Lymphangiogenesis is essential for tumor lymphatic metastasis, yet the molecular mechanisms governing the activation of its key cytokine, VEGF-C, remain unclear. Herein, we identified a circRNA, circFOCAD, through VEGF-C maturation-associated multiple transcription sequencing. CircFOCAD is overexpressed in lymph node (LN)-metastatic bladder cancer (BCa) and is associated with poor prognosis. In footpad popliteal LN metastasis and orthotopic BCa models, circFOCAD enhances VEGF-C-dependent lymphangiogenesis and LN metastasis in BCa. Mechanistically, circFOCAD potentiates pro-VEGF-C cleavage by facilitating the expression of CCBE1 and its newly identified partner, the metalloprotease ADAM10. Specifically, circFOCAD promotes ADAM10 promoter H3K9 acetylation by recruiting YBX1. ADAM10 requires CCBE1 as a scaffold, binding at residue R301/R302, to interact with N-terminal propeptide of pro-VEGF-C at residue E58, provoking VEGF-C maturation and sustaining lymphangiogenesis in BCa. Clinically, neutralizing antibodies against CCBE1 and ADAM10 diminished the LN metastatic of BCa in a patient-derived xenograft (PDX) model. Our findings indicate that circFOCAD acts as an initiator of VEGF-C maturation and may represent a promising therapeutic target in LN metastatic BCa.

CRISPR‒Cas systems represent powerful tools for genome regulation. However, the large size of Cas proteins limits their efficient delivery via an adeno-associated virus (AAV), thereby restricting their clinical translation. Here, we engineer the IS200/IS605 transposon-encoded nuclease TnpB, along with its ωRNA scaffold, to create an enhanced TnpB system, which serves as a compact toolkit for gene activation, genome editing, and base editing. The gene activator enTnpBa increases expression by 2889-fold with a minimized 93 nt ωRNA and robustly activates endogenous genes in mammalian cells. We develop a single-AAV-based regimen for immune activation (AAV-ImmunAct) that delivers enTnpBa to activate CXCL9, IL-15, and IFN-γ. AAV-ImmunAct effectively enhances T cell migration and activation, increases killing of cancer cell lines and patient-derived organoids, and synergizes with anti-PD-1 therapy in humanized mice. Here, we establish enTnpB as a compact and versatile platform for genome regulation and a promising tool for cancer immunotherapy.

