Impact of obesity on male urethral sling outcomes.

BACKGROUND: The impact of obesity on AdVance male urethral sling outcomes has been poorly evaluated. Anecdotally, male urethral sling placement can be more challenging due to body habitus in obese patients. The objective of this study was to evaluate the impact of obesity on surgical complexity using operative time as a surrogate and secondarily to evaluate the impact on postoperative pad use. METHODS: A retrospective cohort analysis was performed using all men who underwent AdVance male urethral sling placement at a single institution between 2013 and 2019. Descriptive statistics comparing obese and non-obese patients were performed. RESULTS: A total of 62 patients were identified with median (IQR) follow up of 14 (4-33) months. Of these, 40 were non-obese and 22 (35.5%) were obese. When excluding patients who underwent concurrent surgery, the mean operative times for the non-obese versus obese cohorts were 61.8 min versus 73.7 min (p = 0.020). No Clavien 3-5 grade complications were noted. At follow up, 47.5% of the non-obese cohort and 63.6% of the obese cohort reported using one or more pads daily (p = 0.290). Four of the five patients with a history of radiation were among the patients wearing pads following male urethral sling placement. CONCLUSION: Obese men undergoing AdVance male urethral sling placement required increased operative time, potentially related to operative complexity, and a higher proportion of obese compared with non-obese patients required postoperative pads for continued urinary incontinence. Further research is required to better delineate the full impact of obesity on male urethral sling outcomes.

Robotic and open partial nephrectomy for intermediate and high complexity tumors: a matched-pairs comparison of surgical outcomes at a single institution.

Objective: To compare peri-operative factors and renal function following open partial nephrectomy (OPN) and robotic partial nephrectomy (RPN) for intermediate and high complexity tumors when controlling for tumor and patient complexity.Methods: A retrospective review of 222 patients undergoing partial nephrectomy was performed. Patients with intermediate (nephrometry score NS 7-9) or high (NS 10-12) complexity tumors were matched 2:1 for RPN:OPN using NS, Charlson Comorbidity Index (CCI), and BMI. Patient demographics, peri-operative values, renal function, and complication rates were analyzed and compared.Results: Seventy-four OPN patients were matched to 148 RPN patients with no difference in patient demographics. Estimated blood loss in OPN patients was significantly higher (368.5 vs 210.5 mL, p < 0.001) as was transfusion rate (17% vs 1.6%, p < 0.001). Warm ischemia time was longer in OPN (25.5 vs 19.7 min, p = 0.001) while operative time was reduced (200.5 vs 226.5 min, p = 0.010). RPN patients had significantly shorter hospitalizations (5.3 vs 3.0 days, p < 0.001). GFR decrease after one month was not statistically significant (12.9 vs 6.6 ml/min, p = 0.130). Clavien III-V complications incidence was higher for OPN compared to RPN although not significantly (20.3% vs 10.8%, p = 0.055).Conclusion: When matching for tumor and patient complexity, RPN patients had fewer high grade post-operative complications, decreased blood loss, and shorter hospitalizations. RPN is a safe option for patients with intermediate and high complexity tumors.

Assessing Cost of Robotic Utilization in Partial Nephrectomy with Increasing Utilization.

PURPOSE: To evaluate trends in utilization of robotic assistance in partial nephrectomy (PN) and assess the association between cost and utilization. PATIENTS AND METHODS: Using the 2009-2012 Nationwide Inpatient Sample database, we identified all adult (>17 years) patients undergoing PN for localized primary renal malignancy. Coding for robotic assistance (17.4 × ) began in the final quarter of 2008. The primary outcome was total hospital cost exclusive of physician fees. A multiple linear regression model was used to adjust for patient and hospital characteristics. RESULTS: Between 2009 and 2012, there were 32,664 (58%) open, 3498 (6%) laparoscopic, and 20,350 (36%) robot-assisted partial nephrectomies performed in the United States. Between 2009 and 2012, the total number of partial nephrectomies semiannually increased by 93% (5114-9845) with robotic partial nephrectomies (RPNs) representing >80% of the increase. RPN increased from 1029 cases in the first half of 2009 to 4840 in the last half of 2012 and surpassed utilization of open nephrectomy. The proportion of all partial nephrectomies performed with robotic assistance increased from 20% to 49% during the same period. After adjusting for demographics, Charlson comorbidity index, and hospital region, RPN went from $1,464 (p = 0.009) more than open in 2009 to $456 (p = 0.28) less than open in 2012. CONCLUSIONS: Utilization of RPN surpassed open in 2012 in the United States. The difference in cost between the robotic and open approaches decreased during the study period and by 2011 was not statistically different.

