Don McMahon

Molecular staging of prostate cancer with the use of an enhanced reverse transcriptase-PCR assay

OBJECTIVEnBecause up to 40 percent of surgically treated patients with prostate cancer are subsequently found to be clinically understaged, a more sensitive staging modality to identify extraprostatic disease prior to surgery is required.nnnMETHODSnWe describe an enhanced reverse transcriptase [RT] polymerase chain reaction (PCR) assay utilizing oligonucleotide primers specific for the human prostate-specific antigen (PSA). This assay identifies PSA-synthesizing cells from reverse transcribed mRNA. This assay was applied to RNAs extracted from the peripheral blood lymphocytes of 65 patients with clinically localized prostate cancer. In addition, blood from 20 women, 20 young men, 25 age-matched control men under treatment for benign prostatic hyperplasia (BPH), and 18 men with established, untreated metastatic prostate cancer was tested.nnnRESULTSnAn RT-PCR assay for PSA can recognize one PSA-expressing cell diluted into one hundred thousand lymphocytes. The sensitivity of this assay can be enhanced by the addition of digoxigenin-modified nucleotides to the PCR reaction and this assay was applied to RNAs extracted from the peripheral lymphocyte fraction of 148 prostate cancer patients and controls at this institution. Although no specimen from women or men without cancer was positive in this assay, 14 of 18 metastatic prostate cancer patients were positive (77.8%). Additionally, 25 of 65 (38.5%) patients with clinically localized disease (T1-2b) were positive from blood specimens obtained prior to surgery. Final pathologic results from this group of patients identified a correlation between positivity on this assay and the presence of capsular tumor penetration (sensitivity, 68%; specificity, 84%) as well as strong correlation with the finding of carcinoma at the surgical margin (sensitivity, 87%; specificity, 76%). Logarithmic regression analysis of the results of the RT-PCR assay indicates its remarkable superiority to digital rectal examination, computed tomography scan, endorectal coil magnetic resonance imaging, PSA, prostate-specific antigen density, or Gleason score for predicting the true pathologic stage of prostate cancer in these surgically treated patients.nnnCONCLUSIONSnAn RT-PCR assay using PSA primers to detect prostate cells in the peripheral circulation of surgical-candidate patients is significantly correlated with capsular penetration and tumor-positive surgical margins. This molecular assay provides a sensitive and specific means to stage correctly apparent localized prostate cancer prior to radical prostatectomy.

Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy

Objective: Antiepileptic drugs (AEDs) may have adverse effects on bone mineral density (BMD) and metabolism. We previously reported biochemical evidence of increased bone turnover in premenopausal women with epilepsy on phenytoin monotherapy compared with those on carbamazepine, lamotrigine, and valproate. We therefore hypothesized that rates of bone loss would be higher in young women treated with phenytoin. Methods: Ninety-three premenopausal women with epilepsy receiving a single AED (carbamazepine, lamotrigine, phenytoin, or valproate) participated. Subjects completed nutritional and physical activity questionnaires. Biochemical indices of bone and mineral metabolism and BMD of the proximal femur and lumbar spine were measured at baseline and 1 year. Results: Participants reported high calcium intake (>1,000 mg/day) and were physically active. Significant loss (2.6%) was seen at the femoral neck in the phenytoin group. BMD remained stable in the other AED groups. Bone turnover markers and calciotropic hormones were unchanged after 1 year in all groups except for a significant decline in urine N-telopeptide in the phenytoin group. In women receiving phenytoin, lower serum 25-hydroxyvitamin D concentrations were associated with higher parathyroid hormone, bone alkaline phosphatase, and urine N-telopeptide levels, a biochemical pattern consistent with secondary hyperparathyroidism and increased remodeling. Conclusion: In this study, young women treated with phenytoin had significant femoral neck bone loss over 1 year. In contrast, those treated with carbamazepine, lamotrigine, and valproate did not have detectable adverse effects on bone turnover or bone mineral density. These results raise concerns about the long-term effects of phenytoin monotherapy on bone in young women with epilepsy. GLOSSARY: 1,25(OH)2D = 1,25-dihydroxyvitamin D; AED = antiepileptic drug; ANOVA = analysis of variance; BCE = bone collagen equivalent; BMD = bone mineral density; BMI = body mass index; BSAP = bone-specific alkaline phosphatase; CBZ = carbamazepine; FN = femoral neck; LS = lumbar spine; LTG = lamotrigine; NTx = cross-linked N-telopeptide of type I bone collagen; OHD = 25-hydroxyvitamin D; PHT = phenytoin; PTH = parathyroid hormone; TH = total hip; VPA = valproate.

