A phase 2 trial of buparlisib in patients with platinum-resistant metastatic urothelial carcinoma.

BACKGROUND: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the pan-isoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC. METHODS: Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors. The primary endpoint was the 2-month progression-free survival rate. A rate of ≥80% was considered promising using a Simon 2-stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome. RESULTS: Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA-activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment-related toxicities, 2 of whom had to discontinue therapy. CONCLUSIONS: Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform-selective PI3K inhibitors in genomically selected patients. LAY SUMMARY: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway frequently is upregulated in patients with metastatic urothelial carcinoma (UC). This trial explored buparlisib, an inhibitor of the pathway, in patients with heavily pretreated metastatic UC. Although the drug was found to have modest efficacy, with 6 patients experiencing stable disease and 1 patient achieving a partial response at 8 weeks on therapy, significant side effects also were observed. Patients with specific genetic alterations responded to treatment. Further studies of PI3K pathway inhibition are warranted using newer agents that have superior toxicity profiles and are more selective inhibitors of the pathway.

AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth.

BACKGROUND: Treatment of prostate cancer (PCa) may be improved by identifying biological mechanisms of tumor growth that directly impact clinical disease progression. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and recurrence. METHODS: Radical prostatectomy (RP) specimens (±disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts (total N = 675) and in silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa invasion, proliferation, and tumor growth. RESULTS: Four candidate genes were differentially expressed in PCa recurrence. Of these, low AXIN2 expression was internally validated in the discovery cohort. Validation in external cohorts and in silico demonstrated that low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. Functionally, siRNA-mediated depletion of AXIN2 significantly increased invasiveness, proliferation, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth. CONCLUSIONS: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation, and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies.

Bladder biopsy of normal-appearing mucosa is not helpful in patients with unexplained positive cytology after nonmuscle invasive bladder cancer.

PURPOSE: Malignant voided cytology with normal endoscopic evaluation represents a diagnostic and therapeutic challenge in many patients with a history of nonmuscle invasive bladder cancer. Bladder biopsy is often advised but its efficacy is unclear. We evaluated the usefulness of bladder biopsy in patients with unexplained positive cytology and describe recurrence patterns in this unique patient subset. MATERIALS AND METHODS: From an institutional database we retrospectively identified patients with a history of nonmuscle invasive bladder cancer and surveillance cystoscopy from 2008 to 2012 who had malignant voided urine cytology but normal cystoscopy. Patients underwent systematic bladder biopsy or cystoscopic surveillance and were followed for recurrence and progression. RESULTS: Of 444 patients 343 were followed with surveillance only and 101 underwent a total of 118 biopsies of normal-appearing bladder mucosa. Three biopsies (2.5%) showed carcinoma in situ and none revealed invasive carcinoma. During the median 32-month followup recurrence developed in the bladder in 194 patients (44%), in the upper tract in 24 (5%) and in the prostatic urethra in 5 (1%) while 219 (49%) had no recurrence. A previous diagnosis of upper tract urothelial carcinoma and a history of bacillus Calmette-Guérin treatment were associated with an increased recurrence risk on multivariate analysis. Recurrence rates and patterns were similar in the biopsy and surveillance groups. CONCLUSIONS: Patients with malignant cytology despite normal cystoscopy have a high recurrence rate. Biopsy of normal-appearing bladder mucosa in this setting is rarely positive and does not alter the recurrence pattern.

Age is Associated with Upgrading at Confirmatory Biopsy among Men with Prostate Cancer Treated with Active Surveillance.

