Jacques Irani

Inflammation in Benign Prostatic Hyperplasia: Correlation With Prostate Specific Antigen Value

PURPOSE We attempted to identify morphological parameters of benign prostatic hyperplastic inflammation that correlate with pre-biopsy prostate specific antigen (PSA) concentrations. MATERIALS AND METHODS Patients undergoing prostate biopsy at our department were prospectively studied between January 1995 and January 1996. preoperative blood and 24-hour urine samples were measured for PSA. Biopsy samples harboring exclusively benign prostatic tissue were graded on a 4-point scale for inflammation (0-no inflammatory cells, 1-scattered inflammatory cell infiltrate, 2-nonconfluent lymphoid nodules and 3-large inflammatory areas with confluence of infiltrate) and aggressiveness (0-no contact between inflammatory cells and glandular epithelium; 1-contact between inflammatory cell infiltrate and glandular epithelium; 2-clear but limited, that is less than 25% of the examined material, glandular epithelium disruption, and 3-glandular epithelium disruption on more than 25% of the examined material). RESULTS A total of 66 patients with exclusively benign prostatic tissue on prostate biopsies was analyzed. Difference between inflammation graded groups was not significant when considering serum or urinary PSA. There was a significant correlation between aggressiveness grading and serum PSA (rho = 0.51, p < 0.0001), whereas aggressiveness grading and urinary PSA did not correlate (rho = -0.06, p = 0.6). CONCLUSIONS Prostatic subclinical inflammation is not associated with high urinary PSA. Unless associated with glandular epithelial disruption, density of prostatic interstitial inflammatory cell infiltrate is not significantly correlated with serum PSA concentration. We believe that this issue should be considered when interpreting a prostate biopsy.

Clinical Evaluation of the PCA3 Assay in Guiding Initial Biopsy Decisions

PURPOSE We evaluated the clinical utility of the PCA3 assay in guiding initial biopsy decisions in prostate cancer. MATERIALS AND METHODS A European, prospective, multicenter study enrolled men with a serum total prostate specific antigen of 2.5 to 10 ng/ml scheduled for initial biopsy. After digital rectal examination first catch urine was collected. PCA3 scores were determined using the PROGENSA(®) PCA3 assay and compared to biopsy outcome. The diagnostic accuracy of PCA3 was compared to total prostate specific antigen, prostate specific antigen density and %free prostate specific antigen. RESULTS In 516 men the positive biopsy rate was 40%. An increasing PCA3 score corresponded with an increasing probability of a positive biopsy. The mean PCA3 score was higher in men with a positive vs a negative biopsy (69.6 vs 31.0, median 50 vs 18, p <0.0001). The PCA3 score was independent of age, total prostate specific antigen and prostate volume. The PCA3 score (cutoff of 35) had a sensitivity of 64% and specificity of 76%. ROC analysis showed a significantly higher AUC for the PCA3 score vs total prostate specific antigen, prostate specific antigen density and %free prostate specific antigen. The PCA3 score was significantly higher in men with biopsy Gleason score 7 or greater vs less than 7, greater than 33% vs 33% or fewer positive cores and significant vs indolent prostate cancer. Inclusion of PCA3 in multivariable models increased their predictive accuracy by up to 5.5%. CONCLUSIONS The PROGENSA PCA3 assay can aid in guiding biopsy decisions. It is superior to total prostate specific antigen, prostate specific antigen density and %free prostate specific antigen in predicting initial biopsy outcome, and may be indicative of prostate cancer aggressiveness.

