Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).

PURPOSE: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). METHODS: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. RESULTS: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. CONCLUSION: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

A multicenter, open-label, phase II trial of pemetrexed plus bevacizumab in elderly patients with previously untreated advanced or recurrent nonsquamous non-small cell lung cancer.

BACKGROUND: Although the incidence of lung cancer in elderly individuals has been increasing in recent years, the number of clinical trials designed specifically for elderly patients with advanced non-small cell lung cancer (NSCLC) is still limited. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of pemetrexed (PEM) plus bevacizumab (Bev) combination chemotherapy in elderly patients with nonsquamous NSCLC. METHODS: A total of 29 elderly patients (≥75 years old) with nonsquamous NSCLC were enrolled in this multicenter, open-label, phase II study, and 27 patients were finally analyzed. PEM at 500 mg/m2 on day 1 plus Bev at 15 mg/kg on day 1 were administered triweekly. The primary endpoint was the investigator-assessed objective response rate. RESULTS: The median age at initiating chemotherapy was 80 years old. Almost all patients (92.6%) had adenocarcinoma histology. The median number of cycles administered was 6, and the objective response rate was 40.7%. The median progression-free survival, overall survival and 1-year survival were 8.8 months, 27.2 months and 79%, respectively. The treatment was well-tolerated, and no treatment-related death was observed. CONCLUSION: Combination chemotherapy with PEM plus Bev in elderly patients with previously untreated advanced non-squamous NSCLC exhibited favorable antitumor activity and tolerability, suggesting that a combination of PEM plus Bev might be a promising treatment option for this population.

Surgical resection combined with perioperative chemotherapy for a patient with locally recurrent, previously stage IV thymic small-cell carcinoma: A case report.

An 83-year-old Japanese man visited our hospital with dyspnea and general fatigue. Computed tomography (CT) revealed a tumor in the anterior mediastinum, bilateral pleural effusion, pericardial fluid, and multiple liver nodules. We performed a CT-guided tumor biopsy, and the patient was diagnosed with thymic small-cell carcinoma, Masaoka-Koga stage classification IVb. The patient received four cycles of carboplatin and etoposide, and all lesions disappeared on CT. However, after 6 months, CT revealed a recurrent tumor in the anterior mediastinum. After one cycle of rechallenge chemotherapy, we performed extended total thymectomy followed by another three cycles of chemotherapy. More than 2.5 years after the last chemotherapy session, the patient's carcinoma did not recur. Thus, this case suggests that salvage surgery may be a treatment option for local recurrence of thymic carcinoma after complete remission with chemotherapy, even in patients with stage IV cancer.

Nationwide retrospective observational study of idiopathic dendriform pulmonary ossification: clinical features with a progressive phenotype.

BACKGROUND: Diffuse pulmonary ossification is a specific lung condition that is accompanied by underlying diseases. However, idiopathic dendriform pulmonary ossification (IDPO) is extremely rare, and the clinical features remain unclear. In this study, we aimed to report the clinical characteristics of IDPO. METHODS: We conducted a nationwide survey of patients with IDPO from 2017 to 2019 in Japan and evaluated the clinical, radiological, and histopathological findings of patients diagnosed with IDPO. RESULTS: Twenty-two cases of IDPO were identified. Most subjects (82%) were male, aged 22-56 years (mean (SD), 37.9 (9.1)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed.)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed. CONCLUSIONS: IDPO develops at a young age with gradually progressive phenotype. Further research and long-term (>20 years) follow-up are required to clarify the pathogenesis and clinical findings in IDPO.

Anti-Inflammatory and/or Anti-Fibrotic Treatment of MPO-ANCA-Positive Interstitial Lung Disease: A Short Review.

