Takaki Akamine

Clinical Significance of PD-L1 Protein Expression in Surgically Resected Primary Lung Adenocarcinoma.

Introduction The clinicopathological features of carcinomas expressing programmed death ligand 1 (PD‐L1) and their associations with common driver mutations, such as mutations in the EGFR gene, in lung adenocarcinoma are not clearly understood. Here, we examined PD‐L1 protein expression in surgically resected primary lung adenocarcinoma and the association of PD‐L1 protein expression with clinicopathological features, EGFR mutation status, and patient outcomes. Methods The expression of PD‐L1 protein in 417 surgically resected primary lung adenocarcinomas was evaluated by immunohistochemical analysis. The cutoff value for defining PD‐L1 positivity was determined according to the histogram of proportions of PD‐L1–positive cancer cells. Results Samples from 85 patients (20.4%) and 144 patients (34.5%) were positive for PD‐L1 protein expression according to 5% and 1% PD‐L1 cutoff values, respectively. Fisher’s exact tests showed that PD‐L1 positivity was significantly associated with male sex, smoking, higher tumor grade, advanced T status, advanced N status, advanced stage, the presence of pleural and vessel invasions, micropapillary or solid predominant histological subtypes, and wild‐type EGFR. Univariate and multivariate survival analyses revealed that patients with PD‐L1 positivity had poorer prognoses than those without PD‐L1 protein expression at the 1% cutoff value (disease‐free survival p < 0.0001, overall survival p < 0.0001). Conclusions PD‐L1 protein expression was significantly higher in smoking‐associated adenocarcinoma and in EGFR mutation–negative adenocarcinoma. PD‐L1 protein expression was associated with poor survival in patients with lung adenocarcinoma. The PD‐L1/programmed cell death 1 pathway may contribute to the progression of smoking‐associated tumors in lung adenocarcinoma.

Predictive impact for postoperative recurrence using the preoperative prognostic nutritional index in pathological stage I non-small cell lung cancer

BACKGROUND The most effective treatment for early-stage non-small cell lung cancer (NSCLC) is surgical resection. Nevertheless, up to 20% of patients, even those with stage I NSCLC, relapse after surgery and die. The prognostic nutritional index (PNI) is used to assess immunonutritional conditions or is a predictor of postoperative recurrence in patients with digestive malignancies. However, the usefulness of the PNI for lung cancer is still unknown. We retrospectively analyzed clinicopathological features of stage I NSCLC patients to identify predictors of recurrence and to investigate effects of preoperative PNI levels. METHODS We selected 141 consecutive stage I NSCLC patients who were treated from August 2005 to August 2010. We measured their preoperative PNI levels in uni- and multivariate Cox regression analyses of recurrence-free survival. RESULTS A low PNI was significantly associated with sex (P=0.0117), preoperative serum carcino embryonic antigen levels (P=0.0228), and postoperative recurrence (P<0.0001). In multivariate analysis, PNI (RR: 9.243; 95% CI: 3.662-25.823; P<0.0001), pleural invasion (RR: 8.664; 95% CI: 2.510-38.056; P=0.0005), and intratumoral blood vessel invasion (RR: 3.151; 95% CI: 1.259-7.681; P=0.0152) were independent prognostic factors. The low-PNI group had a significantly shorter recurrence-free survival than the high-PNI group, regardless of pathological T factors (T1a, P=0.0422; T1b, P<0.0001; T2a, P=0.0098). CONCLUSIONS The preoperative PNI level is a simple and novel predictor of recurrence in stage I NSCLC patients, and might help identify patients who will need multimodality therapy such as induction or adjuvant therapy.

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.

Clinical implications of sarcopenia in patients undergoing complete resection for early non-small cell lung cancer

OBJECTIVES Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength. We aimed to investigate sarcopenia in patients with stage I non-small cell lung cancer (NSCLC) who underwent complete resection, and the relationship of sarcopenia with clinicopathological factors. METHODS All consecutive patients who underwent lung resection between January 2005 and December 2008 were enrolled in this retrospective study. Eligible patients were assigned to one of 2 groups according to the presence or absence of sarcopenia, as assessed by the sum of cross-sectional areas of skeletal muscles in the region of the third lumbar vertebra (L3) on preoperative computed tomography (CT). RESULTS Sixteen of 52 male (30.8%) and 22 of 38 female (57.9%) patients were identified with sarcopenia (p=0.01). Patients with sarcopenia were more likely to have a low body mass index (BMI) (p<0.0001). Kaplan-Meier analysis showed that patients with sarcopenia had a significantly worse outcome than patients without sarcopenia (5-year-survival: 72.8% vs 85.8%, respectively, p=0.028). Multivariate analysis found that sarcopenia was a significant independent prognostic factor (hazard ratio: 7.09, p=0.0008). CONCLUSIONS Sarcopenia identified on a cross-sectional CT image of the L3 level was associated with poor outcome with completely resected early-stage NSCLC.

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.

Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression

Interleukin (IL)-38, a novel member of the IL-1 cytokine family, is homologous to IL-1 receptor antagonist (IL-1Ra) and IL-36Ra, and has been reported to act as an antagonist. IL-38 expression is found in tonsil, placenta, and spleen, and recent studies suggest an association between IL-38 and autoimmune diseases. However, whether IL-38 plays a role in carcinogenesis or cancer growth is unclear. In the present study, we identified increases in IL-38 expression by immunohistochemistry in multiple types of cancer cells. In the examination of 417 surgically resected primary lung adenocarcinomas, Fisher’s exact tests showed significant associations between high IL-38 expression and high tumor grades, an advanced T status, advanced N status, advanced stage, and the presence of pleural and vessel invasions. Survival analyses by the Kaplan-Meier method showed that patients with high expression of IL-38 had significantly shorter disease-free survival and shorter overall survival after surgery than patients with low expression of IL-38 (log-rank test: P = 0.0021 and P = 0.0035, respectively). Moreover, programmed cell death-ligand 1 (PD-L1)-positive cases showed higher expression of IL-38 than PD-L1-negative cases (Wilcoxon rank-sum test: P < 0.0001). In conclusion, IL-38 was expressed in tumor cells of various cancers, and IL-38 expression was associated with poor survival of lung adenocarcinoma patients. IL-38 may affect host immunity or the tumor microenvironment, and contribute to the progression of lung adenocarcinoma.