Treatment Of Bladder Cancer Research Articles

Abstract PR005: Final results from a Phase I trial of intravesical chemoimmunotherapy with gemcitabine and Bacillus Calmette-Guérin (BCG) for patients with BCG-exposed high-grade non-muscle invasive bladder cancer

Abstract Background: Although retreatment with BCG is considered standard of care for patients with BCG-exposed high-grade (HG) non-muscle invasive bladder cancer (NMIBC), less than 50% of patients are expected to respond. As such, the ability to augment the efficacy of BCG in this population remains a critical unmet need. Preclinical studies suggest that intravesical gemcitabine (Gem) may demonstrate synergistic efficacy with BCG by favorably altering the tumor microenvironment. We therefore sought to evaluate the safety, tolerability, and preliminary clinical efficacy of GemBCG in patients with BCG-exposed HG NMIBC through an IRB-approved Phase I/II clinical trial. Methods: Patients with BCG-exposed papillary HG NMIBC (Ta/T1) with or without carcinoma in situ (CIS) that recurred within 24 months of BCG therapy were eligible for this trial. Exclusion criteria included BCG-unresponsive disease, contraindication to BCG therapy, or ureteral/urethral urothelial disease. Consenting patients underwent complete transurethral resection of bladder tumors followed by intravesical Gem twice weekly (weeks 1, 4, 7, 10) for a total of 8 doses. Dose escalation of Gem was performed from 50-2000 mg using a Bayesian modified continual reassessment method. Intravesical Gem instillations alternated with weekly intravesical TICE BCG therapy (weeks 2, 3, 5, 6, 8, 9) for a total of 6 doses fixed at 50 mg followed by maintenance BCG in responders. Complete response (CR) rates and progression to muscle-invasive bladder cancer (MIBC) or cystectomy were evaluated at 12 months of follow up in the Phase I cohort. Results: A total of 25 patients was enrolled (median age 70 years [IQR 64-75]), all of which have at least 12 months of follow up. Of these, 88% (22/25) were male. Median duration of bladder cancer treatment prior to enrollment was 385 days (IQR 173-634), and 28% (7/25) previously received either maintenance therapy (3/25) or >1 induction courses of BCG (4/25). Based on centralized pathology review, a total of 68% had CIS ± papillary disease (8 HGTa, 5 HGT1, and 4 Tis), while 32% had papillary-only disease (4 HGTa and 4 HGT1). No dose limiting toxicities were observed, and 14/25 patients were treated at the maximum tolerated dose. The treatment was well tolerated with no patient experiencing treatment-related Grade 3-5 toxicity. CR rates at 6 months and 12 months were 96% (24/25) and 92% (23/25), respectively. No progression to MIBC or radical cystectomy was observed. Conclusion: Combination GemBCG in BCG-exposed HG NMIBC is well tolerated and appears to provide excellent cancer control. Based on these encouraging findings and the ongoing phase II portion (NCT04179162), a prospective randomized controlled trial comparing GemBCG to BCG alone for BCG-exposed NMIBC is planned through the National Clinical Trial Network (Alliance A032303). Citation Format: Syed M. Alam, Christopher D. Gaffney, Jessica Lavery, Merve Basar, Neeta D'Souza, Christian Hernandez, Melissa McCarter, Patricia Moran, Kristen Stasi, Kara Worth, Daniel Sjoberg, Guido Dalbagni, Timothy Donahue, Sherri Donat, Dean Bajorin, Bernard H. Bochner, Alvin Goh, Judy Sarungbam, Hikmat Al-Ahmadie, Eugene J. Pietzak. Final results from a Phase I trial of intravesical chemoimmunotherapy with gemcitabine and Bacillus Calmette-Guérin (BCG) for patients with BCG-exposed high-grade non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR005.

Advances in preclinical approaches for intravesical therapy of bladder cancer.

