AIMS: Newly graduated paediatric surgery nurses must be able to identify and handle potential risks to ensure patient safety. It is necessary to reinforce their understanding of their roles and responsibilities to achieve this goal. However, the limitations of traditional classroom-based teaching hinder the exploration of learners' potential. This study aimed to evaluate the effectiveness of the Jeffries simulation framework in improving the core competence of new graduate nurses in paediatric surgery. DESIGN: A quasi-experimental study, descriptive design following STROBE checklist. METHODS: A quasi-experimental methodology with a pretest/posttest design was used. The study involved 60 new graduate paediatric nurses who work in the paediatric surgery department of a level A tertiary hospital in Southwest China. Clinical scenario simulation cases, which were designed based on the Jeffries simulation framework, were used to improve clinical competence. Before and after the training, teachers assessed each nurse's core competency and clinical decision-making ability by the Chinese Registered Nurse Core Competency Scale (CIRN) and the Clinical Decision-Making in Nursing Scale (CDMNS). In addition, participants provided self-reported reflective feedback during the debriefing sessions following each simulation scenario. RESULTS: Across all 60 newly graduated paediatric surgical nurses, significant improvements in clinical competence were observed following the simulation-based training (p < 0.001). The total score of core competence increased significantly from 118.48 ± 8.84 pre-training to 142.56 ± 6.11 post-training, with a mean difference of 24.08 ± 9.51 points. Similarly, the total score of clinical decision-making ability showed a marked improvement, rising from 83.92 ± 2.43 to 91.15 ± 3.24, representing a mean increase of 7.23 ± 4.17 points. Moreover, the dimensions of 'clinical nursing', 'critical thinking/scientific' and 'clear goals and values' also showed significant improvements. CONCLUSION: Training new graduate paediatric nurses via the Jeffries simulation framework can enhance their clinical competence by helping them internalize knowledge and skills and improve their core competencies and clinical decision-making abilities. PATIENT OR PUBLIC CONTRIBUTION: The study analysed the core competency levels of newly graduated paediatric surgery nurses, providing a valuable reference for the management, training and evaluation of these nurses as well as establishing qualification criteria for paediatric specialist nurses. Identifying the factors that influence core competitiveness is crucial for developing standardized training programmes and enhancing the construction of nursing safety and paediatric nursing talent. TRIAL REGISTRATION: Clinical Trial Registry registration number: ChiCTR2400082003.

AIM: Standard treatment for muscle-invasive bladder cancer (MIBC) includes radical cystectomy (RC), a highly invasive procedure. We evaluated the utility of the Geriatric-8 (G8) screening tool in guiding treatment and whether the survival benefit of RC differs by G8 score. METHODS: We retrospectively reviewed patients with non-metastatic MIBC who underwent G8 assessment (2020-2024). Patients were grouped by G8: low (<11), intermediate (11-14), and high (>14). Treatment patterns and the effectiveness of RC were evaluated. RESULTS: A total of 152 patients were included (high: n = 55, intermediate: n = 67, low: n = 30). RC was performed in 124 patients (81.6%). Lower G8 was linked to older age, poorer performance status, and dependent instrumental activities of daily living (p < 0.01). Neoadjuvant chemotherapy followed by RC was more frequently planned in the high G8 group (81.8% vs. 53.7% vs. 26.7%, p < 0.0001), while immediate RC was a more common plan in the low G8 group (14.5% vs. 41.8% vs. 53.3%, p = 0.0003). RC was associated with significantly improved overall survival, and the benefit persisted after propensity score matching (p = 0.0013). Inverse probability of treatment weighting, which retained the whole cohort, gave a consistent estimate (hazard ratio [HR] 0.17, 95% confidence interval [CI] 0.08-0.39). Subgroup estimates were less precise in the low G8 group (HR 0.57, 95% CI 0.12-2.73) than in the intermediate (HR 0.14, 95% CI 0.06-0.33) and high (HR 0.10, 95% CI 0.02-0.39) groups. In sliding window analysis, HR estimates were higher at G8 < 9, with wide CIs. Similar results were observed for cancer-specific survival. CONCLUSIONS: RC was associated with a survival benefit in patients with intermediate and high G8 scores, whereas the evidence in the low G8 group was limited and inconclusive; careful risk-benefit evaluation remains warranted in this group.

