To develop and validate a multicenter ultrasound-based predictive model for fluorescence in situ hybridization (FISH) results in HER2 (2+) breast cancer patients, aiming to provide a convenient and cost-effective tool to support clinical decision-making. In this retrospective multicenter study, 5,888 breast cancer patients from six institutions were included. Radiomics features were extracted from ultrasound images using PyRadiomics, and deep learning features were obtained using a Vision Transformer (ViT). Feature selection was performed using least absolute shrinkage and selection operator (LASSO) regression. Multiple machine learning models were developed, and their performance was evaluated with the area under the curve (AUC). The DeLong test was used for model comparison. The proportion of FISH-positive cases ranged from 9.7

e16202 Background: Immune checkpoint inhibitor combined with chemotherapy have shown improved prognosis compared with chemotherapy alone in patients with advanced intrahepatic cholangiocarcinoma (ICC). However, whether adding tyrosine kinase inhibitor (TKI) could further provide more survival benefits remains unclear. This study aims to evaluate the efficacy and safety of apatinib (a VEGFR2-targeted TKI) combined with adebrelimab (PD-L1 inhibitor) and GEMOX chemotherapy as first-line treatment for advanced ICC. Methods: This study (ACADEMY) enrolled adults aged ≤75 years with pathologically confirmed advanced ICC. All patients received apatinib (250 mg daily) combined with adebrelimab (1200 mg, day 1) and GEMOX chemotherapy (Gemcitabine 1000 mg/m 2 , day 1 and day 8; Oxaliplatin 85 mg/m 2 , day 1) per 21-day cycle. Tumor response was assessed using both RECIST 1.1 and mRECIST criteria. Survival outcomes were analyzed using Kaplan-Meier methods. The primary endpoint was objective response rate (ORR) accessed by RECIST 1.1 criteria. The secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR) and treatment-related adverse events (TRAEs). A Simon’s two -stage Optimum design was adopted in this study. If a response is observed in over 3 out of the initial 13 evaluated patients during the first phase, an additional 21 patients would be recruited for the study. Results: As of January 4, 2026, a total of 22 patients were recruited (median age 58.9 years; 59.1% female; 27.2% HBV-positive), with 19 included in efficacy analysis. Baseline characteristics: median tumor size 7.2 cm, median tumor number 3.5, 95.5% with TNM stage III-IV, 45.5% with macrovascular invasion. The ORR was 31.6% (RECIST 1.1) and 63.2% (mRECIST), and DCR was 100% (RECIST 1.1 and mRECIST criteria). With a median follow-up time of 7.9 months, the estimated median PFS was 6.2 months (95% CI: 5.4-NR), the 6-month OS rate was 100%, and the median OS was not reached. 21.1% (4/19) patients underwent radical surgical resection after tumor downstaging. In the respect of safety evaluation, TRAEs were observed in all enrolled patients, 50.0% with grade 3-4, and no grade 5 TRAE occurred. The most frequent AEs were hypoalbuminemia (68.2%), fatigue (59.1%) and liver damage (36.4%). Conclusions: Apatinib combined with adebrelimab and GEMOX regimen demonstrates promising efficacy and acceptable safety profile as first-line treatment for advanced ICC, supporting its potential as a preferred therapeutic option. Clinical trial information: NCT06925516 .

