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Biomedical subjects

R A Stephenson

Publications and source records attributed to R A Stephenson.

At least 19 recordsLinked to original sources
PubMed1998

Serum chromogranin A: early detection of hormonal resistance in prostate cancer patients.

We monitored both chromogranin A (CgA) and neuron specific enolase (NSE) in serial serum specimens from 14 patients with prostate cancer (CAP patients) showing resistance to hormonal treatment. Elevated serum CgA was detected in 10 out of these 14 patients (71%) during treatment, and an early appearance of elevated serum CgA was found in 6 of 14 (43%) of these patients when serum tPSA levels were still in the normal range. If patients with radical prostatectomy were not included, the percentage of patients showing an early appearance of elevated serum CgA would have been much higher. Elevated serum CgA levels also were found in patients not subject to hormonal therapy. Serial specimens from two out of three prostate cancer patients, randomly selected, contained elevated serum CgA. Serum NSE was not detectable in any of the serial specimens we studied, suggesting that CgA, not NSE, should be used as a marker for neuroendocrine differentiation. We also compared the serum CgA in random serum specimens between patients with BPH (benign prostate hyperplasia) and with prostate cancer in the concentration range of serum tPSA between 3-15 ng/mL. Although serum CgA concentrations in BPH patients overlapped considerably with those levels in patients with prostate cancer, levels > 100 ng/mL should suggest prostate cancer. The early appearance of elevated serum CgA allows an early change of therapy to be made and can lead to the effective prevention of any further development of metastases.

Androgen Antagonists↗
PubMed1998

Monitoring percent free PSA in serial specimens: improvement of test specificity, early detection, and identification of occult tumors.

We have measured the serum concentration of prostate specific antigen (tPSA) and determined the percent free PSA (% fPSA) in serial specimens from 64 patients with prostate cancer, 35 patients with benign prostate hyperplasia (BPH), and 3 patients with prostitis. We found that the % fPSAs were not a constant for individual patients during the course of the disease. When we compared only the % fPSA of the first specimen of serial specimens from individual patients, who were largely untreated, 37% of BPH specimens were above 22%, whereas only 1.6% cancer samples were above that value. We also found that 67% of cancer specimens and 14% of BPH samples were below 8%, respectively. Although % fPSA distribution pattern remained similar between two types of specimens, less differentiation was found between BPH and prostate cancer in random specimens compared to the study using first specimens of an individual patient's serial samples. Percent fPSA apparently are affected by treatment. However, the most important benefit for the determination of % fPSA appears to be the sensitivity of % fPSA to identify occult tumors when the tPSAs were in the normal concentration range. Determination of % fPSA also seems to improve the specificity of tPSA, not only during screening for the differentiation between BPH and prostate cancer, but also during monitoring of treatment and recurrence.

Humans↗
PubMed1998

Staging of testis cancer. Combining serum markers, histologic parameters, and radiographic imaging.

Treatment of testis cancer has improved dramatically over the last 25 years with cure rates that now approach 95%. This success in treatment is the result of multimodal therapy that may include cisplatinum-based chemotherapy, surgery, and radiotherapy. Although there is little dispute that chemotherapy is appropriate as initial treatment for advanced testis cancer, controversy remains regarding the management of early stage B and stage A testis cancer. In part, the current controversy is driven by the performance characteristics of presently available staging methods, that may include serum markers, histologic parameters from orchietomy specimens, and radiographic imaging. This article reviews the performance characteristics and use of these staging methods.

Biomarkers, Tumor↗
PubMed1998

Commonly occurring loss and mutation of the MXI1 gene in prostate cancer.

One of the most common chromosomal abnormalities in prostate cancer involves loss of 10q22-qter. Rarely, a smaller deletion, involving 10q24-q25, has been observed, suggesting the presence of a tumor suppressor gene at this site. We previously demonstrated that the MXI1 gene maps to 10q24-q25 and is mutated in some tumors with cytogenetically detectable deletions of this locus. MXI1 encodes a basic-helix-loop-helix protein that suppresses the transcriptional activity of the MYC oncoprotein by competing for the common dimerization partner, MAX, and binding to identical DNA sites. Because more than 90% of prostate tumors contain no cytogenetic abnormality of 10q, the relevance of MXI1 loss and/or mutation to the vast majority of cases remains unclear. We prospectively evaluated prostate tumors for loss of MXI1 by fluorescence in situ hybridization (FISH) and cytogenetic techniques. Twenty-one of 40 tumors (53%) demonstrated loss of a single MXI1 allele as determined by FISH. Ten cases with cytogenetically normal 10qs, but with FISH-documented deletion of MXI1, were examined at the molecular level, and eight mutations were identified, albeit at low frequency. Five of the mutant proteins were unable to bind DNA in association with MAX. We conclude that MXI1 gene loss in prostate cancer is common and most frequently involves a cytogenetically undetectable deletion.

