Use of a physical activity monitor to track perioperative activity of radical cystectomy patients. Our first glimpse at what our patients are doing before and after surgery.

PURPOSE: To optimize recovery after radical cystectomy (RC), providers stress the importance of ambulation and adequate rest. However, little is known about the activity and sleep habits of patients undergoing RC. Therefore, we utilized a wearable physical activity monitor (PAM) in the perioperative period to provide the first objective data on physical activity and sleep habits for RC patients. MATERIALS AND METHODS: We prospectively identified patients ≥60 years old with planned RC. Participants completed a 4-week prehabilitation exercise program prior to surgery. They wore a PAM for 7-day intervals: at baseline, after prehabilitation, at postoperative day (POD) 30 and POD90. We tracked physical activity via metabolic equivalents (METs). METs were categorized by intensity: light (MET 1.5-<3), moderate (MET 3-<6), and vigorous (MET ≥6). We calculated daily step totals. We tracked hours slept and number of sleep awakenings. We correlated activity and sleep with self-reported quality of life (QOL). RESULTS: Forty-two patients completed prehabilitation and RC. Moderate intensity exercise decreased at POD30 (61 minutes/d at baseline, 30 minutes/d at POD30, P = 0.005). Physical activity did not significantly differ for light or vigorous activity at any timepoint. RC did not significantly affect sleep. Sleep and physical activity were associated with mental and physical QOL, respectively. CONCLUSIONS: This is the first study utilizing patient-worn monitors in RC to track physical activity and sleep. This study gives patients and providers a better understanding of postcystectomy recovery expectations. With these results in mind, interventions may be implemented to optimize activity and sleep in the perioperative period.

Computerized Decision Support for Bladder Cancer Treatment Response Assessment in CT Urography: Effect on Diagnostic Accuracy in Multi-Institution Multi-Specialty Study.

This observer study investigates the effect of computerized artificial intelligence (AI)-based decision support system (CDSS-T) on physicians' diagnostic accuracy in assessing bladder cancer treatment response. The performance of 17 observers was evaluated when assessing bladder cancer treatment response without and with CDSS-T using pre- and post-chemotherapy CTU scans in 123 patients having 157 pre- and post-treatment cancer pairs. The impact of cancer case difficulty, observers' clinical experience, institution affiliation, specialty, and the assessment times on the observers' diagnostic performance with and without using CDSS-T were analyzed. It was found that the average performance of the 17 observers was significantly improved (p = 0.002) when aided by the CDSS-T. The cancer case difficulty, institution affiliation, specialty, and the assessment times influenced the observers' performance without CDSS-T. The AI-based decision support system has the potential to improve the diagnostic accuracy in assessing bladder cancer treatment response and result in more consistent performance among all physicians.

Comparison of Robot-Assisted and Open Radical Cystectomy in Recovery of Patient-Reported and Performance-Related Measures of Independence: A Secondary Analysis of a Randomized Clinical Trial.

