Language：English   Publisher：(一社)日本癌学会  

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INTRODUCTION: This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen. METHODS: A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (Cmax) calculated using the existing PopPK model and AEs of special interest (AESIs). RESULTS: Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated Cmax at cycle 1 increased. CONCLUSIONS: In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated Cmax at cycle 1 may be associated with an increased frequency of AESIs.

DOI： 10.1016/j.jtocrr.2024.100683

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Osimertinib induces a marked response in non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) gene mutations. However, acquired resistance to osimertinib remains an inevitable problem. In this study, we aimed to investigate osimertinib-resistant mechanisms and evaluate the combination therapy of afatinib and chemotherapy. We established osimertinib-resistant cell lines (PC-9-OR and H1975-OR) from EGFR-mutant lung adenocarcinoma cell lines PC-9 and H1975 by high exposure and stepwise method. Combination therapy of afatinib plus carboplatin (CBDCA) and pemetrexed (PEM) was effective in both parental and osimertinib-resistant cells. We found that expression of thrombospondin-1 (TSP-1) was upregulated in resistant cells using cDNA microarray analysis. We demonstrated that TSP-1 increases the expression of matrix metalloproteinases through integrin signaling and promotes tumor invasion in both PC-9-OR and H1975-OR, and that epithelial-to-mesenchymal transition (EMT) was involved in H1975-OR. Afatinib plus CBDCA and PEM reversed TSP-1-induced invasion ability and EMT changes in resistant cells. In PC-9-OR xenograft mouse models (five female Balb/c-Nude mice in each group), combination therapy strongly inhibited tumor growth compared with afatinib monotherapy (5 mg/kg, orally, five times per week) or CBDCA (75 mg/kg, intraperitoneally, one time per week) + PEM (100 mg/kg, intraperitoneally, one time per week) over a 28-day period. These results suggest that the combination of afatinib plus CBDCA and PEM, which effectively suppresses TSP-1 expression, may be a promising option in EGFR-mutated NSCLC patients after the acquisition of osimertinib resistance.

DOI： 10.1111/cas.16199

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INTRODUCTION: A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs. METHOD: To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement. RESULT: Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. CONCLUSION: These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

DOI： 10.1002/cam4.7393

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). Liquid biomarkers to predict irAE occurrence are urgently needed. We previously developed an ELISA system to specifically detect soluble PD-L1 (sPD-L1) with PD-1-binding capacity (bsPD-L1). Here, we investigated the relationship between sPD-L1 and bsPD-L1 in gastric cancer (GC) and non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 blockade and their association with irAEs.

Methods: We examined sPD-L1, bsPD-L1, matrix metalloproteinases (MMPs), and proinflammatory cytokine levels by ELISA in plasma samples from 117 GC patients prior to surgery and 72 NSCLC patients prior to and at 2 months after ICI treatment (anti-PD-1, n = 48; anti-PD-L1, n = 24). In mice treated with anti-PD-1/PD-L1 antibodies (Abs), sPD-L1 levels and localization of Abs were examined by ELISA and immunohistochemistry, respectively.

Results:sPD-L1 was detected with higher frequency in GC patients than in NSCLC patients, whereas bsPD-L1 was detected with similar frequencies in GC and NSCLC patients. sPD-L1 levels were correlated with IL-1α, IL-1β, TNF-α, and IL-6 levels, while bsPD-L1 levels were correlated with MMP13, MMP3, and IFN-γ levels. In NSCLC patients, anti-PD-L1, but not anti-PD-1, treatment increased sPD-L1, which was associated with irAE development, but not with clinical outcomes. In mice, trafficking of anti-PD-L1 Abs to lysosomes in F4/80⁺ macrophages resulted in sPD-L1 production, which was suppressed by treatment with lysosomal degradation inhibitor chloroquine and macrophage depletion.

Conclusion: Anti-PD-L1-mediated lysosomal degradation induces sPD-L1 production, which can serve as an indicator to predict irAE development during anti-PD-L1 treatment.

DOI： 10.3389/fphar.2024.1384733

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Background

The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade.

Methods

We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively.

Results

bsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1⁺MMP13^high in GC and bsPD-L1⁺(MMP3 and MMP13)^increased in NSCLC were associated with poor prognosis, whereas bsPD-L1⁺MMP13^low in GC and bsPD-L1⁺(MMP3 or MMP13)^decreased in NSCLC were associated with favorable prognosis.

Conclusion

Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.

DOI： 10.3389/fphar.2024.1384731

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BACKGROUND: In compatible with fibrotic hypersensitivity pneumonitis (HP) of the computed tomography (CT) classification using the American Thoracic Society (ATS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) HP guidelines, the lung fibrosis pattern was classified as either a usual interstitial pneumonia (UIP) pattern or a diffuse ground-glass opacity (GGO) pattern with subtle fibrosis. We investigated whether patients with the same imaging classification had different disease progression. We also attempted to reclassify these patients using the CHEST HP guidelines. METHODS: Patients with fibrotic HP who had compatible CT pattern in the ATS/JRS/ALAT classification were investigated retrospectively. RESULTS: With 62 patients in the UIP pattern group and 25 patients in the diffuse GGO pattern group, 87 patients with fibrotic HP had compatible pattern on CT. Annual forced vital capacity changes in the UIP pattern group and diffuse GGO pattern group were -2.7% and +3.3% (P=0.004), respectively. The 5-year survival rates in the UIP pattern group and diffuse GGO pattern group were 86% and 100% (P=0.02). In UIP pattern group in the ATS/JRS/ALAT classification, 27% patients were classified as typical fibrotic HP pattern in the CHEST guidelines. In the diffuse GGO pattern group, 52% patients were classified as typical pattern of fibrotic HP. In the CHEST guidelines, more patients in the GGO pattern were classified as typical pattern compared with those in the UIP pattern (P=0.02). CONCLUSIONS: The two patterns in compatible with fibrotic HP of CT classification using the ATS/JRS/ALAT HP guidelines had different disease progression. Typical patterns were more frequent in the CHEST guidelines than the ATS/JRS/ALAT guidelines.

DOI： 10.21037/jtd-23-1845

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BACKGROUND: The data on bosentan were lacking for the treatment of exercise-induced elevation of pulmonary artery pressure (eePAP) or less severe PH in COPD. This study was conducted to investigate long-term efficacy and safety of bosentan for the treatment of eePAP or less severe PH in COPD. METHODS: COPD patients diagnosed at this hospital as having COPD (WHO functional class II, III or IV) with eePAP or less severe PH whose respiratory symptoms were stable but remained and gradually progressed even after COPD therapy were randomly assigned in a 1:1 ratio to receive either bosentan or no PH treatment for two years and assessed at baseline and every 6 months for respiratory failure, activities of daily living (ADL), lung and heart functions by right heart catheterization (RHC), and other parameters. RESULTS: A total of 29 patients who underwent RHC for detail examination were enrolled in the current study between August 2010 and October 2018.No death occurred in drug-treated group (n = 14) for 2 years; 5 patients died in untreated group (n = 15). Significant differences were noted between the 2 group in hospital-free survival (686.00 ± 55.87 days vs. 499.94 ± 53.27 days; hazard ratio [HR], 0.18; P = 0.026) and overall survival (727 days vs. 516.36 ± 55.38 days; HR, 0.095; P = 0.030) in all causes of death analysis, but not in overall survival in analysis of respiratory-related death. Bosentan was not associated with increased adverse events including requiring O2 inhalation. CONCLUSIONS: This study suggested that the prognosis for COPD patients with eePAP or less severe PH presenting with respiratory symptoms was very poor and that bosentan tended to improve their prognosis and suppress ADL deterioration without worsening respiratory failure. TRIAL REGISTRATION: This study was registered with UMIN-CTR Clinical Trial as UMIN000004749 . First trial registration at 18/12/2010.

DOI： 10.1186/s12890-024-02895-0

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BACKGROUND: Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD. METHODS: We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases. RESULTS: Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings. CONCLUSIONS: Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.

DOI： 10.1272/jnms.JNMS.2024_91-211

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Language：English   Publisher：(一社)日本癌学会  

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The mechanisms of fibrosis onset and development remain to be elucidated. However, it has been reported that mechanical stretch promotes fibrosis in various organs and cells, and may be involved in the pathogenesis of pulmonary fibrosis. We demonstrated that ventilator-induced lung hyperextension stimulation in mice increased the expression of connective tissue growth factor (CTGF), a profibrotic cytokine, in lung tissue. Increased CTGF expression induced by cyclic mechanical stretch (CMS) was also observed in vitro using A549 human alveolar epithelial cells. Pathway analysis revealed that the induction of CTGF expression by CMS involved MEK phosphorylation. Furthermore, early growth response 1 (Egr-1) was identified as a transcription factor associated with CTGF expression. Finally, the antifibrotic drug pirfenidone significantly reduced CTGF expression, MEK phosphorylation, and Egr-1 levels induced by CMS. Thus, our results demonstrated that profibrotic cytokine CTGF induced by CMS may be a therapeutic target of pirfenidone.

DOI： 10.1016/j.resp.2023.104142

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BACKGROUND: Idiopathic interstitial pneumonias are an independent risk factor of lung cancer, and a chemotherapy-induced acute exacerbation is the most common lethal complication in Japanese patients. The safety and efficacy of carboplatin and weekly paclitaxel for the treatment of non-small cell lung cancer with idiopathic interstitial pneumonias has been previously reported in prospective studies. However, carboplatin + paclitaxel with bevacizumab is currently the standard therapy. We conducted a multicenter, phase II study to confirm the safety and efficacy of carboplatin + weekly paclitaxel + bevacizumab for the treatment of patients with lung cancer complicated by idiopathic interstitial pneumonias. METHODS: Chemotherapy-naïve patients with advanced-stage or patients with post-operative recurrent non-squamous non-small cell lung cancer complicated by idiopathic interstitial pneumonias were enrolled. Patients received carboplatin (area under the curve: 5.0) and bevacizumab (15 mg/kg) on day 1 and paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 4-week cycle. RESULTS: Seventeen patients less than the predetermined number were enrolled and received a median of four treatment cycles (range: 1-6). One patient (5.9%; 95% confidence interval: 0.1-28.7%) had acute exacerbation of interstitial pneumonia related to the study treatment which improved after corticosteroid treatment. The overall response rate was 52.9%. The median progression-free survival, median survival time, and 1-year survival were 5.7 months, 12.9 months, and 52.9%, respectively. CONCLUSION: The addition of bevacizumab to carboplatin and weekly paclitaxel might be safe and effective for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000008189.

DOI： 10.1016/j.resinv.2023.06.002

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INTRODUCTION: In the CAPITAL study, a randomized phase 3 study, wherein carboplatin plus nab-paclitaxel treatment was compared with docetaxel treatment for older patients with squamous-cell lung cancer, the former became the new standard of care for such patients. Our study aimed to evaluate whether the efficacy of second-line immune checkpoint inhibitors (ICIs) affected the primary analysis of overall survival (OS). METHODS: Herein, we performed a post hoc analysis of the impact of second-line ICIs on OS, safety in each group of participants aged more than 75 years, and intracycle nab-paclitaxel skip status. RESULTS: Patients were randomly allocated to the carboplatin plus nab-paclitaxel (nab-PC) arm (n = 95) or the docetaxel (D) arm (n = 95). Of these patients, 74 of 190 (38.9%) were transferred to ICIs for second-line treatment (nab-PC arm: 36, D arm: 38). A survival benefit was numerically observed only for patients for whom first-line therapy was terminated owing to disease progression (median OS [nab-PC arm]: with and without ICIs, 321 and 142 d, respectively; median OS [D arm]: with and without ICIs, 311 and 256 d, respectively). The OS among patients who received ICI after adverse events was similar in the two arms. In the D arm, a significantly higher frequency of grade greater than or equal to 3 adverse events was observed among patients aged more than or equal to 75 years (86.2%) than among those aged less than 75 years (65.6%, p = 0.041), including a significantly higher frequency of neutropenia (84.6% versus 62.5%, p = 0.032); no such differences were observed in the nab-PC arm. CONCLUSIONS: We found that second-line ICI treatment seemed to have a little impact on OS.

DOI： 10.1016/j.jtocrr.2023.100514

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Soluble interleukin-2 receptor (sIL-2R) suppresses effector T-cells. Few studies have assessed serum sIL-2R in patients receiving immunotherapy. We evaluated the association between serum sIL-2R levels and the efficacy of anti-programmed cell death 1/ programmed death-ligand 1 (anti-PD-1/PD-L1) antibody combined with chemotherapy in non-small cell lung cancer (NSCLC) patients. We prospectively enrolled NSCLC patients who received anti-PD-1/PD-L1 antibody combined with platinum-based chemotherapy between 8/2019 and 8/2020 and measured their serum sIL-2R. The patients were divided into high and low sIL-2R groups based on the median of sIL-2R levels at pretreatment. Progression-free survival (PFS) and overall survival (OS) of patients in the high and low sIL-2R groups were compared. The Kaplan-Meier curves of PFS and OS were evaluated using the log-rank test. The multivariate analysis of PFS and OS was performed using the Cox proportional hazard models. Among 54 patients (median age 65, range 34-84), 39 were male and 43 had non-squamous cell carcinoma. The sIL-2R cut-off value was 533 U/mL. Median PFS was 5.1 months (95% CI, 1.8-7.5 months) and 10.1 months (95% CI, 8.3-not reached [NR] months) in the high and low sIL-2R groups (P = 0.007), respectively. Median OS was 10.3 months (95% CI, 4.0-NR months) and NR (95% CI, 10.3-NR months) in the high and low sIL-2R groups (P = 0.005), respectively. Multivariate Cox regression analysis showed that high sIL-2R was significantly associated with shorter PFS and OS. SIL-2R may be a biomarker for the poor efficacy of anti-PD-1/PD-L1 antibody combined with chemotherapy.

DOI： 10.1007/s10637-023-01358-3

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Publisher：金原出版  

DOI： 10.18888/hi.0000003807

CiNii Research

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INTRODUCTION: The efficacy and safety of atezolizumab in previously treated patients with NSCLC have been established in the registrational phase 3 OAK trial. In this study, we evaluated the effectiveness and safety of atezolizumab monotherapy in a large real-world cohort to confirm the reproducibility of the results of the registrational trial. METHODS: This was a multicenter, prospective, single-arm observational study. Consecutive patients with previously treated NSCLC scheduled to receive atezolizumab monotherapy were enrolled. The primary end point was the 18-month overall survival (OS) rate. The incidence of adverse events (AEs) and immune-related AEs was evaluated. RESULTS: Overall, 1002 patients were included in the safety analysis set and 1000 in the full analysis set. Median follow-up was 11.5 months. Of the full analysis set, 62% were ineligible for the OAK trial (OAK-unlike subpopulation). The 18-month OS rate was 41.1%, with a median OS of 13.0 months (95% confidence interval: 12.2-15.1). The 18-month OS rate was 49.4% and 36.1% in OAK-like and OAK-unlike subpopulations, respectively; that in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2 was 14.3%. The incidence of AEs overall, in the OAK-like, and OAK-unlike subpopulations was 43.9%, 46.2%, and 42.5%; that of immune-related AEs was 19.0%, 20.1%, and 18.3%, respectively. CONCLUSIONS: The findings suggest that atezolizumab may be effective and safe for previously treated patients with NSCLC in real-world settings; however, atezolizumab administration should be considered carefully regarding the benefit-risk balance for the OAK-unlike subpopulation, especially in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2.

DOI： 10.1016/j.jtocrr.2023.100484

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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BACKGROUND: Nab-paclitaxel (nab-PTX) has better transfer to tumor tissue than cremophor-based paclitaxel. It suggests that the optimum dose of nab-PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab-PTX in patients with previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomly allocated (1:1) to receive nab-PTX monotherapy at 100 mg/m2 (group A) or 70 mg/m2 (group B). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. CONCLUSION: Both standard dose and low dose of nab-PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab-PTX 70 mg/m2 dose and schedule in the trial would be a reasonable option.

DOI： 10.1002/cam4.5652

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BACKGROUND: Versatile biomarkers for immune checkpoint inhibitors (ICI) efficacy in patients with cancer remain to be identified. Liquid biopsy using serum-derived exosomal microRNAs (miRNAs) are widely investigated as diagnostic and therapeutic outcome predictors in patients with cancer. However, exosomal miRNAs linked to the response to ICI in patients with non-small cell lung cancer (NSCLC) remain elusive thus far. METHODS: The value of serum-derived exosomal miRNAs in predicting the effect of anti-programmed cell death-1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) monotherapy in 41 patients with advanced NSCLC was assessed. We performed functional analysis of candidate miRNAs using NSCLC cell lines. RESULTS: Exosomal miR-125a-3p was associated with response to treatment with ICI. Exosomal miR-125a-3p was more useful in predicting response to ICI versus tumoral PD-L1 in patients with low PD-L1 expression (≤50%). Moreover, high expression of miR-125a-3p was associated with worse progression-free and overall survival. In H1975 and H441 cells, induction of miR-125a-3p regulated PD-L1 expression via suppression of neuregulin 1 (NRG1). CONCLUSIONS: Exosomal miR-125a-3p is a potential predictor of response to anti-PD-1/PD-L1 therapy in advanced NSCLC patients with low PD-L1 expression.

DOI： 10.1016/j.gene.2023.147177

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Sarcoidosis is a multisystem disease with an unknown etiology and is characterized by the formation of noncaseating granulomas in the affected organs. We present the case of a 69-year-old male Japanese patient with bilateral hilar lymphadenopathy on chest radiographs for more than 10 years, left without further investigation. The patient reported no clinical symptoms. Chest computed tomography revealed ground-glass opacities and reticular shadows in both lungs, along with bilateral hilar and mediastinal lymphadenopathy. Lymphocytosis was observed in bronchoalveolar lavage fluid. Pathological examination of transbronchial lung biopsy revealed noncaseating, epithelioid granulomas congruous with sarcoidosis, together with other findings. There were no abnormalities on electrocardiogram, echocardiogram, and ophthalmic examination.For progressive dyspnea on exertion, systemic corticosteroid therapy with oral prednisolone (25 mg/day) was initiated in 2017 and gradually tapered. Despite this intervention, the decline in forced vital capacity (FVC) was accelerated. Three years later, the patient noticed swelling in his right wrist. Further investigation revealed elevated anti-cyclic citrullinated peptide antibodies and absence of noncaseating epithelioid granuloma on surgical biopsy, leading to the diagnosis of rheumatoid arthritis (RA). Thereafter, the anti-fibrotic agent nintedanib was initiated, because interstitial lung disease (ILD) was considered to have converted into a progressive fibrosing phenotype (PF-ILD) with overlapping RA-associated lung involvement. With treatment, the progression of decline in FVC was slowed, although home oxygen therapy was introduced.

DOI： 10.1177/17534666231158279

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Objective. Although data accumulated in clinical trials have higher accuracy compared to real-world data and are irreplaceably valuable, most previous clinical trial data have been left unutilized. Methods. The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced non-small cell lung cancer (NSCLC) to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. Results. Eight trials, JCOG9812, JCOG 0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30-93) years; sex (male/female) 1064/224; histological type (squamous cell carcinoma/adenocarcinoma/other NSCLC/unknown) 517/629/138/4; and stage IIIA/B, 536/752. The median overall survival was 24.6 months, with 2-, 5-, and 10-year survival rates of 51.1%, 22.5%, and 13.8%, respectively, in all enrollments. The median progression-free survival (PFS) was 9.5 months, with 2-, 5-, and 10-year PFS rates of 22.4%, 13.0%, and 9.1%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database. Conclusion. The integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.

DOI： 10.2482/haigan.63.161

Scopus

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Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017. Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS. Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status (p < 0.0001), histology (p = 0.0118), previous chemotherapy (p = 0.0007), programmed death-ligand 1 expression status (p = 0.0195), and previous steroid use (p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported. Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab.

DOI： 10.1016/j.jtocrr.2022.100404

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：The Japan Lung Cancer Society  

Background. The frequency of pseudo-progression caused by immune-checkpoint inhibitors in non-small cell lung cancer (NSCLC) is approximately 5%. Thus far, most reports of pseudo-progression in NSCLC have been due to immune-checkpoint inhibitor monotherapy. We report a case of pseudo-progression-like pleurisy after combined treatment with nivolumab and ipilimumab for lung adenocarcinoma. Case. A 70-year-old man with adenocarcinoma (pT3N0M1a, stage IVA) with pleural dissemination received combination therapy consisting of carboplatin, pemetrexed, nivolumab, and ipilimumab as first-line treatment. After treatment, he had fever, dyspnea, elevated CRP, and developed pleural effusion on the affected side. Thoracic drainage was subsequently performed. Abundant T lymphocytes with predominant CD4-positive cells infiltration were observed in pleural fluid cell-block specimens. Afterwards, his symptoms improved. No further accumulation of pleural effusion was observed, even though he continued receiving chemotherapy. Hence, he was diagnosed with pseudo-progression rather than an immune-related adverse event (irAE). Conclusion. This is the first report of pseudo-progression-like pleurisy in a lung cancer patient after combined nivolumab and ipilimumab treatment. It is important to distinguish pseudo-progression from irAE-induced pleurisy.

DOI： 10.2482/haigan.62.400

CiNii Research

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Language：English   Publishing type：Research paper (scientific journal)  

Among the various histopathological patterns of drug-induced interstitial lung disease (DILD), diffuse alveolar damage (DAD) is associated with poor prognosis. However, there is no reliable biomarker for its accurate diagnosis. Here, we show stratifin/14-3-3σ (SFN) as a biomarker candidate found in a proteomic analysis. The study includes two independent cohorts (including totally 26 patients with DAD) and controls (total 432 samples). SFN is specifically elevated in DILD patients with DAD, and is superior to the known biomarkers, KL-6 and SP-D, in discrimination of DILD patients with DAD from patients with other DILD patterns or other lung diseases. SFN is also increased in serum from patients with idiopathic DAD, and in lung tissues and bronchoalveolar lavage fluid of patients with DAD. In vitro analysis using cultured lung epithelial cells suggests that extracellular release of SFN occurs via p53-dependent apoptosis. We conclude that serum SFN is a promising biomarker for DAD diagnosis.

DOI： 10.1038/s41467-022-33160-9

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper (scientific journal)  

RATIONALE: Black pleural effusion is a rare medical condition and a diagnostic marker. Pancreaticopleural fistula is one of the causes of black pleural effusion. Thus far, black pleural effusions caused by pancreaticopleural fistulae have mostly been reported in patients with alcohol-induced chronic pancreatitis. In this report, we present a case of black pleural effusion caused by a pancreaticopleural fistula associated with autoimmune pancreatitis. PATIENT CONCERNS AND DIAGNOSIS: A 59-year-old female without a history of alcohol drinking presented to our hospital with a chief complaint of dyspnea, as well as chest and back discomfort. She had left pleural effusion, and thoracentesis showed black pleural effusion. Computed tomography revealed the presence of encapsulated fluid from the pancreatic tail to the left pleural cavity, which was diagnosed as a pancreaticopleural fistula. It also showed diffuse pancreatic swelling. Serum testing showed a high IgG4 level (363 mg/dL). These findings led to the diagnosis of autoimmune pancreatitis. INTERVENTIONS AND OUTCOME: The patient underwent endoscopic pancreatic sphincterotomy and pancreatic duct stent placement and received treatment with steroids. After treatment, there was no further accumulation of pleural effusion observed. CONCLUSION: This is the first report of black pleural effusion due to a pancreaticopleural fistula associated with autoimmune pancreatitis. The characteristic appearance of black pleural effusion may assist diagnosis. We report this case to emphasize that autoimmune pancreatitis can be a cause of black pleural effusion.