Basic Helix-Loop-Helix Proteins↗
PubMed1997

Age, genetic, and nongenetic factors influencing variation in serum sex steroids and zonal volumes of the prostate and benign prostatic hyperplasia in twins.

BACKGROUND: We have observed that hereditary and environmental factors have a substantial influence on the plasma content of sex steroids in normal male twins and in men of families with prostatic disease. METHODS: The contribution of genetic and nongenetic familial factors on the variation of plasma sex steroid concentrations and of the volume of zones of the prostate measured by transrectal ultrasound (TRUS) has now been investigated in pairs of male monozygotic (MZ) and dizygotic (DZ) twin pairs between age 25-75 years. Bioelectric impedance permitted quantitation of body fat, lean body mass, and water. Morphometrics and testicular volume were also determined. RESULTS: The intraclass correlation (rI) was > 0.40 for the variation of the total volume (TV), the transition zone (TZ), the peripheral zone (PZ), and the ratio of TZ/PZ in both MZ and DZ twins, and heredity affected 22% of the variation of the PZ and TZ and 30% of the ratio of TZ/PZ. None of the TV and environmental factors influenced the remainder of the variation. Heredity accounted for 25% or more of the variation of dihydrotestosterone (DHT), and the ratios of DHT/testosterone (T), estradiol (E2)/T, androstanediol glucuronide, sex hormone-binding globulin (SHBG)-bound T, T/SHBG, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and dehydroepiandrosterone sulfate (DHEA-S). In MZ twin pairs the variation of the volumes of the prostate became greater with age. In contrast, the variation of the sex hormone concentrations did not show greater variation with age. Heredity also affected > 30% of the variation for waist measurement, weight, body fat, body mass, water and lean body mass, body mass/fat, and testicular size. CONCLUSIONS: Our results indicated that both MZ and DZ twin pairs had zonal prostate volumes more like their twin pair than like unrelated twins. However, nongenetic factors exerted stronger influences than genetic factors on zonal volumes of the prostate. In contrast, hereditary factors had stronger influences on determining the variation of many sex hormones and morphometric characteristics than did nongenetic factors.

Adult↗
PubMed1997

Population-based prostate cancer trends in the United States: patterns of change in the era of prostate-specific antigen.

We reviewed prostate cancer trends prior to and during the prostate-specific antigen (PSA) era using data reported from population-based tumor registries in the United States. On the basis of a summary of reports from several population-based tumor registries, prostate cancer incidence rose abruptly during the PSA era, peaked in 1992, and then fell just as abruptly. Prostate cancer incidence in the United States now appears to be approaching levels seen in the pre-PSA era. The flux in prostate cancer incidence (in both magnitude and slope) during the years 1988-1995 is without precedent in oncology. As expected, an age and stage migration toward early age and early stage has been observed. Unexpectedly, grade has shifted heavily toward moderate differentiation, whereas rates of poorly and well-differentiated disease have remained relatively stable. Local treatment rates, particularly radical prostatectomy rates, have risen substantially. Mortality rates appear to have leveled or declined slightly since 1991 after years of steady rise.

Aged↗
PubMed1997

Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system.

OBJECTIVES: This study examined the effects of testosterone replacement using a nonscrotal testosterone transdermal (TTD) system on prostate size and prostate-specific antigen (PSA) levels in hypogonadal men. METHODS: As part of an open-label, multicenter study, prostate volume as measured by transrectal ultrasound and PSA were assessed in 29 hypogonadal men during treatment with intramuscular testosterone enanthate (+TE), followed by 8 weeks of androgen withdrawal (-T), and then during 1 year of therapy with Androderm Testosterone Transdermal System, a nonscrotal permeation-enhanced TTD system (+TTD). RESULTS: Mean prostate volume decreased significantly from the +TE period (17 g) compared with the -T period (14 g) (P < 0.001). Prostate volume increased significantly from the -T period compared with the +TTD period (18 g) (P < 0.001). Maximum prostate size, comparable to that measured during +TE (P = 0.125), was reached by month 3 of +TTD therapy; prostate volume did not increase further during the remaining 9 months of +TTD therapy. Prostate volume correlated with age (P < 0.01) during all three periods of observation (+TE: r = 0.69; -T: r = 0.64; and +TTD: r = 0.55). No patient developed symptomatic benign prostatic hyperplasia during the treatment period. PSA levels decreased during androgen withdrawal compared with levels measured during +TE treatment (P < 0.001) and rose with resumption of androgen therapy with TTD (P < 0.006). However, PSA levels during +TTD replacement remained significantly lower (P < 0.001) than during +TE replacement. CONCLUSIONS: Physiologic testosterone replacement in hypogonadal men was achieved using the TTD system. Prostate size during therapy with TTD was comparable to that reported for normal men. In these men treated with TTD, PSA levels were also within the normal range.