Importance: No data exist on time to recovery of patient-reported and performance-related measures of functional independence after radical cystectomy (open or robotic). Objective: To determine recovery of functional independence after radical cystectomy and whether robot-assisted radical cystectomy (RARC) is associated with any advantage over open procedures. Design, Setting, and Participants: Data for this secondary analysis from the RAZOR (Randomized Open vs Robotic Cystectomy) trial were used. RAZOR was a phase 3 multicenter noninferiority trial across 15 academic medical centers in the US from July 1, 2011, to November 18, 2014, with a median follow-up of 2 years. Participants included the per-protocol population (n = 302). Data were analyzed from February 1, 2017, to May 1, 2021. Interventions: Robot-assisted radical cystectomy or open radical cystectomy (ORC). Main Outcomes and Measures: Patient-reported (activities of daily living [ADL] and independent ADL [iADL]) and performance-related (hand grip strength [HGS] and Timed Up & Go walking test [TUGWT]) measures of independence were assessed. Patterns of postoperative recovery for the entire cohort and comparisons between RARC and ORC were performed. Exploratory analyses to assess measures of independence across diversion type and to determine whether baseline impairments were associated with 90-day complications or 1-year mortality were performed. Findings: Of the 302 patients included in the analysis (254 men [84.1%]; mean [SD] age at consent, 68.0 [9.7] years), 150 underwent RARC and 152 underwent ORC. Baseline characteristics were similar in both groups. For the entire cohort, ADL, iADL, and TUGWT recovered to baseline by 3 postoperative months, whereas HGS recovered by 6 months. There was no difference between RARC and ORC for ADL, iADL, TUGWT, or HGS scores at any time. Activities of daily living recovered 1 month after RARC (mean estimated score, 7.7 [95% CI, 7.3-8.0]) vs 3 months after ORC (mean estimated score, 7.5 [95% CI, 7.2-7.8]). Hand grip strength recovered by 3 months after RARC (mean estimated HGS, 29.0 [95% CI, 26.3-31.7] kg) vs 6 months after ORC (mean estimated HGS, 31.2 [95% CI, 28.8-34.2] kg). In the RARC group, 32 of 90 patients (35.6%) showed a recovery in HGS at 3 months vs 32 of 88 (36.4%) in the ORC group (P = .91), indicating a rejection of the primary study hypothesis for HGS. Independent ADL and TUGWT recovered in 3 months for both approaches. Hand grip strength showed earlier recovery in patients undergoing continent urinary diversion (mean HGS at 3 months, 31.3 [95% CI, 27.7-34.8] vs 33.9 [95% CI, 30.5-37.3] at baseline; P = .09) than noncontinent urinary diversion (mean HGS at 6 months, 27.4 [95% CI, 24.9-30.0] vs 29.5 [95% CI, 27.2-31.9] kg at baseline; P = .02), with no differences in other parameters. Baseline impairments in any parameter were not associated with 90-day complications or 1-year mortality. Conclusions and Relevance: The results of this secondary analysis suggest that patients require 3 to 6 months to recover baseline levels after radical cystectomy irrespective of surgical approach. These data will be invaluable in patient counseling and preparation. Hand grip strength and ADL tended to recover to baseline earlier after RARC; however, there was no difference in the percentage of patients recovering when compared with ORC. Further study is needed to assess the clinical significance of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT01157676.

TERT Promoter Mutations in Keratinizing and Nonkeratinizing Squamous Metaplasia of the Urinary Tract.

We identified urothelial tract biopsy and resection specimens with keratinizing squamous metaplasia (KSM), nonkeratinizing squamous metaplasia (NKSM), and urothelial and squamous carcinomas over a 20-yr period, focusing on cases with neurogenic lower urinary tract dysfunction (NLUTD) and/or those with spatial or temporal variation in sampling. TERT promoter mutations as assessed via allele-specific polymerase chain reaction were surprisingly common in our testing cohort, identified not only in 15 (94%) invasive cancer foci but also in 13 (68%) examples of KSM and seven (70%) examples of NKSM. TERT promoter mutations were present in 23 foci from NLUTD specimens and 11 foci from bladder diverticula, including in foci of KSM, NKSM, and unremarkable urothelium from cases with no clinical association with previous, concurrent, or subsequent cancer. Our demonstration of temporally and spatially persistent TERT promoter mutation in examples of KSM and NKSM in cases of bladder cancer and in morphologically benign cases with neurogenic dysfunction suggests a molecular mechanism by which such pre-neoplastic lesions can potentially progress and develop into overt carcinoma. Given the interest in TERT promoter mutations as a potential biomarker for the development of bladder cancer, these findings possibly explain the association between conditions with chronic urinary bladder injury (such as the natural history of NLUTD) and higher risk of bladder cancer. TERT promoter mutations may represent an early event in bladder cancer tumorogenesis, and our findings expand on the clinical ramifications and predictive value of TERT promoter mutations in this context. PATIENT SUMMARY: Mutations in the TERT gene are the most common genetic changes in bladder cancer. We found that these mutations are also sometimes present in patients with chronic bladder irritation such as neurogenic bladder dysfunction and changes to the lining of the bladder that pathologists would consider "benign." This finding might explain why such conditions are associated with the development of bladder cancer.

