James Bailen

A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer.

BACKGROUND The 4Kscore combines measurement of four kallikreins in blood with clinical information as a measure of the probability of significant (Gleason ≥7) prostate cancer (PCa) before prostate biopsy. OBJECTIVE To perform the first prospective evaluation of the 4Kscore in predicting Gleason ≥7 PCa in the USA. DESIGN, SETTING, AND PARTICIPANTS Prospective enrollment of 1012 men scheduled for prostate biopsy, regardless of prostate-specific antigen level or clinical findings, was conducted at 26 US urology centers between October 2013 and April 2014. INTERVENTION The 4Kscore. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was Gleason ≥7 PCa on prostate biopsy. The area under the receiver operating characteristic curve, risk calibration, and decision curve analysis (DCA) were determined, along with comparisons of probability cutoffs for reducing the number of biopsies and their impact on delaying diagnosis. RESULTS AND LIMITATIONS Gleason ≥7 PCa was found in 231 (23%) of the 1012 patients. The 4Kscore showed excellent calibration and demonstrated higher discrimination (AUC 0.82) and net benefit compared to a modified Prostate Cancer Prevention Trial Risk Calculator 2.0 model and standard of care (biopsy for all men) according to DCA. A possible reduction of 30-58% in the number biopsies was identified with delayed diagnosis in only 1.3-4.7% of Gleason ≥7 PCa cases, depending on the threshold used for biopsy. Pathological assessment was performed according to the standard of care at each site without centralized review. CONCLUSION The 4Kscore showed excellent diagnostic performance in detecting significant PCa. It is a useful tool in selecting men who have significant disease and are most likely to benefit from a prostate biopsy from men with no cancer or indolent cancer. PATIENT SUMMARY The 4Kscore provides each patient with an accurate and personalized measure of the risk of Gleason ≥7 cancer to aid in decision-making regarding the need for prostate biopsy.

PCA3 Molecular Urine Test as a Predictor of Repeat Prostate Biopsy Outcome in Men with Previous Negative Biopsies: A Prospective Multicenter Clinical Study

PURPOSE We evaluated the clinical usefulness of the PROGENSA® PCA3 Assay for predicting repeat prostate biopsy outcome. MATERIALS AND METHODS Men with at least 1 prior negative prostate biopsy who were scheduled for repeat prostate biopsy based on best clinical judgment were enrolled at 14 centers. Whole blood and post-digital rectal examination urine samples were collected before extended template transrectal biopsy with 12 or more cores. Urinary PCA3 scores and biopsy outcomes were assessed by logistic regression analysis, which also included age, race, serum prostate specific antigen, clinical stage, family history of prostate cancer and the number of previous negative biopsy sessions. RESULTS A total of 466 men were included in study and prostate cancer was identified in 21.9%. A PCA3 score cutoff of 25 yielded 77.5% sensitivity, 57.1% specificity, and negative and positive predictive values of 90% and 33.6%, respectively. On multivariable logistic regression men with a PCA3 score of less than 25 were 4.56 times as likely to have a negative repeat biopsy as men with a score of 25 or greater. PCA3 score significantly increased the predictive accuracy of the logistic regression model. At 90% sensitivity adding the PCA3 score to the model increased specificity, and positive and negative predictive values by 22.6%, 6.4% and 7.1%, respectively, relative to the model without the PCA3 score. CONCLUSIONS The PCA3 score supplements serum prostate specific antigen and other clinical information to provide more accurate prediction of repeat biopsy outcome. Thus, it provides clinicians and patients with independent, clinically useful information to make more informed repeat biopsy decisions.

