Search Results (1,066)

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized the management of several malignancies, including melanoma, non-small cell lung cancer, and urothelial carcinoma. However, these therapies frequently cause endocrine immune-related adverse events (irAEs), such as thyroid dysfunction, hypophysitis, or autoimmune diabetes, and may carry important prognostic implications. This systematic review and meta-analysis aimed to determine the incidence, spectrum, and clinical significance of endocrine irAEs across major tumor types. Methods: Following PRISMA guidelines and PROSPERO registration (CRD42025646504), we systematically searched PubMed, Embase, Cochrane CENTRAL, Web of Science, and Scopus for studies reporting endocrine irAEs in ICI-treated patients. Random-effects meta-analyses estimated pooled hazard ratios (HRs) for overall (OS) and progression-free survival (PFS) and odds ratios (ORs) for adverse events. Subgroup and meta-regression analyses explored associations by cancer type, ICI class, and event severity. Results: Forty-three studies comprising 17,399 patients were included. Endocrine irAEs occurred in 11–30% of patients and were associated with improved OS (HR: 0.60, 95% CI: 0.54–0.67; p < 0.001) and PFS (HR: 0.61, 95% CI: 0.54–0.68; p < 0.001). Severe events were most frequent with pembrolizumab in melanoma and non-small cell lung cancer and with anti-programmed death-ligand 1 therapy in urothelial carcinoma. In exploratory meta-regression analyses accounting for cancer type, ICI subclass, and irAE severity, no statistically significant correlation was observed between the occurrence of endocrine irAEs (OR) and survival benefit (PFS HR: 0.20, 95% CI −0.10 to 0.51; p = 0.19; OS HR: 0.14, p > 0.05). Conclusions: The development of endocrine irAEs coincides with favorable long-term survival outcomes but may represent surrogate markers of immune activation rather than direct predictors of ICI efficacy. However, the lack of consistent ≥ 3-year follow-up across studies warrants cautious interpretation. Routine endocrine monitoring and interdisciplinary management are essential to optimize the safety and effectiveness of immunotherapy. Full article

Objective: To describe the clinical use of URO17^®, a noninvasive, urine-based immunocytochemistry assay targeting Keratin 17 (K17), as an adjunct to conventional diagnostic methods for urothelial carcinoma. Materials and Methods: These illustrative cases summarize the real-world use of URO17^® in diagnostic workflows for patients presenting with hematuria and those undergoing surveillance for non-muscle invasive bladder cancer (NMIBC). Urine samples were processed via standard immunocytochemistry and interpreted alongside cystoscopic, cytological, and radiographic findings. Discussion: URO17^® was used as a complementary diagnostic tool to help guide clinical management. Negative results supported deferral of invasive procedures in selected patients, while positive findings prompted further evaluation when standard tests were inconclusive. Conclusions: In the seven illustrative cases presented, URO17^® aided clinical decision-making as part of routine diagnostic and surveillance workflows. The test’s integration with existing cytology processes supports its potential role as a noninvasive adjunct for evaluating patients with suspected or recurrent urothelial carcinoma. Full article

Background: Bladder cancer is the ninth most prevalent cancer globally. Most cases are urothelial carcinoma, classified as non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC); approximately 70% are diagnosed as NMIBC. Current standard of care for high-risk NMIBC includes transurethral tumour resection, followed by intravesical therapy with Bacillus Calmette-Guérin (BCG). However, significant unmet needs persist due to disease recurrence, BCG unresponsiveness, or progression to MIBC. Radical cystectomy is recommended after BCG unresponsiveness but may not be viable due to its invasiveness and morbidity. The paucity of treatment options for BCG-unresponsive NMIBC has driven research into alternatives such as gene therapy. The bladder’s anatomy allows direct vector–tumour contact, while urine and tissue samples allow for easy monitoring of therapeutic effects. Methods: This narrative review integrates findings from recent clinical and preclinical studies identified through comprehensive searches of peer-reviewed literature to provide an overview of the current landscape of gene therapy for BCG-unresponsive NMIBC. Results: Nadofaragene firadenovec, a recombinant adenovirus delivering interferon alpha-2b (IFNα2b), is the first FDA-approved gene therapy for BCG-unresponsive NMIBC with carcinoma in situ (CIS). A phase III nadofaragene firadenovec study (NCT02773849) demonstrated a 53% complete response (CR) rate at 3 months; and 43% of patients with CIS had bladder preservation at 60 months. Cretostimogene grenadenorepvec (CG0070), an oncolytic vector, demonstrated a 47% 6-month CR rate in a phase II study (NCT02365818). Detalimogene voraplasmid (EG-70), a nonviral gene therapy, demonstrated a 47% 6-month CR in a phase I/II study (NCT04752722). Future advances are likely to focus on patient selection, novel vectors, and combination strategies to improve treatment outcomes. Conclusions: Gene therapy represents a significant addition to the bladder cancer treatment landscape by offering bladder-sparing alternatives where conventional therapies are limited. Full article

