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Introduction: Urothelial carcinoma (UC) is a refractory disease for which achieving satisfactory outcomes remains challenging with current surgical interventions. Antibody-drug conjugates (ADCs) are a novel class of targeted therapeutics that have demonstrated encouraging results for UC. Although there is a limited number of high-quality randomized control trials (RCTs) examining the use of ADCs in patients with UC, some prospective non-randomized studies of interventions (NRSIs) provide valuable insights and pertinent information. We aim to assess the efficacy and safety of ADCs in patients with UC, particularly those with locally advanced and metastatic diseases. Methods: A systematic search was conducted across PubMed, Embase, the Cochrane Library, and Web of Science databases to identify pertinent studies. Outcomes, such as the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events (AEs), and treatment-related adverse events (TRAEs), were extracted for further analyses. Results: Twelve studies involving 1,311 patients were included in this meta-analysis. In terms of tumor responses, the pooled ORR and DCR were 40% and 74%, respectively. Regarding survival analysis, the pooled median PFS and OS were 5.66 months and 12.63 months, respectively. The pooled 6-month PFS and OS were 47% and 80%, while the pooled 1-year PFS and OS were 22% and 55%, respectively. The most common TRAEs of the ADCs were alopecia (all grades: 45%, grades ≥ III: 0%), decreased appetite (all grades: 34%, grades ≥ III: 3%), dysgeusia (all grades: 40%, grades ≥ III: 0%), fatigue (all grades: 39%, grades ≥ III: 5%), nausea (all grades: 45%, grades ≥ III: 2%), peripheral sensory neuropathy (all grades: 37%, grades ≥ III: 2%), and pruritus (all grades: 32%, grades ≥ III: 1%). Conclusion: The meta-analysis in this study demonstrates that ADCs have promising efficacies and safety for patients with advanced or metastatic UC. [ABSTRACT FROM AUTHOR]

A 15-year-old spayed female mixed-breed dog was presented to the Ohio State University Veterinary Medical Center with a gingival mass and progressive anorexia. The dog had a history of dental disease, liver issues, and urinary tract infections. Fine-needle aspirate preparations of the gingival mass were evaluated and diagnosed as carcinoma, concerning for metastatic urothelial cell carcinoma (UC). Additional abnormalities were found on computed tomography (CT), including a left dorsal intracranial mass, cavitated left hepatic mass, and urinary bladder trigonal nodule. The dog was eventually diagnosed with UC with maxillary metastasis and likely metastasis to the retropharyngeal lymph node. UC is a common form of canine urinary tract neoplasia and has a high metastatic rate. The presence of eosinophilic inclusions consistent with Melamed-Wolinska bodies in neoplastic cells should prompt an evaluation of the urinary tract for a primary UC. [Extracted from the article]

Objective: To evaluate near‐infrared (NIR) spectroscopy in differentiating between benign and malignant bladder pathologies ex vivo immediately after resection, including the grade and stage of malignancy. Patients and Methods: A total of 355 spectra were measured on 71 bladder specimens from patients undergoing transurethral resection of bladder tumour (TURBT) between April and August 2022. Scan time was 5 s, undertaken using a portable NIR spectrometer within 10 min from excision. Specimens were then sent for routine histopathological correlation. Machine learning models were applied to the spectral dataset to construct diagnostic algorithms; these were then tested for their ability to predict the histological diagnosis of each sample using its NIR spectrum. Results: A two‐group algorithm comparing low‐ vs high‐grade urothelial cancer demonstrated 97% sensitivity, 99% specificity, and the area under the receiver operating characteristic curve (AUC) was 0.997. A three‐group algorithm predicting stages Ta vs T1 vs T2 achieved 97% sensitivity, 92% specificity, and the AUC was 0.996. Conclusions: This first study evaluating the diagnostic potential of NIR spectroscopy in urothelial cancer shows that it can be accurately used to assess tissue in an ex vivo setting immediately after TURBT. This offers point‐of‐care assessment of bladder pathology, with potential to influence the extent of resection, reducing both the need for re‐resection where invasive disease may be suspected, and also the potential for complications where extent of diagnostic resection can be limited. Further studies utilising fibre‐optic probes offer the potential for in vivo assessment. [ABSTRACT FROM AUTHOR]

Bladder cancer, the 10th most common cancer globally, primarily manifests as urothelial cell carcinoma. Risk factors involve acquired genetic mutations and congenital predispositions, impacting diagnosis and management. This article discusses the risk factors, clinical presentation, and treatment strategies, with emphasis on providing comprehensive nursing support and patient education to patients with bladder cancer. Bladder cancer, the 10th most common cancer globally, primarily manifests as urothelial cell carcinoma. This article discusses risk factors, treatment strategies, nursing support, and patient education. [ABSTRACT FROM AUTHOR]

Non-muscle-invasive bladder cancer (NMIBC) has one of the highest recurrence rates among all solid cancers and the highest lifetime treatment cost per patient. Therefore, the development of chemoprevention strategies for reducing the occurrence and recurrence of NMIBC as well as its burdens on the healthcare system is valuable. Our aim was to determine whether flavokawain A (FKA), a kava chalcone isolated from the kava plant, can target the in vivo activated Ha-ras pathway for prevention and treatment of NMIBC. UPII-mutant Ha-ras transgenic mice that develop papillary urothelial cell carcinoma were fed orally with vehicle control or FKA-formulated food for 6 months starting at 6 weeks of age. Seventy-nine percent (15/19) of male mice fed with 6 g FKA per kilogram (kg) of food survived beyond the 6 months of treatment, while 31.6% (6/19) of control food-fed male mice survived the 6-month treatment period (p = 0.02). The mean bladder weights in FKA vs. control food-fed mice were 0.216 ± 0.033 vs. 0.342 ± 0.039 g in male mice (p = 0.0413) and 0.043 ± 0.004 vs. 0.073 ± 0.004 g in female mice (p < 0.0001); FKA reduced bladder weight by 37% and 41%, respectively. The tumor burdens, determined by the wet bladder weight, in these mice were inversely related to plasma FKA concentrations. In addition to decreased bladder weight, FKA treatment significantly reduced the incidences of hydronephrosis and hematuria. FKA-treated mice exhibited more well-differentiated tumors in the bladder and ureter. Immunohistochemical analysis of FKA-treated tumors compared to those in the control group revealed fewer Ki-67- and survivin-positive cells and an increased number of p27- and TUNEL-positive cells, indicating that FKA inhibits proliferation and induces apoptosis. Overall, the results suggest that FKA can target the in vivo activated Ha-ras pathway for the prevention and treatment of NMIBC.

