Search Results (288)

We found, retrospectively, that BCG therapy in non-muscle invasive bladder cancer (NMIBC) reduces the rate of Alzheimer’s disease. Blockade of the ligand PD-L1 or its checkpoint receptor PD-1 has been shown to improve cognitive function and reduce brain pathology features in a mouse model of Alzheimer’s disease (AD). Given that peripheral blood mononuclear cells (PBMCs) are involved in aging brain pathology and thus represent a potential AD therapeutic target, we analyzed the impact of BCG on the expression of PD-1, PD-L1, and inflammation modulators in PBMCs. Cryopreserved PBMCs pre- and post-BCG-treated six melanoma and six NMIBC patients were repurposed for immunoelectrophoretic analysis of PBMC-extracted proteins. PBMCs, post-BCG treatment in melanoma patients, were harvested only 4 months after the start of treatment (short BCG period), whereas the PBMCs of NMIBC patients were harvested 24 to 52 months after starting the BCG treatment. In melanoma PBMCs, BCG upregulated PD-L1 (p = 0.052) while downregulating PD-1 (insignificantly, p = 0.16). In contrast, in NMIBC patients, BCG downregulated PD-L1 (insignificantly, p = 0.67), while upregulating PD-1 (p = 0.0082). PD-L1 positive correlation with p-IkB (r = 0.7228) under BCG is inverted to that of PD-L1 against IkB (p = −0.9491). The difference between these opposite correlations is significant (p = 0.011), indicating that PD-L1 is upregulated early after BCG treatment, in association with p-IKB, which enables inflammation. This association subsided later, and for PD-1, did not occur at the short or long BCG periods. Experiments with a larger number of patients may substantiate the hypothesis that an increase in PD-1 by BCG relative to PD-L1 may protect against AD. Full article

Non-muscle invasive bladder cancer (NMIBC) accounts for about 75% of new bladder cancer diagnoses. Early detection improves survival, yet routine white-light cystoscopy is invasive, costly, and can miss up to 45% of flat or small lesions. These shortcomings have prompted development of label-free diagnostic tools that read the intrinsic optical, electrical, or mechanical signatures of urinary biomarkers without added labels. This review examines recent engineering advances in such platforms for NMIBC detection, focusing on analytical performance, readiness for clinical translation, and remaining barriers to adoption. We compare each technology with conventional cytology using key metrics such as limit of detection, diagnostic accuracy, analysis time, cohort size, and stage of clinical development. Surface-enhanced Raman spectroscopy and interferometric flow cytometry offer femtomolar sensitivity and more than 98% accuracy within minutes, while compact electrochemical sensors targeting NMP22, Galectin-1, and microRNAs reach sub-picogram levels on disposable chips. Standardized sample handling, multicenter validation, and robust cost-effectiveness data are now essential for these tools to advance point-of-care NMIBC surveillance. Full article

Introduction: Hypoxic cancers are radioresistant, but biomarkers based on expression of multiple genes can identify patients who will benefit from hypoxia modification. Most studies identifying relevant genes exposed cells in culture to 1% oxygen, which activates hypoxia-inducible factor (HIF). However, oxygen concentrations in hypoxic tumours are heterogeneous ranging from <0.1%. As lower oxygen levels would likely affect transcriptional responses, we aimed to investigate how gene selection at different oxygen levels affects the genes identified and their prognostic capability. Methods: Four MIBC (J82, T24, UMUC3, HT1376) and two non-MIBC (RT4, RT112) bladder cancer cell lines were exposed to varying oxygen levels (20%, 1%, 0.2% and 0.1% O₂) for 24 h and were then harvested and frozen. RNA was extracted and transcriptomes analysed using Clariom S microarrays. Differences in gene expression were investigated. Prognostic and predictive significance of a published 24-gene signature was compared with one generated from genes identified at lower oxygen levels. Results: The number of upregulated genes increased with decreasing O₂ level. The number of biological pathways involved also increased. Differences between cell lines dominated those due to hypoxia. Some genes were commonly upregulated in MIBC and NMIBC cells and others increased exclusively in either MIBC or NMIBC cells. The median expression of a published 24-gene bladder cancer hypoxia-associated signature increased with decreasing oxygen levels. Seventy-seven genes were upregulated in at least three cell lines by exposure to 0.1% O₂. The median expression of the 77 genes was of borderline prognostic significance in the bladder cancer cohort in the TCGA (The Cancer Genome Atlas). Five of the seventy-seven genes upregulated by hypoxia were present in the twenty-four-gene bladder hypoxia signature. The median expression of the 5 genes demonstrated identical prognostication to the 24-gene signature but failed to predict benefit from hypoxia modification. Conclusions: The number of genes upregulated by exposure of bladder cancer cells to hypoxia increases as O₂ level is decreased from 1% to 0.2% to 0.1%. Differential upregulation of gene expression by MIBC and NMIBC cells and the associated biological pathways may be useful in understanding the genetics of bladder cancer invasiveness. Based on a search of the literature, this is the first study that assessed the expression of genes in bladder cancer using three hypoxic concentration levels to identify biomarkers for disease progression and prognosis among differentially expressed bladder cancer genes. Full article

