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John D McConnell

Publications and source records attributed to John D McConnell.

18 recordsLinked to original sources
PubMed2006

Combination therapy with doxazosin and finasteride for benign prostatic hyperplasia in patients with lower urinary tract symptoms and a baseline total prostate volume of 25 ml or greater.

PURPOSE: We examined data from the Medical Therapy of Prostatic Symptoms trial to determine the relationship between baseline TPV and the effect of medical therapy in men with LUTS secondary to BPH. MATERIALS AND METHODS: A total of 3,047 patients with LUTS were randomized to placebo, 4 to 8 mg doxazosin, 5 mg finasteride or the combination of doxazosin and finasteride. Average treatment duration was 4.5 years The primary outcome was time to overall clinical progression of BPH, defined as a confirmed 4 point or greater increase in AUA SS, acute urinary retention, incontinence, renal insufficiency or recurrent urinary tract infection. Secondary outcomes were the need for invasive therapy for BPH, and changes in AUA SS and the maximum urinary flow rate with time. TPV was measured by transrectal ultrasound at baseline and study end. RESULTS: In patients with a small prostate (baseline TPV less than 25 ml) combination therapy was no better than doxazosin alone for decreasing the risk of clinical progression of BPH and need for invasive therapy as well as improving AUA SS and the maximum urinary flow rate. However, in patients with moderate size (25 to less than 40 ml) or enlarged (40 ml or greater) glands combination therapy led to a clinical benefit in these outcomes that was superior to that of doxazosin or finasteride. CONCLUSIONS: Combination therapy with doxazosin and finasteride led to a greater decrease in the risk of clinical progression of BPH than either drug alone in patients with LUTS with a baseline TPV of 25 ml or greater.

Aged↗
PubMed2006

Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo.

PURPOSE: We analyzed data from the placebo arm of the MTOPS trial to determine clinical predictors of BPH progression. MATERIALS AND METHODS: A total of 3,047 patients with LUTS were randomized to either placebo, doxazosin (4 to 8 mg), finasteride (5 mg), or a combination of doxazosin and finasteride. Average length of followup was 4.5 years. The primary outcome was time to overall clinical progression of BPH, defined as either a confirmed 4-point or greater increase in AUA SS, acute urinary retention, incontinence, renal insufficiency, or recurrent urinary tract infection. We analyzed BPH progression event data from the 737 men who were randomized to placebo. RESULTS: The rate of overall clinical progression of BPH events in the placebo group was 4.5 per 100 person-years, for a cumulative incidence (among men who had at least 4 years of followup data) of 17%. The risk of BPH progression was significantly greater in patients on placebo with a baseline TPV of 31 ml or greater vs less than 31 ml (p <0.0001), a baseline PSA of 1.6 ng/dl or greater vs PSA less than 1.6 ng/dl (p = 0.0009), a baseline Qmax of less than 10.6 ml per second vs 10.6 ml per second or greater (p = 0.011), a baseline PVR of 39 ml or greater vs less than 39 ml (p = 0.0008) and baseline age 62 years or older vs younger than 62 years (p = 0.0002). CONCLUSIONS: Among men in the placebo arm, baseline TPV, PSA, Qmax, PVR and age were important predictors of the risk of clinical progression of BPH.

Adrenergic alpha-Antagonists↗
PubMed2005

Alpha(2) macroglobulin, a PSA binding protein, is expressed in human prostate stroma.