BACKGROUND:Cardiovascular disease (CVD) is the leading cause of non-cancer mortality in prostate cancer (PCa) patients. The management of CVD, including hypertension, holds equal significance to cancer treatment. However, the optimal antihypertensive agent for blood pressure management in PCa patients receiving abiraterone acetate (AA) is still unclear. This study aims to investigate the association between various antihypertensive regimens and survival outcomes in PCa patients treated with AA. METHODS:We performed a post-hoc observational analysis using data from COU-AA-301 and COU-AA-302. Radiographic progression-free survival (rPFS), overall survival (OS) and prostate cancer-specific survival (PCSS) were evaluated using the Kaplan-Meier method. Cox proportional hazards models were used to obtain hazard ratios (HRs) and associated 95% confidence intervals (CIs). RESULTS:Among the AA groups of COU-AA-301 and COU-AA-302, angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) monotherapy was associated with longer rPFS (HR 0.82, 95% CI 0.59-1.13; HR 0.71, 95% CI 0.53-0.95), OS (HR 0.66, 95% CI 0.41-1.06; HR 0.70, 95% CI 0.53-0.92) and PCSS (HR 0.72, 95% CI 0.44-1.19; HR 0.67, 95% CI 0.49-0.92). Multiple-class antihypertensive treatment regimens including ACEI/ARBs were associated with longer rPFS (HR 0.74, 95% CI 0.59-0.92; HR 0.71, 95% CI 0.54-0.94), OS (HR 0.76, 95% CI 0.57-1.01; HR 0.72, 95% CI 0.55-0.94) and PCSS (HR 0.71, 95% CI 0.51-0.99; HR 0.62, 95% CI 0.46-0.83). Multivariable analysis indicated that ACEI/ARBs were associated with improved rPFS (HR 0.72, 95% CI 0.60-0.86; HR 0.75, 95% CI 0.60-0.94), OS (HR 0.71, 95% CI 0.56-0.91; HR 0.70, 95% CI 0.56-0.88) and PCSS (HR 0.73, 95% CI 0.55-0.96; HR 0.64, 95% CI 0.50-0.82). CONCLUSIONS:In this post-hoc analysis, concomitant use of ACEI/ARBs was associated with longer rPFS, OS and PCSS in PCa patients treated with AA. The potential role of ACEI/ARB-containing antihypertensive regimens in these patients warrants further investigation. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00638690, NCT00887198.

Lactate in the tumor microenvironment (TME) is typically generated by cells exhibiting high glycolytic flux, exemplified by tumor cells. However, in glycolysis-low malignancies such as prostate cancer, stroma-derived lactate may drive noncanonical signaling and functions that remain unclear. Here, we identified APCDD1+ cancer-associated fibroblasts (CAFs) as a distinct stromal population that secretes lactate into the TME in response to androgen deprivation therapy (ADT). Lactate uptake by prostate cancer cells induces androgen receptor variant 7 expression, thereby conferring resistance to ADT. Mechanistically, lactate-induced lactylation of the spliceosome component SNRPA at Lys123 (K123) enhances its recognition of cis-acting elements, increases chromatin binding, and promotes androgen receptor splicing. Targeting lactate transport with monocarboxylate transporter inhibitors effectively restores ADT sensitivity. These findings reveal a metabolic-epigenetic axis linking lactate in the microenvironment to alternative splicing regulation and suggest a promising therapeutic strategy to overcome ADT resistance.

