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INTRODUCTION AND OBJECTIVE:(I) To evaluate clinical efficacy of three different BCG strains in patients with intermediate/high-risk non-muscle invasive bladder cancer (NMIBC). (II) To determine the...

INTRODUCTION AND OBJECTIVES:The advantage of health-related quality of life (HRQoL) in continent (C) urinary diversions (UD) over non-continent (NC) UD remains controversial. We compared outcomes b...

INTRODUCTION AND OBJECTIVES:Health-related quality of life (HRQoL) can be significantly affected following radical cystectomy (RC) and factors affecting it have not been well studied in this popula...

INTRODUCTION AND OBJECTIVES:NGS allows a comprehensive analysis of the genomic profile of rectal microbiota and, most importantly, the identification of resistance genes to the standard antibacteri...

Clinical staging in patients with muscle invasive bladder cancer misses up to 25% of lymph node metastasis. These patients are at high risk for disease recurrence and improved clinical staging is critical to guide management.Whole transcriptome expression profiles were generated in 199 patients who underwent radical cystectomy and extended pelvic lymph node dissection. The cohort was divided randomly into a discovery set of 133 patients and a validation set of 66. In the discovery set features were identified and modeled in a KNN51 (K-nearest neighbor classifier 51) to predict pathological lymph node metastases. Two previously described bladder cancer gene signatures, including RF15 (15-gene cancer recurrence signature) and LN20 (20-gene lymph node signature), were also modeled in the discovery set for comparison. The AUC and the OR were used to compare the performance of these signatures.In the validation set KNN51 achieved an AUC of 0.82 (range 0.71-0.93) to predict lymph node positive cases. It significantly outperformed RF15 and LN20, which had an AUC of 0.62 (range 0.47-0.76) and 0.46 (range 0.32-0.60), respectively. Only KNN51 showed significant odds of predicting LN metastasis with an OR of 2.65 (range 1.68-4.67) for every 10% increase in score (p0.001). RF15 and LN20 had a nonsignificant OR of 1.21 (range 0.97-1.54) and 1.39 (range 0.52-3.77), respectively.The new KNN51 signature was superior to previously described gene signatures for predicting lymph node metastasis. If validated prospectively in transurethral resection of bladder tumor samples, KNN51 could be used to guide patients at high risk to early multimodal therapy.

Due to the high recurrence risk of nonmuscle invasive urothelial carcinoma it is crucial to distinguish patients at high risk from those with indolent disease. In this study we used a machine learning algorithm to identify the genes in patients with nonmuscle invasive urothelial carcinoma at initial presentation that were most predictive of recurrence. We used the genes in a molecular signature to predict recurrence risk within 5 years after transurethral resection of bladder tumor.Whole genome profiling was performed on 112 frozen nonmuscle invasive urothelial carcinoma specimens obtained at first presentation on Human WG-6 BeadChips (Illumina®). A genetic programming algorithm was applied to evolve classifier mathematical models for outcome prediction. Cross-validation based resampling and gene use frequencies were used to identify the most prognostic genes, which were combined into rules used in a voting algorithm to predict the sample target class. Key genes were validated by quantitative polymerase chain reaction.The classifier set included 21 genes that predicted recurrence. Quantitative polymerase chain reaction was done for these genes in a subset of 100 patients. A 5-gene combined rule incorporating a voting algorithm yielded 77% sensitivity and 85% specificity to predict recurrence in the training set, and 69% and 62%, respectively, in the test set. A singular 3-gene rule was constructed that predicted recurrence with 80% sensitivity and 90% specificity in the training set, and 71% and 67%, respectively, in the test set.Using primary nonmuscle invasive urothelial carcinoma from initial occurrences genetic programming identified transcripts in reproducible fashion, which were predictive of recurrence. These findings could potentially impact nonmuscle invasive urothelial carcinoma management.

