A histopathological and epidemiological study of urothelial carcinoma at a tertiary care centre in Peshawar, Pakistan.

Bladder cancer is the ninth leading cause of death worldwide and 14th leading cause of death in Pakistan. The objective of this study was to determine the frequency of urothelial carcinoma in various age groups, its gender distribution, and grades. A total of 131 cases of urothelial carcinoma, received at Department of Pathology, Peshawar Medical College, Peshawar, between January 2017 to December 2022, were included in the study; of them 107 (81.6%) were males while 24 (18.3%) were females with a mean age of 62±13 years. The most common histological subtype was papillary urothelial carcinoma in 117(89.3%) cases, followed by Squamous and Glandular in 5(3.8%) cases. Majority of the urothelial carcinoma with high grade showed a statistically significant relation with muscle invasion 38 (50.66%). Males were four times more likely to have urothelial carcinoma while older age groups were more likely to have high grade urothelial carcinoma.

Similar genetic profile in early and late stage urothelial tract cancer.

INTRODUCTION: Urothelial tract cancer (UTC) ranks as the tenth most prevalent cancer and holds the seventh position in terms of mortality worldwide. Despite its prevalence and mortality ranking, there are still gaps in the knowledge of the mutational landscape in patients with advanced disease who have limited therapeutic options after multiple lines of prior treatment. This study compares the genomic and transcriptomic landscape, and targeted treatment options between metastatic UTC (mUTC) patients treated with multiple lines of therapy compared to newly diagnosed, untreated Muscle Invasive Bladder Cancer (MIBC). METHODS: We compared genomic and clinical data from two cohorts: mUTC patients who received multiple lines of therapy and were referred to the Copenhagen Prospective Personalized Oncology (CoPPO) project at Rigshospitalet, University of Copenhagen. Data for MIBC UTC patients were acquired from the Cancer Genome Atlas Bladder Cancer (TCGA BLCA) cohort. Biopsies in CoPPO were performed at the time of enrollment. 523 highly important cancer-related genes (TrueSight Oncology-500 targeted sequencing panel) were used from both cohorts for comparative analysis. Analyses included RNA count data to compare predicted molecular subtypes in each cohort separately. RESULTS: Patients from the CoPPO cohort had a lower median age at first-line treatment than the TCGA BLCA cohort, with no significant gender disparity. The predominant histology was urothelial cell carcinoma in both cohorts. Genomic analysis revealed no significant difference between the top mutated genes in the two cohorts, specifically looking into DNA damage repair genes. Molecular subtyping indicated a higher frequency of neuroendocrine differentiation in the CoPPO cohort. 13% of patients in the CoPPO cohort received targeted therapy based on genomic findings, and 16% received non-targeted treatment, totaling 29% receiving CoPPO treatment (9 patients). The remaining 71% received best supportive care. Kaplan-Meier analysis showed a non-significant survival benefit for the intervention group in the CoPPO cohort. CONCLUSION: When focusing on 523 highly relevant cancer genes, the mutational profile of mUTC patients who have undergone numerous treatment lines resembles that of newly diagnosed MIBC. These alterations can be targeted, indicating the potential advantage of early genomic testing for personalized treatment within clinical trials.

Optimal Number of Cycles of First-line Platinum-based Chemotherapy for Metastatic Urothelial Carcinoma.

BACKGROUND/AIM: In recent years, switch maintenance after platinum-based chemotherapy has been a standard of care. However, the appropriate number of systemic chemotherapy cycles against advanced-stage urothelial carcinoma (UC) remains unclear. This study assessed the survival outcomes of first-line platinum-based chemotherapy according to treatment cycles in patients with metastatic disease. PATIENTS AND METHODS: We retrospectively evaluated patients with metastatic bladder and upper urinary tract cancer who received platinum-based combination therapy. Overall survival (OS) was evaluated using the Kaplan-Meier method and the log-rank test. RESULTS: Of 179 patients, 47 (26.3%) were women, and 73 (40.8%) had upper urinary tract cancer. Furthermore, 47 (26.3%) who were not eligible for cisplatin received carboplatin. The median number of treatment cycles was 3 (range=1-14 cycles). The rates of progressive disease within two cycles, from two to four cycles, and from four to six cycles were 18.4%, 19.2%, and 30.6%, respectively. The median OS of patients with 2, 3, 4, 5-6, and ≥7 treatment cycles were 8.6, 14.3, 21.3, 24.4, and 26.1 months, respectively. The OS did not significantly differ between patients receiving four treatment cycles and those receiving ≥5 treatment cycles. In patients with disease control (complete or partial response or stable disease) receiving ≥4 treatment cycles, there was no significant difference in terms of OS between patients receiving four cycles and those receiving six cycles. CONCLUSION: Four cycles of first-line platinum-based chemotherapy can be effective in patients with metastatic UC.

