Introduction Providing precise oncologic treatment for patients with refractory solid tumors is still an unmet need in clinical practice. This study aimed to assess whether treatments recommended by a molecular tumor board (MTB) can improve clinical outcomes in patients with refractory solid tumors. Methods We screened all patients with refractory solid tumors during the period from 2017 to 2022 at the authors' center. The patients with actionable molecular alterations (mainly including druggable tier 2 genetic variants identified using next-generation sequencing [NGS]) were presented to MTB. We compared the overall survival (OS) and progression-free survival (PFS) between the patients treated with a matched therapy recommended by MTB and those who did not receive the MTB-recommended therapy. Patients with no actionable molecular alterations served as an additional control. Results A total of 338 patients with refractory solid tumors were screened. Among the 305 patients for whom NGS testing was conducted, 217 patients available for survival outcomes were included in the final analysis. A total of 129 patients had at least one actionable molecular alteration and were presented to MTB; 82 received the MTB-recommended therapy, while the remaining 47 did not. Those who received the recommended therapy had significantly longer median OS (17.7 vs. 4.4 months; HR 0.31, 95% CI: 0.14-0.66; P < .001) and median PFS (7.0 vs. 2.3 months, HR 0.32, 95% CI: 0.16-0.65; P < .001). Conclusions MTB improves oncologic prognosis in patients with refractory solid tumors, and matching MTB-recommended therapy is an independent factor for OS and PFS.

Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape for advanced cancers; however, a substantial proportion of patients fail to benefit from ICI therapy, and reliable predictive biomarkers remain limited. This study aimed to investigate the immunological relevance of helicase-like transcription factor (HLTF) and its potential therapeutic implications in hepatocellular carcinoma (HCC). HLTF expression was elevated across multiple cancer types, with particularly high levels observed in HCC. Increased HLTF expression was significantly associated with advanced tumor stage, higher histological grade, TP53 mutations, and lymph node metastasis. Moreover, high HLTF expression correlated with poorer overall survival, disease-specific survival, and progression-free interval in patients with HCC, indicating its potential value as a prognostic biomarker. Consistent with data from the Human Protein Atlas, HLTF protein expression was 74.51

Effects of UA on CD8+ T cell function in B16 and LLC tumors

4176 Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a poorly differentiated and highly aggressive malignancy with poor prognosis. Platinum (cisplatin or carboplatin) plus etoposide (EC/EP) remains the standard first-line regimen. However, clinical outcomes are suboptimal, highlighting the need for more effective strategies. Camrelizumab is a programmed cell death-1 (PD-1) inhibitor, and apatinib is a vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor. Both have demonstrated antitumor activity in multiple solid tumors. Therefore, we investigated a sequential regimen consisting of induction EC/EP plus camrelizumab followed by maintenance camrelizumab plus apatinib in treatment-naive patients with advanced or metastatic EP-NEC. Methods: This multicenter, single-arm trial enrolled patients with previously untreated advanced or metastatic EP-NEC. Patients received 4–6 cycles of induction therapy with cisplatin (25 mg/m² iv, d1-3, q3w) or carboplatin (AUC = 5 iv, d1, q3w) plus etoposide (100 mg/m² iv, d1-3, q3w) in combination with camrelizumab (200 mg iv, d1, q3w). Patients without disease progression received maintenance camrelizumab (200 mg iv, q3w) plus apatinib (250 mg, qd) until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Tumor response was assessed every 6 weeks per RECIST v1.1. The trial is registered on ClinicalTrials.gov, NCT05142865. Results: As of January 2026, 30 patients were enrolled (median age of 59.5 years, range 30–73), and all 30 patients were evaluable for efficacy. The ORR was 66.7% and the DCR was 83.3%. Median PFS was 9.87 months (95% CI, 6.23–NA). Median OS was not reached, and the 1-year OS rate was 74.6%. All patients experienced adverse events (AEs), with grade ≥3 AEs observed in 43.3% (13/30). Grade ≥3 AEs were mainly hematologic toxicities, including anemia (13.3%), neutropenia (13.3%) and thrombocytopenia (13.3%). Common non-hematologic AEs included elevated transaminases (43.3%), mainly grade 1–2, with grade ≥3 events in 10.0%. Conclusions: Induction EC/EP plus camrelizumab followed by maintenance camrelizumab plus apatinib showed encouraging activity and manageable safety in treatment-naive advanced or metastatic EP-NEC. Further studies are warranted to confirm these findings. Clinical trial information: NCT05142865 .

