A Pilot Study of 68Ga-PSMA11 and 68Ga-RM2 PET/MRI for Biopsy Guidance in Patients with Suspected Prostate Cancer.

Targeting of lesions seen on multiparametric MRI (mpMRI) improves prostate cancer (PC) detection at biopsy. However, 20%-65% of highly suspicious lesions on mpMRI (PI-RADS [Prostate Imaging-Reporting and Data System] 4 or 5) are false-positives (FPs), while 5%-10% of clinically significant PC (csPC) are missed. Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptors (GRPRs) are both overexpressed in PC. We therefore aimed to evaluate the potential of 68Ga-PSMA11 and 68Ga-RM2 PET/MRI for biopsy guidance in patients with suspected PC. Methods: A highly selective cohort of 13 men, aged 58.0 ± 7.1 y, with suspected PC (persistently high prostate-specific antigen [PSA] and PSA density) but negative or equivocal mpMRI results or negative biopsy were prospectively enrolled to undergo 68Ga-PSMA11 and 68Ga-RM2 PET/MRI. PET/MRI included whole-body and dedicated pelvic imaging after a delay of 20 min. All patients had targeted biopsy of any lesions seen on PET followed by standard 12-core biopsy. The SUVmax of suspected PC lesions was collected and compared with gold standard biopsy. Results: PSA and PSA density at enrollment were 9.8 ± 6.0 (range, 1.5-25.5) ng/mL and 0.20 ± 0.18 (range, 0.06-0.68) ng/mL2, respectively. Standardized systematic biopsy revealed a total of 14 PCs in 8 participants: 7 were csPC and 7 were nonclinically significant PC (ncsPC). 68Ga-PSMA11 identified 25 lesions, of which 11 (44%) were true-positive (TP) (5 csPC). 68Ga-RM2 showed 27 lesions, of which 14 (52%) were TP, identifying all 7 csPC and also 7 ncsPC. There were 17 concordant lesions in 11 patients versus 14 discordant lesions in 7 patients between 68Ga-PSMA11 and 68Ga-RM2 PET. Incongruent lesions had the highest rate of FP (12 FP vs. 2 TP). SUVmax was significantly higher for TP than FP lesions in delayed pelvic imaging for 68Ga-PSMA11 (6.49 ± 4.14 vs. 4.05 ± 1.55, P = 0.023) but not for whole-body images, nor for 68Ga-RM2. Conclusion: Our results show that 68Ga-PSMA11 and 68Ga-RM2 PET/MRI are feasible for biopsy guidance in suspected PC. Both radiopharmaceuticals detected additional clinically significant cancers not seen on mpMRI in this selective cohort. 68Ga-RM2 PET/MRI identified all csPC confirmed at biopsy.

Correlation of 68Ga-RM2 PET with Postsurgery Histopathology Findings in Patients with Newly Diagnosed Intermediate- or High-Risk Prostate Cancer.

68Ga-RM2 targets gastrin-releasing peptide receptors (GRPRs), which are overexpressed in prostate cancer (PC). Here, we compared preoperative 68Ga-RM2 PET to postsurgery histopathology in patients with newly diagnosed intermediate- or high-risk PC. Methods: Forty-one men, 64.0 ± 6.7 y old, were prospectively enrolled. PET images were acquired 42-72 min (median ± SD, 52.5 ± 6.5 min) after injection of 118.4-247.9 MBq (median ± SD, 138.0 ± 22.2 MBq) of 68Ga-RM2. PET findings were compared with preoperative multiparametric MRI (mpMRI) (n = 36) and 68Ga-PSMA11 PET (n = 17) and correlated to postprostatectomy whole-mount histopathology (n = 32) and time to biochemical recurrence. Nine participants decided to undergo radiation therapy after study enrollment. Results: All participants had intermediate- (n = 17) or high-risk (n = 24) PC and were scheduled for prostatectomy. Prostate-specific antigen was 8.8 ± 77.4 (range, 2.5-504) and 7.6 ± 5.3 ng/mL (range, 2.5-28.0 ng/mL) when participants who ultimately underwent radiation treatment were excluded. Preoperative 68Ga-RM2 PET identified 70 intraprostatic foci of uptake in 40 of 41 patients. Postprostatectomy histopathology was available in 32 patients in which 68Ga-RM2 PET identified 50 of 54 intraprostatic lesions (detection rate = 93%). 68Ga-RM2 uptake was recorded in 19 nonenlarged pelvic lymph nodes in 6 patients. Pathology confirmed lymph node metastases in 16 lesions, and follow-up imaging confirmed nodal metastases in 2 lesions. 68Ga-PSMA11 and 68Ga-RM2 PET identified 27 and 26 intraprostatic lesions, respectively, and 5 pelvic lymph nodes each in 17 patients. Concordance between 68Ga-RM2 and 68Ga-PSMA11 PET was found in 18 prostatic lesions in 11 patients and 4 lymph nodes in 2 patients. Noncongruent findings were observed in 6 patients (intraprostatic lesions in 4 patients and nodal lesions in 2 patients). Sensitivity and accuracy rates for 68Ga-RM2 and 68Ga-PSMA11 (98% and 89% for 68Ga-RM2 and 95% and 89% for 68Ga-PSMA11) were higher than those for mpMRI (77% and 77%, respectively). Specificity was highest for mpMRI with 75% followed by 68Ga-PSMA11 (67%) and 68Ga-RM2 (65%). Conclusion: 68Ga-RM2 PET accurately detects intermediate- and high-risk primary PC, with a detection rate of 93%. In addition, 68Ga-RM2 PET showed significantly higher specificity and accuracy than mpMRI and a performance similar to 68Ga-PSMA11 PET. These findings need to be confirmed in larger studies to identify which patients will benefit from one or the other or both radiopharmaceuticals.

