Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer.

Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.

Racial and ethnic representation in primary research contributing to pelvic organ prolapse treatment guidelines.

INTRODUCTION AND HYPOTHESIS: To evaluate whether the studies contributing to the national treatment guidelines on pelvic organ prolapse adequately represent the racial and/or ethnic makeup of the American population. METHODS: This analysis examines the racial and ethnic makeup of all primary study cohorts contributing to the American College of Obstetricians and Gynecologists/American Urogynecologic Society Practice Bulletin No. 214 on pelvic organ prolapse. References were excluded if they lacked a primary patient population or were from outside the US. Mean proportional representation of racial/ethnic groups was compared to the 2018 United States Census data on race/ethnicity. The representation quotient was also calculated to evaluate for relative representation of each group. Descriptive statistics were used. RESULTS: Of the 110 references, 53 primary studies were included in the final analysis with 30 studies reporting on race/ethnicity. On average, 82% (SD = 15%) of study populations were White, while Blacks, Hispanics, and Asians represented 67% (SD = 7%), 4% (SD = 8%), and < 1% (SD = 1%), respectively, differing significantly from the 2018 US Census (p < 0.01.) The representation quotients for White women was 1.36, demonstrating a 36% overrepresentation, while Black, Hispanic, and Asian women were underrepresented among studies of all evidence levels, with representative quotients of 0.50, 0.23, and 0.09, respectively. CONCLUSIONS: Our study demonstrates a significant underrepresentation of non-White populations in primary cohorts of studies contributing to the ACOG/AUGS Practice Bulletin No. 214 on POP. This analysis reinforces that more efforts are required to include and report on racial and ethnically diverse cohorts to better serve all patients.

The Timing of Radical Cystectomy for bacillus Calmette-Guérin Failure: Comparison of Outcomes and Risk Factors for Prognosis.

PURPOSE: We compared the pathological and survival outcomes of patients who underwent radical cystectomy soon after bacillus Calmette-Guérin failure with those of patients who received additional salvage intravesical chemotherapy before cystectomy for nonmuscle invasive bladder cancer. We also identified predictors of prognosis in the entire cohort. MATERIALS AND METHODS: We retrospectively analyzed the records of 117 patients who underwent radical cystectomy for recurrent nonmuscle invasive bladder cancer at our institution from 1990 to 2012. The cohort was divided into group 1 of 61 patients treated only with bacillus Calmette-Guérin with or without interferon-α and group 2 of 56 who received at least 1 additional salvage intravesical chemotherapy after bacillus Calmette-Guérin. RESULTS: Final pathology and survival outcomes did not differ significantly between the groups. Five-year overall and cancer specific survival was similar in groups 1 and 2 at 80% and 85%, respectively, at approximately equivalent followups. Median bladder retention was 1.7 years longer in group 2 (p <0.001). On multivariate Cox regression analysis delayed cystectomy in group 2 did not convey a significant hazard for all cause mortality after cystectomy (HR 1.08, p = 0.808). Only up-staging to cT1 (HR 1.88, p = 0.045), lymph node invasion (HR 2.58, p = 0.023) and prostatic urethra involvement (HR 1.95, p = 0.029) achieved significance. CONCLUSIONS: With appropriate selection for salvage intravesical chemotherapy patients who elect bladder sparing treatment instead of earlier radical cystectomy after bacillus Calmette-Guérin fails do not sacrifice positive pathological or oncologic outcomes while retaining bladder function for a significantly longer duration.

Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure.

PURPOSE: Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10% and 30%. Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes. Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation. We now report the results of a phase II trial to assess efficacy. MATERIALS AND METHODS: This study was an investigator initiated, single center, single arm, phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Guérin failed. Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was evaluated with cystoscopy, biopsy, cytology and imaging. If complete response was achieved, patients were treated with full dose monthly maintenance treatments for 6 months. RESULTS: A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of these responses remained durable after maintenance therapy. At a mean followup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their bladders without progression or distant metastases. A single patient had progression to muscle invasive disease at radical cystectomy. Treatment related adverse events were noted in 9 of 28 (32.1%) patients and were limited to grade 1 or 2. CONCLUSIONS: Intravesical nab-paclitaxel has minimal toxicity and a 35.7% response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Guérin failure. Complete response remained durable at 1 year followup in this heavily pretreated patient population.

Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus Calmette-Guérin therapy.

PURPOSE: Docetaxel is a safe agent for intravesical therapy. Adding monthly maintenance treatments can extend response durability. We report our cumulative experience with intravesical docetaxel in a larger cohort with extended followup. MATERIALS AND METHODS: A total of 54 patients received salvage intravesical docetaxel for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer between 2003 and 2012, including 18 treated during the original phase I trial. All patients received 6 weekly instillations of intravesical docetaxel. After the phase I trial, those with a complete response to induction treatment were offered single dose monthly maintenance treatments for a total of up to 12 months of docetaxel therapy. Recurrence was defined as positive biopsy or urine cytology. Recurrence-free, disease specific and overall survival was determined by Kaplan-Meier analysis. RESULTS: Median followup was 39.1 months. Of the 54 patients 32 (59%) had a complete initial response after induction therapy, including 18 who received additional monthly maintenance treatments. Median time to recurrence in initial responders treated with vs without docetaxel maintenance was 39.3 vs 19.0 months. One and 3-year recurrence-free survival rates for the entire cohort were 40% and 25%, respectively. Of the 54 patients 17 (24%) underwent radical cystectomy at a median of 24 months of followup. Five-year disease specific and overall survival rates were 85% and 71%, respectively. CONCLUSIONS: Intravesical docetaxel appears to be a promising agent with significant efficacy and durability for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer. Adding maintenance treatments may increase the duration of recurrence-free survival.

Experience with newer intravesical chemotherapy for high-risk non-muscle-invasive bladder cancer.

The definitive treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) who fail to respond to intravesical bacillus Calmette-Guérin (BCG) is cystectomy. However, many patients who experience recurrence after BCG are either poor operative candidates or refuse surgery due to the long-term impact on their quality of life. In the last decade, there has been an increased interest in alternative intravesical therapies, and several novel chemotherapeutics have emerged as promising agents for high-risk NMIBC patients unable or unwilling to undergo cystectomy. Additionally, extended treatment regimens with combined induction and maintenance therapy have been investigated, and may increase the durability of response to these new agents, as has been shown for conventional intravesical therapy.

A comparison of the outcomes of neoadjuvant and adjuvant chemotherapy for clinical T2-T4aN0-N2M0 bladder cancer.

BACKGROUND: Despite evidence supporting perioperative chemotherapy, few randomized studies compare neoadjuvant and adjuvant chemotherapy for bladder cancer. Consequently, the standard of care regarding the timing of chemotherapy for locally advanced bladder cancer remains controversial. We compared patient outcomes following neoadjuvant or adjuvant systemic chemotherapy for cT2-T4aN0-N2M0 bladder cancer. METHODS: In a retrospective review of a single institutional database from 1988 through 2009, we identified patients receiving neoadjuvant or adjuvant multiagent platinum-based systemic chemotherapy for locally advanced bladder cancer. Survival analysis was performed comparing disease-specific survival (DSS) and overall survival (OS). RESULTS: A total of 146 patients received systemic perioperative chemotherapy (73 neoadjuvant, 73 adjuvant). Of these, 84% (122/146) received cisplatin-based chemotherapy compared with carboplatin-based chemotherapy (24/146, 16.4%). Most patients receiving cisplatin-based chemotherapy were treated with methotrexate/vinblastine/adriamycin/cisplatin (79/122, 64.8%), whereas the remaining patients received gemcitabine/cisplatin (GC) (43/122, 35.2%). In multivariable analysis, there was no significant difference in DSS (P = .46) or OS (P = .76) between neoadjuvant or adjuvant chemotherapy groups. There was statistically significant improvement in DSS when patients received neoadjuvant GC rather than adjuvant GC (P = .049, hazard ratio, 10.6; 95% confidence interval, 1.01-112.2). CONCLUSION: In this study, there was no statistically significant difference in OS and DSS between patients receiving neoadjuvant versus adjuvant systemic platinum-based chemotherapy for locally advanced bladder cancer. In addition, there was no significant difference between neoadjuvant and adjuvant cisplatin- or carboplatin-based chemotherapy. Chemotherapy sequence relative to surgery appeared less important than whether or not a patient actually received perioperative chemotherapy.

A phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer.

