Intravesical sequential gemcitabine and docetaxel versus bacillus calmette-guerin (BCG) plus interferon in patients with recurrent non-muscle invasive bladder cancer following a single induction course of BCG.

INTRODUCTION: Repeat BCG induction remains an option for select non-muscle invasive bladder cancer (NMIBC) patients who fail initial therapy. Alternative salvage intravesical regimens such as Gemcitabine and Docetaxel (Gem/Doce) have been investigated. We aimed to compare the efficacy BCG plus interferon a-2b (BCG/IFN) and Gem/Doce in patients with recurrent NMIBC after a single prior BCG course. METHODS: The National Phase II BCG/IFN trial database and multi-institutional Gem/Doce database were queried for patients with recurrent NMIBC after one prior BCG induction course, excluding those with BCG unresponsive disease. Stabilized inverse probability treatment weighted survival curves were estimated using the Kaplan-Meier method and compared. Propensity scores were derived from a logistic regression model. The primary outcome was recurrence free survival (RFS); secondary outcomes were high-grade (HG) RFS and risk factors for treatment failure. RESULTS: We identified 197 BCG/IFN and 93 Gem/Doce patients who met study criteria. Patients receiving Gem/Doce were older and more likely to have HG disease, CIS, and persistent disease following induction BCG (all P < 0.01). After propensity score-based weighting, the adjusted 1- and 2-year RFS was 61% and 53% after BCG/IFN versus 68% and 46% after Gem/Doce (P = 0.95). Adjusted 1- and 2-year HG-RFS was 60% and 51% after BCG/IFN versus 63% and 42% after Gem/Doce (P = 0.68). Multivariable Cox regression revealed that Gem/Doce treatment was not associated with an increased risk of failure (HR = 0.97, P = 0.89) as compared to BCG/IFN. CONCLUSION: Patients with recurrent NMIBC after a single induction BCG failure and not deemed BCG unresponsive had similar oncologic outcomes with Gem/Doce and BCG/IFN in a post-hoc analysis. Additional prospective studies are needed.

Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer.

PURPOSE: Rescue intravesical therapies for patients with bacillus Calmette-Guérin failure nonmuscle invasive bladder cancer remain a critical focus of ongoing research. Sequential intravesical gemcitabine and docetaxel therapy has shown safety and efficacy in 2 retrospective, single institution cohorts. This doublet has since been adopted as an intravesical salvage option at multiple institutions. We report the results of a multi-institutional evaluation of gemcitabine and docetaxel. MATERIALS AND METHODS: Each institution retrospectively reviewed all records of patients treated with intravesical gemcitabine and docetaxel for nonmuscle invasive bladder cancer between June 2009 and May 2018. Only patients with recurrent nonmuscle invasive bladder cancer and a history of bacillus Calmette-Guérin treatment were included in the analysis. If patients were disease-free after induction, maintenance was instituted at the treating physician's discretion. Posttreatment surveillance followed American Urological Association guidelines. Survival analysis was performed using the Kaplan-Meier method and risk factors for treatment failure were assessed with Cox regression models. RESULTS: Overall 276 patients (median age 73 years, median followup 22.9 months) received treatment. Nine patients were unable to tolerate a full induction course. One and 2-year recurrence-free survival rates were 60% and 46%, and high grade recurrence-free survival rates were 65% and 52%, respectively. Ten patients (3.6%) had disease progression on transurethral resection. Forty-three patients (15.6%) went on to cystectomy (median 11.3 months from induction), of whom 11 (4.0%) had progression to muscle invasion. Analysis identified no patient, disease or prior treatment related factors associated with gemcitabine and docetaxel failure. CONCLUSIONS: Intravesical gemcitabine and docetaxel therapy is well tolerated and effective, providing a durable response in patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin therapy. Further prospective study is warranted.

Expectant long-term follow-up of patients with chronic urinary retention.