Transitional cell carcinoma (TCC) of the bladder that extends directly into contiguous organs (pT4) portends a poor prognosis. The 2002 American Joint Committee on Cancer staging system does not include seminal vesicle involvement by primary TCC of the bladder. In this analysis we evaluated the clinical outcomes and prognostic significance of seminal vesicle involvement with TCC of the bladder after radical cystectomy.From 1971 to 2001, 1,682 patients underwent radical cystectomy and pelvic lymphadenectomy for bladder cancer. Only those tumors that involved adjacent organs through the bladder wall (pT4) were included. Overall 132 male patients with a median age of 68 years (range 36 to 98) qualified for analysis. Patients were stratified into 4 subgroups of 1) direct extravesical prostatic stromal involvement only in 37 patients (28%), 2) prostatic stroma and seminal vesicle involvement in 37 patients (28%), 3) seminal vesicle involvement only in 10 patients (8%) and 4) other contiguous pelvic organ involvement (stage pT4b) in 48 patients (36%). Overall 88 patients (67%) received some form of adjuvant therapy. At a median followup of 12.5 years (range 0 to 15.2) clinical outcomes were analyzed including overall and recurrence-free survival using Kaplan-Meier plots.There was no significant difference in clinical outcomes or prognosis for groups 2 and 3, thus they were combined for analysis. Five-year overall survival for any seminal vesicle involvement (10%) was significantly worse than prostatic stromal involvement only (38%) but was similar to pT4b tumors (7%, p0.0001). The 5-year recurrence-free survival for seminal vesicle involvement (14%) was also significantly worse than prostatic stromal involvement alone (68%) but similar to that pT4b disease (25%, p = 0.01). Results were controlled for lymph node status.Patients with extravesical tumor extension into seminal vesicles and contiguous pelvic organs are at high risk for recurrence and progression. Involvement of the seminal vesicles by direct extension of bladder TCC portends a prognosis similar to that of pT4b disease and should, therefore, be classified as such.

Prior phase II studies of intravesical gemcitabine have shown it to be active and well tolerated, but durable responses in patients with nonmuscle invasive bladder cancer who have experienced recurrence after bacillus Calmette-Guérin treatment are uncommon. We performed a multi-institutional phase II study within the SWOG (Southwest Oncology Group) cooperative group to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting.Eligible patients had recurrent nonmuscle invasive bladder cancer, stage Tis (carcinoma in situ), T1, Ta high grade or multifocal Ta low grade after at least 2 prior courses of bacillus Calmette-Guérin. Patients were treated with 2 gm gemcitabine in 100 cc normal saline intravesically weekly × 6 and then monthly to 12 months. Cystoscopy and cytology were performed every 3 months, with biopsy at 3 months and then as clinically indicated. Initial complete response was defined as negative cystoscopy, cytology and biopsy at 3 months.A total of 58 patients were enrolled in the study and 47 were evaluable for response. Median patient age was 70 years (range 50 to 88). Of the evaluable patients 42 (89%) had high risk disease, including high grade Ta in 12 (26%), high grade T1 in 2 (4%) and carcinoma in situ in 28 (60%) with or without papillary lesions. At the initial 3-month evaluation 47% of patients were free of disease. At 1 year disease had not recurred in 28% of the 47 patients, all except 2 from the high risk group, and at 2 years disease had not recurred in 21%.Intravesical gemcitabine has activity in high risk nonmuscle invasive bladder cancer and offers an option for patients with recurrence after bacillus Calmette-Guérin who are not suitable for cystectomy. However, less than 30% of patients had a durable response at 12 months even with maintenance therapy.

Orthotopic neobladder reconstruction is the preferred method of urinary diversion after radical cystoprostatectomy. We evaluated urinary functional outcomes in male patients after orthotopic neobladder using a patient questionnaire.Between 2002 and 2009 patients with bladder cancer were enrolled in a clinical trial, randomly assigned to undergo T pouch or Studer pouch diversion after radical cystoprostatectomy. Male patients were mailed a questionnaire 12 or more months after surgery including items on urinary function, intermittent catheterization, number/size/wetness of pads and mucus leakage.The questionnaire response rate was 68%. Mean followup was 4.5 years (range 1 to 8). Only 22.3% of patients did not use pads. In the daytime 47% of patients used at least 1 pad, 32.2% used small/mini pads and 22.6% used diapers. At night 72% used pads, 14.7% used small/mini pads and 38.9% used diapers. During the day and night 47% said their pads were dry/barely wet. Overall 62.5% of patients reported mucus leakage. Only 9.5% of patients performed clean intermittent self-catheterization, of whom 70.6% started clean intermittent self-catheterization within the first year after surgery. Increasing age and diabetes mellitus were predictors of urinary function (p = 0.005 and 0.03, respectively) but did not affect pad use.Ileal orthotopic neobladder offers good functional results but most patients wear at least 1 pad and many require diapers at night. Increasing age and diabetes mellitus predict worse urinary function but are not associated with pad use. Emptying failure is uncommon and occurs early in the postoperative period. Pad size/wetness and mucus leakage should be considered when evaluating urinary incontinence.

