Negative-predictive value of SUVmax for Ascertaining the efficacy of osimertinib in EGFR mutation-positive non-small cell lung cancer.

BACKGROUND: Fluorine-18 2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is routinely used to stage non-small cell lung cancer (NSCLC). However, whether 18F-FDG accumulation in primary tumors affects the efficacy of osimertinib in patients with epidermal growth factor receptor (EGFR) mutation-positive NSCLC remains unclear. METHODS: We retrospectively investigated 74 patients with advanced or postoperative recurrent EGFR mutation-positive NSCLC who underwent 18F-FDG PET/CT and were treated with osimertinib as first-line therapy between September 2018 and March 2023 at Kumamoto University Hospital. The maximum standardized uptake value (SUVmax) of each primary tumor was measured, and the patients were divided into two groups according to the median SUVmax. The effects of SUVmax on progression-free survival (PFS) and overall survival (OS) were assessed using a multivariate Cox proportional hazards model. RESULTS: The median SUVmax was 8.2 (interquartile range: 5.5-11.4). The median PFS in the high SUVmax group (≥8.2) was significantly shorter than that in the low SUVmax group (<8.2). The respective median PFSs were 11.2 months (95% confidence interval [CI]: 3.1-19.3 months) vs. 22.9 months (95% CI: 12.4-33.4 months) (P = 0.015), although the OS values did not differ significantly. Multivariate analysis showed that a high SUVmax was an independent negative predictive factor for PFS in patients treated with osimertinib (hazard ratio, 2.25; 95% CI: 1.15-4.39, P = 0.017). CONCLUSIONS: High primary-lesion SUVmax in patients with EGFR mutation-positive NSCLC correlated with shorter PFS with first-line osimertinib therapy, suggesting that SUVmax is a useful predictive marker for the antitumor efficacy of osimertinib.

Prevalence and characteristics of dysfunctional breathing in patients with asthma in the Japanese population.

BACKGROUND: Dysfunctional breathing (DB) is a major asthma comorbidity; however, it is not well recognized in Japan. Moreover, it has rarely been reported in the asthma population, and its clinical characteristics are unclear. We aimed to clarify the clinical characteristics of DB as a comorbidity in patients with asthma in Japan. Questionnaire surveys were conducted among patients with asthma at medical facilities in three regions of Japan (Niigata, Kumamoto, and Tokyo). METHODS: This cross-sectional questionnaire survey targeting patients with asthma who had regularly visited medical institutions and their doctors was conducted from September to November 2021. The questionnaire addressed the control status and method of treatment. The diagnosis of DB was evaluated using the Nijmegen questionnaire (NQ). RESULTS: There were 2087 eligible participants. Based on their NQ scores, 217 patients were classified into the DB group (NQ ≥ 19). There were significant differences with respect to sex, disease duration, Asthma Control Test (ACT) scores, Patient Health Questionnaire-9 (PHQ-9) scores, type-2 biomarkers, pulmonary function indices, treatment methods, severity, and asthma exacerbations in the previous year between the DB and non-DB groups. In the multivariate analysis, there were significant differences in sex, disease duration (≥15 y), ACT scores (<20), and PHQ-9 scores (≥10). The cluster analysis of cases with DB classified the population into four clusters. CONCLUSIONS: The asthma population with DB exhibited several characteristics, including depression and poorly controlled asthma. Further large-scale interventional investigations with longer follow-up periods are necessary to verify these findings.

Real-World Efficacy and Safety of Durvalumab Administration Following Chemoradiotherapy in Elderly Patients With Unresectable Locally Advanced Nonsmall Cell Lung Cancer: A Multicenter, Retrospective Study.

