Bladder Cancer Screening Research Articles

Insights into Porphyromonas somerae in Bladder Cancer Patients: Urinary Detection by ddPCR.

To date, the increased awareness of the impact of microbes on human health has promoted scientific interest in microbiome studies for diagnostic and therapeutic purposes, revealing correlations between specific taxa and cancer. In particular, numerous species of Porphyromonas have been associated with several types of tumors. Previously, we studied the urobiome using Next-Generation Sequencing (NGS), and found an increase in Porphyromonas somerae in first morning urine of subjects affected by bladder cancer (BCa). Here, we aimed to confirm the presence of P. somerae in BCa patients by using droplet digital Polymerase Chain Reaction (ddPCR), testing a cohort of 102 male subjects over 50 years. Our findings showed a significant increase in P. somerae in the urine of the BCa group within both ddPCR and NGS, and a correlation between the two methods was observed at a statistical level. Moreover, P. somerae's identification with ddPCR confirmed a significant association between this bacterium and the presence of BCa, highlighting its potential role as a biomarker. This allows us to propose the ddPCR as a suitable method for first-stage BCa screening and follow-up.

Screening Model for Bladder Cancer Early Detection With Serum miRNAs Based on Machine Learning: A Mixed-Cohort Study Based on 16,189 Participants.

Early detection of bladder cancer (BCa) can have a positive impact on patients' prognosis. However, there is currently no widely accepted method for early screening of BCa. We aimed to develop an efficient, clinically applicable, and noninvasive method for the early screening of BCa by detecting specific serum miRNA levels. A mixed-cohort (including BCa, 12 different other cancers, benign disease patients, and health population) study was conducted using a sample size of 16,189. Five machine learning algorithms were utilized to develop screening models for BCa using the training dataset. The performance of the model was evaluated using receiver operating characteristic curve and decision curve analysis on the testing dataset, and subsequently, the model with the best predictive power was selected. Furthermore, the selected model's screening performance was evaluated using both the validation set and external set. The BCaS3miR model, utilizing only three serum miRNAs (miR-6087, miR-1343-3p, and miR-5100) and based on the KNN algorithm, is the superior screening model chosen for BCa. BCaS3miR consistently performed well in both the testing, validation, and external sets, exceeding 90% sensitivity and specificity levels. The area under the curve was 0.990 (95% CI: 0.984-0.991), 0.964 (95% CI: 0.936-0.984), and 0.917 (95% CI: 0.836-0.953) in the testing, validation, and external set. The subgroup analysis revealed that the BCaS3miR model demonstrated outstanding screening accuracy in various clinical subgroups of BCa. In addition, we developed a BCa screening scoring model (BCaSS) based on the levels of miR-1343-3p/miR-6087 and miR-5100/miR-6087. The screening effect of BCaSS is investigated and the findings indicate that it has predictability and distinct advantages. Using a mixed cohort with the largest known sample size to date, we have developed effective screening models for BCa, namely BCaS3miR and BCaSS. The models demonstrated remarkable screening accuracy, indicating potential for the early detection of BCa.

Total Abnormal Cells in Bladder Cancer Screening: The Role of Artificial Intelligence-Based Logistic Models in Urine Cytology

Total Abnormal Cells in Bladder Cancer Screening: The Role of Artificial Intelligence-Based Logistic Models in Urine Cytology

Optimizing Z-Stack Plane Selection within Urothelial Clusters in 3D Urine Cytology via AI to Improve Bladder Cancer Screening and Surveillance: Ongoing Multicenter Study

Optimizing Z-Stack Plane Selection within Urothelial Clusters in 3D Urine Cytology via AI to Improve Bladder Cancer Screening and Surveillance: Ongoing Multicenter Study

A Comprehensive Review of Advancements in Bladder Cancer Screening: Harnessing Mathematics and Artificial Intelligence for Early Detection and Personalized Management

A Comprehensive Review of Advancements in Bladder Cancer Screening: Harnessing Mathematics and Artificial Intelligence for Early Detection and Personalized Management

Exploring the DNA Methylation Profile of Genes Associated with Bladder Cancer in Bladder Tissue of Patients with Neurogenic Lower Urinary Tract Dysfunction.