PURPOSE: Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albumin-bound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. MATERIALS AND METHODS: Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. RESULTS: A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. CONCLUSIONS: Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen.

The relationship between age at time of surgery and risk of biochemical failure after radical prostatectomy.

OBJECTIVES: To evaluate the effects of age at radical prostatectomy (RP) on recurrence-free survival (RFS) in patients with prostate cancer stratified by established preoperative risk factors (such as prostate-specific antigen (PSA) level, Gleason score, and tumour stage), as increasing age has been associated with more indolent behaviour in some cancers. PATIENTS AND METHODS: A retrospective analysis of men treated with RP from 1988 to 2008 was conducted. Patients were divided into two groups by age at the time of RP, and RFS rates were analysed using Kaplan-Meier survival curves. The subgroups were stratified by preoperative PSA level, biopsy Gleason score, and clinical stage; multivariate analyses with Cox proportional hazards models were used to identify independent predictors of recurrence. Recurrence was defined as a single PSA level of > or =0.2 ng/mL at least 28 days after RP. RESULTS: In all, 1984 patients met inclusion criteria and were divided into groups 1 (1325 men aged 40-64 years) and 2 (659 men aged > or =65 years). The 5-year RFS rates were 80.6% (confidence interval, CI 78.0-82.9%) and 75.6% (CI 71.5-79.1%) for groups 1 and 2, respectively. In the univariate model, advanced age was significantly associated with an increased overall risk of recurrence (hazard ratio, HR 1.30, P = 0.012). However, in multivariate analyses accounting for PSA level, Gleason score, and clinical stage, age was not an independent predictor of recurrence (HR 1.04, P = 0.76). CONCLUSION: Older patients who undergo RP appear to have an increased risk of recurrence. However, age is not an independent predictor of recurrence when accounting for PSA level, grade, and stage.

Predicting renal functional outcomes after surgery for renal cortical tumours: a multifactorial analysis.

OBJECTIVE: To examine the functional outcomes after radical (RN) and partial nephrectomy (PN) stratified by variables before and after surgery, using estimated glomerular filtration rate (eGFR), as nephrectomy is the standard treatment for localized renal tumours, but the risk of developing chronic kidney disease (CKD) increases after surgery. PATIENTS AND METHODS: We retrospectively analysed patients treated with PN or RN for renal cancer at one institution from 1988 to 2008. Chronic renal function before and after surgery was measured using the eGFR computed using the Modification of Diet in Renal Disease equation. Four outcomes were measured: (i) presence of new-onset renal insufficiency (eGFR <60 mL/min/1.73m(2)); (ii) the percentage change in eGFR; (iii) the change in CKD stage; and (iv) the presence of CKD upstaging. Regression models were used to determine the effect of surgical procedure (RN vs PN), access technique (open vs laparoscopic) and several preoperative characteristics on functional outcomes. RESULTS: In all, 276 patients met the inclusion criteria (174 RN and 102 PN) of whom 209 had a preoperative eGFR of >60 mL/min/1.73m(2). After >or=3 months from surgery, 108/209 (52%) patients developed new-onset eGFR of <60 mL/min/1.73m(2). On multivariate analysis, preoperative CKD stage (P < 0.001) and procedure (P= 0.001) were both independent predictors of all four functional outcomes measured. Also, hypertension was an independent predictor of CKD upstaging (P= 0.02). Surgical access technique was not an independent predictor of any of the renal functional outcomes measured. CONCLUSION: Patients undergoing renal surgery have a high rate of new-onset CKD afterward. After controlling for preoperative risk factors, patients undergoing RN are at greater risk of a decline in renal function. However, surgical access technique was not a significant predictor for renal impairment.

The novel use of intravesical docetaxel for the treatment of non-muscle invasive bladder cancer refractory to BCG therapy: a single institution experience.