BACKGROUND: Neoadjuvant radiotherapy (RT) has been the standard of care for locally advanced rectal cancer (LARC) for over two decades. Adjuvant RT use in LARC represents a deviation from standard care and warrants further investigation. OBJECTIVES: To identify factors associated with adjuvant RT utilization. We hypothesized that sociodemographic determinants contribute to differences in the sequence of radiation treatment among patients with rectal cancer. METHODS: This retrospective cohort study utilized the National Cancer Database (2015-2022) to identify adults with clinical stage II-III rectal adenocarcinoma undergoing surgery and RT. Patients were categorized by RT sequence (neoadjuvant vs. adjuvant). Multivariable logistic regression identified factors associated with use of adjuvant RT. RESULTS: Of the included 48 452 patients, 6.9% received adjuvant RT. Compared with the neoadjuvant group, adjuvant RT recipients exhibited higher rates of pathologic upstaging (20.5% vs. 10.3%), positive margins (14.7% vs. 6.3%), and lymphovascular invasion (17.4% vs. 11.3%; all p < 0.001). On multivariable analysis, positive margins (aOR 1.78, 95% CI 1.43-2.22), lymphovascular invasion (aOR 1.96, 95% CI 1.66-2.31), upstaging (aOR 1.63, 1.31-2.02) were independently associated with adjuvant RT. CONCLUSIONS: Adjuvant RT appeared to be used in patients who were found to have high-risk tumor pathology postoperatively.

Invasive fungal infections (IFIs) cause substantial morbidity and mortality, yet optimal antifungal prophylaxis in adult acute lymphoblastic leukemia (ALL) remains uncertain given unclear incidence and drug interaction constraints. We performed a PRISMA 2020-compliant systematic review and meta-analysis (PROSPERO CRD420251048884) of PubMed, Embase, and Cochrane CENTRAL from inception through September 2025, including adults with ALL receiving antineoplastic therapy, excluding HSCT and pediatric cohorts. Primary outcome was IFI incidence per European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) criteria; invasive aspergillosis (IA) was secondary. Of 1,789 records, 36 studies met eligibility; 23 contributed to meta-analyses. Pooled incidence of proven/probable IFI was 9% (95% CI 7-11%;  = 3,316), proven/probable/possible IFI 16% (12-21%;  = 806), and IA 5% (4-8%;  = 3,190). IFIs remain clinically significant in adult ALL, supporting risk-adapted prophylaxis during higher-risk treatment phases. Heterogeneity reflected differences in prophylaxis, treatment, and limited comparative data on strategies across studies.

The ion channel gene GJB2 emerges as a therapeutic target for LUAD with significant prognostic value. Herein, the potential mechanisms of GJB2 were investigated. GJB2 expression was analyzed by bioinformatics, RT-qPCR and western blotting. In vitro functional assays and A549 xenografts detected the role of GJB2. The upstream mechanism of GJB2 was explored. GJB2 was up-regulated and associated with the poor overall survival of LUAD patients. GJB2 knockdown inhibited cell malignancy and impaired mitochondrial homeostasis. HSF4 enhanced GJB2 transcription. GJB2 knockdown lowered PI3K/AKT activity. SC79 reversed the in vitro impacts of GJB2 inadequacy and promoted tumor growth when HSF4 was up-regulated and GJB2 was down-regulated simultaneously. GJB2, transcriptionally activated by HSF4, activates PI3K/AKT pathway to support LUAD tumorigenesis and development.

