Noninvasive Tests for Bladder Cancer Detection and Surveillance: A Systematic Review of Commercially Available Assays.

BACKGROUND: An important reason for the high health care costs associated with bladder cancer is the need for frequent cystoscopy for detection and surveillance of this disease. Cytologic analysis of voided urine specimens can assist, but is too inaccurate to replace cystoscopy. In an effort to create reliable, objective, noninvasive mechanisms for detecting bladder cancer, a number of urine-based molecular tests have been developed with the ultimate goal of reducing the frequency of cystoscopy. OBJECTIVE: To summarize the performance of urine-based biomarker tests, currently commercially available in the US, as part of the initial workup for hematuria and for bladder cancer surveillance. METHODS: In accordance with PRISMA guidelines we performed a systematic review of the literature on the performance of NMP22, BTA, UroVysion, ImmunoCyt/uCyt, CxBladder, and Bladder EpiCheck. Median sensitivity, specificity, negative (NPV) and positive predictive values (PPV) were calculated for each test based on the included studies. RESULTS: Twenty-eight studies met inclusion criteria for the performance of five urine-based biomarker tests in the setting hematuria workup. Median sensitivity ranged from 65.7% -100% and specificity ranged from 62.5% -93.8%. Median NPV ranged from 94.2% -98.3% and PPV ranged from 29% -58.7%. Fourteen studies met inclusion criteria for the performance of six tests in the setting of bladder cancer surveillance. Median sensitivity ranged from 22.6% -92.0% and specificity from 20.5% -97.9%. Median NPV ranged from 52.9% -96.5% and PPV ranged from 48.1% -75.7%. CONCLUSIONS: Our analysis finds that while these tests may provide some clinical utility, none of the assays have thus far demonstrated objective evidence to supplant the gold diagnostic standard.

Robotic post-chemotherapy retroperitoneal lymph node dissection for testicular cancer: A multicenter collaborative study.

OBJECTIVES: To evaluate the perioperative and oncological/functional outcomes of robotic post-chemotherapy retroperitoneal lymph node dissection for testicular cancer. METHODS AND MATERIALS: In this retrospective study, we included patients who underwent robotic post-chemotherapy retroperitoneal lymph node dissection at 7 academic centers between 2011 and 2021. Patients' characteristics, perioperative findings, as well as oncological and functional outcomes are reviewed. Relationships with the main outcome (90-day complications) were analyzed using multivariable logistic regression. RESULTS: A total of 90 patients with a median (IQR) age of 30 (25-37) years were included. The main primary histologic type was non-seminomatous germ cell tumor (89%). Seven patients (8%) were electively converted to open. Median estimated blood loss, operative time, and length of hospital stay were 150 ml, 5.6 hours, and 2 days, respectively. Final pathology revealed teratoma in 49 (55%), necrosis/fibrosis in 29 (32%), and viable germ cell tumor in 12 (13%) patients. The 90-day complication rate was 16.7%, most of which were low-grade (Clavien-Dindo < III) and managed conservatively. On multivariable analysis, pure seminoma (odds ratio 17.4) and bilateral dissection template (odds ratio 4.2) were independently associated with 90-day complications. No 90-day hospital readmission was recorded. With a median (IQR) follow-up of 16 (4-32) months, 6 (6.7%) patients had disease recurrence and there was 1 cancer-related death. CONCLUSION: With appropriate patient selection at centers with expertise in testicular cancer and minimally invasive surgery, robotic post-chemotherapy retroperitoneal lymph node dissection appears safe and effective, although longer follow-up is warranted.

Lentiviral interferon: A novel method for gene therapy in bladder cancer.

Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may limit therapeutic activity. Lentiviral vectors can achieve stable transgene expression and are less immunogenic. In this study, we evaluated lentiviral vectors expressing murine IFNα (LV-IFNα) and demonstrate IFNα expression by transduced murine BLCA cell lines, bladder urothelium, and within the urine following intravesical instillation. Murine BLCA cell lines (MB49 and UPPL1541) were sensitive to IFN-mediated cell death after LV-IFNα, whereas BBN975 was inherently resistant. Upregulation of interleukin-6 (IL-6) predicted sensitivity to IFN-mediated cell death mediated by caspase signaling, which when inhibited abrogated IFN-mediated cell killing. Intravesical therapy with LV-IFNα/Syn3 in a syngeneic BLCA model significantly improved survival, and molecular analysis of treated tumors revealed upregulation of apoptotic and immune-cell-mediated death pathways. In particular, biomarker discovery analysis identified three clinically actionable targets, PD-L1, epidermal growth factor receptor (EGFR), and ALDHA1A, in murine tumors treated with LV-IFNα/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNα and the study of novel combination strategies with IFNα gene therapy for the BLCA treatment.

Management Trends and Outcomes of Patients Undergoing Radical Cystectomy for Urothelial Carcinoma of the Bladder: Evolution of the University of Southern California Experience over 3,347 Cases.

PURPOSE: There are conflicting reports on outcome trends following radical cystectomy (RC) for bladder cancer. MATERIALS AND METHODS: Evolution of modern bladder cancer management and its impact on outcomes was analyzed using a longitudinal cohort of 3,347 patients who underwent RC at an academic center between 1971 and 2018. Outcomes included recurrence-free survival (RFS) and overall survival (OS). Associations were assessed using univariable and multivariable models. RESULTS: In all, 70.9% of cases underwent open RC in the last decade, although trend for robot-assisted RC rose since 2009. While lymphadenectomy template remained consistent, nodal submission changed to anatomical packets in 2002 with increase in yield (p <0.001). Neoadjuvant chemotherapy (NAC) use increased with time with concomitant decrease in adjuvant chemotherapy; this was notable in the last decade (p <0.001) and coincided with improved pT0N0M0 rate (p=0.013). Median 5-year RFS and OS probabilities were 65% and 55%, respectively. Advanced stage, NAC, delay to RC, lymphovascular invasion and positive margins were associated with worse RFS (all, multivariable p <0.001). RFS remained stable over time (p=0.73) but OS improved (5-year probability, 1990-1999 51%, 2010-2018 62%; p=0.019). Among patients with extravesical and/or node-positive disease, those who received NAC had worse outcomes than those who directly underwent RC (p ≤0.001). CONCLUSIONS: Despite perioperative and surgical advances, and improved pT0N0M0 rates, there has been no overall change in RFS trend following RC, although OS rates have improved. While patients who are downstaged with NAC derive great benefit, our real-world experience highlights the importance of preemptively identifying NAC nonresponders who may have worse post-RC outcomes.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

Enhanced recovery after cystectomy in patients with preoperative narcotic use.

INTRODUCTION: The aim of this study was to evaluate the outcomes of radical cystectomy with an enhanced recovery after surgery (ERAS) protocol in patients with a history of chronic preoperative narcotic use compared to narcotic-naive patients. METHODS: We identified 553 patients who underwent open radical cystectomy with ERAS. Preoperative narcotic use was identified in 34 patients who were then matched to 68 narcotic-naive patients. Postoperative outcomes, opioid use, and visual analog scale (VAS) pain scores were analyzed and compared. All routes of opioid use were recorded and converted to a morphine equivalent dose (MED). RESULTS: Patients with preoperative narcotic use reported higher median VAS pain scores per day (postoperative day [POD1]: 5.2 vs. 3.9, p=0.003; POD2: 5.1 vs. 3.6, p<0.001; POD3: 4.6 vs. 3.8, p=0.004) and used significantly more opioids (median MED) per day (POD1: 13.2 vs. 10.0, p=0.02; POD2: 11.3 vs. 6.4, p=0.003; POD3: 10.2 vs. 5.0, p=0.005) following surgery. Preoperative narcotic users were noted to have a significantly higher incidence of 90-day re-admissions (41.2% vs. 20.6%, p=0.03). There was no difference in median hospital stay (4 vs. 4 days, p=0.6), 30-or 90-day complications (64.7% vs. 60.3%, p=0.8 and 82.4% vs. 75.0%, p=0.4, respectively) or gastrointestinal complications (29.4% vs. 26.5%, p=0.8), including postoperative ileus (11.8% vs. 20.6%, p=0.2). CONCLUSIONS: Patients with preoperative narcotic exposure report higher pain scores and require more opioid use following radical cystectomy with ERAS and are more likely to be re-admitted within 90 days. However, there was no observed difference in hospital stay or complications.