DNA methylation is an epigenetic process that commonly occurs in genes' promoters and results in the transcriptional silencing of genes. DNA methylation is a frequent event in bladder cancer, participating in tumor initiation and progression. Bladder cancer is a major health issue in patients suffering from neurogenic lower urinary tract dysfunction (NLUTD), although the pathogenetic mechanisms of the disease remain unclear. In this population, bladder cancer is characterized by aggressive histopathology, advanced stage during diagnosis, and high mortality rates. To assess the DNA methylation profiles of five genes' promoters previously known to be associated with bladder cancer in bladder tissue of NLUTD patients, we conducted a prospective study recruiting NLUTD patients from the neuro-urology unit of a public teaching hospital. Cystoscopy combined with biopsy for bladder cancer screening was performed in all patients following written informed consent being obtained. Quantitative methylation-specific PCR was used to determine the methylation status of RASSF1, RARβ, DAPK, hTERT, and APC genes' promoters in bladder tissue samples. Twenty-four patients suffering from mixed NLUTD etiology for a median duration of 10 (IQR: 12) years were recruited in this study. DNA hypermethylation was detected in at least one gene of the panel in all tissue samples. RAR-β was hypermethylated in 91.7% samples, RASSF and DAPK were hypermethylated in 83.3% samples, APC 37.5% samples, and TERT in none of the tissue samples. In 45.8% of the samples, three genes of the panel were hypermethylated, in 29.2% four genes were hypermethylated, and in 16.7% and in 8.3% of the samples, two and one gene were hypermethylated, respectively. The number of hypermethylated genes of the panel was significantly associated with recurrent UTIs (p = 0.0048). No other significant association was found between DNA hypermethylation or the number of hypermethylated genes and the clinical characteristics of the patients. Histopathological findings were normal in 8.3% of patients, while chronic inflammation was found in 83.3% of patients and squamous cell metaplasia in 16.7% of patients. In this study, we observed high rates of DNA hypermethylation of genes associated with bladder cancer in NLUTD patients, suggesting an epigenetic field effect and possible risk of bladder cancer development. Recurrent UTIs seem to be associated with increased DNA hypermethylation. Further research is needed to evaluate the impact of recurrent UTIs and chronic inflammation in DNA hypermethylation and bladder cancer etiopathogenesis in NLUTD patients.

Abstract IA020: AI-powered tool for rapid & reliable bladder cancer screening and surveillance: multicenter validation efforts

