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Purpose: Cisplatin-based chemotherapy followed by radical cystectomy (RC) is recommended in patients with muscle-invasive bladder cancer (MIBC). However, up to 50% of patients are cisplatin ineligible. The aim of this study was to compare clinical outcomes after ≥ 3 cycles of preoperative gemcitabine–carboplatin (gem–carbo) versus gemcitabine–cisplatin (gem–cis). Methods: We identified 1865 patients treated at 19 centers between 2000 and 2013. Patients were included if they had received ≥ 3 cycles of neoadjuvant (cT2-4aN0M0) or induction (cTanyN + M0) gem–carbo or gem–cis followed by RC. Results: We included 747 patients treated with gem–carbo (n = 147) or gem–cis (n = 600). Patients treated with gem–carbo had a higher Charlson Comorbidity Index (p = 0.016) and more clinically node-positive disease (32% versus 20%; p = 0.013). The complete pathological response (pCR; ypT0N0) rate did not significantly differ between gem–carbo and gem–cis (20.7% versus 22.1%; p = 0.73). Chemotherapeutic regimen was not significantly associated with pCR (OR 0.99 [95%CI 0.61–1.59]; p = 0.96), overall survival (OS) (HR 1.20 [95%CI 0.85–1.67]; p = 0.31), or cancer-specific survival (CSS) (HR 1.35 [95%CI 0.93–1.96]; p = 0.11). Median OS of patients treated with gem–carbo and gem–cis was 28.6 months (95%CI 18.1–39.1) and 45.1 months (95%CI 32.7–57.6) (p = 0.18), respectively. Median CSS of patients treated with gem–carbo and gem–cis was 28.8 months (95%CI 9.8–47.8) and 71.0 months (95%CI median not reached) (p = 0.02), respectively. Subanalyses of the neoadjuvant and induction setting did not show significant survival differences. Conclusion: Our results show that a subset of cisplatin-ineligible patients with MIBC achieve pCR on gem–carbo and that survival outcomes seem comparable to gem–cis provided patients are able to receive ≥ 3 cycles and undergo RC.

Figure S2. Primary prostate tissue samples demonstrate no uridine 5'-diphospho-glucuronosyltransferase (UGT) activity when cultured ex vivo in Tunl. A positive control consisting of grossly homogenized LNCaP xenograft tissues was included for comparison. Error bars represent the SD of biological triplicates.

Figure S3. T serves as a co-substrate of 5α-reductase but does not considerably alter the kinetics of AD metabolism in primary prostate tissues under mixed substrate conditions.

Supplementary legend

Purpose:Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets.Experimental Design:Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC).Results:Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model.Conclusions:Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.

Purpose: A major mechanism of castration-resistant prostate cancer (CRPC) involves intratumoral biosynthesis of dihydrotestosterone (DHT) from adrenal precursors. We have previously shown that adrenal-derived androstenedione (AD) is the preferred substrate over testosterone (T) for 5α-reductase expressed in metastatic CRPC, bypassing T as an obligate precursor to DHT. However, the metabolic pathway of adrenal-derived DHT biosynthesis has not been rigorously investigated in the setting of primary disease in the prostate.Experimental Design: Seventeen patients with clinically localized prostate cancer were consented for fresh tissues after radical prostatectomy. Prostate tissues were cultured ex vivo in media spiked with an equimolar mixture of AD and T, and stable isotopic tracing was employed to simultaneously follow the enzymatic conversion of both precursor steroids into nascent metabolites, detected by liquid chromatography-tandem mass spectrometry. CRPC cell line models and xenograft tissues were similarly assayed for comparative analysis. A tritium-labeled steroid radiotracing approach was used to validate our findings.Results: Prostatectomy tissues readily 5α-reduced both T and AD. Furthermore, 5α-reduction of AD was the major directionality of metabolic flux to DHT. However, AD and T were comparably metabolized by 5α-reductase in primary prostate tissues, contrasting the preference exhibited by CRPC in which AD was favored over T. 5α-reductase inhibitors effectively blocked the conversion of AD to DHT.Conclusions: Both AD and T are substrates of 5α-reductase in prostatectomy tissues, resulting in two distinctly nonredundant metabolic pathways to DHT. Furthermore, the transition to CRPC may coincide with a metabolic switch toward AD as the favored substrate. Clin Cancer Res; 23(20); 6351–62. ©2017 AACR.

Figure S1. Validation of a mixed substrate approach to track 5α-reductase activity by LC-MS/MS.

