BACKGROUND:Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer (BC). However, the development of cisplatin resistance limits its antitumor effects. While, the mechanism of cisplatin resistance remains unclear. METHODS:Bioinformatics techniques were used to analyse genes and pathways associated with cisplatin therapy resistance. A variety of biological techniques were used to identify the role of ITGB4 in cisplatin sensitivity in BC and its potential molecular mechanism. RESULTS:In this study, we demonstrated that ITGB4 plays a key role in regulating the sensitivity of p53 wild-type (WT) BC to cisplatin therapy. Our findings revealed that ITGB4 inhibits the activation of p53 by suppressing the phosphorylation at the p53-S15 site and promotes the degradation of p53 by facilitating the binding of MDM2 to p53, thereby reducing the sensitivity of BC to cisplatin.Additionally, we showed that ITGB4 influences the antitumor effects of MDM2 inhibitors when they are combined with cisplatin therapy. Furthermore, we found that the elevated expression of ITGB4 in cisplatin-resistant BC cells were mediated by STAT3 activation. The combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin in BC. CONCLUSIONS:ITGB4 is a key molecule influencing cisplatin sensitivity in p53 WT BC, and the combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin.

A high-fat diet (HFD) promotes tumor progression and therapeutic resistance, but its mechanistic role in prostate cancer (PCa) remains unclear. In this study, we show that an HFD not only accelerates PCa progression but also significantly reduces sensitivity to CDK4/6 inhibitors. Mechanistically, an HFD activates CDK4, inducing RB1 phosphorylation and facilitating E2F1 release. Meanwhile, phosphorylation of RB1 at the S249/T252 site enhances its interaction with ETS1 and suppresses ETS1's transcriptional activity. Treatment with CDK4/6 inhibitors induces dephosphorylation at this site, relieving ETS1 suppression and promoting PCYT2 expression and phosphatidylcholine metabolic reprogramming. The resulting metabolic products further disrupt RB1-E2F1 binding, leading to additional E2F1 release and increased resistance to CDK4/6 inhibitors. In conclusion, our results identify a diet-metabolism-transcriptional regulatory axis centered on RB1 phosphorylation and ETS1 reactivation, reveal a mechanism of acquired resistance to CDK4/6 inhibitors of castration-resistant PCa, and provide a theoretical basis for combinatorial strategies targeting metabolic and oncogenic signals.

To assess the effectiveness of prophylactic laxative use compared to symptom-based management for preventing constipation in patients undergoing surgery for urological cancers. Of 2,024 screened patients (aged 18–80) with urological tumors, 1,724 eligible (no severe gastrointestinal disease, non-pregnant, scheduled for surgery) were non-randomly assigned to prevention (prophylactic laxatives, n = 965) or non-prevention groups (symptom-based, n = 748). Propensity score matching with a 1:1 optimal matching strategy was used to minimize baseline differences between the two groups. The primary outcome was the incidence of constipation within 7 days post-surgery. Secondary outcomes included complete spontaneous bowel movements (CSBM), patient assessment of constipation quality of life (PAC-QOL) scores, and patient assessment of constipation symptoms (PAC-SYM) scores at 7 days post-surgery. A nomogram was developed for predicting postoperative constipation. Compared to non-prevention, the incidence of postoperative constipation was significantly lower in the prevention group (12.3 www.chictr.org.cn ).