PURPOSE: Active surveillance is increasingly recommended for older men with low risk prostate cancer. Although older men have higher all cause mortality, they also have higher prostate cancer specific mortality. We hypothesized that older age is associated with an increased risk of Gleason score upgrading at confirmatory biopsy when controlling for prostate volume. MATERIALS AND METHODS: We retrospectively reviewed data on 1,130 patients with prostate cancer who were treated with active surveillance from 1991 through 2011. We included 646 patients with clinical Gleason 6 or less, stage T2a or less prostate cancer, a confirmatory biopsy within 2 years of diagnostic biopsy and prostate magnetic resonance imaging before confirmatory biopsy. The primary outcome was Gleason score upgrading to 7 or greater on confirmatory biopsy. We used logistic regression to estimate the effect of age on upgrading, adjusting for magnetic resonance imaging prostate volume and other potential confounders. RESULTS: Median age was 66 years (IQR 61-72) and median magnetic resonance imaging prostate volume was 41 ml (IQR 29-55). At confirmatory biopsy disease was upgraded in 55 of 646 patients (9%) and unchanged in 290 (45%) and biopsy was negative in 297 (46%). Older age was associated with higher odds of upgrading (adjusted OR 1.05, 95% CI 1.01-1.09, p=0.009). Larger prostate volume was associated with lower odds of upgrading (adjusted OR 0.80/10 ml increase, 95% CI 0.7-0.9, p=0.012). CONCLUSIONS: Our findings suggest that older age is associated with an increased risk of misclassification on diagnostic biopsy. Older men who are interested in active surveillance should be counseled about the risks and benefits of confirmatory biopsy.

The effect of restaging transurethral resection on recurrence and progression rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin.

PURPOSE: We determined whether restaging resection before initiating induction intravesical bacillus Calmette-Guérin improves the recurrence-free rate in patients with high risk nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We retrospectively analyzed data on 1,021 patients treated at our institution with intravesical bacillus Calmette-Guérin for nonmuscle invasive high risk bladder cancer. All patients underwent a second resection except those already receiving bacillus Calmette-Guérin at the time of initial consultation and those who refused restaging resection. All patients were assessed every 3 to 12 months for a minimum of 5 years. Univariate and multivariate regression was used to identify predictors of 5-year recurrence. RESULTS: Restaging transurethral resection was performed in 894 patients (87.5%). At restaging resection viable tumor was found in 496 patients (55.5%). At 3 months patients with a single resection had a 44.3% recurrence rate compared to 9.6% in those with restaging resection (p <0.01). On multivariate analysis a single transurethral resection was the only predictor of recurrence at 5 years (OR 2.1, 95% CI 1.3-3.3, p = 0.01). Time to recurrence in patients with a single resection was significantly shorter than in those with restaging resection (median 22 vs 36 months, p <0.001). CONCLUSIONS: Failure to repeat resection before initiating intravesical bacillus Calmette-Guérin therapy for high risk nonmuscle invasive bladder cancer significantly increases the risk of recurrence. Therefore, we believe that restaging resection should be performed before initiating bacillus Calmette-Guérin therapy in all patients with high risk nonmuscle invasive bladder cancer.

Impact of recurrent copy number alterations and cancer gene mutations on the predictive accuracy of prognostic models in clear cell renal cell carcinoma.

PURPOSE: Several recently reported recurrent genomic alterations in clear cell renal cell carcinoma are linked to pathological and clinical outcomes. We determined whether any recurrent cancer gene mutations or copy number alterations identified in the TCGA (The Cancer Genome Atlas) clear cell renal cell carcinoma data set could add to the predictive accuracy of current prognostic models. MATERIALS AND METHODS: In 413 patients who underwent nephrectomy/partial nephrectomy we investigated whole exome, copy number array analyses and clinical variables. We identified 65 recurrent genomic alterations based on prevalence and combined them into 35 alterations, including 12 cancer gene mutations. Genomic markers were modeled using the elastic net algorithm with preoperative variables (tumor size plus patient age) and in the postoperative setting using the externally validated Mayo Clinic SSIGN (stage, size, grade and necrosis) prognostic scoring system. These models were subjected to internal validation using bootstrap. RESULTS: Median followup in survivors was 45 months. Several markers correlated with adverse cancer specific survival and time to recurrence on univariate analysis. However, most of them lost significance when controlling for tumor size with or without age in the preoperative models or for SSIGN score in the postoperative setting. Adding multiple genomic markers selected by the elastic net algorithm failed to substantially add to the predictive accuracy of any preoperative or postoperative model for cancer specific survival or time to recurrence. CONCLUSIONS: While recurrent copy number alterations and cancer gene mutations are biologically significant, they do not appear to improve the predictive accuracy of existing models of clinical cancer specific survival or time to recurrence for clear cell renal cell carcinoma.

