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Papers by Gouji Toyokawa

Research paper thumbnail of Radiological features of resected lung adenocarcinoma with epithelial–mesenchymal transition

The Annals of Thoracic Surgery, 2020

BACKGROUND Epithelial-mesenchymal transition plays a crucial role in cancer progression and is a ... more BACKGROUND Epithelial-mesenchymal transition plays a crucial role in cancer progression and is a significant prognosticator for postoperative survival in patients with lung cancer. Predicting epithelial-mesenchymal transition preoperatively using computed tomography may help to determine the optimal surgical strategy. METHODS We performed an immunohistochemical analysis of E-cadherin and vimentin expressions using tumor specimens from resected primary lung adenocarcinoma and classified the results into three subgroups according to the expressions: epithelial, intermediate, and mesenchymal. The intermediate and mesenchymal groups were classified as the epithelial-mesenchymal transition conversion group. We analyzed the association between epithelial-mesenchymal transition and radiological characteristics, especially computed tomographic features. RESULTS The epithelial-mesenchymal transition conversion group constituted 162 (49.1%) patients. Computed tomography revealed that tumors with epithelial-mesenchymal transition conversion showed a high consolidation/tumor ratio compared with those without conversion. Additionally, univariate analysis demonstrated that tumors with epithelial-mesenchymal transition were significantly associated with bronchial and/or vascular convergence (P=0.0001) and notching (P=0.0282). When the cut-off value for the consolidation/tumor ratio was set by receiver operating characteristic curve, a high ratio (>0.7946) and the presence of convergence were independent predictive factors for epithelial-mesenchymal transition by multivariate analysis (P=0.0007 and 0.0500, respectively). Tumors with a high consolidation/tumor ratio and convergence had a four-fold higher odds ratio for epithelial-mesenchymal transition, and patients had significantly poorer survival. CONCLUSIONS Convergence and a high consolidation/tumor ratio were independently associated with epithelial-mesenchymal transition conversion. These preoperative radiological results will help to predict epithelial-mesenchymal transition conversion in lung adenocarcinoma.

Research paper thumbnail of Spread through air spaces in lung neuroendocrine tumor

Translational Lung Cancer Research, 2019

Research paper thumbnail of The significant influence of having children on the postoperative prognosis of patients with nonsmall cell lung cancer: A propensity score‐matched analysis

Cancer Medicine, 2018

This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Research paper thumbnail of Clinical and Prognostic Significance of the Epithelial–Mesenchymal Transition in Stage IA Lung Adenocarcinoma: A Propensity Score–Matched Analysis

Clinical Lung Cancer, 2019

We aimed to analyze the clinical significance of the epithelialemesenchymal transition (EMT) in s... more We aimed to analyze the clinical significance of the epithelialemesenchymal transition (EMT) in stage IA lung adenocarcinoma. Tumors with the EMT phenotype were identified in 43.1% of patients with a high ratio of consolidation to tumor diameter. Propensity score matching indicated a significant association of the EMT with shorter survival. Background: The epithelialemesenchymal transition (EMT) describes the process through which cells lose epithelial characteristics and gain a mesenchymal phenotype. The EMT contributes to tumor invasion and cancer progression, and is associated with metastasis and poor survival of patients with nonesmall-cell lung cancer. However, little is known about the relationships between the EMT and the clinicopathologic characteristics of patients with stage IA lung adenocarcinoma. Patients and Methods: We conducted immunohistochemical analysis of the expression of the EMT markers E-cadherin and vimentin of specimens acquired from 183 consecutive patients with stage IA lung adenocarcinoma. The clinicopathologic significance of the association of the EMT status with E-cadherin and vimentin expression was analyzed after propensity score matching. Results: E-cadherin and vimentin were detected in 68.3% and 18.6% of stage IA lung adenocarcinomas, respectively. The presence of cells with EMT conversion was associated with older patient age. A propensity scoreematched cohort (128 patients) was used for further analyses. Computed tomography revealed that tumors with EMT conversion showed solid-dominant nodules compared to those without conversion. Survival analysis after propensity score matching showed that the EMT correlated with poor disease-free survival (hazard ratio ¼ 2.57, P ¼ .0451) and overall survival (hazard ratio ¼ 4.23, P ¼ .0471). Multivariate analysis revealed that the EMT was an independent predictor of shorter disease-free survival. Conclusion: The EMT was a significant predictor of poor prognosis of patients with stage IA lung adenocarcinoma. The EMT status may serve as an indicator for administering adjuvant therapy.

Research paper thumbnail of Prognostic impact of controlling nutritional status score in resected lung squamous cell carcinoma

Journal of Thoracic Disease, 2017

Background: The preoperative immune-nutritional status has been shown to predict the postoperativ... more Background: The preoperative immune-nutritional status has been shown to predict the postoperative prognosis in various types of cancer; however, the prognostic significance of the controlling nutritional status (CONUT) score in resected lung squamous cell carcinoma (SCC) has yet to be elucidated. Methods: A total of 108 patients with resected lung SCC were analyzed for their clinicopathological factors, including the CONUT score, which can be calculated from the serum albumin, total cholesterol, and total peripheral lymphocyte count. The patients were divided into two groups: CONUT low (0 or 1) or high (≥2). Results: Among 108 patients, 76 (70.4%) were CONUT low, while 32 (29.6%) were CONUT high. No significant association between the CONUT score and the clinicopathological factors was found. Patients with CONUT high exhibited significantly shorter disease-free and overall survivals (DFS and OS) than those with CONUT low (P=0.016 and P=0.006, respectively). Multivariate analyses showed that the CONUT score [hazard ratio (HR): 1.

