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Background: The PACIFIC trial established durvalumab administration after chemoradiotherapy as the standard of care for unresectable locally advanced nonsmall cell lung cancer (LA-NSCLC). However, the efficacy and safety of durvalumab in elderly patients aged 75 years or above remains unclear. This study aimed to investigate the real-world efficacy and safety of durvalumab for LA-NSCLC, with a specific focus on elderly patients., Patients and Methods: We reviewed 214 patients who received durvalumab out of 278 patients with unresectable LA-NSCLC who underwent chemoradiotherapy at 7 institutions between July 2018 and March 2022. Propensity score matching (PSM) analysis was performed to evaluate the efficacy of durvalumab in elderly patients., Results: The 2-year progression-free survival (PFS) and 2-year overall survival (OS) rates were 42.2% (95% confidence interval [CI], 34.7%-49.5%) and 77.1% (95% CI, 70.1-82.7%), respectively. Grade ≥ 3 immune-related adverse events (irAEs) occurred in 8.2% of patients. PSM analysis revealed that OS was significantly shorter in elderly patients (≥ 75 years) than in younger patients (< 75 years) (hazard ratio [HR]; 95% CI, 1.39-8.99; P = .008), whereas PFS did not differ significantly between the 2 groups (HR: 1.50, 95% CI, 0.84-2.68, P = .169). The frequency of irAEs did not differ between these groups., Conclusions: The real-world efficacy and safety of durvalumab administration following chemoradiotherapy for LA-NSCLC coincided with the PACIFIC trial's findings. Disease control achieved with this protocol did not differ significantly between elderly and younger patients but had acceptable tolerability, demonstrating its benefit even in elderly LA-NSCLC patients aged 75 years or above., Competing Interests: Disclosure Kenta Murotani received honoraria from Chugai Pharmaceutical Co., Ltd and AstraZeneca K.K. Takaaki Tokito received honoraria from AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., MSD K.K., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., Ltd., Nippon Kayaku Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd. Yoshihiko Sakata received honoraria from AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb Co., Ltd. Chugai Pharmaceutical Co., Ltd. Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., MSD K.K., and Novartis Pharma K.K. Koichi Azuma received honoraria from AstraZeneca K.K., Bristol-Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co. Ltd., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A 64-year-old light-smoking woman was clinically diagnosed with lung large-cell neuroendocrine carcinoma (LCNEC) with a metastatic brain tumor. An Oncomine Dx Targeted Test using metastatic brain tissue revealed that the patient's lung cancer cells had an EML4-ALK rearrangement. Patients with LCNEC and anaplastic lymphoma kinase (ALK) gene rearrangements are rare, and there is currently no standard treatment. Based on the genomic analysis, we treated the patient with brigatinib, an ALK inhibitor. We describe here a patient with LCNEC who responded significantly to brigatinib without serious adverse events., Competing Interests: Declaration of competing interest K.T has a conflict of interest with Chugai Pharmaceutical, but the other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Background: Concurrent chemoradiotherapy is the standard therapy for locally advanced non-small cell lung cancer (NSCLC). However, there is little evidence supporting its use in older adults. Low-dose daily carboplatin combined with thoracic radiotherapy is considered a standard regimen for this population. To establish a simple and feasible carboplatin administration method, we conducted a study of weekly carboplatin and concurrent radiotherapy for older adults with locally advanced NSCLC., Methods: This prospective, single-arm, multicenter, phase II clinical trial included patients aged ≥75 years with unresectable stage III NSCLC and Eastern Cooperative Oncology Group performance status 0-1. Patients received chemoradiotherapy (60 Gy/30 fractions plus concurrent weekly carboplatin at an area under curve of 2 mg mL -1  min -1 ). The primary endpoint was the overall response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety., Results: From July 2020 to June 2022, 37 patients were enrolled from 15 institutions, and 36 patients were evaluable for efficacy and safety. The ORR was 63.9% (95% confidence interval [CI] = 47.6-77.5). Median PFS was 14.6 months (95% CI = 9.1-18.1). Median OS was 25.5 months (95% CI = 17.4-not reached). Grade 4 leucopenia, neutropenia, and thrombocytopenia were observed in one patient (2.8%) each., Conclusion: Weekly carboplatin and concurrent radiation therapy was safe in older adults with locally advanced NSCLC, and promising activity was observed., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Accumulating evidence suggests that the passenger strands microRNAs (miRNAs) derived from pre-miRNAs are closely involved in cancer pathogenesis. Analysis of our miRNA expression signature of lung adenocarcinoma (LUAD) and The Cancer Genome Atlas (TCGA) data revealed that miR-144-5p (the passenger strand derived from pre- miR-144 ) was significantly downregulated in LUAD tissues. The aim of this study was to identify therapeutic target molecules controlled by miR-144-5p in LUAD cells. Ectopic expression assays demonstrated that miR-144-5p attenuated LUAD cell aggressiveness, e.g., inhibited cell proliferation, migration and invasion abilities, and induced cell cycle arrest and apoptotic cells. A total of 18 genes were identified as putative cancer-promoting genes controlled by miR-144-5p in LUAD cells based on our in silico analysis. We focused on a family with sequence similarity 111 member B ( FAM111B ) and investigated its cancer-promoting functions in LUAD cells. Luciferase reporter assay showed that expression of FAM111B was directly regulated by miR-144-5p in LUAD cells. FAM111B knockdown assays showed that LUAD cells significantly suppressed malignant phenotypes, e.g., inhibited cell proliferation, migration and invasion abilities, and induced cell cycle arrest and apoptotic cells. Furthermore, we investigated the FAM111B -mediated molecular networks in LUAD cells. Identifying target genes regulated by passenger strands of miRNAs may aid in the discovery of diagnostic markers and therapeutic targets for LUAD.

