Upper Tract Research Articles

Radiomics-based machine learning approach for the prediction of grade and stage in upper urinary tract urothelial carcinoma-a step towards virtual biopsy.

Upper tract urothelial carcinoma is a rare, aggressive lesion, with early detection a key to its management. This study aimed to utilise computed tomographic urogram data to develop machine learning models for predicting tumour grading and staging in upper urothelial tract carcinoma patients and to compare these predictions with histopathological diagnosis used as reference standards. Protocol-based computed tomographic urogram data from 106 patients were obtained and visualised in 3D. Digital segmentation of the tumours was conducted by extracting textural radiomics features. They were further classified using 11 predictive models. The predicted grades and stages were compared to the histopathology of radical nephroureterectomy specimens. Classifier models worked well in mining the radiomics data and delivered satisfactory predictive machine learning models. The MultiLayer Panel showed 84% sensitivity and 93% specificity while predicting upper tract urothelial carcinoma grades. The Logistic Regression model showed a sensitivity of 83% and a specificity of 76% while staging. Similarly, other classifier algorithms (e.g., Support Vector classifier) provided a highly accurate prediction while grading upper tract urothelial carcinoma compared to clinical features alone or ureteroscopic biopsy histopathology. Data mining tools could handle medical imaging datasets from small (<2cm) tumours for upper tract urothelial carcinoma. The radiomics-based machine learning algorithms provide a potential tool to model tumour grading and staging with implications for clinical practice and the upgradation of current paradigms in cancer diagnostics. Machine learning based on radiomics features can predict upper tract urothelial cancer grading and staging with significant improvement over ureteroscopic histopathology. The study showcased the prowess of such emerging tools in the set objectives with implications towards virtual biopsy.

Bladder Cancer: Upper Tract Transitional Cell Carcinoma III (PD41)

Bladder Cancer: Upper Tract Transitional Cell Carcinoma III (PD41)

Bladder Cancer: Upper Tract Transitional Cell Carcinoma I (PD20)

Bladder Cancer: Upper Tract Transitional Cell Carcinoma I (PD20)

Bladder Cancer: Upper Tract Transitional Cell Carcinoma II (MP38)

Bladder Cancer: Upper Tract Transitional Cell Carcinoma II (MP38)

Endoscopic Cryoablation Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

Background and objectiveCryoablation is a traditional antitumor therapy with good prospects for development. The efficacy of endoscopic management as a kidney-sparing surgery for high-risk upper tract urothelial carcinoma (UTUC) remains controversial. Our aim was to evaluate the impact of endoscopic cryoablation (ECA) versus radical nephroureterectomy (RNU) on survival outcomes, renal function, and complications. MethodsWe retrospectively analyzed data for 116 patients with newly diagnosed high-risk UTUC who underwent either ECA (n = 13) or RNU (n = 103) from March 25, 2019 to December 8, 2021. Propensity score matching (1:4) using the nearest neighbor method was performed before analysis. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), intravesical recurrence-free survival (RFS), the change in renal function, and treatment-emergent adverse events (TEAEs). Key findings and limitationsAt median follow-up of 28.2 mo for the ECA group and 27.6 mo for the RNU group, 2-yr OS (82% vs 84%), PFS (73% vs 71%), and intravesical RFS (81% vs 83%) rates after matching did not significantly differ. A decline in renal function was observed after RNU, but not after ECA. Five (41.7%) patients in the ECA group reported six TEAEs, and 17 patients (35.4%) in the RNU group reported 20 TEAEs. Conclusions and clinical implicationsIn comparison to RNU, ECA for UTUC resulted in noninferior oncological outcomes and superior preservation of renal function. Patient summaryOur study suggests that a treatment called endoscopic cryoablation for high-risk cancer in the upper urinary tract can help in preserving kidney function, with similar survival outcomes to those after more extensive surgery. This option can be considered for selected patients with a strong preference for kidney preservation.