Research paper thumbnail of A phase II randomized trial of adjuvant chemotherapy with S-1 versus S-1 plus cisplatin for completely resected pathological stage II/IIIA non-small cell lung cancer

Lung cancer (Amsterdam, Netherlands), 2018

Platinum-based combination chemotherapy is the standard postoperative adjuvant treatment for path... more Platinum-based combination chemotherapy is the standard postoperative adjuvant treatment for pathological stage II/III non-small cell lung cancer (NSCLC). Oral S-1 therapy has good efficacy and relatively low toxicity for the treatment of advanced NSCLC. We investigated whether long-term S-1 monotherapy is also useful as an adjuvant therapy after surgery in patients with NSCLC. We conducted a phase II randomized open-label multi-institutional study in patients with pathological stage II/IIIA NSCLC (7 TNM classification) who underwent complete resection from 2009 to 2013. The primary endpoint, the 2-year disease-free survival (DFS) rate, was evaluated using the Bayesian method. Eligible patients were randomly assigned to two arms: oral S-1 monotherapy (S-1 arm) and S-1 plus cisplatin combination therapy followed by S-1 (S-1 plus cisplatin arm) both for a total of 1 year. A total of 70 and 71 patients were enrolled in S-1 arm and S-1 plus cisplatin arm, respectively. The 2-year DFS ra...

Research paper thumbnail of PD-L2 Expression as a Potential Predictive Biomarker for the Response to Anti-PD-1 Drugs in Patients with Non-small Cell Lung Cancer

Anticancer research, 2018

To investigate the role of programmed cell death-ligand 2 (PD-L2) expression as a predictive biom... more To investigate the role of programmed cell death-ligand 2 (PD-L2) expression as a predictive biomarker for response to anti-programmed cell death-1 (PD-1) drugs in patients with non-small cell lung cancer (NSCLC). Ten patients who had undergone curative lung resection and received the anti-PD-1 drugs for the recurrence were enrolled. The cut-off value for PD-L2 (antibody clone 176611) expression on tumor cells was set at 50%. Tumor response was evaluated according to immune-related response criteria. Seven patients (70.0%) were positive for PD-L2. The response rates were 28.6% (2/7) and 33.3% (1/3) in patients with PD-L2-positive and PD-L2-negative NSCLC, respectively. Disease control was obtained in 2 patients despite the programmed cell death-ligand 1 (PD-L1)-negativity (antibody clone 22C3: 0%, antibody clone SP142: 0%), and these tumors expressed PD-L2 (≥1%). PD-L2 expression may be a target of immunotherapy in patients with PD-L1-negative NSCLC.

Research paper thumbnail of Prognostic Impact of PD-L2 Expression and Association with PD-L1 in Patients with Small-cell Lung Cancer

Anticancer research, 2018

Although some previous studies suggested that programmed cell death-ligand 1 (PD-L1) expression w... more Although some previous studies suggested that programmed cell death-ligand 1 (PD-L1) expression was significantly associated with a favorable postoperative prognosis in patients with small-cell lung cancer (SCLC), the prognostic significance of PD-L2 expression remains unknown. The aim of the current study was to investigate the prognostic significance of PD-L2 expression in patients with SCLC. Thirty-eight patients who underwent resection of SCLC were analyzed. A monoclonal anti-human PD-L1 antibody (clone SP142) and a monoclonal anti-human PD-L2 antibody (clone 176611) were used as the primary antibodies. Cut-off value for PD-L1 and PD-L2 expression was set to 1%. Among 38 patients, 15 (39.5%) were positive for PD-L2 expression. No significant associations between PD-L2-positivity and clinicopathological factors, including PD-L1 positivity or prognosis were identified. No significant differences in disease-free survival and overall survival were observed between PD-L2-positive pat...

Research paper thumbnail of {"__content__"=>"Metabolic characteristics of programmed cell death-ligand 1-expressing lung cancer on F-fluorodeoxyglucose positron emission tomography/computed tomography.", "sup"=>{"__content__"=>"18"}}

Cancer medicine, 2017

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have been identified as... more Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have been identified as novel targets of immunotherapy of lung cancer. In present study, we evaluated the metabolic characteristics of lung cancer by using F-fluorodeoxyglucose positron emission tomography/computed tomography ( F-FDG PET/CT) with regard to PD-L1 protein expression. PD-L1 protein expression was evaluated by immunohistochemistry with the antibody clone SP142 in 579 surgically resected primary lung cancer patients. Cases with less than 5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 protein expression and the maximum standardized uptake value (SUVmax) in preoperative F-FDG PET/CT. The cut-off values for SUVmax were determined by receiver operating characteristic curve analyses. The SUVmax was significantly higher in nonsmall cell lung cancer (NSCLC) patients with PD-L1 protein expression compared with those without PD-L1 protein expr...

Research paper thumbnail of Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung

Annals of surgical oncology, Jan 2, 2018

Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study... more Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446)....

Research paper thumbnail of Radiological Features of the Surgically Resected Small-sized Small-cell Lung Cancer on Computed Tomography

Anticancer Research, 2017

Background/Aim: Surgical resection can be applied in cases of early-stage small-cell lung cancer ... more Background/Aim: Surgical resection can be applied in cases of early-stage small-cell lung cancer (SCLC). Predicting the histology of SCLC and discriminating SCLC from other histologies would be useful for determining the optimal treatment strategies for small pulmonary nodules that have not been preoperatively diagnosed. Materials and Methods: The study population included 17 patients with resected SCLC and 296 patients with adenocarcinoma (ADC) whose preoperative CT were available. The tumors of all patients were smaller than 3.0 cm. Results: Univariate and multivariate analyses demonstrated that SCLC was significantly associated with the presence of notching and the absence of surrounding ground glass opacity, air bronchogram, pleural indentation, and spiculation in comparison to ADC. Conclusion: The CT scans of patients with SCLC of less than 3.0 cm in size showed notching more frequently than those of patients with ADC, whereas surrounding GGO, air bronchogram, pleural indentation and spiculation were observed less frequently compared to ADC. Small-cell lung cancer (SCLC) is a devastating neoplasm. Unlike NSCLC, its prognosis is yet to be fully prolonged because of its more aggressive and metastatic natures (1). Chemotherapy and radiotherapy are considered to be the standard-of-care treatment options for SCLC patients. SCLC patients with limited-disease and extensive-disease are usually treated with chemoradiotherapy and chemotherapy, respectively (2, 3). Antibodies against immune checkpoint factors, such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), are expected to become the standard treatment option for both SCLC and NSCLC (4, 5). However, surgical resection can be performed for patients with clinical stage I SCLC because of its survival benefit: the five-year survival rates as high as 60-70% can be achieved by surgical treatment combined with chemotherapy (6-9). When performing surgical resection in lung cancer patients, a precise interpretation of the pulmonary nodular shadows on computed tomography (CT) prior to the operation is important, because the findings can help the thoracic surgeons to predict whether they are malignant or benign (10). The radiological features on CT include surrounding ground glass opacity (GGO), air bronchogram, notching, pleural indentation, spiculation, and cavitation. With regard to adenocarcinoma (ADC) that is radiologically smaller than 2.0 cm, a consolidation/tumor (C/T) of >0.25 is known to indicate radiological invasiveness, since it reflects pathological invasiveness with very high sensitivity (11). This finding is important in determining operative procedures, such as lobectomy or limited resection, such as segmentectomy or partial resection. However, the CT features of early-stage SCLC have not been fully clarified, and predicting SCLC, while discriminating it from other histologies (specifically ADC), would be useful for determining the optimal treatment strategies for small pulmonary nodules for which the preoperative diagnosis is not determined. In the study, we investigated CT characteristics, such as surrounding GGO, air bronchogram, notching, pleural indentation, spiculation, and cavitation, in a total of 17 SCLC patients and 296 ADC patients. All of the patients had undergone resection for tumors smaller than 3.0 cm in size and had undergone preoperative thin-section CT. The CT and histological findings were compared Patients and Methods Patients. We retrospectively examined patients who underwent surgical resection of primary lung SCLC and ADC between January 2003