Abstract Bladder cancer is the most recurrent form of cancer, requiring frequent screening and surveillance, which contributes to its status as the costliest per capita. While urine cytology serves as a crucial adjunct to invasive cystoscopy, it is high volume, labor-intensive, and relatively inconsistent. Despite the implementation of The Paris System, which introduced updated quantitative guidelines, implementation of digital tools for urine cytology still trails the technological advancements seen in semi-automated Pap smear screenings. This lag can be attributed to the diverse cytomorphology of urine specimens and variation in specimen preparation and screening. Our team has developed AutoParis-X (APX), a state-of-the-art technology leveraging deep learning algorithms to extract objective (e.g., nucleus-to-cytoplasm ratio) and subjective (e.g., hyperchromasia) features from whole slide images (WSI). APX transforms these features into the Atypia Burden Score (ABS), offering a quantitative assessment of malignancy and recurrence risks on a scale from 0 to 1. Initially validated with 1300 samples (ThinPrep; Leica Aperio GT450) at Dartmouth Hitchcock, achieving an AUROC of 0.9, APX has evolved into APX-WEB, a user-friendly, web-based tool for cytopathologists. Notable challenges persist, including: 1) validating across nationally representative cohorts with varied specimen preparations and imaging, 2) addressing the intricacies of z-stacking for imaging non-monolayer preparations, and 3) integration of genomics to heighten the sensitivity of imaging assays. This study aimed to establish a performance baseline for APX's adaptability to these challenges without algorithmic adjustments. APX was applied across three distinct cohorts: 1) a preliminary national validation on 500 ThinPrep WSI in collaboration with Hologic; 2) assessment on non-monolayer specimen preparations (e.g., SurePath), using z-stacking, conducted with Johns Hopkins (n=100 WSI); and 3) a pilot study at Dartmouth (n=19) for integrating APX's imaging features with whole exomic sequencing (WES). Preliminary findings indicate: 1) Promising performance on a held-out Hologic national cohort (sensitivity=0.87, specificity=0.73; original APX study: sensitivity=0.88, specificity=0.83). 2) In SurePath z-stack WSI, the number of detected urothelial cells per cluster decreased with distance from the focus plane (rho =-0.13, p<0.001). 3) Of eight cases deemed negative or atypical by cytology, three exhibited TERT mutations, suggesting subclinical recurrence, in contrast to the consistent findings in all nine suspicious or positive cases. This highlights the potential of integrating genomics with image-based classifiers to enhance diagnostic precision. The findings underscore the need for future multicenter work aimed at refining machine learning models to achieve enhanced predictive performance across various operational parameters and settings, facilitating their implementation. Citation Format: Joshua Levy, Keluo Yao, Jonathan Marotti, Darcy Kerr, Edward Gutmann, Sam Harvey, Yoseph Sayegh, Chris VandenBussche, Michael Quick, Peter Costa, Lauren Wainman, Donald Green, Parth Shah, Xiaoying Liu, Louis Vaickus. AI-powered tool for rapid & reliable bladder cancer screening and surveillance: multicenter validation efforts [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 IA020.

Enzyme-labeled liquid-based cytology (ELLBC): a new noninvasive diagnostic method for bladder cancers

BackgroundBased on liquid-based cytology, we performed an enzyme histochemical staining using acid phosphatase as a marker and termed it ELLBC. The aim of this study was to investigate the value of ELLBC in the diagnosis of bladder cancer.MethodsFifty patients who were initially diagnosed with suspected bladder cancers (hematuria or bladder irritation symptoms, urinary ultrasound suggestive of bladder mass) at the Second Affiliated Hospital of Anhui Medical University (Anhui, China) from January 2022 to December 2022 were selected as the study subjects, all of whom underwent ELLBC, CC, and histopathology Histopathology was used as the gold standard to calculate the diagnostic efficacy of ELLBC, CC and ELLBC combined with CC in bladder cancer.ResultsHistopathological examination revealed 35 positive cases in 50 patients, including 15 cases of high-grade uroepithelial carcinoma (HGUC) and 20 cases of low-grade uroepithelial carcinoma (LGUC.) The sensitivity of ELLBC was 82.86%, the specificity was 93.33%, the positive predictive value (PPV) was 96.67%, the negative predictive value (NPV) was 70.00%, and the accuracy was 86.00%; CC had a sensitivity of 37.14%, specificity of 80.00%, PPV of 81.25%, NPV of 35.29%, and accuracy of 50%; ELLBC combined with CC had a sensitivity of 88.57%, specificity of 73.33%, PPV of 88.57%, NPV of 73.33%, and accuracy of 84.00%. The sensitivity and specificity of ELLBC were higher than that of CC, and the difference was statistically significant (p < 0.05), ELLBC combined with CC achieved higher sensitivity, but the diagnostic accuracy decreased. For clinical staging, the diagnostic accuracy was 86.36% for ELLBC and 40.91% for CC in patients in Stage I, and 90.91% for ELLBC and 36.36% for CC in patients in Stage II.ConclusionELLBC has high clinical application value for the diagnosis of bladder cancer and can provide new options and methods for the early screening of bladder cancer.

Exploration of potential biomarkers for early bladder cancer based on urine proteomics.