BACKGROUND: Benign prostatic hyperplasia (BPH) is characterized as a stromal process. The stroma smooth muscle (SM) may alter its phenotype during the progression of BPH. We have identified gene transcripts that may be differentially expressed in BPH using a differential display method. Among the fragments isolated, alpha(2) macroglobulin (alpha(2)-M) is one of the most interesting. alpha(2)-M is a binding protein of a variety of proteinases, including prostatic specific antigen (PSA). It also plays roles in molecular trapping and targeting. In this study, we characterized alpha(2)-M expression in the human prostate. METHODS: Differential display was used to identify and isolate the differentially expressed transcripts between normal prostate and BPH tissues. RT-PCR, Western blot, in situ hybridization, and immunohistochemistry were utilized to confirm and characterize alpha(2)-M expression in the prostate. RESULTS: Real-time RT-PCR results revealed that a 3.2-fold increase in alpha(2)-M mRNA expression is observed in BPH compared with normal prostate tissue. A 1.9-fold increase at protein level was also observed. In situ hybridization and immunohistochemistry showed that alpha(2)-M expression is primarily localized to the stromal compartment. Cultured primary stroma cells maintained alpha(2)-M expression, while prostate epithelial cells had a significantly lower level of alpha(2)-M expression. Furthermore, stromal cells in culture produce and secrete alpha(2)-M in the medium. CONCLUSIONS: We identified alpha(2)-M expression in the human prostate. An increased alpha(2)-M expression appears to be associated with BPH. Considering the unique features of its protein binding and targeting properties, alpha(2)-M expressed in the prostate may play an important role in regulating benign and malignant prostatic growth.

Blotting, Western↗
PubMed2004

The effect of combined androgen ablation on the expression of alpha1A-adrenergic receptor in the human prostate.

BACKGROUND: This study was designed to determine whether androgen ablation (AA) affects expression of alpha1A-adrenergic receptors (AR) in the human prostate. METHODS: Concentrations of alpha1A-AR mRNA were determined in benign prostatic tissue from patients undergoing surgery after a 3-month course of combined androgen ablation (CAD) therapy with leuprolide and flutamide, and a matched group of untreated patients with clinical BPH. RESULTS: Mean concentration of alpha1A-AR in the AA group was 0.53 +/- 0.53 SD (range 0.026-1.55) attomol/mg. Control mean was 0.29 +/- 0.22 SD (range 0.02-0.69; P = 0.3, two tailed t-test). Tissue composition did not statistically differ between the two groups. Expression of alpha1A-AR correlated with concentration of smooth muscle myosin heavy chain (SMMHC) (r = 0.84, P = 0.001). No significant differences were observed after adjusting for SMMHC content. CONCLUSIONS: A 3-month course of CAD does not appear to have a significant effect on alpha1A-AR mRNA expression in the human prostate.

Aged↗
PubMed2004

Sustained decrease in incidence of acute urinary retention and surgery with finasteride for 6 years in men with benign prostatic hyperplasia.

PURPOSE: We determined the effect of long-term treatment with finasteride on the incidence of acute urinary retention (AUR) and benign prostatic hyperplasia (BPH) related surgery in men with BPH. MATERIALS AND METHODS: The Proscar (Merck and Co., Inc., Whitehouse Station, New Jersey) Long-Term Efficacy and Safety Study (PLESS) was comprised of 3040 men with enlarged prostates, moderate to severe symptomatic BPH and no clinical evidence of prostate cancer. Patients were randomized to placebo or 5 mg finasteride daily for 4 years. Of the 3016 randomized patients with available efficacy data 62% completed the original 4-year study (1006 on finasteride and 891 on placebo) and 89% of these (908 from the original finasteride arm and 785 from the placebo arm) continued in a 2-year open extension on finasteride. Followup was attempted in discontinued patients. Complete 6-year outcomes data, including 6-year followup in 770 men who had discontinued treatment during years 1 to 6, were available for 2463 (82%) of the 3016 originally randomized patients. RESULTS: For patients on continuous finasteride treatment the decrease in incidence of AUR and/or BPH related surgery in the 4-year base study was sustained during the open extension. In patients who were switched from placebo to finasteride in the extension, the incidence of AUR and/or BPH related surgery was similar to that in the continuous finasteride arm. CONCLUSIONS: The 6-year data from PLESS confirmed and further extended the findings from the original 4-year trial, demonstrating that finasteride treatment led to a sustained decrease in the incidence of AUR and/or BPH related surgery in men with BPH and enlarged prostates.

