Resolution of bleomycin-induced murine pulmonary fibrosis via a splenic lymphocyte subpopulation.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality, and the pathogenesis of the disease is still incompletely understood. Although lymphocytes, especially CD4+CD25+FoxP3+ regulatory T cells (Tregs), have been implicated in the development of IPF, contradictory results have been reported regarding the contribution of Tregs to fibrosis both in animals and humans. The aim of this study was to investigate whether a specific T cell subset has therapeutic potential in inhibiting bleomycin (BLM)-induced murine pulmonary fibrosis. METHODS: C57BL/6 mice received BLM (100 mg/kg body weight) with osmotic pumps (day 0), and pulmonary fibrosis was induced. Then, splenocytes or Tregs were adoptively transferred via the tail vein. The lungs were removed and subjected to histological and biochemical examinations to study the effects of these cells on pulmonary fibrosis, and blood samples were collected by cardiac punctures to measure relevant cytokines by enzyme-linked immunosorbent assay. Tregs isolated from an interleukin (IL)-10 knock-out mice were used to assess the effect of this mediator. To determine the roles of the spleen in this model, spleen vessels were carefully cauterized and the spleen was removed either on day 0 or 14 after BLM challenge. RESULTS: Splenocytes significantly ameliorated BLM-induced pulmonary fibrosis when they were administered on day 14. This effect was abrogated by depleting Tregs with an anti-CD25 monoclonal antibody. Adoptive transfer of Tregs on day 14 after a BLM challenge significantly attenuated pulmonary fibrosis, and this was accompanied by decreased production of fibroblast growth factor (FGF) 9-positive cells bearing the morphology of alveolar epithelial cells. In addition, BLM-induced plasma IL-10 expression reverted to basal levels after adoptive transfer of Tregs. Moreover, BLM-induced fibrocyte chemoattractant chemokine (CC motif) ligand-2 production was significantly ameliorated by Treg adoptive transfer in lung homogenates, accompanied by reduced accumulation of bone-marrow derived fibrocytes. Genetic ablation of IL-10 abrogated the ameliorating effect of Tregs on pulmonary fibrosis. Finally, splenectomy on day 0 after a BLM challenge significantly ameliorated lung fibrosis, whereas splenectomy on day 14 had no effect. CONCLUSIONS: These findings warrant further investigations to develop a cell-based therapy using Tregs for treating IPF.

XPLN is modulated by HDAC inhibitors and negatively regulates SPARC expression by targeting mTORC2 in human lung fibroblasts.

Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extracellular matrix, whose expression is regulated by transforming growth factor (TGF)-ß1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown. Herein, we investigated the regulatory mechanisms of XPLN in human lung fibroblasts. Effect of XPLN on mTORC2 activity was evaluated by silencing XPLN in human foetal lung fibroblasts (HFL-1 cells), using small interfering RNA. SPARC expression was quantified by quantitative real-time RT-PCR and western blotting. Fibroblasts were treated with TGF-ß1, histone deacetylase (HDAC) inhibitors, entinostat, or vorinostat, to assess their effects on XPLN expression. Moreover, the effect of mTORC1 inhibition on SPARC and XPLN was examined. XPLN depletion stimulated SPARC expression and Akt phosphorylation on Ser473. TGF-ß1 treatment down-regulated XPLN via Smad 2/3. XPLN mRNA expression was up-regulated upon treatment with HDAC inhibitors in a concentration-dependent manner, and TGF-ß1-induced SPARC expression was reversed by entinostat treatment. mTORC1 inhibition by rapamycin and Raptor depletion stimulated SPARC expression. In conclusion, this is the first study describing the involvement of XPLN in the regulation of SPARC. These findings may help uncover the regulatory mechanisms of the mTORC2-SPARC axis. The up-regulation of XPLN by HDAC inhibitors may be a novel therapeutic approach in patients with IPF.

Osimertinib plus local treatment for brain metastases versus osimertinib alone in patients with EGFR-Mutant Non-Small Cell Lung Cancer.

OBJECTIVES: Osimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib. MATERIALS AND METHODS: This multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors. RESULTS: Of the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan-Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR-NR vs. 31.2, 21.7-33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16-0.87) and 0.36 (95 %CI, 0.15-0.87), respectively. CONCLUSIONS: The OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib.

[Long-term survival of patient with brain metastases from lung cancer treated by pemetrexed monotherapy].

