ObjectiveThe objective of this pilot study was to assess the effectiveness of a (multimodal) structured training program, using (stepwise) stages of experience, to improve laparoscopic partial nephrectomy (LPN) skills among two groups of urology (URO) trainees. Key metrics of performance (KPIs) were recorded and compared between the groups.ResultsTime to being ready for the first supervised laparoscopic partial nephrectomy (LPN) for the structured training group was significantly less than the control group (5.65 months vs. 6.80 months; p < 0.001), as was duration for performing the first LPN (88.15 min vs. 101.35 min; p < 0.001). The structured training group received higher faculty performance scores than the control group (8.30 vs. 7.15, p < 0.001).ConclusionThe development of a standardized structured training curriculum resulted in enhanced skill acquisition and an improved initial operative performance compared to a control group. However, while these results are encouraging, they are preliminary and limited by the lack of an equivalent concurrently documented control. Therefore, these results should be interpreted as evidence demonstrating the benefit of a systematic approach to surgical education and require further investigation through multicenter studies.

Homeobox B4 (HOXB4) is a homeobox transcription factor implicated in development and oncogenesis; however, its role in bladder cancer (BCa) remains insufficiently defined. Bladder cancer is among the most common malignancies worldwide, and its high rates of recurrence and progression highlight the need to identify new molecular drivers and therapeutic targets. In this study, we show that HOXB4 is overexpressed in BCa and that elevated levels of HOXB4 are associated with unfavorable clinical outcomes. Functionally, HOXB4 knockdown markedly suppressed cellular proliferation, migration, invasion, and experimental lung colonization in vitro and in vivo. Furthermore, transcriptomic analyses and validation assays, including quantitative PCR, immunoblotting, RNA-sequencing, luciferase reporter, and chromatin immunoprecipitation (ChIP) assays, demonstrated that perturbing HOXB4 modulates Hedgehog signaling. Mechanistically, HOXB4 bound to the Smoothened (SMO) promoter and transcriptionally activated SMO, thereby amplifying Hedgehog pathway activity and promoting malignant phenotypes in BCa cells. Collectively, these findings delineate a HOXB4-SMO axis that drives BCa progression and suggest this pathway as a candidate target for patient stratification and therapeutic exploration. Future studies should validate these findings in larger multi-center cohorts and assess the therapeutic potential of SMO inhibition in preclinical BCa models.

Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS, NIH category Ⅲ) remains a challenging condition with no universally accepted treatment. Although alpha-blockers and antibiotics are commonly used, their efficacy is inconsistent. Purpose In this study, we aimed to evaluate the efficacy and safety of Qianlieshutong Capsules (QLSTCs, a standardized traditional Chinese medicine) combined with tamsulosin versus tamsulosin alone in patients with CP/CPPS. Methods In this post-marketing, multicenter, randomized, double-blind, single-dummy clinical trial, 240 male patients aged 18–50 years diagnosed with CP/CPPS were randomly assigned (1:1) to receive either QLSTCs (0.4 g/capsule, 3 capsules, three times daily) plus tamsulosin (0.2 mg nightly) or a matching placebo plus tamsulosin for 8 weeks. The primary endpoint was the change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score from baseline to week 8. Secondary outcomes included changes in the NIH-CPSI score at week 4, domain-specific scores (pain, urinary symptoms, quality of life), and treatment response rates. Safety was assessed through adverse events (AEs), laboratory tests, vital signs, and ECG. Results Of the 240 randomized patients, baseline characteristics were comparable. At week 8, the combination group showed a significantly greater reduction in the total NIH-CPSI score than the control group (−14.30 ± 0.53 vs. −10.60 ± 0.54; mean difference = 3.70, 95% CI: 2.36–5.04; P < 0.0001). The effective response rate and marked improvement rate were significantly higher in the combination group. Improvements were also significant in all NIH-CPSI domains at week 8. AE incidences were low and comparable between groups (10.00% vs. 9.24%), with no serious AEs reported. Conclusion The combination of QLSTCs and tamsulosin is a safe and more effective treatment than tamsulosin alone for CP/CPPS, offering superior symptom relief, particularly in pain, urinary symptoms, and quality of life. This approach may serve as a promising multimodal therapeutic option in clinical practice.

