The efficacy and safety of stereotactic body radiotherapy combined with systematic therapy for metastatic renal cell carcinoma: a systematic review and meta-analysis.

There is considerable interest in the potential of stereotactic body radiation therapy (SBRT) combined with systemic therapy such as tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs). However, its efficacy and safety remain unclear. The purpose of this study was to evaluate the efficacy and safety of conducting SBRT during ICI or TKI treatment in different disease settings for patients with metastatic renal cell carcinoma (mRCC). A total of 16 studies were ultimately included. Under the random effects model, the pooled 1-year local control rate (1-yr LCR) and objective response rate (ORR) were 90% (95% confidence interval [CI]: 80%-95%, I 2 = 67%) and 52% (95% CI: 37%-67%, I 2 = 90%), respectively. SBRT concomitant with different systemic therapy yield significant different 1-yr LCR (p < 0.01) and ORR (p = 0.02). Regarding survival benefits, the pooled 1-year progression-free survival (1-yr PFS) and 1-year overall survival (1-yr OS) rates were 45% (95% CI: 29%-62%, I 2 = 91%) and 85% (95% CI: 76%-91%, I 2 = 66%), respectively. 1-yr PFS and 1-yr OS in different disease settings demonstrated significant difference (p < 0.01). As for toxicity, the pooled incidence of grade 3-4 adverse events was 14% (95% CI: 5%-26%, I 2 = 90%). This study highlights the feasibility of utilizing these strategies in mRCC patients, especially those with a low metastatic tumor burden.

Establishment of bladder cancer spheroids and cultured in microfluidic platform for predicting drug response.

Cisplatin-containing combination chemotherapy has been used as the standard treatment for bladder cancer patients at advanced stage. However, nearly 50% of patients are nonresponders. To guide the selection of more effective chemotherapeutic agents, a bladder cancer spheroids microfluidic drug sensitivity analysis system was established in this study. Bladder cancer spheroids were established and successfully cultured in a customized microfluidic device to assess their response to different chemotherapeutic agents. The in vitro drug sensitivity results were also compared to patient-derived xenograft (PDX) models and clinical responses of patients. As a result, bladder cancer spheroids faithfully recapitulate the histopathological and genetic features of their corresponding parental tumors. Furthermore, the in vitro drug sensitivity outcomes of spheroids (n = 8) demonstrated a high level of correlation with the PDX (n = 2) and clinical response in patients (n = 2). Our study highlights the potential of combining bladder cancer spheroids and microfluidic devices as an efficient and accurate platform for personalized selection of chemotherapeutic agents.

Preoperative low plasma creatine kinase levels predict worse survival outcomes in bladder cancer after radical cystectomy.

BACKGROUND AND AIMS: To evaluate the prognostic significance of preoperative creatine kinase (CK) levels in bladder cancer (BCa) patients who underwent radical cystectomy (RC). MATERIALS AND METHODS: 570 BCa patients with RC were identified between 2010 and 2020. 108.5 U/L of CK levels were defined as the cutoff value. Logistic regression analysis and Cox regression models were performed to evaluate the association between CK levels and oncologic outcomes. Subgroup analyses were performed to address cofounding factors. RESULTS: Preoperative low CK levels were associated with worse recurrence-free survival (RFS, log-rank P = 0.001) and overall survival (OS, log-rank P = 0.002). Multivariate analysis revealed that preoperative low CK levels were an independent predictor for worse RFS (hazard ratio [HR]: 1.683; P < 0.001) and OS (HR: 1.567; P = 0.002). CONCLUSIONS: The preoperative low CK level independently predicts worse survival outcomes in BCa after RC. Incorporating it into prediction models might be valuable to assist risk stratification.

Targeting histone modifiers in bladder cancer therapy - preclinical and clinical evidence.