The purpose of this review is to explore new strategies to treat bladder cancer. This article addresses challenges and opportunities in intravesical therapy of bladder cancer. The review examines the latest advances in the development of preclinical approaches for intravesical therapy of bladder cancer. It discusses strategies to improve drug delivery efficiency by using synthesized diverse carriers. Immunotherapy with protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride has been shown to be more effective than intravesical Bacillus Calmette-Guerin. Novel drug delivery systems such the urinary drug-disposing strategy and intravesical nanoparticle formulations improve the drug delivery efficiency while minimizing adverse reactions. Innovative imaging techniques using near-infrared fluorescence probes and multifunctional nano-transformers enable real-time detection and targeted therapy in bladder cancer treatment. Treatment of bladder cancer is clinically challenging. However, recent progress in drug delivery technologies shows promise. Optimizing these technologies helps improve patient outcomes, and facilitates clinical translation of different treatment modalities.

Circular RNA LMBR1 inhibits bladder cancer progression by enhancing expression of the protein ALDH1A3

BackgroundCircular RNAs (circRNAs) have been identified as playing an integral role in the development of bladder cancer (BC). However, the mechanism by which circRNAs operate in the chemical carcinogenesis of BC remains unclear. MethodsTo explore this mechanism, we used RNA high-throughput sequencing to identify differentially expressed circRNA in bladder epithelial cells and chemically induced malignant transformed BC cells. Subsequently, in vitro experiments were conducted to investigate the biological function and molecular mechanism of circLMBR1 in BC. Finally, animal experiments were conducted to examine the clinical relevance of circLMBR1 in vivo. ResultsOur profiling of circular RNA expression during cellular malignant transformation induced by chemical carcinogens identified a subset of circRNAs associated with cell transformation. We verified that the expression of circLMBR1 in bladder epithelial malignant transformed cells was decreased compared with control cells, as well as in BC tissues and bladder cell lines. Furthermore, circLMBR1 was seen to inhibit the proliferation, invasion, and migration of BC cells both in vitro and in vivo. Mechanistically, circLMBR1 was found to exert its antitumor effect by binding to the protein ALDH1A3. ConclusionsOur findings have revealed that circLMBR1 inhibits the progression of BC cells by binding to ALDH1A3 and upregulating its expression. As such, circLMBR1 serves as a promising predictor of BC and may provide a novel therapeutic target for the treatment of BC.

Contemporary Views on Performance Indicators with Audit-Feedback for Bladder Cancer Treatment

Contemporary Views on Performance Indicators with Audit-Feedback for Bladder Cancer Treatment

Glutathione S-transferase omega class 1 (GSTO1)-associated large extracellular vesicles are involved in tumor-associated macrophage-mediated cisplatin resistance in bladder cancer.

Bladder cancer poses a significant challenge to chemotherapy due to its resistance to cisplatin, especially at advanced stages. Understanding the mechanisms behind cisplatin resistance is crucial for improving cancer therapy. The enzyme glutathione S-transferase omega class 1 (GSTO1) is known to be involved in cisplatin resistance in colon cancer. This study focused on its role in cisplatin resistance in bladder cancer. Our analysis of protein expression in bladder cancer cells stimulated by secretions from tumor-associated macrophages (TAMs) showed a significant increase in GSTO1. This prompted further investigation into the role of GSTO1 in bladder cancer. We found a strong correlation between GSTO1 expression and cisplatin resistance. Mechanistically, GSTO1 triggered the release of large extracellular vesicles (EVs) that promoted cisplatin efflux, thereby reducing cisplatin-DNA adduct formation and enhancing cisplatin resistance. Inhibition of EV release effectively counteracted the cisplatin resistance associated with GSTO1. In conclusion, GSTO1-mediated EV release may contribute to cisplatin resistance caused by TAMs in bladder cancer. Strategies to target GSTO1 could potentially improve the efficacy of cisplatin in treating bladder cancer.

