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.

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.

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.

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.

Urinary Tumor DNA MRD Analysis to Identify Responders to Neoadjuvant Immunotherapy in Muscle-invasive Bladder Cancer.

PURPOSE: Bladder preservation is a viable option for some patients with muscle-invasive bladder cancer (MIBC), but an effective noninvasive biomarker test to accurately identify promising candidates is lacking. Here we present the clinical application of a novel tissue-agnostic, urine-based minimal residual disease (MRD) assay in the neoadjuvant setting for personalized disease surveillance and actionable target identification to facilitate bladder-sparing treatment approaches. PATIENTS AND METHODS: The urinary tumor DNA (utDNA) analysis was evaluated in an investigator-initiated phase I trial RJBLC-I2N003 in which 20 patients diagnosed with resectable MIBC were treated presurgically with the PD-1 inhibitor toripalimab followed by radical cystectomy (RC). RESULTS: We showed that neoadjuvant toripalimab therapy was feasible, safe, and induced a 40% rate (8/20) of pathologic complete response. Longitudinal utDNA profiling outperformed radiographic assessment and conventional biomarkers to predict the pathologic outcome of immune checkpoint blockade. In addition to detecting 3 exceptional responders with molecular MRD-negative status, we identified 7 other individuals characterized for utDNA response and 4 harboring FGFR3 mutants, all of whom (60%, 12/20) could have postponed or avoided RC. CONCLUSIONS: These findings demonstrate the safety and efficacy of neoadjuvant toripalimab, and suggest the immense potential of noninvasive utDNA MRD testing to guide tailored decision-making with regard to bladder preservation and change the current treatment paradigm for patients with MIBC.

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.

In vivo detection demonstrates circulating tumor cell reduction instead of baseline number has prognostic value in bladder cancer patients receiving neoadjuvant chemotherapy.

PURPOSE: Previous studies have suggested the potential prognostic value of circulating tumor cells (CTCs) in bladder cancer (BC) patients. This study aims to validate the prognostic value of in vivo detection of CTCs in muscle invasive bladder cancer (MIBC) patients receiving neoadjuvant chemotherapy (NAC). METHODS: A total of 107 MIBC patients were enrolled in this study. All patients had one in vivo detection of CTCs before initial treatment as baseline, and those who received neoadjuvant chemotherapy (NAC) had a second detection after NAC and before radical cystectomy. CTCs dynamic change after NAC was analyzed. Prognostic value of in vivo CTCs detection was investigated. RESULTS: Among 68 patients who received NAC, 45 patients (66%) had a CTC reduction after NAC. CTC reduction instead of baseline CTC positivity was a key prognostic factor for better progression free survival (PFS) among all MIBC patients receiving NAC in Kaplan-Meier analysis (P < 0.01) and in both crude (HR 6.14, 95%CI 1.63-23.21) and adjusted regression model (HR 6.76, 95% CI 1.59-28.88). The AUC was 0.85. CONCLUSION: Our study demonstrated the prognostic value of in vivo detection of CTCs. The dynamic change of CTCs count may help evaluate the efficacy of NAC.

In vivo detection of circulating tumor cells predicts high-risk features in patients with bladder cancer.

Previous studies have suggested the potential diagnostic value of circulating tumor cells (CTCs). This study aims to validate the efficacy of in vivo detection of CTCs in bladder cancer (BC) patients. A total of 216 BC patients were enrolled in this study. All patients had one in vivo detection of CTCs before initial treatment as a baseline parameter. The results of CTCs were associated with different clinicopathological features including molecular subtypes. PD-L1 expression on CTCs was also assessed and compared with its expression on tumors. CTC positive was defined as > 2 CTCs detected. Among all 216 patients, 49 (23%) were detected as CTC positive (> 2 CTCs) at baseline. Positive detection of CTCs was associated with multiple high-risk clinicopathological features including the multiplicity of the tumor (P = 0.02), tumor size (P < 0.01), tumor stage (P < 0.01), tumor grade (P < 0.01) and tumor PD-L1 expression (P = 0.01). The expression of PD-L1 on tumor and CTCs were not coordinated. Only 55% (74/134) matched the same status of PD-L1 expression on tumor and CTCs, along with 56 CTC (+) Tissue (-) and 4 CTC (-) Tissue (+) (P < 0.01). Our study has demonstrated the efficacy of in vivo detection of CTCs. The positive detection of CTCs is associated with multiple clinicopathological features. PD-L1 expression on CTCs has the potential to be a supplementary biomarker for immunotherapy.

