RNF4 controls the extent of replication fork reversal to preserve genome stability.

Replication fork reversal occurs via a two-step process that entails reversal initiation and reversal extension. DNA topoisomerase IIalpha (TOP2A) facilitates extensive fork reversal, on one hand through resolving the topological stress generated by the initial reversal, on the other hand via its role in recruiting the SUMO-targeted DNA translocase PICH to stalled forks in a manner that is dependent on its SUMOylation by the SUMO E3 ligase ZATT. However, how TOP2A activities at stalled forks are precisely regulated remains poorly understood. Here we show that, upon replication stress, the SUMO-targeted ubiquitin E3 ligase RNF4 accumulates at stalled forks and targets SUMOylated TOP2A for ubiquitination and degradation. Downregulation of RNF4 resulted in aberrant activation of the ZATT-TOP2A-PICH complex at stalled forks, which in turn led to excessive reversal and elevated frequencies of fork collapse. These results uncover a previously unidentified regulatory mechanism that regulates TOP2A activities at stalled forks and thus the extent of fork reversal.

Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised, open-label, phase 3 trial.

BACKGROUND: Rezvilutamide, a novel androgen-receptor inhibitor with low blood-brain barrier penetration, has shown potent antitumour activity against metastatic castration-resistant prostate cancer. In this study, we aimed to evaluate the efficacy and safety of rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy (ADT) for high-volume, metastatic, hormone-sensitive prostate cancer. METHODS: CHART is a randomised, open-label, phase 3 study done at 72 hospitals in China, Poland, Czech Republic, and Bulgaria. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had high-volume metastatic, hormone-sensitive prostate cancer. Previous chemotherapy or other localised treatment for prostate cancer were not allowed. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. Randomisation was done via an interactive response technology system (block size of four) and stratified according to ECOG performance status and presence of visceral metastasis (excluding lymph nodes). Herein, we present the results of the preplanned interim analyses for the two co-primary endpoints of radiographic progression-free survival assessed by a blinded independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study medication. This study is ongoing, but is closed to recruitment. This trial is registered with ClinicalTrials.gov, NCT03520478. FINDINGS: Between June 28, 2018, and Aug 6, 2020, 792 patients were screened and 654 patients were randomly assigned to receive rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). At the preplanned interim analysis for radiographic progression-free survival (data cutoff May 16, 2021), the median follow-up duration was 21·2 months (IQR 16·6-25·8). Rezvilutamide significantly improved radiographic progression-free survival compared with bicalutamide (median radiographic progression-free survival not reached [95% CI not reached-not reached] vs 25·1 months [95% CI 15·7-not reached]; hazard ratio [HR] 0·44 [95% CI 0·33-0·58]; p<0·0001). At the preplanned interim analysis for overall survival (data cutoff Feb 28, 2022), the median follow-up duration was 29·3 months (IQR 21·0-33·3). Rezvilutamide significantly improved overall survival compared with bicalutamide (HR 0·58 [95% CI 0·44-0·77]; p=0·0001; median overall survival was not reached [95% CI not reached-not reached] vs not reached [36·2-not reached]). The most common grade 3 or worse adverse events of any cause in the safety population were hypertension (26 [8%] of 323 patients in the rezvilutamide group vs 24 [7%] of 324 patients in the bicalutamide group), hypertriglyceridaemia (24 [7%] vs seven [2%]), increased weight (20 [6%] vs 12 [4%]), anaemia (12 [4%] vs 16 [5%]), and hypokalaemia (11 [3%] vs four [1%]). Serious adverse events were reported in 90 (28%) of 323 patients in the rezvilutamide group and 69 (21%) of 324 patients in the bicalutamide group. No treatment-related deaths occurred in patients in the rezvilutamide group; one treatment-related death of unknown specific cause (<1%) occurred in the bicalutamide group. INTERPRETATION: In the two interim analyses, rezvilutamide plus ADT significantly improved radiographic progression-free survival and overall survival compared with bicalutamide plus ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, with a tolerable safety profile. FUNDING: Jiangsu Hengrui Pharmaceuticals.