OBJECTIVES: Since the success of our Phase I trial of intravesical docetaxel for treatment-refractory non-muscle invasive bladder cancer (NMIBC), we have found this agent to be a favorable alternative for BCG-refractory patients unable or unwilling to undergo cystectomy. This study analyzes the safety and efficacy of intravesical docetaxel in a larger patient population with extended follow-up. METHODS: A retrospective analysis of all patients who received salvage intravesical docetaxel at our institution was conducted, including 18 patients treated during the Phase I trial and 15 patients treated after the trial's completion. Toxicity, efficacy and recurrence-free survival were analyzed. RESULTS: Thirty-three patients with refractory NMIBC received salvage intravesical docetaxel therapy between 2003 and 2008 at a single institution. Twenty of thirty-three (61%) patients had a complete response (CR) after six weekly induction treatments. Ten patients with CRs were given maintenance docetaxel therapy, and one patient received maintenance BCG and interferon. With a median follow-up of 29 months, 1 and 2-year recurrence-free survival rates were and 45 and 32%, respectively. Twelve of thirty-three patients (36%) had Grade 1 or 2 local toxicities. No patients experienced Grade 3 or 4 toxicities. CONCLUSIONS: Docetaxel is a promising intravesical agent with minimal toxicity and significant efficacy and durability for the management of BCG-refractory NMIBC.

The Correlation of Media Ranking's "Best" Hospitals and Surgical Outcomes Following Radical Cystectomy for Urothelial Cancer.

OBJECTIVE: To evaluate whether there is a correlation between publicized health ranking systems and surgical outcomes after radical cystectomy (RC) in New York State (NYS). MATERIALS AND METHODS: Using the Statewide Planning and Research Cooperative System, data were collected in an aggregated fashion per hospital for the 20 hospitals with the highest RC volume in NYS from 2009 to 2012. Hospital characteristics were obtained from the publicly available sources such as the Centers for Medicare and Medicaid Services. Publicized ranking systems evaluated included the US News & World Health Report for Urology ranking (USHR), Healthgrades (HG) score, and Consumer Reports (CR) safety ranking. Outcomes measured included mortality, readmissions, and causes of readmissions. RESULTS: CR safety scores were inversely associated with overall death at 90 days after surgery (R = -0.527, P = .030), number of readmissions (R = -0.608, P = .030), and readmissions because of surgical complications (R = -0.523, P = .031) on a Pearson correlation test. On Kendall rank tau test, USHR and HG were not associated with any outcome of interest, although the scores correlated with increasing RC volume. CONCLUSION: In our analysis of 20 hospitals with the highest RC volume in NYS, USHR and HG scores were not strongly associated with any clinical outcome after RC. CR performed well in comparison with USHR and HG. Nevertheless, better metrics are needed to compare hospitals and to incorporate curative rates for morbid surgeries.

Single luminal epithelial progenitors can generate prostate organoids in culture.

The intrinsic ability to exhibit self-organizing morphogenetic properties in ex vivo culture may represent a general property of tissue stem cells. Here we show that single luminal stem/progenitor cells can generate prostate organoids in a three-dimensional culture system in the absence of stroma. Organoids generated from CARNs (castration-resistant Nkx3.1-expressing cells) or normal prostate epithelia exhibit tissue architecture containing luminal and basal cells, undergo long-term expansion in culture and exhibit functional androgen receptor signalling. Lineage-tracing demonstrates that luminal cells are favoured for organoid formation and generate basal cells in culture. Furthermore, tumour organoids can initiate from CARNs after oncogenic transformation and from mouse models of prostate cancer, and can facilitate analyses of drug response. Finally, we provide evidence supporting the feasibility of organoid studies of human prostate tissue. Our studies underscore the progenitor properties of luminal cells, and identify in vitro approaches for studying prostate biology.

Serum tumor markers in the evaluation of male germ cell tumors.

Serum tumor markers play a critical role in the diagnosis, staging, risk stratification, and surveillance of patients with testicular germ cell tumors (GCTs). Production of the oncofetal substances α fetoprotein and human chorionic gonadotropin can aid the diagnosis of testicular GCTs, and specific patterns of marker elevation can be used to determine the type of tumor, particularly as it pertains to nonseminoma. These markers, in addition to lactate dehydrogenase, have been incorporated in the standard TNM staging system for testicular tumors; the S stage category corresponds to serum elevation of these proteins. Furthermore, the degree of serum tumor marker elevation has been incorporated into standardized patient risk groupings, which are used to guide therapeutic management. The rate of tumor marker decay after radical orchiectomy is an important index to monitor, as a slow decline might be indicative of metastatic disease and should prompt a thorough systemic survey. The rate of tumor marker decline is already being utilized in the setting of metastatic GCTs to determine response to chemotherapy, and has been used in some scenarios to individualize the type of chemotherapy patients received. Compared to any other solid organ malignancy, the role of serum tumor markers in GCT is unprecedented; these markers are instrumental in the diagnosis and management of testicular GCT.