Bacillus Calmette-Guérin (BCG) therapy is an adjuvant treatment for urothelial carcinomas of the upper urinary tract (UTUC). BCG therapy can result in various side effects. We present a case of a 67-year-old female with a history of UTUC who developed disseminated tuberculosis following BCG instillation into the upper urinary tract after conservative management. This complex clinical scenario required a multidisciplinary approach, including antibiotic therapy, immunoglobulin infusion, and tailored tuberculosis treatment. The case underscores the importance of vigilance, early detection, and tailored interventions in managing disseminated tuberculosis arising from BCG therapy and rare complications like hemophagocytic syndrome.

Introduction: Radical cystectomy combined with orthotopic urinary diversion is a chosen approach for treating invasive bladder cancer. However, urothelial cell carcinoma is characterized by its potential for recurrence and the development of multiple tumors in the urinary tracts. In the natural progression of transitional cell carcinoma, the remaining ureteral stump is considered a predicted site for possible recurrence after radical cystectomy. Currently, there is no specific recommendation for the diagnosis and management of this condition. Objective: We report a rare case in a 74-year-old male patient who was diagnosed with anterior urethral carcinoma following a history of radical cystectomy and Hautmann ileal neobladder reconstruction. Additionally, we summarize some novel findings regarding risk factors, diagnosis, treatment, and prognosis in patients with recurrent bladder cancer in the urethra after radical cystectomy. Methods: A case report and mini review. Results: The patient was diagnosed with recurrent bladder cancer in the urethral after radical cystectomy using magnetic resonance imaging of the pelvis, cystoscopy, and biopsy. Complete urethrectomy and creation of a permanent percutaneous urinary diversion were performed. No intraoperative or postoperative complications were recorded. The patient was discharged 3 days after the surgery. Conclusion: Urethral cancer following radical cystectomy for bladder cancer treatment is a rare condition. Risk factors for this occurrence include male gender, non-use of orthotopic neobladder reconstruction technique, invasive tumors in the prostatic urethra, and multifocal tumors. The treatment of these tumors can be determined based on the extent of invasion and histological characteristics, leading to the choice between radical urethrectomy or alternative conservative treatments. [ABSTRACT FROM AUTHOR]

The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of immunotherapy, immune checkpoint inhibitors (ICIs) like nivolumab, ipilimumab, pembrolizumab, and atezolizumab play a pivotal role by disturbing signaling pathways that limit the immune system’s ability to fight tumor cells. Despite the profound impact of these treatments, not all tumors are responsive. Recent research efforts have been focused on understanding how cancer cells manage to evade the immune response and identifying the possible mechanisms behind resistance to immunotherapy. In response, ICIs are being combined with other treatments to reduce resistance and attack cancer cells through multiple cellular pathways. Additionally, novel, targeted strategies are currently being investigated to develop innovative methods of overcoming resistance and treatment failure. This article presents a comprehensive overview of the mechanisms of immunotherapy resistance in GU cancers as currently described in the literature. It explores studies that have identified genetic markers, cytokines, and proteins that may predict resistance or response to immunotherapy. Additionally, we review current efforts to overcome this resistance, which include combination ICIs and sequential therapies, novel insights into the host immune profile, and new targeted therapies. Various approaches that combine immunotherapy with chemotherapy, targeted therapy, vaccines, and radiation have been studied in an effort to more effectively overcome resistance to immunotherapy. While each of these combination therapies has shown some efficacy in clinical trials, a deeper understanding of the immune system’s role underscores the potential of novel targeted therapies as a particularly promising area of current research. Currently, several targeted agents are in development, along with the identification of key immune mediators involved in immunotherapy resistance. Further research is necessary to identify predictors of response. [ABSTRACT FROM AUTHOR]

Background: Metastatic urothelial carcinoma bladder at the time of diagnosis is a rare entity with lymph nodes, bones, lung and liver as common metastatic sites. Sometimes metastasis can be seen in various atypical sites. Case Presentation: Unusual location of metastasis can be seen in perinephric region, renal fascia and ovaries as seen in the described case. Primary urothelial carcinoma of ovary needs to be differentiated from the metastasis. There are no standard lines of management and the treatment needs to be individualised. Prognosis of metastatic urothelial carcinoma remains fatal with a limited life expectancy. Conclusion: We present a case of metastatic urothelial carcinoma bladder with metastasis to perinephric region and ovaries with her course of treatment. [ABSTRACT FROM AUTHOR]

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Abstract Background Applying deep learning to digital histopathology is hindered by the scarcity of manually annotated datasets. While data augmentation can ameliorate this obstacle, its methods are far from standardized. Our aim was to systematically explore the effects of skipping data augmentation; applying data augmentation to different subsets of the whole dataset (training set, validation set, test set, two of them, or all of them); and applying data augmentation at different time points (before, during, or after dividing the dataset into three subsets). Different combinations of the above possibilities resulted in 11 ways to apply augmentation. The literature contains no such comprehensive systematic comparison of these augmentation ways. Results Non-overlapping photographs of all tissues on 90 hematoxylin-and-eosin-stained urinary bladder slides were obtained. Then, they were manually classified as either inflammation (5948 images), urothelial cell carcinoma (5811 images), or invalid (3132 images; excluded). If done, augmentation was eight-fold by flipping and rotation. Four convolutional neural networks (Inception-v3, ResNet-101, GoogLeNet, and SqueezeNet), pre-trained on the ImageNet dataset, were fine-tuned to binary classify images of our dataset. This task was the benchmark for our experiments. Model testing performance was evaluated using accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve. Model validation accuracy was also estimated. The best testing performance was achieved when augmentation was done to the remaining data after test-set separation, but before division into training and validation sets. This leaked information between the training and the validation sets, as evidenced by the optimistic validation accuracy. However, this leakage did not cause the validation set to malfunction. Augmentation before test-set separation led to optimistic results. Test-set augmentation yielded more accurate evaluation metrics with less uncertainty. Inception-v3 had the best overall testing performance. Conclusions In digital histopathology, augmentation should include both the test set (after its allocation), and the remaining combined training/validation set (before being split into separate training and validation sets). Future research should try to generalize our results.

