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Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.

BACKGROUND: Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. METHODS: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. FINDINGS: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5-13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3-4·8] vs 2·8 months [2·6-2·9]; HR 0·696 [95% CI 0·573-0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9-11·4) in the ramucirumab group versus 7·9 months (7·0-9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724-1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. INTERPRETATION: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. FUNDING: Eli Lilly and Company.

BackgroundLower urinary tract transitional cell carcinoma (TCC) is an important but rarely described disease of cats.ObjectivesTo report the clinical characteristics, treatments, and outcomes in a cohort of cats with lower urinary tract TCC and to test identified variables for prognostic relevance.AnimalsOne-hundred eighteen client-owned cats with lower urinary tract carcinoma.MethodsMedical records were retrospectively reviewed to obtain information regarding clinical characteristics, treatments, and outcomes. Recorded variables were analyzed statistically.ResultsMedian age of affected cats was 15 years (range, 5.0-20.8 years) and median duration of clinical signs was 30 days (range, 0-730 days). The trigone was the most common tumor location (32/118; 27.1%) as assessed by ultrasound examination, cystoscopy, or both. Treatment was carried out in 73 of 118 (61.9%) cats. Metastatic disease was documented in 25 of 118 (21.2%) cats. Median progression-free survival and survival time for all cats were 113 days (95% confidence interval [CI], 69-153) and 155 days (95% CI, 110-222), respectively. Survival increased significantly (P

Purpose The aim of this study was to investigate the association between angiolymphatic invasion (ALI) and bladder cancer in patients who underwent radical cystectomy (RC). Materials and Methods Multicenter retrospective data from 495 bladder cancer patients who underwent RC between 2007 and 2019 were enrolled in this study. Patients were stratified into 2 groups according to the presence of ALI. The effect of ALI was analyzed by the Kaplan-Meier method and Cox regression hazard models for patients’ cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS). Results The median age of the 495 patients in the study was 65 years, with median and mean follow-up durations of 23.3 months and 37.1 months, respectively. ALI was present in 182 patients (36.8%). ALI was significantly associated with worse RFS as well as CSS and OS (p

Background The relationship between cystitis glandularis (CG) and bladder malignancy remains unclear. Methods We identified the oncologic significance of CG at the molecular level using liquid chromatography-tandem mass spectrometry-based proteomic analysis of 10 CG, 12 urothelial carcinoma (UC), and nine normal urothelium (NU) specimens. Differentially expressed proteins (DEPs) were identified based on an analysis of variance false discovery rate < 0.05, and their functional enrichment was analyzed using a network model, Gene Set Enrichment Analysis, and Gene Ontology annotation. Results We identified 9,890 proteins across all samples and 1,139 DEPs among the three entities. A substantial number of DEPs overlapped in CG/NU, distinct from UC. Interestingly, we found that a subset of DEP clusters (n = 53, 5%) was differentially expressed in NU but similarly between CG and UC. This “UC-like signature” was enriched for reactive oxygen species (ROS) and energy metabolism, growth and DNA repair, transport, motility, epithelial-mesenchymal transition, and cell survival. Using the top 10 shortlisted DEPs, including SOD2, PRKCD, CYCS, and HCLS1, we identified functional elements related to ROS metabolism, development, and transport using network analysis. The abundance of these four molecules in UC/CG than in NU was consistent with the oncologic functions in CG. Conclusions Using a proteomic approach, we identified a predominantly non-neoplastic landscape of CG, which was closer to NU than to UC. We also confirmed a small subset of common DEPs in UC and CG, suggesting that altered ROS metabolism might imply potential cancerous risks in CG.

Purpose: The relationship with endothelial activation and stress index (EASIX), which represents the degree of endothelial dysfunction, is unwell known in upper tract urothelial carcinoma (UTUC). The present study aims to assess the prognostic value of the EASIX for recurrence-free survival (RFS) and overall survival (OS) in patients with UTUC who underwent radical nephroureterectomy (RNU). Materials and Methods: We retrospectively reviewed the clinical data of 627 patients with UTUC who underwent RNU without neoadjuvant chemotherapy at three hospitals between 2002 and 2019. EASIX scores were calculated using the formula “serum lactate dehydrogenase (U/L)×creatinine (mg/dL)/platelet count (109/L)” and evaluated based on log2-transformed values. We divided the patients according to the EASIX score (>1.27 vs. ≤1.27). Results: Among 627 patients, 380 were finally analyzed. Using maximally selected log-rank statistics, the optimal EASIX cutoff value was 1.27 on the log2 scale. The baseline characteristics were similar between the two groups except for age. The high EASIX score group had worse RFS and OS than the low EASIX score group (log-rank p=0.001 and p=0.006, respectively). At 5 years, the mean RFS and OS difference between the low and high EASIX score groups was 11.1 and 7.35 months, respectively. High EASIX score remained a key prognosticator of RFS and OS after RNU in multivariable analysis. Conclusions: EASIX score may represent endothelial dysfunction in patients with UTUC and may serve as a readily available prognostic factor for oncologic outcomes.

Introduction: As a high-quality TUR-BT is important to ensure adequate treatment for bladder cancer patients, the aim of the current study is to investigate the impact of patient-related, surgical and tumor-specific parameters on detrusor muscle (DM) absence (primary objective) and to assess the impact of DM on the prognosis after a TUR-BT (secondary objective). Patients and methods: Transurethral resection of bladder tumors (TUR-BTs) between 2009 and 2021 were retrospectively screened (n = 3237). We included 2058 cases (1472 patients) for the primary and 472 patients for secondary objective. Clinicopathological variables including tumor size, localization, multifocality, configuration, operation time and skill-level of the urologist were assessed. We analyzed predictors for missing DM and prognostic factors for recurrence-free survival (RFS) for the complete cohort and subgroups. Results: DM was present in 67.6% (n = 1371/2058). Surgery duration (continuous, minutes) was an independent predictor for absence of DM in the complete cohort (OR:0.98, r:0.012, 95%CI:0.98–0.99, p = 0.001). Other significant risk factors for missing DM were papillary tumors (OR:1.99, r:0.251, 95%CI:1.22–3.27, p = 0.006) in the complete cohort and bladder-roof and posterior-bladder-wall localization for re-resections. Absence of DM in high-grade BC correlated with reduced RFS (HR:1.96, 95%CI:1.0–3.79, p = 0.045). Conclusion: Sufficient time for a TUR-BT is mandatory to assure DM in the TUR-BT specimen. Also, cases with more difficult locations of bladder tumors should be performed with utmost surgical diligence and endourological training should incorporate how to perform such operations. Of note, DM correlates with improved oncological prognosis in high-grade BC. [ABSTRACT FROM AUTHOR]