Bladder cancer in the most advanced, muscle-invasive stage is lethal, and very limited therapeutic advances have been reported for decades. To date, cisplatin-based chemotherapy remains the first-line therapy for advanced bladder cancer. Late-line options have historically been limited. In the past few years, next-generation sequencing technology has enabled chromatin remodelling gene mutations to be characterized, showing that these alterations are more frequent in urothelial bladder carcinoma than in other cancer types. Histone modifiers have functional roles in tumour progression by modulating the expression of tumour suppressors and oncogenes and, therefore, have been considered as novel drug targets for cancer therapy. The roles of epigenetic reprogramming through histone modifications have been increasingly studied in bladder cancer, and the therapeutic efficacy of targeting those histone modifiers genetically or chemically is being assessed in preclinical studies. Results from preclinical studies in bladder cancer encouraged the investigation of some of these drugs in clinical trials, which yield mixed results. Further understanding of how alterations of histone modification mechanistically contribute to bladder cancer progression, drug resistance and tumour microenvironment remodelling will be required to facilitate clinical application of epigenetic drugs in bladder cancer.

Bladder sparing by short-course radiotherapy combined with toripalimab in high-risk/extremely high-risk non-muscle invasive bladder cancer (HOPE-04): study protocol for a single-arm, prospective, phase II trial.

INTRODUCTION: Radical cystectomy remains the standard treatment for intravesical Bacille Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) because potential bladder-preserving therapies are not well established. Combination of radiotherapy with programmed death-1 (PD-1) antibody may offer an optional bladder preservation treatment for high-risk/extremely high risk NMIBC. Hence, the current study aims to investigate the safety and efficacy of short-course radiotherapy (5×5 Gy) and toripalimab (PD-1 antibody) as a novel bladder sparing treatment in this population. METHODS AND ANALYSIS: HOPE-04 is an open-label, single-arm, phase II study, designed to evaluate the safety and efficacy of short-course radiotherapy and toripalimab in patients with high-risk/extremely high risk NMIBC. Fifty-five patients with pathological and imaging diagnosed NMIBC with or without BCG treatment will be recruited. Radiotherapy of 5×5 Gy will be given to the whole bladder followed by a focal tumour bed boost and concomitant administration of toripalimab of 240 mg intravenous infusion every 21 days for 12 cycles (about 1 year). The primary endpoints are disease-free survival and safety. The secondary endpoint is overall survival. Additional indicators include implementation rate of salvage surgery and quality of life. ETHICS AND DISSEMINATION: This trial has been approved by the Ethics Committee of West China Hospital, Sichuan University. Trial findings will be disseminated via peer reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: Chinese Ethics Committee of Registering Clinical Trials (ChiCTR2200059970).

Utilization trend of prebiopsy multiparametric magnetic resonance imaging and its impact on prostate cancer detection: Real-world insights from a high-volume center in southwest China.

BACKGROUND: Data on the utilization and effects of prebiopsy prostate multiparametric magnetic resonance imaging (mpMRI) to support its routine use in real-world setting are still scarce. OBJECTIVE: To evaluate the change of clinical practice of prebiopsy mpMRI over time, and assess its diagnostic accuracy. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed data from 6168 patients who underwent primary prostate biopsy (PBx) between January 2011 and December 2021 and had prostate-specific antigen (PSA) values ranging from 3 to 100 ng/mL. INTERVENTION: Prebiopsy MRI at the time of PBx. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed general linear regression and to elucidate trends in the annual use of prebiopsy mpMRI and conducted multivariable logistic regression to evaluate the potential benefits of incorporating prebiopsy mpMRI for prostate cancer (PCa) detection. RESULTS AND LIMITATIONS: The utilization of prebiopsy mpMRI significantly increased from 9.2% in 2011 to 75.0% in 2021 (p < 0.001). In addition, prebiopsy mpMRI significantly reduced negative PBx by 8.6% while improving the detection of clinically significant PCa (csPCa) by 7.0%. Regression analysis showed that the utilization of prebiopsy mpMRI was significantly associated with a 48% (95% confidence interval [CI]: 1.19-1.84) and 36% (95% CI: 1.12-1.66) increased PCa detection rate in the PSA 3-10 ng/mL and 10-20 ng/mL groups, respectively; and a 34% increased csPCa detection rate in the PSA 10-20 ng/mL group (95% CI: 1.09-1.64). The retrospective design and the single center cohort constituted the limitations of this study. CONCLUSIONS: Our study demonstrated a notable rise in the utilization of prebiopsy mpMRI in the past decade. The adoption of this imaging technique was significantly associated with an increased probability of detecting prostate cancer. PATIENT SUMMARY: From 2011 to 2021, we demonstrated a steady increase in the utilization of prebiopsy mpMRI among biopsy-naïve men. We also confirmed the positive impact of prebiopsy mpMRI utilization on the detection of prostate cancer.