Purpose: Tegafur-uracil (UFT) is the standard postoperative adjuvant therapy for stage IB lung adenocarcinoma (LUAD) in Japan. This study aimed to determine whether UFT is effective in stage IB LUAD with and without epidermal growth factor receptor (EGFR) mutations., Methods: This retrospective study included 169 patients with stage IB LUAD who underwent complete resection at our department between 2010 and 2021. We investigated the clinicopathological and prognostic impact of EGFR mutations as well as the postoperative use of UFT., Results: EGFR mutation-positive cases tended to show a higher cumulative recurrence rate than EGFR mutation-negative cases (p = 0.081), while overall survival was comparable between the groups (p = 0.238). In the entire cohort, UFT administration was not an independent prognostic factor in the multivariate regression analysis (p = 0.112). According to a stratification analysis, UFT administration was independently associated with favorable overall survival (p = 0.031) in EGFR mutation-negative cases, while it was not associated with recurrence-free survival (p = 0.991) or overall survival (p = 0.398) in EGFR mutation-positive cases., Conclusion: UFT administration can improve the prognosis of EGFR mutation-negative LUAD but not EGFR mutation-positive LUAD. Thus, clinical trials of adjuvant-targeted therapy for EGFR mutation-positive stage IB LUAD should also be conducted in Japan.

Lung cancer is the most common cause of cancer-related death worldwide, accounting for 1.8 million deaths annually. Analysis of The Cancer Genome Atlas data showed that all members of the minichromosome maintenance (MCM) family (hexamers involved in DNA replication: MCM2-MCM7) were upregulated in lung adenocarcinoma (LUAD) tissues. High expression of MCM4 (P = 0.0032), MCM5 (P = 0.0032), and MCM7 (P = 0.0110) significantly predicted 5-year survival rates in patients with LUAD. Simurosertib (TAK-931) significantly suppressed the proliferation of LUAD cells by inhibiting cell division cycle 7-mediated MCM2 phosphorylation. This finding suggested that MCM2 might be a therapeutic target for LUAD. Moreover, analysis of the epigenetic regulation of MCM2 showed that miR-139-3p, miR-378a-5p, and miR-2110 modulated MCM2 expression in LUAD cells. In patients with LUAD, understanding the role of these miRNAs may improve prognoses., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The involvement of passenger strands of miRNAs in the molecular pathogenesis of human cancers is a recent concept in miRNA research, and it will broaden our understanding of the molecular mechanisms of miRNA-mediated cancer. The analysis of our miRNA signature of LUAD revealed that both strands of pre- miR-486 ( miR-486-5p and miR-486-3p ) were downregulated in LUAD tissues. Ectopic expression of both miRNAs induced cell cycle arrest in LUAD cells, suggesting both strands of miRNAs derived from pre- miR-486 were tumor suppressive. Our in silico analysis showed a total of 99 genes may be under the control of both miRNAs in LUAD cells. Importantly, among these targets, the high expression of seven genes ( MKI67 , GINS4 , RRM2 , HELLS , MELK , TIMELESS , and SAPCD2 ) predicted a poorer prognosis of LUAD patients ( p < 0.05). We focused on GINS4 , a DNA replication complex GINS protein that plays an essential role in the initiation of DNA replication. Our functional assays showed that GINS4 was directly controlled by both strands of pre- miR-486 , and its aberrant expression facilitated the aggressive behavior of LUAD cells. GINS4 is attractive as a therapeutic target for this disease. MiRNA analysis, including passenger strands, will further improve our understanding of the molecular pathogenesis of LUAD.