C-reactive Protein Is a Prognostic Factor for Survival in Metastatic Upper Tract Urothelial Carcinoma Patients Receiving Pembrolizumab.

BACKGROUND/AIM: The number of available treatment options for urothelial carcinoma has increased recently. Upper tract urothelial carcinoma (UTUC) is relatively rare compared with bladder cancer. There are few reports on the efficacy of immune checkpoint inhibitors (ICIs) for metastatic UTUC, and ICIs may occasionally show less efficacy and cause severe side effects. Therefore, it is important to predict the treatment response and change the treatment strategy as appropriate. We investigated the prognostic factors for treatment response in patients with metastatic UTUC treated with pembrolizumab at our hospital. PATIENTS AND METHODS: Patients who received pembrolizumab for UTUC between January 2018 and June 2023 were analyzed. Patients who presented with bladder cancer complications at initial diagnosis were excluded. The primary endpoints assessed were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted using laboratory values obtained before and after pembrolizumab administration. The relationship between cancer and inflammation is important. Therefore, we analyzed this relationship using prognostic factors for urothelial carcinoma as previously reported. Specifically, pretreatment C-reactive protein (CRP) level, neutrophil-to-lymphocyte ratio (NLR), and NLR/albumin values were examined. RESULTS: Forty-seven patients were analyzed. The median PFS was 66 days (24-107 days), and the median OS was 164 days (13-314 days). A CRP level <1 before the first cycle was a useful factor in the multivariate analysis for both OS and PFS [OS: p=0.004, hazard ratio (HR)=3.244, 95% confidence interval (CI)=1.464-7.104; PFS: p=0.003, HR=2.998, 95%CI=1.444-6.225]. CONCLUSION: CRP level is a prognostic factor for pembrolizumab treatment response in patients with UTUC.

Violation of onco-surgical principles is associated with survival outcomes in upper tract urothelial carcinomas after radical nephroureterectomy.

OBJECTIVE: Disease recurrence, particularly intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), is common. We investigated whether violations of onco-surgical principles before or during RNU, collectively referred to as surgical violation (SV), were associated with survival outcomes.  Material and methods: Data from a consecutive series of patients who underwent RNU for UTUC 2001-2012 at Skåne University Hospital Lund/Malmö were collected. Preoperative insertion of a nephrostomy tube, opening the urinary tract during surgery or refraining from excising the distal ureter were considered as SVs. Survival outcomes in patients with and without SV (IVR-free [IVRFS], disease-specific [DSS] and overall survival [OS]) were assessed using multivariate Cox regression analyses (adjusted for tumour stage group, prior or concomitant bladder cancer, comorbidity and preoperative urinary cytology). RESULTS: Of 150 patients, 47 (31%) were subjected to at least one SV. Overall, SV was not associated with IVRFS (HR 0.81, 95% CI 0.4-1.6) but with worse DSS (HR 1.9, 95% CI 1.03-3.7) and OS (HR 1.9, 95% CI 1.2-3) in multivariable analysis. Additional analyses with a broader definition of SV including also preoperative instrumentation of the upper urinary tract (ureteroscopy and/or double J stenting) showed similar outcomes for DSS (HR 2.1, 95% CI 1.1-4.3). CONCLUSION: Worse survival outcomes, despite no difference in IVR, for patients that were subjected to the violation of sound onco-surgical principles before or during RNU for UTUC strengthen the notion that adhering to such principles is a cornerstone in upper tract urothelial cancer surgery.