Cell softness reveals tumorigenic potential via ITGB8/AKT/glycolysis signaling in a mice model of orthotopic bladder cancer.

BACKGROUND: Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a micro-barrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells. METHODS: The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin ß8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. RESULTS: Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts. CONCLUSIONS: The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

Transperineal magnetic resonance imaging targeted biopsy versus transrectal route in the detection of prostate cancer: a systematic review and meta-analysis.

PURPOSE: Magnetic resonance imaging (MRI) has deeply altered the prostate biopsy strategy to detect prostate cancer. However, it is still debatable whether the detection rate differs between transrectal (TR) and transperineal (TP) MRI-targeted biopsy (MRI-TB). To compare the effectiveness of these two methods for detecting both overall prostate cancer (PCa) and clinically significant PCa (csPCa), We performed a review and meta-analysis. METHODS: Until January 2023, we conducted a thorough search of Cochrane, Embase, Ovid, and PubMed. In total, 1482 references were identified, and 15 records were finally included. For PCa and csPCa discovered by TP and TR MRI-TB, we combined the relative sensitivity (RR) with 95% confidence intervals (CI). The RR between the TP and TR routes was established. RESULTS: Our study included 8826 patients in total and revealed that TP MRI-TB detected more PCa (RR 1.25 [95% CI 1.12, 1.39], p < 0.0001). In patients who underwent TP MRI-TB and TR MRI-TB at the same time or separately, TP MRI-TB had a greater detection rate of csPCa in per-patient analysis (one cohort (RR 1.33 [95% CI 1.09, 1.63], p = 0.005); two cohorts (RR 1.37 [95% CI 1.16, 1.61], p = 0.0002)). However, the detection rate of csPCa between the TP route and the TR route was comparable in per-lesion analysis (RR 0.91 [95% CI 0.76, 1.08], p = 0.28). Additionally, in the prostate's anterior region, we found that TP MRI-TB detected more csPCa (per-lesion (RR 1.52 [95% CI 1.04, 2.23], p = 0.03); per-patient (RR 2.55 [95% CI 1.56, 4.16], p = 0.0002)). CONCLUSION: According to this comprehensive study, TP MRI-TB is more effective than TR MRI-TB at detecting PCa and csPCa. Significant results persisted for detecting csPCa located in the anterior zone. The results need to be taken carefully notwithstanding the heterogeneity among the included studies.

Characterization of site-specific N-glycosylation signatures of isolated uromodulin from human urine.

