Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer.

Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8+ T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4+ T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4+ T cell states that are clonally expanded. These CD4+ T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4+ T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.

HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

"I think my vagina is still there?": Women's perspectives on sexual function and dysfunction following radical cystectomy for bladder cancer, a qualitative study.

BACKGROUND: Women's sexual health after radical cystectomy is an important but poorly understood aspect of bladder cancer survivorship. Dedicated investigation is needed to elucidate patient perceptions on sexual function and dysfunction in this setting. AIMS: In this study we sought to qualitatively examine women's perceptions and experiences of sexual health following radical cystectomy for bladder cancer. METHODS: We conducted one-on-one qualitative telephone interviews with 40 women who underwent radical cystectomy in the past 6 months to 5 years and signed a research consent form to be contacted for future studies. We examined women's experiences of engaging in sexual activity after surgery and their attitudes toward sex and body image. We audio recorded, transcribed, and coded the interviews using ATLAS.ti software and applied grounded theory methods for analysis. OUTCOMES: For data that emerged during the qualitative interviews that was related to lack of knowledge about how physical and psychological sexual health would be affected after surgery, we reviewed and discussed transcripts that enabled coding of the data into emerging topic areas. RESULTS: Our analysis yielded 4 main themes. (1) Women reported receiving little to no information from providers about female sexual dysfunction prior to or after radical cystectomy. Women wished they had been provided more information about female sexual dysfunction from their clinicians, including strategies for postoperative self-pleasure and nonintercourse methods of sexual pleasure with partners. (2) Women shared that they were not sexually active following surgery due to physical and mental barriers. (3) When women did try to engage in sex, they described feeling disappointed that it did not feel the same as prior to surgery. (4) Some women found that physical therapy helped them to physically and mentally recover their strength to engage in sexual activity again. CLINICAL IMPLICATIONS: Clinicians must directly address sexual health concerns with patients who undergo radical cystectomy. STRENGTHS AND LIMITATIONS: This study has several key strengths. Investigation into women's sexual function and dysfunction addresses a gap in understanding of this component of women's health-related quality of life after radical cystectomy, which represents an unmet need. The large number of interviews conducted as well as the in-depth information obtained through one-on-one interviews are additional strengths. This study also has limitations, including possible shortcomings of telephone interviews compared with in-person interviews. However, telephone interviews were beneficial because the interviews took place during the COVID-19 pandemic and spared patients from extra visits or from having to travel long distances to the respective medical centers. Other possible limitations were that patients may have been reluctant to share all of their experiences and that patients who underwent urostomies, also termed ileal conduits, were overrepresented in this study compared with women who underwent continent urine diversions, which allow greater control over urine output. CONCLUSION: Broadening the understanding of sexual health beyond sexual intercourse to encompass sexuality and self-pleasure can provide clinicians, patients, and their families with more effective preparation and strategies to care for an essential aspect of their wellbeing.

Protocol of the Comparison of Intravesical Therapy and Surgery as Treatment Options (CISTO) study: a pragmatic, prospective multicenter observational cohort study of recurrent high-grade non-muscle invasive bladder cancer.

BACKGROUND: Bladder cancer poses a significant public health burden, with high recurrence and progression rates in patients with non-muscle-invasive bladder cancer (NMIBC). Current treatment options include bladder-sparing therapies (BST) and radical cystectomy, both with associated risks and benefits. However, evidence supporting optimal management decisions for patients with recurrent high-grade NMIBC remains limited, leading to uncertainty for patients and clinicians. The CISTO (Comparison of Intravesical Therapy and Surgery as Treatment Options) Study aims to address this critical knowledge gap by comparing outcomes between patients undergoing BST and radical cystectomy. METHODS: The CISTO Study is a pragmatic, prospective observational cohort trial across 36 academic and community urology practices in the US. The study will enroll 572 patients with a diagnosis of recurrent high-grade NMIBC who select management with either BST or radical cystectomy. The primary outcome is health-related quality of life (QOL) at 12 months as measured with the EORTC-QLQ-C30. Secondary outcomes include bladder cancer-specific QOL, progression-free survival, cancer-specific survival, and financial toxicity. The study will also assess patient preferences for treatment outcomes. Statistical analyses will employ targeted maximum likelihood estimation (TMLE) to address treatment selection bias and confounding by indication. DISCUSSION: The CISTO Study is powered to detect clinically important differences in QOL and cancer-specific survival between the two treatment approaches. By including a diverse patient population, the study also aims to assess outcomes across the following patient characteristics: age, gender, race, burden of comorbid health conditions, cancer severity, caregiver status, social determinants of health, and rurality. Treatment outcomes may also vary by patient preferences, health literacy, and baseline QOL. The CISTO Study will fill a crucial evidence gap in the management of recurrent high-grade NMIBC, providing evidence-based guidance for patients and clinicians in choosing between BST and radical cystectomy. The CISTO study will provide an evidence-based approach to identifying the right treatment for the right patient at the right time in the challenging clinical setting of recurrent high-grade NMIBC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03933826. Registered on May 1, 2019.

