Shandong Tumor Hospital

Coronavirus disease 2019 (COVID-19) remains a global health threat, particularly for patients with cancer, who experience greater susceptibility and worse outcomes. Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is standard first-line therapy for advanced EGFR-mutated non-small cell lung carcinoma (NSCLC). However, the impact of COVID-19 on TKI efficacy remains unclear. This multicenter retrospective study included patients with stage IV EGFR-mutated NSCLC who received first-line EGFR-TKI treatment at four Chinese hospitals. Leveraging China's policy change (December 2022), we compared a pre-pandemic COVID-19-negative cohort (January 2019-November 2022) with a COVID-19-positive cohort (January-June 2023). After 1:1 propensity score matching (PSM), Kaplan-Meier and Cox regression analyses evaluated progression-free survival (PFS) and prognostic factors. Among 711 patients (median follow-up, 37.90 months), the COVID-19-negative group had significantly longer median PFS (18.17 vs. 12.89 months; p = .001). After PSM, we analyzed 426 well-matched patients (213/cohort). Before and after matching, COVID-19-negative patients exhibited better PFS with all EGFR-TKI generations (unmatched: p1st <.001, p2nd = .030, and p3rd = .001; matched: p1st <.001, p2nd = .049, and p3rd = .015). COVID-19 infection worsened outcomes in both monotherapy and combination therapy. Multivariable analysis identified COVID-19 infection as an independent predictor of worse PFS (hazard ratio 1.650, 95% confidence interval: 1.286-2.116; p < .001). Adenocarcinoma, ≤3 metastatic organs, smoking index >570, concurrent systemic therapy, and third-generation TKI were also prognostic. COVID-19 infection markedly reduces EGFR-TKI efficacy in patients with advanced NSCLC, warranting closer monitoring during and after infection and supporting adaptive management strategies.

Abstract Precise evaluation of cervical lymph node metastasis (CLNM) and genetic mutations (BRAF V600E /TERT promoter, TERTp) is pivotal for tailoring surgical and prognostic evaluation and adjuvant strategies in thyroid cancer (TC). Although current methods have limitations, we aim to develop deep learning (DL) models to predict CLNM and genetic mutations from TC frozen sections. We developed a DL framework using 2499 frozen‐section whole‐slide images from 2176 TC patients across five centers. The model was trained with a transfer learning‐based feature extractor and an attention‐based multiple instance learning (MIL) classifier, and validated on both internal and external cohorts. StyleGAN3‐based data augmentation was employed to tackle class imbalance for TERTp prediction, while interpretability was assessed via attention heatmaps and Leiden clustering. The CLNM prediction model achieved a patient‐level AUROC of 0.918 internally and 0.803–0.885 across three external validation datasets. For BRAF V600E prediction, AUROCs attained 0.814 internally and spanned 0.750––0.811 in external validation. In TERTp mutation prediction, GAN‐based augmentation increased the AUROC to 0.804 (internal) and 0.732 (external), up from 0.782 and 0.724, respectively. Attention maps visualized CLNM correlations with invasive tumor margins, while mutations localized to specific cellular morphology features. Our DL models accurately predict CLNM and genetic mutations from TC frozen sections, potentially reducing unnecessary procedures and providing a rapid alternative to traditional molecular testing.

Patients with peripheral T cell lymphoma (PTCL) who achieved tumor response with first-line standard therapy were at high risk of disease relapse. We explored golidocitinib (150 mg once daily) as maintenance therapy for this group of patients (JACKPOT26, NCT06511869). This study included two cohorts: patients achieving a complete response (Cohort 1 (CR), N = 30) and a partial response (Cohort 2 (PR), N = 18) during induction stage. All enrolled patients were transplant ineligible or did not have a transplant plan. All dosed patients were included in the efficacy and safety analysis. In Cohort 1, the 24-month disease free survival (DFS) rate was 74.2% with golidocitinib treatment. In nodal subtypes (AITL, NOS, ALK- ALCL), the 24-month DFS rate was 62.7%. In Cohort 2, median progression free survival (PFS) was 17.4 months, and 24-month PFS rate was 48.6%. Nine out of 18 patients with initial PR achieved complete response, leading to a complete response rate of 50.0%, and median duration of response of 23.9 months. The most common ≥grade 3 treatment-related treatment-emergent adverse events (TRAEs) were hematological adverse events in nature, including neutrophil count decreased (47.9%), white blood cell count decreased (31.3%), lymphocyte count decreased (14.6%) and leukopenia (12.5%). The majority of these TRAEs were reversible and clinically manageable. TRAEs leading to treatment interruption and discontinuation occurred in 60.4% and 10% of patients, respectively. No TRAEs leading to fatal outcomes were reported. This study suggests the potential of golidocitinib as maintenance therapy for patients with PTCL.

Mitochondrial dysfunction is a hallmark of heart failure (HF), but its upstream regulatory pathways remain incompletely understood. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, is crucial for maintaining enzymatic activity through deacetylation. This study investigates whether SIRT3 downregulation leads to mitochondrial metabolic impairment in HF by enhancing acetylation of tricarboxylic acid (TCA) cycle enzymes. A chronic HF model was established in male C57BL/6J mice via transverse aortic constriction (TAC). Cardiac function and morphology were evaluated by echocardiography, histological staining, and transmission electron microscopy. Mitochondrial function was assessed using ATP quantification, Seahorse XF analysis, and enzymatic activity assays. Protein acetylation and SIRT3 expression were examined through Western blotting and acetyl-proteomics. Angiotensin II-treated cardiomyocytes served as an in vitro model. TAC-induced HF led to cardiac remodeling and mitochondrial damage. Proteomic analysis revealed increased global protein acetylation, especially in mitochondrial proteins related to the TCA cycle. SIRT3 was significantly downregulated, corresponding with hyperacetylation and suppressed activity of pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and citrate synthase (CS), which was associated with impaired respiration and reduced ATP output. Ang II-treated cells showed similar changes. SIRT3 downregulation in HF drives TCA enzyme hyperacetylation and metabolic dysfunction, suggesting a key mechanism linking protein acetylation imbalance to mitochondrial impairment in disease progression.