Research paper thumbnail of Evaluation of erlotinib for the treatment of patients with non-small cell lung cancer with epidermal growth factor receptor wild type

Oncology Letters, 2017

Erlotinib is one of the treatment choices for patients with advanced non-small cell lung cancer (... more Erlotinib is one of the treatment choices for patients with advanced non-small cell lung cancer (NSCLC), regardless of the epidermal growth factor receptor (EGFR) mutation status. However, its efficacy for the treatment of patients with NSCLC with EGFR wild type or who are beyond the usage of gefitinib remains controversial. The present study therefore retrospectively assessed the efficacy of erlotinib in patients with wild type EGFR who had previously undergone gefitinib therapy. A total of 222 patients with NSCLC who received chemotherapeutic treatment with erlotinib between July 2007 and February 2013 were evaluated. The background variables, response rates, progression-free survival (PFS) and overall survival rates were retrospectively analyzed. The male/female ratio of patients was 103/119, and patients had a median age of 63 years (range, 33-95 years). A total of 10 of the 222 patients had clinical stages IIIB/IV, 191 had adenocarcinoma, 5 had large cell carcinoma, 10 had squamous cell carcinoma and 6 had NSCLC of a variety not otherwise specified. The EGFR mutation was positive, wild type or unknown in 95, 52 and 75 patients, respectively. In the 52 patients with EGFR wild type, there were 3 partial responders, 25 with stable disease and 24 with progressive disease, for a response rate of 6% [95% confidence interval (CI), 1.3-15%]. The median PFS of EGFR wild type and positive were 1.1 months (95% CI, 1.04-1.16 months) and 5.42 months (95% CI, 5.43-5.68 months), respectively. The results of the study demonstrated that erlotinib is not sufficiently effective for patients with NSCLC who possess the EGFR wild type status.

Research paper thumbnail of Invasive features of small-sized lung adenocarcinoma adjoining emphysematous bullae

European Journal of Cardio-Thoracic Surgery, 2017

OBJECTIVES: Radiologically small-sized adenocarcinomas are special entities of lung cancer, as th... more OBJECTIVES: Radiologically small-sized adenocarcinomas are special entities of lung cancer, as their radiological and pathological invasiveness determines the surgical procedures applied; however, the clinicopathological features of small-sized lung adenocarcinoma adjoining cystic airspaces (Ca-ADJ) have yet to be fully clarified. The aim of this study was to elucidate the clinicopathological characteristics, including the programmed death ligand 1 (PD-L1) expression, in patients with Ca-ADJ < _3.0 cm. METHODS: A total of 283 patients with resected adenocarcinoma, whose radiological tumour size was < _3.0 cm without lymph node or distant metastases on preoperative high-resolution computed tomography, were analysed for their clinicopathological and radiological features. Furthermore, the PD-L1 expression was evaluated by immunohistochemistry using an anti-human PD-L1 rabbit monoclonal antibody (clone SP142). RESULTS: Among the 283 patients, 31 (11.0%) patients were reported to have Ca-ADJ. The Fisher's exact test demonstrated that Ca-ADJ was significantly associated with male gender (P < 0.001), a history of smoking (P < 0.001), a high consolidation/tumour ratio (P = 0.026), advanced pathological stage (P < 0.001), the presence of pleural (P < 0.001) and vessel invasion (P < 0.001), histological invasive subtypes (P < 0.001) and wild-type epidermal growth factor receptor (P = 0.001). The patients with Ca-ADJ had a significantly higher maximum standardized uptake value than those without Ca-ADJ (8.4 vs 4.1, P < 0.001). Furthermore, Ca-ADJ was significantly associated with the PD-L1 expression (P < 0.001). Log-rank test showed that patients with Ca-ADJ had a significantly shorter disease-free survival than those without Ca-ADJ (P = 0.001). CONCLUSIONS: This study showed that patients with radiologically small-sized Ca-ADJ might exhibit radiologically and pathologically invasive features.

Research paper thumbnail of Favorable Disease-free Survival Associated with Programmed Death Ligand 1 Expression in Patients with Surgically Resected Small-cell Lung Cancer

Anticancer research, 2016

The prognostic significance of programmed death ligand 1 (PD-L1) has been reported in non-small c... more The prognostic significance of programmed death ligand 1 (PD-L1) has been reported in non-small cell lung cancer; however, the significance of PD-L1 expression in patients with resected small-cell lung cancer (SCLC) remains to be clarified. Forty patients with SCLC whose resected specimens were available for immunohistochemistry for PD-L1 were evaluated to determine the association between its expression and the clinicopathological factors and prognosis. Among 40 patients, PD-L1 was expressed in tumor cells (TCs) of six (15%), tumor-infiltrating cells (ICs) of 16 (40%), and TCs and/or ICs cells of 18 (45%) patients. Patients with PD-L1-positve ICs and TCs and/or ICs exhibited significantly longer disease-free survival than those without PD-L1-expression (hazard ratio (HR)=0.268; 95% confidence interval (CI)=0.100-0.645; p=0.003 and HR=0.301; 95% CI=0.118-0.702; p=0.005, respectively). This study provides important evidence on the prognostic value of the PD-L1 expression in resected ...