DOI： 10.1097/MD.0000000000030322

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Language：Japanese   Publisher：The Japan Lung Cancer Society  

Background. Fulminant type 1 diabetes mellitus caused by immune checkpoint inhibitors is a rare adverse event. In lung cancer, several cases have been reported in non-small-cell lung cancer. We herein report a patient with small-cell lung cancer who developed fulminant type 1 diabetes mellitus after administration of durvalumab. Case. A 71-year-old man with extensive-stage small-cell lung cancer (cT4N3M1b, stage IVA) with no history of diabetes mellitus received combination therapy of carboplatin, etoposide, and durvalumab on May 20XX. He became aware of anorexia and fatigue on day 27. He was diagnosed with fulminant type 1 diabetes mellitus caused by durvalumab with hyperglycemia of 761 mg/dl, positive urine ketones, and urinary C-peptide of 3.9 μg/day on the second course of treatment (day 30). After his blood glucose level had been stabilized with insulin therapy, an additional three cycles of chemotherapy with carboplatin and etoposide were administered. A significant response was achieved, and the patient survived without disease progression. Conclusion. Fulminant type 1 diabetes mellitus caused by durvalumab for small-cell lung cancer is a rare but urgent immune-related adverse event that requires attention.

DOI： 10.2482/haigan.62.323

CiNii Research

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

症例は23歳女性。シェーグレン症候群に対して免疫抑制薬を長期内服中であった。2ヵ月前から倦怠感、発熱、腰痛を認め、全身精査で肺野に活動性病変を認めず、全身リンパ節、骨、皮下、腹膜、腸管に多彩な病変を認めた。インターフェロンγ遊離試験(interferon gamma release assay:IGRA)は陰性であった。縦隔リンパ節生検から結核菌が培養され、播種性結核と診断した。免疫抑制宿主において、複数の病変を認める際は、IGRAが陰性で活動性肺病変を認めない場合でも、播種性結核を念頭におく必要がある。(著者抄録)

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

症例は23歳女性。シェーグレン症候群に対して免疫抑制薬を長期内服中であった。2ヵ月前から倦怠感、発熱、腰痛を認め、全身精査で肺野に活動性病変を認めず、全身リンパ節、骨、皮下、腹膜、腸管に多彩な病変を認めた。インターフェロンγ遊離試験(interferon gamma release assay:IGRA)は陰性であった。縦隔リンパ節生検から結核菌が培養され、播種性結核と診断した。免疫抑制宿主において、複数の病変を認める際は、IGRAが陰性で活動性肺病変を認めない場合でも、播種性結核を念頭におく必要がある。(著者抄録)

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Some of the most common causes of chronic cough include cough variant asthma (CVA), bronchial asthma (BA), and asthma-COPD overlap (ACO). Although there is some overlap in the etiology of these diseases, it is clinically important to attempt an early differential diagnosis due to treatment strategies and prognoses. Spirometry and impulse oscillometry (IOS) before and after bronchodilator inhalation were analyzed for clinically diagnosed CVA (cCVA, n = 203), BA (cBA, n = 222), and ACO (cACO, n = 61).A significant difference in ΔFEV1 was observed between cBA and cCVA (ΔFEV1 improvement of 122.5 mL/5.4% and 65.7mL/2.2%, respectively), but no difference was observed in ΔPEF, ΔV50, or ΔV25. Except for R20 (resistance at 20 Hz), significant differences between the three groups were observed in IOS. In IOS, cCVA and cBA showed comparable peripheral airway response to bronchodilator which was thought to be commensurate with changes in V50 and V25. cACO improved ΔFEV1 improvement of 81.0 mL/6.2% and was distinguished by a downward Xrs (respiratory system reactance) waveform with a limited bronchodilator response. FEV1/FVC, %FEV1, and %V25 had relatively strong correlations with the three IOS parameters, X5 (reactance at 5 Hz), Fres (resonant frequency), and ALX (low-frequency reactance area), in the correlation between IOS and spirometers.Changes in IOS parameters were more sensitive in this study than changes in FEV1 or the flow-volume curve. Considering the benefits and relevance of the two different tests, simultaneous IOS and spirometry testing were useful in the diagnosis of asthmatic cough.

DOI： 10.1080/02770903.2022.2094803

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BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive disease with a poor prognosis. Although most patients initially respond to topoisomerase inhibitors, resistance rapidly emerges. The aim, therefore, is to overcome resistance to topoisomerase I (irinotecan) or II (etoposide) inhibitors in SCLCs. METHODS: To identify key factors in the chemoresistance of SCLCs, we established four cell lines resistant to etoposide or an active metabolite of irinotecan, SN-38, from SCLC cell lines and evaluated RNA profiles using parental and newly established cell lines. RESULTS: We found that the drug efflux protein, ATP-binding cassette sub-family B member 1 (ABCB1), was associated with resistance to etoposide, and ATP-binding cassette sub-family G member 2 (ABCG2) was associated with resistance to SN-38 by RNA sequencing. The inhibition of ABCB1 or ABCG2 in each resistant cell line induced synergistic apoptotic activity and promoted drug sensitivity in resistant SCLC cells. The ABC transporter inhibitors, elacridar and tariquidar, restored sensitivity to etoposide or SN-38 in in vitro and in vivo studies, and promoted apoptotic activity and G2-M arrest in resistant SCLC cells. CONCLUSIONS: ABC transporter inhibitors may be a promising therapeutic strategy for the purpose of overcoming resistance to topoisomerase inhibitors in patients with SCLC.

DOI： 10.1111/1759-7714.14527

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：東邦大学医学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：東邦大学医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We conducted a post-marketing surveillance study to evaluate the clinical tolerability and safety of atezolizumab in Japanese patients with non-small-cell lung cancer (NSCLC). METHODS: This prospective, observational post-marketing cohort study was conducted in NSCLC patients who received atezolizumab 1200 mg every 3 weeks at 770 facilities in Japan between April 18, 2018, and March 31, 2020 (study number UMIN000031978). Case report forms were completed, recording patient characteristics, treatment details, adverse events, adverse drug reactions (ADRs), their severity, onset and outcomes. Follow-up was for 12 months or until atezolizumab discontinuation. RESULTS: Overall, 2570 patients were included, median age was 69.0 years, and 69.9% were males. ADRs were reported in 29.1% of patients, most commonly pyrexia (4.2%). Grade ≥ 3 ADRs occurred in 9.7% of patients aged <75 and 9.7% of those aged ≥75 years. The incidence of Grade ≥ 3 ADRs was not affected by the number of lines of previous treatment or the presence or history of an autoimmune disorder. Immune-related ADRs of interest that occurred in >1% of patients were interstitial lung disease (ILD; 4.4%), endocrine disorder (4.3%), and hepatic dysfunction (2.8%). ILD was significantly more common in patients with a history of, or concurrent, ILD versus those without (P ≤ 0.001). Risk factors of Grade ≥ 3 ADRs were a history of, or concurrent, ILD. Grade 5 ADRs occurred in 35 patients, 11 of whom had concurrent ILD. CONCLUSIONS: This large cohort study confirmed the clinical tolerability of atezolizumab in a real-world group of Japanese patients with NSCLC.

DOI： 10.1093/jjco/hyac024

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Following COVID-19 vaccination, ipsilateral axillary and cervical lymphadenopathy may occur, called vaccine-related hypermetabolic lymphadenopathy, which is considered reactive lymphadenopathy. We report here a case of Kikuchi-Fujimoto disease, which occurred three months after vaccination with COVID-19 vaccine. The patient had cervical and axillary lymph node enlargement and a short-term fever that resolved spontaneously after the first and second vaccines. On the 90th day after the first vaccination, the patient developed a high fever and pathologically diagnosed necrotizing lymphadenitis in the axilla, which was diagnosed as Kikuchi-Fujimoto disease. Gallium scintigraphy showed localized swelling and strong uptake in the ipsilateral axilla. It implies the possibility of Kikuchi-Fujimoto Disease in axillary drainage lymph nodes in association with COVID-19 vaccine. Although only a few cases have been reported so far, this case is novel because of its later onset and diagnosis based on pathological and gallium scintigraphy imaging findings.

DOI： 10.1080/21645515.2022.2071080

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BACKGROUND: Research has shown that some microbiomes are linked to cancer. Hence, we hypothesize that alterations in the respiratory microbiome might be associated with lung cancer. METHODS: Through droplet digital polymerase chain reaction analysis, we investigated the abundance of Acidovorax in surgically resected primary tumors and corresponding nontumor lung tissues obtained from 50 Japanese patients with non-small cell lung cancer. RESULTS: The rate of positivity for Acidovorax in tumor and nontumor tissues was 44 and 26%, respectively. The abundance of Acidovorax in tumor tissues was significantly higher in patients with nonsquamous cell carcinoma complicated by chronic obstructive pulmonary disease (COPD) and those who relapsed after surgical resection (p < 0.05). In tumor tissues, the results of the univariate and multivariate analyses revealed that only COPD exerted a direct effect on the abundance of Acidovorax (p < 0.05). Furthermore, the presence of Acidovorax was high in lung cancer patients with COPD comorbidity (65%) and TP53 gene mutation; only one of the nontumor tissues was positive for Acidovorax. In patients with lung cancer complicated by COPD, Acidovorax tended to be present in both the tumor and nontumor areas. CONCLUSIONS: This study identified novel microbiota involved in lung cancer with COPD comorbidity. The results suggested that Acidovorax may be a useful biomarker in the screening for lung cancer. Further studies are warranted to validate the clinical significance of the microbiome in a larger independent patient cohort.

DOI： 10.1111/1759-7714.14463

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Introduction: Although data accumulated in clinical trials have higher accuracy compared with real-world data and are irreplaceably valuable, most previous clinical trial data have been left unused. Methods: The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced NSCLC to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. Results: A total of eight trials, JCOG9812, JCOG0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30-93) years; sex (male/female) 1064/224; pathological type (squamous cell carcinoma, adenocarcinoma, other NSCLC, and unknown) 517, 629, 138, and 4; and stage IIIA and B, 536 and 752. The median overall survival was 26.0 months, with 2-, 5-, and 10-year survival rates of 53.7%, 24.8%, and 15.2%, respectively, in all enrollments. The median progression-free survival was 9.6 months, with 2-, 5-, and 10-year progression-free survival rates of 23.6%, 14.0%, and 9.4%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database. Conclusions: The integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.

DOI： 10.1016/j.jtocrr.2022.100317

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although corticosteroids are expected to be a candidate therapy for coronavirus disease 2019 (COVID-19) through the suppression of cytokine production, the efficacy in non-severe patients who do not require supplemental oxygen remains controversial. The aim of this study was to investigate the efficacy of corticosteroid therapy for non-severe patients. METHODS: We performed a retrospective observational study for 10 patients with non-severe COVID-19 who received corticosteroid therapy at our institute between July 1, 2020, and January 31, 2021. RESULTS: The median age of the 10 patients was 60 years, and nine patients were male. Nine of the 10 patients had multiple comorbid conditions (e.g., hypertension, diabetes and obesity). Although blood oxygen saturation was maintained above 95%, all patients showed persistent fever and deterioration of their chest imaging findings. Thus, we decided to initiate corticosteroid treatment. The median duration from the onset of symptoms to the initiation of corticosteroid therapy was eight days. All patients used dexamethasone (6 mg/day) as corticosteroid therapy, and the median period was 7.5 days. After the start of corticosteroid therapy, all patients showed a rapid clinical improvement, and no patients showed severe progression. CONCLUSION: The latest World Health Organization guidance recommends against corticosteroid treatment for non-severe patients. In this report, we showed that the early administration of corticosteroids during the non-critical phase, when oxygen supplementation is not required, was useful for the early improvement and prevention of severe disease in patients with risk factors for severe COVID-19 and worsening clinical symptoms.

DOI： 10.1272/jnms.JNMS.2022_89-409

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Superior mesenteric artery (SMA) syndrome is a rare disease, characterized by the narrowing of the third portion of the duodenum between the aorta and SMA. The cause of the stenosis is a decrease in retroperitoneal fat between the aorta and SMA. In this report, we present two cases of SMA syndrome that occurred during chemotherapy for lung cancer. The first case was a 61-year-old male treated with nanoparticle albumin-bound-paclitaxel (nab-PTX) for lung adenocarcinoma. On day 23 of the first course of nab-PTX, he was admitted to our hospital due to vomiting and weight loss of 15.6 kg in 10 months. He was diagnosed with SMA syndrome through computed tomography, and drainage was performed using a nasogastric tube. Conservative treatment was successful, and the patient was able to continue therapy with nab-PTX. The second case was a 70-year-old male with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. He was admitted to our hospital due to vomiting and dizziness while receiving treatment with pembrolizumab, as well as weight loss of 14.6 kg in 6 months. He was diagnosed with SMA syndrome using computed tomography. Conservative treatment using a nasogastric tube led to improvement, and the patient was able to continue treatment with pembrolizumab after discharge. This is the first report of SMA syndrome in patients with lung cancer undergoing chemotherapy with nab-PTX or pembrolizumab. Late diagnosis and treatment render SMA syndrome a potentially fatal disease. Vomiting and weight loss during chemotherapy are known treatment-related side effects; in patients developing these adverse effects, the presence of SMA syndrome should be suspected and managed appropriately.

DOI： 10.1007/s13691-022-00534-1

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Thymic carcinoma is a relatively rare type of malignant tumor. The present retrospective study evaluated the efficacy and safety of carboplatin plus nanoparticle albumin-bound paclitaxel for the treatment of advanced thymic carcinoma. The study included data from 12 patients with advanced thymic carcinoma treated in the Nippon Medical School Hospital (Tokyo, Japan). Response to treatment, patient survival and treatment safety were assessed. The objective response rate was 66.7% (8/12 patients). Disease control was achieved in 11 patients (91.7%). At the median follow-up time of 27.6 months (range, 6.2-75.1 months), the median progression-free survival and median first-line overall survival times were 16.7 months [95% confidence interval (CI), 13.2-37.7] and 14.3 months (95% CI, 4.7-54.6), respectively. There was no occurrence of febrile neutropenia or treatment-related death. The results of the present study showed that carboplatin plus nanoparticle albumin-bound paclitaxel was effective and safe. Therefore, it is a promising chemotherapy regimen for the treatment of advanced thymic carcinoma.

DOI： 10.3892/mco.2022.2520

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Although adjuvant tegafur/uracil (UFT) is recommended for patients with completely resected stage I non-small-cell lung cancer (NSCLC) in Japan, only one-third of cases has received adjuvant chemotherapy (ADJ) according to real-world data. Therefore, robust predictive biomarkers for selecting ADJ or observation (OBS) without ADJ are needed. Patients who underwent complete resection of stage I lung adenocarcinoma with or without adjuvant UFT were enrolled. The status of ACTN4 gene amplification was analyzed by FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were carried out. Formalin-fixed, paraffin-embedded samples from 1136 lung adenocarcinomas were submitted for analysis of ACTN4 gene amplification. Ninety-nine (8.9%) of 1114 cases were positive for ACTN4 gene amplification. In the subgroup analysis of patients aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009-0.806; P = .032). The difference in RFS between the ADJ group and the OBS group was not significant in ACTN4-negative cases (all ages: HR, 1.214; 95% CI, 0.848-1.738; P = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side-effects of ADJ, and saving medical costs.

DOI： 10.1111/cas.15228

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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BACKGROUND/AIM: Synergistic effects of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy have been reported. Here, we evaluated the therapeutic potential of combining osimertinib with pemetrexed and investigated the molecular mechanisms. MATERIALS AND METHODS: We analyzed the antitumor effects of osimertinib± pemetrexed in PC-9 and H1975 cells. Gene expression on exposure to osimertinib±pemetrexed was assessed in these cultured cells. Cell lines resistant to osimertinib±pemetrexed were established to explore mechanisms of resistance. RESULTS: Osimertinib+pemetrexed treatment delayed the emergence of resistance relative to monotherapy in vitro and in vivo. Expression of the anti-apoptotic gene PLK1 was down-regulated in PC-9 and H1975 exposed to osimertinib+ pemetrexed, whereas it was up-regulated in resistant cells. Furthermore, inhibition of PLK1 induced apoptosis and inhibited proliferation of resistant cells. CONCLUSION: Blocking PLK1 contributes to mediating the synergistic anti-proliferative effect of osimertinib+pemetrexed. PLK1 over-expression may be a critical mechanism for acquired resistance to osimertinib+pemetrexed.

DOI： 10.21873/anticanres.15529

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Pembrolizumab is an immune checkpoint inhibitor (ICI) that targets programmed death-1. Although ICIs have shown efficacy in the treatment of lung cancer, they have also been reported to cause a variety of immune-related adverse events (irAEs). Hepatotoxicity is a known irAEs, but currently, there is not enough information on its pathological characteristics and treatment. We report the case of a 70-year-old man with advanced squamous-cell lung cancer who developed severe grade 4 hepatitis on day 8 after receiving carboplatin, nab-paclitaxel, and pembrolizumab as fourth-line therapy. We treated him with steroid therapy the day after a liver biopsy was performed to investigate his pathological features, which led to a rapid and remarkable improvement. Confirmation of immune-related hepatotoxicity by pathological findings allowed the early tapering and discontinuation of steroid therapy. Performing a liver biopsy and verifying histological characteristics are needed for successful treatment with short-term steroids when drug-induced hepatitis caused by anti-cancer therapy including pembrolizumab is considered.

DOI： 10.2147/OTT.S361467

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A 59-year-old woman complaining of wet cough, hemoptysis, slight fever, anorexia, and malaise was admitted to hospital with suspected lobar pneumonia. She received treatment for myocardial infarction and deep venous thrombosis caused by familial protein C deficiency. Rapid deterioration due to respiratory failure occurred despite intensive care with broad-spectrum antibiotics. At a later date, sputum examination revealed the presence of Aspergillus niger. Based on clinical and autopsy findings, she was diagnosed with acute respiratory failure due to pulmonary aspergillosis with acute fibrinous and organizing pneumonia. This is the first reported case of pulmonary aspergillosis with acute fibrinous and organizing pneumonia complicated by calcium oxalate resulting from Aspergillus niger infection, leading to severe inflammation and tissue injury in the lungs.

DOI： 10.1016/j.rmcr.2022.101641

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Background: In Japan, docetaxel, a cytotoxic monotherapy, is the standard drug administered to older patients with advanced non-small-cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel has shown a high objective response rate in patients with squamous histology and was suggested to improve overall survival in patients aged 70 years and older. The CAPITAL trial aimed to assess the safety and efficacy of carboplatin plus nab-paclitaxel versus docetaxel as first-line therapy for patients aged 70 years and older with advanced squamous NSCLC. Methods: This multicentre, open-label, randomised, phase 3 trial was carried out at 92 medical institutions in Japan. Eligible patients were aged 70 years and older, had advanced squamous NSCLC with no previous systemic chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Using an electronic data capture system, patients were randomly assigned (1:1) to intravenous carboplatin (area under the concentration-time curve of 6 mg/mL per min for 30 min) on day 1 of a 21-day cycle and intravenous nab-paclitaxel (100 mg/m2 for 60 min) on days 1, 8, and 15 every 3 weeks or intravenous docetaxel (60 mg/m2 for 60 min) on day 1 every 3 weeks. Randomisation was computer-generated per participant and stratified by ECOG performance status, clinical stage, sex, age, and institution. The primary endpoint was overall survival, measured in the full analysis set and defined as the time from registration to the date of death due to any cause. Safety was assessed in all patients who received at least one dose of the trial treatment. This trial is registered with the UMIN Clinical Trials Registry, UMIN000019843, and the Japan Registry of Clinical Trials, jRCTs041180110. After the planned interim analysis in Aug 3, 2020, the independent data monitoring committee recommended that the trial be stopped early. This report represents the final analysis. Findings: Between Feb 24, 2016, and Aug 11, 2020, 196 patients were enrolled and were randomly assigned to the carboplatin plus nab-paclitaxel group (n=98) or the docetaxel group (n=98). Of these patients, four (carboplatin plus nab-paclitaxel group, n=3; docetaxel group, n=1) did not receive any treatment and two patients in the docetaxel group were excluded from the full analysis set. Median overall survival in the full analysis set was 16·9 months (95% CI 12·6–25·4) in the carboplatin plus nab-paclitaxel group and 10·9 months (8·5–12·4) in the docetaxel group (hazard ratio 0·52 [90% CI 0·38–0·70]; p=0·0003). Grade 3–4 adverse events occurred in 79 (83%) patients in the carboplatin plus nab-paclitaxel group and 77 (79%) patients in the docetaxel group (p=0·63). The most common grade 3–4 adverse events in the carboplatin plus nab-paclitaxel group and the docetaxel group were leukopenia (44 [46%] vs 55 [57%]; p=0·20), neutropenia (60 [63%] vs 75 [77%]; p=0·046), febrile neutropenia (nine [10%] vs 19 [20%]; p=0·073), and anaemia (37 [39%] vs two [2%]; p<0·0001). Serious treatment-related adverse events of all grades occurred in 13 (14%) patients in the carboplatin plus nab-paclitaxel group and 11 (11%) patients in the docetaxel group. Treatment-related deaths occurred in two (2%; respiratory failure n=1, visceral arterial ischaemia n=1) patients in the carboplatin plus nab-paclitaxel group and one (1%; sepsis) patient in the docetaxel group. Interpretation: Our study showed that overall survival was longer with carboplatin plus nab-paclitaxel than with docetaxel, suggesting that carboplatin plus nab-paclitaxel can be used as standard first-line treatment for patients aged 70 years and older with advanced squamous NSCLC. Funding: Taiho Pharmaceutical.

DOI： 10.1016/S2666-7568(21)00255-5

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Introduction: To investigate the genomic profiles of patients with lung cancer with idiopathic pulmonary fibrosis (IPF-LC), mechanism of carcinogenesis, and potential therapeutic targets. Methods: We analyzed 29 matched, surgically resected, cancerous and noncancerous lung tissues (19 IPF-LC and 10 non-IPF-LC) by whole-exome sequencing and bioinformatics analysis and established a medical-engineering collaboration with the Department of Engineering of the Tokyo University of Science. Results: In IPF-LC, CADM1 and SPC25 were mutated at a frequency of 47% (9 of 19) and 53% (10 of 19), respectively. Approximately one-third of the IPF-LC cases (7 of 19; 36%) had both mutations. Pathway analysis revealed that these two genes are involved in transforming growth factor-β1 signaling. CADM1 and SPC25 gene mutations decreased the expression of CADM1 and increased that of SPC25 revealing transforming growth factor-β1-induced epithelial-to-mesenchymal transition and cell proliferation in lung cancer cells. Furthermore, treatment with paclitaxel and DNMT1 inhibitor suppressed SPC25 expression. Conclusions: CADM1 and SPC25 gene mutations may be novel diagnostic markers and therapeutic targets for IPF-LC.

DOI： 10.1016/j.jtocrr.2021.100232

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Postmarketing surveillance of Japanese patients with unresectable, previously treated, advanced or recurrent non-small-cell lung cancer treated with nivolumab was undertaken during the conditional approval period. The study aim was to evaluate the occurrence of treatment-related adverse events of nivolumab in the real world. Patients were registered between December 2015 and March 2016 at 536 sites. Nivolumab was given intravenously (3 mg/kg every 2 weeks); the observation period was 12 months after the first dose of nivolumab. Patients were evaluated for safety (n = 3601; 18.2% ≥75 years, 22.4% ECOG performance status ≥2) and effectiveness (n = 3570). The frequencies of any grade and grade 3 or higher treatment-related adverse events were 47.1% and 15.9%, respectively. The most frequent treatment-related adverse events (any grade) were interstitial lung disease (6.4%), hypothyroidism (5.7%), and diarrhea (4.4%). Treatment-related adverse events of special interest (priority items) occurring at a frequency of 5% or more were adverse events related to interstitial lung disease, thyroid dysfunction, liver dysfunction, colitis/severe diarrhea, infusion reaction, and infusion reaction within 24 hours. Significant risk factors for these priority items were identified by competing risk analysis: interstitial lung disease (previous/comorbid interstitial lung disease, abnormal findings on chest imaging, and smoking history); liver dysfunction (previous/comorbid liver disease, smoking history, and metastasis); thyroid dysfunction (previous/comorbid thyroid disease and performance status); and colitis/severe diarrhea (treatment line 2 vs ≥3). The 12-month survival rate was 40.7%. In conclusion, the safety profile of nivolumab in this postmarketing surveillance was similar to that in clinical trials, and no new safety signals were identified. The study was registered with the Japan Pharmaceutical Information Center (clinicaltrials.jp: Japic-163271).