BACKGROUND:Accurate detection of lymph node metastasis is crucial for precise tumour staging and treatment planning. Conventional pathological examination can overlook lymph node micrometastasis, resulting in underdiagnosis and suboptimal clinical outcomes. This study aimed to develop a pan-cancer artificial intelligence diagnostic model (PanCAM) for detecting lymph node metastasis across cancer types. METHODS:In this multicentre diagnostic study, patients who had undergone tumour resection and lymph node dissection from 17 hospitals in China were included. The entire dataset included nine common and 24 rare cancers. Histological slides of resected lymph nodes were collected and scanned to generate whole slide images (WSIs). PanCAM was developed by use of supervised learning and incremental learning strategies and trained and internally validated retrospectively on WSIs from nine common cancers at Sun Yat-sen Memorial Hospital of Sun Yat-sen University (Guangzhou, China). Its generalisability was retrospectively validated by use of WSIs from 15 external hospitals in China and the publicly available CAMELYON16 dataset from the Netherlands, representing both common and rare cancers. Prospective validation was done in a multicentre study (NCT06517979) across nine hospitals in China. The primary outcome was diagnostic sensitivity for detecting lymph node metastasis. In a secondary analysis, we compared performance between PanCAM and pathologists. FINDINGS:Between Jan 1, 2013, and Nov 30, 2024, 9256 patients from 17 hospitals in China were included in the study (4735 [51·2%] men; 4521 [48·8%] women; median age 60 years [IQR 50-69]; 3486 [37·7%] with lymph node metastasis). The dataset comprised 1303 patients in the training set, 558 in the internal validation set, 6006 in the external validation sets, and 1389 in the prospective validation sets, totalling 69 502 images and 153 985 lymph nodes. The CAMELYON16 dataset consisted of 399 images. In the retrospective validation, the diagnostic sensitivity of PanCAM for detecting lymph node metastasis ranged from 0·97 (95% CI 0·92-0·99) to 1·00 (0·98-1·00) across 16 hospitals, and was 0·96 (0·92-0·99) on the CAMELYON16 dataset. In the prospective validation, PanCAM exhibited sensitivity ranging from 0·93 (0·78-0·99) to 1·00 (0·98-1·00) across nine hospitals. Despite being trained solely on images from common cancers, PanCAM achieved a sensitivity of 0·98 (0·95-1·00) for rare cancers in both retrospective and prospective validations. At the patient level, PanCAM identified 120 additional patients with lymph node metastasis who were missed by pathologists in the retrospective validation and 21 additional cases in the prospective validation. INTERPRETATION:PanCAM provided a generalisable solution for detecting lymph node metastasis across cancer types. With high sensitivity and robust performance, the model could assist pathologists in diagnosing lymph node metastasis, improving diagnostic accuracy, supporting treatment decision making, and ultimately enhancing patient outcomes. FUNDING:National Natural Science Foundation of China, National Science and Technology Major Project, Science and Technology Projects in Guangzhou, Guangdong Provincial Clinical Research Centre for Urological Diseases, and Science and Technology Planning Project of Guangdong Province.

4592 Background: With the evolution of different treatment eras, the clinical complete response (cCR) rate of bladder cancer has been progressively increasing, while the lymph node metastasis rate has still not improved significantly. Particularly, patients with HER2 overexpression are at a higher risk of lymph node metastasis, which poses a major challenge to bladder-sparing therapy for patients with muscle-invasive bladder cancer (MIBC). This study aims to establish a novel bladder-preserving treatment model by combining local therapy enhanced with pelvic lymph node dissection (PLND) and systemic therapy with Disitamab Vedotin and Toripalimab. Methods: Patients with cT2-4aN0M0 MIBC and HER2 expression ≥2+ were enrolled, The primary endpoint was 2-year bladder-intact disease-free survival rate. After maximal transurethral resection of bladder tumor (TURBT), patients received Toripalimab (3mg/kg, Q2W) combined with Disitamab Vedotin (2mg/kg, Q2W) for 6 cycles, followed by TURBT and PLND. Those with cCR or partial response (PR) continued the combined therapy for another 6 cycles. Patients achieving cCR after 12 cycles of combined therapy received maintenance Toripalimab (240mg, Q3W) for 1 year. Non-cCR patients received comprehensive treatment or salvage radical cystectomy(RC). Results: As of December 2025, 21 patients were enrolled, with a median age of 66 years (range: 37–82). The primary endpoint was not yet reached. Efficacy assessment was performed in 14 patients at Week 12: 10/12 (85.8%) achieved cCR, while 1 patient had stable disease (SD) and 1 had progressive disease (PD). Among 10 patients who underwent TURBT and PLND, pathological complete response (pT0N0M0) was achieved in 90.0%, and 1 patient was postoperatively staged as pT0N1M0. Patients with SD or PD underwent RC. All patients experienced treatment-related adverse events (TRAEs) of any grade. The most common TRAEs were pruritus (75.00%), paresthesia (68.75%), and elevated ALT (43.75%), all of which were Grade 1–2. One patient developed a Grade 3 adverse event (AE), which was severe urinary tract infection. No TRAEs of Grade ≥4 were observed. Conclusions: The novel bladder-sparing modality of Disitamab Vedotin combined with Toripalimab plus PLND after maximal TURBT currently demonstrates favorable efficacy and safety. Long-term outcomes warrant further investigation. Clinical trial information: ChiCTR2400081555.