Selective estrogen receptor alpha agonist GTx-758 decreases testosterone with reduced side effects of androgen deprivation therapy in men with advanced prostate cancer

BACKGROUND A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly earlier in the disease course. OBJECTIVE To assess the ability of an oral selective estrogen receptor α agonist (GTx-758) to lower testosterone concentrations compared with leuprolide while minimizing estrogen deficiency-related side effects of androgen-deprivation therapy. DESIGN, SETTING, AND PARTICIPANTS Hormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000 mg/d, 2000 mg/d, or leuprolide depot. INTERVENTION GTx-758 and leuprolide. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was the proportion of patients achieving total testosterone ≤ 50 ng/dl by day 60. Secondary end points included serum free testosterone, prostate-specific antigen (PSA), sex hormone-binding globulin, hot flashes, bone turnover markers, and insulin-like growth factor (IGF)-1 levels. RESULTS AND LIMITATIONS Of 159 randomized patients, leuprolide reduced total testosterone to ≤ 50 ng/dl in a greater proportion of patients than GTx-758 by day 60 (43.4%, 63.6%, and 88.2% of subjects receiving GTx-758 1000 mg [p<0.001], GTx-758 2000 mg [p=0.004], and leuprolide, respectively). GTx-758 reduced free testosterone and PSA earlier and to a greater degree than leuprolide. GTx-758 led to fewer hot flashes, decreases in bone turnover markers, and alterations in IGF-1 compared with leuprolide. A higher incidence of venous thromboembolic events (VTEs) was seen with GTx-758 (4.1%) compared with leuprolide (0.0%). CONCLUSIONS Although leuprolide reduced total testosterone to ≤ 50 ng/dl in a greater proportion of patients compared with GTx-758, GTx-758 was superior in lowering free testosterone and PSA. GTx-758 reduced estrogen deficiency side effects of hot flashes, bone loss, and insulin resistance but with a higher incidence of VTEs. PATIENT SUMMARY This paper reports findings that leuprolide lowered total testosterone more than GTx-758 but that GTx-758 lowered free testosterone and prostate-specific antigen more than leuprolide. GTx-758 also reduced estrogen deficiency side effects, albeit at a higher rate of vascular events. TRIAL REGISTRATION Clinicaltrials.gov identifier NCT01615120.

Decreased Fistula Formation with Modified Denis Browne Hypospadias Repair

Many surgeons have abandoned the Denis Browne technique of hypospadias repair because of the associated high rate of postoperative fistulas. We reviewed retrospectively 40 cases of perineal or penoscrotal hypospadias in which a previously described modification of the Denis Browne technique had been used. The low rate of associated postoperative fistula formation makes this modified technique a valuable procedure in selected cases of hypospadias.

Bacteroides Fragilis Perinephric Abscess

Although urinary tract infection caused by Bacteroides fragilis has been recognized since the turn of the century it is not frequently recognized in clinical practice. Only a small number of significant upper urinary tract infections in which Bacteroides fragilis has had a significant pathogenic role have been reported previously. The use of systemic metronidazole in the treatment of this rare and unusually refractory form of urinary tract infection is described.

Evaluation of an experimental urodynamic platform to identify treatment effects: A randomized, placebo-controlled, crossover study in patients with overactive bladder†‡

To evaluate a urodynamic platform designed to identify treatment effects in small numbers of patients after a short duration of treatment using a medication with known efficacy in overactive bladder (OAB).

Phase I study of patients with non-muscle invasive bladder cancer (NMIBC) treated with vesigenurtacel-L (HS-410) after Bacillus Calmette-Guérin (BCG)

Meeting abstracts Vesigenurtacel-L (HS-410), consists of an allogeneic bladder cancer cell line, selected for high expression of a series of tumor antigens that are known to be shared by a high proportion of bladder tumors. The cell line secretes gp96-Ig, a modified heat shock protein which

Effect of GTx-758, an ERα agonist, on serum-free testosterone and serum PSA in men with advanced prostate cancer.