Utility of Blue Light Cystoscopy for Post-bacillus Calmette-Guérin Bladder Cancer Recurrence Detection: Implications for Clinical Trial Recruitment and Study Comparisons.

PURPOSE: The utility of blue light cystoscopy (BLC) in patients receiving bacillus Calmette-Guérin (BCG) during post-treatment cystoscopy is not well understood. Our objective was to determine if BLC improves recurrence detection in patients with non-muscle invasive bladder cancer (NMIBC) undergoing BCG. MATERIALS AND METHODS: Using the prospective multi-institutional Cysview® Registry (2014-2019), patients with NMIBC who received BCG within 1 year prior to BLC were identified. Primary outcomes were recurrences and whether lesions were detected on white light cystoscopy (WLC), BLC or both. We calculated the percentage of cystoscopies with recurrences that were missed with WLC alone. The cystoscopy-level BLC false-positive rate was the proportion of cystoscopies with biopsies only due to BLC suspicious lesions without recurrence. RESULTS: Of 1,703 BLCs, 282 cystoscopies were in the analytic cohort. The overall recurrence rate was 45.0% (127). With only WLC, 13% (16/127) of recurrences would have been missed as 5.7% (16/282) of cystoscopies performed had recurrence only identified with BLC. Among 16 patients with recurrence missed with WLC, 88% (14) had carcinoma in situ. The cystoscopy-level BLC false-positive rate was 5% (15). CONCLUSIONS: BLC helped detect recurrences after recent BCG that would have been missed with WLC alone. Providers should consider BLC for high-risk patients undergoing BCG and should discuss the risk of false-positives with these patients. As clinical trials of novel therapies for BCG-unresponsive disease increase and there are no clear guidelines on BLC use for post-treatment cystoscopies, it is important to consider how variable BLC use could affect enrollment in and comparisons of these studies.

Role of blue-light cystoscopy in detecting invasive bladder tumours: data from a multi-institutional registry.

OBJECTIVES: To evaluate the role of blue-light cystoscopy (BLC) in detecting invasive tumours that were not visible on white-light cystoscopy (WLC). PATIENTS AND METHODS: Using the multi-institutional Cysview registry database, patients who had at least one white-light negative (WL-)/blue-light positive (BL+) lesion with invasive pathology (≥T1) as highest stage tumour were identified. All WL-/BL+ lesions and all invasive tumours in the database were used as denominators. Relevant baseline and outcome data were collected. RESULTS: Of the 3514 lesions (1257 unique patients), 818 (23.2%) lesions were WL-/BL+, of those, 55 (7%) lesions were invasive (48 T1, seven T2; 47 unique patients) including 28/55 (51%) de novo invasive lesions (26 unique patients). In all, 21/47 (45%) patients had WL-/BL+ concommitant carcinoma in situ and/or another T1 lesions. Of 22 patients with a WL-/BL+ lesion who underwent radical cystectomy (RC), high-risk pathological features leading to RC was only visible on BLC in 18 (82%) patients. At time of RC, 11/22 (50%) patients had pathological upstaging including four (18%) with node-positive disease. CONCLUSIONS: A considerable proportion of invasive lesions are only detectable by BLC and the rate of pathological upstaging is significant. Our present findings suggest an additional benefit of BLC in the detection of invasive bladder tumours that has implications for treatment approach.

Use of a Convex Pouching System in the Postoperative Period: A National Consensus.

Convex pouching systems have been available for ostomy patients for decades; however, controversy remains over the use of convexity in the postoperative period. A group of 10 nurses and physicians with expertise caring for patients with an ostomy completed a scoping review identifying research-based evidence and gaps in our knowledge of the safety and effectiveness related to the use of a convex pouching system following ostomy surgery. Results of this scoping review demonstrated the need for a structured consensus to define best practices when selecting a pouching system that provides a secure and reliable seal around the stoma, avoids undermining and leakage of effluent from the pouching system, and contributes to optimal health-related quality of life for patients following ostomy surgery. The expert panel reached consensus on 8 statements for the use of convex products immediately after surgery and throughout the first 6 months after stoma creation, as well as describing goals in choosing the best pouching system for the patient with an ostomy.

