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.

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.

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.

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.

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.

Association of Triglyceride-Glucose Index with Risk of Large for Gestational Age: A Prospective Cohort Study.

Background: To evaluate the association of the baseline triglyceride-glucose (TyG) index in the first trimester of pregnancy with the risk of large for gestational age (LGA) in Southeast Chinese pregnant women. Methods: A prospective birth cohort study recruiting 12,108 pregnant women at their first prenatal visit before 13 gestation weeks was conducted in 2019-2022. Baseline characteristics were collected from medical records or using questionnaires and blood samples were collected in the first trimester. The TyG index was obtained through the formula: ln[triglyceride (mg/dl)×fasting plasma glucose (mg/dl)/2]. The binary logistic regression model was performed to calculate the odds ratio (OR) and 95% confidence intervals (CI) to reveal the relationship between TyG index and LGA. Receiver-operating characteristic curve analysis was conducted to evaluate the ability of the TyG index to predict the risks of LGA. Results: The overall incidence of LGA in the current study was 11.4% and the incidence of LGA increased with the baseline TyG index increasing. The risk of LGA was 2.05 (1.64, 2.57) for per unit increase in baseline TyG index. The increasing trend was found across the TyG index quartiles and the highest TyG quartiles raised the risk of LGA to 1.86 (95% CI: 1.51, 2.27) compared to the bottom TyG quartiles after full adjustment. The risk of LGA remained positive after stratification analysis. The AUC was 0.584 (95% CI: 0.569~0.600) in the entire subject, and the threshold was 8.34, with a sensitivity of 0.74 and specificity of 0.38. Conclusion: The findings suggested that a higher TyG index in the first trimester was independently associated with higher risk of LGA and high TyG index in the first trimester may play as a early predictor for LGA.

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.

Effect of heat-clearing and dampness-eliminating Chinese medicine for high-risk cervical cancer papillomavirus infection: a systematic review and meta-analysis of randomized controlled trials.

Background: Heat-clearing and dampness-eliminating Chinese medicine (HDCM) has been studied in clinical trials for cervical HPV infection for decades. However, there has been little comprehensive assessment of the strength and quality of the evidence. Therefore, this study conducted a systematic review and meta-analysis to assess the effectiveness and safety of HDCM in high-risk cervical HPV-infected patients. Methods: The research focus questions were constructed in accordance with the criteria of participants, intervention, comparison, and outcomes (PICO), and a protocol was registered in PROSPERO. Comprehensive and systematic searches and inquiries in eight electronic databases were conducted from their inception to 30th June 2022. Further, a systematic review and meta-analysis of all randomized controlled trials (RCTs) were conducted to evaluate the HDCM therapy methods. Results: A total of 12 studies were eligible for inclusion, including 1,574 patients. Data synthesis showed that the HPV clearance rate of HDCM groups was superior to both interferon and follow-up groups (RR = 1.40,95% CI:1.15, 1.71, P < 0.01) and (RR = 3.15, 95% CI:2.43,4.08, P < 0.01), respectively. HDCM was proven to exhibit greater potential in reducing HPV-DNA virus load (MD = -5.16, 95% CI: -5.91, -4.41, P < 0.01). The reversal rate of cervical intraepithelial neoplasia (CIN) for HDCM groups was approximately 2.8 times (RR = 2.80, 95% CI: 2.19, 3.57, P < 0.01), as high as the follow-up groups. Additionally, the recurrence rate of HR-HPV at the end of follow-up in this meta-analysis was reported to be lower in HDCM groups compared to follow-up groups [6.81% (16/235) and 14.65% (29/198), respectively]. The most commonly used Chinese herbal remedies were as follows: Huangbai (Phellodendron chinense var.Glabriusculum C.K. Schneid.), Kushen (Sophora flavescens Aiton), Daqingye (Isatis indigotica Fortune), Zicao (Arnebia hi-spidissima DC.), Baihuasheshecao (Hedyotis diffusa Spreng.), Banlangen (Isatis tinctoria subsp.tinctoria L.), Huzhang (Reynoutria japonica Houtt.), and Huangqi (Orobanche astragali Mouterde). Conclusion: HDCM interventions appeared to generate significant effects on enhancing the rate of HR-HPV clearance, reducing the HPV-DNA virus load, and increasing the CIN regression rate. Some active components were confirmed to be responsible for this efficacy, which deserves further exploration. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022333226.

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.

Clinical features of uterine sarcomas presenting mainly with uterine masses: a retrospective study.

BACKGROUND: Uterine sarcomas are uncommon mesenchymal tumors of the uterus. The clinical problem is that the features of uterine sarcomas can sometimes mimic uterine fibroids. This study aims to investigate the clinical characteristics of patients with uterine sarcomas who were preoperative presenting mainly with uterine masses. METHODS: A retrospective analysis of patients who underwent gynecological surgery for uterine sarcomas at the Obstetrics & Gynecology Hospital of Fudan University, between January 2016 and December 2021. RESULTS: Over the 5-year period, 277 patients were final diagnosed of uterine sarcomas. A total of 162 patients were preoperatively diagnosed as uterine fibroids for surgical treatment, the majority of whom were diagnosed of uterine leiomyosarcoma (uLMS) (49/162) and low-grade endometrial stromal sarcoma (LG-ESS) (100/162). Ninety people underwent total hysterectomy and bilateral salpingo-oophorectomy (TH + BSO), while 72 underwent myomectomy followed by supplemental TH + BSO. The group with direct hysterectomy had a higher average age than the group with prior myomectomy (47.20 ± 8.94 vs. 40.86 ± 5.88, p < 0.001). Among patients preoperatively diagnosed as uterine fibroids, patients with uLMS had a higher proportion of previous myomectomy (26.53% vs. 5.00%, p < 0.001), a larger uterine mass diameter on ultrasound (8.38 ± 3.39 cm vs. 6.41 ± 1.92 cm, p < 0.001), and richer hypervascularity (34.69% vs. 18%, p = 0.024) compared with LG-ESS. CONCLUSIONS: Analysis of our data showed that a large proportion of uterine sarcomas, especially uLMS and LG-ESS, present mainly with uterine masses. Ultrasound features including a large uterine mass diameter and rich hypervascularity, and with a history of myomectomy may alert clinicians in suspicion of uLMS when compared with LG-ESS.