Müllerian Adenosarcoma of the Urinary Bladder: Clinicopathologic and Immunohistochemical Features With Novel Genetic Aberrations.

BACKGROUND: Müllerian adenosarcoma is a biphasic neoplasm most commonly occurring in the uterus and less frequently of the ovary. It has been rarely described to occur in other sites such as peritoneum and liver. PATIENTS AND METHODS: In this study, we report the clinicopathologic, immunohistochemical and molecular features of a primary Müllerian adenosarcoma of the urinary bladder in a 62-year-old woman. To our knowledge, this is the first report of detailed pathologic characterization of Müllerian adenosarcoma primary to the urinary bladder in the literature. RESULTS: Light microscopy showed a biphasic epithelial and stromal tumor with benign-appearing glands surrounded by densely cellular endometrial-type stroma that is densely cellular with increased mitotic figures. The stroma surrounding the glands was more cellular than the intervening areas, which were more loose and edematous. Immunohistochemistry staining revealed positive staining for Pax-2/8 within the glands, for positive CD10 and WT-1 within the spindle cell stroma, and for estrogen and progesterone receptors in both. Staining for desmin, GATA3, p63, and human papillomavirus was negative. Molecular analyses identified mutations in protein kinase B E17K, fms related tyrosine kinase 3 D835N, KRAS proto-oncogene, GTPase G12D, and HRAS proto-oncogene, GTPase G12S. These novel molecular aberrations have yet to be reported in the medical literature. X chromosome inactivation analysis revealed a clonal pattern in the stromal component and a nonclonal pattern in the epithelial component. Currently, the patient is disease/recurrence-free after regular follow-up of approximately 84 months. CONCLUSION: This case represents, to our knowledge, the first reported diagnosis of Müllerian adenosarcoma arising in the urinary bladder with extensive clinicopathologic, immunohistochemical, and molecular analyses.

Preoperative Nomograms for Predicting Renal Function at 1 Year After Partial Nephrectomy.

INTRODUCTION: Partial nephrectomy (PN) reduces the risk of postoperative chronic renal insufficiency (CRI). However, some patients still develop CRI after PN, and may eventually require dialysis. Being able to predict renal function before PN helps in counseling patients and managing expectations. We aimed to construct nomograms that predict estimated glomerular filtration rates (eGFRs), defined by the modification of diet in renal disease (MDRD) and the chronic kidney disease epidemiology collaboration (CKD-EPI) formulae, at 1 year after PN, using only preoperative covariates as predictors. PATIENTS AND METHODS: We identified patients who underwent PN in our institution between 2004 and 2016, with known postoperative serum creatinine levels at 1 year. The preoperative covariates included patients' demographics, chronic comorbid conditions, tumor characteristics, and preoperative renal status. The endpoints were eGFRs at 1 year after PN, calculated using the MDRD and the CKD-EPI formulae. We first identified preoperative covariates with significant associations with the endpoints by Pearson correlation and independent samples t-test. Suitable covariates were then included in two multivariate linear regression models, for constructing and internally validating two nomograms. RESULTS: 461 patients were eligible for analysis. The percentage of patients with eGFR below 60 mL/min/1.73 m2 increased from 25% before PN to 35% at 1 year after PN. We included age, gender, African American race, body mass index, preoperative creatinine level, ipsilateral renal volume, solitary kidney status, tumor diameter, hypertension, diabetes, ischemic heart disease, and previous stroke in the multivariate linear regression models for nomogram construction. Internal validation showed bootstrap-corrected coefficients of determination of 0.61 and 0.70, for predicting eGFRs defined by the MDRD and CKD-EPI formulae, respectively. CONCLUSIONS: We constructed and internally validated two nomograms to predict eGFRs at 1 year after PN, using only preoperative covariates as predictors.

Prognostic Effect of Carcinoma In Situ in Muscle-invasive Urothelial Carcinoma Patients Receiving Neoadjuvant Chemotherapy.