Abstract Background 177Lu-PSMA-617 is a radioligand therapy targeting cells expressing prostate-specific membrane antigen (PSMA). The pharmacokinetics, dosimetry, and safety of 177Lu-PSMA-617 in participants with metastatic castration-resistant prostate cancer are described previously. In this study, we describe the blood pharmacokinetics behavior, biodistribution, and dosimetry of 177Lu-PSMA-617 to support its clinical use in Chinese participants. Results Nine participants were infused with 177Lu-PSMA-617 (range: 6985.6–8036.0 MBq). The geometric (Geo)-mean blood terminal half-life was 52.6 h, corresponding to an effective half-life of approximately 40 h. The Geo-mean maximum blood concentration of 11.3 ng/mL was achieved at a median time of 0.217 h post administration. The Geo-mean volume of distribution and clearance were 123 L and 1.62 L/h, respectively. The lacrimal glands received the highest absorbed dose of 3.1 mGy/MBq (Geo-coefficient of variation, 93.7%), followed by the thyroid, kidneys, and salivary glands. The Geo-mean whole-body effective dose was 890 mSv (Geo-coefficient of variation, 112.4%). Conclusions The blood pharmacokinetics and organ dosimetry of 177Lu-PSMA-617 in Chinese participants with progressive metastatic castration-resistant prostate cancer were consistent with those previously reported. The cumulative absorbed dose, corresponding to six cycles of treatment, was consistent with published literature. This analysis was conducted as part of a phase II study registered as NCT05670106 at ClinicalTrials.gov on November 7, 2022.

Metastatic castration-resistant prostate cancer (mCRPC) after treatment with docetaxel and androgen receptor signaling inhibitors (ARSIs) has limited treatment options. Although enzalutamide has shown activity after abiraterone and docetaxel, robust evidence from randomized phase III trials is lacking. Deutenzalutamide, a novel derivative with slower metabolism and improved pharmacokinetics, may offer enhanced safety and efficacy. This phase III, double-blind trial conducted at 36 centers in China enrolled patients whose disease progressed on or who were intolerant to abiraterone and docetaxel, or who were ineligible for docetaxel. Patients were randomized (2:1) to receive deutenzalutamide 80 mg once daily or placebo until progression or unacceptable toxicity; the primary endpoint was radiographic progression-free survival (rPFS). Of 417 patients (276 deutenzalutamide; 141 placebo), all had previously received abiraterone, and 68% had also received docetaxel. Deutenzalutamide significantly improved rPFS (HR, 0.58; P = 0.0001), reducing the risk of progression by 42%. Although the initial OS analysis was not significant (HR, 0.95), sensitivity analyses adjusting for subsequent therapies showed significant OS benefits (HR, 0.65-0.73). Treatment-related grade 3 or higher adverse events occurred in 22.3% of patients treated with deutenzalutamide, compared with 15.0% with placebo. The most common treatment-related adverse event was anemia, reported at any grade in 21.2% versus 17.9%, with grade 3/4 anemia in 6.6% versus 2.9%, respectively. Notably, no seizures or falls were reported. In summary, deutenzalutamide significantly prolonged rPFS and, after adjustment, showed a potential OS benefit with a favorable safety profile, supporting its promise as a new treatment option for mCRPC. Clinical trial registration: NCT03851640.