Figure S1, Supplementary Table, Figure S2, Figure S3, Figure S4, Figure S5

Purpose To assess the association of patient age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer (MIBC). Materials and methods We analyzed data from 1105 patients with MIBC. Patients age was evaluated as continuous variable and stratified in quartiles. Pathologic objective response (pOR; ypT0-Ta-Tis-T1N0) and pathologic complete response (pCR; ypT0N0), as well survival outcomes were assessed. We used data of 395 patients from The Cancer Genome Atlas (TCGA) to investigate the prevalence of TCGA molecular subtypes and DNA damage repair (DDR) gene alterations according to patient age. Results pOR was achieved in 40% of patients. There was no difference in distribution of pOR or pCR between age quartiles. On univariable logistic regression analysis, patient age was not associated with pOR or pCR when evaluated as continuous variables or stratified in quartiles (all p > 0.3). Median follow-up was 18 months (IQR 6–37). On Cox regression and competing risk regression analyses, age was not associated with survival outcomes (all p > 0.05). In the TCGA cohort, patient with age ≤ 60 years has 7% less DDR gene mutations (p = 0.59). We found higher age distribution in patients with luminal (p p = 0.002) compared to those with luminal papillary subtype. Conclusions While younger patients may have less mutational tumor burden, our analysis failed to show an association of age with response to preoperative chemotherapy or survival outcomes. Therefore, the use of preoperative chemotherapy should be considered regardless of patient age.

We examined rates of Grade Group 4 downgrading at radical prostatectomy among men diagnosed with high and very high risk prostate cancer at biopsy.A pooled cohort of 1,776 patients from 3 tertiary referral centers who underwent radical prostatectomy for National Comprehensive Cancer Network® high risk (prostate specific antigen greater than 20 ng/ml, or Grade Group 4-5, or clinical stage T3 or greater) or very high risk (primary Gleason pattern 5, or more than 4 biopsy cores with Grade Group 4-5, or 2 or more high risk features) disease from 2005 to 2015 were reviewed. Overall 893 patients with Grade Group 4 disease at biopsy were identified and 726 patients were available for analysis. Multivariable logistic regression models were fit to determine factors associated with downgrading to Grade Group 3 or less at radical prostatectomy.Overall 333 (45%) cases were downgraded to Grade Group 3 or less at radical prostatectomy. Of these cases 198 (27%) had concordant Grade Group 4 biopsy and radical prostatectomy pathology and 195 (27%) were upgraded at radical prostatectomy to Grade Group 5. Of high risk cases with biopsy Grade Group 4 disease 49% had any downgrading vs 29% of very high risk cases (p0.0001). Downgrading to Grade Group 2 or less occurred in 16% (98 of 604) of high risk and 7% (8 of 122) of very high risk cases (p0.01). Downgraded cases had a lower prostate specific antigen, fewer positive biopsy cores and lower clinical stage (p0.01). On multivariable analysis fewer positive biopsy cores were significantly associated with downgrading at radical prostatectomy (p0.01).In this cohort of patients with high risk/very high risk prostate cancer, downgrading from biopsy Grade Group 4 at radical prostatectomy occurred less frequently than in other published reports. Any downgrading was significantly less common in very high risk compared to high risk patients, and downgrading to Grade Group 2 or less occurred in a minority of cases in high risk and very high risk patients.

OBJECTIVE To assess the differential response to neoadjuvant chemotherapy (NAC) in patients with urothelial carcinoma of the bladder (UCB) compared to upper tract urothelial carcioma (UTUC) treated with radical surgery. PATIENTS AND METHODS Data from 1299 patients with UCB and 276 with UTUC were obtained from multicentric collaborations. The association of disease location (UCB vs UTUC) with pathological complete response (pCR, defined as a post-treatment pathological stage ypT0N0) and pathological objective response (pOR, defined as ypT0-Ta-Tis-T1N0) after NAC was evaluated using logistic regression analyses. The association with overall (OS) and cancer-specific survival (CSS) was evaluated using Cox regression analyses. RESULTS A pCR was found in 250 (19.2%) patients with UCB and in 23 (8.3%) with UTUC (P

This study aims to describe the pathological features and clinical outcomes in anterior-dominant prostate cancer (APCA) compared to posterior/posterolateral-dominant prostate cancer (PPCA) among men treated with radical prostatectomy for localized prostate cancer. This is a single-institution, matched case-control analysis of short-term clinical outcomes stratified by pathologic tumor location at radical prostatectomy. Pathologic data extracted by expert genitourinary pathologists on tumor location was linked to clinical and oncologic outcomes data from a prospective institutional database for analysis. From 2005 to 2013, 1580 patients were identified for analysis with 150 (9.5%) having APCA. One-hundred and thirty two of these APCA men had complete clinical data and were matched to 353 men with PPCA (~1:3 ratio) by GrdGrp at surgery, margin status, and pathologic T stage. There were no racial/ethnic differences between APCA and PPCA (p = 0.13). Men with APCA demonstrated a higher median PSA at diagnosis (6.4 [4.6–9.1] ng/mL vs 5.6 [4.4–8.1] ng/mL; p = 0.04), a higher rate of GrdGrp 1 disease at diagnosis (57.7% vs. 40.0%, p = 0.003), and lower rates of abnormal digital rectal examination (DRE) (10.1% vs. 23.2%, p = 0.003) when compared to PPCA. The rate of surgical upgrading was higher among men with APCA vs. PPCA (55.3% vs 42.0%, p = 0.015). Freedom from biochemical failure (BF) at 5-years was 85.1% (95% CI 73.1–98.9) for APCA and 82.9% (95% CI 69.2–99.5) for men with PPCA (p = 0.70, log-rank test). The majority of anterior tumors were undetectable by DRE and were associated with higher PSA at diagnosis. Despite presenting mostly as low/intermediate grade cancers, more than half of the men with APCA had upgrading at surgery and slightly more than 40% had positive margins and/or extraprostatic disease. When matched to a cohort of posterior predominant tumors, no differences were seen in the rate of biochemical-failure after prostatectomy.