The clinical significance of PD-1 expression in patients with bladder cancer without lymph node metastasis: a comparative study with drained lymph nodes and tumor tissues

ABSTRACT Objective In light of the increasing importance of immunotherapy in bladder cancer treatment, this study is aim to investigate the expression and clinical significance of programmed cell surface death-1 (PD-1) in bladder cancer patients without lymph node metastasis, and to compare and analyze the difference of PD-1 in draining lymph nodes and tumor tissues. Methods The expression of PD-1 on T cells and the proportion of positive PD-1 + T cells of IFN-γ and CD105a were detected by flow cytometry, and the correlation between PD-1 expression and clinical parameters was analyzed. Results The percentage of PD-1 positive cells in drainage lymph nodes was higher than that in tumor tissues (P < 0.001). PD-1 positive cells accounted for the highest proportion in CD3 + T cells. The proportion of IFN-γ-positive PD-1 + T cells in draining lymph nodes was significantly higher than that in tumor tissues (P < 0.001), while there was no significant difference in CD105a positive PD-1 + T cells between tumor tissues and draining lymph nodes. Pathological grade, tumor size and stage were positively correlated with PD-1 expression level in the lymph nodes. Conclusion The high expression of PD-1 in patients with bladder cancer without lymph node metastasis, especially in draining lymph nodes, suggests that PD-1 may play a key role in the regulation of tumor immune microenvironment. The correlation between PD-1 and clinical parameters indicates its potential prognostic value. These findings provide important clinical implications for PD-1 targeted therapy, but further prospective studies are needed to determine the application value of PD-1 in therapeutic strategies.

Induction and maintenance of sequential intravesical gemcitabine/docetaxel for intermediate and high-risk non-muscle invasive bladder cancer with different dosage protocols.

The combination of sequential intravesical gemcitabine and docetaxel (Gem/Doce) chemotherapy has been considered a feasible option for BCG(Bacillus Calmette-Guérin) treatment in non-muscleinvasive bladder cancer (NMIBC), gaining popularity during BCG shortage period. We seek to determine the efficacy of the treatment by comparing Gem/Doce induction alone vs induction with maintenance, and to evaluate the treatment outcomes of two different dosage protocols. A bi-center retrospective analysis of consecutive patients treated with Gem/Doce for NMIBC between 2018 and 2023 was performed. Baselinecharacteristics, riskgroup stratification (AUA 2020 guidelines), pathological, and surveillance reports were collected. Kaplan-Meier survival analysis was performed to detect Recurrence-free survival (RFS). Overall, 83 patients (68 males, 15 females) with a median age of 73 (IQR 66-79), and a median follow-up time of 18months (IQR 9-25), were included. Forty-one hadan intermediate-risk disease (49%) and 42 hada high-risk disease (51%). Thirty-sevenpatients (45%) had a recurrence; 19 (23%) had a high-grade recurrence. RFS of Gem/Doce induction-only vs induction + maintenance was at 6months 88% vs 100%, at 12months 71% vs 97%, at 18months 57% vs 91%, and at 24months 31% vs 87%, respectively (log-rank, p < 0.0001). Patients who received 2g Gemcitabine with Docetaxel had better RFS for all-graderecurrences (log-rank, p = 0.017). However, no difference was found for high-grade recurrences. Gem/Doce induction with maintenance resulted in significantly better RFS than induction-only. Combining 2g gemcitabine with docetaxel resulted in better RFS for all-grade but not for high-grade recurrences. Further prospective trials are necessary to validate our results.

Treatment Modalities for Non-Muscle Invasive Bladder Cancer: An Updated Review.

The landscape of treatment for non-muscle invasive bladder cancer is rapidly changing. A complete and careful transurethral resection is the mainstay of initial treatment and is followed by intravesical therapy in intermediate or high-risk cases. The standard of care is intravesical BCG. Many alternative or additive approaches to this are being explored. We divided this review into three relevant spaces to consider these novel treatment approaches: (1) low-risk disease, for which intravesical therapy is not usually considered, (2) BCG-naïve disease (i.e., considering alternatives to the standard therapy), and (3) BCG-unresponsive disease. We performed a review of published literature and summarized ongoing trials in the United States. Novel approaches that we explored include surgical techniques for resection, alterations in dwell time for intravesical therapy, delivery method and schedule of intravesical therapies, new intravesical therapy agents, and systemic therapies (especially immunotherapy). These are thoroughly outlined throughout this review article, and the numerous modalities being studied demonstrate significant promise for the future treatment of the expanding space of NMIBC.

