Bladder Cancer

Research efforts targeting the identification of bladder cancer biomarkers have been extensive during the past decade. Investigations have been performed at the genome, transcriptome, proteome, and metabolome levels and outputs have started appearing including the sketching of disease molecular subtypes. Proteins are directly linked to cell phenotype hence they accumulate special interest as both biomarkers and therapeutic targets. Multiple technical challenges exist, of the main, being the protein concentration vast dynamic range and presence of proteins in modified forms. The scope of this review is to summarize the contribution of proteomics research in this quest of bladder cancer biomarkers. To obtain an unbiased and comprehensive overview, the scientific literature was searched for manuscripts describing proteomic studies on urothelial cancer from the last ten years and those including independent verification studies in urine, tissue and blood are briefly presented. General observations include: a) in most cases, suboptimal experimental design including healthy controls in biomarker discovery and frequently biomarker verification, is followed; b) variability in protein findings between studies can be observed, to some extent reflecting complexity of experimental approaches and proteome itself; c) consistently reported biomarkers include mainly plasma proteins and d) compilation of protein markers into diagnostic panels appears the most promising way forward. Two main avenues of research can now be foreseen: targeting integration of the existing disparate data with proteomic findings being placed in the context of existing knowledge on bladder cancer subtypes and in parallel, accumulation of clinical samples to support proper validation studies of promising marker combinations.

Local-regional recurrence for patients with ≥pT3 disease after radical cystectomy is a significant problem. Chemotherapy has not been shown to reduce the risk of local-regional recurrences in randomized prospective trials, and salvage therapies for local-regional failure are rarely successful. There is promising evidence, particularly from a recent Egyptian NCI trial, that radiation therapy plus chemotherapy can significantly reduce local recurrences compared to chemotherapy alone, and that this improvement in local-regional control may translate to meaningful improvements in disease-free and overall survival with acceptable toxicity. In light of the high rates of local failure following cystectomy for locally advanced disease and the progress that has been made in identifying patients at high risk of failure and the patterns of failure in the pelvis, the NCCN guidelines were revised in 2016 to include post-operative radiotherapy as an option to consider for patients with ≥pT3 disease. Despite advances in our understanding of the problem of local-regional failure after cystectomy and the potential role of adjuvant radiotherapy, the question of whether adjuvant radiotherapy should have a defined role for patients with locally advanced urothelial carcinoma has not yet been determined. The results of the NRG, European, Indian, and Egyptian trials on adjuvant radiotherapy are eagerly awaited. While none of these trials on their own may provide definitive conclusions, their aggregate outcomes will help clarify whether this treatment should have a role in the management of patients with locally advanced bladder cancer.

We have previously provided molecular evidence of expression of aquaporin 3 (AQP3) in normal human urothelium and in UBC of various stages. Whereas former studies demonstrated that loss of AQP3 was associated with invasive and high-grade disease and worse progression-free and cancer-specific survival, this report investigates the expression of AQP3 in associated CIS. Contrary to what we had expected, all CIS specimens were shown to exhibit strong AQP3 expression, suggesting loss of AQP3 in UBC is primarily associated with the ability of tumor cells for invasion but not with grading as sign of dedifferentiation.

Introduction: Level I evidence supports the use of cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer prior to radical cystectomy (RC). On average, 30–40% of patients achieve a complete pathologic response (i.e., stage pT0) after receiving NAC. Some centers risk-stratify patients, suggesting that there may be a higher-risk population that would derive the most benefit from NAC. Recently, a risk-stratification model developed at M.D. Anderson Cancer Center (MDACC) specified criteria for clinical staging and patient selection for NAC. We applied this model to our own RC patient cohort and evaluated our own experience with clinical risk stratification and the effect of NAC on post treatment risk categories.

Methods: We retrospectively reviewed the charts of consecutive patients who underwent RC at two institutions between 2004 and 2014 and noted whether or not they received NAC. We determined the clinical stage by reviewing the exam under anesthesia, transurethral resection biopsy (TURBT) pathology, and preoperative imaging. Patients with cT2-T4a node-negative disease were included. Those with sarcomatoid features or adenocarcinoma were excluded. Patients were classified as high risk if they had tumor-associated hydronephrosis, clinical stage≥T3b-T4a disease, variant histology (i.e., micropapillary or small cell), or lymphovascular invasion (LVI), as specified by the MDACC model. Variables were examined for associations with cancer-specific survival (CSS), overall survival (OS), and risk-category reclassification.

