Mutational signature and prognosis in adenocarcinoma of the bladder.

Adenocarcinoma of the bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here, we aimed to reveal the mutational and transcriptomic landscapes of adenocarcinoma of the bladder and assess any relationship with prognosis. Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of the bladder were enrolled. These included 16 patients with primary bladder adenocarcinomas and seven patients with urachal adenocarcinoma. Whole exome sequencing (16 patients), whole genome sequencing (16 patients), bulk RNA sequencing (RNA-seq) (19 patients), and single-cell RNA-seq (5 patients) were conducted for the specimens. Correlation analysis, survival analysis, and t-tests were also performed. Prevalent T>A substitutions were observed among somatic mutations, and major trinucleotide contexts included 5'-CTC-3' and 5'-CTG-3'. This pattern was mainly contributed by COSMIC signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes were also enriched in the KEGG term 'chemical carcinogenesis'. Transcriptomic analysis suggested high immune cell infiltration and luminal-like features in the majority of samples. Interestingly, a small fraction of samples with an APOBEC-derived mutational signature exhibited a higher risk of disease progression compared with samples with only a chemical carcinogen-related signature, confirming the molecular and prognostic heterogeneity of bladder adenocarcinoma. This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and indicates that a chemical carcinogen-related mutational signature may be related to a better prognosis compared with an APOBEC signature in adenocarcinoma of the bladder. © 2024 The Pathological Society of Great Britain and Ireland.

Synergistic induction of tertiary lymphoid structures by chemoimmunotherapy in bladder cancer.

BACKGROUND: A substantial number of patients with bladder cancer fail to benefit from immune checkpoint inhibitors (ICIs). We aim to investigate whether the addition of other therapeutic modalities into immunotherapy may augment the immune reactivity, thereby improving the overall response rate. METHODS: We conducted a comprehensive assessment of the immunological changes following immunotherapy and chemotherapy, employing both single-cell RNA sequencing and bulk RNA sequencing analyses. RESULTS: The bladder cancer patient treated with ICIs exhibited a higher abundance of B cells and T follicular helper cells compared to the treatment-naïve patient. Analysis of public datasets and the in-house RJBLC-I2N003 cohort revealed the induction of tertiary lymphoid structure (TLS) neogenesis and maturation by immunotherapy. The IMvigor 210 study suggested that TLS could serve as a predictor of immunotherapy response and patient prognosis. In addition, genome-wide transcriptome data unveiled a shift towards the immune-enriched subtype over the desert subtype in patients receiving neoadjuvant chemotherapy. Notably, the proportions of CD20 + B cells, T follicular helper cells, and TLSs were significantly increased. In patients treated with a combination of neoadjuvant chemotherapy and ICIs, TLS positivity and maturity were improved compared to the baseline. Furthermore, neoadjuvant chemoimmunotherapy resulted in a higher rate of pathological complete response compared to monotherapies. CONCLUSIONS: This work pinpointed the individual effect of immunotherapy and chemotherapy in fostering TLS development, and underscored the superior effectiveness of combined modalities in enhancing TLS maturation and response rates.

Long-Term Outcomes of Orthotopic Neobladder Versus Ileal Conduit Urinary Diversion in Robot-Assisted Radical Cystectomy (RARC): Multicenter Results from the Asian RARC Consortium.

PURPOSE: Robot-assisted radical cystectomy (RARC) has gained traction in the management of muscle invasive bladder cancer. Urinary diversion for RARC was achieved with orthotopic neobladder and ileal conduit. Evidence on the optimal method of urinary diversion was limited. Long-term outcomes were not reported before. This study was designed to compare the perioperative and oncological outcomes of ileal conduit versus orthotopic neobladder cases of nonmetastatic bladder cancer treated with RARC. PATIENTS AND METHODS: The Asian RARC consortium was a multicenter registry involving nine Asian centers. Consecutive patients receiving RARC were included. Cases were divided into the ileal conduit and neobladder groups. Background characteristics, operative details, perioperative outcomes, recurrence information, and survival outcomes were reviewed and compared. Primary outcomes include disease-free and overall survival. Secondary outcomes were perioperative results. Multivariate regression analyses were performed. RESULTS: From 2007 to 2020, 521 patients who underwent radical cystectomy were analyzed. Overall, 314 (60.3%) had ileal conduit and 207 (39.7%) had neobladder. The use of neobladder was found to be protective in terms of disease-free survival [Hazard ratio (HR) = 0.870, p = 0.037] and overall survival (HR = 0.670, p = 0.044) compared with ileal conduit. The difference became statistically nonsignificant after being adjusted in multivariate cox-regression analysis. Moreover, neobladder reconstruction was not associated with increased blood loss, nor additional risk of major complications. CONCLUSIONS: Orthotopic neobladder urinary diversion is not inferior to ileal conduit in terms of perioperative safety profile and long-term oncological outcomes. Further prospective studies are warranted for further investigation.