Acute Disease↗
PubMed2004

Lymphovascular invasion is a pathological feature of biologically aggressive disease in patients treated with radical prostatectomy.

UNLABELLED: We examined whether invasion of lymphatic and/or vascular vessels (LVI), or perineural spaces (PNI) is associated with prostate cancer features and outcome. MATERIALS AND METHODS: A total of 630 consecutive men underwent radical retropubic prostatectomy for clinically localized disease. LVI and PNI examination was part of the routine specimen evaluation. RESULTS: Foci of LVI were identified in 32 patients (5%) and 381 (60.5%) had PNI. LVI and PNI were associated with clinical stage T2 disease, higher biopsy and final Gleason sum, extraprostatic extension, seminal vesicle involvement, positive surgical margins and a higher percent of positive biopsy cores (p <0.001). LVI was associated with metastases to regional lymph nodes and higher preoperative serum prostate specific antigen (p <0.001 and 0.004, respectively). PNI and LVI were associated with an increased risk of rapid biochemical progression after radical prostatectomy on univariate (p <0.001 and 0.001, respectively) but not on multivariate analysis. LVI was associated with shorter prostate specific antigen doubling time after biochemical progression (p = 0.012) and higher probabilities of failed local salvage radiation therapy (p = 0.0169), distant metastases (p <0.001) and death (p <0.001). CONCLUSIONS: Only LVI is associated with metastases to regional and distant sites, and most importantly with overall survival. LVI and PNI are associated with established markers of biologically aggressive disease and rapid biochemical progression in patients who underwent radical prostatectomy. Our findings support the routine evaluation of LVI status in radical prostatectomy specimens and its inclusion in predictive models for clinical outcomes, since it appears to be a pathological marker of the lethal phenotype of prostate cancer.

Adult↗
PubMed2004

The percent of biopsy cores positive for cancer is a predictor of advanced pathological stage and poor clinical outcomes in patients treated with radical prostatectomy.

PURPOSE: We examined if the percent of positive biopsies is associated with features of biologically aggressive prostate cancer, biochemical progression and development of distant metastases in patients undergoing radical prostatectomy (RP). MATERIALS AND METHODS: Multivariate analyses of preoperative features in 605 consecutive patients who underwent RP for clinically localized disease were evaluated to determine the association between the percent positive biopsy cores (PosBx), pathological stage and grade, and biochemical progression following RP. The percent of PosBx cores was defined using the formula, (number of positive biopsy cores/total number of biopsy cores) x 100. RESULTS: The mean number of biopsy cores and percent PosBx cores +/- SE was 8.8 +/- 6.0 and 31.4 +/-21.1, respectively. Higher percent PosBx was significantly associated with higher preoperative prostate specific antigen (PSA), extracapsular extension, seminal vesicle invasion, positive surgical margins, higher final Gleason sum, lymphovascular invasion, perineural invasion and metastases to regional lymph nodes. On multivariate analyses adjusted for the effects of standard preoperative features percent PosBx was associated with nonorgan confined disease, seminal vesicle invasion and biochemical progression after surgery (p = 0.049, 0.050 and 0.006, respectively). Percent PosBx retained its independent association with PSA progression after adjustment for the effects of postoperative pathological features (p = 0.015). Higher percent PosBx was associated with shorter PSA doubling time after PSA progression, and an increased risk of distant metastases and overall mortality (p = 0.039, 0.001 and 0.018, respectively). CONCLUSIONS: Percent PosBx is associated with established pathological features, biochemical progression, distant metastases and overall death in patients who undergo RP for clinically localized disease. Percent PosBx should be included in preoperative predictive models for prognosticating outcomes after primary treatment and it may assist in selecting patients for inclusion in neoadjuvant and/or adjuvant therapy trials.

Adult↗
PubMed2004

Predictive value of primary Gleason pattern 4 in patients with Gleason score 7 tumours treated with radical prostatectomy.