Tertiary lymphoid structures (TLSs) promote antigen-specific anti-tumor immunity, but the regulators of TLSs homeostasis in cancer remain unclear. Using single-cell RNA-sequencing and spatial transcriptomics, we identify an IGLL5+ B cell subset in bladder cancer (BCa). In genetically engineered and humanized mouse models, these IGLL5+ B cells disrupt TLS's integrity and impair immunotherapy responses. Mechanistically, IGLL5+ B cells bind high endothelial venules (HEVs) via IGLL5-LTβR ligand-receptor interactions, with IGLL5 inducing a conformational change in LTβR that inhibits non-canonical NF-κB signaling, leading to TLSs disassembly. Clinically, blocking IGLL5 preserves TLSs and enhances immunotherapy efficacy in patient-derived xenograft (PDX) and pan-cancer models. Our findings suggest that targeting IGLL5+ B cells offers a promising strategy to boost TLS-dependent cancer immunotherapy.

The prognosis for patients with bladder cancer (BCa) with lymph node (LN) metastasis is poor, and it is not improved by current treatments. Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumors, including BCa. However, the role of Differentiation antagonizing non-protein coding RNA (DANCR) in BCa LN metastasis remains unclear. In this study, we discover that DANCR was significantly upregulated in BCa tissues and cases with LN metastasis. DANCR expression was positively correlated with LN metastasis status, tumor stage, histological grade, and poor patient prognosis. Functional assays demonstrated that DANCR promoted BCa cell migration, invasion, and proliferation in vitro and enhanced tumor LN metastasis and growth in vivo. Mechanistic investigations revealed that DANCR activated IL-11-STAT3 signaling and increased cyclin D1 and PLAU expression via guiding leucine-rich pentatricopeptide repeat containing (LRPPRC) to stabilize mRNA. Moreover, oncogenesis facilitated by DANCR was attenuated by anti-IL-11 antibody or a STAT3 inhibitor (BP-1-102). In conclusion, our findings indicate that DANCR induces BCa LN metastasis and proliferation via an LRPPRC-mediated mRNA stabilization mechanism. DANCR may serve as a multi-potency target for clinical intervention in LN-metastatic BCa.

