Correlation of PSA and survival in metastatic hormone-sensitive prostate cancer treated with rezvilutamide plus ADT in the CHART trial.

BACKGROUND: This exploratory analysis of the CHART trial (ClinicalTrials.gov: NCT03520478) investigated prostate-specific antigen (PSA) kinetics and the correlation between PSA and survival outcomes in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC). METHODS: A total of 654 patients were randomized 1:1 to receive either rezvilutamide plus androgen deprivation therapy (ADT; n = 326) or bicalutamide plus ADT (n = 328). PSA kinetics were evaluated, and the correlation between survival and the achievement of undetectable PSA (≤0.2 ng/mL) or ≥90% PSA reduction (PSA90) was assessed. FINDINGS: The rezvilutamide group exhibited higher proportions of ≥50% PSA reduction (PSA50; 98.2% vs. 87.5%), PSA90 (88.7% vs. 63.1%), and undetectable PSA (38.3% vs. 17.7%) responses compared to the bicalutamide group by 3 months. The rezvilutamide group demonstrated superior efficacy in delaying PSA progression compared to the bicalutamide group (hazard ratio [HR] 0.21, 95% confidence interval 0.16-0.27). The achievement of undetectable PSA and PSA90 by 6 months in the rezvilutamide group was associated with prolonged overall survival (undetectable PSA, HR = 0.34; PSA90, HR = 0.22), radiographic progression-free survival (HR = 0.36, HR = 0.26), time to PSA progression (HR = 0.25, HR = 0.17), and time to castration resistance (HR = 0.34, HR = 0.23) compared to those who did not achieve these PSA milestones. Stratification by baseline PSA level revealed consistent survival improvements with rezvilutamide plus ADT across quartiles. CONCLUSIONS: PSA kinetics is a valuable prognostic factor in mHSPC treated with rezvilutamide plus ADT, and the achievement of undetectable PSA and PSA90 is associated with improved survival. These findings highlight the importance of monitoring PSA kinetics in the management of mHSPC. FUNDING: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

ILC2-derived CGRP triggers acute inflammation and nociceptive responses in bacterial cystitis.

Calcitonin gene-related peptide (CGRP), a neuropeptide involved in nociceptor neuronal function, plays a critical role in mediating neuroinflammation and pain. In this study, we find that bladder group 2 innate lymphoid cells (ILC2s) function as primary producers of CGRP in the early phase of bacterial cystitis, contributing to increased inflammation, altered voiding behavior, and heightened pelvic allodynia. Furthermore, we demonstrate that interleukin (IL)-33, a cytokine secreted by urothelial cells, upregulates CGRP production by ILC2s in the bladder during uropathogenic Escherichia coli (UPEC) infection. Moreover, our research reveals that monocytes expressing high levels of receptor activity-modifying protein 1 (RAMP1), a CGRP receptor, mediate the pro-inflammatory effects of CGRP-producing ILC2s. In summary, our results underscore the significance of the immune cell-derived neuropeptides in the pathology of UPEC infection, suggesting a promising therapeutic approach targeting the IL-33-ILC2-CGRP axis for managing lower urinary tract symptoms in bacterial cystitis.

Analysis of Variable Frequency Stimulation Sacral Neuromodulation for Different Genders: A Chinese Multicentric Prospective Clinical Study.