Safety and oncological outcome of early intraoperative intravesicle mitomycin C vs. deferred instillation in patients receiving robot-assisted radical nephroureterectomy

IntroductionRadical nephroureterectomy with concurrent bladder cuff excision (RNUBCE) is the gold standard surgical approach for high-risk primary upper tract urothelial carcinoma (UTUC). Given the notably high incidence of bladder tumor recurrence following this procedure, this study aimed to evaluate the effect and safety of intraoperative mitomycin-C (MMC) instillation vs. deferred instillation on overall oncological outcomes following robot-assisted RNUBCE.MethodsThis is a retrospective chart review study. Patients with non-invasive (N0, not T3/T4) UTUC who underwent robotic RNUBCE combined an intraoperative MMC instillation or a deferred MMC instillation after surgery at a medical center in Taiwan between November 2013 and June 2020 were eligible for inclusion. Patients with prior bladder UC, carcinomas of other origins, received neoadjuvant chemotherapy, and had undergone kidney transplantation were excluded. All surgeries were executed by a single surgical team under the guidance of the same surgeon. The primary outcomes was the risk of bladder tumor recurrence between patients received intraoperative (IO) vs. deferred MMC instillation postoperatively (PO) during one-year follow-up. The secondary outcome was postoperative adverse events assessed by the Clavien–Dindo classification. Univariate and multivariable Cox regression analyses were performed to determine the associations between study variables and the outcomes.ResultsA total of 54 patients were included in the analysis. 12 (22.2%) patients experienced a bladder tumor recurrence during follow-up (IO: 7.7%, PO: 35.7%, p &amp;lt; 0.021). After adjustment in the multivariable, intraoperative MMC instillation was significantly associated with lower risk of bladder recurrence [adjusted hazard ratio (aHR) = 0.15, 95% CI: 0.03–0.81, p = 0.028]. No MMC-related Clavien–Dindo Grade III–IV adverse events were found in either group.ConclusionIIntraoperative MMC instillation is safe and associated with a lower bladder tumor recurrence risk in patients undergoing robotic RNUBCE for UTUC than deferred instillation. Future large, prospective studies are still warranted to confirm the findings.

Automated Upper Tract Urothelial Carcinoma Tumor Segmentation During Ureteroscopy Using Computer Vision Techniques.

Endoscopic tumor ablation of upper tract urothelial carcinoma (UTUC) allows for tumor control with the benefit of renal preservation but is impacted by intraoperative visibility. We sought to develop a computer vision model for real-time, automated segmentation of UTUC tumors to augment visualization during treatment. We collected twenty videos of endoscopic treatment of UTUC from two institutions. Frames from each video (N=3387) were extracted and manually annotated to identify tumors and areas of ablated tumor. Three established computer vision models (U-Net, U-Net++ and UNext) were trained using these annotated frames and compared. Eighty percent of the data was used to train the models while 10% was used for both validation and testing. We evaluated the highest performing model for tumor and ablated tissue segmentation using a pixel-based analysis. The model and a video overlay depicting tumor segmentation were further evaluated intraoperatively. All twenty videos (mean 36 seconds ± 58s) demonstrated tumor identification and 12 depicted areas of ablated tumor. The U-Net model demonstrated the best performance for segmentation of both tumors (AUC-ROC of 0.96) and areas of ablated tumor (AUC-ROC of 0.90). Additionally, we implemented a working system to process real-time video feeds and overlay model predictions intraoperatively. The model was able to annotate new videos at 15 fps. Computer vision models demonstrate excellent real-time performance for automated upper tract urothelial tumor segmentation during ureteroscopy.

A Comprehensive Review on Upper Tract Urothelial Carcinoma: An Update in 2023

It is our pleasure to serve as the guest editors for the Cancers journal for this Special Issue, titled “Comprehensive Review on Upper Tract Urothelial Carcinoma: An Update in 2023” [...]

