Finasteride Use and Risk of Bladder Cancer in a Multiethnic Population.

PURPOSE: Finasteride use has been associated with a reduced incidence of bladder cancer. However, the majority of studies have been conducted primarily in East Asian or White populations. Given differences in the incidence of bladder cancer among racial/ethnic groups, it is important to determine whether the effect of finasteride use on bladder cancer varies by race/ethnicity. MATERIALS AND METHODS: We identified all patients with a diagnosis of benign prostatic hyperplasia between 2000 and 2016 at our academic health center in Bronx, New York via an electronic medical record database. We then identified patients who were prescribed finasteride, and those who developed bladder cancer during followup. We used competing risk analysis to examine associations of finasteride use with risk of bladder cancer, adjusting for age, smoking and race/ethnicity. RESULTS: We identified 42,406 patients with benign prostatic hyperplasia (average±SD age 67±12.9 years), of whom 27.7% were Black and 14.8% were Hispanic. Finasteride was prescribed in 5,698 patients (13.4%). Bladder cancer was diagnosed in 84 of 5,698 finasteride users (1.5%), compared to 762 of 36,708 nonusers (2.1%, log-rank p=0.003). Finasteride was associated with a 36% reduction in risk of bladder cancer (HR: 0.64, 95% CI: 0.51-0.80; p <0.0001) among all patients. When data were stratified by race/ethnicity, finasteride use was associated with a reduction in risk of bladder cancer in White men (HR: 0.61, 95% CI: 0.43-0.86; p=0.005) and Hispanic men (HR: 0.44, 95% CI: 0.21-0.90; p=0.026), but there was no association among Black men (HR: 1.01, 95% CI: 0.67-1.51; p=0.964). CONCLUSIONS: Our study corroborates previous findings that men who are on finasteride have a lower bladder cancer incidence. However, the reduction in risk was seen only in White and Hispanic men, but not among Black men. Therefore, race/ethnicity represents an important stratification factor for future larger studies on finasteride as chemoprevention for bladder cancer.

Clinical Restaging and Tumor Sequencing are Inaccurate Indicators of Response to Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer.

BACKGROUND: Standard of care for patients with muscle-invasive bladder cancer (MIBC) includes neoadjuvant cisplatin-based chemotherapy (NAC) followed by consolidative therapy with either chemoradiation or radical cystectomy (RC). Some patients experience robust pathologic responses to NAC, and these have been reported to associate with somatic mutations in specific gene pathways including DNA damage response genes. OBJECTIVE: To evaluate the ability of post-NAC clinical restaging, with or without tumor sequencing, to predict final RC pathologic staging. DESIGN, SETTING, AND PARTICIPANTS: We reviewed our institutional review board-approved institutional database to identify patients with MIBC who underwent NAC followed by RC from 2003 to 2016. Following NAC prior to RC, cystoscopy was performed routinely, with resection of residual visible tumor and/or tumor base (transurethral resection [TUR]). For patients with pre-NAC tumor tissue available, tumor sequencing was performed. Outcome measurements and statistical analysis: Clinical restaging and tumor sequencing were evaluated for their ability to predict the final pathologic stage accurately at RC using chi-square or Fisher's exact test. RESULTS AND LIMITATIONS: A total of 114 patients underwent restaging TUR following NAC and prior to RC. The diagnostic accuracy of post-NAC clinical restaging including TUR was poor, with 32% of patients being downstaged falsely when compared with their final RC pathology. Forty-nine patients had sequencing of pre-NAC tumor tissue, of whom 32 showed at least one mutation of interest. However, NAC responses and rates of false downstaging did not differ significantly according to tumor mutation status. CONCLUSIONS: This study highlights the inaccuracy of post-NAC clinical restaging TUR with or without adjunctive tumor mutation analysis, to assess pathologic residual disease accurately. Caution must be taken when performing post-NAC restaging, especially when considering conservative management strategies such as active surveillance on this basis. Patient summary: Several groups are evaluating whether certain patients, whose bladder cancer responds well to upfront chemotherapy, may be able to forego cystectomy safely. We demonstrate that currently available staging tools and tumor DNA sequencing cannot identify such patients reliably and accurately.