RNA-Seq enrichment analyses, molecular docking predictions and JunB CUT&Tag-Seq

Lysine methylation is a critical post-translational modification (PTM) involved in diverse physiological and pathological processes. Interferon regulatory factor 3 (IRF3) plays a pivotal role in antitumor immunity; however, the regulatory mechanisms and functional impact of IRF3 methylation within the tumor microenvironment remain incompletely understood. This study demonstrates that monomethylation of IRF3 at lysine 193(K193) suppresses its phosphorylation-dependent activation. Mass spectrometry-based protein interactome analysis identified lysine methyltransferase 5A (KMT5A) as the key enzyme responsible for IRF3 K193 monomethylation. In colorectal cancer (CRC), aberrantly high expression of KMT5A impaired in vivo antitumor immune responses. Mechanistically, KMT5A catalyzes IRF3 monomethylation at K193, which impedes IRF3 phosphorylation and subsequent activation, thereby suppressing the production of type I interferons (IFN-I). Collectively, these findings elucidate KMT5A-mediated IRF3 K193 methylation as a critical regulatory axis promoting tumor immune evasion and progression. Furthermore, IRF3 K193 methylation represents a promising therapeutic target for CRC intervention.

BK virus-associated nephropathy (BKVN) is an important cause of kidney allograft failure and involves complex immune responses. This study aimed to characterize gene expression changes and immune microenvironment features in BKVN tissues using transcriptomic analysis. Using the public dataset GSE47199, we performed differential expression, functional enrichment, and immune infiltration analyses on renal biopsy samples from patients with BKVN (n = 3) and transplant controls (n = 14), followed by immunohistochemistry (IHC) and immunofluorescence (IF) validation. We identified 2,838 differentially expressed genes (DEGs) between the groups. Functional enrichment analysis showed significant enrichment of immune- and inflammation-related terms, including “leukocyte proliferation,” “regulation of T cell activation,” and the “NF-kappa B signaling pathway.” Immune checkpoint molecules (CD274/PD-L1, CTLA4, TIGIT), pro-inflammatory factors (IFNG, IL6), and interferon-induced genes (MX1, IFIT2) were significantly upregulated in BKVN tissues (P < 0.05), whereas IRF3 showed an upward trend. CIBERSORT analysis indicated decreased relative proportions of CD8⁺ T cells and regulatory T cells (Tregs). In contrast, IHC showed increased PD-L1 but reduced IRF3 protein expression, while IF demonstrated marked CD8⁺ T-cell infiltration with increased PD-1 expression and partial spatial overlap with CD8.Overall, BKVN was characterized by broad immune activation and inflammatory responses. The discrepancy between reduced relative CD8⁺ T-cell proportions and increased local infiltration may reflect the complexity of the BKVN immune microenvironment. Increased immune checkpoint expression may suggest T-cell exhaustion or local immunosuppression, providing further insight into immune-mediated allograft injury associated with BKV infection and supporting further investigation of local immune dysregulation in BKVN.

Abstract T-cell exhaustion in the tumor microenvironment undermines antitumor immunity and limits immunotherapy efficacy. Further defining the metabolic triggers of this dysfunctional state could provide therapeutic targets for circumventing immunosuppression. In this study, we identified soluble uric acid (UA)—an abundant purine metabolite frequently elevated in patients with cancer—as a metabolic checkpoint that drives the exhaustion of CD8+ T cells and immune evasion in colorectal cancer. In hyperuricemic mouse models, elevated UA accelerated tumor progression in immunocompetent hosts, but not in T cell–deficient ones, by functionally exhausting tumor-infiltrating CD8+ T cells. Mechanistically, UA directly bound the kinase scaffold kinase suppressor of Ras 1 (KSR1) and hyperactivated MEK–ERK signaling, leading to chronic MAPK stimulation that upregulated inhibitory receptors, including PD-1 and Tim-3, on CD8+ T cells and blunted their cytotoxic function. Genetic disruption of this UA–KSR1–MAPK axis via Tim-3 knockout or Ksr1 knockdown restored T-cell effector activity and tumor control. Notably, pharmacologic UA depletion with the clinical xanthine oxidase inhibitor febuxostat reinvigorated CD8+ T cells, slowing tumor growth and markedly enhancing the efficacy of both chemotherapy and adoptive T-cell therapy in vivo. These findings establish soluble UA as a metabolic immune checkpoint that subverts antitumor T-cell immunity. Targeting UA metabolism may offer a strategy to overcome immune resistance and improve the efficacy of cancer immunotherapies. Significance: A common metabolic byproduct, soluble uric acid, can act as an immune checkpoint that drives T-cell exhaustion, redefining how systemic metabolism shapes cancer progression.