Research paper thumbnail of High Frequency of Programmed Death-ligand 1 Expression in Emphysematous Bullae-associated Lung Adenocarcinomas

Clinical lung cancer, Jan 9, 2016

Emphysematous bullae (EB) are known to be associated with a high incidence of lung cancer; howeve... more Emphysematous bullae (EB) are known to be associated with a high incidence of lung cancer; however, the reason for this has yet to be elucidated. The objective of the present study was to clarify the prevalence of programmed death-ligand-1 (PD-L1) expression in EB-associated lung adenocarcinomas. A total of 369 patients with resected lung adenocarcinoma whose preoperative computed tomography findings were available for the examination of EB were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and EB-related adenocarcinomas. Among 369 patients, EB and cancer adjoining EB (Ca-ADJ) were identified in 81 (22.0%) and 50 (13.6%) patients, respectively. EB and Ca-ADJ were significantly associated with male gender, a smoking habit, a decreased forced expiratory volume in 1 second, a relatively higher tumor grade, advanced T status and stage, the presence of pleural and vessel invasion, invasive pathologic subtypes, an...

Research paper thumbnail of A Comprehensive Analysis of Programmed Cell Death Ligand-1 Expression With the Clone SP142 Antibody in Non-Small-Cell Lung Cancer Patients

Clinical lung cancer, Jan 2, 2017

Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as... more Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as novel targets for immunotherapy, with anti-PD-1 therapy currently the standard treatment for non-small-cell lung cancer (NSCLC) patients after the failure of first-line chemotherapy treatment. The recent phase II POPLAR and phase III OAK studies showed that atezolizumab, a representative PD-L1 inhibitor, exhibited a survival benefit compared with standard therapy in patients with NSCLC. We examined PD-L1 expression in NSCLC using the clone SP142 of POPLAR and OAK studies. PD-L1 expression in 499 surgically resected NSCLC patients was evaluated using immunohistochemistry using SP142. We set cutoff values as 1%, 5%, 10%, and 50%. The samples from 189 (37.9%), 119 (23.8%), 71 (14.2%), and 39 (7.8%) patients were positive for PD-L1 expression at cutoff values of 1%, 5%, 10%, and 50%, respectively. Fisher exact tests showed that PD-L1 positivity was significantly associated with male sex, sm...

Research paper thumbnail of Computed Tomography Features of Lung Adenocarcinomas With Programmed Death Ligand 1 Expression

Clinical lung cancer, Jan 16, 2017

The development of immune checkpoint inhibitors against programmed death 1 has paved the way for ... more The development of immune checkpoint inhibitors against programmed death 1 has paved the way for a new era of treatment of lung cancer. Programmed death-ligand 1 (PD-L1) is expected to predict the response of immune checkpoint inhibitors in lung cancer. Predicting PD-L1 expression using a noninvasive method before immunotherapy would, therefore, help identify patients for whom immunotherapy can be successful. A total of 394 patients with resected lung adenocarcinoma who had undergone preoperative thin-section computed tomography (CT) were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and CT characteristics, including convergence, surrounding ground glass opacity (GGO), air bronchogram, notching, pleural indentation, spiculation, and cavitation. Of the 394 patients, 78 (19.8%) were positive and 316 (80.2%) were negative for PD-L1 expression. Univariate analysis demonstrated that PD-L1(+) adenocarcinoma was si...

Research paper thumbnail of P1-17-3CHEMOTHERAPY with Cisplatin and Pemetrexed for Non-Small Cell Lung Cancer Patients: A Retrospective Single Center Study

Annals of Oncology, 2014

Background: Cisplatin and pemetrexed combination regimen (CP) is one of the promising therapies f... more Background: Cisplatin and pemetrexed combination regimen (CP) is one of the promising therapies for non-squamous NSCLC patients. The PARAMOUT trial demonstarated the survival benefits of continuation maintenance chemotherapy with pemetrexed (PEM) after four cycles of CP. In Japan, only one phase II study showed feasibility and effectiveness of CP therapy.

Research paper thumbnail of Mutations of the EGFR, K-ras, EML4–ALK, and BRAF genes in resected pathological stage I lung adenocarcinoma

Surgery Today, 2015

Conclusions In patients with stage I adenocarcinoma, mutation of the K-ras gene was a poor progno... more Conclusions In patients with stage I adenocarcinoma, mutation of the K-ras gene was a poor prognostic factor for recurrence. The presence of a mutation of the EGFR or EML4-ALK gene was not a prognostic factor.

Research paper thumbnail of Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary?

Cancer and Metastasis Reviews, 2015

Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity thro... more Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity through its rearrangement in non-small cell lung cancer (NSCLC), and patients (pts) with ALK rearrangement can be treated more successfully with ALK inhibitors, such as crizotinib, alectinib, and ceritinib, than with chemotherapy. Despite the excellent efficacy of ALK inhibitors, resistance to these drugs is inevitably encountered in most ALK-rearranged pts. Cases of resistance are subtyped into three groups, i.e., systemic, oligo, and central nervous system (CNS) types, with the CNS being used to be considered a sanctuary. With regard to the management of CNS lesions in pts with ALK+ NSCLC, a growing body of evidence has gradually demonstrated the intracranial (IC) efficacy of ALK inhibitor (ALKi) in ALK+ NSCLC pts with brain metastases (BMs). Although the efficacy of crizotinib for the CNS lesions remains controversial, a recent retrospective investigation of ALK+ pts with BM enrolled in PROFILE 1005 and PROFILE 1007 demonstrated that crizotinib is associated with a high disease control rate for BM. However, BM comprises the most common site of progressive disease in pts with or without baseline BMs, which is a serious problem for crizotinib. Furthermore, alectinib can be used to achieve strong and long-lasting inhibitory effects on BM. In addition to alectinib, the IC efficacy of other next-generation ALK inhibitors, such as ceritinib, AP26113 and PF-06463922, has been demonstrated. In this article, we review the latest evidence regarding the BM and IC efficacy of ALK inhibitors in pts with ALK+ NSCLC.