DOI： 10.1111/cas.15117

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Background The role of inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) is unclear. Hence, this study aimed to evaluate the efficacy of ICS as an add-on to long-acting muscarinic antagonist (LAMA)/long-acting beta 2 agonist (LABA), which was assessed using the impulse oscillation system (IOS), in patients with COPD. Methodology We included patients with COPD whose treatment was changed from LAMA/LABA (≥four weeks) to ICS/LAMA/LABA between April 2019 and March 2021. To gain insight into the effect and safety of ICS-containing triple therapy for COPD, pulmonary function; Short-Form 36, St. George's Respiratory Questionnaire, COPD Assessment Test, and modified Medical Research Council scores; and airway resistance assessed using the IOS from one week before LAMA/LABA was switched to ICS/LAMA/LABA therapy until more than eight but less than twelve weeks after switching were evaluated. Results In total, 46 patients with COPD (mean age: 72.28 ± 7.81 years) were included in the study. None of the pulmonary function test parameters significantly changed from baseline values (mean difference in forced expiratory volume in one second [FEV1.0]: +0.032, P = 0.12; percentage FEV1.0 [FEV1.0%]/forced vital capacity [FVC]: -0.58, P = 0.42; and FVC: +0.087, P = 0.058). Meanwhile, the IOS showed that resonant frequency (mean difference from baseline: -2.12, P < 0.0001) and bodily pain scores in the St. George's Respiratory Questionnaire (mean difference: -7.03, P = 0.031) significantly decreased. Conclusions Switching from LAMA/LABA to ICS/LAMA/LABA therapy reduces airway elasticity-to-inertial resistance ratios, which may lead to structural airway improvements in patients with COPD.

DOI： 10.7759/cureus.19168

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.annonc.2021.08.1934

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Combination therapy, consisting of immune checkpoint inhibitors and traditional chemotherapeutic agents, has significantly improved the clinical outcomes of non-small cell lung cancer. Therefore, it will be a promising first-line therapy, whereas, there is a prospect that associated kidney injury may increase during treatment. We presented four patients, diagnosed with advanced non-small cell lung cancer, who received combination therapy, consisting of pembrolizumab, cisplatin, and pemetrexed as first-line treatment. All of them had been referred to nephrologists and had undergone renal biopsy. We observed that three of four patients presented a very rapid time course for acute kidney injury development. Notably, the three patients received only one or two cycles of the combined chemotherapy. In a renal biopsy, one patient showed severe acute tubular injury rather than interstitial nephritis. Another patient presented focal segmental glomerular sclerosis concomitant with tubulointerstitial nephritis. However, it was challenging to distinguish which agent was primarily responsible for kidney injury. Regarding the treatment, all the patients discontinued pembrolizumab and received corticosteroid treatment. We adjusted the dose and duration of corticosteroid according to the pathological results and patient conditions. The current cases provide a further understanding of clinical features and appropriate management in patients treated with combination therapy including pembrolizumab.

DOI： 10.1007/s13730-021-00636-4

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Background: Immune-checkpoint inhibitors (ICIs) have been increasingly used for non-small cell lung cancer (NSCLC) treatment in recent years. Although insufficient, the rate of programmed death-ligand 1 expression has been adopted as a predictor of ICI efficacy. We evaluated tumor growth rate as a clinically easy-to-use predictor of the therapeutic effect of ICIs. Methods: This study is a single-institution retrospective study in Japan. NSCLC patients treated with nivolumab, pembrolizumab, or atezolizumab at Saitama Medical Center from January 1, 2016 to December 31, 2018 were enrolled, and followed until December 31, 2020. We defined and calculated the initial rapidity of tumor progression (IRP) as: the increase in the sum of the diameters of intrathoracic tumors and lymph nodes on two series of chest computed tomography (CT) scans (one obtained at an initial checkup and the other obtained immediately before the first treatment) divided by the number of days between these CT scans. Two coefficients were calculated: the maximal information coefficient (MIC) between IRP and time to treatment failure (TTF) using the Python package with minepy library, and the Spearman's rank correlation coefficient. Results: A total of 55 patients (median age, 70 years; 47 men) were enrolled. The median TTF with ICIs was 126 days, and four patients continued to receive ICI treatment at the end of the follow-up. The MIC between IRP and TTF was 0.302 with weak correlation, and the Spearman's rank correlation coefficient was -0.347 (P=0.00938). Conclusions: The initial tumor growth rate had a negative linear correlation with the therapeutic effect of ICIs.

DOI： 10.21037/jtd-21-774

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BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the mechanisms of acquired drug resistance to osimertinib have not as yet been clarified. Exosomes and microRNAs (miRNAs) are involved in carcinogenesis and drug resistance in human cancers. METHODS: We used previously established osimertinib-resistant HCC827 (HCC827-OR) and PC-9 (PC-9-OR) cells. We evaluated the profiles of exosomal miRNA associated with resistance to osimertinib in EGFR-mutant NSCLC cells. RESULTS: Epithelial-mesenchymal transition (EMT) phenomenon was observed in HCC827-OR and PC-9-OR cells. Microarray and quantitative reverse transcription-polymerase chain reaction analysis revealed that miR-210-3p was co-upregulated in exosomes isolated from HCC827-OR and PC-9-OR cells compared with those isolated from parental HCC827 and PC-9 cells. HCC827-OR cell-derived exosomes induced EMT changes and resistance to osimertinib in HCC827 cells. Subsequently, the induction of miR-210-3p directly promoted the EMT phenomenon and resistance to osimertinib in HCC827 cells. CONCLUSIONS: Exosomal miR-210-3p may play a crucial role in resistance to osimertinib in the tumor microenvironment of EGFR-mutant NSCLC.

DOI： 10.1111/1759-7714.13943

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INTRODUCTION: MET exon 14 skipping mutation, observed in 3-4% of non-small cell lung cancer (NSCLC), is emerging as a targetable alteration. In recent years, immune checkpoint inhibitors (ICI) have been effective in treating several NSCLCs. Our research aimed to investigate the characteristics of patients with NSCLCs harboring MET exon 14 mutations and their response to ICI in Japan. METHODS: Among the 1954 consecutive NSCLCs diagnosed at Saitama Cancer Center between 2010 and 2019, MET exon 14 skipping mutations were detected in 68 (3.5%) NSCLCs. We evaluated their characteristics such as programmed cell death ligand 1 (PD-L1) expression. RESULTS: Median age of patients with NSCLCs harboring MET exon 14 skipping mutations was 73 years. PD-L1 was highly expressed in 17 (70.8%) of the 24 patients examined. Seven patients received ICI monotherapy, and three out of seven had a remarkable treatment response, resulted in objective response rate (ORR) of 42.9% and progression-free survival of 24.7 months. Three patients with donor splice-site mutations showed a long-term treatment response, despite the fact that two with acceptor splice-site mutations demonstrated no response and experienced early disease progression with ICI monotherapy. CONCLUSION: Our results indicated that patients with NSCLCs harboring MET exon 14 mutations presented with a high rate of positive PD-L1 expression. ICI treatment showed a high ORR and long-term efficacy for NSCLCs harboring MET exon 14 mutations. Variants of MET exon 14 splice-site mutations may be associated with ICI response.

DOI： 10.1007/s10147-021-01893-0

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BACKGROUND/AIM: Pulmonary pleomorphic carcinoma (PPC) is a rare and aggressive tumor that is resistant to treatment. The expression and prognostic value of programmed cell death-ligand 1 (PD-L1) and its association with epithelial-mesenchymal transition (EMT) in PPC remains unclear. PATIENTS AND METHODS: The expression of PD-L1 and EMT markers, such as E-cadherin, vimentin, zinc finger E-box-binding homeobox 1 (ZEB-1), and cellular mesenchymal-epithelial transition (c-Met) was evaluated by immuno - histochemistry in 16 patients with PPC who underwent surgical resection. RESULTS: The expression of PD-L1 varied between carcinomatous and sarcomatous areas. Positive correlations between PD-L1 and vimentin expression in carcinomatous areas (r=0.668, p=0.005) and PD-L1 and ZEB-1 expression in sarcomatous areas (r=0.562, p=0.023) were found. High PD-L1 and ZEB-1 expression in sarcomatous areas predicted poor survival (p=0.045 and p=0.012, respectively). CONCLUSION: PD-L1 expression associated with ZEB1 expression in the sarcomatoid component of patients with PPC may be useful for predicting patient prognosis.

DOI： 10.21873/anticanres.15028

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(1) Background: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable problem for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR-mutated lung cancer remains largely unknown. (2) Methods: Osimertinib- and afatinib-resistant EGFR-mutated lung cancer cells were established using a stepwise method. A microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells and evaluated by bioinformatics analysis through medical-industrial collaboration. (3) Results: Colorectal neoplasia differentially expressed (CRNDE) and DiGeorge syndrome critical region gene 5 (DGCR5) lncRNAs were highly expressed in EGFR-TKI-resistant cells by microarray analysis. RNA-protein binding analysis revealed eukaryotic translation initiation factor 4A3 (eIF4A3) bound in an overlapping manner to CRNDE and DGCR5. The CRNDE downregulates the expression of eIF4A3, mucin 1 (MUC1), and phospho-EGFR. Inhibition of CRNDE activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity, and restored sensitivity to EGFR-TKIs. (4) Conclusions: The results showed that CRNDE is associated with the development of resistance to EGFR-TKIs. CRNDE may be a novel therapeutic target to conquer EGFR-mutant NSCLC.

DOI： 10.3390/ijms22084005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background/Aim: The Renin?Angiotensin system (RAS) induces immunosuppression in the tumor microenvironment, and RAS inhibitors (RASi) improve the tumor immune microenvironment. We evaluated the impact of RASi on the efficacy anti-programmed cell death1/Ligand-1 (anti-PD-1/PD-L1) antibodies. Patients and Methods: This retrospective study analyzed non-small cell lung cancer (NSCLC) patients who received anti-PD-1/PDL1 antibodies monotherapy as second-or later-line treatment. We classified patients into those with or without use of RASi. Results: A total of 256 NSCLC patients were included and 37 patients used RASi. The median PFS of patients treated with RASi was significantly longer than that of patients treated without (HR=0.59, 95%CI=0.40-0.88). The median OS of patients treated with RASi tended to be longer than that of patients treated without (HR=0.71, 95%CI=0.45-1.11). Conclusion: The use of RASi was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibodies. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibodies.

DOI： 10.21873/anticanres.14980

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BACKGROUND: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. METHODS: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. RESULTS: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated β-galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice. CONCLUSIONS: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

DOI： 10.1186/s12885-021-07905-6

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BACKGROUND: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). METHODS: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. RESULTS: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75-91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5-19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2-not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported. CONCLUSION: Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS. TRIAL REGISTRATION: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

DOI： 10.1186/s12885-021-07861-1

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Osimertinib is the standard treatment for epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer. However, drug-induced interstitial lung disease (ILD) is recognized as a serious adverse event associated with EGFR-tyrosine kinase inhibitors (TKIs). We herein report a 78-year-old woman with stage IV lung adenocarcinoma harboring an EGFR L858R mutation on exon 21 who received rechallenge treatment with afatinib after osimertinib-induced ILD with an organizing pneumonia pattern. This is the first report of successful rechallenge with afatinib after osimertinib-induced ILD. Treatment with other EGFR-TKIs after osimertinib-induced ILD may be an option for subsequent therapy.

DOI： 10.2169/internalmedicine.5435-20

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BACKGROUND: Pleural mesothelioma, a devastating asbestos-associated malignancy, urgently requires a novel effective therapy. Heat shock protein 70 (HSP70), which is synthesized in the cell response to protein damage, is expected to be a new target for antitumor treatment. In addition to its well-known protein refolding function, HSP70 regulates cell proliferation through different pathways, including PI3K/AKT/mTOR, and autophagy in malignant cells. In this study, we attempted to clarify the effects of VER-155008, an HSP70 inhibitor, on pleural mesothelioma. METHODS: Human pleural mesothelioma cell lines 211H, H2452 and H28 were cultured with VER-155008, and protein expression, cell proliferation, colony formation, cell cycle, synergistic effect with cisplatin, and autophagy induction were analyzed. RESULTS: In mesothelioma cell lines, VER-155008 (5.0 μM or more) inhibited cell growth and colony formation, accompanied by G1 cell cycle arrest. According to western blot analysis, VER-155008 reduced p-AKT expression. However, VER-155008 failed to show a synergistic effect with cisplatin on cell growth. Mesothelioma cells transfected with the novel plasmid pMRX-IP-GFP-LC3-RFP-LC3ΔG, which was developed for the quantitative and statistical estimation of macroautophagy, showed enhanced macroautophagy upon treatment with VER-155008 and gefitinib which is an EGFR-tyrosine kinase inhibitor. In addition, fetal bovine serum deprivation induced macroautophagy was further enhanced by VER-155008. CONCLUSIONS: On the basis of these results, functional HSP70 inhibition by VER-155008 suppressed cell growth in pleural mesothelioma cells, accompanied by enhanced macroautophagy. HSP70 inhibition is thus expected to become a new strategy for treating mesothelioma. KEY POINTS: Significant findings of the study In pleural mesothelioma cells, inhibition of HSP70 function by VER-155008 suppressed cell proliferation accompanied by induction of autophagy which was synergistically enhanced under the starvation condition, whereas gefitinib, an EGFR-TKI, did not show the same synergistic effect in autophagy. What this study adds The inhibition of HSP70 induced autophagy and suppressed cell proliferation in mesothelioma cells.

DOI： 10.1111/1759-7714.13784

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Idiopathic pulmonary fibrosis (IPF), a progressive disorder of unknown etiology, is characterized by pathological lung fibroblast activation and proliferation resulting in abnormal deposition of extracellular matrix proteins within the lung parenchyma. The pathophysiological roles of exosomal microRNAs in pulmonary fibrosis remain unclear; therefore, we aimed to identify and characterize fibrosis-responsive exosomal microRNAs. We used microRNA array analysis and profiled the expression of exosome-derived miRNA in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. The effect of microRNAs potentially involved in fibrosis was then evaluated in vivo and in vitro. The expression of exosomal microRNA-16 was increased by up to 8.0-fold on day 14 in bleomycin-treated mice, compared to vehicle-treated mice. MicroRNA-16 mimic administration on day 14 after bleomycin challenge ameliorated pulmonary fibrosis and suppressed lung and serum expression of secreted protein acidic and rich in cysteine (SPARC). Pretreatment of human lung fibroblasts with the microRNA-16 mimic decreased the expression of rapamycin-insensitive companion of mTOR (Rictor) and TGF-β1-induced expression of SPARC. This is the first study reporting the anti-fibrotic properties of microRNA-16 and demonstrating that these effects occur via the mTORC2 pathway. These findings support that microRNA-16 may be a promising therapeutic target for IPF.

DOI： 10.1016/j.yexcr.2020.112416

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BACKGROUND: Metastasis is the primary cause of death in cancer patients, and its management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been implicated in the process of cancer metastasis, and its pharmacological interference holds therapeutic promise. METHODS: Traf2- and Nck-interacting kinase (TNIK) functions as a transcriptional coregulator of Wnt target genes. Given the convergence of Wnt and transforming growth factor-β (TGFβ) signalling, we examined the effects of a small-molecule TNIK inhibitor (named NCB-0846) on the TGFβ1-induced EMT of lung cancer cells. RESULTS: NCB-0846 inhibited the TGFβ1-induced EMT of A549 cells. This inhibition was associated with inhibition of Sma- and Mad-Related Protein-2/3 (SMAD2/3) phosphorylation and nuclear translocation. NCB-0846 abolished the lung metastasis of TGFβ1-treated A549 cells injected into the tail veins of immunodeficient mice. The inhibition of EMT was mediated by suppression of the TGFβ receptor type-I (TGFBR1) gene, at least partly through the induction of microRNAs targeting the TGFBR1 transcript [miR-320 (a, b and d) and miR-186]. CONCLUSIONS: NCB-0846 pharmacologically blocks the TGFβ/SMAD signalling and EMT induction of lung cancer cells by transcriptionally downregulating TGFBRI expression, representing a potentially promising approach for prevention of metastasis in lung cancer patients.

DOI： 10.1038/s41416-020-01162-3

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Antibody-drug conjugate (ADC) was novel type of anticancer drugs. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2) targeting ADC, can be a novel treatment option for HER2 alternation (mutation, expression, amplification) advanced-stage non-small-cell lung cancer (NSCLC) from DESTINY-Lung01 result. Herein, we report a successful treatment with T-DXd for NSCLC harboring HER2 exon 20 insertion mutation in a patient with poor performance status (PS). We presented a case of a 52-year-old heavily pretreated female patient diagnosed with lung adenocarcinoma (cT1bN3M0, stage IIIB). After fifth-line pretreatment of systemic chemotherapy, primary tumor recurrence, pleural effusion, and miliary lung metastases were observed. The patient presented with hypoxia requiring oxygen therapy via nasal cannula at a flow rate of 4 L per minute, cancer pain, and cachexia requiring opioid treatment. Her Eastern Cooperative Oncology Group PS score was assessed 3. Comprehensive genomic profiling revealed HER2 exon 20 insertion mutation. After treatment with T-DXd was approved by the ethical review committee of Nippon Medical School Hospital, treatment was started. The tumor size decreased significantly, and her PS score decreased from 3 to 1, with improvement of hypoxia, cancer pain, and cachexia. The patient is still receiving treatment, without disease progression 6 months after starting treatment with T-DXd. Despite cases of poor PS, NGS should be performed and target therapy including ADCs should be considered.

DOI： 10.2147/OTT.S341290

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INTRODUCTION: Using real-world Japanese postmarketing data, we characterized interstitial lung disease (ILD) development during the second- or later-line osimertinib treatment for EGFR mutation-positive NSCLC. Retrospective radiologic image evaluation of patients developing ILD was also performed. METHODS: Patients who had ILD events reported as an adverse drug reaction by their physicians and who were assessed as having developed ILD as assessed by an ILD expert committee in Japan were included. RESULTS: Among 3578 patients, 252 ILD events were reported in 245 patients (6.8%) by their attending physicians. The median (range) time to the first onset of ILD after osimertinib treatment initiation was 63.0 (5-410) days, and 29 patients with a fatal outcome were reported. The ILD expert committee assessed 231 of 3578 patients (6.5%) as having ILD. A previous history of nivolumab therapy (adjusted OR: 2.84; 95% confidence interval: 1.98-4.07) and a history or concurrence of ILD (3.51; 2.10-5.87) were identified as factors potentially associated with ILD onset during osimertinib treatment. In patients who had received a previous nivolumab treatment, the number and proportion of patients developing ILD were highest for patients who discontinued nivolumab treatment within the first month before initiating osimertinib; trends for decreasing incidence and proportion were observed, with an increasing duration between the end of nivolumab treatment and the initiation of osimertinib treatment. CONCLUSIONS: The frequency of ILD was consistent with the known osimertinib safety profile in the Japanese population. A history or concurrence of ILD and history of previous nivolumab therapy are factors potentially associated with ILD onset during osimertinib treatment.

DOI： 10.1016/j.jtho.2020.08.025

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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BACKGROUND: Measuring lung compliance is useful for evaluating interstitial lung disease (ILD) progression because reduced lung compliance by fibrosis progression is the main primary cause of decreased vital capacity. However, because of the invasiveness of the method, requiring the insertion of a balloon into the esophagus, lung compliance is rarely measured. A recently developed, possible method estimates intrathoracic pressure using fingertip photoplethysmography. This method non-invasively measures the lung dynamic compliance (Cdyn) by simultaneously measuring tidal volume. We evaluated the efficacy of this method in assessing ILD. METHODS: We conducted a single-center, observational cross-sectional study to evaluate the efficacy of this method in subjects with ILD as compared with that in healthy control subjects. The main outcome was the estimated Cdyn (eCdyn) determined using this method. We also evaluated potential confounding factors of eCdyn in the baseline characteristics. RESULTS: In the ILD group (n = 14) the median eCdyn was significantly lower than that in the control group (n = 49) (0.122 vs. 0.183; P = 0.011). In univariate regression analysis, eCdyn was significantly correlated with height, weight, forced vital capacity, forced expiratory volume in one second, diffusing capacity for carbon monoxide, and usual interstitial pneumonia (UIP). In multivariate regression analysis, both weight (β = 0.49, P = 0.011) and UIP (β = 0.52, P = 0.007) were significantly associated with eCdyn. CONCLUSIONS: We demonstrated a significant reduction in Cdyn in subjects with ILD using photoplethysmography. This non-invasive method might be a novel, promising tool for evaluating fibrosis progression in ILD.

DOI： 10.1272/jnms.JNMS.2021_88-411

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Background The efficacy of anti-programmed cell death-1/ligand 1 antibody monotherapy (anti-PD-1/PD-L1 monotherapy) in patients with active brain metastases (BMs) is not established. Here, we aimed to evaluate the efficacy of anti-PD-1/PD-L1 monotherapy in non-small cell lung cancer (NSCLC) patients with active BMs. Methods This retrospective study included NSCLC patients treated with second-line or later-line anti-PD-1/PD-L1 monotherapy between December 2015 and August 2019. Patients were classified into those with or without active BMs, including symptomatic BMs requiring systemic steroids and untreated BMs. The progression-free survival (PFS) and overall survival (OS) of the patients with and without active BMs were compared. Intracranial and extracranial tumor responses were evaluated in patients with active BMs. Results We analyzed 197 patients who had received anti-PD-1/PD-L1 monotherapy. Among them, 24 had active BMs. Among those without active BMs, 145 had no BMs and 28 had treated asymptomatic BMs. The PFS and OS of patients with active BMs were significantly shorter than those of patients without active BMs (1.3 vs. 2.7 months;P < 0.001, and 4.5 vs. 16.3 months;P= 0.001 respectively). For patients with active BMs, the intracranial and extracranial response rates were 13.3% and 26.7%, respectively. On multivariate analysis, active BMs, poor performance status (PS), and EGFR/ALK positivity were significant factors associated with shorter PFS. Active BMs and poor PS were significant factors associated with shorter OS. Conclusions This study suggested that anti-PD-1/PD-L1 monotherapy was not effective for NSCLC patients with active BMs. Further studies on immunotherapy are needed for patients with active BMs. Key points Significant findings of the study: The present study showed that anti-PD-1/PD-L1 antibody monotherapy was not effective for non-small cell lung cancer patients with active brain metastases. Intracranial and extracranial response rates were 13.3% and 26.7%, respectively. What this study adds: Further studies on immunotherapy are needed for patients with active BMs.

DOI： 10.1111/1759-7714.13557

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OBJECTIVE: Adverse drug reactions (ADRs) during real-world osimertinib use were investigated in Japan. METHODS: Patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer treated with second-line or later oral osimertinib per the Japanese package insert (80 mg once daily) were included. Data were collected between 28 March 2016 and 31 August 2018. RESULTS: The median observation period in the safety analysis population (n = 3578) was 343.0 days. ADRs (defined as adverse events whose causality to osimertinib could not be denied by the attending physicians or manufacturer) were reported in 58.1% (2079/3578) of patients. ADRs of interstitial lung disease events were reported in 6.8% (245/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, of whom 29 (11.8%) died (0.8% of patients overall). ADRs of QT interval prolonged, liver disorder and haematotoxicity were reported in 1.3% (45/3578; Grade ≥ 3, 0.1% [5/3578]), 5.9% (212/3578; Grade ≥ 3, 1.0% [35/3578]) and 11.4% (409/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, respectively. In the efficacy analysis population (n = 3563), 119 (3.3%) patients had complete responses, 2373 (66.6%) had partial responses and 598 (16.8%) had stable disease. The objective response rate was 69.9%; disease control rate was 86.7%; and median progression-free survival (PFS) was 12.3 months. At 6 and 12 months, PFS rates were 77.4% (95% confidence interval [CI], 75.9-78.9) and 53.2% (95% CI, 51.3-55.1) and overall survival rates were 88.3% (95% CI, 87.2-89.4) and 75.4% (95% CI, 73.8-77.0), respectively. CONCLUSIONS: These data support the currently established benefit-risk assessment of osimertinib in this patient population.