Bricker versus Wallace ureteroileal anastomosis: A multi-institutional propensity score-matched analysis.

The aim of our study is to evaluate the difference in stricture rate between matched groups of Bricker and Wallace techniques for ureteroileal anastomosis. A retrospective analysis of patients undergoing urinary diversion (UD) with Bricker and Wallace ureteroileal anastomosis at two university hospitals. Two groups of Bricker and Wallace patients were matched in a 1:1 ratio based on the age, sex, body mass index (BMI), Charlson comorbidity index (CCI), preoperative hydronephrosis, prior radiation therapy or abdominal surgery, pathologic T and N stages and 30-days-Clavien grade complications≥III. A multivariable Cox regression analysis was conducted to identify predictors of ureteroenteric stricture (UES) in all patients. Overall, 740 patients met the inclusion criteria and 209 patients in each group were propensity matched. At a similar median follow-up of 25 months, UES was detected in 25 (12%) and 30 (14.4%) patients in Bricker and Wallace groups, respectively (p = 0.56). However, only one patient in the Bricker group developed a bilateral stricture compared to 15 patients in the Wallace group, resulting in a significantly higher number of affected renal units in the Wallace group: 45 (10.7%) versus only 26 (6.2%) in the Bricker group (p = 0.00). On multivariable extended Cox analysis, prior radiotherapy, presence of T4 pelvic malignancy and nodal positive disease were independent predictor of UES formation. The technique of ureteroileal anastomosis itself does not increase the rate of stricture; however, conversion of two renal units into one is associated with a higher incidence of bilateral upper tract involvement.

The gender gap in stone-related surgery: A comprehensive analysis from an Israeli perspective.

To investigate the gender gap in the context of stone-related surgery within an Israeli population. We conducted a retrospective cohort study using administrative databases from Clalit Health Services to identify adults aged 18 and above who had their initial surgical treatment for upper tract urolithiasis. We employed descriptive statistics to outline the baseline patient characteristics, and the Cochran-Armitage test for trend was utilized to analyze surgical trends. Between 2003 and 2020, a total of 36,624 adult patients underwent surgical treatment for upper tract urinary stones. The mean age of patients was 55.01 years (standard deviation (SD) 16.6) for ureteroscopy (URS), 55.05 years (SD 15.1) for percutaneous nephrolithotripsy (PCNL), and 51.07 years (SD 15.1) for shockwave lithotripsy (SWL). When considering the distribution of procedures by gender, males accounted for 69.5% of URS cases, 58.3% of PCNL cases, and 70.6% of SWL cases, whereas females represented 30.5%, 41.7%, and 29.4% of URS, PCNL, and SWL cases, respectively. Across all surgical modalities, the male-to-female ratio exhibited fluctuations without a consistent trend, with both increases and decreases observed. In URS, the ratio saw a modest increase from 1.967 in 2003 to 2.173 in 2020. For PCNL, the ratio initially increased from 2.361 in 2003 to 2.549 in 2014, followed by subsequent fluctuations, but an overarching trend was not apparent. In contrast, for SWL, the ratio decreased from 2.15 in 2003 to 1.32 in 2020, with varying changes in between. This study highlights the dynamic nature of gender gap in stone-related surgery outcomes. While the male-to-female ratio exhibited fluctuations over a 17-year period, no consistent trend emerged. The absence of a clear trend underscores the complex and multifaceted factors influencing the gender gap in urolithiasis.

Multi-Institutional Bladder Exstrophy Consortium After 8 Years: The Short- and Intermediate-Term Outcomes.