Activity and safety of SHR3680, a novel antiandrogen, in patients with metastatic castration-resistant prostate cancer: a phase I/II trial.

BACKGROUND: Antagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC. METHODS: This phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12. RESULTS: A total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0-74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2-95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7-47.7) of 61 patients. CONCLUSION: SHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study. TRIAL REGISTRATION: Clinical trials.gov NCT02691975; registered February 25, 2016.

A comprehensive analysis of renal cell carcinoma as first and second primary cancers.

OBJECTIVE: Second primary renal cell carcinoma (2nd RCC) refers to renal cell carcinoma (RCC) diagnosed after another unrelated malignancy. This study aims to compare the clinical manifestation, pathology, treatment, and prognostic features of patients with 2nd RCC and first primary renal cell carcinoma (1st RCC). MATERIALS AND METHODS: Data of the patients with localized RCC were retrospectively collected. They were classified as 2nd RCC or 1st RCC according to a previously diagnosed cancer, including 113 cases of 2nd RCC and 749 cases of 1st RCC. RESULTS: The most common types of extrarenal malignancies in patients with 2nd RCC include lung, colorectal, breast, gynecological, and gastric cancers. The age and smoking rate of 2nd RCC patients were significantly higher than in those of 1st RCC patients. For 2nd RCC patients, fewer had clinical symptoms and renal masses tend to be smaller. One hundred and eight (95.6%) patients with 2nd RCC received surgical interventions. All patients with 1st RCC underwent renal surgery. More patients with 2nd RCC underwent a partial nephrectomy. Pathologically, there was no significant difference in postoperative pathological types between the 2nd and 1st RCCs. However, the 2nd RCCs were commonly identified in the early stages. The median overall survival (OS) of 2nd RCC patients was 117 months, which was shorter than that of 1st RCC patients. CONCLUSIONS: Second RCC is not uncommon. More attention should be paid to screening for 2nd RCC in cancer survivors. There are some differences between patients with 2nd and 1st RCCs that should be viewed separately.

Tislelizumab in Asian patients with previously treated locally advanced or metastatic urothelial carcinoma.

Tislelizumab, an anti-programmed death protein-1 (PD-1) monoclonal antibody, was engineered to minimize binding to the FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. This single-arm phase 2 trial (NCT04004221/CTR20170071) assessed the safety, tolerability, and efficacy of tislelizumab in patients with PD-L1-positive urothelial carcinoma who progressed during/following platinum-containing therapy and had no prior PD-(L)1 inhibitor treatment. Patients were considered PD-L1 positive if ≥ 25% of tumor/immune cells expressed PD-L1 when using the VENTANA™ PD-L1 (SP263) assay. The primary endpoint was objective response rate by independent review committee. As of September 16, 2019, 113 patients had a median study follow-up time of 9.4 mo. Most patients (76%) had visceral metastases, including 24% with liver and 23% with bone metastases. Among 104 efficacy-evaluable patients, confirmed objective response rate was 24% (95% confidence interval, 16, 33), including 10 complete and 15 partial responses. Median duration of response was not reached. Among 25 responders, 17/25 (68%) had ongoing responses. Median progression-free survival and overall survival times were 2.1 and 9.8 mo, respectively. The most common treatment-related adverse events were anemia (27%) and pyrexia (19%). Anemia (7%) and hyponatremia (5%) were the only grade 3-4 treatment-related adverse events and occurred in ≥ 5% of patients. Three investigator-assessed deaths were considered to be possibly related to study treatment (hepatic failure, n = 2; respiratory arrest, n = 1). Tislelizumab demonstrated meaningful clinical benefits in patients with previously treated locally advanced or metastatic PD-L1-positive urothelial carcinoma and had a manageable safety profile.

The clinical research of 5 steps sequential method for whole treatment of hemorrhagic radiation cystitis in china.