BackgroundAdvanced renal failure remains a major global health burden. Mitochondrial dysfunction is frequently observed during progressive kidney injury and chronic allograft dysfunction (CAD), but observational data cannot distinguish causal involvement from secondary consequences. We applied a multi-omic genetic prioritization framework to evaluate whether inherited variation affecting mitochondrial gene regulation is associated with a proxy phenotype for advanced renal failure and fibrotic allograft remodeling.MethodsWe integrated cis-mQTL (DNA methylation), cis-eQTL (gene expression), and cis-pQTL (plasma protein) data for MitoCarta3.0 genes with a UK Biobank GWAS of kidney transplant recipient status (369 cases, 397,602 controls) as a proxy endpoint for advanced renal failure. Summary-data-based Mendelian randomization (SMR; Wald ratio) was performed using a single lead cis-QTL instrument per gene per layer, with HEIDI heterogeneity testing and Bayesian colocalization to assess whether molecular QTL and outcome signals were consistent with a shared causal variant (PPH4 ≥ 0.70). Because no association survived false discovery rate (FDR) correction across the mitochondrial gene set, we used a tiered, exploratory prioritization scheme based on nominal MR evidence and colocalization. Instrument strength metrics (F-statistics and R²) are reported.ResultsAt a nominal threshold (p < 0.05; none surviving FDR < 0.05), we observed suggestive SMR associations in the methylation and expression layers, with generally weaker signals in the protein layer. Integrating MR evidence with colocalization support prioritized eight mitochondrial candidate genes (C20orf72/MGME1, NDUFA13, MRPS18C, MTIF3, ECHDC1, MTHFD1L, QDPR, and TST). Translational evaluation showed dysregulation of several prioritized candidates in human CAD allograft tissues and in a murine allogeneic kidney transplantation model of chronic allograft fibrosis. In TGF-β–stimulated HK-2 cells, mitochondrial dysfunction accompanied profibrotic responses, and functional perturbation supported NDUFA13 as a plausible node linking mitochondrial bioenergetics to fibrotic remodeling.ConclusionsGiven the limited number of outcome cases, the proxy nature of transplant recipient status, and no FDR-significant associations, the genetic results should be interpreted as exploratory and hypothesis-generating rather than causal proof. Nonetheless, multi-omic genetic prioritization with kidney-relevant experimental data highlights mitochondrial pathways as plausible contributors to advanced renal failure and fibrotic allograft remodeling, motivating replication in larger outcome GWAS and kidney-relevant QTL resources.

BackgroundProgrammed cell death (PCD) plays a complex and critical role in the progression of colon adenocarcinoma (COAD). Elucidating PCD-related characteristics is expected to provide new insights for tumor subtyping, prognosis assessment, and personalized therapy.MethodsThis study integrated multi-omics data from COAD and employed 10 clustering algorithms for molecular subtyping. Based on PCD-related genes, a Programmed cell death signature (PCDS) predictive model was constructed using 113 machine learning algorithms. The focus then shifted to the core gene of the model, TERT. Single-cell and spatial transcriptomic data were incorporated to decipher its cellular localization and regulatory pathways. Finally, the function of TERT was validated through in vitro experiments.ResultsWe categorized COAD into 5 molecular subtypes with distinct prognostic differences. Subsequently, we successfully developed an 18-gene PCDS. This model effectively predicted patient risk and overall survival in both the training set and multiple independent validation cohorts. The PCDS was closely associated with the tumor microenvironment, mutation burden, and response to immunotherapy. Single-cell and spatial transcriptomic analyses revealed that the core gene, TERT, was specifically highly expressed in malignant epithelial cells. In vitro experiments confirmed that knocking down TERT significantly inhibited the proliferation, migration, invasion, and clonogenic formation abilities of COAD cells. Mechanistically, TERT may inhibit apoptosis, regulate the cell cycle, and promote proliferation potentially through the E2F, G2/M checkpoint, and MYC signaling pathways.ConclusionThis study defines novel molecular subtypes of COAD through multi-omics clustering analysis and develops a robust PCD-related prognostic signature. Furthermore, it reveals the significant value of TERT as a potential therapeutic target in COAD.

