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Patrick C Walsh

Publications and source records attributed to Patrick C Walsh.

At least 73 records · Page 4Linked to original sources
PubMed2004

Mutational analysis of PINX1 in hereditary prostate cancer.

BACKGROUND: Telomerase activity is increased in most tumors. PinX1 has recently been identified as a critical component in regulating telomerase activity. The PinX1 gene is located within chromosomal region 8p22-23, a region associated with LOH and potentially linked to increased prostate cancer risk. METHODS: PINX1 was re-sequenced in 159 hereditary prostate cancer (HPC) probands. Four non-synonymous coding variants were genotyped in 159 HPC families. RESULTS: Thirty-nine polymorphisms were identified in the HPC screening panel. Ten coding polymorphisms were identified, seven (Gln50His, Leu91Met, Gln206His, Arg215Ile, Thr220Ala, Ser254Cys, and Glu414Ala) of which were non-synonymous. The most common variants Thr220Ala and Ser254Cys were not significantly over-transmitted from affected parent to affected offspring. CONCLUSIONS: Based on these results, we conclude that PINX1 is not a major factor for HPC risk.

Cell Cycle Proteins↗
PubMed2004

Combined genome-wide scan for prostate cancer susceptibility genes.

BACKGROUND: Prostate cancer represents a substantial public health burden worldwide. It is the second leading cause of cancer death among men in the United States. A family history of the disease is among the most well-established risk factors for prostate cancer. Efforts to localize prostate cancer susceptibility alleles by using genetic linkage analysis methods have been hindered by genetic heterogeneity, incomplete penetrance, disease phenocopies, and the lack of DNA samples from parents of individuals with late-onset prostate cancer. METHODS: We performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer (HPC) study populations to systematically search for prostate cancer susceptibility genes. To decrease the degree of locus heterogeneity, we analyzed subsets of families with similar clinical and demographic characteristics. Nonparametric multipoint linkage was the primary method of analysis. Results are presented as allele-sharing logarithm of the odds (LOD) scores, and all reported P values are two-sided. RESULTS: The strongest evidence for prostate cancer linkage was found at chromosome region 17q22 (nonparametric multipoint Kong and Cox allele-sharing LOD score = 3.16 at marker D17S787; P =.00007). Stratified analyses revealed several additional chromosomal regions that are likely to segregate prostate cancer susceptibility genes among specific subsets of HPC families, including 15q11 among families with late-onset disease (allele-sharing LOD = 5.57 at marker D15S128; P<.00001) and 4q35 among families with four or more affected family members (allele-sharing LOD = 3.10 at marker D4S1615; P =.00008). CONCLUSION: Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.

Biomarkers, Tumor↗
PubMed2004

Interaction effect of PTEN and CDKN1B chromosomal regions on prostate cancer linkage.

The tumor suppressor functions of PTEN and CDKN1B have been extensively characterized. Recent data from mouse models suggest that, for some organs, the combined action of both PTEN and CDKN1B has a stronger tumor suppressor function than each alone; for the prostate, heterozygous knockout of both genes leads to 100% penetrance for prostate cancer. To assess whether such an interaction contributes to an increased risk of prostate cancer in humans, we performed a series of epistatic PTEN and CDKN1B interaction analyses in a collection of 188 high-risk hereditary prostate cancer families. Two different analytical approaches were performed; a nonparametric linkage (NPL) regression analysis that simultaneously models allele sharing at these two regions in all families, and an ordered subset analysis (OSA) that assesses linkage evidence at a target region in a subset of families based on the magnitude of allele sharing at the reference region. The strongest evidence of interaction effect was observed at 10q23-24 and 12p11-13 from both the NPL regression analysis (P = 0.0002) in all families and the OSA analyses in subsets of families. A LOD-delta of 3.15 (P = 0.01) was observed at 10q23-24 among 54 families with the highest NPL scores at 12p11-13, and a LOD-delta of 2.63 (P = 0.02) was observed at 12p11-13 among 34 families with the highest NPL scores at 10q23-24. The evidence for the interaction was stronger when using additional fine-mapping markers in the PTEN (10q23) and CDKN1B (12p13) regions. Our data are consistent with epistatic interactions between the PTEN and CDKN1B genes affecting risk for prostate cancer and demonstrate the utility of modeling epistatic effects in linkage analysis to detect susceptibility genes of complex diseases.

Aged↗
PubMed2004

Ability to predict metastasis based on pathology findings and alterations in nuclear structure of normal-appearing and cancer peripheral zone epithelium in the prostate.