The presence of a lung lesion is common in microscopic polyangiitis (MPA), and interstitial lung disease (ILD) can lead to a poor prognosis. Although myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) are often present in patients with MPA, patients with ILD and MPO-ANCA positivity but without other manifestations of systemic vasculitis have also been reported. Therefore, the possible association between MPO-ANCA, MPA, and idiopathic ILD remains unclear. This problematic matter has influenced the treatment strategy of MPO-ANCA-positive ILD patients without systemic vasculitis. Clinicians should undertake treatment with careful consideration of the four major causes of death in MPO-ANCA-positive ILD: acute exacerbation of ILD, progressive lung fibrosis, infectious comorbidities, and diffuse alveolar hemorrhage. Further, clinicians need to carefully judge whether inflammation or fibrosis is the dominant condition with reference to the patient's clinical domain and radiopathological lung features. Recently, anti-fibrotic agents such as nintedanib and pirfenidone were shown to be effective in treating various etiologies associated with ILD and have thus led to the widening of treatment options. In this review, the clinical characteristics, radiopathology, prognosis, and therapeutic options in patients with MPO-ANCA-positive ILD are summarized using limited information from previous studies.

2020 guide for the diagnosis and treatment of interstitial lung disease associated with connective tissue disease.

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

Human metapneumovirus-associated community-acquired pneumonia in adults during the first wave of COVID-19.

Objective: The clinical course of human metapneumovirus (hMPV) infection is similar to that of coronavirus 2019 disease (COVID-19). However, community-acquired hMPV infections in adults have not yet been sufficiently investigated. We examined the detection status of hMPV antigens and the clinical features of positive patients during the first wave of COVID-19, which coincided with the epidemic season of hMPV infection in Japan. Methods: In this cross-sectional, observational, and single-center study, we recruited consecutive individuals who visited the Japan Agricultural Cooperatives Kochi Hospital due to fever, respiratory symptoms, or close contact with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected persons during the period from January to May 2020. Results: The positive rate of immunochromatography for hMPV antigens from nasopharyngeal swabs was 9.5% (4/42), and four positive cases were community-acquired pneumonia (CAP) (5.3% of all CAP). The positive rate of hMPV antigens in the CAP group (30.8%, 4/13) was higher than that in the non-pneumonia group (0.0%, 0/19) (p < 0.05). The average age of the four adult patients with CAP was 69.8 years (range 35-93). Mean white blood cell counts and C-reactive protein blood levels were 6,250 cells/µL (3,500-12,180) and 4.30 mg/dL (4.05-7.04), respectively. Chest computed tomography images were diverse and two patients showed dense consolidation. No multi-organ disorder was noted during the clinical course in any of the four cases, and their prognoses were good. Conclusion: hMPV infection may be considered in the differential diagnosis of COVID-19 and CAP in Japan under the preventive measures for SARS-CoV-2 infection, at least during the epidemic season of hMPV infection.

Neuropsychiatric systemic lupus erythematosus with cerebellar vasculitis and obstructive hydrocephalus requiring decompressive craniectomy.

A 36-year-old woman who had been diagnosed with systemic lupus erythematosus (SLE) was admitted to our hospital due to increasing disease SLE activity. Despite the intensification of immunosuppressive treatment, headache newly developed and worsened. Magnetic resonance imaging (MRI) revealed spreading of a high-intensity area along the sulci of the bilateral cerebellar hemispheres. She was diagnosed with neuropsychiatric SLE and methylprednisolone (mPSL) pulse therapy was started. However, consciousness disorder due to cerebellar oedema with obstructive hydrocephalus appeared and required decompressive craniectomy. The histological findings of the biopsy specimens from cerebellar vermis were compatible with features of vasculitis. She was successfully treated adding intravenous cyclophosphamide therapy.

Development of improved method to identify and analyze lung fibrocytes with flow cytometry in a reporter mouse strain.