BACKGROUND AND AIMS: Autoimmune gastritis (AIG) is characterized by chronic hypergastrinemia and is associated with an increased risk of gastric neuroendocrine neoplasms (gNENs). Because proton pump inhibitors (PPIs) further increase gastrin secretion, concerns have been raised regarding a potential additive effect on gastric neoplastic risk. This study aimed to evaluate the association between PPI exposure and gNEN occurrence in patients with AIG using a large real-world database. METHODS: We conducted a retrospective propensity score-matched cohort study using the TriNetX Global Collaborative Network. Patients with AIG were identified using diagnostic codes for chronic atrophic gastritis or pernicious anaemia, excluding Helicobacter pylori infection, gastric cancer, multiple endocrine neoplasia or other competing gastric conditions. Two cohorts were defined: patients with AIG receiving PPIs and patients without PPI exposure. The primary outcome was the overall occurrence of gNENs. A prespecified secondary analysis excluded patients with gNENs diagnosed before the index date to evaluate incident tumours. Secondary outcomes included hypergastrinemia, intestinal metaplasia and gastric polyps. RESULTS: A total of 153,687 patients with AIG were identified. After 1:1 propensity score matching, 40,489 patients were included in each cohort. After propensity score matching, gNENs were recorded in 241 patients (0.60%) without PPI exposure and 360 patients (0.89%) receiving PPIs. PPI exposure was associated with a significantly higher occurrence of gNENs (risk ratio [RR] 1.49, 95% CI 1.27-1.76), which was confirmed by time-to-event analysis (hazard ratio [HR] 1.44, 95% CI 1.22-1.70; log-rank p < 0.001). The association persisted after exclusion of patients with pre-existing gNENs (RR 1.61, 95% CI 1.26-2.06; HR 1.52, 95% CI 1.19-1.95). PPI exposure was also associated with higher occurrences of hypergastrinemia (HR 1.17, 95% CI 1.00-1.37), intestinal metaplasia (HR 1.53, 95% CI 1.36-1.71) and gastric polyps (HR 2.48, 95% CI 2.25-2.73). No gastric adenocarcinomas were identified during follow-up. CONCLUSIONS: In this large real-world propensity score-matched study, PPI exposure was associated with a greater occurrence of both overall and incident gNENs in patients with AIG. PPI use was also consistently associated with gastric mucosal alterations, including hypergastrinemia, intestinal metaplasia and gastric polyps. Although the absolute risk of gNENs remained low, these findings support judicious long-term PPI prescribing in patients with AIG and reinforce the importance of appropriate endoscopic surveillance in this high-risk population.

INTRODUCTION: With recent approvals in Japan, identifying optimal first-line therapy for metastatic castration-sensitive prostate cancer (mCSPC) is critical. We evaluated real-world outcomes of androgen-deprivation therapy (ADT) plus androgen receptor signaling inhibitors (ARSIs) as first-line therapies using prostate-specific antigen (PSA) responses and treatment duration. METHODS: This retrospective study used the Medical Data Vision database (May 2020-April 2024). The study population included males with mCSPC, with two cohorts: cohort 1 (with PSA data); cohort 2 (all eligible patients). PRIMARY ENDPOINT: cumulative incidence of ≥ 90% PSA reduction (PSA90) during the first-line period. Secondary endpoints: PSA50; PSA ≤ 0.2 ng/mL; time to PSA progression (TTPP); time-to-treatment discontinuation (TTD). Endpoints were estimated using the Kaplan-Meier method evaluated using the Cox proportional hazards model, adjusted for baseline characteristics. RESULTS: In cohort 1 (n = 1306), cumulative PSA90 response rates were higher with ADT + ARSI ± docetaxel (ARSI-based treatments) than with ADT alone or ADT + nonsteroidal antiandrogens (NSAAs) (at 3 months: ADT alone, 63.2%; ADT + NSAAs, 69.3%; ADT + enzalutamide, 91.8%; ADT + apalutamide, 90.9%; ADT + abiraterone, 90.7%; ADT + darolutamide + docetaxel, 81.2%). Cumulative PSA50 and PSA ≤ 0.2 ng/mL response rates were consistent with PSA90 findings. Median TTPP was longer for ARSI-based treatments versus ADT alone and ADT + NSAA. No significant differences were observed among ARSI-based treatments across these PSA-related endpoints. In cohort 2 (n = 11,737), the median TTD was longer for ARSI-based treatments versus ADT alone and ADT + NSAAs. Notably, ADT + apalutamide showed a shorter median TTD than other ARSI-based treatments. CONCLUSION: Compared with ADT alone or ADT + NSAA, ARSI-based treatments showed faster PSA declines and longer treatment durations. While ARSI-based treatments demonstrated similar PSA-lowering effects, differences in treatment continuation likely reflect real-world clinical management influenced by not only PSA response but also adverse events and patient characteristics.