Administration, Cutaneous↗
PubMed1997

Effects of age and sex hormones on transition and peripheral zone volumes of prostate and benign prostatic hyperplasia in twins.

Benign prostatic hyperplasia has been shown to increase with age and be influenced by sex hormones. The relationship between aging and hormonal influences on growth of zones of the prostate is unresolved. We studied the relationship of age and sex hormones on volume of prostate zones in 214 male twins between 25 and 75 yr old. Volumes of the total prostate (TV), transition zone (TZ), and peripheral zones (PZ) were measured using transrectal ultrasound, and sex steroid concentrations were measured using RIA. Using transformed data corrected for age, TV (r = 0.54, P < 0.00001), TZ (r = 0.58, P < 0.00001), and PZ (r = 0.39, P < 0.00001) volumes increased with age. However, the PZ volume rose more rapidly than the TZ before age 50, and TZ showed a steeper increase after age 50 yr than the PZ volume. The TZ, PZ, and ratio TZ/PZ correlated significantly (r = 0.87, 0.90, and 0.52, respectively; P < 0.00001). After a TV exceeded 30 g, the rise of the PZ became attenuated, and the slope of the TZ became steeper. Age-adjusted sex hormone concentration was not evaluated in men with larger prostate volumes. Men with American Urological Association symptom scores above 10 had significantly (P < 0.001) larger total prostate volume (TV) and TZ volume, but not PZ volumes, than men with scores below 10. Prostate volumes correlated inversely with age-adjusted serum testosterone (T), dihydrotestosterone, sex hormone binding globulin, and sex hormone binding globulin-bound T concentrations. These results demonstrate that before age 50 yr or before a prostate weight exceeds 30 g, prostate growth may be mainly from enlargement of the PZ and after age 50, the TZ. In addition, elevated T and dihydrotestosterone concentrations do not predispose men to prostate enlargement or symptoms of benign prostatic hyperplasia.

Adult↗
PubMed1997

Wide excision (nonnerve sparing) radical retropubic prostatectomy using an initial perirectal dissection.

PURPOSE: Positive surgical margin rates after radical retropubic prostatectomy are reported to range from 25 to 50% in contemporary series. We report on 53 nonnerve sparing radical retropubic prostatectomies performed with attention paid to extending the margin of attached periprostatic tissue. This was accomplished primarily by initial perirectal release of periprostatic tissues at the level of longitudinal rectal fibers posterior and lateral to the prostate. This perirectal release ensures that maximal quantities of periprostatic tissue will remain with the prostate specimen and will not be attenuated or sheared away at subsequent stages of the procedure. MATERIALS AND METHODS: Pathological material was examined for capsular penetration and surgical margins using transverse whole mount sections of the prostate at 4 to 5 mm. intervals. Patients were followed at regular intervals with physical examinations and serum prostate specific antigen (PSA) determinations. RESULTS: The series consisted of 6, 5, 14 and 28 cases of clinical stages T1b, T1c, T2a and T2b cancer, respectively. Mean PSA was 10.0 ng./ml. and mean Gleason score was 5.9. Capsular penetration was observed in 47 of 53 cases (89%) and positive surgical margins were noted in 7 (13%). With a median followup of 3.61 years 2 patients experienced PSA defined recurrence. CONCLUSIONS: We believe that positive surgical margin rates may be decreased when technical modifications are directed at increasing the amount of periprostatic tissue excised with the surgical specimen.

Follow-Up Studies↗
PubMed1997

Allelic loss detected on chromosomes 8, 10, and 17 by fluorescence in situ hybridization using single-copy P1 probes on isolated nuclei from paraffin-embedded prostate tumors.