Research paper thumbnail of Radiological features of resected lung adenocarcinoma with epithelial–mesenchymal transition

The Annals of Thoracic Surgery, 2020

BACKGROUND Epithelial-mesenchymal transition plays a crucial role in cancer progression and is a ... more BACKGROUND Epithelial-mesenchymal transition plays a crucial role in cancer progression and is a significant prognosticator for postoperative survival in patients with lung cancer. Predicting epithelial-mesenchymal transition preoperatively using computed tomography may help to determine the optimal surgical strategy. METHODS We performed an immunohistochemical analysis of E-cadherin and vimentin expressions using tumor specimens from resected primary lung adenocarcinoma and classified the results into three subgroups according to the expressions: epithelial, intermediate, and mesenchymal. The intermediate and mesenchymal groups were classified as the epithelial-mesenchymal transition conversion group. We analyzed the association between epithelial-mesenchymal transition and radiological characteristics, especially computed tomographic features. RESULTS The epithelial-mesenchymal transition conversion group constituted 162 (49.1%) patients. Computed tomography revealed that tumors with epithelial-mesenchymal transition conversion showed a high consolidation/tumor ratio compared with those without conversion. Additionally, univariate analysis demonstrated that tumors with epithelial-mesenchymal transition were significantly associated with bronchial and/or vascular convergence (P=0.0001) and notching (P=0.0282). When the cut-off value for the consolidation/tumor ratio was set by receiver operating characteristic curve, a high ratio (>0.7946) and the presence of convergence were independent predictive factors for epithelial-mesenchymal transition by multivariate analysis (P=0.0007 and 0.0500, respectively). Tumors with a high consolidation/tumor ratio and convergence had a four-fold higher odds ratio for epithelial-mesenchymal transition, and patients had significantly poorer survival. CONCLUSIONS Convergence and a high consolidation/tumor ratio were independently associated with epithelial-mesenchymal transition conversion. These preoperative radiological results will help to predict epithelial-mesenchymal transition conversion in lung adenocarcinoma.

Research paper thumbnail of Spread through air spaces in lung neuroendocrine tumor

Translational Lung Cancer Research, 2019

Research paper thumbnail of The significant influence of having children on the postoperative prognosis of patients with nonsmall cell lung cancer: A propensity score‐matched analysis

Cancer Medicine, 2018

This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Research paper thumbnail of Clinical and Prognostic Significance of the Epithelial–Mesenchymal Transition in Stage IA Lung Adenocarcinoma: A Propensity Score–Matched Analysis

Clinical Lung Cancer, 2019

We aimed to analyze the clinical significance of the epithelialemesenchymal transition (EMT) in s... more We aimed to analyze the clinical significance of the epithelialemesenchymal transition (EMT) in stage IA lung adenocarcinoma. Tumors with the EMT phenotype were identified in 43.1% of patients with a high ratio of consolidation to tumor diameter. Propensity score matching indicated a significant association of the EMT with shorter survival. Background: The epithelialemesenchymal transition (EMT) describes the process through which cells lose epithelial characteristics and gain a mesenchymal phenotype. The EMT contributes to tumor invasion and cancer progression, and is associated with metastasis and poor survival of patients with nonesmall-cell lung cancer. However, little is known about the relationships between the EMT and the clinicopathologic characteristics of patients with stage IA lung adenocarcinoma. Patients and Methods: We conducted immunohistochemical analysis of the expression of the EMT markers E-cadherin and vimentin of specimens acquired from 183 consecutive patients with stage IA lung adenocarcinoma. The clinicopathologic significance of the association of the EMT status with E-cadherin and vimentin expression was analyzed after propensity score matching. Results: E-cadherin and vimentin were detected in 68.3% and 18.6% of stage IA lung adenocarcinomas, respectively. The presence of cells with EMT conversion was associated with older patient age. A propensity scoreematched cohort (128 patients) was used for further analyses. Computed tomography revealed that tumors with EMT conversion showed solid-dominant nodules compared to those without conversion. Survival analysis after propensity score matching showed that the EMT correlated with poor disease-free survival (hazard ratio ¼ 2.57, P ¼ .0451) and overall survival (hazard ratio ¼ 4.23, P ¼ .0471). Multivariate analysis revealed that the EMT was an independent predictor of shorter disease-free survival. Conclusion: The EMT was a significant predictor of poor prognosis of patients with stage IA lung adenocarcinoma. The EMT status may serve as an indicator for administering adjuvant therapy.

Research paper thumbnail of Prognostic impact of controlling nutritional status score in resected lung squamous cell carcinoma

Journal of Thoracic Disease, 2017

Background: The preoperative immune-nutritional status has been shown to predict the postoperativ... more Background: The preoperative immune-nutritional status has been shown to predict the postoperative prognosis in various types of cancer; however, the prognostic significance of the controlling nutritional status (CONUT) score in resected lung squamous cell carcinoma (SCC) has yet to be elucidated. Methods: A total of 108 patients with resected lung SCC were analyzed for their clinicopathological factors, including the CONUT score, which can be calculated from the serum albumin, total cholesterol, and total peripheral lymphocyte count. The patients were divided into two groups: CONUT low (0 or 1) or high (≥2). Results: Among 108 patients, 76 (70.4%) were CONUT low, while 32 (29.6%) were CONUT high. No significant association between the CONUT score and the clinicopathological factors was found. Patients with CONUT high exhibited significantly shorter disease-free and overall survivals (DFS and OS) than those with CONUT low (P=0.016 and P=0.006, respectively). Multivariate analyses showed that the CONUT score [hazard ratio (HR): 1.