AIM: Sacral neuromodulation (SNM) is widely recognized as the essential treatment modality for patients suffering from various lower urinary tract disorders, particularly overactive bladder (OAB). This prospective study recruited patients who underwent variable frequency SNM treatment at six Chinese medical centers, aiming to evaluate the gender-specific effects of this intervention and provide precise guidance on its application for clinical management. METHODS: This prospective study was managed by Beijing Hospital, and six Chinese medical centers participated in this prospective research. Inclusion and exclusion criteria were established to screen patients based on the indication for SNM. During the research, all patients were required to record 72-h voiding diaries, urgency scores, and visual analogue scale (VAS) scores to reflect their disease symptoms. Additionally, subjective questionnaire surveys such as OAB symptom score (OABSS) and quality-of-life (Qol) score were recorded to reflect the patients' quality of life and treatment satisfaction. RESULTS: In this study, 52 patients (male patients: 25; female patients: 27) with OAB symptoms agreed to undergo variable frequency stimulation SNM therapy and finally convert to Stage II. Regarding the baseline outcomes, no significant differences were observed between the male and female groups. In terms of postoperative indicators, male patients showed a greater improvement in Qol scores compared to their female counterparts (20.06 ± 13.12 vs. 40.83 ± 26.06, p = 0.005). The results from VAS scores indicated that pain remission was more pronounced in male patients than in female patients (0.31 ± 0.87 vs. 1.67 ± 2.16, p = 0.02). Importantly, there was a statistically significant disparity in urinary urgency between males and females (male patients: 1.19 ± 1.56; female patients: 2.17 ± 1.52, p = 0.04). CONCLUSIONS: In our study, we found that variable frequency SNM treatment yielded sex-specific differences in therapeutic effects, with male patients having a better outcome in some metrics. This suggests that a patient's sex may influence when variable frequency SNM is used, and in the patient's follow-up. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ChiCTR2000036677.

Early Sacral Neuromodulation Prevented Detrusor Overactivity in Rats With Spinal Cord Injury.

OBJECTIVES: Sacral neuromodulation (SNM) has been shown to alleviate bladder dysfunction in patients with overactive bladder and nonobstructive urinary retention. However, the therapeutic effect and mechanism of SNM in neurogenic bladder dysfunction are still not fully understood. Using a rat model of spinal cord injury (SCI), this study aims to investigate the therapeutic effect of early SNM in the bladder-areflexia phase on neurogenic bladder dysfunction and evaluate its possible mechanism. MATERIALS AND METHODS: Basic physiological parameters such as body/bladder weight, blood pressure, and electrocardiogram results were measured to evaluate the safety of SNM. Enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reaction were used to examine the expression of proinflammatory factors. Hematoxylin and eosin and Masson's trichrome staining were used to observe morphological changes, and cystometry was used to evaluate urodynamic changes after SNM treatment. Western blotting and immunofluorescence staining were used to measure the levels of transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in the L6-S1 dorsal root ganglia (DRGs) and bladder. Capsaicin desensitization was used to investigate whether inhibiting TRPV1 could prevent detrusor overactivity in SCI rats. RESULTS: Early SNM did not affect the body/bladder weight, heart rate, blood pressure, or the expression of proinflammatory cytokines (PGE2, IL-1, IL-2, IL-6, TGF-ß, or TNF-α) in the bladders of SCI rats. Morphologically, early SNM prevented urothelial edema (p = 0.0248) but did not influence collagen/smooth muscle in the bladder. Compared with untreated rats with SCI, the rats treated with SNM exhibited increased bladder capacity (p = 0.0132) and voiding efficiency (p = 0.0179), and decreased nonvoiding contraction (NVC) frequency (p = 0.0240). The maximum pressure, basal pressure, postvoid residual, and NVC amplitude did not change significantly. After the SNM treatment, the expression of TRPV1 in the bladder and CGRP in L6-S1 DRGs weredecreased (L6, p = 0.0160; S1, p = 0.0024) in SCI rats. In capsaicin-desensitized SCI rats, urodynamic results showed an increase in bladder capacity (p = 0.0116) and voiding efficiency (p = 0.0048), and diminished NVC frequency (p = 0.0116), while other parameters did not change significantly. CONCLUSIONS: Early SNM prevented urothelial edema morphologically and detrusor overactivity in SCI rats. Inhibition of TRPV1 in the bladder and DRGs may be one of the potential mechanisms for preventing detrusor overactivity by SNM.

PD-L1 expression and its correlation with tumor biomarkers in Chinese urothelial bladder cancer.