VB15010 is a next-generation, highly selective PARP1 inhibitor (Fang D. et al., AACR 2024, abstract 4537). Unlike first-generation PARP inhibitors (e.g., olaparib, niraparib), which inhibit both PARP1 and PARP2, VB15010 minimizes PARP2 inhibition, which is implicated in hematologic toxicities such as anemia, neutropenia, and thrombocytopenia. PARP1 selectivity is hypothesized to improve tolerability while preserving antitumor activity in homologous recombination repair (HRR) gene-mutated cancers. This multicenter, open-label, phase 1/2 trial (NCT06819215) evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of oral VB15010 in patients with advanced solid tumors harboring HRR gene mutations. In the dose-escalation phase, VB15010 was administered once daily (QD) at 10, 30, 50, and 80 mg doses using a standard 3+3 design. The primary endpoints were safety, dose-limiting toxicities (DLTs), and recommended phase 2 dose (RP2D) determination. Secondary endpoints included PK, PD (PARylation inhibition), and efficacy assessed by RECIST v1.1. As of July 1, 2025, 8 patients (2 males, 6 females; median age 58 [range 46–75]) were enrolled at 10, 30, and 50 mg QD dose levels. Tumor types included ovarian (n=4), breast (n=2), and prostate cancers (n=2). No DLTs were reported. The most frequent treatment-emergent adverse events (TEAEs; ≥2 patients) were decreased white blood cell count, anemia, neutropenia, nausea, and thrombocytopenia. Three cases of upper respiratory tract infection were deemed unrelated to study drug. Two serious adverse events (SAEs) of anemia resolved with treatment interruption and dose reduction. No TEAEs led to treatment discontinuation or death. PK analysis showed dose-proportional increases in exposure (Cmax and AUC) across 10–50 mg with a mean half-life of 8.5 hours, supporting QD dosing. VB15010 achieved ≥90% PARylation inhibition sustained over 72 hours at all dose levels. Among 7 evaluable patients, the objective response rate (ORR) was 42.8%, disease control rate (DCR) 57%, and median progression-free survival (PFS) 5.6 months (median follow-up: 3.9 months). VB15010 demonstrated favorable tolerability, promising PK/PD properties, and preliminary antitumor activity in advanced solid tumors with HRR gene mutations. These results support further clinical development in this patient population. Jinming Yu, Yuping Sun, Tiejun Yang, Li Wang, Ruifang An, Jin Yang, Yefeng Lu, Jia Song, Jing Han, Chenxi Li, Douglas Fang, Charles Z. Ding. Preliminary safety, PK and efficacy of a PARP1 selective inhibitor VB15010 in patients with advanced solid tumors in phase 1/2 study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B005.

4519 Background: Nectin-4 is an adhesion molecule that is highly expressed in variety of solid tumors. Previous study of 9MW2821 has shown promising efficacy and tolerable toxicity in different advanced cancers, especially in urothelial cancer, cervical cancer, esophageal cancer and breast cancer. Here we report preliminary results of 9MW2821 combined with Toripalimab in treatment-naïve patients with la/mUC. Methods: This is an open-label, multicenter, phase 1b/2 study to evaluate the safety and efficacy of 9MW2821 combined with Toripalimab in la/mUC. Patients received 9MW2821 on D1/D8 and Toripalimab on D1, 21 days per cycle. Primary objective was safety, and secondary objectives were efficacy, pharmacokinetics and immunogenicity. Results: 40 treatment-naïve patients with la/mUC were enrolled and received the combination therapy of 9MW2821(1.25mg/kg) and Toripalimab(240mg). Median age was 66.5 years [36-78], and 73% patients were ECOG 1. 55% primary tumor sites were upper tract urothelial carcinoma. As of Dec 19, 2024, ORR was 87.5% [35/40, 95%CI 73.2-95.8], including 7.5% CR rate (comfirmed ORR was 80%). DCR was 92.5% [37/40, 95%CI 79.6-98.4]. Median PFS and DoR were not reached, 6-month PFS rate and 3-month DoR rate were 79.1% and 100%. Furthermore, ORR of subgroups in liver metastasis, bladder cancer and tumor with negative expression of Nectin-4 were 88.2%, 94.4%, 100%, respectively. These showed that different subgroups of treatment-naïve patients could benefit from the combination therapy of 9MW2821 and Toripalimab. The most common treatment-related AEs(TRAEs) were grade 1 or 2, 23.8% patients experienced TRAEs of grade 3 or above, including neutrophil count decreased (7.1%), rash (4.8%), ALT increased (4.8%), etc. No TRAEs led to death occurred. No new safety signals of 9MW2821 or Toripalimab were observed in this study. Conclusions: 9MW2821 combined with Toripalimab in treatment-naïve patients with la/mUC demonstrated remarkable efficacy and well-tolerated safety profile. A pivotal phase 3 study is ongoing currently. Clinical trial information: NCT06079112 .

