Prophylactic indomethacin reduces grades III and IV intraventricular hemorrhages when compared to early indomethacin treatment of a patent ductus arteriosus.

OBJECTIVE: To determine the relative risk of severe intraventricular hemorrhage (IVH) between two very early indomethacin treatment strategies. STUDY DESIGN: Retrospective chart review of infants <29 weeks gestation and <1350 g who received either indomethacin prophylaxis or very early echocardiography with indomethacin treatment only if the ductus arteriosus was patent. RESULTS: A total of one hundred and two infants received prophylactic indomethacin (pINDO). Echochardiography was performed on 158 infants, of whom 117 received indomethacin. Infants receiving pINDO had lower gestational age, but similar birth weight, gender, race, antenatal steroid exposure, delivery mode, Apgar scores, and need for resuscitation as infants evaluated by echocardiography. Grades III to IV IVH was observed less frequently in infants who received pINDO (OR 0.27, 95% CI 0.10 to 0.77, p=0.014). Frequency of side effects and recurrent patent ductus arteriosus did not differ between treatment groups. CONCLUSION: pINDO reduces severe IVH when compared to an early echocardiography strategy.     

Endocrine effects of dehydroepiandrosterone and its fluorinated analog,fluasterone, in rats

Cancer chemoprevention is the use of pharmacologic agents to inhibit the development of cancer. The adrenal steroid dehydroepiandrosterone (DHEA) has demonstrated chemopreventive efficacy in animal models of tumorigenesis. However, due to DHEA's undesirable hormonal actions, the fluorinated analog fluasterone (fl‐DHEA), which also has chemopreventive characteristics, was synthesized as a potential alternate agent. It is not known whether fl‐DHEA has hormonal actions. The endocrinologic effects of DHEA and fl‐DHEA in adult male and female Fischer 344 rats were examined following 28 days of daily oral treatment. Initial doses tested were 30 and 300 mg/kg/day for each drug (n=12/sex/group), which are equivalent to 104 and 1,042 µmoles/kg/day DHEA, and 103 and 1,034 µmoles/kg/day fl‐DHEA. However, due to weight loss at the high dose, doses were lowered to 150 mg/kg/day for each drug (521 and 517 µmoles/kg/day DHEA and fl‐DHEA, respectively). Administration of DHEA resulted in dose‐dependent increases in plasma DHEA and DHEA‐S 1 h after dosing in week 4. DHEA produced an estrogenic effect in female rats expressed as decreased plasma FSH and LH, inhibition of ovulation, prolonged estrus, and increased uterine estrogen receptors. DHEA also increased plasma levels of androstenedione in males and females. Administration of fl‐DHEA increased the estrus cycle length due to a prolonged diestrus II phase and decreased the weights of the uterus, prostate, seminal vesicles, and testes. In addition, fl‐DHEA decreased plasma FSH, LH, and tissue estradiol, and increased plasma dihydrotestosterone levels in both sexes. These results indicate that fl‐DHEA is hormonally active and additional studies are warranted to further describe its endocrinologic effects. Drug Dev. Res. 58:169–178, 2003. © 2003 Wiley‐Liss, Inc.     

Inverse association between prostate cancer and the use of calcium channel blockers.

Calcium channel blockers block calcium signal-mediated apoptosis. It is hypothesized that the use of these drugs may be associated with the development of cancer. This study investigated the association between daily use of calcium channel blockers and prostate cancer in a community-based cohort of men who participated in a longitudinal study of lower urinary tract symptoms. Study subjects were men ages 40 to 79 years by January 1, 1990, and were randomly selected from Olmsted County in Minnesota. At baseline, participants underwent an interview to determine all medications taken on a daily basis, including calcium channel blockers and to elicit a family history of prostate cancer. During follow-up, all men with a histological diagnosis of prostate cancer were identified through patient self-report and by a review of the complete medical record. Over 12,668 person years of follow-up, 15 (6.8%) of 220 calcium channel blocker users and 120 (10.5%) of 1142 nonusers developed prostate cancer (P = 0.09; odds ratio, 0.62; 95% confidence interval, 0.36-1.10). With adjustment for age and family history of prostate cancer, the risk (odds ratio, 95% confidence interval) of prostate cancer was 0.55 (0.31-0.97) in calcium channel blocker users compared with nonusers. In analyses stratified by family history of prostate cancer, the risk of prostate cancer was 0.45 (0.23-0.88) in men without a family history and 2.64 (0.82-8.47) in men with a family history of prostate cancer (P = 0.006). These findings suggest an association between prostate cancer and daily use of calcium channel blockers that varies by family history of prostate cancer.     