Objective We report NHS England data for patients with bladder cancer (BC), upper tract urothelial cancer (UTUC: renal pelvic and ureteric), and urethral cancers from 2013 to 2019. Materials and Methods Hospital episode statistics, waiting times, and cancer registrations were extracted from NHS Digital. Results Registrations included 128 823 individuals with BC, 16 018 with UTUC, and 2533 with urethral cancer. In 2019, 150 816 persons were living with a diagnosis of BC, of whom 113 067 (75.0%) were men, 85 117 (56.5%) were aged >75 years, and 95 553 (91.7%) were Caucasian. Incidence rates were stable (32.7-34.3 for BC, 3.9-4.2 for UTUC and 0.6-0.7 for urethral cancer per 100 000 population). Most patients 52 097 (mean [range] 41.3% [40.7-42.0%]) were referred outside the 2-weekwait pathway and 15 340 (mean [range] 12.2% [11.7-12.6%]) presented as emergencies. Surgery, radiotherapy, chemotherapy, or multimodal treatment use varied with disease stage, patient factors and Cancer Alliance. Between 27% and 29% (n = 6616) of muscle-invasive BCs did not receive radical treatment. Survival rates reflected stage, grade, location, and tumour histology. Overall survival rates did not improve over time (relative change: 0.97, 95% confidence interval 0.97-0.97) at 2 years in contrast to other cancers. Conclusion The diagnostic pathway for BC needs improvement. Increases in survival might be delivered through greater use of radical treatment. NHS Digital data offers a population-wide picture of this disease but does not allow individual outcomes to be matched with disease or patient features and key parameters can be missing or incomplete. [ABSTRACT FROM AUTHOR]

Background: Applying deep learning to digital histopathology is hindered by the scarcity of manually annotated datasets. While data augmentation can ameliorate this obstacle, its methods are far from standardized. Our aim was to systematically explore the effects of skipping data augmentation; applying data augmentation to different subsets of the whole dataset (training set, validation set, test set, two of them, or all of them); and applying data augmentation at different time points (before, during, or after dividing the dataset into three subsets). Different combinations of the above possibilities resulted in 11 ways to apply augmentation. The literature contains no such comprehensive systematic comparison of these augmentation ways. Results: Non-overlapping photographs of all tissues on 90 hematoxylin-and-eosin-stained urinary bladder slides were obtained. Then, they were manually classified as either inflammation (5948 images), urothelial cell carcinoma (5811 images), or invalid (3132 images; excluded). If done, augmentation was eight-fold by flipping and rotation. Four convolutional neural networks (Inception-v3, ResNet-101, GoogLeNet, and SqueezeNet), pre-trained on the ImageNet dataset, were fine-tuned to binary classify images of our dataset. This task was the benchmark for our experiments. Model testing performance was evaluated using accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve. Model validation accuracy was also estimated. The best testing performance was achieved when augmentation was done to the remaining data after test-set separation, but before division into training and validation sets. This leaked information between the training and the validation sets, as evidenced by the optimistic validation accuracy. However, this leakage did not cause the validation set to malfunction. Augmentation before test-set separation led to optimistic results. Test-set augmentation yielded more accurate evaluation metrics with less uncertainty. Inception-v3 had the best overall testing performance. Conclusions: In digital histopathology, augmentation should include both the test set (after its allocation), and the remaining combined training/validation set (before being split into separate training and validation sets). Future research should try to generalize our results. [ABSTRACT FROM AUTHOR]

Purpose: The incidence of urethral recurrence (UR) following radical cystectomy (RC) for transitional cell carcinoma (TCC) of the bladder varies between 1.5 and 6%. There is debate over the timing of urethrectomy for patients undergoing RC. We evaluated the requirement for a formal surveillance programme for UR in patients after RC. Methods: We retrospectively reviewed the outcomes of patients who underwent RC between 2006 and 2019. Females, non-TCC cases and patients with neo-bladder diversions were excluded. Histological prostatic urethral involvement at the time of RC was deemed high risk for UR. Carcinoma in-situ, multifocal tumours and bladder neck involvement were deemed intermediate risk and the absence of the above features was considered low risk. Results: 417 patients underwent RC, 300 cases remained after exclusion criteria were applied. 42 patients were high-risk for UR, 102 patients were intermediate risk and 156 were low risk. Of the 300, 24 urethrectomy cases were recorded. Six cases of UR occurred. Of these, 5 presented with symptoms and only 1 case was detected by surveillance. Only 1 low-risk patient developed UR, 7 years post RC. Using our risk stratification, UR rates for high, intermediate and low-risk cohorts were 25%, 10.5% and 0.8%, respectively. Conclusions: In our cohort, routine surveillance for all patients with annual urethroscopy was of limited value in detecting UR post RC. Staged Urethrectomy for high and intermediate-risk patients, and patient counselling in self-identification of recurrence symptoms for low-risk patients will improve the early detection of UR. [ABSTRACT FROM AUTHOR]

