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.

Interstitial Lung Disease in Adulthood Associated with Surfactant Protein C Gene Mutation in a Patient with a History of Lipoid Pneumonia in Infancy.

Mutations in the surfactant protein C gene (SFTPC) are responsible for hereditary interstitial lung disease (ILD), which is a rare disease. We herein report a patient with a clinical history of endogenous lipoid pneumonia in infancy who developed diffuse progressive pulmonary fibrosis in adulthood associated with SFTPC mutations. A surgical lung biopsy and genetic sequencing revealed fibrotic interstitial pneumonia and two SFTPC mutations (c.215G>A and c.578C>A). Based on these findings, we diagnosed the series of lung diseases as sporadic ILD caused by SFTPC mutations. Physicians should suggest genetic sequencing in patients with early-onset ILD.

Successful treatment with dupilumab for mucus plugs in severe asthma.

A 29-year-old man presented to our hospital with severe eosinophilic asthma. He needed a short OCS burst for exacerbation of asthma once every 1 or 2 months, although he used a high dose of inhaled corticosteroids and a long-acting beta-2 agonists. Chest CT showed multiple mucous plugs with bronchiectasis, but further examination found that he did not meet the diagnostic criteria for allergic bronchopulmonary aspergillosis. After starting dupilumab for his severe eosinophilic asthma, his asthma control improved without exacerbation. Furthermore, most mucus plugs disappeared on chest CT after 16 weeks from initiating dupilumab. This case suggests that dupilumab may be an effective treatment against mucus plugs associated with severe eosinophilic asthma.

Primary lung sebaceous carcinoma successfully treated with radiotherapy and pembrolizumab: A case report.

Sebaceous carcinoma is a rare cutaneous malignant tumor, usually occurring on the eyelids, head, neck, and trunk. There have been few reports about sebaceous carcinoma with primary lung cancer, for which optimal therapy has not yet been established. A 70-year-old man presented with a mass in the left iliac bone and tumor of the lower left lung. The morphological characteristics of the iliac bone biopsy pathology and immunostaining results showed sebaceous gland differentiation. After systemic examination, we diagnosed a primary lung sebaceous carcinoma with intrapulmonary and bone metastases. PD-L1 was positive in 1%-24% of tumor cells, and microsatellites were stable. We detected protein kinase B (AKT1) mutations using the Oncomine Dx target test. Palliative radiotherapy (RT) of a total of 45 Gy was provided in 15 fractions to the left iliac region, which resulted in a 25% reduction in the tumor size. Subsequently, four courses of first-line pembrolizumab led to a 30% reduction in the total tumor count. RT and pembrolizumab may be treatment options for certain rare primary sebaceous carcinomas of the lungs. A synergistic effect from RT and subsequent administration of immune checkpoint inhibitors may have contributed to tumor reduction.

Association of Clostridium butyricum Therapy Using the Live Bacterial Product CBM588 with the Survival of Patients with Lung Cancer Receiving Chemoimmunotherapy Combinations.

The gut microbiota has emerged as a key regulator of immune checkpoint inhibitor (ICI) efficacy. Therapeutic approaches aimed at manipulating the microbiota through targeted reconstitution to enhance cancer treatment outcomes have garnered considerable attention. A single live microbial biotherapeutic bacterium, Clostridium butyricum MIYAIRI 588 strain (CBM588), has been shown to enhance the effects of ICI monotherapy in patients with advanced lung cancer. However, whether CBM588 affects the outcomes of chemoimmunotherapy combinations in lung cancer remains unknown. We hypothesized that CBM588 augments the effect of chemoimmunotherapy combinations and restores diminished effectiveness in patients with non-small cell lung cancer (NSCLC) receiving dysbiosis-inducing drugs. To validate this hypothesis, we retrospectively analyzed 106 patients with stage IV or recurrent metastatic NSCLC consecutively treated with chemoimmunotherapy combinations. A survival analysis was performed employing univariate and multivariate Cox proportional hazard models with inverse probability of treatment weighting (IPTW) using propensity scores. Forty-five percent of patients received Clostridium butyricum therapy. CBM588 significantly extended overall survival in patients with NSCLC receiving chemoimmunotherapy. The favorable impact of CBM588 on the efficacy of chemoimmunotherapy combinations varied based on tumor-programmed cell death ligand 1 (PD-L1) expression. The survival benefit of CBM588 in the PD-L1 <1% cohort was higher than that in the PD-L1 1-49% and PD-L1 ≥ 50% cohorts. Furthermore, CBM588 was associated with improved overall survival in patients receiving proton pump inhibitors and/or antibiotics. CBM588-induced manipulation of the commensal microbiota holds the potential to enhance the efficacy of chemoimmunotherapy combinations, warranting further exploration of the synergy between CBM588 and immunotherapy.

