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Objectives: In non-small cell lung cancer (NSCLC), T factor plays an important role in determining staging. The present study aimed to determine the validity of preoperative evaluation of clinical T (cT) factor by comparing radiological and pathological tumor sizes., Methods: Data for 1,799 patients with primary NSCLC who underwent curative surgery were investigated. The concordance between cT and pathological T (pT) factors was analyzed. Furthermore, we compared groups with an increase or decrease of ≥ 20% and groups with an increase or decrease of < 20% in the size change between preoperative radiological and pathological diameters., Results: The mean sizes of the radiological solid components and the pathological invasive tumors were 1.90 cm and 1.99 cm, respectively, correlation degree = 0.782. The group with increased pathological invasive tumor size (≥ 20%) compared with the radiologic solid component was significantly more likely female, consolidation tumor ratio (CTR) ≤ 0.5, and within cT1. Multivariate logistic analysis identified CTR < 1, cT ≤ T1, and adenocarcinoma as independent risk factors for increased pT factor., Conclusion: The radiological invasive area of tumors with cT1, CTR < 1, or adenocarcinoma on preoperative CT may be underestimated compared with pathological invasive diameter., (© 2023. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Background: Programmed death-ligand 1 (PD-L1) expression on lung cancer cells is a prognostic marker and a predictive biomarker for response to immunotherapy. However, previous clinical trials have suggested that other programmed cell death 1 ligands, including programmed death-ligand 2 (PD-L2), might have clinical impacts. This study aimed to analyze the prognostic significance of PD-L2 expression in lung adenocarcinoma patients., Methods: The study included 433 patients who underwent surgical resection for lung adenocarcinoma between 2003 and 2012 at Kyushu University Hospital. Both PD-L1 and PD-L2 expression were evaluated by immunohistochemistry. The cutoff value for PD-L2 positivity was set at 1% according to a time-dependent receiver operating characteristic curve for 5-year survival., Results: Of the 433 patients, 306 (70.7%) were positive for PD-L2. No significant association between PD-L1 and PD-L2 expression was observed (P = 0.094). The multivariate analysis showed that the independent predictors of PD-L2 positivity were never-smoker status (P = 0.002), poor differentiation grade (P = 0.008), and advanced stage (P = 0.048). The PD-L2-positive patients had significantly shorter disease-free survival (DFS) (P = 0.018) and overall survival (OS) (P = 0.016). Both PD-L1 and PD-L2 positivity were independent predictors of OS (P < 0.001 and P = 0.027, respectively). In the subgroup analysis of the PD-L1-negative patients, PD-L2 positivity was significantly associated with shorter DFS (P = 0.018)., Conclusions: The study demonstrated that the clinical characteristics of patients with PD-L1 expression may differ from those of patients with PD-L2 expression, and that both might contribute to poor prognoses. The potential role of PD-L2 expression as a predictive biomarker for response to immunotherapy should be investigated in future studies.

Background: Immunotherapy targeting programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has shown dramatic therapeutic effects for lung squamous cell carcinoma (SCC), and PD-L1 expression has been shown not only to be a predictive biomarker for response to immunotherapy but also a prognostic factor for lung SCC. However, the clinical significance of programmed death-ligand 2 (PD-L2), another PD-1 ligand, remains unclear. Therefore, we analyzed PD-L2 expression by immunohistochemistry in surgically resected primary lung SCC., Patients and Methods: PD-L1 and PD-L2 expression on tumor cells were analyzed in 211 primary lung SCC specimens by immunohistochemistry. Additionally, numbers of CD3 + , CD4 + , and CD8 + tumor-infiltrating lymphocytes were also examined., Results: The rates of positive PD-L2 expression were 77.3% and 67.3% using 5% and 10% cut-off values, respectively. Low PD-L2 expression on tumor cells was statistically associated with histological type (non-keratinizing/keratinizing) and lymphatic invasion. PD-L2-positive patients had significantly longer postoperative survival time (log-rank test; p = 0.0170 at 5% cut-off and p = 0.0500 at 10% cut-off). Furthermore, survival analysis according to PD-L1 and PD-L2 expression revealed that PD-L1-positive and PD-L2-negative patients had the most unfavorable prognosis., Conclusions: PD-L2 protein expression was associated with prognosis in primary lung SCC patients. PD-L2 expression might be a potential biomarker for response to PD-1/PD-L1-targeted immunotherapy, which should be investigated in future studies.