Uromodulin (Umod, Tamm-Horsfall protein) is the most abundant urinary N-glycoprotein produced exclusively by the kidney. It can form filaments to antagonize the adhesion of uropathogens. However, the site-specific N-glycosylation signatures of Umod in healthy individuals and patients with IgA nephropathy (IgAN) remain poorly understood due to the lack of suitable isolation and analytical methods. In this study, we first presented a simple and fast method based on diatomaceous earth adsorption to isolate Umod. These isolated glycoproteins were digested by trypsin and/or Glu-C. Intact N-glycopeptides with or without HILIC enrichment were analyzed using our developed EThcD-sceHCD-MS/MS. Based on the optimized workflow, we identified a total of 780 unique intact N-glycopeptides (7 N-glycosites and 152 N-glycan compositions) from healthy individuals. As anticipated, these glycosites exhibited glycoform heterogeneity. Almost all N-glycosites were modified completely by the complex type, except for one N-glycosite (N275), which was nearly entirely occupied by the high-mannose type for mediating Umod's antiadhesive activity. Then, we compared the N-glycosylation of Umod between healthy controls (n = 9) and IgAN patients (n = 9). The N-glycosylation of Umod in IgAN patients will drastically decrease and be lost. Finally, we profiled the most comprehensive site-specific N-glycosylation map of Umod and revealed its alterations in IgAN patients. Our method provides a high-throughput workflow for characterizing the N-glycosylation of Umod, which can aid in understanding its roles in physiology and pathology, as well as serving as a potential diagnostic tool for evolution of renal tubular function.

Utilizing the Lactate Dehydrogenase-to-Albumin Ratio for Survival Prediction in Patients with Bladder Cancer After Radical Cystectomy.

Purpose: Previous studies have suggested that the preoperative lactate dehydrogenase-to-albumin ratio (LAR) is correlated with survival in several cancers except bladder cancer (BCa). This study aimed to determine the prognostic value of the LAR in patients with urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC). Patients and Methods: A total of 595 UCB patients with RC in West China Hospital from December 2010 to May 2020 were enrolled. A receiver operating characteristic (ROC) curve was used to determine the optimal cutoff value of the LAR. Kaplan-Meier curves and Cox regression analyses were applied to evaluate the association of the LAR with overall survival (OS) and recurrence-free survival. Independent factors in multivariate analyses were selected to construct nomograms. Calibration curves, ROC curves, concordance index (C-index) and decision curve analyses were used to evaluate the performance of the nomograms. Results: The optimal cutoff value of the LAR was determined to be 3.8. Preoperative low LAR was associated with decreased OS (P < 0.001) and RFS (P < 0.001), especially in patients with ≥ pT2 disease. LAR was an independent factor for OS (hazard ratio [HR]: 1.719; P <0.001) and RFS (HR: 1.429; P = 0.012). The addition of the LAR into nomograms could result in better prediction performance. The areas under the curves of the nomograms were 0.821 and 0.801 for the prediction of 3-year OS and RFS, respectively. The C-indexes of the nomograms were 0.760 and 0.741 for the prediction of OS and RFS, respectively. Conclusion: The preoperative LAR is a novel and reliable independent prognostic biomarker for survival in UCB after RC.

Comparison of the survival outcomes between primary and secondary muscle-invasive bladder cancer: a propensity score-matched study.

BACKGROUND: Studies have classified muscle-invasive bladder cancer (MIBC) into primary (initially muscle-invasive, PMIBC) and secondary subtypes (initially non-muscle-invasive but progresses, SMIBC), for which controversial survival outcomes were demonstrated. This study aimed to compare the survival outcomes between PMIBC and SMIBC patients in China. METHODS: Patients diagnosed with PMIBC or SMIBC at West China Hospital from January 2009 to June 2019 were retrospectively included. Kruskal-Wallis and Fisher tests were employed to compare clinicopathological characteristics. Kaplan-Meier curves and Cox competing proportional risk model were used to compare survival outcomes. Propensity score matching (PSM) was employed to reduce the bias and subgroup analysis was used to confirm the outcomes. RESULTS: A total of 405 MIBC patients were enrolled, including 286 PMIBC and 119 SMIBC, with a mean follow-up of 27.54 and 53.30 months, respectively. The SMIBC group had a higher proportion of older patients (17.65% [21/119] vs. 9.09% [26/286]), chronic disease (32.77% [39/119] vs . 22.38% [64/286]), and neoadjuvant chemotherapy (19.33% [23/119] vs . 8.04% [23/286]). Before matching, SMIBC had a lower risk of overall mortality (OM) (hazard ratios [HR] 0.60, 95% confidence interval [CI] 0.41-0.85, P  = 0.005) and cancer-specific mortality (CSM) (HR 0.64, 95% CI 0.44-0.94, P  = 0.022) after the initial diagnosis. However, higher risks of OM (HR 1.47, 95% CI 1.02-2.10, P  = 0.038) and CSM (HR 1.58, 95% CI 1.09-2.29, P  = 0.016) were observed for SMIBC once it became muscle-invasive. After PSM, the baseline characteristics of 146 patients (73 for each group) were well matched, and SMIBC was confirmed to have an increased CSM risk (HR 1.83, 95% CI 1.09-3.06, P  = 0.021) than PMIBC after muscle invasion. CONCLUSIONS: Compared with PMIBC, SMIBC had worse survival outcomes once it became muscle-invasive. Specific attention should be paid to non-muscle-invasive bladder cancer with a high progression risk.