Purpose: Microhematuria is a highly prevalent condition with a low associated risk of urothelial and upper tract malignancy. The AUA Guidelines recently changed recommendations for imaging favoring renal ultrasound for low- and intermediate-risk patients with microhematuria.We summarize the diagnostic test characteristics of computed tomography urography, renal ultrasound, and magnetic resonance urography in comparison with surgical pathology for the diagnosis of upper urinary tract cancer in microhematuria and gross hematuria patients. Materials and Methods: This study is a systematic review and meta-analysis using PRISMA (Preferred Reporting Items for Systematic Reviews and Metaanalyses) guidelines from evidence collected for the 2020 AUA Microhematuria Guidelines report, including studies assessing imaging following diagnosis of hematuria published from January 2010 through December 2019. Results: The search identified 20 studies which reported the prevalence of malignant and benign diagnoses in relation to imaging modality, of which 6 were included in the quantitative analysis. For the detection of renal cell carcinoma and upper urinary tract carcinoma in patients with microhematuria and gross hematuria, computed tomography urography had a sensitivity of 94% (95% CI, 84%-98%) and a specificity of 99% (95%CI, 97%-100%) with a certainty of evidence rating of very low and low, respectively when 4 studies were pooled. In comparison, ultrasound demonstrated a sensitivity ranging from 14%-96% (low certainty of evidence) and a specificity of 99%-100% in 2 studies (moderate certainty of evidence), while magnetic resonance urography demonstrated a sensitivity of 83% and specificity of 86% in 1 study with a low certainty of evidence. Conclusions: In a limited data set for each individual imaging modality, computed tomography urography appears the most sensitive imaging modality for the diagnostic evaluation of microhematuria. Future studies will be needed to evaluate the clinical and health system financial impacts of the change in guideline recommendations from computed tomography urography to renal ultrasound in evaluating low- and intermediate-risk patients with microhematuria. [ABSTRACT FROM AUTHOR]

Purpose: We compare health-related quality of life using a broad range of validated measures in patients randomized to robotic-assisted radical cystectomy vs open radical cystectomy. Methods: We retrospectively analyzed patients that had enrolled in both a randomized controlled trial comparing robotic-assisted laparoscopic radical cystectomy vs open radical cystectomy and a separate prospective study of health-related quality of life. The prospective health-related quality of life study collected 14 patient-reported outcomes measures preoperatively and at 3, 6, 12, 18, and 24 months postoperatively. Linear mixed-effects models with an interaction term (study arm×time) were used to test for differences in mean domain scores and differing effects of approach over time, adjusting for baseline scores. Results: A total of 72 patients were analyzed (n=32 robotic-assisted radical cystectomy, n=40 open radical cystectomy). From 3-24 months post-radical cystectomy, no significant differences in mean scores were detected. Mean differences were small in the following European Organization for Research and Treatment of Cancer QLQ-C30 (Core Quality of Life Questionnaire) domains: Global Quality of Life (−1.1; 95% CI −8.4, 6.2), Physical Functioning (−0.4; 95% CI −5.8, 5.0), Role Functioning (0.7; 95% CI −8.6, 10.0). Mean differences were also small in bladder cancer–specific domains (European Organization for Research and Treatment of Cancer QLQ-BLM30 [Muscle Invasive Bladder Cancer Quality of Life Questionnaire]): Body Image (2.9; 95% CI −7.2, 13.1), Urinary Symptoms (8.0; 95% CI −3.0, 19.0). In Urostomy Symptoms, there was a significant interaction term (P < .001) due to lower open radical cystectomy scores at 3 and 24 months. Other domains evaluating urinary, bowel, sexual, and psychosocial health-related quality of life were similar. Conclusions: Over a broad range of health-related quality of life domains comparing robotic-assisted radical cystectomy and open radical cystectomy, there are unlikely to be clinically relevant differences in the medium to long term, and therefore health-related quality of life over this time period should not be a consideration in choosing between approaches. [ABSTRACT FROM AUTHOR]

Purpose: We explored the accuracy of a urine-based epigenetic test for detecting upper tract urothelial carcinoma. Materials and Methods: Under an Institutional Review Board–approved protocol, urine samples were prospectively collected from primary upper tract urothelial carcinoma patients before radical nephroureterectomy, ureterectomy, or ureteroscopy between December 2019 and March 2022. Samples were analyzed with Bladder CARE, a urine-based test that measures the methylation levels of 3 cancer biomarkers (TRNA-Cys, SIM2, and NKX1-1) and 2 internal control loci using methylation-sensitive restriction enzymes coupled with quantitative polymerase chain reaction. Results were reported as the Bladder CARE Index score and quantitatively categorized as positive (>5), high risk (2.5-5), or negative (<2.5). The findings were compared with those of 1:1 sex/age-matched cancer-free healthy individuals. Results: Fifty patients (40 radical nephroureterectomy, 7 ureterectomy, and 3 ureteroscopy) with a median (IQR) age of 72 (64-79) years were included. Bladder CARE Index results were positive in 47, high risk in 1, and negative in 2 patients. A significant correlation was found between Bladder CARE Index values and tumor size. Urine cytology was available for 35 patients, of whom 22 (63%) results were false-negative. Upper tract urothelial carcinoma patients had significantly higher Bladder CARE Index values compared to the controls (mean 189.3 vs 1.6, P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value of the Bladder CARE test for detecting upper tract urothelial carcinoma were 96%, 88%, 89%, and 96%, respectively. Conclusions: Bladder CARE is an accurate urine-based epigenetic test for the diagnosis of upper tract urothelial carcinoma, with much higher sensitivity than standard urine cytology. [ABSTRACT FROM AUTHOR]

Large-cell undifferentiated carcinoma of the urinary bladder is an extremely rare and aggressive neoplasm. We present a unique case of painless gross hematuria and a past surgical history of cystolithotomy. The patient underwent transurethral resection of the bladder tumor, which revealed high-grade urothelial cell carcinoma with lamina propria involvement. Subsequent radical cystoprostatectomy with orthotopic neobladder urinary diversion and pelvic lymphadenectomy was performed, and the postoperative pathologic examination indicated large-cell undifferentiated. This case report highlights the importance of accurate diagnosis and management for this rare malignancy and adds to the limited existing literature on Large-cell undifferentiated carcinoma. [ABSTRACT FROM AUTHOR]

Tubo-ovarian transitional cell carcinoma (TCC) is grouped with high-grade serous carcinoma (HGSC) in the current World Health Organization classification. TCC is associated with BRCA mutations and a better prognosis compared with HGSC. Previous papers examining the immunohistochemical features of TCC have studied limited numbers of samples. No marker reflecting the biological difference between TCC and HGSC is known. We collected a large cohort of TCC to determine whether TCC and HGSC could be distinguished by immunohistochemistry. A tissue microarray was built from 89 TCC and a control cohort of 232 conventional HGSC. Immunohistochemistry was performed, scored, and statistically analyzed for routine markers of HGSC and urothelial tumors: PAX8, WT1, p53, p16, ER, p63, and GATA3. Using scoring cutoffs commonly employed in clinical practice, the immunohistochemical profile of TCC was indistinguishable from HGSC for all markers. However, more detailed scoring criteria revealed statistically significant differences between the 2 groups of tumors with respect to ER, PAX8, and WT1. HGSC showed more diffuse and intense staining for PAX8 (P=0.004 and 0.001, respectively) and WT1 (P=0.002 and 0.002, respectively); conversely, TCC showed more intense staining for ER (P=0.007). TCC and HGSC therefore show subtle differences in their immunohistochemical profiles which might reflect underlying (epi)genetic differences. Further studies using proteomic analysis will focus on the identification of differentially expressed proteins that might serve as markers of TCC-like differentiation, which could help explain biologic differences between TCC and HGSC and might identify other cases of HGSC with a better prognosis.