Background: Curing hemorrhagic cystitis remains a challenge. We explore a continuous and effective treatment for hemorrhagic radiation cystitis. Methods: The data of patients in 6 provincial cancer hospital urology departments between April 2015 and December 2019 was reviewed retrospectively. Patients were classified as moderate and severe groups. The 5-steps sequential method was adopted. Two groups were initiated with step 1 and step 3 respectively. Step 1 was symptomatic treatment. Thrombin solution or sodium hyaluronate was administrated for bladder irrigation in step 2. Step 3 was transurethral electrocoagulation. Step 4 was interventional embolization. Step 5 was HBO therapy. OABSS was used to assess the improvement of patients' symptoms. The outcome was evaluated after at least 6 months of follow-up. Results: A total of 650 patients (56 men and 594 women), mean age 71.2 years, were enrolled in the 5 steps sequential method. 582 patients were classified as moderate and 68 severe group. In moderate group, the cure rate of step 1 was 61.2% (356/582), 80.4% (468/582) after step 2, 93.1% (542/582) after step 3, 96.2% (560/582) after step 4, and 99.8% (581/582) after step 5. In severe group, the cure rate was 54.4% (37/68) after step 3, 76.5% (52/68) after step 4, and 94.1% (64/68) after the step 5 respectively. The mean OABSS scores of both groups significantly decreased after 5 steps sequential method treatment (P<0.01). Conclusions: Our results show hemorrhagic radiation cystitis can be cured in 5 steps, and the 5 steps sequential method is welcomed and effective. Therapy efficacy depends on the number of steps adopted and the severity of hematuria.

MiR-124 suppresses cell motility and adhesion by targeting talin 1 in prostate cancer cells.

BACKGROUND: MicroRNA is a type of endogenous non-coding RNA implicated in various cellular processes, and has been intensely investigated in the field of cancer research for many years. Here, we investigated the functions and mechanisms of miR-124 in prostate cancer, which is a putative tumor suppressor reported in many carcinomas. METHODS: Using bioinformatics, talin 1 was indicated as a potential target of miR-124. We examined the expression levels of miR-124 and talin 1 in tissue specimens and cell lines. To explore the relationship between miR-124 and talin 1, miR-124 mimics, miR-124 inhibitors, and talin 1 small interfering RNA (siRNA) were transiently transfected into cancer cell lines, followed by analysis using luciferase reporter assays. Next, to investigate the functions of miR-124 in prostate cancer, we performed cell attachment, migration, and invasion assays. A rescue experiment was also conducted to demonstrate whether miR-124 suppressed cell adhesion and motility by targeting talin 1. Finally, we examined the related signaling pathways of miR-124 and talin 1. RESULTS: MiR-124 was down-regulated in prostate cancer specimens and cell lines, while talin 1 was over-expressed in prostate cancer specimens and cell lines. These results showed an inverse correlation of miR-124 and talin 1 expression. Similar to talin 1 siRNA, overexpression of miR-124 by transient transfection of mimics led to a significant decrease in talin 1 levels. Luciferase report assays showed that the seed sequence of the talin 1 3'-untranslated region was a target of miR-124. Functional investigations revealed anti-attachment, anti-migration, and invasion-promoting effects of miR-124 in prostate cancer cells. The rescue experiment confirmed that miR-124 exerted its biological functions by targeting talin 1. Finally, we found that miR-124 and talin 1 impaired cellular adhesion and motility through integrins and the focal adhesion kinase/Akt pathway. CONCLUSIONS: Our study demonstrated biological roles and the related mechanism of miR-124 in prostate cancer. The results indicate that talin 1 is very likely a novel player in the anti-metastatic signaling network of miR-124. By down-regulation of talin 1, miR-124 impairs the adhesion, migration, and invasion of prostate cancer cells.

Changing trends in the causes and management of male urethral stricture disease in China: an observational descriptive study from 13 centres.