DOI： 10.1093/jjco/hyaa067

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OBJECTIVE: A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan. METHODS: Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30-60 minutes) in routine clinical settings (observation period: 96 weeks). RESULTS: Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4-8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P < 0.001). Among 654 patients in the effectiveness analysis data set, the response and clinical benefit rates were 6.7% (95% confidence interval 4.9-8.9) and 53.2% (95% confidence interval 49.3-57.1), respectively. The median progression-free survival was 18.3 weeks (95% confidence interval 16.9-21.1). CONCLUSIONS: The safety and effectiveness profile of temsirolimus observed in this study was similar to that observed in the multinational phase 3 study. The results are generalizable to the real-world scenario at the time of this research, and safety and effectiveness of temsirolimus as a subsequent anticancer therapy for renal cell carcinoma warrants further investigation. (ClinicalTrials.gov identifier NCT01210482, NCT01420601).

DOI： 10.1093/jjco/hyaa062

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01244&link_issn=&doc_id=20200914250001&doc_link_id=130007896391&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007896391&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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BACKGROUND: Although aberrant proliferation and activation of lung fibroblasts are implicated in the initiation and progression of idiopathic pulmonary fibrosis (IPF), the underlying mechanisms are not well characterized. Numerous microRNAs (miRNAs) have been implicated in this process; however, miRNAs derived from exosomes and the relevance of such miRNAs to fibroblast-to-myofibroblast differentiation are not well understood. In this study, we attempted to identify exosome-derived miRNAs relevant to fibrosis development. METHODS: Using miRNA array analysis, we profiled exosome-derived miRNA expression in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. After validating a selected miRNA by quantitative reverse-transcription polymerase chain reaction, its effect on fibroblast-to-myofibroblast differentiation was investigated in human lung fibroblasts. Furthermore, we determined the role of the selected miRNA in an in vivo model of pulmonary fibrosis. RESULTS: MiRNA array analysis revealed that miR-22 expression was increased by up to 2 fold on day 7 after bleomycin treatment compared with that in vehicle-treated mice. In vitro, miR-22 transfection suppressed TGF-β1-induced α-SMA expression. This was mediated via inhibition of the ERK1/2 pathway. Baseline α-SMA expression was increased upon miR-22 inhibitor transfection. Furthermore, miR-22 negatively regulated connective tissue growth factor expression in the presence of TGF-β1. In vivo, administration of a miR-22 mimic on day 10 after bleomycin challenge ameliorated pulmonary fibrosis lesions accompanied by decreased α-SMA expression in the model mice. CONCLUSIONS: Exosomal miR-22 modulates fibroblast-to-myofibroblast differentiation. The present findings warrant further study, which could shed light on miR-22 as a novel therapeutic target in IPF.

DOI： 10.1272/jnms.JNMS.2020_87-302

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER  

Background: The NEJ026 Phase 3 study demonstrated that erlotinib and bevacizumab (BE)-treated NSCLC patients with EGFR mutations had significantly better progression-free survival (PFS) than those treated with erlotinib alone (E). This study included a prospective analysis of the relationship between the mutational status of EGFR in plasma circulating tumor DNA (ctDNA) and the efficacy of TKI monotherapy or combination therapy. We describe these results herein.Methods: Plasma samples were collected from patients enrolled in NEJ026 at the start of treatment (P0), 6 weeks after the start of treatment (P1), and upon confirmation of progressive disease (P2). Plasma ctDNA was analyzed using a modified PNA-LNA PCR clamp method. PFS and OS according to EGFR status at the time of plasma collection were evaluated.Findings: Plasma activating EGFR mutation (aEGFR) at P0 was detected in 68% of cases; patients without plasma aEGFR had longer PFS. The frequency of T790M mutation at P2 was similar in both arms: 8 (19.0%) in BE and 11 (20.8%) in E. Based on the aEGFR profiles, PFS was evaluated among three groups: type A [P0(-), P1 (-)], type B [P0(+), P1(-)], and type C [P0(+), P1(+)]. This revealed that BE was more efficacious than E, and that BE was associated with improved PFS in all types.Interpretation: Pre-treatment plasma aEGFR status have a potential of early predictor of response of TKI efficacy. Monitoring plasma aEGFR mutation will contribute to selection and continuation of treatment with BE or E.

DOI： 10.1016/j.ebiom.2020.102861

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BACKGROUND: Pleurodesis is the standard of care for non-small cell lung cancer (NSCLC) patients with symptomatic malignant pleural effusion (MPE). However, there is no standard management for MPE uncontrolled by pleurodesis. Most patients with unsuccessful MPE control are unable to receive effective chemotherapy. Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of MPE. This multicenter, phase II study investigated the effects of bevacizumab plus chemotherapy in nonsquamous NSCLC patients with unsuccessful management of MPE. METHODS: Nonsquamous NSCLC patients with MPE following unsuccessful tube drainage or pleurodesis received bevacizumab (15 mg/kg) plus chemotherapy every three weeks. The primary endpoint was pleural effusion control rate (PECR), defined as the percentage of patients without reaccumulation of MPE at eight weeks. Secondary endpoints included pleural progression-free survival (PPFS), safety, and quality of life (QoL). RESULTS: A total of 20 patients (median age: 69 years; 14 males; 20 adenocarcinomas; six epidermal growth factor receptor mutations) were enrolled in nine centers. The PECR was 80% and the primary end point was met. The PPFS and the overall survival (OS) were 16.6 months and 19.6 months, respectively. Patients with high levels of VEGF in the MPE had shorter PPFS (P = 0.010) and OS (P = 0.002). Toxicities of grade ≥ 3 included neutropenia (50%), thrombocytopenia (10%), proteinuria (10%), and hypertension (2%). The cognitive QoL score improved after treatment. CONCLUSIONS: Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE, and should be considered as a standard therapy in this setting. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE. WHAT THIS STUDY ADDS: Bevacizumab plus chemotherapy should be considered as a standard treatment option for patients with uncontrolled MPE. CLINICAL TRIAL REGISTRATION: UMIN000006868 was a phase II study of efficacy of bevacizumab plus chemotherapy for the management of malignant pleural effusion (MPE) in nonsquamous non-small cell lung cancer patients with MPE unsuccessfully controlled by tube drainage or pleurodesis (North East Japan Study Group Trial NEJ-013B) (http://umin.sc.jp/ctr/).

DOI： 10.1111/1759-7714.13472

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INTRODUCTION: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics. METHODS: We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC. RESULTS: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PCs that had relapsed after surgical resection. CONCLUSIONS: In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort.

DOI： 10.1016/j.lungcan.2020.03.027

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BACKGROUND: The participation of patients in the decision-making process related to their treatment is strongly recommended. This study was conducted to develop and evaluate a support tool that can help patients make decisions related to their own treatment. METHODS: Twenty cancer patients who were hospitalized for first line treatment were enrolled on the study. Before hospitalization, a 'Check sheet on treatment selection', which contained 14 questions, was distributed to patients and/or their families. After hospitalization, the attending physician explained the treatment while referring to the written check sheet. Also, at the time of discharge, the patients's responses to the 'Questionnaire on check sheet and treatment selection' were collected in order to evaluate the utility of the check sheet. Finally, the 'Questionnaire of the check sheet' was handed to the attending physician to evaluate. RESULTS: Of the fourteen patients who responded to the questionnaire, all indicated that the check sheets were helpful for decision-making, and that using the sheets empowered them to ask their doctors questions. Only one person felt uncomfortable with compiling the check sheet.Physicians stated that the check sheet facilitated patient decision-making and improved communication with patients. However, there was an opinion that this activity increased the administrative burden of medical professionals. CONCLUSION: Almost all patients stated that the check sheet used in this study was useful as a decision support tool, and also facilitated the communication between doctors and patients. Before incorporation into general clinical practice, this increased benefit should be weighed against the potential extra administrative workload imposed on clinicians.

DOI： 10.1272/jnms.JNMS.2021_88-401

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BACKGROUND: Most patients with hormone receptor (HR)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer can be cured by surgery and endocrine therapy, but a significant proportion suffer recurrences. Actinin-4 is associated with cancer invasion and metastasis, and its genetic alteration may be used for breast cancer prognostication. METHODS: The copy number of the actinin-4 (ACTN4) gene was determined by fluorescence in situ hybridisation (FISH) in two independent cohorts totalling 597 patients (336 from Japan and 261 from the USA) with HR-positive, HER2-negative, node-negative breast cancer. RESULTS: In the Japanese cohort, multivariate analysis revealed that a copy number increase (CNI) of ACTN4 was an independent factor associated with high risks of recurrence (P = 0.01; hazard ratio (HR), 2.95) and breast cancer death (P = 0.014; HR, 4.27). The prognostic significance of ACTN4 CNI was validated in the US cohort, where it was the sole prognostic factor significantly associated with high risks of recurrence (P = 0.04; HR, 2.73) and death (P = 0.016; HR, 4.01). CONCLUSIONS: Copy number analysis of a single gene, ACTN4, can identify early-stage luminal breast cancer patients with a distinct outcome. Such high-risk patients may benefit from adjuvant chemotherapy.

DOI： 10.1038/s41416-020-0821-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Objectives: : Docetaxel (DTX) efficacy increases in patients with non-small cell lung cancer (NSCLC) who had received anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) therapy. However, the effect of ramucirumab (Ram) on DTX efficacy following anti-PD-1/L1 therapy is unknown. Here, we aimed to evaluate the effect of Ram on DTX efficacy following anti-PD-1/L1 therapy.Materials and methods: This retrospective study included 99 patients with NSCLC, who were divided into those who had (pre-ICI group) or had not (no-ICI group) received anti-PD-1/L1 antibody before DTX. Both groups were then treated with DTX or DTX plus Ram (DTX/Ram). Patient characteristics were compared between the DTX and DTX/Ram groups and adjusted with inverse probability of treatment weighting using propensity scores and the following confounding variables: age, sex, performance status, smoking status, histology, driver mutation, and line of treatment. We compared DTX/Ram and DTX in terms of efficacy in both the pre-ICI and no-ICI groups.Results: In the pre-ICI group, 18 and 21 patients received DTX and DTX/Ram, respectively. In the no-ICI group, 35 and 25 patients received DTX and DTX/Ram. In the no-ICI group, progression-free survival (PFS) and overall survival (OS) were not significantly different between DTX/Ram- and DTX-treated patients (median PFS, 2.6 versus 1.6 months; p = 0.30, median OS; 8.2 versus 8.0 months; p = 0.30). In the pre-ICI group, PFS was significantly longer in DTX/Ram-treated than in DTX-treated patients (median, 5.9 versus 2.8 months; p = 0.03). Hazard ratio for disease progression or death was 0.75 (95% confidence interval, 0.20-0.96). The OS of DTX/Ram-treated patients tended to be longer than that of DTX-treated patients (median, 19.8 versus 8.6 months; p = 0.10).Conclusions: DTX efficacy following anti-PD-1/L1 therapy may be enhanced by Ram. Further studies are needed to validate the efficacy of inhibiting the vascular endothelial growth factor pathway following anti-PD-1/L1 therapy.

DOI： 10.1016/j.lungcan.2020.04.021

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PURPOSE: Combination carboplatin and S-1 is active in the treatment of non-small cell lung cancer (NSCLC). However, data on this combination for elderly patients with NSCLC are insufficient. METHODS: Eligibility criteria were no prior chemotherapy, Stage IIIB or IV NSCLC, performance status 0-1, age ≥ 75 years, and adequate hematological, hepatic, and renal functions. Carboplatin was administered on day 1 and S-1 was administered orally, twice a day, between days 1 and 14, repeated every 3 weeks. In phase I, the primary purpose was determination of the recommended dose. Starting doses of carboplatin and S-1 were area under the curve (AUC) of 4 and 80 mg/m2/day, respectively. In the extension study, the effects and tolerability of this combination therapy of recommended dose were confirmed. RESULTS: A total of 10 patients were entered into phase I and 14 patients were entered into the extension study. The recommended doses for this drug combination are AUC 5 for carboplatin and 80 mg/m2/day every 3 weeks for S-1. With carboplatin and S-1 combination therapy at the recommended dose, the response rate was 30.0% [95% confidence interval (CI) 12-54%] and the disease control rate was 90.0% (95% CI 68-99%). Thrombocytopenia and neutropenia were major adverse events. CONCLUSIONS: The recommended doses for this combination therapy are carboplatin AUC 5 and S-1 80 mg/m2/day every 3 weeks, and this combination is effective with tolerable toxicities for advanced NSCLC patients ≥ 75 years old.

DOI： 10.1007/s10147-020-01629-6

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BACKGROUND: Interstitial lung disease (ILD) induced by immune checkpoint inhibitors (ICIs) is a potentially life-threatening adverse event. The purpose of this study was to evaluate whether the development of immune-related adverse events (irAEs), especially ILD, was associated with treatment efficacy and to research the features and risk factors of ILD in advanced non-small cell lung cancer (NSCLC). METHODS: Between December 2015 and November 2018, 130 advanced NSCLC patients were treated with nivolumab, pembrolizumab or atezolizumab. The patients were categorized into two groups (irAEs group or non-irAEs group). Subsequently, we divided the irAEs group into two groups based on the incidence of ILD (ILD group and irAEs-non-ILD group). Treatment efficacy and the characteristics of ILD were evaluated. RESULTS: A total of 39 (30%) patients developed irAEs. ILD was observed in 16 (12%) patients. Patients with ILD had a higher objective response rate (ORR) compared with irAEs-non-ILD patients and non-irAEs patients (63%, 43% and 22%, respectively). Median progression-free survival (mPFS) was 15.9 months in ILD patients, 5.4 months in irAEs-non-ILD patients and 3.3 months in non-irAEs patients (log-rank test, P = 0.033). Pre-existing interstitial pneumonia (IP) was an independent risk factor for ILD-induced ICIs (odds ratio [OR] 14.7; 95% confidence interval [CI]: 2.16-99.6, P = 0.006). CONCLUSIONS: ORR and PFS were significantly better in ILD patients than in irAEs-non-ILD and non-irAEs patients. Pre-existing history of IP was an independent risk factor for ILD-induced ICIs.

DOI： 10.1111/1759-7714.13364

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Background: Chemotherapy-induced acute exacerbation (AEx) of idiopathic interstitial pneumonias (IIPs) seriously compromises the success of treatment of Japanese lung cancer patients. Here, we conducted a nationwide surveillance to clarify the risk of AEx and compare it with the survival benefit of chemotherapy for this population. Methods: Advanced nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC) patients with IIPs were retrospectively analysed. For the surveillance of first-line chemotherapy in 2009, we gathered clinical data from 396 patients who received chemotherapy at 19 institutions between January 1990 and July 2009. In a consecutive retrospective study in 2012, we analysed data from 278 patients from 17 institutions who received second-line chemotherapy between April 2002 and March 2012. Results: Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively. Conclusion: Combination chemotherapies consisting of CP or CE are candidates for standard first-line treatments for patients with advanced lung cancer accompanied by IIP. Second-line chemotherapy should be considered for patients remaining fit enough to receive it.

DOI： 10.1183/23120541.00184-2019

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Background Dissociated responses (DR) are phenomena in which some tumors shrink, whereas others progress during treatment of patients with cancer. The purpose of the present study was to evaluate the frequency and prognosis of DR in non-small cell lung cancer (NSCLC) patients treated with anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) inhibitors. Methods This retrospective study included NSCLC patients who received anti-PD-1/L1 inhibitor as second- or later-line treatment. We excluded patients without radiological evaluation. In patients who showed progressive disease (PD) according to the RECIST 1.1 at the initial CT evaluation, we evaluated all measurable lesions in each organ to identify DR independently of RECIST 1.1. We defined DR as a disease with some shrinking lesions as well as growing or emerging new lesions. Cases not classified as DR were defined as 'true PD'. Overall survival was compared between patients with DR and those with true PD using Cox proportional hazards models. Results The present study included 62 NSCLC patients aged 27-82 years (median: 65 years). DR and true PD were observed in 11 and 51 patients, respectively. The frequency of DR in NSCLC patients who showed PD to anti-PD-1/L1 was 17.7%. Median overall survival was significantly longer in patients with DR versus true PD (14.0 vs. 6.6 months, respectively; hazard ratio for death: 0.40; 95% confidence interval: 0.17-0.94). Conclusions Patients with DR exhibited a relatively favorable prognosis.

DOI： 10.1186/s12885-020-6704-z

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PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor combined with cytotoxic chemotherapy is highly effective for the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations; however, little is known about the efficacy and safety of this combination compared with that of standard therapy with EGFR- tyrosine kinase inhibitors alone. METHODS: We randomly assigned 345 patients with newly diagnosed metastatic NSCLC with EGFR mutations to gefitinib combined with carboplatin plus pemetrexed or gefitinib alone. Progression-free survival (PFS), PFS2, and overall survival (OS) were sequentially analyzed as primary end points according to a hierarchical sequential testing method. Secondary end points were objective response rate (ORR), safety, and quality of life. RESULTS: The combination group demonstrated a better ORR and PFS than the gefitinib group (ORR, 84% v 67% [P < .001]; PFS, 20.9 v 11.9 months; hazard ratio for death or disease progression, 0.490 [P < .001]), although PFS2 was not significantly different (20.9 v 18.0 months; P = .092). Median OS in the combination group was also significantly longer than in the gefitinib group (50.9 v 38.8 months; hazard ratio for death, 0.722; P = .021). The rate of grade ≥ 3 treatment-related adverse events, such as hematologic toxicities, in the combination group was higher than in the gefitinib group (65.3% v 31.0%); there were no differences in quality of life. One treatment-related death was observed in the combination group. CONCLUSION: Compared with gefitinib alone, gefitinib combined with carboplatin plus pemetrexed improved PFS in patients with untreated advanced NSCLC with EGFR mutations with an acceptable toxicity profile, although its OS benefit requires further validation.

DOI： 10.1200/JCO.19.01488

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

背景.末梢肺病変に対するガイドシース併用気管支腔内超音波断層法(endobronchial ultrasonography with a guide sheath:EBUS-GS)を用いた肺生検(EBUS-GS-TBB)の有用性が示されているが、診断に影響を与える因子は明らかになっていない。目的.EBUS-GS-TBBの診断に影響を与える因子を明らかにすることを目的とした。方法.日本医科大学付属病院において2016年7月から2018年4月までにEBUS-GSを用いて肺生検が施行された118例の中で、最終的に確定診断が得られた101例を後方視的に検討した。EBUSのプローブの位置によって、エコー所見を'within'、'outside'、'broadly adjacent to'、'narrowly adjacent to'の4つに分類した。Adjacent toの中でプローブ周囲の180度以上360度未満の範囲に病変が描出されたものをbroadly adjacent toと新たに定義し、それ以外をnarrowly adjacent toと新たに定義した。結果.EBUS-GSによる確定診断率は78.2%であった。多変量解析にて、エコー所見がwithinまたはbroadly adjacent toの患者は診断率が有意に高かった(オッズ比4.25、P<0.01)。肺気腫を合併する患者では有意に診断率が低かった(オッズ比0.29、P=0.02)。検査前のthin-section CTにおけるbronchus sign陽性は診断に寄与する有意な因子であった(オッズ比6.86、P=0.03)。結論.EBUS-GS-TBBでは、エコー所見がbroadly adjacent toの場合でも診断率は高く、withinが得られない症例でもよりよいエコー描出を目指すべきである。肺気腫合併例は診断率が低い可能性があり、検査前の背景肺の評価も重要である。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J00298&link_issn=&doc_id=20200219190004&doc_link_id=%2Fcf0brond%2F2020%2F004201%2F005%2F0014-0020%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2020%2F004201%2F005%2F0014-0020%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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OBJECTIVES: Vascular endothelial growth factor-A (VEGF-A) plays important roles in tumor immune suppression and thus correlates with the efficacy of anti-programmed cell death-1/ligand 1 (anti-PD-1/PD-L1) antibodies. We aimed to determine the association between change in plasma VEGF-A levels and the efficacy of chemotherapy combined with anti-PD-1/PD-L1 antibodies (chemo-PD1) in non-small cell lung cancer (NSCLC) patients. METHODS: We included NSCLC patients treated with chemo-PD1. Plasma VEGF-A levels were measured at baseline (Pre) and days 7 (D7) and 14 (D14) after the initiation of chemo-PD1. Continuous VEGF-A decrease was determined by comparing Pre with the median value of maximum change rate of posttreatment VEGF-A as cutoff. Patients whose change rates of VEGF-A at both D7 and D14 were consistently lower than the cutoff value were classified into the VEGF-A decrease group, whereas those whose VEGF-A at D7 or D14 were higher than the cutoff level were classified into the VEGF-A no-decrease group. The primary outcome was progression-free survival (PFS). RESULTS: A total of 32 patients were evaluated. The median Pre VEGF-A levels was 49 (range, 13-257). The median change rate of VEGF-A at D7 and D14 was -25.6% (range, -77.5-376.9) and -42.3% (range, -100-138.5) respectively. The cutoff value of posttreatment VEGF-A change rate was -9.3%. The PFS was significantly longer in the VEGF-A decrease group than that in the VEGF-A no-decrease group (median, not reached vs 2.4 months; p = 0.017). CONCLUSIONS: Continuous decrease of plasma VEGF-A levels during treatment may be associated with the efficacy of chemo-PD1.

DOI： 10.1016/j.ctarc.2020.100249

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We report a case of pneumonitis with alveolar hemorrhage induced by herbal medicines in a 73-year-old woman who was admitted to our hospital because of dyspnea and an abnormal shadow on a chest radiograph. She had received treatment with numerous drugs, including the herbal medicines Seisin-renshi-in, Chotosan, Rikkunshi-to, and Shakuyakukannzo-to. Chest radiography revealed diffuse ground-glass shadows in both lungs, and bronchoalveolar lavage fluid was progressively hemorrhagic. A culture of the fluid showed no evidence of microorganisms. Moreover, there were no findings suggestive of rheumatic disease or vasculitides. On the basis of this evidence, we suspected drug-induced diffuse alveolar hemorrhage. She discontinued all medicines and started treatment with corticosteroids. Her respiratory condition and chest radiographic findings improved. The timing of administration and rechallenge with other drugs suggested that the herbal medicines were the causative drugs. The primary concern was Seisin-renshi-in, because it contains Ougon (skullcap; a known cause of pneumonitis) and because a drug lymphocyte stimulation test was positive for Seisin-renshi-in. This is the first report indicating that Seisin-renshi-in may cause diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage due to herbal medicines is a rare but emergent disorder. Therefore, treating physicians should be aware that it may be caused by herbal medicines, including Seisin-renshi-in.

DOI： 10.1272/jnms.JNMS.2019_86-504

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Type III collagen is the major protein in the walls of blood vessels and hollow organs; it is decreased in patients with vascular Ehlers-Danlos syndrome (EDS). A 52-year-old man was admitted for severe back pain, and right hemothorax was suspected by chest computed tomography. Immediately after embolization for bleeding bronchial artery, aortic dissection occurred and was treated conservatively in the intensive-care unit. Vascular EDS with a mutation of COL3A1 cDNA (c.3175G>A) was diagnosed. When vascular EDS is suspected, the patient should be treated prophylactically, and a genetic examination should be performed to confirm the diagnosis.

DOI： 10.2169/internalmedicine.2983-19

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BACKGROUND: In the eighth edition of the TNM classification of lung cancer, the M1b and M1c descriptors are newly defined by the number of extrathoracic metastases. To verify the prognostic value of these descriptors in Japan, we reclassified our cases and re-evaluated prognosis in M1b and M1c patients. METHODS: All non-small cell lung cancer (NSCLC) patients with extrathoracic metastases who visited Saitama Medical Center from 2010 to 2016 were evaluated, divided according to the eighth edition of the TNM classification criteria into two groups (M1b, patients with single extrathoracic metastasis, and M1c, patients with multiple extrathoracic metastases), and followed up until December 31, 2017. Survival time analysis was performed using the Kaplan-Meier method, and between-group differences in overall survival time (OS) were evaluated by the log-rank test. RESULTS: A total of 231 NSCLC patients were divided into 57 patients with M1b and 174 with M1c. Median OS was 15.2 months (95% confidence interval [CI]: 9.3-19.9) and 7.3 months (95% CI 5.7-10.7) for M1b and M1c, respectively, with no significant between-group difference (P = 0.239). However, after excluding patients with epidermal growth factor receptor (EGFR) mutation or echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene, median OS was 12.9 months (95% CI 7.2-19.9) for M1b and 5.4 months (95% CI 3.8-6.3) for M1c, respectively, showing a significant difference (P = 0.029). CONCLUSIONS: The effect of therapy directed toward EGFR mutation or EML4-ALK fusion gene might obscure the significant prognostic difference between M1b and M1c.