Background: Urothelial cell carcinoma is quite prevalent, making up close to 90 % of all cases. Men are more likely to suffer from it than women, and it mostly affects the elderly. Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cell proliferation and cancer progression., Aim: this study was conducted to assess the association between FGFR4 gene polymorphism and the risk of Urothelial Cell Carcinoma in Iraq., Methods: genomic DNA samples were extracted from a total 200 samples of blood. Three primers were designed to enhance three commonly observed genetic variation, rs2011077, rs351855, and rs1966265. The single strand conformation polymorphisms technique (SSCP) was genotyped and confirmed by further sequencing protocols., Results: The results of this study show that cases with the G/A variant of the rs351855 genotype have a marked increase in risk to Urothelial Cell Carcinoma (P = 0.001, OR 0.32, 95 % CI 0.20 to 0.94). Cases with genotype rs2011077: T\C has also associated with the increased the risk of UCC (P = 0.001, OR= 0.50, 95 % CI = 0.33 to 0.76). The Linkage Disequilibrium revealed a significant relationship between the T allele of the rs2011077 locus and the A allele of the rs351855 locus, leading to the formation of the T\A haplotype in cases diagnosed with the UCC. Our results show that FGFR4 gene polymorphisms (rs351855 and rs2011077) have significant associations with increased risk of Urothelial Cell Carcinoma., Conclusion: current study indicates that the specific polymorphisms have proven to be promising as a major genetic marker for identifying cases who may be more susceptible to diagnosis and recurrence Urothelial Cell Carcinoma., Competing Interests: Declaration of competing interest None., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: Fibro-epithelial polyps (FEPs) of the ureter are rare benign tumours and constitute an important differential for ureteral urothelial cell carcinoma (UCC). Case presentation: We describe a case of a 56-year-old lady presenting with gross haematuria. On initial evaluation elsewhere, she was diagnosed with lower ureteric UCC and was advised left nephroureterectomy. Careful evaluation at our centre established the diagnosis of a left ureteral FEP. Robot-assisted excision of the ureteral FEP was successfully done. Conclusion: Diagnosis of these rare tumours may be made with a combination of imaging, ureteroscopy and histopathological analysis. Resection of giant FEPs may be done with a robot-assisted technique. Proper diagnosis and management of these tumours are essential to avoid unnecessary nephroureterectomies. Level of evidence: 4 [ABSTRACT FROM AUTHOR]

Bladder urothelial cell carcinoma (UCC) incidence is about three times higher in men compared with women. There are several indications for the involvement of hormonal factors in the aetiology of UCC. Here, we provide evidence of androgen signalling in UCC progression. Microarray and qPCR analysis revealed that the androgen receptor (AR) mRNA level is upregulated in a subset of UCC cases. In an AR‐positive UCC‐derived cell line model, UM‐UC‐3‐AR, androgen treatment increased clonogenic capacity inducing the formation of big stem cell‐like holoclones, while AR knockdown or treatment with the AR antagonist enzalutamide abrogated this clonogenic advantage. Additionally, blockage of AR signalling reduced the cell migration potential of androgen‐stimulated UM‐UC‐3‐AR cells. These phenotypic changes were accompanied by a rewiring of the transcriptome with almost 300 genes being differentially regulated by androgens, some of which correlated with AR expression in UCC patients in two independent data sets. Our results demonstrate that AR signals in UCC favouring the development of an aggressive phenotype and highlights its potential as a therapeutic target for bladder cancer.

Background: About 17%–34% of patients with non‐prostatic genitourinary (GU) cancer had stable disease (SD) as their best response to programmed cell death protein 1/programmed death‐ligand 1 (PD‐1/PD‐L1) inhibitors. However, most efficacy studies of PD‐1/PD‐L1 inhibitors are focused on the response and its durability. Little is known about patients' clinical outcomes with SD as their initial response to PD‐1/PD‐L1 inhibitors. Methods: We retrospectively reviewed the clinical outcomes of patients with renal cell carcinoma (RCC) (n = 102) and urothelial carcinoma (UC) (n = 101) treated with PD‐1/PD‐L1 inhibitors. The duration of SD (DoSD) was calculated for patients who had SD as their best response and was defined from the time of SD to radiologically confirmed progressive disease (PD) or death. Results: Fifty‐five patients (27.1%) had SD as the initial response. Among them, 10 patients (18.2%) achieved a response on subsequent assessments. With a median follow‐up duration of 15.2 months, the median DoSD was 8.5 months (range: 3.2–13.8), which was significantly different according to the disease; 9.4 months in RCC and 2.3 months in UC (p = 0.03). If the disease did not progress in 4 months (long SD subgroup), the DoSD (11.0 months) was comparable to the duration of response (12.9 months) in patients who achieved a complete or partial response to PD‐1/PD‐L1 inhibitors. In addition to the cancer type, the clinical factors associated with short DoSD were liver metastases (p = 0.003), neutrophil‐lymphocyte ratio (NLR) > 4.0 (p = 0.001), and platelet‐lymphocyte ratio (PLR) > 194 (p = 0.003). Conclusion: For RCC patients with SD to PD‐1/PD‐L1 inhibitors, if there are no liver metastases and NLR/PLR is below the certain level, they would have similar duration of disease control and survival benefit as those who achieve the response. [ABSTRACT FROM AUTHOR]

Proteins involved in tumor cell migration can potentially serve as markers of invasive disease. Activated Leukocyte Cell Adhesion Molecule (ALCAM) promotes adhesion, while shedding of its extracellular domain is associated with migration. We hypothesized that shed ALCAM in biofluids could be predictive of progressive disease. ALCAM expression in tumor (n = 198) and shedding in biofluids (n = 120) were measured in two separate VUMC bladder cancer cystectomy cohorts by immunofluorescence and enzyme-linked immunosorbent assay, respectively. The primary outcome measure was accuracy of predicting 3-year overall survival (OS) with shed ALCAM compared to standard clinical indicators alone, assessed by multivariable Cox regression and concordance-indices. Validation was performed by internal bootstrap, a cohort from a second institution (n = 64), and treatment of missing data with multiple-imputation. While ALCAM mRNA expression was unchanged, histological detection of ALCAM decreased with increasing stage (P = 0.004). Importantly, urine ALCAM was elevated 17.0-fold (P < 0.0001) above non-cancer controls, correlated positively with tumor stage (P = 0.018), was an independent predictor of OS after adjusting for age, tumor stage, lymph-node status, and hematuria (HR, 1.46; 95% CI, 1.03-2.06; P = 0.002), and improved prediction of OS by 3.3% (concordance-index, 78.5% vs. 75.2%). Urine ALCAM remained an independent predictor of OS after accounting for treatment with Bacillus Calmette-Guerin, carcinoma in situ, lymph-node dissection, lymphovascular invasion, urine creatinine, and adjuvant chemotherapy (HR, 1.10; 95% CI, 1.02-1.19; P = 0.011). In conclusion, shed ALCAM may be a novel prognostic biomarker in bladder cancer, although prospective validation studies are warranted. These findings demonstrate that markers reporting on cell motility can act as prognostic indicators.