SIU-ICUD consultation on bladder cancer: treatment of muscle-invasive bladder cancer.

PURPOSE: To provide a comprehensive overview and update of the Joint Société Internationale d'Urologie-International Consultation on Urological Diseases (SIU-ICUD) Consultation on Bladder Cancer for muscle-invasive presumably node-negative bladder cancer (MIBC). METHODS: Contemporary literature was analyzed for the latest evidence in treatment options, outcomes, including radical surgery, neoadjuvant and adjuvant treatment modalities, and bladder-sparing approaches. An international multi-disciplinary expert panel evaluated and graded the data according to guidelines from the Oxford Centre for Evidence-Based Medicine. RESULTS: Radical cystectomy (RC) is the standard of care for MIBC patients considered to be surgical candidates. While associated with substantial morbidity and mortality, this has been mitigated with improved technique, minimally invasive technology, and better perioperative care pathways (e.g., enhanced recovery after surgery). Neoadjuvant (NA) cisplatin-based combination chemotherapy improves overall survival and should be offered to eligible ≥ cT2N0 patients. Adjuvant (Adj) cisplatin-based combination chemotherapy may be considered, particularly for pT3-4 and/or pN+ disease without prior NA chemotherapy. Trimodal bladder-preserving treatment via maximum transurethral resection of bladder tumor followed by concurrent chemoradiation is safe and, when combined with early salvage RC for recurrence, offers long-term survival rates in selected patients comparable to RC. Immunotherapy is still experimental and is given either alone or in combination with chemotherapy and/or radiation. CONCLUSION: A multi-disciplinary approach is paramount to achieving optimal outcomes for MIBC patients, irrespective of their age, performance and nutritional status, fitness/frailty, renal and other organ function, or disease severity.

Implications of micropapillary urothelial carcinoma variant on prognosis following radical cystectomy: A multi-institutional investigation.

PURPOSE: To determine the association of micropapillary urothelial carcinoma (MUC) variant histology with bladder cancer outcomes after radical cystectomy. MATERIALS AND METHODS: Information on MUC patients treated with radical cystectomy was obtained from five academic centers. Data on 1,497 patients were assembled in a relational database. Tumor histology was categorized as urothelial carcinoma without any histological variants (UC; n = 1,346) or MUC (n = 151). Univariable and multivariable models were used to analyze associations with recurrence-free (RFS) and overall (OS) survival. RESULTS: Median follow-up was 10.0 and 7.8 years for the UC and MUC groups, respectively. No significant differences were noted between UC and MUC groups with regard to age, gender, clinical disease stage, and administration of neoadjuvant and adjuvant chemotherapy (all, P ≥ 0.10). When compared with UC, presence of MUC was associated with higher pathologic stage (organ-confined, 60% vs. 27%; extravesical, 18% vs. 23%; node-positive, 22% vs. 50%; P < 0.01) and lymphovascular invasion (29% vs. 58%; P < 0.01) at cystectomy. In comparison with UC, MUC patients had poorer 5-year RFS (70% vs. 44%; P < 0.01) and OS (61% vs. 38%; P < 0.01). However, on multivariable analysis, tumor histology was not independently associated with the risks of recurrence (P = 0.27) or mortality (P = 0.12). CONCLUSIONS: This multi-institutional analysis demonstrated that the presence of MUC was associated with locally advanced disease at radical cystectomy. However, clinical outcomes were comparable to those with pure UC after controlling for standard clinicopathologic predictors.

Hospital Charges and Length of Stay Following Radical Cystectomy in the Enhanced Recovery After Surgery Era.

