A case report of sustained remission after radiotherapy combined with ICI in NEPC with primary drug resistance to chemotherapy.

Advanced prostate cancer (PCa) is usually treated initially with androgen deprivation therapy (ADT). Although they experience a period of disease regression, most patients progress to metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC now have an unprecedented number of approved treatment options, including chemotherapies, hormone therapies, targeted therapies, etc. However, the improvement of overall survival (OS) in patients with mCRPC and its special subtype neuroendocrine prostate cancer (NEPC) is limited. In recent years, with the use of immune checkpoint inhibitors (ICIs), such as PD1/PDL1 and CTLA4 inhibitors, immunotherapy has once again become a promising treatment choice to stimulate antitumor immunity. However, the efficacy of NEPC receiving ICI has not been reported. Here, we describe a patient with mCRPC who developed primary resistance to current endocrine and chemotherapy regimens and progressed to mCRPC with NEPC as the main component, showing a significant and lasting response to PD1 monoclonal antibody combined with radiotherapy.

Wogonoside Ameliorates Airway Inflammation and Mucus Hypersecretion via NF-κB/STAT6 Signaling in Ovalbumin-Induced Murine Acute Asthma.

Asthma is recognized as a chronic respiratory illness characterized by airway inflammation and airway hyperresponsiveness. Wogonoside, a flavonoid glycoside, is reported to significantly alleviate the inflammation response and oxidative stress. Herein, this study aimed to investigate the therapeutic effect and underlying mechanism of wogonoside on airway inflammation and mucus hypersecretion in a murine asthma model and in human bronchial epithelial cells (16HBE). BALB/c mice were sensitized and challenged with ovalbumin (OVA). Pulmonary function and the number of cells in the bronchoalveolar lavage fluid (BALF) were examined. Pathological changes in lung tissue in each group were evaluated via hematoxylin and eosin and periodic acid-Schiff staining, and changes in levels of cytokines in BALF and of immunoglobulin E in serum were determined via an enzyme-linked immunosorbent assay. The expression of relevant genes in lung tissue was analyzed via real-time PCR. Western blotting and immunofluorescence were employed to detect the expression of relevant proteins in lung tissue and 16HBE cells. Treatment with 10 and 20 mg/kg wogonoside significantly attenuated the OVA-induced increase of inflammatory cell infiltration, mucus secretion, and goblet cell percentage and improved pulmonary function. Wogonoside treatment reduced the level of T-helper 2 cytokines including interleukin (IL)-4, IL-5, and IL-13 in BALF and of IgE in serum and decreased the mRNA levels of cytokines (IL-4, IL-5, IL-6, IL-13, and IL-1ß and tumor necrosis factor-α), chemokines (CCL-2, CCL-11, and CCL-24), and mucoproteins (MUC5AC, MUC5B, and GOB5) in lung tissues. The expression of MUC5AC and the phosphorylation of STAT6 and NF-κB p65 in lung tissues and 16HBE cells were significantly downregulated after wogonoside treatment. Thus, wogonoside treatment may effectively decrease airway inflammation, airway remodeling, and mucus hypersecretion via blocking NF-κB/STAT6 activation.

Targeting oxidative phosphorylation to increase the efficacy of immune-combination therapy in renal cell carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard of care for metastatic renal cell carcinoma (RCC); however, most patients develop de novo or acquired resistance to ICIs. Oxidative phosphorylation (OXPHOS) has been rarely explored as a potential target for correcting ICI resistance. METHODS: We systematically analyzed RNA sequencing and clinical data from CheckMate, JAVELIN Renal 101, and NCT01358721 clinical trials, and clinicopathological data of 25 patients from Tongji Hospital to investigate the relationship between OXPHOS and ICI resistance. The Ndufb8-knockdown Renca cell line was derived to determine the effect of OXPHOS on RCC immunotherapy in vivo. RESULTS: An analysis of the CheckMate series data revealed that high OXPHOS levels are risk factors for ICI in patients with RCC, but are affected by thevon Hippel-Lindau protein (VHL) and hypoxia-inducible factor-1α status. This result is consistent with correlation between clinicopathological characteristics and prognostic observations at our institute. Knockdown of the mitochondrial complex I subunit Ndufb8 of the Renca cell line had no effect on cell growth and migration in vitro, but slowed down cell growth in vivo. Among anti-programmed death ligand 1 (PD-L1)-treated BALB/c mice, shNdufb8 Renca tumors grew slower than shControl Renca tumors and the corresponding mice survived longer. Flow cytometry revealed that CD8+ T cells in shNdufb8 Renca tumors, which were exposed to a lower degree of hypoxia and expressed less programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3), secreted more interferon-γ after stimulation. Immunofluorescence demonstrated that the shNdufb8 Renca tumors had a higher proportion of CD8+ T cells and the proportion of these cells was lower in the hypoxic area. CONCLUSIONS: OXPHOS is a reliable predictor of immunotherapy response in RCC and is more pronounced in metastatic lesions. RCC cells generate a hypoxic tumor microenvironment and inhibit T-cell function through oxidative metabolism, thereby leading to immunotherapy resistance.