Bladder cancer is a common malignant tumor of the urinary system. The progression of the condition is associated with a poor prognosis, so it is necessary to identify new biomarkers to improve the diagnostic rate of bladder cancer. In this study, 338 urine samples (144 bladder cancer, 123 healthy control, 32 cystitis, and 39 upper urinary tract cancer samples) were collected, among which 238 samples (discovery group) were analyzed by LC-MS. The urinary proteome characteristics of each group were compared with those of bladder cancer, and the differential proteins were defined by bioinformatics analysis. The pathways and functional enrichments were annotated. The selected proteins with the highest AUC score were used to construct a diagnostic panel. One hundred samples (validation group) were used to test the effect of the panel by ELISA. Compared with the healthy control, cystitis and upper urinary tract cancer samples, the number of differential proteins in the bladder cancer samples was 325, 158 and 473, respectively. The differentially expressed proteins were mainly related to lipid metabolism and iron metabolism and were involved in the proliferation, metabolism and necrosis of bladder cancer cells. The AUC of the panel of APOL1 and ITIH3 was 0.96 in the discovery group. ELISA detection showed an AUC of 0.92 in the validation group. This study showed that urinary proteins can reflect the pathophysiological changes in bladder cancer and that important molecules can be used as biomarkers for bladder cancer screening. These findings will benefit the application of the urine proteome in clinical research.

The causal relationship between osteoarthritis and bladder cancer: A Mendelian randomization study.

The causal association between osteoarthritis (OA) and bladder cancer remains unclear. This Mendelian randomization (MR) study was carried out to assess the potential causal effects of any OA, knee OA and hip OA, and bladder cancer. Genome-wide association study (GWAS) summary data for OA and bladder cancer were obtained in GWAS CATALOG, UK Biobank, and FinnGen Consortium. Inverse-variance weighted (IVW) approach was primarily conducted to evaluate the causal relationships between OA and bladder cancer, and MR-Egger intercept and Cochran's Q test were mainly used to estimate heterogeneity and pleiotropy. MR-PRESSO was used to test the presence of horizontal outliers. Leave-one-out analysis was utilized to ensure the reliability of the results. A higher genetic predisposition to any OA has a causal association with bladder cancer risk, while neither knee OA nor hip OA is causally linked to bladder cancer. MR-Egger intercept analysis exhibited that any OA and knee OA had no pleiotropic effect on the risk of bladder cancer, and Cochran's Q test showed that any OA, knee OA and hip OA had no heterogeneity on bladder cancer risk. Neither MR PRESSO analysis nor leave-one-out analysis revealed any outlier SNPs. This MR study exhibited a positive cause-and-effect relationship between any type of OA and bladder cancer risk, but not between site-specific OA, knee OA and hip OA, and bladder cancer. Attention should be paid to the screening and prevention of bladder cancer in OA patients at any site.

Heterogeneous MXene Hybrid-Oriented Exosome Isolation and Metabolic Profiling for Early Screening, Subtyping and Follow-up Evaluation of Bladder Cancer.

Exosome metabolite-based noninvasive liquid biopsy is an emerging research hotspot that tends to substitute current means in clinics. Nanostructure-based mass spectrometry enables continuous exosome isolation and metabolic profiling with superior analysis speed and high efficiency. Herein, we construct a heterogeneous MXene hybrid that possesses ternary binding sites for exosome capture and outstanding matrix performance for metabolite analysis. Upon optimizing experimental conditions, the average extraction of exosomes and their metabolic patterns from a 60 mL urine sample is completed within 45 s (40 samples per batch for 30 min). According to the exosomal metabolic patterns and the subsequently established biomarker panel, we distinguish early bladder cancer (BCa) from healthy controls with an area under the curve (AUC) value greater than 0.995 in model training and validation sets. As well, we realize subtype classification of BCa in the blind test on metabolic patterns, with an AUC value of 0.867. We also explore the significant biomarkers that are sensitive to follow-up patients, which indeed present reverse change levels compared with pathological progression. This study has the potential to guide the development of the liquid biopsy approach.

