Masafumi Yamaguchi

OBJECTIVES: The impact of epidermal growth factor receptor (EGFR) status and the use of EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy have not been well discussed only in recurrent non-small-cell lung cancer (NSCLC). The purpose of this study was to identify the prognostic factors associated with post-recurrence survival after surgical resection of NSCLC in terms of the EGFR mutation status and the use of EGFR-TKI therapy. METHODS: From 2000 through 2011, 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of these patients, 280 experienced postoperative recurrence by the end of 2012. We reviewed the cases of recurrence and analysed the predictors and length of post-recurrence survival. RESULTS: The median post-recurrence survival time and the 5-year survival rate of all patients were 25 months and 20.8%, respectively. A multivariate analysis identified the Eastern Cooperative Oncology Group (ECOG) performance status (PS), brain metastasis, number of sites of recurrence and EGFR mutation status to be independent prognostic factors for post-recurrence survival. Among all cases, the median post-recurrence survival time according to the use of EGFR-TKI therapy was as follows: 49 months in the EGFR mutation-positive patients treated with EGFR-TKI therapy, 20 months in the EGFR wild or unknown cases treated with EGFR-TKI therapy and 17 months in the patients not treated with EGFR-TKI therapy. As to EGFR mutation-positive cases, the patients treated with EGFR-TKIs exhibited significantly longer post-recurrence survival time than the patients treated without EGFR-TKIs (49 vs 12 months). CONCLUSIONS: It is essential for recurrent NSCLC patients to be examined for the EGFR mutation status. Patients with a positive EGFR mutation status receive significant benefits from EGFR-TKI therapy.

Purpose: Regular exercise significantly influences chronic obstructive pulmonary disease (COPD) outcomes. However, the associations of exercise habits during adolescence compared to current exercise habits on physical activity (PA), body composition, pulmonary function, and CT imaging parameters remain unclear. Therefore, the present study aimed to clarify the associations of adolescent and current exercise habits with current conditions. Patients and Methods: This cross-sectional study enrolled 86 participants, including 72 with COPD and 14 with pre-COPD. Adolescent exercise habits were defined as regular exercise during ages 16 to 22 years, while current exercise habits were defined as regular exercise for at least 1 year. PA was assessed using a triaxial accelerometer, body composition was assessed using bioelectrical impedance analysis, and pulmonary function was assessed using spirometry and computed tomography. Results: Adolescent exercise habits were not significantly associated with PA or body composition, although they were associated with an increased lung volume. Compared to adolescent exercise habits, current exercise habits were associated with an increased duration of active engagement, less sedentary behavior, and increased diffusing capacity. Moreover, current exercise habits were associated with increased fat-free mass index, bone mineral content, and phase angle, which is an indicator of muscle quality. The influence of current exercise habits on these musculoskeletal indicators remained significant even after adjusting for age, sex, disease severity, and adolescent exercise habits. In addition, the relationship between PA and musculoskeletal health was more pronounced in patients with moderate-to-severe COPD than in those with mild COPD. Conclusion: Exercise during adolescence may promote increased lung volume. However, even after the onset of COPD, especially if the disease has progressed, regular exercise routines can help maintain PA, better body composition, and pulmonary function.

Resistance of NSCLCs to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), is mediated by pleotropic mechanisms that pose a significant challenge for subsequent treatment. We report that the oncogenic MUC1-C/M1C protein confers resistance to osimertinib by regulating the STAT1 and interferon (IFN) type I/II pathways. Studies of osimertinib-resistant NSCLC cell lines selected for growth in the absence of drug demonstrate dependence on MUC1-C and the STAT1 pathway for memory of the refractory phenotype. This inflammatory memory of TKI resistance is mediated through activation of the MUC1 gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN/AP-1, and PBAF. Our results further reveal that the MUC1-C-driven STAT1 inflammatory response promotes resistance of patient-derived (i) EGFR mutant NSCLC cells with MET amplification to the combination of osimertinib+MET TKIs, and (ii) EGFR(T790M/C797S) NSCLC cells to the 4th generation EGFR TKI TQB3804. Of clinical significance, we report that NSCLC cells dependent on MUC1-C for TKI resistance are druggable with an antibody-drug conjugate (M1C ADC) in vitro and in a PDX tumor model. These findings demonstrate that MUC1-C (i) is essential for TKI resistance of NSCLC cells by driving an inflammatory memory response and (ii) is a target for M1C ADC treatment of TKI-refractory NSCLCs.

spp. and often causes intractable asthma. Studies have been conducted on biologics administered to patients with allergic bronchopulmonary aspergillosis; however, treatment may not always be successful. This may be due to the limitations of the current biologics that selectively target a single cytokine. Tezepelumab, a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, broadly suppresses type 2 inflammation by regulating the upstream cascade of airway inflammation. Therefore, it is expected to have favorable effects in patients with allergic bronchopulmonary aspergillosis. We report three cases of allergic bronchopulmonary aspergillosis with uncontrolled symptoms despite the maximal use of conventional anti-asthmatic drugs such as inhalative agents, anti-leukotriene receptor antagonists, and antifungal drugs. None of the patients had previously received biologics. The addition of tezepelumab produced a marked clinical response in all three patients, which included fewer exacerbations and a reduced dosage of oral systemic corticosteroids and/or reduced as-needed short-acting beta-2 agonists. The patients' pulmonary symptoms were better controlled, peripheral blood eosinophil counts and immunoglobulin E levels decreased, and quality of life scores and respiratory function parameters improved. Mucous plugs accompanied by atelectasis and infiltrative shadows observed on chest computed tomography also improved. Tezepelumab may be a promising treatment option for allergic bronchopulmonary aspergillosis in patients with severe asthma, offering effective symptom control and enabling reduction in systemic corticosteroid use.

Background: Denosumab is widely used to prevent skeletal-related events (SREs) in patients with bone metastases. However, rebound bone resorption after discontinuation is recognized. In osteoporosis, discontinuation of low-dose denosumab increases multiple vertebral fractures, but data on high-dose discontinuation remain limited. Methods: Among 493 patients treated with high-dose denosumab at our institution (2014-2023), 78 met eligibility criteria. SREs during and after treatment were compared using each patient as their own control. SREs were defined as pathological fracture, spinal cord compression, or radiotherapy/surgery for metastatic bone pain. Hypercalcemia, benign fragility fractures, and serum ALP level were also assessed. Results: A total of 11 SREs were observed during denosumab and 24 after discontinuation. Post-discontinuation incidence was 14.1 per 1,000 person-months, 3.3 times higher than during treatment (95 % CI, 1.4-7.8). The increase was significant at 6-15 months, peaking at 12-15 months (IRR 8.7, 95 % CI, 2.8-27.5), and declined thereafter. Fewer denosumab doses were also associated with a higher risk of SREs after discontinuation. Two benign fragility fractures occurred during denosumab and four after discontinuation. Grade ≥ 3 hypercalcemia occurred only after discontinuation (3 cases). Transient ALP elevation at 9-18 months was observed in patients with post-discontinuation SREs, and ALP ≥ 95 U/L at 6 months predicted subsequent SREs (AUC 0.80). Conclusion: SREs increased significantly 6-15 months after high-dose denosumab discontinuation. Elevated ALP was associated with post-discontinuation SREs. These findings emphasize that discontinuation contributes to SRE risk, possibly via rebound bone resorption, and underscore the importance of continuation of therapy whenever possible.