OBJECTIVE: To report our center's experience with enhanced recovery after surgery (ERAS) pathway for radical cystectomy (RC), specifically evaluating complications, LOS, 30- and 90-day readmissions, and hospital charges. Pathways of this type have been shown to decrease the length of stay (LOS) and postoperative ileus. However, concerns persist that ERAS is costly and increases readmissions. To date, limited studies have evaluated these concerns. MATERIALS AND METHODS: Our ERAS protocol was implemented for RC in December 2015. Outcomes in ERAS patients were compared with those in RC patients from the time period before ERAS. Patients were excluded if they underwent concomitant nephroureterectomy. RESULTS: Fifty-six consecutive ERAS patients were compared with 54 pre-ERAS patients. The median charge for index hospitalization was $31,090 in the ERAS group and $35,489 in the pre-ERAS group (P = .036). The median LOS was 5.0 days in the ERAS group and 8.5 days in the pre-ERAS group (P = < .001). The pre-ERAS group had a significantly increased use of nasogastric tube (13.8% vs 30.0%) and parenteral nutrition (6.9% vs 20.4%). The overall complication rate (including infectious, renal, deep vein thrombosis and pulmonary embolism, myocardial infarction and stroke, and respiratory and gastrointestinal-related complications) was similar between the 2 groups (51.7% in the ERAS group and 62.0% in the pre-ERAS group, P = .28). Thirty- and 90-day readmissions also remained similar (19.0% vs 14.8%, P = .55, and 31.0% vs 27.7%, P = .64). The most common readmission reason was infection, specifically urinary tract infection. CONCLUSION: Implementation of the ERAS pathway at our center resulted in significantly reduced LOS and total hospital charge, with comparable rates of complication and readmission, highlighting the need for ERAS pathways in patients undergoing RC.

Oncological Outcomes of Sequential Intravesical Gemcitabine and Docetaxel in Patients with Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Bacillus Calmette-Guérin (BCG) unresponsive/relapsing patients with non-muscle invasive bladder cancer (NMIBC) who prefer bladder preservation over radical cystectomy (RC) or those who do not qualify for surgery may be offered intravesical therapies. Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH). OBJECTIVE: To evaluate experience with GEM/DOCE, to confirm safety of the regimen, to identify populations that may benefit most, and to consider the appropriate endpoints for judging efficacy of second line therapies. METHODS: Thirty-three patients who received full induction GEM/DOCE since 2011, per the protocol adapted from U. Iowa, were identified and characterized. Multivariable logistic regression was used to determine factors associated with recurrence. Cox proportional hazard models evaluated risk factors for disease-free survival (DFS) and high-grade recurrence-free survival (HG-RFS). RESULTS: There were no serious adverse effects of therapy. Across all patients, median follow-up time was 18.6 months with a median DFS of 6.5 months, 42% 1-year, and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2-year HG-RFS. Among patients initially presenting with HG-NMIBC, 46% (13/28) had HG recurrence. BCG unresponsive/relapsing patients (N = 25) displayed 49% 1-year HG-RFS and 34% 2-year HG-RFS. In total, there were 5 LG and 16 HG recurrences, with 5 progressions and 8 cystectomies among these. CONCLUSIONS: GEM/DOCE is a well-tolerated therapy that deserves further study as an alternative to immediate RC for highly selected patients with HG-NMIBC. BCG naïve patients responded more effectively than BCG unresponsive/relapsing patients. As anticipated, GEM/DOCE efficacy was improved for HG only patients.

The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3.

The B7-CD28 family of ligands and receptors play important roles in T-cell co-stimulation and co-inhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules (B7-H3 [CD276], B7x [B7-H4/B7S1], and HHLA2 [B7H7/B7-H5]/TMIGD2 [IGPR-1/CD28H]) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7-H3, B7x, HHLA2, and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, transplantation, and infection. Various immunotherapeutical approaches are emerging including antagonistic monoclonal antibodies and agonistic fusion proteins to inhibit or potentiate these molecules and pathways in cancers and autoimmune diseases.

Biomanufacturing Seamless Tubular and Hollow Collagen Scaffolds with Unique Design Features and Biomechanical Properties.

A versatile process to develop designer collagen scaffolds for hollow and tubular tissue engineering applications is presented. This process creates seamless and biomechanically tunable scaffolds ranging from ureter-like microsized tubings to structures with highly customized lumens that resemble intestinal villi, fluid bladders, and alveolar sacs that together with stem cells can potentially be used in preclinical and clinical settings.

A review of the PD-1/PD-L1 checkpoint in bladder cancer: From mediator of immune escape to target for treatment.