The diagnostic value of fluorescence in situ hybridization in secondary electroresection of bladder cancer.

OBJECTIVE: To investigate the utility of fluorescence in situ hybridization (FISH) in secondary electroresection of bladder cancer. METHODS: From January 2016 to April 2022, bladder cancer patients who had undergone secondary electroresection in Tongji Hospital and had preoperative urine FISH were recruited, and the positive rate, accuracy, sensitivity, specificity, genetic material changes and predictive power on malignancy degree of FISH in the secondary electroresection of bladder cancer were examined. RESULTS: Twenty-six patients with bladder cancer were included in this study, and 8 were confirmed by secondary electroresection, including 6 cases positive for FISH positive and 2 negative for FISH. Besides, among the subjects, 18 were without tumor recurrence, including 1 case with positive FISH results and 17 with negative FISH results. Tumor recurrence was diagnosed in 85.71% (6/7) of FISH-positive patients in secondary electroresection while only 10.53% (2/19) of FISH-negative patients were found to develop tumor recurrence in the secondary electroresection. The sensitivity of FISH for the detection of bladder cancer before secondary electroresection was 75%, with a specificity of 94.44%, and an accuracy of 88.46%. A 6-month follow-up revealed that 2 of the 8 recurrent patients underwent radical resection of bladder cancer, and the remaining 6 patients had no recurrence, as confirmed by regular bladder perfusion and microscopy. In the 18 non-recurrent patients during secondary electroresection, no recurrence developed. CONCLUSIONS: Urine FISH can achieve a high detection rate and specificity for secondary electroresection of bladder cancer. If a bladder cancer patient who are indicated for secondary electroresection is negative for urine FISH, the recurrence rate after secondary electroresection will be low, and the cystoscopy can be performed before deciding whether to perform secondary electroresection.

UroVysion™ fluorescence in situ hybridization (FISH) possibly has a high positive rate in carcinoma of non-urothelial lineages.

Background: Positive UroVysion™ fluorescence in situ hybridization (FISH) is generally considered as urothelial carcinoma (UC). We clarify if UroVysion™ FISH can be positive in carcinoma of non-urothelial lineages (CNUL), and verify the consistency of urine FISH and histological FISH in CNUL. Methods: All CNUL subjects detected by urine FISH assay due to haematuria from Tongji Hospital were screened. Meanwhile, 2 glandular cystitis and 2 urothelial carcinoma were served as negative or positive control. Paraffin-embedded tissue sections of all subjects were sent to the pathology department for histological FISH detection. Results: A total of 27 patients were included in this study, including 9 with adenocarcinomas, 11 with squamous cell carcinomas, and 7 with other tumour types. The overall positive rate in urine FISH was 64.00% (16/25) in patients with CNUL, 77.78% (7/9) in those with adenocarcinoma and 54.55% (6/11) in those with squamous carcinoma. There was a significant difference in the GLP p16 gene deletion rate between UC and CNUL (100% vs. 8.00%, p = 0.017). Histological FISH results showed that the histological results of 19 patients were consistent with their urine FISH results, and only one patient with stage Ⅲa urachal carcinoma had inconsistent histological FISH results (positive) and urine FISH (negative) results. Conclusion: We demonstrated for the first time the application value of FISH in CNUL on urine samples. Positive urine FISH tests indicate not only UC, but also CNUL. UroVysion™ FISH possibly has a high positive rate in CNUL. CNUL and UC have different genetic changes shown by FISH.

Identification of alternative splicing associated with clinical features: from pan-cancers to genitourinary tumors.