PURPOSE: Malignant transformation in the prostate produces significant alterations in glandular architecture (Gleason grade) and nuclear structure that provide valuable prognostic information. Normal-appearing nuclei (NN) adjacent to cancer may also have altered functions in response to malignancy. We studied NN adjacent to peripheral zone (PZ) prostate cancer (PCa), as well as the PZ cancer nuclei (CaN) using quantitative image cytometry. The nuclear structure information was combined with routine pathological findings to predict metastatic PCa progression and/or death. EXPERIMENTAL DESIGN: Tissue microarrays of normal-appearing and cancer areas were prepared from 182 pathologist-selected paraffin blocks. Feulgen-stained CaN and NN were captured from the tissue microarrays using the AutoCyte Pathology Workstation. Multivariate logistic regression was used to calculate quantitative nuclear grade (QNG) solutions based on nuclear morphometric descriptors determined from NN and CaN. Multivariate logistic regression and Kaplan-Meier plots were also used to predict risk for distant metastasis and/or PCa-specific death using QNG solutions and routine pathology. RESULTS: The pathology model yielded an area under the receiver operator characteristic curve of 72.5%. The QNG-NN and QNG-CaN solutions yielded an area under the receiver operator characteristic curve of 81.6 and 79.9%, respectively, but used different sets of nuclear morphometric descriptors. Kaplan-Meier plots for the pathology variables, the QNG-NN and QNG-CaN solutions, were combined with pathology to defined three statistically significantly distinct risk groups for distant metastasis and/or death (P < 0.0001). CONCLUSIONS: Alterations in cancer or normal-appearing nuclei adjacent to peripheral zone cancer areas can predict PCa progression and/or death. The QNG-NN and QNG-CA solutions could be combined with pathology variables to improve the prediction of distant metastasis.

Adult↗
PubMed2004

Biochemical failure after radical prostatectomy in men with pathologic organ-confined disease: pT2a versus pT2b.

BACKGROUND: The 1997 TNM staging system for prostate carcinoma defines a pT2a disease as a tumor histologically involving one lobe of the prostate and pT2b disease as a tumor histologically involving both prostatic lobes. Whether this distinction provides prognostic significance is unclear. The authors evaluated biochemical outcomes between men with pT2aN0 and pT2bN0 disease. METHODS: The authors identified 1606 men with organ-confined disease (pT2N0) who were treated with radical prostatectomy between 1982 and 2003 by one surgeon. Clinical characteristics were compared between men with pT2a and pT2b tumors using rank-sum analysis, and prostate-specific antigen (PSA) recurrence data were compared using log-rank analysis. The significant independent predictors of PSA recurrence were determined using a multivariate Cox proportional hazards model. RESULTS: There were no significant differences between men with pT2a and pT2b tumors at the time of surgery in terms of clinicopathologic characteristics (biopsy and pathologic Gleason score, serum PSA level, clinical stage, and age). Log-rank analysis revealed no significant differences in time to PSA recurrence between men with pT2a and pT2b tumors (P = 0.755). The 10-year PSA progression-free survival rate was 95% (confidence interval [CI], 92-97%) for men with pT2a tumors and 93% (CI, 90-95%) for men with pT2b tumors. Multivariate analysis showed that the significant predictors of PSA recurrence included serum PSA level, biopsy and pathologic Gleason score, and clinical stage. In the current cohort of men with organ-confined disease, pathologic stage (pT2a vs. pT2b) was not a significant predictor of PSA recurrence on multivariate analysis. CONCLUSIONS: There was no difference in PSA recurrence rates between men with pT2aN0 versus pT2bN0 tumors. In men with organ-confined disease, radical prostatectomy provided excellent 10-year PSA progression-free survival regardless of tumor burden (pT2a vs. pT2b). Consideration should be given to modifying the TNM staging system to eliminate substratification of pT2 tumors.

Aged↗
PubMed2004

A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer.

The loss of cell cycle control is believed to be an important mechanism in the promotion of carcinogenesis. CDKN1B (p27) belongs to the Cip/Kip family and functions as an important cell cycle gatekeeper. Several lines of evidence from clinical studies and laboratory experiments demonstrate that CDKN1B is an important tumor suppressor gene in prostate cancer etiology. In addition, a case-control study has shown that the 326T/G (V109G) polymorphism in CDKN1B is associated with advanced prostate cancer. In light of the evidence for linkage between the chromosomal location of the CDKN1B gene (12p13) and prostate cancer susceptibility in several hereditary prostate cancer (HPC) populations, we hypothesized that sequence variants of CDKN1B play a role in HPC. To test this hypothesis, we first resequenced this gene in 96 HPC probands to identify germ-line mutations and sequence variants. We then genotyped the identified sequence variants among all family members of 188 HPC families and tested for their cosegregation with prostate cancer. In total, 10 sequence variants were identified, including three nonsynonymous changes. A family-based test, which is free from the effects of population stratification, revealed a significant association between single nucleotide polymorphism (SNP) -79C/T and prostate cancer (with a nominal P of 0.0005). The C allele of -79C/T was overtransmitted from parents to their affected offspring. Evidence for this association was primarily contributed by affected offspring whose age at diagnosis was <65 years. Together with the previous association study in a sporadic prostate cancer population, our new findings additionally suggest that germ-line variants of this gene play a role in prostate cancer susceptibility.