Small-cell lung cancer (SCLC) is associated with a high mortality rate and limited treatment efficacy. We created a microRNA (miRNA) expression signature by RNA sequencing using specimens from patients with SCLC who had failed treatment. Forty-nine miRNAs were downregulated in SCLC tissues and were candidate tumor-suppressive miRNAs. In this signature, both guide and passenger strands were downregulated for five miRNAs (miR-30a, miR-34b, miR-34c, miR-223, and miR-4529). Recent studies have revealed that passenger strands of miRNAs are involved in the molecular pathogenesis of human cancer. Although miR-30a-5p (the guide strand) has been shown to be a tumor-suppressive miRNA in various types of cancers, miR-30a-3p (the passenger strand) function is not well characterized in SCLC cells. We investigated the functional significance of miR-30a-3p and oncogenic genes regulated by miR-30a-3p in SCLC cells. Ectopic expression assays showed that miR-30a-3p expression inhibited cell proliferation and induced cell cycle arrest and apoptosis in two SCLC cell lines. Furthermore, in silico database searches and gene expression assays identified 25 genes as putative targets of miR-30a-3p in SCLC cells. Luciferase reporter assays revealed that downstream neighbor of SON (DONSON) was directly regulated by miR-30a-3p in SCLC cells. Knockdown of DONSON induced cell cycle arrest in SCLC cells and DONSON overexpression were detected in SCLC clinical samples. Analyzing the regulatory networks of tumor-suppressive miRNAs may lead to the identification of therapeutic targets in SCLC., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Immune checkpoint inhibitors (ICI) are key drugs in systemic therapy for advanced non-small-cell lung cancer (NSCLC) and have recently been incorporated into neoadjuvant and adjuvant settings for surgical resection. Currently, ICI combinations with cytotoxic agents are frequently used in clinical practice, although several ICI clinical trials have failed to produce long-term clinical benefits. Unfortunately, clinical benefit is moderate and limited considering physical and financial burden. Therefore, selecting appropriate patients and regimens for ICI therapy is important, and biomarkers are necessary for their selection. Tumor PD-L1 expression is universally used as a biomarker; however, PD-L1 assays show low analytical validity and reproducibility due to the visual-scoring system by pathologists. Recent tumor immunology studies explore that neoantigens derived from somatic mutations and the collaboration between T and B cells efficiently elicit antitumor responses. This suggests that high tumor mutational burden and T-cell infiltration are predictive biomarkers. However, B cells producing antibody (Ab) remain poorly understood and analyzed as biomarkers. We found that NY-ESO-1 and XAGE1 of cancer-testis antigen frequently elicit spontaneous humoral and cellular immune responses in NSCLC. Serum Ab against these antigens were detected in approximately 25% of NSCLC patients and predicted ICI monotherapy responses. In addition, the Ab levels were decreased with tumor shrinkage after ICI therapy. Thus, NY-ESO-1 and XAGE1 Ab are potentially biomarkers predicting and monitoring response to ICI therapy. For clinical applications, a fully-automated assay system measuring the Ab was developed. Here, we review current ICI therapy, tumor immunology, and biomarkers in NSCLC, and discuss the applicability of the serum biomarkers NY-ESO-1 and XAGE1 Ab., Competing Interests: Declaration of competing interest The Department of Immuno-Oncology (Dr. Oka) is endowed to Kawasaki Medical School by Pole Star Co., Ltd., which does not influence the work reported in this paper. Sakaeda K, Sakai Y, Atarashi Y, Irino Y, and Sato T are employees of Sysmex Corporation. The other authors declare no financial competing interests related to this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Asparagine-linked glycosylation (N-glycosylation) of proteins in the cancer secretome has been gaining increasing attention as a potential biomarker for cancer detection and diagnosis. Small extracellular vesicles (sEVs) constitute a large part of the cancer secretome, yet little is known about whether their N-glycosylation status reflects known cancer characteristics. Here, we investigated the N-glycosylation of sEVs released from small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC) cells. We found that the N-glycans of SCLC-sEVs were characterized by the presence of structural units also found in the brain N-glycome, while NSCLC-sEVs were dominated by typical lung-type N-glycans with NSCLC-associated core fucosylation. In addition, lectin-assisted N-glycoproteomics of SCLC-sEVs and NSCLC-sEVs revealed that integrin αV was commonly expressed in sEVs of both cancer cell types, while the epithelium-specific integrin α6β4 heterodimer was selectively expressed in NSCLC-sEVs. Importantly, N-glycomics of the immunopurified integrin α6 from NSCLC-sEVs identified NSCLC-type N-glycans on this integrin subunit. Thus, we conclude that protein N-glycosylation in lung cancer sEVs may potentially reflect the histology of lung cancers., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Lung adenocarcinoma (LUAD) is the most aggressive cancer and the prognosis of these patients is unfavorable. We revealed that the expression levels of both strands of miR-99a ( miR-99a-5p and miR-99a-3p ) were significantly suppressed in several cancer tissues. Analyses of large The Cancer Genome Atlas (TCGA) datasets showed that reduced miR-99a-5p or miR-99a-3p expression is associated with worse prognoses in LUAD patients (disease-free survival (DFS): p = 0.1264 and 0.0316; overall survival (OS): p = 0.0176 and 0.0756, respectively). Ectopic expression of these miRNAs attenuated LUAD cell proliferation, suggesting their tumor-suppressive roles. Our in silico analysis revealed 23 putative target genes of pre- miR-99a in LUAD cells. Among these targets, high expressions of 19 genes were associated with worse prognoses in LUAD patients (OS: p < 0.05). Notably, FAM64A was regulated by both miR-99a-5p and miR-99a-3p in LUAD cells, and its aberrant expression was significantly associated with poor prognosis in LUAD patients (OS: p = 0.0175; DFS: p = 0.0276). FAM64A knockdown using siRNAs suggested that elevated FAM64A expression contributes to cancer progression. Aberrant FAM64A expression was detected in LUAD tissues by immunostaining. Taken together, our miRNA-based analysis might be effective for identifying prognostic and therapeutic molecules in LUAD.