Preoperative serum albumin is associated with mortality and complications after radical cystectomy.

OBJECTIVE: To determine the association between preoperative serum albumin and mortality and postoperative complications after radical cystectomy (RC) and urinary diversion. PATIENTS AND METHODS: We conducted a retrospective review of 1097 RCs performed for the treatment of bladder cancer between 1992 and 2005. All data were entered prospectively into a hospital-based complications database. We used multivariable logistic regression to assess the association between preoperative serum albumin and complications and mortality ≤90 days of RC, while controlling for preoperative patient and disease characteristics. RESULTS: Low preoperative serum albumin was identified in 14% of the cohort. Preoperative serum albumin was a predictor of postoperative complications (adjusted odds ratio [OR] per unit increase in albumin: 0.61, 95% confidence interval [CI] 0.42-0.90) and 90-day mortality (OR 0.33, 95% CI 0.14-0.75) when controlling for sex, race, age-adjusted Charlson score, body mass index, prior history of abdominal surgery, clinical stage, and neoadjuvant chemotherapy. As serum albumin decreased, the risk of complications and mortality increased. CONCLUSIONS: In addition to age-adjusted Charlson score, low preoperative serum albumin is a significant predictor of complications and mortality after RC. Serum albumin testing can be used to identify individuals at high-risk of morbidity and mortality.

Reflex fluorescence in situ hybridization assay for suspicious urinary cytology in patients with bladder cancer with negative surveillance cystoscopy.

OBJECTIVE: To assess the ability of reflex UroVysion fluorescence in situ hybridization (FISH) testing to predict recurrence and progression in patients with non-muscle-invasive bladder cancer (NMIBC) with suspicious cytology but negative cystoscopy. PATIENTS AND METHODS: Patients under NMIBC surveillance were followed with office cystoscopy and urinary cytology every 3-6 months. Between March 2007 and February 2012, 500 consecutive patients with suspicious cytology underwent reflex FISH analysis. Clinical and pathological data were reviewed retrospectively. Predictors for recurrence, progression and findings on subsequent cystoscopy (within 2-6 months after FISH) were evaluated using univariate and multivariate Cox regression. RESULTS: In all, 243 patients with suspicious cytology also had negative surveillance cystoscopy. Positive FISH was a significant predictor of recurrence (hazard ratio [HR] = 2.35, 95% confidence interval [CI]: 1.42-3.90, P = 0.001) in multivariate analysis and for progression (HR = 3.01, 95% CI: 1.10-8.21, P = 0.03) in univariate analysis, compared with negative FISH. However, positive FISH was not significantly associated with evidence of tumour on subsequent surveillance cystoscopy compared with negative FISH (odds ratio = 0.8, 95% CI: 0.26-2.74, P = 1). CONCLUSIONS: Positive FISH predicts recurrence and progression in patients under NMIBC surveillance with suspicious cytology but negative cystoscopy. However, there was no association between the FISH result and tumour recurrence in the immediate follow-up period. Reflex FISH testing for suspicious cytology might have limited ability to modify surveillance strategies in NMIBC.

The impact of smoking on pathologic response to neoadjuvant cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer.

PURPOSE: Smoking is the primary etiologic risk factor for bladder cancer and has been implicated in mechanisms of chemoresistance. We investigated smoking as a potential predictor for pathologic outcomes after neoadjuvant chemotherapy (NC) and radical cystectomy (RC) for muscle-invasive bladder cancer. METHODS: We identified 139 patients treated with neoadjuvant cisplatin-based chemotherapy followed by RC for T2-4aN0M0 bladder cancer. Logistic regression was used to evaluate associations between smoking characteristics and pathologic outcomes (pT0, complete response; pT0/pTis/pT1, any response). In a secondary analysis, multivariate Cox regression was used to assess associations between smoking and recurrence-free and cancer-specific survival. RESULTS: Our cohort consisted of 99 (71 %) males, with a median age of 65 (interquartile range 56, 71). Prevalence of never, former, and current smokers was 25, 45, and 29 %, respectively. In total, 63 patients experienced disease recurrence, 39 died of disease, and 11 died of other causes. There were no statistically significant associations between smoking characteristics and complete (p = 0.5) or any (p = 0.2) pathologic response to NC. Similarly, we did not find any association between smoking characteristics and recurrence (p = 0.6) or cancer-specific survival (p = 0.9). CONCLUSIONS: In this series, smoking characteristics were not found to be predictive of pathologic response after NC and RC, although this analysis was limited by the small study sample size. However, the harmful effects of smoking warrants continued emphasis on smoking cessation counseling in bladder cancer patients.