Although immunotherapy has shown promise in improving outcomes for bladder cancer (BCa) patients, treatment responses remain highly variable. A comparative examination of the tumor microenvironment (TME) between responders and non-responders may reveal key resistance mechanisms and identify potential therapeutic targets. We integrated spatial transcriptomics, single-cell RNA sequencing, and multiplexed immunofluorescence to characterize spatial structures within the TME that influence response to anti-PD-1 therapy in BCa patients. In non-responders, we observed an accumulation of stem-like malignant epithelial cells with high MYBL2 expression near the tumor boundary. Furthermore, we identified a spatial triad structure-composed of SPP1+ tumor-associated macrophages (TAMs), POSTN+ cancer-associated fibroblasts (CAFs), and endothelial cells-located at the tumor periphery. This structure was associated with T-cell exclusion and reduced efficacy of immune checkpoint blockade. In a preclinical model, inhibiting SPP1 enhanced the response to anti-PD-1 therapy, resulting in reduced CAF infiltration and increased recruitment of cytotoxic T cells. Our study reveals a triad cellular structure mediated by SPP1+ TAMs, POSTN+ CAFs, and endothelial cells that contribute to immunotherapy resistance in BCa. Targeting this structure, particularly through SPP1 blockade, represents a promising strategy to augment the efficacy of immune checkpoint inhibitors.

Background: Bladder cancer (BCa) is a prevalent and aggressive malignancy characterized by high recurrence and metastasis rates. Despite advances in treatment, the prognosis for patients with advanced BCa remains poor. This study aimed to investigate the role of SAPCD2 in BCa progression and its potential as a therapeutic target. Methods: We performed a series of in vitro and in vivo experiments to assess the expression and function of SAPCD2 in BCa. The correlation between SAPCD2 expression and clinicopathological features was analyzed using tissue samples from BCa patients. Functional assays, including cell proliferation, migration, invasion, and metastasis tests, were conducted to evaluate the biological impact of SAPCD2. Mechanistic studies focused on the MAPK signaling pathway, TANK stabilization, and the interaction between SAPCD2 and the PLAGL2-CREB feedback loop. Results: Our results showed that SAPCD2 was significantly upregulated in BCa tissues and correlated with advanced clinicopathological features and poor prognosis. Overexpression of SAPCD2 promoted cell proliferation, migration, invasion, and metastasis, while its silencing led to the opposite effects. Mechanistically, SAPCD2 activated the MAPK signaling pathway by stabilizing TANK and preventing its degradation by SYVN1. Furthermore, we identified a positive feedback loop in which SAPCD2 enhanced PLAGL2 expression through CREB phosphorylation, further amplifying SAPCD2 expression and MAPK signaling. Conclusions: This study indicated that SAPCD2 could serve as a critical driver of BCa malignancy, emphasizing its role in sustaining oncogenic signaling through the SAPCD2-TANK-MAPK axis and the PLAGL2-SAPCD2-CREB feedback loop. Targeting this pathway may offer novel therapeutic strategies for treating aggressive BCa.

Lysine acetyltransferase 2A (KAT2A) is a transcriptional coactivator and a member of the Histone Acetyltransferase (HAT) family. While altered KAT2A activity has been implicated in various cancers, its role in bladder cancer (BLCA) remains poorly understood. Post-translational modifications (PTMs), such as O-GlcNAcylation, play a critical role in cancer biology. In this study, we investigated the impact of O-GlcNAcylation on KAT2A stability and its oncogenic potential in BLCA. We analyzed 96 paired BLCA and normal tissue samples using quantitative real-time PCR (qPCR) and immunohistochemistry to assess KAT2A expression. Functional assays, including siRNA-mediated knockdown, co-immunoprecipitation (co-IP), ubiquitination, and chromatin immunoprecipitation (ChIP), were conducted in BLCA cell lines and xenograft models to understand KAT2A O-GlcNAcylation mechanisms. We found that KAT2A expression was significantly increased in BLCA tissues. O-GlcNAcylation at serine 583 (S583) stabilized KAT2A by inhibiting TRIM22-mediated ubiquitination. Hyper-O-GlcNAcylation increased H3K9 acetylation and upregulated oncogenes like TGFB1, E2F1, and GPX4, promoting cell proliferation and tumor growth. Mutation of S583 destabilized KAT2A, impaired H3K9 acetylation, and suppressed oncogene expression. Our results highlight the pivotal role of KAT2A in BLCA and demonstrate that O-GlcNAcylation at S583 is a crucial regulatory mechanism driving tumor progression. Targeting KAT2A O-GlcNAcylation may provide a promising therapeutic strategy for BLCA patients.