744 Background: There are limited 1L therapy options for cisplatin-ineligible patients with locally advanced or metastatic UC (la/mUC), indicating an unmet need for novel treatment strategies. Sac-TMT (MK-2870/SKB264) is a TROP2-directed ADC with a unique bifunctional linker that maximizes delivery of a novel belotecan-derived topo I inhibitor payload to tumor cells, that has shown promising antitumor activity in several tumor types, including as monotherapy in UC (Ye, D, et al. J Clin Oncol 2025;43[suppl 5]:796). We present efficacy and safety data for cohort B in 1L cisplatin-ineligible pts with la/mUC from the phase 2, open-label 2870-002/SKB264-II-06 study (NCT05642780) evaluating sac-TMT + pembro in pts with select solid tumors. Methods: Eligible pts in cohort B were aged ≥18 y, previously untreated, cisplatin-ineligible with la/mUC. Pts with prior adjuvant or neoadjuvant platinum-based therapy or nivolumab were eligible if they had disease recurrence >12 mo after completing therapy. Pts received sac-TMT 4 or 5 mg/kg IV (non-randomized) on days 1, 15, and 29 of each 42-day cycle + pembro 400 mg IV on day 1 of each 42-day cycle for up to 2 years until PD or unacceptable toxicity. Primary endpoints were safety and ORR per RECIST v1.1 by investigator assessment. Secondary endpoints included DCR, DOR, and PFS by investigator assessment. Results: As of May 21, 2025, 40 pts were treated with sac-TMT (26 pts at 4 mg/kg and 14 pts at sac-TMT 5 mg/kg) + pembro. Median follow-up was 14.5 (range, 11.6–21.8) mo. Median age was 66.5 y, 37 pts (93%) were Asian, and 24 (60%) had upper tract UC. Confirmed ORR was 68%, median DOR was 15.4 mo, and median PFS was 11.2 mo (Table). 39 pts (98%) experienced treatment-related AEs including 23 (58%) with grade 3 or 4 treatment-related AEs. Anemia (15%), decreased neutrophil count (15%), and stomatitis (10%) were the most common (incidence ≥10%) grade 3 or 4 treatment-related AEs. No treatment-related deaths occurred. Conclusions: Sac-TMT + pembro showed promising antitumor activity at both 4 and 5 mg/kg in previously untreated, cisplatin-ineligible pts with la/mUC, with a manageable safety profile consistent with that of the individual treatment components. Further studies are warranted. Clinical trial information: NCT05642780 . Outcome Sac-TMT 4 mg/kg + Pembro 400 mgn = 26 Sac-TMT 5 mg/kg + Pembro 400 mgn = 14 Total N = 40 Confirmed ORR, % (95% CI) 65 (44.3–82.8) 71 (41.9–91.6) 68 (50.9–81.4) DCR, % (95% CI) 89 (69.8–97.6) 86 (57.2–98.2) 88 (73.2–95.8) BOR, n (%) CR 0 (0) 1 (7) 1 (3) PR 17 (65) 9 (64) 26 (65) SD 6 (23) 2 (14) 8 (20) PD 1 (4) 1 (7) 2 (5) No assessment a 2 (8) 1 (7) 3 (8) Median DOR, mo (range) 15.4 (3.6–15.4) NR (2.0–17.7+) b 15.4 (2.0–17.7+) b Median PFS, mo (95% CI) 10.9 (5.7–NE) NR (3.7–NE) 11.2 (5.8–NE) NE, not estimable; NR, not reached. a Includes pts without post-baseline assessment on data cutoff date. b “+” indicates no event by time of last disease assessment.

BackgroundAssessment of lymph node status is essential for guiding surgical decisions, prognosis evaluation, and recurrence risk estimation in prostate cancer (PCa). Therefore, this research seeks to establish and corroborate an integrated prediction model that leverages T2-weighted MRI scans to accurately identify lymph node involvement (LNI) in PCa patients.MethodsA retrospective cohort of 339 prostate cancer patients who underwent preoperative whole-prostate MRI followed by radical prostatectomy and extended pelvic lymph node dissection (ePLND) was evaluated. To non-invasively predict LNI, we developed a composite machine learning model integrating MRI-derived radiomics, deep learning features, and clinical parameters based on the 2012 Briganti nomogram. Model performance and clinical utility were assessed using the area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA).ResultsThe DRBN model demonstrated excellent predictive power in both the training and validation sets, with ROC-AUC scores of 0.963 and 0.920, and PR-AUC values of 0.950 and 0.921, correspondingly. Additionally, the DRBN model exhibited satisfactory calibration and clinical utility in both cohorts.ConclusionIntegrating clinical, radiomic, and deep learning features from whole-prostate MRI provides a feasible non-invasive approach for predicting LNI.

Following the publication of the above article and an Expression of Concern statement that was issued in light of concerns raised by an interested reader (doi: 10.3892/or.2025.9006) regarding the possible presentation of the same mouse twice in Fig. 7A, which showed how Bmi1 silencing suppresses the tumorigenicity of SP T24 cells in vivo, the authors have now responded to the enquiry posed by the Editorial Office. After consulting their original data, the authors have realized that the images of the first and third mouse in Fig. 7A were inadvertently mistakenly used during the manuscript preparation and figure editing stage. The authors were also asked to offer an explanation for the apparent discrepancy in the tumor sizes, given that the sizes of the tumors in situ appeared to be significantly larger than the measured sizes of the associated excised tumors. The authors acknowledged this concern, and attributed it to visual distortion from skin/fur, together with non‑standard approximate size recording practices at the time, while also admitting that detailed original measurement data were no longer available. The revised version of Fig. 7, now showing the correct mice in Fig. 7A, is shown on the next page. Note that the errors made in assembling this figure did not affect the overall results and conclusions reported in the paper. The authors are grateful to the Editor of Oncology Reports for granting them the opportunity to publish this corrigendum, and all the authors agree with its publication; furthermore, they apologize to the readership of the journal for any inconvenience caused. [Oncology Reports 31: 727‑736, 2014; DOI: 10.3892/or.2013.2919].