We have implemented a reliable new technique for preparing isolated prostate cancer nuclei from paraffin-embedded tissue sections followed by analysis with single-copy fluorescence in situ hybridization (FISH). Our initial validation is described by comparison of our data with fresh prostate tumor tissue and loss of heterozygosity (LOH) studies. We also describe evaluation of 36 previously unstudied prostate cancer patients. Fifteen archival samples were selected from patients who underwent radical prostatectomy in which direct FISH and LOH data were available. Isolated nuclei were prepared and allelic loss was detected on 17q using a single-copy DNA (P1 phage) probe by FISH. A high (80%) concordance was found when comparing isolated nuclei data with 17q results from fresh preparations and LOH studies. We also examined loss at sites on 8p, 10q, and 17q in samples from 36 patients for whom clinical information was available. Loss was found at any of the three loci in 32/36 (89%) of the specimens with specific loss in 53% of the cases at the 8p locus, 33% at the 10q locus, and 61% at the 17q locus. Studies indicate that, as well as providing potential clinical information, isolated nuclei preparations are as reliable as fresh tissue for single-copy FISH studies.

Aged↗
PubMed1996

Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.

Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.

Animals↗
PubMed1996

The fall in incidence of prostate carcinoma. On the down side of a prostate specific antigen induced peak in incidence--data from the Utah Cancer Registry.

BACKGROUND: In the 1980s, prostate specific antigen (PSA) came into wide use as a prostate carcinoma screening and detection method in the United States. Following the introduction of PSA, the age-adjusted incidence of prostate carcinoma reported by the Surveillance, Epidemiology, and End Results (SEER) program in the United States rose rapidly (from 84.4/100,000 in 1984 to 163/100,000 in 1991). When an increase in incidence is observed following the introduction of a screening method, a subsequent decrease in incidence may be expected as prevalent cases are removed from the population (a cull effect). Incidence rates may also fall due to factors such as decreased intensity of screening. The Utah Cancer Registry data were examined for a decrease in prostate cancer incidence. METHODS: We tracked age-adjusted prostate carcinoma incidence trends from the population-based Utah Cancer Registry and compared them with rates from the SEER national registry. RESULTS: A rapid and highly correlated rise in prostate carcinoma incidence has been observed in both SEER and Utah incidence rates between 1988 and 1991, the last year for which SEER data are available. In 1992, Utah incidence rates peaked at 236.2 per 100,000. In 1993 and 1994, Utah incidence rates fell to 195.0, and an estimated 164.0 per 100,000, respectively. CONCLUSIONS: Population-based data from the Utah Cancer Registry indicates that the incidence of prostate carcinoma is decreasing rapidly after a similarly rapid increase.

Age Factors↗
PubMed1996

Renal cryoablation in a canine model.

OBJECTIVES: To assess the potential safety and utility of cryoablation for treatment of selected renal tumors in a canine model. METHODS: Ultrasound and direct physical measurements (depth and width) of five cryolesions were compared. Cryolesions were examined histologically in 6 animals, which were killed at 4 hours, 2 days, 1 week, 3 weeks, 6 weeks, and 12 weeks. Mortality/morbidity was assessed in 12 animals over a 1-month interval, where 6 animals received small (approximately 2 cm) cryolesions and 6 animals received large (one third to one half of kidney) cryolesions. Laparoscopic cryoablation was performed in 2 animals. RESULTS: A statistically significant association of physical and ultrasound dimensions was observed (correlation coefficient R = 0.9295; P = 0.0001). Histologic studies in animals killed up to 1 week after cryoablation revealed complete coagulative necrosis within the cryolesion. The boundary transition from normal to complete tissue necrosis occurred in 1 to 2 mm. Animals killed 3 weeks to 3 months after cryoablation revealed progressive organization with granulation tissue, chronic inflammation, hemosiderosis, fibrosis, and contraction of the cryolesion with parenchymal loss. Untreated renal tissue was histologically normal in all kidneys. No mortality or morbidity was detected in the 12 animals followed for 30 days regardless of the size of the cryolesion. Laparoscopic cryoablation was performed successfully in 2 animals without modification of standard laparoscopic methods. CONCLUSIONS: Sonographic, histologic, and laparoscopic data in a canine model suggest that cryoablation may be a safe, feasible, and useful method for treatment of selected renal neoplasms.

Animals↗
PubMed1996

Evidence for a tumor suppressor gene distal to BRCA1 in prostate cancer.