Understanding the Barriers to Neoadjuvant Chemotherapy in Patients with Muscle Invasive Bladder Cancer: A Quality Improvement Initiative.

PURPOSE: Utilization of neoadjuvant chemotherapy (NAC) for the management of muscle-invasive bladder cancer remains low. We sought to understand our practice of NAC use in order to design a quality improvement initiative geared towards optimizing medical oncology referral. MATERIALS AND METHODS: We identified 339 patients with ≥cT2 bladder cancer treated with radical cystectomy between 2012-2017 at our institution. We assessed the rate of referral to medical oncology, rate of NAC administration, as well as medical, patient and provider variables associated with NAC use. Bayesian logistic regression modeling identified variables associated with NAC use and chart review provided granular patient-level data. RESULTS: 85% (n=289) of patients were referred to medical oncology and 62.5% (n=212) received NAC. Renal insufficiency, hearing loss, and treating urologist were conclusively associated with lower odds of NAC use. 46 patients were not referred to medical oncology and 50% of these had medical contraindications to cisplatin cited as the reason for no referral. 38 patients met with medical oncology but did not receive NAC. 30 (79%) had comorbidities that impacted this decision with 15 (39%) ineligible based on impaired renal function. CONCLUSIONS: Despite the relatively high rates of medical oncology referral and NAC use in this cohort, there are still opportunities to improve the efficiency of this practice. Quality improvement initiatives could optimize the referral of patients with ≥T2 bladder cancer for consideration of cisplatin-based NAC and establish an important quality metric in the management of these patients.

Partial nephrectomy should be classified as an inpatient procedure: Results from a statewide quality improvement collaborative.

OBJECTIVES: To examine length of stay (LOS) and readmission rates for all minimally-invasive partial nephrectomy (MIPN) and MI radical nephrectomy (MIRN) performed for localized renal masses ≤7 cm in size (cT1RM) within 12 Michigan urology practices. Both RN and PN are commonly performed in treating cT1RM. Although technically more complex and associated with higher complication rates, Centers for Medicare & Medicaid Services considers MIPN an outpatient procedure and MIRN is inpatient. METHODS: We collected data for renal surgeries for cT1RM at MUSIC-KIDNEY practices between May 2017-February 2020. Data abstractors recorded clinical, radiographic, pathologic, surgical, and short-term follow-up data into the registry for cT1RM patients. RESULTS: Within MUSIC-KIDNEY, 807 patients underwent MI renal surgery at 12 practices. Median LOS for cT1RM patients after MIPN (n = 531, 66%) was 2 days and after MIRN (n = 276, 34%) was also 2 days. Among patients undergoing laparoscopic or robotic PN, 171 (32%), 230 (43%), and 130 (24%) stayed ≤1, 2, ≥3 days. Among patients undergoing laparoscopic or robotic RN, 81 (29%), 112 (41%), and 83 (30%) stayed ≤1, 2, ≥3 days. No significant difference was observed between MIPN and MIRN on LOS commensurate with outpatient surgery (≤1-day, OR = 0.97, P = 0.87). CONCLUSIONS: Less than one-third of patients had a LOS ≤1-day and LOS was comparable for MIPN and MIRN. Centers for Medicare & Medicaid Services should be advised that MIPN is a more complex surgery than MIRN, most patients receiving a MIPN will require a ≥2-day hospital stay and it would be more appropriate to classify MIPN an inpatient procedure with MIRN.

Validation of an mRNA-based Urine Test for the Detection of Bladder Cancer in Patients with Haematuria.