Mitomycin C (MMC) is a widely employed chemotherapeutic agent, particularly in non-muscle invasive bladder cancer (NMIBC), where it functions by inducing DNA cross-linking and promoting tumor cell apoptosis. However, the tumor microenvironment (TME) significantly influences the therapeutic efficacy of MMC. Among the key regulators within the TME, the complement system and the coagulation pathway play a crucial role in modulating immune responses to cancer therapies, including MMC. This article explores the interaction between platinum nanoparticles (PtNPs) with human serum (HS) of NMIBC patients (T1 and Ta subtypes) at three different points: before the chemotherapy instillation of MMC (t₀) and three (t₃) and six months (t₆) after the treatment with MMC. This novel nanoproteomic strategy allowed the identification of a TME proteomic signature associated with the response to MMC treatment. Importantly, two proteins involved in the immune response were found to be deregulated across all patients (T1 and Ta subtypes) during MMC treatment: prothrombin (F2) downregulated and complement component C7 (C7) upregulated. By understanding how these biomarker proteins interact with MMC treatment, novel therapeutic strategies can be developed to enhance treatment outcomes and overcome resistance in NMIBC. Full article

Background/Objectives: Bladder cancer is a malignant disease that causes more than 199,922 deaths a year globally, in which ~75% of all newly diagnosed cases are non-muscle-invasive bladder cancer (NMIBC). Despite a number of treatments available, most NMIBC patients with high-grade tumors eventually recur. To add a novel therapy to complement the deficits of the current treatments, this study assesses the antitumor activity and mechanisms of action of intravesical xenogeneic urothelial cell (XUC) treatment as monotherapy and in combination with either chemotherapy or immune checkpoint inhibition (ICI). Methods: The orthotopic NMIBC graft tumor-bearing mice were randomly assigned into different treatment groups, receiving either intravesical XUCs, gemcitabine, anti-programmed death-ligand 1 (PD-L1) antibodies alone or in combination with gemcitabine or anti-PD-1 antibodies. The tumor responses, survival, and immune reactions were analyzed. Results: Intravesical XUC treatment exhibited significantly more antitumor activity to delay tumor progression than the control group and a similar effect to chemotherapy and ICI. In addition, there were significantly higher effects in the combined groups than single treatments. Immune tumor microenvironment and immune cell proliferation, cytotoxicity, and cytokine secretion were also activated by XUC treatment. Moreover, the combined groups have the highest effects. Conclusions: In vivo and ex vivo studies showed increased antitumor efficacy and immune responses by intravesical XUC treatment in single and combined treatments, suggesting a potential utility of this xenogeneic cell immunotherapeutic agent. Intravesical XUC treatment has the potential to address the substantial unmet need in NMIBC therapy as a bladder-sparing treatment option for NMIBC. Full article