Background:: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. Objective:: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. Design, setting, and participants:: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. Outcome measurements and statistical analysis:: A nomogram for bladder cancer–specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. Results and limitations:: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2–52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4–2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3–2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7–4.6}; p < 0.001] and ypT3–4 [HR 5.9 {95 % CI: 3.8–9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1–82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. Conclusions:: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. Patient summary:: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability. We developed a nomogram predicting bladder cancer–specific mortality after neoadjuvant chemotherapy and radical cystectomy in a large, multi-institutional patient cohort.

INTRODUCTION AND OBJECTIVE:Renal cell carcinoma (RCC) tumors vary widely with respect to oncologic risk and are composed of heterogenous histological subtypes that can affect treatment decisions an...

We investigated the pathological response rates and survival associated with 3 vs 4 cycles of cisplatin-based neoadjuvant chemotherapy (NAC) in patients with cT2-4N0M0 muscle invasive bladder cancer.In this cohort study we analyzed clinical data of 828 patients treated with NAC and radical cystectomy between 2000 and 2020. A total of 384 and 444 patients were treated with 3 and 4 cycles of NAC, respectively. Pathological objective response (pOR; ypT0-Ta-Tis-T1 N0), pathological complete response (pCR; ypT0 N0), cancer-specific survival and overall survival were investigated.pOR and pCR were achieved in 378 (45%; 95% CI 42, 49) and 207 (25%; 95% CI 22, 28) patients, respectively. Patients treated with 4 cycles of NAC had higher pOR (49% vs 42%, p=0.03) and pCR (28% vs 21%, p=0.02) rates compared to those treated with 3 cycles. This effect was confirmed on multivariable logistic regression analysis (pOR OR 1.46 p=0.008, pCR OR 1.57, p=0.007). On multivariable Cox regression analysis, 4 cycles of NAC were significantly associated with overall survival (HR 0.68; 95% CI 0.49, 0.94; p=0.02) but not with cancer-specific survival (HR 0.72; 95% CI 0.50, 1.04; p=0.08).Four cycles of NAC achieved better pathological response and survival compared to 3 cycles. These findings may aid clinicians in counseling patients and serve as a benchmark for prospective trials. Prospective validation of these findings and assessment of cumulative toxicity derived from an increased number of cycles are needed.

Purpose: To show whether subcutaneous repository corticotropin injection (RCI, Acthar® Gel, a repository corticotropin injection, can be an effective potential therapeutic agent for noninfectious retinal vasculitis. Methods: Patients with active retinal vasculitis were followed with serial ultra-wide-field fluorescein angiograms and treated with 80 units of subcutaneous repository corticotropin injection twice weekly. Results: Primary outcome of ≥ 50% improvement in response level (RL) for retinal vasculitis and percent improvement in retinal vasculitis severity scoring (RVSS) by more than one quartile ( ≥ 25%) at week 12 was met in 15 and 16 of the 30 total eyes, respectively, including 1 eye with severe retinal vasculitis in each group. Complete resolution of retinal vasculitis was seen in seven eyes with a mean time of 17.1 weeks. Intraocular pressure elevation requiring therapy and cataract progression were noted in two and three eyes, respectively. One patient stopped medication due to side effects (injection site reaction). Conclusion: Repository corticotropin injection was well-tolerated overall. Repository corticotropin injection may be an effective therapeutic agent in the treatment of noninfectious retinal vasculitis.

