Development of prognostic model incorporating a ferroptosis/cuproptosis-related signature and mutational landscape analysis in muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a prevalent and aggressive malignancy. Ferroptosis and cuproptosis are recently discovered forms of programmed cell death (PCD) that have attracted much attention. However, their interactions and impacts on MIBC overall survival (OS) and treatment outcomes remain unclear. METHODS: Data from the TCGA-BLCA project (as the training set), cBioPortal database, and GEO datasets (GSE13507 and GSE32894, as the test sets) were utilized to identify hub ferroptosis/cuproptosis-related genes (FRGs and CRGs) and develop a prognostic signature. Differential expression analysis (DEA) was conducted, followed by univariate and multivariate Cox's regression analyses and multiple machine learning (ML) techniques to select genetic features. The performance of the ferroptosis/cuproptosis-related signature was evaluated using Kaplan-Meier (K-M) survival analysis and receiver-operating characteristics (ROC) curves. Mutational and tumour immune microenvironment landscapes were also explored. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) experiments confirmed the expression patterns of the hub genes, and functional assays assessed the effects of SCD knockdown on cell viability, proliferation, and migration. RESULTS: DEA revealed dysregulated FRGs and CRGs in the TCGA MIBC cohort. SCD, DDR2, and MT1A were identified as hub genes. A prognostic signature based on the sum of the weighted expression of these genes demonstrated strong predictive efficacy in the training and test sets. Nomogram incorporating this signature accurately predicted 1-, 3-, and 5-year survival probabilities in the TCGA cohort and GSE13507 dataset. Copy number variation (CNV) and tumour immune microenvironment analysis revealed that high risk score level groups were associated with immunosuppression and lower tumour purity. The associations of risk scores with immunotherapy and chemical drugs were also explored, indicating their potential for guiding treatment for MIBC patients. The dysregulated expression patterns of three hub genes were validated by RT-qPCR experiments. CONCLUSIONS: Targeting hub FRGs and CRGs could be a promising therapeutic approach for MIBC. Our prognostic model offers a new framework for MIBC subtyping and can inform personalized therapeutic strategies.

Integrative Drug Screening and Multiomic Characterization of Patient-derived Bladder Cancer Organoids Reveal Novel Molecular Correlates of Gemcitabine Response.

BACKGROUND AND OBJECTIVE: Predicting response to therapy for each patient's tumor is critical to improving long-term outcomes for muscle-invasive bladder cancer. This study aims to establish ex vivo bladder cancer patient-derived organoid (PDO) models that are representative of patients' tumors and determine the potential efficacy of standard of care and curated experimental therapies. METHODS: Tumor material was collected prospectively from consented bladder cancer patients to generate short-term PDO models, which were screened against a panel of clinically relevant drugs in ex vivo three-dimensional culture. Multiomic profiling was utilized to validate the PDO models, establish the molecular characteristics of each tumor, and identify potential biomarkers of drug response. Gene expression (GEX) patterns between paired primary tissue and PDO samples were assessed using Spearman's rank correlation coefficients. Molecular correlates of therapy response were identified using Pearson correlation coefficients and Kruskal-Wallis tests with Dunn's post hoc pairwise comparison testing. KEY FINDINGS AND LIMITATIONS: A total of 106 tumors were collected from 97 patients, with 65 samples yielding sufficient material for complete multiomic molecular characterization and PDO screening with six to 32 drugs/combinations. Short-term PDOs faithfully represent the tumor molecular characteristics, maintain diverse cell types, and avoid shifts in GEX-based subtyping that accompany long-term PDO cultures. Utilizing an integrative approach, novel correlations between ex vivo drug responses and genomic alterations, GEX, and protein expression were identified, including a multiomic signature of gemcitabine response. The positive predictive value of ex vivo drug responses and the novel multiomic gemcitabine response signature need to be validated in future studies. CONCLUSIONS AND CLINICAL IMPLICATIONS: Short-term PDO cultures retain the molecular characteristics of tumor tissue and avoid shifts in expression-based subtyping that have plagued long-term cultures. Integration of multiomic profiling and ex vivo drug screening data identifies potential predictive biomarkers, including a novel signature of gemcitabine response. PATIENT SUMMARY: Better models are needed to predict patient response to therapy in bladder cancer. We developed a platform that uses short-term culture to best mimic each patient's tumor and assess potential sensitivity to therapeutics.