Background/Objectives: In non-muscle-invasive bladder cancer (NMIBC), the decision for immediate postoperative single-dose intravesical chemotherapy (SI) is based on clinical and presumed pathological features, as a definitive pathology is unknown at the time of surgery. This study aims to assess how accurately urologists can predict the pathological features of bladder tumors based solely on cystoscopic appearance and evaluate their ability to identify patients eligible for SI. Methods: A total of 104 patients with bladder masses were included. Seven senior urologists and four residents participated. Before transurethral resection, both groups predicted tumor stage, grade, and the presence of carcinoma in situ (CIS). Resident predictions were collected for all 104 patients, while senior predictions were collected for 72 patients. Based on these predictions, patient eligibility for SI was determined according to the EAU NMIBC guidelines. After final pathology reports, risk scores were recalculated and compared with the surgeons’ predictions. Cohen’s Kappa (κ) coefficient was used to assess agreement between predictions and pathology. Positive and negative predictive values were also calculated for both groups. Results: Strong agreement with final pathology could not be demonstrated for stage, grade, or CIS for either group. Urology residents’ predictions were slightly more accurate than those of senior urologists. Overall, 19.4% (14/72) (based on senior urologists’ predictions) and 18.2% (19/104) (based on resident predictions) of patients were misclassified and either overtreated or undertreated. Conclusions: Cystoscopic visual prediction alone is insufficient for determining eligibility for immediate postoperative intravesical chemotherapy, regardless of the urologist’s experience. More objective criteria are needed to improve the selection of appropriate patients for SI. Full article

Background and Objectives: Urothelial bladder carcinoma includes a spectrum of malignant lesions with heterogeneous molecular, biological, and clinical features and a variable risk of progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) and ultimately to metastatic urothelial carcinoma (mUC). Sarcopenia, a condition secondary to a catabolic state, is characterized by progressive loss of skeletal muscle mass and function and is highly prevalent across all stages of bladder cancer. This review aims to synthesize current evidence regarding the clinical impact of sarcopenia and its dynamic changes throughout the disease course. Materials and Methods: A narrative literature review was conducted using PubMed, Scopus, and Cochrane databases, incorporating the most relevant published sources. Search terms included “bladder carcinoma”, “sarcopenia”, “body composition”, “NMIBC”, and “MIBC”. Case reports and congress abstracts were excluded. Results: In NMIBC treated with intravesical Bacillus Calmette–Guérin (BCG), sarcopenia has been shown to have a negative predictive value in some studies. Among patients receiving neoadjuvant chemotherapy (NAC) for MIBC, sarcopenia has been associated with increased toxicity, dose reductions, and treatment delays. In the context of radical surgery, sarcopenia correlates with increased postoperative mortality and a higher rate of severe complications. In mUC, low muscle mass is a negative prognostic factor regardless of treatment type and is associated with chemotherapy-related hematologic toxicity, although it does not appear to predict immune-related adverse events (irAEs). Conclusions: Sarcopenia is a highly prevalent and clinically relevant phenotype of urothelial bladder cancer patients, impacting prognosis, treatment response, and chemotherapy toxicity. Incorporating sarcopenia with other relevant components of body composition (BC) and systemic inflammatory markers may facilitate the development of more robust risk scores. Current evidence is primarily limited by the retrospective design of most studies. Future prospective research is needed to clarify the prognostic role of sarcopenia and support its integration into routine clinical decision-making. Full article

Background/Objectives: Given the increasing interest in the predictive role of inflammation in oncology, we aimed to assess the association between inflammatory factors (IFs) and the histopathological characteristics of bladder cancer (BC). Our objective was to correlate some of these IFs with BC progression and recurrence, identifying possible new diagnostic tools. Methods: We retrospectively analyzed 285 patients (79.8% male, 20.4% female; median age 73) who underwent transurethral resection of the bladder (TURB) between January 2016 and January 2022. The preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), systemic inflammation response index (SIRI), and standard clinical variables were collected one month before TURB and evaluated as predictors of recurrence and progression. Patients were stratified using the Youden Index and ROC analysis. Cox regression models were applied to identify independent predictors. Results: High-grade tumors were present in 74.6% of cases, and 34% were recurrent. Carcinoma in situ was found in 5%. After 72 months, 53% underwent radical cystectomy, and 13.7% died within 5 years. The optimal cutoffs were PLR 139, SIRI 1.12, PIV 248.49, NLR 2, SII 327. Smoking, primary MIBC, age, and lymph node status were significantly associated with recurrence. Elevated PLR correlated with recurrence and T2 progression (p = 0.004). Higher SIRI, PIV, and PLR levels were significantly associated with lymphovascular invasion and nodal metastasis (p < 0.05). PLR was linked to recurrence in tumors ≥ 3 cm post-BCG (p = 0.004); high SIRI predicted recurrence within 48 months (p = 0.05). Conclusions: High PLR and SIRI levels were associated with recurrence. Our findings support the emerging role of IFs in predicting BC outcomes and suggest their potential inclusion in future prognostic models. Full article