68Ga-PSMA-11 PET/MRI in Patients with Newly Diagnosed Intermediate- or High-Risk Prostate Adenocarcinoma: PET Findings Correlate with Outcomes After Definitive Treatment.

Prostate-specific membrane antigen (PSMA) PET offers an accuracy superior to other imaging modalities in initial staging of prostate cancer and is more likely to affect management. We examined the prognostic value of 68Ga-PSMA-11 uptake in the primary lesion and presence of metastatic disease on PET in newly diagnosed prostate cancer patients before initial therapy. Methods: In a prospective study from April 2016 to December 2020, 68Ga-PSMA-11 PET/MRI was performed in men with a new diagnosis of intermediate- or high-grade prostate cancer who were candidates for prostatectomy. Patients were followed up after initial therapy for up to 5 y. We examined the Kendall correlation between PET (intense uptake in the primary lesion and presence of metastatic disease) and clinical and pathologic findings (grade group, extraprostatic extension, nodal involvement) relevant for risk stratification, and examined the relationship between PET findings and outcome using Kaplan-Meier analysis. Results: Seventy-three men (age, 64.0 ± 6.3 y) were imaged. Seventy-two had focal uptake in the prostate, and in 20 (27%) PSMA-avid metastatic disease was identified. Uptake correlated with grade group and prostate-specific antigen (PSA). Presence of PSMA metastasis correlated with grade group and pathologic nodal stage. PSMA PET had higher per-patient positivity than nodal dissection in patients with only 5-15 nodes removed (8/41 vs. 3/41) but lower positivity if more than 15 nodes were removed (13/21 vs. 10/21). High uptake in the primary lesion (SUVmax > 12.5, P = 0.008) and presence of PSMA metastasis (P = 0.013) were associated with biochemical failure, and corresponding hazard ratios for recurrence within 2 y (4.93 and 3.95, respectively) were similar to or higher than other clinicopathologic prognostic factors. Conclusion: 68Ga-PSMA-11 PET can risk-stratify patients with intermediate- or high-grade prostate cancer before prostatectomy based on degree of uptake in the prostate and presence of metastatic disease.

Renal Morbidity Following Radical Cystectomy in Patients with Bladder Cancer.

BACKGROUND: Patients with chronic kidney disease (CKD) are poor candidates for standard treatments for muscle-invasive bladder cancer (MIBC) and may be more likely to experience adverse outcomes when diagnosed with MIBC. OBJECTIVE: To investigate factors associated with the development of advanced CKD following radical cystectomy. DESIGN SETTING AND PARTICIPANTS: Using national Veterans Health Administration utilization files, we identified 3360 patients who underwent radical cystectomy for MIBC between 2004 and 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined factors associated with the development of advanced CKD (estimated glomerular filtration rate [eGFR] of <30 ml/min/1.73 m2) after radical cystectomy using multivariable logistic and proportional hazard regression, with and without consideration of competing risks. We examined survival using Kaplan-Meier product limit estimates and proportional hazard regression. RESULTS AND LIMITATIONS: The median age at surgery was 67 yr and the mean preoperative eGFR was 69.1 ± 20.3 ml/min/1.73 m2. Approximately three out of ten patients (n = 962, 29%) progressed to advanced CKD within 12 mo. Older age (hazard ratio [HR] per 5-yr increase 1.15, 95% confidence interval [CI] 1.10-1.20), preoperative hydronephrosis (HR 1.50, 95% CI 1.29-1.76), adjuvant chemotherapy (HR 1.19, 95% CI 1.00-1.41), higher comorbidity index (HR 1.13, 95% CI 1.11-1.16 per point), and lower baseline kidney function (HR 0.75, 95% CI 0.73-0.78) were associated with the development of advanced CKD. Baseline kidney function at the time of surgery was associated with survival. Generalizability is limited due to the predominantly male cohort. CONCLUSIONS: Impaired kidney function at baseline is associated with progression to advanced CKD and mortality after radical cystectomy. Preoperative kidney function should be incorporated into risk stratification algorithms for patients undergoing radical cystectomy. PATIENT SUMMARY: Impaired kidney function at baseline is associated with progression to advanced chronic kidney disease and mortality after radical cystectomy.