INTRODUCTION:[68Ga]Ga-prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)/computed tomography (CT) imaging has demonstrated clinical value for individuals with prostate cancer (PC). In this phase 2 study, we measured the pharmacokinetics and dosimetry of [68Ga]Ga-PSMA-11 in Chinese participants. METHODS:Adult Chinese participants with progressive metastatic castration-resistant PC (mCRPC) received a single intravenous [68Ga]Ga-PSMA-11 dose of approximately 150 MBq. Blood samples were collected at 5, 15, 30, 45, 85, 175, and 245 min post injection for pharmacokinetics assessments. Whole-body PET scans and low/ultra-low-dose CT scans were acquired at 30, 60, 120, and 255 min post injection for dosimetry assessments. RESULTS:Pharmacokinetics and dosimetry assessments were completed in seven participants who received a [68Ga]Ga-PSMA-11 dose (range: 108.3-236.7 MBq). In the blood, the geometric mean effective terminal half-life was 1.34 h (geometric coefficient of variation [geo-CV], 182%); geometric mean clearance was 9.80 L/h (geo-CV, 106%). The highest absorbed doses were seen in the kidneys, urinary bladder walls, and lacrimal glands. In the study population, the geometric mean (geo-CV) effective dose of [68Ga]Ga-PSMA-11 was 4.2 mSv (32.9%). CONCLUSIONS:The pharmacokinetic and dosimetry profiles of [68Ga]Ga-PSMA-11, assessed using a validated method in participants with progressive mCRPC, make it very suitable with proves its suitability.

To identify metabolic predictors of urolithiasis recurrence and investigate whether the predictive value of urinary citrate differs across metabolic subgroups, with the aim of developing a subgroup-specific prediction model. We retrospectively analyzed patients who experienced a first episode of urolithiasis between 2013 and 2015 and subsequently underwent metabolic evaluation at the Department of Urology of our institution. Baseline assessment included demographic characteristics, blood biochemical parameters, and 24-h urinary metabolic indices. Follow-up data on stone recurrence were collected through standardized telephone interviews conducted between 2023 and 2025. Multivariable logistic regression and subgroup analyses were performed to identify predictors of recurrence. A prediction model for patients with hyperuricemia was developed using stepwise logistic regression and internally validated by tenfold cross-validation. A total of 184 patients were included. Multivariable logistic regression identified 24-h urinary citrate as the only metabolic parameter independently associated with stone recurrence (P = 0.04). Correlation analysis demonstrated significant associations between urinary citrate and serum uric acid, urinary calcium, urinary oxalate, and age. Subgroup analysis showed that the inverse association between urinary citrate and recurrence remained significant only among patients with hyperuricemia (P = 0.03), whereas similar trends in other metabolic subgroups did not reach statistical significance. The interaction between serum uric acid and urinary citrate was not statistically significant (P = 0.40). A preliminary prediction model incorporating urinary citrate, age, BMI, triglycerides, and parathyroid hormone demonstrated moderate discriminative performance, with a mean cross-validated AUC of 0.747. Urinary citrate was independently associated with urolithiasis recurrence, with this association being particularly evident among patients with hyperuricemia. These findings suggest that the predictive value of urinary citrate may vary across different metabolic backgrounds and support further investigation of metabolically stratified approaches to recurrence risk assessment. External validation in larger prospective cohorts is warranted.

