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Patrick C Walsh

Publications and source records attributed to Patrick C Walsh.

At least 19 recordsLinked to original sources
PubMed2005

Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease.

BACKGROUND: One of the difficulties confronting genetic studies of prostate cancer is the complex and heterogeneous etiology. Given the high population frequency of lesions meeting the histological definition of prostate cancer, a significant portion of men with a positive family history may be diagnosed due to increased surveillance and associated higher likelihood of biopsy. Over diagnosis decreases power to detect genes that increase susceptibility to a clinically significant prostate cancer. METHODS: We re-evaluated all 623 men with prostate cancer in our 188 hereditary prostate cancer families and identified a subset of 244 men with more aggressive disease based upon meeting at least one of the following clinical and/or pathologic criteria: tumor grade Gleason score > or = 7, tumor stage T2c or higher, pretreatment PSA > or = 20 ng/ml, rising PSA after treatment, evidence of metastasis, or death from prostate cancer. RESULTS: Genome-wide screens were re-performed by defining men as affected only if they met the criteria for clinically significant disease. The new analyses identified stronger evidence for linkage in Xq27-28 and 22q, as well as several novel loci, including 3p and 9p. CONCLUSIONS: Although, these results need to be confirmed in independent studies, our approach represents an important step to overcome the impact of over diagnosis in genetic studies of prostate cancer. Larger studies that incorporate this approach are needed.

Family Health↗
PubMed2005

Evidence for a general cancer susceptibility locus at 3p24 in families with hereditary prostate cancer.

To identify genes that generally increase the risk of cancer, we performed a systematic search throughout the genome in 188 families primarily ascertained for prostate cancer but which also included individuals with other cancers. We observed significant evidence for linkage between susceptibility to all cancers and markers at 3p24, with a peak HLOD of 3.08 (P=0.0002). Compared to families with less than three other cancers and prostate cancer only, evidence for linkage at this region was stronger among families with at least three other cancers. This is the first reported example of a genome-wide search for general cancer susceptibility genes among hereditary prostate cancer families.

Chromosomes, Human, Pair 3↗
PubMed2005

A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk.

Prostate cancer is a leading and increasingly prevalent cause of cancer death in men. Whereas family history of disease is one of the strongest prostate cancer risk factors and suggests a hereditary component, the predisposing genetic factors remain unknown. We first showed that KLF6 is a tumor suppressor somatically inactivated in prostate cancer and since then, its functional loss has been further established in prostate cancer cell lines and other human cancers. Wild-type KLF6, but not patient-derived mutants, suppresses cell growth through p53-independent transactivation of p21. Here we show that a germline KLF6 single nucleotide polymorphism, confirmed in a tri-institutional study of 3,411 men, is significantly associated with an increased relative risk of prostate cancer in men, regardless of family history of disease. This prostate cancer-associated allele generates a novel functional SRp40 DNA binding site and increases transcription of three alternatively spliced KLF6 isoforms. The KLF6 variant proteins KLF6-SV1 and KLF6-SV2 are mislocalized to the cytoplasm, antagonize wtKLF6 function, leading to decreased p21 expression and increased cell growth, and are up-regulated in tumor versus normal prostatic tissue. Thus, these results are the first to identify a novel mechanism of self-encoded tumor suppressor gene inactivation and link a relatively common single nucleotide polymorphism to both regulation of alternative splicing and an increased risk in a major human cancer.

Alleles↗
PubMed2005

Radical retropubic prostatectomy. How often do experienced surgeons have positive surgical margins when there is extraprostatic extension in the region of the neurovascular bundle?