AIMS: To describe urologic complications in patients with chronically elevated post-void residual (PVR) volumes and to evaluate other related risk factors during a long-term follow-up in patients managed conservatively. METHODS: Non-neurogenic patients who refused surgical intervention of the prostate and had PVR volumes >300 mL on two or more separate occasions at least 6 months apart were included. We followed this cohort over time, recorded complications and evaluated risk factors for complications. RESULTS: Twenty-eight men with a mean age of 74 were followed for a median of 56 months (IQR: 26-101 months); 26 had benign prostatic hyperplasia with a median prostate size of 55 cc. Baseline median PVR was 468 cc (IQR: 395-828) and follow-up median PVR was 508 cc (IQR: 322-714). During follow-up, 13 patients (46%) had at least one complication with acute urinary retention being the most common occurring in 10 patients (36%) with 15 episodes. Other complications presented in less than 15%, and no patients developed permanent renal insufficiency. Patients with prostate size ≥ 100 cc had significantly higher total number of acute retention episodes (P-value: 0.01). CONCLUSIONS: Although the presence of CUR could commonly predispose to episodes of acute retention, severe complications are infrequent although present. Additionally, prostate size may play a role in increasing some adverse outcomes. With proper counseling about different complications, patients with retention who denied surgical treatment can be safely followed for at least 5 years without renal deterioration.

Gleason Misclassification Rate Is Independent of Number of Biopsy Cores in Systematic Biopsy.

OBJECTIVE: To compare the utility of saturation core biopsy and 12-core biopsy in detecting true Gleason grades, using final pathology in prostatectomy specimens as outcome measures, with a particular interest in Gleason upgrading. PATIENTS AND METHODS: We compared the concordance rates of Gleason grades diagnosed on biopsies and prostatectomy specimens in 375 consecutive patients, including 106 saturation biopsies (18-33 cores, median = 20 cores) and 269 12-core biopsies. Grading bias was addressed by a central rereview of all cases that had discordance in reporting high Gleason grades (Gleason grade ≥ 4) on biopsies and prostatectomy specimens. RESULTS: For patients with high Gleason grades on final pathology, saturation and 12-core biopsy schemes had a comparable sensitivity, specificity, negative and positive predictive values (72.5% vs 69.5%, 91.9% vs 97.6%, 64.2% vs 58.4%, and 94.3% vs 98.5%, respectively) in detecting high Gleason grades. On multivariate analysis, prebiopsy serum prostate-specific antigen and clinical T stage independently predicted Gleason upgrading; saturation biopsy was not a significant predictor. Approximately one-third of cases where high Gleason grade was not present in the biopsy were attributed to the confinement of high-grade tumors to unusual anatomic locations such as anterior lobes, apex, bladder neck, and parasagittal zones. CONCLUSION: Our study showed that Gleason misclassification rate is independent of the number of biopsy cores in systematic biopsy. One of the reasons for missing high Gleason grade tumors on systematic biopsy was unusual tumor location outside of the biopsy grid, supporting the need for improved detection technique such as magnetic resonance imaging-guided targeted biopsies.

Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary results.

This report presents our experience with T therapy in a cohort of T-deficient men on active surveillance (AS) for Gleason 3 + 3 and Gleason 3 + 4 prostate cancer (PCa). A retrospective chart review identified 28 men with T deficiency who underwent T therapy (T group) for at least 6 months while on AS for PCa. A comparison group of 96 men on AS for PCa with untreated T deficiency (no-T group) was identified at the same institution. The AS protocol followed a modified Epstein criteria and allowed inclusion of men with a single core of low-volume Gleason 3 + 4 PCa. Mean age was 59.5 and 61.3 years, and mean follow-up was 38.9 and 42.4 months for the T and no-T groups, respectively. Of all 28 men in the T group, 3 (10.7%) men developed an increase in Gleason score while on AS. Of 22 men in the T group with Gleason 3 + 3 disease, 7 (31.8%) men developed biopsy progression including 3 men (13.6%) who developed Gleason 3 + 4 PCa. Of 6 men with Gleason 3 + 4 disease at baseline, 2 (33.3%) men developed an increase in tumor volume, and none developed upgrading beyond Gleason 3 + 4. All 96 men in the no-T group had Gleason 3 + 3 disease at baseline and, 43 (44.7%) developed biopsy progression, including 9 men (9.38%) with upgrading to Gleason 7 (3 + 4). Biopsy progression rates were similar for both groups and historical controls. Biopsy progression in men on AS appears unaffected by T therapy over 3 years. Prospective placebo-controlled trials of T therapy in T-deficient men on AS should be considered given the symptomatic benefits experienced by treated men.

