Naoki Haratake

The expression of PD-L1 protein as a prognostic factor in lung squamous cell carcinoma.

BACKGROUND Programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway-targeted immunotherapy has become the standard option of care in the management of lung cancer. The expression of the PD-L1 protein in lung cancer is expected to be a prognostic factor or to predict the response to PD-1-blocking antibodies. However, the association between PD-L1 positivity and the clinicopathological features and patient outcomes in lung squamous cell carcinoma (SCC) remains unclear because the definitive cut-off value for the expression of PD-L1 protein remains to be established. MATERIALS AND METHODS The expression of PD-L1 protein in 205 surgically resected primary lung SCC patients was evaluated by immunohistochemistry with the antibody clone SP142. We generated a histogram to show the proportion of PD-L1-positive carcinoma cells, and set the cut-off values as 1%, 5%, 10% and 50%. Moreover, we examined the proliferative capacity of these tumors using Ki-67 immunohistochemistry. RESULTS The samples from 106 (51.7%), 72 (35.1%), 61 (29.7%) and 37 (18.0%) patients were positive for the expression of PD-L1 protein at cut-off values of 1%, 5%, 10% and 50%, respectively. Fishers exact test showed that, for almost all of the factors, PD-L1 positivity was not associated with the clinicopathological features with any of the four cut-off values. Univariate and multivariate survival analyses revealed that the PD-L1-positive patients only had a poorer prognosis than the PD-L1-negative patients at the 1% cut-off value. The Ki-67 labeling index in the PD-L1-positive patients was higher than that in the PD-L1-negative patients. CONCLUSIONS The expression of PD-L1 protein was associated with a poor prognosis in lung SCC patients. The 1% cut-off value for PD-L1 might become a better predictive marker than the other cut-off values.

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

BACKGROUND 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. PATIENTS AND METHODS 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%. RESULTS 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, smoking, advanced stage, the presence of vascular invasion, squamous cell carcinoma, and wild type epidermal growth factor receptor gene mutation status at all cutoff values. Univariate and multivariate survival analyses revealed that PD-L1-positive patients had a worse prognosis than PD-L1-negative patients only at the 1% cutoff value. Forest plot analyses showed that the 1% cutoff provided a more sensitive value for the prediction of postoperative prognosis. CONCLUSION PD-L1 expression varied greatly according to different cutoff values. This study might be a useful reference to understand the results of POPLAR and OAK studies and to select patients likely to benefit from atezolizumab.

Metabolic characteristics of programmed cell death-ligand 1-expressing lung cancer on 18F-fluorodeoxyglucose positron emission tomography/computed tomography

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 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (18F‐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 18F‐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 expression (P < 0.0001). However, there was no correlation between SUVmax and PD‐L1 protein expression in patients with neuroendocrine tumors (P = 0.6545). Multivariate analysis revealed that smoking, the presence of pleural invasion, and high SUVmax were independent predictors of PD‐L1 positivity. PD‐L1‐expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative 18F‐FDG PET/CT was a predictor of PD‐L1 protein expression in patients with NSCLC.

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

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): 1.902, 95% confidence interval (CI): 1.045-3.373, P=0.036], age (HR: 2.286, 95% CI: 1.246-4.304, P=0.007), pathological stage (HR: 2.527, 95% CI: 1.391-4.644, P=0.002), and lymphatic invasion (HR: 2.321, 95% CI: 1.110-4.493, P=0.027) were independent prognostic factors for the DFS. Furthermore, in a multivariate analysis, the CONUT score (HR: 1.909, 95% CI: 0.902-3.860, P=0.081), age (HR: 2.455, 95% CI: 1.208-5.178, P=0.013), pathological stage (HR: 2.488, 95% CI: 1.201-5.306, P=0.014), and lymphatic invasion (HR: 3.409, 95% CI: 1.532-7.240, P=0.004) were shown to be independent prognostic factors for the OS. Conclusions The current study showed that the CONUT score was an independent prognostic factor for the DFS and OS in patients with resected lung SCC.

Prognostic significance of immune-nutritional parameters for surgically resected elderly lung cancer patients: a multicentre retrospective study

OBJECTIVES The worlds population is rapidly ageing, and the age of patients with lung cancer will increase as well. The prognostic nutritional index, controlling nutritional status and the geriatric nutritional risk index (GNRI) are useful parameters for evaluating immune-nutritional status. We aimed to perform a multicentre retrospective study to investigate the correlations of these immune-nutritional parameters with postoperative comorbidities or surgical outcomes of elderly patients with non-small-cell lung cancer (NSCLC). METHODS We selected 272 consecutive patients with NSCLC aged >75 years treated from January 2005 to December 2012 and evaluated 3 preoperative immune-nutritional parameters as potential predictive factors of postoperative comorbidities or as prognostic factors for surgically resected elderly patients with NSCLC. RESULTS Prognostic nutritional index, GNRI, sex and preoperative respiratory comorbidities were significantly associated with postoperative comorbidities. Multivariate analyses revealed that preoperative GNRI, sex, preoperative serum carcinoembryonic antigen levels, preoperative serum cytokeratin 19 fragment levels, pathological N factor and pleural invasion were significantly associated with overall survival (OS). Abnormal GNRI was significantly associated with histology and outcomes. The Kaplan-Meier analysis of OS as a function of preoperative GNRI revealed that patients with an abnormal GNRI experienced significantly shorter OS compared with those with normal GNRI (5-year OS, 45.15% vs 64.10%, respectively; P = 0.0007, log-rank test). The controlling nutritional status score was not significantly associated with postoperative comorbidities or surgical outcomes. CONCLUSIONS Preoperative GNRI is a novel preoperative predictor of postoperative comorbidities and a prognostic factor that may identify high-risk elderly patients with NSCLC.