Bladder exstrophy (BE) poses challenges both during the surgical repair and throughout follow-up. In 2013, a multi-institutional BE consortium was initiated, which included utilization of unified surgical principles for the complete primary repair of exstrophy (CPRE), real-time coaching, ongoing video capture and review of video footage, prospective data collection, and routine patient data analysis, with the goal of optimizing the surgical procedure to minimize devastating complications such as glans ischemia and bladder dehiscence while maximizing the rate of volitional voiding with continence and long-term protection of the upper tracts. This study reports on our short-term complications and intermediate-term continence outcomes. A single prospective database for all patients undergoing surgery with a BE epispadias complex diagnosis at 3 institutions since February 2013 was used. For this study, data for children with a diagnosis of classic BE who underwent primary CPRE from February 2013 to February 2021 were collected. Data recorded included sex, age at CPRE, adjunct surgeries including ureteral reimplantations and hernia repairs at the time of CPRE, osteotomies, and immobilization techniques, and subsequent surgeries. Data on short-term postoperative outcomes, defined as those occurring within the first 90 days after surgery, were abstracted. In addition, intermediate-term outcomes were obtained for patients operated on between February 2013 and February 2017 to maintain a minimum follow-up of 4 years. Outcomes included upper tract dilation on renal and bladder ultrasound, presence of vesicoureteral reflux, cortical defects on nuclear scintigraphy, and continence status. Bladder emptying was assessed with respect to spontaneous voiding ability, need for clean intermittent catheterization, and duration of dry intervals. All operating room encounters that occurred subsequent to initial CPRE were recorded. CPRE was performed in 92 classic BE patients in the first 8 years of the collaboration (62 boys), including 46 (29 boys) during the first 4 years. In the complete cohort, the median (interquartile range) age at CPRE was 79 (50.3) days. Bilateral iliac osteotomies were performed in 89 (97%) patients (42 anterior and 47 posterior). Of those undergoing osteotomies 84 were immobilized in a spica cast (including the 3 patients who did not have an osteotomy), 6 in modified Bryant's traction, and 2 in external fixation with Buck's traction. Sixteen (17%) patients underwent bilateral ureteral reimplantations at the time of CPRE. Nineteen (21%) underwent hernia repair at the time of CPRE, 6 of which were associated with orchiopexy. Short-term complications within 90 days occurred in 31 (34%), and there were 13 subsequent surgeries within the first 90 days. Intermediate-term outcomes were available for 40 of the 46 patients, who have between 4 and 8 years of follow-up, at a median of 5.7 year old. Thirty-three patients void volitionally, with variable dry intervals. Cumulative efforts of prospective data collection have provided granular data for evaluation. Short-term outcomes demonstrate no devastating complications, that is, penile injury or bladder dehiscence, but there were other significant complications requiring further surgeries. Intermediate-term data show that boys in particular show encouraging spontaneous voiding and continence status post CPRE, while girls have required modification of the surgical technique over time to address concerns with urinary retention. Overall, 40% of children with at least 4 years of follow-up are voiding with dry intervals of > 1 hour.

Should a Refluxing Internal Diversion Be Considered a Temporizing Procedure? Extended Follow-Up and Outcomes After Side-to-Side Ureterovesicostomy for Primary Obstructive Megaureter in Young Children.

We describe long-term outcomes, including UTIs and need for reimplantation, after ureterovesicostomy (UV) as a lasting surgical procedure for children with primary obstructive megaureter (POM). Children referred to our institution between 2016 and 2023 who underwent refluxing UV were analyzed. POM was defined as hydroureteronephrosis with distal ureteral dilatation > 7 mm and a negative workup for other etiologies of hydronephrosis. We assessed for surgical outcomes, complications, rate of UTI, and improvement in upper tract dilatation. Statistical analyses assessed for change in hydronephrosis metrics over follow-up. Among 183 patients diagnosed with POM, 47 (24%) underwent UV. Median age of presentation, surgery, and follow-up was 2, 9, and 43 months, respectively. A total of 7 patients developed 30-day complications: Clavien-Dindo grade 1 in 2 (transient urinary retention) and grade 2 in 5 (UTIs). During monitoring 14 (30%) developed UTIs and 7 (15%) required ureteral reimplant or UV takedown. After surgery there was a significant decrease in the proportion of patients with high-grade hydronephrosis, anteroposterior renal pelvis diameter, and maximum ureteral dilatation. Refluxing UV is a safe alternative to cutaneous diversion in POM. Most patients had improvement in upper tract dilatation with an acceptable short-term complication rate and need for reoperation (in comparison to routine later reimplantation). Our experience suggests that monitoring alone after UV is feasible, and that selective subsequent reconstruction is a reasonable strategy.