Combining clinical parameters and multiparametric magnetic resonance imaging to stratify biopsy-naïve men for an optimum diagnostic strategy with prostate-specific antigen 4 ng ml-1 to 10 ng ml-1.

We attempted to perform risk categories based on the free/total prostate-specific antigen ratio (%fPSA), prostate-specific antigen (PSA) density (PSAD, in ng ml-2), and multiparametric magnetic resonance imaging (mpMRI) step by step, with the goal of determining the best clinical diagnostic strategy to avoid unnecessary tests and prostate biopsy (PBx) in biopsy-naïve men with PSA levels ranging from 4 ng ml-1 to 10 ng ml-1. We included 439 patients who had mpMRI and PBx between August 2018 and July 2021 (West China Hospital, Chengdu, China). To detect clinically significant prostate cancer (csPCa) on PBx, receiver-operating characteristic (ROC) curves and their respective area under the curve were calculated. Based on %fPSA, PSAD, and Prostate Imaging-Reporting and Data System (PI-RADS) scores, the negative predictive value (NPV) and positive predictive value (PPV) were calculated sequentially. The optimal %fPSA threshold was determined to be 0.16, and the optimal PSAD threshold was 0.12 for %fPSA ≥0.16 and 0.23 for %fPSA <0.16, respectively. When PSAD <0.12 was combined with patients with %fPSA ≥0.16, the NPV of csPCa increased from 0.832 (95% confidence interval [CI]: 0.766-0.887) to 0.931 (95% CI: 0.833-0.981); the detection rate of csPCa was similar when further stratified by PI-RADS scores (P = 0.552). Combining %fPSA <0.16 with PSAD ≥0.23 ng ml-2 predicted significantly more csPCa patients than those with PSAD <0.23 ng ml-2 (58.4% vs 26.7%, P < 0.001). Using PI-RADS scores 4 and 5, the PPV was 0.739 (95% CI: 0.634-0.827) when further stratified by mpMRI results. In biopsy-naïve patients with PSA level of 4-10 ng ml-1, stratification of %fPSA and PSAD combined with PI-RADS scores may be useful in the decision-making process prior to undergoing PBx.

RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2-positive locally advanced muscle-invasive urothelial bladder cancer: a multi-center phase Ib/II study (HOPE-03).

