Dasatinib Suppresses TGFß-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis.

PURPOSE: Transforming growth factor ß (TGFß)-mediated epithelial-mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFß1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo. METHODS: TGFß1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM). RESULTS: A549 and BEAS-2B cells exposed to TGFß1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGFß1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model. CONCLUSIONS: These findings suggest that DAS inhibited TGFß-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGFß/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.

Surfactant protein-D predicts prognosis of interstitial lung disease induced by anticancer agents in advanced lung cancer: a case control study.

BACKGROUND: Interstitial lung diseases induced by anticancer agents (ILD-AA) are rare adverse effects of anticancer therapy. However, prognostic biomarkers for ILD-AA have not been identified in patients with advanced lung cancer. Our aim was to analyze the association between serum biomarkers sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), and clinical characteristics in patients diagnosed with ILD-AA. METHODS: Between April 2011 and March 2016, 1224 advanced lung cancer patients received cytotoxic agents and epidermal growth factor receptor tyrosine kinase inhibitors at Juntendo University Hospital and Juntendo University Urayasu Hospital. Of these patients, those diagnosed with ILD-AA were enrolled in this case control study. ΔKL-6 and ΔSP-D were defined as the difference between the levels at the onset of ILD-AA and their respective levels prior to development of ILD-AA. We evaluated KL-6 and SP-D at the onset of ILD-AA, ΔKL-6 and ΔSP-D, the risk factors for death related to ILD-AA, the chest high resolution computed tomography (HRCT) findings, and survival time in patients diagnosed with ILD-AA. RESULTS: Thirty-six patients diagnosed with ILD-AA were enrolled in this study. Among them, 14 patients died of ILD-AA. ΔSP-D in the patients who died was significantly higher than that in the patients who survived. However, ΔKL-6 did not differ significantly between the two groups. Moreover, ΔSP-D in patients who exhibited diffuse alveolar damage was significantly higher than that in the other patterns on HRCT. Receiver operating characteristic curve analysis was used to set the optimal cut off value for ΔSP-D at 398 ng/mL. Survival time for patients with high ΔSP-D (≥ 398 ng/mL) was significantly shorter than that for patients with low ΔSP-D. Multivariate analysis revealed that ΔSP-D was a significant prognostic factor of ILD-AA. CONCLUSIONS: This is the first research to evaluate high ΔSP-D (≥ 398 ng/mL) in patients with ILD-AA and to determine the risk factors for ILD-AA in advanced lung cancer patients. ΔSP-D might be a serum prognostic biomarker of ILD-AA. Clinicians should evaluate serum SP-D during chemotherapy and should carefully monitor the clinical course in patients with high ΔSP-D.

Cerebral infarction in advanced non-small cell lung cancer: a case control study.

BACKGROUND: Advanced non-small cell lung cancer (NSCLC) patients often develop thromboembolic events, including cerebral infarction (CI). However, the relationship between advanced NSCLC and CI has not been thoroughly investigated. We examined the association between advanced NSCLC and CI and risk factors for CI in advanced or post-operative recurrent NSCLC patients. METHODS: We retrospectively investigated 515 patients diagnosed with advanced or post-operative recurrent NSCLC at Juntendo University Hospital between April 2009 and March 2014. RESULTS: Among the 515 patients evaluated, 15 patients (2.9%) developed CI after diagnosis of advanced or post-operative recurrent NSCLC. Univariate and multivariate analyses were conducted, and brain metastasis was the only significant independent risk factor for CI (odds ratio 5.24, 95% confidence interval 1.72-16.10, p = 0.004). The incidence was 6.3% in these patients. The median survival time was 36 days, and 1-year survival rate was 6.7% after development of CI. Overall survival from diagnosis of advanced NSCLC or post-operative recurrence was significantly shorter in patients with CI than in patients without CI (223 days versus 895 days; HR, 3.46; 95% confidence interval, 2.04-6.02; p = 0.001). CONCLUSIONS: The incidence of CI is high in advanced or post-operative recurrent NSCLC, and is especially higher in patients with brain metastasis than in those without brain metastasis. Moreover, CI may affect patient's prognosis. Careful monitoring for the development of CI in patients with advanced or post-operative recurrent NSCLC is needed, especially for patients with brain metastasis.