Background: Statins are commonly used cholesterol-lowering drugs with evidence of additional chemoprotective and immunomodulatory effects resulting from the inhibition of DNA replication, cell proliferation, and TH1-cell inhibition. There are conflicting reports regarding the potential benefit of concurrent statin treatment on non-muscle invasive bladder cancer (NMIBC) and specifically on intravesical Bacillus Calmette–Guerin (BCG) outcomes. We therefore aimed to analyze the effects of concurrent BCG and statin use in patients with NMIBC. Methods: National Veterans Affairs databases were used to retrospectively identify men with NMIBC between 2000 and 2010 who were treated with BCG. Pharmacy data was interrogated, and patients were divided according to statin therapy status. Statins had to be given at the beginning of BCG treatments and continued for at least 6 months. Cox proportional hazard ratios after inverse propensity score-weighted and competing risks adjustments were calculated for recurrence, secondary events (e.g., progression), cancer-specific survival, and overall survival. Results: Among 8814 patients, with a median follow-up of 11.3 years, statins were used by 38% of the patients. Patients taking statins were older (71 vs. 68, p < 0.0001), had more comorbidities (Charlson Comorbidity Index (CCI > 2; 38.6% vs. 31.4%, p < 0.0001), and had a higher-grade disease (40.2% vs. 34.3%, p < 0.0001) compared to those not on statins. After adjusting for stage, grade, age, race, CCI, agent orange exposure, and year of diagnosis, Cox proportional hazard analysis revealed no association with recurrence (HR 1.05, 95% CI 0.97–1.15, p = 0.23), secondary events (HR 0.91, 95% CI 0.80–1.05, p = 0.189), or bladder cancer specific survival (HR 0.88, 95% CI 0.76–1.02, p = 0.09) of statin use. However, statins were associated with improved overall survival (HR 0.89, 95% CI 0.83–0.96, p = 0.002). Conclusions: Concurrent statin and BCG use in patients with NMIBC was associated with improved overall survival, but not recurrence, secondary events, or bladder cancer-specific survival. These results confirm the real-world well-established cardiovascular benefit of statin treatment and primary preventive care. However, this large population study did not find any association between statins and the outcomes of patients with NMIBC treated with BCG immunotherapy. Full article

Several studies showed that the incidence of Alzheimer’s disease (AD) is significantly lower in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical bacillus Calmette–Guérin (BCG) instillations compared to treatment by alternative methods. Hypothetically, failure to clear misfolded and aggregated proteins (i.e., beta-amyloid) in AD brains and peripheral blood mononuclear cells (PBMCs) implicates BCG in upgrading the unfolded protein response (UPR). To test this hypothesis, pre- versus post-BCG PBMC proteins of the UPR pathway were compared in six NMIBC patients by capillary immunoelectrophoresis on an Abby instrument. PERK, the endoplasmic reticulum (ER) resident kinase, a stress-activated sensor, and its substrate alpha component of the eIF2 translation factor (eIF2a) complex inactivation were considered as potentially proapoptotic via a downstream proapoptotic transcription factor only if persistently high. GAPDH, a glycolytic marker of innate immunocyte training by BCG, and eight other UPR proteins were considered antiapoptotic. Summation of antiapoptotic %change scores per patient showed that the older the age, the lower the antiapoptotic %change. Higher antiapoptotic scores were observed upon a longer time from BCG treatment (with the exception of the patient in her ninth decade of life). Studies with more individuals could substantiate that BCG enhances the antiapoptotic aggregate-clearance effect of the UPR in PBMCs of NMIBC patients, which hypothetically protects brain cells against AD. Full article