Non-Muscle Invasive Bladder Cancer: Many More Patients Die With It Than Of It.

BACKGROUND: The National Cancer Institute SEER Program regularly publishes bladder-cancer specific survival statistics. However, this data is for all bladder cancers, and information for non-muscle invasive bladder cancer (NMIBC) is difficult to obtain. OBJECTIVE: To quantify 5-year overall and bladder cancer-specific survival in a cohort of Department of Veterans Affairs (VA) patients diagnosed with NMIBC. METHODS: We identified VA patients diagnosed with NMIBC who underwent a transurethral resection from 2003-2013. The patient demographics and Charlson Comorbidity Index were categorized. We acquired the patients' date of death from the Veterans Health Administration's Death Ascertainment File and their cause of death from the Mortality Data Repository. We calculated Kaplan Meier estimates of survival. RESULTS: A total of 27,008 patients were included; median age was 69 and almost all were male (99%). The median comorbidity score was 4. The most prevalent comorbidity indicators included Chronic Pulmonary Disease (48%), cancer other than Bladder (41%), and diabetes (40%). This cohort was found to have a 5-year overall survival of 68% (99% CI 67% -69%) and a 5-year bladder cancer-specific survival of 93% (99% CI 92% -94%). CONCLUSIONS: The 5-year bladder cancer-specific survival in patients diagnosed with non-muscle invasive bladder cancer is substantially higher than the 5-year overall survival. This difference may be related to the severity and number of comorbidities that patients in this population must manage. This warrants further research into the necessity of currently recommended high-intensity cancer surveillance for individuals with NMIBC.

The Evolution of Nadofaragene Firadenovec: A Review and the Path Forward.

BACKGROUND: The intravesical gene therapy nadofaragene firadenovec (rAd-IFNα/Syn3) was FDA approved in 2022 for non-muscle invasive bladder cancer (NMIBC) unresponsive to frontline treatment with BCG, and the first gene therapy developed for bladder cancer. This non-replicating recombinant adenovirus vector delivers a copy of the human interferon alpha-2b gene into urothelial and tumor cells, causing them to express this pleotropic cytokine with potent antitumor effects. OBJECTIVE: To provide a historical overview describing how several decades of preclinical and clinical studies investigating the role of interferon in the treatment of bladder cancer ultimately led to the development of gene therapy with nadofaragene for NMIBC. METHODS: We conducted a review of the literature using PubMed, Google Scholar, and ClinicalTrials.gov to summarize our knowledge of the evolution of interferon-based therapy in NMIBC. RESULTS: The FDA approval of this therapy represents an important landmark in urologic oncology and several decades of research dedicated to the study of interferon's direct and indirect antitumor properties in NMIBC. The data gathered from the phase 1, 2, and 3 clinical trials continue to provide additional insights into the precise mechanisms underlying both the efficacy of and resistance to nadofaragene. CONCLUSIONS: Nadofaragene leverages the cytotoxic, anti-angiogenic, and immune-modulatory roles of interferon to effectively treat NMIBC that is resistant to BCG. Ongoing studies of resistance mechanisms and prognostic biomarkers have been promising; these will ultimately improve patient selection and allow for the modulation of factors in the tumor or immune microenvironment to further increase therapeutic response.

Invasive Mycobacterium bovis Infection Outside the Genitourinary Tract Following Bacille Calmette-Guerin Therapy for Non-muscle Invasive Bladder Cancer.

Bladder cancer significantly impacts global health, particularly non-muscle-invasive bladder cancer (NMIBC), which is typically treated with transurethral resection of bladder tumor (TURBT) and intravesical Bacillus Calmette-Guérin (BCG) therapy. While there is evidence that BCG can effectively prevent tumor recurrence and progression, it can cause adverse effects, including disseminated infection, necessitating the exclusion of active tuberculosis and the assessment of immunosuppressive conditions before treatment. We present two cases of disseminated BCG infection. The first involves an 85-year-old male who developed an abscess in his right thigh post-BCG therapy, successfully treated with isoniazid (INH), ethambutol, and rifampin. The second case is a 63-year-old male who, three years post-BCG therapy and abdominal aortic aneurysm repair, developed a right psoas abscess and a mycotic aneurysm. He was also treated with ethambutol, INH, and rifampin, in addition to surgical intervention. Effective management of BCG-related infections requires early identification of Mycobacterium bovis, a multidisciplinary approach, thorough pre-treatment evaluations, and aggressive treatment strategies, including anti-tubercular drugs and surgical intervention as necessary.