Data on prevalence of programmed death ligand-1 (PD-L1) expression and its correlation with tumor biomarkers in Chinese patients with muscle-invasive urothelial bladder cancer (MIUBC) are scarce. We investigated the prevalence of PD-L1 expression, PD-L1 expression in tumor cells (TC) and immune cells (IC), and its correlation with tumor biomarkers (CD8+ T cells and tumor mutation burden [TMB]) in Chinese patients with newly diagnosed MIUBC (NCT03433924). Of 248 patients enrolled, 229 with PD-L1 data available were analysed. High PD-L1 expression (≥ 25% of TC or IC with PD-L1 expression) was observed in 120 (52.4%) patients. 59 cases showed positive staining in ≥ 25% of TC, and 82 cases had positive staining in ≥ 25% of IC. High expression of CD8+ T cell and TMB (> 10 mutations/megabase) was observed in 44.5% and 54.1% patients, respectively. A positive correlation was observed between percentage of TC with membrane PD-L1 positivity and CD8+ T cells (0.34; P < 0.001) and between IC with membrane PD-L1 positivity and CD8+ T cells (0.44; P < 0.001). There is high prevalence of PD-L1 expression in Chinese patients with MIUBC, suggesting that a sizable subset of patients could benefit from immunotherapy. The correlation of PD-L1 expression with tumor biomarkers provide clues for mechanisms underlying the effects of biomarkers for predicting efficacy.

A single-arm, multicenter, phase 2 clinical study of recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate (MRG002) in HER2-positive unresectable locally advanced or metastatic urothelial carcinoma.

BACKGROUND: MRG002 is a novel HER2-targeted antibody-drug conjugate being investigated in the MRG002-006 trial to evaluate the efficacy and safety in HER2-positive urothelial carcinoma patients. METHODS: This is an open-label, single-arm, multicenter phase II study. Eligibility criteria included: histologically confirmed HER2 IHC 2 + or 3 + UC, prior received ≥ 1 standard treatment. Patients in this study received MRG002 every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was confirmed ORR per RECIST 1.1. RESULTS: As of February 24, 2023, a total of 43 patients were enrolled. The median age was 60. 9 patients were dosed at 2.6 mg/kg and 34 patients were dosed at 2.2 mg/kg. At baseline, most patients (29/43) received ≥ 2 lines of treatment and 35 (81.4%) patients had prior ICI therapy. FISH test was performed in 41 patients and 9 (22.0%) were positive. By the cut-off date, 41 patients were evaluable and the ORR was 53% (95%CI：38.9%-67.5%), with 6.9% CR, and the DCR was 83.7% (95%CI：70.0%-91.9%). The median PFS and OS for the 43 patients were 7.0 months (95%CI：5.4-NE) and 14.9 months (95%CI：11.9-NE), respectively. The ORR was 77.8% in 9 patients with positive HER2 FISH results. Most common treatment-related AEs were anemia (51.2%), alopecia (44.2%) and neutropenia (39.5%); most were grade 1 or 2. CONCLUSION: Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients. MRG002 at 2.2 mg/kg was well tolerated with a manageable toxicity.

Tumor-neutrophil cross talk orchestrates the tumor microenvironment to determine the bladder cancer progression.

The immune landscape of bladder cancer progression is not fully understood, and effective therapies are lacking in advanced bladder cancer. Here, we visualized that bladder cancer cells recruited neutrophils by secreting interleukin-8 (IL-8); in turn, neutrophils played dual functions in bladder cancer, including hepatocyte growth factor (HGF) release and CCL3highPD-L1high super-immunosuppressive subset formation. Mechanistically, c-Fos was identified as the mediator of HGF up-regulating IL-8 transcription in bladder cancer cells, which was central to the positive feedback of neutrophil recruitment. Clinically, compared with serum IL-8, urine IL-8 was a better biomarker for bladder cancer prognosis and clinical benefit of immune checkpoint blockade (ICB). Additionally, targeting neutrophils or hepatocyte growth factor receptor (MET) signaling combined with ICB inhibited bladder cancer progression and boosted the antitumor effect of CD8+ T cells in mice. These findings reveal the mechanism by which tumor-neutrophil cross talk orchestrates the bladder cancer microenvironment and provide combination strategies, which may have broad impacts on patients suffering from malignancies enriched with neutrophils.