DOI： 10.1007/s10147-019-01525-8

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BACKGROUND: Idiopathic interstitial pneumonias (IIPs) are associated with increased risk of lung cancer. In Japan, acute exaberation of IIPs induced by anticancer treatment is a critical issue. For this reason, there is limited available evidence regarding the optimal treatment approach for lung cancer patients complicated with IIPs. Our previous prospective pilot study demonstrated the safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer (NSCLC) with IIPs. The current study was conducted to confirm the results of the same combination therapy used in a larger patient population. METHODS: Chemotherapy-naïve patients with advanced stage or post-operative recurrent NSCLC patients complicated by IIPs were enrolled. Patients received paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (AUC 5.0) once every 4 weeks. RESULTS: Thirty-three of 35 enrolled patients were evaluable for analysis and received a median of four treatment cycles (range 1-6). Four patients (12.1%; 95% confidence interval 3.4-28.2%) had acute exacerbation (AEx)-related IIPs to the study treatment. However, no fatalities due to AEx were observed. The overall response was 69.7%. The median progression-free survival, median survival time, and 1-year survival were 6.3 months, 19.8 months, and 55.4%, respectively. CONCLUSIONS: The efficacy of carboplatin plus weekly paclitaxel treatment for advanced NSCLC patients with IIPs was comparable to that of conventional chemotherapy in advanced NSCLC patients without IIPs. Moreover, the primary endpoint was set to the frequency of treatment-related acute exacerbation, and the primary endpoint was met. These results suggest that patients with advanced NSCLC complicated by IIPs may benefit from this combination chemotherapy.

DOI： 10.1007/s10147-019-01516-9

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Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.

DOI： 10.1016/j.resinv.2019.06.001

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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BACKGROUND: Several observational studies suggest that gloves of health care workers are major routes of multidrug-resistant Acinetobacter baumannii transmission. However, limited experimental data are available assessing Acinetobacter transmission from gloves to environmental surfaces. This study determined whether A baumannii was easily transferred from nitrile gloves to polypropylene plastic compared with other gram-negative bacteria that cause health care-associated infections in laboratory-controlled experiments. METHODS: Gloved fingerpad-to-fomite transfer efficiency was determined for drug-resistant and -sensitive strains of A baumannii, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa. RESULTS: Only A baumannii transferred from gloves to fomites 3 minutes after the bacterial transfer event. Transfer efficiency of A baumannii was 0.1%-33% at that time point. DISCUSSION: Bacterial transfer from contaminated gloves to the hospital environment may be related to the type of contaminating bacteria, inoculated bacterial level, fomites, and glove materials. Therefore, it is important to need a comprehensive assessment of the transfer efficiency. CONCLUSIONS: A baumannii can transfer easily from nitrile gloves to fomite compared with other gram-negative bacteria that cause health care-associated infections. These findings support data from previous observational studies that gloves of health care workers can be major routes of A baumannii transmission in clinical settings.

DOI： 10.1016/j.ajic.2019.04.009

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The patient was a 65-year-old man who developed dyspnea after 6 courses of S-1 and oxaliplatin(SOX)chemotherapy for advanced stomach cancer. The chemotherapy regimen consisted of SOX chemotherapy. The patient developed hypoxemia, and chest radiography revealed ground-glass opacity in both lungs. Bronchoscopy and DLST led to a diagnosis of druginduced lung injury caused by S-1. Although steroid pulse therapy was administered, the patient's condition deteriorated rapidly and was ultimately fatal. Based on the clinical course and histopathological findings, a DAD-type lung disorder was diagnosed. This description of a DAD-type drug-induced lung injury caused by S-1, for which histopathological findings were available in the early stages, is clinically valuable. We report this case along with a review of the relevant literature.

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The original article can be found online.

DOI： 10.1007/s10147-019-01488-w

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BACKGROUND: S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine. METHODS: Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1-14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4-6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL). RESULTS: From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9-8.7), 21.4 months (95% CI: 14.7-not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen. CONCLUSIONS: S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.

DOI： 10.1093/jjco/hyz064

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Objective: Post-marketing surveillance (PMS) was performed in Japan to obtain information on the safety and efficacy of crizotinib.Methods: Target patients included almost all patients with anaplastic lymphoma kinase-positive non-small cell lung cancer who were administered crizotinib. The observation period was 52 weeks. In the present study, we focused on the treatment status and safety of crizotinib therapy and analyzed the real-world data obtained by this PMS (ClinicalTrials. gov: NCT01597258).Results: The safety analysis set included 2028 Japanese patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of adverse drug reactions (ADRs) was 91.6%, and common ADRs (incidence >= 15%) were nausea (32.2%), diarrhea (24.3%), photopsia (18.9%), vomiting (17.5%) and dysgeusia (16.8%). Many patients (623 patients) discontinued treatment of crizotinib because of adverse events within 12 weeks after therapy initiation, which tended to frequently occur in the following cases: (1) elderly, (2) body weight <40 kg, (3) body surface area <1.2 m(2) (4) ECOG PS 2-4, (5) higher Brinkman index and (6) history of occupational/environmental exposure such as asbestos/pneumoconiosis. The proportions of patients remaining on crizotinib therapy were 68.2% for 3 months, 55.2% for 6 months and 36.1% for 12 months, with a median duration of 7.9 months. Multivariate analysis with a Cox proportional hazard model identified 10 statistically significant patient background factors influencing the duration of crizotinib therapy.Conclusions: No new safety concerns were observed in this PMS study. Our results provide useful information regarding the status of crizotinib therapy in the clinical setting.

DOI： 10.1093/jjco/hyz049

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Although mammalian target of rapamycin inhibitors (mTORi) are used to treat various malignancies, they frequently induce active alveolitis and dyslipidemia. Abnormal lipid metabolism affects alveolar surfactant function and results in pulmonary disorders; however, the pathophysiology of lung injury and its relationship with lipid metabolism remain unknown. We investigated the relationship between lipid metabolism and alveolar epithelial injury, focusing on peroxisome proliferator-activated receptor-γ (PPAR-γ) as a lipid stress-related factor in mTORi-induced lung injury. We clinicopathologically examined three patients with mTORi-induced lung injury. We constructed an mTORi injury mouse model using temsirolimus in mice (30 mg/kg/day), with the vehicle control and bleomycin injury groups. We also constructed a cultured alveolar epithelial cell injury model using temsirolimus (0-40 μM) in the mouse lung epithelial cell line MLE-12 and performed analysis with or without pioglitazone (PPAR-γ agonist) treatment. All three patients had dyslipidemia and lung lesions of hyperplastic pneumocytes with foamy and enlarged changes. In the mouse model, temsirolimus induced significantly higher levels of total cholesterol and free fatty acids in serum and higher levels of surfactant protein D in serum and BAL fluid with an increase in inflammatory cytokines in the lung compared to control. Temsirolimus also induced hyperplastic foamy pneumocytes with increased lipid-associated spots and larger round electron-lucent bodies compared to the control or bleomycin groups in microscopic analyses. Multiple lipid-associated spots within the cytoplasm were also induced by temsirolimus administration in MLE-12 cells. Temsirolimus downregulated PPAR-γ expression in mouse lung and MLE-12 cells but upregulated cleaved caspase-3 in MLE-12 cells. Pioglitazone blocked the upregulated cleaved caspase-3 expression in MLE-12 cells. The pathogenesis of mTORi-induced lung disease may be involved in alveolar epithelial injury, via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.

DOI： 10.1038/s41374-018-0158-9

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Background: Osimertinib exhibits good efficacy in patients with T790M-positive non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Compared with the clinical trials, in real-world clinical practice, osimertinib must be administered to older patients and those with poor Eastern Cooperative Oncology Group performance status (ECOG-PS). Therefore, we investigated the association between osimertinib efficacy/safety and PS score, age, and other clinical features in patients with T790M-positive NSCLC. Methods: We reviewed all patients with T790M-positive NSCLC and acquired resistance to initial EGFR-TKIs who were administered osimertinib between March 2016 and January 2018 at the Tokyo Metropolitan Cancer and Infectious Diseases Center in Komagome Hospital, Japan. Results: In total, 31 patients, including 8 young (<65 years) and 23 elderly (≥65 years) patients, were included in the study. Of these, 10 (32.3%) patients had poor PS scores. The progression-free survival (PFS) was significantly shorter in young patients was than elderly patients [3.5 vs. 6.4 months, P=0.041; hazard ratio (HR), 2.41]. The overall survival (OS) of the young patients tended to be shorter than that of the elderly patients (5.3 vs. 19.4 months, P=0.067; HR, 2.58). The PFS (9.1 vs. 5.5 months; P=0.071; HR, 0.38) and the OS (not reached vs. 6.6 months, P=0.061; HR, 0.39) were shorter in patients with poor ECOG-PS than those with good ECOG-PS. The toxic effects of osimertinib were manageable. By multivariate analysis, both age and ECOG-PS were independent predictors of osimertinib efficacy. Conclusions: Poor ECOG-PS and younger age were associated with lower efficacy of osimertinib in T790M-positive NSCLC.

DOI： 10.21037/jtd.2019.06.03

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We report a case of pneumonitis with alveolar hemorrhage induced by herbal medicines. A 73-year-old female was admitted to our hospital due to dyspnea and the presence of an abnormal shadow on the chest roentgenogram. She had received treatment with numerous drugs, including the following herbal medicines: Seisin-renshi-in, Chotosan, Rikkunshi-to, and Shakuyakukannzo-to. Chest radiography revealed diffuse ground-glass shadows in both lungs. The bronchoalveolar lavage fluid was progressively bloody. In addition, culture did not show the presence of microorganisms in the fluid. Moreover, there were no findings suggestive of rheumatic disease or vasculitides. Based on this evidence, we suspected drug-induced diffuse alveolar hemorrhage. She discontinued the use of all previous agents, and received treatment with corticosteroids. Her respiratory condition and the chest roentgenogram improved. According to the timing of administration and rechallenge with other drugs, the herbal medicines were suspected to be the causative drugs. Among those, Seisin-renshi-in was the most suspicious. Firstly, Seisin-renshi-in contains Ougon (skullcap), which is known to cause pneumonitis. Secondly, a dr

DOI： 10.1272/jnms.JNMS.2019_86-504

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BACKGROUND: Resistance to first-generation or second-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy develops in almost half of patients with EGFR-positive non-small-cell lung cancer (NSCLC) after 1 year of treatment. The JO25567 phase 2 trial comparing erlotinib plus bevacizumab combination therapy with erlotinib monotherapy established the activity and manageable toxicity of erlotinib plus bevacizumab in patients with NSCLC. We did a phase 3 trial to validate the results of the JO25567 study and report here the results from the preplanned interim analysis. METHODS: In this prespecified interim analysis of the randomised, open-label, phase 3 NEJ026 trial, we recruited patients with stage IIIB-IV disease or recurrent, cytologically or histologically confirmed non-squamous NSCLC with activating EGFR genomic aberrations from 69 centres across Japan. Eligible patients were at least 20 years old, and had an Eastern Cooperative Oncology Group performance status of 2 or lower, no previous chemotherapy for advanced disease, and one or more measurable lesions based on Response Evaluation Criteria in Solid Tumours (1.1). Patients were randomly assigned (1:1) to receive oral erlotinib 150 mg per day plus intravenous bevacizumab 15 mg/kg once every 21 days, or erlotinib 150 mg per day monotherapy. Randomisation was done by minimisation, stratified by sex, smoking status, clinical stage, and EGFR mutation subtype. The primary endpoint was progression-free survival. This study is ongoing; the data cutoff for this prespecified interim analysis was Sept 21, 2017. Efficacy was analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of treatment and had at least one response evaluation. Safety was analysed in all patients who received at least one dose of study drug. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000017069. FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were randomly assigned to receive erlotinib plus bevacizumab (n=114) or erlotinib alone (n=114). 112 patients in each group were evaluable for efficacy, and safety was evaluated in 112 patients in the combination therapy group and 114 in the monotherapy group. Median follow-up was 12·4 months (IQR 7·0-15·7). At the time of interim analysis, median progression-free survival for patients in the erlotinib plus bevacizumab group was 16·9 months (95% CI 14·2-21·0) compared with 13·3 months (11·1-15·3) for patients in the erlotinib group (hazard ratio 0·605, 95% CI 0·417-0·877; p=0·016). 98 (88%) of 112 patients in the erlotinib plus bevacizumab group and 53 (46%) of 114 patients in the erlotinib alone group had grade 3 or worse adverse events. The most common grade 3-4 adverse event was rash (23 [21%] of 112 patients in the erlotinib plus bevacizumab group vs 24 [21%] of 114 patients in the erlotinib alone group). Nine (8%) of 112 patients in the erlotinib plus bevacizumab group and five (4%) of 114 patients in the erlotinib alone group had serious adverse events. The most common serious adverse events were grade 4 neutropenia (two [2%] of 112 patients in the erlotinib plus bevacizumab group) and grade 4 hepatic dysfunction (one [1%] of 112 patients in the erlotinib plus bevacizumab group and one [1%] of 114 patients in the erlotinib alone group). No treatment-related deaths occurred. INTERPRETATION: The results of this interim analysis showed that bevacizumab plus erlotinib combination therapy improves progression-free survival compared with erlotinib alone in patients with EGFR-positive NSCLC. Future studies with longer follow-up, and overall survival and quality-of-life data will be required to further assess the efficacy of this combination in this setting. FUNDING: Chugai Pharmaceutical.

DOI： 10.1016/S1470-2045(19)30035-X

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OBJECTIVES: In the past two decades several antineoplastic agents have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC), and the management of these patients has drastically changed. However, there is limited information regarding the impact of these advances on patient survival in clinical practice. MATERIALS AND METHODS: We analyzed the survival of patients with stage IV NSCLC who received any treatment in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) between January 1, 1995 and March 1, 2017. A total of 1,547 consecutive patients were included in this case series. In this analysis, five diagnostic periods were evaluated: 1995-1999 (period A), 2000-2004 (period B), 2005-2009 (period C), 2010-2014 (period D), and 2015-2017 (period E). We compared overall survival (OS) between the periods before and after propensity score matching (PSM) and in patients with EGFR mutation, with ALK fusion gene, or without driver mutation. RESULTS: In the past two decades the OS of patients with stage IV NSCLC improved. The median OSs for periods A, B, C, D, and E were 9.0, 11.0, 13.7, 17.9 months, and not reached, respectively. After PSM with known baseline characteristics, the trend of improvement in OS was similar. However, the OS of patients with EGFR mutation or ALK fusion gene did not improve between periods, despite the availability of several tyrosine kinase inhibitors in Japan. The OS of patients without a driver mutation was slightly longer in the period E. CONCLUSION: The introduction of new classes of drugs has significantly improved the survival of patients with stage IV NSCLC. However, the approval of similar types of drugs may not be associated with further improvement in survival.

DOI： 10.1016/j.lungcan.2019.03.008

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DOI： 10.1007/s10147-019-01439-5

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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INTRODUCTION: The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib, in a real-world clinical setting. METHODS: Post-marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase-positive NSCLC who received crizotinib during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of five medical specialists. RESULTS: The safety analysis set included 2028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade 3 or greater. Pulmonary edema-like shadows with or without diffuse alveolar damage pattern were observed in crizotinib-associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age 55 years or older, Eastern Cooperative Oncology Group performance status 2-4, smoking history, previous or concomitant ILD, and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib-induced ILD. CONCLUSIONS: Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD.

DOI： 10.1016/j.jtho.2018.11.022

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We conducted a large-scale surveillance study as a post-marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (all grades, 19.8%; grade ≥3, 2.0%), decreased neutrophil and/or white blood cell count (all grades, 7.6%; grade ≥3, 1.1%), and interstitial lung disease (all grades, 3.8%; grade ≥3, .7%). Median OS was not estimable. The 18-month cumulative OS rate was longer in patients with ECOG performance status ≤1 (vs 2 or ≥3; 83.7% vs 44.5% or 27.2%), without prior crizotinib (vs with; 81.1% vs 73.4%), receiving first-line alectinib (vs second and third or later line; 83.0% vs 79.2% or 71.9%), without brain metastases (vs with; 79.5% vs 71.5%). These data confirm the favorable safety and effectiveness of alectinib in patients with ALK-positive NSCLC in Japan.

DOI： 10.1111/cas.13977

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INTRODUCTION: The East Asia S-1 Trial in Lung Cancer (EAST-LC) was a randomized phase III study conducted in East Asia that demonstrated the non-inferiority of S-1 to docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC). Here, we reported the results of the Japanese subgroup treated with docetaxel 60 mg/m2, the standard dosage in Japan. PATIENTS AND METHODS: Patients were randomized 1:1 to receive either S-1 or docetaxel. The primary endpoint was overall survival (OS); the secondary endpoints included progression-free survival (PFS), response rate (RR), quality of life (QOL), and safety. RESULTS: Patient characteristics in the Japanese subgroup (n = 724) were similar to those in the overall EAST-LC population. Median OS was 13.4 months in the S-1 group and 12.6 months in the docetaxel group. In pemetrexed-pretreated patients, OS with S-1 was similar to that with docetaxel. Median PFS was 2.9 and 3.0 months in the S-1 and docetaxel groups, respectively. RR was 9.4% and 10.3% in the S-1 and docetaxel groups, respectively. The QOL of patients treated with S-1 was better compared with that of patients treated with docetaxel. Decreased appetite and diarrhea were more common in the S-1 group, whereas the frequency of neutropenia and febrile neutropenia was markedly higher in the docetaxel group. CONCLUSIONS: This Japanese subgroup analysis showed that S-1 had similar efficacy to docetaxel in patients with previously treated advanced NSCLC. These results are similar to those of the overall EAST-LC population.

DOI： 10.1007/s10147-019-01396-z

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BACKGROUND: Pembrolizumab, an anti-programmed cell death-1 protein monoclonal antibody, is effective for patients with advanced non-small-cell lung cancer. However, immune checkpoint inhibitors such as pembrolizumab induce various immune-related adverse events, involving the lung, liver, gastrointestinal, endocrine system, and skin. Intralymphatic histiocytosis (ILH) is a rare, chronic cutaneous disorder with a reactive inflammatory component, which often occurs in patients with rheumatoid arthritis. CASE PRESENTATION: We present a 67-year-old man with lung adenocarcinoma who developed ILH associated with pembrolizumab treatment. He was treated with palliative thoracic radiotherapy for superior vena cava syndrome. Subsequently, he received four cycles of pembrolizumab. Approximately 2.5 months after the initiation of pembrolizumab, he developed erythema on the trunk of his body. Based on findings of skin biopsies, he was diagnosed with pembrolizumab-induced ILH. Moreover, the upregulation of tumor necrosis factor-α was observed during pembrolizumab therapy. CONCLUSIONS: This is the first report of ILH induced by pembrolizumab in a patient with lung adenocarcinoma.

DOI： 10.1186/s40425-019-0534-z

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Background: Nanoparticle albumin-bound paclitaxel is indicated for the treatment of patients with lung cancer. It can induce interstitial lung disease, but the incidence of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease in clinical practice has not been determined. We investigated the incidence of interstitial lung disease in patients with lung cancer who had received nanoparticle albumin-bound paclitaxel therapy at our institution. Methods: We reviewed clinical data for patients with advanced lung cancer who received nanoparticle albumin-bound paclitaxel with or without carboplatin or bevacizumab therapy at the Nippon Medical School Main Hospital between April 2013 and September 2017. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and exclusion of other diseases. Results: A total of 110 advanced lung cancer patients received nanoparticle albumin-bound paclitaxel, and nine of them (8.2%) developed interstitial lung disease. Of those who developed interstitial lung disease, eight were treated with corticosteroids and three received cyclophosphamide pulse therapy. High-resolution computed tomography images demonstrated diffuse alveolar damage pattern pneumonitis in seven patients and organized pneumonia pattern pneumonitis in two patients. Six of the patients with diffuse alveolar damage pattern pneumonitis died from respiratory failure. The two patients with organized pneumonia pattern pneumonitis recovered. The incidence of interstitial lung disease was 19.0% (8/42) among patients with preexisting interstitial pneumonia and 1.5% (1/68) among those without preexisting interstitial pneumonia. Six patients with preexisting interstitial pneumonia met the criteria for acute exacerbation of interstitial pneumonia (14.3%). Conclusion: Nanoparticle albumin-bound paclitaxel-associated interstitial lung disease was a severe and potentially fatal adverse event. We found it demonstrated diffuse alveolar damage or organized pneumonia pattern pneumonitis, and preexisting interstitial pneumonia was associated with higher rate of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease.

DOI： 10.1093/jjco/hyy180

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BACKGROUND/AIM: Malignant mesothelioma (MM) is an aggressive tumor with poor prognosis. The establishment of a new diagnostic and therapeutic approach for MM is expected. This study investigated the diagnostic significance of tenascin XB (TNXB) for MM. MATERIALS AND METHODS: TNXB gene expression was found to be significantly higher in MM tumor tissues compared to paired normal tissues, as assessed by the Gene Expression Omnibus database. The inhibition of TNXB using small interfering RNAs suppressed the proliferation and colony formation of MM cells. Expression of TNXB and calretinin, a current diagnostic marker of MM, was evaluated by immunohistochemistry. RESULTS: The sensitivity and specificity of TNXB for MM were 80.0% and 69.5%, respectively. When the detection of TNXB was combined with that of calretinin, 83.3% of MM cases were detected. CONCLUSION: These findings suggest that TNXB is a novel diagnostic biomarker for MM. A combination of detecting TNXB and calretinin may be useful for the differential diagnosis of MM from lung adenocarcinoma.

DOI： 10.21873/anticanres.13156

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DOI： 10.1111/ajd.12868

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DOI： 10.1111/ajd.12868

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DOI： 10.1016/j.rmcr.2019.01.021

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BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) is 8.6% in Japan and 10% worldwide. Unfortunately, many patients with COPD are not correctly identified and appropriately educated regarding the condition. In this paper, we demonstrate that some citizens of Ebina City with symptoms suspicious for COPD, such as cough, sputum production, and shortness of breath, have undiagnosed COPD. We describe our activities to raise awareness of COPD through a 10-year campaign. METHODS: From 2006 to 2015, we developed activities to raise awareness of COPD, including public lectures, utilization of pulmonary function tests, and questionnaires on subjective symptoms and knowledge of COPD. RESULTS: Among 1,206 participants aged>40 years, COPD was suspected in 5.6%, as indicated by airway obstruction (i.e. forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio (FVC) <0.70). However, most of these participants were not diagnosed with COPD. Furthermore, half of these participants had not consulted a medical institution despite demonstrating symptoms. Results of the COPD awareness questionnaire, which was administered to 1,055 people, indicated that 65% of survey respondents were unaware of COPD. CONCLUSIONS: There are individuals with symptoms suspicious for COPD who are unaware of the disease at the Plaza in Ebina City. Clinicians have a responsibility to raise public awareness of COPD and to reduce the prevalence of COPD and its associated mortality.

DOI： 10.1272/jnms.JNMS.2019_86-6

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Acute exacerbation of pre-existing interstitial lung disease (ILD) associated with systemic anticancer therapy is recognized as a life-threatening adverse event of lung cancer treatment. Programmed cell death 1 (PD-1) checkpoint inhibitors, such as nivolumab, often induce pneumonitis in patients with cancer; however, the tolerance and safety of nivolumab for advanced lung cancer with ILD are unclear. We report a 72-year-old patient with lung cancer with pathologically proven idiopathic pulmonary fibrosis who was treated with nivolumab. She demonstrated pneumonitis with an organized pneumonia (OP) pattern, but no acute exacerbation of ILD featuring a diffuse alveolar damage (DAD) pattern. She was successfully treated with corticosteroid therapy, and maintained good disease control after the discontinuation of nivolumab. She also showed pseudoprogression of the primary tumor, implying infiltration of T-cells into the lung. These findings suggest that T-cell activation by nivolumab treatment might not be directly associated with acute ILD exacerbation, and that treatable OP might be a major pulmonary complication of nivolumab in patients with pre-existing ILD, similar to patients with

DOI： 10.1272/jnms.JNMS.2019_86-8

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DOI： 10.1272/jnms.JNMS.2019_86-8

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We report a case of non-small-cell lung cancer (NSCLC) to small-cell lung cancer (SCLC) transformation after epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. The patient was a man who diagnosed with EGFR-mutant advanced NSCLC. After he was introduced afatinib, his tumor had been reduced by the treatment. However, plasma pro-gastrin-releasing peptide (ProGRP) became higher with disease progression, and SCLC was detected at the second biopsy. It is suggested that elevation of plasma ProGRP level before EGFR-TKI therapy is useful for predicting EGFR-mutant NSCLC to SCLC transformation.