Hyperglycemia is a recognized risk factor for bladder cancer (BC). Enfortumab vedotin (EV), the first NECTIN4-targeting antibody-drug conjugate, demonstrates promising clinical efficacy in patients with advanced BC. In this study, we show that EV treatment is less effective in BC patients with diabetes than in those with normoglycemia. The subsequent in vitro and in vivo experiments indicate that high glucose decreases the sensitivity of BC cells to EV. Mechanistically, lactate overproduction associated with high glucose promotes AARS1-mediated YTHDC1 lactylation and enhances RNF183-mediated YTHDC1 ubiquitination. Downregulated YTHDC1 reduces JUND mRNA stability in an m6A-dependent manner, subsequently decreasing NECTIN4 expression and EV responsiveness. Our study identifies a high-glucose-associated lactate-AARS1-YTHDC1-JUND-NECTIN4 axis that affects EV sensitivity in BC. Targeting this axis with JUND activators or β-alanine may offer therapeutic strategies to enhance the sensitivity of BC cells to EV.

585 Background: Collecting duct carcinoma (CDC) originates from the principal cells of the collecting ducts in the renal medulla and accounts for less than 2% of all renal cell carcinomas (RCCs). Due to its low incidence, the transcriptomic features and molecular subtypes of CDC have only been described in small-sample studies. This study employs a multi-omics approach to investigate CDC, aiming to deepen our understanding of CDC and provide some references for future treatment options. Methods: A total of 103 tumor samples and 15 paired adjacent non-tumor samples underwent whole transcriptome sequencing. Clinical pathological characteristics, treatments, and prognostic information were collected for all patients. Molecular typing of CDC was performed using Non-negative Matrix Factorization. The clinical and biological characteristics of each subtype were analyzed. Tissues from different NMF classifications were collected for single-cell sequencing to compare the biological characteristics. To enhance clinical accessibility, plasma was analyzed by LC-MS/MS and correlated with RNAseq data to identify representative plasma biomarkers for different NMF subtypes. Results: Compared to normal tissue, CDC exhibited significant differences in various biological functions including mechanisms and regulation of ion and substance transport across cellular membranes, as well as pathways such as proximal tubule bicarbonate reclamation, aldosterone-regulated sodium reabsorption and protein digestion. Tumor samples were classified into two transcriptional subtypes through machine learning: NMF1 and NMF2. NMF1 subtype had a significantly longer overall survival compared to those with the NMF2 subtype (median OS of 7.06 months vs 2.04 months, P =0.014). The infiltration proportions of T cells, CD8+ T cells, cytotoxic lymphocytes, endothelial cells, myeloid dendritic cells, NK cells, and neutrophils were all higher in NMF1 tumor tissues compared to NMF2, while the proportions of fibroblasts and monocytic lineage were lower in NMF1. These immune infiltration results were further validated by single-cell sequencing analysis. Using Lasso regression combined with survival data, we identified characteristic gene sets for each NMF subtype. Further association analysis with plasma LC-MS/MS revealed distinct protein expression profiles for each NMF subtype. These findings suggest that the NMF1 subtype has a relatively better prognosis and a 'hotter' tumor microenvironment, potentially benefiting from immunotherapy and/or anti-angiogenic therapy. Plasma biopsies could serve as a basis for molecular typing. Conclusions: This study is the largest to date to integrate clinical prognostic information in a multi-omics investigation of CDC. It provides critical insights for clinical research on targeted therapies for specific molecular subtypes of CDC.