INTRODUCTION: Fibrocytes are emerging myeloid-derived circulating cells that can migrate into damaged tissues and usually contribute to their repair. Key features of fibrocytes include the expression myeloid markers, production of extracellular matrix proteins, and secretion of various humoral factors that activate resident fibroblasts; they also have the potential to differentiate into fibroblasts. However, no specific surface markers have been identified to identify fibrocytes in vivo. One reason could be that the method used to detect fibrocytes requires intracellular collagen staining. METHODS: In the present study, to establish an improved method for the detection of lung fibrocytes and to analyze viable fibrocytes, we used collagen I(α)2-green fluorescent protein (Col-GFP) reporter mice, which had undergone the intratracheal instillation of bleomycin (BLM). RESULTS: Using flow cytometry to gate out cells with autofluorescence, we clearly found that CD45+ GFP+  cells resided in the lungs of Col-GFP mice at a steady state and these cells increased after BLM injury, peaking at Day 14. These cells expressed not only known cell surface markers of fibrocytes, but also some novel markers, in addition to a low level of collagen I in comparison to CD45- GFP+  cells. CONCLUSION: Our findings suggest that the improved method can be a useful for the detection of pure lung fibrocytes and allows us to further analyze the characteristics of viable fibrocytes.

Complete response of squamous cell carcinoma of the lung following treatment with pembrolizumab in an elderly patient: A case report.

Complete response of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitor (ICI) monotherapy is rare. Here, we encountered an elderly patient who showed complete response of NSCLC following treatment with pembrolizumab. An 84-year-old man with a history of bloody sputum for several weeks visited a general physician. At that time, a chest X-ray revealed a tumor shadow in the left middle lung field, and the patient was referred to our hospital. Following transbronchial biopsy, he was diagnosed with squamous cell carcinoma of the lung. Expression of programmed death ligand 1 (PD-L1) in tumor cells was 80% or more by immunostaining. Based on the above, immunotherapy with pembrolizumab was performed as first-line therapy. The cancer cells completely disappeared at the end of the fifth cycle. There were no side effects during the therapeutic course. Treatment with pembrolizumab continued for two years and was then discontinued at the patient's request. Since then, no tumor recurrence has been detected for about one and a half years without treatment. There have been few reports of lung cancer disappearing after treatment with pembrolizumab. In conclusion, in elderly NSCLC patients with PD-L1 expression of 50% or more, pembrolizumab should be considered as first-line treatment with the treatment period, and mechanism suggested in this report.

Distinct improvement of pulmonary function, ground-glass opacity, hypoxia and physical findings in an idiopathic pulmonary fibrosis patient after pirfenidone treatment : a case report with a review of the literature.

Background : Pirfenidone (PFD), an anti-fibrosis drug for idiopathic pulmonary fibrosis (IPF), suppresses disease progression and delays decline of forced vital capacity. However, this drug rarely makes marked improvement of pulmonary function, chest high-resolution computed tomography (HRCT) findings and hypoxia. Case presentation : A 59 year-old-man, who was a former smoker and had a history of alcoholic liver cirrhosis, developed exertional dyspnea and was referred to our hospital. HRCT showed honeycomb changes with surrounding ground-glass opacity (GGO) in a predominantly basal and subpleural distribution. He was diagnosed with IPF and the treatment with PFD was started. At 16 months after the start of treatment, the predicted forced vital capacity value markedly improved from 82.9% to 98.6%. His resting-state partial pressure of arterial oxygen while breathing room air increased from a minimum of 54.7 mmHg (at 2 months treatment) to 72.5 mmHg. The GGO observed at diagnosis disappeared in HRCT. But after 32 months of treatment, his general condition got worse gradually, and he died from chronic progression of IPF after 48 months of treatment. Conclusion : Our case suggests that a complication of chronic liver disease and the existence of GGO may be characteristics of super-responder to PFD treatment for IPF patients. J. Med. Invest. 67 : 358-361, August, 2020.

Blockade of Pan-Fibroblast Growth Factor Receptors Mediates Bidirectional Effects in Lung Fibrosis.