Location-specific diagnostic efficiency of photodynamic diagnosis-guided biopsy in bladder mapping biopsies.

BACKGROUND: Photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumors (TURBT) has emerged as a promising complementary tool to white light (WL) cystoscopy, potentially improving cancer detection and replacing conventional mapping biopsies. This study aimed to investigate the diagnostic accuracy of PDD by anatomical locations in mapping biopsies through lesion-based analysis. METHODS: PDD and WL findings were prospectively recorded in 102 patients undergoing mapping biopsies and PDD-assisted TURBT using oral 5-aminolevulinic acid. We evaluated 673 specimens collected from flat tumor or normal-looking lesions on WL cystoscopy, after excluding 98 specimens collected from papillary or nodular tumors. RESULTS: Among the 673 lesions, cancer was detected in 110 (16%) by lesion-based analysis. PDD demonstrated significantly higher sensitivity (65.5% vs. 46.4%, p < 0.001) and negative predictive value (92.5% vs. 89.5%, p < 0.001) compared to WL. The sensitivity of PDD findings varied by location: posterior (100%), right (78.6%), dome (73.3%), left (70.6%), trigone (58.8%), bladder neck (41.7%), anterior (40.0%), and prostatic urethra (25.0%). Incorporating targeted biopsies of specific locations (bladder neck, anterior, and prostatic urethra) into the PDD-guided biopsies, regardless of PDD findings, significantly increased the overall sensitivity from 65.5% to 82.7% (p = 0.001). CONCLUSIONS: This study first demonstrated the detection rate of location-specific mapping biopsies using PDD, revealing difficulties in accuracy assessment in areas susceptible to tangential fluorescence. While PDD-guided biopsy improves cancer detection compared to WL cystoscopy even for flat tumors or normal-looking lesions, more careful decisions, including mapping biopsies, may be beneficial for an assessment in these tangential areas.

Optimal Management for Primary High Grade Ta Bladder Cancer: Role of re-staging TURBT and Intravesical Adjuvant Therapy.

Objective: This study aims to investigate the impact of risk group classification, restaging transurethral resection (re-TURBT), and adjuvant treatment intensity on recurrence and progression risks in high-grade Ta tumours in patients with non-muscle invasive bladder cancer (NMIBC). Materials and methods: Data from a comprehensive bladder cancer database were utilized for this study. Patients with primary high-grade Ta tumours were included. Risk groups were classified according to AUA/SUO criteria. Tumour characteristics and patient demographics were analysed using descriptive statistics. Cox proportional hazard regression models were used to assess the effect of re-TURBT and other clinical/treatment-related predictors on recurrence- and progression-free survivals. The survivals by selected predictors were estimated using Kaplan-Meier method, and groups were compared by the log-rank test. Results: Among 218 patients with high-grade Ta bladder cancer, those who underwent re-TURBT had significantly better 5-year recurrence-free survival (71.1% vs. 26.8%, p = 0.0009) and progression-free survival (98.6% vs. 73%, p = 0.0018) compared with those with initial TURBT alone. Full BCG treatment (induction and maintenance) showed lower recurrence risk, especially in high-risk patients. However, residual disease at re-TURBT did not significantly affect recurrence risk. Conclusions: This study highlights the significance of risk group classification, the role of re-TURBT, and the intensity of adjuvant treatment in the management of high-grade Ta tumours. A risk-adapted model is crucial to reduce the burden of unnecessary intravesical treatment and endoscopic procedures.

Monopolar versus bipolar transurethral resection of bladder Tumour: post-hoc analysis of a prospective trial.

