Cuproptosis: Mechanism, role, and advances in urological malignancies.

Prostate, bladder, and kidney cancers are the most common malignancies of the urinary system. Chemotherapeutic drugs are generally used as adjuvant treatment in the middle, late, or recurrence stages after surgery for urologic cancers. However, traditional chemotherapy is plagued by problems such as poor efficacy, severe side effects, and complications. Copper-containing nanomedicines are promising novel cancer treatment modalities that can potentially overcome these disadvantages. Copper homeostasis and cuproptosis play crucial roles in the development, adaptability, and therapeutic sensitivity of urological malignancies. Cuproptosis refers to the direct binding of copper ions to lipoylated components of the tricarboxylic acid cycle, leading to protein oligomerization, loss of iron-sulfur proteins, proteotoxic stress, and cell death. This review focuses on copper homeostasis and cuproptosis as well as recent findings on copper and cuproptosis in urological malignancies. Furthermore, we highlight the potential therapeutic applications of copper- and cuproptosis-targeted therapies to better understand cuproptosis-based drugs for the treatment of urological tumors in the future.

Outcome comparison of radical prostatectomy versus seed brachytherapy for clinically localized prostate cancer using two biochemical recurrence definitions.

OBJECTIVE: We compared the outcome of radical prostatectomy (RP) with seed brachytherapy (BT) in clinically localized prostate cancer (LPCa) using two different biochemical recurrence (BCR) definitions. METHODS: Clinical data of 1117 patients with non-metastatic prostate cancer (PCa) treated with either RP or BT as the basis of the multimodal therapy from a single tertiary hospital between 2007 and 2021 were retrospectively analyzed. 843 LPCa patients (RP = 737, BT = 106) with at least one prostate-specific antigen (PSA) test after treatment were finally included. The BCR survival was evaluated by direct comparison and one-to-one propensity score matching (PSM) analysis using surgical definition (PSA ≥ 0.2ng/ml) for RP and surgical/Phoenix definition (PSA nadir + 2ng/ml ) for BT. The propensity score (PS) was calculated by multivariable logistic regression based on the clinicopathological parameters. RESULTS: Median follow-up was 43 months for RP patients and 45 months for BT patients. Kaplan-Meier analysis did not show any statistically significant differences in terms of BCR-free survival (BFS) between the two groups when using Phoenix definition for BT (P > 0.05). Similar results were obtained in all D'Amico risk groups when stratified analyses were conducted. However, RP achieved improved BFS compared to BT in the whole cohort and all risk groups with the surgical definition for BT(P < 0.05). After adjusting PS, 192 patients were divided into RP and BT groups (96 each). RP presented a better BFS than BT when using the surgical definition (P < 0.001), but no significant difference was found when using the Phoenix definition (P = 0.609). CONCLUSION: Inconsistent BCR-free survival outcomes were acquired using two different BCR definitions for BT patients. RP provided comparable BFS with BT using the Phoenix definition but better BFS using the surgical definition, regardless of whether the PSM was performed. Our findings indicated that an exact BCR definition was critical for prognostic assessment. The corresponding results will assist physicians in pretreatment consultation and treatment selection.

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Prostate cancer (PCa) is a pernicious tumor with high heterogeneity, which creates a conundrum for making a precise diagnosis and choosing an optimal treatment approach. Multiparametric magnetic resonance imaging (mp-MRI) with anatomical and functional sequences has evolved as a routine and significant paradigm for the detection and characterization of PCa. Moreover, using radiomics to extract quantitative data has emerged as a promising field due to the rapid growth of artificial intelligence (AI) and image data processing. Radiomics acquires novel imaging biomarkers by extracting imaging signatures and establishes models for precise evaluation. Radiomics models provide a reliable and noninvasive alternative to aid in precision medicine, demonstrating advantages over traditional models based on clinicopathological parameters. The purpose of this review is to provide an overview of related studies of radiomics in PCa, specifically around the development and validation of radiomics models using MRI-derived image features. The current landscape of the literature, focusing mainly on PCa detection, aggressiveness, and prognosis evaluation, is reviewed and summarized. Rather than studies that exclusively focus on image biomarker identification and method optimization, models with high potential for universal clinical implementation are identified. Furthermore, we delve deeper into the critical concerns that can be addressed by different models and the obstacles that may arise in a clinical scenario. This review will encourage researchers to design models based on actual clinical needs, as well as assist urologists in gaining a better understanding of the promising results yielded by radiomics.