Initial [18F]DCFPyL PET/CT in treatment-naïve prostate cancer: correlation with post-ADT PSA outcomes and recurrence.

PURPOSE: Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) targeting tracers has emerged as a valuable diagnostic tool for prostate cancer (PCa), androgen deprivation therapy (ADT) stands as the cornerstone treatment for advanced PCa, yet forecasting the response to hormonal therapy poses a significant clinical hurdle. METHODS: In a prospective cohort of 86 PCa patients undergoing short-term ADT, this study evaluated the prognostic potential of [18F]DCFPyL PET/CT scans. Comprehensive data encompassing clinical profiles, baseline prostate-specific antigen (PSA) levels, and imaging metrics were assessed. We developed predictive models for assessing decreases in PSA levels (PSA50 and PSA70) based on a combination of PET-related parameters and clinical factors. Kaplan-Meier survival analysis was utilized to ascertain the prognostic value of PET-based metrics. RESULTS: In this study, elevated [18F]DCFPyL uptake within the primary tumor, as indicated by a SUV ≥ 6.78 (p = 0.0024), and a reduction in the tumor volume (TV) of primary PSMA-avid tumor with PSMA-TV < 41.96 cm3 (p = 0.038), as well as an increased burden of metastatic PSMA-avid tumor, with PSMA-TV (PSMA-TV ≥ 71.39 cm3) (p = 0.012) were identified in association with diminished progression-free survival (PFS). PET and clinical parameters demonstrated constrained predictive capacity for PSA50 response as indicated by an area under the curve (AUC) of 0.442. CONCLUSION: Our study revealed that pretreatment [18F]DCFPyL uptake in primary or metastatic tumor sites is prognostically relevant in high-risk PCa patients undergoing ADT. Further research is needed to develop robust predictive models in this multifaceted landscape of PCa management.

Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance.

BACKGROUND: CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been identified, the deubiquitination pathway for CDC6 has not been investigated. METHODS: The proteome-wide deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6. RESULTS: OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder cancer. CONCLUSIONS: We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for cancer treatment.

Different diagnostic strategies combining prostate health index and magnetic resonance imaging for predicting prostate cancer: A multicentre study.

OBJECTIVE: To explore how prostate health index (PHI) and multiparametric magnetic resonance imaging (mpMRI) should be used in concert to improve diagnostic capacity for clinically significant prostate cancers (CsCaP) in patients with prostate-specific antigen (PSA) between 4 and 20 ng/ml. METHODS: About 426 patients fulfilling the inclusion criteria were included in this study. Univariable and multivariable logistic analyses were performed to analyze the association between the clinical indicators and CaP/CsCaP. We used the Delong test to compare the differences in the area under the curve (AUC) values of four models for CaP and CsCaP. Decision curve analysis (DCA) and calibration plots were used to assess predictive performance. We compared clinical outcomes of different diagnostic strategies constructed using different combinations of the models by the chi-square test and the McNemar test. RESULTS: The AUC of PHI-MRI (a risk prediction model based on PHI and mpMRI) was 0.859, which was significantly higher than those of PHI (AUC = 0.792, P < 0.001) and mpMRI (AUC = 0.797, P < 0.001). PHI-MRI had a higher net benefit on DCA for predicting CaP and CsCaP in comparison to PHI and mpMRI. Adding the PHI-MRI in diagnostic strategies for CsCaP, such as use PHI-MRI alone or sequential use of PHI followed by PHI-MRI, could reduce the number of biopsies by approximately 20% compared to use PHI followed by mpMRI (256 vs 316, 257 vs 316, respectively). CONCLUSIONS: The PHI-MRI model was superior to PHI and MRI alone. It may reduce the number of biopsies and ensure the detection rate of CsCaP under an appropriate sensitivity at the cost of an increased number of MRI scans.