Increased Incidence of Melanoma, Prostate, Lung, Bladder, Renal and Thyroid Cancer after Diagnosis of Primary Cutaneous B-Cell Lymphoma: A SEER Database Analysis

Background: Primary cutaneous B-cell lymphomas (PCBCLs) are a subset of non-Hodgkin lymphomas originating in the skin. The risk of developing other malignancies in PCBCL patients is not known. We evaluated the risk of developing a second primary malignancy after a PCBCL diagnosis. Methods: We utilized the surveillance, epidemiology, and end results (SEER-17) data registry of 9,208,295 patients from 2000-2020 to generate a cohort of 5,435 patients with PCBCL to identify patients at risk for a second primary malignancy. Relative risk was calculated by using the Standardized Incidence Ratio (SIR), defined as the ratio between observed cases (O) and expected cases (E) of malignancies (SIR = O/E). Statistical significance was established based on 95% confidence intervals (CI). Results: Of the 5,435 patients with PCBCL, 847 (16%) received diagnoses of a second malignancy, identifying a higher risk than the general population (SIR, 1.54; 95% CI, 1.43-1.64). Males had a higher chance of developing prostate cancer (SIR, 1.29; 95% CI, 1.07-1.54), melanoma (SIR, 1.49; 95% CI, 1.03-2.09), and bladder cancer (SIR, 1.42; 95% CI, 1.01-1.94). Females were more predisposed to cancers of the lung (SIR, 1.69; 95% CI, 1.25-2.24), thyroid (SIR, 3.06; 95% CI, 1.63-5.23), and kidney (SIR, 2.13; 95% CI 1.06-3.81). For males with PCBCL, there was an increased risk of prostate cancer in patients 60-69 (SIR, 1.53; 95% CI, 1.14-2.02). For females, there was an increased risk of lung cancer in patients over 70, especially in the age group of 70-79 (SIR, 1.84; 95% CI, 1.12-2.84). For cutaneous melanoma, bladder, renal, and thyroid cancer, there was no age group identified to be at a significantly greater risk. Prostate cancer risk was increased within the first year (SIR, 2.09; 95% CI, (1.28 - 3.23) and between 5-10 years after PCBCL diagnosis (SIR, 1.45; 95% CI, 1.04-1.97) .For males, melanoma and bladder cancer were associated with an increased risk between 1-5 years after PCBCL (SIR, 1.91; 95% CI, 1.09-3.11 and SIR, 1.7; 95% CI, 1.01-2.68). Females were at the highest risk of developing thyroid cancer within the first year of PCBCL diagnosis (SIR, 21.11; 95% CI, 10.12-38.83) and lung cancer 1-5 years after PCBCL diagnosis (SIR, 1.7; 95% CI, 1.04-2.62). For renal cancer, there was no latency identified carrying an increased risk. Conclusion: These data, should inform screening strategies for melanoma, prostate, bladder, lung, renal, and thyroid cancer in patients with PCBCL. Males 60-69 within 10 years of PCBCL can benefit from prostate screening. Males within 1-5 years of PCBCL diagnosis can benefit from screening for melanoma and bladder cancer. Females can benefit from thyroid, lung, and renal cancer surveillance. Specifically for females over 70, screening for lung cancer should be considered, and for females within the first year of PCBCL diagnosis, thyroid cancer screening should be considered.

Association between cigarette smoke exposure and urinary bladder cancer in Scottish terriers in a cohort study