Introduction of immune checkpoint inhibitors and targeted agents has markedly improved outcomes and extended survival in urothelial and renal cell carcinoma. However, the substantial subset of cases are treatment-resistant. Emerging strategies aim to enhance the effectiveness of immunotherapy. One area of growing interest and promise is the microbiome. The microbiome plays a complex and dynamic role in regulating the immune system, and represents a new frontier as a promising target for modulating response to immunotherapy. This review summarizes recent advances in our understanding of the microbiome, its interactions with immunotherapy, novel avenues for microbiome modification, and potential implications for the treatment of urothelial and renal cell carcinoma. Full article

Introduction: Bladder cancer is associated with a high recurrence rate, and outcomes for muscle-invasive and metastatic disease remain poor. New targeted therapies, such as the FGFR inhibitor erdafitinib, have been introduced, but the progression from non-muscle-invasive to muscle-invasive disease remains a major clinical challenge. Methods: In this study, we performed immunohistochemical staining for FGFR1-FGFR4 on surgical specimens from 192 cases of urothelial carcinoma. We also conducted various functional assays on human bladder cancer cell lines to assess protein/gene expression, cell proliferation, migration, invasion, and colony formation. Results: FGFR2 and FGFR3 expressions were found to be significantly down-regulated in high-grade (0.014) and muscle-invasive (0.002) tumors, respectively. Functionally, the FGFR inhibitor erdafitinib suppressed cell proliferation and migration, and FGFR3 silencing also markedly reduced proliferation, migration, invasion, and colony formation in cancer cell lines. Conclusions: The down-regulation of FGFR3 in muscle-invasive bladder cancer, coupled with the inhibitory effect of its inactivation on cell growth, suggests a significant role for FGFR3 in bladder cancer progression. Full article

Avelumab maintenance therapy is approved in Japan for patients with aUC without progression after PBC. This report presents subgroup analysis data from the JAVEMACS chart review of avelumab maintenance in patients who received 1L ddMVAC and GC. This retrospective study reviewed medical charts of patients with aUC (February 2021–December 2023). Overall, 350 patients (ddMVAC, n = 32 and GC, n = 196) were included in the study. Baseline characteristics were balanced between the two PBC groups. Median duration from PBC start to avelumab start was 13.2 and 21.1 weeks; median overall survival (OS) was not reached (both groups), progression-free survival (PFS) was 12.0 and 7.4 months, and PFS2 was 27.6 and 21.3 months for the ddMVAC and GC groups, respectively. At data cutoff (June 2024), 25.0% of patients in the ddMVAC and 17.3% in the GC groups were ongoing avelumab treatment. Second-line treatments included EV (64.3% ddMVAC; 64.5% GC), pembrolizumab (21.4% ddMVAC; 8.3% GC), and PBC (14.3% ddMVAC and 21.5% GC). This real-world data from patients with aUC in Japan showed consistent OS patterns with avelumab maintenance across treatment subgroups vs. the overall population despite their inherent heterogeneity. Although patients were not resistant to PBC, 2L EV was more common than 2L PBC. Full article