PURPOSE: We determined the frequency of positive surgical margins (PSMs) in patients with extraprostatic extension (EPE) in the region of the neurovascular bundle (NVB) who underwent open radical retropubic prostatectomy by 2 experienced surgeons. MATERIALS AND METHODS: A total of 204 men with EPE in the region of the NVB underwent surgery by 2 experienced surgeons. The frequency of PSMs in the area of the NVB as well as the nerve sparing status of each lobe of the prostate were determined through a retrospective investigation of the pathology database as well as the physician's database. The recovery of sexual function was determined and compared to controls. RESULTS: The age, clinical stage, biopsy Gleason sum and serum prostate specific antigen of the patients operated on by surgeons 1 and 2 were similar. Surgeon 1 widely excised at least 1 neurovascular bundle in 16% of the patients and surgeon 2 in 63%. The overall frequency of PSMs at the NVB was 5.9% for surgeon 1 and 5.8% for surgeon 2. Of the evaluable patients followed for 12 months or longer 83.5% of those operated on by surgeon 1 were potent compared to 63.8% of those operated on by surgeon 2. CONCLUSIONS: Visual and tactile assessment during open surgery by an experienced surgeon provides valuable information on when and where it is safe to preserve the neurovascular bundle in patients with EPE in the region of the NVB. Surgical approaches in which tactile sensation is muted or absent, laparoscopic and robotic, need to undergo a similar evaluation to determine whether magnification of the operative field is sufficient to overcome the lack of haptic feedback and ability to palpate the tissue.

Adult↗
PubMed2005

Prediction of extraprostatic extension in the neurovascular bundle based on prostate needle biopsy pathology, serum prostate specific antigen and digital rectal examination.

PURPOSE: There are few studies on predictors of extraprostatic extension (EPE) in the region of the neurovascular bundle (NVB). We investigated whether clinical information and prostate biopsy data could predict EPE of clinical localized prostate cancer. MATERIALS AND METHODS: Through a retrospective analysis of the pathology database we identified 2,660 cases of clinically localized prostate cancer treated with radical retropubic prostatectomy without preoperative adjuvant therapy at The Johns Hopkins Hospital. The study sample involved a total of 3,006 lobes with prostate cancer including 2,070 with organ confined disease, 620 with EPE in the NVB at the posterolateral edge of the prostate and 316 with EPE in a region other than the NVB (EPE elsewhere). Through univariate and multivariate logistic regression analysis we determined whether patient age, year of surgery, serum prostate specific antigen, digital rectal examination, biopsy highest Gleason score, perineural invasion, percent of side specific biopsy cores with cancer, percent of each core involved with cancer and the maximum percent of a core involved with cancer was predictive of EPE in the NVB. RESULTS: Prostate specific antigen (10 or greater vs less than 10), biopsy Gleason score (7 or greater vs 6 or less), digital rectal examination (abnormal vs normal), percent of side specific cores with tumor (greater than 33.3% vs 33.3% or less) and average percent involvement of each positive core (greater than 20% vs 20% or less) were all found to be statistically significant independent predictors of NVB penetration in multivariate analysis. The generated model stratifies each of these variables into high and low risk. The probability of EPE in the NVB was less than 10% in cases with 1 or fewer of the higher risk variables and was 10% or greater in cases with more than 1 of the higher risk variables. CONCLUSIONS: The model generated in this study allows for the preoperative identification of patients with 10% or greater probability of EPE in the NVB. Our algorithm will help provide objective parameters that aid in the decision to spare the NVB safely.

Biopsy, Needle↗
PubMed2004

Trefoil factor 3 overexpression in prostatic carcinoma: prognostic importance using tissue microarrays.

BACKGROUND: Human intestinal trefoil factor 3 (TFF3) is a member of a family of polypeptides encoded by a cluster of genes on chromosome 21. Through gene expression profiling studies TFF3 mRNA has been found to be overexpressed in prostate cancer. METHODS: We used immunochemistry on tissue microarrays and software tools, collectively referred to as TMAJ, for online assessment of staining to analyze samples from 294 primary tumors and 61 metastatic lesions. RESULTS: Applying a cutoff of 20% of cells staining as positive, the frequency of staining was 18.8% in normal (51 of 272) and 47.0% in primary tumors (126 of 268), P < 0.0001, Wilcoxon rank sum). Expression of TFF3 in metastatic prostate cancer was similar to that in primary tumors. TFF3 expression was not associated with time to biochemical recurrence, development of distant metastasis, or death due to prostate cancer. Scoring data derived from visual estimation of expression correlated highly with semi-automated image analysis using the Automated Cellular Imaging System (ACIS) from Chromavision, Inc. CONCLUSIONS: These studies validate that TFF3 is overexpressed at the protein level in a subset of primary and metastatic prostate cancers, show the first use of the TMAJ database, and demonstrate the ability to semi-automatically scan and score immunohistochemically stained tissue microarray slides.

Biomarkers, Tumor↗