PURPOSE: Recent observations have focused attention on the means that human tumors employ to evade host defense systems critical to immune surveillance. The concepts of immunotherapy are familiar to urologists because of the use of bacillus Calmette-Guérin in bladder cancer. Research demonstrating the importance of checkpoint inhibitors in suppressing immune responses against tumors has heightened interest in immunotherapy at a time when there is a need for alternatives to bacillus Calmette-Guérin. We review the literature on the application of immunotherapeutic agents targeting a key checkpoint pathway, programmed death 1 (PD-1) and its ligand (PD-L1), in the field of bladder cancer. MATERIALS AND METHODS: A comprehensive literature review was performed using Medline/Pubmed and Embase. RESULTS: The PD-1/PD-L1 pathway may be manipulated by cancer cells to subvert the immune system. PD-1/PD-L1 blockade has been tested in clinical trials for various malignancies including metastatic urothelial carcinoma, with significant response rates and limited side effects. PD-L1 expression has also been proposed as a prognostic marker for bladder cancer with mixed results. CONCLUSIONS: PD-1 is one of several key receptors mediating immune escape, and agents targeting its ligand PD-L1 have already been successfully applied to patients with metastatic urothelial cancer. More research is needed to standardize criteria for PD-L1 positivity, explore its use as a biomarker, and optimize its use in the treatment for bladder cancer.

Vesigenurtacel-L (HS-410) in the management of high-grade nonmuscle invasive bladder cancer.

Unlike other malignancies, the death rate of bladder cancer has not declined in several decades, highlighting the need for new treatment options. In the emerging era of immunotherapy, therapeutic cancer vaccines are an attractive option to cure, control and prevent cancer. Despite this, finding a feasible and efficacious vaccine platform has proven elusive across all malignancies. Vesigenurtacel-L is the first whole cell, allogeneic vaccine intended to treat high-grade, nonmuscle invasive bladder cancer. This type of vaccine technology for bladder cancer is novel, and has the potential to be both economically and logistically feasible.

Microhematuria assessment an IBCN consensus-Based upon a critical review of current guidelines.

RATIONALE: Assessment of patients with asymptomatic microhematuria (aMh) has been a challenge to urologists for decades. The aMh is a condition with a high prevalence in the general population and also an established diagnostic indicator of bladder cancer. Acknowledging aMh needs to be assessed within a complex context, multiple guidelines have been developed to identify individuals at high risk of being diagnosed with bladder cancer. MATERIAL & METHODS: This structured review and consensus of the International Bladder Cancer Network (IBCN) identified and examined 9 major guidelines. These recommendations are partly based on findings from a long-term study on the effects of home dipstick testing, but also on the assumption that early detection of malignancy might be beneficial. RESULTS: Despite similar designs, these guidelines differ in a variety of parameters including definition of aMh, rating of risks, use of imaging modalities, and the role of urine cytology. In addition, recommendations for further follow-up after negative initial assessment are controversial. In this review, different aspects for aMh assessment are analyzed based upon the evidence currently available. DISCUSSION: We question whether adherence to the complicated algorithms as recommended by most guidelines is practical for routine use. Based upon a consensus, the authors postulate a need for better tools. New concepts for risk assessment permitting improved risk stratification and prepone cystoscopy before refined imaging procedures (computed tomography scan and magnetic resonance imaging) are suggested.

Infectious complications in transfused patients after radical cystectomy.