BACKGROUND: Indoor solid fuels, outdoor air pollution (PM, PM, and PM), and heatwave are all modifiable environmental factors. However, their mixed effects on Cardiometabolic Multimorbidity (CMM) and its core component diseases (diabetes, heart disease, and stroke) remain unclear. METHODS: In this study, four diseases analysis cohorts (CMM: n = 10,273; diabetes: n = 9,893; heart disease: n = 9,536; and stroke: n = 10,466) were constructed using data from the five waves (2011, 2013, 2015, 2018, and 2020) of the CHARLS. A time-varying Cox proportional hazards model was used to estimate the hazard ratio (HR) for environmental factor exposure. The Cumulative Risk Index (CRI) and the Quantile g-computation (Qgcomp) model were employed to assess the cumulative effect and component weights of coexposure to multiple environmental factors. RESULTS: The single-exposure analysis indicated that indoor solid fuels use significantly increased heart disease (HR = 1.118, 95% CI 1.016-1.231) and stroke (HR = 1.149, 95% CI 1.007-1.310) risks. PM, PM, and PM were the most consistent risk factors for CMM, diabetes, and heart disease (all HRs > 1, P < 0.001), and heatwave was sometimes associated with higher risks of CMM, diabetes, and heart disease. The CRI analysis demonstrated that coexposure to multiple environmental factors increased the CMM, diabetes, and heart disease risks. The Qgcomp model further showed that these coexposure increased the risk of four diseases, with ORs (95% CIs) (CMM:1.650, 1.375-1.979; diabetes: 1.675, 1.475-1.903; heart disease: 1.228, 1.080-1.397; stroke: 1.205, 1.011-1.437), with indoor solid fuels use as the primary contributor. CONCLUSIONS: In conclusion, long-term coexposure to indoor solid fuels, outdoor air pollution, and heatwave increased the risk of CMM and its core component diseases. Indoor solid fuels play a main role in these effects.

CircARHGAP10 is significantly downregulated in colorectal cancer (CRC), but its functional role and underlying molecular mechanism in CRC progression remain unelucidated. Here, we first detected circARHGAP10 expression in CRC tissues and adjacent normal tissues, as well as in CRC cell lines and normal intestinal epithelial cells. Functional analyses using CCK-8, EdU, colony formation, wound healing, and transwell assays demonstrated that circARHGAP10 overexpression notably inhibits CRC cell proliferation, migration, and invasion, while circARHGAP10 knockdown promotes these malignant phenotypes. Mechanistically, bioinformatic predictions, dual-luciferase reporter assays, and RNA immunoprecipitation (RIP) assays confirmed that circARHGAP10 acts as a competing endogenous RNA (ceRNA) to sponge miR-29a-5p, thereby upregulating the expression of its downstream target gene LPP. Furthermore, we found that circARHGAP10 modulates LPP, the Wnt/β-catenin signaling pathway and reverses epithelial-mesenchymal transition (EMT) through the miR-29a-5p, as validated by rescue experiments. Collectively, our findings reveal that circARHGAP10 functions as a tumor suppressor in CRC via two independent regulatory branches downstream of the circARHGAP10/miR-29a-5p cascade. On one hand, it restores LPP expression to block the malignant proliferation, migration and invasion of CRC cells; on the other hand, this signaling cascade mitigates excessive Wnt/β-catenin pathway activation and reverses EMT. This newly identified circRNA-centered regulatory network provides a promising novel therapeutic target for CRC intervention.