Integrated longitudinal circulating tumor DNA profiling predicts immunotherapy response of metastatic urothelial carcinoma in the POLARIS-03 trial.

Non-invasive biomarkers for immunotherapy response remain a compelling unmet medical need. POLARIS-03 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-programmed cell death 1) in refractory metastatic urothelial carcinoma (mUC). We assessed the predictive utility of longitudinal circulating tumor DNA (ctDNA) analysis from a single-institution biomarker cohort. Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled. Serial plasma specimens were obtained at baseline and then every two cycles during treatment. The 600-gene panel (PredicineATLAS™) liquid biopsy assay was applied to probe somatic variants and cancer cell fraction (CCF). Low-pass whole genome sequencing was used to determine the copy number abnormality (CNA) score. Across the entire cohort, we observed different degrees of concordance between somatic aberrations detected by ctDNA and those inferred by matched tumor samples. Although the baseline CCF or CNA had limited predictive value, early ctDNA response at week 8 was associated with toripalimab efficacy and prolonged patient survival. Integrating CCF and CNA decrease achieved a superior accuracy of 90.5% in classifying responders and non-responders and predicted long-term benefit from toripalimab. Dynamic changes in the CCF and CNA in blood exquisitely reflected radiographic assessment of malignant lesions, including those with FGFR3-TACC3 gene fusion or microsatellite instability. This study demonstrates the feasibility and effectiveness of integrated longitudinal ctDNA profiling as a potential biomarker in mUC patients undergoing immunotherapy and supports further clinical evaluation of minimally invasive liquid biopsy assays for treatment stratification and therapy monitoring. © 2023 The Pathological Society of Great Britain and Ireland.

Predicting perioperative outcomes of robot-assisted radical cystectomy: Data from the Asian Robot-Assisted Radical Cystectomy Consortium.

OBJECTIVES: To report the perioperative outcomes of robot-assisted radical cystectomy and elucidate their risk factors. METHODS: A review of the Asian Robot-Assisted Radical Cystectomy Consortium database from 2007 to 2020 was performed. The perioperative outcomes studied included complication rates, time to solid food intake, estimated blood loss, length of hospital stay, and 30-day readmission rates. RESULTS: Of 568 patients, the overall complication rate was 49.2%, comprising major complications in 15.6%. Preoperative hydronephrosis was associated with an increased risk of major complications (odds ratio 3.27, 95% confidence interval 1.48-7.26, P = 0.004) while neoadjuvant chemotherapy was protective (odds ratio 0.46, 95% confidence interval 0.25-0.84, P = 0.012). The median time to solid food intake was 4 days (interquartile range 3-7) and smoking was a risk factor (odds ratio 4.28, 95% confidence interval 2.36-7.79, P < 0.001) for prolonged time to solid food intake. Median length of hospital stay was 13 days (interquartile range 9-19), and diabetes mellitus (odds ratio 1.66, 95% confidence interval 1.08-2.56, P = 0.021), neoadjuvant chemotherapy (odds ratio 2.21, 95% confidence interval 1.46-3.33, P < 0.001), and orthotopic bladder substitute creation (odds ratio 2.82, 95% confidence interval 1.90-4.18, P < 0.001) were independent risk factors for prolonged length of hospital stay. The 30-day readmission rate was 23.4% and higher in those with bilateral hydronephrosis (odds ratio 4.58, 95% confidence interval 1.97-10.65, P < 0.001) and orthotopic bladder substitute creation (odds ratio 1.87, 95% confidence interval 1.16-3.02, P = 0.010). CONCLUSIONS: There are preoperative conditions which are significant risk factors for adverse perioperative outcomes in robot-assisted radical cystectomy. Most are potentially modifiable and can direct strategies to reduce surgical morbidity related to this major oncological procedure.