Survey Results on Use of a Convex Pouching System in the Postoperative Period.

PURPOSE: The purpose of this study was to validate time frames for postoperative care following stoma surgery and to determine participants' current practice with convex pouching systems during the postoperative period. DESIGN: A Cross-sectional survey. SUBJECTS AND SETTING: The sample comprised 332 ostomy care specialists practicing in the United States. Most (n = 220; 66%) had more than 10 years' experience caring for patients with ostomies, 82% (n = 272) were certified WOC or ostomy care nurses (CWOCN and COCN), and 7% (n = 23) were board-certified colorectal surgeons. METHODS: A 23-item online questionnaire was created for purposes of the study. Items in the questionnaire queried professional background and experience caring for patients with an ostomy. A single item was used to identify postoperative care periods following ostomy surgery. Additional items queried current practice patterns related to use of convex pouching systems and the timing of their use. Data were collected from January 18 to February 8, 2021. RESULTS: Most respondents (n = 270; 90%) agreed with the following postoperative periods after ostomy surgery: immediate postoperative period (days 0-8); postoperative period (days 9-30); and transition phase (days 31-180). Most respondents (n = 274; 95%) indicated they would use a convex pouching system when clinically appropriate during the first 30 days following ostomy surgery and 79% (n = 228) indicated using a convex pouching system regardless of when the surgery was performed. Less than 1% (n = 2) indicated never using convexity within the first 30 days following stoma surgery, and only 3% (n = 8) indicated avoidance of convexity pouching systems in the immediate postoperative period. CONCLUSIONS: Findings indicate that use of convexity during the postoperative period is prevalent to provide a secure seal and predictable wear time.

The Diagnostic Performance of Cxbladder Resolve, Alone and in Combination with Other Cxbladder Tests, in the Identification and Priority Evaluation of Patients at Risk for Urothelial Carcinoma.

PURPOSE: Cxbladder (Cxb) tests combine genomic biomarkers in urine with phenotypic and clinical data to classify hematuria patients into those at low/high probability of urothelial carcinoma (UC). Cxbladder Resolve (CxbR) is designed for use after Cxb Triage (CxbT) and Detect (CxbD), where CxbT-positive tests reflex to CxbD and CxbD-positive to CxbR to identify patients at high probability of high-impact tumors (HIT; high grade Ta, Tis or T1-T3). This study validated the diagnostic performance of CxbR in identifying HIT, and validated the algorithm of Cxb tests to segregate high-impact from low-impact tumors. MATERIALS AND METHODS: CxbR was developed in 863 hematuria patients in 3 studies in United States, Australia and New Zealand. CxbR, separately and combined with other Cxb tests, was validated in a prospective, observational U.S. study in 548 hematuria patients. All UC diagnoses were confirmed by histopathology. RESULTS: In the development data set, CxbR sensitivity was 92.4% (95% CI 83.3-96.7) and specificity 93.8% (95% CI 86.8-97.2) for identifying HIT within the high priority category. During external validation, sequential Cxb tests correctly ruled out 87.6% of patients from further workup (negative predictive value 99.4%); 100% of HIT were correctly identified (specificity 96.3%), and 3 low-grade tumors were missed. In both studies, all patients with HIT were correctly assigned to prioritized evaluation. CONCLUSIONS: CxbR has high sensitivity and specificity, correctly identifying all HIT. Sequential Cxb tests accurately segregate patients with a low vs high probability of HIT, focusing resources on those patients, with a diagnostic yield 4.8-fold higher than American Urological Association guideline stratification.

Bladder cancer in patients younger than 40 years: outcomes from the National Cancer Database.