A 61-year-old female was diagnosed with cT2N1M0 adenocarcinoma in the right lung. Following resection of the right middle lobe and dissection of the second group of lymph nodes in July 2007, she was found to have pN2 disease, and carboplatin plus paclitaxel was administered as postoperative chemotherapy. Recurrence was found and gefitinib was administered as first-line chemotherapy. While the patient was followed on an outpatient basis, dysgeusia and headache developed in March 2009. As multiple brain metastases were confirmed by contrast-enhanced computed tomography, cranial irradiation (30 Gy in 10 fractions)was administered. Upon improvement of the patient's status to a level treatable by chemotherapy, a new second-line chemotherapy with pemetrexed was started. Since then, the patient has been followed on an outpatient basis and has currently completed 21 courses of chemotherapy. No recurrence has been observed thus far. The results suggest that pemetrexed is an effective agent for the treatment of brain metastases from lung adenocarcinoma.

[The value of transbronchial lung biopsy findings in the diagnosis of a case of TS-1-induced pulmonary toxicity].

We report the case of a 67-year-old man with a diagnosis of stage IV stomach cancer in May 2010 who was treated with outpatient chemotherapy using TS-1, paclitaxel and lentinan. Dyspnea and coughing developed after drug administration in November and the patient was hospitalized on day 5 after the appearance of symptoms due to hypoxemia and the presence of ground-glass opacities in the right middle and lower lung fields. On the same day, bronchoscopy was performed for differentiation from infection and lymphangitic carcinomatosis. A transbronchial lung biopsy suggested drug-induced pulmonary toxicity, and a drug lymphocyte stimulation test was highly positive for TS-1. Discontinuation of TS-1 alone improved his respiratory status and imaging findings. TS-1 is available only in Japan, and because it is administered orally and its toxicity is minimal, its use has been expanded to treat a variety of malignancies. Drug-induced pulmonary toxicity due to TS-1 occurs in only 0.03% of all cases, and there are few reports regarding the histopathological findings of TS-1-related pulmonary toxicity. Although it can be difficult to diagnose drug-induced pulmonary toxicity because it demonstrates a variety of imaging findings, the present case suggests that it is important to proactively perform transbronchial lung biopsy at the early stage of diagnosis and promptly determine a course of treatment.

Corticosteroids for hospitalized patients with mild to critically-ill COVID-19: a multicenter, retrospective, propensity score-matched study.

Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score-matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January-April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388-0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323-2.337; p < 0.001), regardless of baseline clinical status. The duration of invasive mechanical ventilation was shorter in corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841-2.554; p = 0.177). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse versus standard dose group (HR, 2.831; 95% CI, 1.347-5.950; p = 0.006). In conclusion, corticosteroids for hospitalized patients with COVID-19 did not improve clinical status on Day 15, but reduced the time to improvement in radiological findings for all patients regardless of disease severity and also reduced the duration of invasive mechanical ventilation in patients who required intubation.Trial registration: This study was registered in the University hospital Medical Information Network Clinical Trials Registry on April 21, 2020 (ID: UMIN000040211).

Assessment of left ventricular dyssynchrony during development of heart failure by a novel program using ECG-gated myocardial perfusion SPECT.

BACKGROUND: A novel program, "cardioGRAF", has been developed to analyze regional left ventricular (LV) systolic/diastolic function and dyssynchrony, so the present study aimed to use it confirm the presence of LV dyssynchrony, and to correlate LV function and dyssynchrony with plasma B-type natriuretic peptide (BNP) levels during the early to advanced stages of heart failure (HF). METHODS AND RESULTS: Fourteen control subjects (G-C) and 50 patients (New York Heart Association functional class I: G-1, 21 patients; class II: G-2, 15 patients; and class III: G-3, 14 patients) were examined by ECG-gated myocardial perfusion single-photon emission computed tomography, using the new index of dyssynchrony, maximal difference (MD), which is the difference between the earliest and latest temporal parameters among 17 segments. First-third filling rate (FR) and the MD of time to peak FR revealing diastolic dyssynchrony were significantly different between G-C subjects and G-1 patients. Ejection fraction, peak ejection rate, peak FR, MD of time to end-systole, and MD of time to peak ejection rate were significantly correlated with plasma BNP levels. CONCLUSION: Diastolic dyssynchrony was demonstrated even in the early stage of HF, but, although not correlated with the plasma BNP level, systolic dyssynchrony might affect it.

Löffler's endocarditis associated with unusual ECG change mimicking posterior myocardial infarction.

A73-year-old man with a history of bronchial asthma and atrial fibrillation was admitted to our hospital because of dyspnea and back pain. Blood analysis revealed a marked increase in total blood cell and eosinophil counts. The creatine kinase and creatine kinase-MB increased slightly. The ECG demonstrated significant ST-segment depression that mimicked acute posterior myocardial infarction. Emergent coronary angiography showed no stenotic lesions. The histological findings in endomyocardial biopsy showed thickened endocardium associated with significant eosinophilic infiltration, which was compatible with Löffler's endocarditis. After the administration of prednisolone, the patient's general condition, eosinophilia, ECG abnormalities, and histological findings were improved dramatically. The endomyocardial biopsy in the acute phase was helpful for diagnosis and therapeutic decision-making.