Trends in partial and radical nephrectomy: an analysis of case logs from certifying urologists.

PURPOSE: Surgical treatment options for renal masses include radical vs partial nephrectomy and the open vs laparoscopic approach. Using American Board of Urology (ABU) case log data, we investigated contemporary trends in these treatment options, and how surgeon and practice characteristics may influence these trends. MATERIALS AND METHODS: Annualized case log data for nephrectomy were obtained from the ABU for all urologists certifying or recertifying from 2002 to 2010. We evaluated trends in nephrectomy use. Logistic regression was used to evaluate surgeon and practice characteristics as predictors of partial and laparoscopic procedures. RESULTS: From the 3,852 case logs submitted by nonpediatric urologists we analyzed a total of 48,384 nephrectomies. From 2002 to 2010 the proportion of annual nephrectomies performed as open radical nephrectomy gradually decreased from 54% to 29%. During the same period, there was a moderate gradual increase in laparoscopic radical nephrectomies (from 30% to 39%). The proportion of open partial nephrectomies remained stable at 15%, while laparoscopic partial nephrectomy increased from 2% to 17%. On multivariable analysis the use of partial nephrectomy and laparoscopy was predicted by urologist annual nephrectomy volume, initial or recertification status, subspecialty, practice area size and geographic region. CONCLUSIONS: Since 2002, the use of laparoscopic nephrectomy and partial nephrectomy has increased. However, the diffusion of these techniques is not uniform. Initial certification, higher surgical volume, and practicing in areas with more than 1,000,000 population and in the Northeast region were associated with greater use of laparoscopy and partial nephrectomy. Factors that affect the adoption of these techniques require further research.

Trends in the use of incontinence procedures after radical prostatectomy: a population based analysis.

PURPOSE: Urinary incontinence is a frequent complication of radical prostatectomy with a detrimental impact on quality of life. We identified predictors and trends in the use of procedures for post-prostatectomy incontinence. MATERIALS AND METHODS: Using SEER (Surveillance, Epidemiology and End Results) cancer registry data linked with Medicare claims, we identified men 66 years old or older who were treated with radical prostatectomy in 2000 to 2007. The primary outcome was performance of an incontinence procedure. Demographic and clinical predictors of incontinence surgery were evaluated by multivariable regression analysis. RESULTS: Of 16,348 men treated with radical prostatectomy 1,057 (6%) had undergone at least 1 incontinence procedure by a median of 20 months after the procedure, including 61% who underwent the first incontinence procedure within 2 years of prostatectomy. Older age and residence in the South were associated with greater probability of an incontinence procedure. Black men and those living in nonmetropolitan areas were less likely than their peers to undergo an incontinence procedure. Of men treated with any incontinence procedure 15% underwent more than 1 type. Of those treated with bulking agents 39% also received a urethral sling or artificial urinary sphincter and 13% who received a sling also had an artificial urinary sphincter. In 34% of the men who underwent any incontinence surgery artificial urinary sphincter placement was the only procedure performed. CONCLUSIONS: In this population based cohort of older men with prostate cancer only 6% underwent an incontinence procedure after prostatectomy. This low rate may reflect the underuse of potentially beneficial procedures.

Early comparison of nephrectomy options in children (open, transperitoneal laparoscopic, laparo-endoscopic single site (LESS), and robotic surgery).