Research paper thumbnail of A phase II randomized trial of adjuvant chemotherapy with S-1 versus S-1 plus cisplatin for completely resected pathological stage II/IIIA non-small cell lung cancer

Lung cancer (Amsterdam, Netherlands), 2018

Platinum-based combination chemotherapy is the standard postoperative adjuvant treatment for path... more Platinum-based combination chemotherapy is the standard postoperative adjuvant treatment for pathological stage II/III non-small cell lung cancer (NSCLC). Oral S-1 therapy has good efficacy and relatively low toxicity for the treatment of advanced NSCLC. We investigated whether long-term S-1 monotherapy is also useful as an adjuvant therapy after surgery in patients with NSCLC. We conducted a phase II randomized open-label multi-institutional study in patients with pathological stage II/IIIA NSCLC (7 TNM classification) who underwent complete resection from 2009 to 2013. The primary endpoint, the 2-year disease-free survival (DFS) rate, was evaluated using the Bayesian method. Eligible patients were randomly assigned to two arms: oral S-1 monotherapy (S-1 arm) and S-1 plus cisplatin combination therapy followed by S-1 (S-1 plus cisplatin arm) both for a total of 1 year. A total of 70 and 71 patients were enrolled in S-1 arm and S-1 plus cisplatin arm, respectively. The 2-year DFS ra...

Research paper thumbnail of PD-L2 Expression as a Potential Predictive Biomarker for the Response to Anti-PD-1 Drugs in Patients with Non-small Cell Lung Cancer

Anticancer research, 2018

To investigate the role of programmed cell death-ligand 2 (PD-L2) expression as a predictive biom... more To investigate the role of programmed cell death-ligand 2 (PD-L2) expression as a predictive biomarker for response to anti-programmed cell death-1 (PD-1) drugs in patients with non-small cell lung cancer (NSCLC). Ten patients who had undergone curative lung resection and received the anti-PD-1 drugs for the recurrence were enrolled. The cut-off value for PD-L2 (antibody clone 176611) expression on tumor cells was set at 50%. Tumor response was evaluated according to immune-related response criteria. Seven patients (70.0%) were positive for PD-L2. The response rates were 28.6% (2/7) and 33.3% (1/3) in patients with PD-L2-positive and PD-L2-negative NSCLC, respectively. Disease control was obtained in 2 patients despite the programmed cell death-ligand 1 (PD-L1)-negativity (antibody clone 22C3: 0%, antibody clone SP142: 0%), and these tumors expressed PD-L2 (≥1%). PD-L2 expression may be a target of immunotherapy in patients with PD-L1-negative NSCLC.

Research paper thumbnail of Prognostic Impact of PD-L2 Expression and Association with PD-L1 in Patients with Small-cell Lung Cancer

Anticancer research, 2018

Although some previous studies suggested that programmed cell death-ligand 1 (PD-L1) expression w... more Although some previous studies suggested that programmed cell death-ligand 1 (PD-L1) expression was significantly associated with a favorable postoperative prognosis in patients with small-cell lung cancer (SCLC), the prognostic significance of PD-L2 expression remains unknown. The aim of the current study was to investigate the prognostic significance of PD-L2 expression in patients with SCLC. Thirty-eight patients who underwent resection of SCLC were analyzed. A monoclonal anti-human PD-L1 antibody (clone SP142) and a monoclonal anti-human PD-L2 antibody (clone 176611) were used as the primary antibodies. Cut-off value for PD-L1 and PD-L2 expression was set to 1%. Among 38 patients, 15 (39.5%) were positive for PD-L2 expression. No significant associations between PD-L2-positivity and clinicopathological factors, including PD-L1 positivity or prognosis were identified. No significant differences in disease-free survival and overall survival were observed between PD-L2-positive pat...

Research paper thumbnail of {"__content__"=>"Metabolic characteristics of programmed cell death-ligand 1-expressing lung cancer on F-fluorodeoxyglucose positron emission tomography/computed tomography.", "sup"=>{"__content__"=>"18"}}

Cancer medicine, 2017

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have been identified as... more Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have been identified as novel targets of immunotherapy of lung cancer. In present study, we evaluated the metabolic characteristics of lung cancer by using F-fluorodeoxyglucose positron emission tomography/computed tomography ( F-FDG PET/CT) with regard to PD-L1 protein expression. PD-L1 protein expression was evaluated by immunohistochemistry with the antibody clone SP142 in 579 surgically resected primary lung cancer patients. Cases with less than 5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 protein expression and the maximum standardized uptake value (SUVmax) in preoperative F-FDG PET/CT. The cut-off values for SUVmax were determined by receiver operating characteristic curve analyses. The SUVmax was significantly higher in nonsmall cell lung cancer (NSCLC) patients with PD-L1 protein expression compared with those without PD-L1 protein expr...

Research paper thumbnail of Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung

Annals of surgical oncology, Jan 2, 2018

Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study... more Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446)....

Research paper thumbnail of Radiological Features of the Surgically Resected Small-sized Small-cell Lung Cancer on Computed Tomography

Anticancer Research, 2017

Background/Aim: Surgical resection can be applied in cases of early-stage small-cell lung cancer ... more Background/Aim: Surgical resection can be applied in cases of early-stage small-cell lung cancer (SCLC). Predicting the histology of SCLC and discriminating SCLC from other histologies would be useful for determining the optimal treatment strategies for small pulmonary nodules that have not been preoperatively diagnosed. Materials and Methods: The study population included 17 patients with resected SCLC and 296 patients with adenocarcinoma (ADC) whose preoperative CT were available. The tumors of all patients were smaller than 3.0 cm. Results: Univariate and multivariate analyses demonstrated that SCLC was significantly associated with the presence of notching and the absence of surrounding ground glass opacity, air bronchogram, pleural indentation, and spiculation in comparison to ADC. Conclusion: The CT scans of patients with SCLC of less than 3.0 cm in size showed notching more frequently than those of patients with ADC, whereas surrounding GGO, air bronchogram, pleural indentation and spiculation were observed less frequently compared to ADC. Small-cell lung cancer (SCLC) is a devastating neoplasm. Unlike NSCLC, its prognosis is yet to be fully prolonged because of its more aggressive and metastatic natures (1). Chemotherapy and radiotherapy are considered to be the standard-of-care treatment options for SCLC patients. SCLC patients with limited-disease and extensive-disease are usually treated with chemoradiotherapy and chemotherapy, respectively (2, 3). Antibodies against immune checkpoint factors, such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), are expected to become the standard treatment option for both SCLC and NSCLC (4, 5). However, surgical resection can be performed for patients with clinical stage I SCLC because of its survival benefit: the five-year survival rates as high as 60-70% can be achieved by surgical treatment combined with chemotherapy (6-9). When performing surgical resection in lung cancer patients, a precise interpretation of the pulmonary nodular shadows on computed tomography (CT) prior to the operation is important, because the findings can help the thoracic surgeons to predict whether they are malignant or benign (10). The radiological features on CT include surrounding ground glass opacity (GGO), air bronchogram, notching, pleural indentation, spiculation, and cavitation. With regard to adenocarcinoma (ADC) that is radiologically smaller than 2.0 cm, a consolidation/tumor (C/T) of >0.25 is known to indicate radiological invasiveness, since it reflects pathological invasiveness with very high sensitivity (11). This finding is important in determining operative procedures, such as lobectomy or limited resection, such as segmentectomy or partial resection. However, the CT features of early-stage SCLC have not been fully clarified, and predicting SCLC, while discriminating it from other histologies (specifically ADC), would be useful for determining the optimal treatment strategies for small pulmonary nodules for which the preoperative diagnosis is not determined. In the study, we investigated CT characteristics, such as surrounding GGO, air bronchogram, notching, pleural indentation, spiculation, and cavitation, in a total of 17 SCLC patients and 296 ADC patients. All of the patients had undergone resection for tumors smaller than 3.0 cm in size and had undergone preoperative thin-section CT. The CT and histological findings were compared Patients and Methods Patients. We retrospectively examined patients who underwent surgical resection of primary lung SCLC and ADC between January 2003