INTRODUCTION: Infectious complications are common after radical cystectomy (RC), and allogeneic blood transfusions may increase infection risk by an immunosuppressive effect. While it has been suggested that perioperative blood transfusion (PBT) may be associated with adverse oncologic outcomes after RC, no large analyses have assessed whether PBT increases the risk of perioperative infection after RC. MATERIALS AND METHODS: We used the Nationwide Inpatient Sample (1998 to 2011) to study the rate of PBT during RC for bladder cancer and identify infectious complications. We compared rates of infectious complications in patients who did and did not receive PBT and developed a multivariable model to assess the independent risk of infectious complication associated with PBT controlling for age, year of surgery, obesity, chronic kidney disease, comorbidity score, and type of urinary diversion. RESULTS: We identified 126,454 RCs performed during the study period. A total of 34,203 (27%) received a PBT. The use of PBT increased over the study period, from 18.4% in 1998 to 31.6% in 2011 (p < 0.0001). Patients who received a PBT had an increased risk of perioperative infectious complications [36.7% versus 27.7%, unadjusted OR (95% CI) = 1.51 (1.43-1.60), p < 0.0001]. After adjusting for potential confounders, PBT remained an independent predictor of infectious complications [adjusted OR (95% CI) = 1.46 (1.38-1.55), p < 0.0001]. CONCLUSIONS: This analysis provides strong observational evidence that PBT is associated with an increased risk of perioperative infectious complications, which may be secondary to transfusion-related immunomodulation. Urologists should aggressively pursue blood conservation strategies and adhere to evidence-based restrictive transfusion thresholds, particularly given the rising rate of PBT.

Accuracy of urethral frozen section during radical cystectomy for bladder cancer.

OBJECTIVE: Our objective was to determine the accuracy of urethral frozen section (FS) by analyzing our clinical experience. MATERIALS AND METHODS: A total of 298 patients undergoing radical cystectomy for bladder cancer with benign or malignant urethral FS were identified between 2000 and 2012. Urethral FS were compared with rereviewed FS to calculate the positive and negative predictive values of the FS. To assess the ability of the positive FS to be cleared with further sampling/resection, FS were then compared with the final urethral margin. The cases of positive urethral FS were then specifically analyzed to assess rates of urethral recurrence and survival. RESULTS: All negative FS were confirmed to be negative on FS rereview and on final pathology, resulting in a NPV of 100%. Urethral FS were positive in 28 (8.7%) patients, of whom 2 (7%) were negative on FS rereview, yielding a positive predictive value of 93%. Both false positives were because of contamination of detached cancer from the bladder being present in the FS. After additional sampling/resection, the final margin was negative in 13 (46%) patients. CONCLUSIONS: A negative urethral FS reliably identifies individuals for whom urethrectomy is unnecessary and provides robust information for decision-making regarding the safety of orthotopic reconstruction. Nearly half of the patients with a positive FS were ultimately determined to have a negative final margin. Accordingly, we recommend that surgeons and pathologists discuss positive FS findings at the time of surgery and consider whether additional tissue should be analyzed in real time.

Do African American Patients Treated with Radical Cystectomy for Bladder Cancer have Worse Overall Survival? Accounting for Pathologic Staging and Patient Demographics Beyond Race Makes a Difference.

Background: It is estimated that 74,000 men and women in the United States will be diagnosed with bladder cancer and 16,000 will die from the disease in 2015. The incidence of bladder cancer in Caucasian males is double that of African American males, but African American men and women have worse survival. Although factors contributing to this disparity have been analyzed, there is still great uncertainty as to why this disparity exists. Objective: To evaluate whether the disparities in bladder cancer survival after radical cystectomy for transitional cell carcinoma (TCC) of the bladder amongst African American (AA) and Caucasian patients is attributable to patient demographics, year of diagnosis, and/or tumor characteristics. Methods: Using Surveillance, Epidemiology, and End Results Program (SEER) data from 1973-2011, African American and Caucasian patients treated with a radical cystectomy for TCC of the bladder were identified. Primary outcomes were all-cause and cancer-specific mortality. Differences in survival between African Americans and Caucasian patients were assessed using chi-square tests for categorical variables and Student's t-tests for continuous variables. Cox proportional hazards regression was used to measure the hazard ratio for African Americans compared to Caucasians for all-cause and cancer-specific mortality. In addition, coarsened matching techniques within narrow ranges, were used to match African American and Caucasian patients on the basis of age, sex, and cancer stage. Following matching, differences in all-cause and cancer-specific mortality were again assessed using a stratified Cox proportional hazards model, using the matching strata for the regression strata. Results: The study cohort consisted of 21,406 African American and Caucasian patients treated with radical cystectomy for bladder urothelial cancer, with 6.2% being African American and 73.9% male. African American patients had worse all-cause and cancer-specific mortality in the univariable analysis (all-cause: HR: 1.23; 95% CI 1.15-1.32, p <  0.001); bladder-cancer specific: HR 1.21; 95% CI 1.11-1.33; p <  0.001). However, after accounting for sex, age, year of diagnosis, marital status, region of treatment, and stage at cystectomy, all-cause mortality was significant (HR 1.20; 95% CI 1.12-1.29; p <  0.0001), but not bladder-cancer specific mortality (HR 1.09; 95% CI 1.00-1.20; p <  0.053). Predictors of bladder cancer specific mortality were age, sex, stage of disease, and marital status. The matched analysis yielded a roughly 1 : 15 match, with 22,511 Caucasians being matched to 1,509 African American patients. In the matched analysis, African Americans had increased all-cause mortality (HR 1.17; 95% CI 1.09-1.26; p <  0.0001), but bladder-cancer specific mortality was no longer significant (HR 1.08; 95% CI 0.99-1.18; p <  0.102). Conclusions: African Americans who undergo a cystectomy are more likely to die, but not necessarily solely because of bladder cancer. Although African American patients have worse all-cause and cancer-specific mortality in univariable models, after controlling for sex, age, year of diagnosis, marital status, region of treatment, and stage at cystectomy, African American patients still have worse overall survival, but equivalent bladder-cancer specific survival. Differences in age, sex, and stage at diagnosis explain some, but not all of the differences in survival.