Background: Alternative splicing events (ASEs) are vital causes of tumor heterogeneity in genitourinary tumors and many other cancers. However, the clinicopathological relevance of ASEs in cancers has not yet been comprehensively characterized. Methods: By analyzing splicing data from the TCGA SpliceSeq database and phenotype data for all TCGA samples from the UCSC Xena database, we identified differential clinical feature-related ASEs in 33 tumors. CIBERSORT immune cell infiltration data from the TIMER2.0 database were used for differential clinical feature-related immune cell infiltration analysis. Gene function enrichment analysis was used to analyze the gene function of ASEs related to different clinical features in tumors. To reveal the regulatory mechanisms of ASEs, we integrated race-related ASEs and splicing quantitative trait loci (sQTLs) data in kidney renal clear cell carcinoma (KIRC) to comprehensively assess the impact of SNPs on ASEs. In addition, we predicted regulatory RNA binding proteins in bladder urothelial carcinoma (BLCA) based on the enrichment of motifs around alternative exons for ASEs. Results: Alternative splicing differences were systematically analyzed between different groups of 58 clinical features in 33 cancers, and 30 clinical features in 24 cancer types were identified to be associated with more than 50 ASEs individually. The types of immune cell infiltration were found to be significantly different between subgroups of primary diagnosis and disease type. After integrating ASEs with sQTLs data, we found that 63 (58.9%) of the race-related ASEs were significantly SNP-correlated ASEs in KIRC. Gene function enrichment analyses showed that metastasis-related ASEs in KIRC mainly enriched Rho GTPase signaling pathways. Among those ASEs associated with metastasis, alternative splicing of GIT2 and TUBB3 might play key roles in tumor metastasis in KIRC patients. Finally, we identified several RNA binding proteins such as PCBP2, SNRNP70, and HuR, which might contribute to splicing differences between different groups of neoplasm grade in BLCA. Conclusion: We demonstrated the significant clinical relevance of ASEs in multiple cancer types. Furthermore, we identified and validated alternative splicing of TUBB3 and RNA binding proteins such as PCBP2 as critical regulators in the progression of urogenital cancers.

Assessment of oculomotor function after prolonged computer use.

To analyze the specific effects of prolonged computer use on oculomotor function, we propose an oculomotor function evaluation system to analyze changes in oculomotor movement function by using an eye tracker to record eye movement data when performing gaze, smooth pursuit, and saccade under normal condition, after one hour and one and a half hours of continuous working at a computer. The captured eye movement data is pre-processed, and then data features are calculated and analyzed to understand the specific effects of continuously using the computer on the oculomotor function. The results show that the oculomotor function decreases as we gaze at the computer screen for longer periods, as evidenced by a decrease in the stability of the gaze function, a reduction in the gaze focus, a reduction in the speed of eye saccades, and a decrease in the smooth pursuit function. In short, the oculomotor function worsens after prolonged working at a computer. This paper presents the effects of continuously using the computer quantificationally for the first time. The proposed oculomotor function evaluation system could also be used to assess patients who have a disability in oculomotor function and specific individuals, e.g. pilots.

Sirtuin1 inhibits calcium oxalate crystal-induced kidney injury by regulating TLR4 signaling and macrophage-mediated inflammatory activation.

Sirtuin1 (Sirt1) activation significantly attenuated calcium oxalate (CaOx) crystal deposition and renal inflammatory injury by regulating renal immune microenvironment. Here, to elucidate the molecular mechanism underlying the therapeutic effects of Sirt1 on macrophage related inflammation and tubular epithelial cells (TECs) necrosis, we constructed a macrophage and CaOx monohydrate (COM)-stimulated tubular cell co-culture system to mimic immune microenvironment in kidney and established a mouse model of CaOx nephrocalcinosis in wild-type and myeloid-specific Sirt1 knockout mice. Target prediction analyses of Gene Expression Omnibus Datasets showed that only miR-34b-5p is regulated by lipopolysaccharides and upregulated by SRT1720 and targets the TLR4 3'-untranslated region. In vitro, SRT1720 suppressed TLR4 expression and M1 macrophage polarization and decreased reactive oxygen species (ROS) production and mitochondrial damage in COM-stimulated TECs by targeting miR-34b-5p. Mechanically, Sirt1 promoted miR-34b-5p expression by suppressing the tri-methylation of H3K27, which directly bound to the miR-34b-5p promoter and abolished the miR-34b-5p transcription. Furthermore, loss of Sirt1 aggravated CaOx nephrocalcinosis-induced inflammatory and oxidative kidney injury, while AgomiR-34b reversed these effects. Therefore, our data suggested that Sirt1 inhibited TLR4 signaling and M1 macrophage polarization and decreased inflammatory and oxidative injury of TECs in vitro and in vivo.

Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of ß2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

Development and validation of a clinic machine-learning nomogram for the prediction of risk stratifications of prostate cancer based on functional subsets of peripheral lymphocyte.

BACKGROUND: Non-invasive risk stratification contributes to the precise treatment of prostate cancer (PCa). In previous studies, lymphocyte subsets were used to differentiate between low-/intermediate-risk and high-risk PCa, with limited clinical value and poor interpretability. Based on functional subsets of peripheral lymphocyte with the largest sample size to date, this study aims to construct an easy-to-use and robust nomogram to guide the tripartite risk stratifications for PCa. METHODS: We retrospectively collected data from 2039 PCa and benign prostate disease (BPD) patients with 42 clinical characteristics on functional subsets of peripheral lymphocyte. After quality control and feature selection, clinical data with the optimal feature subset were utilized for the 10-fold cross-validation of five Machine Learning (ML) models for the task of predicting low-, intermediate- and high-risk stratification of PCa. Then, a novel clinic-ML nomogram was constructed using probabilistic predictions of the trained ML models via the combination of a multivariable Ordinal Logistic Regression analysis and the proposed feature mapping algorithm. RESULTS: 197 PCa patients, including 56 BPD, were enrolled in the study. An optimal subset with nine clinical features was selected. Compared with the best ML model and the clinic nomogram, the clinic-ML nomogram achieved the superior performance with a sensitivity of 0.713 (95% CI 0.573-0.853), specificity of 0.869 (95% CI 0.764-0.974), F1 of 0.699 (95% CI 0.557-0.841), and AUC of 0.864 (95% CI 0.794-0.935). The calibration curve and Decision Curve Analysis (DCA) indicated the predictive capacity and net benefits of the clinic-ML nomogram were improved. CONCLUSION: Combining the interpretability and simplicity of a nomogram with the efficacy and robustness of ML models, the proposed clinic-ML nomogram can serve as an insight tool for preoperative assessment of PCa risk stratifications, and could provide essential information for the individual diagnosis and treatment in PCa patients.

Neoadjuvant therapy with Disitamab vedotin in treating muscle-invasive bladder cancer: A case report.

Purpose: Platinum-based regimens are regarded as the preferred alternative for neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC) patients. However, some patients cannot tolerate platinum-based regimens. We report an MIBC case with severe renal insufficiency treated by neoadjuvant therapy with gemcitabine and Disitamab Vedotin. Materials and Methods: A 68-year-old man with severe renal insufficiency was admitted to our department and diagnosed with cT3N0M0 MIBC. Immunohistochemical staining of the biopsy tissues showed human epidermal growth factor receptor 2 expression (1+). This patient received neoadjuvant therapy with gemcitabine 1600 mg and DV 120 mg intravenously every three weeks 3 times. We compared the imaging results of the patient before and after neoadjuvant therapy. In addition, the white blood cell count, alanine aminotransferase, aspartate aminotransferase, and serum creatinine were followed up during neoadjuvant therapy. Abnormal symptoms such as hair loss, fatigue, and hypoesthesia were also recorded. Results: According to the imaging examinations, the lesions were significantly reduced after receiving neoadjuvant therapy. Significant adverse side effects did not occur during neoadjuvant therapy. Conclusions: In this T3N0M0 cisplatin-ineligible patient, gemcitabine combined with DV as neoadjuvant therapy achieved radiological partial response, and no significant adverse events were observed during neoadjuvant therapy.

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

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

Aerobic granular sludge formation and stability in enhanced biological phosphorus removal system under antibiotics pressure: Performance, granulation mechanism, and microbial successions.