µ-opioid receptor agonist facilitates circulating tumor cell formation in bladder cancer via the MOR/AKT/Slug pathway: a comprehensive study including randomized controlled trial.

BACKGROUND: µ-opioid receptor agonists (MORAs) are indispensable for analgesia in bladder cancer (BC) patients, both during surgery and for chronic pain treatment. Whether MORAs affect BC progression and metastasis remains largely unknown. This study focused on the effects of MORAs on the formation of circulating tumor cells (CTCs) in BC and aimed to provide potential therapeutic targets, which would retain the pain-relieving effects of MORAs in BC patients without sacrificing their long-term prognosis. METHODS: Different preclinical models were used to identify the effects of MORAs on the progression of BC. A novel immunocapture microfluidic chip was utilized to analyze whether MORAs affected the number of CTCs in mouse models and clinical BC patients. Bioinformatic analyses, total transcriptome sequencing, and molecular biology methods were then used to investigate the underlying mechanisms in these models and in BC cell lines. RESULTS: Mouse models of hematogenous metastasis and in situ BC demonstrated that tumor metastasis was significantly increased after MORA treatment. A significant increase in the number of mesenchymal and/or epithelial CTCs was detected after MORA treatment in both the mouse models and clinical trial patients. Mechanistically, MORAs facilitated the formation of CTCs by activating the MOR/PI3K/AKT/Slug signaling pathway, hereby promoting the epithelial-mesenchymal transition (EMT) of BC cells, as knockdown of MOR, Slug or blockade of PI3K inhibited the EMT process and CTC formation. CONCLUSION: MORAs promoted BC metastasis by facilitating CTC formation. The EMT-CTC axis could be targeted for preventive measures during MORA treatment to inhibit the associated tumor metastasis or recurrence in BC patients.

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.

Neoadjuvant immunotherapy, chemotherapy, and combination therapy in muscle-invasive bladder cancer: A multi-center real-world retrospective study.

To parallelly compare the efficacy of neoadjuvant immunotherapy (tislelizumab), neoadjuvant chemotherapy (gemcitabine and cisplatin), and neoadjuvant combination therapy (tislelizumab + GC) in patients with muscle-invasive bladder cancer (MIBC) and explore the efficacy predictors, we perform a multi-center, real-world cohort study that enrolls 253 patients treated with neoadjuvant treatments (combination therapy: 98, chemotherapy: 107, and immunotherapy: 48) from 15 tertiary hospitals. We demonstrate that neoadjuvant combination therapy achieves the highest complete response rate and pathological downstaging rate compared with neoadjuvant immunotherapy or chemotherapy. We develop and validate an efficacy prediction model consisting of pretreatment clinical characteristics, which can pinpoint candidates to receive neoadjuvant combination therapy. We also preliminarily reveal that patients who achieve pathological complete response after neoadjuvant treatments plus maximal transurethral resection of the bladder tumor may be safe to receive bladder preservation therapy. Overall, this study highlights the benefit of neoadjuvant combination therapy based on tislelizumab for MIBC.

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.

Surface-Enhanced Raman Spectroscopy of Pretreated Plasma Samples Predicts Disease Recurrence in Muscle-Invasive Bladder Cancer Patients Undergoing Neoadjuvant Chemotherapy and Radical Cystectomy.