INTRODUCTION: Previously, in a randomised trial we demonstrated bipolar transurethral resection of bladder tumor (TURBT) could achieve a higher detrusor sampling rate than monopolar TURBT. We hereby report the long-term oncological outcomes following study intervention. METHODS: This is a post-hoc analysis of a randomized phase III trial comparing monopolar and bipolar TURBT. Only patients with pathology of non-muscle invasive bladder cancer (NMIBC) were included in the analysis. Per-patient analysis was performed. Primary outcome was recurrence-free survival (RFS). Secondary outcomes included progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). RESULTS: From the initial trial, 160 cases were randomised to receive monopolar or bipolar TURBT. 24 cases of non-urothelial carcinoma, 22 cases of muscle-invasive bladder cancer, and 9 cases of recurrences were excluded. A total of 97 patients were included in the analysis, with 46 in the monopolar and 51 in the bipolar group. The median follow-up was 97.1 months. Loss-to-follow-up rate was 7.2%. Regarding the primary outcome of RFS, there was no significant difference (HR = 0.731; 95%CI = 0.433-1.236; P = 0.242) between the two groups. PFS (HR = 1.014; 95%CI = 0.511-2.012; P = 0.969), CSS (HR = 0.718; 95%CI = 0.219-2.352; P = 0.584) and OS (HR = 1.135; 95%CI = 0.564-2.283; P = 0.722) were also similar between the two groups. Multifocal tumours were the only factor that was associated with worse RFS. CONCLUSION: Despite the superiority in detrusor sampling rate, bipolar TURBT was unable to confer long-term oncological benefits over monopolar TURBT.

Impact of Angiotensin Converting Enzyme Inhibitors on Pathologic Complete Response With Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer.

INTRODUCTION: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. RESULTS: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS. CONCLUSION: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC.

A novel laser resection approach: efficacy of rotatable bi-channel en bloc resection of bladder tumor in a pilot in-vivo study.

En bloc resection of bladder tumor (ERBT) involves removing bladder tumors and their base. Laser resection has been used to reduce complications including bleeding and obturator nerve reflex (ONR). We developed a novel approach (rotatable bi-channel en bloc resection of bladder tumor (RBC-ERBT)) and assessed its efficacy in a pilot in-vivo study to enhance laser ERBT's applicability in challenging bladder regions. In the laser RBC-ERBT procedure, lesions were excised by inserting a holmium laser through the rotating external working channel, while forceps were inserted through the internal working channel provided traction on the tissue. Fifteen laser RBC-ERBT procedures were performed in five different bladder areas of three live pigs. The technical success rate (TSR), procedure time, lesion size, occurrence of complications (bleeding, perforation, ONR), and detrusor muscle (DM) presence rate and DM thickness were evaluated. All 15 procedures were performed with a 100% TSR. The resections were successful in all bladder regions (posterior, left, right and anterior walls and dome). Median procedure time was 20 min. The resected specimen size was 10 mm × 7 mm to 17 mm × 13 mm. Mild bleeding occurred in two procedures (13.3%) but was effectively managed. No incidents of ONR or perforation were observed. Histological examination confirmed presence of DM in all specimens with a median DM thickness of 1.26 mm. Our pilot in-vivo study suggested the feasibility and effectiveness of laser RBC-ERBT for bladder tumors in various locations. This technique offers effective traction, improved visualization, and enhanced laser accessibility. Further studies are required to validate its effectiveness in humans.

Preoperative blood-based nutritional biomarkers as significant prognostic factors after intravesical BCG therapy in patients with non-muscle-invasive bladder cancer.

The aim of this study was to investigate the prognostic role of blood-based nutritional biomarkers, including red blood cell (RBC count), hemoglobin (Hb), total protein (TP), albumin, the serum albumin to globulin ratio (AGR) and the prognostic nutritional index (PNI) in patients who underwent intravesical treatment for non-muscle invasive bladder cancer (NMIBC). A total of 501 NMIBC patients who received intravesical Bacillus Calmette-Guerin (BCG) treatment following transurethral resection of bladder tumor (TURBT) were included. The optimal cutoff values for these nutrition-based indicators were determined using receiver operating characteristic curve analysis. We observed a significantly higher recurrence-free survival (RFS) rate in patients with elevated levels of RBC count, Hb, TP, and albumin. Cox univariate and multivariate Cox regression analyses demonstrated that serum albumin (P = 0.002, HR = 0.51, 95%CI: 0.33-0.78), RBC count (P = 0.002, HR = 0.50, 95%CI: 0.32-0.77), TP (P = 0.028, HR = 0.62, 95%CI: 0.41-0.95), Hb (P = 0.004, HR = 0.53, 95%CI: 0.33-0.84), AGR (P = 0.003, HR = 0.46, 95%CI: 0.27-0.76) and PNI (P = 0.019, HR = 0.56, 95%CI: 0.35-0.91) were significant independent factors predicting RFS. These cost-effective and convenient blood-based nutritional biomarkers have the potential to serve as valuable prognostic indicators for predicting recurrence in NMIBC patients undergoing BCG-immunotherapy.