DOI： 10.1016/j.rmcr.2019.100837

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DOI： 10.1016/j.rmcr.2019.01.012

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DOI： 10.1007/s10147-018-1321-4

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An 82-year-old man with a recurrence of pulmonary pleomorphic carcinoma was treated with pembrolizumab. He achieved partial response after three cycles of pembrolizumab. However, he developed febrile neutropenia. A bone marrow aspiration sample revealed a decrease of mature neutrophils, and anti-neutrophil antibody was detected in blood. Computed tomography scans revealed consolidation in the right lung. Pathological findings in lung biopsy tissue revealed organizing pneumonia. Pembrolizumab-induced agranulocytosis and interstitial lung disease (ILD) were diagnosed. We initiated antibacterial therapy and granulocyte colony-stimulating factor (G-CSF). The neutrophil count immediately increased, and the fever decreased. The improvement of ILD was achieved without using systemic steroids. Moreover, the patient developed ocular myasthenia gravis induced by pembrolizumab. This is the first case report of pembrolizumab-induced agranulocytosis. Agranulocytosis was improved by administration of G-CSF without using systemic steroids. However, further studies are needed to determine the optimal treatment for patients with anti-neutrophil antibody whose tumor has progressed.

DOI： 10.1093/omcr/omy094

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Language：English   Publisher：WILEY  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs. We found that ANKRD1 which is associated with the epithelial-mesenchymal transition (EMT) phenomenon and anti-apoptosis, was overexpressed in the second-and third-generation EGFR-TKIs-resistant cells at the mRNA and protein expression levels. When ANKRD1 was silenced in the EGFR-TKIs-resistant cell lines, afatinib and osimertinib could induce apoptosis of the cell lines. Imatinib could inhibit ANKRD1 expression, resulting in restoration of the sensitivity to afatinib and osimertinib of EGFR-TKI-resistant cells. In EGFR-mutant NSCLC patients, ANKRD1 was overexpressed in the tumor after the failure of EGFR-TKI therapy, especially after long-duration EGFR-TKI treatments. ANKRD1 overexpression which was associated with EMT features and anti-apoptosis, was commonly involved in resistance to second-and third-generation EGFR-TKIs. ANKRD1 inhibition could be a promising therapeutic strategy in EGFR-mutant NSCLC patients.

DOI： 10.1038/s41598-018-33190-8

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Language：English   Publisher：OXFORD UNIV PRESS  

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BACKGROUND: Treatment with carboplatin (CBDCA) with weekly paclitaxel (PTX) has shown survival benefits compared with vinorelbine or gemcitabine in elderly patients with non-small-cell carcinoma (NSCLC). Docetaxel (DOC), however, remains a standard treatment in NSCLC. The 130-nm albumin-bound formulation of PTX (nab-PTX) has shown activity in NSCLC. Treatment with CBDCA with weekly nab-PTX showed significantly higher efficacy than CBDCA with PTX in patients with squamous histology and significantly increased overall survival (OS) in patients aged 70 years and older. PATIENTS AND METHODS: This randomized, multicenter, phase III trial (UMIN000019843) was designed to compare the efficacy and safety of CBDCA with nab-PTX with DOC in patients aged 70 years and older with advanced squamous NSCLC. Elderly patients who have received no previous chemotherapy for advanced/metastatic squamous NSCLC with Eastern Cooperative Oncology Group performance status of 0 or 1 will be randomized 1:1 to DOC (60 mg/m2 intravenous [I.V.] on day 1) or CBDCA (area under the blood concentration time curve 6 on day 1) with nab-PTX (100 mg/m2 I.V. on days 1, 8, and 15) of each 21-day cycle. The primary end point is OS. Recruitment began in December 2015 and planned enrollment is 250 patients. CONCLUSION: If OS is greater in patients treated with CBDCA with nab-PTX than with DOC, this study will provide a new standard of care for elderly patients with squamous NSCLC.

DOI： 10.1016/j.cllc.2018.05.005

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Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public.

DOI： 10.1016/j.resinv.2018.03.003

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non-small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)-resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI resistance and EMT changes in both ALK-TKI-resistant and TGF-β1-exposed H2228 cells. Tumor volumes of xenograft mice implanted with established H2228-ceritinib-resistant (H2228-CER) cells were significantly reduced after treatment with ganetespib, or ganetespib in combination with ceritinib. Some ALK-positive NSCLC patients with AXL overexpression showed a poorer response to crizotinib therapy than patients with a low expression of AXL. ALK signaling-independent AXL overexpressed in drug-tolerant cancer cell subpopulations with EMT and CSC features may be commonly involved commonly involved in intrinsic and acquired resistance to ALK-TKIs. This suggests AXL and HSP90 inhibitors may be promising therapeutic drugs to overcome drug-tolerant cancer cell subpopulations in ALK-positive NSCLC patients for the reason that ALK-positive NSCLC cells do not live through ALK-TKI therapy.

DOI： 10.18632/oncotarget.25531

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

Elotuzumab, a humanized immunoglobulin G1 monoclonal antibody targeted against signaling lymphocytic activation molecule F7 (SLAMF7), has recently been used in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma. The clinical characteristics of drug-induced interstitial lung disease (ILD) due to elotuzumab have not been clarified. In this report, we describe a patient with refractory multiple myeloma who received elotuzumab in combination with lenalidomide and dexamethasone in whom fatigue, fever and diffuse pulmonary infiltration developed. The patient had a history of long-term therapy with lenalidomide without pulmonary toxicity. Bronchoscopy with bronchoalveolar lavage was negative for infection, and transbronchial lung biopsies showed active alveolitis with lymphocytic infiltration and myxomatous change of the thick alveolar wall. After the discontinuation of elotuzumab and lenalidomide, the patient's clinical symptoms gradually improved, and spontaneous remission of the pulmonary infiltration was observed. Based on the chest CT and lung pathology findings, the exclusion of infection and pulmonary edema, and according to the clinical course, we established a diagnosis of drug-induced ILD due to elotuzumab. Clinicians should bear in mind the potential for pulmonary toxicity in patients receiving elotuzumab-containing therapy.

DOI： 10.1093/jjco/hyy049

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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.

DOI： 10.1186/s12931-018-0783-2

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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.

DOI： 10.1186/s12931-018-0783-2

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Objectives Acute exacerbation of idiopathic pulmonary fibrosis (IPF-AE) has been recognized as a fatal pulmonary disorder, but the exact prognostic factors are unknown. The aim of the present study was to analyze the clinical characteristics of patients with IPF-AE and identify the prognostic factors. Methods The medical records of 59 cases of IPF-AE were retrospectively reviewed. Clinical data, laboratory data, radiographic findings, treatment, and time from the onset of symptoms to the initiation of corticosteroid pulse therapy, i.e. symptom duration, and outcome were analyzed. Results The IPF Stage, Gender-Age-Physiology (GAP) Index, symptom duration, and the high-resolution computed tomography (HRCT) score were significantly related to the prognosis in the univariate analysis. In the multivariate analysis, the symptom duration remained a significant prognostic factor (hazard ratio of 1-day increase, 1.11; 95% confidence interval, 1.01-1.15; p=0.0427). The area under the receiver operating characteristics curve of symptom duration was statistically significant for survivors versus non-survivors (area under the curve, 0.73; p=0.012). The survival period was significantly shorter in the late-treatment groups (≥5 days; n=30) than in the early-treatment groups (<5 days; n=29; log-rank test; p<0.0001). Conclusion The time interval between the onset of symptoms and the initiation of corticosteroid pulse therapy may be an independent prognostic factor in patients with IPF-AE.

DOI： 10.2169/internalmedicine.9331-17

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Objectives Acute exacerbation of idiopathic pulmonary fibrosis (IPF-AE) has been recognized as a fatal pulmonary disorder, but the exact prognostic factors are unknown. The aim of the present study was to analyze the clinical characteristics of patients with IPF-AE and identify the prognostic factors. Methods The medical records of 59 cases of IPF-AE were retrospectively reviewed. Clinical data, laboratory data, radiographic findings, treatment, and time from the onset of symptoms to the initiation of corticosteroid pulse therapy, i.e. symptom duration, and outcome were analyzed. Results The IPF Stage, Gender-Age-Physiology (GAP) Index, symptom duration, and the high-resolution computed tomography (HRCT) score were significantly related to the prognosis in the univariate analysis. In the multivariate analysis, the symptom duration remained a significant prognostic factor (hazard ratio of 1-day increase, 1.11; 95% confidence interval, 1.01-1.15; p=0.0427). The area under the receiver operating characteristics curve of symptom duration was statistically significant for survivors versus non-survivors (area under the curve, 0.73; p=0.012). The survival period was significantly shorter in the late-treatment groups (≥5 days; n=30) than in the early-treatment groups (<5 days; n=29; log-rank test; p<0.0001). Conclusion The time interval between the onset of symptoms and the initiation of corticosteroid pulse therapy may be an independent prognostic factor in patients with IPF-AE.

DOI： 10.2169/internalmedicine.9331-17

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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DOI： 10.1111/ajd.12643

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DOI： 10.1111/ajd.12643

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

Background/Aim: Programmed cell death ligand 1 (PD-L1) expression is a predictive marker for immunotherapy effects in advanced non-small cell lung cancer (NSCLC), but its association with patient characteristics or specimens is controversial. We aimed to retrospectively analyze the association of PD-L1 expression with clinicopathological features of NSCLC patients. Materials and Methods: The PD-L1 expression and clinicopathological features of NSCLC patients were assessed from January 2017 to June 2017 in the Tokyo Metropolitan Cancer and Infectious Diseases Centre, Komagome Hospital were reviewed (n=108). Results: For PD-L1 expressions of 0% and &gt
1%, multivariate analysis showed that lymph node sample results were associated with positive PD-L1 expression. Archival samples and high serum carcinoembryonic antigen (CEA) levels were associated with negative PD-L1 expression. Sample preservation time and CEA levels correlated with PD-L1 expression. Conclusion: Nodal metastasis, sample preservation time and CEA levels were associated with PD-L1 expression in NSCLC.

DOI： 10.21873/anticanres.12326

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BACKGROUND/AIM: Recent clinical trials have shown that immune checkpoint blockades that target either PD-1 or PD-L1 yield remarkable responses in a subgroup of patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We retrospectively examined, by immunohistochemical analysis, 211 NSCLC samples. Using 32 independent samples, we also evaluated PD-L1 expression in NSCLC patients with EGFR gene mutations treated by EGFR-TKIs. RESULTS: Overall survival of PD-L1-positive stages I-III NSCLC and stage I NSCLC and stages I-III squamous cell carcinoma (SQ) were significantly shorter than those of PD-L1-negative NSCLC (p<0.01 and p=0.02 and p=0.01, respectively). In stage I NSCLC and stages I-III SQ, PD-L1 expression was found to be independent predictor of death after multivariate analysis. Response to EGFR-TKIs was not significantly different between PD-L1-positive and PD-L1-negative NSCLC patients with EGFR mutations. CONCLUSION: PD-L1 expression was a significant independent predictor of poor outcome in NSCLC patients.

DOI： 10.21873/anticanres.12281

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

It was previously revealed that Wnt signaling is activated in mesothelioma cells. Although epidermal growth factor receptor (EGFR) is expressed in mesothelioma cells, EGFR‑tyrosine kinase inhibitors (TKIs) are not effective for mesothelioma treatment. However, in non‑small cell lung cancer, the blocking of Wnt signaling has been identified to enhance the anticancer effect of EGFR‑TKIs. To confirm the anticancer effect of blocking Wnt signaling in combination with EGFR‑TKI treatment in mesothelioma, the present study evaluated the effect of simultaneous suppression of human dishevelled‑3 (Dvl‑3) expression with Dvl‑3 small interfering RNA (siRNA) and of EGFR inhibition with gefitinib on mesothelioma cell viability. Mesothelioma cell lines with and without β‑catenin gene expression were transfected with Dvl‑3 siRNA and were cultured with gefitinib, and cell viability, colony formation and cell cycle analyses were performed. Dvl‑3 siRNA downregulated the expression of Dvl‑3 in mesothelioma cells. The combination of Dvl‑3 siRNA with gefitinib acted synergistically to induce concomitant suppression of cell viability and colony formation, suggesting that inhibition of Wnt signaling by downregulating Dvl‑3 with siRNA and inhibiting EGFR with gefitinib leads to significant antitumor effects.

DOI： 10.3892/ol.2017.7382

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with a worse prognosis than some types of cancer. In patients with IPF, lung cancer is critical because of the associated high mortality rate from its progression and fatal complications from anticancer treatments. Therefore, preventing lung cancer in patients with IPF is primordial. Pirfenidone is an anti-fibrotic agent that reduces the decline in forced vital capacity. This study aimed to assess the effect of pirfenidone in the development of lung cancer in patients with IPF. Methods: Data from 261 patients with IPF with and without pirfenidone were retrospectively reviewed, and the incidence of lung cancer was analyzed. Results: In the pirfenidone group, the incidence of lung cancer was significantly lower than in the non-pirfenidone group (2.4% vs. 22.0%, P &lt
0.0001). Multivariate Cox proportional hazards regression analysis demonstrated that pirfenidone decreased the risk of lung cancer (hazard ratio, 0.11
95% confidence interval, 0.03 to 0.46
P = 0.003), whereas coexisting emphysema increased the incidence of lung cancer (hazard ratio, 3.22
95% confidence interval, 1.35 to 7.70
P = 0.009). Conclusions: Pirfenidone might correlate with a decreased risk of lung cancer in patients with IPF. However, no definite conclusion can be drawn from this retrospective study, and a multicenter, prospective cohort study is still warranted to confirm the effect of pirfenidone on lung cancer in patients with IPF.

DOI： 10.1016/j.resinv.2017.09.007

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We herein describe the case of a 67-year-old woman with advanced lung adenocarcinoma who developed interstitial lung disease (ILD) with alveolar hemorrhage induced by pembrolizumab. She received four courses of pembrolizumab therapy and achieved a partial response. She had no respiratory symptoms; however, chest radiography and computed tomography (CT) revealed ground-glass opacities (GGOs) and crazy-paving pattern. Based on findings of bloody bronchoalveolar lavage fluid and transbronchial lung biopsy samples, pembrolizumab-induced ILD with alveolar hemorrhage was diagnosed. Corticosteroid therapy rapidly improved alveolar hemorrhage and regressed GGOs on CT scan. This is the first report on ILD with alveolar hemorrhage induced by pembrolizumab.

DOI： 10.2147/OTT.S169321

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Background: The North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events. Patients and methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cut-off point (March 2017) for the entire population (n=80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report. Conclusions: This updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the EGFR-mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice. Trial registration number: UMIN C000002789, Post-results.

DOI： 10.1136/esmoopen-2017-000313

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A 41-year-old woman presented complaining of cough and purpura for one month. On her first visit, a blood test demonstrated peripheral blood eosinophilia, but chest radiography showed no abnormalities. However, 2 days after the first visit, she went to the emergency room because of fever and right-sided chest pain. Contrast-enhanced computed tomography of the chest showed pulmonary embolism and air space consolidation. Thrombosis was present in the popliteal vein. Bronchoscopy revealed alveolar hemorrhage and increased eosinophils in the bronchoalveolar lavage fluid, and a skin biopsy demonstrated a perivascular eosinophilic infiltrate. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). We started steroid therapy and low-molecular-weight heparin (LMWH). The chest pain and fever disappeared, and the peripheral eosinophil count normalized. However, the thrombosis in the leg worsened. It was dramatically improved by changing from LMWH to oral rivaroxaban. The thrombogenic risk of eosinophilia should be recognized. This case suggests that oral rivaroxaban is useful when thrombosis is uncontrolled by LMWH in a patient with EGPA.

DOI： 10.1016/j.rmcr.2018.05.008

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Immuno-checkpoint inhibitors (ICI) have become an effective treatment option for non-small-cell lung cancer patients. However, ICI therapy was reported to be less effective in patients with epidermal growth factor receptor (EGFR) mutations than in those with wild-type EGFR. We report here that an non-small-cell lung cancer patient with the EGFR mutant T790M showed a programmed cell death ligand 1 (PD-L1) expression level that increased from <25% to >90% after eighth-line osimertinib therapy. He was treated with pembrolizumab as a ninth-line treatment, and attained stable disease. After the pembrolizumab therapy, he was treated with gemcitabine, which produced a good response despite being the 10th-line treatment. We should consider administering ICI and chemotherapy even to EGFR mutant patients after failure of EGFR tyrosine kinase inhibitor, especially in cases with high PD-LI expression.

DOI： 10.2147/OTT.S168598

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Background: The aim of this trial was to evaluate the safety and efficacy of oral hydration as a substitute for intravenous hydration after cisplatin (CDDP) administration. Methods: The major eligibility criteria included patients with lung cancer, indications for a CDDP-based regimen at a dose of 60 mg/m2 or higher, an age of between 20 and 74 years and adequate renal function. Antiemetic prophylaxis consisted of an appropriate dose of palonosetron, aprepitant, dexamethasone and magnesium sulfate (8 mEq). Five hundred millilitres of commercially available oral hydration solution (OS-1: Otsuka Pharmaceutical Factory, Tokushima, Japan) was used as a substitute for intravenous posthydration. The planned sample size was 46 to reject a proportion of 70% under an expectation of 88% with a power of 90% and an alpha error of 5%. Results: Between May and November 2013, 31 men and 15 women with a median (range) age of 65 (33-74) years were enrolled from three institutions. Of these, five received adjuvant chemotherapy, 17 received definitive chemoradiotherapy and 24 received chemotherapy for advanced diseases. The median (range) number of chemotherapy cycles was 4 (1-5). After the first cycle of CDDP administration, none of the patients experienced a creatinine elevation of grade 2 or higher, thereby meeting the primary endpoint. Of the 46 patients, 45 (97.8%, 95% CI 88.2 to 99.9) completed the CDDP-based chemotherapy without grade 2 or higher renal dysfunction. Conclusion: Oral hydration can be used as a safe and convenient substitute for intravenous posthydration for CDDP administration at the standard dose. Trial registration number: UMIN000010201.

DOI： 10.1136/esmoopen-2017-000288

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: No drugs have been approved for the treatment of patients with pulmonary hypertension (PH) secondary to idiopathic pulmonary fibrosis (IPF), particularly those with idiopathic honeycomb lung. This study was conducted to investigate the long-term efficacy and safety of bosentan for PH based on changes in prognosis and respiratory failure.
Methods: IPF patients with borderline or less severe PH and completely organized honeycomb lung were randomized (1:1) to bosentan or no treatment for PH for 2 years and assessed at baseline and every 6 months for respiratory failure, activities of daily living (ADL), lung and heart functions by right cardiac catheterization, and other parameters. An interim analysis was performed, however, following detection of a significant survival benefit favoring bosentan therapy.
Results: Significant differences were noted for the bosentan-treated (n = 12) vs. untreated (n = 12) groups in hospital-free survival (603.44 +/- 50.074 days vs. 358.87 +/- 68.65 days; hazard ratio [HR], 0.19; P = 0.017) and overall survival (671 days vs. 433.78 +/- 66.98 days; HR, 0.10; P = 0.0082). Again, significant improvements were noted for the bosentan-treated group from baseline to month 6 or 12 in several indices in ADL, pulmonary circulation, and %DLCO. Without requiring O-2 inhalation, bosentan was associated with no increase but a trend toward a decrease in adverse events and an improvement in respiratory status.
Conclusions: Bosentan tended to improve prognosis and ADL without worsening respiratory failure in IPF patients with borderline or less severe PH and completely organized honeycomb lung alone.

DOI： 10.1186/s12890-017-0523-2

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Objective: Erlotinib plus gemcitabine is approved in Japan for the treatment of metastatic pancreatic cancer. The POLARIS surveillance study investigated safety (focusing on interstitial lung disease [ILD]) and efficacy of erlotinib plus gemcitabine in Japanese pancreatic cancer patients.
Methods: Patients receiving erlotinib plus gemcitabine for pancreatic cancer in Japan between July 2011 and August 2012 were enrolled. ILD-like events were independently confirmed by a review committee. Overall survival (OS) and progression-free survival (PFS) were assessed, and risk factors for ILD occurrence were analyzed by multivariate Cox regression analysis.
Results: Safety data were available for 843 patients and efficacy data for 841. Adverse drug reactions were reported in 83.5% of patients, no new safety signals were identified. ILD events were confirmed by the review committee in 52 patients (6.2%), with two fatal cases (0.2%). Median time from initial erlotinib treatment to ILD events was 70.5 days. Of the 52 patients with ILD events, 86.5% improved or fully recovered from ILD (median time 24 days). Multivariate analysis identified previous or concurrent lung disease (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.0-4.5; P = 0.0365) and = 3 organs with metastases (HR, 4.2; 95% CI, 2.2-8.2; P &lt; 0.0001) as potential ILD risk factors. Accumulated OS rate at 28 weeks was 68.2%, and median PFS was 92 days (95% CI, 86-101).
Conclusions: Erlotinib plus gemcitabine has an acceptable safety and efficacy profile in pancreatic cancer; however, patients should be assessed for previous/concurrent lung disease and metastatic burden, before and during treatment.

DOI： 10.1093/jjco/hyx075

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A 62-year-old woman was diagnosed with stage IV lung adenocarcinoma. After resection of a metastatic brain tumor, she had received first-line chemotherapy consisting of 6 courses of carboplatin and pemetrexed, then 14 courses of maintenance therapy of pemetrexed until disease progression. As second-line treatment, she was administered nanoparticle albuminbound paclitaxel(nab-paclitaxel)monotherapy. A nearly complete response(nearly CR)has been maintained for 3 years without any severe adverse events. Although there is insufficient evidence for the use of nab-paclitaxel monotherapy as second-line chemotherapy, it could be an effective treatment option for patients with recurrent advanced non-small cell lung cancer.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Cyclic mechanical stretching (CMS) of the alveolar epithelium is thought to contribute to alveolar epithelial injury through an increase in oxidative stress. The aim of this study was to investigate the mechanisms of CMS induced oxidative stress in alveolar epithelial cells (AECs). A549 cells were subjected to CMS, and the levels of 8-isoprostane and 3-nytrotyrosine were measured. Twenty-four hours of CMS induced a significant increase in the levels of 8-isoprostane and 3-nytrotyrosine. Although CMS did not increase the xanthine oxidase activity or the mitochondrial production of reactive oxygen species, it upregulated the expression of nicotine adenine dinucleotide phosphate oxidase (NOX) 2, 4, 5 and DUOX2. The NOX inhibitors DPI and GKT137831 significantly attenuated CMS-induced oxidative stress. Furthermore, the measurement of annexin V/propidium iodide by flow cytometry showed that CMS induced late-phase apoptosis/necrosis, which was also attenuated by both DPI and GKT137831. These data suggest that CMS mainly induces oxidative stress, which may lead to cell injury by activating NOX in AECs.