Objective: To explore the value of surface-enhanced Raman spectroscopy analysis of pretreated plasma samples in prediction of bladder cancer (BCa) recurrence after neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Patients and Methods: SERS was used to analyze plasma samples collected before biopsy and treatment in BCa patients undergoing NAC and RC. The value of clinicopathological parameters and distinctive SERS peaks in the prediction of disease recurrence were analyzed in Cox regression proportional hazard analysis and Log rank test. Principal component analysis and linear discriminant analysis (PCA-LDA) were employed to process spectral data and construct diagnostic algorithms. Results: A total of 88 patients with 440 plasma SERS spectra were collected. The SRES spectra from recurrent patients were compared with patients who remained recurrence free. The SERS demonstrated higher levels of circulating free nucleic acid components in recurrent population, which is represented by significantly higher intensities at SERS peaks of 725 cm-1, 1328 cm-1 and 1455 cm-1. The SERS also detected significantly lower levels of tryptophan shown as lower significantly intensities at the 1558 cm-1, which is proved to be an independent predictor of BCa recurrence. The addition of SERS peaks of 1558 cm-1 to classic clinicopathological predictors including pathological tumor stage, lymph node metastasis and pathological downstaging can significantly enhance the power of the predictive model from 0.66 to 0.76 in the area under curve (AUC) of receiver operating characteristic (ROC) curves. Meanwhile, the PCA-LDA diagnostic model based on SERS spectra reveals a high accuracy of 85.2% in prediction of disease recurrence and the AUC of 0.92 in the ROC curve. When validated in the leave-one-out cross-validation method, the accuracy of the model remained 84.1%. Conclusion: We show that SERS analysis of plasma before NAC treatment can accurately classify patients with different risks of disease recurrence after surgery and improve the power of clinicopathological predictive models, thus refining clinical decision-making.

Prospective Clinical Trial of the Oncologic Outcomes and Safety of Extraperitoneal Laparoscopic Extended Retroperitoneal Lymph Node Dissection at Time of Nephroureterectomy for Upper Tract Urothelial Carcinoma.

Purpose: To determine the safety and feasibility of extraperitoneal laparoscopic extended lymph node dissection (LND) at the time of extraperitoneal laparoscopic radical nephroureterectomy (RNU). Materials and Methods: Between May 2018 and March 2019, 39 patients with upper tract urothelial carcinoma (UTUC) received extraperitoneal laparoscopic RNU and concomitant extraperitoneal laparoscopic extended LND. All patients were followed for at least 90 days. Perioperative and pathological data including nodal status and perioperative complications were collected. Results: Among all 39 patients, 12 patients had pT1, 6 had pT2, 20 had pT3 disease, and 1 had T4 disease. The median (range) lymph node count was 10 (5-22), with 8 patients having pathologically proven lymph node metastasis. The median (range) operating time was 225 (165-430) min, and the median estimated blood loss was 200 (60-800) ml. The median postoperative hemoglobin loss was 1.6 (0-4.2) g/dl. The median (range) postoperative hospital stays were 6 (3-26) days. Overall, 7 patients experienced minor (Clavien Grade I-II) postoperative complications with five patients having Clavien Grade I complications and two patients having Clavien Grade II complications. No major complication (Clavien grade III-IV) occurred. With a median follow-up of 38 months, a total of 8 patients (20.5%) developed local or distant recurrence and no regional LNs where extended LND were performed had recurrence. Conclusions: The present prospective study demonstrated that extraperitoneal laparoscopic extended LND during extraperitoneal laparoscopic RNU for UTUC is a feasible and safe procedure which provides minimal invasion, rapid recovery, and potentially lower risk of regional LN recurrence. Larger prospective clinical trials with survival endpoints are needed to further determine its potential therapeutic benefits. Trial Registration: ClinicalTrials.gov identifier NCT03544437 www.clinicaltrials.gov.