Adaptive radiotherapy for muscle invasive bladder cancer: a retrospective audit of two bladder filling protocols.

BACKGROUND: Radical radiotherapy for muscle-invasive bladder cancer (MIBC) is challenging due to large variations in bladder shape, size and volume during treatment, with drinking protocols often employed to mitigate geometric uncertainties. Utilising adaptive radiotherapy together with CBCT imaging to select a treatment plan that best fits the bladder target and reduce normal tissue irradiation is an attractive option to compensate for anatomical changes. The aim of this retrospective study was to compare a bladder empty (BE) protocol to a bladder filling (BF) protocol with regards to variations in target volumes, plan of the day (PoD) selection and plan dosimetry throughout treatment. METHODS: Forty patients were included in the study; twenty were treated with a BE protocol and twenty with a BF protocol to a total prescribed dose of 55 Gy in 20 fractions. Small, medium and large bladder plans were generated using three different CTV to PTV margins. Bladder (CTV) volumes were delineated on planning CTs and online pre-treatment CBCTs. Differences in CTV volumes throughout treatment, plan selection, PTV volumes and resulting dose metrics were compared for both protocols. RESULTS: Mean bladder volume differed significantly on both the planning CTs and online pre-treatment CBCTs between the protocols (p < 0.05). Significant differences in bladder volumes were observed between the planning CT and pre-treatment CBCTs for BF (p < 0.05) but not for BE (p = 0.11). Both protocols saw a significant decrease in bladder volume between first and final treatment fractions (p < 0.05). Medium plans were preferentially selected for BE whilst when using the BF protocol the small plan was chosen most frequently. With no significant change to PTV coverage between the protocols, the volume of body receiving 25.0-45.8 Gy was found to be significantly smaller for BE patients (p < 0.05). CONCLUSIONS: This work provides evidence in favour of a BE protocol compared to a BF protocol for radical radiotherapy for MIBC. The smaller treatment volumes observed in the BE protocol led to reduced OAR and total body doses and were also observed to be more consistent throughout the treatment course. These results highlight improvements in dosimetry for patients who undergo a BE protocol for MIBC.

Association between CYP1A2 gene variants -163 C/A (rs762551) and -3860 G/A (rs2069514) and bladder cancer susceptibility.

BACKGROUND: Bladder cancer (BLCA) poses a significant global health challenge due to its high incidence, poor prognosis, and limited treatment options. AIMS AND OBJECTIVES: This study aims to investigate the association between two specific polymorphisms, CYP1A2-163 C/A and CYP1A2-3860G/A, within the Cytochrome P450 1A2 (CYP1A2) gene and susceptibility to BLCA. METHODS: The study employed a case-control design, genotyping 340 individuals using Polymerase Chain Reaction-High-Resolution Melting Curve (PCR-HRM). Various genetic models were applied to evaluate allele and genotype frequencies. Genetic linkage analysis was facilitated using R packages. RESULTS: The study reveals a significant association with the - 163 C/A allele, particularly in the additive model. Odds ratio (OR) analysis links CYP1A2-163 C/A (rs762551) and CYP1A2-3860G/A(rs2069514) polymorphisms to BLCA susceptibility. The rs762551 C/A genotype is prevalent in 55% of BLCA cases and exhibits an OR of 2.21. The A/A genotype has an OR of 1.54. Regarding CYP1A2-3860G/A, the G/A genotype has an OR of 1.54, and the A/A genotype has an OR of 2.08. Haplotype analysis shows a predominant C-C haplotype at 38.2%, followed by a C-A haplotype at 54.7%, and a less frequent A-A haplotype at 7.1%. This study underscores associations between CYP1A2 gene variants, particularly rs762551 (CYP1A2-163 C/A), and an increased susceptibility to BLCA. Haplotype analysis of 340 individuals reveals a predominant C-C haplotype at 38.2%, followed by a C-A haplotype at 54.7%, and a less frequent A-A haplotype at 7.1%. CONCLUSION: In conclusion, the - 163 C/A allele, C/A genotype of rs762551, and G/A genotype of rs2069514 emerge as potential genetic markers associated with elevated BLCA risk.