Phase 1b Trial Evaluating Tolerability and Activity of Targeted Fibroblast Growth Factor Receptor Inhibition in Localized Upper Tract Urothelial Carcinoma.

We initiated a biomarker-informed preoperative study of infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, in patients with localized upper tract urothelial carcinoma (UTUC), a population with high unmet needs and tumor with a high frequency of FGFR3 alterations. Patients with localized UTUC undergoing ureteroscopy or nephroureterectomy/ureterectomy were enrolled on a phase 1b trial (NCT04228042). Once-daily infigratinib 125 mg by mouth × 21 days (28-day cycle) was given for 2 cycles. Tolerability was monitored by Bayesian design and predefined stopping boundaries. The primary endpoint was tolerability, and the secondary endpoint was objective response based on tumor mapping, done after endoscopic biopsy and post-trial surgery. Total planned enrollment: 20 patients. Targeted sequencing performed using a NovaSeq 6000 solid tumor panel. From May 2021 to November 2022, 14 patients were enrolled, at which point the trial was closed due to termination of all infigratinib oncology trials. Two patients (14.3%) had treatment-terminating toxicities, well below the stopping threshold. Responses occurred in 6 (66.7%) of 9 patients with FGFR3 alterations. Responders had median tumor size reduction of 67%, with 3 of 5 patients initially planned for nephroureterectomy/ureterectomy converted to ureteroscopy. Median follow-up in responders was 24.7 months (14.9-28.9). In this first trial of targeted therapy for localized UTUC, FGFR inhibition was well tolerated and had significant activity in FGFR3 altered tumors. Renal preservation was enabled in a substantial proportion of participants. These data support the design of a biomarker-driven phase 2 trial of FGFR3 inhibition in this population with significant unmet clinical needs.

NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.

Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan-Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression-free survival, cancer-specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K-AKT-mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT-mTOR pathway. Furthermore, the overexpression of NTRK3 in UM-UC-14 cells promoted AKT-mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT-mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC.

Evaluation of histological variants of upper tract urothelial carcinoma as prognostic factor after radical nephroureterectomy

PurposeTo evaluate the impact of variant histology on patients with upper tract urothelial carcinoma (UTUC) survival outcomes.Materials and methodsA total of 519 patients underwent radical nephroureterectomy without neoadjuvant therapy for UTUC at a single institution between May 2003 and December 2019. Multivariate Cox regression analysis evaluated the impact of variant histology on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS).ResultsAmong 84 patients (16.2%) with variant histology, the most frequent variant type was squamous cell differentiation (64.3%), followed by glandular differentiation (25.0%) and sarcomatoid variant (2.4%). They showed pathologically advanced T stage (for ≥ T3, 59.5% vs 33.3%, p < 0.001), higher tumor grade (96.4% vs 85.7%, p = 0.025), and higher rates of lymph node metastasis (17.9% vs 7.8%, p = 0.015), angiolymphatic invasion (41.7% vs 25.7%, p = 0.003), tumor necrosis (57.1% vs 29.0%, p < 0.001) and positive surgical margin (13.1% vs 5.7%, p = 0.015). On multivariate Cox regression analyses, variant histology was significantly associated with worse PFS (hazard ratio [HR] 2.23; 95% confidence interval [CI] 1.55–3.21; p < 0.001), CSS (HR 2.67; 95% CI 1.35–5.30; p = 0.005) and OS (HR 2.22; 95% CI 1.27–3.88; p = 0.005). In subgroup analysis, no significant survival gains of adjuvant chemotherapy occurred in patients with variant histology.ConclusionsVariant histology was associated with adverse pathologic features and poor survival outcomes. Our results suggest that patients with variant histology may require a close follow-up schedule and novel adjuvant therapy other than chemotherapy postoperatively.