Background:Rezvilutamide has demonstrated significant clinical benefits in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC) in the phase III CHART study. However, patients enrolled in clinical trials may not fully represent those encountered in routine clinical practice, and real-world evidence in this population remains limited. This study aimed to evaluate the real-world effectiveness of rezvilutamide in combination with androgen deprivation therapy (ADT) in patients with high-volume mHSPC. Methods:This multicenter retrospective cohort study included patients with high-volume mHSPC who received rezvilutamide plus ADT between August 29, 2023, and April 1, 2026 across 21 offline centers and one online center in China. Outcomes included prostate-specific antigen (PSA) 50 (defined as a ≥50% decline from baseline), PSA90 (defined as a ≥90% decline from baseline), and undetectable PSA (PSA <0.2 ng/mL) rates at 3, 6, 9, and 12 months, as well as the 12-month PSA progression-free rate. Prespecified subgroup analyses were performed according to age, Eastern Cooperative Oncology Group performance status, and Gleason score. Results:A total of 1,888 patients were included, with a median age of 73 years [interquartile range (IQR), 68-79 years]. The median baseline PSA was 70.9 ng/mL (IQR, 5.9-146.0 ng/mL). At 3 months, the PSA50, PSA90, and undetectable PSA rates were 83.3% [1,572/1,888, 95% exact confidence interval (CI): 81.5-84.9%], 71.7% (1,353/1,888, 95% exact CI: 69.6-73.7%), and 44.8% (845/1,888, 95% exact CI: 42.5-47.1%), respectively. Overall, the PSA response rates showed a gradual increasing trend over time. By month 12, the PSA50, PSA90, and undetectable PSA rates had reached 86.0% (282/328, 95% exact CI: 81.7-89.6%), 78.7% (258/328, 95% exact CI: 73.8-83.0%), and 72.0% (236/328, 95% exact CI: 66.8-76.8%), respectively. The PSA progression-free rate at 12 months was 93.4%. Conclusions:These real-world findings support the clinical utility of rezvilutamide combined with ADT in achieving durable PSA suppression in patients with high-volume mHSPC. However, the absence of comprehensive safety data and the retrospective nature of the study warrant cautious interpretation, and further prospective validation is needed.

Contrast-enhanced magnetic resonance lymphography (CE-MRL) plays a crucial role in preoperative diagnostic for evaluating tumor metastatic sentinel lymph node (T-SLN), by integrating detailed lymphatic information about lymphatic anatomy and drainage function from MR images. However, the clinical gadolinium-based contrast agents for identifying T-SLN is seriously limited, owing to their small molecular structure and rapid diffusion into the bloodstream. Herein, we propose a novel albumin-modified manganese-based nanoprobes enhanced MRL method for accurately assessing micro- and macro-T-SLN. Specifically, the inherent concentration gradient of albumin between blood and interstitial fluid aids in the movement of nanoprobes into the lymphatic system. The micro-T-SLN exhibits a notably higher MR signal due to the formation of new lymphatic vessels and increased lymphatic flow, allowing for a greater influx of nanoprobes. In contrast, the macro-T-SLN shows a lower MR signal as a result of tumor cell proliferation and damage to the lymphatic vessels. Additionally, a highly accurate and sensitive machine learning model has been developed to guide the identification of micro- and macro-T-SLN by analyzing manganese-enhanced MR images. In conclusion, our research presents a novel comprehensive assessment framework utilizing albumin-modified manganese-based nanoprobes for a highly sensitive evaluation of micro- and macro-T-SLN in breast cancer.

BACKGROUND:HBV, which contributes to liver fibrosis and HCC, is associated with autophagy and epithelial-mesenchymal transition (EMT). However, the relationship between HBV infection, autophagy, and EMT remains unknown. METHODS:In this study, we used HBV cell lines (HepAD38, Huh7.5.1-NTCP) to evaluate this relationship. RESULTS:HBV replication or infection promoted autophagy, EMT, and liver fibrogenesis. HBV-induced EMT/fibrogenesis was dependent on autophagy. HBV X and HBV core (C) were each involved during this process. TGF-β1 partially participated in HBV-induced autophagy/EMT/fibrosis. c-Jun N-terminal kinase (JNK) expression was increased in HepAD38 cells, HBV-X (HBV-C)-transfected Huh7.5.1 cells, and HBV-infected Huh7.5.1-NTCP cells. JNK silencing attenuated HBV-induced autophagy and EMT/fibrosis signaling as well. Moreover, overexpression of HBV-X(C) and augmentation of autophagy were shown to promote pJNK expression. Finally, we confirmed an HBV-JNK-autophagy-EMT/fibrosis signaling pathway in a primary human hepatocyte model. CONCLUSIONS:In conclusion, HBV induces autophagy through JNK, thus triggering downstream EMT and fibrogenesis signaling pathways. These findings suggest that JNKs could be potential targets for the treatment of HBV-related liver diseases.