Urinary Molecular Pathology for Patients with Newly Diagnosed Urothelial Bladder Cancer.

PURPOSE: Next-generation sequencing (NGS)-based profiling of both urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) shows promise for noninvasive detection and surveillance of urothelial bladder cancer (UBC). However, the analytical performance of these assays remains undefined in the real-world setting. Here, we sought to evaluate the concordance between tumor DNA (tDNA) profiling and utDNA or ctDNA assays using a UBC patient cohort from the intended-use population. MATERIALS AND METHODS: Fifty-nine cases with pathologically confirmed disease and matching tissue/urine pairs were prospectively enrolled. Baseline peripheral blood mononuclear cell and plasma specimens were collected during clinic visits. The PredicineCARETM NGS assay was applied for ultra-deep targeted sequencing and somatic alteration identification in tDNA, utDNA and ctDNA. RESULTS: Diverse quantitative metrics including cancer cell fraction, variant allele frequency and tumor mutation burden were invariably concordant between tDNA and utDNA, but not ctDNA. The mutational landscapes captured by tDNA or utDNA were highly similar, whereas a considerable proportion of ctDNA aberrations stemmed from clonal hematopoiesis. Using tDNA-informed somatic events as reference, utDNA assays achieved a specificity of 99.3%, a sensitivity of 86.7%, a positive predictive value of 67.2%, a negative predictive value of 99.8% and a diagnostic accuracy of 99.1%. Higher preoperative utDNA or tDNA abundance correlated with worse relapse-free survival. Actionable variants including FGFR3 alteration and ERBB2 amplification were identified in utDNA. CONCLUSIONS: Urine-based molecular pathology provides a valid and complete genetic profile of bladder cancer, and represents a faithful surrogate for genotyping and monitoring newly diagnosed UBC.

Perioperative Outcomes of Robot-Assisted Radical Cystectomy with Intracorporeal Versus Extracorporeal Urinary Diversion.

PURPOSE: This study was designed to investigate and compare the perioperative outcomes of intracorporeal urinary diversion (ICUD) versus extracorporeal urinary diversion (ECUD) following robotic-assisted radical cystectomy (RARC) in patients with localized bladder cancer from the Asian Robot-Assisted Radical Cystectomy (RARC) Consortium. METHODS: The Asian RARC registry was a multicenter registry involving nine centers in Asia. Consecutive patients who underwent RARC were included. Patient and disease characteristics, intraoperative details, and perioperative outcomes were reviewed and compared between the ICUD and ECUD groups. Postoperative complications were the primary outcomes, whereas secondary outcomes were the estimated blood loss and the duration of hospitalization. Multivariate regression analyses were performed to adjust potential confounders. RESULTS: From 2007 to 2020, 556 patients underwent RARC; 55.2% and 44.8% had ICUD and ECUD, respectively. ICUD group had less estimated blood loss (423.1 ± 361.1 vs. 541.3 ± 474.3 mL, p = 0.002) and a shorter hospital stay (15.7 ± 12.3 vs 17.8 ± 11.6 days, p = 0.042) than the ECUD group. Overall complication rates were similar between the two groups. Upon multivariate analysis, ICUD was associated with less estimated blood loss (Regression coefficient: - 143.06, 95% confidence interval [CI]: - 229.60 to - 56.52, p = 0.001) and a shorter hospital stay (Regression coefficient: - 2.37, 95% CI: - 4.69 to - 0.05, p = 0.046). In addition, ICUD was not associated with any increased risks of minor, major, and overall complications. CONCLUSIONS: RARC with ICUD was safe and technically feasible with similar postoperative complication rates as ECUD, with additional benefits of reduced blood loss and a shorter hospitalization.

Combining DWI radiomics features with transurethral resection promotes the differentiation between muscle-invasive bladder cancer and non-muscle-invasive bladder cancer.