OBJECTIVE: To determine whether there have been any changes in the causes and management of urethral strictures in China. PATIENTS AND METHODS: The data from 4,764 men with urethral stricture disease who underwent treatment at 13 medical centres in China between 2005 and 2010 were retrospectively collected. The databases were analysed for the possible causes, site and treatment techniques for the urethral stricture, as well as for changes in the causes and management of urethral strictures. RESULTS: The most common cause of urethral strictures was trauma, which occurred in 2,466 patients (51.76%). The second most common cause was iatrogenic injures, which occurred in 1,643 patients (34.49%). The most common techniques to treat urethral strictures were endourological surgery (1,740, 36.52%), anastomotic urethroplasty (1,498, 31.44%) and substitution urethroplasty (1,039, 21.81%). A comparison between the first 3 years and the last 3 years showed that the constituent ratio of endourological surgery decreased from 54% to 32.75%, whereas the constituent ratios of anastomotic urethroplasty and substitution urethroplasty increased from 26.73% and 19.18% to 39.93% and 27.32%, respectively (P < 0.05). CONCLUSIONS: During recent years, there has been an increase in the incidence of urethral strictures caused by trauma and iatrogenic injury. Endourological urethral surgery rates decreased significantly, and open urethroplasty rates increased significantly during the last 3 years.

The iatrogenic injury of double vena cava due to misdiagnosis during the radical nephroureterectomy and cystectomy.

Double inferior vena cava (d-IVC) is a subtype of vascular anomaly that rarely needs treatment. Here, we present a rare case of d-IVC accompanied with concurrent renal pelvis and bladder carcinoma. Due to misdiagnosis, the anomalous left inferior vena cava (IVC) entering the left renal vein was mistaken as the gonadal vein and was then severed during the radical nephroureterectomy. Fortunately, the injured left IVC was recognized correctly during the following cystectomy. The vascular reconstruction operation was performed to recanalize the left iliac veins by anastomosing the ligated vascular stump to the right IVC in an 'end-to-side' way. During the hospitalization, the patient was treated with 'low molecular weight heparin' and then warfarin to ensure an ideal international normalized ratio. He recovered well from the surgery. A meticulous and comprehensive analysis of radiographic imaging is critical to avoid misdiagnosis of d-IVC.

Associations between vascular endothelial growth factor polymorphisms and prostate cancer risk: a meta-analysis.

Angiogenesis is crucial for the development and metastasis of common cancers, and vascular endothelial growth factor (VEGF) is a key mediator in the process of angiogenesis. Numerous studies assessed the associations of VEGF 1154G/A and 2578C/A polymorphisms with prostate cancer risk, but the results were inconsistent. We performed a meta-analysis to investigate the possible associations. Relevant studies were searched in PubMed and Embase databases. The pooled odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to evaluate the associations. Finally, eight individual case-control studies from seven publications were finally included into the meta-analysis. There were a total of 3,879 cases and 4,285 controls from those eight studies. Meta-analysis of those four case-control studies for VEGF 1154G/A polymorphism showed that VEGF 1154G/A polymorphism was weakly associated with risk of prostate cancer under the allele model (A versus G: OR = 0.68, 95 % CI 0.46-1.00, P = 0.05). Meta-analysis of four case-control studies for VEGF 2578C/A polymorphism showed that there was an association between VEGF 2578C/A polymorphism and prostate cancer under the recessive model (AA versus CC/CA: OR = 1.53, 95 % CI 1.01-2.30, P = 0.04). However, there was no obvious association in the other comparison models. Therefore, there is limited evidence for the associations of VEGF 1154G/A and 2578C/A polymorphisms with prostate cancer risk, and more studies are needed to further assess the associations above.

Primary ectopic atypical meningioma in the renal hilum: a case report.