This report presents our early experience at Cleveland Clinic replacing conventional ultrasound with a novel 29 MHz high-resolution micro-ultrasound system for both systematic sampling and real-time targeting of suspicious regions during prostate biopsy. The added value of micro-ultrasound and MRI over systematic biopsy is presented. Sixty-seven consecutive subjects (January–August 2018) from our prospective database who underwent prostate biopsy using the micro-ultrasound system were included. 19/67 had prostate MRI imaging available. MRI targets were sampled using the UroNav fusion system. Patients had a median PSA of 5.37 ng/mL (IQR 4.13–8.74). 38/67 (56.7%) subjects were positive for prostate cancer. In six of these cases, systematic biopsy was negative with only micro-ultrasound targeted samples detecting cancer. In two other cases, patients were upgraded from Grade Group 1 to Grade Groups 4 and 2 based on micro-ultrasound targets. Micro-ultrasound targets detected cancer in two subjects where MRI was negative (Grade Groups 3 and 2). MRI targets alone did not change the overall diagnosis of any subjects. Switching biopsy guidance to real-time micro-ultrasound increased detection rate on prostate biopsy from 44.8% (30/67) to 56.7% (38/67), a relative increase of 26.7%. High-resolution micro-ultrasound identified clinically significant cancer that would have, otherwise, been missed by both MRI fusion and systematic biopsy and was useful in both biopsy naive and repeat negative patients. Early results from this small, single-center cohort are promising, particularly given the ease with which micro-ultrasound can replace the conventional ultrasound in standard prostate biopsy procedures.

Purpose Sunitinib is a vascular endothelial growth factor receptor (VEGFR) inhibitor with antitumor activity against bladder cancer. We hypothesized that treatment with sunitinib may decrease progression or recurrence in non-muscle invasive bladder cancer (NMIBC) refractory to intra-vesical BCG. Patients and Methods This is a single-arm phase II study of sunitinib in patients (pts) with NMIBC who progressed after BCG. Treatment included sunitinib 37.5 g daily for 12 weeks followed by 12± 2-week cystoscopy and surveillance for one year. The primary endpoint was the complete response rate at 12 months. Secondary endpoints included recurrence free survival (RFS), progression free survival (PFS), overall survival (OS), and safety of sunitinib. Correlative studies on effects of sunitinib on myeloid derived suppressor cells (MDSC) and humoral immune responses were also performed. This trial was registered on ClinicalTrials.gov, number NCT01118351. Results Between June 2011 and September 2011, 15/19 pts. completed 12 weeks of therapy. The remaining 4 pts. had treatment related adverse events leading to discontinuation of sunitinib with one patient withdrawing consent. On the 12-week cystoscopy, 44% (8/18) of the pts. showed remission, 50% (9/18) progression and 1/18 recurrence. Overall, 22% (4/18) of pts. remained free of progression for >12 months. Grade (G) 4 toxicities were noted in 2 pts. (anemia and thrombocytopenia) while G3 were noted in 58%. Sunitinib resulted in reversal of MDSC mediated immunosuppression. Conclusions In NMIBC refractory to BCG, treatment with sunitinib was safe but not associated with improved clinical outcomes. The immune effects of sunitinib deserve further investigation.

Background Despite definitive local therapy, patients with high-risk prostate cancer have a significant risk for local and distant failure. To date, no systemic therapy given prior to surgery has been shown to improve outcomes. The phosphatidilinositol 3-kinase/AKT/mTOR pathway is commonly dysregulated in men with prostate cancer. We sought to determine the clinical efficacy and safety of the mTOR/TORC1 inhibitor everolimus in men with high-risk prostate cancer undergoing radical prostatectomy. Methods This is a randomized phase II study of everolimus at two different doses (5 and 10 mg daily) given orally for 8 weeks before radical prostatectomy in men with high-risk prostate cancer. The primary endpoint was the pathologic response (histologic P0, margin status, extraprostatic extension) and surgical outcomes. Secondary endpoints included changes in serum PSA level and treatment effects on levels of expression of mTOR, p4EBP1, pS6 and pAKT. Results Seventeen patients were enrolled: nine at 10 mg dose and eight at 5 mg dose. No pathologic complete responses were observed and the majority of patients (88%) had an increase in their PSA values leading to this study being terminated early due to lack of clinical efficacy. Treatment-related adverse events were similar to those previously reported with the use of everolimus in other solid tumors and no additional surgical complications were observed. A significant decrease in the expression of p4EBP1 was noted in prostatectomy samples following treatment. Conclusions Neoadjuvant everolimus given at 5 mg or 10 mg daily for 8 weeks prior to radical prostatectomy did not impact pathologic responses and surgical outcomes of patients with high-risk prostate cancer. Trial registration NCT00526591 .