Proteins involved in tumor cell migration can potentially serve as markers of invasive disease. Activated Leukocyte Cell Adhesion Molecule (ALCAM) promotes adhesion, while shedding of its extracellular domain is associated with migration. We hypothesized that shed ALCAM in biofluids could be predictive of progressive disease. ALCAM expression in tumor (n = 198) and shedding in biofluids (n = 120) were measured in two separate VUMC bladder cancer cystectomy cohorts by immunofluorescence and enzyme-linked immunosorbent assay, respectively. The primary outcome measure was accuracy of predicting 3-year overall survival (OS) with shed ALCAM compared to standard clinical indicators alone, assessed by multivariable Cox regression and concordance-indices. Validation was performed by internal bootstrap, a cohort from a second institution (n = 64), and treatment of missing data with multiple-imputation. While ALCAM mRNA expression was unchanged, histological detection of ALCAM decreased with increasing stage (P = 0.004). Importantly, urine ALCAM was elevated 17.0-fold (P < 0.0001) above non-cancer controls, correlated positively with tumor stage (P = 0.018), was an independent predictor of OS after adjusting for age, tumor stage, lymph-node status, and hematuria (HR, 1.46; 95% CI, 1.03-2.06; P = 0.002), and improved prediction of OS by 3.3% (concordance-index, 78.5% vs. 75.2%). Urine ALCAM remained an independent predictor of OS after accounting for treatment with Bacillus Calmette-Guerin, carcinoma in situ, lymph-node dissection, lymphovascular invasion, urine creatinine, and adjuvant chemotherapy (HR, 1.10; 95% CI, 1.02-1.19; P = 0.011). In conclusion, shed ALCAM may be a novel prognostic biomarker in bladder cancer, although prospective validation studies are warranted. These findings demonstrate that markers reporting on cell motility can act as prognostic indicators.

UnlabelledUtilizing a polymorphism ratio sequencing platform, we performed a complete somatic mutation analysis of the mitochondrial D-loop region in 14 urothelial cell carcinomas. A total of 28 somatic mutations, all heteroplasmic, were detected in 8 of 14 individuals (57.1 %). Insertion/deletion changes in unstable mono- and dinucleotide repeat segments comprise the most pervasive class of mutations (9 of 28), while two recurring single-base substitution loci were identified. Seven variants, mostly insertion/deletions, represent population shifts from a heteroplasmic germline toward dominance in the tumor. In four cases, DNA from matched urine samples was similarly analyzed, with all somatic variants present in associated tumors readily detectable in the bodily fluid. Consistent with previous findings, mutant populations in urine were similar to those detected in tumor and in three of four cases were more prominent in urine.Key messagesPRS accurately detects high mtDNA mutations in UCCs and their body fluids. mtDNA mutations are universally heteroplasmic and often appear at low levels. The PRS technology could be a viable approach to develop mitochondrial biomarkers.

Human urothelial cell carcinoma (UCC) and non‐Hodgkin lymphoma are considered environmental cancers in people, but less is known about environment risk for UCC and lymphoma in dogs. The objective of this study was to determine whether dogs with these cancers, compared to unaffected control dogs, live in counties with higher tap water contaminants or higher levels of air pollution as measured by the Environmental Protection Agency (EPA) and by National Air Toxics Assessment chemical exposure risk estimates. Dogs with available home addresses from two previously published case–control populations were included: 66 dogs with UCC and 70 unaffected controls; and 56 boxer dogs with lymphoma and 84 unaffected boxer controls. Tap water total trihalomethanes, which are water disinfection by‐products, were more than threefold higher in UCC case counties of residence compared to controls (p <.0001), and a higher proportion of dogs with UCC lived in counties exceeding EPA ozone limits (41.8%) compared to controls (13.6% p =.0008). More boxers with lymphoma lived in counties exceeding EPA ozone limits (52.1%) compared to controls (29.0%; p =.018), with higher exposure risk estimates for airborne 1,3‐butadiene and formaldehyde (p =.004–.005). These data support the hypothesis that tap water contaminants and airborne environmental pollutants contribute to the risk of both urothelial carcinoma and lymphoma in dogs. If these findings reflect causal relationships, then it is possible that tap water filtration units and more effective air pollution controls could decrease the overall incidence of these cancers in dogs. [ABSTRACT FROM AUTHOR]

Introduction: Accurate prediction of recurrence is important for patients with non-muscle invasive bladder cancer (NMIBC). Objective: To study the association of tumour location with recurrence-free survival (RFS) of patients with primary solitary tumours. Methods: Patients (N=184) with primary, solitary NMIBC (2000–2018). In cases of overlapping areas, the most involved area was selected. Subsequently, the areas were dichotomised into dorsal versus non-dorsal tumours. The dorsal area was defined as the diamond-shaped area bordered by bladder neck, trigone, posterior wall, and orifices. The non-dorsal areas are the lateral walls, dome, and anterior wall. The association of location with RFS was assessed using Cox regression. Median RFS was estimated using the Kaplan–Meier method. Results: Altogether, 25 (14%) and 69 (38%) patients had a recurrence at 1 year and 5 years, respectively. Median RFS was 103 months. Primary tumours located at the anterior wall were associated with the lowest RFS (median: 74 months) and at the posterior wall with highest RFS (median: 133 months). After dichotomisation, 54% of the patients had a tumour in the dorsal area with a median 1-year recurrence rate of 9% versus 19% in the non-dorsal area. Median RFS in the dorsal area was 133 months versus 48 months in the non-dorsal area (p=0.02). Cox analysis showed worse 1- and 5-year RFS on adjusted analysis (hazard ratio [HR]: 2.41; 95% confidence interval [CI]: 1.07–5.46; p=0.04; and HR: 1.77; 95% CI: 1.10–2.85; p=0.02, respectively) for tumours in the non-dorsal area. Conclusion: The tumours in the dorsal area appear to have a lower recurrence rate. There was no association with specific tumour location and RFS.

Most patients with partial intestinal obstruction can be managed without surgical intervention. Here, we report the case of a patient who presented with partial intestinal obstruction. He had been diagnosed with high-grade urothelial cell carcinoma (UCC) 1.5 years previously, for which the surgery and adjuvant chemotherapy had been successfully performed. He showed a poor response to medical treatment for the partial intestinal obstruction, and surgery provided only a short-term benefit. Such cases of intractable small-bowel obstruction are infrequent and pose a challenge to clinicians. Although very rare, the possibility of UCC metastasis to the gastrointestinal tract should be considered in the differential diagnosis of refractory intestinal obstruction and history of UCC.