OBJECTIVE: To compare the perioperative parameters of paediatric patients who underwent nephrectomy via laparo-endoscopic single site (LESS) surgery (also known as single incision laparoscopic surgery or SILS) with those who underwent nephrectomy via conventional laparoscopy (LAP), robotic-assisted laparoscopy (RALN), and open surgery (OPEN). PATIENTS AND METHODS: The medical records of 69 paediatric patients at a single institution who underwent nephrectomies for non-functioning kidneys in 72 renal units (39 OPEN, 11 LAP, 11 RALN and 11 LESS) were reviewed for patient demographics and perioperative clinical parameters. RESULTS: The minimally invasive modalities in children, including LESS nephrectomy, were associated with shorter lengths of hospital stay (P < 0.001) and decreased postoperative pain medication usage (P < 0.001) than with open surgery. Similar surgical times were noted with LESS and the other minimally invasive modalities (LAP and RALN) (P= 0.056). However, the minimally invasive modalities (LESS, LAP and RALN) were associated with slightly longer surgical times when compared with open surgery (P < 0.001), which may, in part, be secondary to learning curve factors. No differences were noted among the minimally invasive modalities for postoperative pain medication usage (P= 0.354) and length of hospital stay (P= 0.86). CONCLUSIONS: The minimally invasive modalities for nephrectomy in children, including LESS nephrectomy, are associated with shorter lengths of hospital stay and decreased postoperative pain medication use when compared with open surgery. LESS nephrectomy in children is associated with similar surgical times, lengths of hospital stay and postoperative pain medication use as the other minimally invasive modalities (LAP and RALN). Slightly longer surgical times are noted with the minimally invasive modalities, including LESS nephrectomy, when compared with open surgery, which may, in part, be secondary to learning curve factors.

Disparities in Stage at Diagnosis in an Equal-access Integrated Delivery System: A Retrospective Cohort Study of 7244 Patients With Bladder Cancer.

BACKGROUND: Disparities in bladder cancer survival by race/ethnicity and gender are likely related to differences in diagnosis. We assessed disparities in stage at diagnosis and potential contributing factors within a large, integrated delivery system. PATIENTS AND METHODS: We conducted a retrospective cohort study of 7244 patients with bladder cancer age ≥ 21 years diagnosed from January 2001 to June 2015 within Kaiser Permanente Southern California. Bivariate analyses compared stage at diagnosis - as well as comorbidities, health plan membership length, and health care utilization prior to diagnosis - by race/ethnicity, gender, and age. Multivariable generalized linear mixed models with urologist as a random effect were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for diagnosis of muscle-invasive bladder cancer (MIBC) versus non-muscle-invasive bladder cancer. RESULTS: In multivariable analyses, stage at diagnosis varied significantly by race/ethnicity (P < .001). Non-Hispanic black patients had significantly higher odds of being diagnosed with MIBC than non-Hispanic white patients (OR, 1.33; 95% CI, 1.05-1.67), whereas Asian patients had significantly lower odds (OR, 0.67; 95% CI, 0.49-0.91). Women were significantly more likely to be diagnosed with MIBC than men (OR, 1.40; 95% CI, 1.22-1.61). Non-Hispanic black women had the highest proportion (39%) of MIBC diagnoses. Among Hispanic and Asian patients, a greater proportion of diagnoses occurred at younger ages. CONCLUSIONS: Health care coverage within an equal-access system did not eliminate disparities in stage at diagnosis by race/ethnicity or gender. Studies are needed to identify etiologic factors and aspects of care delivery (eg, patient-physician interactions) that may affect the diagnostic process to inform efforts to improve health equity.

Outcomes of patients with clinical CIS-only disease treated with radical cystectomy.