The stanford prostate cancer calculator: Development and external validation of online nomograms incorporating PIRADS scores to predict clinically significant prostate cancer.

BACKGROUND: While multiparametric MRI (mpMRI) has high sensitivity for detection of clinically significant prostate cancer (CSC), false positives and negatives remain common. Calculators that combine mpMRI with clinical variables can improve cancer risk assessment, while providing more accurate predictions for individual patients. We sought to create and externally validate nomograms incorporating Prostate Imaging Reporting and Data System (PIRADS) scores and clinical data to predict the presence of CSC in men of all biopsy backgrounds. METHODS: Data from 2125 men undergoing mpMRI and MR fusion biopsy from 2014 to 2018 at Stanford, Yale, and UAB were prospectively collected. Clinical data included age, race, PSA, biopsy status, PIRADS scores, and prostate volume. A nomogram predicting detection of CSC on targeted or systematic biopsy was created. RESULTS: Biopsy history, Prostate Specific Antigen (PSA) density, PIRADS score of 4 or 5, Caucasian race, and age were significant independent predictors. Our nomogram-the Stanford Prostate Cancer Calculator (SPCC)-combined these factors in a logistic regression to provide stronger predictive accuracy than PSA density or PIRADS alone. Validation of the SPCC using data from Yale and UAB yielded robust AUC values. CONCLUSIONS: The SPCC combines pre-biopsy mpMRI with clinical data to more accurately predict the probability of CSC in men of all biopsy backgrounds. The SPCC demonstrates strong external generalizability with successful validation in two separate institutions. The calculator is available as a free web-based tool that can direct real-time clinical decision-making.

Bupivacaine local anesthetic to decrease opioid requirements after radical cystectomy: Does formulation matter?

INTRODUCTION: Reduction of opioids is an important goal in the care of patients undergoing radical cystectomy (RC). Liposomal bupivacaine (LB) has been shown to be a safe and effective pain reliever in the immediate postoperative period and has been reported to reduce postoperative opioid requirements. Since the liposomal formulation is predicated on slow systemic absorption, the amount of bupivacaine administered is notably higher than that typically used with standard bupivacaine (SB) formulations. In addition, LB is costly, not universally available, and studies comparing this formulation to SB are lacking. We sought to determine if there is a difference in postoperative opioid requirements in patients who receive LB vs. high dose SB at the time of RC. METHODS: In May 2019 we transitioned to administration of high-volume SB injected intraoperatively at the time of RC. This prospective cohort was compared to a historical cohort of patients who received injection of LB at the time of surgery. Primary endpoints included postsurgical opioid use measured in morphine equivalent dose (MED) and patient-reported Numeric Rating Scale (NRS) pain scores and length of stay. All patients were managed using principles of enhanced recovery after surgery (ERAS). RESULTS: From May 2019 through August 2019, 28 patients underwent RC and met eligibility criteria to receive SB at the time of surgery. They were compared to a historical cohort of 34 patients who received LB between November 2017 and July 2018. There was no difference in MED exposure either in the postanesthesia care unit (SB 9.0 ± 8.9 MED vs. LB 6.5 ± 9.4 MED, P= 0.29) or during the remainder of the hospital stay (SB 36.8 ± 56.9 MED vs. LB 42.1 ± 102.5 MED, P= 0.81), no difference in NRS pain scores on postoperative day 1 (SB 2.6 ± 1.6 vs. LB 2.1 ± 1.7, P= 0.23), day 2 (SB 2.4 ± 1.8 vs. LB 1.9 ± 1.6, P= 0.19), or day 3 (SB 1.9 ± 1.8 vs. LB 1.7 ± 1.7, P= 0.69) and no difference in length of stay (SB 5.0 ± 1.7 days, LB 4.9 ± 3.3 days, P= 0.93). Subgroup analysis of open RC and robotic-assisted RC showed no significant difference in MED or pain scores between LB and SB patients. CONCLUSIONS: Among patients undergoing RC under ERAS protocol there was no significant difference in postoperative opioid consumption, NRS pain scores, or length of stay among patients receiving SB compared to LB.