The benefit of adding neoadjuvant chemotherapy to bladder-sparing chemoradiation for muscle-invasive bladder cancer remains unclear. This retrospective, large database study of 2566 patients found no survival benefit with the addition of neoadjuvant chemotherapy to definitive chemoradiation. These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, which should be investigated under prospective clinical trials. Background: Bladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown. Patients and Methods: We identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias. Results: We identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P = .19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P = .921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation. Conclusion: These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials. [ABSTRACT FROM AUTHOR]

Objectives: To report our urethral surveillance programme and urethral cancer recurrence rate following radical cystoprostatectomy (RC). Patients and methods: A retrospective analysis of clinical and histopathological data of men who underwent RC and urethral surveillance, between January 2011 and October 2016. Results: RC was performed for 491 men; 31 and 19 men had a synchronous (malignancy, n = 10, 32.3%) and interval (malignancy, n = 6, 31.6%) urethrectomy, respectively. The remaining 441 men underwent surveillance; 183 (41.5%) men had at least one urethroscopy, 14 (3.2%) urethrectomies were performed and 12 (2.7%) specimens confirmed urethral recurrence (UR). Within the URs, 7/12 (58.3%) men presented symptomatically and 5/12 (41.7%) were detected through surveillance. At a median (interquartile range) follow-up of 21.8 (9.7–36.7) months, the 2-year disease-specific survival in men who had synchronous urethrectomy was 71.4% (versus no urethrectomy (84.6%) interval urethrectomy (92.9%) and urethrectomy for recurrence (83.8%)). Conclusion: UR following RC is low in men without risk factors for urethral disease. Annual urethroscopy and urine cytology may not be feasible and appropriate in all men after RC, and does not appear to impact survival at 2 years. A risk-adapted approach may allow the avoidance of annual urethroscopy in asymptomatic men post RC. Level of Evidence: 3b [ABSTRACT FROM AUTHOR]

Bladder urothelial cell carcinoma (UCC) incidence is about three times higher in men compared with women. There are several indications for the involvement of hormonal factors in the aetiology of UCC. Here, we provide evidence of androgen signalling in UCC progression. Microarray and qPCR analysis revealed that the androgen receptor (AR) mRNA level is upregulated in a subset of UCC cases. In an AR‐positive UCC‐derived cell line model, UM‐UC‐3‐AR, androgen treatment increased clonogenic capacity inducing the formation of big stem cell‐like holoclones, while AR knockdown or treatment with the AR antagonist enzalutamide abrogated this clonogenic advantage. Additionally, blockage of AR signalling reduced the cell migration potential of androgen‐stimulated UM‐UC‐3‐AR cells. These phenotypic changes were accompanied by a rewiring of the transcriptome with almost 300 genes being differentially regulated by androgens, some of which correlated with AR expression in UCC patients in two independent data sets. Our results demonstrate that AR signals in UCC favouring the development of an aggressive phenotype and highlights its potential as a therapeutic target for bladder cancer. [ABSTRACT FROM AUTHOR]

Background: The modified Glasgow prognostic score (mGPS), a clinical tool that incorporates albumin and C‐reactive protein, has proven useful in the prognostication of multiple cancers. Several immune checkpoint inhibitors (ICIs) have been approved for the treatment of metastatic urothelial cell carcinoma (mUC), but a prognostic biomarker is needed. We investigated the impact of mGPS on survival outcomes in patients with mUC receiving ICIs. Materials and Methods: We retrospectively reviewed patients with mUC treated with ICIs (programmed cell death protein 1 or programmed cell death ligand 1 inhibitors) at Winship Cancer Institute from 2015 to 2018. Overall survival (OS) and progression‐free survival (PFS) were measured from the start date of ICI until death or clinical or radiographic progression, respectively. mGPS was defined as a summary score with one point given for C‐reactive protein >10 mg/L and/or albumin <3.5 g/dL. Univariate (UVA) and multivariate (MVA) analyses were carried out using Cox proportional hazard model. These outcomes were also assessed by Kaplan‐Meier analysis. Results: A total of 53 patients were included with a median follow‐up 27.1 months. The median age was 70 years, with 84.9% male and 20.8% Black. Baseline mGPS was 0 in 43.4%, 1 in 28.3% and 2 in 28.3%. Increased mGPS at the time of ICI initiation was associated with poorer OS and PFS in UVA, MVA, and Kaplan‐Meier analyses. Conclusion: The mGPS may be a useful prognostic tool in patients with mUC when treatment with ICI is under consideration. These results warrant a larger study for validation. Implications for Practice: The ideal prognostic tool for use in a busy clinical practice is easy‐to‐use, cost‐effective, and capable of accurately predicting clinical outcomes. There is currently no universally accepted risk score in metastatic urothelial cell carcinoma (mUC), particularly in the immunotherapy era. The modified Glasgow prognostic score (mGPS) incorporates albumin and C‐reactive protein and may reflect underlying chronic inflammation, a known risk factor for resistance to immune checkpoint inhibitors (ICIs). This study found that baseline mGPS is associated with survival outcomes in patients with mUC treated with ICIs and may help clinicians to prognosticate for their patients beginning immunotherapy. Several immune checkpoint inhibitors have been approved for the treatment of metastatic urothelial cell carcinoma, but a prognostic biomarker is needed. This article reports on the effect of the Glasgow prognostic score on survival outcomes in patients with metastatic urothelial cell carcinoma receiving immune checkpoint inhibitor therapy. [ABSTRACT FROM AUTHOR]

Urothelial cell carcinoma (UCC) is a type of malignant cancer that affects thousands of people worldwide, especially those who smoke and have certain occupational exposures. Plasmacytoid urothelial carcinoma (PUC) is a rare histological variant of UCC that can present aggressively and insidiously. Small bowel obstruction secondary to malignancy is a rare presentation of UCC because the small bowel is a rare site of metastasis. We showcase a patient who presented with small bowel obstruction secondary to high-grade metastatic UCC with plasmacytoid features, exhibiting minimal urologic symptoms and no apparent risk factors. This case highlights the importance of high clinical suspicion for patients with possible malignancies that present with limited or unusual symptomatology and no risk factors. Further research into PUC to understand its symptoms and metastatic pattern is warranted to advance current early diagnostic criteria and further improve patient outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Guzman et al.)