BACKGROUND: The PACIFIC trial established durvalumab administration after chemoradiotherapy as the standard of care for unresectable locally advanced nonsmall cell lung cancer (LA-NSCLC). However, the efficacy and safety of durvalumab in elderly patients aged 75 years or above remains unclear. This study aimed to investigate the real-world efficacy and safety of durvalumab for LA-NSCLC, with a specific focus on elderly patients. PATIENTS AND METHODS: We reviewed 214 patients who received durvalumab out of 278 patients with unresectable LA-NSCLC who underwent chemoradiotherapy at 7 institutions between July 2018 and March 2022. Propensity score matching (PSM) analysis was performed to evaluate the efficacy of durvalumab in elderly patients. RESULTS: The 2-year progression-free survival (PFS) and 2-year overall survival (OS) rates were 42.2% (95% confidence interval [CI], 34.7%-49.5%) and 77.1% (95% CI, 70.1-82.7%), respectively. Grade ≥ 3 immune-related adverse events (irAEs) occurred in 8.2% of patients. PSM analysis revealed that OS was significantly shorter in elderly patients (≥ 75 years) than in younger patients (< 75 years) (hazard ratio [HR]; 95% CI, 1.39-8.99; P = .008), whereas PFS did not differ significantly between the 2 groups (HR: 1.50, 95% CI, 0.84-2.68, P = .169). The frequency of irAEs did not differ between these groups. CONCLUSIONS: The real-world efficacy and safety of durvalumab administration following chemoradiotherapy for LA-NSCLC coincided with the PACIFIC trial's findings. Disease control achieved with this protocol did not differ significantly between elderly and younger patients but had acceptable tolerability, demonstrating its benefit even in elderly LA-NSCLC patients aged 75 years or above.

Impacts of cytoplasmic p53 aggregates on the prognosis and the transcriptome in lung squamous cell carcinoma.

The tumor suppressor TP53 gene, the most frequently mutated gene in human cancers, produces the product tumor protein p53, which plays an essential role in DNA damage. p53 protein mutations may contribute to tumorigenesis by loss of tumor suppressive functions and malignancy of cancer cells via gain-of-oncogenic functions. We previously reported that mutant p53 proteins form aggregates and that cytoplasmic p53 aggregates were associated with poor prognosis in human ovarian cancer. However, the prognostic impact of p53 aggregation in other tumors including lung squamous cell carcinoma (SCC) is poorly understood. Here, we demonstrated that lung SCC cases with cytoplasmic p53 aggregates had a significantly poor clinical prognosis. Analysis via patient-derived tumor organoids (PDOs) established from lung SCC patients and possessing cytoplasmic p53 aggregates showed that eliminating cytoplasmic p53 aggregates suppressed cell proliferation. RNA sequencing and transcriptome analysis of p53 aggregate-harboring PDOs indicated multiple candidate pathways involved in p53 aggregate oncogenic functions. With lung SCC-derived cell lines, we found that cytoplasmic p53 aggregates contributed to cisplatin resistance. This study thus shows that p53 aggregates are a predictor of poor prognosis in lung SCC and suggests that detecting p53 aggregates via p53 conventional immunohistochemical analysis may aid patient selection for platinum-based therapy.

Durable Response of Pembrolizmab for EGFR Mutation-positive Lung Adenocarcinoma with Early Progression to Osimertinib in First-line Treatment.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the standard first-line treatment for EGFR mutation-positive non-small-cell lung cancer (NSCLC) and demonstrates favorable disease control. Conversely, immune checkpoint inhibitors (ICIs) that target programmed cell death-1/programmed cell death ligands demonstrate a restrictive tumor response. We herein report a patient who achieved a durable response to pembrolizumab following early progression within two months of osimertinib administration for EGFR mutation-positive lung adenocarcinoma. Our findings suggest that treatment with ICIs for patients with EGFR mutation-positive NSCLC experiencing early progression to osimertinib as first-line treatment might represent a viable approach.

18F-FDG accumulation at the early onset of acute exacerbation of idiopathic interstitial pneumonia on 18F-FDG PET/CT: A case report.