Background/Objectives: Systemic immunotherapy, previously used mainly for advanced urothelial carcinoma, now plays an important role in the treatment of non-muscle invasive bladder cancer (NMIBC), either alone or combined with intravesical BCG instillations. Methods: We conducted a collaborative, comprehensive review to summarize the key evidence and future perspectives on therapeutic intensification strategies involving immune checkpoint inhibitors in NMIBC. A total of 51 references published between 2000 and 2025 were included. Results: Four phase II studies evaluated pembrolizumab, atezolizumab, durvalumab, and cetrelimab as monotherapy in 28 to 132 BCG-unresponsive NMIBC patients. They reported complete response rates ranging from 12% to 43% after 3 to 12 months of treatment, with a durable response rate ranging from 49% to 57.4% at 12 months. To improve these results, a phase II trial launched this year tests a new systemic combination targeting both the PD-1/PD-L1 axis and the emerging HLA-E/NKG2A pathway. Regarding BCG-naïve high-risk (HR) NMIBC, four phase III studies are evaluating BCG instillations combined with systemic immunotherapy: sasanlimab (CREST), durvalumab (POTOMAC), atezolizumab (ALBAN), and pembrolizumab (KEYNOTE-676), with significant results reported for the CREST and POTOMAC trials. The key challenge remains selecting patients most likely to benefit from this combination therapy while avoiding overtreatment. Identifying predictive biomarkers of tumor aggressiveness and response to immunotherapy also represents a major future challenge. Conclusions: Therapeutic intensification using systemic immunotherapy applies to both BCG-unresponsive NMIBC, with a new target pathway (HLA-E/NKG2A), and BCG-naïve HR NMIBC, where the combination of BCG instillations and immunotherapy represents a major breakthrough. Full article

Canine prostatic carcinoma is a highly aggressive neoplasm with a strong tendency to metastasize, most commonly to regional lymph nodes, lungs, and bones. However, skeletal muscle and myocardial involvement are rarely reported. This report describes an 11-year-old intact male Maltese dog with a two-month history of anorexia and lethargy, referred for further evaluation after failing to respond to piroxicam therapy. Diagnostic imaging revealed a prostatic mass and multiple rim-enhancing lesions in the epaxial musculature and left ventricular wall, without evidence of metastasis to the lymph nodes, lungs, or other visceral organs. Hemostatic analysis indicated a hypercoagulable state. Postmortem examination confirmed metastatic prostatic carcinoma involving the semispinalis, multifidus, and myocardium. Histologically, the neoplastic cells exhibited similar morphology at the primary and metastatic sites. Immunohistochemistry revealed strong cytokeratin expression and absence of uroplakin III, consistent with a non-urothelial epithelial origin. No evidence of lymphatic involvement was observed. To the best of our knowledge, this is the first documented case of canine prostatic carcinoma with exclusive myotropic and myocardial metastases. These findings suggest a possible hematogenous metastatic route and highlight the importance of including muscle and cardiac tissues in staging protocols for canine prostatic carcinoma, even when lymphadenopathy or pulmonary lesions are absent. Full article

Background: Patients with systemic autoimmune diseases (SAID) are at a higher risk of developing neoplasms, such as solid tumors and hematologic malignancies. Chronic stimulation of the immune system and some treatments for these diseases increase the risk of developing solid tumors. Also, it is known that patients with SAID are usually excluded from clinical trials, but immune checkpoint inhibitors (ICI) are still used in these patients in everyday practice. Objectives: The objective of this article is to review the most up-to-date and robust literature on the use of ICI in patients with SAID for the treatment of solid tumors to obtain information on the efficacy and safety of these drugs in this subgroup of patients. Methods: A literature review was performed through international databases that included PubMed, Medline, Scopus, and Google Scholar. Articles about the use of ICI for solid tumors in patients with SAID were included; the types of articles included were retrospective studies, systematic reviews, and meta-analyses. A summarized descriptive analysis was performed about the efficacy and safety of ICI treatment for the main solid tumors (lung, melanoma, and other cutaneous malignancies, as well as renal and urothelial carcinoma). Conclusions: In general, it seems that ICI treatment is safe in patients with asymptomatic SAID. Close follow-up with a multidisciplinary team should be performed when ICI therapy is prescribed. A substitution of selective immunosuppressants (SIM) in place of nonselective immunosuppressants (NSIM) in asymptomatic patients is recommended before the initiation of ICI. Full article

Metastatic urothelial carcinoma (mUC) is a common tumor associated with high mortality. To date, the standard chemotherapy-based treatment has yielded suboptimal outcomes, characterized by limited survival and a substantial impact on patients’ quality of life. The introduction of new therapies has significantly improved overall survival (OS) and progression-free survival (PFS) rates. However, bringing novel treatments into clinical practice comes with an unfamiliar toxicity profile that may influence the choice of systemic therapy. The aim of this review is to analyze the toxicity of these new therapies and reflect on the role of appropriate management in treatment selection and planning of therapeutic sequencing in patients with mUC. Full article