BACKGROUND This study aims to assess the effect of statin therapy on outcomes among men managed with active surveillance. METHODS This is a retrospective cohort study evaluating 635 men managed with active surveillance from 2005 to 2015 at a large, academic medical center. The primary endpoints of analyses are disease reclassification (i.e., change in volume or grade of cancer on subsequent biopsies after diagnosis), progression to definitive therapy with curative intent (i.e., surgery or radiotherapy), and surveillance failure-defined as the development of either biochemical failure after definitive therapy, metastases, or prostate cancer-specific mortality-among statin and non-statin users. Secondary analyses were performed to assess the effect of statin use on outcomes among men who progressed to definitive treatment. RESULTS Three hundred fifty-six (56.1%) patients in the cohort were on statin therapy at the initiation of surveillance. The median age was 66.7 and 63.3 years among statin and non-statin users, respectively. On univariate analysis, there were no differences in the rates of disease reclassification, progression to definitive treatment, and surveillance failure between the statin and non-statin users in the cohort (all p > 0.05). There was no difference in the rate of biochemical failure among men who progressed to definitive therapy when stratified by statin use (p = 0.89). Pathologic data were available for 105 men who progressed to radical prostatectomy while on surveillance at our institution. Duration of statin use (months) was inversely correlated with adverse pathology for radical prostatectomy on both univariate (OR: 0.99; 95% CI 0.98, 0.99; p = 0.03) and multivariate analysis (OR: 0.98; 95% CI 0.97, 0.99; p = 0.02). CONCLUSION Statin use was not associated with any clinical benefit with regard to disease reclassification, progression to definitive treatment, or surveillance failure among men selecting active surveillance at our institution. There was a 2% decrease in the odds of adverse pathology for each month of statin use among the men who progressed to radical prostatectomy while on active surveillance, but it is unclear at this time if this association has any durable impact on surveillance outcomes among men with favorable risk prostate cancer.

We sought to evaluate the correlation between MRI phenotypes of prostate cancer as defined by PI-RADS v2 and the Decipher Genomic Classifier (used to estimate the risk of early metastases). This single-center, retrospective study included 72 nonconsecutive men with prostate cancer who underwent MRI before radical prostatectomy performed between April 2014 and August 2017 and whose MRI registered lesions were microdissected from radical prostatectomy specimens and then profiled using Decipher (89 lesions; 23 MRI invisible [PI-RADS v2 scores ≤ 2] and 66 MRI visible [PI-RADS v2 scores ≥ 3]). Linear regression analysis was used to assess clinicopathologic and MRI predictors of Decipher results; correlation coefficients (r) were used to quantify these associations. AUC was used to determine whether PI-RADS v2 could accurately distinguish between low-risk (Decipher score

Purpose: Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets. Experimental Design: Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC). Results: Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model. Conclusions: Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.

Neoadjuvant chemotherapy (NAC) has been increasingly adopted in the management of high-grade upper tract urothelial carcinoma (UTUC), largely extrapolating from level I evidence in urothelial carcinoma of the bladder. Studies examining pathologic outcomes in patients with UTUC receiving NAC are mostly limited to retrospective, single-center studies with limited sample size, with results of a phase II trial recently presented. Hypothesizing that NAC is associated with improved pathologic response (PR), we compared pathologic outcomes in patients with high-grade UTUC who did and did not receive NAC before extirpative surgery.A total of 6174 patients with nonmetastatic, high-grade UTUC who underwent extirpative surgery from 2006 to 2014 were identified from the National Cancer Database. Patients were stratified by NAC status. PR was defined as pathologic stage less than clinical stage. Univariate and multivariable logistic regression analysis was employed to identify predictors of PR.Two hundred sixty (4.2%) patients received NAC. A higher incidence of PR was observed in patients receiving NAC (25.2% vs. 1.8%; P .001), with complete PR observed in 6.1% of patients receiving NAC and 0.4% of patients undergoing surgery alone. NAC (odds ratio [OR], 19.8; 95% confidence interval [CI], 11.8-33.5), nonwhite race (OR, 3.2; 95% CI, 1.7-6.3), and ureteral tumor location (OR, 1.6; 95% CI, 1.02-2.6) were independently associated with PR.Examining a large national cancer registry, we observed a higher incidence of PR in patients with UTUC receiving NAC, validating findings of prior studies. Our findings support consideration of NAC in high grade UTUC. Prospective trials will better define the impact of NAC on pathologic and survival outcomes.

Objective To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC). Methods Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses. Results A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75–1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71–1.58, P = 0.77). Conclusion Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage.

INTRODUCTION AND OBJECTIVE:External beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), EBRT with a brachytherapy boost (EBRT+BT) with ADT, and radical prostatectomy (RP) with or with...

INTRODUCTION AND OBJECTIVE:Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard and recommended treatment for clinical T2-T4aN0M0 bladder cancer. Howev...

Introduction: Treatment delay among patients with muscle invasive bladder cancer is associated with reduced survival. With limited existing literature examining institutional causes of treatment delay, we identified such causes of delay to radical cystectomy among patients with high risk bladder cancer.Methods: We conducted a retrospective review of 176 patients with bladder cancer who underwent radical cystectomy at our tertiary referral center in 2013 to 2014. Process mapping was used to define each step in the path to cystectomy and the time interval between each step was quantified. Patients experiencing treatment delay (more than 90 days to cystectomy or chemotherapy initiation) were identified and the causes of delay examined.Results: Median time from diagnosis to referral was 17 days (IQR 9–36). Following referral the urology and medical oncology evaluations occurred at a median of 5 (IQR 2–9) and 6 days (IQR 1–9), respectively. Median time from urological evaluation to transurethral resect...

