RESUMO
BACKGROUND: Predictive biomarkers and models of immune checkpoint inhibitors (ICIs) have been extensively studied in non-small cell lung cancer (NSCLC). However, evidence for many biomarkers remains inconclusive, and the opaqueness of machine learning models hinders practicality. We aimed to provide compelling evidence for biomarkers and develop a transparent decision tree model. METHODS: We consolidated data from 3,288 ICI-treated patients with NSCLC across real-world multicenter, public cohorts and the Choice-01 trial (ClinicalTrials.gov: NCT03856411). Over 50 features were examined for predicting durable clinical benefits (DCBs) from ICIs. Noteworthy biomarkers were identified to establish a decision tree model. Additionally, we explored the tumor microenvironment and peripheral CD8+ programmed death-1 (PD-1)+ T cell receptor (TCR) profiles. FINDINGS: Multivariate logistic regression analysis identified tumor histology, PD-ligand 1 (PD-L1) expression, tumor mutational burden, line, and regimen of ICI treatment as significant factors. Mutation subtypes of EGFR, KRAS, KEAP1, STK11, and disruptive TP53 mutations were associated with DCB. The decision tree (DT10) model, using the ten clinicopathological and genomic markers, showed superior performance in predicting DCB in the training set (area under the curve [AUC] = 0.82) and consistently outperformed other models in test sets. DT10-predicted-DCB patients manifested longer survival, an enriched inflamed tumor immune phenotype (67%), and higher peripheral TCR diversity, whereas the DT10-predicted-NDB (non-durable benefit) group showed an enriched desert immune phenotype (86%) and higher peripheral TCR clonality. CONCLUSIONS: The model effectively predicted DCB after front-/subsequent-line ICI treatment, with or without chemotherapy, for squamous and non-squamous lung cancer, offering clinicians valuable insights into efficacy prediction using cost-effective variables. FUNDING: This study was supported by the National Key R&D Program of China.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Árvores de Decisões , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Masculino , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Feminino , Pessoa de Meia-Idade , Imunoterapia/métodos , Idoso , Biomarcadores Tumorais , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Background: Various inherited traits contribute to the overall risk of venous thromboembolism (VTE). In addition, the epidemiology of thrombophilia in the East-Asian VTE population remains unclear; thus, we aimed to assess the proportion of hereditary thrombophilia via a meta-analysis. Methods: Publications from PubMed, EMBASE, web of science, and Cochrane before December 30, 2022, were searched. Studies from Japan, Korea, China, Hong Kong, Taiwan, Singapore, Thailand, Vietnam, Myanmar, and Cambodia were included. Congenital thrombophilia was described as diseases including protein C (PC) deficiency, protein S (PS) deficiency, antithrombin (AT) deficiency, factor (F)V Leiden (FVL), and prothrombin G20210A mutations. Studies were selected by 2 reviewers for methodological quality analysis. A random-effects model was used for the meta-analysis, assuming that estimated effects in the different studies are not identical. Results: Forty-four studies involving 6453 patients from 7 counties/regions were included in the meta-analysis. The prevalence of PC, PS, and AT deficiencies were 7.1%, 8.3%, and 3.8%, respectively. Among 2924 patients from 22 studies, 5 patients were carriers of FVL mutation. Among 2196 patients from 10 studies, 2 patients were carriers of prothrombin G20210A mutation in a Thailand study. Conclusion: The prevalence of PC, PS, and AT deficiencies was relatively high, while a much lower prevalence of FVL and prothrombin G20210A mutations were identified in East-Asian patients with VTE. Our data stress the relative higher prevalence of PC, PS, and AT deficiencies for thrombophilia in the East-Asian VTE population.
RESUMO
Background: Distal symmetric polyneuropathy (DSPN) is the most common chronic complication of type 2 diabetes mellitus (T2DM). DSPN may lead to more serious complications, such as diabetic foot ulcer, amputation, and reduced life expectancy. Observational studies have suggested that vitamin D deficiency may be associated with the development of DSPN in T2DM. However, interventional studies have found that low-dose vitamin D supplementation does not significantly improve neuropathy in DSPN. This study aims to evaluate the efficacy and safety of intramuscular injection of high-dose vitamin D (HDVD) in T2DM with DSPN combined with vitamin D insufficiency. Methods and analysis: We will conduct a multicenter, randomized, double-blinded, and placebo-controlled trial in four large hospitals. All eligible participants will be randomly assigned to either the vitamin D2 supplement or placebo control group and injected intramuscularly monthly for 3 months. Additionally, anthropometric measurements and clinical data will be collected at baseline and 3 months. Adverse events will be collected at 1, 2, and 3 months. The primary outcome measure is the change in the mean Michigan Neuropathy Screening Instrument (MNSI) score at baseline and 3 months post-intervention. We will use the gold-standard liquid chromatography-tandem mass spectrometry method to distinguish between 25(OH)D2 and 25(OH)D3 levels. The MNSN score before the intervention will be used as a covariate to compare the changes between both groups before and after the intervention, and the analysis of covariance will be used to analyze the change in the MNSI score after HDVD supplementation. Discussion: Glycemic control alone does not prevent the progression of DSPN in T2DM. Some studies have suggested that vitamin D may improve DSPN; however, the exact dose, method, and duration of vitamin D supplementation are unknown. Additionally, neuropathy repair requires HDVD supplementation to sustain adequate vitamin D levels. This once-a-month intramuscular method avoids daily medication; therefore, compliance is high. This study will be the first randomized controlled trial in China to analyze the efficacy and safety of HDVD supplementation for patients with T2DM and DSPN and will provide new ideas for pharmacological research and clinical treatment of diabetic neuropathy. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2200062266.