Effects of neoadjuvant VEGF­TKI treatment on surgery for renal cell carcinoma: A systematic review and meta­analysis.

To evaluate the effects of neoadjuvant vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) treatment on surgery in patients with renal cell carcinoma (RCC), sources from Embase, PubMed and the Cochrane Library databases collected from inception to December, 2022 were used for analysis in the present study, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data regarding surgical outcomes were collected. The pooled effect sizes were calculated in terms of the risk ratio (RR)/standard mean difference (SMD) with 95% confidence intervals (CIs) using the random-effects model. Subgroup and sensitivity analyses were used to explore the source of heterogeneity within the data. In total, 9 identified articles involving 829 patients (336 in the neoadjuvant + surgery group; 493 in the surgery group) were included in the present study, according to the criteria. The results demonstrated that there were no significant differences in blood loss (SMD=-0.11; 95% CI, -0.63-0.41; P=0.68), postoperative length of hospital stay or total length of hospital stay (SMD=0.23; 95% CI, -0.55-1.01; P=0.57) or complications (RR=1.16; 95% CI, 0.80-1.67; P=0.44) between the two groups. However, neoadjuvant therapy reduced the operation time (SMD=-0.67; 95% CI, -1.25- -0.09; P=0.02) and resulted in a greater proportion of patients choosing partial nephrectomy (RR=1.84; 95% CI, 1.47-2.31; P<0.00001). In the subgroup analysis, the blood loss was significantly lower in patients with RCC with inferior vena cava tumor thrombus in the neoadjuvant group (SMD=-1.10; 95% CI, -1.82- -0.38; P=0.003). In conclusion, the results of the present study indicated that neoadjuvant VEGF-TKI treatment in patients with RCC shortened operation time, decreased blood loss and did not cause an increase in perioperative complications. In addition, this treatment modality may encourage patients to opt for partial nephrectomy to preserve renal function.

Real-world effectiveness and safety of goserelin 10.8-mg depot in Chinese patients with localized or locally advanced prostate cancer.

OBJECTIVE: Real-word data on long-acting luteinizing hormone-releasing hormone (LHRH) agonists in Chinese patients with prostate cancer are limited. This study aimed to determine the real-world effectiveness and safety of the LHRH agonist, goserelin, particularly the long-acting 10.8-mg depot formulation, and the follow-up patterns among Chinese prostate cancer patients. METHODS: This was a multicenter, prospective, observational study in hormone treatment-naïve patients with localized or locally advanced prostate cancer who were prescribed goserelin 10.8-mg depot every 12 weeks or 3.6-mg depot every 4 weeks with or without an anti-androgen. The patients had follow-up evaluations for 26 weeks. The primary outcome was the effectiveness of goserelin in reducing serum testosterone and prostate-specific antigen (PSA) levels. The secondary outcomes included testosterone and PSA levels, attainment of chemical castration (serum testosterone <50 ng/dL), and goserelin safety. The exploratory outcome was the monitoring pattern for serum testosterone and PSA. All analyses were descriptive. RESULTS: Between September 2017 and December 2019, a total of 294 eligible patients received ≥ 1 dose of goserelin; 287 patients (97.6%) were treated with goserelin 10.8-mg depot. At week 24 ± 2, the changes from baseline [standard deviation (95% confidence interval)] in serum testosterone (n = 99) and PSA (n = 131) were -401.0 ng/dL [308.4 ng/dL (-462.5, -339.5 ng/dL)] and -35.4 ng/mL [104.4 ng/mL (-53.5, -17.4 ng/mL)], respectively. Of 112 evaluable patients, 100 (90.2%) achieved a serum testosterone level < 50 ng/dL. Treatment-emergent adverse events (TEAEs) and severe TEAEs occurred in 37.1% and 10.2% of patients, respectively. The mean testing frequency (standard deviation) was 1.6 (1.5) for testosterone and 2.2 (1.6) for PSA. CONCLUSIONS: Goserelin 10.8-mg depot effectively achieved and maintained castration and was well-tolerated in Chinese patients with localized and locally advanced prostate cancer.