FGFs (fibroblast growth factors) are major factors associated with the pathogenesis of pulmonary fibrosis. On the one hand, nintedanib, a tyrosine kinase inhibitor targeting several growth factor receptors, including the FGF receptor (FGFR), has been approved for the treatment of idiopathic pulmonary fibrosis. On the other hand, recent reports suggest that FGFs are required for epithelial recovery. In this study, we focused on FGF signaling to both fibroblasts and alveolar epithelial cells (AECs), and we examined the effect of a pan-FGFR blocker on experimental pulmonary fibrosis in mice. The effects of BGJ398, a pan-FGFR inhibitor, on the migration and proliferation of fibroblasts and AECs were assessed using Transwell migration or [3H]thymidine incorporation assays. The expression of FGFR was analyzed using IB or flow cytometry. We also investigated the effect of BGJ398 on pulmonary fibrosis induced by bleomycin in mice. Both lung fibroblasts and AECs expressed FGFRs. BGJ398 significantly inhibited the proliferation and migration of lung fibroblasts stimulated with FGF2. BGJ398 also reduced the proliferation of AECs in response to FGF2. Although the administration of BGJ398 ameliorated pulmonary fibrosis in bleomycin-treated mice, it increased mortality resulting from alveolar injury and inhibition of AEC regeneration. These data suggest that the total inhibition of FGFR signaling can suppress lung fibrosis by inhibiting fibroblast activities, although alveolar injury is simultaneously caused.

The novel inhibitor PRI-724 for Wnt/ß-catenin/CBP signaling ameliorates bleomycin-induced pulmonary fibrosis in mice.

Purpose/Aim of the Study: Wnt/ß-catenin signaling was reported to be activated in pulmonary fibrosis, and was focused on as a target for antifibrotic therapy. However, the mechanism how the inhibition of Wnt/ß-catenin signaling ameliorate pulmonary fibrosis has not been fully elucidated. The purpose of this study is to explore the target cells of Wnt/ß-catenin inhibition in pulmonary fibrosis and to examine the antifibrotic effect of the novel inhibitor PRI-724 specifically disrupting the interaction of ß-catenin and CBP. Materials and Methods: The effect of C-82, an active metabolite of PRI-724, on the expression of TGF-ß1 and α-smooth muscle actin (SMA) was examined on fibroblasts and macrophages. We also examined the effects of PRI-724 in mouse model of bleomycin-induced pulmonary fibrosis. Results: The activation and increased accumulation of ß-catenin in the canonical pathway were detected in lung fibroblasts as well as macrophages stimulated by Wnt3a using Western blotting. Treatment with C-82 reduced CBP protein and increased p300 protein binding to ß-catenin in the nucleus of lung fibroblasts. In addition, C-82 inhibited the expression of SMA in lung fibroblasts treated with TGF-ß, indicating the inhibition of myofibroblast differentiation. In the fibrotic lungs induced by bleomycin, ß-catenin was stained strongly in macrophages, but the staining of ß-catenin in alveolar epithelial cells and fibroblasts was weak. The administration of PRI-724 ameliorated pulmonary fibrosis induced by bleomycin in mice when administered with a late, but not an early, treatment schedule. Analysis of bronchoalveolar fluid (BALF) showed a decreased number of alveolar macrophages. In addition, the level of TGF-ß1 in BALF was decreased in mice treated with PRI-724. C-82 also inhibited the production of TGF-ß1 by alveolar macrophages. Conclusions: These results suggest that the ß-catenin/CBP inhibitor PRI-724 is a potent antifibrotic agent that acts by modulating the activity of macrophages in the lungs.

Clinical features of interstitial pneumonia associated with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) commonly affects the lungs. However, the incidence of interstitial pneumonia (IP) related to SLE was reported to be about 10%, less than in the case of other connective tissue diseases, and the mechanism via which IP is related to SLE remains to be elucidated. METHODS: We retrospectively reviewed the medical records and high-resolution computed tomography (HRCT) images of 69 SLE patients who were admitted to our hospital between January 2011 and December 2015. RESULTS: Fifty-five of the patients were female (80%), and the mean age at the onset of SLE was 42.4 years. IP developed in 20 patients (29%), 14 of whom were female (70%), and the mean age at SLE onset was 53.4 years, significantly older than those without IP (38.0 years) (p = 0.003). Half of the patients were found to have IP during the initial diagnosis of SLE. The IP pattern on the HRCT images was consistent with that of usual interstitial pneumonia (UIP) in 25% of the patients and of nonspecific interstitial pneumonia (NSIP) in 55%. One patient exhibited acute exacerbation but survived. The radiological findings revealed that the disease progressed slowly in most of the patients; however, pulmonary function was retained. No significant differences were observed in the survival rates between patients with and without IP. CONCLUSION: In SLE cases, IP primarily occurred in male and elderly patients. In addition to the NSIP pattern, the UIP pattern was evident on HRCT scans of IP-related SLE. The survival of SLE patients was unrelated to IP.