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

Introduction 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. Patients and Methods 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. Results 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 significantly associated with the presence of convergence (P < .01), notching (P < .01), spiculation (P < .01), and cavitation (P < .01) and the absence of surrounding GGO (P < .01) compared with PD‐L1− cases. On multivariate analysis, the presence of convergence (P < .01) and cavitation (P < .01) and the absence of surrounding GGO (P = .02) and air bronchogram (P = .03) were significantly associated with PD‐L1 expression. Conclusion PD‐L1+ adenocarcinoma cases showed convergence and cavitation more frequently than did PD‐L1− cases. In contrast, surrounding GGO and air bronchogram were observed less frequently in PD‐L1+ cases than in PD‐L1− cases. These results will prove helpful in identifying PD‐L1–expressing adenocarcinoma by CT before immunotherapy. Micro‐Abstract Our objective was to clarify the computed tomography features of programmed death‐ligand 1 (PD‐L1)–expressing lung adenocarcinomas. Among 394 patients, 78 (19.8%) were positive for PD‐L1 expression. On multivariate analysis, the presence of convergence (P < .01) and cavitation (P < .01) and the absence of surrounding ground glass opacity (P = .02) and air bronchogram (P = .03) were shown to be significantly associated with PD‐L1 expression.

Initial Experience of Single-Incision Thoracoscopic Surgery for 100 Patients with Primary Spontaneous Pneumothorax

PURPOSE The aim of this retrospective study was to evaluate single-incision thoracoscopic surgery (SITS) for primary spontaneous pneumothorax (PSP). METHODS Among 141 patients who underwent surgery for PSP from July 2009 to December 2013, a total of 100 patients underwent SITS. Their data were examined for clinical characteristics and surgical results. RESULTS More patients with younger age, female sex, and who had social indications were treated by SITS than by three-port video-assisted thoracic surgery (VATS). The mean operative time for SITS was 48.8 min. There were no conversions from SITS to three-port VATS or thoracotomy. After SITS, the median duration of chest drainage was 1 day, and the median hospital stay was 2 days. Early complications included one surgical-site infection and one case of air leakage. Four patients (4.0%) had ipsilateral recurrence of PSP. CONCLUSION SITS is feasible when performed for selected patients with PSP. Long-term follow-up and further examinations are required to evaluate patient selection, efficacy, and comparability of SITS with conventional open and three-port VATS approaches.

Association of preoperative serum CRP with PD-L1 expression in 508 patients with non-small cell lung cancer: A comprehensive analysis of systemic inflammatory markers.

OBJECTIVES Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio. METHODS We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression. RESULTS Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P = .0336, .0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P = .0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P < .0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P < .0001). CONCLUSIONS Our results indicate that among all systemic inflammatory markers examined, serum CRP seems to predict PD-L1 expression in patients with NSCLC however the clinical applicability is limited given the obtained area under the receiver operating characteristic curve values.

Significance of Spread Through Air Spaces in Resected Lung Adenocarcinomas With Lymph Node Metastasis

Micro‐Abstract: To clarify the prognostic impact of spread through air spaces (STAS) on survival in completely resected adenocarcinomas with lymph node metastasis, we observed STAS in 45 (73.0%) of 63 patients. Those with STAS had a significantly shorter recurrence‐free survival (RFS) than those without STAS (P = .04). Positivity for STAS was an independent prognostic parameter for RFS. Background: Spread through air spaces (STAS) is a recently recognized invasive pattern of lung cancer defined by the World Health Organization as micropapillary clusters, solid nests, or single cells spreading within air spaces beyond the edge of the main tumor. Although STAS has been shown to be a significant prognosticator for the postoperative survival in early‐stage lung cancer treated with limited resection, its prognostic impact on the survival in completely resected adenocarcinomas with lymph node metastasis remains unclear. Patients and Methods: STAS was assessed in a total of 63 adenocarcinomas with lymph node metastasis in patients who underwent complete resection. STAS was defined as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. We evaluated the association between STAS and the clinicopathologic characteristics and the postoperative survival. Results: Among 63 patients, 31 (49.2%) and 32 (50.8%) had disease that was pathologically positive for N1 and N2, respectively. STAS was observed in 45 patients (73.0%) and was not significantly associated with any clinicopathologic characteristics. Patients with the STAS had significantly shorter recurrence‐free survival (RFS) but not overall survival than those without STAS (P = .04 and P = .35, respectively). The 5‐year RFS in patients with and without STAS was 25.1% and 56.7%, respectively. According to a multivariate analysis, positivity for STAS remained an independent prognostic parameter for RFS (hazard ratio = 3.09; 95% confidence interval, 1.47–7.16; P < .01). Conclusion: STAS was predictive of a poor RFS in completely resected adenocarcinomas with lymph node metastasis.

Radiological features of brain metastases from non-small cell lung cancer harboring EGFR mutation

Aim: To investigate the radiological features on computed tomography (CT) of brain metastasis (BM) from epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Patients and Methods: Thirty-four patients with NSCLC with BMs who underwent surgical resection of the BMs at the Department of Neurosurgery, Kyushu University from 2005 to 2016 were enrolled in the study. The EGFR statuses of the 34 BMs were investigated. Radiological features, including the number, size, and location of the tumor, were delineated by CT. Results: Patients with EGFR-mutated BMs had significantly higher frequencies of multiple metastases than those with the non-EGFR-mutated type (p=0.042). BMs harboring mutations in EGFR were more frequently observed in the central area of the brain compared to those without mutations in EGFR (p=0.037). Conclusion: Careful follow-up of patients with EGFR-mutated NSCLC may be necessary given the high frequencies of multiple BMs and their location in the central area of the brain.