Nomogram to predict the presence of PSMA-negative but FDG-positive lesion in castration-resistant prostate cancer: a multicenter cohort study.

Background: PSMA-negative but FDG-positive (PSMA-/FDG+) lesion in dual-tracer (68Ga-PSMA and 18F-FDG) positron emission tomography/computed tomography (PET/CT) is associated with an unfavorable response to Lutetium-177 (177Lu)-PSMA-617. This study sought to develop both radiomics and clinical models for the precise prediction of the presence of PSMA-/FDG+ lesions in patients with castration-resistant prostate cancer (CPRC). Methods: A cohort of 298 patients who underwent dual-tracer PET/CT with a less than 5-day interval was included. The evaluation of the prognostic performance of the radiomics model drew upon the survival data derived from 40 patients with CRPC treated with 177Lu-PSMA-617 in an external cohort. Two endpoints were evaluated: (a) prostate-specific antigen (PSA) response rate, defined as a reduction exceeding 50% from baseline and (b) overall survival (OS), measured from the initiation of 177Lu-PSMA-617 to death from any cause. Results: PSMA-/FDG+ lesions were identified in 56 (18.8%) CRPC patients. Both radiomics (area under the curve [AUC], 0.83) and clinical models (AUC, 0.78) demonstrated robust performance in PSMA-/FDG+ lesion prediction. Decision curve analysis revealed that the radiomics model yielded a net benefit over the 'screen all' strategy at a threshold probability of ⩾4%. At a 5% probability threshold, the radiomics model facilitated a 21% reduction in 18F-FDG PET/CT scans while only missing 2% of PSMA-/FDG+ cases. Patients with a low estimated score exhibited significantly prolonged OS (hazard ratio = 0.49, p = 0.029) and a higher PSA response rate (75% versus 35%, p = 0.011) compared to those with a high estimated score. Conclusion: This study successfully developed two models with accurate estimations of the risk associated with PSMA-/FDG+ lesions in CRPC patients. These models held potential utility in aiding the selection of candidates for 177Lu-PSMA-617 treatment and guiding 68Ga-PSMA PET/CT-directed radiotherapy.

Predictive nomogram for PSMA-/FDG+ lesion This study developed two models with accurate estimations of the risk associated with specific lesions in prostate cancer.

Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials.

PURPOSE: To evaluate the efficacy and safety of disitamab vedotin (DV, RC48-ADC), a novel humanized anti-human epidermal growth factor receptor 2 (HER2) antibody conjugated with monomethyl auristatin E, in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (UC) refractory to standard or regular therapies. PATIENTS AND METHODS: The data analyzed and reported are from two phase II, open-label, multicenter, single-arm studies (RC48-C005 and RC48-C009) in patients with HER2-positive (immunohistochemistry 3+ or 2+) locally advanced or metastatic UC who have progressed on at least one previous line of systemic chemotherapy. Patients received DV treatment (2 mg/kg IV infusion, once every 2 weeks). The primary end point was objective response rate (ORR) assessed by a blinded independent review committee (BIRC). Progression-free survival (PFS), overall survival (OS), and safety were also assessed. RESULTS: One hundred and seven patients were enrolled in total. The overall confirmed ORR by BIRC was 50.5% (95% CI, 40.6 to 60.3). Consistent results were observed in prespecified subgroups including patients with liver metastasis and patients previously treated with anti-PD-1/L1 therapies. By the cutoff date of May 10, 2022, the median duration of response was 7.3 months (95% CI, 5.7 to 10.8). The median PFS and OS were 5.9 months (95% CI, 4.3 to 7.2) and 14.2 months (95% CI, 9.7 to 18.8), respectively. The most common treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (68.2%), leukopenia (50.5%), AST increased (42.1%), and neutropenia (42.1%). Fifty-eight (54.2%) patients experienced grade ≥3 TRAEs, including peripheral sensory neuropathy (18.7%) and neutropenia (12.1%). CONCLUSION: DV demonstrated a promising efficacy with a manageable safety profile in patients with HER2-positive locally advanced or metastatic UC who had progressed on at least one line of systemic chemotherapy.