PURPOSE: The breast-ovarian cancer susceptibility gene, BRCA1, has been implicated by both epidemiologic and genetic studies to be involved in prostate cancer. We wished to test the frequency of BRCA1 deletion and that of other markers in the region of proximal 17q in prostate tumor cells. MATERIALS AND METHODS: We used a dual-color fluorescence in situ hybridization (FISH) assay using P1 phage probes for the BRCA1 gene and 3 flanking sites at 17q12-21, as well as a chromosome 17 centromere-specific alpha-satellite probe, to detect deletions in single-cell suspensions and touch preparations from 23 primary clinical stage B prostate tumors and adjacent nontumor prostate tissues. Lymphoblastoid cells and prostate cells from a normal donor were used to determine control loss values. RESULTS: Significant loss (p < 0.05) of at least 1 of the P1s was detected in 16 of 23 (70%) cases, and in 4 of those cases all markers were lost, consistent with whole chromosome loss. Of the 12 cases with subchromosomal loss, 8 had loss distal to BRCA1. Loss was detected in 5 cases previously reported by using allelic imbalance (AI) methodologies, and was detected in an additional 11 non-AI cases, suggesting that FISH is more sensitive than AI for deletion detection in prostate tumor cells. CONCLUSIONS: The data suggest that the region distal to BRCA1 may contain 1 or more prostate-specific tumor suppressor genes and that BRCA1 itself plays only a minor role in prostate cancer development.

BRCA1 Protein↗
PubMed1996

Repair of rectourinary fistulas using a posterior sagittal transanal transrectal (modified York-Mason) approach: an update.

PURPOSE: We report our experience with posterior sagittal, transanal, transrectal repair of rectourinary fistulas. MATERIALS AND METHODS: A total of 16 fistula repairs was done in 15 patients. RESULTS: Of the fistulas 13 occurred after a variety of prostatic procedures, 1 after Y-V plasty and 1 after pelvic trauma (2 repairs were attempted in the latter case). Six patients underwent repair without colostomy. No patient experienced fecal or anal complications and all repairs were successful. CONCLUSIONS: Our surgical approach for repair of rectourinary fistulas is simple, effective, associated with minimal morbidity and cost-effective.

Fractures, Bone↗
PubMed1996

Cellular proliferative fraction of metastatic lymph nodes predicts survival in stage D1 (TxN+M0) prostate cancer.

PURPOSE: We assessed the ability of tumor cellular proliferative fraction to predict long-term survival among patients with lymphatic metastases from prostate cancer. MATERIALS AND METHODS: We studied 50 patients with stage D1 (TxN+M0) prostate cancer who underwent pelvic lymphadenectomy and 125iodine seed implantation between 1970 and 1978. We used the MIB-1 monoclonal antibody to Ki67 to stain sections of the lymphatic metastases in these patients. The Ki67 proliferative fraction was defined as the fraction of positively stained malignant nuclei. We also used flow cytometry to determine the deoxyribonucleic acid content of the lymphatic metastases. RESULTS: Median followup was 6.1 years. Patients whose metastases had a Ki67 proliferative fraction of less than 0.1 had significantly longer survival compared to those with a proliferative fraction of greater than 0.1 (8.7 years versus 4.4 years, respectively, p = 0.005, log rank test). The Ki67 proliferative fraction and ploidy were not independent variables. Patients whose metastases were diploid had a significantly longer survival than those with aneuploid metastases (8.8 years versus 4.4 years, respectively, p = 0.01, log rank test). Multivariate analysis showed that ploidy had a slightly stronger effect on survival than did the Ki67 proliferative fraction. CONCLUSIONS: Cellular proliferative fraction of lymphatic metastases is useful to predict survival in patients with stage D1 prostatic carcinoma. Proliferative fraction may be useful as a marker of progression among patients with other stages of disease.

Biomarkers, Tumor↗
PubMed1996

Does transurethral resection of the prostate compromise the radical treatment of prostate cancer?

Obstructive voiding symptoms are frequent complaints in men with prostate cancer. Some men with prostate cancer require transurethral resection of the prostate (TURP) for relief of these symptoms. Two central questions have been raised regarding whether TURP may have adverse effects on morbidity and mortality in patients with prostate cancer. The first question deals with potential tumor cell dissemination at the time of TURP, resulting increased progression and mortality rates. A review of the literature suggests the risk of tumor dissemination during a TURP is small or negligible. However, patients with prostate cancer and obstructive symptoms appear to have a greater likelihood of high-stage disease at presentation. When the pathological stage is known, progression and mortality outcomes are similar in TURP and non-TURP treated patients with prostate cancer. The second question deals with the potential that TURP increases treatment-related morbidity of radiation therapy or radical prostatectomy. When TURP is required before radiation therapy, the literature suggests that delaying radiation 6 to 8 weeks from the time of the TURP will minimize incontinence and bladder neck contracture to acceptable levels. The literature also indicates that radical prostatectomy may be performed with no increased morbidity following a TURP.

Humans↗