Research paper thumbnail of Evaluation of erlotinib for the treatment of patients with non-small cell lung cancer with epidermal growth factor receptor wild type

Oncology Letters, 2017

Erlotinib is one of the treatment choices for patients with advanced non-small cell lung cancer (... more Erlotinib is one of the treatment choices for patients with advanced non-small cell lung cancer (NSCLC), regardless of the epidermal growth factor receptor (EGFR) mutation status. However, its efficacy for the treatment of patients with NSCLC with EGFR wild type or who are beyond the usage of gefitinib remains controversial. The present study therefore retrospectively assessed the efficacy of erlotinib in patients with wild type EGFR who had previously undergone gefitinib therapy. A total of 222 patients with NSCLC who received chemotherapeutic treatment with erlotinib between July 2007 and February 2013 were evaluated. The background variables, response rates, progression-free survival (PFS) and overall survival rates were retrospectively analyzed. The male/female ratio of patients was 103/119, and patients had a median age of 63 years (range, 33-95 years). A total of 10 of the 222 patients had clinical stages IIIB/IV, 191 had adenocarcinoma, 5 had large cell carcinoma, 10 had squamous cell carcinoma and 6 had NSCLC of a variety not otherwise specified. The EGFR mutation was positive, wild type or unknown in 95, 52 and 75 patients, respectively. In the 52 patients with EGFR wild type, there were 3 partial responders, 25 with stable disease and 24 with progressive disease, for a response rate of 6% [95% confidence interval (CI), 1.3-15%]. The median PFS of EGFR wild type and positive were 1.1 months (95% CI, 1.04-1.16 months) and 5.42 months (95% CI, 5.43-5.68 months), respectively. The results of the study demonstrated that erlotinib is not sufficiently effective for patients with NSCLC who possess the EGFR wild type status.

Research paper thumbnail of Invasive features of small-sized lung adenocarcinoma adjoining emphysematous bullae

European Journal of Cardio-Thoracic Surgery, 2017

OBJECTIVES: Radiologically small-sized adenocarcinomas are special entities of lung cancer, as th... more OBJECTIVES: Radiologically small-sized adenocarcinomas are special entities of lung cancer, as their radiological and pathological invasiveness determines the surgical procedures applied; however, the clinicopathological features of small-sized lung adenocarcinoma adjoining cystic airspaces (Ca-ADJ) have yet to be fully clarified. The aim of this study was to elucidate the clinicopathological characteristics, including the programmed death ligand 1 (PD-L1) expression, in patients with Ca-ADJ < _3.0 cm. METHODS: A total of 283 patients with resected adenocarcinoma, whose radiological tumour size was < _3.0 cm without lymph node or distant metastases on preoperative high-resolution computed tomography, were analysed for their clinicopathological and radiological features. Furthermore, the PD-L1 expression was evaluated by immunohistochemistry using an anti-human PD-L1 rabbit monoclonal antibody (clone SP142). RESULTS: Among the 283 patients, 31 (11.0%) patients were reported to have Ca-ADJ. The Fisher's exact test demonstrated that Ca-ADJ was significantly associated with male gender (P < 0.001), a history of smoking (P < 0.001), a high consolidation/tumour ratio (P = 0.026), advanced pathological stage (P < 0.001), the presence of pleural (P < 0.001) and vessel invasion (P < 0.001), histological invasive subtypes (P < 0.001) and wild-type epidermal growth factor receptor (P = 0.001). The patients with Ca-ADJ had a significantly higher maximum standardized uptake value than those without Ca-ADJ (8.4 vs 4.1, P < 0.001). Furthermore, Ca-ADJ was significantly associated with the PD-L1 expression (P < 0.001). Log-rank test showed that patients with Ca-ADJ had a significantly shorter disease-free survival than those without Ca-ADJ (P = 0.001). CONCLUSIONS: This study showed that patients with radiologically small-sized Ca-ADJ might exhibit radiologically and pathologically invasive features.

Research paper thumbnail of Favorable Disease-free Survival Associated with Programmed Death Ligand 1 Expression in Patients with Surgically Resected Small-cell Lung Cancer

Anticancer research, 2016

The prognostic significance of programmed death ligand 1 (PD-L1) has been reported in non-small c... more The prognostic significance of programmed death ligand 1 (PD-L1) has been reported in non-small cell lung cancer; however, the significance of PD-L1 expression in patients with resected small-cell lung cancer (SCLC) remains to be clarified. Forty patients with SCLC whose resected specimens were available for immunohistochemistry for PD-L1 were evaluated to determine the association between its expression and the clinicopathological factors and prognosis. Among 40 patients, PD-L1 was expressed in tumor cells (TCs) of six (15%), tumor-infiltrating cells (ICs) of 16 (40%), and TCs and/or ICs cells of 18 (45%) patients. Patients with PD-L1-positve ICs and TCs and/or ICs exhibited significantly longer disease-free survival than those without PD-L1-expression (hazard ratio (HR)=0.268; 95% confidence interval (CI)=0.100-0.645; p=0.003 and HR=0.301; 95% CI=0.118-0.702; p=0.005, respectively). This study provides important evidence on the prognostic value of the PD-L1 expression in resected ...