PURPOSE: To investigate the value of radiomics features from diffusion-weighted imaging (DWI) in differentiating muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC). METHODS: This retrospective study included 218 pathologically confirmed bladder cancer patients (training set: 131 patients, 86 MIBC; validation set: 87 patients, 55 MIBC) who underwent DWI before biopsy through transurethral resection (TUR) between July 2014 and December 2018. Radiomics models based on DWI for discriminating state of muscle-invasive were built using random forest (RF) and all-relevant (AR) methods on the training set and were tested on validation set. Combination models based on TUR data were also built. Discrimination performances were evaluated with the area under the receiver operating characteristic (ROC) curve (AUC), accuracy, sensitivity, specificity, and F1 and F2 scores. Qualitative MRI evaluation based on morphology was performed for comparison. RESULTS: No significant difference was found between RF and AR models. RF model was more sensitive than TUR (0.873 vs 0.655, p = 0.019) for discriminating muscle-invasive bladder cancer. When combining RF with TUR, the sensitivity increased to 0.964, significantly higher than TUR (0.655, p < 0.001), MRI evaluation (0.764, p = 0.006), and the combination of TUR and MRI (0.836, p = 0.046). Combining RF and TUR achieved the highest accuracy of 0.897 and F2 score of 0.946. CONCLUSION: Combining DWI radiomics features with TUR could improve the sensitivity and accuracy in discriminating the presence of muscle invasion in bladder cancer for clinical practice. Multicenter, prospective studies are needed to confirm our results. KEY POINTS: • Twenty-seven to 51% of superficial bladder cancers diagnosed by transurethral resection are upstaged to muscle-invasive at radical cystectomy, suggesting its poor sensitivity for discriminating muscle-invasive bladder cancer. • A small subset of selected all-relevant radiomics features exhibited an equivalent performance compared to that of all the extracted features, confirming that radiomics data contained redundant or irrelevant features and that feature selection should be performed in building radiomics models. • Combining DWI radiomics features with transurethral resection could improve in clinical practice the sensitivity and accuracy for the detection of muscle invasion in bladder cancer.

Diffusion kurtosis imaging to assess correlations with clinicopathologic factors for bladder cancer: a comparison between the multi-b value method and the tensor method.

OBJECTIVES: To assess the efficacy of diffusion kurtosis imaging (DKI) in differentiating low-grade from high-grade tumors and evaluating the aggressiveness of bladder cancer. METHODS: From January 2017 to July 2017, 35 patients (28 males, 7 females; mean age 63 ± 9 years) diagnosed with bladder cancer underwent diffusion-weighted imaging (DWI) with two types of DKI protocols: (1) multi-b value ranging from 0 to 2000 s/mm2 to obtain mean diffusivity/kurtosis (MDb/MKb) and (2) the tensor method with 32 directions with 3 b values (0, 1000, and 2000s/mm2) to obtain mean/axial/radial diffusivity (MDt/Da/Dr), mean/axial/radial kurtosis (MKt/Ka/Kr), and fractional anisotropy (FA) before radical cystectomy. Comparisons between the low- and high-grade groups, non-muscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC) were performed with the areas under the receiver operating characteristic curves (AUCs). RESULTS: The MKt and Kr values were significantly (p = 0.017 and p = 0.048) higher in patients with high-grade bladder tumors than in those with low-grade tumors. The MKt, Kr, and MKb values were significantly (p = 0.022, p = 0.000, and p = 0.044, respectively) higher in patients with MIBC than in those with NMIBC, while no significant differences (p > 0.05) were found in other values. The AUC of Kr (0.883) was the largest and was significantly higher than those of other metrics (all p < 0.05) for differentiating MIBC from NMIBC, with a sensitivity and specificity of 81.8% and 91.7%, respectively. CONCLUSIONS: Kurtosis metrics performed better than diffusion metrics in differentiating MIBC from NMIBC, and directional kurtosis and Kr metrics may also have great potential in providing additional information regarding bladder cancer invasiveness. KEY POINTS: • Kurtosis metrics performed better than diffusion metrics in differentiating muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC). • Directional kurtosis can provide additional directional microstructural information regarding bladder cancer invasiveness.

Prevalence and clonality of synchronous primary carcinomas in the bladder and prostate.