This paper describes the rationale and radiology considerations in the implementation of the Preventing Liver Cancer Mortality through Imaging with Ultrasound versus MRI (PREMIUM) study. PREMIUM is a multicenter, randomized controlled trial sponsored by the Department of Veterans Affairs comparing dynamic contrast-enhanced (DCE) abbreviated MRI (aMRI) plus serum AFP versus ultrasound (US) plus serum AFP for hepatocellular carcinoma (HCC) screening in patients with cirrhosis. PREMIUM aims to randomize 4,700 participants across over 47 Veterans Affairs Medical Centers to semiannual surveillance for up to eight years, with HCC-related mortality as the primary endpoint. To date, 35 sites have been activated with 1,085 patients randomized. To ensure uniform implementation and reporting of per-protocol screening, the PREMIUM Radiology Workgroup developed standardized imaging protocols, structured LI-RADS-based reporting templates, and a centralized training program for radiologists and technologists. They also perform ongoing quality control on both scans and reports. The aMRI protocols utilize multiphasic post-contrast imaging to allow LI-RADS scoring. A non-contrast-enhanced aMRI protocol is available for participants who develop renal impairment or contrast allergy during the study. US protocols conform to US LI-RADS standards. Structured reporting promotes consistency in documentation of findings, visualization scores, and follow-up recommendations. A centralized Image Repository was established, incorporating advanced de-identification methods to remove metadata and pixel-embedded protected health information from imaging files. More than 20,000 curated liver MRI and US exams are anticipated, supporting both trial outcomes and future radiomics and artificial intelligence research. PREMIUM aims to determine whether screening for HCC with a DCE aMRI protocol reduces HCC-related mortality and also facilitates ancillary studies utilizing the Image Repository.

PURPOSE: To investigate the value of extracellular volume fraction (ECV) derived from T1 mapping and apparent diffusion coefficient (ADC) for non-invasive assessment of tumor stroma percentage (TSP) in rectal cancer. METHODS: This prospective study enrolled 158 patients (104 men, 54 women; mean age 65.96 ± 10.87 years) with rectal adenocarcinoma. All patients underwent 3.0T MRI including pre- and post-contrast T1 mapping and diffusion-weighted imaging. ECV was calculated from native and post-contrast T1 values. TSP was histopathologically assessed on surgical specimens. Interobserver reproducibility, correlations with TSP, diagnostic performance for stroma-rich tumors (TSP > 50%), and associations with clinicopathological features were evaluated. RESULTS: The pre- and post-contrast T1 measurements used to calculate ECV showed excellent interobserver reproducibility (ICC = 0.978 and 0.964, respectively). ECV showed a moderate positive correlation with TSP (ρ = 0.520, P < 0.001), whereas ADC showed no significant correlation (ρ = 0.070, P > 0.05). ECV demonstrated good discrimination of stroma-rich tumors (AUC, 0.819; 95% CI 0.742-0.897), whereas ADC derived from the two-b-value DWI protocol did not discriminate between stroma-rich and stroma-poor tumors (AUC, 0.495; 95% CI: 0.398-0.592; P < 0.001 vs. ECV). Adding ADC to ECV did not significantly improve diagnostic performance compared with ECV alone (AUC = 0.845, P > 0.05; DeLong P > 0.05). ECV differed across tumor differentiation grades after correction (P < 0.05), but not according to LVI status (P > 0.05). CONCLUSION: T1 mapping-derived ECV was reproducible and showed a moderate association with histological TSP, with good performance for distinguishing stroma-rich from stroma-poor tumors.

PURPOSE: The CIRSE Emprint Microwave Ablation (MWA) Registry (CIEMAR) was designed to evaluate real-world effectiveness of MWA for colorectal liver metastases (CRLM). This analysis reports on local tumour control and includes post-hoc analyses of ablation margin size and confirmation software use. MATERIALS AND METHODS: Patients were eligible if MWA was indicated as part of a curative-intent strategy for ≤9 local treatment-naïve CRLM measuring ≤3 cm, with no extrahepatic disease except ≤5 lung nodules. Baseline, treatment and follow-up data from September 2019 to December 2025 were analysed. Ablation margin categories were reported locally according to centre-specific practice. The primary endpoint was the 1-year local tumour control rate after the last MWA. RESULTS: In total, 491 patients with 1083 CRLM from 30 sites in 11 countries were included. Reported margins were <5mm (12.3%), 5-10mm (35.5%) or >10mm (44.5%); for 1.5% and 6.2% of lesions, ablation was incomplete and data were missing, respectively. The 1-year local tumour control rate was 88.9% (95% CI 83.2-94.6) on a per-lesion basis and 81.2% (95% CI 77.2-84.6) on a per-patient basis. Larger margins were independently associated with lower odds of local failure (5-10 mm: OR 0.30; >10 mm: OR 0.10; both p<0.01 vs <5 mm). Use of confirmation software was associated with wider reported margins (p<0.001). CONCLUSION: MWA for CRLM achieved high 12 month local tumour control. These findings support routine verification that adequate ablation margins have been achieved, while exploratory association between confirmation software use and wider margins warrants further confirmation. TRIALS REGISTRATION: NCT03775980.

