Synchronous and metachronous urothelial carcinoma of the upper urinary tract and the bladder: Are they clonally related? A systematic review

Purpose: Following radical nephroureterectomy for upper urinary tract urothelial carcinoma (UTUC), intravesical recurrence (IVR) is found in 22% to 47% of patients. Patients with a primary urothelial carcinoma of the bladder (UCB) have an increased risk of a future UTUC (1%–5%). Paired UTUC and UCB might represent clonally related tumors due to intraluminal seeding of tumor cells or might be separate entities of urothelial carcinoma caused by field cancerization. We systematically reviewed all the relevant literature to address the possible clonal relation of UTUC and paired UCB. Materials and Methods: MEDLINE, EMBASE, and COCHRANE databases were systematically searched for relevant citations published between January 2000 and July 2019. This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Of 5038 citations identified, 86 full papers were screened, and 9 studies met the inclusion criteria. Results: The populations studied and the molecular techniques used to assess clonality of UTUC and paired UCB differed largely over time. Eight studies reported on primary UTUC and meta- or synchronous IVR without a history of UCB. A total of 118 tumors

The clonal relation of primary upper urinary tract urothelial carcinoma and paired urothelial carcinoma of the bladder

The risk of developing urothelial carcinoma of the bladder (UCB) in patients treated by radical nephroureterectomy (RNU) for an upper urinary tract urothelial carcinoma (UTUC) is 22% to 47% in the 2 years after surgery. Subject of debate remains whether UTUC and the subsequent UCB are clonally related or represent separate origins. To investigate the clonal relationship between both entities, we performed targeted DNA sequencing of a panel of 41 genes on matched normal and tumor tissue of 15 primary UTUC patients treated by RNU who later developed 19 UCBs. Based on the detected tumor-specific DNA aberrations, the paired UTUC and UCB(s) of 11 patients (73.3%) showed a clonal relation, whereas in four patients the molecular results did not indicate a clear clonal relationship. Our results support the hypothesis that UCBs following a primary surgically resected UTUC are predominantly clonally derived recurrences and not separate entities

Biological and prognostic implications of biopsy upgrading for high-grade upper tract urothelial carcinoma at nephroureterectomy

Objectives Technical limitations of ureteroscopic (URS) biopsy has been considered responsible for substantial upgrading rate in upper tract urothelial carcinoma (UTUC). However, the impact of tumor specific factors for upgrading remain uninvestigated. Methods Patients who underwent URS biopsy were included between 2005 and 2020 at 13 institutions. We assessed the prognostic impact of upgrading (low-grade on URS biopsy) versus same grade (high-grade on URS biopsy) for high-grade UTUC tumors on radical nephroureterectomy (RNU) specimens. Results This study included 371 patients, of whom 112 (30%) and 259 (70%) were biopsy-based low- and high-grade tumors, respectively. Median follow-up was 27.3 months. Patients with high-grade biopsy were more likely to harbor unfavorable pathologic features, such as lymphovascular invasion (p < 0.001) and positive lymph nodes (LNs; p < 0.001). On multivariable analyses adjusting for the established risk factors, high-grade biopsy was significantly associated with worse overall (hazard ratio [HR] 1.74; 95% confidence interval [CI], 1.10-2.75; p = 0.018), cancer-specific (HR 1.94; 95% CI, 1.07-3.52; p = 0.03), and recurrence-free survival (HR 1.80; 95% CI, 1.13-2.87; p = 0.013). In subgroup analyses of patients with pT2-T4 and/or positive LN, its significant association retained. Furthermore, high-grade biopsy in clinically non-muscle invasive disease significantly predicted upstaging to final pathologically advanced disease (>= pT2) compared to low-grade biopsy. Conclusions High tumor grade on URS biopsy is associated with features of biologically and clinically aggressive UTUC tumors. URS low-grade UTUC that becomes upgraded to high-grade might carry a better prognosis than high-grade UTUC on URS. Tumor specific factors are likely to be responsible for upgrading to high-grade on RNU

Comparing Oncological and Perioperative Outcomes of Open versus Laparoscopic versus Robotic Radical Nephroureterectomy for the Treatment of Upper Tract Urothelial Carcinoma: A Multicenter, Multinational, Propensity Score-Matched Analysis