PURPOSE:To investigate the expression patterns of Human Epidermal Growth Factor Receptor 2 (HER2) and their clinicopathological associations across the full spectrum (negative, low, and overexpression) in a large cohort of Chinese urothelial carcinoma (UC) patients. MATERIALS AND METHODS:A multicenter registry study (April 2023-March 2024) across eight Chinese tertiary hospitals included 1054 UC patients. Demographic, clinical, and pathological data were analyzed to identify factors associated with different HER2 expression levels (IHC 0 vs. 1+ vs. 2+/3+). A subset of patients was evaluated for additional IHC markers (e.g., CK20, GATA3, P16, Uroplakin3, Ki-67). RESULTS:Of 1054 patients, 18.6% were HER2-negative (IHC 0), 23.0% were HER2-low (IHC 1+), and 58.4% exhibited HER2 overexpression (IHC 2+/3+). Increasing HER2 expression was significantly associated with bladder tumor location (63.1% in IHC 2+/3+, p < 0.001), infiltrative tumors (61.1% in IHC 2+/3+, p < 0.001), and high-grade tumors (62.5% in IHC 2+/3+, p < 0.001). In a sub-analysis comparing HER2-low (1+) and HER2-overexpressing (2+/3+) groups, multivariable logistic regression confirmed bladder primary site (OR = 1.783, p = 0.001), infiltrative status (OR = 1.492, p = 0.027), and high-grade differentiation (OR = 1.918, p = 0.001) as independent predictors of HER2 overexpression, though the model's predictive ability was modest (AUC = 0.64). Expression of CK20, GATA3, P16, and Uroplakin3 also differed significantly between HER2-negative and HER2-positive groups. CONCLUSIONS:This study delineates distinct clinicopathological profiles for HER2-negative, HER2-low, and HER2-overexpressing UC in Chinese patients. These findings provide a crucial evidence base for refining personalized treatment strategies, particularly for HER2-targeted therapies like antibody-drug conjugates (ADCs), across the entire spectrum of HER2 expression.

PURPOSE:To evaluate the efficacy and safety of BL-B01D1, a potential first-in-class epidermal growth factor receptor (EGFR)-human EGFR 3 bispecific antibody-drug conjugated (ADC) with Ed-04, in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) refractory to standard or regular therapies. METHODS:BL-B01D1-201 is a multicenter, single-arm, phase II study of BL-B01D1 in patients with la/mUC who have progressed on systemic therapy. Patients received BL-B01D1 at a dose of 2.2, 2.5, or 2.75 mg/kg intravenously over approximately 60 minutes on days 1 and 8 once every 3 weeks. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), and safety. RESULTS:A total of 41 patients were enrolled, 34 in 2.2 mg/kg, four in 2.5 mg/kg, and three in the 2.75 mg/kg group. In the 2.2 mg/kg group, the confirmed ORR was 44.1% (95% CI, 27.2 to 62.1) and the DCR was 88.2% (95% CI, 72.5 to 96.7). Among 15 patients who had received only one previous line of chemotherapy (either platinum-based or ADCs), the confirmed ORR achieved 80% (95% CI, 51.9 to 95.7). With a median follow-up of 10.2 months, the median PFS was 7.3 months (95% CI, 5.5 to 9.8) and the median DOR was 11.3 months (95% CI, 4.3 to not reached). The most common treatment-related adverse events (all grade/≥grade 3) were anemia (88.2%/38.2%), leukopenia (76.5%/38.2%), neutropenia (64.7%/41.2%), thrombocytopenia (64.7%/32.4%), appetite decrease (52.9%/2.9%), and nausea (52.9%/2.9%). CONCLUSION:BL-B01D1 showed promising preliminary efficacy and a favorable safety profile at 2.2 mg/kg in patients with la/mUC who had progressed after systemic therapy. These results suggest that BL-B01D1 could be a promising new agent for patients with la/mUC with few treatment options.