BACKGROUND: Primary ectopic atypical meningioma involving the renal hilum is rare. This is, to our knowledge, only the second case report of a primary retroperitoneal meningioma and the first case of an atypical subtype in this location. CASE PRESENTATION: A 53-year-old Han Chinese man presented with a 2-year history of left-side flank pain. An oval-shaped retroperitoneal mass was found in the left renal hilum on computed tomography, which was resected en bloc along with the kidney via laparotomy. According to the World Health Organization criteria, the tumor was histopathologically classified as a meningioma (Grade II, atypical). Five years later, the tumor recurred at the primary site with a similar histopathology. The patient received palliative resection, followed by radiotherapy (4500 cGy in 25 fractions). No relapse was found at 6-month follow-up. CONCLUSION: We describe the clinical, radiographic and histopathological features of an unusual case of aggressive ectopic meningioma in the renal hilum. The patient presented with a massive retroperitoneal tumor without primary cerebral or secondary metastatic lesions; the preoperative diagnosis was naturally confined to the common retroperitoneal malignancies. This case is of interest to oncologists, because of both its rare location and aggressiveness; it not only enriched the spectrum of primary ectopic meningioma, but also reminded us of potential recurrence of an atypical meningioma. This case raises the issue of the etiology of such a rare tumor that needs further investigation, and more importantly demands long-term follow-up result.

Validation and identification of anoikis-related lncRNA signatures for improving prognosis in clear cell renal cell carcinoma.

BACKGROUND: Clear cell carcinoma (ccRCC) usually has a high metastasis rate and high mortality rate. To enable precise risk stratification, there is a need for novel biomarkers. As one form of apoptosis, anoikis results from the disruption of cell-cell connection or cell-ECM attachment. However, the impact of anoikis-related lncRNAs on ccRCC has not yet received adequate attention. METHODS: The study utilized univariate Cox regression analysis in order to identify the overall survival (OS) associated anoikis-related lncRNAs (ARLs), followed by the LASSO algorithm for selection. On this basis, a risk model was subsequently established using five anoikis-related lncRNAs. To dig the inner molecular mechanism, KEGG, GO, and GSVA analyses were conducted. Additionally, the immune infiltration landscape was estimated using the ESTIMATE, CIBERSORT, and ssGSEA algorithms. RESULTS: The study constructed a novel risk model based on five ARLs (AC092611.2, AC027601.2, AC103809.1, AL133215.2, and AL162586.1). Patients categorized as low-risk exhibited significantly better OS. Notably, the study observed marked different immune infiltration landscapes and drug sensitivity by risk stratification. Additionally, the study preliminarily explored potential signal pathways associated with risk stratification. CONCLUSION: The study exhibited the crucial role of ARLs in the carcinogenesis of ccRCC, potentially through differential immune infiltration. Furthermore, the established risk model could serve as a valuable stratification factor for predicting OS prognosis.

Integrative bioinformatics and in vitro exploration of EVI2A expression: unraveling its immunological and prognostic implications in kidney renal clear cell carcinoma.

EVI2A has emerged as a significant biomarker in various diseases; however, its biological role and mechanism in kidney renal clear cell carcinoma (KIRC) remains unexplored. We used TCGA and GEO databases to analyze EVI2A gene expression comprehensively and performed pan-cancer assessments. Clinical relevance was evaluated through Kaplan-Meier analysis and ROC curves. The gene's immune relevance was explored through analyses of the tumor microenvironment (TME), Tumor Immune Single-cell Hub (TISCH), immune checkpoints, and immunotherapy sensitivity. Our results indicate that EVI2A expression is upregulated in KIRC, showing correlations with tumor grade and T/N/M stage. EVI2A demonstrates high diagnostic accuracy (AUC=0.906) and predicts poor overall and progression-free survival in KIRC patients. Furthermore, EVI2A expression exhibits significant associations with immunity, including TME scores and specific immune cell types such as Tfh cells, CD4 memory T cells, and CD8+ T cells. Elevated EVI2A expression suggests increased sensitivity to PD-1/CTLA-4 and tyrosine kinase inhibitors. In vitro assays confirmed the impact of EVI2A on KIRC behavior, with its knockdown resulting in reduced cell proliferation and migration. In conclusion, our comprehensive analysis identifies EVI2A as a promising biomarker and a novel therapeutic target for intervening in KIRC. These findings hold significant implications for further research and potential clinical applications.