Wastewater containing antibiotics can pose a significant threat to biological wastewater treatment processes. This study investigated the establishment and stable operation of enhanced biological phosphorus removal (EBPR) by aerobic granular sludge (AGS) under mixed stress conditions induced by tetracycline (TC), sulfamethoxazole (SMX), ofloxacin (OFL), and roxithromycin (ROX). The results show that the AGS system was efficient in removing TP (98.0%), COD (96.1%), and NH4+-N (99.6%). The average removal efficiencies of the four antibiotics were 79.17% (TC), 70.86% (SMX), 25.73% (OFL), and 88.93% (ROX), respectively. The microorganisms in the AGS system secreted more polysaccharides, which contributed to the reactor's tolerance to antibiotics and facilitated granulation by enhancing the production of protein, particularly loosely bound protein. Illumina MiSeq sequencing revealed that putative phosphate accumulating organisms (PAOs)-related genera (Pseudomonas and Flavobacterium) were enormously beneficial to the mature AGS for TP removal. Based on the analysis of extracellular polymeric substances, extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) theory, and microbial community, a three-stage granulation mechanism was proposed including adaption to the stress environment, formation of early aggregates and maturation of PAOs enriched microbial granules. Overall, the study demonstrated the stability of EBPR-AGS under mixed antibiotics pressure, providing insight into the granulation mechanism and the potential use of AGS for wastewater treatment containing antibiotics.

Cytoreductive partial and radical nephrectomies provide equivalent oncologic outcomes in T1-2M1 renal cell carcinoma.

Background: To compare the effectiveness of cytoreductive partial nephrectomy (CPN) and cytoreductive radical nephrectomy (CRN) in the treatment of metastatic T1-T2 renal cell carcinoma (RCC). Methods: We obtained the clinical and pathological data of patients with metastatic T1-T2 RCC who underwent CPN or CRN from the Surveillance, Epidemiology, and End Results (SEER) database (https://seer.cancer.gov). Propensity score matching (PSM) was used to balance differences in characteristics between CPN and CRN cases. Kaplan-Meier survival analysis and univariate and multivariate Cox regression were used to assess the effect of partial nephrectomy (PN) versus radical nephrectomy (RN) on overall survival (OS) and cancer-specific survival (CSS). Results: After screening, 866 eligible cases were obtained. During the 1-107 months of follow-up, 500 patients died, 453 (90.6%) of whom died of RCC. The tumor size in the CRN group was significantly greater than that in the CPN group. Kaplan-Meier survival analysis showed that there was no significant difference in OS and CSS between the CPN group and the CRN group before and after matching. Univariate and multivariate Cox regression analysis found that the risk factors for OS were older age at diagnosis [hazard ratio (HR) =1.02, P=0.008], non-clear cell renal cell carcinoma (ccRCC) pathological type (HR =1.69, P=0.002), number of metastases ≥2 (HR =2.13, P<0.001), and regional lymph node involvement (HR =2.22, P=0.004), while the risk factors for CSS were non-ccRCC pathological type (HR =1.51, P=0.021) and the number of metastases ≥2 (HR =2.24, P <0.001). Conclusions: CPN can provide similar oncologic outcomes as can CRN in T1-2M1 cases, and tumor metastatic burden is a major risk factor for survival in these patients with metastatic renal cell carcinoma (mRCC).

Partial and radical cystectomy provides equivalent oncologic outcomes in bladder cancer when combined with adequate lymph node dissection: A population-based study.

PURPOSE: To compare the oncologic outcomes of bladder cancer (BCa) patients after partial cystectomy (PC) or radical cystectomy (RC) combined with lymph node dissection (LND). METHODS: Relevant data from BCa patients who had >3 lymph nodes (LNs) removed were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Different thresholds of LN count in LND were tested to eliminate potential selection bias, and the optimal threshold was applied to screen patients who underwent adequate LND. After propensity score matching, the oncologic outcomes after PC or RC were compared in patients who underwent adequate LND. RESULTS: After preliminary screening, 6,785 BCa cases diagnosed between 2004 and 2015 with removal of > 3 LNs were enrolled in the analysis, including 633 (9.3%) PC cases and 6,152 (90.7%) RC cases. The PC and RC groups presented entirely different profiles in clinical parameters such as sex, T stage, number of lymph nodes (LNs) removed, and adjuvant therapy. In particular, the LN-positive rate and count were higher in the RC group, even after adjusting for other confounding factors. After comparison using different thresholds, the LN positive rate and count were similar when the LN count in LND was restricted to > 12. In patients who had > 12 LNs removed, after propensity score matching, PC and RC presented similar oncologic outcomes. Further exploration found that the prognosis of patients was associated with age, T stage, and the number of positive LNs. CONCLUSION: PC and RC could provide equivalent oncologic outcomes in BCa when combined with adequate LND. The conclusion needs further validation in future studies.