Robotic adrenalectomy in the pediatric population: initial experience case series from a tertiary center.

BACKGROUND: Laparoscopic resection is the most well described minimally-invasive approach for adrenalectomy. While it allows for improved cosmesis, faster recovery and decreased length of hospital stay compared with the open approach, instrument articulation limitations can hamper surgical dexterity in pediatric patients. Use of robotic assistance can greatly enhance operative field visualization and instrument control, and is in the early stages of adoption in academic centers for pediatric populations. CASE PRESENTATION: We present a single-institution series of pediatric adrenalectomy cases. The da Vinci Xi surgical system was used to perform adrenalectomies on three consecutive patients (ages, 2-13 years) at our center. Final pathology revealed ganglioneuroblastoma (n = 2) and pheochromocytoma (n = 1). Median operating time was 244 min (range, 244-265 min); median blood loss was estimated at 100 ml (range, 15-175 ml). Specimens were delivered intact and all margins were negative. Median post-operative hospital stay was 2 days (range, 1-6 days). All patients remain disease-free at median follow-up of 19 months (range, 12-30 months). CONCLUSION: Our experience continues to evolve, and suggests that robotic surgery is safe, feasible and oncologically effective for resection of adrenal masses in well-selected pediatric patients.

Heterotopic Bone Formation in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma is associated with calcium deposition in a significant percentage of patients. However, frank ossification within a tumor is extremely rare. We report a case of a 41-year-old male with a slow-growing left renal mass who underwent minimally invasive nephron-sparing surgery. Final pathology revealed clear cell renal cell carcinoma with focal areas of heterotopic bone formation. While prognostic implications of this variant are unclear, patients with renal cell carcinoma with osseous metaplasia can present with slow growth kinetics and early-stage disease.

Pelvic hemangiopericytoma: A case report and review of the literature.

Extrauterine pelvic hemangiopericytomas are rare tumors with malignant potential. Herein, we report a case of a 55-year-old male who presented with hydronephrosis and obstructive urinary symptoms. Cystoscopy, imaging and biopsy were unable to provide a definitive preoperative diagnosis. He underwent pelvic mass resection, and final pathology revealed malignant hemangiopericytoma. The patient is being closely monitored with serial imaging, and remains disease-free at 23 months of post-operative follow-up without adjuvant therapy. Our experience and evidence from the existing literature suggests that given the rarity of these tumors, adherence to standard oncologic principles is necessary to ensure adequate resection and appropriate follow-up.

Perioperative complications and oncological outcomes following radical cystectomy among different racial groups: A long-term, single-center study.

INTRODUCTION: Current literature on perioperative and oncological outcomes following radical cystectomy among different racial groups is limited, especially among Hispanics and Asians. The objective of this study was to assess the impact of racial differences on perioperative and oncological outcomes in a large cohort of bladder cancer patients who underwent radical cystectomy. METHODS: We retrospectively reviewed the records of 3293 patients who underwent radical cystectomy with curative intent at our institution between 1971 and 2017. Based on race, patients were categorized as Hispanic (n=190), Asian (n=145), African American (n=67), and Caucasian (n=2891). Baseline characteristics, pericystectomy complications, and oncological outcomes, including recurrence-free and overall survival, were compared between the racial groups. RESULTS: Mean patient age was 68±10.6 years. Median followup was 10.28 years. Body masss index and American Society of Anesthesiologists scores were significantly higher in Hispanic and African American population, and smoking incidence was lower in Asian patients. Hispanics presented with significantly higher clinical stage and longer time interval from diagnosis to treatment (mean 85.5 vs. 75.4 days in Caucasians, p<0.001). Overall 90-day complication and readmission rates were higher in Hispanics (41.06% and 18.95%, respectively). Oncological outcomes, however, were comparable between different race groups. In multivariate analysis, pathological nodal status and lymphovascular invasion were independent predictors of oncological outcomes, but race was not. CONCLUSIONS: In this very large, ethnically diverse patient cohort who underwent radical cystectomy with curative intent, pericystectomy complications were more common in Hispanics; however, race was not an independent predictor of long-term oncological outcome.