BACKGROUND: In patients with haematuria, a fast, noninvasive test with high sensitivity (SN) and negative predictive value (NPV), which is able to detect or exclude bladder cancer (BC), is needed. A newly developed urine assay, Xpert Bladder Cancer Detection (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC. OBJECTIVE: To validate the performance of Xpert in patients with haematuria. DESIGN, SETTING, AND PARTICIPANTS: Voided precystoscopy urine specimens were prospectively collected at 22 sites from patients without prior BC undergoing cystoscopy for haematuria. Xpert, cytology, and UroVysion procedures were performed. Technical validation was performed and specificity (SP) was determined in patients without BC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion. RESULTS AND LIMITATIONS: We included 828 patients (mean age 64.5 yr, 467 males, 401 never smoked). Xpert had an SN of 78% (95% confidence interval [CI]: 66-87) overall and 90% (95% CI: 76-96) for high-grade (HG) tumours. The NPV was 98% (95% CI: 97-99) overall. The SP was 84% (95% CI: 81-86). In patients with microhaematuria, only one HG patient was missed (NPV 99%). Xpert had higher SN and NPV than cytology and UroVysion. Cytology had the highest SP (97%). In a separate SP study, Xpert had an SP of 89% in patients with benign prostate hypertrophy and 92% in prostate cancer patients. CONCLUSIONS: Xpert is an easy-to-use, noninvasive test with improved SN and NPV compared with cytology and UroVysion, representing a promising tool for identifying haematuric patients with a low likelihood of BC who might not need to undergo cystoscopy. PATIENT SUMMARY: Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help identify (micro)haematuria patients with a very low likelihood to have bladder cancer.

The Feasibility and Impact of a Presurgical Exercise Intervention Program (Prehabilitation) for Patients Undergoing Cystectomy for Bladder Cancer.

OBJECTIVE: To assess the feasibility of a prehabilitation program for cystectomy patients and to determine the effectiveness of the program in improving strength and functional capacity in the peri-operative period. MATERIALS AND METHODS: This phase I/II study accrued patients ≥60 years old from January 2013 to October 2017 with biopsy-proven bladder cancer, Karnofsky performance score ≥70 and a sedentary baseline lifestyle to participate in a 4-week supervised preoperative exercise training program. Primary outcomes were feasibility and safety; secondary outcomes included changes in fitness, patient-reported QOL, peri-operative complications and readmissions. Student's ttests and Wilcoxon signed-rank test were performed. RESULTS: Fifty-four patients enrolled in the program. Successful completion, defined as patients who began the program and adhered to >70% of the sessions, was attained by 41 of 51 patients (80.4%, 90% CI [71%-90%]). There were no adverse events. Fitness and patient-reported QOL improved postintervention, with sustained improvements in general and mental health 90-days postsurgery. The primary limitation is no control group. CONCLUSION: Prehabilitation prior to cystectomy is feasible, safe, and results in improvements in patient strength, endurance and sustained improvements in patient-reported QOL from baseline. Efforts to further evaluate the impact of prehabilitation in this population in an expanded and randomized fashion are warranted.

Rethinking the one-size-fits-most approach to venous thromboembolism prophylaxis after radical cystectomy.

OBJECTIVES: Empirically dosed enoxaparin is routinely given in the postoperative period for venous thromboembolism (VTE) prophylaxis after radical cystectomy (RC). Patient-specific factors may alter its pharmacokinetics, and it is unclear whether this leads to levels sufficient for antithrombosis. We sought to evaluate variability of anti-factor Xa levels in a cohort of RC patients receiving perioperative enoxaparin prophylaxis. MATERIAL AND METHODS: Patients undergoing RC at a single institution were placed on a postoperative pathway that included enoxaparin. An anti-factor Xa level was drawn 2 to 4 hours after the third dose. The target range for prophylaxis was 0.3 IU/ml to 0.5 IU/ml. RESULTS: The primary outcome was anti-factor Xa level. Demographics, operative time, hospital course, and 30-days post-operative VTE were compared by anti-factor Xa level group using univariate and multivariable analyses. Between January 2018 and 2019, 107 RC patients remained on pathway and were included in our analysis. Sixty-five (61%) were below target range for VTE prophylaxis.  A single VTE event (0.9%) occurred in a subprophylactic individual. The subprophylactic group had a significantly higher body mass index (P < 0.01) than those within target range. CONCLUSIONS: Higher body mass index was associated with subprophylactic enoxaparin dosing after RC. Nearly two-thirds of patients had below target anti-factor Xa levels. This suggests that dosing could be further individualized, but given the low incidence of VTE, implications of dose-adjusted prophylaxis on VTE prevention remain unknown.