Background: Bladder cancer with high expression of human epidermal growth factor receptor-2 (HER2) is related to pathological malignancy and poor prognosis. The standard care for muscle-invasive urothelial bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) with pelvic lymph node dissection. For HER2-positive MIBC, the efficacy of cisplatin-based NAC is unsatisfactory, and adverse reactions are inevitable or even intolerable. New regimens with higher efficiency and lower toxicity need to be explored in the neoadjuvant setting for this population. Methods: HOPE-03 is a multi-center, open-label, single-arm, phase Ib/II study aiming to evaluate the safety and efficacy of RC48-ADC (disitamab vedotin (DV)), a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, and tislelizumab (PD-1 antibody) as a novel neoadjuvant treatment combination in patients with HER2-positive locally advanced urothelial MIBC. Fifty-one patients with cT2-4bN0-3M0-1a pathology- and imaging-diagnosed HER2 positive (immunohistochemistry status 3+ or 2+ or 1+) MIBC were recruited. Of these patients, six were enrolled in the dose-escalation phase (three patients in the RC48-ADC 1.5 mg/kg group and three patients in the 2.0 mg/kg group), and 45 patients were enrolled in the phase II study (the expected recommended phase II dose for RC48-ADC was 2.0 mg/kg). Patients without disease progression received radical cystectomy or bladder-sparing therapies as their preference after neoadjuvant treatment. The primary endpoints were clinical complete remission rate (cCR rate; T0/Ta/Tis), pathological complete remission rate (pCR rate), and safety. The secondary endpoints were overall survival (OS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and quality of life. Discussion: The HOPE-03 trial provides a description of the safety profile of RC-48 and tislelizumab combination in the neoadjuvant treatment of HER2-positive locally advanced urothelial MIBC, and the efficacy is explored as well in this population. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=137111, identifier ChiCTR2200060153.

Proteomic Landscape of Human Spermatozoa: Optimized Extraction Method and Application.

Human spermatozoa proteomics exposed to some physical, biological or chemical stressors is being explored. However, there is a lack of optimized sample preparation methods to achieve in-depth protein coverage for sperm cells. Meanwhile, it is not clear whether antibiotics can regulate proteins to affect sperm quality. Here, we systematically compared a total of six different protein extraction methods based the combination of three commonly used lysis buffers and physical lysis strategies. The urea buffer combined with ultrasonication (UA-ultrasonication) produced the highest protein extraction rate, leading to the deepest coverage of human sperm proteome (5685 protein groups) from healthy human sperm samples. Since the antibiotics, amoxicillin and clarithromycin, have been widely used against H. pylori infection, we conduct a longitudinal study of sperm proteome via data-independent acquisition tandem mass spectrometry (DIA-MS/MS) on an infected patient during on and off therapy with these two drugs. The semen examination and morphological analysis were performed combined with proteomics analysis. Our results indicated that antibiotics may cause an increase in the sperm concentration and the rate of malformed sperm and disrupt proteome expression in sperm. This work provides an optimized extraction method to characterize the in-depth human sperm proteome and to extend its clinical applications.

The prognostic value of the systemic immune-inflammation index for patients with bladder cancer after radical cystectomy.

Background: Biomarkers acquired from blood samples are easy to obtain and cost-effective, have attracted considerable interest, and have been widely investigated. Inflammation plays a crucial role in cancer cell initiation, proliferation, and metastasis. We aimed to evaluate the association of the preoperative systemic immune-inflammation index (SII) with the clinical outcomes of patients diagnosed with bladder cancer and who underwent radical cystectomy (RC). Materials and methods: Data from patients diagnosed with bladder cancer and who underwent RC from December 2010 to May 2020 in West China Hospital were retrospectively collected according to the inclusion and exclusion criteria. Patients were divided into a low-SII group and a high-SII group according to the SII level. Survival outcomes were obtained during follow-up. The primary endpoints were overall survival (OS) and recurrence-free survival (RFS). Cox proportional hazard models were performed to estimate the effect of SII on OS and RFS and control for potential confoundings. Subgroup analyses were conducted, and the log likelihood ratio test was used to inspect the interaction. Results: A total of 725 patients who underwent RC were ultimately involved in this study. Of these patients, 621 (85.66%) were men and 104 (14.34%) were women. The median age was 65 years. The median follow-up was 36 months for OS and 33.6 months for RFS. The optimal cutoff value was identified as 554.23 × 109/l. A total of 467 (64.41%) patients were divided into the low-SII group (SII <554 × 109/l), and 258 (35.59%) patients were divided into the high-SII group (SII ≥554 × 109/l) accordingly. Multivariable Cox proportional hazard regression demonstrated that a high SII was an independent prognostic factor for worse OS (HR: 1.69 95% CI: 1.02-2.81, P = 0.0436) and RFS (HR: 1.88, 95% CI: 1.09-3.24, P = 0.0229) in NMIBC patients. A high SII was found to be an independent prognostic factor for worse RFS in patients with HBP (HR: 2.11, 95% CI: 1.34-3.30, P = 0.0012), with DM (HR: 3.76, 95% CI: 1.73-8.15, P = 0.0008), and without PNI (HR: 1.32, 95% CI: 1.04-1.69, P = 0.0238). Conclusions: The SII was a potential prognostic predictor for bladder cancer patients who underwent RC. Further prospective multicenter investigations are warranted.