Abstract LB105: Sensitive urothelial cancer detection via high volume urine DNA analysis

Abstract Background: The detection of cancer-associated DNA in urine samples has significant potential in urothelial cancer (UC) detection and surveillance. Every year millions of patients with urinary symptoms undergo cystoscopy, an examination of the bladder using a flexible scope. Only 10% of these invasive examinations result in a cancer diagnosis. Cystoscopy is also used in post-operative surveillance, with many UC patients requiring life-long cystoscopies. Methods: We developed a high-volume urine DNA collection kit and laboratory platform and prospectively analyzed 433 urine samples collected from diagnostic and post-operative timepoints from 167 UC patients and 95 negative controls from January 2021 to September 2023. We used a hybridization capture assay targeting the coding regions of 21 commonly mutated genes in urothelial tumors, as well as 8 frequently copy number altered loci. Samples were sequenced using Illumina NovaSeq instruments. Mutations, copy number alterations, and chromosomal rearrangements were computationally identified. Key Findings: In the diagnostic settings our assay achieved a sensitivity of 100% for pT1+ bladder cancer, 97% for pTa bladder cancer, and 91% for upper tract urothelial cancer (UTUC) (100% for pT1+ or high grade) in an all-comers UC cohort, at a specificity of 93%. Post-operative urine DNA surveillance informed by preoperative urine mutations detected 28/30 (93%) residual cancer cases found in cystoscopy or surgery, with two pTa low grade recurrences missed. Using a secondary, highly stringent urine tumor DNA detection threshold (100% specificity for UC), we show that urine DNA testing in the diagnostic setting may allow up to 68% of UC patients to be scheduled directly to operating room procedures, reducing hospital workload and expediting care. In addition, we demonstrate the feasibility of urine DNA for detecting underlying Lynch syndrome in UC patients by identifying three UTUC patients who carried germline defects in mismatch repair genes MSH2 or MSH6, indicative of Lynch syndrome. In two of these patients our assay also found a somatic second hit and high mutation load. Conclusions and Clinical Implications: These results show promise in urine DNA based cancer diagnostics even in patients with low grade tumors. The assay is designed to offer a non-invasive and cost-effective alternative for cystoscopies. Citation Format: Jussi Nikkola, Lauri Ryyppö, Juuso Vuorinen, Heini Kallio, Hanna Selin, Pyry Jämsä, Jonne Åkerla, Tarmo Pekkarinen, Antti Kaipia, Matti Nykter, Thea Veitonmäki, Matti Annala. Sensitive urothelial cancer detection via high volume urine DNA analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB105.

Comparison of European and American Guidelines for Upper Tract Urothelial Carcinoma: How Are They different?