Abstract Background The G protein-coupled bile acid receptor (TGR5) is a cell surface receptor which induces the production of intracellular cAMP and promotes epithelial-mesenchymal transition in gastric cancer cell lines. TGR5 is found in a wide variety of tissues including the kidney. However, the patterns of TGR5 expression have not been well characterized in physiologic kidney or renal neoplasms. We explore the expression of TGR5 in benign renal tissue and renal neoplasms and assess its utility as a diagnostic marker. Methods Sixty-one renal cortical neoplasms from 2000 to 2014 were retrieved. TGR5 protein expression was examined by immunohistochemistry. TGR5 mRNA was also measured by real-time PCR. Results In normal renal tissue, TGR5 was strongly positive in collecting ducts, distal convoluted tubules and thin loop of Henle. Proximal convoluted tubules showed absent or focal weak staining. In clear cell renal cell carcinomas (RCCs), 25 of 27 cases (92%) were negative for TGR5 (p

Chemotherapy and radiotherapy are gold standard treatment for bladder cancer (BC) for over 50 years. The efficacy on early stage BC patients is virtuous. However, patients with aggressive cancer growth benefited less from the therapy. Aberrant p53 was found in more than 50% of high-grade BC patients. Therefore, targeting p53 in a subset of high-grade BC patients expressing aberrant p53 is a promising strategy. In this paper, p53 role in BC carcinogenesis is discussed. Followed by p53-targeting strategies in current BC treatment. Besides, p53-targeting strategies that have been implemented in other types of cancer and their potential to be adapted in BC will be deliberated. Although targeting p53 is promising, none of the strategies studied were successfully implemented in healthcare settings. Restoration of p53 as the guardian of the genome is an exciting area for translational research. It has potential to replace the genotoxic chemotherapy and radiotherapy, thus, eliminating the notorious painful sideeffects on a subset of high-grade BC patients. Searches were performed on PubMed and Google Scholar web using the keywords "bladder cancer" or "urothelial cancer" or "urothelial cell carcinoma" and "p53". Only full papers of research articles and review papers were included for analysis. Papers were categorized as either p53 function, current treatment using p53 and future potential treatment using p53 for details analysis. [ABSTRACT FROM AUTHOR]

Urothelial Cell Carcinoma (UCC), also called transitional cell carcinoma of the bladder, is the most common malignancy in urinary tract. The prognosis of this disease is highly dependent on the histological grading at diagnosis. Fas/CD95 has a role in apoptotic process, whereas HSP70 has an antiapoptotic role. This study aimed to analyze the expression of Fas/CD95 and HSP70 in low grade and high grade urothelial cell carcinoma in the bladder. This was an analytic observational study with cross sectional approach. Population and sample were paraffin blocks of urothelial cell carcinoma in the Laboratory of Anatomic Pathology, Dr. Soetomo Hospital, Surabaya in the period of January 2011-December 2016. Each grading of urothelial cell carcinoma was randomly sampled. Immunohistochemystry with Fas/CD95 and HSP70 were performed. Expression of Fas/CD95 and HSP70 were assessed semiquantitatively. Expression of Fas/CD95 and HSP70 were analyzed using Mann-Whitney test and Spearman test. The results showed there was significant different in expression of Fas/CD95 and HSP70 in low and high grades in urothelial cell carcinoma. There was no significant correlation between the expression of Fas/CD95 and HSP70 in urothelial cell carcinoma. As a conclusion, the role of CD95 and HSP70 expression can be useful as marker for the diagnosis, especially in the determination of the grade of differentiation.

Abstract Background Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates. Methods The phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon’s two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment. Discussion The progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564).

Introduction: Prostate specific membrane antigen (PSMA) has become a target for radionuclide imaging and therapy. Previous studies have shown that the expression of PSMA is not specific to prostate tissue. In this study we examine the expression of PSMA in urothelial cell carcinoma (UCC). Methods: Immunhistochemical PSMA-staining was performed in 89 UCC samples. PSMA expression in tumor tissue, adjacent healthy tissue and blood vessels was examined. We furthermore analyzed PSMA-mRNA expression in nine human UCC cell lines. We correlated our findings with clinical data regarding recurrence and progression of UCC. Results: UCC tissue showed a significantly higher PSMA expression compared to healthy urothelial tissue (p < 0.001). Non muscle invasive bladder cancer revealed significantly higher PSMA expression compared to muscle invasive bladder cancer (p < 0.05). PSMA expression significantly differed between various T-stages (p < 0.05) and tumor differentiation (p < 0.001). In four human UCC cell lines PSMA-mRNA was detectable. Those patients who suffered recurrence showed a higher rate of PSMA expression but no correlation to recurrence-free survival was evident. Progression of disease correlated significantly with a higher PSMA expression (p = 0.036). Conclusions: Both UCC tissue and healthy urothelial tissue express PSMA, with significantly higher levels in UCC. We confirmed these findings in human UCC cell lines. In this small first cohort expression of PSMA correlates significant with progression of disease but not with recurrence and recurrence-free survival. These first results make PSMA a promising target for future diagnosis and therapy of UCC. [ABSTRACT FROM AUTHOR]

Urothelial cell carcinoma (UCC) of the bladder is exceedingly rare in pediatric patients. Limited data are available to guide management in this population. The authors systematically searched MEDLINE, Cochrane Library, and Google Scholar (through February 2019) for case reports and series to summarize data regarding presentation, evaluation, management, and follow-up for patients ≤ 18 years diagnosed with UCC of the bladder. Patient-level data were abstracted, and adjusted logistic regression was used to identify factors associated with a combined outcome of recurrence or death. One hundred two articles describing 243 patients from 26 countries met criteria. Average age was 12.5 years, 32.6% were female, 15.3% had medical comorbidities, and 13.2% had known risk factors for bladder cancer. Initial management was transurethral resection in 95.5% of patients, whereas 6.2% required secondary intervention. Tumor stage was TaN0M0 in 86.4% and low grade in 93.4%. Recurrence and death occurred in 8.6% and 3.7%, respectively. Mean time to recurrence or death was 8.6 months (standard deviation [SD] 7.6) for 10.7%. Mean disease free follow-up without recurrence or death was 56.9 months (SD 54.2) for 89.3%. Patients with comorbidities, risk factors, or family history (odds ratio [OR]: 2.4, 95% confidence interval [CI]: 1.02–5.6); ≥TaN0M0 disease (OR: 6.2, 95% CI: 2.5–15.6); and larger tumors at diagnosis (OR: 1.7, 95% CI: 1.2–2.4) had significantly greater adjusted odds of recurrence or death after initial treatment. Based on pooled results, disease recurrence or death occurred in 10.7% of pediatric patients and within 9 months for most and within 32 months for all patients. This may suggest that low-grade and stage UCC of the bladder in pediatric patients can be systematically monitored for at least 3 years. However, prospective evaluation of this clinical strategy is warranted. [ABSTRACT FROM AUTHOR]