Circular RNAs (circRNAs) have been recognized as pivotal regulators in tumorigenesis, yet the biological functions as well as molecular mechanisms of the majority of circRNAs in hepatocellular carcinoma (HCC) remain elusive.We sought to unveil the expression profile and biological role of circMYBL2 in HCC.Initial microarray analyses were conducted to probe the expression profile of circMYBL2 in HCC cells, and qRT-PCR analysis was then performed in HCC cell lines and tissues, revealing significant upregulation of circMYBL2.Subsequent experiments were conducted to evaluate the biological function of circMYBL2 in HCC progression.Furthermore, bioinformatics analysis, qRT-PCR analysis, luciferase reporter assays, and western blot analysis were employed to investigate the interplay among circMYBL2, miR-1205, and E2F1.CircMYBL2 was found to exhibit marked upregulation in tumor tissues as well as HCC cell lines.Elevated expression of circMYBL2 increased the proliferation and migration of HCC cells, whereas circMYBL2 knockdown elicited contrasting effects.Mechanistically, our results indicated that circMYBL2 promoted E2F1 expression and facilitated HCC progression by sponging miR-1205.Our findings revealed that circMYBL2 contributed to HCC progression through the circMYBL2/miR-1205/E2F1 axis, suggesting the potential of circMYBL2 as a novel target for HCC treatment or a prognostic biomarker for HCC.

Hepatocellular carcinoma (HCC) is a complex disease with advanced presentation that significantly affects survival rates. Therefore, novel therapeutic strategies are needed. In this study, we investigate the tumor microenvironment (TME) in HCC by analyzing 13 HCC samples at single cell level. We identified key cell populations, including CD8 + T cells, Tregs, M1/M2 macrophages, and CD4 + memory T cells, and explored their roles and interactions. Our research revealed an early enrichment of CD8 + T cells, which could potentially lead to their exhaustion and facilitate tumor progression. We also investigated the impact of percutaneous radiofrequency ablation (RFA) on the immune microenvironment. Using a dual tumor mouse model, we demonstrated that RFA induces necrosis, enhancing antigen presentation and altering immune responses. Our results indicate that RFA increases PD-L1 expression in residual liver tissue, suggesting potential immune escape mechanisms. Furthermore, the combination of RFA and anti-PD-L1 therapy in the mouse model resulted in significant improvements in immune modulation. This included increased CD8 + T cell efficacy and decreased Treg infiltration. This combination shows promise as an approach to counteract HCC progression by altering the immune landscape. This study highlights the critical interaction within the TME of HCC and suggests the possibility of improving patient outcomes by targeting immune evasion mechanisms through combined therapeutic strategies.

e17075 Background: Previous studies showed that combination of androgen deprivation therapy (ADT) with abiraterone acetate plus prednisone was associated with longer survival than ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). The aim of this retrospective propensity score-matched study was to compare the effects of sequential treatment of ADT and abiraterone acetate plus prednisone (sequential treatment cohort), and combination treatment of ADT with abiraterone acetate plus prednisone (combination treatment cohort), in men with newly diagnosed mCSPC. Methods: The sequential treatment cohort received ADT or ADT plus first-generation nonsteroidal antiandrogen (NSAA) as first-line therapy, then ADT and abiraterone acetate plus prednisone after progression. The combination treatment cohort received ADT and abiraterone acetate plus prednisone as first-line therapy. Patients with newly diagnosed mCSPC treated with ADT, ADT plus first-generation NSAA, or ADT plus abiraterone acetate in our center between June 2014 and July 2022, were respectively identified. Patients treated with sequential treatment or combination treatment were evaluated through propensity score matching (PSM) based on baseline clinical characteristics. The primary outcome was abiraterone failure-free survival (aFFS). Secondary outcomes including overall survival (OS), PSA response. Results: Clinical characteristics were balanced after PSM and 117 patients were included in each cohort. The aFFS was 30.7 and 30.6 months in sequential and combination treatment cohort, respectively, no statistically significant difference was observed (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.64 -1.27; p = 0.526). Similarly, there was no statistically significant difference in overall survival (OS, HR 0.92, 95% CI 0.57 -1.49; p = 0.388) between sequential and combination treatment. Conclusions: Patientswith newly diagnosed mCSPC treated with sequential ADT and abiraterone acetate plus prednisone, had similar aFFS and OS, compared to men treated with combined ADT and abiraterone acetate plus prednisone, according to our preliminary results. Our data indicate that sequential treatment of ADT and abiraterone acetate might be considered as an alternative to newly diagnosed mCSPC.