Background Bone metastasis is a principal cause of mortality in patients with prostate cancer (PCa). Increasing evidence indicates that high expression of stromal interaction molecule 1 (STIM1)-mediated store-operated calcium entry (SOCE) significantly activates the calcium (Ca 2+ ) signaling pathway and is involved in multiple steps of bone metastasis in PCa. However, the regulatory mechanism and target therapy of STIM1 is poorly defined. Methods Liquid chromatography-mass spectrometry analysis was performed to identify tetraspanin 18 (TSPAN18) as a binding protein of STIM1. Co-IP assay was carried out to explore the mechanism by which TSPAN18 inhibits STIM1 degradation. The biological function of TSPAN18 in bone metastasis of PCa was further investigated in vitro and in vivo models. Result We identified that STIM1 directly interacted with TSPAN18, and TSPAN18 competitively inhibited E3 ligase tripartite motif containing 32 (TRIM32)-mediated STIM1 ubiquitination and degradation, leading to increasing STIM1 protein stability. Furthermore, TSPAN18 significantly stimulated Ca 2+ influx in an STIM1-dependent manner, and then markedly accelerated PCa cells migration and invasion in vitro and bone metastasis in vivo. Clinically, overexpression of TSPAN18 was positively associated with STIM1 protein expression, bone metastasis and poor prognosis in PCa. Conclusion Taken together, this work discovers a novel STIM1 regulative mechanism that TSPAN18 protects STIM1 from TRIM32-mediated ubiquitination, and enhances bone metastasis of PCa by activating the STIM1-Ca 2+ signaling axis, suggesting that TSPAN18 may be an attractive therapeutic target for blocking bone metastasis in PCa.

Single-cell RNA sequencing (scRNA-seq) is a widely used method for classifying cell types and states and revealing disease mechanisms. However, most contemporary scRNA-seq platforms fail to explore the multilandscape of RNA. Here, a microfluidic chip is designed that combines oligo-dT primers and Random Bridging Co-labeling (RBCL) RNA sequencing to develop an innovative Chigene scRNA-seq technology that can identify gene expression, mutations, and RNA splicing landscapes at the single-cell level. The Chigene scRNA-seq platform demonstrated exceptional performance, with minimal doublet rates of 0.94% (Chigene V1) and 1.93% (Chigene V2). Both versions exhibit high sensitivity, with Chigene V2 achieving nearly 100% RNA coverage and detecting over 1800 genes per cell on average. Targeted capture of single-cell gene mutations enhances mutation detection sensitivity. Moreover, this Chigene V2 platform is validated in clinical samples for its ability to detect mutations, gene fusions, and alternative splicing. The reliability of the platform is further corroborated via known functional gene mutation (CDKN1A) and fusion (FGFR3-TACC). To validate this method's potential for discovering novel gene mutations in clinical samples, the investigation revealed an intriguing cell subpopulation carrying an ARHGAP5 mutation in urothelial carcinoma. These cells exhibited high-frequency mRNA splicing and exhibited specific crosstalk with T cells, distinguishing them from the subpopulation with the ARHGAP5 wild-type phenotype. Overall, this method provides a robust scRNA-seq platform suitable for comprehensive analyses of clinical specimens at different genetic information levels, thereby offering significant potential in the discovery of novel genes and interactions at the single-cell level.