Acute exacerbation of idiopathic interstitial pneumonias (AE-IIPs) is a disease associated with a poor prognosis in patients with IIPs. However, the specific characteristics of fluorine-18 2-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging for AE-IIPs remain unclear. Herein, we present the case of a patient with lung cancer combined with IIPs who underwent 18F-FDG PET/CT at the early onset of AE-IIPs. The scan, conducted 18 days post-bronchoscopy for lung cancer evaluation, revealed AE-IIPs before the onset of respiratory failure. New ground-glass opacities appeared, accompanied by significant 18F-FDG accumulation extending beyond these regions. To the best of our knowledge, this report represents the first assessment of 18F-FDG PET/CT images at the early onset of AE-IIPs before respiratory failure in humans. The observed features in this PET image could potentially contribute to our understanding of the pathophysiology of AE-IIPs.

Multicenter Pharmacokinetic and Pharmacodynamic Study of Pembrolizumab for Non-small-Cell Lung Cancer in Patients Aged 75 Years and Older.

Pembrolizumab is a major treatment for recurrent or advanced non-small-cell lung cancer (NSCLC). However, data on its use and pharmacokinetics (PK) in older patients are limited. This open-label, multicenter, observational study evaluated real-world data on the safety, efficacy, and PK of pembrolizumab in older patients with NSCLC. In 99 patients aged ≥75 years, PK was determined by liquid chromatography-mass spectrometry on pretreatment samples. Performance status (PS), geriatric assessment (GA), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. The median age was 78 (75-87) years. PS was 2-3 in 14 patients. The median ORR, PFS, and OS were 47.5%, 8.0, and 20.5 months, respectively. Although PK and ORR were not significantly associated, patients with the lowest Cycle 1-trough quartile (Q1) experienced poorer PFS (Q1 vs. Q2-4; 3.4 vs. 11.8 months, P = 0.006) and OS (Q1 vs. Q2-4; 9.9 vs. 21.7 months, P = 0.005) than in other quartiles overall, and even in the PD-L1 ≥50% subset (PFS, Q1 vs. Q2-4; 4.1 vs. 14.7 months, P = 0.005; OS, Q1 vs. Q2-4; 9.4 vs. 22.1 months, P = 0.010). The Q1 subgroup was characterized by poor PS and lower albumin, and more frequent "weight loss ≥ 10%" on the GA. Pembrolizumab therapy had similar PK and efficaciousness in older as well as younger patients. In patients with PS ≥2, low albumin, and vulnerable GA, early increases in PK levels are less likely, potentially diminishing efficacy even when PD-L1 ≥50%.

Case of Pulmonary Tumor Embolism due to Oropharyngeal Carcinoma Diagnosed by a Transbronchial Lung Biopsy.

Pulmonary tumor embolisms (PTEs) are primarily caused by adenocarcinoma. However, only a few cases of oropharyngeal carcinoma have been reported. We herein report a 47-year-old man who presented with a fever, cough, and dyspnea 6 months after treatment for stage II oropharyngeal carcinoma. Chest computed tomography revealed centrilobular granular and nodular shadows and subpleural consolidation. A transbronchial lung biopsy revealed a mass of squamous tumor cells forming emboli in the small vessels, resulting in the diagnosis of PTE due to oropharyngeal carcinoma. Therefore, PTE should be considered for patients with a history of hypoxia.

Tension Pneumomediastinum in Anti-MDA5 Antibody-positive Dermatomyositis-associated Interstitial Lung Disease: A Case Report and Literature Review.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM)-associated interstitial lung disease (ILD) can sometimes be complicated by pneumomediastinum, although tension pneumomediastinum is extremely rare. We herein report a case of anti-MDA5 antibody-positive DM-ILD that worsened subcutaneous and mediastinal emphysema during treatment. Hypotension and worsening respiratory failure were observed on day 20 of treatment. Mediastinal drainage under video-assisted thoracoscopic surgery promptly improved the patient's circulatory and respiratory status. Tension pneumomediastinum is a rare complication; however, it is a serious condition that may lead to hypotension or cardiac arrest and requires a prompt diagnosis and treatment.