Introduction: Acute myeloid leukemia is characterized by high heterogeneity, and the current European Leukemia Net (ELN) risk stratification system is not universally applicable to all AML patients, requiring approximately three weeks for testing. Aim: This study aimed to develop an applicable prognostic tool capable of addressing the limitations of current methods. We selected AML patients from the clinic and TCGA database to explore the role of ER stress in response to chemotherapy. Methods: Patients from the TCGA database were employed as the training cohort, and two GEO datasets were used as external validation cohorts. Univariate/multivariate COX and LASSO regression were exemplified to establish the prognostic model. Kaplan-Meier and timedependent ROC were used to assess and compare the efficiency of the model with ELN stratification and other models. In the training cohort, we selected 5 ER stress-related genes to predict chemosensitivity and establish the ERS-5 prognostic model. Results: The model successfully predicted the overall survival of patients (p < 0.0001, HR = 4.86 (2.79-8.44); AUC = 0.83). It was verified in validation cohorts and could further stratify the risk of various AML subgroups. It also enhanced the ability of ELN to predict the response of patients with AML to main chemotherapeutic drugs. Finally, an “ERS-5” risk score was constructed by the nomogram based on the ERS-5 model and age. Conclusion: Consequently, in this study, the ERS-5 model was constructed, which allowed more rapid (about 3 hours) and accurate risk stratification and complemented the ability of ELN to assess chemosensitivity.

Effects of UA on CD8+ T cell function in vitro, results of adoptive T cell transfer experiments and ICB therapy

Introduction: Mesenchymal stem cells (MSCs) hold significant potential for tissue repair and cell therapy. A primary obstacle in their application is the loss of stemness and onset of senescence during in vitro expansion, which compromises therapeutic efficacy. Plant-derived bioactive compounds like quercetin (Que) offer promise for enhancing MSC-based therapies; however, its poor aqueous solubility due to high lipophilicity and phenolic hydroxyl groups limits pharmaceutical utility. Methods: To address this, we engineered homogeneous poly(lactic-co-glycolic acid) (PLGA) microspheres (hPLGA-Ms) using microfluidic technology to encapsulate hydrophobic Que, enabling its sustained release in physiological aqueous environments. Results: The results showed the hPLGA-Ms loaded Que (Que/hPLGA-Ms) were uniform, well dispersed. The size of the hPLGA-Ms can be precisely controlled by adjusting the flow rates of two phases. Gene expression analysis demonstrated the hPLGA-Ms delivery of Que enhanced MSCs cellular viability, stemness, anti-senescence, secretion and migration abilities of cells. Conclusions: In summary, the scalable and reproducible Que/hPLGA-Ms provide controlled release kinetics and significantly potentiate MSCs bioactivities. This delivery system represents a promising strategy for tissue engineering and regenerative therapies.

Renal fibrosis is the core pathological process in the progression of chronic kidney disease to its end stage. There is to date no novel therapeutic strategies that are both safe and efficient in reversing renal fibrosis in humans. Exosomes, as key mediators of intercellular communication, play significant regulatory roles in renal fibrosis. Translating mechanistic studies on exosome-mediated promotion or inhibition of renal fibrosis into clinically applicable anti-fibrotic strategies remains a challenging issue in this field. In this review, we systematically elucidate the distinct dual role of exosomes, highlighting how they function as either pro-fibrotic drivers or anti-fibrotic protectors depending on their cellular origin. In particular, we examine how renal tubular epithelial cell-derived exosomes promote renal fibrosis through multiple mechanisms by delivering specific cargoes—including miRNAs (e.g., miR-21, miR-19b-3p), mRNA (TGF-β1), and proteins (OPN, TNFAIP8)—via signaling pathways such as PTEN/Akt, NF-κB, and HIF-1α. Furthermore, we discuss exosome-based therapeutic strategies, focusing on the anti-fibrotic potential of mesenchymal stem cell-derived exosomes and targeted engineering strategies, such as drug loading and surface modification. Finally, we also summarize the value of urinary and blood exosomes as biomarkers in the diagnosis of renal fibrosis. In conclusion, by decoding the dual nature of exosomes, we offer a comprehensive framework to accelerate the clinical translation of these nanovesicles into precise diagnostics and targeted therapeutics.