MRI-Derived Radiomics Model to Predict the Biochemical Recurrence of Prostate Cancer Following Seed Brachytherapy.

OBJECTIVE: We aimed to investigate the predictive value of imaging features derived from magnetic resonance imaging (MRI) and develop a radiomics model predicting the biochemical recurrence-free survival (BFS) in prostate cancer (PCa) patients treated with seed brachytherapy (seed-BT). METHODS: The data of 272 patients with PCa treated with seed-BT at Peking University Third Hospital from 2007 to 2019 was retrospectively investigated. Based on the eligibility criteria, 83 patients were finally included in our study. The cohort was divided into two groups in a ratio of 8:2 (training set: n = 67, test set: n = 16). The Cox survival model combined with the least absolute shrinkage and selection operator (LASSO) algorithm was applied to select the radiomics features from T2WI of pretreatment MRI. A radiomics model with selected features was established to predict the BFS. RESULTS: Nineteen patients experienced biochemical recurrence (BCR) during a median follow-up period of 46 months. Three features with non-zero coefficients were selected from 1598 features and used to construct a radiomics model for BCR prediction. The model accurately predicted the BCR in both the training and test groups, for which the concordance index (C-index) were 0.83 and 0.78, respectively. Receiver operating characteristic (ROC) analysis of the test set was conducted to assess the prediction accuracy. The model achieved a high area under the operator curve (AUC) performance for BCR prediction in the test cohort. CONCLUSIONS: Our study revealed the considerable potential of a radiomics model based on MRI-derived imaging features in BCR prediction of PCa patients after seed-BT. Radiomics provides a new perspective to clinicians assessing the outcome of radiotherapy, facilitating accurate prognostic evaluation and preoperative consultation for PCa patients followed by seed-BT.

MRI-Derived Radiomics Model to Predict the Biochemical Recurrence of Prostate Cancer Following Seed Brachytherapy

Objective: We aimed to investigate the predictive value of imaging features derived from magnetic resonance imaging (MRI) and develop a radiomics model predicting the biochemical recurrence-free survival (BFS) in prostate cancer (PCa) patients treated with seed brachytherapy (seed-BT). Methods: The data of 272 patients with PCa treated with seed-BT at Peking University Third Hospital from 2007 to 2019 was retrospectively investigated. Based on the eligibility criteria, 83 patients were finally included in our study. The cohort was divided into two groups in a ratio of 8:2 (training set: n = 67, test set: n = 16). The Cox survival model combined with the least absolute shrinkage and selection operator (LASSO) algorithm was applied to select the radiomics features from T2WI of pretreatment MRI. A radiomics model with selected features was established to predict the BFS. Results: Nineteen patients experienced biochemical recurrence (BCR) during a median follow-up period of 46 months. Three features with non-zero coefficients were selected from 1598 features and used to construct a radiomics model for BCR prediction. The model accurately predicted the BCR in both the training and test groups, for which the concordance index (C-index) were 0.83 and 0.78, respectively. Receiver operating characteristic (ROC) analysis of the test set was conducted to assess the prediction accuracy. The model achieved a high area under the operator curve (AUC) performance for BCR prediction in the test cohort. Conclusions: Our study revealed the considerable potential of a radiomics model based on MRI-derived imaging features in BCR prediction of PCa patients after seed-BT. Radiomics provides a new perspective to clinicians assessing the outcome of radiotherapy, facilitating accurate prognostic evaluation and preoperative consultation for PCa patients followed by seed-BT (AU)

MRI-derived tumor volume as a predictor of biochemical recurrence and adverse pathology in patients after radical prostatectomy: a propensity score matching study.