BACKGROUND: Carcinoma in situ (CIS) is a poor prognostic finding in urothelial carcinoma. However, its significance in muscle-invasive urothelial carcinoma (MIUC) treated with neoadjuvant chemotherapy (NAC) is uncertain. We assessed the effect of CIS found in pretreatment transurethral resection of bladder tumor (TURBT) biopsies on the pathologic and clinical outcomes. MATERIALS AND METHODS: Subjects with MIUC treated with NAC before cystectomy were identified. The pathologic complete response (pCR) rates stratified by TURBT CIS status were compared. The secondary analyses included tumor response, progression-free survival (PFS), overall survival (OS), and an exploratory post hoc analysis of patients with pathologic CIS only (pTisN0) at cystectomy. RESULTS: A total of 137 patients with MIUC were identified. TURBT CIS was noted in 30.7% of the patients. The absence of TURBT CIS was associated with a significantly increased pCR rate (23.2% vs. 9.5%; odds ratio, 4.08; 95% confidence interval, 1.19-13.98; P = .025). Stage pTisN0 disease was observed in 19.0% of the TURBT CIS patients. TURBT CIS status did not significantly affect the PFS or OS outcomes. Post hoc analysis of the pTisN0 patients revealed prolonged median PFS (104.5 vs. 139.9 months; P = .055) and OS (104.5 vs. 152.3 months; P = .091) outcomes similar to those for the pCR patients. CONCLUSION: The absence of CIS on pretreatment TURBT in patients with MIUC undergoing NAC was associated with increased pCR rates, with no observed differences in PFS or OS. Isolated CIS at cystectomy was frequently observed, with lengthy PFS and OS durations similar to those for pCR patients. Further studies aimed at understanding the biology and clinical effect of CIS in MIUC are warranted.

A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157.

Purpose: To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant, molecularly enriched non-muscle-invasive urothelial carcinoma of the bladder (NMIUC) population.Experimental Design: A multi-site pilot phase II trial was conducted. Key eligibility criteria included the following: Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC (>2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory. Patients received oral dovitinib 500 mg daily (5 days on/2 days off). The primary endpoint was 6-month TURBT-confirmed complete response (CR) rate.Results: Between 11/2013 and 10/2014, 13 patients enrolled (10 IHC+ Mut-, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included the following: median age 70 years; 85% male; carcinoma in situ (CIS; 3 patients), Ta/T1 (8 patients), and Ta/T1 + CIS (2 patients); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3-4 event. Six-month CR rate was 8% (0% in IHC+ Mut-; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94-5,812 nmol/L) dovitinib concentrations in urothelial tissue were observed in all evaluable patients. Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment.Conclusions: Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition. These results support systemic administration as a viable approach to clinical trials in patients with NMIUC. Long-term dovitinib administration was not feasible due to frequent toxicity. Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma. Clin Cancer Res; 23(12); 3003-11. ©2016 AACR.

A Parallel Randomized Clinical Trial Examining the Return of Urinary Continence after Robot-Assisted Radical Prostatectomy with or without a Small Intestinal Submucosa Bladder Neck Sling.

PURPOSE: Urinary continence is a driver of quality of life after radical prostatectomy. In this study we evaluated the impact of a biological bladder neck sling on the return of urinary continence after robot-assisted radical prostatectomy. MATERIALS AND METHODS: This study compared early continence in patients undergoing robot-assisted radical prostatectomy with a sling and without a sling in a 2-group, 1:1, parallel, randomized controlled trial. Patients were blinded to group assignment. The primary outcome was defined as urinary continence (0 to 1 pad per day) at 1 month postoperatively. Inclusion criteria were organ confined prostate cancer and a prostate specific antigen less than 15 ng/ml. Exclusion criteria were any prior surgery on the prostate, a history of neurogenic bladder and history of pelvic radiation. A chi-squared test was used for the primary outcome. RESULTS: A total of 147 patients were randomized (control 74, sling 73) and 92% were available for primary end point analysis at 1 month. There were no significant differences in baseline or perioperative data except that operating room time was 20.1 minutes longer for the sling group (p=0.04). The continence rate was similar between the control and sling groups at 1 month (47.1% vs 55.2%, p=0.34) and 12 months (86.7% vs 94.5%, p=0.15), respectively. Adverse events were similar between the control and sling groups (10.8% vs 13.7%, p=0.59). CONCLUSIONS: The application of an absorbable urethral sling at robot-assisted radical prostatectomy was well tolerated with no increase in obstructive symptoms in this randomized trial. However, the sling failed to show a significant improvement in continence.

Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity.

OBJECTIVES: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC). MATERIALS AND METHODS: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test. RESULTS: The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had

Risk for Clostridium difficile infection after radical cystectomy for bladder cancer: Analysis of a contemporary series.

INTRODUCTION: This study seeks to evaluate the incidence and associated risk factors of Clostridium difficile infection (CDI) in patients undergoing radical cystectomy (RC) for bladder cancer. METHODS: We retrospectively reviewed a single institution׳s bladder cancer database including all patients who underwent RC between 2010 and 2013. CDI was diagnosed by detection of Clostridium difficile toxin B gene using polymerase chain reaction-based stool assay in patients with clinically significant diarrhea within 90 days of the index operation. A multivariable logistic regression model was used to identify demographics and perioperative factors associated with developing CDI. RESULTS: Of the 552 patients who underwent RC, postoperative CDI occurred in 49 patients (8.8%) with a median time to diagnosis after RC of 7 days (interquartile range: 5-19). Of the 122 readmissions for postoperative complications, 10% (n = 12) were related to CDI; 2 patients died of sepsis directly related to severe CDI. On multivariate logistic regression, the use of chronic antacid therapy (odds ratio = 1.9, 95% CI: 1.02-3.68, P = 0.04) and antibiotic exposure greater than 7 days (odds ratio = 2.2, 95% CI: 1.11-4.44, P = 0.02) were independently associated with developing CDI. The use of preoperative antibiotics for positive findings on urine culture within 30 days before surgery was not statistically significantly associated with development of CDI (P = 0.06). CONCLUSIONS: The development of CDI occurs in 8.8% of patients undergoing RC. Our study demonstrates that use of chronic antacid therapy and long duration of antimicrobial exposure are associated with development of CDI. Efforts focusing on minimizing antibiotic exposure in patients undergoing RC are needed, and perioperative antimicrobial prophylaxis guidelines should be followed.

A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: This phase II open-label study evaluated the effect of concurrent or sequential administration of abiraterone acetate plus prednisone (AA + P) on sipuleucel-T manufacture and immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients. EXPERIMENTAL DESIGN: mCRPC patients received sipuleucel-T followed by AA + P 1 day (concurrent) or 10 weeks (sequential) after the first sipuleucel-T infusion. AA + P treatment continued for 26 weeks. The primary endpoint was cumulative antigen presenting cell (APC) activation, and secondary endpoints included cumulative APC number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) as well as safety. RESULTS: Sixty-nine mCRPC patients were enrolled, with 35 and 34 patients randomized to the concurrent and sequential arms, respectively. Ex vivo APC activation was significantly greater at the second and third infusions compared with baseline in both arms (P < 0.05), indicative of an immunologic prime-boost effect. In both arms, sipuleucel-T product parameter profiles and peripheral immune responses were consistent with previously conducted sipuleucel-T phase III trials. Antigen spread was similarly observed in both arms and consistent with the other immunologic endpoints. CONCLUSIONS: These data suggest that sipuleucel-T can be successfully manufactured during concurrent administration of AA + P without blunting immunologic effects or altering immune parameters that correlate with sipuleucel-T's clinical benefit. Combination of these agents was well tolerated, with no new safety signals emerging.

Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome.

PURPOSE: Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen). EXPERIMENTAL DESIGN: Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n = 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels. RESULTS: In patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P < 0.01), but not control. IgG responses (≥ 2-fold elevation posttreatment) occurred in ≥ 25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T-treated patients from IMPACT (P ≤ 0.05). CONCLUSIONS: Sipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies. See related commentary by Hellstrom and Hellstrom, p. 3581.

National Trends in the Performance of Robot-Assisted Sacral Colpopexy.

