Masahiro Katsurada

Purpose: Thyroid transcription factor-1 (TTF-1) is a good prognostic factor for non-small cell lung carcinoma (NSCLC). It is unclear how much TTF-1 staining is sufficient to predict therapeutic response in immunochemotherapy. We evaluated the cut-off of TTF-1 considering the percentage of positive cells and staining intensity as a predictive factor. Patients and Methods: We conducted a retrospective multicenter study of patients with advanced lung adenocarcinoma or NSCLC favor adenocarcinoma treated with immunochemotherapy. One pathologist centrally examined the immunohistochemical staining of TTF-1 using 8G7G3/1 and provided scores of 0– 5 based on the staining intensity and ratio. Results: We analyzed 95 patients. As TTF-1 has previously been shown to be a predictive factor for pemetrexed, there were significant differences in PFS of patients treated with pemetrexed-based immunochemotherapy between TTF-1 scores of 5 (diffuse and strong staining) and ≤ 4, but not between 0 (no staining) and 2– 4 (partial or weak staining). We defined a TTF-1 score of ≥ 5 as positive for the predictive factor and the positivity ratio was 61.1%. Patients who tested negative for TTF-1 had a significantly higher proportion of programmed death ligand 1 (PD-L1) tumor proportion score (TPS) < 1%. Excluding mutation-positive patients, PFS in TTF-1 positivity was significantly longer than in negativity (8.0 and 5.9, hazard ratio (HR): 0.58 (0.34– 0.98), p = 0.04), while TTF-1 negativity was not inferior to positivity in PFS with taxane-based immunochemotherapy. Patients treated with pemetrexed-based immunochemotherapy who tested positive for TTF-1 had significantly longer PFS than those who tested negative (HR: 0.51 (0.27– 0.99), p = 0.045) in the multivariate analysis incorporating age, PD-L1, PS, and TTF-1. Conclusion: Diffuse and strong TTF-1 positivity may be useful for the predictive factor for pemetrexed-based immunochemotherapy. TTF-1 staining may be desirable to develop a more optimal immunochemotherapy for lung adenocarcinoma.

Accurate prognostic tools for mortality in patients with healthcare-associated pneumonia (HCAP) are needed to provide appropriate medical care, but the efficacy for mortality prediction of tools like PSI, A-DROP, I-ROAD, and CURB-65, widely used for predicting mortality in community-acquired and hospital-acquired pneumonia cases, remains controversial. In this study, we conducted a systematic review and meta-analysis using PubMed, Cochrane Library (trials), and Ichushi web database (accessed on August 22, 2022). We identified articles evaluating either PSI, A-DROP, I-ROAD, or CURB-65 and the mortality outcome in patients with HCAP, and calculated the pooled sensitivities, specificities, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the summary area under the curves (AUCs) for mortality prediction. Additionally, the differences in predicting prognosis among these four assessment tools were evaluated using overall AUCs pooled from AUC values reported in included studies. Eventually, 21 articles were included and these quality assessments were evaluated by QUADAS-2. Using a cut-off value of moderate in patients with HCAP, the range of pooled sensitivity, specificity, PLR, NLR, and DOR were found to be 0.91–0.97, 0.15–0.44, 1.14–1.66, 0.18–0.33, and 3.86–9.32, respectively. Upon using a cut-off value of severe in those patients, the range of pooled sensitivity, specificity, PLR, NLR, and DOR were 0.63–0.70, 0.54–0.66, 1.50–2.03, 0.47–0.58, and 2.66–4.32, respectively. Overall AUCs were 0.70 (0.68–0.72), 0.70 (0.63–0.76), 0.68 (0.64–0.73), and 0.67 (0.63–0.71), respectively, for PSI, A-DROP, I-ROAD, and CURB-65 (p = 0.66). In conclusion, these severity assessment tools do not have enough ability to predict mortality in HCAP patients. Furthermore, there are no significant differences in predictive performance among these four severity assessment tools.

Purpose: Caspase recruitment domain-containing protein 9 (CARD9) is expressed at high levels in bone marrow cells and has a crucial role in innate immunity. Current studies indicate that CARD9 also plays a key role in tumor progression, but there are few reports on the role of CARD9 in lung cancer. The aim of this study was to clarify the role of CARD9 in lung adenocarcinoma. Patients and Methods: Lung adenocarcinoma tumor samples from 74 patients who underwent complete resection at Kobe University Hospital from January 2014 to December 2014 were analyzed by immunohistochemistry. The role of CARD9 in cancer cells was analyzed using lung cancer cell lines treated with CARD9 siRNA. Results: High expression of CARD9 was observed in 32.4% of tumors, and compared to low expression of CARD9, high expression was associated with poorer overall survival (P = 0.0365). Univariate and multivariate analyses showed that high expression of CARD9 was an independent prognostic factor. Knockdown of CARD9 in lung adenocarcinoma cells inhibited proliferation but did not increase apoptosis. In addition, CARD9 activated the NF-κB pathway in a lung adenocarcinoma cell line. Conclusion: CARD9 was shown to be an independent prognostic factor of poor outcome for lung cancer and may represent a molecular target for treatment.