Novel intravesical therapies for non-muscle-invasive bladder cancer refractory to BCG.

The definitive treatment for patients with non-muscle-invasive bladder cancer (NMIBC) who fail to respond to intravesical BCG is cystectomy. When a patient is deemed BCG-refractory and cannot or will not undergo cystectomy, alternative intravesical therapy may be the most effective way to minimize recurrence and progression. A number of immunotherapeutic and chemotherapeutic agents have been given intravesically over the years, and several recently and currently investigated novel agents appear to be particularly promising for the management of BCG-refractory NMIBC. The most effective treatments in the future will likely utilize targeted therapies based on the underlying genetic mutations associated with each individual diagnosis of NMIBC.

Has the advent of minimally invasive surgery altered the risk profile of patients undergoing prostatectomy?

OBJECTIVES: To determine whether the decreased short-term morbidity associated with minimally invasive surgery (MIS) has resulted in an alteration in the disease-specific risk profile of prostatectomy patients. MIS in many fields has resulted in an expansion in the pool of patients willing to undergo surgery. METHODS: The Columbia Urologic Oncology Database was queried, and 1751 patients undergoing radical prostatectomy between 2000 and 2007 were identified. The cohort was divided into 2 groups: patients who received surgery before or after the initiation of robotic-assisted laparoscopic radical prostatectomy (RALRP) at our institution (from 2003 onward). Age at surgery, Kattan Nomogram (KN) score, prostate-specific antigen (PSA), Gleason score sum, and tumor stage were compared using unpaired t tests with Welch correction and Mann-Whitney tests. RESULTS: A total of 663 patients underwent prostatectomy from 2000 to 2002 ("pre-MIS era"), and 1088 patients had surgery in 2003 or later ("MIS era"), of which 519 and 569 underwent RALRP and open prostatectomy, respectively. There was no significant difference between the 2 eras regarding age, Kattan Nomogram score, or tumor stage. However, there was a significant difference in preoperative PSA (P = .01) and Gleason sum (P = .0002). In a comparison of the pre-MIS era with RALRP patients, only PSA differed significantly (P = .0002). CONCLUSIONS: The advent of MIS for prostate cancer did not significantly alter the characteristics of patients undergoing prostatectomy at our institution. Although advancements in surgical techniques may improve clinical outcomes, this study does not suggest a consequential effect on the risk stratification of patients choosing surgery for prostate cancer.

Long-term clinical outcomes of a phase I trial of intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to standard intravesical therapy.

OBJECTIVES: To report the long-term clinical outcomes and durability of response after treatment with induction intravesical docetaxel. Most novel agents used to treat bacillus Calmette-Guerin refractory high-grade non-muscle-invasive (NMI) bladder cancer are evaluated only after short follow-up periods. Our previously published phase I trial demonstrated that docetaxel is a safe agent for intravesical therapy with minimal toxicity and no detectable systemic absorption. We sought to determine long-term clinical outcomes after treatment with intravesical docetaxel. METHODS: Eighteen patients with recurrent Ta (n = 7), T1 (n = 5), and Tis (n = 6) transitional cell carcinoma who experienced treatment failure with at least 1 prior intravesical therapy completed the phase I trial. Docetaxel was administered as 6 weekly intravesical instillations using a dose-escalation model terminated at 0.75 mg/mL. Efficacy was evaluated by interval cystoscopy with biopsies when indicated, cytology, and computed tomography imaging. Follow-up consisted of quarterly cystoscopy, cytology, computed tomography, and biopsy when indicated. RESULTS: With a median follow-up of 48.3 months, 4 patients (22%) have demonstrated a complete durable response and currently remain disease-free without further treatment. Three patients (17%) had a partial response, defined as a single NMI recurrence with no further therapy for bladder cancer. Eleven patients (61%) failed treatment, and required another intervention. One patient developed stage progression. No delayed toxicities were noted. The median disease-free survival time was 13.3 months. CONCLUSIONS: After 4 years of follow-up without maintenance therapy, intravesical docetaxel has demonstrated the ability to prevent recurrence in a select number of patients with refractory NMI bladder cancer and warrants further investigation.