Naozumi Hashimoto

BACKGROUND: The increasing prevalence of lung cancer in the elderly population necessitates a closer evaluation of diagnostic and therapeutic approaches. This study aimed to compare the safety and diagnostic efficacy of transbronchial lung cryobiopsy (TBLC) between patients ≥ 80 years and younger patients. METHODS: A retrospective review was conducted of 96 patients diagnosed with peripheral lung cancer who underwent TBLC between April 2021 and October 2023. The patients were categorized into two groups: the elderly group (age ≥ 80 years, n = 20) and younger group (age < 80 years; n = 76). Data regarding the biopsy yield, complications, and feasibility of molecular analyses were collected and analyzed. RESULTS: The diagnostic yield of TBLC was comparable between the elderly and younger groups (95% vs. 89.5%, p = 0.679). Biomarker testing, including programmed death-ligand 1 expression and genetic mutations, were feasible in all cases diagnosed with cancer using TBLC samples. No significant differences were observed in major complications such as pneumothorax or bleeding. CONCLUSIONS: TBLC was found to be a safe and effective diagnostic tool for peripheral lung cancer in elderly patients and provided adequate samples for molecular testing. Since the complication rates did not significantly differ between the two age groups, age alone should not be considered a contraindication for the procedure.

BACKGROUND: Multiple first-line treatment options have been developed for advanced non-small cell lung cancer (NSCLC) in each subgroup determined by predictive biomarkers, specifically driver oncogene and programmed cell death ligand-1 (PD-L1) status. However, the methodology for optimal treatment selection in individual patients is not established. This study aimed to develop artificial intelligence (AI)-based personalized survival prediction model according to treatment selection. METHODS: The prediction model was built based on random survival forest (RSF) algorithm using patient characteristics, anticancer treatment histories, and radiomics features of the primary tumor. The predictive accuracy was validated with external test data and compared with that of cox proportional hazard (CPH) model. RESULTS: A total of 459 patients (training, n = 299; test, n = 160) with advanced NSCLC were enrolled. The algorithm identified following features as significant factors associated with survival: age, sex, performance status, Brinkman index, comorbidity of chronic obstructive pulmonary disease, histology, stage, driver oncogene status, tumor PD-L1 expression, administered anticancer agent, six markers of blood test (sodium, lactate dehydrogenase, etc.), and three radiomics features associated with tumor texture, volume, and shape. The C-index of RSF model for test data was 0.841, which was higher than that of CPH model (0.775, P < 0.001). Furthermore, the RSF model enabled to identify poor survivor treated with pembrolizumab because of tumor PD-L1 high expression and those treated with driver oncogene targeted therapy according to driver oncogene status. CONCLUSIONS: The proposed AI-based algorithm accurately predicted the survival of each patient with advanced NSCLC. The AI-based methodology will contribute to personalized medicine. TRIAL REGISTRATION: The trial design was retrospectively registered study performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Nagoya University Graduate School of Medicine (approval: 2020 - 0287).

The presence of anti-thyroid antibodies (ATAs) is a biomarker for the development of thyroid dysfunction induced by anti-programmed cell death-1 antibodies (PD-1-Abs). While patients with thyroid dysfunction reportedly showed better overall survival (OS), it remains unknown if ATAs at baseline can predict OS. Therefore, in this study, we examined the association of ATAs at baseline with OS in non-small cell lung cancer (NSCLC) patients with different levels of programmed cell death-1 ligand 1 (PD-L1) positivity associated with PD-1-Ab treatment efficacy. A total of 81 NSCLC patients treated with PD-1-Abs were evaluated for ATAs at baseline and prospectively for OS. Among the 81 patients, 49 and 32 patients had ≥50% (group A) and <50% (group B) PD-L1 positivity, respectively. Median OS did not differ significantly between patients with (n = 13) and without (n = 36) ATAs at baseline in group A. In contrast, median OS was significantly longer in patients with (n = 10) versus without (n = 22) ATAs at baseline in group B (not reached vs 378 days, respectively; 95% CI, 182 to 574 days, p = 0.049). These findings suggest that the presence of ATAs at baseline is a biomarker to predict better treatment efficacy of PD-1-Abs in NSCLC patients with low PD-L1 positivity, while the difference in OS in those with high PD-L1 positivity may be masked by increased tumor expression of PD-L1.

BACKGROUND: Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF. METHODS: Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed. RESULTS: mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time. CONCLUSIONS: Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.