A novel risk signature based on liquid-liquid phase separation-related genes reveals prognostic and tumour microenvironmental features in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma(ccRCC) is one of the most common malignancies. However, there are still many barriers to its underlying causes, early diagnostic techniques and therapeutic approaches. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA)- Kidney renal clear cell (KIRC) cohort differentially analysed liquid-liquid phase separation (LLPS)-related genes from the DrLLPS website. Univariate and multivariate Cox regression analyses and LASSO regression analyses were used to construct prognostic models. The E-MTAB-1980 cohort was used for external validation. Then, potential functions, immune infiltration analysis, and mutational landscapes were analysed for the high-risk and low-risk groups. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) experiments as well as single-cell analyses validated the genes key to the model. RESULTS: We screened 174 LLPS-related genes in ccRCC and constructed a risk signature consisting of five genes (CLIC5, MXD3, NUF2, PABPC1L, PLK1). The high-risk group was found to be associated with worse prognosis in different subgroups. A nomogram constructed by combining age and tumour stage had a strong predictive power for the prognosis of ccRCC patients. In addition, there were differences in pathway enrichment, immune cell infiltration, and mutational landscapes between the two groups. The results of qRT-PCR in renal cancer cell lines and renal cancer tissues were consistent with the biosignature prediction. Three single-cell data of GSE159115, GSE139555, and GSE121636 were analysed for differences in the presence of these five genes in different cells. CONCLUSIONS: We developed a risk signature constructed based on the five LLPS-related genes and can have a high ability to predict the prognosis of ccRCC patients, further providing a strong support for clinical decision-making.

RC48-Antibody-Drug Conjugate in Metastatic Urothelial Carcinoma: A Multicenter Real-World Study in China.

OBJECTIVES: RC48 is an antibody-drug conjugate (ADC) that targets HER2. In China, RC48 is approved for patients with HER-2-positive metastatic urothelial carcinoma (mUC) who have failed at least platinum-based chemotherapy. This study aimed to evaluate RC48 for mUC in a cohort of real-world patients. MATERIALS AND METHODS: We retrospectively collected data from 103 mUC patients from 12 centers between July 2021 and August 2023 in China. RC48 alone or with immunotherapy was administered until disease progression, intolerable toxicity, death, or other reasons. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-related adverse events (TRAEs) were evaluated. RESULTS: The median age of the patients was 68 years, and 68.0% were men. Twenty-nine (28.2%) patients received RC48 alone; 73 (70.9%) received RC48 combination therapy. The response rates were as follows: complete response in 2 (1.9%) patients, partial response in 50 (48.5%) patients, stable disease in 30 (29.1%) patients. The ORR was 50.5%. In patients with ≥80 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and creatinine clearance rate (CCr) <30 mL/min, the ORR was 75%, 48.6%, and 40.0%, respectively. The median PFS was 6 (3.9-8.1) months, and the median OS was not reached. The most reported TRAEs were peripheral sensory neuropathy (53.4%), alopecia (42.7%), asthenia (38.8%), decreased appetite (35.9%) and weight loss (35.9%) and TRAE did not increase in patients with poor condition or impaired renal function. CONCLUSION: Administration of RC48 for real-world patients is both effective and safe. mUC patients can benefit from RC48-based therapy, regardless of their poor condition or impaired renal function.

Real-world effectiveness and safety of goserelin 10.8-mg depot in Chinese patients with localized or locally advanced prostate cancer.