Development, validation, and comparison of gene analysis methods for detecting EGFR mutation from non-small cell lung cancer patients-derived circulating free DNA.

The feasibility and required sensitivity of circulating free DNA (cfDNA)-based detection methods in second-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment are not well elucidated. We examined T790M and other activating mutations of EGFR by cfDNA to assess the clinical usability. In 45 non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations, cfDNAs were prepared from the plasma samples. EGFR mutations in cfDNA were detected using highly sensitive methods and originally developed assays and these results were compared to tissue-based definitive diagnoses. The specificity of each cfDNA-based method ranged 96-100% whereas the sensitivity ranged 56-67%, indicating its low pseudo-positive rate. In EGFR-TKI failure cohort, 41-46% samples were positive for T790M by each cfDNA-based method, which was comparable to re-biopsy tissue-based T790M positive rates in literature. The concordance of the results for each EGFR mutation ranged from 83-95%. In eight patients, the results of the cfDNA-based assays and re-biopsy-derived tissue-based test were compared. The observed overall agreement ranged in 50-63% in T790M, and in 63-100% in activating EGFR mutations. In this study, we have newly developed three types of assay which have enough sensitivity to detect cfDNA. We also detected T790M in 44% of patients who failed prior EGFR-TKI treatment, indicating that cfDNA-based assay has clinical relevance for detecting acquired mutations of EGFR.

Systemic Sarcoidosis Presenting with Renal Involvement Caused by Various Sarcoidosis-associated Pathophysiological Conditions.

A 61-year-old man was diagnosed with sarcoidosis involving the lungs, eyes, parotid gland and extrathoracic lymph nodes complicated by chronic kidney injury and hypercalcemia. Kidney biopsy showed non-specific interstitial nephritis and nephrosclerosis. However, immunohistochemical staining of cell surface markers revealed a multinucleated giant macrophage surrounded by T-cells, suggesting granulomatous interstitial nephritis. Corticosteroid improved the kidney function, and reduced the serum levels of calcium and angiotensin-converting enzyme. Sarcoid nephropathy may be caused by the combination of several sarcoidosis-associated pathophysiological conditions and a comprehensive kidney examination should be performed to assess the type of injury when determining a treatment strategy.

The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Lung Fibrosis in Mice.

The signaling pathways of growth factors, including platelet-derived growth factor, can be considered specific targets for overcoming the poor prognosis of idiopathic pulmonary fibrosis. Nintedanib, the recently approved multiple kinase inhibitor, has shown promising antifibrotic effects in patients with idiopathic pulmonary fibrosis; however, its efficacy is still limited, and in some cases, treatment discontinuation is necessary owing to toxicities such as gastrointestinal disorders. Therefore, more effective agents with less toxicity are still needed. TAS-115 is a novel multiple tyrosine kinase inhibitor that preferably targets platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, and c-FMS in addition to other molecules. In this study, we evaluated the antifibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo. TAS-115 inhibited the phosphorylation of PDGFR on human lung fibroblast cell line MRC-5 cells and suppressed their platelet-derived growth factor-induced proliferation and migration. Furthermore, TAS-115 inhibited the phosphorylation of c-FMS, a receptor of macrophage colony-stimulating factor, in murine bone marrow-derived macrophages and decreased the production of CCL2, another key molecule for inducing pulmonary fibrosis, under the stimulation of macrophage colony-stimulating factor. Importantly, the inhibitory effects of TAS-115 on both PDGFR and c-FMS were 3- to 10-fold higher than those of nintedanib. In a mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 significantly inhibited the development of pulmonary fibrosis and the collagen deposition in bleomycin-treated lungs. These data suggest that strong inhibition of PDGFR and c-FMS by TAS-115 may be a promising strategy for overcoming the intractable pathogenesis of pulmonary fibrosis.