Modifiable factors affect cancer’s survival but literature did not differentiate prior to versus after cancer diagnosis. It is essential to provide references for the intervention prioritized at different stages. In this prospective cohort study, we analyzed national data from the UK Biobank, including 121,399 participants, to assess the association of modifiable factors with cancer-specific survival (CSS) in two independent cohorts: a pre-cancer cohort (n = 78,027) and a post-cancer cohort (n = 43,372). Additionally, a weighted standardized score was derived to evaluate the joint effects across different domains. Interactions between the six domains and age at diagnosis, sex, and cancer site were evaluated using likelihood ratio tests. Subgroup analyses were then performed for factors showing significant effect modification. Population-attributable fractions (PAF) of different domains on 5-year cancer-specific death were calculated. Our study comprehensively presented the differential patterns of modifiable factors’ impact on CSS among pre-cancer and post-cancer cohorts, sexes and different cancer sites. In the pre-cancer cohort, CSS were predominantly attributable to smoking/alcohol consumption (PAF 9·2

Bladder cancer's high mortality underscores the need for precise staging, especially to differentiate between nonmuscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) types. This prospective study evaluated the efficacy of contrast-enhanced ultrasound (CEUS) for preoperative staging, focusing on its ability to distinguish NMIBC from MIBC. Conducted from April 2020 to September 2021, the study involved 163 patients (median age: 64.0 years; 137 males, 26 females), with 133 NMIBC (81.6%) and 30 MIBC (18.4%). Each patient underwent CEUS followed by transurethral resection of bladder tumor or radical cystectomy. CEUS demonstrated high diagnostic accuracy in determining muscle invasion status (sensitivity 83.3%, specificity 92.5%, accuracy 90.8%, area under the receiver operating characteristic curve [AUC] 0.88). Comparative analyses against MRI (AUC 0.77) showed CEUS outperforming in muscle invasion detection. Combining CEUS with MRI improved diagnostic accuracy, particularly when MRI vesical imaging reporting and data system score was 3 points. The combined approach achieved an AUC of 0.73, with sensitivity, specificity, and accuracy of 76.2, 70.2, and 71.6%, respectively. Thus, CEUS emerges as a valuable diagnostic tool for preoperative staging of bladder cancer, particularly in its role in assessing muscle invasion status and thereby aiding in clinical decision-making and intervention outcomes.

BACKGROUND:Although congenital abnormalities of the kidney and urinary tract (CAKUT) is the leading cause of childhood-onset chronic kidney disease and kidney failure, comprehensive information on the disease burden among children and adolescents globally is lacking. We aim to report the trends and socioeconomic inequality of CAKUT burden for people aged 0-24 years from 1990 to 2019. METHODS:We reported the prevalence, mortality and disability-adjusted life-years (DALYs) for CAKUT based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, quantified the association of disease burden and socio-demographic index (SDI), and calculated the slope index of inequality, the relative index of inequality and concentration index. RESULTS:In 2019, the global prevalence, mortality and DALYs of CAKUT among individuals aged 0-24 years were 167.11 (95% confidence interval 166.97, 167.25), 0.30 (0.29, 0.30) and 32.22 (32.16, 32.29), respectively, per 100 000 population. The greatest prevalence, mortality and DALYs were recorded in the 0-4 years age group. The greatest mortality and DALYs were recorded in low SDI countries and territories. During 1990 to 2019, the prevalence, mortality and DALYs decreased globally, while in low and low-middle countries and territories the reduction was much less slower. India, Nigeria and Pakistan had the highest DALYs. Saudi Arabia and China exhibited a markedly decrease of CAKUT burden. Globally for every 0.1 increase in SDI, there was a 20.53% reduction in mortality and a 16.31% decrease in DALYs, but a 0.38% rise in prevalence. CONCLUSIONS:Inequality for disease burden of varying SDI was increasing globally. Thus, specific preventive and health service measures are needed to reduce the global burden from CAKUT.