Tomoyuki Miyazawa

Survival significance of coexisting chronic obstructive pulmonary disease in patients with early lung cancer after curative surgery

The impact of chronic obstructive pulmonary disease (COPD) severity on survival after curative resection of early‐stage lung cancer (NSCLC) has not been sufficiently elucidated.

Accuracy of the cobas EGFR Mutation Assay in Non–small-cell Lung Cancer Compared With Three Laboratory-developed Tests

Micro‐Abstract Rapid and precise mutation assays are essential to select patients with lung cancer who may respond to treatment with epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors. Using the same specimens, the reliability of the cobas EGFR assay was compared with 3 commonly used laboratory‐developed tests. High concordance rates and &kgr;‐coefficients were obtained between the cobas EGFR assay and the laboratory‐developed tests. Background: The reliability of the cobas EGFR assay to detect epidermal growth factor receptor (EGFR) mutations in non–small‐cell lung cancer (NSCLC) as an in vitro diagnostic test was compared with 3 laboratory‐developed tests (LDTs). Materials and Methods: After screening for EGFR mutations using formalin‐fixed‐paraffin‐embedded NSCLC tissue sections using the cobas EGFR assay, 151 samples were further tested with 3 LDTs; the peptide nucleic acid‐locked nucleic acid polymerase chain reaction (PCR) clamp, PCR invader, and Cycleave assays. The cobas EGFR assay performance was evaluated by determining the concordance rate and &kgr;‐coefficient between the assays. In samples exhibiting discrepancies in the EGFR mutation status in the 4 assays, next‐generation sequencing was performed to confirm mutated sequences. Results: Concordance rates and &kgr;‐coefficients between the cobas EGFR assay and the other tests were 96.0% and 0.921 for the peptide nucleic acid‐locked nucleic acid PCR clamp assay, 94.0% and 0.881 for the PCR invader assay, and 96.7% and 0.934 for the Cycleave assay, respectively. Data showed very good agreement with the other assays. Precise mutated sequences or exons in the EGFR gene matched in 137 samples (90.7%). Different results were obtained in 4 samples (2.6%), owing to systemic limitations of the assay. Next‐generation sequencing of 10 (6.6%) samples with discordant results exhibited a concordance rate of 60% to 80% in each assay. Conclusions: The cobas EGFR assay showed high concordance rates and &kgr;‐coefficients between the 3 compared LDTs and can be used to select patients who would benefit from EGFR‐tyrosine kinase inhibitors.

Difference in Postsurgical Prognostic Factors between Lung Adenocarcinoma and Squamous Cell Carcinoma

PURPOSE The aim of this study was to compare the clinicopathologic prognostic factors between patients who underwent lung resection for adenocarcinoma (AD) and those with squamous cell carcinoma (SQ). METHODS A database of patients with lung AD or SQ who underwent surgery with curative intent in our department from January 2008 to December 2014 was reviewed. Associations between various clinicopathologic factors, postsurgical recurrence-free survival (RFS), and overall survival (OS) were analyzed to find significant prognostic factors. RESULTS A total of 537 lung cancer patients (AD, 434; SQ, 103) were included in this study. Although RFS was similar in patients with AD and SQ, OS was significantly poorer in those with SQ. Multivariate analysis in patients with AD revealed that age (≥69 vs. <69), lymphatic invasion, and histologic pleural invasion (p0 vs. p1-3) were associated with RFS, while gender and pleural invasion were associated with OS. In SQ, however, smoking, clinical stage, and pulmonary metastasis were associated with RFS in the multivariate analysis. CONCLUSION Since significant postoperative prognostic factors are quite different between lung AD and SQ, these two histologic types should be differently analyzed in a clinical study.

Differential prognostic values of mRNA expression of CEACAM gene family members in nonsmall cell lung cancer

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Different EGFR gene mutations in two patients with synchronous multiple lung cancers: A case report

Routine clinical and pathological evaluations to determine the relationship between different lesions are often not completely conclusive. Interestingly, detailed genetic analysis of tumor samples may provide important additional information and identify second primary lung cancers. In the present study, we report cases of two synchronous lung adenocarcinomas composed of two distinct pathological subtypes with different EGFR gene mutations: a homozygous deletion in exon 19 of the papillary adenocarcinoma subtype and a point mutation of L858R in exon 21 of the tubular adenocarcinoma. The present report highlights the clinical importance of molecular cancer biomarkers to guide management decisions in cases involving multiple lung tumors.