Intraobserver Variability in Bladder Cancer Treatment Response Assessment With and Without Computerized Decision Support.

We evaluated the intraobserver variability of physicians aided by a computerized decision-support system for treatment response assessment (CDSS-T) to identify patients who show complete response to neoadjuvant chemotherapy for bladder cancer, and the effects of the intraobserver variability on physicians' assessment accuracy. A CDSS-T tool was developed that uses a combination of deep learning neural network and radiomic features from computed tomography (CT) scans to detect bladder cancers that have fully responded to neoadjuvant treatment. Pre- and postchemotherapy CT scans of 157 bladder cancers from 123 patients were collected. In a multireader, multicase observer study, physician-observers estimated the likelihood of pathologic T0 disease by viewing paired pre/posttreatment CT scans placed side by side on an in-house-developed graphical user interface. Five abdominal radiologists, 4 diagnostic radiology residents, 2 oncologists, and 1 urologist participated as observers. They first provided an estimate without CDSS-T and then with CDSS-T. A subset of cases was evaluated twice to study the intraobserver variability and its effects on observer consistency. The mean areas under the curves for assessment of pathologic T0 disease were 0.85 for CDSS-T alone, 0.76 for physicians without CDSS-T and improved to 0.80 for physicians with CDSS-T (P = .001) in the original evaluation, and 0.78 for physicians without CDSS-T and improved to 0.81 for physicians with CDSS-T (P = .010) in the repeated evaluation. The intraobserver variability was significantly reduced with CDSS-T (P < .0001). The CDSS-T can significantly reduce physicians' variability and improve their accuracy for identifying complete response of muscle-invasive bladder cancer to neoadjuvant chemotherapy.

Health Related Quality of Life of Patients with Bladder Cancer in the RAZOR Trial: A Multi-Institutional Randomized Trial Comparing Robot versus Open Radical Cystectomy.

PURPOSE: We evaluated health related quality of life following robotic and open radical cystectomy as a treatment for bladder cancer. MATERIALS AND METHODS: Using the Randomized Open versus Robotic Cystectomy (RAZOR) trial population we assessed health related quality of life by using the Functional Assessment of Cancer Therapy (FACT)-Vanderbilt Cystectomy Index and the Short Form 8 Health Survey (SF-8) at baseline, 3 and 6 months postoperatively. The primary objective was to assess the impact of surgical approach on health related quality of life. As an exploratory analysis we assessed the impact of urinary diversion type on health related quality of life. RESULTS: Analyses were performed in subsets of the per-protocol population of 302 patients. There was no statistically significant difference between the mean scores by surgical approach at any time point for any FACT-Vanderbilt Cystectomy Index subscale or composite score (p >0.05). The emotional well-being score increased over time in both surgical arms. Patients in the open arm showed significantly better SF-8 sores in the physical and mental summary scores at 6 months compared to baseline (p <0.05). Continent diversion (versus noncontinent) was associated with worse FACT-bladder-cystectomy score at 3 (p <0.01) but not at 6 months, and the SF-8 physical component was better in continent-diversion patients at 6 months (p=0.019). CONCLUSIONS: Our data suggests lack of significant differences in the health related quality of life in robotic and open cystectomies. As robotic procedures become more widespread it is important to discuss this finding during counseling.

Multiparameter urine analysis for quantitative bladder cancer surveillance of orthotopic xenografted mice.

The human-derived orthotopic xenograft mouse model is an effective platform for performing in vivo bladder cancer studies to examine tumor development, metastasis, and therapeutic effects of drugs. To date, the surveillance of tumor progression in real time for orthotopic bladder xenografts is highly dependent on semi-quantitative in vivo imaging technologies such as bioluminescence. While these imaging technologies can estimate tumor progression, they are burdened with requirements such as anesthetics, specialized equipment, and genetic modification of the injected cell line. Thus, a convenient and non-invasive technology to quantitatively monitor the growth of bladder cancer in orthotopic xenografts is highly desired. In this work, using a microfluidic chemiluminescent ELISA platform, we have successfully developed a rapid, multiparameter urine-based and non-invasive biomolecular prognostic technology for orthotopic bladder cancer xenografts. This method consists of two steps. First, the concentrations of a panel of four urinary biomarkers are quantified from the urine of mice bearing orthotopic bladder xenografts. Second, machine learning and principal component analysis (PCA) algorithms are applied to analyze the urinary biomarkers, and subsequently, a score is assigned to indicate the tumor growth. With this methodology, we have quantitatively monitored the orthotopic growth of human bladder cancer that was inoculated with low, medium, and high cancer cell numbers. We also employed this method and performed a proof of principle experiment to examine the in vivo therapeutic efficacy of the EGFR inhibitor, dacomitinib.