Aged↗
PubMed2004

Hypermethylation of CpG islands in primary and metastatic human prostate cancer.

Aberrant DNA methylation patterns may be the earliest somatic genome changes in prostate cancer. Using real-time methylation-specific PCR, we assessed the extent of hypermethylation at 16 CpG islands in DNA from seven prostate cancer cell lines (LNCaP, PC-3, DU-145, LAPC-4, CWR22Rv1, VCaP, and C42B), normal prostate epithelial cells, normal prostate stromal cells, 73 primary prostate cancers, 91 metastatic prostate cancers, and 25 noncancerous prostate tissues. We found that CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85% of prostate cancers and cancer cell lines but not in normal prostate cells and tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate rates of hypermethylation in prostate cancer tissues and cancer cell lines but were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3, MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate cancers. Receiver operator characteristic curve analyses suggested that CpG island hypermethylation changes at GSTP1, APC, RASSF1a, PTGS2, and MDR1 in various combinations can distinguish primary prostate cancer from benign prostate tissues with sensitivities of 97.3-100% and specificities of 92-100%. Hypermethylation of the CpG island at EDNRB was correlated with the grade and stage of the primary prostate cancers. PTGS2 CpG island hypermethylation portended an increased risk of recurrence. Furthermore, CpG island hypermethylation patterns in prostate cancer metastases were very similar to the primary prostate cancers and tended to show greater differences between cases than between anatomical sites of metastasis.

Adult↗
PubMed2004

Identification of a prostate cancer susceptibility locus on chromosome 7q11-21 in Jewish families.

Results from over a dozen prostate cancer susceptibility genome-wide scans, encompassing some 1,500 hereditary prostate cancer families, indicate that prostate cancer is an extremely heterogeneous disease with multiple loci contributing to overall susceptibility. In an attempt to reduce locus heterogeneity, we performed a genomewide linkage scan for prostate cancer susceptibility genes with 36 Jewish families, which represent a stratification of hereditary prostate cancer families with potentially increased locus homogeneity. The 36 Jewish families represent a combined dataset of 17 Jewish families from the Fred Hutchinson Cancer Research Center-based Prostate Cancer Genetic Research Study dataset and 19 Ashkenazi Jewish families collected at Johns Hopkins University. All available family members, including 94 affected men, were genotyped at markers distributed across the genome with an average interval of <10 centimorgans. Nonparametric multipoint linkage analyses were the primary approach, although parametric analyses were performed as well. Our strongest signal was a significant linkage peak at 7q11-21, with a nonparametric linkage (NPL) score of 3.01 (P = 0.0013). Simulations indicated that this corresponds to a genomewide empirical P = 0.006. All other regions had NPL P values >/=0.02. After genotyping additional markers within the 7q11-21 peak, the NPL score increased to 3.35 (P = 0.0004) at D7S634 with an allele-sharing logarithm of odds of 3.12 (P = 0.00007). These studies highlight the utility of analyzing defined sets of families with a common origin for reducing locus heterogeneity problems associated with studying complex traits.

Adult↗
PubMed2004

Preservation of accessory pudendal arteries during radical retropubic prostatectomy: surgical technique and results.

INTRODUCTION: Our institution previously described a surgical technique for preservation of accessory pudendal arteries at radical retropubic prostatectomy. Since then, we have expanded our experience. We now report our refinements in the surgical technique, illustrated with video, and the influence of accessory artery preservation on the recovery of sexual function after radical retropubic prostatectomy (RRP). TECHNICAL CONSIDERATIONS: Between 1987 and 2003, 2399 potent men underwent RRP. Of the 2399 men, 84 (4%) were identified with accessory pudendal arteries. Of the 84 men, 52, who underwent bilateral nerve-sparing surgery, were available for evaluation. We identified a control population, without accessory pudendal arteries, who were matched for age, stage, and neurovascular bundle status. Potency was defined as the ability to achieve unassisted intercourse with or without the use of sildenafil. In a Cox proportional hazards model, the effect of artery preservation increased the likelihood of potency more than twofold (relative risk 2.65; 95% confidence interval 1.11 to 6.32; P = 0.028). Kaplan-Meier analysis showed a significantly shorter median time to regain potency among those with artery preservation, 6 versus 12 months (P = 0.020). CONCLUSIONS: Preservation of accessory pudendal arteries may favorably influence the recovery of sexual function and interval to recovery after RRP.