The clinical features of older patients with lung cancer in comparison with their younger counterparts.

BACKGROUND: Older patients with lung cancer have increased over the past decades. Several standard treatments for older patients were established, but their clinical features in real world clinics remain unknown. Thus, we performed a retrospective study to clarify the clinical features of them. METHODS: The patients with lung cancer who were admitted to our hospital between April 1, 2012 and March 31, 2015 were retrospectively analyzed. Patients older than 75 years were defined as older patients. Standard treatments were based on the guidelines. RESULTS: In total, 333 patients were analyzed. The older patients had a poor performance status (PS), more comorbidities, and fewer opportunities to receive standard treatments. The prognosis of the older patients who received standard treatments was superior to that of those who did not. The therapeutic efficacy of standard treatments for older patients with stages I and II diseases was similar to their younger counterparts. However, the prognosis of older patients with advanced stage, especially stage III disease, was poor. The tolerability of first-line chemotherapy by older patients was comparable with their younger counterparts, but the older patients had fewer opportunities to receive several chemotherapy regimens, even second line chemotherapy. CONCLUSIONS: We should positively consider standard treatments for older patients. However, not only their shorter life expectancy but also their poor PS and multiple comorbidities that sometimes render patients unable to receive standard treatments and several chemotherapy regimens, make their prognosis poor. The standard treatments for older patients, especially in locally advanced stages, require modification.

A multicenter, open-label, phase II trial of S-1 plus carboplatin in advanced non-small cell lung cancer patients with interstitial lung disease.

OBJECTIVES: The clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remain unclear. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of S-1 in combination with carboplatin (CBDCA) in NSCLC patients with ILD. MATERIALS AND METHODS: A total of 33 advanced or recurrent NSCLC patients with ILD were prospectively enrolled in this multicenter, open-label, phase II study. Every 4 weeks, CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered. The primary endpoint was the investigator-assessed objective response rate. RESULTS: The median age at initiating chemotherapy was 70. Sixteen patients (48.5%) had squamous cell carcinoma histology. With respect to the types of ILD, the usual interstitial pneumonia pattern was dominant (66.7%). The median number of cycles administered was 3, and the overall response rate and disease control rate were 33.3% and 78.8%, respectively. The median progression-free survival, the median survival time and the 1-year survival rate were 4.8 months, 12.8 months and 51.4%, respectively. Acute exacerbation of ILD caused by chemotherapy was noted in 2 patients (6.1%). CONCLUSION: This is the first prospective study designed to evaluate the efficacy of a specific chemotherapeutic regimen as the primary endpoint in patients with advanced NSCLC with ILD. The combination of S-1 with CBDCA may be a treatment option for advanced NSCLC patients with ILD (The clinical trial registration number: UMIN000011046).

A case of pulmonary pleomorphic carcinoma with malignant phenotypes induced by ZEB1-associated epithelial-mesenchymal transition.

A 60-year-old man was admitted to our hospital with non-small cell lung cancer (NSCLC). Imaging and pathological studies revealed NSCLC, not otherwise specified (NOS), at clinical stage T3N1M0 stage IIIA. We started radiotherapy alone because of obstructive pneumonia and end-stage renal disease, but the tumors progressed rapidly and resulted in death due to air obstruction by pharyngeal metastasis. The cancer was diagnosed as pleomorphic carcinoma in an autopsy. Viable lung tumor cells, which were resistant to radiotherapy, and the pharyngeal metastasis had mesenchymal phenotypes and expressed ZEB1 but not SNAI1. These observations indicated that ZEB1-associated epithelial-mesenchymal transition has malignant features including resistance to radiotherapy and aggressive metastatic potential. ZEB1-associated EMT may be an important mechanism to understand the pathophysiology of pleomorphic carcinoma.