Patients with pathological T3N0 stage urothelial carcinoma of the bladder show a range of outcomes after radical cystectomy. Given that nomograms have included heterogeneous groups of patients, we focused on and stratified patients with pT3N0 urothelial carcinoma of the bladder after radical cystectomy into prognostically different risk groups to facilitate the development of adjuvant therapy trials for those at high risk.The study comprised a total of 578 patients from 9 centers worldwide with pT3N0 urothelial carcinoma of the bladder who underwent radical cystectomy without perioperative chemotherapy. We evaluated the effect of pT3 substage at radical cystectomy, age, grade, lymphovascular invasion, margin status and number of lymph nodes removed on recurrence-free survival using Cox regression analysis. A weighted prognostic model was devised.Median followup was 39.4 months (IQR 64). On multivariate analysis pT3 substage at radical cystectomy (pT3b vs pT3a HR 2.056, p0.0001), lymphovascular invasion (positive vs negative HR 2.004, p0.0001) and margin status (positive vs negative HR 2.503, p = 0.002) were associated with recurrence-free survival (concordance index 0.66) in the context of generally adequate lymph node dissection, that is with a median of 17 removed. Three risk groups were devised based on weighted variables with a 5-year recurrence-free survival rate of 79% (95% CI 70-84), 57% (95% CI 50-64) and 37% (95% CI 26-48) in the low, intermediate and high risk groups, respectively.We constructed a user friendly prognostic risk model for patients with pT3N0 urothelial carcinoma of the bladder treated with radical cystectomy based on pT3 substage at radical cystectomy, lymphovascular invasion and margin status. These data warrant validation and may enable tailored monitoring and selection of appropriate patients for adjuvant therapy trials.

Purpose: Radical cystectomy for bladder cancer is associated with many changes in bodily function with sexual and urinary dysfunction most prevalent. However, little research has been done on how efforts to improve erectile function relate to quality of life. Also, the psychological benefits associated with continent urinary diversion have not been fully explored. We compared long-term quality of life outcomes among 3 urinary diversion groups, and between patients who had and had not received an inflatable penile prosthesis.Materials and Methods: The 224 participating patients completed 4 self-reporting questionnaires, including the profile of mood states, and adapted versions of the sexual history form, body image dissatisfaction scale and quality of life questionnaire. We compared self-reports of emotional distress, global quality of life, sexuality, body image dissatisfaction, urinary diversion problems, and problems with social, physical and functional activities in patients with advanced blad...

We assessed the prognostic value of pT3 bladder urothelial carcinoma substaging.We reviewed the records of 2,605 patients treated with radical cystectomy for bladder urothelial carcinoma at 6 international centers, of whom 808 (31.0%) had pT3 disease. No patient received systemic chemotherapy or radiotherapy preoperatively. Median followup was 45 months in survivors at last followup.Median patient age was 68 years. Stage was pT3a in 310 patients (38.4%) and pT3b in 498 (61.6%). Of the patients 352 (43.6%) had metastasis to regional lymph nodes. Five-year recurrence-free (43.8% and 41.4%) and cancer specific (48.6% and 46.8%) survival estimates were similar in pT3a and pT3b cases (p = 0.277 and 0.625, respectively). Conversely in patients with pathologically negative lymph nodes pT3b substaging was associated with worse 5-year recurrence-free (60.7% vs 47.9%) and cancer specific (64.4% vs 55.0%) survival (p = 0.020 vs 0.048).Macroscopic perivesical fat extension (pT3b) is associated with a worse outcome than pT3a disease in lymph node negative cases of bladder urothelial carcinoma. Together with other features pT3 substaging may help identify patients with pT3 who could benefit from adjuvant chemotherapy.