Objectives: We conducted a subanalysis of data from the multicentre, retrospective observational Nivolumab Japan Real World (CA209-9CR) study to evaluate nivolumab effectiveness and safety in elderly patients (aged ≥75 years) with advanced/metastatic non-small cell lung cancer., Materials and Methods: Medical record data of patients initiating nivolumab treatment between April 2016 and December 2016 were collected using electronic data capture from 23 cancer hospitals in Japan between March 2017 and August 2018. Nivolumab treatment data were collected to investigate the treatment patterns by age group (<75 and ≥75 years), and the effectiveness and safety of nivolumab treatment., Results: Of the 901 patients evaluated, 178 (19.8%) were aged ≥75 years. Overall, patients received a median of five nivolumab treatments regardless of age group. Comparable progression-free survival was observed, with a median of 2.1 months in patients aged <75 years and 2.1 months in patients aged ≥75 years (p=0.5441). No significant differences were found in duration of response, overall response rate or disease control rate between the two age groups. Median overall survival in patients aged <75 and ≥75 years was 14.7 months and 12.3 months, respectively. Grade ≥3 adverse events (AEs) occurred in 29.2% and 28.1% of patients aged <75 and ≥75 years, respectively. Immune-related AEs decreased slightly with increasing age; time to onset and rates of improvement were similar for patients aged <75 and ≥75 years. The most common grade 3-4 AEs were interstitial lung disease in both age groups (4.0% in patients aged <75 years and 2.8% in those aged ≥75 years). Poor performance status was associated with worse outcomes in both age groups., Conclusion: Based on Japanese real-world data, the effectiveness and safety of nivolumab were confirmed regardless of age., Competing Interests: Competing interests: KO reports personal fees from Ono Pharmaceutical Co, Ltd and MSD K.K. outside the submitted work; JS reports personal fees from Bristol-Myers Squibb K.K. and Ono Pharmaceutical CO, Ltd outside the submitted work; HS reports grants from Chugai Pharmaceutical Co, Ltd, AstraZeneca K.K. and MSD K.K. and personal fees from Ono Pharmaceutical Co, Ltd, Nippon Boehringer Ingelheim Co, Ltd and Novartis Pharma K.K. outside the submitted work; HS reports personal fees from Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb K.K. during the conduct of the study, personal fees from Chugai Pharmaceutical Co, Ltd and MSD K.K. outside the submitted work; OS reports other from Ono Pharmaceutical Co, Ltd during the conduct of the study, personal fees and other from Novartis Pharma K.K., Nippon Boehringer Ingelheim Co, Ltd and AstraZeneca K.K. and other from Kyorin Pharmaceutical Co, Ltd, Bayer Health, Daiichi Sankyo Co, Ltd, GlaxoSmithKline K.K. and Ono Pharmaceutical Co, Ltd outside the submitted work; MY reports personal fees from Chugai Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd and AstraZeneca K.K. outside the submitted work; MN reports grants and non-financial support from Ono Pharmaceutical Co, Ltd during the conduct of the study, grants and personal fees from Ono Pharmaceutical Co, Ltd, Bristol-Myers Squibb K.K., Pfizer Japan Inc, Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan K.K., Taiho Pharmaceutical Co, Ltd, AstraZeneca K.K., MSD K.K., Novartis Pharma K.K., Takeda Pharmaceutical Co, Ltd and Daiichi Sankyo Healthcare Co, Ltd and grants from Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from Nippon Boehringer Ingelheim Co, Ltd outside the submitted work; KA reports grants and personal fees from Ono Pharmaceutical Co, Ltd, Bristol-Myers Squibb K.K., AstraZeneca K.K. and Eli Lilly Japan K.K. and grants from MSD K.K. and Novartis Pharma K.K. outside the submitted work; TK reports grants and personal fees from Ono Pharmaceutical Co, Ltd, AstraZeneca K.K., Taiho Pharmaceutical Co, Ltd, MSD K.K., Novartis Pharma K.K., Nippon Boehringer Ingelheim Co, Ltd, Eli Lilly Japan K.K., Pfizer Japan Inc and Chugai Pharmaceutical Co, Ltd, and grants from Takeda Pharmaceutical Co, Ltd, Regeneron Pharmaceuticals, Inc and Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from Teijin Pharma Ltd and Bristol-Myers Squibb K.K. outside the submitted work; SO reports grants and personal fees from Bristol-Myers Squibb K.K. and Ono Pharmaceutical Co, Ltd during the conduct of the study, grants and personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co, Ltd and Taiho Pharmaceutical Co, Ltd and grants from Kyowa Hakko Kirin Co, Ltd (currently Kyowa Kirin Co, Ltd) and Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from MSD K.K. and Eli Lilly Japan K.K. outside the submitted work; DF reports personal fees from Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb K.K. during the conduct of the study, personal fees from AstraZeneca K.K., Taiho Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, MSD K.K., Nippon Boehringer Ingelheim Co, Ltd and Eli Lilly Japan K.K. outside the submitted work; HT reports grants and personal fees from Bristol-Myers Squibb K.K., Eli Lilly Japan K.K., MSD K.K., Taiho Pharmaceutical Co, Ltd, Pfizer Japan Inc, Chugai Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd, AstraZeneca K.K. and Nippon Boehringer Ingelheim Co, Ltd and grants from Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from Novartis Pharma K.K. outside the submitted work; TK reports grants and personal fees from Chugai Pharmaceutical Co, Ltd, AstraZeneca K.K., Eli Lilly Japan K.K. and Bristol-Myers Squibb K.K., and personal fees from Taiho Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd, MSD K.K., Pfizer Japan Inc, Kyowa Hakko Kirin Co, Ltd (currently Kyowa Kirin Co, Ltd), Nippon Boehringer Ingelheim Co, Ltd, and Nippon Kayaku Co, Ltd and grants from Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) outside the submitted work; HS reports other from Mebix, Inc during the conduct of the study, personal fees from AstraZeneca K.K. outside the submitted work; IS reports grants from Nippon Boehringer Ingelheim