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Patrick C Walsh

Publications and source records attributed to Patrick C Walsh.

At least 145 records · Page 8Linked to original sources
PubMed2002

Sequence variants in the human 25-hydroxyvitamin D3 1-alpha-hydroxylase (CYP27B1) gene are not associated with prostate cancer risk.

BACKGROUND: 1,25-dihydroxyvitamin D(3) has been shown to have antiproliferative properties on normal and neoplastic prostatic cells. 25-hydroxyvitamin D(3) 1-alpha-hydroxylase, the enzyme that catalyzes the final step of vitamin D synthesis, converting 25-hydroxyvitamin D(3) to 1,25-dihydroxyvitamin D(3), is expressed in the prostate. METHODS: The human 25-hydroxyvitamin D(3) 1-alpha-hydroxylase gene (CYP27B1) was resequenced in a case/control panel consisting of 64 individuals (48 Caucasians and 16 African Americans), with equal numbers of hereditary prostate cancer cases, sporadic cases, and unaffected controls. Three frequent single nucleotide polymorphisms (SNPs) were genotyped in 245 prostate cancer cases and 222 controls. RESULTS: Six noncoding SNPs were identified in the CYP27B1 gene. No significant difference was found in allele and genotype frequencies between sporadic cases and unaffected controls for the three genotyped SNPs. CONCLUSION: This study suggests that the CYP27B1 gene does not play a major role as a prostate cancer susceptibility gene.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2002

Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.

Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.

Aged↗
PubMed2002

Transmission/disequilibrium tests of androgen receptor and glutathione S-transferase pi variants in prostate cancer families.

Population-based case-control studies have found relationships between risk of prostate cancer and genetic polymorphisms in the CAG repeat and GGC repeat of the X-linked androgen receptor gene (AR) as well as the autosomal gene coding for glutathione S-transferase pi (GSTP1). This family-based study utilized the transmission disequilibrium test to examine whether there was evidence that these polymorphisms could account for familial aggregation of prostate cancer. Seventy-nine North American pedigrees were studied. Most of these families had 3 or more affected first-degree relatives. Genotype information was obtained on 578 individuals. The reconstruction combined transmission disequilibrium test (RC-TDT) was used to test for linkage. There was no evidence of linkage to the CAG and GGC repeat sequences in the AR gene or the pentanucleotide (ATAAA) repeat in the GSTP1 gene when each allele was analyzed separately or when alleles were grouped by repeat length. Our findings do not support the hypothesis that familial clustering of prostate cancer in high-risk families is attributable to these genetic variants.

Adult↗
PubMed2002

Associations between hOGG1 sequence variants and prostate cancer susceptibility.

8-Hydroxyguanine is a mutagenic base lesion produced by reactive oxygen species. The hOGG1 gene encodes a DNA glycosylase/AP lyase that can suppress the mutagenic effects of 8-hydroxyguanine by catalyzing its removal from oxidized DNA. A population-based (245 cases and 222 controls) and family-based (159 hereditary prostate cancer families) association study was performed to test the hypothesis that sequence variants of hOGG1 increase susceptibility to prostate cancer. We found that the genotype frequency of two sequence variants (11657A/G and Ser326Cys) was significantly different between cases and controls. The association with 11657A/G is confirmed and strengthened by our family-based association study. These results suggest that sequence variants in this gene are associated with prostate cancer risk, presumably through defective DNA repair function of hOGG1.

Case-Control Studies↗
PubMed2002

Joint effect of HSD3B1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility.

3beta-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3'-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing. Eleven single nucleotide polymorphisms (SNPs) were identified, four of which, including a missense change (B1-N367T), were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak association between prostate cancer risk and a missense SNP (B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Men with the variant genotypes at either B1-N367T or B2-c7519g had a significantly higher risk to develop prostate cancer, especially the hereditary type of prostate cancer. Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association. Additional studies are warranted to confirm these findings.

3-Hydroxysteroid Dehydrogenases↗
PubMed2002

Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk.

Androgen receptor (AR) has long been hypothesized to play an important role in prostate cancer etiology. Two trinucleotide repeat polymorphisms (CAG and GGC repeats in exon 1 of the AR gene) have been investigated as risk factors for prostate cancer in several studies. However, the results are inconclusive, probably because of the variations of study designs, characteristics of study samples, and choices of analytical methods. In this study, we evaluated evidence for linkage and association between the two AR repeats and prostate cancer by using the following comprehensive approaches: (1) a combination of linkage and association studies, (2) a test for linkage by parametric analysis and the male-limited X-linked transmission/disequilibrium test (XLRC-TDT), (3) a test for association by using both population-based and family-based tests, and (4) a study of both hereditary and sporadic cases. A positive but weak linkage score (HLOD=0.49, P=0.12) was identified in the AR region by parametric analysis; however, stronger evidence for linkage in the region, especially at the GGC locus, was observed in the subset of families whose proband had < or = 16 GGC repeats (HLOD=0.70, P=0.07) or by using XLRC-TDT ( z'=2.65, P=0.008). Significantly increased frequencies of the < or = 16 GGC repeat alleles in 159 independent hereditary cases (71%) and 245 sporadic cases (68%) cases compared with 211 controls (59%) suggested that GGC repeats were associated with prostate cancer ( P=0.02). Evidence for the association between the < or = 16 GGC repeats and prostate cancer risk was stronger with XLRC-TDT ( z'=2.66, P=0.007). No evidence for association between the CAG repeats and prostate cancer risk was observed. The consistent results from both linkage and association studies strongly implicate the GGC repeats in the AR as a prostate cancer susceptibility gene. Further studies on this polymorphism in other independent data sets and functional analysis of the GGC repeat length on AR activity are warranted.