Pemigatinib, a pan-FGFR inhibitor, is approved to treat intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusion mutations. Improving its targeting of FGFR2 fusions remains an unmet clinical need due to its pan selectivity and resistance. Here, we report a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting the chimeric site in FGFR2-AHCYL1 (F-A Cho-HDO) that accumulates in ICC through endocytosis of low-density lipoprotein receptor (LDLR), which is highly expressed in both human and murine ICC. F-A Cho-HDO was determined to be a highly specific, sustainable, and well-tolerated agent for inhibiting ICC progression through posttranscriptional suppression of F-A in ICC patient-derived xenograft mouse models. Moreover, we identified an EGFR-orchestrated bypass signaling axis that partially offset the efficacy of F-A Cho-HDO. Mechanistically, EGFR-induced STAT1 upregulation promoted asparagine (Asn) synthesis through direct transcriptional upregulation of asparagine synthetase (ASNS) and dictated cell survival by preventing p53-dependent cell cycle arrest. Asn restriction with ASNase or ASNS inhibitors reduced the intracellular Asn, thereby reactivating p53 and sensitizing ICC to F-A Cho-HDO. Our findings highlight the application of genetic engineering therapies in ICC harboring FGFR2 fusions and reveal an axis of adaptation to FGFR2 inhibition that presents a rationale for the clinical evaluation of a strategy combining FGFR2 inhibitors with Asn depletion.

Background A predictive model for biochemical recurrence (BCR) of prostate cancer (PCa) after neoadjuvant androgen deprivation therapy (nADT) has not been established. This study was aimed at determining multiparameter variables that could be used to construct a nomogram to predict the post-nADT BCR of PCa. Methods Overall, 43 radical prostatectomy specimens from PCa patients who had undergone nADT were collected. Multiparameter variables were analyzed by univariate and then multivariate logistic analyses to identify the independent prognostic factors for predicting BCR. The predictive model was established using Lasso regression analysis. Results Univariate logistic analysis revealed six variables, pathology stage; margins; categorization as group A, B, or C; nucleolus grading; percentage of tumor involvement (PTI); and PTEN status were significantly associated with the BCR of PCa (all p < 0.05). Multivariate logistic regression analysis suggested that categorization as group C, severe nucleolus grading, PTI less than or equal to 5%, and PTEN loss were positively correlated with BCR (all p < 0.05). A nomogram comprising the four variables predicting BCR was constructed, and it exhibited good discrimination (AUC: 0.985; specificity: 86.2%; sensitivity: 100%). Calibration plots for the probability of freedom from BCR at 1 and 2 years showed a good match between the prediction by the nomogram. Conclusions We constructed and validated a nomogram to predict the risk of BCR in PCa patients after nADT. This nomogram is a complement to the existing risk stratification systems for PCa, which could have marked implications for clinical decision-making for PCa patients after nADT.