Bladder cancer is the ninth most common cancer globally, with most cases classified as non-muscle-invasive bladder cancer (NMIBC). While transurethral resection of the bladder tumor (TURBT) remains the gold-standard treatment, its complications, high recurrence rates, and economic burden have prompted interest in alternative strategies like active surveillance (AS) for low-grade and low-grade NMBIC recurrences. AS minimizes surgical interventions and patient burden, but lacks standardized protocols for inclusion criteria and follow-up schedules. Most studies suggest intensive monitoring during the first year, with criteria often based on tumor size, number, and grade. Acquisition of evidence: A comprehensive literature search was conducted in December 2024 using Pubmed, Cochrane, and Trip databases to identify studies on AS for low-grade NMBIC recurrences. Only English studies were included, with Boolean operators used to refine the search. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Population, Intervention, Comparison and Outcomes (PICO) selection criteria were followed. The Newcastle–Ottawa quality assessment scale was used to analyze the quality of the included studies. Evidence synthesis: This systematic review included 11 studies evaluating AS for NMIBC. Early studies, such demonstrated AS as a feasible alternative to TURBT, with low progression rates. Subsequent research confirmed its safety in selected patients, with tumor growth and positive cytology being the main reasons for intervention. More recent investigations, further supported AS as a viable strategy, highlighting the low risk of stage and grade progression and its potential to reduce surgical interventions. Conclusions: AS may be considered an alternative approach for low-risk NMIBC recurrences. However, there is need for prospective studies and personalized approaches to optimize AS, addressing follow-up strategies, inclusion criteria and progression thresholds. Full article

Introduction: Kidney transplant recipients present a higher risk of developing malignancies than the general population. Malignancies represent the third leading cause of death for kidney transplant recipients. There is an increased risk of developing urothelial carcinoma among kidney transplant recipients, but it is not as high as the risk of renal cell carcinoma, which is the most common urologic malignancy. Although the bladder is the most common location for urothelial carcinoma, urothelial carcinomas of the upper tracts of the native kidneys and the allograft are also reported. The estimated incidence of urothelial carcinomas arising on kidney grafts is 0.019%. Case report: We present a case of a kidney transplant recipient who developed non-muscle-invasive bladder cancer 10 years after the transplant. This was successfully treated with TURBT (transurethral resection of the bladder tumor) and BCG (bacillus Calmette–Guerin) instillations. Two years later, this patient developed metastatic urothelial carcinoma of the allograft. Discussion: Nephroureterectomy of the transplant with bladder preservation after BCG treatment, no systemic chemotherapy, and cessation of immunotherapy were the treatments of choice in this case. Local oncologic control and spontaneous complete regression of pulmonary metastasis were obtained at a 2-year follow-up. Conclusions: With this case, we emphasize the fact that managing urothelial carcinomas in kidney transplant recipients is a provocative challenge for surgeons, nephrologists, and oncologists, as there are no treatment guidelines or protocols. Full article

Background: Desmocollin3, a transmembrane protein, is expressed in the basal/suprabasal layer of normal stratified epithelium. DSC3 gene expression is described in muscle-invasive bladder cancer (MIBC). DSC3-protein-expressing recurrent non-muscle-invasive bladder cancer (NMIBC) had a durable response to CADI-03, a DSC3-specific active immunotherapy. Methods: We evaluated DSC3 protein expression and its correlation with tumor-infiltrating immune cells in bladder cancer. DSC3 gene expression and its correlation with 208 immune encoding genes, treatment outcome, and survival were evaluated using the “ARRAYEXPRESS” and “TCGA” datasets. Immune genes were grouped as tumor-controlling immune genes (TCIGs) and tumor-promoting immune genes (TPIGs) as per their functions. Results & conclusions: NMIBC had higher DSC3 expression compared to MIBC. More immune genes were correlated with DSC3 in MIBC (21) compared to NMIBC (11). Amongst the TCIGs, six in NMIBC and one in MIBC had a negative correlation while two in NMIBC and nine in MIBC had a positive correlation with DSC3. Amongst the TPIGs, nine in NMIBC and five in MIBC had a negative correlation. Seven TPIGs had a positive correlation with DSC3 in MIBC and none in NMIBC. Of the T cell exhaustion markers, none were correlated with DSC3 in MIBC. Among NMIBC, CTLA4 and TIGIT were the only markers of exhaustion that demonstrated a negative correlation with DSC3. DSC3 expression was also higher in p53 mutant compared to wild p53, non-papillary MIBC compared to papillary MIBC, and in basal, squamous molecular subtype compared to luminal MIBC. MIBC with lower DSC3 expression had better outcomes (response, survival) compared to those with higher DSC3 expression. Full article