Negative impact of ratio of the microvascular area to tumor area on the response to EGFR-TKI in non-small cell lung cancer with an EGFR mutation.

Background: The clinical impact of tumor microvessels on the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutation-positive non-small cell lung cancer (NSCLC) is unclear. Thus, the aim of this study was to investigate whether a tumor microenvironment, abundant in microvessels, affects EGFR-TKI efficacy in patients with NSCLC and EGFR mutations. Methods: We retrospectively studied the data of 40 post-operative patients with recurrent NSCLC and EGFR mutations who received EGFR-TKIs as a first-line treatment at Kumamoto University Hospital from January 2010 to February 2021. Tumor sections were retrieved from the tissue registry and analyzed for CD34-positive microvessels using immunohistochemical techniques. The ratio of microvascular area to tumor area (RMV), which is the CD34-positive microvascular area compared to the total tumor area, was measured using StrataQuest. The predictive value of RMV on treatment outcome, assessed via progression-free survival (PFS), was evaluated using a multivariate Cox proportional hazard model. Results: The median PFS in the high RMV group (≥0.058) was significantly shorter than that in the low RMV group [<0.058; 296 days, 95% confidence interval (CI): 217-374 vs. 918 days, 95% CI: 279-1,556, P=0.002]. Multivariate analysis revealed that high RMV was an independent negative predictor of PFS (hazard ratio, 3.21; 95% CI: 1.18-8.76, P=0.022). Conclusions: High RMV may critically affect EGFR-TKI resistance in patients with NSCLC and EGFR mutations.

The impact of factor Xa inhibitors on bleeding risk in patients with respiratory diseases.

It is unclear which factor Xa (FXa) inhibitors are associated with higher bleeding risk in patients with respiratory diseases, and there are no studies on the association between prothrombin time-international normalized ratio (PT-INR) and bleeding risk. We conducted a retrospective cohort study comparing 1-year-outcomes and PT-INR between patients with respiratory diseases treated with rivaroxaban (R group, n = 82) or edoxaban (E group, n = 138) for atrial fibrillation or venous thromboembolism from 2013 to 2021. The most frequent event of all bleeding discontinuations was respiratory bleeding in both groups (7.3 and 4.3%, respectively). The cumulative incidence of bleeding discontinuation was significantly higher in the R group (25.6%) than in the E group (14.4%) (hazard ratio [HR], 2.29; 95% confidence interval [CI] 1.13-4.64; P = 0.023). PT-INR after initiation of therapy significantly increased and was higher in the R group than in the E group (median value, 1.4 and 1.2, respectively; P < 0.001). Multivariate analysis using Cox proportional hazards and Fine-Gray models revealed that PT-INR after initiation of therapy was an independent risk factor of bleeding discontinuation events (HR = 4.37, 95% CI 2.57-7.41: P < 0.001). Respiratory bleeding occasionally occurs in patients receiving FXa inhibitors, and monitoring the PT-INR may need to ensure safety.

Comparison of nintedanib-induced gastrointestinal adverse events between patients with systemic sclerosis-associated interstitial lung disease and idiopathic interstitial pneumonias.

BACKGROUND: Gastrointestinal symptoms, such as diarrhea and nausea, are common adverse events associated with nintedanib. Systemic sclerosis is associated with a high prevalence of gastrointestinal symptoms that may increase with nintedanib administration. In clinical practice, we aimed to determine whether patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) experience more adverse gastrointestinal events associated with nintedanib than patients with idiopathic interstitial pneumonias (IIPs). METHODS: We retrospectively examined the clinical records of patients with SSc-ILD and IIPs newly treated with nintedanib at Kumamoto University Hospital between January 2020 and September 2022 and compared adverse events. RESULTS: In total, 27 patients with SSc-ILD and 34 with IIPs were enrolled. No significant differences were observed in the duration of nintedanib treatment. The most frequent adverse event in both groups was diarrhea, which was more frequent in the SSc-ILD group (81.5 % vs. 61.8 %, p = 0.157). Nausea was significantly more frequent in the SSc-ILD group than in the IIPs group (37.0 % vs. 11.8 %, p = 0.031). The permanent discontinuation rate of nintedanib during the study period between the two groups was not different (40.7 % vs. 32.4 %, p = 0.595). However, the most common reasons for discontinuation varied. The most frequent reason in the SSc-ILD group was nausea, due to the progression of ILD in the IIPs group. CONCLUSIONS: Patients with SSc-ILD experienced significantly more nintedanib-induced nausea than those with IIPs. Gastrointestinal adverse events are often the reason for discontinuation of nintedanib in the SSc-ILD group, which requires better management of gastrointestinal symptoms.