Background: CD44 isoforms serve as a marker for cancer stem cells. CD44 variant 9 (CD44v9) contributes to the defense against reactive oxygen species, resulting in resistance to chemoradiotherapy. However, the significance of CD44v9 in patients with lung adenocarcinoma is unknown., Methods: We used immunohistochemical analysis to retrospectively analyze CD44v9 expression in 268 surgically resected lung adenocarcinomas and investigated the association between CD44v9 expression and patients' clinicopathological features., Results: The expression of CD44v9 in 193 of 268 (72.0%) patients was significantly associated with early-stage cancer, low-grade tumors, absence of vessel and pleural invasion, and a mutated epidermal growth factor receptor (EGFR) gene. Multivariate logistic analysis revealed that CD44v9 expression was significantly associated with early-stage disease [odds ratio (OR) 0.29, 95% confidence interval (CI) 0.14-0.59; p < 0.001] and mutant EGFR (OR 2.53, 95% CI 1.06-6.04; p = 0.036). The percentage of CD44v9-positive tumors was higher in the earlier stages of disease; however, there was no significant difference in the survival of patients in each stage of disease who had positive or negative CD44v9 expression., Conclusion: CD44v9 was highly expressed in EGFR-mutant tumors, particularly in early-stage lung adenocarcinoma, suggesting that CD44v9 expression may play an important role in EGFR-mutant tumors.

Takotsubo cardiomyopathy (TC) is a syndrome characterized by transient local systolic dysfunction of the left ventricle with no evidence of coronary artery disease or acute plaque rupture. We present the case of 71-year-old woman who developed TC after two-stage surgery for double primary lung cancer. On computed tomography, lung nodules were identified in the left upper and right middle lobes. Based on the diagnosis of double primary lung cancer, we performed two-stage surgery (left upper lobectomy followed by right middle lobectomy). One day after the second surgery, respiratory failure developed. Electrocardiography showed ST segment elevation, serum troponin levels were elevated, and chest x-ray showed acute pulmonary edema. Cardiac catheterization showed no coronary artery disease and apical akinesia. Based on these findings, we diagnosed TC and the patient recovered with supportive treatment., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Surgical outcomes of early-stage non-small cell lung cancer (NSCLC) are poor. The Geriatric Nutritional Risk Index (GNRI) is a useful parameter for evaluating nutritional status. We aimed to investigate if preoperative GNRI could be a predictive factor for pathological stage I NSCLC patients., Patients and Methods: We retrospectively selected 141 consecutive pathological stage I NSCLC patients treated from August 2005 to August 2010. We analyzed their preoperative GNRI in univariate and multivariate Cox regression analyses for postoperative recurrence-free survival (RFS)., Results: A preoperative abnormal GNRI was significantly associated with postoperative recurrence (P = 0.0107). Univariate analyses showed that serum carcinoembryonic antigen (CEA) levels (P = 0.0013), preoperative serum albumin level (P < 0.0001), preoperative GNRI (P = 0.0009), pleural invasion (P < 0.0001) and blood vessel invasion (P = 0.0137) significantly affected RFS. In multivariate analysis, preoperative GNRI (P = 0.0084), CEA level (P = 0.0031), preoperative serum albumin level (P = 0.0041) and pleural invasion (P = 0.0018) were independent prognostic factors. In Kaplan-Meier analysis of RFS, cancer-specific survival (CS), and overall survival (OS) by preoperative GNRI, the abnormal GNRI group had significantly shorter RFS, CS, and OS (5-year RFS, CS, and OS: 52.81% vs. 89.15%; P < 0.0001, 81.73% vs. 94.73%; P = 0.0014 and 50.84% vs. 89.57%; P < 0.0001, log-rank test, respectively)., Conclusions: Preoperative GNRI is a novel prognostic factor for pathological stage I NSCLC patients, which can identify high-risk patients for postoperative recurrence and cancer-related death., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/aim: Few studies have so far described the conversion of programmed death-ligand 1 (PD-L1) after treatment. In particular, the effect of nivolumab on the