Automatic analysis of nuclear features reveals a non-tumoral predictor of tumor grade in bladder cancer.

BACKGROUND & OBJECTIVES: Tumor grade determines prognosis in urothelial carcinoma. The classification of low and high grade is based on nuclear morphological features that include nuclear size, hyperchromasia and pleomorphism. These features are subjectively assessed by the pathologists and are not numerically measured, which leads to high rates of interobserver variability. The purpose of this study is to assess the value of a computer-based image analysis tool for identifying predictors of tumor grade in bladder cancer. METHODS: Four hundred images of urothelial tumors were graded by five pathologists and two expert genitourinary pathologists using a scale of 1 (lowest grade) to 5 (highest grade). A computer algorithm was used to automatically segment the nuclei and to provide morphometric parameters for each nucleus, which were used to establish the grading algorithm. Grading algorithm was compared to pathologists' agreement. RESULTS: Comparison of the grading scores of the five pathologists with the expert genitourinary pathologists score showed agreement rates between 88.5% and 97.5%.The agreement rate between the two expert genitourinary pathologists was 99.5%. The quantified algorithm based conventional parameters that determine the grade (nuclear size, pleomorphism and hyperchromasia) showed > 85% agreement with the expert genitourinary pathologists. Surprisingly, the parameter that was most associated with tumor grade was the 10th percentile of the nuclear area, and high grade was associated with lower 10th percentile nuclei, caused by the presence of more inflammatory cells in the high-grade tumors. CONCLUSION: Quantitative nuclear features could be applied to determine urothelial carcinoma grade and explore new biologically explainable parameters with better correlation to grade than those currently used.

Investigating cellular similarities and differences between upper tract urothelial carcinoma and bladder urothelial carcinoma using single-cell sequencing.

Background: Upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BLCA) both originate from uroepithelial tissue, sharing remarkably similar clinical manifestations and therapeutic modalities. However, emerging evidence suggests that identical treatment regimens may lead to less favorable outcomes in UTUC compared to BLCA. Therefore, it is imperative to explore molecular processes of UTUC and identify biological differences between UTUC and BLCA. Methods: In this study, we performed a comprehensive analysis using single-cell RNA sequencing (scRNA-seq) on three UTUC cases and four normal ureteral tissues. These data were combined with publicly available datasets from previous BLCA studies and RNA sequencing (RNA-seq) data for both cancer types. This pooled analysis allowed us to delineate the transcriptional differences among distinct cell subsets within the microenvironment, thus identifying critical factors contributing to UTUC progression and phenotypic differences between UTUC and BLCA. Results: scRNA-seq analysis revealed seemingly similar but transcriptionally distinct cellular identities within the UTUC and BLCA ecosystems. Notably, we observed striking differences in acquired immunological landscapes and varied cellular functional phenotypes between these two cancers. In addition, we uncovered the immunomodulatory functions of vein endothelial cells (ECs) in UTUC, and intercellular network analysis demonstrated that fibroblasts play important roles in the microenvironment. Further intersection analysis showed that MARCKS promote UTUC progression, and immunohistochemistry (IHC) staining revealed that the diverse expression patterns of MARCKS in UTUC, BLCA and normal ureter tissues. Conclusion: This study expands our multidimensional understanding of the similarities and distinctions between UTUC and BLCA. Our findings lay the foundation for further investigations to develop diagnostic and therapeutic targets for UTUC.