Purpose Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis of patients presenting with GS 10 PCa are largely unknown because of its rarity. Methods and Materials The study included 112 patients with biopsy-determined GS 10 PCa who received treatment with radical prostatectomy (RP, n = 26), external beam radiation therapy (EBRT, n = 48), or EBRT with a brachytherapy boost (EBRT-BT, n = 38) between 2000 and 2013. Propensity scores were included as covariates for comparative analysis. Overall survival, prostate cancer–specific survival, and distant metastasis–free survival (DMFS) were estimated by the Kaplan-Meier method with inverse probability of treatment weighting to control for confounding. Results The median follow-up period was 4.9 years overall (3.9 years for RP, 4.8 years for EBRT, and 5.7 years for EBRT-BT). Significantly more EBRT patients than EBRT-BT patients received upfront androgen deprivation therapy (98% vs 79%, P Conclusions To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy-determined GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease 5 years after treatment.

Context Currently, salvage radiotherapy (SRT) is the only known curative intervention for men with recurrent disease following prostatectomy. Critical issues in the optimal selection and management of men being considered for SRT include the threshold prostate-specific antigen (PSA) value at which to initiate treatment (ie, pre-SRT PSA) and the role of concurrent hormonal therapy (HT). Objective To review the published evidence pertaining to the optimal timing for SRT and the role of concurrent HT. Evidence acquisition MEDLINE (via PubMed), EMBASE, the Cochrane Central Register of Controlled Trials, and guideline statements from professional organizations were queried from January 1, 2000 through January 10, 2018. Evidence synthesis Thirty-three independent reports, including two randomized trials evaluating HT with SRT, were identified. Retrospective data suggest that SRT initiation at lower pre-SRT PSA levels is associated with better clinical outcomes. Prospective data suggest an overall survival benefit with concurrent HT that manifests during long-term follow-up, with the caveat that hypothesis-generating subgroup analyses suggest that this benefit may be limited to patients with higher pre-SRT PSA levels. Patients with adverse risk factors, such as Gleason grade group 4–5 disease, are likely to benefit the most from earlier SRT initiation and/or the use of HT. Conclusions Given the limitations of the available data, it is imperative that physicians participate in shared decision-making, with the recommendation tailored for each man's desire to maximize oncologic benefit (with a risk of overtreatment) versus potential quality-of-life optimization (with a risk of undertreatment). Within that framework, a significant body of retrospective data supports initiation of SRT at low pre-SRT PSA values, without an arbitrary absolute threshold. Prospective data suggest a benefit of HT, but this benefit may be greatest in patients with a pre-SRT PSA that is higher than the typical level in most patients receiving “early” SRT. Further research is necessary before absolute recommendations can be made. Patient summary Two ways to potentially improve outcomes following salvage radiotherapy for prostate cancer that recurs after prostatectomy are to start treatment at a lower prostate-specific antigen level and to use concurrent hormonal therapy. Our review suggests that the available evidence is imperfect, but highlights that both measures are likely to improve clinical outcomes in general, but perhaps not uniformly and/or consistently for all patients. Physician-patient shared decision-making and further research are critical.

Background Squamous cell carcinoma (SCC) is an uncommon histologic subtype of bladder cancer with limited data on treatment patterns, outcomes, and prognostic factors. “Real world” information might inform decision-making, prognostic estimates, and clinical trial designs. Patients and Methods A retrospective review of patients with tissue-confirmed bladder SCC treated at Cleveland Clinic from 2007 to 2016 was performed. Data on patient characteristics, treatment patterns, and clinical follow-up were extracted. Univariate analysis was used to identify predictors of overall survival (OS), recurrence-free survival (RFS) and time to recurrence. Results Of 58 identified patients, 42 had complete data available. Median age at diagnosis was 67 years (range, 37-90). Hematuria was the most common (71%) presenting symptom; 32 patients had pure SCC and 10 predominant/extensive squamous differentiation without major differences noted in clinicopathologic variables or outcomes among those 2 groups. Overall, 35 patients underwent cystectomy with 5 receiving neoadjuvant and 1 adjuvant chemotherapy, whereas 3 had chemotherapy for recurrent disease. Of patients with cystectomy, most had locally advanced disease (75% pT3/4, 35% pN+). Overall, 10 patients progressed and 14 died; median OS was not reached. The 2-year estimated OS, RFS, and cumulative incidence of recurrence were 61% ± 9%, 50% ± 9%, and 32% ± 9%, respectively. Hydronephrosis, older age (70 years or older), lymphovascular invasion, nodal metastases, and advanced T stage were associated with 1 or more poor outcomes. Conclusion In patients with resectable bladder SCC, radical cystectomy remains the main treatment modality. The role of perioperative chemotherapy remains unclear. The identified prognostic factors might be helpful for prognostication, treatment discussion, and trial eligibility/stratification.