BACKGROUND: Savolitinib is a highly selective small-molecule inhibitor of the mesenchymal-epithelial transition (MET) factor tyrosine kinase, which was approved by the National Medical Products Administration (NMPA) of China for patients with MET exon 14 (METex14)-altered locally advanced or metastatic non-small cell lung cancer (NSCLC). However, the pharmacokinetics profiles of savolitinib and its active metabolite M2 have not been comprehensively characterised in an integrated manner across different studies, tumour types and treatment settings. METHODS: A non-linear mixed-effects model was developed to characterise the population pharmacokinetics of savolitinib and its active metabolite M2 in patients with advanced solid tumours. The analysis included 7192 savolitinib concentration observations from 704 participants and 7162 M2 concentration observations from 702 participants pooled across eight clinical studies. RESULTS: A joint parent-metabolite model with first-order absorption and two-compartment distribution and elimination for both savolitinib and M2 adequately described the observed concentration-time data. Body weight, alkaline phosphatase, creatinine clearance and total bilirubin were identified as statistically significant covariates for the apparent clearance of savolitinib, whilst body weight and renal impairment categories were retained for apparent M2 clearance. Although these covariates influenced model-predicted pharmacokinetic parameters, the magnitude of the effects was generally modest relative to overall inter-individual variability. CONCLUSIONS: The population pharmacokinetics of savolitinib and M2 can be adequately characterised in patients with advanced solid tumours using an integrated parent-metabolite framework. Within the range of this pooled dataset, the identified covariate effects are considered insufficient, on the basis of the present pharmacokinetic analysis, to support routine initial dose adjustment.

Cell division inevitably shortens telomeric DNA owing to the end-replication problem. Eukaryotic chromosomes possess specialized telomere structures to maintain genomic stability. In most proliferative cells, telomerase adds telomeric repeats during S-phase. In differentiated cells where telomerase is silenced, telomeres shorten progressively, thereby compromising genomic integrity. Consequently, cancer cells universally activate alternative telomere maintenance mechanisms during malignant transformation: ~80% reactivate telomerase, while a portion of the rest rely on BIR (break-induced replication)-mediated homologous recombination-based ALT (alternative lengthening of telomeres). Although these mechanisms are stable once established, the initial determinants influencing a cancer cell's choice remain poorly understood. This review discusses recent molecular insights into how telomeric chromatin properties profoundly impact this choice. After briefly introducing telomere chromatin characteristics and key players in its maintenance and dynamics, we discuss the mechanisms by which cancer cells acquire distinct telomere replication capabilities. In particular, we present an in-depth analysis linking telomere heterochromatin status to ALT. Furthermore, based on recent advances, we propose a coupled feedforward loop model explaining how the ALT state becomes "locked in" once initiated. Finally, we offer novel perspectives on rational, telomere-centric therapeutic interventions for ALT-positive cancers, focusing on strategies designed to disrupt such feedforward loops by manipulating telomeric chromatin structure.