Low free testosterone levels predict disease reclassification in men with prostate cancer undergoing active surveillance.

OBJECTIVE: To determine whether total testosterone and free testosterone levels predict disease reclassification in a cohort of men with prostate cancer (PCa) on active surveillance (AS). PATIENTS AND METHODS: Total testosterone and free testosterone concentrations were determined at the time the men began the AS protocol. Statistical analysis was performed using Student's t-test and a chi-squared test to compare groups. Odds ratios (ORs) with 95% confidence intervals (CIs) were obtained using univariate logistic regression. Receiver-operator characteristic curves were generated to determine the investigated testosterone thresholds. Kaplan-Meier curves were used to estimate time to disease reclassification. A Cox proportional hazard regression model was used for multivariate analysis. RESULTS: A total of 154 men were included in the AS cohort, of whom 54 (35%) progressed to active treatment. Men who had disease reclassification had significantly lower free testosterone levels than those who were not reclassified (0.75 vs 1.02 ng/dL, P = 0.03). Men with free testosterone levels <0.45 ng/dL had a higher rate of disease reclassification than patients with free testosterone levels ≥0.45 (P = 0.032). Free testosterone levels <0.45 ng/dL were associated with a several-fold increase in the risk of disease reclassification (OR 4.3, 95% CI 1.25-14.73). Multivariate analysis showed that free testosterone and family history of PCa were independent predictors of disease reclassification. CONCLUSIONS: Free testosterone levels were lower in men with PCa who had reclassification during AS. Men with moderately severe reductions in free testosterone level are at increased risk of disease reclassification.

Diagnosis of relevant prostate cancer using supplementary cores from magnetic resonance imaging-prompted areas following multiple failed biopsies.

OBJECTIVES: To establish the value of MRI in targeting re-biopsy for undiagnosed prostate cancer despite multiple negative biopsies and determine clinical relevance of detected tumors. MATERIALS AND METHODS: Thirty-eight patients who underwent MRI after 2 or more negative biopsies due to continued clinical suspicion and later underwent TRUS-guided biopsy supplemented by biopsy of suspicious areas depicted by MRI were identified. Diagnostic performance of endorectal 3T MRI in diagnosing missed cancer foci was assessed using biopsy results as the standard of reference. Ratio of positive biopsies using systematic versus MRI-prompted approaches was compared. Gleason scores of detected cancers were used as surrogate for clinical relevance. RESULTS: Thirty-four percent of patients who underwent MRI before re-biopsy had prostate cancer on subsequent biopsy. The positive biopsy yield with systematic sampling was 23% versus 92% with MRI-prompted biopsies(p<0.0001). Seventy-seven percent of tumors were detected exclusively in the MRI-prompted zones. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of MRI to provide a positive biopsy were 92%, 60%, 55%, 94% and 71%, respectively. The anterior gland and apical regions contained most tumors; 75% of cancers detected by MRI-prompted biopsy had Gleason score≥7. CONCLUSIONS: Clinically relevant tumors missed by multiple TRUS-guided biopsies can be detected by a MRI-prompted approach.

Comparing costs of robotic, laparoscopic, and open partial nephrectomy.