PurposeWhile radical nephroureterectomy (RNU) is the gold standard treatment for upper tract urothelial carcinoma (UTUC), select patients may benefit from endoscopic treatment (ET). European Association of Urology guidelines recommend ET for patients with low-risk (LR) disease: unifocal,

Purpose: Treatment options for the management of upper tract urothelial cancer are based on accurate staging. However, the performance of conventional cross-sectional imaging for clinical lymph node staging (Nstaging) remains poorly investigated. This study aims to evaluate the diagnostic accuracy of conventional cross-sectional imaging for upper tract urothelial cancer Nstaging. Materials and Methods: This study was a multicenter, retrospective, observational study. We included 865 nonmetastatic (M0) upper tract urothelial cancer patients treated with curative intended surgery and lymph node dissection who had been staged with conventional cross-sectional imaging before surgery. We compared clinical (c) and pathological (p) N-staging results to evaluate the concordance of node-positive (ND) and node-negative (N0) disease and calculate cN-staging's diagnostic accuracy. Results: Conventional cross-sectional imaging categorized 750 patients cN0 and 115 cND. Lymph node dissection categorized 641 patients pN0 and 224 pND. The cN-stage was pathologically downstaged in 6.8% of patients, upstaged in 19%, and found concordant in 74%. The sensitivity and specificity of cN-staging were 25% (95% CI 20; 31) and 91% (95% CI 88; 93). Positive and negative likelihood ratios were 2.7 (95% CI 2.0; 3.8) and 0.83 (95% CI 0.76; 0.89). The area under the receiver operating characteristics curve (0.58, 95% CI 0.55; 0.61) revealed low diagnostic accuracy. Conclusions: Conventional cross-sectional imaging had low sensitivity in detecting upper tract urothelial cancer pND disease. However, cND increased the likelihood of pND by almost threefold. Thus, conventional cross-sectional imaging is a rule-in but not a rule-out test. Lymph node dissection should remain the standard during extirpative upper tract urothelial cancer surgery to obtain accurate N-staging. cND could be a strong argument for early systemic treatment. [ABSTRACT FROM AUTHOR]

Primary transitional cell carcinoma of the ureter is a rare type of cancer with metastasis presented in approximately 25% at diagnosis. Due to its rarity and poor prognosis, the management of this neoplasm is still controversial, and the development of new therapies is of uttermost importance. Herein, we describe a case of a 54-year-old patient diagnosed with transitional cell carcinoma of the left ureter submitted to left nephroureterectomy (pT3N2M0) and methotrexate, vinblastine, doxorubicin, and cisplatin adjuvant chemotherapy. A single liver metastasis was detected and combination chemotherapy with gemcitabine and carboplatin was initiated along with stereotactic body radiation therapy. Despite these 2 previous chemotherapy regimens, the patient presented disease progression and transarterial selective internal radiation therapy (SIRT) with yttrium-90 was indicated. This locoregional treatment was performed with the administration of 1.2 GBq yttrium-90 resin microspheres (SIR-Spheres®, Sirtex Medical Limited, Sydney, NSW, Australia) into the right hepatic artery. Another systemic treatment was immunotherapy using nivolumab with excellent tolerability. After 10 years of follow-up, at the last clinical evaluation, the patient had no clinical symptoms and the last imaging follow-up using positron emission tomography-computed tomography scan showed complete response. This report introduces upper urinary tract urothelial carcinoma as a distinct type of malignancy in which SIRT can be safely implemented. As a transition method to nivolumab, it was successful. There might be a potential therapeutic synergism between these 2 treatment modalities. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitor therapy and nab-paclitaxel have each shown efficacy in platinum-refractory advanced urothelial cancer. We conducted a single-arm phase 2 trial of the combination of nab-paclitaxel and pembrolizumab in platinum-refractory or cisplatin-ineligible advanced urothelial cancer (NCT03240016). Materials and Methods: Eligible patients had RECIST 1.1 measurable and cisplatin-ineligible or platinum-refractory advanced urothelial cancer. Patients received nab-paclitaxel at starting dose of 125 mg/m2 intravenously on days 1 and 8 and pembrolizumab 200 mg intravenously on day 1 in 21-day cycles until progression, intolerable toxicity, or death. Nab-paclitaxel was permitted to be discontinued after 6 cycles. The nab-paclitaxel starting dose was reduced to 100 mg/m2 after planned interim analysis. Primary end point was overall response rate by RECIST 1.1. Secondary end points included safety/toxicity, duration of response, progression-free survival), and overall survival. Results: Between February 2018 and April 2021, 36 response-evaluable patients were enrolled. There was an equal split of platinum-refractory and cisplatin-ineligible patients. Confirmed overall response rate was 50.0% (18/36) including 3 complete and 15 partial responses; 31/36 patients experienced some tumor shrinkage. At a median follow-up of 19.7 months, median duration of response was 4.4 months (95% CI: 4.0-8.6), median progression-free survival 6.8 months (95% CI: 4.4-not reached), and median overall survival 18.2 months (95% CI: 10.6-not reached). Grade ≤ 3 adverse events occurred in 21/36 patients including fatigue (n=6) and anemia (n=4). Ten patients had immune-mediated adverse events. Conclusions: The combination of nab-paclitaxel and pembrolizumab exhibited promising activity in advanced urothelial cancer and warrants further study in this population. After reduction in nab-paclitaxel starting dose, no unanticipated or unexpected toxicities emerged. [ABSTRACT FROM AUTHOR]

Background: Concurrent chemoradiotherapy (CRT) as a definitive treatment option for patients with nonmetastatic muscle-invasive bladder carcinoma (MIBC) is increasingly being applied in clinical practice. Objective: To assess the oncological and toxicity outcomes in a contemporary cohort of nonmetastatic MIBC patients treated with concurrent CRT in daily practice. Design, setting, and participants: Patients with nonmetastatic MIBC (cT2-4aN0M0) who had received CRT with curative intent between January 2010 and April 2020 in three centers were retrospectively identified. The CRT consisted of 66 Gy (or biologically equivalent) plus either mitomycin C and fluorouracil/capecitabine or cisplatinum. Outcome measurements and statistical analysis: The primary endpoint was the 2-yr locoregional disease-free survival (LDFS) estimate. Secondary endpoints were complete response, disease-specific survival (DSS), overall survival (OS), bladder intact event-free survival (BI-EFS), and severe adverse events (

IntroductionCytotoxic chemotherapy might prime urothelial cancer (UC) to checkpoint inhibition, prompting a trial of chemotherapy with the programmed death receptor-1 inhibitor pembrolizumab.Patients and methodsPatients with advanced, platinum-refractory UC received pembrolizumab and either docetaxel (arm A) or gemcitabine (arm B). Primary end points were assessments of maximum tolerated dose and dose-limiting toxicity (DLT). Secondary end points were overall response rate (ORR) and progression-free survival (PFS).ResultsTwelve patients were enrolled in the initial cohorts; 6 in each arm. One DLT was seen in each arm: Grade 3 hypophosphatemia (arm A), Grade 3 diarrhea (arm B). Adverse events of Grade >3 were observed in 7 (54%), the most common being anemia (6; 50%), fatigue (6; 50%), hyponatremia (4; 33%) and neutropenia (3; 25%), with no treatment-related deaths. There were 5 confirmed responses (1 complete, 4 partial), with an ORR of 42% and disease control rate (DCR) of 58%. Arm A had an ORR of 50% and DCR of 67%, whereas arm B had an ORR of 33% and DCR of 50%. Median PFS was 4.8, 5.7, and 3.7 months for the overall cohort, arm A, and arm B, respectively.ConclusionPembrolizumab with either docetaxel or gemcitabine is feasible for treatment of platinum-refractory advanced UC patients. Preliminary efficacy was observed. Further examination is warranted.