Prostate Magnetic Resonance Imaging Interpretation Varies Substantially Across Radiologists.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) interpreted by experts is a powerful tool for diagnosing prostate cancer. However, the generalizability of published results across radiologists of varying expertise has not been verified. OBJECTIVE: To assess variability in mpMRI reporting and diagnostic accuracy across radiologists of varying experience in routine clinical care. DESIGN, SETTING, AND PARTICIPANTS: Men who underwent mpMRI and MR-fusion biopsy between 2014-2016. Each MRI scan was read by one of nine radiologists using the Prostate Imaging Reporting and Data System (PIRADS) and was not re-read before biopsy. Biopsy histopathology was the reference standard. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were the PIRADS score distribution and diagnostic accuracy across nine radiologists. We evaluated the association between age, prostate-specific antigen, PIRADS score, and radiologist in predicting clinically significant cancer (Gleason ≥7) using multivariable logistic regression. We conducted sensitivity analyses for case volume and changes in accuracy over time. RESULTS AND LIMITATIONS: We analyzed data for 409 subjects with 503 MRI lesions. While the number of lesions (mean 1.2 lesions/patient) did not differ across radiologists, substantial variation existed in PIRADS distribution and cancer yield. The significant cancer detection rate was 3-27% for PIRADS 3 lesions, 23-65% for PIRADS 4, and 40-80% for PIRADS 5 across radiologists. Some 13-60% of men with a PIRADS score of <3 on MRI harbored clinically significant cancer. The area under the receiver operating characteristic curve varied from 0.69 to 0.81 for detection of clinically significant cancer. PIRADS score (p<0.0001) and radiologist (p=0.042) were independently associated with cancer in multivariable analysis. Neither individual radiologist volume nor study period impacted the results. MRI scans were not retrospectively re-read by all radiologists, precluding measurement of inter-observer agreement. CONCLUSIONS: We observed considerable variability in PIRADS score assignment and significant cancer yield across radiologists. We advise internal evaluation of mpMRI accuracy before widespread adoption. PATIENT SUMMARY: We evaluated the interpretation of multiparametric magnetic resonance imaging of the prostate in routine clinical care. Diagnostic accuracy depends on the Prostate Imaging Reporting and Data System score and the radiologist.

Concordance between patient-reported and physician-reported sexual function after radical prostatectomy.

PURPOSE: Accurately tracking health-related quality-of-life after radical prostatectomy is critical to counseling patients and improving technique. Physicians consistently overestimate functional recovery. We measured concordance between surgeon-assessed and patient-reported outcomes and evaluated a novel method to provide feedback to surgeons. MATERIALS AND METHODS: Men treated with radical prostatectomy self-completed the International Index of Erectile Function-6 questionnaire at each postoperative visit. Separately, physicians graded sexual function on a 5-point scale. International Index of Erectile Function -6 score<22 and grade ≥3 defined patient-reported and physician-assessed erectile dysfunction (ED), respectively. Feedback on concordance was given to physicians starting in May 2013 with the implementation of the Amplio feedback system. Chi-square tests were used to assess agreement proportions and linear regression to evaluate changes in agreement after implementation. RESULTS: From 2009 to 2015, 3,053 men completed at least 1 postprostatectomy questionnaire and had a concurrent independent physician-reported outcome. Prior to implementation of feedback in 2013, patients and physicians were consistent as to ED 83% of the time; in 10% of cases, physicians overestimated function; in 7% of cases, physicians, but not patients reported ED. Agreement increased after implementation of feedback but this was not statistically significant, likely owing to a ceiling effect. Supporting this hypothesis, increase in agreement postfeedback was greater during late follow-up (≥12mo), where baseline agreement was lower compared to earlier follow-up. CONCLUSIONS: Agreement was higher than expected at baseline; implementation of feedback regarding discrepancies between patient-reported and physician-assessed outcomes did not further improve agreement significantly. Our observed high rate of agreement may be partly attributed to our institutional practice of systematically capturing patient-reported outcomes as part of normal clinical care.

Comparative Effectiveness of Targeted Prostate Biopsy Using Magnetic Resonance Imaging Ultrasound Fusion Software and Visual Targeting: a Prospective Study.