Adenocarcinoma↗
PubMed2004

Positive proximal (bladder neck) margin at radical prostatectomy confers greater risk of biochemical progression.

OBJECTIVES: To identify the prognostic significance of positive bladder neck margin as the sole positive margin after radical retropubic prostatectomy for treatment of prostate cancer. METHODS: We retrospectively analyzed the data from patients who underwent radical retropubic prostatectomy at Johns Hopkins Hospital between 1984 and 2001. Of 164 patients with positive margins, 38 had a positive margin only at the bladder neck margin and 126 had a positive margin at one or more locations separate from the bladder neck margin. RESULTS: Kaplan-Meier analyses showed that patients with a positive bladder neck margin had a greater biochemical progression risk than patients with positive margins at one or more locations other than the bladder neck margin. The 5-year actuarial risk of progression in men with positive and negative bladder neck margins was 69.8% and 33.0%, respectively. A positive bladder neck margin was statistically an independently significant predictor of progression (P = 0.001), along with the prostatectomy Gleason score (P = 0.0001) in the multivariate analysis. The hazard ratio for predicting progression for postoperative Gleason score and bladder neck positivity was 2.1 and 2.5, respectively. Serum prostate-specific antigen values, clinical stage, age, and the percentage of tumor at the bladder neck margin were not predictors of progression in either univariate or multivariate analysis. CONCLUSIONS: Patients with a positive bladder neck margin as the sole positive margin at radical retropubic prostatectomy have a greater risk of biochemical progression than patients with one or more positive margins at other locations, although not as adverse as the risk reported for those with Stage T4 disease.

Adenocarcinoma↗
PubMed2004

Effect of methylprednisolone on return of sexual function after nerve-sparing radical retropubic prostatectomy.

OBJECTIVES: To determine whether postoperative methylprednisolone improves the recovery of sexual function after nerve-sparing radical retropubic prostatectomy. METHODS: We randomized men undergoing bilateral nerve-sparing radical retropubic prostatectomy by a single surgeon to receive 6 days of placebo or methylprednisolone beginning on postoperative day 1. At 3, 6, and 12 months postoperatively, we assessed potency with the abbreviated International Index of Erectile Function questionnaire and urinary continence with participant-reported pad use. We used the chi-square test, Fisher's exact test, and the two-sample t test with equal variances for comparisons between study groups. RESULTS: No operative complications occurred and 70 (100%) of 70 participants experienced normal wound healing. The odds of being potent for participants who received methylprednisolone (n = 34) compared with those who received placebo (n = 36) did not significantly differ at 3 (odds ratio 0.29, 95% confidence interval 0.08 to 1.05), 6 (odds ratio 0.63, 95% confidence interval 0.17 to 2.4), or 12 (odds ratio 1.18, 95% confidence interval 0.29 to 4.8) months. The mean International Index of Erectile Function scores did not significantly differ at 3 (P = 0.08), 6 (P = 0.50), or 12 (P = 0.71) months. At 12 months, 74% of the methylprednisolone and 71% of the placebo participants were potent (P = 0.8). The proportions of participants who were continent did not differ significantly at 3 (P = 0.89), 6 (P = 0.25), or 12 (P = 0.49) months. At 12 months, 96% of the methylprednisolone and 100% of the placebo participants were continent. CONCLUSIONS: At doses sufficient to produce a systemic anti-inflammatory effect, postoperative methylprednisolone was not associated with improved potency at up to 12 months after bilateral nerve-sparing radical retropubic prostatectomy in men 40 to 60 years old.

Adenocarcinoma↗
PubMed2004

An evaluation of the decreasing incidence of positive surgical margins in a large retropubic prostatectomy series.