Molecular Stating of Prostate Cancer. II. A Comparison of the Application of an Enhanced Reverse Transcriptase Polymerase Chain Reaction Assay for Prostate Specific Antigen Versus Prostate Specific Membrane Antigen

AbstractCurrent imaging modalities used to stage prostate cancer clinically fail to detect extracapsular disease in a significant subset of patients. A molecular based peripheral blood assay using the reverse transcriptase polymerase chain reaction has recently been shown to be a highly sensitive staging modality for detecting extraprostatic disease preoperatively. The assay uses primers that are specific for prostate specific antigen (PSA). We compare the application of the reverse transcriptase polymerase chain reaction assay using primers specific for the human prostate specific membrane antigen with results obtained from the same specimens by reverse transcriptase polymerase chain reaction for PSA. Prostate specific membrane antigen, a recently cloned prostatic antigen, is a transmembrane glycoprotein that has been described as prostate specific. These assays were applied to ribonucleic acids extracted from the peripheral blood lymphocyte fraction of 80 patients with clinically localized prostate canc...

Vitamin D deficiency is associated with subclinical carotid atherosclerosis: the Northern Manhattan Study

Background and Purpose— The purpose of this study was to assess the association of vitamin D deficiency and indices of mineral metabolism with subclinical carotid markers that predict cardiovascular events. Methods— Two hundred three community-dwelling adults (Northern Manhattan Study; age, 68±11; age range, 50 to 93 years) had serum measurements (calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone) and carotid ultrasound (plaque presence, number, maximal carotid plaque thickness, intima-media thickness). Results— Adjusting for cardiovascular risk factors, plaque number was associated with phosphorus levels (&bgr;=0.39 per 1-mg/dL increase; P=0.02) and calcium–phosphorus product (&bgr;=0.36 per 10-U increase; P=0.03). In those with plaque (N=116 [57%]), the association of plaque number with phosphorus and calcium–phosphorus product persisted. In addition, 25-hydroxyvitamin D was inversely associated with both intima-media thickness (&bgr;=−0.01 per 10-ng/mL increase; P=0.05) and maximal carotid plaque thickness (&bgr;=−0.10 per 10-ng/mL increase; P=0.03). In a model containing traditional cardiac risk factors and indices of mineral metabolism, 25-hydroxyvitamin D accounted for 13% of the variance in both intima-media thickness and maximal carotid plaque thickness. Calcium, parathyroid hormone, and 1,25-dihydroxyvitamin D levels were not associated with carotid measures. Conclusions— After adjusting for cardiovascular risk factors and renal function, serum phosphorus and calcium–phosphorus product were associated with a greater burden of subclinical carotid atherosclerosis. Low 25-hydroxyvitamin D levels were associated with increased intima-media thickness and maximal carotid plaque thickness in those with plaque, and 25-hydroxyvitamin D contributed in a robust manner to the variance in both. These results confirm and extend data on the association of low vitamin D levels with subclinical carotid atherosclerosis. The precise nature of this association and the optimum levels of vitamin D for vascular health remain to be elucidated.

Characteristics of elderly patients admitted to an urban tertiary care hospital with osteoporotic fractures: correlations with risk factors, fracture type, gender and ethnicity.