Pemetrexed for advanced non-small cell lung cancer patients with interstitial lung disease.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) need to be approached carefully given the high incidence of pulmonary toxicity. Pemetrexed (PEM) is the key drug for the treatment of NSCLC. However, its safety, especially with respect to the exacerbation of ILD, and efficacy in NSCLC patients with ILD have yet to be established. METHOD: We investigated the safety and efficacy of PEM monotherapy in NSCLC patients with or without idiopathic interstitial pneumonia (IIPs). The medical charts of these patients were retrospectively reviewed. RESULTS: Twenty-five patients diagnosed as having IIPs (IIPs group) and 88 patients without ILD (non-ILD group) were treated with PEM monotherapy at Juntendo University Hospital between 2009 and 2013. In the IIPs group, 12 patients were found to have usual interstitial pneumonitis (UIP) on chest computed tomography (CT) (UIP group) and the other 13 patients showed a non-UIP pattern on chest CT (non-UIP IIPs group). Three patients in the IIPs group (2 in the UIP group and 1 in the non-UIP IIPs group) and 1 in the non-ILD group developed pulmonary toxicity during treatment (3.5% overall, 12.0% in the IIPs group versus 1.1% in the non-ILD group). Moreover, all 3 patients in the IIPs group died of pulmonary toxicity. Overall survival tended to be longer in the non-ILD group than in the IIPs group (p = 0.08). Multivariate analyses demonstrated that IIPs was the only significant independent risk factor for PEM-related pulmonary toxicity. CONCLUSION: We found that the incidence of PEM-related pulmonary toxicity was significantly higher amongst NSCLC patients with IIPs than among those without IIPs. Particular care must be taken when administering PEM to treat NSCLC patients with IIPs.

Trophoblast Cell Surface Antigen 2 Expression in Thymic Carcinoma: Brief Report.

Introduction: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma. Methods: TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University. Results: RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%-100%) and 25.0 (range: 0-200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival. Conclusions: TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.

Second malignancy in advanced or recurrent non-small cell lung cancer after the advent of molecular targeted drugs and immunotherapy.

OBJECTIVES: This study aimed to investigate the characteristics of patients with recurrent or advanced non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) or immune-checkpoint inhibitors (ICIs) who developed secondary malignancies, as well as evaluate the impact of these secondary malignancies on the course of lung cancer. MATERIALS AND METHODS: This study included 112 patients with postoperative recurrent or advanced NSCLC, who received TKIs, ICIs, or immune combination therapy as the primary treatment modality between April 1, 2013, and March 31, 2020, and achieved long-term survival (≥2 years). Secondary malignancies were defined as newly diagnosed cancers in other organs occurring after NSCLC treatment initiation. RESULTS: Among the 112 patients, 10 (8.9%) developed 12 carcinomas, including third primary malignancies. Univariate analysis, considering secondary malignancies as the outcome, revealed a non-significant trend towards a higher incidence of secondary malignancies in smokers compared to non-smokers. CONCLUSION: This study found that 8.9% of patients with advanced NSCLC who received TKIs, ICIs, or immune combination therapy and survived ≥2 years developed secondary malignancies. This underscores the importance of early diagnosis and treatment, even during lung cancer treatment, to identify suspicious lesions in other organs either via imaging or physical examinations.

Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia.

OBJECTIVES: In this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes. MATERIALS AND METHODS: The efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial. RESULTS: Of the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR [95 % CI]; TKIs vs docetaxel, 2.16 [1.35-3.46]; ICIs vs docetaxel, 1.49 [1.21-1.84]). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR [95 % CI], 0.22 [0.07-0.64]). CONCLUSIONS: After platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

Real-World Data Analysis of Pembrolizumab Monotherapy for NSCLC Using Japanese Postmarketing All-Case Surveillance Data.