PD-L1 Expression in Non-Small-Cell Lung Cancer Including Various Adenocarcinoma Subtypes

Purpose: Knowledge regarding programmed death-ligand 1 (PD-L1) expression in lung cancer is limited. We aim to clarify PD-L1-positive expression in non-small-cell lung cancer (NSCLC), including adenocarcinoma subtypes. Methods: In all, 90 NSCLC specimens containing various adenocarcinoma subtypes, in addition to squamous cell carcinoma and large-cell carcinoma were selected. PD-L1 was immunohistochemically stained by murine monoclonal antibody clone 22C3. Results: When PD-L1-positive expression was defined by tumor proportion score (TPS) ≥1%, the positive cases were 0/11 in adenocarcinoma in situ, 0/12 in minimally invasive adenocarcinoma, 1/10 in lepidic predominant adenocarcinoma, 1/13 in papillary predominant adenocarcinoma, 8/14 in acinar predominant adenocarcinoma, 6/11 in solid predominant adenocarcinoma, 0/3 in micropapillary predominant adenocarcinoma, 0/4 in invasive mucinous adenocarcinoma, 4/9 in squamous cell carcinoma, and 2/3 in large-cell carcinoma. PD-L1 positivity was higher in males, smokers, advanced pathologic stages, positive vessel invasion, and positive lymphatic invasion. Postoperative survival analysis revealed that PD-L1-positive expression was a significantly worse prognostic factor in univariate analysis for recurrence-free survival (RFS). Conclusion: PD-L1-positive tumors were frequent in acinar predominant adenocarcinoma and solid predominant adenocarcinoma than other adenocarcinoma subtypes. PD-L1 expression seemed to increase according to pathologic tumor progression, suggesting a worse postoperative prognosis in NSCLC patients.

Survival significance of epidermal growth factor receptor tyrosine kinase inhibitors and current staging system for survival after recurrence in patients with completely resected lung adenocarcinoma

Objective We previously reported that the staging system and epidermal growth factor receptor (EGFR) mutation status are key factors for treatment strategy and predicting survival. However, the significance of these factors as predictors of overall survival (OS) and postoperative recurrence survival (PRS) has not been sufficiently elucidated. The objective here was to investigate EGFR mutation status and p-stage, which affect PRS and OS in patients with completely resected lung adenocarcinoma, using a different database. Patients and methods We retrospectively reviewed 56 consecutive lung adenocarcinoma patients with disease recurrence in St. Marianna University Hospital between January 2010 and December 2014. Results EGFR mutants (M) were detected in 16/56 patients (29%). The patients with EGFR M had a better OS than those with EGFR wild-type (WT) status (5-year survival: 50.3% vs 43.1, P=0.133). There was no significant difference in the 3-year recurrence-free survival rate between patients with M and WT (6.3% vs 7.7%, P=0.656), and the patients with EGFR M had a significantly better 3-year PRS than those with WT (77.4% vs 51.7%, P=0.033). The 3-year PRS rate for patients with M/pathologic stage (p-stage) I–II (87.5%) was better than that for patients with M/p-stage III (60.0%), WT/p-stage I–II (52.7%), and WT/p-stage III (43.8%). There was a significant difference between patients with M/p-stage I and WT/p-stage I–II or WT/p-stage III (P=0.021 and 0.030, respectively). During the study period, of the 16 patients with mutants, 12 patients (75%) received EGFR-tyrosine kinase inhibitor (TKI) therapy and among the 40 patients with WT, no patient received EGFR-TKI therapy. Multivariate survival analysis showed that patients with EGFR-TKI therapy had a statistically significant association with favorable PRS (hazard ratio 0.271; 95% confidence interval 0.074–1.000; P=0.050). Conclusion EGFR status and p-stage were found to be essential prognostic factors for estimating PRS using this database. The recurrent patients with EGFR M and EGFR-TKI therapy had a statistically significant association with favorable PRS.