Prognostic Significance of Tumor Volume after Radical Prostatectomy: A Multivariate Analysis of Pathological Prognostic Factors

OBJECTIVES To analyze the association between Gleason score, stage and status of surgical margins with tumor volume in prostate cancer progression after radical prostatectomy. METHODS 200 consecutive radical prostatectomy specimens were analyzed. Preoperative clinical stage, PSA, results of prostate biopsies as well as pathological results were noted. A biochemical recurrence was defined as a single, postoperative detectable PSA level (>0.2 ng/ml). Tumor volume was compared to postoperative staging, Gleason score, and surgical margin status to predict tumor progression. Univariate and multivariate analysis using stepwise logistic regression were used to identify parameters with additional prognostic value. RESULTS Pathological results of the prostatectomy specimens showed 149 (74.5%) pT2a-b, 29 (14.5%) pT3a and 22 (11%) pT3b tumors. Tumor volume was 0.57 cc for pT2a, 1.2cc for pT2b, 1.7cc for pT3a and 2.9cc for pT3b, respectively (p<0.05). Taken together, mean volume for pT2 and pT3 were 1.06 and 2.2 cc, respectively (p<0.0001). Five-year progression-free actuarial survival was 69.7%. Using univariate analysis, tumor progression correlated with final Gleason score (p<0.0007), positive surgical margins (p=0.02), tumor volume (p=0.009) and stage (p<0.0001). In a multivariate analysis, tumor progression correlated only with the final Gleason score (p=0.04) and stage (p=0.0002). CONCLUSION Gleason score and pathological stage are independent factors to predict prostate cancer progression after radical prostatectomy. When these parameters are known, tumor volume does not provide additional information.

External Validation of Urinary PCA3-Based Nomograms to Individually Predict Prostate Biopsy Outcome

BACKGROUND Prior to safely adopting risk stratification tools, their performance must be tested in an external patient cohort. OBJECTIVE To assess accuracy and generalizability of previously reported, internally validated, prebiopsy prostate cancer antigen 3 (PCA3) gene-based nomograms when applied to a large, external, European cohort of men at risk of prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS Biopsy data, including urinary PCA3 score, were available for 621 men at risk of PCa who were participating in a European multi-institutional study. INTERVENTION All patients underwent a ≥10-core prostate biopsy. Biopsy indication was based on suspicious digital rectal examination, persistently elevated prostate-specific antigen level (2.5-10 ng/ml) and/or suspicious histology (atypical small acinar proliferation of the prostate, >/= two cores affected by high-grade prostatic intraepithelial neoplasia in first set of biopsies). MEASUREMENTS PCA3 scores were assessed using the Progensa assay (Gen-Probe Inc, San Diego, CA, USA). According to the previously reported nomograms, different PCA3 score codings were used. The probability of a positive biopsy was calculated using previously published logistic regression coefficients. Predicted outcomes were compared to the actual biopsy results. Accuracy was calculated using the area under the curve as a measure of discrimination; calibration was explored graphically. RESULTS AND LIMITATIONS Biopsy-confirmed PCa was detected in 255 (41.1%) men. Median PCA3 score of biopsy-negative versus biopsy-positive men was 20 versus 48 in the total cohort, 17 versus 47 at initial biopsy, and 37 versus 53 at repeat biopsy (all p≤0.002). External validation of all four previously reported PCA3-based nomograms demonstrated equally high accuracy (0.73-0.75) and excellent calibration. The main limitations of the study reside in its early detection setting, referral scenario, and participation of only tertiary-care centers. CONCLUSIONS In accordance with the original publication, previously developed PCA3-based nomograms achieved high accuracy and sufficient calibration. These novel nomograms represent robust tools and are thus generalizable to European men at risk of harboring PCa. Consequently, in presence of a PCA3 score, these nomograms may be safely used to assist clinicians when prostate biopsy is contemplated.