PURPOSE: To evaluate the clinical, pathological, and survival outcomes of bladder cancer in patients aged 18-40 years. METHODS: We identified 362,091 bladder cancer patients from the National Cancer Database between 2004-2013 and compared patients aged 18-40 years to those > 40 years of age with univariate analysis using Chi-square tests. A subset analysis was performed on patients who underwent cystectomy. Multivariable Cox regression was used for overall survival analysis. RESULTS: Our final analysis included 314,177 patients with 3314 (1.1%) patients aged 18-40 years. Patients aged 18-40 years had a lower male-to-female ratio (2.4 versus 3.0), a greater proportion of low-grade tumors (72.7% versus 48.3%, p < 0.001), non-muscle invasive tumors (90.3% versus 81.2%, p < 0.001), and variant histology (4.0% versus 3.3%, p < 0.001). Similar trends were observed at cystectomy including lower male-to-female ratio in the 18-40 years group (1.7 versus 3.1), a greater proportion of variant histology (25.0% versus 10.0%, p < 0.001); and 53.3% of those younger patients with variant histology were women. Patients aged 18-40 years who underwent cystectomy had a higher proportion of locally advanced disease (pT4 19.2% versus 14.6%, p = 0.004). Multivariable analyses in both cohorts demonstrated that variant histology was a predictor of worse overall survival. CONCLUSION: The majority of patients aged 18-40 years with bladder cancer present with low-grade, non-muscle-invasive disease associated with better survival. However, a subset of younger patients with a higher proportion of women presents with aggressive bladder cancer which may be partly explained by a higher prevalence of variant histology.

A Genomic Classifier for Predicting Clinically Aggressive Luminal Bladder Tumors with Higher Rates of Pathological Up Staging.

PURPOSE: Urothelial carcinoma of the luminal molecular subtype is associated with lower rates of pathological up staging from clinical stage T1-T2 to nonorgan confined (pT3 or greater and/or pN+) disease at radical cystectomy. However, approximately a third of luminal urothelial carcinoma cases were up staged to nonorgan confined disease, and these may be under treated if neoadjuvant chemotherapy is withheld. In this study we trained a genomic classifier to predict luminal nonorgan confined disease in patients diagnosed with clinically organ confined (cT1/T2) disease. MATERIALS AND METHODS: Specimens from transurethral resected high grade cT1-T2N0M0 urothelial carcinoma of the bladder that belonged to the luminal subtype (Seiler 2017) were randomly split into training (75) and testing (25) sets for the development of a single sample luminal up staging classifier using lasso/ridge-penalized logistic regression. All patients underwent radical cystectomy without neoadjuvant chemotherapy and the primary end point was up staging to nonorgan confined disease. A radical cystectomy cohort and a platinum treated neoadjuvant chemotherapy cohort were used to evaluate the luminal up staging classifier. RESULTS: Up staging to nonorgan confined disease occurred in 34% of luminal cases. The luminal up staging classifier predicted up staging in 32 of 34 cases, with 6 false-positives (AUC 0.96). The sensitivity for detection of luminal pN+ disease was 95% (20 of 21). Patients with predicted nonorgan confined luminal tumors had worse survival than those with organ confined luminal tumors (p=0.001). On multivariable analysis the luminal up staging classifier was a significant predictor of overall survival after adjusting for clinical variables available at transurethral resection. The luminal up staging classifier also predicted overall survival for aggressive luminal TCGA (The Cancer Genome Atlas) cases (n=83, p=0.043). In the neoadjuvant chemotherapy cohort the luminal up staging classifier predicted 9 up staging cases, all of which had excellent prognosis. CONCLUSIONS: A luminal up staging classifier was developed that distinguishes a subset of cT1-T2N0M0 luminal urothelial carcinoma cases at high risk for up staging to nonorgan confined disease at radical cystectomy and of death. Validation of this model in an independent, large patient cohort is necessary to determine how molecular stratification of luminal tumors could be used to guide treatment of these patients.

Correction to: A comparison of stage-specific all-cause mortality between testicular sex cordstromal tumors and germ cell tumors: results from the National Cancer Database.

An amendment to this paper has been published and can be accessed via the original article.

A comparison of stage-specific all-cause mortality between testicular sex cord stromal tumors and germ cell tumors: results from the National Cancer Database.