PD-L1 expression has never been reported. We investigated the changes in PD-L1 expression after chemotherapy and nivolumab treatment and herein describe the detailed clinical course., Patients and Methods: We retrospectively examined the PD-L1 expression in resected specimens and in the re-biopsy specimens of patients with non-small cell lung cancer by immunohistochemical analysis., Results: Four patients underwent a re-biopsy after treatment. Of those, three showed positive conversion of the PD-L1 expression. One patient underwent a re-biopsy after chemotherapy and nivolumab treatment, and the other two cases underwent a re-biopsy after chemotherapy, radiotherapy and nivolumab treatment., Conclusion: These cases suggest the positive conversion of PD-L1 expression after treatments including nivolumab, suggesting that PD-L1 expression must be assessed in not only the resected specimens, but also in the re-biopsied ones., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: 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., Patients and Methods: 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., Results: 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, and wild-type epidermal growth factor receptor. Seventy patients (19.0%) were positive for PD-L1 expression, whereas the remaining 299 patients (81.0%) were negative. Thirty-six (44.4%) and 29 (58.0%) of 81 and 50 patients with EB and Ca-ADJ, respectively, were positive for PD-L1 expression, which was shown to be significant by the Fisher exact test (P < .001 and P < .001, respectively). Among the 81 lung adenocarcinomas with EB, Ca-ADJ was significantly associated with PD-L1 expression (P = .021). In a multivariate analysis, the presence of Ca-ADJ was found to be an independent predictor of PD-L1 expression., Conclusions: EB-associated lung adenocarcinomas express PD-L1 protein more frequently than those without EB., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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.

Background: Programmed death ligand 1 (PD-L1) was reported to predict the response of immunotherapy; however, the association between PD-L1 expression and radiologic and pathologic features has yet to be elucidated., Methods: In all, 292 patients with resected pathologic stage I adenocarcinoma were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and the radiologic/pathologic invasiveness. Specifically, the radiologic invasiveness and noninvasiveness were determined based on the consolidation/tumor ratio, with a cutoff value of 0.25 by thin-section computed tomography., Results: Among 292 patients, 47 (16.1%) were positive for PD-L1 expression; the remaining 245 patients (83.9%) were negative for PD-L1 expression. Fisher's exact test demonstrated that PD-L1 expression was significantly associated with a higher consolidation/tumor ratio (p = 0.029) and higher maximum standardized uptake value (p = 0.004). The mean values of consolidation/tumor ratio and maximum standardized uptake in patients with and without PD-L1 expression were 0.845 ± 0.052 and 7.241 ± 0.795, and 0.607 ± 0.023 and 3.60 ± 0.364, respectively (p < 0.001 and p < 0.001, respectively). Among 47 adenocarcinomas harboring PD-L1 expression, the frequencies of PD-L1 expression for consolidation/tumor ratios of 0, 0.1 to 0.25, 0.26 to 0.5, and 0.51 or more were 6.4%, 2.1%, 4.3%, and 87.2%, respectively (p = 0.007). Pathologically, PD-L1 was identified exclusively only in more invasive subtypes, not in less invasive ones, such as atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant ones (p < 0.001)., Conclusions: Expression of PD-L1 was significantly associated with radiologic/pathologic invasive adenocarcinomas. This study provides the first evidence of the radiologic and pathologic invasiveness in resected pathologic stage I adenocarcinoma with PD-L1 expression., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The usefulness of the controlling nutritional status (CONUT) score for preoperative nutritional assessment has been reported in resected colorectal and esophageal cancer, but not in lung cancer with obstructive lung disease., Patients and Methods: We retrospectively reviewed 109 patients with adenocarcinoma with obstructive pulmonary disease. We set 1 