Canine urothelial carcinoma (UC) initially responds favorably to treatment, but is ultimately lethal in most cases. Research to identify modifiable risk factors to prevent the cancer is essential. The high breed-associated risk for UC, e.g. 20-fold higher in Scottish terriers, can facilitate this research. The objective was to identify environmental and host factors associated with UC in a cohort of Scottish terriers. Information was obtained through dog owner questionnaires for 120 Scottish terriers ≥ 6 years old participating in a bladder cancer screening study, with comparisons made between dogs that did or did not develop UC during the 3 years of screening. Univariable models were constructed, and variables with P < 0.20 were included when building the multivariable model, and then removed using a backward stepwise procedure. P < 0.05 was considered statistically significant. Urine cotinine concentrations were measured by liquid chromatography-mass spectrometry to further investigate potential cigarette smoke exposure. Biopsy-confirmed UC which was found in 32 of 120 dogs, was significantly associated with the dogs living in a household with cigarette smokers (odds ratio [OR], 6.34; 95 % confidence intervals [CI], 1.16–34.69; P = 0.033), living within a mile of a marsh or wetland (OR, 21.23; 95 % CI, 3.64–123.69; P = 0.001), and history of previous bladder infections (OR, 3.87; 95 % CI, 1.0–14.98; P = 0.050). UC was diagnosed in 18 of 51 dogs (35.3 %) with quantifiable cotinine concentrations, and six of 40 dogs (15.0 %) without quantifiable cotinine concentrations in their urine (P = 0.0165). In conclusion, the main modifiable risk factor for UC in this cohort of dogs was exposure to second-hand tobacco smoke.

Molecular Markers for Bladder Cancer Screening: An Insight into Bladder Cancer and FDA-Approved Biomarkers.

Bladder cancer is one of the most financially burdensome cancers globally, from its diagnostic to its terminal stages. The impact it imposes on patients and the medical community is substantial, exacerbated by the absence of disease-specific characteristics and limited disease-free spans. Frequent recurrences, impacting nearly half of the diagnosed population, require frequent and invasive monitoring. Given the advancing comprehension of its etiology and attributes, bladder cancer is an appealing candidate for screening strategies. Cystoscopy is the current gold standard for bladder cancer detection, but it is invasive and has the potential for undesired complications and elevated costs. Although urine cytology is a supplementary tool in select instances, its efficacy is limited due to its restricted sensitivity, mainly when targeting low-grade tumors. Although most of these assays exhibit higher sensitivity than urine cytology, clinical guidelines do not currently incorporate them. Consequently, it is necessary to explore novel screening assays to identify distinctive alterations exclusive to bladder cancer. Thus, integrating potential molecular assays requires further investigation through more extensive validation studies. Within this article, we offer a comprehensive overview of the critical features of bladder cancer while conducting a thorough analysis of the FDA-approved assays designed to diagnose and monitor its recurrences.

Systematic Evaluation of Imaging Features of Early Bladder Cancer Using Computed Tomography Performed before Pathologic Diagnosis.

Bladder cancer is the sixth most common malignancy in the United States (US). Despite its high prevalence and the significant potential benefits of early detection, no reliable, cost-effective screening algorithm exists for asymptomatic patients at risk. Nonetheless, reports of incidentally identified early bladder cancer on CT/MRI scans performed for other indications are emerging in the literature. This represents a new opportunity for early detection, with over 80 million CT scans performed in the US yearly, 40% of which are abdominopelvic CTs. This investigation aims to define the imaging features of early bladder cancer, with the mission of facilitating early diagnosis. Following IRB approval with a waiver of informed consent, a retrospective review was performed, identifying 624 patients with non-muscle-invasive bladder cancer diagnosed at Johns Hopkins Hospital between 2000 and 2019. Of these patients, 99 patients underwent pelvic CT within the 5 years preceding pathologic diagnosis. These imaging studies were reviewed retrospectively to evaluate for the presence and features of any focal bladder wall abnormality. Median age at the time of pathologic diagnosis was 70 years (range: 51-88 years), and 82% (81/99) of patients were male. A total of 226 CT studies were reviewed. The number of studies per patient ranged from 1 to 33. Median time interval between all available imaging and pathologic diagnosis was 14 months. A total of 62% (141/226) of the scans reviewed were performed for indications other than suspected urinary tract cancer (UTC). A bladder wall mass was visualized in 67% (66/99) of patients and on 35% (78/226) of scans performed before diagnosis. The majority (84%, 67/80) of masses were intraluminal. Mean transverse long- and short-axis measurements were 24 mm and 17 mm, respectively, with long dimension measurements ranging between 5 and 59 mm. Early bladder cancer was visualized on CT preceding pathologic diagnosis in more than 2/3 of patients, and the majority of scans were performed for indications other than suspected urinary tract cancer/UTC symptoms. These results suggest that cross-sectional imaging performed for other indications can serve as a resource for opportunistic bladder cancer screening, particularly in high-risk patients.