OBJECTIVES To identify correlates of survival and perioperative outcomes of upper tract urothelial carcinoma (UTUC) patients undergoing open (ORNU), laparoscopic (LRNU), and robotic (RRNU) radical nephroureterectomy (RNU). METHODS We conducted a retrospective, multicenter study that included non-metastatic UTUC patients who underwent RNU between 1990-2020. Multiple imputation by chained equations was used to impute missing data. Patients were divided into three groups based on their surgical treatment and were adjusted by 1:1:1 propensity score matching (PSM). Survival outcomes per group were estimated for recurrence-free survival (RFS), bladder recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS). Perioperative outcomes: Intraoperative blood loss, hospital length of stay (LOS), and overall (OPC) and major postoperative complications (MPCs; defined as Clavien-Dindo > 3) were assessed between groups. RESULTS Of the 2434 patients included, 756 remained after PSM with 252 in each group. The three groups had similar baseline clinicopathological characteristics. The median follow-up was 32 months. Kaplan-Meier and log-rank tests demonstrated similar RFS, CSS, and OS between groups. BRFS was found to be superior with ORNU. Using multivariable regression analyses, LRNU and RRNU were independently associated with worse BRFS (HR 1.66, 95% CI 1.22-2.28, p = 0.001 and HR 1.73, 95%CI 1.22-2.47, p = 0.002, respectively). LRNU and RRNU were associated with a significantly shorter LOS (beta -1.1, 95% CI -2.2-0.02, p = 0.047 and beta -6.1, 95% CI -7.2-5.0, p < 0.001, respectively) and fewer MPCs (OR 0.5, 95% CI 0.31-0.79, p = 0.003 and OR 0.27, 95% CI 0.16-0.46, p < 0.001, respectively). CONCLUSIONS In this large international cohort, we demonstrated similar RFS, CSS, and OS among ORNU, LRNU, and RRNU. However, LRNU and RRNU were associated with significantly worse BRFS, but a shorter LOS and fewer MPCs

Real-world management of testicular torsion: Level of adherence to the EAU Pediatric Urology guidelines

Background: Testicular torsion is the most frequent cause of irreversible ischemia to the testis. Despite guidelines being available, challenges remain in both diagnosis and management of the disease. Objective: This study aims to determine the adherence of urologists and residents in urology to the European Association of Urology (EAU) Pediatric Guideline on Testicular torsion. Study design: Both Dutch and European urologists, and residents in urology filled in a survey on testicular torsion. Information on demographics, diagnostics, and treatment modalities was retrieved from the questionnaire based on the EAU Guideline on Paediatric Urology. Results: A total of 303 responders participated, of which 214 (71%) were from The Netherlands. Most (61%) responders treated three or more cases of testicular torsion in 2020. Ultrasound was used by 64%, followed by an attempt of manual detorsion by 38% (Summary Fig.). Importantly, 23% preferred not to perform emergency surgery after successful manual detorsion. A Winkelmann procedure was performed by 23%, without fixation of the test is using suture material. A large group of responders (30%) only fixed the contralateral testis by a proven testicular torsion. Discussion: A feasible adherence to the EAU Guideline on Paediatric Urology in treating testicular torsion was reported using this survey, although not all recommendations are implemented as proposed. The fact that outcomes of the different diagnostic and treatment modalities are lacking might be a limitation in interpreting the results of this survey. Conclusion: Majority of the responders followed the EAU Guideline on Paediatric Urology in the diagnosis and treatment of testicular torsion. Ultrasound might contribute to diagnosing testicular torsion as long as this does not cause any delay for surgical exploration. Surprisingly, many urologists do not perform a surgical fixation of the testis after detorsion. Since a wide range of techniques and materials is used in case of surgical fixation, the guideline may provide in preferences for a unified policy among urologists.[Formul

Rising incidence rates and unaltered survival rates for primary upper urinary tract urothelial carcinoma: a Dutch population-based study from 1993 to 2017

Aim: To assess trends in the incidence, disease management and survival rates for upper urinary tract urothelial carcinoma (UTUC) in the Netherlands. Materials and methods: Patients diagnosed with primary UTUC in the Netherlands between 1993 and 2017 were identified through the population-based Netherlands Cancer Registry (NCR). Patient and tumour characteristics, as well as information on treatment and vital status, were retrieved from the NCR. Age-standardized incidence rates were calculated, stratified by age, gender, calendar period and disease stage. Relative survival served as an approximation for cancer-specific survival. Results: We identified 13 314 patients with primary UTUC. The age-standardized incidence rate increased from 2.0 in 1993 to 3.2 per 100 000 person-years in 2017, without change in gender distribution. The increase in incidence held for all disease stages except organ-confined (T1–T2) disease. The most prominent increase was in superficial (Tis/Ta) and metastatic (M+) UTUC, which increased from 0.6 to 1.2 and 0.1 to 0.4 per 100 000 person-years, respectively. The 5-year relative survival did not change over time: 57.0% (95% confidence interval 55.9–58.1). Applied treatments were largely the same over the study period, although fewer radical nephroureterectomies and more kidney-sparing surgeries were performed in the most recent years. The use of peri-operative intravesical chemotherapy modestly increased. Conclusion: Between 1993 and 2017, the age-standardized incidence of primary UTUC in the Netherlands has increased by more than 50%, but the relative survival of UTUC patients remained unchanged. Preventive measures against exposure to risk factors, early detection of disease, and more efficacious treatment methods are needed to improve outcomes of patients with UTUC

Rising incidence rates and unaltered survival rates for primary upper urinary tract urothelial carcinoma