Co, Ltd during the conduct of the study, grants and personal fees from AstraZeneca K.K., Taiho Pharmaceutical Co, Ltd, Nippon Boehringer Ingelheim Co, Ltd, Ono Pharmaceutical Co, Ltd, MSD K.K, Eli Lilly Japan K.K., Bristol-Myers Squibb K.K. and Chugai Pharmaceutical Co, Ltd and grants from Astellas Pharma Inc, Novartis Pharma K.K. and AbbVie GK, and personal fees from Pfizer Japan Inc outside the submitted work; YO reports grants and personal fees from Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb K.K. during the conduct of the study, grants and personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan K.K., Pfizer Japan Inc, MSD K.K., Kyorin Pharmaceutical Co, Ltd, Takeda Pharmaceutical Co, Ltd, Novartis Pharma K.K., Taiho Pharmaceutical Co, Ltd, and AbbVie GK, and personal fees from Celltrion Healthcare Co, Ltd, Amgen Inc, and Nippon Boehringer Ingelheim Co, Ltd, and grants from Kissei Pharmaceutical Co, Ltd, Loxo Oncology, Inc, and Janssen Pharmaceutical K.K. outside the submitted work; HH is an employee of Bristol-Myers Squibb K.K.; NY is an employee of Ono Pharmaceutical Co, Ltd; RM, YHK, OS, KK, HT, KM, TM and TH have nothing to declare., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Objectives: To describe the treatment patterns and determine the effectiveness and safety of nivolumab treatment for non-small cell lung cancer (NSCLC) in real-world setting in Japan., Materials and Methods: Japanese patients with NSCLC who received nivolumab were analyzed retrospectively. Patients who had started nivolumab treatment between April 2016 and December 2016 were enrolled. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness and safety of nivolumab treatment and that of treatments just before and after nivolumab treatment, and programmed death-ligand 1 (PD-L1) expression status, if available, were collected. Factors associated with nivolumab effectiveness identified by univariate and multivariate analyses were further investigated for plotting Kaplan-Meier curves of epidermal growth factor receptor (EGFR) gene mutation status, PD-L1 expression status, and Eastern Cooperative Oncology Group performance status (ECOG PS)., Results: In this study, 901 NSCLC patients were enrolled. Nivolumab was used the most as a second line treatment with a median number of nivolumab doses of five. The median overall survival (OS) was 14.6 months, one-year survival rate was 54.3 %, and median progression-free survival (PFS) was 2.1 months. The objective response rate was 20.5 % and disease control rate was 57.4 %. According to multivariate analyses, better OS and PFS were associated with favorable ECOG PS and absence of liver metastasis. Better PFS was observed in patients without EGFR mutation and patients with smoking history. PFS and best overall response in PD-L1 expression subgroups were expression level-dependent. The overall incidence of irAEs was 45.8 %, and the incidence of adverse events of grade 3 or higher was 14.0 %., Conclusion: The real-world effectiveness and safety of nivolumab is consistent with that reported by previous clinical trials and other real-world data. Subgroup analysis showed that ECOG PS, EGFR mutation status, smoking status, and PD-L1 were associated with the effectiveness of nivolumab., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The prognosis of patients with advanced-stage lung squamous cell carcinoma (LUSQ) is poor, and effective treatment protocols are limited. Our continuous analyses of antitumor microRNAs (miRNAs) and their oncogenic targets have revealed novel oncogenic pathways in LUSQ. Analyses of our original miRNA expression signatures indicated that both strands of miR-144 (miR-144-5p, the passenger strand; miR-144-3p, the guide strand) showed decreased expression in cancer tissues. Additionally, low expression of miR-144-5p significantly predicted a poor prognosis in patients with LUSQ by The Cancer Genome Atlas database analyses (overall survival, P = 0.026; disease-free survival, P = 0.023). Functional assays revealed that ectopic expression of miR-144-5p and miR-144-3p significantly blocked the malignant abilities of LUSQ cells, eg, cancer cell proliferation, migration, and invasion. In LUSQ cells, 13 and 15 genes were identified as possible oncogenic targets that might be regulated by miR-144-5p and miR-144-3p, respectively. Among these targets, we identified 3 genes (SLC44A5, MARCKS, and NCS1) that might be regulated by both strands of miR-144. Interestingly, high expression of NCS1 predicted a significantly poorer prognosis in patients with LUSQ (overall survival, P = 0.013; disease-free survival, P = 0.048). By multivariate analysis, NCS1 expression was found to be an independent prognostic factor for patients with LUSQ patients. Overexpression of NCS1 was detected in LUSQ clinical specimens, and its aberrant expression enhanced malignant transformation of LUSQ cells. Our approach, involving identification of antitumor miRNAs and their targets, will contribute to improving our understanding of the molecular pathogenesis of LUSQ., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: ALK-rearranged lung cancer has been recently identified. Although signet-ring cell morphology and mucinous cribriform pattern are considered to be characteristic of ALK-rearranged lung cancer. Some studies have also suggested cytological features., Methods: This study investigated cytological features of ALK-rearranged lung cancer in eight patients., Results: Cytologically, the tumor cell group varied from isolated to large clusters. Small nucleoli, fine granular to vesicular chromatin, and nuclear groove were observed in all patients. Furthermore, extracellular and intracellular mucin and signet-ring cells were identified in five patients., Conclusion: This study demonstrated that the presence of extracellular and intracellular mucin, signet-ring cells, small nucleoli, fine granular to vesicular chromatin, and nuclear groove in cytological samples may be a diagnostic clue for ALK-rearranged lung cancer., (© 2017 Wiley Periodicals, Inc.)