Background:Elucidation of epigenetic alterations in bladder cancer will lead to further understanding of the biology of the disease and hopefully improved therapies. Our aim was to perform an integrative epigenetic analysis of invasive urothelial carcinoma of the bladder to identify the epigenetic abnormalities involved in the development and progression of this cancer. Methods:Pre-processed methylation data and RNA-seq data were downloaded from The Cancer Genome Atlas (TCGA) and processed using the R package TCGA-Assembler. An R package MethylMix was used to perform an analysis incorporating both methylation and gene expression data on all samples, as well as a subset analysis comparing patients surviving less than 2 years and patients surviving more than 2 years. Genes associated with poor prognosis were individually queried. Pathway analysis was performed on statistically significant genes identified by MethylMix criteria using ConsensusPathDB. Validation was performed using flow cytometry on bladder cancer cell lines. Results:A total of 408 patients met all inclusion criteria. There were a total of 240 genes differentially methylated by MethylMix criteria. Review of individual genes specific to poor-prognosis patients revealed the majority to be candidate tumor suppressors in other cancer types. Pathway analysis showed increase in methylation of genes involved in antioxidant pathways including glutathione and NRF2. Genes involved in estrogen metabolism were also hypermethylated while genes involved in the EGFR pathway were found to be hypomethylated. EGFR expression was confirmed to be elevated in six bladder cancer cell lines. Conclusions:In patients with invasive urothelial carcinoma, we found differential methylation in patients with better and worse prognosis after cystectomy. Differentially methylated genes are involved in many relevant oncologic pathways, including EGFR and antioxidant pathways, that may be a target for therapy or chemoprevention.

ObjectiveTo compare the performance of 3 contemporary ureteroscopic biopsy devices for the histopathologic diagnosis of upper tract urothelial carcinoma (UTUC).MethodsWe retrospectively reviewed 145 patients who underwent 182 urothelial biopsies using 2.4F backloaded cup biopsy forceps, a nitinol basket, or 3F standard cup biopsy forceps at 3 tertiary academic centers between 2011 and 2016. Experienced genitourinary pathologists provided an assessment of each specimen without knowledge of the device used for biopsy. For patients who underwent nephroureterectomy without neoadjuvant chemotherapy within 3 months of biopsy-proven UTUC diagnosis, the biopsy grade was compared with both the grade and stage of the surgical specimen.ResultsBiopsy utilization varied among the 3 institutions (P .05) and was favored over standard cup forceps specimens. Grade concordance was not affected by specimen size (P >.05), morphology (P >.1), or location (P >.5). No difference existed among the devices in the rate of acquiring a grade concordant biopsy; however, the backloaded cup forceps provided concordant biopsies that could be distinguished as low- and high-grade (P = .02).ConclusionThe backloaded cup forceps and nitinol basket obtained a higher quality urothelial specimen compared with standard cup forceps. Ureteroscopic biopsy device selection did not significantly impact the accuracy of the histologic diagnosis of UTUC.

ObjectiveTo evaluate how socioeconomic status and other demographic factors are associated with the receipt of chemotherapy and subsequent survival in patients diagnosed with metastatic bladder cancer.MethodsUsing data from the California Cancer Registry, we identified 3,667 patients diagnosed with metastatic urothelial carcinoma of the urinary bladder between 1988 and 2014. The characteristics of patients who did and did not receive chemotherapy as part of the first course of treatment were compared using chi-square tests. Logistic regression was used to identify predictors of chemotherapy treatment. Fine and Gray competing-risks regression and Cox proportional hazards regression were used to estimate bladder cancer-specific and all-cause mortality, respectively.ResultsLess than half (46.3%) of patients received chemotherapy. Patients from the lowest socioeconomic quintile were half as likely to have chemotherapy as those from highest quintile (odds ratio = 0.5, 95% CI: 0.4, 0.7). Unmarried patients were significantly less likely to receive treatment (odds ratio = 0.6, 95% CI: 0.5, 0.7). Not receiving chemotherapy was associated with greater mortality from bladder cancer (subdistribution hazard ratio = 1.4, 95% CI: 1.3, 1.5) and from all causes (hazard ratio = 2.0, 95% CI: 1.8, 2.1).ConclusionsWe found clear disparities in chemotherapy treatment and survival with respect to socioeconomic and marital status. Future studies should explore the possible reasons why patients with low socioeconomic status and who are unmarried are less likely to have chemotherapy.

BACKGROUND: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC). METHODS: Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes. RESULTS: Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 (TP53) (P = 1.000 and .115, respectively), AT-rich interaction domain 1A (ARID1A) (P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 (ERBB2) (P = .565 and .074, respectively), and fibroblast growth factor receptor 3 (FGFR3) (P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC. CONCLUSIONS: Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker-driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018;124:2115-24. © 2018 American Cancer Society.

Checkpoint inhibitor immunotherapies have had major success in treating patients with late-stage cancers, yet the minority of patients benefit. Mutation load and PD-L1 staining are leading biomarkers associated with response, but each is an imperfect predictor. A key challenge to predicting response is modeling the interaction between the tumor and immune system. We begin to address this challenge with a multifactorial model for response to anti-PD-L1 therapy. We train a model to predict immune response in patients after treatment based on 36 clinical, tumor, and circulating features collected prior to treatment. We analyze data from 21 bladder cancer patients using the elastic net high-dimensional regression procedure and, as training set error is a biased and overly optimistic measure of prediction error, we use leave-one-out cross-validation to obtain unbiased estimates of accuracy on held-out patients. In held-out patients, the model explains 79% of the variance in T cell clonal expansion. This predicted immune response is multifactorial, as the variance explained is at most 23% if clinical, tumor, or circulating features are excluded. Moreover, if patients are triaged according to predicted expansion, only 38% of non-durable clinical benefit (DCB) patients need be treated to ensure that 100% of DCB patients are treated. In contrast, using mutation load or PD-L1 staining alone, one must treat at least 77% of non-DCB patients to ensure that all DCB patients receive treatment. Thus, integrative models of immune response may improve our ability to anticipate clinical benefit of immunotherapy.

Purpose: To evaluate the prognostic impact of the lowest level of tumor location for upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). Materials and methods: Data were collected from patients with UTUC treated with RNU (01/2005-06/2020) at a single center in Taiwan. Patients were stratified by the lowest level of tumor location into three groups: renal pelvis only (RPO), above upper ureter (AUU), and below upper ureter (BUU). We compared characteristics between groups and examined the association of the lowest level of tumor involvement with intravesical recurrence (IVR), systemic metastasis (SM), and cancer-specific mortality (CSM). Results: Overall, 1239 patients (542 RPO, 260 AUU, 437 BUU) were enrolled. Concurrent bladder cancer, multifocality, tumor architecture, lymphovascular invasion, carcinoma in situ, and variant histology were significantly different across different tumor locations. BUU had worse five-year intravesical recurrence (IVR), systemic metastasis (SM) and cancer-specific mortality (CSM) (p < 0.001, p = 0.056 and p = 0.13, respectively). In multivariable models, the lowest level of tumor involvement was an independent predictor of IVR (AUU hazard ratio (HR) = 1.52, p = 0.007; BUU HR = 1.75, p < 0.001), but only BUU was an independent predictor of SM (HR = 1.61, p = < 0.001) and CSM (HR = 1.51, p = 0.008). Conclusion: The lowest level of tumor involvement in UTUC, especially BUU, was associated with a higher risk of IVR, SM and CSM. Assessment of the lowest level of tumor involvement after RNU may help identify patients who require more intensive follow-up. [ABSTRACT FROM AUTHOR]

Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1a) signaling as the use of an IRE1a inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1a signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis. [ABSTRACT FROM AUTHOR]