UNLABELLED: Abstract Background and Purpose: Laparoscopic and robot-assisted partial nephrectomy (LPN and RPN) are common minimally invasive alternatives to open partial nephrectomy (OPN) for management of renal tumors. Cost discrepancies of these approaches warrants evaluation. We compared hospital costs associated with RPN, LPN, and OPN. PATIENTS AND METHODS: Costs were captured for 25 patients in each group who underwent RPN, LPN, or OPN at our institution between November 2008 and September 2010. Variable costs included operating room (OR) time, supplies, anesthesia, and inpatient care costs. Fixed costs included equipment purchase and maintenance. Impact of variable and fixed costs were estimated using sensitivity analysis. RESULTS: Overall variable costs were similar for RPN, LPN, and OPN ($6375 vs $6075 vs $5774, P=0.117, respectively). OR supplies contributed a greater cost for RPN and LPN than OPN ($2179 vs $1987 vs $181, P<0.0001, respectively), while inpatient stay costs were higher for OPN compared with LPN and RPN ($2418 vs $1305 vs $1274, P<0.0001, respectively). Sensitivity analysis of variable costs demonstrates that RPN and LPN can represent less costly alternatives to OPN if hospital stay for RPN and LPN is ≤2 days and OR time <195 and 224 minutes, respectively. Inclusion of fixed costs made OPN less expensive than LPN and RPN unless use of the robot increases and operative times are reduced. CONCLUSION: By minimizing OR time and hospital stay, RPN and LPN can be cost equivalent to OPN regarding variable costs. When including fixed costs, RPN and LPN were more costly than OPN, but equivalence may be possible with improvements in efficiency.

Prediction of prostate cancer extracapsular extension with high spatial resolution dynamic contrast-enhanced 3-T MRI.

OBJECTIVES: To assess the value of dynamic contrast-enhanced (DCE) combined with T2-weighted (T2W) endorectal coil (ERC) magnetic resonance imaging (MRI) at 3 T for determining extracapsular extension (ECE) of prostate cancer. METHODS: In this IRB-approved study, ERC 3-T MRI of the prostate was performed in 108 patients before radical prostatectomy. T2W fast spin-echo and DCE 3D gradient echo images were acquired. The interpretations of readers with varied experience were analysed. MRI-based staging results were compared with radical prostatectomy histology. Descriptive statistics were generated for prediction of ECE and staging accuracies were determined by the area under the receiver-operating characteristic curve. RESULTS: The overall sensitivity, specificity, positive predictive value and negative predictive value for ECE were 75 %, 92 %, 79 % and 91 %, respectively. Diagnostic accuracy for staging was 86 %, 80 % and 91 % for all readers, experienced and less experienced readers, respectively. CONCLUSIONS: ERC 3-T MRI of the prostate combining DCE and T2W imaging is an accurate pretherapeutic staging tool for assessment of ECE in clinical practice across varying levels of reader experience. KEY POINTS : • Endorectal coil (ERC) magnetic resonance imaging is widely used for imaging prostatic disease. • ERC 3-T MRI is reasonably accurate for local prostate cancer staging. • High diagnostic accuracy is achievable across different levels of reader experience. • MRI facilitates therapeutic decisions in patients with prostate cancer.

Expanded prostate cancer index composite for clinical practice: development and validation of a practical health related quality of life instrument for use in the routine clinical care of patients with prostate cancer.