Ethnicity↗
PubMed2002

A critical analysis of the interpretation of biochemical failure in surgically treated patients using the American Society for Therapeutic Radiation and Oncology criteria.

PURPOSE: The use of prostate specific antigen (PSA) to indicate biochemical failure has become an accepted procedure to measure the effectiveness of therapy. Because long-term randomized studies comparing radiation modalities to radical prostatectomy are not available, use of biochemical recurrence as a surrogate measure of efficacy is increasing. Unfortunately, the definition of failure is not uniform among therapies. We evaluate how the American Society for Therapeutic Radiation and Oncology (ASTRO) criteria affect the interpretation of failure when applied to radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed data from 2,691 men who underwent anatomical radical prostatectomy for localized disease between 1985 and 2000. All patients had regular followup visits ranging from 6 months to 15 years (mean 6). No patients were treated with radiation or hormonal therapy preoperatively or postoperatively until clinical recurrence. Biochemical failure was defined as any measurable PSA 0.2 ng./ml. or greater. We evaluated how elements of the ASTRO criteria affected the failure rate when applied to this series. We looked at 1) backdating the failure date to the midpoint between nadir and first PSA greater than 0.2 ng./ml., 2) early censoring if only 1 or 2 increasing values were available and 3) defining failure after 3 consecutive PSA increases and backdating failure time (midpoint of nadir and first PSA increase). RESULTS: Using actuarial analysis of the data defining failure as the first PSA 0.2 ng./ml. or greater, biochemical freedom from failure at 5, 10 and 15 years was 85%, 77% and 68%, respectively. In contrast, when backdating was used in this series, almost all failures occurred early with rare late failures (freedom from failure 82%, 80% and 80% at 5, 10 and 15 years, respectively). The difference in failure became even more pronounced when ASTRO criteria were applied requiring 3 consecutive increases, and backdating failure to the midpoint between nadir and first PSA (freedom from failure 90%, 90% and 90% at 5, 10 and 15 years, respectively). CONCLUSIONS: The application of ASTRO criteria to a mature series of surgically treated patients with localized prostate cancer produced an apparent improvement in the probability of being biochemically free of disease at 15 years from 68% to 90%. Until prospective trials comparing these different therapies become available, caution should be exercised when interpreting outcomes between series due to the inherent differences in definition of biochemical failure.

Actuarial Analysis↗
PubMed2002

Influence of biopsy perineural invasion on long-term biochemical disease-free survival after radical prostatectomy.

OBJECTIVES: To investigate the influence of biopsy perineural invasion (PNI) on long-term prostate-specific antigen recurrence rates, final pathologic stage, and surgical margin status of men treated with radical prostatectomy. Radical prostatectomy offers the best chance for surgical cure when performed for organ-confined disease. However, the histologic identification of PNI on prostate biopsy has been associated with a decreased likelihood of pathologically organ-confined disease. METHODS: Seventy-eight men with histologic evidence of PNI on biopsy underwent radical prostatectomy by a single surgeon between April 1984 and February 1995 and were compared with 78 contemporary matched (biopsy Gleason score, prostate-specific antigen level, clinical stage, age) controls without PNI. Biochemical disease-free survival and pathologic findings were compared. RESULTS: After a mean follow-up of 7.05 +/- 2.2 years and 7.88 +/- 2.7 years (P = 0.04) for patients with biopsy PNI and controls, respectively, no significant difference in the long-term prostate-specific antigen recurrence rates was observed (P = 0.13). The final Gleason score and pathologic staging were also similar in this matched cohort. Although the numbers of neurovascular bundles resected were comparable between the groups, no difference was found in the rate of positive surgical margins identified (13% versus 10%, P = 0.62). CONCLUSIONS: We were unable to show that PNI on needle biopsy influences long-term tumor-free survival.

Analysis of Variance↗
PubMed2002

Intussusception of the reconstructed bladder neck leads to earlier continence after radical prostatectomy.