Bladder cancer, especially muscle-invasive bladder cancer (MIBC), poses significant treatment challenges due to its aggressive nature and poor prognosis, often necessitating cisplatin-based chemotherapy. While cisplatin effectively reduces tumor burden, its nephrotoxic effects, specifically cisplatin-induced acute kidney injury (AKI), limit its clinical use. This study investigates SH3YL1 as a potential biomarker for bladder cancer progression and AKI. Plasma and urine SH3YL1 levels were measured in bladder cancer patients undergoing cisplatin treatment, showing elevated baseline levels compared to controls, suggesting a link with bladder cancer pathology rather than cisplatin-induced AKI. Functional network and Gene Ontology (GO) enrichment analyses identified SH3YL1’s interactions with NADPH oxidase pathways, particularly NOX family genes, and highlighted its roles in cell adhesion, migration, and cytoskeletal organization—processes critical for tumor invasiveness. Notably, SH3YL1 and NOX4 expression were significantly higher in MIBC than in non-muscle-invasive bladder cancer (NMIBC), with a strong correlation between SH3YL1 and NOX4 (r = 0.62) in MIBC, suggesting a subtype-specific interaction. Kaplan–Meier survival analysis using The Cancer Genome Atlas bladder cancer (TCGA-BLCA) data further demonstrated that low SH3YL1 expression is significantly associated with poor overall and disease-specific survival in MIBC patients, reinforcing its role as a prognostic biomarker. In conclusion, SH3YL1 is a promising biomarker for identifying the invasive characteristics of MIBC and predicting patient outcomes. These findings underscore the importance of SH3YL1–NOX4 pathways in MIBC and suggest the need for further research into targeted biomarkers for bladder cancer progression and cisplatin-induced AKI to improve patient outcomes in high-risk cases. Full article

Introduction: Recently, alpha-emitting radionuclides like astatine-211 have offered promising results in clinical development. Non-muscle-invasive bladder cancer (NMIBC) presents a need for novel therapies. One promising approach is radioimmunotherapy targeting Carbonic Anhydrase IX (CA-IX), which is supported by preclinical and clinical evidence. The aim of our preclinical and clinical studies was to evaluate the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) for future use in NMIBC patient care. Methods: The anti-CA-IX antibody, girentuximab (TLX250), was labeled with lutetium-177 and astatine-211 for in vitro studies. Affinity constant measurements of [²¹¹At]At-girentuximab in RT-112 cells were taken, and toxicity evaluations were conducted in vitro and in healthy mice. Additionally, a clinical proof-of-concept study, PERTINENCE, that used [⁸⁹Zr]Zr-girentuximab for PET/CT imaging in bladder cancer patients was conducted. Results: The measurement of the affinity constant of [²¹¹At]At-girentuximab in RT112 cells revealed high binding affinity and significant cytotoxicity compared to [177Lu]Lu-girentuximab. Biodistribution studies in healthy mice indicated low systemic radioactivity uptake, and a bladder post-instillation examination showed no abnormalities in bladder mucosa, suggesting safety. In the PERTINENCE study, which involved patients with NMIBC tumors expressing CA-IX, [⁸⁹Zr]Zr-girentuximab PET/CT showed no extravesical leakage. Wall bladder uptake spots correlated with recurrence or inflammatory reaction. A dosimetric study suggested the potential efficacy and favorable safety profile of intravesical alpha therapy with the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) in NMIBC treatment. Conclusions: Preclinical and clinical data demonstrate the promising therapeutic role of ²¹¹At-targeted alpha agents in NMIBC, and the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) could fulfill this role. A phase I FIH clinical trial is in preparation, and results are expected within the next years. Full article