Identification of predictive factors for outcomes after robot-assisted partial nephrectomy based on three-dimensional reconstruction of preoperative enhanced computerized tomography.

Background: Information from the RENAL score is limited. This study aimed to identify new parameters based on three-dimensional (3D) reconstruction of preoperative enhanced computerized tomography (CT) for predicting outcomes after robot-assisted partial nephrectomy (RPN). Materials and methods: The records of kidney cancer patients who underwent RPN at Tongji Hospital from March 2015 to July 2019 were reviewed. Demographic data, laboratory examinations, postoperative hospitalization time, and enhanced CT were retrospectively collected. Some tumor parameters were obtained from 3D reconstruction of CT data. The association between these predictive factors and outcomes after RPN was analyzed. Results: A larger tumor bed area (TBA) was associated with a longer warm ischemia time (WIT) (P-value <0.001) and tumor resection time (P-value <0.001). Moreover, TBA was significantly associated with the elevation of postoperative creatinine (P-value = 0.005). TBA (P = 0.008), distance from the tumor to the first bifurcation of the renal artery (DTA) (P <0.034), and RENAL score (P = 0.005) were significantly associated with WIT in univariate logistic regression. In multivariate logistic regression, TBA (P = 0.026) and DTA (P = 0.048) were independent risk factors for prolonged WIT (over 25 min). The predictive effect of the combination of TBA, DTA, and RENAL score was higher than the predictive effect of RENAL score alone for WIT (area under curve: 0.786 versus 0.72). Conclusion: TBA and DTA are independently associated with the WIT of RPN, which provides additional assessment value for the complexity of kidney cancer in RPN over the RENAL score.

Proxalutamide in metastatic castration-resistant prostate cancer: Primary analysis of a multicenter, randomized, open-label, phase 2 trial.

We aim to assess the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, for men with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter, randomized, open-label, phase 2 trial. In our study, the enrolled mCRPC patients were randomized to 100, 200 and 300 mg dose groups at 1:1:1. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and time to PSA and radiographic progression. Safety and pharmacokinetics were also assessed. Finally, there were 108 patients from 17 centers being enrolled. By week 16, there were 13 (35.1%), 12 (36.4%) and 15 (42.9%) patients with confirmed 50% or greater PSA decline in 100 mg (n = 37), 200 mg (n = 33) and 300 mg (n = 35) groups, respectively. Among the 19 patients with target lesions at study entry, three (15.8%) had a partial response and 12 (63.2%) had stable disease. The ORRs of 20.0%, 22.2%, 0% and DCRs of 80.0%, 88.9%, 60.0% were, respectively, achieved in 100, 200 and 300 mg groups. By the maximum follow-up time of 24 weeks, there were 42.6% and 10.2% of cases experiencing PSA progression and radiographic progression, respectively. Overall, adverse events (AEs) were experienced by 94.4% of patients, most of which were mild or moderate. There were 28 patients experiencing ≥grade 3 AEs. The most common AEs were fatigue (17.6%), anemia (14.8%), elevated AST (14.8%) and ALT (13.0%), decreased appetite (13.0%). These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial (Clinical trial registration no. CTR20170177).

Preoperative accuracy of diagnostic evaluation of urachal carcinoma.

BACKGROUND: We analyzed the clinical data of patients with urachal carcinoma (UrC) in order to strengthen urologists' understanding of UrC and improve preoperative diagnosis. METHODS: The clinical data of 37 patients with UrC admitted to our hospital from October 2005 to April 2022 were retrospectively analyzed, and 40 patients with urothelial carcinoma (UCa) of bladder were enrolled as the control group. We compared and analyzed the imaging, cystoscopy and immunohistochemistry, serum tumor markers, fluorescence in situ hybridization (FISH) of UrC and bladder UCa for early diagnosis and evaluation of diagnostic accuracy. RESULTS: A total of 37 patients with UrC were enrolled in this study, including 30 males and seven females, with a median age of 52.00 (44.50-63.50) years. Imaging and cystoscopy suggest that UrC grows primarily outside the bladder cavity and is found in the middle line of the dome or anterior wall of the bladder. There was a significant difference in tumor location between the UrC group and the UCa group (10.13 mm vs. -7.06 mm, p < 0.001). Immunohistochemistry revealed that CK20 and CDX-2 were both diffusely and strongly positive. ß-catenin was strongly positive in cytoplasm and membrane, but negative in nuclear staining. Carcinoembryonic antigen (CEA) and carbohydrate antigen 72-4 (CA724) expression levels were significantly higher in the UrC group than in the UCa group (p < 0.05). In the diagnosis of UrC, the area under the curve (AUC) of CEA combined with CA724 was the greatest. FISH's sensitivity in diagnosing UrC (5/7, 71.43%) was not significantly different from that of UCa (71.43% vs. 77.50%, p = 0.659). Imaging examination has the highest sensitivity and specificity among the accuracy evaluation of different diagnostic methods. CONCLUSIONS: Imaging and cystoscopy are the powerful diagnostic methods for UrC. Serum tumor markers may assist in diagnosis, prognosis, and monitoring. Positive urine FISH can easily misdiagnose UrC as UCa.