OBJECTIVE: To examine whether Gleason score (GS) 3 + 4 and 4 + 3 cancers at radical prostatectomy behave differently and whether this behaviour is independently associated with prostate cancer outcome. PATIENTS AND METHODS: From July 1994 to December 2002 309 consecutive men who had a radical retropubic prostatectomy for clinically localized disease had final GS 7 tumours in their prostatectomy specimen. Statistical analyses, including multivariate logistic regression, were used to evaluate the association between variables, i.e. standard preoperative features, stage, PSA progression, standard pathological variables, metastasis and death. RESULTS: In all, 215 patients (70%) had a final GS of 3 + 4 and 94 (30%) of 4 + 3. A final GS of 4 + 3 was associated with clinical stage T2 disease (P = 0.024), a higher biopsy GS (P < 0.001), seminal vesicle involvement (P < 0.001), positive surgical margins (P = 0.036), lymphovascular invasion (P = 0.018), metastases to regional lymph nodes (P = 0.008), higher preoperative serum prostate-specific antigen (PSA) (P = 0.042), and percentage positive biopsy cores (P = 0.006). In univariate analysis, patients with GS 4 + 3 had a significantly higher risk of biochemical progression than those with GS 3 + 4 (P = 0.002). The 5-year actuarial risk of biochemical progression was 17% and 35% for GS 3 + 4 and 4 + 3, respectively (P = 0.0016). In a standard postoperative multivariate analysis, only preoperative PSA and metastases to regional lymph nodes were associated with PSA progression (P < 0.001 and 0.002, respectively). However, patients with final GS 4 + 3 had a shorter PSA doubling time after progression than those with GS 3 + 4 (P = 0.009). CONCLUSIONS: Tumours with a final GS of 4 + 3 are more aggressive than GS 3 + 4 tumours. Recognising the distinction in GS 7 between predominant 4 vs 3 scores after radical prostatectomy should improve the ability of clinicians to counsel patients. The GS 4 pattern deserves further molecular study.

Adult↗
PubMed2003

The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia is commonly treated with alpha-adrenergic-receptor antagonists (alpha-blockers) or 5alpha-reductase inhibitors. The long-term effect of these drugs, singly or combined, on the risk of clinical progression is unknown. METHODS: We conducted a long-term, double-blind trial (mean follow-up, 4.5 years) involving 3047 men to compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of benign prostatic hyperplasia. RESULTS: The risk of overall clinical progression--defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection--was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P=0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. CONCLUSIONS: Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy.

5-alpha Reductase Inhibitors↗
PubMed2003

Long-term 6-year experience with finasteride in patients with benign prostatic hyperplasia.

OBJECTIVES: To summarize the 6-year clinical trial data with finasteride. Benign prostatic hyperplasia is a chronic and progressive disease and therefore assessment of long-term safety and efficacy is important. METHODS: The North American and International Phase III Finasteride trials enrolled symptomatic men with enlarged prostate glands. The initial 1-year placebo-controlled study was followed by a 5-year open-label extension. In total, 6-year finasteride data were available in 487 patients originally randomized to finasteride, and 5-year data were available on 238 patients originally randomized to placebo. RESULTS: After 6 years of treatment with finasteride 5 mg, the mean quasi-American Urological Association Symptom Score improved by 4.0 points, the median prostate volume decreased by 24%, and the mean maximal urinary flow rate increased by 2.9 mL/s (P <0.001 for all parameters). Long-term finasteride treatment was well tolerated, with a low incidence of drug-related sexual adverse events occurring during the first year and even fewer occurrences during the 5-year open extension. CONCLUSIONS: Treatment with finasteride leads to durable improvement in urinary tract symptoms, flow rate, and prostate volume, with no increase in the prevalence of drug-related adverse events over time.

5-alpha Reductase Inhibitors↗
PubMed2003

Factors influencing the outcomes of penile prosthesis surgery at a teaching institution.