PURPOSE: We compared the diagnostic outcomes of magnetic resonance-ultrasound fusion and visually targeted biopsy for targeting regions of interest on prostate multiparametric magnetic resonance imaging. MATERIALS AND METHODS: Patients presenting for prostate biopsy with regions of interest on multiparametric magnetic resonance imaging underwent magnetic resonance imaging targeted biopsy. For each region of interest 2 visually targeted cores were obtained, followed by 2 cores using a magnetic resonance-ultrasound fusion device. Our primary end point was the difference in the detection of high grade (Gleason 7 or greater) and any grade cancer between visually targeted and magnetic resonance-ultrasound fusion, investigated using McNemar's method. Secondary end points were the difference in detection rate by biopsy location using a logistic regression model and the difference in median cancer length using the Wilcoxon signed rank test. RESULTS: We identified 396 regions of interest in 286 men. The difference in the detection of high grade cancer between magnetic resonance-ultrasound fusion biopsy and visually targeted biopsy was -1.4% (95% CI -6.4 to 3.6, p=0.6) and for any grade cancer the difference was 3.5% (95% CI -1.9 to 8.9, p=0.2). Median cancer length detected by magnetic resonance-ultrasound fusion and visually targeted biopsy was 5.5 vs 5.8 mm, respectively (p=0.8). Magnetic resonance-ultrasound fusion biopsy detected 15% more cancers in the transition zone (p=0.046) and visually targeted biopsy detected 11% more high grade cancer at the prostate base (p=0.005). Only 52% of all high grade cancers were detected by both techniques. CONCLUSIONS: We found no evidence of a significant difference in the detection of high grade or any grade cancer between visually targeted and magnetic resonance-ultrasound fusion biopsy. However, the performance of each technique varied in specific biopsy locations and the outcomes of both techniques were complementary. Combining visually targeted biopsy and magnetic resonance-ultrasound fusion biopsy may optimize the detection of prostate cancer.

Accuracy of Self-reported Smoking Exposure Among Bladder Cancer Patients Undergoing Surveillance at a Tertiary Referral Center.

BACKGROUND: Smoking is a risk factor for developing bladder cancer (BCa). Even though continued exposure after diagnosis may adversely affect prognosis, patients may be reluctant to disclose to their physicians that they are currently smoking, leading to inaccurate reporting of exposure and missed opportunities to deliver smoking-cessation advice and treatment in the context of cancer care. OBJECTIVE: We examined the extent of misclassification of recent smoking exposure among patients undergoing BCa surveillance. DESIGN SETTING AND PARTICIPANTS: A consecutive sample of 145 patients with a self-reported smoking history and prior initial diagnosis of BCa was recruited from a tertiary referral urology clinic. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were asked if they had smoked a cigarette or used nicotine replacement therapy (NRT) within the past week and whether they lived with a smoker. At the same visit, we collected urine under a biospecimen protocol. We used urinary cotinine, the primary metabolite of nicotine, as an objective biomarker of recent smoking exposure. Nine patients whose urine could not be interpreted for cotinine were excluded. We calculated the smoking status misreporting rate by comparing biochemically verified smoking status (≥31.5 ng/ml vs <31.5 ng/ml) against self-reported current smoking status (yes vs no) while considering recent NRT use. RESULTS AND LIMITATIONS: Overall, 11% (15 of 136) of patients had cotinine values consistent with current smoking. Of these 15 patients, 7 reported being former smokers, resulting in a 47% misclassification rate. However, three of the seven patients who denied smoking in the past week were currently using NRT. Excluding NRT users, the misclassification rate was 33%. CONCLUSIONS: Future studies investigating the impact of postdiagnosis nicotine exposure on BCa outcomes should use biochemical verification combined with self-reported smoking exposure to classify patients accurately. PATIENT SUMMARY: Bladder cancer patients may misreport smoking exposure, thereby missing opportunities for smoking cessation.

Accuracy of Self-reported Smoking Exposure Among Bladder Cancer Patients Undergoing Surveillance at a Tertiary Referral Center.

BACKGROUND: Smoking is a risk factor for developing bladder cancer (BCa). Even though continued exposure after diagnosis may adversely affect prognosis, patients may be reluctant to disclose to their physicians that they are currently smoking, leading to inaccurate reporting of exposure and missed opportunities to deliver smoking-cessation advice and treatment in the context of cancer care. OBJECTIVE: We examined the extent of misclassification of recent smoking exposure among patients undergoing BCa surveillance. DESIGN, SETTING, AND PARTICIPANTS: A consecutive sample of 145 patients with a self-reported smoking history and prior initial diagnosis of BCa was recruited from a tertiary referral urology clinic. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were asked if they had smoked a cigarette or used nicotine replacement therapy (NRT) within the past week and whether they lived with a smoker. At the same visit, we collected urine under a biospecimen protocol. We used urinary cotinine, the primary metabolite of nicotine, as an objective biomarker of recent smoking exposure. Nine patients whose urine could not be interpreted for cotinine were excluded. We calculated the smoking status misreporting rate by comparing biochemically verified smoking status (≥31.5 ng/ml vs <31.5 ng/ml) against self-reported current smoking status (yes vs no) while considering recent NRT use. RESULTS AND LIMITATIONS: Overall, 11% (15 of 136) of patients had cotinine values consistent with current smoking. Of these 15 patients, 7 reported being former smokers, resulting in a 47% misclassification rate. However, three of the seven patients who denied smoking in the past week were currently using NRT. Excluding NRT users, the misclassification rate was 33%. CONCLUSIONS: Future studies investigating the impact of postdiagnosis nicotine exposure on BCa outcomes should use biochemical verification combined with self-reported smoking exposure to classify patients accurately. PATIENT SUMMARY: Bladder cancer patients may misreport smoking exposure, thereby missing opportunities for smoking cessation.