Bempegaldesleukin plus nivolumab was well tolerated and showed antitumor activity in this preliminary investigation of first-line treatment in patients with locally advanced or metastatic urothelial carcinoma in a phase 2 cohort from the open-label, multicohort phase 1/2 PIVOT-02 study. Despite recent changes in the treatment landscape, there remains an unmet need for effective, tolerable, chemotherapy-free treatments for patients with advanced/metastatic urothelial carcinoma (mUC), especially cisplatin-ineligible patients. To evaluate the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab in patients with advanced/mUC from the phase 2 multicenter PIVOT-02 study. This open-label, multicohort phase 1/2 study enrolled patients with previously untreated locally advanced/surgically unresectable or mUC (N = 41). Patients received BEMPEG 0.006 mg/kg plus nivolumab 360 mg intravenously every 3 wk. The primary objectives were safety and the objective response rate (ORR) in patients with measurable disease at baseline and at least one postbaseline tumor response assessment (response-evaluable). Secondary objectives were overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses via univariate logistic regression were performed to test the association between potential biomarkers (CD8+ tumor-infiltrating lymphocytes, tumor mutational burden, and IFN-γ gene expression profile) and response. The ORR was 35% (13/37 evaluable patients) and the complete response rate was 19% (7/37 patients); the median duration of response was not reached. Median PFS was 4.1 mo (95% confidence interval [CI] 2.1–8.7) and median OS was 23.7 mo (95% CI 15.8–not reached). Overall, 40/41 patients (98%) experienced at least one treatment-related adverse event (TRAE); grade 3/4 TRAEs occurred in 11 patients (27%), most commonly pyrexia (4.9%; 2 patients). Exploratory biomarker analyses showed no association between biomarkers and response. Limitations include the small sample size and single-arm design. BEMPEG plus nivolumab was well tolerated and showed antitumor activity as first-line treatment in patients with locally advanced/mUC. We investigated an immune-stimulating prodrug called bempegaldesleukin plus the antibody nivolumab as the first therapy for patients with advanced or metastatic cancer of the urinary tract. This combination had manageable treatment-related side effects and was effective in a subset of patients. This trial is registered at ClinicalTrials.gov as NCT02983045. [ABSTRACT FROM AUTHOR]

Background. Primary transitional cell carcinoma (TCC) of the ovary is characterized by the presence of papillary projections of malignant transitional epithelial cells or their aggregates in the fibrous stroma. This type of tumor represents nearly 1% of all ovarian surface epithelium carcinomas. We presented the first report of a solitary splenic metastasis of primary ovarian TCC. Case report. A 60-yearold female patient was admitted because of an asymptomatic splenic tumor in December 2018. Two years prior, she underwent a total abdominal hysterectomy, bilateral adnexectomy, and infracolic omentectomy for the primary TCC of the ovary. Control abdominal ultrasonography, computed tomography, and magnetic resonance imaging performed two years after primary surgery showed a splenic tumor. An open splenectomy was performed, with the intraoperative finding of a hilar splenic tumor and the absence of other pathological lesions in the abdomen. Frozen section analysis showed a TCC metastasis, which was subsequently confirmed by definitive histopathological examination. During the one-year follow-up, there was no relapse of the disease. Conclusion. This is the first report of a solitary splenic metastasis of primary ovarian TCC based on the literature review. This case may serve as an example of the diagnostic and therapeutical role of splenectomy in isolated splenic metastases of ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy of voided urine cytology with findings of cystoscopy and histopathology of biopsy specimens in the diagnosis of bladder cancer. Study Design: Comparative cross-sectional study. Place and Duration of Study: Armed forces Institute of Urology (AFIU), Rawalpindi Pakistan from Jan 2019 to Jan 2020. Methodology: All patients presenting to the urology clinic with complaints of haematuria, visible and non-visible, and any radiologic evidence of bladder growth were included in the study after informed consent. Urine cytology was performed for all patients, followed by cystoscopy under anaesthesia, transurethral resection was conducted, and biopsy was taken where needed. Results: 170 patients were included in the study134 (78.8%) were males, while 36 (21.2%) were females. The mean age was 54 ± 9.47 years (range 36 to 73 years). The overall sensitivity of voided urine cytology was 46.7%, while specificity was 79.2%. The positive predictive value was 85.1%, and the negative predictive value was 36.9%. Conclusion: Bladder cancer is a disease which demands an early diagnosis, prompt treatment, and long-term follow-up. Cystoscopy remains the gold standard for this purpose; urine cytology can be used as a supplement as it is non-invasive, more specific and cost-effective. [ABSTRACT FROM AUTHOR]

Aim: We aimed to explore the association between cancer cachexia phenotypes in the early phase of treatment induction and the prognosis of advanced urothelial cancer (aUC) patients receiving pembrolizumab. Methods: This retrospective study included 31 aUC patients treated with pembrolizumab as a second‐ or later‐line therapy. Patients were categorized into three early cancer cachexia phenotypes by changes in skeletal muscle and total adipose indices calculated using computed tomography images taken immediately before and within 3 months after the initiation of pembrolizumab: No Wasting (NW, 11 patients), Fat‐Only Wasting (FW, 13), and Muscle and Fat Wasting (MFW, seven). Its association with objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS) were evaluated. Results: The median follow‐up period was 5.7 months. The median number of cycles of pembrolizumab was five. The ORR in NW/FW/MFW was 86%/38%/0%, respectively (p = 0.001). The PFS and OS rates were the best in NW, followed in order by FW and MFW (PFS, 69%/45%/0% at 12 months, p = 0.008; OS, 100%/65%/0% at 12 months, p < 0.001). In multivariate analysis including posttherapeutic cachexia‐associated parameters, cancer cachexia phenotype (MFW vs. FW/NW) was an independent predictor of poor OS (hazard ratio 8.59, p < 0.001) along with an increase in neutrophil–lymphocyte ratio (p = 0.028). Conclusion: Early cancer cachexia phenotypes were significantly associated with the survival of aUC patients treated with pembrolizumab. In contrast to the very early progression and poor prognosis in the MFW group, long‐term survival can be expected in the NW/FW groups. [ABSTRACT FROM AUTHOR]

Purpose: We sought to evaluate outcomes of lymph node dissection (LND) in patients with upper tract urothelial carcinoma. Materials and Methods: We performed a multicenter retrospective analysis utilizing the ROBUUST (for RObotic surgery for Upper Tract Urothelial Cancer Study) registry for patients who did not undergo LND (pNx), LND with negative lymph nodes (pN0) and LND with positive nodes (pND). Primary and secondary outcomes were overall survival (OS) and recurrence-free survival (RFS). Multivariable analyses evaluated predictors of outcomes and pathological node positivity. Kaplan-Meier analyses (KMAs) compared survival outcomes. Results: A total of 877 patients were analyzed (LND performed in 358 [40.8%]/pND in 73 [8.3%]). Median nodes obtained were 10.2 for pND and 9.8 for pN0. Multivariable analyses noted increasing age (OR 1.1, p <0.001), pND (OR 3.1, p <0.001) and pathological stage pTis/3/4 (OR 3.4, p <0.001) as predictors for all-cause mortality. Clinical high-grade tumors (OR 11.74, p[0.015) and increasing tumor size OR 1.14, p[0.001) were predictive for lymph node positivity. KMAs for pNx, pN0 and pNDdemonstrated 2-year OS of 80%, 86% and 42% (p <0.001) and 2-year RFS of 53%, 61% and 35% (p <0.001), respectively. KMAs comparing pNx, pN0 -10 nodes and pN0 <10 nodes showed no significant difference in 2-year OS (82% vs 85% vs 84%, p[0.6) but elicited significantly higher 2-year RFS in the pN0 -10 group (60% vs 74% vs 54%, p[0.043). Conclusions: LND during nephroureterectomy in patients with positive lymph nodes provides prognostic data, but is not associated with improved OS. LND yields -10 in patients with clinical node negative disease were associated with improved RFS. In high-grade and large tumors, lymphadenectomy should be considered. [ABSTRACT FROM AUTHOR]