Arsenic is an environmental toxicant with long-term exposure associated with the development of urothelial carcinomas. Our lab has developed an in-vitro model of urothelial carcinoma by exposing the immortal, but non-tumorigenic bladder cell line, the UROtsa, to arsenite (As3+). These transformed cells form tumors in immune-compromised mice, which resemble urothelial carcinomas with components of the tumor exhibiting squamous differentiation. The goal of the present study was to determine the differences in global gene expression patterns between the As3+-transformed UROtsa cells and the urospheres (spheroids containing putative cancer initiating cells) isolated from these cell lines and to determine if the genes involved in the development of squamous differentiation were enriched in the urospheres. The results obtained in this study show an enrichment of genes such as KRT1, KRT5, KRT6A, KRT6B, KRT6C, KRT14 and KRT16 associated with squamous differentiation, a characteristic feature seen in aggressive basal subtypes of urothelial cell carcinoma (UCC) in the urospheres isolated from As3+-transformed UROtsa cells. In addition, there is increased expression of several of the small proline-rich proteins (SPRR) in the urospheres and overexpression of these genes occur in UCC's displaying squamous differentiation. In conclusion, the cancer initiating cells present in the urospheres are enriched with genes associated with squamous differentiation. • UROtsa cells transformed with arsenite show areas of squamous differentiation. • Urospheres are enriched in squamous differentiation and keratinization genes. • There is lack of stability in the urosphere gene expression pattern. • Epigenetic regulation does not play a role in maintaining urosphere gene expression. [ABSTRACT FROM AUTHOR]

B‐group vitamins, as components of the one carbon metabolism pathway, are involved in DNA synthesis, repair and methylation. Our aim was to investigate associations between circulating plasma levels of B vitamins and urothelial cell carcinoma (UCC). We conducted a nested case–control study of UCC within the Melbourne Collaborative Cohort Study. B vitamins were measured in pre‐diagnostic plasma samples. Conditional logistic regression was used to estimate odds ratios (OR) for UCC risk associated with circulating B vitamins in 363 matched cases and controls. In a case‐only analysis (N = 390), hazard ratios (HR) for overall survival associated with plasma B vitamins were estimated using Cox regression. There were no strong associations between UCC risk and pre‐diagnostic levels of plasma B vitamins. No heterogeneity in UCC risk was observed by subtype (invasive or superficial), sex, smoking status or alcohol intake. There was no heterogeneity by country of birth for most B vitamins, except for folate (p‐homogeneity = 0.03). In UCC cases, there were no strong associations between plasma B vitamins and overall survival. We found no associations between pre‐diagnostic plasma concentrations of B‐group vitamins and UCC risk or survival. What's new? B vitamins are involved in DNA synthesis, repair, and methylation, and therefore they might affect cancer risk. While they appear to be protective against some cancers, data on the effect of B‐vitamins on bladder cancer have been inconsistent. In this prospective study, the authors examined levels of circulating B vitamins in patients with urothelial‐cell carcinoma (UCC) and matched controls. However, they found no association between pre‐diagnostic concentrations of B vitamins and UCC risk or survival. [ABSTRACT FROM AUTHOR]

Environmental and occupational exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health effects in humans. Uncertainty exists regarding the causation of urinary bladder cancer by benzo[ a ]pyrene (B[ a ]P) due to a lack of sufficient data. In this work, we focused on in-vitro DNA damage and the formation of micronuclei and chromosomal aberrations as predictors of cancer risk, applying a wide range of dosages and time periods to quantify the onset, intensity, and duration of the response. We chose two urothelial cell types to compare susceptibility and the ability to increase the malignity of a pre-existing bladder cancer: a cancer cell line (T24) and a pooled sample of primary urinary bladder epithelia cells (PUBEC) from pigs. The highest level of DNA damage assessed by comet assay was observed following 24-h treatment in both cell types, whereas PUBEC cells were clearly more susceptible. Even 4-h treatment induced DNA damage in PUBEC cells with benchmark doses of 0.0027 µM B[ a ]P and 0.00023 µM after 4-h and 24-h exposure, respectively. Nearly no effect was observed for periods of 48 h. The frequency of micronucleus formation increased more markedly in T24 cells, particularly with 24-h treatment. In PUBEC cells, 48-h exposure notably induced the formation of nucleoplasmic bridges and nuclear buds. Even though only one biological replicate was studied due to the sophisticated study design, our results give a strong indication of the potential of B[ a ]P to induce and increase malignity in human-relevant cell types. • Wide range of benzo[ a ]pyrene (B[ a ]P) exposure time and dose. • DNA damage caused by benzo[ a ]pyrene in two urothelial cell types – PUBEC and T24. • Comet assay and Micronucleus assay combined to assess DNA damage in urothelial cells caused by B[ a ]P. • Primary urothelial cells more susceptible to B[ a ]P DNA damage than urinary tumor cells. [ABSTRACT FROM AUTHOR]

Intravesical Bacillus Calmette-Guérin (BCG) has long been the gold standard treatment of nonmuscle invasive bladder cancer. Recently, there has been an emergence of novel immunotherapeutic agents, which have shown promise in the treatment of urothelial cell carcinoma. These agents aim to augment, modify, or enhance the immune response. Such strategies include recombinant BCG, monoclonal antibodies, vaccines, gene therapy, and adoptive T-cell therapy. Here, we review the emerging immunotherapeutics in the treatment of nonmuscle invasive bladder cancer.