Fibroblast Activation Protein-α and the Immune Landscape: Unraveling T1 Non-muscle-invasive Bladder Cancer Progression.

Background and objective: The tumor microenvironment (TME) in non-muscle-invasive bladder cancer (NMIBC) plays an important role in the anticancer response. We aimed to identify the prognostic biomarkers in the TME of patients with NMIBC for progression to ≥T2. Methods: From our institutional database, 40 patients with T1 high-risk NMIBC who progressed were pair matched for Club Urologico Español de Tratamiento Oncologico (CUETO) progression variables with 80 patients who never progressed despite longer follow-up. Progression was defined as ≥T2 or extravesical disease. Patients were treated at least with bacillus Calmette-Guérin (BCG) induction (five or more of six doses). Immunohistochemical (IHC) markers for the TME were used on tissue at first T1 diagnosis: CD8-PanCK, GZMB-CD8-FOXP3, CD163, PD-L1 SP142/SP263, fibroblast activation protein-α (FAP), and CK5-GATA3. Full tissue slides were annotated digitally. Relative marker area (IHC-positive area/total area) or density (IHC-positive cells per area; n/mm2) was calculated, differentiating between regions of interest (ROIs; T1, Ta, and carcinoma in situ) and between compartments (stromal, epithelial, and combined). Differences in IHC variables were assessed using the t test, for continuous variables using analysis of variance and comparisons of more than two groups using Tukey's test. Conditional logistic regression for progression at 5-yr follow-up was performed with clusters based on pair matching. Key findings and limitations: Only FAP expression (increase per 50%) in T1 (odds ratio [OR]: 1.33; 95% confidence interval [CI]: 1.04-1.70) and all ROIs combined (OR: 1.62; 95% CI: 1.14-2.29) correlated significantly with progression. None of the other clinicopathological/IHC variables correlated with progression. Conclusions and clinical implications: FAP is a potential prognostic biomarker for progression in high-risk NMIBC. FAP is a marker for cancer-associated fibroblasts and is linked to immunosuppression and neoangiogenesis, which makes future investigation clinically relevant. Patient summary: We found that progression of high-risk non-muscle-invasive bladder cancer to muscle-invasive disease is less in patients with lower fibroblast activation protein-α (FAP) expression, which is a marker for cancer-associated fibroblasts.

Histologic subtypes of non-muscle invasive bladder cancer.

The majority of bladder cancers (BCs) are non-muscle invasive BCs (NMIBCs) and show the morphology of a conventional urothelial carcinoma (UC). Aberrant morphology is rare but can be observed. The classification and characterization of histologic subtypes (HS) in UC in BC have mainly been described in muscle invasive bladder cancer (MIBC). However, the currently used classification is applied for invasive urothelial neoplasm and therefore, also valid for a subset of NMIBC. The standard transurethral diagnostic work-up misses the presence of HS in NMIBC in a considerable percentage of patients and the real prevalence is not known. HS in NMIBC are associated with an aggressive phenotype. Consequently, clinical guidelines categorize HS of NMIBC as "(very) high-risk" tumors and recommend offering radical cystectomy to these patients. Alternative strategies for bladder preservation can only be offered to highly selected patients and ideally within clinical trials. Novel treatment strategies and biomarkers have been established MIBC and NMIBC but have not been comprehensively investigated in the context of HS in NMIBC. Further evaluation prior to implementation into clinical practice is needed.

Quantitative CT Morphometrics: A Novel Approach for Predicting the Bladder Cancer Grade.