PURPOSE: To evaluate the psychometric properties of PROMs for measuring body image in breast cancer patients. METHODS: In December 2024, a psychometric systematic review was performed in the nine databases. The COSMIN checklist was employed to evaluate the methodological quality and psychometric properties of the included body image measures. The level of evidence was assessed using the GRADE framework, and final recommendations were formulated for the scale. RESULTS: Thirty-eight articles evaluating fifteen PROMs were included in this review. Structural validity, internal consistency, and hypothesis testing had been most frequently evaluated. Measurement error had not been assessed for all PROMs. Twelve instruments show potential application value but require further research. The BAS-BC, PSPP, and ASI-R are not recommended for use, as these instruments do not meet the strict COSMIN thresholds for full recommendation. CONCLUSION: The BIS can be recommended as a temporary screening tool for assessing body image outcome in clinical practice. The BIRS can be tentatively advised for measuring specific postoperative body image changes. However, further comprehensive studies are required to validate the psychometric properties of existing PROMs.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and PD-L1-mediated immune evasion is a major mechanism of tumor immune suppression and an important target of immune checkpoint blockade. Here, we identified RNF166 as an E3 ubiquitin ligase that promotes immune evasion in HCC. RNF166 expression was upregulated in HCC tissues and correlated with PD-L1 levels, whereas RNF166 did not directly affect the proliferation or apoptosis of HCC cells. In immunocompetent mouse models, RNF166 overexpression accelerated tumor growth and suppressed CD8 + T-cell infiltration and cytotoxic function, while these effects were dependent on PD-L1 signaling and were attenuated in immunodeficient settings. Mechanistically, RNF166 physically interacted with c-Jun and promoted K63-linked ubiquitination of c-Jun at K50/K56, which was associated with reduced K48-linked ubiquitination and enhanced c-Jun stability. Stabilized c-Jun bound to the PD-L1 promoter and promoted PD-L1 transcription, thereby linking RNF166-mediated c-Jun stabilization to tumor immune suppression. Upstream, lactate accumulation increased H3K18la enrichment at the RNF166 promoter and contributed to RNF166 transcriptional upregulation. Therapeutically, pharmacological inhibition of c-Jun with T-5224 enhanced the antitumor effect of anti-PD-L1 blockade. Collectively, our findings delineate a lactate-H3K18la-RNF166-c-Jun-PD-L1 axis that promotes immune evasion in HCC and suggest that targeting RNF166 or the RNF166-c-Jun axis may improve PD-1/PD-L1-based immunotherapy.

Obtaining adequate tissue for histologic diagnoses and genomic testing can be challenging in metastatic lung cancer, particularly when conventional biopsy approaches are nondiagnostic. The study reports an effective salvage strategy using endoscopic ultrasound (EUS)-guided adrenal tissue acquisition in two cases. A 66-year-old woman (case 1) developed recurrent lung adenocarcinoma with progressive metastases to the left adrenal, liver, and lungs following multiple lines of systemic therapy. A percutaneous biopsy of a suspected liver metastasis proved nondiagnostic. Subsequently, transgastric EUS-guided biopsy was performed, which confirmed metastatic adenocarcinoma originating in the lung. Oncomine-based genomic testing detected a human epidermal growth factor receptor 2 exon 20 insertion. Trastuzumab deruxtecan was subsequently introduced, resulting in disease stabilization for 6 months. A 75-year-old man (case 2) developed bilateral pulmonary nodules and a right adrenal mass detected on positron emission tomography. Bronchoscopy failed to yield diagnostic tissue. Following careful review of cross-sectional anatomy, EUS-guided biopsy of the right adrenal gland was safely performed via the duodenal bulb, confirming metastatic squamous cell carcinoma and yielding adequate tissue for genomic testing. EUS-guided adrenal biopsy, including transduodenal sampling of the right adrenal gland, may provide tissue for histopathologic and precision oncology testing, facilitating definitive diagnoses.

BACKGROUND AND OBJECTIVE: The pharmacokinetics of lorlatinib have been characterized in a population pharmacokinetic (PK) model by the license holder, but external validation with real-world data is lacking. As higher trough concentrations are linked to increased toxicity, there may be a role for model-informed precision dosing (MIPD). METHODS: The published lorlatinib population PK model was externally validated using data from 150 patients with non-small cell lung cancer (NSCLC) treated in France and the Netherlands. Model performance was assessed using mean percentage error (MPE) and mean absolute percentage error (MAPE). Suboptimal validation results led to development of a refined population PK model, which was subsequently used to simulate lorlatinib exposure across different doses. A MIPD strategy targeting trough concentrations of 75-125 ng/mL was assessed. RESULTS: External validation revealed significant bias (MPE: -6.1%, 95% CI -11.1 to -0.5%), with the original population PK model systematically underestimating trough concentrations. The refined model included a lower clearance (13.7 versus 14.5 L/h). Simulations with the refined model predicted a median steady state trough level of 127.0 ng/mL (IQR: 96.1-162.0 ng/mL) versus 106.0 ng/mL with the original model for standard 100 mg once-daily (QD) regimen. MIPD increased the proportion of patients within target range from 35 to 62% after one cycle of dose adjustment. CONCLUSIONS: The published population PK model underestimates real-world trough concentrations, underscoring the importance of external validation of clinical trial-derived models. The refined model reflects lorlatinib pharmacokinetics in clinical practice better. Simulations suggest that lower lorlatinib doses may be feasible and MIPD may reduce toxicity.