Abstract The next-generation androgen receptor (AR) inhibitor enzalutamide is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs, treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome enzalutamide resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of enzalutamide-resistant prostate cancer cells to enzalutamide both in vivo and in vitro. Inhibition of PGAM2 together with enzalutamide treatment triggered apoptosis by decreasing levels of the antiapoptotic protein BCL-xL and increasing activity of the proapoptotic protein BAD. Mechanistically, PGAM2 bound to 14–3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to enzalutamide-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of enzalutamide resistance in patients with prostate cancer. Together, these findings provide evidence of a nonmetabolic function of PGAM2 in promoting enzalutamide resistance and identify PGAM2 inhibition as a promising therapeutic strategy for enzalutamide-resistant prostate cancer. Significance: PGAM2 promotes resistance to enzalutamide by activating antiapoptotic BCL-xL and suppressing apoptosis, indicating that PGAM2 is a potential target for overcoming enzalutamide resistance in prostate cancer.

Minichromosome maintenance complex component 6 (MCM6), a member of the MCM family, plays a pivotal role in DNA replication initiation and genome duplication of proliferating cells. MCM6 is upregulated in multiple malignancies and is considered a novel diagnostic biomarker. However, the functional contributions and prognostic value of MCM6 in intrahepatic cholangiocarcinoma (ICC) remain unexplored. In this study, we investigated the molecular function of MCM6 in ICC. Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO, GSE107943) indicated an upregulation of MCM6 in tumor tissues. Immunohistochemical analysis performed on 115 cases of ICC samples confirmed the upregulation of MCM6 and further suggested that a high level of MCM6 expression predicted shorter overall and disease-free survival in ICC patients. Functional studies suggested that MCM6 knockdown significantly suppressed cell viability, blocked cell cycle progression and inhibited metastasis, while the enhancement of MCM6 expression promoted the proliferation and migration of ICC cells both in vitro and in vivo. Mechanistically, Gene Set Enrichment Analysis (GSEA) suggested that the epithelial-mesenchymal transition (EMT) and E2F1-correlated genes were enriched in ICC tissues with high MCM6 expression. Further verification indicated that MCM6 promoted the EMT of ICC cells via upregulating E2F1. In addition, E2F1 knockdown partially blocked the pro-malignant effects of MCM6 overexpression. In summary, MCM6 was found to be a novel prognostic and predictive marker for ICC. MCM6 promoted ICC progression via activation of E2F1-mediated EMT.

Parastomal hernia (PSH) is a common complication in patients receiving ileal conduit urinary diversion after radical cystectomy. In this randomized controlled clinical trial, we validate our previous finding that extraperitonealization of ileal conduit decreases incidence of PSH. In total, 104 consecutive patients undergoing radical cystectomy at Sun Yat-sen University Cancer Center are randomized 1:1 to receive either modified (extraperitonealized) ileal conduit (n = 52) or conventional ileal conduit (n = 52). Primary endpoint is incidence of radiological PSH during follow-up. Incidence of radiological PSH is lower in the modified group than in the conventional group (11.5% vs. 28.8%; p = 0.028) after a median follow-up of 32 months, corresponding to a hazard ratio of 0.374 (95% confidence interval: 0.145-0.965, p = 0.034) in the modified conduit group. The results support our previous finding that extraperitonealization of the ileal conduit is effective for reducing risk of PSH in patients receiving ileal conduit diversion.