BACKGROUND: Testicular sex cord stromal tumors (SCSTs) are managed similarly to germ cell tumors (GCTs); however, few studies have directly compared outcomes between these tumor types. Using the National Cancer Database (NCDB), we sought to compare overall and stage-specific all-cause mortality (ACM) between SCSTs versus GCTs. METHODS: NCDB was queried for patients diagnosed with SCSTs and GCTs between 2004 and 2013. Descriptive statistics were used to compare sociodemographic and clinical characteristics between groups. Univariable and multivariable Cox proportional hazards regression analyses were used to assess associations with ACM. RESULTS: We identified 42,192 patients diagnosed with testicular cancer between 2004 and 2013, with 280 having SCSTs and 41,912 patients having GCTs. Median age for SCSTs and GCTs was 45 (interquartile range [IQR] 34-59) and 34 (IQR 27-43), respectively (p < 0.001). Median follow-up was 39 and 52 months, respectively. Overall, patients with SCSTs had greater risk of ACM compared to those with GCTs (HR 1.69, 95% CI 1.14-2.50). Private insurance, greater education, and fewer comorbidities were associated with reduced risk of ACM (p < 0.05 for all). Among those with stage I disease, tumor type was not associated with ACM on multivariable analysis. Among those with stage II/III disease, patients with SCSTs had increased risk of ACM compared to patients with GCTs (HR 3.29, 95% CI 1.89-5.72). CONCLUSIONS: Patients with advanced SCSTs had worse survival outcomes compared to those with advanced GCTs. These data suggest a need for further investigation to ascertain effective management recommendations for SCSTs.

An evaluation of the real world use and clinical utility of the Cxbladder Monitor assay in the follow-up of patients previously treated for bladder cancer.

BACKGROUND: Surveilling recurrent urothelial carcinoma (UC) requires frequent cystoscopy, which is invasive, expensive and time-consuming. An accurate urinary biomarker has the potential to reduce the number of cystoscopies required during post-treatment surveillance. OBJECTIVE: To audit the clinical utility of a new surveillance protocol incorporating the Cxbladder Monitor (CxbM) test in real-world practice. METHODS: Three hospitals implemented a new surveillance protocol. Patients were risk stratified, and then provided urine samples for CxbM testing. Low-risk CxbM-positive patients and all high-risk patients had cystoscopy at 2-3 months. Low-risk CxbM-negative patients had cystoscopy at ~ 12 months. RESULTS: 443 CxbM tests were conducted on samples from 309 patients: 257 (83.2%) low-risk and 52 (16.8%) high-risk. No pathology-confirmed recurrences were seen in low-risk CxbM-negative patients (n = 108) during the first post-CxbM cystoscopy undertaken a mean ± SD 10.3 ± 3.9 months after testing. Three recurrences were detected during cystoscopy at 2.7 ± 3.4 months in 53 low-risk CxbM-positive patients. In 49 high-risk patients, 39 (79.6%) were CxbM-negative with no pathology-confirmed recurrences. Ten high-risk patients (20.4%) were CxbM-positive with four confirmed recurrences; 2 high-grade and 2 low-grade. The median time to first cystoscopy was 12.13 (95% CI: 11.97-12.4) months in patients with a CxbM-negative result versus 1.63 (95% CI: 1.13-2.3) months in patients with a CxbM-positive result (p < 0.00001). No positive cases were missed, no patients progressed to invasive or metastatic disease, and no patient died of cancer over 35 months of follow-up. CONCLUSIONS: CxbM accurately identified a high proportion of patients (77.8%) who were safely managed with only one cystoscopy per year. Including CxbM in the protocol for patient surveillance provided clinical utility by reducing the average number of annual cystoscopies by approximately 39%, thereby sparing patients the potential discomfort and anxiety, without compromising detection rates. No advantage was observed for risk stratification prior to CxbM.

Gender differences in oncologic and functional outcomes in patients with bladder cancer undergoing radical cystectomy with urinary diversion.

PURPOSE OF REVIEW: The purpose of this article is to review and summarize recent data on gender differences in oncologic and functional outcomes in women undergoing radical cystectomy with urinary diversion as contemporary studies have highlighted a potential disparity in outcomes between men and women. RECENT FINDINGS: Gender (being a woman) as a social determinant of health negatively affects oncologic outcome in women with bladder cancer treated with radical cystectomy secondary to delays in diagnosis, treatment, and misdiagnosis. Sex (being female) negatively affects oncologic outcome in women with bladder cancer treated with radical cystectomy through tumor and host biology. Female patients present with advance stage and basal molecular subtype tumors enriched with squamous and sarcomatoid histology. Preliminary studies implicate the hormonal axis in differential bladder cancer development and progression between women and men. After radical cystectomy, functional outcomes (urinary, sexual, and overall quality of life) are poorly assessed in women yet important for both physicians and patients for clinical decision-making and counseling. SUMMARY: Future research (clinical trials, assessment of functional outcomes using gender-specific measures) must include women with bladder cancer and raise awareness regarding the gaps in knowledge and care for these patients.

Epigenetic Alterations in Bladder Cancer.