High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy

OBJECTIVES To assess the prognostic value of prostatic stromal inflammation in surgically treated localized prostate carcinoma for biochemical recurrence-free survival. METHODS Stromal prostatic inflammation grading was studied in 161 patients who underwent radical prostatectomy for prostate cancer without involvement of the lymph nodes and who did not receive preoperative or postoperative radiotherapy or hormonal therapy until recurrence occurred. Inflammation was graded as high-grade inflammation if confluence of inflammatory cell infiltrate and/or glandular epithelium disruption associated with interstitial inflammatory infiltrate were present and as low-grade inflammation otherwise. Each specimen was graded separately first in the stroma surrounding nonmalignant glands and second in the stroma surrounding malignant glands. Biochemical recurrence based on serum prostate-specific antigen (PSA) level was defined as two successive PSA measurements greater than 1 ng/mL. RESULTS Malignant tissue was significantly less involved in high-grade inflammation than benign adjacent tissue (9.3% and 19.9%, respectively; P <0.01). In a univariate Kaplan-Meier analysis, the 5-year recurrence-free survival rate for patients with high-grade and low-grade classified prostates was 61.0% and 66.7% in benign tissue and 27.0% and 65.3% in malignant tissue, respectively, with a significant difference between grades only in malignant tissue (P <0.02). In a multivariate analysis controlling for Gleason grade, preoperative serum PSA, pathologic stage, and inflammation grade in malignant tissue, the latter factor remained significantly predictive of biochemical recurrence (P = 0.03). CONCLUSIONS Patients with high-grade inflammation surrounding malignant glands in radical prostatectomy specimens had significantly more postoperative biochemical recurrence than patients with low-grade inflammation.

Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: a double-blind, randomised trial

BACKGROUND Hot flushes are the most common complaints reported by men undergoing androgen suppression treatment for prostate cancer. We designed a randomised double-blind trial to compare the efficacy of three drugs, each of which has proven effective for preventing hot flushes in previous studies. METHODS Men with prostate cancer with an indication for androgen suppression were enrolled in the study at 106 urology centres in France between April 14, 2004, and April 20, 2007. All patients were treated for 6 months with leuprorelin (11.25 mg). At month 6, patients who spontaneously asked for treatment, or those who presented with 14 hot flushes or more during the week before the visit, were randomly assigned to either venlafaxine 75 mg daily, medroxyprogesterone acetate 20 mg daily, or cyproterone acetate 100 mg daily. All patients received two indistinguishable pills in the morning and one in the evening from week 1 to week 8, and one indistinguishable pill in the morning from week 9 to week 10, to comply with the double-blind design. Random assignment with a block size of three was done centrally, by fax, and each patient was given a randomisation number. The allocation sequence was stratified by centre. Assessment was done at inclusion, at randomisation, and then at 4 weeks, 8 weeks, and 12 weeks after randomisation. Participants completed a daily hot-flush diary for 1 week, and a quality of life questionnaire before each visit throughout the study. The primary outcome was the change in median daily hot-flush score between randomisation and 1 month. All patients who received at least one study treatment dose were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01011751. FINDINGS Of the 919 men initially enrolled, 311 were randomly assigned to one of the study treatments at 6 months: 102 to venlafaxine, 101 to cyproterone, and 108 to medroxyprogesterone. 309 patients were included in the efficacy analysis, since two were excluded for protocol deviations (one in the cyproterone and one in the medroxyprogesterone group; both were excluded because they were already undergoing treatment with serotonin reuptake inhibitor antidepressants at randomisation). The change in median daily hot-flush score between randomisation and 1 month was -47.2% (IQR -74.3 to -2.5) in the venlafaxine group, -94.5% (-100.0 to -74.5) in the cyproterone group, and -83.7% (-98.9 to -64.3) in the medroxyprogesterone group. The decrease from baseline was significant for all three groups (p<0.0001). Pairwise comparison of treatment groups adjusted by the Bonferroni method confirmed that the decreases in hot-flush score were significantly larger in the cyproterone and medroxyprogesterone groups than in the venlafaxine group, regardless of the interval considered (p<0.0001 in all cases). There was no significant difference between the cyproterone and medroxyprogesterone groups (p>0.2 in all cases). Serious side-effects occurred in four, seven, and five patients in the venlafaxine, cyproterone, and medroxyprogesterone groups, respectively, of which none, one (dyspnoea), and one (urticaria) were considered related to the drug, respectively. INTERPRETATION After 6 months of treatment with leuprorelin, venlafaxine, cyproterone, and medroxyprogesterone proved to be effective in reducing hot flushes. However, the hormonal treatments cyproterone and medroxyprogesterone were significantly more effective than venlafaxine. As cyproterone is a recognised treatment in prostate cancer, and its use could interfere with hormonal therapy, medroxyprogesterone could be considered to be the standard treatment for hot flushes in men undergoing androgen suppression for prostate cancer. FUNDING Takeda Laboratories, Puteaux, France.