Purpose: We evaluated the association of soft tissue surgical margins with characteristics and outcomes of patients treated with radical cystectomy for urothelial carcinoma of the bladder.Materials and Methods: We retrospectively collected the data of 4,410 patients treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant chemotherapy at 12 academic centers in the United States, Canada and Europe. A positive soft tissue surgical margin was defined as presence of tumor at inked areas of soft tissue on the radical cystectomy specimen.Results: Positive soft tissue surgical margins were identified in 278 patients (6.3%). On univariate analysis positive soft tissue surgical margin was significantly associated with advanced pT stage, higher tumor grade, lymphovascular invasion and lymph node metastasis (p

Lymph node metastasis in patients who undergo radical cystectomy for bladder transitional cell carcinoma is considered a poor prognostic factor. However, patients with minimal lymph node involvement likely have a better outcome than those with extensive disease. We examined outcomes in patients with low volume lymph node metastasis and identified variables associated with disease recurrence.Our institution maintains a database of 1,600 patients with bladder transitional carcinoma who underwent radical cystectomy from 1971 to 2005 with intent to cure. All patients with low volume lymph node metastasis, defined as 1 or 2 positive lymph nodes, without concomitant distant metastasis were included in study.A total of 181 patients were identified. Median followup was 12.8 years, during which 96 patients experienced recurrence. Estimated 5 and 10-year recurrence-free survival was 43.8% and 40.9%, respectively. Multivariate analysis indicated that pathological stage/subgroup (RR 1.733, p = 0.015), lymph node density (RR 1.935, p = 0.014) and adjuvant chemotherapy (RR 0.538, p = 0.004) were significant independent predictors of recurrence-free survival.A considerable proportion of patients with low volume lymph node metastasis in our cohort remained free of recurrence during followup. Extravesical tumor extension and lymph node density greater than 4% were associated with a higher recurrence risk and adjuvant chemotherapy was associated with a lower risk. Although some patients with low volume lymph node metastasis may be cured by surgery alone, these data support adjuvant chemotherapy in these patients.

Purpose: Salvage surgery followed by lower urinary tract reconstruction is a viable therapeutic option for patients in whom definitive radiation therapy for localized bladder or prostate cancer has failed. Improvements in surgical technique and postoperative care have significantly improved overall outcome. An enhanced understanding of the rhabdoid sphincteric mechanism responsible for maintaining urinary continence following cystoprostatectomy has helped make the orthotopic neobladder the procedure of choice for patients requiring lower urinary tract reconstruction. We describe our experience with salvage surgery and orthotopic bladder substitution following failed radical radiation therapy.Materials and Methods: We evaluated the complications of 18 patients in whom definitive radiation therapy (total minimum dose 60 Gy. or greater) for bladder or prostate cancer had failed. All patients underwent a salvage procedure with creation of an orthotopic neobladder.Results: Operative characteristics, po...

INTRODUCTION AND OBJECTIVES: Despite optimal imaging, occult lymph node (LN) metastases are found in 25% of patients with muscle invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). These patients are at high risk for subsequent disease recurrence and death. Better prediction of LN metastases is warranted to improve patient management. METHODS: Transcriptome expression profiles of 199 RC samples were generated using a 1.4 million feature Human Exon microarray. All patients underwent RC and extended pelvic LN dissection (1998-2004) at the University of Southern California. The patient cohort was divided into a discovery set (n1⁄4133) and a validation set (n1⁄466). In the discovery set, features were identified using a Wilcoxon test and modeled into a K-nearest neighbor (KNN) classifier for LN metastases prediction. Two additional gene signatures, the 15 gene cancer recurrence signature (Mitra2014) and 20 gene LN signature (Smith2011) were also modeled in the discovery set for comparison. Area under the curve (AUC) and odds ratios (OR) were used to compare the performance of these signatures in the validation set. RESULTS: The KNN51 model was developed from 133 radical cystectomy patients to predict LN metastases. In the validation set, this model achieved an AUC of 0.82 [0.71 e 0.93] for predicting LN positive patients, significantly outperforming Mitra2014 and Smith2011 which had AUCs of 0.62 [0.47 e 0.76] and 0.46 [0.32 e 0.60], respectively. Only KNN51hadsignificantodds for predictingLNmetastasiswith anORof2.65 [1.68 4.67] for every 10% increase in score (p1⁄4 0.0002). Both Mitra2011 and Smith2011 were not found to have significant odds ratios of 1.21 [0.97 e 1.54, p 1⁄4 0.09] and 1.39 [0.52 e 3.77, p 1⁄4 0.5], respectively. CONCLUSIONS: The integrated expression of 51 genes in primary MIBC was successfully used to predict LN metastases and was superior to previously described gene signatures. If validated in TURBT samples, KNN51 could be used to guide the extent of pelvic LN dissection and to direct high risk patients towards treatment intensification, for example with neoadjuvant chemotherapy.