as the cut-off value for the CONUT score and classified patients into high (≥1) and low (0) CONUT groups., Results: Among 109 patients, 35 (32.1%) had low CONUT scores, and 74 (67.8%) had high CONUT scores. The high-CONUT group was significantly associated with a lower body mass index (p=0.025) and wild-type epidermal growth factor receptor mutation status (p=0.011). A multivariate analysis showed that the CONUT score was independently associated with disease-free and overall survival., Conclusion: The results of this study suggest that the CONUT score was an independent prognostic factor for disease-free and overall survival in patients with lung adenocarcinoma with obstructive lung disease., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is deeply involved in the pathogenesis of lung cancer. We evaluated the metabolic characteristics of non-small cell lung cancer (NSCLC) in patients with and without expression of EZH2 using 18 F-fluorodeoxyglucose positron-emission tomography/ computed tomography ( 18 F-FDG PET/CT)., Materials and Methods: The EZH2 protein expression of 268 patients with resected NSCLC, whose preoperative 18 F-FDG PET/CT information was available, was evaluated by immunohistochemistry with clone 6A10 antibody; cases with Allred score ≥3 were considered positive., Results: Maximized standard uptake values in cases of EZH2-positive NSCLC and adenocarcinoma were significantly higher in comparison to EZH2-negative cases (p<0.001, and p<0.001, respectively). The expression of EZH2 in NSCLC and adenocarcinoma was associated with significantly poorer survival., Conclusion: In patients with NSCLC and adenocarcinoma, EZH2 positivity was associated with a high uptake of FDG, suggesting that EZH2 might define metabolically malignant lung cancer., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Preoperative maximum standardized uptake value (SUVmax) of 2‐[18F]‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography and serum carcinoembryonic antigen (CEA) have been reported as prognostic factors for lung adenocarcinoma. However, the significance of combined SUVmax and CEA in early‐stage lung adenocarcinoma is not well known. Methods: We retrospectively evaluated the relationship between the combination of SUVmax and CEA and the prognosis of 410 patients with clinical stage IA lung adenocarcinoma who underwent resection. The cutoff values for SUVmax and CEA were determined by receiver operating characteristic curve analysis, and patients were categorized into high SC (SUVmax and CEA) group (SUVmax ≥2.96 and CEA ≥5.3), moderate SC group (either SUVmax <2.96 and CEA ≥5.3 or SUVmax ≥2.96 and CEA <5.3) and low SC group (SUVmax <2.96 and CEA <5.3). Results: Kaplan–Meier curve analysis showed that patients with clinical stage IA lung adenocarcinoma in the high SC group had significantly shorter overall survival (OS) and recurrence‐free survival (RFS) than the other groups (p = 0.011 and p < 0.0001, respectively). Multivariate analysis showed that high SC was an independent prognostic factor of OS (p = 0.029) and RFS (p < 0.0001). Conclusions: High values of SUVmax and CEA were associated with poor OS and RFS in patients with stage IA lung adenocarcinoma. Simultaneous evaluation of SUVmax and CEA may be an effective prognostic marker to determine the optimal treatment strategy of early‐stage lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Mesenchymal‐epithelial transition (MET) pathway activation is associated with the mechanisms that influence properties affecting cancer cell survival and invasiveness. The MET exon 14 skipping mutation (METex14del) is found in 2%–3% of patients with non‐small cell lung cancer (NSCLC). Previous studies reported that NSCLC patients harboring a METex14del responded well to MET‐tyrosine kinase inhibitors (TKIs), including tepotinib. Tepotinib is a highly selective, once‐daily oral MET inhibitor that has shown promising clinical activity in patients with NSCLC with METex14del. The Food and Drug Administration accepted a new drug application for tepotinib as a treatment for patients with metastatic NSCLC harboring METex14del in February 2021 [Correction added on 5 March 2021, after first online publication: the FDA approval date for tepotinib has been corrected from 'September 2019' to 'February 2021'.]