Frontline immune checkpoint inhibitors in patients ≥ 90 years with advanced urothelial cancer: a single center experience.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are approved for advanced urothelial cancer alone and as first-line in combination with enfortumab vedotin. Platinum based chemotherapy which is another frontline choice is often not a treatment option for older patients due to comorbidities that increase with age. Despite ICIs being better tolerated compared to traditional chemotherapy little is known about their efficacy and toxicity in patients ≥ 90 years due to the rarity of this population in clinical trials. Our objective was to analyze the efficacy and toxicity of immune checkpoint inhibitors in patients ≥ 90 years. MATERIALS AND METHODS: We conducted a single center retrospective review of patients ≥ 90 years treated between July 2019 and September 2023 with standard of care ICIs for advanced urothelial cancer. RESULTS: Six patients treated with pembrolizumab were identified. Four (66.7%) were male and mean age was 93.5 years at the time of treatment initiation. Response rate was 66.7% (4 patients) with 3 complete responses, which were durable off therapy. Median follow up was 18.2 months. Median progression free survival (PFS) was 10.2 months [95%confidence interval (95%CI): 1.77, not reached (NR)] and median overall survival (OS) was 18.2 months (95%CI: 12.1, NR). Side effects presented in 4 (66.7%) patients and included hypothyroidism, diarrhea, anemia, thrombocytopenia, rash, and bullous dermatitis. One patient developed grade 3 anemia and no patients experienced grade 4 events or required hospitalization due to treatment side effects. CONCLUSIONS: Our experience in a small cohort of patients ≥ 90 years indicate that ICIs are well tolerated and effective for the treatment of advanced urothelial carcinoma in this patient population.

Enfortumab vedotin and pembrolizumab combination as a relevant game changer in urothelial carcinoma: What is left behind?

The EV-302 study1 marks a pivotal leap in the management of advanced urothelial carcinoma, setting a new benchmark for frontline therapy. Enfortumab vedotin plus pembrolizumab is the first combination therapy that has ever outperformed standard chemotherapy. The degree of benefit and the reported safety profile should make this combination a first-choice option for most patients with advanced-stage urothelial carcinoma.

Using machine learning to develop preoperative model for lymph node metastasis in patients with bladder urothelial carcinoma.

BACKGROUND: Lymph node metastasis (LNM) is associated with worse prognosis in bladder urothelial carcinoma (BUC) patients. This study aimed to develop and validate machine learning (ML) models to preoperatively predict LNM in BUC patients treated with radical cystectomy (RC). METHODS: We retrospectively collected demographic, pathological, imaging, and laboratory information of BUC patients who underwent RC and bilateral lymphadenectomy in our institution. Patients were randomly categorized into training set and testing set. Five ML algorithms were utilized to establish prediction models. The performance of each model was assessed by the area under the receiver operating characteristic curve (AUC) and accuracy. Finally, we calculated the corresponding variable coefficients based on the optimal model to reveal the contribution of each variable to LNM. RESULTS: A total of 524 and 131 BUC patients were finally enrolled into training set and testing set, respectively. We identified that the support vector machine (SVM) model had the best prediction ability with an AUC of 0.934 (95% confidence interval [CI]: 0.903-0.964) and accuracy of 0.916 in the training set, and an AUC of 0.855 (95%CI: 0.777-0.933) and accuracy of 0.809 in the testing set. The SVM model contained 14 predictors, and positive lymph node in imaging contributed the most to the prediction of LNM in BUC patients. CONCLUSIONS: We developed and validated the ML models to preoperatively predict LNM in BUC patients treated with RC, and identified that the SVM model with 14 variables had the best performance and high levels of clinical applicability.

Marked Response to Nivolumab by a Patient With SMARCA4-Deficient Undifferentiated Urothelial Carcinoma Showing High PD-L1 Expression: A Case Report.

BACKGROUND: SMARCA4 is a component gene of the SWI/SNF (SWItch/Sucrose NonFermentable) chromatin remodeling complex; undifferentiated tumors associated with its functional deletion have been described in several organs. However, no established treatment for these tumors currently exists. CASE: In this study, we report a case of a SMARCA4-deficient undifferentiated urothelial carcinoma with high PD-L1 expression that was effectively treated with nivolumab after early relapse following treatment for non-invasive bladder cancer. The histological morphology of the rhabdoid-like undifferentiated tumor of unknown primary led us to suspect a SWI/SNF-deficient tumor, and subsequent immunostaining led to the diagnosis of a SMARCA4-deficient undifferentiated tumor. This effort also led to the identification of the developmental origin of this SMARCA4-deficient undifferentiated tumor as a non-invasive bladder cancer. We also carried out a detailed immune phenotypic assay on peripheral T cells. In brief, a phenotypic change of CD8+T cells from naive to terminally differentiated effector memory cells was observed. CONCLUSION: Regardless of the organ of cancer origin or cancer type, SWI/SNF-deficient tumors should be suspected in undifferentiated and dedifferentiated tumors, and immune checkpoint inhibitors may be considered as a promising treatment option for this type of tumor. The pathogenesis of SMARCA4-deficient anaplastic tumors awaits further elucidation for therapeutic development.