Background and objective Bladder cancer (BC) is a common urothelial neoplasm, with non-muscle invasive forms comprising about 75% of cases and generally having better outcomes than muscle-invasive types. Accurate preoperative grading and staging of BC are essential for appropriate treatment planning. This study investigates the efficacy of computerized tomography (CT) in correlating the morphological features of tumors to predict the histopathological grades of BC.  Materials and methods This retrospective cohort involved 100 patients diagnosed with non-muscle invasive BC, who underwent transurethral resection of bladder tumor (TUR-BT) between January 2010 and August 2021. CT imaging, utilizing a 128-slice CT scanner, was employed to measure the tumor height (H) and contact length (CL). The study considered morphometric parameters across axial, coronal, and sagittal planes. Statistical analyses were conducted, comparing radiological findings with histopathological evaluations. Tumor grading was determined according to the 2004/2016 WHO classification. Results Among the 100 patients with primary bladder tumors, 15 were female and 85 were male, with a mean age of 65.28 ± 7.11 years. Furthermore, 58 had high-grade bladder tumors, while 42 had low-grade bladder tumors. Across all planes, high-grade tumors exhibited higher values for the tumor H, CL, and the tumor height-to-contact length (H/CL) ratio compared to low-grade tumors (p<0.05). Notably, the specificity, sensitivity, and diagnostic accuracy of the tumor CL were higher than those of the tumor H and the tumor H/CL ratio. A tumor CL exceeding 19.1mm measured in the axial plane demonstrated 83% sensitivity and specificity for high-grade tumors. Conclusion The measured CL of the tumor in the axial plane on computerized tomography urography has high sensitivity and specificity in detecting high-grade tumors.

Prognostic role of the neutrophil/lymphocyte ratio in high-risk BCG-naïve non-muscle-invasive bladder cancer treated with intravesical gemcitabine/docetaxel.

OBJECTIVES: To investigate the role of pretreatment neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in the prediction of response to sequential intravesical therapy, gemcitabine and docetaxel (Gem/Doce), given to patients with bacille Calmette-Guérin (BCG)- naïve high-risk non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A retrospective analysis was conducted on 115 patients who received intravesical Gem/Doce for high-risk NMIBC between January 2011 and December 2021. Data were computed as the median (interquartile range [IQR]) or mean (standard deviation [sd]). Cox regression analysis was performed to determine if neutrophilia, NLR, platelet counts, and PLR before instillation therapy were predictive of recurrence-free survival (RFS) and overall survival (OS). Predictive performance was estimated using Uno's C-statistic. RESULTS: The median (IQR) follow-up for the overall cohort was 23 (13-36) months. The mean (sd) values for NLR, PLR and platelet counts were 3.4 (2.3), 142.2 (85.5), and 225.2 (75.1) × 109/L, respectively. NLR was associated with RFS, with a hazard ratio of 1.32 (95% confidence interval CI 1.19-1.46). Concordance analysis showed that NLR had a good ability to predict RFS (C-index: 0.7, P < 0.01). The PLR and platelet count were not associated with RFS and did not predict recurrence. In terms of OS, none of these cellular inflammatory markers showed any prediction value. CONCLUSION: Pre-treatment NLR provides some predictive accuracy for RFS in high-risk BCG-naïve patients receiving Gem/Doce. Further prospective trials are needed to validate this finding.

Over-expression of KRT17 and MDK genes at mRNA levels in urine-exfoliated cells is associated with early non-invasive diagnosis of non-muscle-invasive bladder cancer.

INTRODUCTION: Current diagnostic approaches for bladder cancer (BLCA) are often invasive or lack the required sensitivity and specificity. This underscores the need for an early non-invasive diagnostic test for BLCA. This work aimed to explore the potential of molecular markers in urine-exfoliated cells for the diagnosis of non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: Urine specimens (n = 140) were collected from NMIBC patients (n = 68) and control subjects (31 healthy volunteers and 41 non-cancer patients with common urological diseases [CUD]. Total RNA was extracted from the cells isolated from urine specimens. mRNA expression of selected genes: CDC20, KRT15, FOXM1, CXCR2, UPK1B, MDK, KRT20, and KRT17 was determined using RT-qPCR. The receiver operating characteristic (ROC) curve was then plotted to obtain the area under the curve (AUC), specificity, and sensitivity of the urinary mRNA markers. RESULTS: The expression of CDC20, MDK, UPK1B, FOXM1, KRT17, and KRT20 was up-regulated in samples obtained from low- and high-grade pathological grades of NMIBC compared to that measured in healthy subjects. Notably, MDK and KRT17 mRNA levels in the low- and high-grade cases were substantially higher than in normal and CUD groups. The AUC of the KRT17 and MDK combination in diagnosing NMIBC was 0.92, surpassing that of single genes. The sensitivity and specificity of the KRT17 and MDK combination were 74% and 94%, respectively. In diagnosing low-grade from healthy and CUD groups, analysis of the KRT17 and MDK combination yielded AUCs of 0.94 and 0.95, respectively, with sensitivities of 85% and 97%, and specificities of 93% and 85%. CONCLUSION: The findings of this study revealed that KRT17 and MDK together are potential urine-based biomarkers for early diagnosis of NMIBC.