Predictors of Recurrence, and Progression-Free and Overall Survival following Open versus Robotic Radical Cystectomy: Analysis from the RAZOR Trial with a 3-Year Followup.

PURPOSE: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival. MATERIALS AND METHODS: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis. RESULTS: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome. CONCLUSIONS: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Quality Indicators for Bladder Cancer Services: A Collaborative Review.

CONTEXT: There is a lack of accepted consensus on what should constitute appropriate quality-of-care indicators for bladder cancer. OBJECTIVE: To evaluate the optimal management of bladder cancer and propose quality indicators (QIs). EVIDENCE ACQUISITION: A systematic review was performed to identify literature on current optimal management and potential quality indicators for both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancer. A panel of experts was convened to select a recommended list of QIs. EVIDENCE SYNTHESIS: For NMIBC, preoperative QIs include tobacco cessation counselling and appropriate imaging before initial transurethral resection of bladder tumour (TURBT). Intraoperative QIs include administration of antibiotics, proper safe conduct of TURBT using a checklist, and performing restaging TURBT with biopsy of the prostatic urethra in appropriate cases. Postoperative QIs include appropriate receipt of perioperative adjuvant therapy, risk-stratified surveillance, and appropriate decision to change therapy when indicated (eg, bacillus Calmette-Guerin [BCG] unresponsive). For MIBC, preoperative QIs include multidisciplinary care, selection for candidates for continent urinary diversion, receipt of neoadjuvant cisplatin-based chemotherapy, time to commencing radical treatment, consideration of trimodal therapy as a bladder-sparing alternative in select patients, preoperative counselling with stoma marking, surgical volume of radical cystectomy, and enhanced recovery after surgery protocols. Intraoperative QIs include adequacy of lymphadenectomy, blood loss, and operative time. Postoperative QIs include prospective standardised monitoring of morbidity and mortality, negative surgical margins for pT2 disease, appropriate surveillance after primary treatment, and adjuvant cisplatin-based chemotherapy in appropriate cases. Participation in clinical trials was highlighted as an important component indicating high quality of care. CONCLUSIONS: We propose a set of QIs for both NMIBC and MIBC based on established clinical guidelines and the available literature. Although there is currently a lack of level 1 evidence for the benefit of implementing these QIs, we believe that the measurement of these QIs could aid in the improvement and benchmarking of optimal care for bladder cancer. PATIENT SUMMARY: After a systematic review of existing guidelines and literature, a panel of experts has recommended a set of quality indicators that can help providers and patients measure and strive towards optimal outcomes for bladder cancer care.

Clinicopathological characterisation of renal cell carcinoma in young adults: a contemporary update and review of literature.

AIMS: Renal cell carcinomas are relatively rare in children and young adults. While well characterised in adults, the morphological and molecular characterisation of these tumours in young patients is relatively lacking. The objective of this study was to explore the spectrum of renal cell carcinoma (RCC) subtypes in children and young adults and to determine their clinico-pathological, immunohistochemical and molecular characteristics by evaluating a large retrospective cohort of renal cell carcinoma patients age 30 years or younger. METHODS AND RESULTS: Sixty-eight cases with confirmed diagnosis of renal cell carcinoma at age 30 years or younger were identified at our institution. Clear cell carcinoma accounted for the most common subtype seen in this age group. Translocation renal cell carcinoma and rare familial syndrome subtypes such as succinate dehydrogenase deficient renal cell carcinoma and tuberous sclerosis complex-associated renal cell carcinoma were found relatively more frequently in this cohort. Despite applying the 2016 WHO classification criteria, a high proportion of the tumours in our series remained unclassified. CONCLUSIONS: Our results suggest that renal cell carcinoma in children and young adults is a relatively rare disease that shares many histological similarities to renal cell carcinoma occurring in adults and yet demonstrate some unique clinical-pathological differences. Microphthalmia-associated transcription (MiT) family translocation RCC and rare familial syndrome subtypes are relatively more frequent in the paediatric and adolescent age groups than in adults. Clear cell RCC still accounted for the most common subtype seen in this age group. MiT family translocation RCC patients presented with advanced stage disease and had poor clinical outcomes. The large and heterogeneous subgroup of unclassified renal cell carcinoma contains phenotypically distinct tumours with further potential for future subcategories in the renal cell carcinoma classification.