No AccessJournal of UrologyExpression of Concern1 Feb 2023Expression of Concern: Lymph Node Mapping in Patients with Penile Cancer Undergoing Pelvic Lymph Node Dissectionis a expression-of-concern ofLymph Node Mapping in Patients with Penile Cancer Undergoing Pelvic Lymph Node Dissection Kai Yao, Yue Chen, Yunlin Ye, Zhiming Wu, Dong Chen, Hui Han, Zaishang Li, Zhuowei Liu, Yanjun Wang, Zike Qin, Yonghong Li, Zhiyong Li, and Fangjian Zhou Kai YaoKai Yao More articles by this author , Yue ChenYue Chen More articles by this author , Yunlin YeYunlin Ye More articles by this author , Zhiming WuZhiming Wu More articles by this author , Dong ChenDong Chen More articles by this author , Hui HanHui Han More articles by this author , Zaishang LiZaishang Li More articles by this author , Zhuowei LiuZhuowei Liu More articles by this author , Yanjun WangYanjun Wang More articles by this author , Zike QinZike Qin More articles by this author , Yonghong LiYonghong Li More articles by this author , Zhiyong LiZhiyong Li More articles by this author , and Fangjian ZhouFangjian Zhou More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003191AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookLinked InTwitterEmail "Expression of Concern: Lymph Node Mapping in Patients with Penile Cancer Undergoing Pelvic Lymph Node Dissection." The Journal of Urology, Publish Ahead of Print, pp. Submitted January 17, 2023; acceptedJanuary 17, 2023; published 000. From the State Key Laboratory of Oncology in Southern China, Guangzhou, China; Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China© 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of Urology5 Aug 2020Lymph Node Mapping in Patients with Penile Cancer Undergoing Pelvic Lymph Node Dissection Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.Metrics Author Information Kai Yao More articles by this author Yue Chen More articles by this author Yunlin Ye More articles by this author Zhiming Wu More articles by this author Dong Chen More articles by this author Hui Han More articles by this author Zaishang Li More articles by this author Zhuowei Liu More articles by this author Yanjun Wang More articles by this author Zike Qin More articles by this author Yonghong Li More articles by this author Zhiyong Li More articles by this author Fangjian Zhou More articles by this author Expand All Submitted January 17, 2023; acceptedJanuary 17, 2023; published 000. Advertisement PDF downloadLoading ...

Cholangiocarcinoma (CCA) is a highly heterogeneous and metastatic malignancy with a poor prognosis even after curative hepatectomy. Studies exploring its pathogenesis and identifying effective therapeutic targets are urgently needed. In this study, we found that TANK-binding kinase 1 (TBK1), a serine/threonine-protein kinase, showed a dynamic increase during the different stages of murine spontaneous CCA carcinogenesis (hyperplasia, dysplasia, and CCA). TBK1 was upregulated in human tissues, including intrahepatic ( n = 182) and extrahepatic ( n = 40) CCA tissues, compared with nontumor tissues, and the elevated expression of TBK1 was positively correlated with larger tumour diameter, lymph node metastasis, and advanced TNM stage. Functional studies indicated that TBK1 promoted CCA growth and metastasis both in vitro and in vivo. TBK1 directly interacts with β-catenin, promoting its phosphorylation at the S552 site and its nuclear translocation, which further activates EMT-related transcriptional reprogramming. GSK-8612, a TBK1 inhibitor or a kinase-inactivating mutation, effectively suppresses the above processes. In addition, we found that low-density lipoprotein receptor (LDLR), which mediates the endocytosis of cholesterol, was upregulated in CCA. Therefore, we designed a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting TBK1 (Cho-TBK1-HDO), which could accumulate in CCA cells via LDLR, reduce the TBK1 mRNA level and inhibit intrahepatic metastasis of CCA. Besides, in the experimental group of 182 ICC patients, high TBK1 expression combined with high nuclear β-catenin expression predicted a worse prognosis. In summary, TBK1 might serve as a potential prognostic biomarker and therapeutic target for patients with CCA.