Purpose: Pseudo-progression (PsPD) is a rare phenomenon observed in Patients and methods: We retrospectively reviewed the clinical records of NSCLC patients treated with ICI monotherapy from December 2015 to October 2018 at Kobe University Hospital, Japan. Twenty-five patients were determined to have either PsPD (n =4) or TPD (n =21). We focused on longitudinal radiological images and NLRs. Results: Here, we report four patients with PsPD. The pre- and post-treatment NLRs were significantly lower in patients with PsPD than in patients with TPD (p = 0.019 and p = 0.007, respectively). The receiver operating characteristic curve according to the pre- and post-treatment NLR showed areas under the curve of 0.82 and 0.94, respectively. The optimal cut-off values for pre- and post-treatment NLR were 4.1 and 3.2, respectively. The pre- and post-treatment NLRs were useful in distinguishing between PsPD and TPD. Both a pre-treatment NLR Conclusion: The NLR could be a viable clue for distinguishing between PsPD and TPD. Patients with a high post-treatment NLR in this study all had TPD, suggesting that these subjects should be considered for an early transition to the next drug treatment regimen.

Extracellular vesicles (EVs) are circulating vesicles secreted by various cell types. EVs are classified into three groups according to size, structural components, and generation process of vesicles: exosomes, microvesicles, and apoptotic bodies. Recently, EVs have been considered to be crucial for cell-to-cell communications and homeostasis because they contain intracellular proteins and nucleic acids. Epithelial cells from mice suffering from bronchial asthma (BA) secrete more EVs and suppress inflammation-induced EV production. Moreover, microarray analyses of bronchoalveolar lavage fluid have revealed that several microRNAs are useful novel biomarkers of BA. Mesenchymal stromal cell-derived EVs are possible candidates of novel BA therapy. In this review, we highlight the biologic roles of EVs in BA and review novel EV-targeted therapy to help understanding by clinicians and biologists.

Background: The combination of gemcitabine (GEM) and paclitaxel (PTX) was appealing for clinical exploration due to different mechanisms of action and partially non-overlapping toxicities. Purpose: The aim of this study was to elucidate a potential effect of this combination on the proliferation of two non-small cell lung cancer (NSCLC) cell lines, A549 and H520. Materials and methods: Cell lines were treated with GEM and PTX for 48 hours to evaluate the half maximal inhibitory concentration (IC50). To determine the combination index (CI), cell lines were exposed to GEM and PTX, in a constant ratio of IC50, by various combination treatments. GEM`s effect on tubulin was assessed by western blotting and immunofluorescent staining. GEM was combined with nanoparticle albumin-bound-paclitaxel (NP) in evaluating tumor growth inhibition. Results: The IC50 of GEM and PTX in A549 and H520 were 6.6 nM and 46.1 nM, and 1.35 nM and 7.59 nM, respectively. Among the sequences explored (GEM→PTX, PTX→GEM, and GEM plus PTX simultaneously [GEM+PTX]), GEM→PTX produced a mean CI Conclusion: The GEM→PTX sequence may represent a promising candidate regimen for the treatment of NSLCL.

We have shown that phospholipase Cε (PLCε), an effector of Ras and Rap1 small GTPases, plays pivotal roles in inflammation and inflammation-associated carcinogenesis by augmenting proinflammatory cytokine production from epithelial cells of various organs. The purpose of this study is to analyze its role in neutrophilic alveolar inflammation accompanying acute lung injury (ALI), focusing on that in alveolar epithelial cells (AECs), which are known to make a major contribution to the pathogenesis of ALI. We examine the effect of the PLCε genotypes on the development of ALI induced by intratracheal administration of lipopolysaccharide (LPS) to PLCε wild-type (PLCε+/+) and knockout (PLCεΔX/ΔX) mice. Pathogenesis of ALI is analyzed by histological examination of lung inflammation and measurements of the levels of various cytokines, in particular neutrophil-attracting chemokines such as Cxcl5, by quantitative reverse transcription-polymerase chain reaction and immunostaining. Primary cultures of AECs, established from PLCε+/+ and PLCεΔX/ΔX mice, are used to analyze the roles of PLCε, protein kinase D (PKD) and nuclear factor-κB (NF-κB) in augmentation of LPS-induced Cxcl5 expression. Compared to PLCε+/+ mice, PLCεΔX/ΔX mice exhibit marked alleviation of lung inflammation as shown by great reduction in lung wet/dry weight ratios, accumulation of inflammatory cells in the alveolar space and thickening of alveolar walls as well as the number of neutrophils and the protein concentration in bronchoalveolar lavage fluid. Also, LPS-induced expression of the CXC family of chemokines, in particular Cxcl5, is substantially diminished in the total lung and AECs of PLCεΔX/ΔX mice. Moreover, LPS-induced Cxcl5 expression in primary cultured AECs is markedly suppressed on the PLCεΔX/ΔX background (p < 0.05 versus PLCε+/+ AECs), which is accompanied by the reduction in phosphorylation of inhibitor κB (IκB), PKD and nuclear translocation of NF-κB p65. Also, it is suppressed by the treatment with inhibitors of PKD and IκB kinase, suggesting the involvement of the PLCε-PKD-IκB-NF-κB pathway. PLCε-mediated augmentation of the production of the CXC family of chemokines, in particular Cxcl5, in AECs plays a crucial role in neutrophilic alveolar inflammation accompanying ALI, suggesting that PLCε may be a potential molecular target for the treatment of acute respiratory distress syndrome.