OBJECTIVES: To evaluate the long-term outcomes of penile prosthesis surgery at a teaching institution. METHODS: Patients who had penile prosthesis surgery from 1988 to 1999 at a private teaching hospital and the Dallas Veterans Affairs Medical Center were identified and charts abstracted for age at first prosthesis, ethnicity, etiology of impotence, comorbid medical disease, previous treatments, surgeon, type of prosthesis, perioperative complications, social history, and outcome. Patient outcomes were determined either from recent clinical documentation within the prior year or by telephone survey of patients. Frequent implanters were defined as those surgeons who performed more than 10 procedures during the study period. Kaplan-Meier curves were used to evaluate survival for patients and prostheses; statistical significance was assessed by the log-rank test. RESULTS: A total of 152 patients were identified, 81 patients at the Veterans Affairs Medical Center and 71 patients at the private hospital. A total of 180 procedures were performed by 15 attending surgeons, 4 of whom performed most (n = 132) of these procedures. No statistically significant difference was noted in patient age between the two hospitals. No statistically significant differences were found in survival of the penile prostheses on the basis of a history of smoking, diabetes, hypertension, or coronary artery disease. First prostheses had statistically significant better survival compared with secondary prostheses (5-year rate 71% versus 42%; 10-year rate 60% versus 35%, P = 0.0002). The overall infection rate at final follow-up was 9.9% and 18.8% for primary and secondary prostheses, respectively (P = 0.03). The 5-year survival outcomes with first prostheses for frequent implanters were superior to those of infrequent implanters (70% versus 63%, P = 0.034). Malleable prostheses had fewer complications than three-piece inflatable prostheses (10-year survival rate 87% versus 50%, P = 0.0081). CONCLUSIONS: Superior penile prosthesis outcomes were achieved with first penile prostheses when implanted by higher volume implanters. Meticulous technique and experience are important in all penile prosthesis surgery; however, outcome analysis emphasizes that the differences in outcomes are most apparent with first prostheses, which represent the best opportunity for the patient to achieve good results.

Adult↗
PubMed2003

Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial.

Alpha-blockers and 5-alpha-reductase inhibitors are medical therapies that are being used as alternatives to surgical interventions to relieve symptoms of benign prostatic hyperplasia (BPH). Taken as monotherapy, alpha-blockers and 5-alpha-reductase inhibitors have each been shown to provide relief from BPH symptoms. Treatment with finasteride over 4 years has been shown to reduce both BPH symptoms and the likelihood of acute urinary retention and the need for surgery. Direct comparison of the alpha-blocker terazosin with finasteride has been done, but only for a period of 1 year. The Medical Therapy of Prostatic Symptoms (MTOPS) trial is a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to evaluate the long-term efficacy of the alpha-blocker doxazosin and the 5-alpha-reductase inhibitor finasteride, whether taken as a monotherapy or in combination, in preventing or delaying the progression of BPH. We describe in this paper the design of the MTOPS trial, the concept of BPH progression, the definition and methods of determining the primary outcome events and the proposed statistical analysis methods. A unique feature of MTOPS is the inclusion of prostate biopsies on a subgroup of randomized participants. Volunteers among randomized participants are to undergo a biopsy of the prostate at predetermined time points during the trial. Studies that will be conducted using the tissue specimens collected in MTOPS can potentially provide information at the molecular level on the natural history of BPH among medically treated and untreated men with moderate to severe symptoms of BPH.

Data Collection↗
PubMed2003

Heterogeneity of 5 alpha-reductase gene expression in benign prostatic hyperplasia.