Prognostic Utility of the Modified Glasgow Prognostic Score in Urothelial Carcinoma: Outcomes from a Pooled Analysis.

Background: Many studies explored the prognostic value of the modified Glasgow Prognostic Score (mGPS) in urothelial carcinoma (UC), but the results are controversial. This study aimed to quantify the relationship between pretreatment mGPS and survival in patients with UC. Methods: A systematic literature search was conducted using Embase, PubMed, and Web of Science to identify eligible studies published before August 2022. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the association between pretreatment mGPS and the prognosis of UC. Results: Thirteen eligible studies involving 12,524 patients were included. A high mGPS was significantly associated with poor overall survival (mGPS 1/0: HR = 1.33, 95% CI 1.12−1.58, p = 0.001; mGPS 2/0: HR = 2.02, 95% CI 1.43−2.84, p < 0.0001), progression-free survival (mGPS 1/0: HR = 1.26, 95% CI 1.03−1.53, p = 0.021; mGPS 2/0: HR = 1.76, 95% CI 1.12−2.77, p = 0.013), recurrence-free survival (mGPS 1/0: HR = 1.36, 95% CI 1.18−1.56, p < 0.0001; mGPS 2/0: HR = 1.70, 95% CI 1.44−2.000, p < 0.0001), and cancer-specific survival (mGPS 2/0: HR = 1.81, 95% CI 1.30−2.52, p < 0.0001). A subgroup analysis of OS also yielded similar results. Conclusions: Evidence suggests that high pretreatment mGPS in UC is closely related to poor survival. Pre-treatment mGPS is a powerful independent prognostic factor in patients with UC.

Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer.

Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.

The Role of Fluorescence In Situ Hybridization in the Surveillance of Non-Muscle Invasive Bladder Cancer: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Fluorescence in situ hybridization (FISH) has become a popular biomarker for subsequent monitoring the recurrence of non-muscle invasive bladder cancer (NMIBC), several studies have investigated the ability of FISH to detect recurrence in the surveillance of NMIBC. However, the results were inconsistent. METHODS: We conducted a systematic literature search extensively on authenticated databases including PubMed/Medline, Embase, Web of Science, Ovid, and Cochrane Library. Meta-analysis was performed to find out the sensitivity and specificity of FISH in predicting recurrence of NMIBC. RESULTS: 15 studies were ultimately included in this meta-analysis, a total of 2941 FISH evaluations from 2385 NMIBC patients were available. The pooled sensitivity of FISH was 68% (95% CI: 0.58-0.76), and the pooled specificity was 64% (95% CI: 0.53-0.74). Subgroup analyses were performed in 7 studies without Bacillus Calmette-Guerin (BCG) treatment, the pooled sensitivity was 82% (95% CI: 0.68-0.90), and the pooled specificity was 63% (95% CI: 0.37-0.82). And in 9 studies using "UroVysion standard" to define positive FISH results showed a pooled sensitivity of 60% (95% CI: 0.50-0.70) and specificity of 70% (95% CI: 0.61-0.78). CONCLUSIONS: The findings of this study indicate that FISH has a satisfactory sensitivity (68%) and specificity (64%) and could be a potential biomarker in the surveillance of NMIBC. Moreover, BCG treatment and different FISH methods may have an impact on the sensitivity and specificity, these factors should be taken into account when making clinical strategy.