Safety, Efficacy, and Biomarker Analysis of Toripalimab in Patients with Previously Treated Advanced Urothelial Carcinoma: Results from a Multicenter Phase II Trial POLARIS-03.

PURPOSE: Immunotherapy offers a second-line option for patients with metastatic urothelial carcinoma (mUC) who failed standard therapy, but the biomarkers for predicting response remain to be explored. This study aims to evaluate the safety, efficacy, and correlative biomarker of toripalimab in patients with previously treated mUC. PATIENTS AND METHODS: Patients with mUC received toripalimab 3 mg/kg Q2W. Clinical response was assessed every 8 weeks by an independent review committee per RECIST v1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated. RESULTS: Among the intention-to-treat population (n = 151), 85% of the patients experienced treatment-related adverse event (TRAE) and 20% experienced grade 3 and above TRAE. The objective response rate (ORR) was 26% with a disease control rate (DCR) of 45%. The median duration of response, progression-free survival (PFS), and overall survival (OS) were 19.7 months [95% confidence interval (CI): 13.9-not estimable], 2.3 months (95% CI, 1.8-3.6), and 14.4 months (95% CI, 9.3-23.1), respectively. Both PD-L1+ and TMB-high (10 mutations/Mb as the cutoff) patients had better ORR than PD-L1- patients (42% vs. 17%, P = 0.002) and TMB-low patients (48% vs. 22%, P = 0.014), respectively. The TMB-high group also showed better PFS (12.9 vs. 1.8 months, P < 0.001) and OS (not reached versus 10.0 months, P = 0.018) than the TMB-low group. CONCLUSIONS: Toripalimab has demonstrated encouraging clinical activity in the second-line treatment of mUC with a manageable safety profile. PD-L1 expression and TMB were two independent biomarkers in the study.

An Artificial Intelligence System for the Detection of Bladder Cancer via Cystoscopy: A Multicenter Diagnostic Study.

BACKGROUND: Cystoscopy plays an important role in bladder cancer (BCa) diagnosis and treatment, but its sensitivity needs improvement. Artificial intelligence has shown promise in endoscopy, but few cystoscopic applications have been reported. We report a Cystoscopy Artificial Intelligence Diagnostic System (CAIDS) for BCa diagnosis. METHODS: In total, 69 204 images from 10 729 consecutive patients from 6 hospitals were collected and divided into training, internal validation, and external validation sets. The CAIDS was built using a pyramid scene parsing network and transfer learning. A subset (n = 260) of the validation sets was used for a performance comparison between the CAIDS and urologists for complex lesion detection. The diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values and 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. RESULTS: The diagnostic accuracies of the CAIDS were 0.977 (95% CI = 0.974 to 0.979) in the internal validation set and 0.990 (95% CI = 0.979 to 0.996), 0.982 (95% CI = 0.974 to 0.988), 0.978 (95% CI = 0.959 to 0.989), and 0.991 (95% CI = 0.987 to 0.994) in different external validation sets. In the CAIDS vs urologists' comparisons, the CAIDS showed high accuracy and sensitivity (accuracy = 0.939, 95% CI = 0.902 to 0.964; sensitivity = 0.954, 95% CI = 0.902 to 0.983) with a short latency of 12 seconds, much more accurate and quicker than the expert urologists. CONCLUSIONS: The CAIDS achieved accurate BCa detection with a short latency. The CAIDS may provide many clinical benefits, from increasing the diagnostic accuracy for BCa, even for commonly misdiagnosed cases such as flat cancerous tissue (carcinoma in situ), to reducing the operation time for cystoscopy.

Efficacy and safety of a novel 450 nm blue diode laser versus plasmakinetic electrocautery for the transurethral resection of non-muscle invasive bladder cancer: The protocol and result of a multicenter randomized controlled trial.