104 Background: Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer, but patients develop castrate resistant prostate cancer (CRPC); one of the causes of which is ineffective castration. Total serum testosterone (T) does not accurately predict prostatic levels of T. Further reduction of androgens in men with CRPC can result in improvement of survival. Herein we compare the effects GTx-758 an oral, selective estrogen receptor alpha (ERα) agonist versus leuprolide on total and free (unbound) serum T levels in men with advanced prostate cancer. METHODS In Phase II studies, men with advanced prostate cancer (n=164) received 1000 mg or 2000 mg GTx-758 daily or Lupron Depot (4 month), while men with CRPC (n=9) received 2000 mg GTx-758 daily. Serum concentrations of total T, free T, SHBG and PSA were determined at baseline and during treatment. RESULTS In ADT naïve advanced prostate cancer patients, 28 days of 1000 mg or 2000 mg daily GTx-758 or Lupron therapy castrated (T<50ng/dL) 50, 31 and 100% of patients, reducing mean serum total T in castrated patients to 23±14, 19±9 and 14±7 ng/dL, respectively. However, treatment with 1000 mg or 2000 mg GTx-758 daily reduced mean free T levels to a greater extent (0.9±0.7 and 0.7±0.7 pg/mL, respectively) than Lupron (1.7±1.1 pg/mL). Changes in PSA at 28 days were more closely associated with the observed changes in free T, with reductions of 74, 72 and 56% for 1000 mg, 2000 mg doses of GTx-758 and Lupron, respectively. In CRPC patients, 2000 mg GTx-758 daily did not further reduce serum total T levels, but did result in free T reductions and PSA decreases from baseline following 15 days of therapy in all of the men maintained on ADT with LHRH agonists alone. CONCLUSIONS Although GTx-758 and LHRH based ADT both reduce total serum T and PSA levels in ADT naïve advanced prostate cancer patients, free T was rapidly reduced to a greater degree in the GTx-758 treated patients. In men with CRPC, GTx-758 therapy resulted in significant reductions in free T and resultant PSA declines. The ability of GTx-758 to reduce free T provides a unique mechanism to treat men with advanced prostate cancer and CRPC. CLINICAL TRIAL INFORMATION NCT01326312.

A Phase I/II study of vesigenurtacel-l (hs-410) or placebo in combination with Bacillus Calmette-Guérin (BCG) in patients with non-muscle invasive bladder cancer (NMIBC)

Meeting abstracts Vesigenurtacel-L is an allogeneic cell-based therapeutic cancer vaccine that was selected based on its expression of a range of tumor antigens (surviving, LAGE-1, MAGE-A3, MAGE-A11, PRAME and others) that are known to be expressed amongst a high proportion of primary bladder

Effect of the ERα agonist GTx-758 on bone turnover markers in men with advanced prostate cancer.

222 Background: Men with advanced prostate cancer are being treated with androgen deprivation therapy (ADT) for longer periods of time. The use of ADT can be limited by estrogen deficiency side effects, including a loss of bone and a higher incidence of fractures. GTx-758 is an ERα agonist that lowers serum free testosterone greater than an LHRH agonist. Herein we compare the effects of GTx-758 and leuprolide on markers of bone turnover, C-terminal telopeptides and bone specific alkaline phosphatase, in men with advanced prostate cancer treated with ADT. METHODS In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Serum samples were collected and analyzed by a reference laboratory. C-terminal telopeptides (pg/ml) and bone specific alkaline phosphatase (U/L) were measured as indicators of bone turnover. All p values describe the comparison of the GTx-758 treatment groups to the leuprolide treated men at day 120. RESULTS Men receiving the 1000 mg and 2000 mg doses of GTx-758 had lower C-terminal telopeptide levels with a mean percentage change of -56.9 ± 12.5 and -54.8 ± 23.1, respectively, as compared with an increase of 46.0 ± 48.9 percentage in the men receiving the leuprolide (p<0.001). Similarly, bone specific alkaline phosphatase levels were lower in men treated with GTx-758, with mean percentage changes of-28.5 ± 11.7 and -19.8 ± 14.7, respectively, compared with an increase of 8.1 ± 24.3 percent in the leuprolide treated group (p<0.001). As a result of an increased risk of venous thromboembolic events (VTEs) at these higher doses of GTx-758, the trial was stopped prior to its completion and not all of the men on the study reached the 120 day treatment dates (71 evaluable). CONCLUSIONS Patients receiving GTx-758 experienced a significant decrease in markers of bone turnover indicating potential improvement and not a loss of bone on ADT. Since changes in bone mineral density are a major side effect that can negatively affect the quality of life in men on ADT, the improvements in bone turnover observed in men treated with GTx-758 could be significant. A Phase II clinical trial utilizing lower doses of GTx-758 (G200712) is currently being performed. CLINICAL TRIAL INFORMATION NCT01326312.