CD93 orchestrates the tumor microenvironment and predicts the molecular subtype and therapy response of bladder cancer.

BACKGROUND: CD93 is newly reported to normalize vasculature and attenuate pancreatic cancer therapy response, but its role in bladder cancer (BLCA) is unknown. METHOD: The immunologic role of CD93 is analyzed across TCGA pan-cancers. The correlation between CD93 and BLCA clinical and tumor microenvironment features, predicted immunotherapy pathways, molecular subtypes, therapeutic signatures and mutation status was evaluated in TCGA-BLCA and other two BLCA cohorts. The impact of CD93 on immunotherapy response was validated by five real-world cohorts, and chemotherapy response was assessed with IC50. CD93-based risk model was constructed with LASSO regression and validated by seven independent cohorts. RESULT: CD93 is positively correlated with immunomodulators, tumor-infiltrating lymphocytes (TILs) and immune checkpoints across pan-cancers. In BLCA, CD93 leads to higher T cell inflamed score and expression of immune checkpoints. However, CD93 is indicative of more aggressive clinical features, worse survival, more tumor-associated macrophages and regulatory T cells recruitment, less recognition and killing of cancer cells by T cells, lower predicted chemotherapy and immunotherapy response, which is further validated by immunotherapy cohorts (IMvigor210: 16.11% vs 29.53%; GSE176307: 15.56% vs 20.93%). Notably, CD93 correlates with enriched neuroendocrine subtype and epithelial-mesenchymal transition differentiation, while CD93-low group has enriched luminal subtype. Pathways including hypoxia and Wnt-ß-catenin are enriched along with CD93 expression, and more frequent FGFR3 mutation is also observed. Lastly, the CD93-based risk model, validated by seven independent cohorts, is powerful in distinguishing the survival probability of BLCA (3-year AUC 0.808). CONCLUSION: CD93 plays a critical role in tumor immune regulation. CD93 expression indicates more aggressive clinicopathological status and molecular subtypes of BLCA and worse therapy response, which implies that combing anti-CD93 therapy with immunotherapy (or chemotherapy) may be potentially beneficial for BLCA in clinical practice.

Comprehensive Plasma N-Glycoproteome Profiling Based on EThcD-sceHCD-MS/MS.

Glycoproteins are involved in a variety of biological processes. More than one-third of the plasma protein biomarkers of tumors approved by the FDA are glycoproteins, and could improve the diagnostic specificity and/or sensitivity. Therefore, it is of great significance to perform the systematic characterization of plasma N-glycoproteome. In previous studies, we developed an integrated method based on the combinatorial peptide ligand library (CPLL) and stepped collision energy/higher energy collisional dissociation (sceHCD) for comprehensive plasma N-glycoproteome profiling. Recently, we presented a new fragmentation method, EThcD-sceHCD, which outperformed sceHCD in the accuracy of identification. Herein, we integrated the combinatorial peptide ligand library (CPLL) into EThcD-sceHCD and compared the performance of different mass spectrometry dissociation methods (EThcD-sceHCD, EThcD, and sceHCD) in the intact N-glycopeptide analysis of prostate cancer plasma. The results illustrated that EThcD-sceHCD was better than EThcD and sceHCD in the number of identified intact N-glycopeptides (two-folds). A combination of sceHCD and EThcD-sceHCD methods can cover almost all glycoproteins (96.4%) and intact N-glycopeptides (93.6%), indicating good complementarity between the two. Our study has great potential for medium- and low-abundance plasma glycoprotein biomarker discovery.