Temporal Trends and Cancer-Specific Mortality in Nonmetastatic Muscle-Invasive Urothelial Carcinoma of the Urinary Bladder Treated With Trimodal Therapy.

INTRODUCTION: Trimodal therapy (TMT) is guideline-recommended for the management of organ confined urothelial carcinoma of urinary bladder (UCUB). However, temporal trends in TMT use and cancer-specific mortality free-survival (CSM-FS) between historical TMT versus contemporary TMT have not been assessed. We addressed this knowledge gap. MATERIAL AND METHODS: Within the Surveillance, Epidemiology, and End Results database (2004-2020), we identified nonmetastatic UCUB patients with cT2-T4aN0-N2 treated with TMT, defined as the combination of transurethral resection of bladder tumor, chemotherapy and radiotherapy. Temporal trends described TMT use over time. Subsequently, patients were divided between historical (2004-2012) versus contemporary (2013-2020) cohorts. Survival analyses consisting of Kaplan-Meier plots and multivariable Cox regression (MCR) models addressed CSM-FS. Separate analyses addressed patients with organ confined (OC: cT2N0M0) versus nonorgan confined (NOC: cT3-4a and/or cN1-2) clinical stages. RESULTS: Of 4,097 assessable UCUB TMT patients, 1744 (43%) were treated in the historical period (2004-2012) versus 2353 (58%) in the contemporary period (2013-2020). TMT use increased over time in OC patients (EAPC:+3.4%, P < .001), as well as in NOC (EAPC:+2.7%, P < .001). In OC stage, median CSM-FS was 55.3% in historical versus 49.0% in contemporary patients (HR:0.75, P < .001). Similarly, in NOC stage, 5-year median CSM-FS was 43.0% in historical versus 32.8% in contemporary patients (HR:0.78, P = .01). CONCLUSION: TMT rates have increased over time in both OC and NOC patients. Contemporary TMT patients benefit of better cancer-specific survival. Interestingly, this benefit applies equally to OC and NOC TMT-treated patients.

Cutaneous and Renal Toxicities of Enfortumab Vedotin for Advanced Urothelial Carcinoma: The UROKYU Study.

BACKGROUND/AIM: The clinical outcomes associated with cutaneous toxicity and changes in the renal function of patients receiving enfortumab vedotin (EV) for advanced urothelial carcinoma (UC) is unclear. PATIENTS AND METHODS: We retrospectively analyzed the relationship between clinical outcomes and EV-related cutaneous toxicity, and the influence on the renal function in 58 patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to July 2023. RESULTS: There were no differences in the overall response and disease control rates between patients with any grade of EV-related cutaneous toxicity and without (p=0.605 and p>0.99, respectively) nor of grade ≥3 (p>0.99 and p=0.173, respectively). Progression-free survival was not significantly associated with EV-related cutaneous toxicity of any grade (5.4 vs. 5.6 months, p=0.557) nor of grade ≥3 (2.7 vs. 5.6 months, p=0.053). Overall survival was not significantly associated with EV-related cutaneous toxicity of any grade (11.8 vs. 8.9 months, p=0.389), nor of grade ≥3 (4.6 vs. 11.4 months, p=0.168). The incidence of EV-related cutaneous toxicity of any grade was significantly higher in patients with any grade of ICI-related cutaneous toxicity (88.9% vs. 36.7%, p=0.008). There was no significant difference in the serum creatinine levels after EV treatment (p=0.211). Divided into two groups according to their renal function, using a serum creatinine cut-off of 2 mg/dl, there were no significant changes after EV treatment in either group (p=0.187 and p=0.938). CONCLUSION: EV-related cutaneous toxicity did not affect clinical outcomes, although it occurred in patients who experienced immune checkpoint inhibitor-related cutaneous toxicity. EV did not affect renal function.

Avelumab first-line maintenance in advanced urothelial carcinoma: Complete screening for prognostic and predictive factors using machine learning in the JAVELIN Bladder 100 phase 3 trial.