Metabolic classifications of renal cell carcinoma reveal intrinsic connections with clinical and immune characteristics.

BACKGROUND: Kidney cancer undergoes a dramatic metabolic shift and has demonstrated responsiveness to immunotherapeutic intervention. However, metabolic classification and the associations between metabolic alterations and immune infiltration in Renal cell carcinoma still remain elucidative. METHODS: Unsupervised consensus clustering was conducted on the TCGA cohorts for metabolic classification. GESA, mRNAsi, prognosis, clinical features, mutation load, immune infiltration and differentially expressed gene differences among different clusters were compared. The prognosis model and nomograms were constructed based on metabolic gene signatures and verified using external ICGC datasets. Immunohistochemical results from Human Protein Atlas database and Tongji hospital were used to validate gene expression levels in normal tissues and tumor samples. CCK8, apoptosis analysis, qPCR, subcutaneously implanted murine models and flowcytometry analysis were applied to investigate the roles of ACAA2 in tumor progression and anti-tumor immunity. RESULTS: Renal cell carcinoma was classified into 3 metabolic subclusters and the subcluster with low metabolic profiles displayed the poorest prognosis, highest invasiveness and AJCC grade, enhanced immune infiltration but suppressive immunophenotypes. ACAA2, ACAT1, ASRGL1, AKR1B10, ABCC2, ANGPTL4 were identified to construct the 6 gene-signature prognosis model and verified both internally and externally with ICGC cohorts. ACAA2 was demonstrated as a tumor suppressor and was associated with higher immune infiltration and elevated PD-1 expression of CD8+ T cells. CONCLUSIONS: Our research proposed a new metabolic classification method for RCC and revealed intrinsic associations between metabolic phenotypes and immune profiles. The identified gene signatures might serve as key factors bridging tumor metabolism and tumor immunity and warrant further in-depth investigations.

Non-SMC condensin I complex subunit H participates in anti-programmed cell death-1 resistance of clear cell renal cell carcinomas.

Non-SMC condensin I complex subunit H (NCAPH) is reported to play an important role and be a poor prognostic factor in various cancers. However, the function and regulatory mechanism of NCAPH in clear cell renal cell carcinoma (ccRCC) remain unknown. The roles of NCAPH on ccRCC growth were detected in vitro and in vivo assays. The regulatory mechanism of NCAPH was explored by immunoprecipitation assay, ubiquitination assay, ChIP assay, RIP assay, luciferase reporter assay and RNA pull-down assay. The role of NCAPH in immunoregulation also was explored by flow cytometry, T cell-mediated tumour cell killing assay and immune-competent mouse model. In this research, we displayed that NCAPH was upregulated in ccRCC and patients with elevated NCAPH expression had an undesirable prognosis. Functionally, NCAPH depletion restrained ccRCC growth in vitro and in vivo. The elevated NCAPH was attributed to FOXP3-mediated transcription, FUS-mediated transcription splicing and METTL3-mediated m6A modification. Moreover, YTHDC1 promoted NCAPH mRNA nuclear export, and IGF2BP3 enhanced NCAPH mRNA stability in an m6A-dependent manner. NCAPH increased PD-L1 expression by inhibiting the degradation of ß-catenin in ccRCC cells, which further facilitated aerobic glycolysis and immune tolerance of ccRCC. Collectively, our findings display the vital function of NCAPH in ccRCC and uncover that NCAPH may be regarded as a potential therapeutic target to reverse the immune tolerance of ccRCC.