DOI： 10.1016/j.resp.2017.04.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Crystal-storing histiocytosis (CSH) is an uncommon finding in lymphoplasmacytic disorders that presents histiocytes with abnormal intralysosomal accumulations of immunoglobulin light chains as crystals of unknown etiology. A 38-year-old woman with antiphospholipid syndrome had a surgical lung biopsy because of multiple lung mass lesions. In a right middle lobe lesion, lymphoplasmacytic cells had a monocytoid appearance, destructive lymphoepithelial lesions, and positive immunoglobulin heavy chain (IGH) gene rearrangements. A right upper lobe lesion manifested proliferating rounded histiocytes with abundant, deeply eosinophilic cytoplasm and negative IGH gene rearrangements. Electron microscopy and mass spectrometry revealed a case of pulmonary CSH: abnormal proliferation of the immunoglobulin k chain of a variable region that may be crystallized within plasma cells and histiocytes. We report a rare case of localized pulmonary CSH complicating pulmonary mucosa-associated lymphoid tissue lymphoma with multiple mass lesions. We demonstrate advances in the understanding of the pathogenesis of CSH by various analyses of these lesions. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2016.10.028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Cancer stem cell (CSC) properties have been recently proposed to explain tumor carcinogenesis and multi drug resistance in several human cancers, including non-small cell lung cancer (NSCLC). The present study examined the protein expression of three CSC-associated markers, namely ATP binding cassette subfamily B member 1 (ABCB1), aldehyde dehydrogenase 1 family member Al (ALDH1A1) and cluster of differentiation (CD) 44, by immunohistochemistry in 194 NSCLC patients who underwent complete resection of NSCLC tumors. The association between the expression of these proteins and patient prognosis was evaluated to clarify the prognostic significance of CSC-associated markers in NSCLC patients. Positive staining for ABCB1 demonstrated a trend toward worse survival compared with negative staining in stage I-III NSCLC. Negative staining for ALDH1 or CD/44 exhibited a trend toward worse survival compared with positive staining in stage I-III NSCLC. It was observed that patients with stage I lung adenocarcinoma (ADC) showing positivity for ABCB1 expression had significantly poorer survival than those with negative ABCB1 staining (P=0.03). Furthermore, stage I ADC patients with wild-type epidermal growth factor receptor (EGFR) who exhibited positive staining for ABCB1 had significantly shorter disease-free survival (DFS) compared with patients with negative staining for ABCB1 (P&lt;0.01). Analyses by univariate and multivariate Cox proportional hazards models revealed that ABCB1-positive staining was significantly associated with DFS and was an independent prognostic factor (hazard ratio, 3.49; P&lt;0.05) in these patients. These results suggest that ABCB1 protein expression is useful for predicting prognosis and selecting patients for post-operative therapy in stage I lung ADC patients, particularly those harboring wild-type EGFR.

DOI： 10.3892/ol.2017.6145

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Nivolumab, a monoclonal antibody targeting the PD-1, has recently been used as a standard treatment for lung cancer, melanoma and renal cell carcinoma. We herein report the case of a patient undergoing treatment for non-small cell lung cancer (NSCLC) who developed interstitial pneumonia which featured nivolumab-induced granuloma formation. An 82-year-old male patient with NSCLC was initially treated with radiation therapy and chemotherapy. Five years later, however, he developed metastatic carcinoma in a hilar lymph node accompanied by ground glass opacity (GGO), suggesting tumor cell invasion. Treatment with nivolumab was initiated. At 21 days after the first dose of nivolumab, he complained of cough and dyspnea. Chest computed tomography scans demonstrated tumor progression and newly formed GGO in the area surrounding the primary tumor. Fibrosing active alveolitis with granuloma formation and organizing pneumonia findings were observed in the pathological examination of a transbronchial lung biopsy (TBLB) specimen. No malignant cells were found in TBLB. A bacteriological analysis of cultures, a PCR, and special staining did not reveal any infections. The patient's pneumonitis improved after treatment with systemic corticosteroids. Granuloma-forming interstitial pneumonia may be a feature of nivolumab-associated pneumonitis.

DOI： 10.1007/s13691-017-0291-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background/Aim: We evaluated the usefulness of reverse transcription-polymerase chain reaction (RT-PCR) for detecting anaplastic lymphoma kinase (ALK) translocations using cytology samples from lung cancer patients. Materials and Methods: We analyzed ALK translocations by RT-PCR in cytology samples from lung cancer patients diagnosed at the Nippon Medical School Hospital between 2013 and 2015. Immunochemistry (IHC) and break-apart fluorescence in situ hybridization (FISH) were also performed on available tissue samples. Results: A total of 155 cytology samples were analyzed in our study. We obtained 115 (68%) samples from bronchial lavage. We were able to determine 153 (99%) results by RT-PCR with 4 (3%) positive samples. The four samples positive by RT-PCR were also positive by IHC and FISH performed on the tissue samples collected simultaneously. Conclusion: RT-PCR is a suitable method for detecting ALK translocations using cytology samples from patients with primary lung cancer, especially when tissue samples are not available.

DOI： 10.21873/anticanres.11696

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

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 extra cellular matrix, whose expression is regulated by transforming growth factor (TGF)-beta 1 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-beta 1, 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-beta 1 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-beta 1-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. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.pupt.2017.03.003

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AXL, a receptor tyrosine kinase implicated in cell survival, proliferation, and migration, is also associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy. However, its prognostic significance in lung adenocarcinoma (AD) remains unclear. We therefore evaluated the prognostic significance of the expression of AXL and/or its ligand, growth arrest specific 6 (GAS6), in completely resected lung AD. We evaluated the relationship between AXL, GAS6, and vimentin expression, as determined by immunohistochemistry (IHC) analysis, with overall survival and disease-free survival in 113 patients with stages I-III lung AD. Protein expression was also assayed using western blot analysis in 10 lung AD cell lines. AXL-positive (AXL(+)), GAS6-positive (GAS6(+)), or AXL(+)/GAS6(+) staining was significantly associated with vimentin-positive (vimentin) expression. AXL(+)/GAS6(+) and vimentin showed a negative tendency toward an association with EGFR mutation. AXL(+), GAS6(+), or AXL(+)/GAS6(+) status significantly correlated with poor overall survival. In stage I cases, AXL(+)/VGAS6(+) status significantly correlated with poor overall survival and disease-free survival, especially in cases with wild-type EGFR. In multivariate analysis, AXL/GAS6 classifications in stage I as well as in stages I-III lung AD were found to be independent factors for poor patient outcomes. Unlike lung AD cell lines with mutant EGFR, almost all cells with wild-type EGFR showed AXL and vimentin co-expression as determined by western blotting. AXL(+) and GAS6(+) expression is relevant to a poor prognosis in resected lung AD patients at stage I. AXL/GAS6 might serve as crucial predictive and prognostic biomarkers and targets to identify individuals at high risk of post-operative death.

DOI： 10.3892/or.2017.5594

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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)-β1 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-β1, 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-β1 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-β1-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.

DOI： 10.1016/j.pupt.2017.03.003

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DOI： 10.3892/mco.2017.1214

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DOI： 10.1200/JCO.2017.35.15_suppl.e21660

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Background and objectiveThe exacerbation-prone phenotype of COPD is particularly important, as exacerbations lead to poor quality of life and disease progression. We previously found that COPD patients who lack Siglec-14, a myeloid cell protein that recognizes bacteria and triggers inflammatory responses, are less prone to exacerbation. We hypothesized that the variations in other SIGLEC genes could also influence COPD exacerbation frequency, and investigated the association between SIGLEC9 polymorphisms and the exacerbation-prone phenotype of COPD.
MethodsWe examined whether SIGLEC9 polymorphisms affect the frequency of COPD exacerbation in 135 subjects within our study population, and also analysed the correlation between the genotypes and the severity of airflow obstruction and emphysema in 362 Japanese smokers including 244 COPD patients. The association between these single nucleotide polymorphisms (SNPs) and COPD phenotypes were also assessed in a Caucasian population of ECLIPSE study. The effects of these coding SNPs (cSNPs) on Siglec-9 protein functions were analysed using in vitro assays.
ResultsThe G allele of rs2075803 and rs2075803 G/rs2258983 A(GA) haplotype in SIGLEC9 was associated with higher frequency of exacerbations and the extent of emphysema in COPD. These results did not replicate in the ECLIPSE study. A myeloid cell line expressing the Siglec-9 variant corresponding to GA haplotype produced more TNF- than the one expressing the variant corresponding to the other major haplotype.
ConclusionThe SIGLEC9 rs2075803 G/rs2258983 A haplotype, which corresponds to a Siglec-9 variant that is less effective at suppressing inflammatory response, may be a risk factor for the development of emphysema.
A haplotype of SIGLEC9 gene was associated with exacerbation frequency and emphysema in Japanese COPD patients (but not in ECLIPSE cohort). The Siglec-9 protein encoded by this haplotype was hypomorphic in its ability to suppress myeloid cell inflammatory responses. This study reinforces the connections between endogenous lectins and COPD phenotypes.

DOI： 10.1111/resp.12952

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Background The efficacy and safety of bevacizumab in elderly patients with non-small cell lung cancer remain controversial. This study focused on both selecting fit elderly patients and overcoming interpatient variability with respect to pharmacodynamics. Methods Elderly (age: &gt;= 70 years) patients with advanced non-squamous non-small cell lung cancer were enrolled. Patients with uncontrolled congestive heart failure and uncontrolled diabetes were excluded. The treatment regimen comprised carboplatin at an area under the curve of 5 mg/ml/min on day 1, paclitaxel at 90 mg/m(2) on days 1 and 8, and bevacizumab at 15 mg/kg on day 1 every 21 days for up to 4 cycles, followed by maintenance bevacizumab. Dose reduction due to side effects was performed, with a wide range of doses of paclitaxel from 23 mg/m(2)/week to 60 mg/m(2)/week. Results Of the 36 patients entered, 38.9% required a dose reduction or cancellation of paclitaxel administration on day 8, and 75% patients were able to complete 4 cycles of triplet therapy. The response rate, primary endpoint, was 69.4% (95% confidence interval [CI]: 51.9-83.7). The median progression free survival and overall survival were 8.4 months and 29.2 months, respectively. The most common adverse events included neutropenia, hypertension, anemia, and infection. Although Grade &gt;= 3 adverse events were observed in 24 patients (66.7%), there were no deaths due to toxicity. Conclusion Carboplatin plus weekly paclitaxel with bevacizumab is a feasible, effective first-line regimen for elderly non-small cell lung cancer patients. (UMIN00006622).

DOI： 10.1007/s10637-017-0436-1

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer Singapore  

Anaplastic lymphoma tyrosine kinase (ALK) inhibitors have strong antitumor effects in patients with non-small cell lung cancer (NSCLC) with ALK fusion gene. The ALK inhibitors crizotinib, ceritinib, and alectinib were developed. Companion diagnostic and therapeutic agents for specific ALK inhibition have been simultaneously approved, but this is causing severe inconvenience in clinical practice for diagnosing ALK-positive lung cancer. The therapeutic strategy for the patients is mainly by molecularly targeted therapy. The current status of ALK inhibitors and specificity of biomarkers in ALK-positive lung cancer are reviewed in this study. In summary, there are many arguments relating to the appropriate use of crizotinib, ceritinib, or alectinib as the situation demands and regarding which agent to use first. Many clinicians question the limitations of companion diagnostics and therapeutic agents
a more flexible response will be expected in order to accurately diagnose and provide proper treatment of ALK-positive lung cancer.

DOI： 10.1007/978-981-10-2002-5_11

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Introduction: There are no validated molecular methods that prospectively identify patients with surgically resected lung squamous cell carcinoma (SCC) at high risk for recurrence. By focusing on the expression of genes with known functions in development of lung SCC and prognosis, we sought to develop a robust prognostic classifier of early stage lung SCC.
Methods: The expression of 253 genes selected by literature search was evaluated in microarrays from 107 stage I/II tumors. Associations with survival were evaluated by Cox regression and Kaplan-Meier survival analyses in two independent cohorts of 121 and 91 patients with SCC, respectively. A classifier score based on multivariable Cox regression was derived and exam fined in six additional publicly available data sets of stage I/II lung SCC expression profiles (n = 358). The prognostic value of this classifier was evaluated in meta analysis of patients with stage I/II (n = 479) and stage I (n = 326) lung SCC.
Results: Dual specificity phosphatase 6 gene (DUSP6) and actinin alpha 4 gene (ACTN4) were associated with prognostic outcome in two independent patient cohorts. Their expression values were utilized to develop a classifier that identified patients with stage I/II lung SCC at high risk for recurrence (hazard ratio [HR] = 4.7, p = 0.018) or cancer-specific mortality (HR = 3.5, p = 0.016). This classifier also identified patients at high risk for recurrence (HR = 2.7, p = 0.008) or death (HR = 2.2, p = 0.001) in publicly available data sets of stage I/II and in meta analysis of stage I patients.
Conclusions: We have established and validated a prognostic classifier to inform clinical management of patients with lung SCC after surgical resection. Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.

DOI： 10.1016/j.jtho.2016.08.141

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Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) was recently proposed as an entity to be included among rare idiopathic interstitial pneumonias (IIPs). However, the cause, clinical features and prognosis of this rare entity have not been elucidated. Objectives: We aimed to examine the clinical features, outcomes and prognostic factors for IPPFE in comparison to those of idiopathic pulmonary fibrosis (IPF). Methods: We retrospectively analyzed 20 patients with IPPFE and 71 with IPF. We compared clinical features, blood examination data, and respiratory functions at the time of diagnosis. Results: The IPPFE group had a significantly lower body mass index (BMI), percent forced vital capacity (% FVC), total lung capacity (% TLC) and expiratory reserve volume (% ERV), as well as a higher residual volume to TLC (RV/TLC) ratio than the IPF group. The annual FVC changes in the IPPFE group (-326ml/year) were significantly larger than those in the IPF group (-142ml/year). Survival was significantly poorer in the IPPFE than in the IPF group (P = 0.021). BMI and the partial pressure of oxygen in arterial blood (PaO2) were significantly related to the outcome of IPPFE. Conclusions: Our present results indicate the prognosis of IPPFE patients to be poorer than that of IPF patients. We advocate that BMI and arterial blood PaO2 be determined at the first visit as these parameters are closely related to patients' outcomes. Prospective evaluation of IPPFE starting in the subclinical phase is necessary to assure that appropriate measures are taken before progression.

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A 72-year-old woman was admitted to our hospital and was diagnosed with interstitial pneumonia (IP) associated with amyopathic dermatomyositis (ADM). The patient experienced three acute IP exacerbations in the 7 years that followed, which were each treated and resolved with steroid pulse therapy. The patient was closely examined for respiratory failure with right heart catheterization (RHC), which demonstrated that she had a mean pulmonary artery pressure (mPAP) of 34 mmHg. The patient was thus diagnosed as having pulmonary hypertension (PH) associated with anti-synthetase syndrome (ASS) and was started on bosentan therapy, which led to improvements in mPAP as well as in subjective symptoms over time. Indeed, she had had no acute exacerbations with serum markers of IP remaining low over 6 years following initiation of bosentan therapy, suggesting that bosentan may have a role in controlling IP. In addition, she was confirmed to be anti-ARS antibody-positive after 5 years of bosentan therapy, when anti-aminoacyl tRNA synthetase (anti-ARS) antibody testing became available.

DOI： 10.1016/j.rmcr.2017.03.021

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Background: Chemotherapy-induced nausea and vomiting (CINV) is a major adverse toxicity of cancer chemotherapy. Recommended treatments for prevention of CINV vary among published guidelines, and optimal care for CINV caused by moderately emetogenic chemotherapy has not been established. This study assessed the efficacy and safety of triple antiemetic therapy comprising palonosetron, dexamethasone and aprepitant for carboplatin-based chemotherapy. Chemotherapy-naive patients with lung cancer scheduled for a first course of a carboplatin-containing regimen formed the study cohort. Patients were pretreated with antiemetic therapy comprising palonosetron (0.75 mg, i.v.) and dexamethasone (9.9 mg, i.v.) on day 1, and aprepitant (125 mg, p.o.) on day 1 followed by 80 mg on days 2 and 3. Primary endpoint was the proportion of patients who did not experience vomiting and did not require rescue medication [complete response (CR)] in the acute phase (0-24 h), late phase (24-168 h) and overall. Secondary endpoint was the proportion of patients who experienced no vomiting episodes and no more than mild nausea without the need for rescue medication [complete control (CC)].
Results: Prevalence of a CR during the acute phase, delayed phase, and overall was 100, 91.9 and 91.9%, whereas that of CC was 100, 84.4 and 84.4%, respectively. The most common adverse event was mild constipation; severe adverse events related to antiemetic treatment were not observed.
Conclusion: Triple antiemetic therapy comprising palonosetron, dexamethasone and aprepitant shows excellent effects in the prevention of CINV in patients receiving a carboplatin-containing regimen.

DOI： 10.1186/s40064-016-3769-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Context: CC chemokine ligand 18 (CCL18) is suggested to play a role in the development of pulmonary fibrosis. Macrophages are thought to be the main source of CCL18, and the effect of pirfenidone, an anti-fibrotic agent for idiopathic pulmonary fibrosis, on the expression of CCL18 in macrophages warrants investigation.Objective: The purpose of this study was to investigate the effect of pirfenidone on the expression of CCL18 in macrophages.Materials and methods: U937 cells were differentiated into macrophages by phorbol myristate acetate and then stimulated with recombinant IL-4 to induce the production of CCL18. The cells were treated with pirfenidone, and the mRNA and protein levels for CCL18 were measured by a reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The effects of pirfenidone on the IL-4 receptor (IL-4R) expression and STAT6 activation were investigated and on the JAK kinase activity were measured using the Z-LYTE kinase assay.Results: Pirfenidone significantly suppressed the expression of CCL18 when the cells were treated with concentrations of 50-250g/mL. Pirfenidone did not affect the expression of the IL-4R components. The selective STAT6 inhibitor AS1517499 suppressed CCL18 expression. Both AS1517499 and pirfenidone suppressed STAT6 phosphorylation (p&lt;.05), although the effect of pirfenidone was less marked than that of AS1517499. The Z-LYTE kinase assay showed a reduction in the activities of JAK1, JAK3 and TYK2 by pirfenidone.Conclusion: Pirfenidone suppresses CCL18 expression in macrophages and this effect is thought to be attributed partly to the inhibition of STAT6 phosphorylation.

DOI： 10.1080/08923973.2016.1247852

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

In the CATS (Cisplatin And TS-1) randomized trial comparing cisplatin plus either docetaxel (DP arm) or TS-1 (SP arm) in lung cancer, efficacy was found to be equivalent but the global quality of life (QOL) score was higher in the SP arm. The purpose of the current study was to identify which of the adverse events (AEs) contributed to the deterioration of QOL.
QOL and AE data from the CATS trial were used to quantitatively analyze the relationship between deterioration of QOL score and occurrence of AEs. Subtracted values of the QOL score from post-chemotherapy to pre-chemotherapy were fully compared between patients with or without each AE (Student's t test, significance level = 0.001). Multivariate linear regression analysis was also performed. Analysis of variance was performed to identify whether grade of AE(s) might be significantly correlated with the deterioration of the QOL score (significance level of 0.05).
As expected, gastrointestinal (GI) toxicities were associated with worsening of a variety of QOL items in both trial arms, detected by both univariate and multivariate analysis (p &lt; 0.001 and p &lt; 0.0001, respectively). Multivariate analysis unpredictably indicated that an increase in serum bilirubin level was the only AE that was uniquely associated with worsening of physical functioning (p = 0.0002), cognitive functioning (p &lt; 0.0001), and financial problems (p = 0.0005) in the DP arm, although not in the SP arm. GI toxicities tended to be prolonged in the SP arm.
An increase in serum bilirubin level may contribute to the worse global QOL of subjects in the DP arm in the CATS trial. The method we used here may be a unique approach to identify unpredictable AE(s) that worsen the QOL of patients treated by chemotherapy.

DOI： 10.1007/s10147-016-0960-6

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The social or familial factors influencing the location chosen for end-of-life (EOL) care for terminally ill breast cancer patients are unknown.
We retrospectively analyzed 195 patients with recurrent or progressive breast cancer who received anticancer treatment at the National Cancer Center Hospital between January 2008 and May 2012. Detailed data concerning the patients' demographic, familial, and clinical characteristics were collected, and multivariate and Cox logistic regression analyses were performed to evaluate the impact of these characteristics on the place of EOL care and on survival, respectively.
Sixty-eight patients (34.9 %) died in a hospital, 26 patients (13.3 %) at home, and 101 patients (51.8 %) in hospice. Most of the patients having caregivers received EOL care at palliative care facilities (hospice or home) [odds ratio (OR) 2.57; 95 % confidence interval (CI) 1-6.6; p = 0.05]. In contrast, patients with factors suggesting a clinically severe status (performance status aeyen2, use of opioids, delirium, and ascites) more often received EOL care in a hospital. Among patients who received EOL care at hospice or home, patients with minor children received EOL care at home (OR 0.08; 95 % CI 0.02-0.38; p = 0.001). Patients with brain metastases chose hospice (OR 12.37; 95 % CI 2.25-68.13; p = 0.004). Furthermore, having a caregiver was associated with prolonged survival (hazard ratio 0.62; 95 % CI 0.39-0.97; p = 0.035).
Familial factors such as having children and caregivers significantly influenced the place of EOL care for terminally ill breast cancer patients.

DOI： 10.1007/s12282-015-0643-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Objective: Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution.
Methods: We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases.
Results: We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiation fibrosis (n = 3). No patients showed the presence of honeycomb lung. Among the 13 patients, 1 (7.7%) developed interstitial lung disease after amrubicin chemotherapy.
Conclusion: Interstitial lung disease occurred in 3.3% of the patients in our study; this appeared to be less frequent than the rates in previous reports. Preexisting pulmonary fibrosis may be a risk factor for interstitial lung disease; however, no fatal cases were found among the patients with asymptomatic pulmonary fibrosis without honeycomb lung. It is thus considered to be necessary to carefully assess the possibility of preexisting pulmonary fibrosis and clarify the presence or absence of honeycomb lung before starting amrubicin chemotherapy.

DOI： 10.1093/jjco/hyw043

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Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Differentiating low-grade lymphoma from preexisting sarcoidosis is difficult because of their pathological similarity. This article describes a case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis. The patient, a 45-year-old Japanese man, presented with a 10-year history of pulmonary sarcoidosis and 5-year history of ocular sarcoidosis with histologic findings. Because only the right S3 lung nodule had gradually enlarged, partial resection was performed. Pathological study revealed noncaseous epithelioid granulomas with lymphoplasmacytic proliferation but also marked lymphoid cell proliferation with lymphoepithelial lesion findings that differed from findings of typical sarcoid lesions. Our lymphoepithelial lesion evaluation via immunohistochemistry and analysis of Ig heavy-chain gene rearrangements with assessment of Propionibacterium acnes specific antibody reactions allow us to report, for the first time, this case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis in exactly the same location, which may be significant for differentiating these diseases and understanding their pathogenic association. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2015.12.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Cisplatin is a highly effective anticancer drug for treatment of various tumors including non-small-cell lung cancer (NSCLC), and is especially useful in cases nonresponsive to molecular-targeted drugs. Accumulating evidence has shown that cisplatin activates the p53-dependent apoptotic pathway, but it also induces apoptosis in p53-mutated cancer cells. Here we demonstrated that DNA-damage inducible proapoptotic BH3 (Bcl-2 homology region 3)-only Bcl-2 family members, Noxa, Puma, Bim and Bid, are not involved in cisplatin-induced apoptosis in human NSCLC cell lines. In contrast, the expression of proapoptotic multidomain Bcl-2-family members, Bak and Bax, was induced by cisplatin in p53 dependent and-independent manners, respectively. Moreover, in wild-type p53-expressing cells, cisplatin mainly used the Bak-dependent apoptotic pathway, but this apoptotic pathway shifted to the Bax-dependent pathway by loss-of-function of p53. Furthermore, both Bak- and Bax-induced apoptosis was enhanced by the antiapoptotic Bcl-2 family member, Bcl-X-L knockdown, but not by Mcl-1 knockdown. From this result, we tested the effect of ABT-263 (Navitoclax), the specific inhibitor of Bcl-2 and Bcl-XL, but not Mcl-1, and found that ABT-263 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells in the presence or absence of p53. These results indicate a novel regulatory system in cisplatin-induced NSCLC cell apoptosis, and a candidate efficient combination chemotherapy method against lung cancers. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2016.03.053

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We report a case of 50-year-old Japanese female with anaplastic lymphoma kinase (ALK)-positive, crizotinib-resistant lung adenocarcinoma, whose leptomeningeal carcinomatosis and spinal cord metastases were dramatically improved by the second-generation ALK inhibitor alectinib. Magnetic resonance imaging (MRI) revealed multiple brain metastases at diagnosis of lung cancer. Carboplatin/paclitaxel/bevacizumab chemotherapy was administered, but enlargement of brain tumors was observed after 3 months. Gamma knife radiosurgery was performed and then the patient received second-line chemotherapy with crizotinib. After 4 months brain MRI revealed the development of leptomeningeal carcinomatosis. Despite the patient undergoing whole brain radiotherapy, spinal cord metastases appeared. Third-line chemotherapy with alectinib was initiated for the management of metastases in central nervous system (CNS) including those in the leptomeninges and spine cord. After 3 months, marked tumor responses were observed in both the leptomeningeal carcinomatosis and spinal cord metastases. This report suggests that alectinib is a promising drug for ALK-positive lung adenocarcinoma with CNS metastases.