Effects of a high-selenium yeast supplement on celecoxib plasma levels: a randomized phase II trial.

A combination of celecoxib and selenium was used in a randomized double-blind Phase II trial as a preliminary study to a multicenter Phase III colorectal cancer chemoprevention trial using these two agents together. The purpose of this trial was to determine whether high-selenium baker's yeast [(Saccharomyces cerevisiae) 200 microg once daily] in combination with celecoxib (400 mg once daily) altered the steady-state plasma concentration of celecoxib or produced clinically significant toxicities. Seventy-three healthy subjects (ages 40-75 years) were recruited to the 6-week study from the general local population and were randomized to either the celecoxib plus selenized baker's yeast group or the celecoxib plus placebo group after a 2-week run in period of celecoxib only. Blood samples were taken at baseline (to document that there was no evidence of celecoxib intake), after the 2-week run-in period on celecoxib to verify steady-state blood levels of this agent, and at end of study (4 weeks postrandomization). Toxicities were monitored at 2 weeks after initiation of celecoxib, at 4 weeks after initiation, and at the end of the study. Blood level concentrations of celecoxib did not differ between the two groups as determined by high-performance liquid chromatography analysis nor were there significant differences in blood chemistry values between the two groups. Subjects' self-report of general physical toxicities was uncommon and limited to National Cancer Institute toxicity grade 2 or less; however, 2 female participants (3%) were removed from the study medications because of grade 2 edema and significant weight gain after 2 and 2.5 weeks of celecoxib administration. In conclusion, high-selenium yeast and celecoxib can be taken at the described doses with minimum short-term negative effects. In future Phase III chemoprevention trials of celecoxib, weight gain should be carefully monitored, and participants should be made aware of this potential side effect before study entry.     

Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor genotype.

PURPOSE: The unique immunoglobulin idiotype (Id) expressed by each B-cell lymphoma is a target for immunotherapy. Vaccination with Id induces humoral and/or cellular anti-Id immune responses. However, the clinical impact of these anti-Id immune responses is unknown. We and others have previously reported that immunoglobulin G Fc receptor (FcgammaR) polymorphisms predict the clinical response of lymphoma patients to passive anti-CD20 antibody infusions. In this study, we tested whether anti-Id immune responses or FcgammaR polymorphisms associate with clinical outcome of patients who received Id vaccination. PATIENTS AND METHODS: We analyzed 136 patients with follicular lymphoma who had received Id vaccination. The anti-Id immune responses were measured and FcgammaRIIIa and FcgammaRIIa polymorphisms were determined and correlated with clinical outcome for these patients. RESULTS: Patients who mounted humoral immune responses had a longer progression-free survival (PFS) than those who did not (8.21 v 3.38 years; P = .018). Patients with FcgammaRIIIa 158 valine/valine (V/V) genotype also had a longer PFS than those with valine/phenylalanine (V/F) or phenylalanine/phenylalanine (F/F) genotypes (V/V, 8.21 v V/F, 3.38 years; P = .004; v F/F, 4.47 years; P = .035). Multivariate analysis using the Cox proportional hazards model showed that V/V genotype and humoral immune responses were independent positive predictors for PFS. CONCLUSION: This study is the first to identify the predictive value of FcgammaR polymorphism on clinical outcome in patients who received active immunotherapy with tumor antigen vaccines. Our results imply that the antibodies induced against a tumor antigen are beneficial and that FcgammaR-bearing cells mediate an antitumor effect by killing antibody-coated tumor cells.     

Basaloid squamous cell cancer arising in Barrett’s esophagus

Basaloid squamous cell carcinoma (BSCC) is a rare form of cancer that arises primarily in the upper aerodigestive tract. Esophageal BSCC is extremely rare, accounting for less than 2% of primary esophageal malignancies. It is histopathologically distinct from squamous cell carcinoma and has an aggressive biological behavior with poor survival outcomes. There is no known association of Barrett’s esophagus with esophageal BSCC. Here, we report what we believe is the first such case of esophageal BSCC occurring in the setting of Barrett’s esophagus.     

