) on the short arm of chromosome 17 (17p) was found in 27 of 52 (52%) previously untreated primary breast cancers. There was a significant correlation between this 17p allelic loss and two parameters associated with aggressive tumor behavior: high cellular proliferative fraction and DNA aneuploidy. These correlations with high cellular proliferative fraction and DNA aneuploidy were not found in tumors with LOH at nine other chromosome locations. The p53 gene, a putative tumor suppressor gene located at 17p13, was examined for aberrations to determine whether it is the target for the 17p LOH in breast cancer. Unlike other types of human cancer, there were no homozygous deletions or rearrangements of the p53 gene, and only 2 of 13 (15%) were mutated in the conserved region where mutational "hot spots" have been previously located. Therefore, we hypothesize that, in breast cancer, either loss or inactivation of gene(s) on chromosome 17p other than the p53 gene or a different mechanism of p53 gene inactivation may be responsible for the observed high labeling index and DNA aneuploidy associated with LOH at 17p.

Laboratory evaluation of jaundice in newborns. Frequency, cost, and yield.

Neonates with hyperbilirubinemia commonly undergo a battery of laboratory tests. We used a computerized database and medical records to study the frequency, cost, and yield of these tests in 2443 infants born at the University of California, San Francisco, between 1980 and 1982. Four hundred forty-seven (18%) of the infants met standard criteria for "nonphysiologic" hyperbilirubinemia; the incidence varied from 9% in blacks to 31% in Asian infants. About 55% of these 447 infants received a $125 "hyperbilirubinemia workup." Hospital discharge diagnoses on all 447 hyperbilirubinemic infants were reviewed. In 214 (48%), no cause of the jaundice was identified. An additional 145 (32%) had a possible cause apparent from history, physical examination, or initial hematocrit determination. The only diagnosis made as a result of routine investigations of hyperbilirubinemia was possible ABO or Rh isoimmunization in 75 infants (17%). Nonphysiologic hyperbilirubinemia may be more common than previously reported. The recommended tests are expensive and rarely lead to diagnoses other than ABO or Rh isoimmunization. Their routine use should be reevaluated.

Improving the homogeneity of diagnosis-related groups (DRGs) by using clinical laboratory, demographic, and discharge data.

For 48 of the most common diagnosis-related groups (DRGs) at our hospital, we examined the ability of clinical laboratory tests, demographic data, and ICD-9-CM codes, which provide a measure of severity of illness, to predict patients' length of stay (LOS) more accurately than DRGs alone. For 10 of 20 medical DRGs and 13 of 23 surgical DRGs examined, we were able to increase the ability to predict LOS by at least 10 per cent. The laboratory tests that proved most predictive of LOS over all DRGs were the mean serum sodium, potassium, bicarbonate, and albumin. The system is data driven, objective, and flexible, thus ensuring its utility for the purpose of equitable reimbursement.

Conversion of androgens to estrogens in the male squirrel monkey (Saimiri sciureas).

Many New World primates such as the squirrel monkey have extraordinarily high plasma levels of steroid hormones including cortisol, testosterone, progesterone and vitamin D3. While plasma estrogen levels in female squirrel monkeys apparently are approximately the same as those found in other species no information is available for males. The present results indicate that the plasma levels of estrone (E1), estradiol (E2), and E1 sulfate are approximately 10-fold higher than those found in men. Comparative in vitro studies of androgen metabolism in genital skin fibroblasts indicate that squirrel monkey cells have higher aromatase and lower 5-alpha-reductase activity than human cells. Estimation of aromatase activity in vivo by a radiometric assay indicates that the high plasma estrogens are derived by peripheral conversion from testicular and/or adrenal androgens.

Ketoconazole-induced increase in estradiol-testosterone ratio. Probable explanation for gynecomastia.

Ketoconazole, an antifungal drug, causes gynecomastia in some patients. It also inhibits androgen and glucocorticoid synthesis. In four volunteer male subjects, 600-mg doses of ketoconazole depressed serum testosterone concentrations markedly, but serum estradiol to a much lesser degree. The bound and free percentages of both hormones were not significantly altered. The net result was a significant elevation of the estradiol-testosterone ratio, expressed as either total circulating hormone or free hormone. In five male patients receiving long-term high-dose ketoconazole therapy, the testosterone concentrations fell, but the effect on estradiol was variable. In these patients the estradiol-testosterone ratio was persistently increased. Since gynecomastia appears to be the result of an elevated estradiol-testosterone ratio, the selective hormonal effect demonstrated may explain the side effect of gynecomastia after ketoconazole therapy.