Efficacy and Safety of Resveratrol in the Treatment of Bladder Cancer Derived Organoids

AbstractIntravesical instillation is a prevalent approach in bladder cancer (BC) management, yet it often causes adverse reactions and drug resistance. Safer and more effective alternative is therefore in urgent need, and resveratrol (RES) emerges as a promising candidate. However, the effectiveness of RES against BC remains unexplored. In this study, BC‐derived organoids (BCOs) are established to evaluate the efficacy of RES in comparison to conventional anti‐BC drugs (epirubicin (EPI), cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR)). After a 96‐h treatment, RES demonstrates superior anti‐BCOs efficacy (64.00%; 16/25) compared to the other chemotherapeutics (15.38% to 53.85%). Eighteen BCOs are treated with RES, EPI, or a combination of RES and EPI (RES/EPI) in short‐term (3 h per day for four times) to mimic intravesical instillation. RES exhibits the stronger efficacy (44.44%; 8/18) than EPI against BCOs, and the RES/EPI enhances sensitivity of a single drug (50.00%; 9/18). RES inhibits the activation of β‐catenin/CD44 axis in RES‐sensitive BCOs. The organoid‐forming potential of mouse bladder is preserved after intravesical instillation of RES, and 200 × 10−6 m RES demonstrates no adverse effects on patient‐derived bladder urothelial organoids. The findings highlight the potential of RES, particularly in combination with EPI, to improve intravesical instillation outcomes in BC management.

Robot-Assistant Radical Cystectomy as a Modern Method of Personalized Treatment for Patients with Muscle-Invasive Bladder Cancer

Introduction. Radical cystectomy (RC) is the “gold standard” treatment for muscle-invasive bladder cancer (MIBC). Robot-assisted RC (RARC) can act as a safe and effective method of treating MIBC.The aim of the study was to analyze our own experience with the use of RARC with intraoperative indocyanine green fluorescence (ICG) and postoperative determination of tumor macrophage levels in the treatment of patients with MIBC.Materials and methods. A study was conducted at the Clinic of the Bashkir State Medical University with the participation of 202 patients aſter RARC. 30 patients underwent intraoperative ICG fluorescence testing. The levels of tumor macrophages in the removed macropreparations were determined in all patients. In the postoperative period, a survival analysis was performed.Results. The sensitivity of the ICG fluorescence method was 94.4 %, and the specificity was 83.3 %. High levels of expression of macrophage markers CD68 and CD163 significantly predominate in the group with the cN+ stage (according to the clinical TNM classification, there are signs of damage) (p = 0.027 and p = 0.018, respectively). ICG fluorescence of regional lymph nodes (100 %) was observed in all patients with high CD68 and CD163 levels. A significant decrease in survival was recorded in patients with high pathomorphological stage T (pT according to the TNM classification) (r = 0.952, p &lt; 0.05) and statistically significant survival rates were obtained for pT1–pT4 groups (p &lt; 0.05 for overall, cancer-specific and recurrence-free survival (OS, CSS, RFS, respectively)).Discussion. More and more studies are appearing in the world literature proving the effectiveness of RARC in the treatment of patients with MIBC. Compared with open and laparoscopic techniques, better surgical and comparable oncological results are demonstrated.Conclusion. The results of the analysis of the RARC’s own experience indicate the effectiveness of this method of treating MIBC. The use of ICG fluorescence and verification of tumor macrophages makesit possible to provide personalized care to oncourological patients.

Identification of a pyroptosis-immune-related lncRNA signature for prognostic and immune landscape prediction in bladder cancer patients

PurposeIndividualized medicine has become increasingly important in bladder cancer treatment, whereas useful biomarkers for prognostic prediction are still lacking. The current study, therefore, constructed a novel risk model based on pyroptosis- and immune-related long noncoding RNAs (Pyro-Imm lncRNAs) to evaluate the potential prognosis of bladder cancer.MethodsCorresponding data of bladder cancer patients were downloaded from the Cancer Genome Atlas (TCGA) database. The univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, and multivariate Cox regression analysis were employed to establish a predictive signature, which was evaluated by receiver operator characteristic (ROC) analysis and Kaplan–Meier analysis. Furthermore, the immune infiltration, immune checkpoints, and responses to chemotherapeutic drugs were analyzed with this model.ResultsThree Pyro-Imm lncRNAs (MAFG-DT, AC024060.1, AC116914.2) were finally identified. Patients in the low-risk group demonstrated a significant survival advantage. The area under the ROC curve (AUC) at 1, 3, and 5 years was 0.694, 0.709, and 0.736 respectively in the entire cohort. KEGG and GO analyses showed that the Wnt pathway plays a crucial role in the high-risk group. The risk score was significantly related to the degree of infiltration of different immune cells, the expression of multiple immune checkpoint genes, and the sensitivity of various chemotherapeutic drugs.ConclusionThis novel signature provides a theoretical basis for cancer immunology and chemotherapy, which might help develop individualized therapy.