BackgroundBladder cancer (BLCA), the 10th most common cancer worldwide, presents a worsening prognosis as the disease progresses. Reliable tools for predicting BLCA prognosis and treatment efficacy remain urgently needed.MethodsExpression profiles of lactylation related genes were analyzed utilizing the Cancer Genome Atlas (TCGA) database and BLCA data from the GSE13507 dataset. Two distinct clusters were identified through unsupervised clustering analysis. Lactylation associated gene signatures were established and subsequently validated using training cohort and different validation cohorts. Immune cell infiltration patterns and drug response profiles were systematically evaluated. Parallel analyses of lactylation related genes were conducted at the single-cell resolution. A series of in vivo and in vitro experiments were subsequently performed to validate the findings.ResultsWe examined the mRNA expression profiles of 22 lactylation related genes in BLCA tissues. Through comprehensive analysis, we identified two distinct lactylation clusters that exhibited significantly different clinical outcomes and tumor immune microenvironment characteristics. Building upon these findings, we subsequently stratified patients into two molecular subtypes according to the lactylation clusters and established a robust genetic signature for predicting survival outcomes in BLCA patients. The lactylation risk score showed a strong connection with survival outcomes and correlated with the tumor microenvironment (TME) immunosignature and predicted immunotherapy efficacy. DHCR7 emerged as a pivotal prognostic gene from the nine gene model, prompting subsequent focused analyses. Single-cell analysis confirmed that DHCR7 reached peak expression in tumor epithelial cells, whereas TCGA data and single-cell data demonstrated strong associations between DHCR7 and diverse immune-cell populations. For the first time, we identified that knockdown of DHCR7 enhances the efficacy of both cisplatin chemotherapy and immunotherapy, highlighting DHCR7 as a key player in cisplatin resistance and its influence on immunotherapy effectiveness in BLCA. These findings offer valuable insights into potential combined therapeutic strategies.ConclusionsWe developed a robust lactylation risk prediction model for accurately forecasting BLCA prognosis and identified DHCR7 as a pivotal biomarker involved in cisplatin resistance and influencing immunotherapy efficacy in BLCA.

IntroductionThe most common sites of clear cell renal cell carcinoma(ccRCC) metastasis are the lung, bones, liver and brain; eyelid metastasis is a rare occurrence.Case presentationWe report a case of ccRCC metastasis to the left eyelid after radical nephrectomy, and remission after sunitinib treatment.ConclusionsAlthough the probability of eyelid metastasis rate is very low, tumor metastasis to the eyelid skin is possible after radical nephrectomy. Therefore, any rash like changes on the skin during the review procedure cannot be ignored by the physician.

Objective:The aim of this study is to summarize the surgical experience of renal artery cold perfusion combined with laparoscopic nephron preserving surgery for the treatment of complex renal angiomyolipoma and to evaluate the safety and feasibility of this surgical protocol.Materials and methods:Clinical data of nine patients who received renal artery cold perfusion combined with laparoscopic nephron preserving surgery for complex renal angiomyolipoma in our hospital from February 2017 to August 2020 were retrospectively analyzed. The study parameters included imaging findings, total renal function before and after surgery, glomerular filtration rate (GFR) of affected kidney before and after surgery, and related complications.Results:Eight of the nine patients successfully completed the operation, one patient was intolerant to renal artery balloon implantation, and the success rate of the operation was 88.89%. The mean maximum tumor diameter was 6.8 cm, and RENAL score was 7 points. Postoperative total renal function and GFR of the affected kidney had no significant changes compared with that before surgery, and imaging examination showed no tumor residue or recurrence.Conclusion:This surgical procedure is safe and feasible for complex renal angiomyolipoma and can be used as a surgical option for renal hamartoma. The long-term effect needs to be confirmed by further studies.

BACKGROUND:In recent years, hyperthermia has been widely applied as a novel strategy for cancer treatment due to its multiple antitumour effects. In particular, the potential influences of hyperthermia on the tumour immune microenvironment may improve the efficacy of immunotherapies. However, the effect of hyperthermia on renal cell carcinoma (RCC) has not been well characterized until now.METHODS:In the present study, we primarily evaluated the effects of hyperthermia on cellular function via cellular proliferation, migration, invasion and apoptosis assays. In addition, the influence of hyperthermia on the immunogenicity of RCC cells was analysed using flow cytometry analysis, enzyme-linked immunosorbent assays, and immunofluorescent (IF) staining.RESULTS:Our results demonstrate that hyperthermia significantly inhibits RCC cell proliferation, migration, and invasion and promotes cell apoptosis. In addition, we verified that hyperthermia improves the immunogenicity of RCC cells by inducing immunogenic cell death.CONCLUSION:Our findings suggest that hyperthermia is a promising therapeutic strategy for RCC.