Incidental prostate adenocarcinoma (IPCa) has been frequently discovered during postoperative histopathological evaluation of radical cystoprostatectomy specimens in patients with bladder cancer (BCa). However, there is currently no conclusive study addressing the clinical significance of IPCa and the clonal relatedness of IPCa and BCa. Here, we performed a retrospective single-center review of 919 BCa cases and an additional meta-analysis including a total of 19 868 individuals who underwent radical cystectomy for bladder cancer. IPCa, mostly clinically insignificant, was detected in 67 of 919 BCa patients (7.3%) and was significantly associated with greater age. In the meta-analysis, a lower prevalence was observed in Asian than in non-Asian countries (19% versus 32%), presumably due to their different rates of prostate cancer occurrence. Whole-exome sequencing on matched BCa and IPCa samples unambiguously revealed independent clonal origins of the synchronous tumors. BCa and IPCa lesions from each patient displayed distinctive genomic abnormalities and largely unrelated mutational signatures of single nucleotide variations, indicating disparate mutational processes underlying bladder and prostate oncogenesis. These findings provide important insights into the incidental nature of prostate adenocarcinoma in patients with bladder cancer, and suggest that the two concurrent diseases can be managed separately. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Investigation of diffusion kurtosis imaging for discriminating tumors from inflammatory lesions after treatment for bladder cancer.

BACKGROUND: The bladder wall may thicken resulting from chronic inflammation after initial treatment (transurethral resection [TUR] or neoadjuvant chemotherapy), which may mimic the feature of recurrent or residual bladder tumors (RBT). Therefore, it is critical to discriminate RBT from benign lesions after initial treatment. PURPOSE: To investigate whether diffusion kurtosis imaging (DKI) could discriminate RBT from post-therapy bladder inflammatory lesions. STUDY TYPE: Retrospective. SUBJECTS: Fifty patients diagnosed with bladder cancer underwent TUR or received neoadjuvant chemotherapy. FIELD STRENGTH/SEQUENCE: 3.0T MRI/conventional T1 -weighted imaging (T1 WI), T2 WI, and diffusion-weighted imaging (DWI) with nine b-values ranging from 0-2000 s/mm2 . ASSESSMENT: Mean diffusion coefficients (MDa , MDb , and MDc ) and mean kurtosis values (MKa , MKb , and MKc ) were obtained from three different measurement methods. The region of interest (ROI) was placed 1) to encompass the entire portion of the thickening bladder wall or to portions that were the most restricted, with a b-value of 2) 2000 s/mm2 or 3) 1000 s/mm2 . STATISTICAL TESTS: The independent-samples t-test was used to compare the differences between RBT and the inflammatory group. Differences in DKI parameters were analyzed by comparing the areas under the receiver-operator characteristic curves (AUCs). RESULTS: In patients with RBT, the MD (MDa , MDb , MDc ) values were significantly lower and the MK (MKa , MKb , MKc ) values were significantly higher than those in patients in the inflammatory lesions group (all P < 0.01). The AUC of MKb (0.934) was significantly larger than those of MDb , MKa , and MKc (0.793, P < 0.05; 0.694, P < 0.01; 0.719, P < 0.01, respectively). DATA CONCLUSION: MK obtained from DKI provided better performance than conventional DWI in distinguishing RBT from inflammatory lesions after bladder cancer treatment. MK calculated with high b-values setting provided better performance in differentiation. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage 3 J. Magn. Reson. Imaging 2017.

SERS measurement of the bladder cancer cells with the nanoparticles.

The surfaced enhanced Raman spectroscopy (SERS) of bladder cancer cells and tissues were measured in this paper. Both depth SERS and map SERS of SCABER bladder cancer cells were measured with confocal Raman microscope using gold nanoparticles as the enhance substrate. We also measured SERS of normal bladder tissue and bladder cancer tissue, and analyzed the difference of two different tissues. The SERS spectra of more samples need to be measured and analyzed for bladder cancer tissue and the normal bladder tissue in the future and the spectra will be helpful for bladder cancer diagnosis.

Single-nucleotide polymorphisms of GPX1 and MnSOD and susceptibility to bladder cancer: a systematic review and meta-analysis.