MicroRNA-150-5p-mediated Inhibition of Cell Proliferation, G1/S Transition, and Migration in Bladder Cancer through Targeting NEDD4-binding Protein 2-like 1 Gene.

MicroRNA-150-5p (miR-150-5p) has been implicated in the progression of several cancer types, yet its specific functional role and regulatory mechanisms in bladder cancer (BC) remain largely unexplored. Our study revealed significant downregulation of miR-150-5p and upregulation of NEDD4-binding protein 2-like 1 gene (N4BP2L1) in BC tissues compared to controls using quantitative real-time polymerase chain reaction and western blot analysis, respectively. Reduced miR-150-5p expression correlated with advanced tumor stage and lymph node metastasis, while increased N4BP2L1 levels were associated with larger tumor size by the Chi-square test. Functionally, miR-150-5p exerted significant inhibitory effects on BC cell proliferation, migration, inducing G0/G1 phase arrest, and apoptosis. We confirmed N4BP2L1 as a direct target of miR-150-5p in BC cells using luciferase reporter assay. Crucially, N4BP2L1 knockdown mimicked, while overexpression counteracted the inhibitory impacts of miR-150-5p on BC cell proliferation, migration, and invasion. In addition, N4BP2L1 overexpression reversed miR-150-5p-induced alterations in CDK4, Cyclin D1, Bcl-2, PCNA, Ki-67, N-cadherin, Bad, and E-cadherin levels in BC cells. Based on these results, it can be inferred that the miR-150-5p/N4BP2L1 axis might constitute a promising candidate for therapeutic targeting in the treatment of BC.

Engineered IL2 for improved treatment of bladder cancer

Abstract Bladder cancer (BC) remains a formidable challenge despite its immunogenic nature and responsiveness to FDA-approved immunotherapy. Interleukin-2 (IL2), a potent cytokine with potential for cancer treatment, faces obstacles such as the simultaneous activation of immunosuppressive regulatory T cells (Tregs), high toxicity, and a short half-life. CD122-directed IL2 therapy (IL2c) has shown success in mouse BC models. To address clinical challenges, we engineered two IL2/anti-IL2 antibody (F10) fusion proteins: F10 IC (native IL2), potentially biased toward effector cell activation, and F10 H9T (H9T, an engineered IL2), potentially favoring memory T cells. In vitro F10 H9T induced stem-like T cells (TCF-1+) and central memory T cells (CD44+CD62L+), while IL2c promoted Teff cell (CD44+CD62L-) differentiation. In vivo, using an orthotopic mouse bladder cancer model (n=10/group), F10 IC was superior in activating anti-tumor Teff and NK cells over F10 H9T and IL2c. Unexpectedly, F10 IC also induced TCF-1+ T cells, suggesting a potentially valuable dual effect, but further validation is required. We provide a roadmap for designing and translating immunomodulatory cytokine/antibody fusion proteins to overcome challenges associated with IL2-based cancer therapies.

Clofarabine Has a Superior Therapeutic Window as compared to Gemcitabine in Preclinical Bladder Cancer Models