OBJECTIVE: Real-word data on long-acting luteinizing hormone-releasing hormone (LHRH) agonists in Chinese patients with prostate cancer are limited. This study aimed to determine the real-world effectiveness and safety of the LHRH agonist, goserelin, particularly the long-acting 10.8-mg depot formulation, and the follow-up patterns among Chinese prostate cancer patients. METHODS: This was a multicenter, prospective, observational study in hormone treatment-naïve patients with localized or locally advanced prostate cancer who were prescribed goserelin 10.8-mg depot every 12 weeks or 3.6-mg depot every 4 weeks with or without an anti-androgen. The patients had follow-up evaluations for 26 weeks. The primary outcome was the effectiveness of goserelin in reducing serum testosterone and prostate-specific antigen (PSA) levels. The secondary outcomes included testosterone and PSA levels, attainment of chemical castration (serum testosterone <50 ng/dL), and goserelin safety. The exploratory outcome was the monitoring pattern for serum testosterone and PSA. All analyses were descriptive. RESULTS: Between September 2017 and December 2019, a total of 294 eligible patients received ≥ 1 dose of goserelin; 287 patients (97.6%) were treated with goserelin 10.8-mg depot. At week 24 ± 2, the changes from baseline [standard deviation (95% confidence interval)] in serum testosterone (n = 99) and PSA (n = 131) were -401.0 ng/dL [308.4 ng/dL (-462.5, -339.5 ng/dL)] and -35.4 ng/mL [104.4 ng/mL (-53.5, -17.4 ng/mL)], respectively. Of 112 evaluable patients, 100 (90.2%) achieved a serum testosterone level < 50 ng/dL. Treatment-emergent adverse events (TEAEs) and severe TEAEs occurred in 37.1% and 10.2% of patients, respectively. The mean testing frequency (standard deviation) was 1.6 (1.5) for testosterone and 2.2 (1.6) for PSA. CONCLUSIONS: Goserelin 10.8-mg depot effectively achieved and maintained castration and was well-tolerated in Chinese patients with localized and locally advanced prostate cancer.

Autophagy-related gene LAPTM4B promotes the progression of renal clear cell carcinoma and is associated with immunity.

Renal cell carcinoma (RCC) is a common urologic disease. Currently, surgery is the primary treatment for renal cancer; immunotherapy is not as effective a treatment strategy as expected. Hence, understanding the mechanism in the tumor immune microenvironment (TME) and exploring novel immunotherapeutic targets are considered important. Recent studies have demonstrated that autophagy could affect the immune environment of renal cell carcinoma and induce proliferation and apoptosis of cancer cells. By comparing lysosomal genes and regulating autophagy genes, we identified the LAPTM4B gene to be related to RCC autophagy. By analyzing the TCGA-KIRC cohort using bioinformatics, we found M2 macrophages associated with tumor metastasis to be significantly increased in the immune microenvironment of patients with high expression of LAPTM4B. GO/KEGG/GSEA/GSVA results showed significant differences in tumor autophagy- and metastasis-related pathways. Single-cell sequencing was used to compare the expression of LAPTM4B in different cell types and obtain the differences in lysosomal and autophagy pathway activities in different ccRCC cells. Subsequently, we confirmed the differential expression of LAPTM4B in renal cell carcinoma of different Fuhrman grades using western blotting. Downregulation of LAPTM4B expression significantly reduced the proliferation of renal cell carcinoma cells and promoted cell apoptosis through cell experiments. Overall, our study demonstrated that the autophagy-related gene LAPTM4B plays a critical role in the TME of RCC, and suggested that LAPTM4B is a potential therapeutic target for RCC immunotherapy.

Collecting Duct Carcinoma of the Kidney: Analysis of 74 Cases From Multiple Centers.

OBJECTIVE: To comprehensively describe the manifestations, diagnosis, treatment and prognosis of the collecting duct carcinoma (CDC) of the kidney. MATERIALS AND METHODS: We retrospectively collected data from 74 patients with CDC from two centers between January 2001 and December 2020. The clinical characteristics, imaging and pathological features, and diagnostic and treatment methods were analyzed. RESULTS: The mean age of the patients was 61.5 years, and 54.1% were males. The most common symptoms were low back pain, hematuria, and fatigue. Computed tomography was not specific, with 10.8% of the patients diagnosed with urothelial carcinoma and 4.1% with infectious disease. Thirty-two patients had metastasis at presentation, while 17.6% had tumor thrombus in the venous system. Twenty-two patients underwent renal biopsy, and 50% of the patients were diagnosed with CDC. Sixty-one renal surgeries were performed, and the pathological median diameter was 6.5 cm. Eight patients received immune checkpoint inhibitors, and the objective remission rate was 50%. The median follow-up time was 16 months, while the median overall survival was 24.0 months. The univariate and multivariable analysis showed that sarcomatoid differentiation and absence of renal surgery were predictors of mortality. CONCLUSION: CDC is highly aggressive. Patients are commonly diagnosed at an advanced stage. Early surgical treatment can improve prognosis. Though there is still a lack of standard treatment, immune checkpoint inhibitors bring new hope for the treatment of CDC.