Aim: To assess trends in the incidence, disease management and survival rates for upper urinary tract urothelial carcinoma (UTUC) in the Netherlands. Materials and methods: Patients diagnosed with primary UTUC in the Netherlands between 1993 and 2017 were identified through the population-based Netherlands Cancer Registry (NCR). Patient and tumour characteristics, as well as information on treatment and vital status, were retrieved from the NCR. Age-standardized incidence rates were calculated, stratified by age, gender, calendar period and disease stage. Rela

A deep-learning workflow to predict upper tract urothelial carcinoma protein-based subtypes from H&amp;E slides supporting the prioritization of patients for molecular testing

Upper tract urothelial carcinoma (UTUC) is a rare and aggressive, yet understudied, urothelial carcinoma (UC). The more frequent UC of the bladder comprises several molecular subtypes, associated with different targeted therapies and overlapping with protein-based subtypes. However, if and how these findings extend to UTUC remains unclear. Artificial intelligence-based approaches could help elucidate UTUC's biology and extend access to targeted treatments to a wider patient audience. Here, UTUC protein-based subtypes were identified, and a deep-learning (DL) workflow was developed to predict them directly from routine histopathological H&amp;E slides. Protein-based subtypes in a retrospective cohort of 163 invasive tumors were assigned by hierarchical clustering of the immunohistochemical expression of three luminal (FOXA1, GATA3, and CK20) and three basal (CD44, CK5, and CK14) markers. Cluster analysis identified distinctive luminal (N = 80) and basal (N = 42) subtypes. The luminal subtype mostly included pushing, papillary tumors, whereas the basal subtype diffusely infiltrating, non-papillary tumors. DL model building relied on a transfer-learning approach by fine-tuning a pre-trained ResNet50. Classification performance was measured via three-fold repeated cross-validation. A mean area under the receiver operating characteristic curve of 0.83 (95% CI: 0.67–0.99), 0.8 (95% CI: 0.62–0.99), and 0.81 (95% CI: 0.65–0.96) was reached in the three repetitions. High-confidence DL-based predicted subtypes showed significant associations (p &lt; 0.001) with morphological features, i.e. tumor type, histological subtypes, and infiltration type. Furthermore, a significant association was found with programmed cell death ligand 1 (PD-L1) combined positive score (p &lt; 0.001) and FGFR3 mutational status (p = 0.002), with high-confidence basal predictions containing a higher proportion of PD-L1 positive samples and high-confidence luminal predictions a higher proportion of FGFR3-mutated samples. Testing of the DL model on an independent cohort highlighted the importance to accommodate histological subtypes. Taken together, our DL workflow can predict protein-based UTUC subtypes, associated with the presence of targetable alterations, directly from H&amp;E slides.</p

Short-term Changes in Health-related Quality of Life of Patients Undergoing Radical Surgery for Upper Urinary Tract Urothelial Carcinoma:Results from a Prospective Phase 2 Clinical Trial

Background and objective: The possible negative impact of radical surgery on patients’ health-related quality of life (HRQoL) plays an important role in preoperative counseling. Here, we analyzed the HRQoL of patients treated for upper urinary tract urothelial carcinoma (UTUC) in the context of a single-arm phase 2 multicenter study, in which the safety and efficacy of a single preoperative intravesical instillation with mitomycin C were investigated. Our objective was to investigate early changes in HRQoL in patients undergoing radical surgery for UTUC and identify factors associated with these outcomes. Methods: Patients with pTanyN0-1M0 UTUC were prospectively included. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) questionnaire at baseline, and at 1 and 3 mo after surgery. A linear mixed model was used to evaluate the changes in HRQoL over time and identify the variables associated with these outcomes. The clinical effect size was used to assess the clinical impact and level of perceptibility of HRQoL changes for clinicians and/or patients based on given thresholds. Key findings and limitations: Between 2017 and 2020, 186 patients were included. At baseline, 1 mo after surgery, and 3 mo after surgery, response rates were 91%, 84%, and 78%, respectively. One month after surgery, a statistically significant and clinically relevant deterioration was observed in physical, role, and social functioning, and for the included symptom scales: constipation, fatigue, and pain. An improvement in emotional functioning was observed. At 3 mo, HRQoL returned to baseline levels, except emotional functioning, which improved at 1 mo and persisted to be better than that before surgery. Age &gt;70 yr was associated with worse physical functioning, but better social and emotional functioning. Male patients reported better emotional functioning than females. Postoperative complications were negatively associated with social functioning. Conclusions and clinical implications: UTUC patients treated with radical surgery experienced a significant, albeit temporary, decline in HRQoL. Three months following surgery, HRQoL outcomes returned to baseline levels. This information can be used to counsel UTUC patients before undergoing radical surgery and contextualize recovery after surgery. Patient summary: We investigated the changes in quality of life as reported by patients who underwent surgery for upper tract urothelial carcinoma (UTUC). We found that patients experienced a decline in quality of life 1 mo after surgery, but this was temporary, with full recovery of quality of life 3 mo after surgery. These findings can help doctors and other medical staff in counseling UTUC patients before undergoing radical surgery.</p