Osimertinib as first-line treatment for elderly patients with advanced EGFR mutation-positive non-small cell lung cancer in a real-world setting (OSI-FACT-EP).

OBJECTIVES: Osimertinib is the primary treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer. However, evidence of the outcomes of osimertinib treatment in patients over 75 years of age in the real-world setting is limited. MATERIALS AND METHODS: This retrospective study analyzed the data of 538 patients (203 elderly and 335 non-elderly) with EGFR mutation-positive lung cancer in whom osimertinib was initiated as first-line treatment between August 2018 and December 2019. Patients over 75 years of age were classified as elderly. The data cut-off date was February 28, 2022. RESULTS: The progression-free survival (PFS) did not significantly differ between the elderly and non-elderly groups [elderly group: median PFS, 16.9 months (95 % confidence interval (CI), 14.3-20.2); non-elderly group: median PFS, 22.1 months (95 % CI: 19.5-26.3); hazard ratio (HR) for the elderly against the non-elderly: 1.21 (95 % CI: 0.98-1.50), p = 0.079]. However, the time to treatment failure (TTF) was significantly shorter in the elderly than in the non-elderly [elderly group: median TTF, 14.0 months (95 % CI: 0.98-1.50); non-elderly group: median TTF, 21.8 months (95 % CI: 18.2-24.6); HR for the elderly against the non-elderly: 1.46 (95 % CI: 1.20-1.77), p < 0.001]. Furthermore, the rate of treatment discontinuation because of adverse events was 28.6 % in the elderly and 14.9 % in the non-elderly (p < 0.001). Among patients who discontinued treatment, the conversion rate to second-line treatment was 39.6 % in the elderly and 72.8 % in the non-elderly. In addition, the median overall survival was 30 months (95 % CI: 25.8-37.7) in the elderly and not reached (NR) (95 % CI: NR-NR) in the non-elderly (p < 0.001). CONCLUSION: In a real-world clinical setting, elderly patients receiving osimertinib as first-line treatment should be aware of the frequent inability to transition to second-line treatment due to adverse events.

An observational cohort study of interstitial lung abnormalities (ILAs) in a large Japanese health screening population (Kumamoto ILA study in Japan: KILA-J).

BACKGROUND: Interstitial lung abnormalities (ILAs) are subtle or mild parenchymal abnormalities observed in more than 5% of the lungs on computed tomography (CT) scans in patients in whom interstitial lung disease was not previously clinically suspected and is considered. ILA is considered to be partly undeveloped stages of idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). This study aims to clarify the frequency of subsequent IPF or PPF diagnosis, the natural course from the preclinical status of the diseases, and the course after commencing treatment. METHODS: This is an ongoing, prospective, multicentre observational cohort study of patients with ILA referred from general health screening facilities with more than 70,000 annual attendances. Up to 500 participants will be enrolled annually over 3 years, with 5-year assessments every six months. Treatment intervention including anti-fibrotic agents will be introduced in disease progression cases. The primary outcome is the frequency of subsequent IPF or PPF diagnoses. Additionally, secondary and further endpoints are associated with the efficacy of early therapeutic interventions in cases involving disease progression, including quantitative assessment by artificial intelligence. DISCUSSION: This is the first prospective, multicentre, observational study to clarify (i) the aetiological data of patients with ILA from the largest general health check-up population, (ii) the natural course of IPF or PPF from the asymptomatic stage, and (iii) the effects and outcomes of early therapeutic intervention including anti-fibrotic agents for progressive cases of ILA. The results of this study could significantly impact the clinical practice and treatment strategy for progressive fibrosing interstitial lung diseases. TRIAL REGISTRATION NUMBER: UMIN000045149.