Bladder cancer (BC), particularly its muscle-invasive subtype (MIBC), remains a clinical challenge due to high recurrence and limited therapeutic options. Emerging evidence suggests that probiotics may offer selective anticancer effects while preserving healthy tissue. In this study, we evaluated the antitumor potential of OxxySlab, a multistrain probiotic formulation, in two BC cell lines (T24 and 5637) and a non-tumorigenic urothelial cell line (SV-HUC1). OxxySlab lysate dose-dependently inhibited BC cell proliferation, clonogenicity, and migration, while sparing normal cells. Mechanistically, the treatment suppressed epithelial–mesenchymal transition (EMT), induced senescence, and disrupted redox homeostasis in malignant cells. These effects were associated with the induction of oxidative stress and impaired antioxidant defenses. Co-treatment with vitamin C attenuated ROS accumulation and senescence, implicating oxidative stress as a key mediator. Notably, SV-HUC1 cells retained viability and phenotype, confirming the formulation’s selectivity. Overall, these findings support OxxySlab as a promising adjunctive strategy in BC therapy, capable of reducing tumor aggressiveness through redox-mediated senescence and EMT inhibition without harming normal urothelial cells. Full article

Bladder cancer is a prevalent malignancy with high morbidity and mortality, particularly when diagnosed at an advanced stage. Early detection is critical, as it significantly improves prognosis and the patient’s outcomes. Bladder cancer also has a high recurrence rate, necessitating long-term surveillance. While cystoscopy remains the gold standard for diagnosis and monitoring, it is invasive and costly. Urine cytology, though widely used, has high specificity for detecting high-grade urothelial carcinoma but suffers from low sensitivity and limited effectiveness as a stand-alone diagnostic tool. Urinary biomarkers offer a promising, noninvasive alternative for early detection and disease surveillance. This review examines FDA-approved urinary biomarker tests, including NMP 22, UroVysion, and BTA, highlighting their clinical utility and limitations. Additionally, we explore emerging biomarkers such as DNA methylation assays, genomic alterations, and proteomic signatures as well as advanced technologies like next-generation sequencing and machine learning-based platforms. These innovations have the potential to enhance diagnostic accuracy, risk stratification, and recurrent monitoring, ultimately improving early detection and long-term disease management. By evaluating both established and emerging urinary biomarkers, this review aims to provide clinicians and researchers with insights into evolving tools for bladder cancer diagnosis and surveillance. Full article

Background and Objectives: Non-urothelial bladder tumors and secondary bladder involvement from extravesical primaries are uncommon but clinically challenging. We compared clinicopathologic patterns between primary non-urothelial tumors and secondaries, and explored correlates of adverse pathologic features to inform diagnostic triage and surgical planning. Methods: We performed a single-center retrospective cohort (2014–2024) of consecutive bladder lesions meeting WHO 2022 criteria and AJCC 8th staging. Eligible cases were primary non-urothelial malignancies (squamous cell carcinoma (SCC), adenocarcinoma (ADK), small-cell/neuroendocrine (NEC), sarcomatoid) or secondary bladder involvement (colorectal, prostate, cervix, ovary, uterus, breast). Outcomes included advanced pT (≥pT3), lympho–vascular invasion (LVI), perineural invasion (PNI), nodal metastasis, margin status, and composite adverse events. Results: Of 235 analyzable cases, 59 were primary and 176 were secondary. Age and sex distributions were similar. Secondaries had a higher adverse burden: advanced pT 56.8% vs. 23.7%, LVI 47.2% vs. 27.1%, PNI 40.3% vs. 22.0%, node-positive 11.9% vs. 0%, and any adverse 65.3% vs. 33.9% (all significant). Histology composition differed (p < 10⁻⁶): secondaries were ADK-dominant (59.1%), whereas primaries were enriched for SCC (38.5%), sarcomatoid (28.8%), and NEC (21.2%). Among secondaries, prostate origin showed the most ominous profile (advanced pT 97.5%, PNI 77.5%, positive margins 64.7%); colorectal cases combined high advanced pT (70.2%) with lower margin positivity (27.6%). Adverse-feature count correlated with pT (ρ = 0.586). Conclusions: Secondary bladder involvement carries substantially higher adverse-pathology rates than primary non-urothelial tumors, with origin-specific risk gradients (prostate > colorectal ≳ cervix). Rigorous origin adjudication and a margin-focused, anatomy-adapted surgical strategy may improve outcomes; prospective outcome-linked validation is warranted. Full article