BACKGROUND: Avelumab first-line (1 L) maintenance is a standard of care for advanced urothelial carcinoma (aUC) based on the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab 1 L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in patients who were progression free after receiving 1 L platinum-containing chemotherapy. Here, we comprehensively screened JAVELIN Bladder 100 trial datasets to identify prognostic factors that define subpopulations of patients with longer or shorter OS irrespective of treatment, and predictive factors that select patients who could obtain a greater OS benefit from avelumab 1 L maintenance treatment. METHODS: We performed machine learning analyses to screen a large set of baseline covariates, including patient demographics, disease characteristics, laboratory values, molecular biomarkers, and patient-reported outcomes. Covariates were identified from previously reported analyses and established prognostic and predictive markers. Variables selected from random survival forest models were processed further in univariate Cox models with treatment interaction and visually inspected using correlation analysis and Kaplan-Meier curves. Results were summarized in a multivariable Cox model. RESULTS: Prognostic baseline covariates associated with OS included in the final model were assignment to avelumab 1 L maintenance treatment, Eastern Cooperative Oncology Group performance status, site of metastasis, sum of longest target lesion diameters, levels of C-reactive protein and alkaline phosphatase in blood, lymphocyte proportion in intratumoral stroma, tumor mutational burden, and tumor CD8+ T-cell infiltration. Potential predictive factors included site of metastasis, tumor mutation burden, and tumor CD8+ T-cell infiltration. An analysis in patients with PD-L1+ tumors had similar findings to those in the overall population. CONCLUSIONS: Machine learning analyses of data from the JAVELIN Bladder 100 trial identified potential prognostic and predictive factors for avelumab 1 L maintenance treatment in patients with aUC, which warrant further evaluation in other clinical datasets.

Relapse and Survival in Bladder Cancer Patients Undergoing microRNA-129 and microRNA-145 Assays.

OBJECTIVE: The lack of indicators to measure tumor's invasive biological behavior is an important issue. The aim of this study was to examine the effect of miRNAs 129 and 145 on tumor progression as well as patient survival. METHOD: Seventy five breast cancer (BC) patients and 75 controls were included in this research. Two miRNA expressions were estimated using real-time PCR. Biomarkers for BC detection was tested using ROC curves and AUC. RESULT: miR-129 and miR-145 expressions were significant. miR-129 and miR-145 classifiers (AUC = 0.943 and 0.748, respectively) help diagnose BC. Unlike miR-145, miR-129 did not affect the Kaplan-Meier survival curve analysis for progression-free survival at the end of the trial. The development of transitional cell carcinoma disease was found to have a strong correlation with miR-145 in both univariate and multivariate Cox regression analyses. Additionally, infiltrating + invasive urothelial carcinoma was also found to be correlated with miR-145. Conversely, elevated miR-129 expression in BC patients did not lead to an increase in cancer-specific recurrence or mortality, as observed in both univariate and multivariate Cox regression studies. CONCLUSION: The miRNA signature can help detect survival-associated miRNAs and develop BC miRNA therapeutics.

Robotic distal ureterectomy for high-risk distal ureteral urothelial carcinoma: a retrospective multicenter comparative analysis (ROBUUST 2.0 collaborative group).

BACKGROUND: The role of kidney-sparing surgery in patients with high-risk upper urinary tract urothelial carcinoma is controversial. The present study aimed to assess oncological and functional outcomes of robot-assisted distal ureterectomy in patients with high-risk distal ureteral tumors. METHODS: The ROBUUST 2.0 multicenter international (2015-2022) dataset was used for this retrospective cohort analysis. High-risk patients with distal ureteral tumors were divided based on type of surgery: robot-assisted distal ureterectomy or robot-assisted nephroureterectomy. A survival analysis was performed for local recurrence-free survival, distant metastasis-free survival, and overall survival. After adjusting for clinical features of the high-risk prognostic group, Cox proportional hazard model was plotted to evaluate significant predictors of time-to-event outcomes. RESULTS: Overall, 477 patients were retrieved, of which 58 received robot-assisted distal ureterectomy and 419 robot-assisted nephroureterectomy, respectively, with a mean (±SD) follow-up of 29.6 months (±2.6). The two groups were comparable in terms of baseline features. At survival analysis, no significant difference was observed in terms of recurrence-free survival (P=0.6), metastasis-free survival (P=0.5) and overall survival (P=0.7) between robot-assisted distal ureterectomy and robot-assisted nephroureterectomy. At Cox regression analysis, type of surgery was never a significant predictor of worse oncological outcomes. At last follow-up patients undergoing robot-assisted distal ureterectomy had significantly better postoperative renal function. CONCLUSIONS: Comparable outcomes in terms of recurrence-free survival, metastasis-free survival, and overall survival between robot-assisted distal ureterectomy and robot-assisted nephroureterectomy patients, and better postoperative renal function preservation in the former group were observed. Kidney-sparing surgery should be considered as a potential option for selected patients with high-risk distal ureteral UTUC.