Dietary factors and the risk of squamous cell esophageal cancer among black and white men in the United States

Objectives: To investigate dietary factors for squamous cell esophageal cancer and whether these factors may contribute to the five-fold higher incidence of this cancer in the black versus white population of the United States.Methods: Data from a food frequency questionnaire were analyzed for 114 white men and 219 black men with squamous cell esophageal cancer, and 681 white and 557 black male controls from three areas of the United States who participated in a population-based case-control study of esophageal cancer.Results: Protective effects were associated with intake of raw fruits and vegetables (odds ratio for high versus low consumers=0.3 in both white and black men) and use of vitamin supplements (especially vitamin C; odds ratio for high versus low consumers=0.4 in both races), with the frequency of consumption of raw fruits and vegetables and vitamin supplements being greater for white than black controls. In addition, elevated risks were associated with high versus low intake of red meat (OR=2.7 for blacks and 1.5 for whites) and processed meat (OR=1.6 for blacks and 1.7 for whites), with the levels of consumption being greater for black than white controls.Conclusions: In the United States, these dietary factors may contribute in part to the much higher incidence of squamous cell esophageal cancer among black compared to white men.     

A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin

CONTEXT: The hypothalamic-pituitary-adrenal axis is a major determinant of the host response to stress. The relationship between its activation and patient outcome is not known. OBJECTIVE: To evaluate the prognostic value of cortisol levels and a short corticotropin stimulation test in patients with septic shock. DESIGN AND SETTING: Prospective inception cohort study conducted between October 1991 and September 1995 in 2 teaching hospital adult intensive care units in France. PARTICIPANTS: A total of 189 consecutive patients who met clinical criteria for septic shock. INTERVENTION: A short corticotropin stimulation test was performed in all patients by intravenously injecting 0.25 mg of tetracosactrin; blood samples were taken immediately before the test (T0) and 30 (T30) and 60 (T60) minutes afterward. MAIN OUTCOME MEASURES: Twenty-eight-day mortality as a function of variables collected at the onset of septic shock, including cortisol levels before the corticotropin test and the cortisol response to corticotropin (delta max, defined as the difference between T0 and the highest value between T30 and T60). RESULTS: The 28-day mortality was 58% (95% confidence interval [CI], 51%-65%) and median time to death was 17 days (95% CI, 14-27 days). In multivariate analysis, independent predictors of death (P < or = .001 for all) were McCabe score greater than 0, organ system failure score greater than 2, arterial lactate level greater than 2.8 mmol/L, ratio of PaO2 to fraction of inspired oxygen no more than 160 mm Hg, cortisol level at T0 greater than 34 microg/dL and delta max no more than 9 microg/dL. Three groups of patient prognoses were identified: good (cortisol level at T0 < or = 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 26%), intermediate (cortisol level at T0 34 microg/dL and delta max < or = 9 microg/dL or cortisol level at T0 > 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 67%), and poor (cortisol level at T0 > 34 microg/dL and delta max < or = 9 microg/dL; 28-day mortality rate, 82%). CONCLUSION: Our data suggest that a short corticotropin test has a good prognostic value and could be helpful in identifying patients with septic shock at high risk for death.     

Alcohol intake is associated with altered pulmonary function.

Little is known about the effect of moderate alcohol intake on lung function in the general population. Because moderate alcohol intake appears to reduce cardiovascular disease risk, we hypothesized that moderate alcohol intake is associated with better pulmonary function. To test this hypothesis, we examined the association between alcohol intake and pulmonary function, measured by spirometry, in a representative sample of U.S. adults who participated in the Third National Health and Nutrition Examination Survey. A stratified multistage clustered probability design was used to select a population-based sample. Data analyzed included alcohol intake, smoking status, education, body mass, sex, age, race, diabetes status, and CHF status. The Third National Health and Nutrition Examination Survey was conducted from 1988 to 1994 by the National Center for Health Statistics of the Centers for Disease Control and Prevention, Atlanta, GA. We analyzed data from 15,294 study participants who completed extensive questionnaires in the household and a comprehensive physical examination, including pulmonary function testing, either in the household or at a specially equipped mobile examination center. Low-to-moderate alcohol intake was not associated with reduced odds of obstructive lung function. In fact, increased odds for obstructive lung pattern were observed only in former heavy drinkers. In contrast, low-to-moderate alcohol intake was associated with better forced vital capacity and forced exhaled volume in 1s in the absence of obstruction, consistent with reduced odds for lung restriction. Using a logistic regression model, we found that individuals reporting alcohol consumption had a lower risk of lung restriction both before and after adjusting for confounding factors including smoking (P< or =.001). Alcohol intake-related reduced risk for restriction was associated with lower risk of CHF, diabetes, obesity, and lower markers of inflammation (white blood cell, fibrinogen, and C-reactive protein) consistent with less lung congestion, external restriction, and/or lung inflammation. Our analyses indicate that alcohol consumption, even at very modest intake levels, is associated with less lung restriction.