BACKGROUND:Neoadjuvant immune checkpoint blockade (nICB) has revolutionized cancer treatment, yet the underlying mechanisms of resistance in bladder cancer remain to be explored. METHODS:We conducted single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells, tumor tissues, adjacent normal tissues, and metastatic lymph nodes from 2 nICB-naïve and 10 nICB-treated patients with bladder cancer (5 responders and 5 non-responders). Spatial RNA sequencing was performed on tumor slides from two responders and four non-responders. Findings were validated by multiplex immunohistochemistry, mice orthotopic bladder cancer model, and flow cytometry assays. RESULTS:nICB remodeled the tumor microenvironment of bladder cancer from both single-cell and spatial perspectives. scRNA-seq analysis revealed a significant increase in MYBL2hi cancer stem cells (CSCs) among non-responders. Analysis of the myeloid population showed that SPP1+ macrophages associated with angiogenesis were linked to CD8+ T cell exclusion. Further investigation into cell-cell communication revealed a propensity for bidirectional crosstalk between MYBL2hi CSCs and SPP1+ macrophages in non-responders. MYBL2hi CSCs derived CCL15, which bound to CCR1 and induced SPP1 upregulation in macrophages which reciprocally enhanced bladder cancer stemness and resistance to nICB through the SPP1-ITGα9β1 axis. Additionally, we identified an aged CCL3+ neutrophil population that interacted with SPP1+ macrophages through a positive feedback loop, contributing to nICB resistance. Finally, in vivo studies demonstrated that combined MYBL2 knockdown and SPP1 targeting synergistically enhanced ICB efficacy in bladder cancer. CONCLUSIONS:Our research reveals transcriptomic characteristics associated with distinct therapeutic responses to nICB treatment, offering a foundation for optimizing personalized neoadjuvant strategies in bladder cancer.

BACKGROUND:Bladder cancer is a high-incidence malignant tumor in the world. Currently available potential biomarkers lack sufficient diagnostic accuracy, underscoring the need for novel biomarkers. Lipid metabolites have emerged as promising candidates for diagnosing malignant tumors in recent years. Few studies explored the potential value of lipids in bladder cancer. Our study investigated plasma lipid metabolism markers in non-muscle invasive bladder cancer (NMIBC) using liquid chromatography-high resolution mass spectrometry (LC-HRMS). METHODS:Overall, 214 cases were included, with 106 NMIBC patients as NMIBC group and 108 healthy adults as control group. Plasma lipids were profiled using LC-HRMS to distinguish NMIBC group from control group, low-grade NMIBC group from control group and low-grade NMIBC group from high-grade NMIBC group. RESULTS:Apparent separation was observed between NMIBC group and control group. Hydroxy fatty acids, O-TAG, O-LPG and hydrocarbons metabolites were significantly enriched in NMIBC group. A Lipids panel of PE(14:1/20:0), PE(18:2/16:0) and 19-methyl-heneicosanoic acid was used to conduct a predictive model of NMIBC group and control group. The model showed acceptable accuracy for NMIBC diagnosis with the area under the curve (AUC) of 0.88 and 0,82 for training and validation cohorts, respectively, especially for the low-grade NMIBC diagnosis with the AUC of 0.81. For low- and high-grade NMIBC distinction, a panel of four lipids achieved good performance with the AUC value of 0.815 (10-fold cross validation: 0.77; leave-one-out validation (LOOCV):0.77). CONCLUSION:Lipid profiles differed significantly between patients with non-muscle invasive bladder cancer (NMIBC) and healthy adults. The identified lipid biomarkers demonstrated high discriminatory accuracy in diagnosing and grading NMIBC, indicating their promising clinical potential for both detection and monitoring of bladder cancer.

[This corrects the article DOI: 10.3389/fsurg.2024.1348737.].