Objectives: To be the first to apply a novel 450 nm blue diode laser in transurethral resection of bladder tumor (TURBt) to treat patients with non-muscle invasive bladder cancer (NMIBC) and evaluate its efficacy and safety during the preoperative period compared to the conventional plasmakinetic electrocautery. Materials and Methods: Randomized controlled trial (RCT) in five medical centers was designed as a non-inferiority study and conducted from October 2018 to December 2019. Patients with NMIBC were randomized to the blue laser or plasmakinetic electrocautery group for TURBt. As the first study to evaluate this novel blue laser device, the primary outcome was the effective resection rate of bladder tumors, including effective dissection and hemostasis. The secondary outcomes were the perioperative records, including surgical time, postoperative indwelling catheter time, hospital stay length, blood loss, reoperation rate, wound healing and adverse events. Results: A total of 174 patients were randomized to either the blue laser group (85 patients) or plasmakinetic electrocautery group (89 patients). There was no statistical significance in the clinical features of bladder tumors, including tumor site, number and maximum lesion size. Both the blue laser and plasmakinetic electrocautery could effectively dissect all visible bladder tumors. The surgical time for patients in the blue laser group was longer (p=0.001), but their blood loss was less than that of patients in the control group (p=0.003). There were no differences in the postoperative indwelling catheter time, hospital stay length, reoperation rate or other adverse events. However, the patients undergoing TURBt with the blue laser showed a faster wound healing at 3 months after operation. Conclusion: The novel blue laser could be effectively and safely used for TURBt in patients with NMIBC, and this method was not inferior to plasmakinetic electrocautery during the perioperative period. However, TURBt with the blue laser may provide the benefit to reduce preoperative blood loss and accelerate postoperative wound healing. Moreover, longer follow-up to confirm recurrence-free survival benefit was required.

Mutations of METTL3 predict response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

BACKGROUND AND AIM: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the current gold standard treatment for muscle-invasive urothelial bladder cancer (MIBC). Nonetheless, some MIBC patients showed limited pathological response after NAC. Herein, we used whole-exome sequencing (WES) to identify genetic mutations in MIBC that can predict NAC response. METHODS: Forty MIBC patients were enrolled in this study, in which 33 were successfully examined by WES and Sanger sequencing in the discovery cohort (n=13) and the validation cohort (n=20), respectively. ANNOVAR software was used to identify the potential mutations based on the data of WES. In addition, tumor-specific somatic mutations including single nucleotide variants and indels were called with the muTECT and Strelka software. The mutational analysis of specific genes was carried out based on the data from cBioPortal for Cancer Genomics. RESULTS: In the discovery cohort, the mutation frequencies of TP53, MED16, DRC7, CEND1, ATAD5, SETD8, and PIK3CA were significantly higher in 13 MIBC patients. Specifically, the presence of somatic mutations of APC, ATM, CDH9, CTNNB1, METTL3, NBEAL1, PTPRH, RNASEL, and FBXW7 in NAC responder signifies that these mutations were potential predictors of pathological response to NAC. Furthermore, somatic mutations of CCDC141, PIK3CA, CHD5, GPR149, MUC20, TSC1, and USP54 were exclusively identified in NAC nonresponders, suggesting that these mutations may participate in the process of NAC resistance. In the validation cohort, the somatic mutations of CDH9, METTL3, and PTPRH were significantly enriched in NAC responders while the somatic mutation of CCDC141 was significantly enriched in NAC nonresponders. Furthermore, survival analysis revealed that the patients expressing mutated METTL3 have a longer overall survival and disease- or progression-free survival than the patients acquiring wild-type METTL3. CONCLUSION: The somatic mutation of METTL3 can be a potential predictive biomarker of NAC response in MIBC patients. RELEVANCE FOR PATIENTS: MIBC patients bearing mutated METTL3 display a pathological response to NAC and have a significantly longer overall survival or disease/progression-free survival as compared to the patients bearing wild-type METTL3. Thus, the somatic mutation of METTL3 is a potential biomarker for predicting response to NAC in MIBC patients, assisting doctors in making the clinical decision.

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.

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.