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.

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.

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.

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.

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.

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.

Robot-assisted laparoscopic pyeloplasty in an adult with pelvic ectopic kidney with hydronephrosis: a case report and literature review.

Pelvic ectopic kidney is a congenital anomaly with a higher probability of hydronephrosis than a normal kidney. Few studies have reported cases of pelvic ectopic kidney with hydronephrosis in adults treated with robot-assisted laparoscopic pyeloplasty (RALP). We performed RALP on a 22-year-old male and he recovered well after the procedure. The patient's pain disappeared after surgery. No complications occurred during the perioperative period and had a rapid postoperative recovery.

Efficacy and safety of LY01005 versus goserelin implant in Chinese patients with prostate cancer: A multicenter, randomized, open-label, phase III, non-inferiority trial.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04563936.

Neoadjuvant therapy with camrelizumab plus gemcitabine and cisplatin for patients with muscle-invasive bladder cancer: A multi-center, single-arm, phase 2 study.

BACKGROUND: Neoadjuvant chemotherapy followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). However, treatment outcomes are suboptimal. Camrelizumab, a PD-1 blockade, has shown benefits in several tumors. This study aimed to investigate the efficacy and safety of neoadjuvant camrelizumab in combination with gemcitabine plus cisplatin (GC) followed by RC for MIBC patients. METHODS: This was a multi-center, single-arm study that enrolled MIBC patients with a clinical stage of T2-4aN0-1M0, and scheduled for RC. Patients received three 21-day cycles of camrelizumab 200 mg on day 1, gemcitabine 1000 mg/m2 on day 1 and 8, and cisplatin 70 mg/m2 on day 2, followed by RC. The primary endpoint was pathologic complete response (pCR, pT0N0). RESULTS: From May 2020 to July 2021, 43 patients were enrolled and received study medications at nine centers in China. Three of them were deemed ineligible and excluded from efficacy analysis but included in safety analysis. In total 10 patients were unevaluable as they declined RC (two due to adverse events [AEs] and eight due to patient's willingness). Among 30 evaluable patients, 13 patients (43.3%) achieved pCR, and 16 patients (53.3%) achieved pathologic downstaging. No AEs leading to death were observed. The most common AEs were anemia (69.8%), decreased white blood cell count (65.1%), and nausea (65.1%). Immune-related AEs were all grade 1 or 2. Pathologic response was not correlated with PD-L1 expression status or tumor mutation burden. Individual genes as a biomarker for pathologic response were not identified. CONCLUSIONS: Neoadjuvant treatment with camrelizumab and GC regimen demonstrated preliminary anti-tumor activity for MIBC patients with manageable safety profiles. The study met its primary endpoint, and the following randomized trial is ongoing.

Based on ARASENS trial: efficacy and safety of darolutamide as an emerging option of endocrinotherapy for metastatic hormone-sensitive prostate cancer-an updated systematic review and network meta-analysis.

PURPOSE: The newly published ARASENS trial has demonstrated the clinical efficacy of darolutamide for metastatic hormone-sensitive prostate cancer (mHSPC). However, the use of darolutamide as the latest first-line androgen receptor pathway inhibitor for mHSPC has not been compared with other androgen receptor targeted agents (ARTAs). Given the lack of head-to-head randomized trials, we performed this updated meta-analysis to conduct indirect comparison for the efficacy and safety of darolutamide with other new-generation ARTAs. METHODS: By searching the databases of PubMed, Scopus, Cochrane Library, and Embase, 9 large randomized controlled trials evaluating ARTAs for mHSPC patients were eventually screened according to PRISMA. We extracted data from overall survival, castration-resistant progression, and adverse events for network meta-analysis using the Bayesian and standard frequentist models. RESULTS: Darolutamide combination emerged with superiority (HR = 0.68, 95%CrI = 0.57-0.81) among four androgen receptor inhibitors for patients with high Gleason score (HR = 0.71, 95%CrI = 0.59-0.86). Darolutamide was best tolerated in several androgen suppression-related adverse events (AEs). CONCLUSION: Darolutamide appears to be an optional androgen receptor inhibitor for mHSPC patients, especially for patients with Gleason score ≥ 8. Its well-tolerated characteristic may provide a preferred drug option for patients with poor cardiovascular function and bone health.

Metabolic Modulation of Intracellular Ammonia via Intravesical Instillation of Nanoporter-Encased Hydrogel Eradicates Bladder Carcinoma.

Tumor protein 53 (TP53) mutation in bladder carcinoma (BC), upregulates the transcription of carbamoyl phosphate synthetase 1 (CPS1), to reduce intracellular ammonia toxicity. To leverage ammonia combating BC, here, an intravesically perfusable nanoporter-encased hydrogel system is reported. A biomimetic fusogenic liposomalized nanoporter (FLNP) that is decorated with urea transporter-B (UT-B) is first synthesized with protonated chitosan oligosaccharide for bladder tumor-targeted co-delivery of urease and small interfering RNA targeting CPS1 (siCPS1). Mussel-inspired hydrogel featured with dual functions of bio-adhesion and injectability is then fabricated as the reservoir for intravesical immobilization of FLNP. It is found that FLNP-mediated UT-B immobilization dramatically induces urea transportation into tumor cells, and co-delivery of urease and siCPS1 significantly boosts ammonia accumulation in tumor inducing cell apoptosis. Treatment with hybrid system exhibits superior anti-tumor effect in orthotopic bladder tumor mouse model and patient-derived xenograft model, respectively. Combined with high-protein diet, the production of urinary urea increases, leading to an augmented intracellular deposition of ammonia in BC cells, and ultimately an enhanced tumor inhibition. Together, the work establishes that cascade modulation of ammonia in tumor cells could induce tumor apoptosis and may be a practical strategy for eradication of TP53-mutated bladder cancer.