Protocol for the YORKSURe prospective multistage study testing the feasibility for early detection of bladder cancer in populations with high disease-specific mortality risk

IntroductionAround 25% of patients with bladder cancer (BCa) present with invasive disease. Non-randomised studies of population-based screening have suggested reductions in BCa-specific mortality are possible through earlier detection. The low...

Genome-wide exploration of genetic interactions for bladder cancer risk.

Although GWASs have been conducted to investigate genetic variation of bladder tumorigenesis, little is known about genetic interactions that may influence bladder cancer (BC) risk. By leveraging large-scale participants from UK Biobank, we established a discovery database with 4000 Caucasian participants (2000 cases vs 2000 non-cases), a database with 1648 Caucasian participants (824 cases vs 824 non-cases) and 856 non-Caucasian participants (428 cases vs 428 non-cases) as validation. We then performed a genome-wide SNP-SNP interaction investigation related to BC risk based a machine learning approach (ie, GenEpi). Moreover, we used the selected interactions to build a BC screening model with an integrated interaction-empowered polygenic risk score (iPRS) based on Cox proportional hazard model. With Bonferroni correction, we identified 10 statistically significant pairs of SNPs, which located in 17 chromosomes. Of these, four SNP-SNP interactions were found to be positively associated with BC risk among Caucasian participants (ORs 1.57-2.03), while six SNP-SNP interactions showed negatively associated with BC risk (ORs 0.54-0.65). Only four of the SNP-SNP interactions were consistently identified in non-Caucasian participants located in ST7L-ADSS2, FHIT-CHDH, LARP4B-LHPP and RBFOX3-MPRIP. In addition, the iPRS showed a HR of 1.81 (95% CI: 1.46-2.09) compared the highest tertile to the lowest tertile, with an enhanced AUC (0.91; 95% CI:0.85-0.97) than PRS (AUC: 0.86; 95% CI:0.76-0.95; P-DeLong test = 2.2 × 10-4 ). In summary, this study identified several important SNP-SNP interactions for BC risk, and developed an iPRS model for BC screening, which may help to identify the people at high-risk state of BC before early manifestation.

A Study of DNA Methylation of Bladder Cancer Biomarkers in the Urine of Patients with Neurogenic Lower Urinary Tract Dysfunction.

Background: Bladder cancer (BCa) in patients suffering from neurogenic lower urinary tract dysfunction (NLUTD) is a significant concern due to its advanced stage at diagnosis and high mortality rate. Currently, there is a scarcity of specific guidelines for BCa screening in these patients. The development of urine biomarkers for BCa seems to be an attractive non-invasive method of screening or risk stratification in this patient population. DNA methylation is an epigenetic modification, resulting in the transcriptional silencing of tumor suppression genes, that is frequently detected in the urine of BCa patients. Objectives: We aimed to investigate DNA hypermethylation in five gene promoters, previously associated with BCa, in the urine of NLUTD patients, and in comparison with healthy controls. Design, setting and participants: This was a prospective case-control study that recruited neurourology outpatients from a public teaching hospital who had suffered from NLUTD for at least 5 years. They all underwent cystoscopy combined with biopsy for BCa screening following written informed consent. DNA was extracted and DNA methylation was assessed for the RASSF1, RARβ, DAPK, TERT and APC gene promoters via quantitative methylation-specific PCR in urine specimens from the patients and controls. Results: Forty-one patients of mixed NLUTD etiology and 35 controls were enrolled. DNA was detected in 36 patients' urine specimens and in those of 22 controls. In the urine specimens, DNA was hypermethylated in at least one of five gene promoters in 17/36 patients and in 3/22 controls (47.22% vs. 13.64%, respectively, p = 0.009). RASSF1 was hypermethylated in 10/17 (58.82%) specimens with detected methylation, APC in 7/17 (41.18%), DAPK in 4/17 (23.53%), RAR-β2 in 3/17 (17.56%) and TERT in none. According to a multivariate logistic regression analysis, NLUTD and male gender were significantly associated with hypermethylation (OR = 7.43, p = 0.007 and OR = 4.21; p = 0.04, respectively). In the tissue specimens, histology revealed TaLG BCa in two patients and urothelial squamous metaplasia in five patients. Chronic bladder inflammation was present in 35/41 bladder biopsies. Conclusions: DNA hypermethylation in a panel of five BCa-associated genes in the urine was significantly more frequent in NLUTD patients than in the controls. Our results warrant further evaluation in longitudinal studies assessing the clinical implications and possible associations between DNA hypermethylation, chronic inflammation and BCa in the NLUTD population.