Summary Background Early prediction of treatment response to neoadjuvant chemotherapy (NACT) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer can facilitate timely adjustment of treatment regimens. We aimed to develop and validate a Siamese multi-task network (SMTN) for predicting pathological complete response (pCR) based on longitudinal ultrasound images at the early stage of NACT. Methods In this multicentre, retrospective cohort study, a total of 393 patients with biopsy-proven HER2-positive breast cancer were retrospectively enrolled from three hospitals in china between December 16, 2013 and March 05, 2021, and allocated into a training cohort and two external validation cohorts. Patients receiving full cycles of NACT and with surgical pathological results available were eligible for inclusion. The key exclusion criteria were missing ultrasound images and/or clinicopathological characteristics. The proposed SMTN consists of two subnetworks that could be joined at multiple layers, which allowed for the integration of multi-scale features and extraction of dynamic information from longitudinal ultrasound images before and after the first /second cycles of NACT. We constructed the clinical model as a baseline using multivariable logistic regression analysis. Then the performance of SMTN was evaluated and compared with the clinical model. Findings The training cohort, comprising 215 patients, were selected from Yunnan Cancer Hospital. The two independent external validation cohorts, comprising 95 and 83 patients, were selected from Guangdong Provincial People's Hospital, and Shanxi Cancer Hospital, respectively. The SMTN yielded an area under the receiver operating characteristic curve (AUC) values of 0.986 (95% CI: 0.977–0.995), 0.902 (95%CI: 0.856–0.948), and 0.957 (95%CI: 0.924–0.990) in the training cohort and two external validation cohorts, respectively, which were significantly higher than that those of the clinical model (AUC: 0.524–0.588, Pall < 0.05). The AUCs values of the SMTN within the anti-HER2 therapy subgroups were 0.833-0.972 in the two external validation cohorts. Moreover, 272 of 279 (97.5%) non-pCR patients (159 of 160 (99.4%), 53 of 54 (98.1%), and 60 of 65 (92.3%) in the training and two external validation cohorts, respectively) were successfully identified by the SMTN, suggesting that they could benefit from regime adjustment at the early-stage of NACT. Interpretation The SMTN was able to predict pCR in the early-stage of NACT for HER2-positive breast cancer patients, which could guide clinicians in adjusting treatment regimes. Funding Key-Area Research and Development Program of Guangdong Province (No.2021B0101420006); National Natural Science Foundation of China (No.82071892, 82171920); Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (No.2022B1212010011); the National Science Foundation for Young Scientists of China (No.82102019, 82001986); Project Funded by China Postdoctoral Science Foundation (No.2020M682643); the Outstanding Youth Science Foundation of Yunnan Basic Research Project (202101AW070001); Scientific research fund project of Department of Education of Yunnan Province(2022J0249). Science and technology Projects in Guangzhou (202201020001;202201010513); High-level Hospital Construction Project (DFJH201805, DFJHBF202105).

Background The biological phenotype of tumours evolves during neoadjuvant chemotherapy (NAC). Accurate prediction of pathological complete response (pCR) to NAC in the early-stage or posttreatment can optimize treatment strategies or improve the breast-conserving rate. This study aimed to develop and validate an autosegmentation-based serial ultrasonography assessment system (SUAS) that incorporated serial ultrasonographic features throughout the NAC of breast cancer to predict pCR. Methods A total of 801 patients with biopsy-proven breast cancer were retrospectively enrolled from three institutions and were split into a training cohort (242 patients), an internal validation cohort (197 patients), and two external test cohorts (212 and 150 patients). Three imaging signatures were constructed from the serial ultrasonographic features before (pretreatment signature), during the first-second cycle of (early-stage treatment signature), and after (posttreatment signature) NAC based on autosegmentation by U-net. The SUAS was constructed by subsequently integrating the pre, early-stage, and posttreatment signatures, and the incremental performance was analysed. Results The SUAS yielded a favourable performance in predicting pCR, with areas under the receiver operating characteristic curve (AUCs) of 0.927 [95% confidence interval (CI) 0.891-0.963] and 0.914 (95% CI 0.853-0.976), compared with those of the clinicopathological prediction model [0.734 (95% CI 0.665-0.804) and 0.610 (95% CI 0.504-0.716)], and radiologist interpretation [0.632 (95% CI 0.570-0.693) and 0.724 (95% CI 0.644-0.804)] in the external test cohorts. Furthermore, similar results were also observed in the early-stage treatment of NAC [AUC 0.874 (0.793-0.955)-0.897 (0.851-0.943) in the external test cohorts]. Conclusions We demonstrate that autosegmentation-based SAUS integrating serial ultrasonographic features throughout NAC can predict pCR with favourable performance, which can facilitate individualized treatment strategies.