Reactive oxygen species-related damage plays a critical role in carcinogenesis. Glutathione peroxidase 1 (GPX1) and mitochondrial superoxide dismutase (MnSOD) are two key antioxidant enzymes in the defense system against reactive oxygen species. This systematic review and meta-analysis was designed to evaluate the association of single-nucleotide polymorphisms in GPX1 and MnSOD genes with susceptibility to bladder cancer risk. Online databases of PubMed, Embase, China National Knowledge Infrastructure, and SinoMed were searched to identify eligible studies. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimated the association strength. The fixed effects model and random effects model were used to pool the data from different studies. By pooling all eligible studies, we found that the GPX1 Pro198Leu polymorphism was associated with a significantly increased risk of bladder cancer (Leu vs. Pro, OR = 2.111, 95% CI = 1.020-4.368, heterogeneity (p < 0.001); LeuPro/LeuLeu vs. ProPro, OR = 1.876, 95% CI = 1.011-3.480, heterogeneity (p < 0.001)). No significant association of MnSOD Ala-9Val polymorphism with cancer risk was observed (AlaVal/ValVal vs. AlaAla, OR = 0.966, 95% CI = 0.754-1.239, heterogeneity (p = 0.390); Vla vs. Ala, OR = 1.038, 95% CI = 0.782-1.377, heterogeneity (p = 0.015)). This systematic review and meta-analysis demonstrated that the GPX1 Pro198Leu polymorphism significantly increased susceptibility to bladder cancer, while the MnSOD Ala-9Val polymorphism was not associated with bladder cancer risk.

The Value of Dual Time Point 18F-FDG PET/CT Imaging in Differentiating Lymph Node Metastasis From Reactive Hyperplasia in Bladder Urothelial Carcinoma.

RATIONALE AND OBJECTIVES: This study explored the clinical value of dual time-point 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging for differentiating lymph node metastasis from lymph nodes with reactive hyperplasia. METHODS: 250 lymph nodes from 153 bladder cancer patients who underwent 18F-FDG PET/computed tomography (CT) delayed diuretic imaging were analyzed. The maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumor volume (MTV), and related delay indices before and after PET delayed imaging were obtained. Relationships with outcomes were analyzed using nonparametric and multivariate analyses. Receiver operating characteristic curves and nomograms were drawn to predict lymph node metastasis. RESULTS: Delayed PET/CT imaging showed better detection of hyperplasia and metastatic lymph nodes. Delayed imaging with a cutoff SUVmax of 2.0 or 2.5 increased the detection rate of metastatic lymph nodes by 4.1%, and 6.9%, respectively. Delayed imaging often showed speckle-like radioactive foci in lymph nodes with reactive hyperplasia and increased FDG uptake throughout the nodes in metastatic lymph nodes. The lymph node short-axis diameter, SUVmean, and delayed index of MTV (DIMTV) were independent predictors for differentiating metastatic lymph nodes from reactive hyperplasia, and their combination showed better differentiation performance than the individual predictors. In high-risk patients, the probability of lymph node metastasis was as high as 97.6%. CONCLUSION: Dual time-point imaging can detect more metastatic lymph nodes. Some lymph nodes with hyperplasia show speckle-like radioactive foci on delayed imaging. The lymph node short-axis diameter, SUVmean, and DIMTV are three important parameters for predicting lymph node metastasis.

Enhanced Sensitivity of Cell Identification in Complex Environments Using Chirally Inverted L-DNA-Based Logic Devices.

Accurate identification and isolation of target cells are crucial for precision diagnosis and treatment. DNA aptamer-based logic devices provide a distinct advantage in this context, as they can logically analyze multiple cell surface markers with high efficiency. However, the susceptibility of natural DNA (D-DNA) to degradation can compromise the sensitivity and specificity of these devices, potentially leading to false-positive and false-negative results, particularly in complex biological environments. To address this issue, dual- and triple-aptamer-based cell-surface logic devices are designed and developed using mirror-image L-DNA, a chiral molecule of D-DNA with high biostability. These devices allow for simultaneous analysis of multiple cell surface proteins, achieving greater specificity in cell identification and isolation than D-DNA-based logic devices. The L-DNA probes realized 98.7% and 70.5% sensitivities in FBS buffer with dual- and triple-aptamer-based logic devices for target cell identification, while D-DNA probes only showed 27.9% and 0.1%. It is believed that the high stability of L-DNA and the high efficiency of the devices for labeling cell subpopulations will have broad applications in the life sciences, biomedical engineering, and personalized medicine.