PURPOSE: Measuring the health related quality of life of patients with prostate cancer in routine clinical practice is hindered by the lack of instruments enabling efficient, real-time, point of care scoring of multiple health related quality of life domains. Thus, we developed an instrument for this purpose. MATERIALS AND METHODS: The Expanded Prostate Cancer Index Composite for Clinical Practice is a 1-page, 16-item questionnaire that we constructed to measure urinary incontinence, urinary irritation, and the bowel, sexual and hormonal health related quality of life domains. We eliminated conceptually overlapping items from the 3-page Expanded Prostate Cancer Index Composite-26 and revised the questionnaire format to mirror the AUA symptom index, thereby enabling practitioners to calculate health related quality of life scores at the point of care. We administered the Expanded Prostate Cancer Index Composite for Clinical Practice to a new cohort of patients with prostate cancer in community based and academic oncology, radiation, and urology practices to evaluate instrument validity as well as ease of use in clinical practice. RESULTS: A total of 175 treated and 132 untreated subjects with prostate cancer completed the Expanded Prostate Cancer Index Composite for Clinical Practice. The domain scores of the Expanded Prostate Cancer Index Composite for Clinical Practice correlated highly with the respective domain scores from longer versions of the Expanded Prostate Cancer Index Composite (r≥0.93 for all domains). The Expanded Prostate Cancer Index Composite for Clinical Practice showed high internal consistency (Cronbach's α 0.64-0.84) and sensitivity to prostate cancer treatment related effects (p<0.05 in each of 5 health related quality of life domains). Patients completed the Expanded Prostate Cancer Index Composite for Clinical Practice efficiently (96% in less than 10 minutes and with 11% missing items). It was deemed very convenient by clinicians in 87% of routine clinical encounters and clinicians accurately scored completed questionnaires 94% of the time. CONCLUSIONS: The Expanded Prostate Cancer Index Composite for Clinical Practice is a valid instrument that enables patient reported, health related quality of life to be measured efficiently and accurately at the point of care, and thereby facilitates improved emphasis and management of patient reported outcomes.

Risk stratification and validation of prostate specific antigen density as independent predictor of progression in men with low risk prostate cancer during active surveillance.

PURPOSE: We assessed risk stratification in patients with low grade prostate cancer managed by active surveillance using a 20-core saturation biopsy technique. MATERIALS AND METHODS: A total of 135 consecutive patients with low risk prostate cancer were prospectively entered in an active surveillance program in a 10-year period. The study entrance requirement and progression definition followed Epstein criteria using only pathological parameters, ie fewer than 3 positive cores, Gleason score 6 or less and 50% or less of any single core involved. All patients were monitored by restaging 20-core saturation biopsy every 12 to 18 months. A total of 120 patients with at least 1 rebiopsy form the basis of this report. RESULTS: Of the cohort 30% progressed during a median of 2.4 years. Three multivariate analyses were performed. The first analysis used variables only at diagnosis biopsy and revealed that prostate specific antigen density greater than 0.08 ng/ml/cc and prostate cancer family history were significant predictors of progression. When combined in a 3-level risk factor score, they were significant (p = 0.003). The second multivariate analysis considered changes in characteristics between diagnosis biopsy and first rebiopsy. Prostate specific antigen velocity along with prostate specific antigen density and family history highly predicted progression according to a 4-level risk factor score (p <0.0001). The third multivariate analysis validated the previously reported prostate specific antigen density cutoff of 0.08 ng/ml/cc at first rebiopsy as a significant predictor of subsequent progression (HR 3.16, 95% CI 1.12, 8.93; p = 0.03). CONCLUSIONS: Risk factor stratification can be used to significantly predict the outcome in patients on active surveillance. Prostate specific antigen density 0.08 ng/ml/cc at first rebiopsy was validated as a significant predictor of subsequent progression.

The human cancer and stem cell marker podocalyxin interacts with the glucose-3-transporter in malignant pluripotent stem cells.