PSMD2 promotes the progression of bladder cancer and is correlated with immune infiltration.

Introduction: PSMD2 plays an oncogenic role in multiple human malignancies, while it is still unclear that the potential roles and underlying mechanisms of PSMD2 in BCa. Methods: The RNA-seq from TCGA and GTEx database was utilized to preliminarily analyze the expression of PSMD2 in BCa tissues, qRT-PCR was adopted to verify the PSMD2 expression in BCa cell lines. Cox regression analyses were applied to assess the prognostic values of PSMD2 in BCa. GSEA analysis was used to explore the underlying mechanisms of PSMD2. In vitro assays such as wound healing and colony formation assays were applied to determine the carcinogenesis of PSMD2 in BCa. xCell and ssGSEA algorithms were applied to analyze the associations of PSMD2 with TIME. Results: The results revealed that in comparison with normal bladder tissues and cell line, PSMD2 was found to be significantly elevated in BCa tissues and cell lines. Elevated expression of PSMD2 can independently predict unfavorable OS for BCa patients. The PSMD2 expression and other clinicopathologic factors were combined to develop a nomogram, which can help to predict OS for BCa patients. GSEA analyses revealed that PSMD2 is correlated with the cell cycle, antigen processing and presentation, JAK-STAT signaling pathway, Toll like receptor signaling pathway, P53 and MAPK signaling pathway. Knockdown of PSMD2 could remarkably inhibit the wound healing and colony formation efficiency of BCa cells. xCell analysis revealed that overexpressed PSMD2 is positively related to the Th2 cells infiltrates and expression levels of immune escape markers, and negatively associated with the infiltrating levels of NK T cell and CD8+ T cell. Discussion: In conclusion, overexpressed PSMD2 is tightly linked to the immune infiltrates and promotes the progression of BCa.

Systematical analysis of ferroptosis regulators and identification of GCLM as a tumor promotor and immunological biomarker in bladder cancer.

Bladder cancer (BCa) is a life-threaten disease with an increasing incidence with age, and immunotherapy has become an important treatment for BCa, while the efficiency of the immune system declines with age. It is vital to reveal the mechanisms of tumor immune microenvironment (TIME) and identify novel immunotherapy targets for BCa. Through analyzing the RNA-seq of TCGA-BLCA cohort, we distinguished two ferroptosis-related BCa clusters, and we discovered that in comparation with cluster 2, the cluster 1 BCa patients showed higher PD-L1 expression, more unfavorable overall survival and higher tumor stage and grade. XCELL analyses showed that higher level of Th2 cell and Myeloid dendritic cell were enriched in cluster 1, while NK T cell was enriched in cluster 2, and TIDE analysis revealed that cluster 2 was more sensitive to immunotherapy than cluster 1. GSEA analysis implied that Toll-like signaling pathway and JAK_STAT signaling pathway were significantly enriched in cluster 1. Subsequently, through performing bioinformatic analysis and cell experiments, we demonstrated that GCLM is overexpressed in BCa and indicates dismal prognosis, and knockdown of GCLM can significantly suppress the colony formation ability of BCa cells. Furthermore, we also found that GCLM might be correlated with immune infiltration in BCa, and can serve as a tumor promotor and immunological biomarker in BCa, our research showed the vital roles of ferroptosis regulators in TIME of BCa, and GCLM is a latent therapeutic target for cancer immunotherapy.