BACKGROUND:The underexplored potential of PD-L1 blockade in advanced renal cell carcinoma highlights an urgent need for novel agents. This trial aimed to compare benmelstobart (a novel PD-L1 inhibitor) plus anlotinib with sunitinib as first-line treatment for advanced renal cell carcinoma. METHODS:ETER100 was a multicentre, randomised, open-label, phase 3 trial conducted at 37 medical sites in China. We included patients aged 18-80 years, who had previously untreated, advanced, clear-cell renal cell carcinoma, and an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned (1:1) patients to receive either benmelstobart (intravenous, 1200 mg, once every 3 weeks) plus anlotinib (oral, 12 mg, once daily for the first 2 weeks of a 3-week cycle) or sunitinib (oral, 50 mg, once daily for the first 4 weeks of a 6-week cycle) until disease progression, unacceptable toxicity, investigator's decision, or patient withdrawal. Randomisation was done centrally with stratified block randomisation (block size 4) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk. The primary endpoint was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumours version 1.1 in the full analysis set (ie, randomly assigned patients who received at least one dose of study drug without the violation of key inclusion criteria) and per-protocol set (ie, randomly assigned patients who received at least one cycle of protocol treatment without major protocol violations and had at least one efficacy assessment). In this Article, we report the results of a prespecified interim analysis. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT04523272. FINDINGS:Between Aug 25, 2020, and Feb 6, 2023, we assessed 687 patients for eligibility, 531 (77%) of whom were randomly assigned to receive either benmelstobart plus anlotinib (266 [50%] patients) or sunitinib (265 [50%] patients). 527 (99%) patients were included in the full analysis set (263 [50%] patients who received benmelstobart plus anlotinib and 264 [50%] who received sunitinib). All patients were Chinese (400 [76%] men and 127 [24%] women), with a median age of 60 years (IQR 54-67). As of the cutoff date (Jan 31, 2024), the median follow-up was 22·8 months (IQR 15·2-29·7). In the full analysis set, median progression-free survival was significantly longer with benmelstobart plus anlotinib than with sunitinib (19·0 months [95% CI 15·3-22·8] vs 9·8 months [8·4-12·4]; hazard ratio [HR] 0·53 [95% CI 0·42-0·67]; p<0·0001). In the per-protocol set, median progression-free survival was 19·0 months (16·5-22·8) in the benmelstobart-anlotinib group versus 11·0 months (8·5-13·6) in the sunitinib group (HR 0·55 [0·43-0·70]; p<0·0001). The most common grade 3 or worse treatment-related adverse event was hypertension (occurring in 91 [34%] of 264 patients in the benmelstobart-anlotinib group vs 55 [21%] of 264 in the sunitinib group). Serious treatment-related adverse events occurred in 63 (24%) patients in the benmelstobart-anlotinib group and in 42 (16%) patients in the sunitinib group. In the benmelstobart-anlotinib group, three (1%) deaths occurred due to treatment-related adverse events (one each with cardiac-respiratory arrest, unknown reason, and renal failure) and no deaths occurred in the sunitinib group. INTERPRETATION:Benmelstobart plus anlotinib improved progression-free survival compared with sunitinib among patients with previously untreated, advanced clear-cell renal cell carcinoma. These findings suggest the potential of benmelstobart plus anlotinib as a treatment option for this population. FUNDING:Chia Tai Tianqing Pharmaceutical Group and CSCO Clinical Oncology Research Foundation. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

BACKGROUND:Simenafil, a potent and highly selective oral phosphodiesterase type 5 (PDE5) inhibitor, is currently under investigation for erectile dysfunction (ED) treatment. AIMS:To evaluate the efficacy and safety of simenafil for ED treatment. METHODS:This was a multicenter, randomized, double-blind, placebo-controlled, parallel group, phase 3 study in men aged 18-75 years with a history of ED of 6 months or more. The subjects were randomized in a ratio of 1:1:1:1 to on-demand receive fixed-dose either placebo or simenafil (2.5 mg, 5 mg or 10 mg) for 12 weeks. OUTCOMES:Primary efficacy endpoints were the least square mean (LSM) changes from baseline to week 12 in the erectile function (EF) domain of the International Index of Erectile Function (IIEF), percentages of "yes" responses to sexual encounter profile (SEP) diary question 2 (SEP Q2: Were you able to insert your penis into your partner's vagina?) and question 3 (SEP Q3: Did your erection last long enough for you to have successful intercourse?). RESULTS:A total of 765 patients were randomized and 92.3% completed the study. The mean age of subjects was 41.3 years and 81.6% had moderate to severe ED (mean overall International Index of Erectile Function-Erectile Function (IIEF-EF) domain score 13.4). After 12 weeks of treatment, doses of 2.5, 5, and 10 mg of simenafil exhibited substantial increases than placebo in IIEF-EF score (12.3, 12.3, 12.7 vs. 9.6), the percentages of "yes" responses to SEP Q2 (40.58%, 42.43%, 43.98% vs. 32.05%), and SEP Q3 (61.91%, 63.70%, 65.19% vs. 46.70%) (all P < .001). Adverse drug reactions (ADRs) occurred in 36.2% of patients who received simenafil (32.6% in simenafil 5 mg group, the clinically recommended dose) and in 30.9% of those who received placebo. The most common (≥2%) ADRs were dizziness, headache, flushing, nasal congestion, and dry mouth, and most were mild or moderate. Furthermore, abnormal vision (PDE6 related) and myalgia (PDE11 related) did not occur in patients who received simenafil. CLINICAL IMPLICATIONS:Simenafil is highly effective in all 3 dose groups and has a low effective dose and good safety profile, providing a novel, favorable treatment option for patients with ED. STRENGTHS AND LIMITATIONS:The efficacy and safety evaluation of simenafil in difficult-to-treat patients with ED, ED patients with other concomitant diseases, and other ethnic populations was not performed. CONCLUSION:Simenafil is an effective and well-tolerated therapy for patients with ED.