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.

Pulmonary Intravascular Large B-cell Lymphoma (IVLBCL) Disguised as an Asthma Exacerbation in a Patient with Asthma.

A 62-year-old man with asthma presented with a 1-month history of wheezing and exertional dyspnea. Although the wheezing symptoms disappeared after systemic corticosteroid therapy, the exertional dyspnea and hypoxemia did not improve. A diagnosis of intravascular large B-cell lymphoma (IVLBCL) with pulmonary involvement was suspected because of the increased serum lactic dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) level, increased alveolar-arterial oxygen difference (AaDO2), decreased pulmonary diffusing capacity for carbon monoxide (DLCO) and scintigraphic, computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT findings. The patient was diagnosed as having IVLBCL with pulmonary involvement based on a pathological analysis of a random skin biopsy and a transbronchial lung biopsy. IVLBCL should be considered in patients with symptoms of asthma that are refractory to corticosteroid treatment.

LSD1/KDM1 isoform LSD1+8a contributes to neural differentiation in small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid progression. The mechanisms that lead to a shift from initial therapeutic sensitivity to ultimate therapeutic resistance are poorly understood. Although the SCLC genomic landscape led to the discovery of promising agents targeting genetic alterations that were already under investigation, results have been disappointing. Achievements in targeted therapeutics have not been observed for over 30 years. Therefore, the underlying disease biology and novel targets urgently require a better understanding. Epigenetic regulation is deeply involved in the cellular plasticity that could shift tumor cells to the malignant phenotype. We have focused on a histone modifier, LSD1, that is overexpressed in SCLC and is a potent therapeutic target. Interestingly, the LSD1 splice variant LSD1+8a, the expression of which has been reported to be restricted to neural tissue, was detected and was involved in the expression of neuroendocrine marker genes in SCLC cell lines. Cells with high expression of LSD1+8a were resistant to CDDP and LSD1 inhibitor. Moreover, suppression of LSD1+8a inhibited cell proliferation, indicating that LSD1+8a could play a critical role in SCLC. These findings suggest that LSD1+8a should be considered a novel therapeutic target in SCLC.

Prognostic factors in non-small cell lung cancer patients who are recommended to receive single-agent chemotherapy (docetaxel or pemetrexed) as a second- or third-line chemotherapy: in the era of oncogenic drivers and molecular-targeted agents.

PURPOSE: Docetaxel or pemetrexed monotherapy is recommended either as a second-line treatment for non-small cell lung cancer (NSCLC) patients without EGFR mutation or ALK fusion genes or as a third-line treatment for patients with EGFR mutation or ALK fusion. However, efficacy and survival for these two settings have not been compared, leaving it unclear whether these two populations can be included in the same clinical trials. Moreover, prognostic factors for patients who are recommended to receive docetaxel/pemetrexed monotherapy are largely unknown. METHODS: Docetaxel or pemetrexed was administered to 67 EGFR wild-type patients as a second-line treatment following one platinum-based combination chemotherapy and to 17 EGFR mutant patients as a third-line treatment following EGFR tyrosine kinase inhibitors and one platinum-based combination chemotherapy. Docetaxel and pemetrexed were administered at 60 and 500 mg/m(2), respectively, every 3 weeks until disease progression, intolerable toxicity, or patient refusal. Overall survivals (OSs) between the two groups were compared using the log-rank test, and prognostic factors were evaluated via Cox's proportional hazards models. RESULTS: The median OS was 345.5 days in the EGFR wild-type second-line group and 616 days in the EGFR mutant third-line group. Multivariate analyses revealed that the stage before first-line treatment, performance status, and EGFR status were significant prognostic factors. CONCLUSIONS: When planning clinical studies of NSCLC patients recommended to receive docetaxel or pemetrexed as single-agent chemotherapy, the EGFR status and stage before first-line treatment should be considered as stratification factors of randomized clinical studies.