Unexpected Long-term Improvements in Urinary and Erectile Function in a Large Cohort of Men with Self-reported Outcomes Following Radical Prostatectomy.

BACKGROUND: It is generally assumed that if a man does not regain urinary continence or erectile function within 12 mo of radical prostatectomy (RP), then the chance of subsequent recovery is low. OBJECTIVE: To determine the probability of achieving good urinary function (UF) or erectile function (EF) up to 48 mo postoperatively in men who reported poor UF or EF at 12 mo after RP. DESIGN, SETTING, AND PARTICIPANTS: We identified 3187 patients who underwent RP from 2007 through 2013 at a tertiary institution and had extended multidisciplinary follow-up with patient-reported UF and EF scores at ≥12 mo. INTERVENTION: Open or minimally invasive RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was good UF as defined by a urinary score ≥17 (range: 0-21) or good EF as defined by a modified International Index of Erectile Function-6 score ≥22 (range: 1-30). The probability of functional recovery beyond 12 mo was determined by Kaplan-Meier analyses. RESULTS AND LIMITATIONS: Among patients incontinent at 12 mo, the probability of achieving good UF at 24, 36, and 48 mo was 30%, 49%, and 59%. In patients experiencing erectile dysfunction at 12 mo, the probability of recovering EF at 24, 36, and 48 mo was 22%, 32%, and 40%. On multivariable analyses, 12-mo functional score and age were associated with recovery, but only score was consistently significant. CONCLUSIONS: Men with incontinence or erectile dysfunction at 12 mo have higher than anticipated rates of subsequent functional improvement. Probability of recovery is strongly influenced by score at 12 mo. Further research should address the impact of ongoing multidisciplinary follow-up care on our observed rates of recovery. PATIENT SUMMARY: Many prostate cancer patients continue to recover urinary and erectile function after 12 mo. The level of functional recovery by 12 mo is associated with long-term recovery and should be discussed by the physician and patient when deciding on rehabilitative interventions.

Development of a realistic in vivo bone metastasis model of human renal cell carcinoma.

About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastases. The incidence of RCC is increasing and bone metastatic RCC merits greater focus. Realistic preclinical bone metastasis models of RCC are lacking, hampering the development of effective therapies. We developed a realistic in vivo bone metastasis model of human RCC by implanting precision-cut tissue slices under the renal capsule of immunodeficient mice. The presence of disseminated cells in bone marrow of tissue slice graft (TSG)-bearing mice was screened by human-specific polymerase chain reaction and confirmed by immunohistology using human-specific antibody. Disseminated tumor cells in bone marrow of TSG-bearing mice derived from three of seven RCC patients were detected as early as 1 month after tissue implantation at a high frequency with close resemblance to parent tumors (e.g., CAIX expression and high vascularity). The metastatic patterns of TSGs correlated with disease progression in patients. In addition, TSGs retained capacity to metastasize to bone at high frequency after serial passaging and cryopreservation. Moreover, bone metastases in mice responded to Temsirolimus treatment. Intratibial injections of single cells generated from TSGs showed 100 % engraftment and produced X-ray-visible tumors as early as 3 weeks after cancer cell inoculation. Micro-computed tomography (µCT) and histological analysis revealed osteolytic characteristics of these lesions. Our results demonstrated that orthotopic RCC TSGs have potential to develop bone metastases that respond to standard therapy. This first reported primary RCC bone metastasis model provides a realistic setting to test therapeutics to prevent or treat bone metastases in RCC.

Relating prognosis in chromophobe renal cell carcinoma to the chromophobe tumor grading system.