DOI： 10.1007/s13691-015-0231-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Dove Medical Press Ltd.  

Background: COPD is concomitantly present in ~30% of patients with heart failure. Here, we investigated the pulmonary function test parameters for left ventricular (LV) diastolic dysfunction and the relationship between pulmonary function and LV diastolic function in patients with COPD. Patients and methods: Overall, 822 patients who underwent a pulmonary function test and echocardiography simultaneously between January 2011 and December 2012 were evaluated. Finally, 115 patients with COPD and 115 age- and sex-matched control patients with an LV ejection fraction of ≥50% were enrolled. Results: The mean age of the patients was 74.4±10.4 years, and 72.3% were men. No significant differences were found between the two groups regarding comorbidities, such as hypertension, diabetes mellitus, and anemia. The index of LV diastolic function (E/e') and the proportion of patients with high E/e' (defined as E/e' ≥ 15) were significantly higher in patients with COPD than in control patients (10.5% vs 9.1%, P=0.009
11.3% vs 4.3%, P=0.046). E/e' was significantly correlated with the residual volume/total lung capacity ratio. Univariate and multivariate analyses revealed severe COPD (Global Initiative for Chronic Obstructive Lung Disease III or IV) to be a significant predictive factor for high E/e' (odds ratio [OR] 5.81, 95% confidence interval [CI] 2.13-15.89, P=0.001 and OR 6.00, 95% CI 2.08-17.35, P=0.001, respectively). Conclusion: Our data suggest that LV diastolic dysfunction as a complication of COPD may be associated with mechanical exclusion of the heart by pulmonary overinflation.

DOI： 10.2147/COPD.S101082

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Nintedanib (BIBF1120) is a multi-targeted angiokinase inhibitor and has been evaluated in idiopathic pulmonary fibrosis and advanced non-small cell lung cancer (NSCLC) patients in clinical studies. In the present study, we evaluated the antitumor effects of nintedanib in 16 NSCLC cell lines and tried to identify microRNA (miRNA) associated with sensitivity to nintedanib. No correlations between FGFR, PDGFR and VEGFR family activation and sensitivity to nintedanib were found. The difference in miRNA expression profiles between 5 nintedanib-sensitive and 5 nintedanib-resistant cell lines was evaluated by miRNA array and quantitative RT-PCR analysis (qRT-PCR). Expression of miR-200b, miR-200a and miR-141 belonging to the miR-200 family which contributes to epithelial-mesenchymal transition (EMT), was significantly lower in 5 nintedanib-resistant than in 5 nintedanib-sensitive cell lines. We examined the protein expression of EMT markers in these 10 NSCLC cell lines. E-cadherin expression was lower, and vimentin and ZEB1 expression were higher in 5 nintedanib-resistant cell lines. PC-1 was the most sensitive of the NSCLC cell lines to nintedanib. We established nintedanib-resistant PC-1 cells (PC-1R) by the stepwise method. PC-1R cells also showed decreased expression of miR-200b, miR-141 and miR-429 and increased expression of ZEB1 and ZEB2. We confirmed that induction of miR-200b or miR-141 enhanced sensitivity to nintedanib in nintedanib-resistant A549 and PC1-R cells. In addition, we evaluated the response to gefitinib in combination with nintedanib after TGF-beta 1 exposure of A549 cells. Nintedanib was able to reverse TGF-beta 1-induced EMT and resistance to gefitinib caused by miR-200b and miR-141 upregulation and ZEB1 downregulation. These results suggested that the miR-200/ZEB axis might be predictive biomarkers for sensitivity to nintedanib in NSCLC cells. Furthermore, nintedanib combined with gefitinib might be a novel therapeutic strategy for NSCLC cells with EMT phenotype and resistance to gefitinib.

DOI： 10.3892/ijo.2016.3331

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Language：Japanese   Publisher：(公財)日本感染症医薬品協会  

菌の増殖速度、培養上清による気道上皮細胞への傷害性、トータルプロテアーゼ(TP)、ピオシアニン(PC)産生量、バイオフィルム(BF)形成能、遊走アッセイ(MA)、病原因子の遺伝子発現への影響について検討した。クラリスロマイシン(CAM)長期服用中の慢性気道感染症患者より分離された緑膿菌(Pa)11株、CAM未投与患者から分離されたPa2株(ムコイド型)、標準株としてPa P.aeruginosa PAO1の合計14株を対象とした。増殖速度はCAM投与菌群ではCAM未投与菌群と比べ増殖速度は緩徐な傾向であった。CAM投与菌の培養上清による肺胞上皮細胞への傷害性はCAM投与菌群においてCAM未投与菌群と比べ低かった。TPアッセイはCAM投与菌11株中7株でTPが非産生、CAM未投与菌では2株中2株ともTPを産生し、CAM投与菌ではTP産生株が少ない傾向にあった。PC産生量はCAM投与菌群ではCAM未投与菌群と比べ低い傾向であった。CAM投与菌群とCAM未投与菌群間でBF形成に有意差はなかったがCAM投与菌では菌株間でBF形成にばらつきが認められた。MAについて遊走は両群間に差は認められなかった。病原因子の遺伝子発現への影響は、CAM投与菌11株中4株でQS関連遺伝子であるLasI、rhlI遺伝子の発現を認めなかったのに対し、CAM未投与菌では2株中2株ともに発現を認めた。aprA、exoS、exoT、exoYでは両群間に差を認めなかった。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Purpose Histological vascular invasion (VI) by tumors is a risk factor for recurrence after surgical resection. However, VI features vary histologically. The aim of this study was to identify characteristic VI features that are associated with recurrence in squamous cell carcinoma (SCC) of the lung. Methods We enrolled 149 patients with pathological stage I primary lung SCC in this study and examined whether the presence, frequency, and size of VI were associated with recurrence. We also evaluated immunophenotypes of carcinoma cells and stromal cells within VI areas.
Results Of the 149 patients, 58 had tumors with VI. The presence of VI was significantly correlated with shorter recurrence-free survival (RFS) (P = 0.018). Although VI frequency was not associated with RFS, larger VI size (&gt; 425 A mu m) was significantly correlated with shorter RFS (P = 0.003). Carcinoma cells within larger VI areas expressed significantly higher levels of podoplanin, cancer stem cell marker (P = 0.039); higher numbers of CD34(+) microvessels (P = 0.009), CD204(+) macrophages (P = 0.026), and alpha-SMA(+) myofibroblasts (P = 0.056) were present within larger VI areas than within smaller VI ones.
Conclusions Our results indicate that larger VI areas are a predictor for recurrence in lung SCC; also, within the larger blood vessel, cancer stem cells and abundant stromal cells can create a more favorable microenvironment for tumor metastasis.

DOI： 10.1007/s00432-015-2068-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

To date, a number of potential biomarkers for lung squamous cell cancer (SCC) have been identified; however, sensitive biomarkers are currently lacking to detect early stage SCC due to low sensitivity and specificity. In the present study, we compared the 7 serum proteomic profiles of 11 SCC patients, 7 chronic obstructive pulmonary disease (COPD) patients and 7 healthy smokers as controls to identify potential serum biomarkers associated with SCC and COPD. Two-dimensional difference gel electrophoresis (2D-DIGE) and mass-spectrometric analysis (MS) using an affinity column revealed two candidate proteins, haptoglobin (HP) and apolipoprotein 4, as biomarkers of SCC, and alpha-1-antichymotrypsin as a marker of COPD. The iTRAQ technique was also used to identify SCC-specific peptides. HP protein expression was significantly higher in SCC patients than in COPD patients. Furthermore, two HP protein peptides showed significantly higher serum levels in SCC patients than in COPD patients. We established novel polyclonal antibodies for the two HP peptides and subsequently a sandwich enzyme-linked immunosorbent assay (ELISA) for the quantification of these specific peptides in patient and control sera. The sensitivity of detection by ELISA of one HP peptide (HP216) was 70% of SCC patients, 40% of COPDs patients and 13% of healthy controls. We also measured CYFRA, a cytokeratin fragment clinically used as an SCC tumor marker, in all the 28 cases and found CYFRA was detected in only seven SCC cases. However, when the measurement of HP216 was combined with that of CYFRA, 100% (10 of 10 patients) of SCC cases were detected. Our proteomic profiling demonstrates that the SCC-specific HP peptide HP216 may potentially be used as a diagnostic biomarker for SCC.

DOI： 10.3892/ijo.2016.3330

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

Objective: Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution. Methods: We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases. Results: We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiation fibrosis (n = 3). No patients showed the presence of honeycomb lung. Among the 13 patients, 1 (7.7%) developed interstitial lung disease after amrubicin chemotherapy. Conclusion: Interstitial lung disease occurred in 3.3% of the patients in our study
this appeared to be less frequent than the rates in previous reports. Preexisting pulmonary fibrosis may be a risk factor for interstitial lung disease
however, no fatal cases were found among the patients with asymptomatic pulmonary fibrosis without honeycomb lung. It is thus considered to be necessary to carefully assess the possibility of preexisting pulmonary fibrosis and clarify the presence or absence of honeycomb lung before starting amrubicin chemotherapy.

DOI： 10.1093/jjco/hyw043

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DOVE MEDICAL PRESS LTD  

Background: COPD is concomitantly present in similar to 30% of patients with heart failure. Here, we investigated the pulmonary function test parameters for left ventricular (LV) diastolic dysfunction and the relationship between pulmonary function and LV diastolic function in patients with COPD.
Patients and methods: Overall, 822 patients who underwent a pulmonary function test and echocardiography simultaneously between January 2011 and December 2012 were evaluated. Finally, 115 patients with COPD and 115 age-and sex-matched control patients with an LV ejection fraction of &gt;= 50% were enrolled.
Results: The mean age of the patients was 74.4 +/- 10.4 years, and 72.3% were men. No significant differences were found between the two groups regarding comorbidities, such as hypertension, diabetes mellitus, and anemia. The index of LV diastolic function (E/e') and the proportion of patients with high E/e' (defined as E/e' &gt;= 15) were significantly higher in patients with COPD than in control patients (10.5% vs 9.1%, P=0.009; 11.3% vs 4.3%, P= 0.046). E/e' was significantly correlated with the residual volume/total lung capacity ratio. Univariate and multivariate analyses revealed severe COPD (Global Initiative for Chronic Obstructive Lung Disease III or IV) to be a significant predictive factor for high E/e' (odds ratio [OR] 5.81, 95% confidence interval [CI] 2.13-15.89, P= 0.001 and OR 6.00, 95% CI 2.08-17.35, P= 0.001, respectively).
Conclusion: Our data suggest that LV diastolic dysfunction as a complication of COPD may be associated with mechanical exclusion of the heart by pulmonary overinflation.

DOI： 10.2147/COPD.S101082

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background: Supraventricular and ventricular premature complexes (SVPC and VPC, respectively) are associated with chronic obstructive pulmonary disease (COPD) and with increased mortality in COPD patients. However, there are few reports on the causes of arrhythmia in COPD patients. Objectives: This study explores the associations between cardiopulmonary dysfunction and COPD by comparing patients with defined arrhythmias (&gt; 100 beats per 24 h) and those without, based on 24-hour electrocardiogram (ECG) recordings. Methods: Patients with arrhythmia underwent a 24-hour ECG and subsequent pulmonary function tests, computed tomography, ECG, 6-min walk test (6MWT), and BODE (body mass index, airflow obstruction, modified Medical Research Council Dyspnoea Scale, exercise capacity) index calculation. Results: Of 103 study patients (71 COPD patients and 32 at-risk patients), 36 had VPC, 45 had SVPC, 20 had both, and 42 had neither. The predicted post-bronchodilator forced expiratory volume in 1 s, the proportion of low-attenuation area on computed tomography, and BODE index values were significantly worse in the SVPC and VPC groups compared with the corresponding reference groups. Patients in the VPC group showed significantly increased right ventricular pressure and increased desaturation in the 6MWT compared with the reference group. In the multivariate analyses, bronchodilator use was a significant risk factor in the SVPC group, whereas in the VPC group, all parameters of the BODE index except for the dyspnoea score were identified as risk factors. Conclusions: Increased SVPC might be caused by bronchodilator use, whereas increased VPC is likely related to the peculiar pathophysiology of COPD. (C) 2015 S. Karger AG, Basel

DOI： 10.1159/000442447

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective Although chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation, the association between the neutrophil to lymphocyte ratio (NLR; an indicator of inflammation) and the clinical status of COPD has not been well studied. We hypothesized that the NLR is associated with disease severity and exacerbation in COPD patients.
Methods We performed blood testing, pulmonary function testing, chest computed tomography, a body composition analysis, and a 6-minute walk test and applied the modified Medical Research Council (MMRC) dyspnea scale for 141 stable COPD patients. In addition, we calculated the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index to evaluate the disease severity. Finally, we examined the association between the NLR and clinical parameters in stable COPD patients, and we further investigated changes in the NLR between exacerbation and the stable state.
Results The NLR was positively correlated with the BODE index, extent of emphysema, and MMRC score (p&lt;0.001 for all), while inversely correlated with airflow obstruction (p&lt;0.001), body mass index (p&lt;0.001), fat-free mass index (p=0.001), and the 6-minute walk distance (p&lt;0.001). We obtained the NLR during exacerbation from 49 patients. The NLR was significantly higher at exacerbation compared to the stable state (p&lt; 0.001).
Conclusion The NLR was associated with disease severity and exacerbation in COPD patients. Therefore, the usefulness of the NLR in COPD patients should be elucidated in clinical settings in future investigations.

DOI： 10.2169/internalmedicine.55.5772

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MATTIOLI 1885  

Background and objective: There is growing evidence for anti-inflammatory activities of macrolides in chronic respiratory diseases, such as diffuse panbronchiolitis, cystic fibrosis, or chronic bronchitis. The long-term effect of macrolides in idiopathic pulmonary fibrosis (IPF) is unknown. This study was aimed to investigate the effect of macrolide therapy on the frequency of acute exacerbation (AE) and the mortality in IPF. Methods: A total 52 IPF patients who were treated by combination of conventional agents with or without macrolides were retrospectively reviewed. The primary endpoint was the incidence of AE in IPF patients. We also observed survival rate after the treatment with or without macrolides. Results: AE was observed in 4 of 29 cases (13.8%) treated with macrolides and 8 of 23 cases (34.8%) treated without macrolides, respectively during 36 months. AE free survival rate of macrolide group was significantly better than that of non-macrolide group (logrank p=0.027). Survival rate of IPF patients with macrolide therapy was significantly better than that of patients without macrolide therapy (p=0.047). Conclusion: Our results indicate the potential beneficial efficacy of macrolide therapy combined with oral corticosteroids, immunosuppressive or anti-fibrotic agents in IPF.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W.B. Saunders Ltd  

A 65-year-old Japanese male with type 2 diabetes mellitus was admitted to our hospital with a productive cough and worsening dyspnea. He had started receiving vildagliptin, which is one of the dipeptideylpeptidase-4 (DPP-4) inhibitors, several days before the appearance of his symptoms. Laboratory findings revealed markedly elevated levels of immunoglobulin E and Krebs von den Lungen-6. Chest computed tomography revealed ground-glass opacity with irregular reticulation throughout both lungs. Biopsy specimens by transbronchial lung biopsy showed subacute interstitial pneumonia and an organizing pneumonia pattern with acute alveolar injury. The drug lymphocyte stimulation test showed a positive result for vildagliptin. Withdrawal of vildagliptin and administration of glucocorticoid treatment improved his respiratory condition and radiological findings. Therefore, we diagnosed the patient with vildagliptin-induced interstitial pneumonia based on both his clinical course and pathological findings. Interstitial pneumonia as a side effect of vildagliptin is rare. It may be necessary to monitor the respiratory condition of patients upon administration of DPP-4 inhibitors until further evidence is obtained.

DOI： 10.1016/j.rmcr.2016.03.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the leading causes of severe pulmonary hypertension. According to previously reported studies in the pertinent literature, chronic inflammatory conditions may be implicated in the development of CTEPH. We herein describe the case of a 56-year-old woman who was diagnosed with CTEPH in association with chronic infection. The patient had experienced five episodes of pneumonia in the five years prior to the diagnosis of CTEPH. Blood tests from the previous five years of outpatient follow-up demonstrated that the C-reactive protein level was slightly elevated. This case suggests that a relationship exists between chronic inflammation and CTEPH, and furthermore, may contribute towards elucidating the pathophysiology of CTEPH.

DOI： 10.2169/internalmedicine.55.5146

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Background Drug-induced interstitial lung disease (ILD) is one of the most serious adverse reactions associated with the molecularly targeted drugs. Panitumumab has been approved for advanced or recurrent colorectal cancer. Although there were no adverse reaction reports of ILD in panitumumab monotherapy, 4 cases in combination chemotherapy were reported prior to its approval in Japan in 2010. Several studies also reported that the incidence of drug-induced ILD was higher in Japan than in other countries. The clinical features of ILD and the associated risk factors therefore need investigation.
Methods We analyzed the data from 3085 unresectable, advanced or recurrent colorectal cancer patients enrolled in a postmarketing all-case surveillance study of panitumumab in Japan. ILD case reports were assessed based on the clinical and radiologic findings by a committee of external experts. Multivariate analysis using Cox's hazard model identified the risk factors.
Results ILD incidence (1.3 %) and mortality rates (51.3 %) were similar to those of patients receiving another anti-epidermal growth factor receptor (EGFR) monoclonal antibody in Japan. No specific onset timing was determined. Although panitumumab-specific ILD findings were not observed in computed tomography images or clinical practice, panitumumab can induce ILD with diffuse alveolar damage, as do the other anti-EGFR targeting drugs. A history/complication of ILD, male sex, poor general condition, and 65 years or older were identified as ILD risk factors, and no history of previous drug treatment was an apparent risk factor.
Conclusion Panitumumab-induced ILD can occur at any time after initiation, and close and regular monitoring is needed.

DOI： 10.1007/s10147-015-0834-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Patients with non-small cell lung cancer (NSCLC) EGFR mutations have shown a dramatic response to EGFR inhibitors (EGFR-TKI). EGFR T790M mutation and MET amplification have been recognized as major mechanisms of acquired resistance to EGFR-TKI. Therefore, MET inhibitors have recently been used in NSCLC patients in clinical trials. In this study, we tried to identify the mechanism of acquired resistance to MET inhibitors. We analyzed the antitumor effects of two MET inhibitors, PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC-1 cells with MET amplification were the only cells that were sensitive to both MET inhibitors. We established PHA-665752-resistant EBC-1 cells, namely EBC-1R cells. Activation of KRAS, EGFR, and FGFR2 signaling was observed in EBC-1R cells by FISH and receptor tyrosine kinase phosphorylation antibody arrays. EBC-1R cells also showed overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) as well as phosphorylation of MET. EBC-1R cells grew as cell spheres that exhibited cancer stem cell-like (CSC) properties and epithelial-mesenchymal transition (EMT). The level of miR138 that targeted ABCB1 was decreased in EBC-1R cells. ABCB1 siRNA and the ABCB1 inhibitor elacridar could reduce sphere numbers and suppress EMT. Elacridar could also reverse resistance to PHA-665752 in EBC-1R cells. Our study demonstrated that ABCB1 overexpression, which was associated with CSC properties and EMT, was involved in the acquired resistance to MET inhibitors. Inhibition of ABCB1 might be a novel therapeutic strategy for NSCLC patients with acquired resistance to MET inhibitors. (C) 2015 AACR.

DOI： 10.1158/1535-7163.MCT-15-0050

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Dove Medical Press Ltd.  

Objective: Comorbidities are characteristic of COPD. However, little is known about the secondary manifestations of COPD in the gastrointestinal tract. Therefore, we aimed to explore the long-term effects of gastrectomy in patients with spirometry-defined COPD or those at risk of COPD. Participants: Subjects included 87 patients either with COPD or at risk of COPD (symptomatic) who underwent gastrectomy between December 2003 and October 2013 (group A), and 174 patients either with COPD or at risk of COPD, matched by age (±5 years), sex, and forced expiratory volume in 1 second (FEV1) as percentage of predicted (FEV1% predicted) (±5%) (group B). Methods: All patients underwent routine blood chemistry and pulmonary function tests, arterial blood gas analysis, 6-minute walk test (6MWT), high-resolution chest computed tomography scans, and nutritional assessments. Results: The mean duration postgastrectomy was 18.3±15.4 years. The mean FEV1 and FEV1% predicted were 2.07±0.76 L and 74.6±24.5%, respectively. Univariate analysis indicated that group A patients had significantly lower body mass index, fat-free mass index, and serum hemoglobin and albumin concentration (all P=0.00), and walked a significantly shorter distance in the 6MWT (P&lt
0.05). Multivariate linear regression analysis for the distance in the 6MWT indicated that increased residual volume (RV) to total lung capacity (TLC) as percentage of predicted (%RV/TLC) alone was an independent and significant predictor of reduced distances in the 6MWT. Conclusion: We concluded that nutritional insufficiency in patients with COPD (or those at risk of COPD) who previously underwent gastrectomy might lead to hyperinflation and consequently, decreased exercise capacity.

DOI： 10.2147/COPD.S87135

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer Japan  

Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonias (IIPs), is a fatal disease with a mean survival time of 2-4 years from the time of diagnosis. Therefore, the early and accurate diagnosis of IPF is important and essential for management and induction of optimal therapies. In 2002, the American Thoracic Society and European Respiratory Society (ATS/ERS) published an international statement on the diagnosis and management of IPF. The 2002 ATS/ERS statement defined IPF as a distinct clinical entity associated with the histology of usual interstitial pneumonia (UIP). The revised evidence-based guidelines for diagnosis and management of IPF were published by collaboration between the ATS, ERS, Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT) in 2011. In the revised 2011 criteria, high-resolution CT (HRCT) has a central role for the diagnosis of IPF. The presence of UIP patterns on HRCT is essential and definitive in the diagnosis of IPF without the need for surgical lung biopsy (SLB). The revised 2011 criteria have emphasized the importance of multidisciplinary discussion between clinicians, radiologists, and pathologists experienced in the diagnosis of IPF.

DOI： 10.1007/978-4-431-55582-7_1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Real-life safety and efficacy of sorafenib in advanced renal cell carcinoma in a nationwide patient population were evaluated by post-marketing all-patient surveillance.
All patients with unresectable or metastatic renal cell carcinoma in Japan who started sorafenib therapy from February 2008 to September 2009 were registered and followed for up to 12 months. Baseline characteristics, treatment status, tumor response, survival and safety data were recorded by the prescribing physicians.
Safety and efficacy were evaluated in 3255 and 3171 patients, respectively. The initial daily dose was 800 mg in 78.2% of patients. Median duration of treatment was 6.7 months and the mean relative dose intensity was 68.4%. Overall, 2227 patients (68.4%) discontinued the treatment by 12 months, half of which (52.0% of discontinued patients) were due to adverse events. The most common adverse drug reactions were hand-foot skin reaction (59%), hypertension (36%), rash (25%) and increase in lipase/amylase (23%). The median progression-free survival was 7.3 months (95% confidence intervals: 6.7-8.1), and the overall survival rate at 1 year was 75.4% (73.5-77.1). Prognostic factors for overall survival were mostly consistent with those in previous clinical trials in the univariate analysis and largely similar to those for progression-free survival and duration of treatment in the multivariate analysis.
Sorafenib for the treatment of advanced renal cell carcinoma under the labeled dose was feasible in daily medical practice, for its acceptable toxicity profile and favorable clinical benefit that were consistent with those in clinical trials.

DOI： 10.1093/jjco/hyv099

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DOI： 10.1007/s13691-014-0205-3

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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