Background/Objectives: The therapeutic landscape of advanced or metastatic urothelial carcinoma (UC) has shifted from platinum chemotherapy to precision immuno-oncology. Immune checkpoint inhibitors (ICIs)—pembrolizumab, nivolumab, and avelumab—show efficacy across platinum-refractory, maintenance, and adjuvant settings, yet benefit is limited to subsets, underscoring the need for biomarkers. Antibody–drug conjugates (ADCs), notably enfortumab vedotin(EV), and targeted agents such as FGFR inhibitors further expand options. This review synthesizes current evidence and emerging paradigms to guide combinations and sequencing. Methods: We performed a narrative synthesis of peer-reviewed trials (emphasizing pivotal phase III studies), key translational investigations, and contemporary guidelines on ICIs, ADCs, HER2-directed therapies, FGFR inhibitors, molecular subtyping, and genomic profiling in UC, integrating efficacy signals, biomarker associations, and practical implications for sequencing. Results: ICIs now occupy multiple settings, but heterogeneous benefit highlights the importance of molecularly informed selection. EV alone and with pembrolizumab has produced unprecedented first-line activity, prompting a strategic shift. Molecular subtyping and genomic profiling delineate phenotypes with variable immune responsiveness and targetable vulnerabilities, enabling rational combinations and refined sequencing. Ongoing trials are evaluating next-generation ADCs, HER2-directed approaches, and dual checkpoint blockade to achieve durable, personalized disease control. Conclusions: Management of locally advanced or metastatic UC is converging on precision immuno-oncology, wherein biomarker-driven selection, molecular subtyping, and thoughtful sequencing of ICIs, ADCs, and targeted agents are central to optimizing outcomes. Active trials and translational advances are expected to refine personalized strategies and embed molecular guidance into routine care. Full article

Background/Objectives: Bladder cancer (BC) carries a substantial global burden. Although lead (Pb) exposure has been linked to cancer, its molecular impact on bladder tumors remains unclear. We asked whether Pb-responsive transcriptional programs are present and clinically relevant in BC by integrating toxicogenomic resources with tumor transcriptomes and whether a composite lead-response score has prognostic value. Methods: Differential expression was performed on TCGA bladder urothelial carcinoma (BLCA) RNA-seq data (tumor vs. normal). Lead-associated genes were curated from the Comparative Toxicogenomics Database (CTD) and tested for over-representation among BLCA differentially expressed genes (DEGs) using a hypergeometric framework, with a stricter |log₂FC| ≥ 1 sensitivity. A tumor-level lead-response score was derived from the Pb–DEG overlap. Associations with overall survival (OS) were assessed using Cox models adjusted for age, sex, and pathological stage; secondary endpoints included PFI/DFI/DSS. Results: Lead-associated genes were significantly enriched among BLCA DEGs (background M = 20,530; K = 2618; n = 11,436; k = 1595; p = 4.21 × 10⁻⁹), and enrichment persisted under |log₂FC| ≥ 1 (n = 4275; k = 698; p = 9.86 × 10⁻¹⁵). Pathway over-representation highlighted synaptic/neuronal-like adhesion and transmission, MAPK-centered signaling, and cell-cycle control. Among top candidates, AQP12B was independently prognostic for OS (HR per 1 SD increase = 0.76; 95% CI 0.63–0.92; p = 0.0038; N = 404). The composite lead-response score showed a directionally protective but non-significant association in multivariable OS models (HR per 1 SD = 0.93; 95% CI 0.81–1.05; p = 0.244), while median-split Kaplan–Meier (KM) curves separated (p = 0.045). Conclusions: Lead-responsive transcriptional programs are detectable in BLCA and intersect adhesion, MAPK signaling, and cell-cycle pathways. AQP12B emerges as a plausible prognostic marker, and a composite lead-response score warrants external validation for risk stratification and clinical translation. Full article