PURPOSE OF REVIEW: Epigenetics refers to processes that alter gene expression without altering primary DNA. Over that past decade, there is a growing focus on epigenetic mechanisms in cancer research and its importance in cancer biology. This review summarizes epigenetic dysregulation in bladder cancer. RECENT FINDINGS: Epigenetic alterations are overall shared across various grades and stages of bladder cancer. High grade invasive tumors demonstrate a greater degree and intensity of methylation and may have a unique methylation pattern. Environmental exposures may influence epigenetic alterations directly independent of genomic change. Non-coding RNAs play an important role in cancer phenotype, especially in the context of integrative genomic analyses. DNA hypermethylation and non-coding RNAs have potential as robust bladder cancer biomarkers; however, they require further study and validation. Changes in chromatin and histone modification are attractive targets for therapy and are currently in clinical trials. Epigenetic dysregulation may be an important key in improving the understanding of bladder cancer pathogenesis, especially through integrative genomic analyses. Deeper understanding of these pathways can help identify clinically relevant biomarkers and therapeutic targets to validate for diagnosis, monitoring, prognosis, and treatment for bladder cancer.

The Cancer of the Bladder Risk Assessment (COBRA) score: Estimating mortality after radical cystectomy.

BACKGROUND: Risk stratification of patients with urothelial carcinoma of the bladder (UCB) after cystectomy has important clinical and research implications. The authors assessed the relative effect of tumor stage and lymph node status on cancer-specific survival (CSS) after cystectomy and developed a simplified risk-assessment tool. METHODS: In total, 14,828 patients who underwent cystectomy with lymph node dissection for UCB were identified from the Surveillance, Epidemiology, and End Results database (1988-2011). The relative importance of tumor stage and lymph node status with regard to CSS was assessed using stratified Kaplan-Meier and Cox proportional-hazards analyses. The patients were split randomly into development and validation cohorts. Additional validation using overall survival was performed on 19,362 patients from the National Cancer Data Base. The Cancer of Bladder Risk Assessment (COBRA) tool was created using a Cox model incorporating age, tumor stage, and lymph node density. Performance was validated using observed versus expected survival plots and the Harrell concordance index. RESULTS: Patients with muscle invasive (T2), lymph node-positive disease had a survival curve similar to that in patients with extravesical (T3 and T4), lymph node-negative disease (2-year CSS, 67% and 70%, respectively). Each point increase in the COBRA score (range, 0-7) was associated with a 1.61-fold increase (95% confidence interval, 1.56-fold to 1.65-fold increase) in the risk of bladder cancer death in the development cohort. The model accurately stratified patients across risk levels in the development cohort and the 2 validation cohorts (C-index, 0.712, 0.705, and 0.68, respectively). CONCLUSIONS: The COBRA score offers a straightforward, validated risk-stratification tool that incorporates the relative contribution of tumor stage and lymph node involvement to patient prognosis after cystectomy for UCB. Cancer 2017;123:4574-4582. © 2017 American Cancer Society.

Intravesical chemotherapy in non-muscle-invasive bladder cancer.

Non-muscle-invasive bladder cancer (NMIBC) is characterized by a tendency for recurrence and capacity for progression. Intravesical instillation therapy has been employed in various clinical settings, which are summarized within this review. Several chemotherapeutic agents have shown clinical efficacy in reducing recurrence rates in the post-transurethral resection of bladder tumor (TURBT) setting, including mitomycin C (MMC), doxorubicin, and epirubicin. Mounting evidence also supports the use of intravesical MMC following nephroureterectomy to reduce later urothelial bladder recurrence. In the adjuvant setting, bacillus Calmette-Guérin (BCG) immunotherapy is an established first-line agent in the management of carcinoma in situ (CIS) and high-grade non muscle invasive urothelial carcinoma (UC). Among high and intermediate-risk patients (based on tumor grade, size, and focality) improvements in disease-free intervals have been seen with adjunctive administration of MMC prior to scheduled BCG dosing. Following failure of first-line intravesical therapy, gemcitabine and valrubicin have demonstrated modest activity, though valrubicin remains the only agent currently Food and Drug Administration (FDA)-approved for the treatment of BCG-refractory CIS. Techniques to optimize intravesical chemotherapy delivery have also been explored including pharmacokinetic methods such as urinary alkalization and voluntary dehydration. Chemohyperthermia and electromotive instillation have been associated with improved freedom from recurrence intervals but may be associated with increased urinary toxicity. Improvements in therapeutic selection may be heralded by novel opportunities for genomic profiling and refinements in clinical risk stratification.