PURPOSE: Robot-assisted sacral colpopexy (RASC) utilization trends and influencing factors were examined. RASCs were compared with nonrobotic vaginal suspension procedures (non-RASC) used to treat patients with vaginal prolapse. Hospital costs associated with each approach were also examined. The presence of certain factors may predict increased use of RASC. METHODS: The National (Nationwide) Inpatient Sample database was queried from 2009 to 2011 to identify patients undergoing RASC and non-RASC. Multivariable logistic regression was used to evaluate variables associated with RASC utilization, adjusting for age, comorbidities, concurrent procedures, hospital region, primary payer, and year. Multiple linear regression was used to evaluate variables associated with hospital costs when adjusting for operative approach, concurrent procedures, comorbidities, presence of complications, hospital region, and year. RESULTS: Of the 125,869 patients who underwent vaginal vault suspension of any type, 14,601 (12%) were RASC. Total in-hospital complication rates were similar between RASC and non-RASC (8% RASC, 7% non-RASC, P=0.360). The proportion of patients undergoing RASC increased throughout the study period (odds ratio [OR] 1.58, P<0.001), with this increase being most pronounced in the South (OR 2.22, P<0.001). Fifty-four percent of RASC patients vs 48% of non-RASC patients underwent concurrent hysterectomy (P=0.007). Patients with private insurance (OR 1.73, P=0.001) or Medicare (OR 1.43, P=0.033) as their primary payer were at significantly increased odds of RASC compared with Medicaid patients, and private insurance was associated with increased reimbursement. On multiple linear regression, RASC was independently associated with a $4825 increase in hospital costs (95% confidence interval $4161-$5490, P<0.001). There were independent regional differences in cost associated with vaginal suspension, with the West being the most expensive (P<0.001). CONCLUSION: While RASC utilization increased over the study period as a treatment option for vaginal prolapse, the majority of vaginal suspension procedures were still performed via non-RASC methods. RASC was associated with equivalent complications yet significantly higher costs.

Robotic management of genitourinary injuries from obstetric and gynaecological operations: a multi-institutional report of outcomes.

OBJECTIVE: To evaluate the utility of robotic repair of injuries to the ureter or bladder from obstetrical and gynaecological (OBGYN) surgery PATIENTS AND METHODS: A retrospective review of all patients from four different high-volume institutions between 2002 and 2013 that had a robot-assisted (RA) repair by a urologist after an OBGYN genitourinary injury. RESULTS: Of the 43 OBGYN operations, 34 were hysterectomies: 10 open, 10 RA, nine vaginally, and five pure laparoscopic. Nine patients had alternative OBGYN operations: three caesarean sections, three oophorectomies (one open, two laparoscopic), one RA colpopexy, one open pelvic cervical cerclage with mesh and one RA removal of an invasive endometrioma. In all, 49 genitourinary (GU) injuries were sustained: ureteric ligation (26), ureterovaginal fistula (10), ureterocutaneous fistula (one), vesicovaginal fistula (VVF; 10) and cystotomy alone (two). In all, 10 patients (23.3%) underwent immediate urological repair at the time of their OBGYN RA surgery. The mean (range) time between OBGYN injury and definitive delayed repair was 23.5 (1-297) months. Four patients had undergone prior failed repair: two open VVF repairs and two balloon ureteric dilatations with stent placement. In all, 22 ureteric re-implants (11 with ipsilateral psoas hitch) and 15 uretero-ureterostomies were performed. Stents were placed in all ureteric cases for a mean (range) of 32 (1-63) days. In all, 10 VVF repairs and two primary cystotomy closures were performed. Drains were placed in 28 cases (57.1%) for a mean (range) of 4.1 (1-26) days. No case required open conversion. Two patients (4.1%) developed ureteric obstruction after RA repair requiring dilatation and stenting. The mean (range) follow-up of the entire cohort was 16.6 (1-63) months. CONCLUSIONS: RA repair of GU injuries during OBGYN surgery is associated with good outcomes, appears safe and feasible, and can be used successfully immediately after injury recognition or as a salvage procedure after prior attempted repair. RA techniques may improve convalescence in a patient population where quick recovery is paramount.

The changing reality of urothelial bladder cancer: should non-squamous variant histology be managed as a distinct clinical entity?