Urothelial carcinoma of the upper urinary tract is uncommon and presents unique challenges for diagnosis and management. Nephroureterectomy has been the preferred management option, but it is associated with significant morbidity. Nephron-sparing treatments are a valuable alternative and provide similar efficacy in select cases. A PubMed literature review was performed in English language publications using the following search terms: urothelial carcinoma, upper tract, nephron-sparing, intraluminal and systemic therapy. Contemporary papers published within the last 10 years were primarily included. Where encountered, systematic reviews and meta-analyses were given priority, as were randomized controlled trials for newer treatments. Core guidelines were referenced and citations reviewed for inclusion. A summary of epidemiological data, clinical diagnosis, staging, and treatments focusing on nephron-sparing approaches to upper tract urothelial carcinoma (UTUC) are outlined. Nephron-sparing management strategies are viable options to consider in patients with favorable features of UTUC. Adjunctive therapies are being investigated but the data remains mixed. Protocol variability and dosage differences limit statistical interpretation. New mechanisms to improve treatment dwell times in the upper tracts are being designed with promising preliminary results. Studies investigating systemic therapies are ongoing but implications for nephron-sparing management are uncertain. Nephron-sparing management is an acceptable treatment modality best suited for favorable disease. More work is needed to determine if intraluminal and/or systemic therapies can further optimize treatment outcomes beyond resection alone.

BackgroundEarly signs of canine transitional cell carcinoma (TCC) are frequently assumed to be caused by other lower urinary tract diseases (LUTD) such as urinary tract infections, resulting in late diagnosis of TCC which could be fatal. The development of a non-invasive clinical test for TCC could dramatically reduce mortality. To determine whether microRNAs (miRNAs) can be used as non-invasive diagnostic biomarkers, we assessed miRNA expression in blood and/or urine from dogs with clinically normal bladders (n = 28), LUTD (n = 25), and TCC (n = 17). Expression levels of 5 miRNA associated with TCC pathophysiology (miR-34a, let-7c, miR-16, miR-103b, and miR-106b) were assessed by quantitative real-time PCR.ResultsStatistical analyses using ranked ANOVA identified significant differences in miR-103b and miR-16 levels between urine samples from LUTD and TCC patients (miR-103b, p = 0.002; and miR-16, p = 0.016). No statistically significant differences in miRNA levels were observed between blood samples from LUTD versus TCC patients. Expression levels of miR-34a trended with miR-16, let-7c, and miR-103b levels in individual normal urine samples, however, this coordination was completely lost in TCC urine samples. In contrast, co-ordination of miR-34a, miR-16, let-7c, and miR-103b expression levels was maintained in blood samples from TCC patients.ConclusionsOur combined data indicate a potential role for miR-103b and miR-16 as diagnostic urine biomarkers for TCC, and that further investigation of miR-103b and miR-16 in the dysregulation of coordinated miRNA expression in bladder carcinogenesis is warranted.

BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.

The purpose of this pilot study was to assess the feasibility of Cadence contrast pulse sequencing ultrasound to predict clinical and angiogenic tumor response in dogs undergoing chemotherapy. Contrast ultrasound facilitated visualization of bladder tumors but failed to identify a straightforward relationship between ultrasound measures and clinical outcome.

(1) Introduction and Objective: Upper tract urothelial carcinoma (UTUC) is an uncommon disease, only accounting for 5–10% of all urothelial carcinomas. Current clinical practice guidelines encourage a risk-adapted approach to UTUC management, including lymph node dissection (LND) in patients with muscle-invasive or high-risk tumors. If pathological characteristics could be more accurately predicted from preoperative data, we could optimize perioperative management strategies and outcomes. The aim of this article is to present a detailed revision of preoperative predictors for muscle-invasive UTUC, locally advanced or advanced UTUC, as well as current indications, technique variations, and the reasons as to why LND should be offered to these patients. (2) Methods: We included any kind of studies related to information concerning UTUC, nephroureterectomy, LND, risk factors for recurrence, prediction tools and models for risk stratification. A literature search was conducted following medical subject headings (MeSh), Emtree language, Decs, and text words related. We searched through MEDLINE (OVID), EMBASE (Scopus), LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to May 2021. Evidence acquisition was presented according to the PRISMA diagram. (3) Results: Preoperative risk factors for either muscle-invasive UTUC (≥pT2), extra urothelial recurrence (EUR), locally advanced disease, or high-risk UTUC can either be derived from ureteroscopic (URS) findings, urine cytology, URS biopsy, or from preoperative radiologic findings. It seems reasonable that LND may provide not only staging and prognostic information but also play a therapeutic role in selected UTUC patients. The patients who benefit the most from LND appear to be those with ≥ pT2 disease, because patients with tumors ≤ pT1 rarely metastasized to LNs. UTUC has characteristic patterns of lymphatic spread that are dependent on tumor laterality and anatomical location. Choosing the right patients for LND, designing and standardizing LND templates based on tumor location and laterality is critical to improve LN yield, survival outcomes, and to avoid under-staging or overtreatment. (4) Conclusions: Patients with muscle-invasive or non-organ-confined UTUC have an extremely high risk for disease recurrence and cancer-specific mortality (CSM). Preoperative factors and prediction models must be included in the UTUC management pathway in our clinical practice to improve the accurate determination of high-risk groups that would benefit from LND. We recommend offering LND to patients with ipsilateral hydronephrosis, cHG, cT1 at URS biopsy and renal sinus fat or periureteric fat invasion. The role of lymphadenectomy in conjunction with radical nephroureterectomy (RNU) is still controversial, given that it may result in overtreatment of patients with pTa-pT1 tumors. However, a clear benefit in terms of recurrence-free survival (RFS) and cancer-specific survival (CSS) has been reported in patients with ≥pT2. We try to avoid LND in patients with cLG, cTa, and no ipsilateral hydronephrosis if the patient is expected to be compliant with the follow up schedule. There is still plenty of work to do in this area, and new molecular and non-invasive tests are necessary to improve risk stratification.

Purpose: UGN-101 (mitomycin for pyelocalyceal solution) is a recently approved chemoablative treatment for low-grade (LG) upper tract urothelial carcinoma (UTUC). While approved for retrograde or antegrade administration, previous reports discuss only patients treated by retrograde approach. We report our techniques for antegrade administration along with early outcomes from our cohort of patients who have undergone UGN-101 administration via nephrostomy. Materials and Methods: UGN-101 is administered as 6 weekly instillations in patients who have undergone endoscopic ablation of LG UTUC. We outline our approach in patients thought to have LG UTUC from initial ureteroscopy to nephrostomy placement, UGN-101 administration and eventual nephrostomy removal. We discuss early durability of response along with adverse events with special attention to ureteral strictures. Results: Eight patients underwent antegrade UGN-101 administration during the study period, all of whom underwent followup ureteroscopy with complete response in 4 patients. Three patients reported 5 adverse eventsd3 grade 1, 1 grade 2 requiring 1 week delay of treatment and 1 asymptomatic ureteral stricture. Median followup was 7 months. Conclusions: We outline our approach for antegrade administration of UGN-101 and discuss early results along with adverse events. Future studies should evaluate our method's potential to increase patient comfort, improve logistics and decrease risk of adverse events. [ABSTRACT FROM AUTHOR]