Osteoporosis is a major public health problem in the United States of America and around the world, largely due to the morbidity and mortality associated with osteoporotic fractures. In the past decade, large epidemiologic studies have contributed greatly to our understanding of patients who fracture. However, most studies are limited to postmenopausal white women. In this retrospective review, we analyze data from 185 men and women with acute fragility fractures who received osteoporosis consultations during admission to a single urban hospital between 2001 and 2003. Men and women differed in terms of risk factors for falls and osteoporosis but had areal bone mineral density (BMD) measurements remarkably similar, except at the total hip. Black and Hispanic subjects with fractures were significantly younger than whites yet were much more likely to have serious co-morbidities, such as diabetes mellitus and hypertension. In spite of significantly higher BMD measurements, black patients had the highest rates of vitaminxa0D deficiency and secondary hyperparathyroidism. Patients admitted with hip fractures differed from those with non-hip fractures on a number of important variables. Based on these data, we conclude that elderly subjects admitted to an urban hospital with osteoporotic fractures are a heterogeneous group, with features that vary according to fracture type, gender and ethnicity. Future studies of patients with clinical fragility fractures should include ample numbers of men and ethnic minorities, since differences in underlying risk factors may suggest alternative strategies for fracture prevention.

Use of complementary and alternative medicine among Dominican emergency department patients

This small, pilot study examined presenting complaint, brief health history, use of complementary and alternative medicine (CAM), and sociodemographic characteristics, among patients attending the emergency department (ED) of a large urban hospital. The sample (n = 50) was primarily Dominican and of low socioeconomic status. Almost half had used CAM for their presenting complaint or another health problem during the past year, most commonly in the form of medicinal plants made into herbal teas. CAM users were more likely to be female, longer-term residents of the United States, and to have also used religious practices for health problems. Subjects who had used CAM for any problem other than the presenting complaint during the past year rated its effectiveness higher than subjects who had used CAM for their presenting complaint. In conclusion, it is likely that a significant proportion of Dominican ED patients use CAM, suggesting that they should be asked about their CAM use during triage.

Normal vitamin D and low free estradiol levels in women on enzyme-inducing antiepileptic drugs

Relationships between reproductive hormone levels, bone turnover marker levels, bone mineral density, and rates of bone loss were evaluated in premenopausal women with epilepsy taking enzyme-inducing antiepileptic drugs (EIAEDs: phenytoin or carbamazepine) or lamotrigine. Calciotropic and reproductive hormone levels, bone turnover marker levels, and bone mineral density were measured at baseline and 1 year. Bone mineral density did not differ between groups. Serum calcium (P<0.001) and estrone (P<0.001) levels were lower in the EIAED group. Sex hormone-binding globulin levels were higher (P<0.001) and percentage free estradiol levels were lower (P<0.001) in the EIAED group. We detected no relationship between bone mineral density change and calciotropic hormone or bone turnover marker levels. Women with higher sex hormone-binding globulin and lower free estradiol levels sustained more bone loss at the total hip (P=0.04 and P=0.02) and a trend toward more bone loss at the lumbar spine (P=0.07 and P=0.08). These findings suggest that lower estrogen levels may contribute to bone loss in premenopausal women with epilepsy.

Likelihood of contact with AIDS patients as a factor in medical students' residency selections.

Abstract Results from the National Resident Matching Program for the years 1980, 1983, and 1987 were used to examine changes over time in the matches of U.S. medical students to residencies in cities with high concentrations of patients with acquired immunodeficiency syndrome (AIDS) and to specialties in which the care of AIDS patients was most concentrated. Medical students seeking postgraduate training in categorical surgery residency programs were less likely to be matched with programs located in areas where the numbers of reported AIDS cases were high in 1987 as compared with the “pre‐AIDS” years of 1980 or 1983. This trend was more pronounced for students from medical schools located in cities with high numbers of AIDS cases. There was a decline in matches to residencies in categorical internal medicine nationally, regardless of location; this decline was also greater among the students coming from medical schools in cities with high numbers of AIDS cases. The authors discuss the implications for medical educators of declines in matches to specialties in which the care of AIDS patients is most concentrated. The imperfect nature of available measures of students exposure to AIDS patients makes the data of this study preliminary, and further studies are being undertaken. However, the finding of significant effects in spite of the imprecision of some measures suggests that future work will confirm the results of this study. Acad. Med. 64(1989):588–594.