Urothelial carcinoma (UC) affecting the urinary tract is recognized as one of the prevalent types of cancer, ranking fifth in terms of incidence. However, it is important to note that upper tract urothelial carcinoma (UTUC), in comparison to bladder cancer, is relatively uncommon and represents a minority of UC cases, accounting for ∼5% to 10%. It is worth emphasizing that as much as 60% of UTUC cases are invasive at the time of diagnosis, in contrast to 25% of bladder cancer cases. These statistics highlight the urgent need for well-designed, multidisciplinary strategies to guide optimal management for this vulnerable patient population, aiming to control treatment variability and minimize the risks associated with undertreatment and overtreatment. Methods: In this study, we present a comparative analysis of the contemporary guidelines on UTUC management from the European Association of Urology (EAU) and the American Urological Association/Society of Urologic Oncology (AUA/SUO) released in 2023. Our objective is to contrast the different guidelines and examine the evidence on which their recommendations are based. Results: By thoroughly reviewing the guidelines from both organizations, we observed substantial agreement on the management of UTUC. However, we also identified noticeable differences among these guidelines, leading to a wide range of recommendations. These disparities might stem from variations in clinical practices, regional preferences, and the availability of resources. It is crucial to acknowledge that both the EAU and AUA/SUO base their guidelines on the latest scientific evidence and expert consensus within their respective regions. Conclusions: These findings underscore the importance of ongoing collaboration, knowledge exchange, and harmonization of guidelines to improve the standard of care for UTUC globally. Future research should focus on identifying areas of consensus and bridging the gaps between different international guidelines to enhance the management outcomes for this challenging disease.

Abstract LB327: DNA methylation biomarkers for early bladder cancer detection and treatment response monitoring

Abstract Objectives: Bladder cancer (BC) stands as the 5th most prevalent cancer in the USA, with over 83,000 new cases diagnosed in 2023. The absence of non-invasive diagnostic tools for sensitive early BC detection and treatment response monitoring poses a significant challenge. This study evaluates the clinical potential of the Bladder CARE™ Assay for early BC detection and monitoring treatment response in BC patients. Methods: Under an institutional review board-approved protocol, voided urine samples were prospectively collected from USC patients with prior BC history under surveillance/anticancer treatment, prior genitourinary manipulation. Enrollment spanned February 2019 to September 2021. Samples underwent analysis using the Bladder CARE™ Assay, a DNA methylation test for quantitative BC and upper tract urothelial carcinoma (UTUC) detection from urine. Results were reported as Bladder CARE Index (BCI) and samples were categorized as “positive” (BCI &amp;gt; 5), “low-positive” (2.5 &amp;lt; BCI &amp;lt; 5), or “negative” (BCI &amp;lt; 2.5). Correlations between BCI value and categories, and clinicopathological findings were assessed. Results: A total of 110 previously diagnosed BC patients (median age: 74; 86% male) were enrolled in this study. Within 36 months post-TURBT, 24 patients (21.8%) showed evidence of recurrence. Bladder CARE™ Assay detected all recurrences, averagely 7.35 months earlier than cystoscopy. Of 55 patients (50%) undergoing anticancer therapies (45 BCG, 4 MMC, 2 GEM, 1 9UT, 1 GEM/DOCE, 1 MMC/BCG, and 1 BCG, MMC, and GEM), 7 (12.7%) recur (non-responders) and 11 (20%) did not show evidence of recurrence by 18 months post-TURBT (responders); 18-month post-operative data was unavailable for 37 patients (67.3%), which could not be classified in responders or non-responders. Bladder CARE™ detected 85.7% of non-responders, with BCI increasing prior to positive histology (avg. BCI: 86.1). In responders, BCI remained stable in negative/low-positive range post-TURBT (avg. BCI: 2.5). In addition, data from pre- and post-TURBT assessments were available for 20 of the 110 enrolled patients. The Bladder CARE™ Assay demonstrated a decrease in BCI post-TURBT in 19 of these 20 patients (95%). Conclusions: This prospective pilot study underscores the Bladder CARE™ Assay's capacity to pre-emptively detect BC months ahead of the gold standard. Furthermore, its quantitative nature offers prognostic insight, enabling non-invasive monitoring of patient response to anticancer treatments. A larger-scale study is the next step to validating these promising findings. Citation Format: Paolo Piatti, Sia Daneshmand, Sanam Ladi Seyedian, Saum Ghodossipour, Hamed Ahmadi, Suzanne Roberts, Alireza Ghoreifi, Michael Basin, Simin Hajian, Yap Ching Chew, Jeffrey Bhasin, Benjamin Jara, Lucy Sanossian, Hooman Djaladat, Anne Shuckman, Sumeet Bhavandia, Gangning Liang. DNA methylation biomarkers for early bladder cancer detection and treatment response monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB327.