Results: We identified 166 patients with a median follow-up time of 22.2 months. In all, 117 patients (70.5%) did not receive NAC, 68 (58.1%) of whom we classified as high risk. Among patients not receiving NAC, CSS and OS were significantly decreased in high-risk patients (log-rank test p = 0.01 for both comparisons). The estimated age-adjusted hazard ratios of high-risk classification for cancer-specific and overall death were 3.2 (95% CI: 1.2 to 8.6) and 2.2 (95% CI: 1.1 to 4.4), respectively. On post-RC final pathology, 23 (46.9%) low-risk patients were up-classified to high risk and 17 (25.0%) high-risk patients were down-classified. Complete pathologic responses (pT0) were achieved in 7 (6.0%) patients and partial responses (pT1, pTa, pTis) were achieved in 28 (23.9%) patients. Of the 49 patients who did receive NAC, 43 (87.8%) received cisplatin-based and six (12.2%) received carboplatin-based regimens. Applying the MDACC model, we categorized 41 (83.7%) patients as high risk prior to NAC treatment. On final pathology, 3 (37.5%) low-risk patients were up-classified and 17 (41.5%) high-risk patients were down-classified. Complete pathologic responses (pT0) were seen in 13 (26.5%) patients and partial responses were seen in 10 (20.4%) patients. Although the utilization of NAC was not statistically significantly associated with CSS or OS (log-rank test p > 0.05 for both comparisons), it was associated with a 1.2 times increased odds (95% CI: 0.4 to 2.1) of post-RC reclassification from high to low risk on age-adjusted logistic regression.

Conclusions: We found similar results using the clinical risk-stratification model in our cohort and showed that the high-risk category was associated with lower CSS and OS. NAC was associated with a higher probability of risk reclassification from high to low risk.

Introduction: There is a lack of evidence supporting the routine use of laboratory tests to detect bladder cancer. Identifying a cost-effective and widely available diagnostic aid may improve bladder cancer outcomes. We sought to evaluate the utility of dipstick urinalysis to detect microhematuria and diagnose bladder cancer in a large, diverse, contemporary cohort.

Methods: All non-pregnant women and men 35 and older with a new diagnosis of microhematuria (≥3 RBC/hpf) were identified via a multi-center electronic medical record data warehouse query. Negative controls with no history of hematuria were randomly chosen and included to complete our cohort. Comparison between dipstick urinalysis and microscopic urinalysis on self-matched patients for the detection of microhematuria and diagnosis of bladder cancer was performed via Spearman’s rank correlation coefficient, sensitivity/specificity testing, and ROC curve analysis.

Results: A total of 46,842 patients were included. Spearman’s rank order correlation (rho = 0.66) between degree of microhematuria on dipstick urinalysis and microscopic urinalysis indicated a strong positive relationship. The ROC curve for dipstick urinalysis to identify microhematuria had an AUC of 0.80 (95% CI 0.79–0.81). No difference (p = 0.83) in diagnostic accuracy between dipstick urinalysis (AUC 0.74, 95% CI 0.70–0.78) and microscopic urinalysis (AUC 0.73, 95% CI 0.69–0.78) as a test for bladder cancer was found.

Conclusion: Dipstick urinalysis provides a highly specific test for microhematuria and similar accuracy to microscopic urinalysis when used as a diagnostic tool to detect bladder cancer.

Background: Radical cystectomy (RC) is associated with high risk of early and late perioperative complications, and readmissions. The Enhanced Recovery After Surgery (ERAS) protocol has been applied to RC showing decreased hospital stay without increased morbidity.

Objective: To evaluate the specific causes of hospital readmissions in RC patients treated before and after adoption of an ERAS protocol at our institution.

Methods: We retrospectively evaluated the outcome of 207 RC patients on ERAS protocol at the Stanford University Hospital from January 2012 to December 2014. We focused on early (30-day) and late (90-day) postoperative readmission rate and causes. Results were compared with a pre-ERAS consecutive series of 177 RC patients from January 2009 to December 2011.