Research paper thumbnail of High Frequency of Programmed Death-ligand 1 Expression in Emphysematous Bullae-associated Lung Adenocarcinomas

Clinical lung cancer, Jan 9, 2016

Emphysematous bullae (EB) are known to be associated with a high incidence of lung cancer; howeve... more Emphysematous bullae (EB) are known to be associated with a high incidence of lung cancer; however, the reason for this has yet to be elucidated. The objective of the present study was to clarify the prevalence of programmed death-ligand-1 (PD-L1) expression in EB-associated lung adenocarcinomas. A total of 369 patients with resected lung adenocarcinoma whose preoperative computed tomography findings were available for the examination of EB were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and EB-related adenocarcinomas. Among 369 patients, EB and cancer adjoining EB (Ca-ADJ) were identified in 81 (22.0%) and 50 (13.6%) patients, respectively. EB and Ca-ADJ were significantly associated with male gender, a smoking habit, a decreased forced expiratory volume in 1 second, a relatively higher tumor grade, advanced T status and stage, the presence of pleural and vessel invasion, invasive pathologic subtypes, an...

Research paper thumbnail of A Comprehensive Analysis of Programmed Cell Death Ligand-1 Expression With the Clone SP142 Antibody in Non-Small-Cell Lung Cancer Patients

Clinical lung cancer, Jan 2, 2017

Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as... more Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as novel targets for immunotherapy, with anti-PD-1 therapy currently the standard treatment for non-small-cell lung cancer (NSCLC) patients after the failure of first-line chemotherapy treatment. The recent phase II POPLAR and phase III OAK studies showed that atezolizumab, a representative PD-L1 inhibitor, exhibited a survival benefit compared with standard therapy in patients with NSCLC. We examined PD-L1 expression in NSCLC using the clone SP142 of POPLAR and OAK studies. PD-L1 expression in 499 surgically resected NSCLC patients was evaluated using immunohistochemistry using SP142. We set cutoff values as 1%, 5%, 10%, and 50%. The samples from 189 (37.9%), 119 (23.8%), 71 (14.2%), and 39 (7.8%) patients were positive for PD-L1 expression at cutoff values of 1%, 5%, 10%, and 50%, respectively. Fisher exact tests showed that PD-L1 positivity was significantly associated with male sex, sm...

Research paper thumbnail of Computed Tomography Features of Lung Adenocarcinomas With Programmed Death Ligand 1 Expression

Clinical lung cancer, Jan 16, 2017

The development of immune checkpoint inhibitors against programmed death 1 has paved the way for ... more The development of immune checkpoint inhibitors against programmed death 1 has paved the way for a new era of treatment of lung cancer. Programmed death-ligand 1 (PD-L1) is expected to predict the response of immune checkpoint inhibitors in lung cancer. Predicting PD-L1 expression using a noninvasive method before immunotherapy would, therefore, help identify patients for whom immunotherapy can be successful. A total of 394 patients with resected lung adenocarcinoma who had undergone preoperative thin-section computed tomography (CT) were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and CT characteristics, including convergence, surrounding ground glass opacity (GGO), air bronchogram, notching, pleural indentation, spiculation, and cavitation. Of the 394 patients, 78 (19.8%) were positive and 316 (80.2%) were negative for PD-L1 expression. Univariate analysis demonstrated that PD-L1(+) adenocarcinoma was si...

Research paper thumbnail of P1-17-3CHEMOTHERAPY with Cisplatin and Pemetrexed for Non-Small Cell Lung Cancer Patients: A Retrospective Single Center Study

Annals of Oncology, 2014

Background: Cisplatin and pemetrexed combination regimen (CP) is one of the promising therapies f... more Background: Cisplatin and pemetrexed combination regimen (CP) is one of the promising therapies for non-squamous NSCLC patients. The PARAMOUT trial demonstarated the survival benefits of continuation maintenance chemotherapy with pemetrexed (PEM) after four cycles of CP. In Japan, only one phase II study showed feasibility and effectiveness of CP therapy.

Research paper thumbnail of Mutations of the EGFR, K-ras, EML4–ALK, and BRAF genes in resected pathological stage I lung adenocarcinoma

Surgery Today, 2015

Conclusions In patients with stage I adenocarcinoma, mutation of the K-ras gene was a poor progno... more Conclusions In patients with stage I adenocarcinoma, mutation of the K-ras gene was a poor prognostic factor for recurrence. The presence of a mutation of the EGFR or EML4-ALK gene was not a prognostic factor.

Research paper thumbnail of Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary?

Cancer and Metastasis Reviews, 2015

Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity thro... more Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity through its rearrangement in non-small cell lung cancer (NSCLC), and patients (pts) with ALK rearrangement can be treated more successfully with ALK inhibitors, such as crizotinib, alectinib, and ceritinib, than with chemotherapy. Despite the excellent efficacy of ALK inhibitors, resistance to these drugs is inevitably encountered in most ALK-rearranged pts. Cases of resistance are subtyped into three groups, i.e., systemic, oligo, and central nervous system (CNS) types, with the CNS being used to be considered a sanctuary. With regard to the management of CNS lesions in pts with ALK+ NSCLC, a growing body of evidence has gradually demonstrated the intracranial (IC) efficacy of ALK inhibitor (ALKi) in ALK+ NSCLC pts with brain metastases (BMs). Although the efficacy of crizotinib for the CNS lesions remains controversial, a recent retrospective investigation of ALK+ pts with BM enrolled in PROFILE 1005 and PROFILE 1007 demonstrated that crizotinib is associated with a high disease control rate for BM. However, BM comprises the most common site of progressive disease in pts with or without baseline BMs, which is a serious problem for crizotinib. Furthermore, alectinib can be used to achieve strong and long-lasting inhibitory effects on BM. In addition to alectinib, the IC efficacy of other next-generation ALK inhibitors, such as ceritinib, AP26113 and PF-06463922, has been demonstrated. In this article, we review the latest evidence regarding the BM and IC efficacy of ALK inhibitors in pts with ALK+ NSCLC.