Renal allograft interstitial fibrosis, a key pathological feature of chronic renal allograft dysfunction (CAD), is a critical determinant of long-term graft survival. However, its underlying molecular mechanisms remain incompletely understood. This study uncovers the central role of programmed cell death, particularly the novel PANoptosis modality, in the progression of CAD. PANoptosis integrates features of pyroptosis, apoptosis, and necroptosis, but does not fit within the confines of any single pathway, with its mechanisms previously undefined. By analyzing cell death patterns in CAD tissues through single-cell sequencing and validating findings via in vivo and in vitro experiments, this work demonstrates that in the context of chronic inflammation, tumor necrosis factor-alpha (TNF-α) modulates signal transducer and activator of transcription 1 (STAT1) through dual phosphorylation. This process directly induces tyrosine 701 phosphorylation and activates serine 727 phosphorylation via the p38 MAPK pathway. Phosphorylated STAT1 subsequently upregulates the PANoptosome sensor absent in melanoma 2 (AIM2), driving PANoptosis in renal tubular epithelial cells. This mechanism further exacerbates interstitial fibrosis by promoting the paracrine secretion of interleukin-6 and transforming growth factor-beta, which induces epithelial-mesenchymal transition (EMT) in adjacent tubular cells. These findings represent the first demonstration of the TNF-α/STAT1/AIM2 axis in triggering PANoptosis and its downstream EMT-fibrosis cascade, offering novel therapeutic targets for CAD intervention.

Background: The recently issued ELN 2024 Less-Intensive risk stratification aims to refine prognosis for adults with acute myeloid leukemia (AML) treated with lower-intensity regimens such as venetoclax plus azacitidine (VA). Real-world validation in Asian populations is limited. We assessed the prognostic performance of ELN 2024 versus ELN 2022 in a Chinese cohort. Methods: We retrospectively reviewed 53 newly diagnosed AML patients deemed unfit for intensive chemotherapy who received continuous VA (venetoclax 400 mg qd on days 1-28; azacitidine 75 mg/m² qd on days 1-7, every 28 days) from August 2020 to June 2024. Patients were stratified by both ELN 2024 Less-Intensive and ELN 2022 criteria. Primary endpoints were overall survival (OS) and relapse-free survival (RFS). Secondary analyses included composite complete remission (cCR), measurable residual disease (MRD) status, and mutation impact. Results: Median age was 65 years (range, 20-78); median follow-up, 27.6 months. Under ELN 2024, 15 (28.3 %) patients were favorable, 27 (50.9 %) intermediate, and 11 (20.8 %) adverse. Median OS differed significantly: 39.6, 25.0, and 6.6 months, respectively (log-rank P = 0.025). ELN 2022 failed to discriminate OS (25.4, 33.9, and 25.4 months; P = 0.857). MRD negativity after 1–2 induction cycles (41/53, 77.3 %) predicted longer RFS (P = 0.009). Five of six patients (83 %) harboring PTPN11 mutations relapsed within six months, suggesting adverse prognostic significance. Conclusions: In this real-world Chinese cohort, ELN 2024 Less-Intensive stratification clearly separated survival outcomes and outperformed ELN 2022 in VA-treated AML. MRD negativity remained a robust predictor of favorable RFS, and PTPN11 mutations were associated with early relapse. Larger multicenter studies are warranted.