Onionin A inhibits small-cell lung cancer proliferation through suppressing STAT3 activation induced by macrophages-derived IL-6 and cell-cell interaction with tumor-associated macrophage.

Tumor-associated macrophage (TAM)-derived IL-6 is involved in small-cell lung cancer (SCLC) progression and chemoresistance via the activation of signal transducer and activator of transcription 3 (STAT3) in the tumor microenvironment. This study aimed to identify natural compounds that suppress cell-cell interactions between TAMs and SCLC cells by inhibiting STAT3 activation. We used a library of natural compounds to identify candidate agents possessing anti-SCLC effects by inhibiting macrophage-induced tumor proliferation. SBC-3 and SBC-5, human SCLC cell lines, were used for in vitro experiments. Furthermore, we assessed the efficacy of these candidate agents in a murine xenograft model of human SCLC. Among the natural compounds examined, onionin A (ONA) inhibited IL-6-induced STAT3 activation and SCLC cell proliferation. ONA also reduced the secretion of IL-6 from macrophages and interfered with the direct effect of cell-cell interactions between macrophages and SCLC cells. Furthermore, ONA administration suppressed tumor progression in a tumor-bearing mouse model. ONA was identified as the most useful candidate for targeting cell-cell interactions between cancer cells and TAMs for anti-SCLC therapy.

Diagnostic and Therapeutic Challenges in Disseminated Mycobacterium colombiense Infection Caused by Interferon-γ Neutralizing Autoantibodies.

Adult-onset immunodeficiency due to interferon-γ-neutralizing autoantibodies (nIFNγ-autoAbs) can remain underdiagnosed. We present a case of severe Mycobacterium colombiense infection with nIFNγ-autoAbs. To ensure early diagnosis, clinicians should have a high index of suspicion in patients of Asian descent with opportunistic infections and perform QuantiFERON-TB assay for disease screening.

The ROX index (Index combining the respiratory rate with oxygenation) is a prognostic factor for acute respiratory distress syndrome.

BACKGROUND: There is no existing reliable and practical method for predicting the prognosis of acute respiratory distress syndrome (ARDS). OBJECTIVE: We aimed to clarify the association between the ROX index, which is calculated as the ratio of peripheral oxygen saturation divided by the fraction of inspired oxygen to the respiratory rate, and the prognosis of patients with ARDS under ventilator support. METHODS: In this single-center retrospective cohort study from prospectively collected database, eligible patients were categorized into three groups based on ROX tertiles. The primary outcome was the 28-day survival, and the secondary outcome was 28-day liberation from ventilator support. We performed multivariable analysis using the Cox proportional hazards model. RESULTS: Among 93 eligible patients, 24 (26%) patients died. The patients were divided into three groups according to the ROX index (< 7.4, 7.4-11, ≥ 11), with 13, 7, and 4 patients dying in the groups, respectively. A higher ROX index was associated with lower mortality; adjusted hazard ratios [95% CIs] for increasing tertiles of ROX index: 1[reference], 0.54[0.21-1.41], 0.23[0.074-0.72] (P = 0.011 for trend) and a higher rate of successful 28-day liberation from ventilator support; adjusted hazard ratios [95% CIs] for increasing tertiles of ROX index: 1[reference], 1.41[0.68-2.94], 2.80[1.42-5.52] (P = 0.001 for trend). CONCLUSIONS: The ROX index at 24 h after initiating ventilator support is a predictor of outcomes in patients with ARDS and might inform initiation of more advanced treatments.