Metastatic Urothelial Carcinoma With Sarcomatoid Subtype After Robot-Assisted Radical Cystectomy Successfully Treated With Pembrolizumab.

A 76-year-old man who was diagnosed with urothelial carcinoma (UC) in the bladder diverticulum was referred to our institution. The patient was diagnosed with muscle-invasive bladder cancer, which was confirmed by magnetic resonance imaging that showed tumor invasion into the fatty tissue surrounding the diverticulum. After two cycles of neoadjuvant gemcitabine and cisplatin, he underwent robot-assisted radical cystectomy (RARC) with pelvic lymph node dissection followed by intracorporeal ileal conduit. The histopathologic diagnosis of the bladder tumor was UC with squamous differentiation and sarcomatoid subtype and ypT3bN0M0 without positive surgical margins. The patient refused any adjuvant therapy. Six months after RARC, the patient visited our institution with a complaint of suddenly occurring generalized pain. Because 18F-fluorodeoxyglucose positron emission tomography-CT showed multiple metastases, including bone, para-aortic lymph nodes, and pleura, pembrolizumab was initiated as a second-line treatment. After two courses of pembrolizumab, the patient's symptoms remarkably improved, and the abnormal systemic accumulation on PET-CT almost disappeared. After 26 months of continuous treatment with pembrolizumab, the patient remains disease-free. Several studies have been reported that focused on tumor subtypes and programmed cell death ligand 1 (PD-L1)-positive tumor cells as candidate biomarkers in relation to the efficacy of pembrolizumab. The higher proportion of PD-L1-positive cells in the sarcomatoid subtype may have resulted in favorable oncological outcomes compared with pure UC.

Clinical characteristics and factors associated with survival rate of patients with non-muscle invasive bladder cancer attending at a Tertiary Hospital in Somalia.

BACKGROUND: A few studies regarding the epidemiology and risk factors of Non-muscle Invasive Bladder Cancer (NMIBC) are reported from Sub-Saharan African countries (SSA), including Somalia, and the African literature is scant on the management of NMIBC. The present study aims to evaluate the clinical-histopathological characteristics and factors associated with the survival rate of patients with NMIBC. METHOD: This six-year cohort study included 196 patients with NMIBC. It reviewed the clinical and histopathological characteristics and factors predicting cancer-specific survival for these patients. RESULTS: The mean patient age was 59.01 ± 11.50 years, with a male-to-female ratio of 2.8:1. Urothelial carcinoma (UC) constituted the most common pathological type, accounting for 90.8%; Ta LG and T1HG were the most common histopathological tumour stage and grade (n = 90, 45.9%, vs. n = 56, 28.6%), respectively. The mean tumour size was 4.72 ± 2.81 cm. The cancer-specific mortality(CSM) was 13.3%. Age [2.252(2.310-2.943], p < 0.001], Gender [1.031(0.981-1.1.242),p < 0.001], tumour stage and grade [4.902(3.607-5.614),p < 0.001], tumour location [1.135(0.806-1.172),p < 0.001], number [0.510(0.410-0.920),p = 0.03], tumour size [1.523(0.936-1.541),p < 0.001], use of intravesical chemotherapy or BCG [2.810(1.972-4.381),p < 0.001], preoperative hydronephrosis grade [1.517(1.172-2.154),p < 0.001], and follow-up compliance [3.376(2.633-5.018),p < 0.001] were all associated with CSM. The 5-year overall survival was 57.1%, and cardiovascular diseases were the leading cause of mortality (n = 34), followed by diabetes (n = 28). CONCLUSION: Our study findings revealed that UC constituted the most common pathological subtype, though less than forty per cent of our patients receive intravesical adjuvant therapies, which are crucial to minimizing disease morbidity and mortality. Initiatives improving uro-oncological care, including subspecialty training in oncology and essential cancer therapies, better access to urology services, and cancer screening programs, are much needed for optimal management plans and care in the country.