ROS1-rearranged lung adenocarcinoma has been recently identified. We report a case of ROS1-rearranged lung adenocarcinoma with special emphasis on cytological findings. Here, we report a case of young woman with ROS1-rearranged lung adenocarcinoma diagnosed by cytology and discuss the clinical, cytological, and molecular findings. Cytologically, the tumor consisted of small tight clusters of cells with high nuclear/cytoplasmic ratio. Nuclei were enlarged and small nucleoli were occasionally observed. Signet-ring cells were focally identified. Neoplastic cells were positive for ROS1 immunocytochemistry. Subsequently, the translocation of ROS1 gene was confirmed in a histological specimen. In conclusion, the specific histology of adenocarcinoma on cytological materials should promote testing for ROS1 immunohistochemistry. Immunocytochemical detection of ROS1 protein helps identify patients suitable for molecular targeted therapy., (© 2017 Wiley Periodicals, Inc.)

In the present study, in order to elucidate the aggressive nature of lung squamous cell carcinoma (LUSQ), we investigated the oncogenic RNA networks regulated by antitumor microRNAs (miRNAs or miRs) in LUSQ cells. The analysis of our original miRNA expression signatures of human cancers revealed that microRNA‑150‑5p (miR‑150‑5p) was downregulated in various types of cancer, indicating that miR‑150‑5p acts as an antitumor miRNA by targeting several oncogenic genes. Thus, the aims of this study were to investigate the antitumor roles of miR‑150‑5p in LUSQ cells and to identify oncogenes regulated by miR‑150‑5p that are involved in the aggressive behavior of LUSQ. The downregulation of miR‑150‑5p was validated in clinical samples of LUSQ and cell lines (SK-MES‑1 and EBC‑1). The ectopic overexpression of miR‑150‑5p significantly suppressed cancer cell aggressiveness. Comprehensive gene expression analyses revealed that miR‑150‑5p regulated 9 genes in the LUSQ cells. Among these, matrix metalloproteinase 14 (MMP14) was found to be a direct target of miR‑150‑5p, as shown by luciferase reporter assay. The knockdown of MMP14 using siRNA against MMP14 (si-MMP14) significantly inhibited cancer cell migration and invasion. The overexpression of MMP14 was detected in clinical specimens of LUSQ by immunohistochemistry. On the whole, these findings suggest that the downregulation of miR‑150‑5p and the overexpression of MMP14 may be deeply involved in the pathogenesis of LUSQ.

Background: It is crucial to develop novel diagnostic approaches for determining if peripheral lung nodules are malignant, as such nodules are frequently detected due to the increased use of chest computed tomography scans. To this end, we evaluated levels of napsin A in epithelial lining fluid (ELF), since napsin A has been reported to be an immunohistochemical biomarker for histological diagnosis of primary lung adenocarcinoma., Methods: In consecutive patients with indeterminate peripheral lung nodules, ELF samples were obtained using a bronchoscopic microsampling (BMS) technique. The levels of napsin A and carcinoembryonic antigen (CEA) in ELF at the nodule site were compared with those at the contralateral site. A final diagnosis of primary lung adenocarcinoma was established by surgical resection., Results: We performed BMS in 43 consecutive patients. Among patients with primary lung adenocarcinoma, the napsin A levels in ELF at the nodule site were markedly higher than those at the contralateral site, while there were no significant differences in CEA levels. Furthermore, in 18 patients who were undiagnosed by bronchoscopy and finally diagnosed by surgery, the napsin A levels in ELF at the nodule site were identically significantly higher than those at the contralateral site. In patients with non-adenocarcinoma, there were no differences in napsin A levels in ELF. The area under the receiver operator characteristic curve for identifying primary lung adenocarcinoma was 0.840 for napsin A and 0.542 for CEA., Conclusion: Evaluation of napsin A levels in ELF may be useful for distinguishing primary lung adenocarcinoma.

Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous. In this study, we newly constructed a microRNA (miRNA) expression signature of SCLC by analysis of autopsy specimens. Based on the resultant signature, four miRNAs (miR-27a-5p, miR-485-3p, miR-34-5p and miR-574-3p) were found to be candidate anti-tumor miRNAs. To investigate their functional importance, we first validated the downregulation of miR-27a-5p and miR-34b-3p in SCLC clinical specimens. Next, we demonstrated that ectopic expression of both miR-27a-5p and miR-34b-3p significantly inhibited cancer cell aggressiveness. Our in silico analyses showed that four genes (topoisomerase 2 alpha (TOP2A), maternal embryonic leucine zipper kinase (MELK), centromere protein F (CENPF) and SRY-box 1 (SOX1) were identified as miR-27a-5p- and miR-34b-3p-regulated genes. Based on immunohistochemical analysis, TOP2A, MELK and CENPF were involved in SCLC pathogenesis. These genes might contribute to high proliferation and early metastatic spread of SCLC cells. Elucidation of differentially expressed miRNA-mediated cancer pathways based on SCLC signature may provide new insights into the mechanisms of SCLC pathogenesis.

To the best of our knowledge, there is no description on immunocytochemical study of sclerosing pneumocytoma (SP) using a cell transfer method. In this article, we report imprint cytological and immunocytochemical findings of SP. Three cases of SP possessing both imprint cytological and histological materials were examined. All tumors showed well-defined margin grossly. On microscopic examination, the tumor consisted of surface and stromal round cells. Cytologically, surface and stromal round cells showed fragments or clusters of papillary configuration with low N/C ratio and cell clusters of small to medium-sized cells with high N/C ration. Immunocytochemically, surface cells showed the positive reaction for surfactant apoprotein A (SPA), but stromal round cell exhibited the negative reaction for SPA. Cytologists and pathologists should steadily recognize cytological findings of surface and stromal round cells of SP. Immunocytochemistry of SPA may be useful in the discrimination of both cells. Diagn. Cytopathol. 2017;45:274-278. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In spite of advances in the diagnosis and current molecular target therapies of lung cancer, this disease remains the most common cause of cancer-related death worldwide. Approximately 80% of lung cancers is non-small cell lung cancer (NSCLC), and 5-year survival rate of the disease is ~20%. On the other hand, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. IPF is refractory to treatment and has a very low survival rate. Moreover, IPF is frequently associated with lung cancer. However, the common mechanisms shared by these two diseases remain poorly understood. In the post-genome sequence era, the discovery of noncoding RNAs, particularly microRNAs (miRNAs), has had a major impact on most biomedical fields, and these small molecules have been shown to contribute to the pathogenesis of NSCLC and IPF. Investigation of novel RNA networks mediated by miRNAs has improved our understanding of the molecular mechanisms of these diseases. This review summarizes our current knowledge on aberrantly expressed miRNAs regulating NSCLC and IPF based on miRNA expression signatures.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that is refractory to treatment and carries a high mortality rate. IPF is frequently associated with lung cancer. Identification of molecular targets involved in both diseases may elucidate novel molecular mechanisms contributing to their pathology. Recent studies of microRNA (miRNA) expression signatures showed that microRNA-29a (miR-29a) was downregulated in IPF and lung cancer. The aim of this study was to investigate the functional significance of miR-29a in lung cancer cells (A549 and EBC-1) and lung fibroblasts (MRC-5) and to identify molecular targets modulated by miR-29a in these cells. We confirmed the downregulation of miR-29a in clinical specimens of IPF and lung cancer. Restoration of miR-29a suppressed cancer cell aggressiveness and fibroblast migration. A combination of gene expression data and in silico analysis showed that a total of 24 genes were putative targets of miR-29a. Among them, lysyl oxidase-like 2 (LOXL2) and serpin peptidase inhibitor clade H, member 1 (SERPINH1) were direct targets of miR-29a by luciferase reporter assays. The functions of LOXL2 and SERPINH1 contribute significantly to collagen biosynthesis. Overexpression of LOXL2 and SERPINH1 was observed in clinical specimens of lung cancer and fibrotic lesions. Downregulation of miR-29a caused overexpression of LOXL2 and SERPINH1 in lung cancer and IPF, suggesting that these genes are involved in the pathogenesis of these two diseases.