Background To determine whether transrectal ultrasound and urologist_dually guided pelvic floor muscle exercise is associated with immediate, early and long-term urinary continence after radical prostatectomy. Materials and methods Data from 114 patients with localized prostate cancer (PC) who underwent RP at Henan Cancer Hospital from November 2018 to April 2021 were included in the retrospective study. Of the 114 patients, 50 patients in the observation group underwent transrectal ultrasound and urologist_dually guided PFME, and 64 patients in the control group underwent verbally_guided PFME. Contractile function of the external urinary sphincter was in the observation group was evaluated. The immediate, early and long-term urinary continence rates were assessed in both groups, and the factors affecting urinary continence were analyzed. Results The urinary continence rate at 2 weeks and 1, 3, 6 and 12 months in the observation group after RP was significantly higher than that in the control group (52.0% vs. 29.7%, 70.0% vs. 39.1%, 82% vs. 57.8, 88% vs. 70.3%, 98.0 vs. 84.4%, p < 0.05). The contractile function of the external urinary sphincter was obviously correlated with urinary continence at multiple visits after RP, except for the 12-month visit. Transrectal ultrasound and urologist-dually guided PFME was verified to be an independent positive factor for urinary continence at 2 weeks and 1, 3, 6 and 12 months using logistic regression analysis. However, TURP was a negative factor for postoperative urinary continence at different times. Conclusions Transrectal ultrasound and urologist_dually guided PFME had a significant role in improving immediate, early and long-term urinary continence after RP and acted as an independent prognostic factor.

膀胱扁平状病变临床常见,以非肌层浸润性膀胱癌最为常见.经尿道膀胱肿瘤切除术(transurethral resection of bladder tumor, TURBT)是非肌层浸润性膀胱癌诊断和治疗的重要方式,但常规TURBT(conventional TURBT, cTURBT)存在标本电灼明显影响肿瘤分期及碎片化切除肿瘤增加膀胱腔内播散风险等问题.膀胱肿瘤整块切除术(en bloc resection of bladder tumor, ERBT)通过完整切除病变可较好地解决上述问题,当前ERBT技术日趋成熟,也得到了越来越多同行的认可.自2019年5月,本院利用经尿道双极等离子电切器械,采用ERBT治疗膀胱扁平状病变,临床应用效果满意,现报告如下.

Additional file 1. Clinical information of 48 penile cancer patients.

BackgroundMuscle invasive bladder urothelium carcinoma is a common urinary tract tumor. With the deepening of research, more and more treatment methods are applied in clinical practice, extending the life of patients. Among them, the clinical application of chemotherapeutic intravesical hyperthermia and tumor immunotherapy provides new ideas for our treatment. Case reportAn 81-year-old female patient was diagnosed with stage T2N0M0 bladder cancer in our hospital. Because the patient and her family were keen to preserve her bladder, they declined surgery and opted for combined chemotherapy. After informed consent from the patient and her family, she received cisplatin combined with gemcitabine intravesical hyperthermic infusion. But the side effects of cisplatin made her intolerable to chemotherapy. With their informed consent we changed her to intravenous tislelizumab in combination with gemcitabine intravesical hyperthermic infusion to continue her treatment. During the subsequent follow-up visits, we found a surprising effect of the treatment. ConclusionGemcitabine intravesical hyperthermia therapy combined with intravenous tislelizumab in the treatment of muscle invasive bladder urothelium carcinoma may provide a new possible therapeutic strategy of some patients who are inoperable or refuse surgery.