PURPOSE: The chromophobe subtype of renal cell carcinoma (chRCC) has generally been associated with a better prognosis than the clear cell type; however, debate continues as to absolute prognosis as well as the significance of certain prognostic variables. We investigated the significance of pathologic stage and a recently proposed chromophobe tumor grading (CTG) scheme in predicting chRCC outcomes. MATERIALS AND METHODS: All available chRCCs were identified from our surgical pathology archives from 1987-2010. Original slides were reviewed to verify diagnoses and stage, and each case was graded following a novel chromophobe tumor grade system criteria. Disease status was obtained from a clinical outcome database, and cancer specific deaths and recurrences were recorded. RESULTS: Eighty-one cases of chRCC were identified, and 73 had adequate follow-up information available. There were only 3 instances of cancer related recurrence or mortality, which included 1 disease specific mortality and 2 disease recurrences. Pathologic stage and CTG 3 were found to be significantly associated with the recurrences or death from chRCC, but there was no association with CTG 1 and CTG 2. CONCLUSIONS: chRCC is associated with a very low rate of cancer specific events (4.1%) even at a tertiary referral center. In our study, pathologic stage and CTG 3, but not CTG 1 or 2, were significantly associated with the development of these events.

Tissue slice grafts of human renal cell carcinoma: an authentic preclinical model with high engraftment rate and metastatic potential.

OBJECTIVE: Discovery of curative therapies for renal cell carcinoma (RCC) is hampered by lack of authentic preclinical models. Tumorgrafts, generated by direct implantation of patient-derived tissues into mice, have demonstrated superior ability to predict therapeutic response. We evaluated "tissue slice grafts" (TSGs) as an improved tumorgraft model of RCC. MATERIALS AND METHODS: Cores of fresh RCC were precision-cut at 300 µm and implanted under the renal capsule of RAG2(-/-)γC(-/-) mice. Engraftment rate, histology, biomarker expression, genetic fidelity, and metastatic potential were evaluated. Magnetic resonance imaging (MRI) was tested as a noninvasive method to measure tumor volume, and response to a targeted therapy was determined. RESULTS: All 13 cases of RCC engrafted and displayed characteristic histology and biomarkers. TSG volume quantified noninvasively by MRI highly correlated with graft weights, providing a unique tool for monitoring orthotopic growth. Moreover, in 2 cases, cancer cells from TSGs metastasized to clinically relevant sites, including bone. Microarray analysis and DNA sequencing demonstrated a high degree of correlation of global gene expression and von Hippel-Lindau (VHL) status between TSGs and parental tumors. Treatment of TSGs with sunitinib significantly decreased graft weight and mean vessel density compared with controls. CONCLUSION: The TSG model of RCC faithfully recapitulates tumor pathology, gene expression, genetic mutation, and drug response. The high engraftment rate and metastatic potential of this authentic model, in conjunction with the ability to generate large first-generation animal cohorts and to quantitate tumor volume at the orthotopic site by MRI, proffer significant advantages compared with other preclinical platforms.

Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts.

mTOR is a rational target in renal cell carcinoma (RCC) because of its role in disease progression. However, the effects of temsirolimus, the only first-generation mTOR inhibitor approved by the FDA for first-line treatment of metastatic RCC, on tumor reduction and progression-free survival are minimal. Second-generation mTOR inhibitors have not been evaluated on RCC. We compared the effects of temsirolimus and MLN0128, a potent second-generation mTOR inhibitor, on RCC growth and metastasis using a realistic patient-derived tissue slice graft (TSG) model. TSGs were derived from three fresh primary RCC specimens by subrenal implantation of precision-cut tissue slices into immunodeficient mice that were randomized and treated with MLN0128, temsirolimus, or placebo. MLN0128 consistently suppressed primary RCC growth, monitored by magnetic resonance imaging (MRI), in three TSG cohorts for up to 2 months. Temsirolimus, in contrast, only transiently inhibited the growth of TSGs in one of two cohorts before resistance developed. In addition, MLN0128 reduced liver metastases, determined by human-specific quantitative polymerase chain reaction, in two TSG cohorts, whereas temsirolimus failed to have any significant impact. Moreover, MLN0128 decreased levels of key components of the two mTOR subpathways including TORC1 targets 4EBP1, p-S6K1, HIF1α and MTA1 and the TORC2 target c-Myc, consistent with dual inhibition. Our results demonstrated that MLN0128 is superior to temsirolimus in inhibiting primary RCC growth as well as metastases, lending strong support for further clinical development of dual mTOR inhibitors for RCC treatment.

Estimating the risk of chronic kidney disease after nephrectomy.