PURPOSE: Positive surgical margins adversely affect biochemical recurrence-free survival after radical retropubic prostatectomy (RRP) for prostate cancer. We retrospectively reviewed a large series of men who underwent RRP at a single academic university urology program to define the change in the incidence of organ confined (OC) disease and positive surgical margin (SM+) during the last 2 decades. MATERIALS AND METHODS: Between 1982 and 2001, 9,035 men underwent RRP for clinically localized prostate cancer (T1 to T3a) at a single institution. We compared the incidences of OC disease and SM+ in this population. RESULTS: An increasing proportion of men presented with OC disease over time. The incidence of SM+ in the overall RRP population decreased dramatically over time. However, in men with nonorgan confined disease (pT3), the proportion with SM+ was stable and consistently elevated (22.7% to 27.8%), after the initial decrease from the early 1980s (53%). CONCLUSIONS: Widespread early detection programs for prostate cancer resulted in a downward stage migration in men presenting with clinically localized prostate cancer at our institution during the last 2 decades. The decrease in the percentage of men with SM+ was due to the increasing number of men with organ confined disease. These results imply that the decrease in surgical margin rates in the overall RRP population is most likely due to stage migration and improved patient selection, rather than major improvements in surgical technique. The stable percentage of SM+ among men with pT3 disease dictates the need for continued evaluation of surgical technique and the need for effective adjuvant therapy.

Adenocarcinoma↗
PubMed2004

Nerve sparing radical prostatectomy: effects of hemostatic energy sources on the recovery of cavernous nerve function in a canine model.

PURPOSE: To preserve sexual function following radical prostatectomy, one must avoid injury to the neurovascular bundles (NVBs). In the conventional open surgical technique, the use of energy sources for hemostasis is avoided to prevent damage to the cavernous nerves. In contrast, during laparoscopic radical prostatectomy, electrosurgical and ultrasonic energy sources are frequently used for hemostasis during dissection of the prostate. In this study, we evaluated the acute and chronic physiological effects of various hemostatic energy sources on cavernous nerve function in the canine model. MATERIALS AND METHODS: A total of 12 dogs were divided into 4 groups based on the type of energy source used for hemostasis during unilateral dissection of the NVB. The groups included conventional dissection with suture ligatures (group 1), monopolar (group 2) or bipolar (group 3) electrosurgery and ultrasonic shears (group 4). The contralateral NVB was left undissected as a control. Erectile function was assessed acutely and after 2 weeks of survival by measuring peak intracavernous pressures in response to cavernous nerve stimulation. RESULTS: Following conventional techniques of nerve sparing, the erectile response to nerve stimulation was unaffected. In contrast, the use of energy sources in proximity to the NVB during nerve preservation was associated with a substantial decrease in erectile response both acutely (74% to 91% decrease compared to controls) and after 2 weeks (93% to 96% decrease). CONCLUSIONS: In the chronic canine model, use of hemostatic energy sources in proximity to the prostate during dissection of the neurovascular bundle is associated with a significantly decreased erectile response to cavernous nerve stimulation.

Animals↗
PubMed2004

Prostate specific antigen progression in men with lymph node metastases following radical prostatectomy: results of long-term followup.

PURPOSE: We examined the clinical outcome of patients with lymph node metastases found at prostatectomy with the goal to identify factors that predict freedom from prostate specific antigen (PSA) progression. MATERIALS AND METHODS: We retrospectively reviewed the records of 3,264 consecutive men with clinically localized prostate cancer who underwent extended pelvic lymphadenectomy and radical prostatectomy performed by a single surgeon between April 1982 and March 2003. Patients with pathologically confirmed lymph node metastases and no history of adjuvant treatment were identified. Clinical and histopathological factors were analyzed for an association with time to PSA progression using univariate and multivariable analyses. RESULTS: Of the 143 patients (4.4% of total) in the study with nodal involvement 24 (16.8%) were free of disease at last followup (median 6 years). Median time to failure was 2 years with PSA progression occurring as late as 11 years postoperatively in 2 patients. The 5 and 7-year PSA progression free rate in all lymph node positive patients was 26.5% and 10.9%, respectively. A 15% or greater incidence of positive nodes (p = 0.0008) and high prostatectomy Gleason score (ie score 8 to 10, p = 0.008) were independent predictors of PSA progression in multivariate Cox proportional hazards models. Seminal vesicle invasion (HR 1.45, p = 0.063) or positive surgical margins (HR 1.43, p = 0.063) were marginally significant in the multivariate model. The 5-year PSA progression-free rate was 52% in men with less than 15% positive lymph nodes, prostatectomy Gleason score 7 or less and negative seminal vesicle invasion. CONCLUSIONS: While the incidence of lymph node positive disease in patients undergoing radical prostatectomy is infrequent in the PSA era, patients with nodal involvement may experience disease progression as remote as 1 decade after surgery. Pathological factors such as the percent of positive lymph nodes, prostatectomy Gleason score and seminal vesicle invasion appear to predict an increased risk of PSA failure in this population.

Disease Progression↗