Tolerability of bacille Calmette-Guérin maintenance therapy for superficial bladder cancer.

OBJECTIVES To study the influence of adverse reactions on adherence to an immunotherapy maintenance schedule and the recurrence rate of bladder cancer. Bacille Calmette-Guérin immunotherapy has documented efficacy in the management of high-risk superficial bladder cancer. However, the optimal duration of intravesical bacille Calmette-Guérin therapy and the risk/benefit ratio of maintenance therapy are controversial. METHODS From April 1996 to April 2000, 72 patients with superficial bladder cancer were treated with Immucyst (six consecutive weekly instillations of 81 mg) and then received maintenance therapy consisting of three consecutive weekly instillations 3, 6, 12, 18, 24, 30, and 36 months later. Adverse reactions, studied during 518 instillations, were classified in four categories using a scale based on the World Health Organization recommendations, and their impact on the adherence to therapy was analyzed. RESULTS After an average follow-up of 24 months, a durable disease-free response was observed in 84.9% of the patients; 12.5% of patients had a relapse and 2.6% had disease progression. The response rate was similar in patients with and without adverse reactions. Only 14 patients (19%) received all the scheduled maintenance instillations. The dose was reduced in 41 patients (57%), and treatment was stopped in 28 patients (39%). In multivariate analysis, an adverse event score of 1.5 or greater during induction therapy was significantly associated with cessation or modification of maintenance therapy (P = 0.01). CONCLUSIONS The scale developed in this study to monitor the adverse reactions to bacille Calmette-Guérin and their impact on the adherence to maintenance therapy may be helpful for tailoring maintenance regimens or implementing protective measures (dose reduction or treatment postponement).

Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guerin: results of a retrospective multicenter study of 2451 patients

BACKGROUND The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. OBJECTIVE To assess prognostic factors in patients who received bacillus Calmette-Guérin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. DESIGN, SETTING, AND PARTICIPANTS Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). RESULTS AND LIMITATIONS With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age ≥ 70 yr, size ≥ 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients ≥ 70 yr with tumor size ≥ 3 cm and 13% otherwise. CONCLUSIONS T1G3 patients ≥ 70 yr with tumors ≥ 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. PATIENT SUMMARY Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guérin, there is a subgroup of T1G3 patients with age ≥ 70 yr, tumor size ≥ 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment.

The relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance

Study Type – Diagnostic (exploratory cohort)

Radiographic prognostic criteria for extracorporeal shock-wave lithotripsy: A study of 485 patients

OBJECTIVES We studied 485 patients treated by extracorporeal shock-wave lithotripsy (ESWL) using an ultrasound electrohydraulic apparatus in an effort to define radiographic criteria for better patient selection for ESWL. METHODS Results were assessed according to plain x-ray nephrotomography and ultrasound. The criteria for measuring success (stone free [SF]) excluded all residual fragments. After per-criteria analysis of the results, a multivariate analysis as well as an analysis of stone composition by infrared spectroscopy were performed. RESULTS The SF rate was 57.5% (279 of 485). Calculi that were smooth, denser than bone, located in the lower calyx, and larger than 15 mm had less satisfactory results despite a greater number of impulses. A correlation was established between the radiographic appearance of the calculus, its composition, and ESWL results. Rough, less dense calcium oxalate dihydrate yielded satisfactory results (65%), whereas smooth, dense calcium oxalate monohydrate led to less conclusive results (41%). Multivariate analysis demonstrated the predominant influence of radiographic calculus profile on the results: rough, less dense calculi yielded a 79.4% SF rate, whereas smooth, dense calculi yielded a 33.6% SF rate. CONCLUSIONS We propose that patients with dense, smooth calculi located in the lower calyx and larger than 15 mm be treated by other techniques, such as percutaneous nephrolithotomy. This would not only increase the ESWL effectiveness rate, but would also reduce the cost of treating kidney stones.