Background: Human epidermal growth factor receptor 2 (HER2) positive breast cancer represented approximately 15%-20% of all breast cancers. Liver metastasis was commonly observed in patients treated with trastuzumab and tyrosine kinase inhibitor (TKI), thereby further reducing the overall survival to only 8-14 months. MRG002 is a novel antibody-drug conjugate composed of recombinant humanized anti-HER2 monoclonal antibody MAB802 and potent cytotoxic small molecule MMAE linked by the vc-linker. This study was designed to evaluate the efficacy and safety of MRG002 in liver metastases breast cancer patients after the treatment failure of trastuzumab and TKI. Method: This single-armed, open-label, multicenter, phase II study enrolled patients who had received ≥2 lines of anti-HER2 treatment (including trastuzumab and TKI) and had confirmed tumor progression during or after the most recent treatment. MRG002 was administered at a dose of 2.6 mg/kg every 3 weeks until the end of treatment, initiation of new anti-tumor therapy, withdrawal of informed consent, or death. Result: A total of 102 females were enrolled in this study, with a median age of 53 years (range: 26-73). Forty-four patients had an ECOG score of 0, and 58 scored 1. Forty-one patients (40.2%) were immunohistochemistry (IHC) 3+, and 61 (59.8%) were IHC 2+/ISH+. All patients had liver metastasis, 55 (53.9%) had bone metastasis, and 37 (36.3%) had lung metastasis. All patients had received HER2-mAb and anti-HER2-TKI drug treatment (Pyrotinib 94 cases, 92.2%). The median treatment line was 3 (range: 2-10), wherein 39 patients (38.2%) received two treatment lines, 28 (27.5%) received three, and 35 (34.3%) received ≥ four lines. As of July 19, 2024, the median follow-up time was 14.8 months (range: 0.4-27.2), and 7 patients (6.9%) had a treatment duration of nearly 2 years. The Independent Review Committee (IRC) evaluated the objective response rate (ORR) based on RECIST v1.1 as 60.8% (95% CI: 50.6-70.3), the disease control rate (DCR) as 86.3% (95% CI: 78.0-92.3), the median progression-free survival (mPFS) as 8.6 months (95% CI: 6.9-11.9), and the median duration of response (mDoR) as 9.4 months (95% CI: 6.2-16.8). The investigator assessed the ORR as 56.9% (95% CI: 46.7-66.6), the mPFS as 7.5 months (95% CI: 5.7-8.0), and the mDoR as 6.8 months (95% CI: 6.0-8.9). Subgroup analysis showed that the ORR of IHC 3+ and IHC 2+/FISH+ patients were 70.0% and 60.7%, respectively. The mPFS were 11.9 months and 7.7 months, respectively. The most common treatment-related adverse events (TRAEs) included 70.6% white blood cell count decreased, 64.7% neutrophil count decreased, 62.7% AST increased, and 54.9% ALT increased. TRAEs were mainly Grade 1-2 and recovered after treatment. TRAEs ≥ Grade 3 included 31.4% neutrophil count decreased, 13.7% white blood cell count decreased, and 6.9% peripheral neuropathy. No new safety signals were found, and the adverse events were manageable. Conclusion: MRG002 showed a potential efficacy in trastuzumab and anti-HER2-TKI treatment failed HER2-positive liver metastasis breast cancer patients with a good tolerance and safety profile. The emergence of MRG002 presented a promising treatment option for patients. Clinical trial information: NCT05263869 Citation Format: Qiang Liu, Shaohua Zhang, Yaping Yang, Quchang Ouyang, Tao Sun, Yongsheng Wang, Min Yan, Yongmei Yin, Xiaoyu Liu, Shusen Wang, Xinhong Wu, Qingyuan Zhang, Changlu Hu, Hui Li, Wei Li, Fuming Qiu, Jun Qian, Li Sun, Xiaojia Wang, Zefei Jiang. Efficacy and Safety of MRG002 in Prior TKI-Treated HER2 Positive Breast Cancer Patients: A Single Arm, Open Label, Multicenter, Phase II Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-12-21.