INTRODUCTION: To identify factors associated with the development of chronic kidney disease (CKD) after nephrectomy and to create a clinical model to predict CKD after nephrectomy for kidney cancer for clinical use. MATERIALS AND METHODS: We identified 144 patients who had normal renal function (eGFR > 60) prior to undergoing nephrectomy for kidney cancer. Selected cases occurred between 2007 and 2010 and had at least 30 days follow up. Sixty-six percent (n = 95) underwent radical nephrectomy and 62.5% (n = 90) developed CKD (stage 3 or higher) postoperatively. We used univariable analysis to screen for predictors of CKD and multivariable logistic regression to identify independent predictors of CKD and their corresponding odds ratios. Interaction terms were introduced to test for effect modification. To protect against over-fitting, we used 10-fold cross-validation technique to evaluate model performance in multiple training and testing datasets. Validation against an independent external cohort was also performed. RESULTS: Of the variables associated with CKD in univariable analysis, the only independent predictors in multivariable logistic regression were patient age (OR = 1.27 per 5 years, 95% CI: 1.07-1.51), preoperative glomerular filtration rate (GFR), (OR = 0.70 per 10 mL/min, 95% CI: 0.56-0.89), and receipt of radical nephrectomy (OR = 4.78, 95% CI: 2.08-10.99). There were no significant interaction terms. The resulting model had an area under the curve (AUC) of 0.798. A 10-fold cross-validation slightly attenuated the AUC to 0.774 and external validation yielded an AUC of 0.930, confirming excellent model discrimination. CONCLUSIONS: Patient age, preoperative GFR, and receipt of a radical nephrectomy independently predicted the development of CKD in patients undergoing nephrectomy for kidney cancer in a validated predictive model.

Patient-derived tissue slice grafts accurately depict response of high-risk primary prostate cancer to androgen deprivation therapy.

BACKGROUND: Effective eradication of high-risk primary prostate cancer (HRPCa) could significantly decrease mortality from prostate cancer. However, the discovery of curative therapies for HRPCa is hampered by the lack of authentic preclinical models. METHODS: We improved upon tumorgraft models that have been shown to predict drug response in other cancer types by implanting thin, precision-cut slices of HRPCa under the renal capsule of immunodeficient mice. Tissue slice grafts (TSGs) from 6 cases of HRPCa were established in mice. Following androgen deprivation by castration, TSGs were recovered and the presence and phenotype of cancer cells were evaluated. RESULTS: High-grade cancer in TSGs generated from HRPCa displayed characteristic Gleason patterns and biomarker expression. Response to androgen deprivation therapy (ADT) was as in humans, with some cases exhibiting complete pathologic regression and others showing resistance to castration. As in humans, ADT decreased cell proliferation and prostate-specific antigen expression in TSGs. Adverse pathological features of parent HRPCa were associated with lack of regression of cancer in corresponding TSGs after ADT. Castration-resistant cancer cells remaining in TSGs showed upregulated expression of androgen receptor target genes, as occurs in castration-resistant prostate cancer (CRPC) in humans. Finally, a rare subset of castration-resistant cancer cells in TSGs underwent epithelial-mesenchymal transition, a process also observed in CRPC in humans. CONCLUSIONS: Our study demonstrates the feasibility of generating TSGs from multiple patients and of generating a relatively large number of TSGs from the same HRPCa specimen with similar cell composition and histology among control and experimental samples in an in vivo setting. The authentic response of TSGs to ADT, which has been extensively characterized in humans, suggests that TSGs can serve as a surrogate model for clinical trials to achieve rapid and less expensive screening of therapeutics for HRPCa and primary CRPC.

Stage I testicular seminoma: a SEER analysis of contemporary adjuvant radiotherapy trends.

PURPOSE: Patients with clinical stage I testicular seminoma have historically been treated with adjuvant radiotherapy in the United States. However, nearly 80% of patients on surveillance will not experience relapse and even with relapse, salvage rates approach 100%. It remains unclear how practice patterns have changed with recently accumulating evidence and changes in guidelines. In a population based setting we evaluated contemporary trends and factors that may affect the use of adjuvant radiotherapy. MATERIALS AND METHODS: A total of 8,151 men diagnosed with stage I testicular seminoma from 2000 to 2009 were identified in the national SEER (Surveillance, Epidemiology, and End Results) registry. A multivariate regression model was constructed to analyze the association of year, age, race, socioeconomic status, SEER region, pathological stage and tumor size with the administration of adjuvant radiotherapy. RESULTS: The use of adjuvant radiotherapy decreased significantly from 2000 to 2009. In 2000, 74.7% of patients received radiation, compared with only 37.7% of patients in 2009 (p <0.0001). Later year of diagnosis was significantly associated with decreased odds of receiving adjuvant radiotherapy (p <0.0001, 2000 to 2005 vs 2006 to 2009, OR 0.40, 95% CI 0.36-0.44). Men age 35 years or older (p <0.0002, OR 1.20, 95% CI 1.09-1.32) and men in the highest socioeconomic index quartile (p <0.0001, OR 1.34, 95% CI 1.16-1.54) were more likely to receive adjuvant radiotherapy. CONCLUSIONS: The use of adjuvant radiotherapy for clinical stage I testicular seminoma has decreased significantly in the last decade. Older age and higher socioeconomic status are associated with higher rates of adjuvant radiotherapy.