PURPOSE: The search for molecular markers of benign prostatic hyperplasia in general is based on an analysis of a limited number of biopsy samples. Little is known about the homogeneity of the expression of key genes in different zones of the prostate. We studied the intraprostatic (that is within the same gland) and inter-prostatic (that is between glands) variability of 5 alpha-reductase 2 (5aR2) gene expression. MATERIALS AND METHODS: Ten tissue samples removed by open prostatectomy were the source of tissue specimens. Two frozen sections were generated from each of several random biopsies taken from each adenoma immediately after enucleation, 1 of which was used for 5aR2 gene expression analysis and 1 for morphometric analysis. Results among biopsies were compared using the 5 alpha-reductase index (ratio of 5 alpha-reductase expression to an internal standard measured as electrophoretic band intensity). Morphometric composition was determined for smooth muscle, collagen, epithelium and glandular lumens. Statistical comparisons were performed with ANOVA by pairwise multiple comparison (Dunn) and Spearman's rank correlation procedure. RESULTS: For the 71 biopsies analyzed mean 5 alpha-reductase index was 0.23 +/- 0.16 and overall tissue distribution was smooth muscle 34%, collagen 35%, epithelium 14% and glandular lumens 17%. Inter-prostate and intraprostate variability in 5 alpha-reductase index was statistically significant (p = 0.004) as was the variability in stromal-to-epithelial ratio (p = 0.012). The 5 alpha-reductase index showed strong correlation with stroma (%) and negative correlation with epithelium (%). CONCLUSIONS: Benign prostatic hyperplasia is heterogeneous in terms of tissue morphometry and expression of single important genes. This finding limits the use of single biopsy based markers to predict biological behavior, and has significant impact on the ability of distinguishing longitudinal changes in tissue composition from sampling artifacts.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2003

Surrogate marker for predicting the virus binding of urogenital cancer cells during adenovirus-based gene therapy.

Virus uptake is the first rate-limiting step for the successful gene delivery of any virus-based gene therapy. For adenovirus-based gene therapy, the expression levels of the adenovirus receptor--coxsackievirus and adenovirus receptor (CAR)--play an important role in dictating gene delivery. We have observed a wide spectrum of CAR expression among cancer cell lines and tumor specimens. Therefore, the screening of the CAR expression level in patients becomes crucial for any possible positive outcome. In this paper, we establish a real-time RT-PCR assay for the detection of CAR mRNA levels from cancer cells and tumor specimens. This assay appears to be very quantitative, with sample concentrations ranging within 6 logs, and the sensitivity of this assay could detect as low as 1.8 x 10(2) copies of CAR cDNA per reaction. The results from this assay confirmed that there was a good linear relationship between the CAR mRNA and virus binding from each cell line. With this assay, we were able to detect changes in CAR gene expression in cells treated with histone deacetylase inhibitor. Most importantly, CAR mRNA levels directly correlated with its protein levels prepared from tumor specimens. Taken together, this assay could provide a rapid screening tool for any adenovirus-based gene therapy trial.

Adenoviridae↗
PubMed2002

Differential expression of the mismatch repair gene hMSH2 in malignant prostate tissue is associated with cancer recurrence.

BACKGROUND: Mismatch repair (MMR) genes are responsible for coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating mutations in MMR genes have been described in sporadic cancers and a hereditary cancer predisposition syndrome. Mismatch repair deficiency causes instability at microsatellites and increased mutation rates. Although microsatellite instability (MSI) has been described in high-grade and lymph node positive prostate carcinoma specimens, an analysis comparing hMSH2 expression, MSI, and outcome in clinically organ confined prostate carcinoma has not been reported. METHODS: Immunohistochemical analysis of benign and malignant prostate tissue from 101 patients was performed using a monoclonal antibody specific for the hMSH2 protein. Expression was correlated with MSI using dinucleotide repeat markers and laser-captured microdissected DNA from normal and tumor cells. hMSH2 protein expression and MSI were assessed with respect to pathologic stage, Gleason score, and time to detectable serum prostate specific antigen (PSA) after prostatectomy in patients with clinically localized prostate carcinoma. RESULTS: In normal glands, hMSH2 staining was minimal to low and confined to the basal cell layer. In 32% of benign prostatic hyperplasia cases, hMSH2 staining was increased in the basal and luminal cell layers whereas 71% of cancer specimens had uniform moderate to high staining. Microsatellite instability was detected in 60% of absent to low staining and 26% of moderate to high staining prostate carcinoma specimens. Differential staining in benign versus malignant prostate tissues was statistically significant (P < 0.001) as was the correlation between absent to low hMSH2 staining and presence of MSI (P = 0.028). Decreased risk for PSA recurrence after radical prostatectomy correlated with absent to low hMSH2 staining in malignant prostate tissue but was only marginally significant (P = 0.05 for 24 month recurrence and P = 0.08 for overall time to PSA recurrence). CONCLUSIONS: The results of the current study demonstrate differential hMSH2 expression in benign and malignant prostate tissue. Moreover, hMSH2 expression is altered in a subset of clinically localized prostate carcinoma specimens independent of pathologic stage and Gleason pattern. A statistically significant correlation between hMSH2 immunohistochemical staining intensity and MSI also was identified in prostate carcinoma specimens. Furthermore, the time to cancer recurrence as determined by detectable serum PSA after prostatectomy was associated with hMSH2 staining intensity. Taken together, our results suggest that hMSH2 gene expression in prostate carcinoma may be a useful prognostic marker for outcome in men with clinically organ confined prostate carcinoma.