The purpose of this study was to explore the incremental predictive value of liver fat fraction (LFF) in forecasting major adverse cardiovascular events (MACE) among patients with type 2 diabetes mellitus (T2DM). We prospectively enrolled 265 patients with T2DM who presented to our hospital with symptoms of chest distress and pain suggestive of coronary artery disease (CAD) between August 2021 and August 2022. All participants underwent both coronary computed tomography angiography (CCTA) and upper abdominal dual-layer spectral detector computed tomography (SDCT) examinations within a 7-day interval. Detailed clinical data, CCTA imaging features, and LFF determined by SDCT multi-material decomposition algorithm were meticulously recorded. MACE was defined as the occurrence of cardiac death, acute coronary syndrome (ACS), late-phase coronary revascularization procedures, and hospital admissions due to heart failure. Among 265 patients (41 T2DM is associated with increased MACE rates, underscoring the need for improved risk prediction. CACS is a well-established tool for MACE risk assessment but may not capture all risk factors. Hepatic steatosis is a common comorbidity in metabolic syndrome and T2DM. Does the incorporation of LFF derived from SDCT into existing risk prediction models enhance the accuracy of MACE forecasting in patients with T2DM? SDCT-LFF measurement introduces a more accurate method for assessing hepatic steatosis. LFF as an independent predictor of MACE in T2DM patients is a novel finding. The study presents LFF as an additional tool for risk stratification, complementing FRS and CACS. Study findings may guide personalized prevention for T2DM patients at higher MACE risk.

OBJECTIVES:The optimal first-line treatment for programmed death-ligand 1 (PD-L1)-negative advanced non-small cell lung cancer (NSCLC) without actionable mutations remains uncertain. Histological subtype-driven strategies may enhance outcomes in this population. METHODS:We conducted a systematic review and network meta-analysis (NMA) of 24 randomized controlled trials involving 5035 patients with PD-L1-negative advanced NSCLC. Survival curves were reconstructed (SCR) using WebPlotDigitizer. Analyses were performed using R and Stata. RESULTS:Ten treatment regimens were evaluated. For histology-unselected NSCLC, anti-PD-1 + chemotherapy (CT) ranked highest for objective response rate (94.7 %) and progression-free survival (PFS; 89.3 %; HR = 0.63, 95 % CI: 0.56-0.71 vs. CT), while anti-PD-1 + anti-CTLA-4 ranked highest for duration of response (94.9 %) and overall survival (OS; 85.9 %; HR = 0.65, 95 % CI: 0.51-0.83 vs. CT). Indirect comparisons and SCR analyses showed comparable PFS and OS between anti-PD-1 + anti-CTLA-4 and anti-PD-1 + CT. In non-squamous NSCLC, bevacizumab + anti-PD-(L)1 + CT achieved the longest median PFS (10.02 months) and OS (28.88 months). For squamous NSCLC, anti-PD-1 + CT significantly improved PFS (HR = 0.58, 95 % CI: 0.50-0.68) and OS (HR = 0.71, 95 % CI: 0.57-0.88) versus CT, while anti-PD-L1 + CT showed no significant benefit (PFS: HR = 0.81; OS: HR = 0.87; P > 0.05). CONCLUSIONS:Dual immunotherapy and anti-PD-1 + CT provide comparable survival benefits in PD-L1-negative, histology-unselected NSCLC. Histology-driven strategies-bevacizumab-containing regimens for non-squamous and anti-PD-1 + CT for squamous NSCLC-are associated with optimized outcomes, supporting personalized treatment by subtypes.

Evidence-guided regimens for advanced gastric cancer (AGC) in patients with performance status 2 (PS 2) are limited. Here, we proposed a structured therapeutic framework termed "performance status-matched strategy", and further conducted the APICAL-GC trial (NCT04278222). This open-label, single-arm phase II study evaluated the efficacy and safety of anlotinib combined with toripalimab among 24 treatment-naïve AGC patients with PS 2. The primary outcome was the objective response rate (ORR), with secondary endpoints including disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety profile. This trial met its prespecified endpoints, demonstrating an ORR of 58.3% (95%CI 36.6-77.9) with a DoR of 12.1 months (range: 1.43-48.5), and a DCR of 95.8% (95%CI 78.9-99.9). Median PFS reached 7.33 months (95%CI 3.83-17.1), while median OS was 15.9 months (95%CI 7.73-23.2). Treatment-related adverse events (TRAEs) of any grade occurred in 21 patients (87.5%), with grade-3 TRAEs observed in 7 patients (29.2%). No grade-4/5 TRAEs were reported. These findings provide a rationale for anlotinib plus toripalimab as a promising chemotherapy-free option for the first-line treatment of AGC patients with PS 2 under the performance status-matched strategy, showing comparable anticancer activity and a lower occurrence rate of TRAEs.