The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder.

INTRODUCTION: Randomized controlled trials of platinum-based neoadjuvant chemotherapy (NAC) for bladder cancer have shown that patients who achieve a pathologic response to NAC exhibit 5 y survival rates of approximately 80-90% while NAC resistant (NR) cases exhibit 5 y survival rates of approximately 30-40%. These findings highlight the need to predict who will benefit from conventional NAC and the need for plausible alternatives. METHODS: The pre-treatment biopsy tissues from a cohort of 41 patients with muscle invasive bladder who were treated with NAC were incorporated in tissue microarray and immunohistochemistry for PD-L1, CD8, and FOXP3 was performed. Percentage of PD-L1 positive tumor cells was measured. Tumor-infiltrating lymphocytes (TIL) densities, along with CD8 and Treg-specific TILs, were measured. RESULTS: TIL density was strongly correlated with tumor PD-L1 expression, consistent with the mechanism of adaptive immune resistance in bladder cancer. Tumor cell PD-L1 expression was not a significant predictor of response. Neither was the CD8 nor Treg TIL density associated with response. Intriguingly though, the ratio of CD8 to Treg TIL densities was strongly associated with response (p = 0.0003), supporting the hypothesis that the immune system plays a role in the response of bladder cancer to chemotherapy. DISCUSSION: To our knowledge, this is the first report in bladder cancer showing that the CD8 to Treg TIL density in the pre-treatment tissues is predictive for conventional NAC response. These findings warrant further investigations to both better characterize this association in larger cohorts and begin to elucidate the underlying mechanism(s) of this phenomenon.

Blood Transfusion is Associated with Increased Perioperative Morbidity and Adverse Oncologic Outcomes in Bladder Cancer Patients Receiving Neoadjuvant Chemotherapy and Radical Cystectomy.