Combination bezafibrate and nivolumab treatment of patients with advanced non-small cell lung cancer.

Despite the success of cancer immunotherapies such as programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase 1 trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through up-regulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.

Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer.

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I-IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer.

Clinical impact of SUVmax of interstitial lesions in lung cancer patients with interstitial lung disease who underwent pulmonary resection.

Background: Acute exacerbation of interstitial lung disease often causes fatal respiratory deterioration in lung cancer patients with interstitial lung disease. Here, we examined whether the maximum standardized uptake value of a contralateral interstitial lesion was a predictive factor of acute exacerbation of interstitial lung disease within 30 days postoperatively in lung cancer patients with interstitial lung disease who underwent pulmonary resection. Methods: Overall, 117 consecutive lung cancer patients with interstitial lung disease who underwent pulmonary resection between August 2010 and April 2019 at the Kumamoto University Hospital were retrospectively analysed for the association between the maximum standardized uptake value of the contralateral interstitial lesions and interstitial lung disease parameters. Results: The median maximum standardized uptake value of contralateral interstitial lesions was 1.61, which was regarded as the cut-off point predictive of the incidence of acute exacerbation of interstitial lung disease. Eight patients developed postoperative acute exacerbation of interstitial lung disease. There was no significant association between the maximum standardized uptake value of the contralateral interstitial lesions and postoperative acute exacerbation of interstitial lung disease. The maximum standardized uptake value was weakly but significantly associated with lactate dehydrogenase levels (r=0.211, P=0.022), Krebs von den Lungen-6 (r=0.208, P=0.028), and % diffusing capacity for carbon monoxide (r=-0.290, P=0.002). Moreover, seven patients developed acute exacerbation of the interstitial lung disease during the clinical course after 30 postoperative days, and the incidence rate of acute exacerbation of interstitial lung disease was significantly higher in the high maximum standardized uptake value group (≥1.61) than in the low maximum standardised uptake value group (<1.61) (12.7% vs. 0%, P=0.002, Gray's test). Conclusions: Maximum standardized uptake value was not a predictor of postoperative acute exacerbation of interstitial lung disease in lung cancer patients with interstitial lung disease after pulmonary resection, but could be a predictive tool of an association with interstitial lung disease severity and activity markers.

SPP1 Derived from Macrophages Is Associated with a Worse Clinical Course and Chemo-Resistance in Lung Adenocarcinoma.

Osteopontin, also called secreted phosphoprotein 1 (SPP1), is a multifunctional secreted phosphorylated glycoprotein. SPP1 is also expressed in tumor cells, and many studies demonstrated that a high level of circulating SPP1 is correlated with a poor prognosis in various cancers. SPP1 is expressed not only by tumor cells but also by stromal cells, such as macrophages. However, there have been no studies distinguishing the SPP1 expression of cancer cells and tumor-associated macrophages (TAMs). Thus, in this study, we tried to accurately evaluate the SPP1 expression status on cancer cells and TAMs separately in patients with non-small cell lung cancer by using double immunohistochemistry. We demonstrated that high SPP1 expression on TAMs predicted a poor prognosis in lung adenocarcinoma patients. Additionally, we investigated the expression mechanisms related to SPP1 using human-monocyte-derived macrophages and revealed that the SPP1 expression level increased in macrophage differentiation mediated by granulocyte-macrophage colony-stimulating factor. Furthermore, SPP1 contributed to anti-cancer drug resistance in lung cancer cell lines. In conclusion, SPP1 production on TAMs predicted a poor prognosis in lung adenocarcinoma patients, and TAM-derived SPP1's involvement in the chemo-resistance of cancer cells was suggested.