The vascular and morphological characteristics of tumors under narrow-band imaging as predictors for the grade and stage of bladder cancer: a prospective and multi-center study.

The vascular and morphological features of tumors are important predictors of the nature, grade, and stage of various cancers. However, this association has not been tested in bladder cancer. The aim of our study was to investigate the correlation between the morphological characteristics of tumor vessels and the nature, stage and grade of bladder cancer. Between November 2021 and March 2023, we prospectively collated clinical information and cystoscopy information from a series of patients with bladder cancer. Univariate and multivariate logistic regression analysis were used to identify independent risk factors for the nature, grade and stage of bladder cancer. Our analysis showed that cauliflower-like tumors, dotted vessels, and circumferential vessels were independent risk factors for bladder cancer. Reticular vessels were an independent risk factor for high-grade bladder cancer. Thick branching vessels in bladder tumors, along with a wide base, were independent risk factors for the invasion of bladder cancer into the lamina propria. Primary diagnosis, lesion location (beside the left ureteral orifice) and obscure lesion boundaries were all identified as independent risk factors for muscle invasive bladder cancer.

Histone deacetylase 9 exacerbates podocyte injury in hyperhomocysteinemia through epigenetic repression of Klotho.

Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and the development of cardiovascular complications related to end-stage renal disease, the mechanisms triggering pathogenic actions of hHcys are not fully understood. The present study was mainly designed to investigate the role of HDACs in renal injury induced by hHcys. Firstly, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC9 was preferentially upregulated in the kidney from mice with hHcys. Deficiency or pharmacological inhibition of HDAC9 ameliorated renal injury in mice with hHcys. Moreover, podocyte-specific deletion of HDAC9 significantly attenuated podocyte injury and proteinuria. In vitro, gene silencing of HDAC9 attenuated podocyte injury by inhibiting apoptosis, reducing oxidative stress and maintaining the expressions of podocyte slit diaphragm proteins. Mechanically, we proved for the first time that HDAC9 reduced the acetylation level of H3K9 in the promoter of Klotho, then inhibited gene transcription of Klotho, finally aggravating podocyte injury in hHcys. In conclusion, our results indicated that targeting of HDAC9 might be an attractive therapeutic strategy for the treatment of renal injury induced by hHcys.

Gut microbiome in men with chronic prostatitis/chronic pelvic pain syndrome: profiling and its predictive significance.

PURPOSE: To investigate the difference in gut microbiome composition between patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and healthy controls, and to assess the potential of gut microbiota as predictive markers for CP/CPPS risk. METHODS: The present study included 41 CP/CPPS patients and 43 healthy controls in China. Fecal specimen data were obtained and analysed using 16S rRNA gene sequencing. Alpha and beta-diversity indices, relative microbiome abundances, cluster analysis, and linear discriminant analysis effect size (LEfSe) were employed. Microbial biomarkers were selected for the development of a diagnostic classification model, and the functional prediction was conducted using PICRUSt2. RESULTS: Alpha-diversity measures revealed no statistically significant difference in bacterial community structure between CP/CPPS patients and controls. However, significant differences were observed in the relative abundances of several bacterial genera. Beta-diversity analysis revealed a distinct separation between the two groups. Significant inter-group differences were noted at various taxonomic levels, with specific bacterial genera being significantly different in abundance. The LEfSe analysis indicated that three bacterial species were highly representative and seven bacterial species were low in CP/CPPS patients as compared to the control group. A diagnostic model for CP/CPPS based on microbial biomarkers exhibited good performance. PICRUSt2 functional profiling indicated significant differences in the development and regeneration pathway. CONCLUSION: Significant differences in the gut microbiome composition were found between groups. The study provided a novel diagnostic model for CP/CPPS based on microbiota, presenting promising potential for future therapeutic targets and non-invasive diagnostic biomarkers for CP/CPPS patients.