INTRODUCTION: Although there is no evidence that the reconstructed bladder neck actively contributes to post-radical prostatectomy continence, we set out to determine whether buttressing sutures, which prevent the bladder neck from pulling open as the bladder fills, would result in the earlier return of urinary control. TECHNICAL CONSIDERATIONS: Forty-five men (mean age 57 years, range 37 to 67) with clinical localized prostate cancer underwent anatomic radical retropubic prostatectomy with standard tennis racket bladder neck reconstruction. The bladder neck was then intussuscepted using two 2-0 Maxon Lembert sutures placed lateral and posterior to the reconstructed bladder neck. Filling of the bladder with saline at this point revealed little leakage. Patient-reported continence at 3 months was compared with the published outcome of 64 men using the same quality-of-life instrument (the UCLA Prostate Cancer Index). At 3 months, 82% of men who underwent intussusception of the bladder neck were continent (no pad/dry pad) compared with 54% in our prior report (P = 0.0035). The occurrence of bladder neck contracture was similar: 7% versus 5%. CONCLUSIONS: Intussusception of the bladder neck led to a significant improvement in urinary control at 3 months postoperatively. Longer follow-up will be necessary to determine whether this approach may eliminate the 2% probability of long-term significant problems with urinary control.

Adult↗
PubMed2002

Substratification of stage T1C prostate cancer based on the probability of biochemical recurrence.

OBJECTIVES: To evaluate the influence of preoperative prostate-specific antigen (PSA), biopsy Gleason sum, and prostate biopsy quantitative histologic findings on the probability of biochemical failure in an attempt to identify criteria to substratify Stage T1c prostate cancer more accurately. METHODS: We reviewed the records of 1149 patients who underwent prostatectomy for T1c disease between 1988 and 2000. Biochemical recurrence (PSA 0.2 ng/mL or greater) defined the endpoint in this study. Recursive partitioning analysis was used to establish cutpoints for preoperative PSA level, biopsy Gleason sum, number of positive biopsy cores, and maximal percentage of any single biopsy core involved with cancer. These cutoff values were then evaluated using Kaplan-Meier estimations to determine the probability of remaining biochemically recurrence free. RESULTS: Using a PSA cutpoint of 10 ng/mL or a biopsy Gleason sum of 7, two groups of patients were identified (T1cI and T1cII). The rate of freedom from PSA recurrence at 3, 5, and 10 years after surgery for T1cI was 98%, 96%, and 96%, respectively, and for T1cII was 86%, 83%, and 73%, respectively (P <0.001). For T1cII patients, the greatest percentage of cancer in a single biopsy core was found to be a predictor of biochemical failure on multivariate analysis and, using a cutoff value of 50%, further stratified the PSA recurrence-free rates for the men in group T1cII (90% and 85% versus 75% and 56% at 5 and 10 years after surgery, respectively, P = 0.03). CONCLUSIONS: The results of this study demonstrate that within Stage T1c there are two populations of patients with significantly different recurrence probabilities: T1cI (Gleason sum less than 7 and PSA 10 ng/mL or less) and T1cII (Gleason sum 7 or greater or PSA greater than 10 ng/mL). Furthermore, using a cutpoint of 50% of cancer in a single core of biopsy tissue, additional risk stratification is afforded to men with higher risk "T1cII" cancer.

Aged↗
PubMed2002

Expectant management of nonpalpable prostate cancer with curative intent: preliminary results.

PURPOSE: We evaluate a strategy of expectant management for men with stage T1c prostate cancer. MATERIALS AND METHODS: A total of 81 men (median age 65 years, range 52 to 72) with stage T1c prostate cancer who were thought to have small volume prostate cancer based on needle biopsy findings and prostate specific antigen (PSA) density were followed for more than 1 year with semiannual PSA and digital rectal examination, and annual prostate biopsies (median followup 23 months, range 12 to 58). A recommendation for treatment was made if disease progression was indicated by unfavorable followup needle biopsy findings (Gleason pattern 4 or 5, greater than 2 biopsy cores with cancer, greater than 50% involvement of any core with cancer). Curable disease was defined on pathological examination of radical prostatectomy specimens as 1) organ confined cancer of Gleason score 7 or less, 2) cancer with extraprostatic extension of Gleason score 7 (3+4) or less with negative margins, seminal vesicles and lymph nodes, or 3) cancer of Gleason score 6 or less regardless of margin status or extraprostatic extension if negative seminal vesicles and lymph nodes. RESULTS: Of the 81 men 25 (31%) had progression of disease at followup. PSA density was statistically significantly higher (p = 0.01) and the percentage of free PSA was statistically significantly lower (p = 0.04) in men with compared to those without disease progression. Disease progression occurred in 22 of 39 men (56%) with every followup biopsy showing cancer compared to 3 of 42 (2%) men with 1 or more negative followup biopsies (p <0.001). Of the 25 men with progression 13 underwent radical prostatectomy and 12 of 13 (92%) had curable cancers. CONCLUSIONS: Expectant management with curative intent may be a reasonable alternative for carefully selected older men who are thought to have small volume cancers.

Aged↗