Current standard-of-care systemic therapy options for locally advanced and metastatic bladder cancer (BC), which are predominantly based on cisplatin-gemcitabine combinations, are limited by significant treatment failure rates and frailty-based patient ineligibility. We previously addressed the urgent clinical need for better-tolerated BC therapeutic strategies using a drug screening approach, which identified outstanding antineoplastic activity of clofarabine in preclinical models of BC. To further assess clofarabine as a potential BC therapy component, we conducted head-to-head comparisons of responses to clofarabine versus gemcitabine in preclinical in vitro and in vivo models of BC, complemented by in silico analyses. In vitro data suggest a distinct correlation between the two antimetabolites, with higher cytotoxicity of gemcitabine, especially against several nonmalignant cell types, including keratinocytes and endothelial cells. Accordingly, tolerance of clofarabine (oral or intraperitoneal application) was distinctly better than for gemcitabine (intraperitoneal) in patient-derived xenograft models of BC. Clofarabine also exhibited distinctly superior anticancer efficacy, even at dosing regimens optimized for gemcitabine. Neither complete remission nor cure, both of which were observed with clofarabine, were achieved with any tolerable gemcitabine regimen. Taken together, our findings demonstrate that clofarabine has a better therapeutic window than gemcitabine, further emphasizing its potential as a candidate for drug repurposing in BC. Patient summaryWe compared the anticancer activity of clofarabine, a drug used for treatment of leukemia but not bladder cancer, and gemcitabine, a drug currently used for chemotherapy against bladder cancer. Using cell cultures and mouse models, we found that clofarabine was better tolerated and more efficacious than gemcitabine, and even cured implanted tumors in mouse models. Our results suggest that clofarabine, alone or in combination schemes, might be superior to gemcitabine for the treatment of bladder cancer.

AB002. SOH24AB_126. Qualitative and quality of life study exploring the patient’s perspective in a case of robot-assisted radical cysto-prostatectomy and intra-corporeal neo-bladder for the treatment of bladder cancer

AB002. SOH24AB_126. Qualitative and quality of life study exploring the patient’s perspective in a case of robot-assisted radical cysto-prostatectomy and intra-corporeal neo-bladder for the treatment of bladder cancer

Novel artesunate-metformin conjugate inhibits bladder cancer cell growth associated with Clusterin/SREBP1/FASN signaling pathway.

Bladder cancer remains the 10th most common cancer worldwide. In recent years, metformin has been found to have potential anti-bladder cancer activity while high concentration of IC50 at millimolar level is needed, which could not be reached by regular oral administration route. Thus, higher efficient agent is urgently demanded for clinically treating bladder cancer. Here, by conjugating artesunate to metformin, a novel artesunate-metformin dimer triazine derivative AM2 was designed and synthesized. The inhibitory effect of AM2 on bladder cancer cell line T24 and the mechanism underlying was determined. Anti-tumor activity of AM2 was assessed by MTT, cloning formation and wound healing assays. Decreasing effect of AM2 on lipogenesis was determined by oil red O staining. The protein expressions of Clusterin, SREBP1 and FASN in T24 cells were evaluated by Western blotting. The results show that AM2 significantly inhibited cell proliferation and migration at micromolar level, much higher than parental metformin. AM2 reduced lipogenesis and down-regulated the expressions of Clusterin, SREBP1 and FASN. These results suggest that AM2 inhibits the growth of bladder cancer cells T24 by inhibiting cellular lipogenesis associated with the Clusterin/SREBP1/FASN signaling pathway.

Enhancing Therapeutic Efficacy and Safety of Immune Checkpoint Inhibition for Bladder Cancer: A Comparative Analysis of Injectable vs. Intravesical Administration.

Bladder cancer (BC) presents a significant global health burden, characterized by high recurrence rates post-initial treatment. Gender differences in BC prevalence and response to therapy emphasize the importance of personalized treatment strategies. While Bacillus Calmette-Guérin (BCG) remains a cornerstone of BC therapy, resistance poses a challenge, necessitating alternative strategies. Immune checkpoint inhibitors (ICIs) have shown promise, yet systemic toxicity raises concern. Intravesical administration of ICIs offers a potential solution, with recent studies demonstrating the feasibility and efficacy of intravesical pembrolizumab. Although systemic toxicity remains a concern, its localized administration may mitigate adverse events. Additionally, liposomal delivery of ICIs exhibits promises in enhancing drug penetration and reducing toxicity. Novel imaging modalities compatible with Vesical Imaging-Reporting and Data System (VI-RADS) and capable of predicting high-grade bladder cancer can aid the pre-operative shared decision making of patient and surgeon. Future research should focus on refining treatment approaches, optimizing dosing regimens, and leveraging advanced imaging techniques to improve patient outcomes. In conclusion, intravesical immunotherapy presents a promising avenue for BC treatment, offering enhanced therapeutic effectiveness while minimizing systemic toxicity. Continued research efforts are essential to validate these findings and optimize intravesical immunotherapy's role in BC management, ultimately improving patient outcomes.