PURPOSE: To investigate the predictive value of MRI-derived tumor volume (TV) of biochemical recurrence (BCR) and adverse pathology (AP) in patients following radical prostatectomy (RP). METHODS: The data of 565 patients receiving RP in a single institution between 2010 and 2021 were retrospectively analyzed. All suspicious tumor foci were delineated manually using ITK-SNAP software as the regions of interest (ROIs). The sum of the TV of all lesions was calculated automatically based on the voxel in the ROIs to acquire the final TV parameter. TV was categorized as low-volume (≤ 6.5 cm3) and high-volume (> 6.5 cm3) based on the cut-off value. Univariate and multivariate Cox and logistic regression analyses were performed to identify independent predictors of BCR and AP. The Kaplan-Meier with the log-rank test was conducted to compare the BCR-free survival (BFS) between the low and high-volume groups. RESULTS: All the included patients were divided into the low-volume group (n = 337) and the high-volume group (n = 228). The TV was an independent predictor of BFS in the multivariate Cox regression analysis (Hazard Ratio (HR) [95% CI]: 1.550 [1.066-2.256], P = 0.022). The Kaplan-Meier analysis demonstrated that low volume was associated with a better BFS than high volume before propensity score matching (PSM) (P < 0.001). One hundred and fifty-eight pairs were obtained by 1:1 PSM to balance the baseline parameters between the two groups. After the PSM, low-volume remained to be associated with a better BFS than high-volume (P = 0.006). TV as a categorical variable was an independent factor of AP in multivariate logistic regression analysis (Odd ratio (OR) [95% CI]: 1.821 [1.064-3.115], P = 0.029). After balancing the potential factors influencing AP by 1:1 PSM, 162 new pairs were identified. The high-volume group had a higher AP rate than the low-volume group after PSM (75.9 vs. 64.8%, P = 0.029). CONCLUSION: We adopted a novel approach to acquiring the TV on preoperative MRI. TV was significantly associated with BFS and AP of patients undergoing RP, which was further illustrated by PSM analysis. MRI-derived TV may serve as a predictive marker for assessing BFS and AP in further studies, which will facilitate clinical decision-making and patient counseling.

Metabolic syndrome and its components predict the biochemical recurrence and adverse pathological features of patients following radical prostatectomy: a propensity score matching study.

BACKGROUND: To investigate the predictive value of metabolic syndrome (MetS) and its components in biochemical recurrence (BCR) and adverse pathological features of patients with prostate cancer (PCa) after radical prostatectomy (RP). METHODS: A total of 525 PCa patients who underwent RP between 2010 and 2019 at Peking University Third Hospital were analyzed retrospectively. The Kaplan-Meier method was performed to assess BCR-free survival (BCRFS). Univariate and multivariate Cox regression models and multivariate logistic regression models were conducted to identify the predictive factors of BCRFS and adverse pathological features respectively before and after propensity score matching (PSM). RESULTS: Enrolled patients were allocated into MetS group (n = 136) and non-MetS group (n = 389) according to the presence or absence of MetS, and 127 new matched pairs were identified to balance the baseline characteristics after 1:1 PSM. In propensity matched patients, the Kaplan-Meier analysis revealed that MetS (P = 0.020), hyperglycemia (P = 0.015) and hypertriglyceridemia (P = 0.001) were significantly associated with worse BCRFS; the results of multivariate Cox analyses showed that hyperglycemia (P = 0.040), hypertriglyceridemia (P = 0.017), percentage of positive biopsy cores (P = 0.041) and prostate specific antigen (P = 0.019) were identified as independent prognostic factors for BCRFS. In addition, hypertriglyceridemia was independently associated with non-organ confined disease (NOCD) (P = 0.010), extra-capsular extension (ECE) (P = 0.010) and upgrading (P = 0.017) in the multivariate logistic analyses. CONCLUSIONS: Hyperglycemia and hypertriglyceridemia are the two effective MetS components both identified as independent risk factors for worse BCRFS after RP, while hypertriglyceridemia was independently associated with NOCD, ECE and upgrading as well.

Ultrasonic Microbubble Cavitation Enhanced Tissue Permeability and Drug Diffusion in Solid Tumor Therapy.

Chemotherapy has an essential role not only in advanced solid tumor therapy intervention but also in society's health at large. Chemoresistance, however, seriously restricts the efficiency and sensitivity of chemotherapeutic agents, representing a significant threat to patients' quality of life and life expectancy. How to reverse chemoresistance, improve efficacy sensitization response, and reduce adverse side effects need to be tackled urgently. Recently, studies on the effect of ultrasonic microbubble cavitation on enhanced tissue permeability and retention (EPR) have attracted the attention of researchers. Compared with the traditional targeted drug delivery regimen, the microbubble cavitation effect, which can be used to enhance the EPR effect, has the advantages of less trauma, low cost, and good sensitization effect, and has significant application prospects. This article reviews the research progress of ultrasound-mediated microbubble cavitation in the treatment of solid tumors and discusses its mechanism of action to provide new ideas for better treatment strategies.