Penile-sparing modalities are gaining widespread adoption for the management of low-stage penile cancer due to an increasing demonstration of sound oncologic, cosmetic, sexual, psychosocial, and quality of life outcomes. This review aims to provide a comprehensive overview of the respective treatment options in the armamentarium of the practicing urologist in dealing with this rare but problematic condition.

Background IsoPSA is a serum-based assay that predicts prostate cancer (PCa) risk by partitioning isoforms of prostate-specific antigen (PSA) with an aqueous two-phase reagent. Objectives To determine the diagnostic accuracy of IsoPSA in identifying the presence or absence of PCa and the presence of high-grade disease in a contemporary biopsy cohort. Design, setting, and participants Multicenter prospective study of 261 men scheduled for prostate biopsy at five academic and community centers in the USA enrolled between August 2015 and December 2016. Intervention Performance of the IsoPSA assay. Outcome measurements and statistical analysis Discrimination power was evaluated using receiver operating characteristic (ROC) analysis. The outcome of the IsoPSA assay was transformed into risk probability using logistic regression. Decision curve analysis (DCA) was used to compare the net benefit of IsoPSA against other clinical protocols. Results and limitations The overall prevalence was 53% for any PCa and 34% for high-grade PCa. The area under the ROC curve was 0.79 for any cancer versus none and 0.81 for high-grade PCa versus low-grade PCa/benign histology. In this preliminary study, DCA revealed a superior net benefit of IsoPSA against no biopsy, all biopsy, and the modified Prostate Cancer Prevention Trial Risk Calculator 2.0. At a cutoff selected to recommend biopsy, IsoPSA demonstrated a 48% reduction in false-positive biopsies; at a cutoff selected to identity men at low risk of high-grade disease, there was a 45% reduction in the false-positive rate. Conclusion The structure-based IsoPSA assay outperformed concentration-based PSA measurement, and provided a net benefit against other protocols. Once validated, clinical use of IsoPSA could significantly reduce unnecessary biopsies while identifying patients needing treatment. Patient summary The IsoPSA assay outperformed prostate-specific antigen in predicting the overall risk of prostate cancer and the risk of clinically significant cancer in a preliminary study. The IsoPSA assay could assist in determining the need for prostate biopsy for patients.

Purpose: We compare intermediate term clinical outcomes among men with favorable risk and intermediate/high risk prostate cancer managed by active surveillance.Materials and Methods: A total of 635 men with localized prostate cancer have been on active surveillance since 2002 at a high volume academic hospital in the United States. Median followup is 50.5 months (IQR 31.1–80.3). Time to event analysis was performed for our clinical end points.Results: Of the cohort 117 men (18.4%) had intermediate/high risk disease. Overall 5 and 10-year all cause survival was 98% and 94%, respectively. Cumulative metastasis-free survival at 5 and 10 years was 99% and 98%, respectively. To date no cancer specific deaths had been observed. Overall freedom from intervention was 61% and 49% at 5 and 10 years, respectively. Overall cumulative freedom from failure of active surveillance, defined as metastasis or biochemical failure after local therapy with curative intent, was 97% and 91% at 5 and 10 years, respectively. Of th...

We compare the efficacy and toxicity among the 3 major modalities available used to treat high-risk prostate cancer (HRCaP).From 1996 to 2012, 2557 HRCaP patients were treated: 734 received external beam radiation therapy (EBRT) with or without androgen deprivation therapy (ADT), 515 received low-dose-rate prostate brachytherapy (LDR) with or without ADT, and 1308 received radical prostatectomy (RP) with or without EBRT. Biochemical relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and prostate cancer-specific mortality (PCSM) were assessed. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.03. The log-rank test compared bRFS and cRFS among the modalities, and Cox regression identified factors associated with bRFS and cRFS. Gray's test compared differences in late toxicity and PSCM among the modalities. Competing risk regression identified factors associated with PCSM.The median follow-up time and age were 63.5 months and 65 years, respectively. The bRFS at 5 and 10 years, respectively, was 74% and 53% for EBRT, 74% and 52% for LDR, and 65% and 47% for RP (P=.0001). The cRFS at 5 and 10 years, respectively, was 85% and 73% for EBRT, 90% and 76% for LDR, and 89% and 75% for RP (P=.121). The PCSM at 5 and 10 years, respectively, was 5.3% and 11.2% for EBRT, 3.2% and 3.6% for LDR, and 2.8% and 6.8% for RP (P=.0004). The 10-year cumulative incidence of ≥grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for RP (P.0001). The 10-year cumulative incidence of ≥grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, and 1.0% for RP (P.0001).HRCaP treated with EBRT, LDR, or RP yields efficacy showing better bRFS for LDR and EBRT relative to RP, equivalence for cRFS, and a PCSM advantage of LDR and RP over EBRT. The toxicity is lowest for LDR.