PURPOSE: Perioperative blood transfusion (PBT) has been inconsistently associated with adverse outcomes. Bladder cancer patients are unique as they frequently undergo neoadjuvant chemotherapy (NAC) with resulting immunosuppression, which may be exacerbated by transfusion-related immunomodulation. We examined the effect of leukoreduced PBT on oncologic outcomes and perioperative morbidity in radical cystectomy (RC) patients who received NAC, quantifying exposure with a novel dose-index variable. METHODS: The Johns Hopkins Radical Cystectomy database was queried for patients who had undergone NAC followed by RC from 2010 to 2013. Overall, 119 patients had available PBT and survival data. A multivariable Cox model evaluated risk factors, including pathologic stage, Charlson Comorbidity Index, age, race, year of surgery, surgical margin status, PBT, and preoperative hemoglobin for bladder cancer-specific survival (CSS) and overall survival (OS). Logistic regression models determined factors that were independently associated with perioperative morbidity. RESULTS: Median follow-up was 7.8 months (range 0.2-41.8), and during follow-up there were 25 deaths and 21 cancer deaths. PBT significantly predicted OS (hazard ratio [HR] 1.26, 95 % confidence interval [CI] 1.07-1.49; p = 0.005), CSS (HR 1.32, 95 % CI 1.11-1.57; p = 0.002), and morbidity (odds ratio [OR] 1.67, 95 % CI 1.26-2.21; p = 0.004) in univariate analyses. In multivariable models, PBT was significantly associated with morbidity (OR 1.77, 95 % CI 1.30-2.39; p = 0.0002), but not OS or CSS. Intraoperative transfusion was associated with decreased OS and CSS, and increased morbidity, whereas postoperative transfusion was only associated with increased morbidity. CONCLUSIONS: Intraoperative blood transfusion was associated with increased perioperative morbidity and worsened OS and CSS in patients undergoing RC who had NAC. Although PBT may be life-saving in certain patients, a restrictive transfusion strategy may improve outcomes.

Significance of a minor high-grade component in a low-grade noninvasive papillary urothelial carcinoma of bladder.

To assess the clinicopathological features and prognostic significance of the presence of 5% or less high-grade component in otherwise low-grade noninvasive bladder urothelial carcinoma, referred to as mixed-grade (MG) urothelial carcinoma, we reviewed all archival cases with such diagnosis between 2005 and 2014. Clinicopathological and outcome parameters were compared to those in our previously reported low- and high-grade noninvasive bladder urothelial carcinoma cohorts (LGUC and HGUC, respectively). The study included 31 MG urothelial carcinomas. Mean patient age was 67.6 years, and mean follow-up was 39.7 months. Intravesical treatment was administered in 15 patients (48.4%). Recurrence occurred in 14 cases (45.2%): 10 as LGUC and 4 as HGUC; there was no stage progression. Mean time to progression was 9 months (5-17 months), and there was no death of disease. MG urothelial carcinoma stage progression and dead of disease rates were comparable to that of LGUC. MG urothelial carcinoma stage progression was significantly lower than that of HGUC, P = .002, using Pearson χ(2) test. MG urothelial carcinoma patients with no intravesical treatment had higher incidence rate of grade progression (25%) compared to LGUC patients (7.9%); however, the difference was not statistically significant. MG urothelial carcinoma had a prognosis closer to "pure" LGUC than "pure" HGUC. Untreated MG urothelial carcinoma may have a higher rate of grade progression than LGUC, although more data are needed before this issue can be definitively addressed. Until such data are available, it is reasonable to keep MG urothelial carcinoma as a distinct grade category with potential management implications.

A Retrospective Analysis of the Effect on Survival of Time from Diagnosis to Neoadjuvant Chemotherapy to Cystectomy for Muscle Invasive Bladder Cancer.

PURPOSE: We determine the impact of the timing of radical cystectomy from the diagnosis of muscle invasive bladder cancer on survival in patients also treated with neoadjuvant chemotherapy. MATERIALS AND METHODS: We performed a retrospective chart review of consecutive patients with muscle invasive bladder cancer who received neoadjuvant chemotherapy followed by cystectomy between 1996 and 2014 at a single institution. Cox proportional hazards regression models were used to investigate the effect of treatment time intervals on overall survival. Three treatment intervals were analyzed for survival impact, from diagnosis of muscle invasive bladder cancer to initiation of neoadjuvant chemotherapy, from initiation of neoadjuvant chemotherapy to cystectomy and from diagnosis to cystectomy. Other pretreatment and posttreatment clinicopathological parameters were also analyzed. RESULTS: Median time from the diagnosis of muscle invasive bladder cancer to radical cystectomy was 28 weeks. Cystectomy performed less than 28 weeks from the diagnosis did not result in significant improvement in overall survival outcomes (HR 0.68, 95% CI 0.28-1.63, p=0.388). Neither the timing of neoadjuvant chemotherapy initiation from diagnosis (median 6 weeks) nor the timing of cystectomy from neoadjuvant chemotherapy initiation (median 22 weeks) was associated with survival. Patient age, variant histology, extravesical and/or lymph node involvement (T3-4 and/or N1 or greater) were significantly associated with survival. CONCLUSIONS: The timing of radical cystectomy in relation to muscle invasive bladder cancer diagnosis date does not significantly impact overall survival in patients with muscle invasive bladder cancer receiving neoadjuvant chemotherapy.