Genomic Profiling and Immune Phenotyping of Neuroendocrine Bladder Cancer.

PURPOSE: Neuroendocrine bladder cancer (NEBC) poses a formidable clinical challenge and attracts keen interests to explore immunotherapy as a viable treatment option. However, a comprehensive immunogenomic landscape has yet to be thoroughly investigated. EXPERIMENTAL DESIGN: Leveraging a long-term cohort of natural NEBC cases, we employed a multimodal approach integrating genomic (n = 19), transcriptomic (n = 3), single-cell RNA sequencing (n = 1), and IHC analyses (n = 34) to meticulously characterize the immunogenicity and immunotypes of primary NEBC tumors. Information on clinical, pathologic, medical imaging, and treatment aspects was retrospectively retrieved and analyzed. RESULTS: Our study unveiled that despite a considerable mutational burden, NEBC was typically immunologically inactive, as manifested by the "immune-excluded" or "immune-desert" microenvironment. Interestingly, a subset of mixed NEBC with concurrent urothelial bladder cancer histology displayed an "immune-infiltrated" phenotype with prognostic relevance. When compared with urothelial bladder cancer, NEBC lesions were distinguished by a denser cellular composition and augmented peritumoral extracellular matrix, which might collectively impede lymphatic infiltration. As a result, single-agent immune checkpoint inhibitors demonstrated limited efficacy against NEBC, whereas pharmacologic immunostimulation with combination chemotherapy conferred a more favorable response. CONCLUSIONS: These new insights derived from genomic profiling and immune phenotyping pave the way for rational immunotherapeutic interventions in patients with NEBC, with the potential to ultimately reduce mortality from this otherwise fatal disease.

The prognostic impact of tumor location in nonmuscle-invasive bladder cancer patients undergoing transurethral resection: insights from a cohort study utilizing Chinese multicenter and SEER registries.

OBJECTIVE: Most bladder cancers are nonmuscle invasive bladder cancer (NMIBC), and transurethral resection of bladder tumors (TURBT) is the standard treatment. However, postoperative recurrence remains a significant challenge, and the influence of bladder tumor location on prognosis is still unclear. This study aims to investigate how tumor location affects the prognosis of NMIBC patients undergoing TURBT and to identify the optimal surgical approach. METHODS: A multicenter study was conducted, which included Chinese NMIBC data from 15 hospitals (1996-2019) and data from 17 registries of the Surveillance, Epidemiology, and End Results database (SEER) (2000-2020). Patients initially diagnosed with NMIBC and undergoing TURBT or partial cystectomy were analyzed, with cases lost to follow-up or with missing data excluded. The study investigated the overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) among patients with different tumor locations. Kaplan-Meier, Cox regression, and propensity score matching methods were employed to explore the association between tumor location and prognosis. Stratified populations were analyzed to minimize bias. RESULTS: This study included 118 477 NMIBC patients and highlighted tumor location as a crucial factor impacting post-TURBT prognosis. Both anterior wall and dome tumors independently predicted adverse outcomes in two cohorts. For anterior wall tumors, the Chinese cohort showed hazard ratios (HR) for OS of 4.35 ( P <0.0001); RFS of 2.21 ( P <0.0001); SEER cohort OS HR of 1.10 ( P =0.0001); DSS HR of 1.13 ( P =0.0183). Dome tumors displayed similar trends [Chinese NMIBC cohort OS HR of 7.91 ( P <0.0001); RFS HR of 2.12 ( P <0.0001); SEER OS HR of 1.05 ( P =0.0087); DSS HR of 1.14 ( P =0.0006)]. Partial cystectomy significantly improved the survival of dome tumor patients compared to standard TURBT treatment ( P <0.01). CONCLUSION: This study reveals the significant impact of tumor location in NMIBC patients on the outcomes of TURBT treatment, with tumors in the anterior wall and bladder dome showing poor post-TURBT prognosis. Compared to TURBT treatment, partial cystectomy improves the prognosis for bladder dome tumors. This study provides guidance for personalized treatment and prognosis management for NMIBC patients.