Podocalyxin, an integral plasma membrane cell-adhesion glycoprotein, is a marker of human pluripotent and multipotent stem cells. Podocalyxin is also a marker of many types of cancers and its expression correlates with an aggressive and poor-prognosis tumor phenotype. The function of podocalyxin in stem cells and malignant cells is unknown. Protein sequence data obtained from purified podocalyxin protein isolated from embryonal carcinoma cancer stem cells reveals peptide sequence data for the glucose-3-transporter. Protein-precipitation experiments of embryonal carcinoma protein extracts identify a podocalyxin/glucose-3-transporter protein complex. Cell imaging studies demonstrate co-localization of podocalyxin and glucose-3-transporter and confirm the interaction in vivo. Finally, siRNA podocalyxin-knockdown experiments show decreased expression levels of the glucose-3-transporter. These findings suggest a novel interaction of the glucose-3-transporter and the cell-adhesion protein podocalyxin. In pluripotent stem cells and in human cancer disease, podocalyxin may function in part to regulate and maintain the cell surface expression of the glucose-3-transporter.

The hybrid of basic science and clinical training for the urologic oncologist: Necessity or waste?

OBJECTIVE: To examine the necessity and adequacy of basic science training for urologic oncology training programs. METHODS: Evaluated whether urology physician scientists are adequately trained in the basic sciences. RESULTS: The current urologic oncology training system does not adequately train physician scientists. We propose a major reform to define, train, and maintain the urology physician scientists. CONCLUSIONS: Urology physician scientists have played a major role in advancement of urologic oncology. Major reform is necessary, if we wish to continue to successfully train urologic oncology physician scientists.

MR imaging of renal masses: correlation with findings at surgery and pathologic analysis.

Magnetic resonance (MR) imaging is useful in the characterization of renal masses. The MR imaging manifestations and pathologic diagnoses of 82 renal masses were reviewed and correlated. The MR imaging appearance of clear cell type renal cell carcinoma varies depending on the presence of cystic components, hemorrhage, and necrosis. Papillary renal cell carcinomas appear as well-encapsulated masses with homogeneous low signal intensity on T2-weighted images and homogeneous low-level enhancement after the intravenous administration of contrast material, or as cystic hemorrhagic masses with peripheral enhancing papillary projections. Transitional cell carcinoma may be seen as an irregular, enhancing filling defect in the pelvicaliceal system or ureter. Lymphomatous masses are usually hypointense relative to the renal cortex on T2-weighted images and enhance minimally on delayed gadolinium-enhanced images. Bulk fat is a distinguishing feature of angiomyolipoma. Oncocytoma has a variable and nonspecific appearance at MR imaging. MR imaging findings may allow the characterization of various renal masses and can provide valuable information for their clinical management.

Lower limits of detection using magnetic resonance imaging for solid components in cystic renal neoplasms.

OBJECTIVES: We determined the positive predictive value (PPV) for malignancy in complex renal cysts with focal nodular enhancement seen on magnetic resonance imaging (MRI). METHODS: A surgical database was reviewed to identify all patients having both a preoperative 3 dimensional (3D) renal MRI and a radical or partial nephrectomy from January 2000 through April 2004 at our hospital. A group of 21 patients were identified with focal nodular enhancement within cystic renal masses. Pathologic correlation was made in each case. RESULTS: We performed 286 nephrectomies during the study period. Of these patients, 159 (56%) had a preoperative MRI studies. There were 21 of 159 (13%) patients with complex cystic lesions that displayed focal nodular enhancement, 14 of which (67%) measured 10 mm or larger in size. Twenty (95%) of the 21 lesions were renal cell carcinoma. The single, benign lesion was a cystic nephroma. Fuhrman grade 1 or grade 2 cancers were found in the majority of patients (80%), and there were no grade 4 cancers. Fifteen patients had a preoperative computerized tomography (CT) scan as well and nodular enhancement was suspected in only 4 patients (27%). MRI findings upgraded these lesions in 11 patients (73%). CONCLUSIONS: The demonstration of solid enhancing nodular components with high-resolution 3D MRI provides excellent positive predictive value for diagnosing neoplastic cystic renal lesions, including a large percentage 10 mm or larger in size. Our experience suggests a 95% likelihood that cystic renal lesions with focal nodular enhancement are malignant. We recommend that such lesions be considered malignant.