PURPOSE: IVC segmental resection (SR) during robot-assisted radical nephrectomy and IVC thrombectomy (RARN-IVCT) is selected for wall invasion, occlusion, and collateral outflow, making direct comparison with non-segmental resection (NSR) biased. We compared the perioperative and renal safety of SR versus NSR in the overlap population. METHODS: Retrospective single-center cohort at Peking University Third Hospital (2014-2025): 120 patients with RCC and Mayo level II-IV IVC thrombus undergoing RARN-IVCT, including 45 SR and 75 NSR. Overlap weighting balanced baseline variables. Primary outcomes were AKI, ΔSCr, and ΔeGFR; secondary outcomes were complications and hospital stay, with OS assessed exploratorily. RESULTS: After weighting, no statistically significant differences were observed in AKI, ΔSCr, ΔeGFR, complications, hospital stay, or OS. SR had lower RBC transfusion volume (mean difference - 249.63 mL, 95% CI - 443.20 to - 56.05; P = 0.011). SR met non-inferiority/equivalence for hospital stay and pneumonia; renal non-inferiority was not established. Limitations include retrospective design, limited effective sample size, and unmeasured anatomic/hemodynamic confounding. CONCLUSION: In overlap patients, no statistically significant differences in renal or safety/recovery outcomes were observed, but neither renal non-inferiority nor equivalence was established. Planning should consider thrombus-wall interaction, caval patency, collateral outflow, and renal reserve.

OBJECTIVE: To examine the association between shift work and all-cause and cause-specific mortality in the U.S. population and assess whether biological age acceleration mediates this relationship. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study included 7548 adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2010, with mortality follow-up through 2019. EXPOSURE: Shift work included regular night, evening, or rotating shifts versus daytime schedules. MAIN OUTCOMES AND MEASURES: Primary outcomes were all-cause, cardiovascular (CVD), and cancer mortality. RESULTS: Among 7548 participants (mean follow-up 11.6 years), 358 deaths occurred. Shift work was associated with significantly increased all-cause mortality after full adjustment (HR = 1.52; 95% CI 1.09-2.13). CVD and cancer mortality associations were non-significant. No statistically significant interactions were observed in subgroup analyses of all-cause mortality. Shift workers showed greater PhenoAge acceleration (β = 0.39 years), which statistically accounted for 6.18% of the association between shift work and all-cause mortality. CONCLUSIONS AND RELEVANCE: Shift work was associated with higher all-cause mortality and greater PhenoAge acceleration. PhenoAge acceleration may statistically account for a small proportion of this association, although causal mediation cannot be inferred.

PURPOSE: Male farmers are frequently exposed to various environmental and occupational hazards that may be related to cancer risk. Long-term cancer incidence trends in male farmers in Taiwan remain unclear. This study examined temporal trends in cancer incidence among male farmers over a 24-year period. METHODS: Using Taiwan's Longitudinal Health Insurance Database of Patients with Catastrophic Illnesses (2000-2023), we conducted a nationwide cohort study of agricultural workers whose aged 15-84 (N= 2,426,531). ICD-O-3 and the corresponding ICD-9-CM and ICD-10-CM codes from the Taiwan Cancer Registry Annual Report were used to identify annually incident cancer cases. Age-standardized incidence rates, age-standardized rate ratios, and age-standardized incidence ratios were calculated. A Joinpoint regression and age-period-cohort model were used to identify and examine temporal trends across the study period. RESULTS: Overall cancer incidence was higher among male farmers compared to the male general population, with an increasing temporal trend from 2000 to 2023. Lip and lung cancers showed a significantly increased annual average percentage change (AAPC) value, age effect, period effect, and cohort effect for the study period, while liver cancer showed a decreasing AAPC, period effect, and cohort effect, with an increasing age effect over the entire study period. CONCLUSION: This study provides evidence that lung and lip cancer incidence among male farmers increased significantly over the study period, while liver cancer decreased. As exposure varies by agricultural activity and farm type, further research is needed to identify specific exposures that are related to the higher risk of cancer in this population.