4536 Background: Dual immune checkpoint inhibitors (ICIs) or ICIs plus VEGF-directed therapies, have been approved as first-line treatment in patients (pts) with advanced renal cell carcinoma (RCC). The phase 3 ETER100 trial showed that benmelstobart (PD-L1 blockade) plus anlotinib improved the progression-free survival (PFS) (19.0 months 9.8 months) and objective response rate (ORR) (71.6% vs 25.1%) of advanced clear cell RCC (ccRCC) pts significantly. Pts with factors, such as intermediate-poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, liver metastasis, or bone metastasis were considered to have a poor prognosis. Here we report PFS and ORR in clinically relevant subgroups. Methods: ETER100 (NCT04523272) was a multicentre, randomised, open-label, controlled phase 3 trial conducted at 37 sites in China. Eligible patients were randomly assigned in a 1:1 ratio using stratified block randomisation to receive benmelstobart plus anlotinib or sunitinib. Randomisation was stratified according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk (favourable [score of 0], intermediate [score of 1-2], or poor risk [score of 3-6]). PFS analyses of clinically relevant subgroups were assessed using Kaplan-Meier method and the 95% CIs of response rate were calculated with the Clopper-Pearson method. Results: Overall, 527 pts received the trial treatments (264 in the benmelstobart-anlotinib group and 263 in the sunitinib group) and were evaluated for efficacy. A total of 454 (86%) pts had intermediate-poor IMDC risk, 62 (12%) pts had liver metastasis and 111(21%) had bone metastasis. Data cutoff for the interim analysis occurred on January 31, 2024. The median follow-up was 22.8 months. Benmelstobart plus anlotinib significantly improved PFS of subgroups with intermediate-poor IMDC risk (17.0 months [95% CI 14.0-20.1] vs 9.7 months [8.0-11.3], HR 0.55, 95% CI 0.43-0.72; p < 0.0001), liver metastasis (11.9 months [95% CI 5.8-NE] vs 5.4 months [1.5-6.7], HR 0.44, 95% CI 0.23-0.85; p < 0.0121), or bone metastasis (19.5 months [95% CI 16.5-27.2] vs 8.3 months [4.2-19.8], HR 0.52, 95% CI 0.30-0.89; p < 0.0154). ORR of benmelstobart-anlotinib group was significantly higher in the subgroups with intermediate-poor IMDC risk (70.0% [95%CI, 63.6- 75.9] vs 21.6% [16.4-27.5]), liver metastasis (60.0% [95%CI, 42.1-76.1] vs 7.4% [0.9-24.3]) and bone metastasis (63.2% [95%CI, 49.3-75.6] vs 16.7% [7.9-29.3]). Conclusions: The RCC pts with a poor prognosis such as intermediate-poor IMDC risk, liver metastasis and bone metastasis could significantly benefit from benmelstobart plus anlotinib. Clinical trial information: NCT04523272 .