Aged↗
PubMed2002

The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2.

DOC-2/DAB2 is a member of the disable gene family with tumor-inhibitory activity. Its down-regulation is associated with several neoplasms, and serine phosphorylation of its N terminus modulates DOC-2/DAB2's inhibitory effect on AP-1 transcriptional activity. We describe the cloning of DIP1/2, a novel gene that interacts with the N-terminal domain of DOC-2/DAB2. DIP1/2 is a novel GTPase-activating protein containing a Ras GTPase-activating protein homology domain (N terminus) and two other unique domains (i.e. 10 proline repeats and leucine zipper). Interaction between DOC-2/DAB2 and DIP1/2 is detected in normal tissues such as the brain and prostate. Altered expression of these two proteins is often detected in prostate cancer cells. Indeed, the presence of DIP1/2 effectively blocks mitogen-induced gene expression and inhibits the growth of prostate cancer. Thus, DOC-2/DAB2 and DIP1/2 appear to represent a unique negative regulatory complex that maintains cell homeostasis.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Storage (irritative) and voiding (obstructive) symptoms as predictors of benign prostatic hyperplasia progression and related outcomes.

OBJECTIVES: To assess the utility of voiding and filling symptom subscores in predicting features of benign prostatic hyperplasia (BPH) progression, including acute urinary retention (AUR) and prostate surgery. METHODS: The Proscar Long-term Efficacy and Safety Study (PLESS) was a 4-year study designed to evaluate the effects of finasteride versus placebo in men with lower urinary tract symptoms (LUTS), clinical evidence of BPH, and no evidence of prostate cancer. A self-administered questionnaire was employed to quantify LUTS at baseline. Receiver operating characteristics (ROC) curves were used to assess baseline characteristics from patients treated with placebo as predictors of outcomes. The characteristics assessed included the overall symptom score (Quasi-AUA SI), separate voiding and filling subscores, prostate volume (PV) and serum prostate-specific antigen (PSA) levels. RESULTS: PV and PSA were superior to the symptom scores at predicting episodes of spontaneous AUR and all types of AUR. The Quasi-AUA SI and the filling and voiding subscores were effective at predicting progression to surgery; however, PSA was more effective at predicting this outcome. To better evaluate symptoms as predictors of surgery, patients who experienced a preceding episode of AUR were excluded from the surgery analysis. In the absence of preceding AUR, the best predictors of future surgery were the Quasi-AUA SI and the filling subscore. CONCLUSIONS: Among men with LUTS, clinical BPH and no history of AUR, the overall symptom score and storage subscore are useful parameters to aid clinicians in identifying patients at risk for future prostate surgery. PV and PSA were the best predictors of AUR, while PSA was the best predictor of prostate surgery (for all indications).

Acute Disease↗