The development of targeted molecular therapies has greatly benefited patients with lung adenocarcinomas. In contrast, these treatments have had little benefit in the management of lung squamous cell carcinoma (lung SCC). Therefore, new treatment options based on current genomic approaches are needed for lung SCC. Aberrant microRNA (miRNA) expression has been shown to promote lung cancer development and aggressiveness. Downregulation of microRNA-218 (miR-218) was frequently observed in our miRNA expression signatures of cancers, and previous studies have shown an antitumor function of miR-218 in several types of cancers. However, the impact of miR-218 on lung SCC is still ambiguous. The present study investigated the antitumor roles of miR-218 in lung SCC to identify the target genes regulated by this miRNA. Ectopic expression of miR-218 greatly inhibited cancer cell migration and invasion in the lung SCC cell lines EBC-1 and SK-MES-1. Through a combination of in silico analysis and gene expression data searching, tumor protein D52 (TPD52) was selected as a putative target of miR-218 regulation. Moreover, direct binding of miR-218 to the 3'-UTR of TPD52 was observed by dual luciferase reporter assay. Overexpression of TPD52 was observed in lung SCC clinical specimens, and knockdown of TPD52 significantly suppressed cancer cell migration and invasion in lung SCC cell lines. Furthermore, the downstream pathways mediated by TPD52 involved critical regulators of genomic stability and mitotic checkpoint genes. Taken together, our data showed that downregulation of miR-218 enhances overexpression of TPD52 in lung SCC cells, promoting cancer cell aggressiveness. Identification of tumor-suppressive miRNA-mediated RNA networks of lung SCC will provide new insights into the potential mechanisms of the molecular pathogenesis of the disease.

Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA- (miRNA) mediated oncogenic pathways in lung SCC. It is well known that miR-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p (the passenger strand) on cancer cells is still ambiguous. Expression levels of miR-145-5p and miR-145-3p were markedly reduced in cancer tissues, and ectopic expression of these miRNAs inhibited cancer cell aggressiveness, suggesting that both miR-145-3p as well as miR-145-5p acted as antitumor miRNAs. We identified seven putative target genes (MTDH, EPN3, TPD52, CYP27B1, LMAN1, STAT1 and TXNDC12) that were coordinately regulated by miR-145-5p and miR-145-3p in lung SCC. Among the seven genes, we found that metadherin (MTDH) was a direct target of these miRNAs. Kaplan-Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients. We investigated pathways downstream from MTDH by using genome-wide gene expression analysis. Our data showed that several anti-apoptosis and pro-proliferation genes were involved in pathways downstream from MTDH in lung SCC. Taken together, both strands of miR-145, miR-145-5p and miR-145-3p are functional and play pivotal roles as antitumor miRNAs in lung SCC.

Objective: Disease progression because of acquired resistance is common in advanced or metastatic epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), despite initial response to EGFR-tyrosine kinase inhibitors (TKIs). In Japan, transbronchial tissue biopsy is the most common sampling method used for re-biopsy to identify patients eligible for treatment. We aimed to investigate the success rate of re-biopsy and re-biopsy status of patients with advanced or metastatic NSCLC completing first-line EGFR-TKI therapy., Patients and Methods: This was a retrospective, multi-center, Japanese study. The target patients in the study were EGFR mutation-positive NSCLC patients. The primary endpoint was the success rate (number of cases in which tumor cells were detected/total number of re-biopsies performed×100). Secondary endpoints included differences between the status of the first biopsy and that of the re-biopsy in the same patient population, and the details of cases in which re-biopsy could not be carried out. Re-biopsy-associated complications were also assessed., Results: Overall, 395 patients were evaluated (median age 63 years), with adenocarcinoma being the most common tumor type. Re-biopsy was successful in 314 patients (79.5%). Compared with the sampling method at first biopsy, at re-biopsy, the surgical resection rate increased from 1.8% to 7.8%, and percutaneous tissue biopsy increased from 7.6% to 29.1%, suggesting the difficulty of performing re-biopsy. Approximately half of the patients had T790M mutations, which involved a Del19 mutation in 55.6% of patients and an L858R mutation in 43.0%. Twenty-three patients (5.8%) had re-biopsy- associated complications, most commonly pneumothorax., Conclusions: Success rate for re-biopsy in this study was approximately 80%. Our study sheds light on the re-biopsy status after disease progression in patients with advanced or metastatic NSCLC. This information is important to improve the selection of patients who may benefit from third-generation TKIs., (Copyright © 2016 AstraZeneca K.K. Published by Elsevier Ireland Ltd.. All rights reserved.)