Development and validation of a predictive model for the diagnosis of bladder tumors using narrow band imaging.

PURPOSE: At present, the prediction of bladder tumor nature during cystoscopy is partially dependent on the clinician's own experience. Subjective factors may lead to excessive biopsy or delayed treatment. The purpose of our study is to establish a reliable model for predicting the nature of bladder tumors using narrow band imaging. METHODS: From November 2021 to November 2022, the clinical data of 231 patients who required a cystoscopy were prospectively collected at our center. Cystoscopy was performed in 219 eligible patients, in which both tumor and vascular morphology characteristics were recorded. Pathological results were used as the diagnostic standard. A logistic regression analysis was used to screen out factors related to tumor pathology. Bootstrap resampling was used for internal validation. A total of 71 patients from four other centers served as an external validation cohort. RESULTS: The following diagnostic factors were identified: tumor morphology (cauliflower-like or algae-like lesions), vascular morphology (dotted or circumferential vessels), tumor boundary (clear or unclear), and patients' symptoms (gross hematuria) and were included in the prediction model. The internal validation results showed that the area under the curve was 0.94 (95% CI 0.92-0.97), and the P value from the goodness-of-fit test was 0.97. After external validation, the results showed the area under the curve was 0.89 (95% CI 0.82-0.97) and the P value of the goodness-of-fit test was 0.24. CONCLUSION: A diagnostic prediction nomogram was established for bladder cancer. The verification results showed that the prediction model has good prediction performance.

The effect of the enhanced recovery after surgery program on radical cystectomy: a meta-analysis and systematic review.

Background: Bladder cancer is the ninth most common malignant tumor worldwide. As an effective evidence-based multidisciplinary protocol, the enhanced recovery after surgery (ERAS) program is practiced in many surgical disciplines. However, the function of ERAS after radical cystectomy remains controversial. This systematic review and meta-analysis aims to research the impact of ERAS on radical cystectomy. Methods: A systematic literature search on PubMed, EMBASE, SCOPUS, and the Cochrane Library databases was conducted in April 2022 to identify the studies that performed the ERAS program in radical cystectomy. Studies were selected, data extraction was performed independently by two reviewers, and quality was assessed using a random effects model to calculate the overall effect size. The odds ratio and standardized mean difference (SMD) with a 95% confidence interval (CI) served as the summary statistics for the meta-analysis. A sensitivity analysis was subsequently performed. Results: A total of 25 studies with 4,083 patients were enrolled. The meta-analysis showed that the complications (OR = 0.76; 95% CI: 0.63-0.90), transfusion rate (OR = 0.59; 95% CI: 0.39-0.90), readmission rate (OR = 0.79; 95% CI: 0.64-0.96), length of stay (SMD = -0.79; 95% CI: -1.41 to -0.17), and time to first flatus (SMD = -1.16; 95% CI: -1.58 to -0.74) were significantly reduced in the ERAS group. However, no significance was found in 90-day mortality and urine leakage. Conclusion: The ERAS program for radical cystectomy can effectively decrease the risk of overall complications, postoperative ileus, readmission rate, transfusion rate, length of stay, and time to first flatus in patients who underwent radical cystectomy with relative safety. Systematic Review Registration: https://inplasy.com/, identifier INPLASY202250075.