Results: In the post-ERAS time period a total of 56 patients were readmitted, 41 within the first 30 days after surgery (20%) and 15 within the following 60 days (7%). Fever, often associated with dehydration, was the most common reason for presentation to the hospital, accounting for 57% of all readmissions. At 90 days infection accounted for 53% of readmissions. Of all the patients readmitted during the first 90 days after surgery, 32 had positive urine cultures, mostly caused by Enterococcus faecalis isolated in 18 (56%). Readmission rates did not increase since the introduction of the ERAS protocol, with an incidence of 27% in the post-ERAS group versus 30% in the pre-ERAS group.

Conclusions: Despite accurate adherence to most recent perioperative antibiotic guidelines, the incidence of readmissions after RC due to infection still remains significant.

Objective: Sarcopenia, or the age-related loss of skeletal muscle mass and function, has been investigated as a potential marker of adverse outcomes among surgical patients. Our aim was to assess for changes in psoas muscle volume (PMV) following administration of neoadjuvant chemotherapy (NAC) in patients with bladder cancer and to examine whether changes in PMV following NAC are predictive of perioperative complications, pathologic response or survival.

Methods: During the period of 2009–2013, patients undergoing NAC and radical cystectomy (RC) at our institution with pre and post NAC cross sectional images available were included. Bilateral total psoas muscle volume (PMV) was obtained from pre- and post- NAC images and the proportion of PMV change was calculated by dividing the change PMV by pre-NAC PMV. Analyses for the assessment of factors predicting PMV loss, partial/complete pathologic response (pPR/pCR), complications, readmission, cancer specific (CSS), recurrence-free (RFS) and overall survival (OS) were performed.

Results: Total of 60 patients had complete radiological data available. Post-NAC PMV and BMI declines were statistically significant, 4.9% and 0.05%, respectively. NAC dose reduction/delay was a significant predictor of PMV loss (coefficient B 4.6; 95% CI 0.05–9.2; p = 0.047). The proportion of PMV decline during NAC was not a predictor of pPR, pCR, complications, readmission, CSS, RFS, or OS.

Conclusions: We observed an interval decline in PMV during the period of NAC administration and this decline was more than it could be appreciated with changes in BMI during the same period. PMV decline was associated with the need for dose reduction/dose delay during NAC. In our series, PMV changes occurring during NAC administration were not predictive of pathologic response to chemotherapy, postoperative complications or survival.

Background: We have previously reported the results of a prospective multi-institutional study on the efficacy of MCNA in patients who recurred after intravesical BCG treatment [1]. Since that publication, a new standardized definition for BCG-unresponsiveness has been established [2].

Objective: We re-analyzed the oncologic outcomes following intravesical MCNA in patients classified as BCG-unresponsive according to the new definition.

Methods: For this analysis, we focused on the enrolled patients who satisfied the requirements for BCG Unresponsiveness: i.e. adequate BCG treatment (at least 5/6 induction and 2/3 maintenance instillations) and high grade tumor within 6 months of prior BCG. Treatment course included 6 weekly intravesical instillations of 8 mg MCNA followed by 3 weekly instillations at months 3, 6, 12, 18, and 24. Followup assessments included cystoscopy, urine cytology and biopsy. Patients absent of high grade disease confirmed by central review of biopsy were deemed disease-free.

Results: Of the 129 patients enrolled, 94 (68 CIS with/without papillary tumors, 26 papillary only tumors) fit the criteria for the new BCG Unresponsive definition. Overall, disease free survival (DFS) for all BCG unresponsive patients was 48.9% (95% CI 38.0–59.0%) at 6 months, 34.8% (95% CI 24.7–45%) at 1 year and 28.3% (15.7–34.3%) at 2 years post induction. In the group with papillary tumors, DFS measured at months 6, 12, and 24 were: 61.2% (38.2–77.8%), 61.2(38.2–77.8%), and 50.1% (27.5–69%). In the CIS-containing group, the corresponding DFS were: 44.8% (32.3–56.4%), 26.5% (16.3–37.9%), and 16.6% (8.6–26.9%), respectively.

Conclusions: For patients who are BCG Unresponsive, MCNA has the potential to render 26.5% of patients with CIS and 61.2% of patients with papillary tumors disease-free for at least 1 year with an intact bladder. The higher efficacy noted in the true BCG-unresponsive cohort than was previously reported with all-comers emphasizes the importance of having clearly defined criteria for clinical trials investigating new intravesical therapies after BCG failure.