Large-scale validation study of an improved semiautonomous urine cytology assessment tool: AutoParis-X.

Adopting a computational approach for the assessment of urine cytology specimens has the potential to improve the efficiency, accuracy, and reliability of bladder cancer screening, which has heretofore relied on semisubjective manual assessment methods. As rigorous, quantitative criteria and guidelines have been introduced for improving screening practices (e.g., The Paris System for Reporting Urinary Cytology), algorithms to emulate semiautonomous diagnostic decision-making have lagged behind, in part because of the complex and nuanced nature of urine cytology reporting. In this study, the authors report on the development and large-scale validation ofa deep-learning tool, AutoParis-X, whichcan facilitate rapid, semiautonomous examination of urine cytology specimens. The results of this large-scale, retrospective validation study indicate that AutoParis-X can accurately determine urothelial cell atypia and aggregate a wide variety of cell-related and cluster-related information across a slide to yield an atypia burden score, which correlates closely with overall specimen atypia and is predictive of Paris system diagnostic categories. Importantly, this approach accounts for challenges associated with the assessment of overlapping cell cluster borders, which improve the ability to predict specimen atypia and accurately estimate the nuclear-to-cytoplasm ratio for cells in these clusters. The authors developed a publicly available, open-source, interactive web application that features a simple, easy-to-use display for examining urine cytology whole-slide images and determining the level of atypia in specific cells, flagging the most abnormal cells for pathologist review. The accuracy of AutoParis-X (and other semiautomated digital pathology systems) indicates that these technologies are approaching clinical readiness and necessitates full evaluation of these algorithms in head-to-head clinical trials.

The Impact of the Initial Clinical Presentation of Bladder Cancer on Histopathological and Morphological Tumor Characteristics

This study investigated the impact of the initial clinical presentation of bladder cancer on tumor characteristics. A cross-sectional, retrospective study was performed, and it involved 515 patients who underwent transurethral bladder cancer resection at the University Hospital Center Split between April 2019 and April 2023, excluding recurrent cases. The association between symptomatic versus asymptomatic presentation and bladder cancer characteristics was analyzed. A subgroup analysis compared tumor characteristics between patients with gross and microscopic hematuria. Multiple regression analyses revealed a significant association between symptomatic presentation and the detection of high-grade bladder cancer (OR 3.43, 95% CI 2.22–5.29, p &lt; 0.001), concomitant CIS (OR 3.41, 95% CI 1.31–8.88, p = 0.012), T2 stage bladder cancer (OR 5.79, 95% CI 2.45–13.71, p &lt; 0.001), a higher number of tumors (IRR 1.24, 95% CI 1.07–1.45, p = 0.005), and larger tumor size (B 1.68, 95% CI 1.19–2.18, p &lt; 0.001). In the subgroup analysis, gross hematuria was associated with the detection of high-grade bladder cancer (OR 2.07, 95% CI 1.12–3.84, p = 0.020), T2 stage bladder cancer (OR 6.03, 95% CI 1.42–25.49, p = 0.015), and larger tumor size (B 1.8, 95% CI 0.99–2.6, p &lt; 0.001). The identified associations between symptomatic presentation and unfavorable bladder cancer characteristics, likely attributed to early detection in asymptomatic cases, underscore the importance of additional research in the development of bladder cancer screening strategies.