OBJECTIVES: To report the long-term oncological efficacy of radical cystectomy for patients with presumed clinical CIS only disease, to characterize the likelihood of clinical understaging, and to characterize the pattern of recurrence. METHODS: One thousand six hundred patients have undergone radical cystectomy and pelvic lymph node dissection with intent to cure from August 1971 to December 2005 at the University of Southern California; 27 patients from this cohort who satisfied both the inclusion and exclusion criteria were identified. Relevant clinical and pathological data at time of cystectomy and during follow-up were reported. Overall and recurrence-free survival was estimated using the Kaplan-Meier method. RESULTS: At time of cystectomy, 33% of patients were found to be clinically understaged. Median follow-up was 94 months. Estimated 5- and 10-year overall survival was 87 and 56%, respectively. Estimated 5- and 10-year recurrence-free survival was 100 and 83%, respectively. CONCLUSIONS: Excellent long-term survival outcomes can be achieved with radical cystectomy. Radical cystectomy should be strongly considered for patients who have failed prior intravesical therapy. Long-term surveillance of the retained urethra and of the upper tract is essential, as recurrence can occur years following cystectomy. Patients who recur are at high risk of dying from disease.

Care Quality and Variability in the Use of Intravesical Therapy for Initial Treatment of Nonmuscle Invasive Bladder Cancer Within a Large, Diverse Integrated Delivery System.

OBJECTIVES: To examine treatment variability, disparities, and quality among newly diagnosed nonmuscle invasive bladder cancer (NMIBC) patients, and to identify factors associated with treatment use in a large, diverse integrated delivery system. METHODS: Retrospective cohort study of 5386 NMIBC patients diagnosed between January 2001 and June 2015 within Kaiser Permanente Southern California. Electronic health data were used to identify treatment outcomes and patient, provider, and tumor characteristics. Outcomes were use of (1) postoperative intravesical chemotherapy, (2) induction Bacille Calmette-Guérin (BCG) immunotherapy, and (3) any intravesical therapy. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using generalized linear mixed models with a binary outcome and urologist as a random effect. RESULTS: From 2001 to 2015, 41% of newly diagnosed NMIBC patients were treated with intravesical therapy. Postoperative chemotherapy use increased significantly over this period (OR per-year = 1.16, 95% CI: 1.07-1.25). BCG use was strongly associated with tumor characteristics: patients with high-grade or carcinoma in situ tumors were more likely to receive BCG (OR = 10.10, 95% CI: 8.39-12.16). Few treatment differences were found by sex or race/ethnicity, but were observed by age. Wide treatment variability across urologists was observed, with some urologists never using intravesical therapy as part of initial treatment while others almost always used it. Differences across urologists accounted for more variability in postoperative chemotherapy (intraclass correlation coefficient = 0.52) than BCG immunotherapy (intraclass correlation coefficient = 0.11) use. CONCLUSION: Substantial variability in initial treatment of NMIBC was observed across urologists, accounting for tumor, patient, and provider characteristics. Results suggest a considerable opportunity for quality improvement programs to reduce unwanted treatment variability and improve care for patients.

Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder.

UNLABELLED: Urothelial carcinoma of the bladder (UCB) is genomically heterogeneous, with frequent alterations in genes regulating chromatin state, cell cycle control, and receptor kinase signaling. To identify prognostic genomic markers in high-grade UCB, we used capture-based massively parallel sequencing to analyze 109 tumors. Mutations were detected in 240 genes, with 23 genes mutated in ≥5% of cases. The presence of a recurrent phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation was associated with improved recurrence-free survival (RFS) (hazard ratio [HR]: 0.35; p=0.014) and improved cancer-specific survival (CSS) (HR: 0.35; p=0.040) in patients treated with radical cystectomy (RC). In multivariable analyses controlling for pT and pN stages, PIK3CA mutation remained associated with RFS (HR: 0.39; p=0.032). The most frequent alteration, TP53 mutation (57%), was more common in extravesical disease (69% vs 32%, p=0.005) and lymph node-positive disease (77% vs 56%, p=0.025). Patients with cyclin-dependent kinase inhibitor 2A (CDKN2A)-altered tumors experienced worse RFS (HR: 5.76; p<0.001) and worse CSS (HR: 2.94; p=0.029) in multivariable analyses. Mutations in chromatin-modifying genes were highly prevalent but not associated with outcomes. In UCB patients treated with RC, PIK3CA mutations are associated with favorable outcomes, whereas TP53 and CDKN2A alterations are associated with poor outcomes. Genomic profiling may aid in the identification of UCB patients at highest risk following RC. PATIENT SUMMARY: Using next-generation sequencing, we identified genomic subsets of high-grade urothelial bladder cancer associated with favorable and unfavorable outcomes. These findings may aid in the selection of patients most likely to benefit from novel combined modality approaches.