Objective: Sarcopenia, or the age-related loss of skeletal muscle mass and function, has been investigated as a potential marker of adverse outcomes among surgical patients. Our aim was to assess for changes in psoas muscle volume (PMV) following administration of neoadjuvant chemotherapy (NAC) in patients with bladder cancer and to examine whether changes in PMV following NAC are predictive of perioperative complications, pathologic response or survival. Methods: During the period of 2009–2013, patients undergoing NAC and radical cystectomy (RC) at our institution with pre and post NAC cross sectional images available were included. Bilateral total psoas muscle volume (PMV) was obtained from pre- and post- NAC images and the proportion of PMV change was calculated by dividing the change PMV by pre-NAC PMV. Analyses for the assessment of factors predicting PMV loss, partial/complete pathologic response (pPR/pCR), complications, readmission, cancer specific (CSS), recurrence-free (RFS) and overall survival (OS) were performed. Results: Total of 60 patients had complete radiological data available. Post-NAC PMV and BMI declines were statistically significant, 4.9% and 0.05%, respectively. NAC dose reduction/delay was a significant predictor of PMV loss (coefficient B 4.6; 95% CI 0.05–9.2; p = 0.047). The proportion of PMV decline during NAC was not a predictor of pPR, pCR, complications, readmission, CSS, RFS, or OS. Conclusions: We observed an interval decline in PMV during the period of NAC administration and this decline was more than it could be appreciated with changes in BMI during the same period. PMV decline was associated with the need for dose reduction/dose delay during NAC. In our series, PMV changes occurring during NAC administration were not predictive of pathologic response to chemotherapy, postoperative complications or survival.

We analyzed the rates of disease reclassification at initial and subsequent surveillance prostate biopsy as well as the treatment outcomes of deferred therapy among men on active surveillance for prostate cancer.From a prospective database we identified 300 men on active surveillance who had undergone initial surveillance prostate biopsy, with or without confirmatory biopsy, within 1 year of diagnosis. Of these men 261 (87%) were classified as having NCCN very low or low risk disease at diagnosis. Disease reclassification on active surveillance was defined as the presence of 50% or more positive cores and/or surveillance prostate biopsy Gleason score upgrading. Patients with type I disease reclassification included those with any surveillance prostate biopsy Gleason score upgrading, while patients with type II reclassification had to have primary Gleason pattern 4-5 disease on surveillance prostate biopsy. Outcomes after initial surveillance prostate biopsy were evaluated using actuarial analyses.At the time of initial surveillance prostate biopsy 49 (16%) and 19 (6%) patients had type I and type II disease reclassification, respectively. Those who underwent confirmatory biopsy had significantly reduced rates of type I (9% vs 23%, p=0.001) and type II (3% vs 9%, p=0.01) reclassification at initial surveillance prostate biopsy. For the 251 patients without disease reclassification at initial surveillance prostate biopsy the 2-year rates of subsequent type I and II reclassification were 17% (95% CI 0-24) and 3% (95% CI 0.1-7), respectively. For the 93 patients who received deferred therapy the 5-year biochemical progression-free probability was 89% (95% CI 79-98), including 95%, 82% and 70% among those without, and those with type I and type II disease reclassification, respectively.Patients on active surveillance with stable disease at the time of initial surveillance prostate biopsy may be appropriate candidates for less intensive surveillance prostate biopsy schedules.

Purpose To determine whether a dose-response relationship exists for salvage radiation therapy (RT) of biochemical failure after prostatectomy for prostate cancer. Methods and Materials Individual data from 1108 patients who underwent salvage RT at 10 academic centers were pooled. The cohort was enriched for selection criteria more likely associated with tumor recurrence in the prostate bed (margin positive and pre-RT prostate-specific antigen [PSA] level of ≤2.0 ng/mL) and without the confounding of planned androgen suppression. The cumulative incidence of biochemical failure and distant metastasis over time was computed, and competing risks hazard regression models were used to investigate the association between potential predictors and these outcomes. The association of radiation dose with outcomes was the primary focus. Results With a 65.2-month follow-up duration, the 5- and 10-year estimates of freedom from post-RT biochemical failure (PSA level >0.2 ng/mL and rising) was 63.5% and 49.8%, respectively, and the cumulative incidence of distant metastasis was 12.4% by 10 years. A Gleason score of ≥7, higher pre-RT PSA level, extraprostatic tumor extension, and seminal vesicle invasion were associated with worse biochemical failure and distant metastasis outcomes. A salvage radiation dose of ≥66.0 Gy was associated with a reduced cumulative incidence of biochemical failure, but not of distant metastasis. Conclusions The use of salvage radiation doses of ≥66.0 Gy are supported by evidence presented in the present multicenter pooled analysis of individual patient data. The observational reporting method, limited sample size, few distant metastasis events, modest follow-up duration, and elective use of salvage therapy might have diminished the opportunity to identify an association between the radiation dose and this endpoint.