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This National Cancer Database study of bladder cancer patients treated with definitive (chemo) radiotherapy uncovered significant under-utilization of hypofractionated RT (HFRT). Furthermore, chemotherapy was significantly underused with HFRT compared to patients receiving conventional fractionation. Use of both intensitymodulated RT (IMRT) and HFRT increased over time. IMRT was associated with similar or modestly increased survival, particularly in patients receiving HFRT. Introduction: : Use of hypofractionated radiation (HFRT) and intensity-modulated radiation (IMRT) for organ preservation in bladder cancer is controversial and highly variable. We investigated practice patterns, trends, and predictors of HFRT and IMRT. Patients and Methods: : The National Cancer Database was queried for patients with muscleinvasive, non-metastatic urothelial bladder cancer, treated with definitive (chemo)radiotherapy between 2004 and 2017. HFRT was defined as 50 to 60 Gy at > 2 Gy/fraction. Multivariable logistic regression was used to identify predictors of receiving HFRT or IMRT. Multivariable Cox regression was used to model overall survival (OS), adjusting for potential confounders such as age, comorbidity, and chemotherapy. Results: : Of 5132 patients identified, 490 (9.5%) received HFRT, and only 334 (6.5%) received =2.5 Gy/fraction. HFRT patients were significantly older, less fit, and less likely to receive chemotherapy relative to CFRT, even after controlling for age and comorbidity (adjusted odds ratio 0.36, 95% confidence interval [CI] 0.29-0.45, P < .0001). Utilization of HFRT and IMRT increased over time (P < .0001), reaching 22.5% and 47.7%, respectively, by 2017. Among patients treated with CFRT, OS was similar with or without IMRT (P = .46). Among patients treated with HFRT, IMRT was associated with increased survival (3-year OS 35% vs. 24%, P = .03), which persisted in multivariable analysis (adjusted hazard ratio 0.71, 95% CI 0.52-0.98, P = .04). Conclusion: : HFRT is largely underutilized, being primarily reserved for older, frailer patients. Chemotherapy is significantly underused with HFRT relative to CFRT. IMRT is used frequently and was associated with equivalent or modestly increased overall survival. [ABSTRACT FROM AUTHOR]

PurposeBladder cancer is a common malignancy often diagnosed in older adults. Previous studies have reported racial/ethnic disparities in bladder cancer survival outcomes but have not focused on younger patients. We identified whether factors influencing cause specific survival in adolescents and young adults (ages 15 to 39) differed from older adults, and defined prognostic factors specifically in adolescents and young adults using the California Cancer Registry.Materials and methodsPatients diagnosed with bladder cancer between 1988 through 2012 were included in the study. The primary outcome measure was cause specific survival. A multivariable Cox proportional hazards regression model was used to evaluate predictors of cause specific survival in patients of all ages and in adolescents/young adults. Interactions of age and other variables between younger and older adult patients were assessed.ResultsOf 104,974 patients with bladder cancer we identified 1,688 adolescent and young adult patients (1.6%). Compared to older patients these patients had a 58% reduced risk of bladder cancer death (HR 0.42, p

BackgroundPatients undergoing systemic therapy for urothelial carcinoma (UC) are at increased risk for venous thromboembolic (VTE) events. The objective of the current study was to determine the rate of VTE events in patients undergoing systemic therapy for UC and assess factors affecting this rate.MethodsThis study was registered with the PROSPERO database (CRD42015025774). We searched Pubmed, MEDLINE, EMBASE, The Cochrane Library, CINAHL, and Web of Science libraries through August 2014. As per PRISMA guidelines, 2 reviewers independently reviewed titles and abstracts. Disagreements were arbitrated by a third reviewer. After full text review, data were abstracted and pooled using a random effects model. Authors were contacted for clarification of data. To determine VTE risk factors, subgroup analyses and meta-regression were conducted.ResultsWe identified 3,635 publications in the initial search, of which 410 met inclusion criteria for full text review. Of these, we were able to obtain data on the outcome of interest for 62 publications. A total of 5,082 patients, of which 77% were male, underwent systemic therapy for UC, with 373 VTE events. The proportion of patients who had had prior surgery, chemotherapy, or radiation was 55%, 25%, and 9%, respectively. Fixed effects and random effects models were used to estimate the VTE rate, yielding event rates of 6.7% and 5.4%, respectively.ConclusionsVTE occurs frequently in patients undergoing systemic therapy for UC. The VTE rate was affected by the country of origin, history of radiation, as well as by the systemic treatment class. The study was limited by the incomplete reporting of all variables of interest.

The incidence of urothelial carcinoma of the urinary bladder (bladder cancer) remains high. While other solid organ malignancies have seen significant improvement in morbidity and mortality, there has been little change in bladder cancer mortality in the past few decades. The mortality is mainly driven by muscle invasive bladder cancer, but the cancer burden remains high even in nonmuscle invasive bladder cancer due to high recurrence rates and risk of progression. While apoptosis deregulation has long been an established pathway for cancer progression, nonapoptotic pathways have gained prominence of late. Recent research in the role of autophagy in other malignancies, including its role in treatment resistance, has led to greater interest in the role of autophagy in bladder cancer. Herein, we summarize the literature regarding the role of autophagy in bladder cancer progression and treatment resistance. We address it by systematically reviewing treatment modalities for nonmuscle invasive and muscle invasive bladder cancer.

Anterior gradient 2 (AGR2) is a cancer-associated secreted protein found predominantly in adenocarcinomas. Given its ubiquity in solid tumors, cancer-secreted AGR2 could be a useful biomarker in urine or blood for early detection. However, normal organs express and might also secrete AGR2, which would impact its utility as a cancer biomarker. Uniform AGR2 expression is found in the normal bladder urothelium. Little AGR2 is secreted by the urothelial cells as no measurable amounts could be detected in urine. The urinary proteomes of healthy people contain no listing for AGR2. Likewise, the blood proteomes of healthy people also contain no significant peptide counts for AGR2 suggesting little urothelial secretion into capillaries of the lamina propria. Expression of AGR2 is lost in urothelial carcinoma, with only 25% of primary tumors observed to retain AGR2 expression in a cohort of lymph node-positive cases. AGR2 is secreted by the urothelial carcinoma cells as urinary AGR2 was measured in the voided urine of 25% of the cases analyzed in a cohort of cancer vs. non-cancer patients. The fraction of AGR2-positive urine samples was consistent with the fraction of urothelial carcinoma that stained positive for AGR2. Since cancer cells secrete AGR2 while normal cells do not, its measurement in body fluids could be used to indicate tumor presence. Furthermore, AGR2 has also been found on the cell surface of cancer cells. Taken together, secretion and cell surface localization of AGR2 are characteristic of cancer, while expression of AGR2 by itself is not.