Chronological changes in lung cancer surgery in a single Japanese institution

Background The aim of this study was to evaluate the chronological changes in epidemiological factors and surgical outcomes in patients with lung cancer who underwent surgery in a single Japanese institution. Patients and methods A clinicopathological database of patients with lung cancer who underwent surgery with curative intent from January 1974 to December 2014 was reviewed. The chronological changes in various factors, including patient’s age, sex, histological type, tumor size, pathological stage (p-stage), surgical method, operative time, intraoperative blood loss, 30-day mortality, and postoperative overall survival (OS), were evaluated. Results A total of 1,616 patients were included. The numbers of resected patients, females, adenocarcinomas, p-stage IA patients, and age at the time of surgery increased with time, but tumor size decreased (all P<0.0001). Concerning surgical methods, the number of sublobar resections increased, but that of pneumonectomies decreased (P<0.0001). The mean operative time, intraoperative blood loss, and the postoperative 30-day mortality rate decreased (all P<0.0001). When the patients were divided into two groups (1974–2004 and 2005–2014), the 5-year OS rates for all patients and for p-stage IA patients improved from 44% to 79% and from 73% to 89%, respectively (all P<0.0001). The best 5-year OS rate was obtained for sublobar resection (73%), followed by lobectomy (60%), combined resection (22%), and pneumonectomy (21%; P<0.0001). Conclusion Changes in epidemiological factors, a trend toward less invasive surgery, and a remarkably improved postoperative OS were confirmed, which demonstrated the increasingly important role of surgery in therapeutic strategies for lung cancer.

Pathological upstaging and treatment strategy of clinical stage I small cell lung cancer following surgery

Small cell lung cancer (SCLC) represents approximately 10–15% of all lung cancers, and its incidence has been steadily decreasing in the past two decades, primarily because of reduction in cigarette smoking, which is the primary cause of this type of tumor (1). SCLC originates from neuroendocrine cell precursors and is characterized by rapid growth, early dissemination to regional lymph nodes, and distant metastasis, and resultant poor prognosis along with initial sensitivity to chemotherapy and radiotherapy (2,3).Current standard therapy for SCLC relies on chemotherapy or chemoradiotherapy, even for patients with “limited” disease. In contrast, the role of primary surgical resection in such patients remains controversial because only a minority of early stage SCLC patients presents without metastasis and are candidates for surgery. Recently, based on favorable surgical results reported in several large cohort studies for limited disease SCLC (4-7), the American College of Chest Physicians (ACCP) indicate surgical has recommended resection only for patients with clinical stage I SCLC (T1–2, N0), followed by chemotherapy (8). Similarly, the National Comprehensive Cancer Network (NCCN) guidelines recommend surgery with adjuvant chemotherapy for stage I disease alone and specify lobectomy as the preferred resection procedure (9).

Worse survival after curative resection in patients with pathological stage I non-small cell lung cancer adjoining pulmonary cavity formation

Background A few investigators have suggested an association between lung cancer and pulmonary cavity. However, this clinical association and its carcinogenic correlations are not well recognized. This study aimed to clarify the clinical features and to demonstrate the associated survival outcomes after curative surgery in patients with early non-small cell lung cancer (NSCLC) adjoining pulmonary cavity formation. Methods We retrospectively reviewed 275 patients with pathological stage I NSCLC by re-evaluating their chest computed tomography images. Among them, we detected NSCLC adjoining pulmonary cavity formation in 12 (4.4%) patients. Results The median follow-up period for all 275 patients was 43.2 (range, 6.0-86.0) months. Of these patients, 6 (50.0%) in group CF (patients with NSCLC adjoining pulmonary cavity formation) and 19 (7.2%) in group C (the control group, n=263) died during the study period. Besides, 6 (50.0%) and 32 (12.2%) patients in groups CF and C, respectively, exhibited recurrence of the primary lung cancer. The cumulative overall survival (OS) in groups CF and C at 5 years was 37.0% and 91.7%, respectively (P<0.0001); the recurrence-free survival (RFS) in these groups at 5 years was 55.0% and 86.7%, respectively (P=0.001). Univariate analysis showed that male sex, smoking habits, non-adenocarcinoma, and presence of pulmonary cavity formation were associated with poor OS (P=0.008, P=0.001, P<0.0001, and P<0.0001, respectively). Multivariate analysis demonstrated that smoking, non-adenocarcinoma, and pulmonary cavity formation were independent prognostic factors predicting poor survival (P=0.043, P=0.004 and P<0.0001, respectively). Conclusions Our results suggest that patients with early-stage NSCLC adjoining pulmonary cavity formation have an increased risk of poor OS and RFS after surgical resection. Further prospective, multi-institutional investigations and substantial clinical studies are warranted.