PTRF independently predicts progression and survival in multiracial upper tract urothelial carcinoma following radical nephroureterectomy.

OBJECTIVES: Polymerase I and transcript release factor (PTRF) has been implicated in cancer biology but its role in upper tract urothelial carcinoma (UTUC) is unknown. From a pilot transcriptome, we identified PTRF was significantly upregulated in high stage UTUC. Bladder cancer transcriptome from The Cancer Genome Atlas (TCGA) supported our finding and high PTRF level also predicted poor survival. We, therefore, investigated the correlation of PTRF with patients' clinicopathologic characteristics and outcomes in a multiracial UTUC cohort. MATERIALS AND METHODS: By immunohistochemical staining, PTRF expression was determined using H-score. PTRF expression of 575 UTUCs from 8 institutions, including 118 Asians and 457 Caucasians, was compared with various clinicopathologic parameters. Human urothelial cancer cell lines were used to evaluate the level of PTRF protein and mRNA expression, and PTRF transcript level was assessed in fresh samples from 12 cases of the cohort. The impact of PTRF expression on disease progression, cancer-specific death and overall mortality was also examined. RESULTS: High PTRF expression was significantly associated with multifocality (P = 0.023), high pathologic tumor stage (P < 0.00001), nonurothelial differentiation (P = 0.035), lymphovascular invasion (P = 0.003) and lymph node metastasis (P = 0.031). PTRF mRNA expression was also markedly increased in advanced stage UTUC (P = 0.0003). High PTRF expressing patients had consistently worse outcomes than patients with low PTRF expression regardless of demographic variation (all P < 0.005). In multivariate analysis, high PTRF expression was an independent predictor for progression-free survival (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.07-2.69, P = 0.025), cancer-specific survival (HR 2.09, 95% CI 1.28-3.42, P = 0.003), and overall survival (HR 2.04, 95% CI 1.33-3.14, P = 0.001). CONCLUSIONS: Results indicate that PTRF is a predictive biomarker for progression and survival and an independent prognosticator of UTUC. Elevated PTRF could probably propel clinically aggressive disease and serve as a potential therapeutic target for UTUC.

Clinical and morphologic review of 60 hereditary renal tumors from 30 hereditary renal cell carcinoma syndrome patients: lessons from a contemporary single institution series.

Hereditary renal cell carcinoma syndromes (HRCCS) are characterized by the presence of pathogenic germline variants that predispose patients to renal cell carcinomas as well as additional extra-renal manifestations. The importance of identifying HRCCS patients cannot be overemphasized, as patients and their families can begin surveillance for syndrome-associated manifestations once identified. The present study is a retrospective clinical and morphologic review of 60 hereditary renal tumors from 30 HRCCS patients treated at our institution with either Von Hippel-Lindau disease (VHL), Birt-Hogg-Dubé syndrome (BHD), tuberous sclerosis complex (TSC), hereditary leiomyomatosis and renal cell cancer syndrome, or succinate dehydrogenase (SDH) deficiency syndrome. Hereditary renal cell carcinoma syndromes kidney tumors often demonstrate specific morphologic features, characteristic background changes in renal parenchyma, and extra-renal manifestations, which, when recognized by the pathologist, can trigger genetic testing referral for specific familial cancer syndromes. Our study demonstrates the majority of tumors were consistent with the anticipated clinicopathologic profile of renal tumors found within HRCCS patients, although we found some unique characteristics within this cohort including a case of clear cell papillary renal cell carcinoma within a VHL patient, and a unique renal tumor with tubulopapillary features present in a patient with a germline SDHD mutation. Additionally, although the literature reports the presence of epithelioid angiomyolipoma (AML) as a common occurrence in TSC patients, our cohort of 3 patients with AMLs demonstrated only classic features. The findings we describe facilitate pathologist-based recognition of HRCCS and can prompt genetic evaluation for relevant patients.