Prognostic Value of Tumor Size in Patients with Upper Tract Urothelial Carcinoma: A Systematic Review and Meta-analysis.

Context: The role of tumor size in predicting prognosis in upper tract urothelial carcinoma (UTUC) patients remains poorly defined. Objective: To assess the prognostic value of tumor size in patients with UTUC through a systematic review and meta-analysis. Evidence acquisition: A comprehensive literature search of the PubMed and Embase databases were performed to identify all relevant articles published up to December 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Available hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) were analyzed to evaluate the association between tumor size and survival outcomes. Evidence synthesis: A total of 35 articles representing 32 292 patients met the eligibility criteria and were finally included for the meta-analysis. Tumor size was significantly associated with poor outcomes in terms of overall survival (HR = 1.42, 95% CI = 1.28-1.58), cancer-specific survival (HR = 1.66, 95% CI = 1.47-1.88), recurrence-free survival (HR = 1.25, 95% CI = 1.13-1.38), and intravesical recurrence (HR = 1.12, 95% CI = 1.04-1.20). There was between-study heterogeneity in the effect of tumor size on all these meta-analyses, with p < 0.10 and I2 generally >50%. Subgroup analyses illustrated that the association of tumor size with adverse prognosis in UTUC patients is not affected by treatment modalities. Segmental resection of ureter, whether receiving lymph node dissection, cutoff of tumor size, and region of population were potential sources of heterogeneity. The funnel plot test indicated no significant publication bias in the meta-analysis of survival outcomes. Conclusions: This study shows that larger tumor size is associated with an increased risk of overall and cancer-specific mortality, and disease recurrence in UTUC. Integration of tumor size with other prognostic indicators may help in risk stratification and individualized treatment of UTUC. Patient summary: Through a systematic review and meta-analysis, this study found that larger tumor size is associated with an increased risk of overall and cancer-specific mortality, and disease recurrence in patients with upper tract urothelial carcinoma.

Preoperative Metabolic Syndrome and HDL-C Level Predict the Prognosis of Patients Following Radical Cystectomy: A Propensity Score Matching Study.

Objective: To investigate the prognostic significance of metabolic syndrome (MetS) and its components in patients with bladder cancer (BCa) treated with radical cystectomy (RC). Methods: A total of 335 BCa patients who underwent RC between 2004 and 2019 at Peking University Third Hospital (PUTH) were analyzed retrospectively. The Kaplan-Meier method with the log-rank test was performed to assess overall survival (OS) and progression-free survival (PFS). Univariate and multivariate Cox proportional hazard models were conducted to identify the prognostic factors of OS and PFS before and after propensity score matching (PSM). Results: Enrolled patients were allocated into two groups according to the presence or absence of MetS (n=84 MetS vs n=251 non-MetS), and 82 new matched pairs were identified to balance the baseline characteristics after 1:1 PSM. In the Kaplan-Meier analysis, MetS was associated with better OS (P=0.031) than the group without MetS. In addition, a body mass index (BMI) ≥ 25 was associated with better OS (P=0.011) and PFS (P=0.031), while low high-density lipoprotein cholesterol (HDL-C) was associated with worse OS (P=0.033) and PFS (P=0.010). In all patients, multivariate Cox analysis showed that hemoglobin, pathologic tumor stage and lymph node status were identified as independent prognostic factors for both OS and PFS, while age, MetS and HDL-C were independent prognostic factors only for OS. Reproducible results of multivariate analysis can still be observed in propensity matched patients. The results of further subgroup analysis revealed that the association of MetS with increased OS (P=0.043) and BMI ≥25 with increased OS (P=0.015) and PFS (P=0.029) was observed in non-muscle invasive bladder cancer (NMIBC) patients. Conclusions: MetS was independently associated with better OS in BCa patients after RC, and HDL-C was the only component of MetS that was independently associated with worse OS. MetS and HDL-C may become reliable prognostic biomarkers of OS in BCa patients after RC to provide individualized prognostication and assist in the formulation of clinical treatment strategies.