. However, in the previous clinical trials involving MET‐TKIs, only patients with stable central nervous system metastases were eligible, and those with untreated symptomatic brain metastases (BMs) were excluded. Therefore, the efficacy and safety of MET‐TKIs in that population remains unknown. We herein report a case of dramatic intracranial response to tepotinib in a patient with symptomatic BMs from lung adenocarcinoma harboring METex14del. In the current report, the symptoms derived from multiple BMs (headache and loss of appetite) rapidly disappeared, and brain magnetic resonance imaging (MRI) examination showed that all the lesions were too small to measure only 23 days after the commencement of tepotinib. For NSCLC patients with multiple BMs, whole‐brain irradiation is a standard‐of‐care therapy, but its adverse effects on neurocognition are concerning. Tepotinib might therefore be a therapeutic option for NSCLC patients with symptomatic multiple BMs harboring METex14del. [ABSTRACT FROM AUTHOR]

The transformation of adenocarcinoma to small cell lung cancer has been reported as acquisition of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. We here report a patient who presented histologically confirmed transformation of adenocarcinoma to small cell lung cancer after treatment with immune checkpoint inhibitor. A 65-year-old man was treated with pembrolizumab as first-line therapy and achieved temporarily a stable disease with progression after six cycles of this agent. At that stage, a transbronchial biopsy showed small cell lung cancer, and he was found to have high serum concentrations of neuron-specific enolase despite concentrations of numerous tumor markers, including neuron-specific enolase, having been within normal limits at the time of presentation. The patient thereafter was treated as a small cell carcinoma patient using cisplatin plus irinotecan and amrubicin. [ABSTRACT FROM AUTHOR]

To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2–3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR -tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR -TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis. • Adjuvant chemotherapy may increase the rate of relapse on central nervous system. • Adjuvant chemotherapy may have limited effect on lung cancer harboring EGFR mutations. • Central nervous system metastasis is found before deterioration in performance status. • Central nervous system metastasis may have little impact on treatment after relapse. • Central nervous system metastasis has little impact on survival after relapse. [ABSTRACT FROM AUTHOR]

Objectives It was reported that programmed cell death-ligand 1 (PD-L1) expression is associated with smoking and wild-type epidermal growth factor receptor ( EGFR ) in lung adenocarcinoma. However, the association between PD-L1 expression and EGFR mutation site in EGFR mutation-positive lung adenocarcinoma is unclear. Materials and methods We retrospectively examined the relationship between PD-L1 expression and EGFR status in 441 surgically resected primary lung adenocarcinomas. Membrane PD-L1 expression on tumor cells was evaluated by immunohistochemical analysis using a PD-L1 antibody (clone SP142) and defined by tumor proportion scores (TPSs) of 0%, 1–4%, 5–49%, and ≥50%, respectively. Results Two hundred and eighteen (49.4%) patients had wild-type EGFR , and 223 (50.6%) had mutant EGFR —98 (44.0%) with exon 19 deletion, 116 (52.0%) with exon 21 L858R point mutation, and nine (4.0%) with another EGFR mutation. Overall, Fisher’s exact test showed that PD-L1 positivity was associated with wild-type EGFR , and there was only one case with PD-L1 TPS ≥50% among the cases with mutant EGFR . The analysis of cases with mutant EGFR indicated no significant association between EGFR mutation site and PD-L1 expression. However, the prevalence of PD-L1 TPS 5–49% was higher among patients with EGFR exon 19 deletion than with EGFR exon 21 L858R point mutation. Conclusions PD-L1 expression was significantly associated with wild-type EGFR , and PD-L1 TPS ≥50% seldom overlaps with presence of driver oncogene EGFR . There was no significant difference in PD-L1 expression among the EGFR mutation sites [ABSTRACT FROM AUTHOR]