Cigarette smoking-related OLC1 overexpression associated with poor prognosis in bladder urothelial carcinoma.

AIMS: To explore the clinical significance of OLC1 and cigarette smoking in bladder urothelial carcinoma (UBC). MATERIALS AND METHODS: OLC1 mRNA expression was detected in 106 UBC samples by mRNA array or reverse real-time PCR. OLC1 protein expression in 114 UBC samples was detected by immunohistochemical staining. Wild-type C57BL/6J mice were injected with cigarette smoke condensate (n = 12) or exposed to cigarette smoke (n = 6) to investigate the correlations between cigarette smoking and OLC1 expression using mRNA array. KEY FINDINGS: The mRNA and protein expression of OLC1 were higher in tumor samples (p < 0.01) and significantly correlated with tumor stage (p < 0.05). OLC1 protein expression and smoking history were correlated with disease-free survival (p < 0.05). OLC1 expression was significantly elevated in smoking patients with higher smoking intensity on both mRNA and protein levels (p < 0.05). Cigarette smoke exposure experiments revealed that OLC1 mRNA overexpressed in bladder uroepithelium of mice. SIGNIFICANCE: OLC1 could serve as a potential prognosis biomarker of UBC, especially for smoking patients.

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

OBJECTIVES: Upper tract urothelial carcinoma (UTUC) 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. METHODS: 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. RESULTS: 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 UTUC 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 (SVC)] provided a highly accurate prediction while grading UTUC compared to clinical features alone or ureteroscopic biopsy histopathology. CONCLUSION: Data mining tools could handle medical imaging datasets from small (<2 cm) tumours for UTUC. 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. CLINICAL RELEVANCE: 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.

The identification of a N6-methyladenosin-modifed immune pattern to predict immunotherapy response and survival in urothelial carcinoma.

BACKGROUND: Dysregulation of the immune system and N6-methyladenosine (m6A) contribute to immune therapy resistance and cancer progression in urothelial carcinoma (UC). This study aims to identify immune-related molecules, that are m6A-modified, and that are associated with tumor progression, poor prognosis, and immunotherapy response. METHODS: We identified prognostic immune genes (PIGs) using Cox analysis and random survival forest variable hunting algorithm (RSF-VH) on immune genes retrieved from the Immunology Database and Analysis Portal database (ImmPort). The RM2Target database and MeRIP-seq analysis, combined with a hypergeometric test, assessed m6A methylation in these PIGs. We analyzed the correlation between the immune pattern and prognosis, as well as their association with clinical factors in multiple datasets. Moreover, we explored the interplay between immune patterns, tumor immune cell infiltration, and m6A regulators. RESULTS: 28 PIGs were identified, of which the 10 most significant were termed methylated prognostic immune genes (MPIGs). These MPIGs were used to create an immune pattern score. Kaplan-Meier and Cox analyses indicated this pattern as an independent risk factor for UC. We observed significant associations between the immune pattern, tumor progression, and immune cell infiltration. Differential expression analysis showed correlations with m6A regulators expression. This immune pattern proved effective in predicting immunotherapy response in UC in real-world settings. CONCLUSION: The study identified a m6A-modified immune pattern in UC, offering prognostic and therapeutic response predictions. This emphasizes that immune genes may influence tumor immune status and progression through m6A modifications.