Internal audit of an enhanced recovery after surgery protocol for radical cystectomy.

PURPOSE: To perform an internal audit 5 years after implementation of our enhanced recovery after surgery (ERAS) protocol for patients undergoing radical cystectomy and to investigate the importance of physician driven compliance on outcomes. METHODS: Using a prospectively maintained database, 472 consecutive patients were identified who underwent radical cystectomy with ERAS from July 2013 to July 2017. Compliance was measured by a Composite Compliance Score (CCS) generated as a percentage of 16 interventions. Patients with higher than median compliance were compared to patients with lower compliance. The primary outcome was length of stay. Secondary outcomes included complication and readmission rates. Multivariable regressions were used to control for differences between groups. RESULTS: In 2013, median CCS was 81% and subsequently ranged from 81 to 88%. Five-year median CCS was 88%. Patients with higher compliance (CCS ≥ 88%, n = 262), as compared to those with lower compliance (CCS < 88%, n = 210), were younger (median 70.3 vs 72.7 years, p = 0.047), healthier (ASA3-4 81% vs 89.9%, p = 0.007), received more orthotopic diversions (59.2% vs 37.6%, p < 0.0001), more often had open surgery (78.5% vs 51.9%, p < 0.0001) and had shorter median operative times (5.5 vs 6.3 h, p = 0.005). Median length of stay was 4 days. Higher compliance was associated with shorter hospital stays (ß = - 0.85, 95% CI - 1.62 to - 0.07) and decreased 30-day readmissions (OR 0.58, 95% CI 0.35-0.96). CONCLUSIONS: Greater ERAS compliance was achieved in younger and healthier patients. Patients with greater compliance had a decreased length of stay by almost 1 day and reduced odds of 30-day readmissions.

Intensified and Standardized Digital Communication with Cystectomy Patients as a Potentially Simple and Effective Modality for Early Detection of Postoperative Complications: Results from a Pilot Study.

BACKGROUND: Postoperative readmission rates following radical cystectomy remain significant. Early identification of emerging complications could potentially allow for immediate institution of therapy. OBJECTIVE: To intensify postoperative patient-physician communication via a cellphone-based health care application (CHA) and to evaluate its potential for early detection of complications. DESIGN SETTING AND PARTICIPANTS: This was a pilot study involving 18 radical cystectomy patients. During the first 30 d, patients received a push cellphone notification twice a week requesting data input into the CHA. This was reduced to once a week from day 31 to day 90. De-identified recorded data were reviewed by the surgeon involved. If deemed necessary, patients were contacted by the surgeon via telephone to obtain more detailed clinical information. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics were used. RESULTS AND LIMITATIONS: Of the 18 patients enrolled, all completed the 90-d reporting period. On two occasions, interventions were necessary on the basis of data recorded on the CHA. One neobladder patient was given antibiotic therapy for pyelonephritis. Another patient reported weight loss and nausea with clinical suspicion of metabolic acidosis, and his sodium bicarbonate and fluid intake were increased. Limitations include the small number of cases from a single low-volume center. CONCLUSIONS: CHA-based monitoring of clinical parameters within the crucial 90-d postoperative period following radical cystectomy provides meaningful information. In this pilot study, two potential readmissions were possibly avoided on the basis of recorded basic vital signs and early intervention. PATIENT SUMMARY: Besides regular clinic follow-up visits after radical cystectomy, additional aids such as a cellphone-based health care application can provide treating physicians with relevant clinical information and may help to identify imminent deviations from normal postoperative recovery at an early stage.

Molecular markers in bladder cancer.