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.

Exploiting Neighbor Effect: Conv-Agnostic GNN Framework for Graphs With Heterophily.

Due to the homophily assumption in graph convolution networks (GCNs), a common consensus in the graph node classification task is that graph neural networks (GNNs) perform well on homophilic graphs but may fail on heterophilic graphs with many interclass edges. However, the previous interclass edges' perspective and related homo-ratio metrics cannot well explain the GNNs' performance under some heterophilic datasets, which implies that not all the interclass edges are harmful to GNNs. In this work, we propose a new metric based on the von Neumann entropy to reexamine the heterophily problem of GNNs and investigate the feature aggregation of interclass edges from an entire neighbor identifiable perspective. Moreover, we propose a simple yet effective Conv-Agnostic GNN framework (CAGNNs) to enhance the performance of most GNNs on the heterophily datasets by learning the neighbor effect for each node. Specifically, we first decouple the feature of each node into the discriminative feature for downstream tasks and the aggregation feature for graph convolution (GC). Then, we propose a shared mixer module to adaptively evaluate the neighbor effect of each node to incorporate the neighbor information. The proposed framework can be regarded as a plug-in component and is compatible with most GNNs. The experimental results over nine well-known benchmark datasets indicate that our framework can significantly improve performance, especially for the heterophily graphs. The average performance gain is 9.81%, 25.81%, and 20.61% compared with graph isomorphism network (GIN), graph attention network (GAT), and GCN, respectively. Extensive ablation studies and robustness analysis further verify the effectiveness, robustness, and interpretability of our framework. Code is available at https://github.com/JC-202/CAGNN.

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.

A LASSO-derived prediction model for assessing the risk of lymph node metastasis in T1 and T2 epithelial ovarian cancer: an international retrospective cohort study.

INTRODUCTION: The necessity of lymphadenectomy remains controversial in patients with early ovarian cancer. This study aimed to estimate the prevalence of lymph node metastasis (LNM) in patients with apparent local epithelial ovarian cancer (EOC) and to develop a risk model for the prediction of LNM in local EOC with machine learning algorithms. MATERIALS AND METHODS: A cohort of 4110 patients who underwent lymphadenectomy with apparent local EOC were retrospectively evaluated. In the model development, a least absolute shrinkage and selection operator (LASSO)-derived Cox regression with internal 10-fold cross-validation was used to identify the risk factors of LNM. Clinical performance was assessed using the decision curve analysis, and a nomogram-based analysis was used to identify the risk factors for LNM. RESULTS: The incidence rate of LNM was rare in our cohort, at 7.4% (213/2885) in the primary set and 4.8% (59/1225) in the validation set. After feature selection, 10-fold internal validation, and external validation, our risk model performed well in both the discrimination (area under the curve=0.790 in the primary set and area under the curve=0.752 in the validation set) and the Hosmer-Lemeshow tests (P=0.873 in the primary set and P=0.380 in the validation set). Additionally, decision curve analysis demonstrated the superiority of our model for clinical interventions in daily practice. CONCLUSION: LNM is rare in patients with local EOC. In our study, which is based on machine learning algorithms, we developed a prediction model to identify patients with local EOC who could benefit from lymphadenectomy.

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.

Nomograms Combining PHI and PI-RADS in Detecting Prostate Cancer: A Multicenter Prospective Study.

(1) Background: The study aimed to construct nomograms to improve the detection rates of prostate cancer (PCa) and clinically significant prostate cancer (CSPCa) in the Asian population. (2) Methods: This multicenter prospective study included a group of 293 patients from three hospitals. Univariable and multivariable logistic regression analysis was performed to identify potential risk factors and construct nomograms. Discrimination, calibration, and clinical utility were used to assess the performance of the nomogram. The web-based dynamic nomograms were subsequently built based on multivariable logistic analysis. (3) Results: A total of 293 patients were included in our study with 201 negative and 92 positive results in PCa. Four independent predictive factors (age, prostate health index (PHI), prostate volume, and prostate imaging reporting and data system score (PI-RADS)) for PCa were included, and four factors (age, PHI, PI-RADS, and Log PSA Density) for CSPCa were included. The area under the ROC curve (AUC) for PCa was 0.902 in the training cohort and 0.869 in the validation cohort. The AUC for CSPCa was 0.896 in the training cohort and 0.890 in the validation cohort. (4) Conclusions: The combined diagnosis of PHI and PI-RADS can avoid more unnecessary biopsies and improve the detection rate of PCa and CSPCa. The nomogram with the combination of age, PHI, PV, and PI-RADS could improve the detection of PCa, and the nomogram with the combination of age, PHI, PI-RADS, and Log PSAD could improve the detection of CSPCa.

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.