Diagnostic Efficiency of Pan-Immune-Inflammation Value to Predict Prostate Cancer in Patients with Prostate-Specific Antigen between 4 and 20 ng/mL.

INTRODUCTION: To evaluate the predictive value of the pan-immune-inflammation value (PIV) and other systemic inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), for prostate cancer (PCa) and clinically significant prostate cancer (CSPCa) in patients with a prostate-specific antigen (PSA) value between 4 and 20 ng/mL. PATIENTS AND METHODS: The clinical data of 319 eligible patients who underwent prostate biopsies in our hospital from August 2019 to June 2022 were retrospectively analyzed. CSPCa was defined as a "Gleason grade group of ≥2". A univariable logistic regression analysis and multivariable logistic regression analysis were conducted to analyze the association between the PIV, SII, MLR, and PCa/CSPCa. For the inflammatory indicators included in the multivariable logistic regression analysis, we constructed models by combining the separate inflammatory indicator and other significant predictors and compared the area under the curve (AUC). A nomogram based on the PIV for PCa was developed. RESULTS: We included 148 PCa patients (including 127 CSPCa patients) and 171 non-PCa patients in total. The patients with PCa were older, had higher MLR, SII, PIV, and total PSA (TPSA) values, consumed more alcohol, and had lower free/total PSA (f/T) values than the other patients. Compared with the non-CSPCa group, the CSPCa group had higher BMI, MLR, PIV, TPSA values, consumed more alcohol, and had lower f/T values. The univariable regression analysis showed that drinking history, higher MLR, PIV, and TPSA values, and lower f/T values were independent predictors of PCa and CSPCa. The AUC of the PIV in the multivariable logistic regression model was higher than those of the MLR and SII. In addition, the diagnostic value of the PIV + PSA for PCa was better than the PSA value. However, the diagnostic value for CSPCa was not significantly different from that of using PSA alone, while the AUC of the PIV + PSA was higher than the individual indicator of the PSA value. CONCLUSIONS: Our study suggests that for the patients who were diagnosed with PSA values between 4 and 20 ng/mL, the PIV and MLR are potential indicators for predicting PCa and CSPCa. In addition, our study indicates that the new inflammatory index PIV has clinical value in the diagnosis of PCa and CSPCa.

Nomograms for predicting survival in patients with micropapillary bladder cancer: a real-world analysis based on the surveillance, epidemiology, and end results database and external validation in a tertiary center.

BACKGROUND: The present study aimed to construct and validate nomograms that can be used to predict cancer-specific survival (CSS) and overall survival (OS) in patients with micropapillary bladder cancer. METHODS: The data of 627 patients diagnosed with micropapillary bladder cancer between 2000 and 2018 were obtained from the surveillance, epidemiology, and end results database. Patients were randomly divided into the training and internal validation sets (7:3). The Cox proportional hazards regression model was applied to evaluate the association between variables and survival and then nomograms were constructed to predict the survival of an individual patient. The performance of nomograms was validated by using calibration curves, concordance index, receiver operating characteristic curves with the calculated area under the curve and decision curve analysis in the training and internal validation set. Data from 41 micropapillary bladder cancer patients at Qilu Hospital of Shandong University from 2000 to 2022 were collected for external validation. RESULTS: Several independent risk factors were taken into the two nomograms (CSS and OS), including age, marital status, AJCC TMN stage, surgical approach, lymph node ratio, and tumor size while the OS nomogram additionally contained race. The concordance index of the training set, internal validation set, and external verification set were all over 0.7. The calibration curve indicated good consistence between the nomogram prediction and actual survival. Area under the curve and decision curve analysis results indicated great clinical usefulness of nomograms. CONCLUSIONS: The nomograms predicting the survival outcome of patients with micropapillary bladder cancer would provide a valuable tool to help clinicians to evaluate the risk of patients and make individual treatment strategies.

The function of Prostate Health Index in detecting clinically significant prostate cancer in the PI-RADS 3 population: a multicenter prospective study.

PURPOSE: The purpose of this study is to identify patients in the prostate imaging reporting and data system (PI-RADS) 3 population who need biopsy by using prostate health index (PHI) and other clinical parameters in order to avoid unnecessary biopsies. METHODS: A total of 302 patients from four hospital were enrolled, and 92 patients with PI-RADS 3 were included finally. All patients were biopsy-naïve and had suspicion of prostate cancer (PCa) with PSA level in 4-20 ng/ml and a normal digital rectal exam. Univariable and stepwise forward multivariable logistic regression analyses were used to evaluated the risk factors. The sensitivity, specificity, and positive and negative predictive values of different cut-off value of PHI were calculated for the diagnosis of clinically significant prostate cancer (CSPCa). RESULTS: The overall patient's mean age was 65.65 ± 9.55 years, median PSA was 7.68 (5.28-12.07) ng/ml and median PHI was 43.80 (33.09-64.69). PCa was identified in 32.61% (30/92) of PI-RADS 3 and CSPCa was identified in 28.26% (26/92) of PI-RADS 3. The risk factors for detecting PCa and CSPCa in multivariable regression analysis were age and PHI. When the biopsy was restricted to those PHI ≥ 43.5, 42.39% unnecessary biopsied could avoid. The sensitivity, specificity, positive predictive value and negative predictive value for the detection of CSPCa in the PHI ≥ 43.5 were 92.31%, 63.64%, 50% and 95.45% respectively. CONCLUSION: The inclusion of PHI in the diagnosis of the PI-RADS 3 population may avoid many unnecessary biopsies. The multivariable models could increase the detection of cancer.