Initially metastatic bladder carcinoma in a 31-year-old patient.

Bladder cancer is the fifth most common malignancy, peaks in incidence after the sixth decade of life. reports of the clinical behavior of bladder cancer specifically in young patients are restricted to small series. While some hereditary syndromes such as Li-Fraumeni or retinoblastoma carry an increased risk of urothelial tumors at an early age. their low prevalence means that few clinicians see such cases. This pathology occurs mainly in the male patient and with a prevalence of 4 % in the male patient younger than 40 years old. The same identified factors found in the elderly patient were identified in the youthful patients. Clinically, like in the older patients, hematuria, irritative symptoms (urgency, frequency, dysuria) and clinical decline were described before the confirmed diagnosis. Bladder tumors are usually superficial before the age of 40 therefore have a low aggressivity rate. Treatment of invasive bladder cancer in young patients does not differ from the treatment at an old age. Also, the prognosis of patients under 40 years of age with bladder carcinoma is claimed to be better than of those presenting in later life.

Targeted and immunotherapy for the management of advanced urothelial carcinoma of the bladder.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. The activity of targeted and immunotherapy for the management of advanced bladder cancer is reviewed. Platinum-based chemotherapy is standard first-line treatment for advanced bladder cancer. Pembrolizumab is approved alone as first-line therapy for patients who are ineligible for any platinum-based chemotherapy and with enfortumab for patients ineligible for cisplatin-based chemotherapy. Avelumab is approved for maintenance therapy in patients who have not progressed with first-line platinum-containing therapy. Pembrolizumab, avelumab, and nivolumab are approved second-line therapy in patients who experience progression during or after platinum-containing chemotherapy. Erdafitinib is indicated for advanced disease that has susceptible FGFR2 or FGFR3 genetic alterations and has progressed during or after treatment with at least one line of platinum-containing chemotherapy. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates. They are both approved for patients who have received anti-PD-L1 or anti-PD-1 therapy and treatment with platinum-containing chemotherapy. Enfortumab is also indicated for patients who are ineligible to receive cisplatin-based therapy and have received one or more prior lines of therapy. Six targeted and immunotherapeutic agents have been approved for patients with advanced urothelial bladder cancer. They all have demonstrated activity in patients for whom disease has progressed during or after platinum-based therapy. Pembrolizumab, with and without enfortumab, has demonstrated first-line activity, and avelumab is a key maintenance therapy after first-line treatment. The results of additional clinical trials should provide evidence to establish the exact role in therapy of each agent in patients with advanced disease.

Exposure of Bladder Cancer Cells to Blue Light (λ = 453 nm) in the Presence of Riboflavin Synergistically Enhances the Cytotoxic Efficiency of Gemcitabine.

Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label instillation therapy into the bladder. To reduce potential side effects, continuous efforts are made to optimise the therapeutic potential of drugs, thereby reducing the effective dose and consequently the pharmacological burden of the medication. We recently demonstrated that it is possible to significantly increase the therapeutic efficacy of mitomycin C against a bladder carcinoma cell line by exposure to non-toxic doses of blue light (453 nm). In the present study, we investigated whether the therapeutically supportive effect of blue light can be further enhanced by the additional use of the wavelength-specific photosensitiser riboflavin. We found that the gemcitabine-induced cytotoxicity of bladder cancer cell lines (BFTC-905, SW-1710, RT-112) was significantly enhanced by non-toxic doses of blue light in the presence of riboflavin. Enhanced cytotoxicity correlated with decreased levels of mitochondrial ATP synthesis and increased lipid peroxidation was most likely the result of increased oxidative stress. Due to these properties, blue light in combination with riboflavin could represent an effective therapy option with few side effects and increase the success of local treatment of bladder cancer, whereby the dose of the chemotherapeutic agent used and thus the chemical load could be significantly reduced with similar or improved therapeutic success.