PURPOSE: Use of molecular markers in urine, tissue or blood offers potential opportunities to improve understanding of bladder cancer biology which may help identify disease earlier, risk stratify patients, improve prediction of outcomes or help target therapy. METHODS: A review of the published literature was performed, without restriction of time. RESULTS: Despite the fast-growing literature about the topic and the approval of several urinary biomarkers for use in clinical practice, they have not reached the level of evidence for widespread utilization. Biomarkers could be used in different clinical scenarios, mainly to overcome the limitations of current diagnostic, predictive, and prognostic tools. They have been evaluated to detect bladder cancer in asymptomatic populations or those with hematuria and in surveillance of disease as adjuncts to cystoscopy. There is also a potential role as prognosticators of disease recurrence, progression and survival both in patients with non-invasive cancers and in those with advanced disease. Finally, they promise to be helpful in predicting the response to local and/or systemic chemotherapy and/or immunotherapy. CONCLUSIONS: To date, due to the lack of high-quality prospective trials, the level of evidence provided by the current literature remains low and, therefore, the potential of biomarkers exceeds utilization in clinical practice.

Implications of micropapillary urothelial carcinoma variant on prognosis following radical cystectomy: A multi-institutional investigation.

PURPOSE: To determine the association of micropapillary urothelial carcinoma (MUC) variant histology with bladder cancer outcomes after radical cystectomy. MATERIALS AND METHODS: Information on MUC patients treated with radical cystectomy was obtained from five academic centers. Data on 1,497 patients were assembled in a relational database. Tumor histology was categorized as urothelial carcinoma without any histological variants (UC; n = 1,346) or MUC (n = 151). Univariable and multivariable models were used to analyze associations with recurrence-free (RFS) and overall (OS) survival. RESULTS: Median follow-up was 10.0 and 7.8 years for the UC and MUC groups, respectively. No significant differences were noted between UC and MUC groups with regard to age, gender, clinical disease stage, and administration of neoadjuvant and adjuvant chemotherapy (all, P ≥ 0.10). When compared with UC, presence of MUC was associated with higher pathologic stage (organ-confined, 60% vs. 27%; extravesical, 18% vs. 23%; node-positive, 22% vs. 50%; P < 0.01) and lymphovascular invasion (29% vs. 58%; P < 0.01) at cystectomy. In comparison with UC, MUC patients had poorer 5-year RFS (70% vs. 44%; P < 0.01) and OS (61% vs. 38%; P < 0.01). However, on multivariable analysis, tumor histology was not independently associated with the risks of recurrence (P = 0.27) or mortality (P = 0.12). CONCLUSIONS: This multi-institutional analysis demonstrated that the presence of MUC was associated with locally advanced disease at radical cystectomy. However, clinical outcomes were comparable to those with pure UC after controlling for standard clinicopathologic predictors.

Molecular Prognostication in Bladder Cancer.

Clinical outcomes for patients with bladder cancer have largely remained unchanged over the last three decades despite improvements in surgical techniques, perioperative therapies, and postoperative management. Current management still heavily relies on pathologic staging that does not always reflect an individual patient's risk. The genesis and progression of bladder cancer is now increasingly recognized as being a result of alterations in several pathways that affect the cell cycle, apoptosis, cellular signaling, gene regulation, immune modulation, angiogenesis, and tumor cell invasion. Multiplexed assessment of biomarkers associated with alterations in these pathways offers novel insights into tumor behavior while identifying panels that are capable of reproducibly predicting patient outcomes. Future management of bladder cancer will likely incorporate such prognostic molecular models for risk stratification and treatment personalization.

Molecular substratification of bladder cancer: moving towards individualized patient management.

Despite advances in surgical techniques, perioperative therapies and postoperative management, outcomes for patients with bladder cancer have largely remained unchanged. Current management of bladder cancer still relies on pathologic staging that does not always reflect the risk for an individual patient. Studies assessing molecular alterations in individual tumors are offering insights into the myriad of cellular pathways that are deregulated in bladder tumorigenesis and progression. Alterations in pathways involved in cell-cycle regulation, apoptosis, cell signaling, angiogenesis and tumor-cell invasion have been shown to influence disease behavior. High-throughput assays are now allowing multiplexed assessment of biomarker alterations, thereby enabling characterization of novel molecular subtypes of bladder cancer. Such approaches have also been used for discovery and validation of robust prognostic molecular signatures. The future of bladder cancer management will rely on the use of validated multimarker panels for risk stratification, optimal surgical management, and theranostic strategies to identify and target specific alterations in individual tumors.