OBJECTIVES: To assess the effect of non-squamous differentiation (non-SQD) variant histology on survival in muscle-invasive bladder urothelial cancer (UC). PATIENTS AND METHODS: A cohort of 411 radical cystectomy (RC) cases performed with curative intent for muscle-invasive primary UC was identified between 2008 and June 2013. Survival analysis was evaluated using Kaplan-Meier methodology comparing non-variant (NV) + SQD histology to non-SQD variant histology (non-SQD variants). Multivariable cox proportional hazards regression assessed all-cause and disease-specific mortality. RESULTS: Of the 411 RC cases, 77 (19%) had non-SQD variant histology. The median overall survival (OS) for non-SQD variant histology was 28 months, whereas the NV+SQD group had not reached the median OS at 74 months (log-rank test P < 0.001). After adjusting for sex, age, pathological stage, and any systemic chemotherapy, patients with non-SQD variant histology at RC had a 1.57-times increased adjusted risk of all-cause mortality (P = 0.027) and 1.69-times increased risk of disease-specific mortality (P = 0.030) compared with NV+SQD patients. CONCLUSIONS: While SQD behaves similarly to NV, non-SQD variant histology portends worse OS and disease-specific survival regardless of neoadjuvant or adjuvant chemotherapy and pathological stage. Non-SQD variants of UC could perhaps be considered a distinct clinical entity in UC with goals for developing new treatment algorithms through novel clinical trials.

A transient increase in eosinophils is associated with prolonged survival in men with metastatic castration-resistant prostate cancer who receive sipuleucel-T.

Sipuleucel-T is an autologous cellular immunotherapy used to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Traditional short-term indicators of clinical response commonly used with chemotherapy have not correlated with survival in patients treated with sipuleucel-T. This retrospective study aimed to evaluate laboratory parameters as possible early biomarkers associated with clinical benefit following sipuleucel-T treatment. Patients treated with sipuleucel-T from three randomized, controlled, phase III clinical trials in mCRPC were considered: IMPACT (NCT00065442; n = 512), D9901 (NCT00005947; n = 127), and D9902A (NCT01133704; n = 98). Patients from these trials were included in this study if their samples were analyzed by the central laboratory and if data were available from baseline and ≥ 1 posttreatment time point (n = 377). We found that sipuleucel-T treatment was associated with a transient increase in serum eosinophil count at week 6 that resolved by week 14 in 28% of patients (105 of 377). This eosinophil increase correlated with induced immune response, longer prostate cancer-specific survival [HR, 0.713; 95% confidence interval (CI), 0.525-0.970; P = 0.031], and a trend in overall survival (HR, 0.753; 95% CI, 0.563-1.008; P = 0.057). Median serum globulin protein levels also increased transiently, which was associated with antigen-specific antibody responses; however, this finding did not correlate with longer survival. We conclude that transient increases in eosinophils at week 6 may be a useful, objective, short-term indicator of global immune activation and survival benefit with sipuleucel-T in patients with mCRPC. This observation warrants prospective evaluation in future clinical trials.

Plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm?

OBJECTIVES: Plasmacytoid variant (PCV) urothelial cancer (UC) of the bladder is rare, with poor clinical outcomes. We sought to identify factors that may better inform expectations of tumor behavior and improve management options in patients with PCV UC. MATERIALS AND METHODS: A retrospective analysis of the Indiana University Bladder Cancer Database between January 2008 and June 2013 was performed comparing 30 patients with PCV UC at cystectomy to 278 patients with nonvariant (NV) UC at cystectomy who underwent surgery for muscle-invasive disease. Multivariable logistic regression was used to assess precystectomy variables associated with non-organ-confined disease at cystectomy and Cox regression analysis to assess variables associated with mortality. RESULTS: Patients with PCV UC who were diagnosed with a higher stage at cystectomy (73% pT3-4 vs. 40%, P = 0.001) were more likely to have lymph node involvement (70% vs. 25%, P<0.001), and positive surgical margins were found in 40% of patients with PCV UC vs. 10% of patients with NV UC (P<0.001). Median overall survival and disease-specific survival were 19 and 22 months for PCV, respectively. Median overall survival and disease-specific survival had not been reached for NV at 68 months (P<0.001). Presence of PCV UC on transurethral resection of bladder tumor was associated with non-organ-confined disease (odds ratio = 4.02; 95% CI: 1.06-15.22; P = 0.040), and PCV at cystectomy was associated with increased adjusted risk of mortality (hazard ratio = 2.1; 95% CI: 1.2-3.8; P = 0.016). CONCLUSIONS: PCV is an aggressive UC variant, predicting non-organ-confined disease and poor survival. Differentiating between non-muscle- and muscle-invasive disease in patients with PCV UC seems less important than the aggressive nature of this disease. Instead, any evidence of PCV on transurethral resection of bladder tumor may warrant aggressive therapy.