Pre-Op Hydronephrosis Predicts Outcomes in Patients Receiving Robot-Assisted Radical Cystectomy.

INTRODUCTION: Robot-assisted radical cystectomy (RARC) has gained momentum in the management of muscle invasive bladder cancer (MIBC). Predictors of RARC outcomes are not thoroughly studied. We aim to investigate the implications of preoperative hydronephrosis on oncological outcomes. PATIENTS AND METHODS: This study analysed data from the Asian RARC consortium, a multicentre registry involving nine Asian centres. Cases were divided into two groups according to the presence or absence of pre-operative hydronephrosis. Background characteristics, operative details, perioperative outcomes, and oncological results were reviewed. Outcomes were (1) survival outcomes, including 10-year disease-free survival (DFS) and overall survival (OS), and (2) perioperative and pathological results. Multivariate regression analyses were performed on survival outcomes. RESULTS: From 2007 to 2020, 536 non-metastatic MIBC patients receiving RARC were analysed. 429 had no hydronephrosis (80.0%), and 107 (20.0%) had hydronephrosis. Hydronephrosis was found to be predictive of inferior DFS (HR = 1.701, p = 0.003, 95% CI = 1.196-2.418) and OS (HR = 1.834, p = 0.008, 95% CI = 1.173-2.866). Subgroup analysis demonstrated differences in the T2-or-above subgroup (HR = 1.65; p = 0.004 in DFS and HR = 1.888; p = 0.008 in OS) and the T3-or-above subgroup (HR = 1.757; p = 0.017 in DFS and HR = 1.807; p = 0.034 in OS). CONCLUSIONS: The presence of preoperative hydronephrosis among MIBC patients carries additional prognostic implications on top of tumour staging. Its importance in case selection needs to be highlighted.

FDG-Avid Malakoplakia of the Ureter Mimicking Malignancy.

ABSTRACT: Malacoplakia is a rare chronic granulomatous disease and frequently associated with Escherichia coli infection. We describe the contrast-enhanced CT and FDG PET/CT findings in a case of bladder and ureteral malakoplakia with E. coli urinary tract infection. Contrast-enhanced CT showed multiple enhancing mural nodules in the bladder and left ureter, ranging from several millimeters to 3.1 cm. The ureteral nodules showed significantly increased FDG uptake with SUVmax of 20.4, due to histiocyte, lymphocyte, and plasma cell infiltrates revealed by histopathology.

Identification and Validation of the Prognostic Panel in Clear Cell Renal Cell Carcinoma Based on Resting Mast Cells for Prediction of Distant Metastasis and Immunotherapy Response.

Clear cell renal cell carcinoma (ccRCC) has a high metastatic rate, and its incidence and mortality are still rising. The aim of this study was to identify the key tumor-infiltrating immune cells (TIICs) affecting the distant metastasis and prognosis of patients with ccRCC and to construct a relevant prognostic panel to predict immunotherapy response. Based on ccRCC bulk RNA sequencing data, resting mast cells (RMCs) were screened and verified using the CIBERSORT algorithm, survival analysis, and expression analysis. Distant metastasis-associated genes were identified using single-cell RNA sequencing data. Subsequently, a three-gene (CFB, PPP1R18, and TOM1L1) panel with superior distant metastatic and prognostic performance was established and validated, which stratified patients into high- and low-risk groups. The high-risk group exhibited lower infiltration of RMCs, higher tumor mutation burden (TMB), and worse prognosis. Therapeutically, the high-risk group was more sensitive to anti-PD-1 and anti-CTLA-4 immunotherapy, whereas the low-risk group displayed a better response to anti-PD-L1 immunotherapy. Furthermore, two immune clusters revealing distinct immune, clinical, and prognosis heterogeneity were distinguished. Immunohistochemistry of ccRCC samples verified the expression patterns of the three key genes. Collectively, the prognostic panel based on RMCs is able to predict distant metastasis and immunotherapy response in patients with ccRCC, providing new insight for the treatment of advanced ccRCC.