Massive renal pelvis urothelial carcinoma with invasion of the descending colon and cutaneous metastases: A case report and literature review

Introduction: Skin metastases and gastrointestinal tract involvement in upper tract urothelial carcinoma (UTUC) are uncommon and associated with an adverse prognosis. This report details a case of extensive urothelial carcinoma originating from the renal pelvis, invading the descending colon, and presenting with cutaneous metastases. Case Report: A 63-year-old male patient visited the emergency department on the account of sudden onset of severe left upper abdominal pain and nausea. The computed tomography (CT) revealed soft tissue density at the mesentery adjacent to the left kidney with the involvement of the distal transverse colon. The patient underwent left radical nephroureterectomy, left hemicolectomy, and bladder cuff excision. Six weeks postoperatively, left inguinal cutaneous metastases, approximately 4 cm, were excised. Due to renal dysfunction, the patient received gemcitabine and carboplatin chemotherapy, followed by pembrolizumab for the cutaneous metastatic disease. Follow-up imaging showed no evidence of recurrence or metastasis 15 months postoperatively. Conclusion: In cases of advanced UTUC, a multidisciplinary approach combining surgical intervention, chemotherapy, and immunotherapy can alleviate symptoms and potentially improve survival rates. This integrative treatment strategy highlights the importance of a multidisciplinary approach in managing complex oncological cases.

Clinical performance and utility of a noninvasive urine-based methylation biomarker: TWIST1/Vimentin to detect urothelial carcinoma of the bladder.

Traditional clinical modalities for diagnosing bladder urothelial carcinoma (BUC) remain limited due to their invasive nature, significant costs, discomfort associated with cystoscopy, and low sensitivity to urine cytology. Therefore, there is an urgent need to identify highly sensitive, specific, and noninvasive biomarkers for the early detection of this neoplasm. Hypermethylated TWIST1/Vimentin promoter may be a noninvasive biomarker using urine sample. We assessed the TWIST1/Vimentin promoter methylation status in urine samples using the Methylated Human TWIST1 and Vimentin Gene Detection Kit (Jiangsu MicroDiag Biomedicine Co., Ltd., China). The samples were collected from five groups: group 1 consisted of patients with BUC, group 2 contained other patients with urologic tumors, group 3 consisted of patients with benign diseases (e.g., urinary tract infections, lithiasis, and benign prostatic hyperplasia), Group 4 included UTUC (upper tract urothelial carcinoma) patients and group5 comprised healthy individuals. The study encompassed 77 BUC patients, and we evaluated the degree of methylation of the TWIST1/Vimentin gene in their urine samples. Notably, TWIST1/Vimentin positivity was significantly elevated in comparison to groups 2, 3 and 5 (all p < 0.001) at a rate of 77.9%, but no significant difference was observed when compared to group 4. In the relationship between TWIST1/Vimentin methylation and clinicopathological features of BC patients from our center, we found there was no significant association between TWIST1/Vimentin status and proteinuria and/or hematuria, and hypermethylation of TWIST1 / VIM genes was found in both high and low tumor grade and in both non-muscle invasive bladder cancer (stages Tis, Ta, or T1) and muscle-invasive bladder cancer (stage T2 or above). In the multivariable analysis for cancer detection, a positive TWIST1/Vimentin methylation were significantly linked to a heightened risk of BC. Moreover, TWIST1/Vimentin promoter methylation demonstrated an ability to detect BUC in urine samples with a sensitivity of 78% and a specificity of 83%. Our findings reveal that hypermethylation of the TWIST1/Vimentin promoter occurs in bladder urothelial carcinoma, and its high sensitivity and specificity suggest its potential as a screening and therapeutic biomarker for urothelial carcinoma of the bladder.