Deep Learning Approach for Assessment of Bladder Cancer Treatment Response.

We compared the performance of different Deep learning-convolutional neural network (DL-CNN) models for bladder cancer treatment response assessment based on transfer learning by freezing different DL-CNN layers and varying the DL-CNN structure. Pre- and posttreatment computed tomography scans of 123 patients (cancers, 129; pre- and posttreatment cancer pairs, 158) undergoing chemotherapy were collected. After chemotherapy 33% of patients had T0 stage cancer (complete response). Regions of interest in pre- and posttreatment scans were extracted from the segmented lesions and combined into hybrid pre -post image pairs (h-ROIs). Training (pairs, 94; h-ROIs, 6209), validation (10 pairs) and test sets (54 pairs) were obtained. The DL-CNN consisted of 2 convolution (C1-C2), 2 locally connected (L3-L4), and 1 fully connected layers. The DL-CNN was trained with h-ROIs to classify cancers as fully responding (stage T0) or not fully responding to chemotherapy. Two radiologists provided lesion likelihood of being stage T0 posttreatment. The test area under the ROC curve (AUC) was 0.73 for T0 prediction by the base DL-CNN structure with randomly initialized weights. The base DL-CNN structure with pretrained weights and transfer learning (no frozen layers) achieved test AUC of 0.79. The test AUCs for 3 modified DL-CNN structures (different C1-C2 max pooling filter sizes, strides, and padding, with transfer learning) were 0.72, 0.86, and 0.69. For the base DL-CNN with (C1) frozen, (C1-C2) frozen, and (C1-C2-L3) frozen, the test AUCs were 0.81, 0.78, and 0.71, respectively. The radiologists' AUCs were 0.76 and 0.77. DL-CNN performed better with pretrained than randomly initialized weights.

Prognostic significance of BAP1 expression in high-grade upper tract urothelial carcinoma: a multi-institutional study.

PURPOSE: To evaluate the prognostic value of BRCA1-associated protein-1 (BAP1) expression in upper tract urothelial carcinoma (UTUC), as BAP1 mutations have been associated with prognostic implications in urologic and non-urologic malignancies. METHODS: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990-2008. Immunohistochemistry (IHC) for BAP1 was performed on tissue microarrays. Staining intensity was graded from 0-3, with BAP1 loss defined as an average intensity of < 1. Clinicopathologic characteristics and oncologic outcomes [recurrencefree (RFS), cancer-specific (CSS), and overall survival (OS)] were stratified by BAP1 status. The prognostic role of BAP1 was assessed using Kaplan-Meier (KM) and Cox regression analysis. Significance was defined as p < 0.05. RESULTS: 348 patients were included for analysis and 173 (49.7%) showed BAP1 loss. Median follow-up was 36.0 months. BAP1 loss was associated with papillary architecture and absence of tumor necrosis or CIS. On univariable analysis, BAP1 loss was associated with improved RFS (HR 0.60, p = 0.013) and CSS (HR 0.55, p = 0.007), although significance was lost on multivariable analysis (HR 0.71, p = 0.115 and HR 0.65, p = 0.071; respectively) after adjusting for other significant parameters. BAP1 expression was not significantly associated with OS. CONCLUSIONS: BAP1 loss was associated with favorable pathologic features and better oncologic outcomes in univariate but not multivariate analysis in patients with high-grade UTUC. In contrast to renal cell carcinoma, loss of BAP1 expression appears to confer a better prognosis in high-grade UTUC. The role of the BAP1 pathway in UTUC pathogenesis remains to be further elucidated.