RESUMO
BACKGROUND: The incidence of checkpoint inhibitor-associated pneumonitis (CIP) in advanced non-small cell lung cancer (NSCLC) has been substantiated through large-scale clinical trials or real-world studies. However, reports on CIP incidence within the context of neoadjuvant immunotherapy for resectable NSCLC remain scarce. This study endeavors to investigate the incidence, risk factors, and outcomes of CIP in patients with resectable NSCLC receiving neoadjuvant immunochemotherapy. METHODS: A retrospective, case-control study was conducted on patients diagnosed with NSCLC stages IIA-IIIB who received neoadjuvant immunochemotherapy between January 2018 and September 2022. Patients were stratified into two groups based on the presence or absence of CIP, facilitating a comparative analysis of clinical characteristics, treatment modalities, physiological indicators, and prognostic outcomes . RESULTS: The study cohort comprised 245 patients, with 11.4% (28/245) experiencing CIP. The median period of CIP onset was 70 (range, 40-221) days. The incidence of severe CIP (grade 3-4) was 3.7% (9/245). Patients with CIP showed a higher all-cause mortality rate of 21.4% (6/28) compared to that of patients without CIP. Those who developed CIP exhibited elevated body mass index (BMI) values (p = 0.028) and increased fibrinogen (FIB) levels (p < 0.001), alongside a significant decrease in both diffusing capacity for carbon monoxide (DLCO)% pred (p = 0.001) and DLCO/VA% pred (p = 0.021) after neoadjuvant therapy compared to pre-indicators. Receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve of three assessed variables (FIB levels, BMI, DLCO) reached 0.806 in predicting CIP occurrence at an early stage. CONCLUSIONS: This cohort demonstrated that elevated BMI, increased FIB levels, and decreased pulmonary diffusion function after neoadjuvant therapy are risk factors of CIP occurrence. Early assessment and continuous monitoring of these indicators are imperative for the predictive identification of CIP, enhancing patient management and outcomes.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Terapia Neoadjuvante , Pneumonia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/terapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/epidemiologia , Terapia Neoadjuvante/efeitos adversos , Estudos Retrospectivos , Estudos de Casos e Controles , Fatores de Risco , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estimativa de Kaplan-Meier , Incidência , ComorbidadeRESUMO
BACKGROUND: In order to improve survival outcomes in resectable non-small cell lung cancer (NSCLC), strategies for neoadjuvant therapy need to be revisited. We evaluated and compared the efficacy of different neoadjuvant therapeutic modalities in a real-world setting. METHODS: A total of 258 patients with clinical stage IIA to IIIB NSCLC was included. All the patients underwent surgical resection after one to four cycles of neoadjuvant treatment consisting of chemotherapy (83), immunotherapy (23), and immunotherapy plus chemotherapy (152). RESULTS: The radiologic response rate in the combined immunochemotherapy group was 67.8%, higher than that of 48.2% in the chemotherapy group and 4.3% in the immunotherapy group (p < 0.001). An improved major pathological response (MPR) was also achieved in the combined therapy group compared with the chemotherapy group and the immunotherapy group (53.9% vs. 10.8% vs. 8.7%, p < 0.001). Patients in the combined therapy group had a significant trend toward longer disease-free survival than those in the chemotherapy alone group (3-year disease-free survival [DFS] of 68.79% vs. 50.81%; hazard ratio [HR] for progression or death, 0.477; p = 0.003). Multivariate Cox analysis identified radical surgery (HR, 0.328; p = 0.033), ypN0-1 stage (HR, 0.591; p = 0.038) and MPR result (HR, 0.362; p = 0.007) to be independent prognostic factors for DFS. CONCLUSIONS: Neoadjuvant treatment with a combination of immunotherapy plus chemotherapy appears to achieve higher radiological and pathological responses than monotherapy for IIA-IIIB NSCLC. Log-rank analysis showed that a better outcome could be expected in patients with the addition of immunotherapy to neoadjuvant chemotherapy if compared with patients with chemotherapy alone in terms of DFS.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Terapia Neoadjuvante , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Terapia Neoadjuvante/métodos , Masculino , Feminino , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Imunoterapia/métodos , Estadiamento de Neoplasias , Resultado do Tratamento , Estudos Retrospectivos , Pneumonectomia/métodos , Intervalo Livre de Doença , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
The present study aimed to investigate the interaction between T-cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) and Toll-like receptor 4 (TLR4)/nuclear factor κB (NFκB) signaling in Helicobacter pylori-infected RAW264.7 macrophage cells. RAW264.7 cells were cocultured with H. pylori SS1 at different bacteria/cell ratios, and subsequently the mRNA expression of Tim3, TLR4, and myeloid differentiation factor 88 (MyD88) was measured by reverse transcription-quantitative polymerase chain reaction (RTqPCR). Furthermore, the effect of Tim3 overexpression was examined by transfection of RAW264.7 with pLVX-IRES-ZsGreen-Tim-3 and coculturing with H. pylori. mRNA and protein expression levels were then analyzed for Tim3, TLR4, MyD88, and phosphorylated (p) NFκB by RTqPCR and western blot analysis respectively. The concentrations of proinflammatory cytokines [tumor necrosis factorα (TNFα), interleukin 6 (IL-6), interferonγ (IFNγ) and interleukin 10 (IL10)] released in the culture supernatants were measured by ELISA. H. pylori stimulation resulted in a significant increase of Tim3, TLR4, and MyD88 mRNA expression in RAW264.7 cells. H. pylori stimulation upregulated Tim3 expression even in the Tim3overexpressing RAW264.7 cells compared with unstimulated cells. TLR4, MyD88, and pNFκB protein expression and proinflammatory cytokines (TNFα, IL6, and IFNγ) release levels were increased in the control RAW264.7 cells following H. pylori infection, but not in the Tim-3-overexpressing RAW264.7 cells. By contrast, IL10 levels were decreased following H. pylori infection in both control and Tim3overexpressing RAW264.7 cells. Overexpression of Tim-3 reduced H. pylori-associated inflammation in RAW264.7 macrophages, by downregulating expression of proteins in the TLR4 pathway and release of proinflammatory cytokines. These findings suggest that Tim3 serves a crucial role in the negative regulation of H. pylori-associated inflammation and may be a novel therapeutic target for H. pylori infection.