Genomic Characterization of Upper Tract Urothelial Carcinoma.

BACKGROUND: Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences. OBJECTIVE: To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity. DESIGN, SETTING, AND PARTICIPANTS: Tumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102). RESULTS AND LIMITATIONS: Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed. CONCLUSIONS: High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma. PATIENT SUMMARY: Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.

Identification and preliminary characterization of mouse Adam33.

BACKGROUND: The metalloprotease-disintegrin family, or ADAM, proteins, are implicated in cell-cell interactions, cell fusion, and cell signaling, and are widely distributed among metazoan phyla. Orthologous relationships have been defined for a few ADAM proteins including ADAM10 (Kuzbanian), and ADAM17 (TACE), but evolutionary relationships are not clear for the majority of family members. Human ADAM33 refers to a testis cDNA clone that does not contain a complete open reading frame, but portions of the predicted protein are similar to Xenopus laevis ADAM13. RESULTS: In a 48 kb region of mouse DNA adjacent to the Attractin gene on mouse chromosome 2, we identified sequences very similar to human ADAM33. A full-length mouse cDNA was identified by a combination of gene prediction programs and RT-PCR, and the probable full-length human cDNA was identified by comparison to human genomic sequence in the homologous region on chromosome 20p13. Mouse ADAM33 is 44% identical to Xenopus laevis ADAM13, however a phylogenetic alignment and consideration of functional domains suggests that the two genes are not orthologous. Mouse Adam33 is widely expressed, most highly in the adult brain, heart, kidney, lung and testis. CONCLUSIONS: While mouse ADAM33 is similar to Xenopus ADAM13 in sequence, further examination of its embryonic expression pattern, catalytic activity and protein interactions will be required to assess the functional relationship between these two proteins. Adam33 is expressed in the mouse adult brain and could play a role in complex processes that require cell-cell communication.

Definitive pathology at radical prostatectomy is commonly favorable in men following initial active surveillance.

BACKGROUND: Limited data are currently available regarding the outcomes of radical prostatectomy (RP) in men with low-risk prostate cancer who were initially managed by active surveillance (AS). OBJECTIVE: To evaluate the pathologic outcomes of patients who underwent RP following initial AS. DESIGN, SETTING, AND PARTICIPANTS: We analyzed the records of 67 patients who underwent RP following initial AS begun between 1993 and 2011. All patients underwent confirmatory biopsy to reassess eligibility for AS. RP was recommended for disease progression suggested by follow-up biopsies or imaging. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Unfavorable disease was defined as having at least one of the following pathologic findings: Gleason score (GS) ≥4+3, extracapsular extension of tumor, seminal vesicle invasion, or lymph node involvement. A descriptive analysis was performed to assess pathologic features. RESULTS AND LIMITATIONS: Median time from confirmatory biopsy to RP was 1.7 yr (range: 0.3-7.8). Reasons for discontinuing AS to undergo RP included evidence of increased tumor volume or grade on follow-up biopsy, patient preference/anxiety, and findings on follow-up imaging in 46 patients (68.7%), 17 patients (25.3%), and 4 patients (6.0%), respectively. Pathologic analyses revealed organ-confined disease in 55 patients (82.1%), and GS was ≥4+3 in 9 (13.4%). Positive nodes were observed in three patients (4.4%) and positive surgical margin in two (3.0%). Overall, 19 patients (28.4%) had unfavorable disease. Of the biopsy criteria for triggering RP, Gleason patterns >3 were the most frequently associated with unfavorable disease (43.3%). One patient (1.5%) experienced biochemical recurrence during postoperative follow-up (median: 3.2 yr). Our study may be limited by its retrospective and single-institution nature. CONCLUSIONS: Most patients who started initially on AS after undergoing confirmatory biopsy showed pathologically organ-confined disease with a low GS at RP. Such findings provide further evidence that, overall, AS is a safe treatment approach.