Fusobacterium Nucleatum Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keap1/NRF2 Signaling.

Emerging research has revealed regulation of colorectal cancer metabolism by bacteria. Fusobacterium nucleatum (Fn) plays a crucial role in the development of colorectal cancer, however, whether Fn infection modifies metabolism in patients with colorectal cancer remains unknown. Here, LC-MS/MS-based lipidomics identified the upregulation of cytochrome P450 monooxygenases, primarily CYP2J2, and their mediated product 12,13-EpOME in patients with colorectal cancer tumors and mouse models, which increased the invasive and migratory ability of colorectal cancer cells in vivo and in vitro by regulating the epithelial-mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal Fn and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high Fn levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover, Fn was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that Fn promotes EMT and metastasis in colorectal cancer by activating a TLR4/Keap1/NRF2 axis to increase CYP2J2 and 12,13-EpOME, which could serve as clinical biomarkers and therapeutic targets for Fn-infected patients with colorectal cancer. SIGNIFICANCE: This study uncovers a mechanism by which Fusobacterium nucleatum regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13-EpOME axis in Fn-infected patients.

Ketogenic diet alleviates colitis by reduction of colonic group 3 innate lymphoid cells through altering gut microbiome.

Accumulating evidence suggests that ketogenic diets (KDs) mediate the rise of circulating ketone bodies and exert a potential anti-inflammatory effect; however, the consequences of this unique diet on colitis remain unknown. We performed a series of systematic studies using a dextran sulfate sodium (DSS) animal model of inflammatory colitis. Animals were fed with a KD, low-carbohydrate diet (LCD), or normal diet (ND). Germ-free mice were utilized in validation experiments. Colon tissues were analyzed by transcriptome sequencing, RT2 profiler PCR array, histopathology, and immunofluorescence. Serum samples were analyzed by metabolic assay kit. Fecal samples were analyzed by 16S rRNA gene sequencing, liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. We observed that KD alleviated colitis by altering the gut microbiota and metabolites in a manner distinct from LCD. Quantitative diet experiments confirmed the unique impact of KD relative to LCD with a reproducible increase in Akkermansia, whereas the opposite was observed for Escherichia/Shigella. After colitis induction, the KD protected intestinal barrier function, and reduced the production of RORγt+CD3- group 3 innate lymphoid cells (ILC3s) and related inflammatory cytokines (IL-17α, IL-18, IL-22, Ccl4). Finally, fecal microbiota transplantation into germ-free mice revealed that the KD- mediated colitis inhibition and ILC3 regulation were dependent on the modification of gut microbiota. Taken together, our study presents a global view of microbiome-metabolomics changes that occur during KD colitis treatment, and identifies the regulation of gut microbiome and ILC3s as novel targets involving in IBD dietary therapy.

Alterations in intestinal microbiota of colorectal cancer patients receiving radical surgery combined with adjuvant CapeOx therapy.

An intricate relationship exists and interactions occur between gut microbiota and colorectal cancer (CRC). Radical surgery combined with adjuvant chemotherapy (AC) serves as the mainstream therapeutic scheme for most CRC patients. The current research was conducted to assess the effect of surgery or chemotherapy on gut microbiota. Forty-three CRC patients who received radical surgery and AC were enrolled. Fecal samples were collected preoperatively, postoperatively, and after the first to fifth cycles of postoperative chemotherapy. The microbial community of each sample was analyzed using high throughput 16S rRNA amplicon sequencing. Compared with preoperative samples, fecal samples collected postoperatively exhibited a significant decrease of obligate anaerobes, tumor-related bacteria, and butyric acid-producing bacteria. However, a significant increase of some conditional pathogens was observed. In addition, the AC regimen (CapeOx) was found to alter intestinal microbiota dramatically. In particular, several changes were observed after chemotherapy including an increase of pathogenic bacteria, the "rebound effect" of chemotherapy-adapted bacteria, the shift of lactate-utilizing microbiota from Veillonella to Butyricimonas and Butyricicoccus, as well as the decrease of probiotics. Both radical surgery and CapeOx chemotherapy exert a non-negligible effect on the gut microbiota of CRC patients. Microbiota-based intervention may be beneficial for patients during postoperative clinical management.