Purpose: The incidence and risk factors for metachronous upper tract urothelial carcinoma (UTUC) following radical cystectomy (RC) remain incompletely defined, which has limited the ability to individualize postoperative surveillance. Materials and Methods: A retrospective review of 2 institutional registries was performed to identify patients undergoing RC for urothelial carcinoma. Multivariable Cox proportional hazard models for metachronous post-RC UTUC were developed in one institutional data set and validated in the second institutional data set. A post-RC UTUC risk score was then developed from these models. Results: A total of 3,170 RC patients were included from the training cohort and 959 RC patients from the validation cohort. At a median followup after RC of 4.6 years (IQR 2.1e8.7), 167 patients were diagnosed with UTUC. On multivariable analysis in the training cohort, risk factors for metachronous UTUC were the presence of positive urothelial margin (HR 2.60, p <0.01), history of bacillus Calmette-Guerin treatment prior to RC (HR 2.20, p <0.01), carcinoma in situ at RC (HR 2.01, p <0.01) and pre-RC hydronephrosis (HR 1.48, p[0.04). These factors had similar discriminative capacity in the training and validation cohorts (C-statistic 0.71 and 0.73, respectively). A UTUC risk score was developed with these variables which stratified patients into low (0 points), intermediate (1e3 points), and high risk (4D points) for post-RC UTUC, with respective 5-year UTUC-free survivals of 99%, 96%, 89% in the training cohort and 98%, 96%, and 91% in the validation cohort. Conclusions: We developed and validated a risk score for post-RC UTUC that may optimize UTUC surveillance protocols after RC. [ABSTRACT FROM AUTHOR]

Objective: To understand the feasibility of FGFR3 tests in the Brazilian public health context, and to sample the mutational burden of this receptor in high-grade muscle invasive bladder cancer. Methods: A total of 31 patients with high-grade muscle-invasive bladder cancer were included in the present study. Either transurethral resection of bladder tumor or radical cystectomy specimens were analyzed. Formalin-fixed paraffin-embedded tissue blocks were sectioned, hematoxylin and eosin stained, and histologic sections were reviewed. Total RNA was extracted using the RNeasy DSP formalin-fixed paraffin-embedded kit. Qualitative results were displayed in Rotor-Gene AssayManager software. Results: Six patients were excluded. From the samples analyzed, four (16.7%) were considered inadequate and could not have their RNA extracted. Two patients presented FGFR3 mutations, accounting for 9.5% of material available for adequate analysis. The two mutations detected included a Y373C mutation in a male patient and a S249C mutation in a female patient. Conclusion: FGFR3 mutations could be analyzed in 84% of our cohort and occurred in 9.5% of patients with high-grade muscle invasive bladder cancer in this Brazilian population. FGFR3 gene mutations are targets for therapeutic drugs in muscle-invasive bladder cancer. For this reason, know the frequency of these mutations can have a significant impact on public health policies and costs provisioning. [ABSTRACT FROM AUTHOR]

Melanomas originating within the urinary tract represent a rare and clinically challenging subset of malignancies. Despite extensive research on cutaneous melanomas, urinary tract melanomas remain relatively unexplored, presenting diagnostic dilemmas and limited treatment consensus. In this comprehensive review, we synthesize current knowledge on the epidemiology, risk factors, clinical presentation, histopathological characteristics, and treatment strategies specific to this disease. Enhancing clinical awareness, refining diagnostic approaches, and exploring novel therapeutic interventions hold promise for improving outcomes in this challenging malignancy subset., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Radical open nephroureterectomy (ONU) with bladder cuff excision (BCE) is the traditional gold standard approach for management of high-risk non-metastatic upper tract urothelial cancer. ONU involves two separate procedures; the nephrectomy and distal ureterectomy, with each of these parts being able to be performed with an open or minimally-invasive approach. Multiple approaches have been described for the resection of the distal ureter and bladder cuff after mobilization of the kidney and upper ureter.Materials and Methods: A Medline search of the literature including relevant articles up to March, 2020 was performed. Search terms included "nephroureterectomy", "upper tract urothelial carcinoma", "upper urinary tract carcinoma OR UTUC", "open OR conventional OR ONU OR conventional", "robotic-assisted nephroureterectomy OR RANU", "laparoscop* OR LNU OR LRNU" and "minimally-invasive nephroureterectomy". Original articles, case series and review articles were included.Results: There are no randomised studies. Various techniques have been described to manage the distal ureter during nephroureterectomy. This review provides an overview of these techniques. The perioperative and oncological outcomes following open versus endoscopic techniques and minimally invasive techniques have been described. Although endoscopic approaches have more favourable perioperative outcomes, this comes at the expense of increased risk of tumour spillage and recurrence compared to the traditional open approaches. Minimally-invasive techniques (laparoscopic and robotic-assisted NU) largely have superior perioperative outcomes versus their open NU counterparts, with comparable oncological outcomes.Conclusion: Current non-randomised evidence is open to selection bias and is insufficient to support or refute endoscopic management of the distal ureter as an alternative to open bladder cuff excision. The optimal approach to nephroureterectomy and management of the distal ureter continues to remain a surgical dilemma. [ABSTRACT FROM AUTHOR]

Urothelial tumors are typically a disease affecting elderly individuals and are rare in young patients. Moreover, upper urinary tract urothelial carcinoma is extremely rare in the young age group. In this study, we present a case of urothelial cell carcinoma of the renal pelvis and ureter in a young man without risk factors of urothelial carcinoma, which was misdiagnosed as ureteropelvic junction obstruction and treated with a laparoscopic pyeloplasty. [ABSTRACT FROM AUTHOR]

BackgroundUrinary tract infections (UTI) are believed to be common in dogs with transitional cell carcinoma (TCC), but incidence and contributing factors have not been reported.ObjectivesTo determine the frequency and bacterial agents associated with UTI in dogs with TCC and define contributing factors.AnimalsEighty-five dogs with a history of urogenital TCC undergoing treatment with chemotherapy that had at least 1 urine culture performed.MethodsMedical records and culture results were retrospectively reviewed and ultrasound images were reviewed when available. Clinical factors were evaluated statistically for association with positive culture.ResultsFifty-five percent (47/85) of dogs had at least 1 positive culture during the course of treatment. Female dogs (80%, 40/50) were more likely than male dogs (29%, 10/35) to have at least 1 positive culture. Ultrasound examination determined that female dogs were more likely to have urethral (74%, 31/42) or trigonal tumor involvement (71%, 30/42) compared to male dogs (32%, 9/28 and 43%, 12/28, respectively). The most commonly isolated organisms were Staphylococcus spp. (23.9%, 29/121) and Escherichia coli (19.8%, 24/121). Dogs with urethral involvement of TCC were significantly more likely to have at least 1 positive culture than dogs without urethral involvement (75%, 30/40 versus 30%, 9/30).ConclusionsUrinary tract infection is common in dogs with TCC highlighting the importance of regular monitoring for bacterial cystitis in dogs with TCC. In addition, clinical factors such as tumor location and sex may be predictive of positive culture and can help clinicians assess the risk of UTI.

BackgroundReported response rates of transitional cell carcinoma (TCC) in dogs to piroxicam in combination with either mitoxantrone or carboplatin are similar; however, it is unknown whether either drug might provide superior duration of response.Hypothesis/objectivesTo determine if the progression-free interval (PFI) of dogs with TCC treated with mitoxantrone and piroxicam was different than that of dogs receiving carboplatin and piroxicam. The hypothesis was that the efficacy of mitoxantrone is no different from carboplatin.AnimalsFifty dogs with TCC without azotemia.MethodsProspective open-label phase III randomized study. Either mitoxantrone or carboplatin was administered every 3 weeks concurrently with piroxicam with restaging at 6-week intervals. Twenty-four dogs received carboplatin and 26 received mitoxantrone.ResultsResponse was not different between groups (P = .56). None of the dogs showed complete response. In the mitoxantrone group, there were 2 (8%) partial responses (PR) and 18 (69%) dogs with stable disease (SD). In the carboplatin group, there were 3 PR (13%) and 13 (54%) dogs with SD. The PFI was not significantly different between groups (mitoxantrone = 106 days; carboplatin = 73.5 days; P = .62; hazard ratio 0.86; 95% confidence interval 0.47-1.56). Dogs with prostatic involvement experienced a shorter survival (median, 109 days) compared to dogs with urethral, trigonal, or apically located tumors; this difference was significant (median 300, 190, and 645 days, respectively; P = .005).Conclusions and clinical importanceThis study did not detect a different in outcome in dogs with TCC treated with either mitoxantrone or carboplatin in combination with piroxicam.