Lung cancer remains the most frequent cause of cancer-related death in developed countries. A recent molecular-targeted strategy has contributed to improvement of the remarkable effect of adenocarcinoma of the lung. However, such treatment has not been developed for squamous cell carcinoma (SCC) of the disease. Our recent studies of microRNA (miRNA) expression signatures of human cancers showed that the microRNA-29 family (miR‑29a, miR‑29b and miR‑29c) significantly reduced cancer tissues compared to normal tissues. These findings suggest that miR‑29s act as tumor-suppressors by targeting several oncogenic genes. The aim of the study was to investigate the functional significance of miR‑29s in lung SCC and to identify miR‑29s modulating molecular targets in lung SCC cells. Restoration of all mature members of the miR‑29s inhibited cancer cell migration and invasion. Gene expression data combined in silico analysis and luciferase reporter assays demonstrated that the lysyl oxidase-like 2 (LOXL2) gene was a direct regulator of tumor‑suppressive miR‑29s. Moreover, overexpressed LOXL2 was confirmed in lung SCC clinical specimens, and silencing of LOXL2 inhibited cancer cell migration and invasion in lung SCC cell lines. Our present data suggested that loss of tumor-suppressive miR‑29s enhanced cancer cell invasion in lung SCC through direct regulation of oncogenic LOXL2. Elucidation of the novel lung SCC molecular pathways and targets regulated by tumor-suppressive miR‑29s will provide new insights into the potential mechanisms of oncogenesis and metastasis of the disease.

Expression of the oncogene hepatocyte growth factor receptor (MET) and phosphorylation of the MET protein have been associated with both primary and acquired resistance to tyrosine kinase inhibitors (TKIs) used in therapy targeting the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancers (NSCLCs). Therefore, simultaneous inhibition of both of these receptor tyrosine kinases (RTKs) should improve disease treatment. Our previous study of microRNA (miRNA) expression signatures of lung squamous cell carcinoma (lung-SCC) revealed that microRNA-206 (miR‑206) was significantly reduced in lung-SCC tissues, suggesting that miR‑206 functions as a tumor suppressor in the disease. Furthermore, putative miR‑206 binding sites were annotated in the 3'-UTRs of MET and EGFR RTKs in miRNA databases. The aim of the study was to investigate the functional significance of miR‑206 in lung-SCC and to confirm the inhibition of both MET and EGFR oncogenic signaling by expression of miR‑206 in cancer cells. We found that restoration of mature miR‑206 inhibited cancer cell proliferation, migration, and invasion in EBC-1 cells through downregulation of both mRNA and protein levels of MET and EGFR. Interestingly, phosphorylation of ERK1/2 and AKT signaling were inhibited by restoration of miR‑206 in cancer cells. Overexpression of MET and EGFR were observed in clinical specimens of lung-SCC. Tumor-suppressive miR‑206 inhibited dual signaling networks activated by MET and EGFR, and these findings will provide new insights into the novel molecular mechanisms of lung-SCC oncogenesis and new therapeutic approaches for the treatment of this disease.

Lung cancer is clearly the primary cause of cancer-related deaths worldwide. Recent molecular-targeted strategy has contributed to improvement of the curative effect of adenocarcinoma of the lung. However, such current treatment has not been developed for squamous cell carcinoma (SCC) of the disease. The new genome-wide RNA analysis of lung-SCC may provide new avenues for research and the development of the disease. Our recent microRNA (miRNA) expression signatures of lung-SCC revealed that clustered miRNAs miR-1/133a were significantly reduced in cancer tissues. Here, we found that restoration of both mature miR-1 and miR-133a significantly inhibited cancer cell proliferation, migration and invasion. Coronin-1C (CORO1C) was a common target gene of the miR-1/133a cluster, as shown by the genome-wide gene expression analysis and the luciferase reporter assay. Silencing of CORO1C gene expression inhibited cancer cell proliferation, migration and invasion. Furthermore, CORO1C-regulated molecular pathways were categorized by using si-CORO1C transfectants. Further analysis of novel cancer signaling pathways modulated by the tumor-suppressive cluster miR-1/133a will provide insights into the molecular mechanisms of lung-SCC oncogenesis and metastasis.

Pulmonary epithelioid angiosarcoma is rare, and there are no descriptions of the immunocytochemistry of such a case. We report a case with focus on immunocytochemistry of imprint cytological specimens here. A 43-year-old Japanese man presented with cough. Brushing cytology of the tumor using a bronchoscope showed a malignant neoplasm. Subsequently, left lower lobectomy was undertaken. Imprint cytological material of the neoplastic cells noted some clusters of round, or oval, to polygonal epithelioid cells. Histological examination showed the proliferation of epithelioid neoplastic cells containing erythrocytes in the cytoplasm. The immunocytochemistry in imprint cytological specimens showed a focal positive reaction for von Willebrand factor, and the immunohistochemistry of the surgically resected lung tumor showed a focal positive reaction for Fli-1, von Willebrand factor, CD31, and CD34. Finally, we suggest that the immunocytochemical study of imprint cytological materials may supply available information in diagnosing angiosarcoma with epithelioid features lacking characteristic structures.

A large cell neuroendocrine carcinoma (LCNEC) is a rare neoplasm. In this article, we report a case of LCNEC with stromal calcification. A 46-year-old Japanese man was found to have an abnormal shadow in the left upper lobe in a chest X-ray. As the size of the tumor increased during the follow-up, a left upper lobectomy was performed. Histological examination disclosed neuroendocrine morphology consisting of large cells, and subsequent immunohistochemistry confirmed the neuroendocrine differentiation. A diagnosis of LCNEC was established. Additionally, calcification was observed in the stroma within the tumor. Immunohistochemically, parts of neoplastic cells of LCNEC and calcified foci were positive for osteopontin. Finally, we suggest that osteopontin as well as dystrophy within the tumor may be involved in the stromal calcification of LCNEC.