Multimodal Therapy in the Treatment of Prostate Sarcoma: The Johns Hopkins Experience.

BACKGROUND: The objective of this study was to evaluate the use of neoadjuvant chemoradiation in patients with prostate sarcoma treated at our institution and report oncological outcomes. MATERIALS AND METHODS: The records of patients with intermediate- or high-grade prostate sarcoma treated with curative intent at our institution from 1993 to 2013 were reviewed. Patient demographic information, tumor characteristics, and treatment modalities used were assessed. Overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were calculated. RESULTS: Eight patients met inclusion criteria. The mean age at presentation was 64 years, and urinary obstruction was the most common presenting symptom. All patients underwent surgical resection and neoadjuvant radiation and 6 had concurrent chemotherapy. Four patients received intraoperative radiation. With a median follow-up of 36 months, there were no local recurrences, 6 metastases, 4 deaths from disease, and no deaths from other causes. The median OS and CSS was 67.8 months, with actuarial OS and CSS rates of 100% at 1 year, 75% at 2 years, 62.5% at 3 years, and 62.5% at 5 years. Median RFS was 14.2 months, with actuarial RFS rate of 75% at 1 year, 37.5% at 2 years, and 25% at 3 years. CONCLUSION: Prostate sarcomas are rarely cured using surgical resection alone. Our cohort treated with a multimodality approach had favorable CSS and RFS compared with historic and contemporary series of surgery alone and no local recurrences. Most patients developed metastatic recurrence, highlighting the aggressive nature of this disease.

Gemcitabine and cisplatin neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma: Predicting response and assessing outcomes.

PURPOSE: To evaluate gemcitabine-cisplatin (GC) neoadjuvant cisplatin-based chemotherapy (NAC) for pathologic response (pR) and cancer-specific outcomes following radical cystectomy (RC) for muscle-invasive bladder cancer and identify clinical parameters associated with pR. MATERIALS AND METHODS: We studied 150 consecutive cases of muscle-invasive bladder cancer that received GC NAC followed by open RC (2000-2013). A cohort of 121 patients treated by RC alone was used for comparison. Pathologic response and cancer-specific survival (CSS) were compared. We created the Johns Hopkins Hospital Dose Index to characterize chemotherapeutic dosing regimens and accurately assess sufficient neoadjuvant dosing regarding patient tolerance. RESULTS: No significant difference was noted in 5-year CSS between GC NAC (58%) and non-NAC cohorts (61%). The median follow-up was 19.6 months (GC NAC) and 106.5 months (non-NAC). Patients with residual non-muscle-invasive disease after GC NAC exhibit similar 5-year CSS relative to patients with no residual carcinoma (P = 0.99). NAC pR (≤ pT1) demonstrated improved 5-year CSS rates (90.6% vs. 27.1%, P < 0.01) and decreased nodal positivity rates (0% vs. 41.3%, P<0.01) when compared with nonresponders (≥ pT2). Clinicopathologic outcomes were inferior in NAC pathologic nonresponders when compared with the entire RC-only-treated cohort. A lower pathologic nonresponder rate was seen in patients tolerating sufficient dosing of NAC as stratified by the Johns Hopkins Hospital Dose Index (P = 0.049), congruent with the National Comprehensive Cancer Network guidelines. A multivariate classification tree model demonstrated 60 years of age or younger and clinical stage cT2 as significant of NAC response (P< 0.05). CONCLUSIONS: Pathologic nonresponders fare worse than patients proceeding directly to RC alone do. Multiple predictive models incorporating clinical, histopathologic, and molecular features are currently being developed to identify patients who are most likely to benefit from GC NAC.