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Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is extremely useful for pathological diagnosis of pancreatic ductal adenocarcinoma (PDAC); however, puncturing is difficult in some cases, and there is a risk of needle tract seeding. This study evaluated the indications for endoscopic retrograde pancreatography-based (ERP)-based cytology for the preoperative diagnosis of PDAC.This study included 267 patients with PDAC who underwent preoperative ERP. The diagnostic performance of ERP-based cytology for PDAC was evaluated based on the sample collection method (pancreatic juice cytology [PJC] during ERP, brush cytology, PJC via endoscopic nasopancreatic drainage [ENPD] catheter), lesion site (pancreatic head, body/tail), and lesion size (≤10 mm, 10-20 mm,20 mm), and compared with the diagnostic performance of EUS-FNA.The overall sensitivity of ERP-based cytology was 54.9%; sensitivity by the sampling method was 34.7% for PJC during ERP, 65.8% for brush cytology, and 30.8% for PJC via an ENPD catheter. The sensitivity of EUS-FNA was 85.3%. Brush cytology and PJC via an ENPD catheter were performed more often in pancreatic body/tail lesions than in head lesions (P = 0.016 and P 0.001, respectively), and the overall sensitivity of ERP-based cytology was better for body/tail lesions (63.2% vs. 49.0%, P = 0.025). The sensitivities of ERP-based cytology and EUS-FNA in diagnosing PDAC ≤10 mm were 92.3% and 33.3%, respectively. Post-ERP pancreatitis was observed in 22 patients (8.2%) and significantly less common with ENPD catheters (P = 0.002).ERP-based cytology may be considered the first choice for pathological diagnosis of PDAC ≤10 mm and in the pancreatic body/tail.

Association of antibiotic therapy within 60 days before the start of ICI therapy with survival in patients with NSCLC.

Cox proportional hazards regression models with inverse probability of treatment weighting using propensity score.

Gut dysbiosis caused by antibiotics impairs response to immune checkpoint blockade (ICB). Gut microbiota is becoming an attractive therapeutic target for cancer. The Clostridium butyricum MIYAIRI 588 strain is a probiotic therapy used to improve symptoms related to antibiotic-induced dysbiosis in Japan. We hypothesized that probiotic Clostridium butyricum therapy (CBT) may affect the therapeutic efficacy of ICBs. We retrospectively evaluated 118 patients with advanced non–small cell lung cancer treated with ICBs at Kumamoto University Hospital (Kumamoto-shi, Kumamoto, Japan). Survival analysis comparing patients given CBT before and/or after ICB was conducted using univariate analyses and Cox proportional hazards regression models using propensity score. Propensity score analyses confirmed that probiotic CBT significantly prolonged progression-free survival (PFS) and overall survival (OS). Probiotic CBT significantly associated with longer PFS and OS even in patients who received antibiotic therapy. This study suggests that probiotic CBT may have a positive impact on therapeutic efficacy of ICB in patients with cancer.See articles by Hakozaki et al., p. 1243, and Peng et al., p. 1251

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Supplementary Fig

Invasive lung adenocarcinoma (LADC) can be classified histologically as lepidic, acinar, papillary, micropapillary, or solid. Most LADC tumors manifest several of these histological subtypes, with heterogeneity being related to therapeutic resistance. We report here that in immunodeficient mice, human LADC cells form tumors with distinct histological features, MUC5AC-expressing solid-type or cytokeratin 7 (CK7)-expressing acinar-type tumors, depending on the site of development, and that a solid-to-acinar transition (SAT) could be induced by the tumor microenvironment. The TGFβ-Smad signaling pathway was activated in both tumor and stromal cells of acinar-type tumors. Immortalized cancer-associated fibroblasts (CAF) derived from acinar-type tumors induced SAT in 3D cocultures with LADC cells. Exogenous TGFβ1 or overexpression of an active form of TGFβ1 increased CK7 expression and reduced MUC5AC expression in LADC cells, and knockdown of Tgfb1 mRNA in CAFs attenuated SAT induction. RNA-sequencing analysis suggested that angiogenesis and neutrophil recruitment are associated with SAT in vivo. Our data indicate that CAF-mediated paracrine TGFβ signaling induces remodeling of tumor tissue and determines the histological pattern of LADC, thereby contributing to tumor heterogeneity.Significance:CAFs secrete TGFβ to induce a solid-to-acinar transition in lung cancer cells, demonstrating how the tumor microenvironment influences histological patterns and tumor heterogeneity in lung adenocarcinoma.

Purpose An increasing number of advanced non–small cell lung cancer (NSCLC) cases are being reported in the ageing population. However, studies on the use of afatinib in elderly patients are scarce. We conducted a prospective multicentre, single-arm, and open-label phase II trial for low-dose afatinib (30 mg/day) use in elderly patients with NSCLC with EGFR mutation to assess quality-of-life (QOL) and pharmacokinetic (PK)/pharmacogenomic (PGx) parameters. Patients and methods The primary end-point was the objective response rate (ORR), and the planned number of registered cases was 35, with a threshold ORR of 50%, an expected ORR of 75%, α of 0.05, and β of 0.1. Secondary end-points were progression-free survival (PFS), overall survival (OS), the incidence rate of adverse events (AEs), QOL survey (FACT-L), and trough plasma concentration of afatinib at steady state (Css) and at the occurrence of clinically significant AEs. Results The median age of the patients was 79 years. The ORR was 80.0% and the disease control rate was 91.4%. The median PFS and OS were 15.6 and 29.5 months, respectively. Four patients discontinued because of AEs. Treatment-related death was not observed. No significant change in QOL was observed at baseline and after 4, 8, and 12 weeks. Css was comparable with those in previous reports and was significantly higher in patients with grade 3 AEs. Direct correlations between afatinib treatment and PGx profiles were not observed. Conclusions An afatinib starting dose of 30 mg/day could be an effective and safe treatment option for elderly patients.

The aim of this study was to investigate whether a tumor microenvironment, abundant in microvessels, affects epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) efficacy in patients with non-small cell lung cancer (NSCLC) and EGFR mutations. We retrospectively studied the data of 40 post-operative patients with recurrent NSCLC and EGFRmutations who received EGFR-TKIs as a first-line treatment at Kumamoto University Hospital between January 2010 and February 2021. Tumor sections were retrieved from the tissue registry and analyzed for CD34-positive microvessels using immunohistochemical techniques. The microvascular area ratio (MVR), which is the CD34-positive microvascular area compared to the total tumor area, was measured using StrataQuest. The predictive value of MVR on treatment outcome, assessed via progression-free survival (PFS), was evaluated using a multivariate Cox proportional hazard model. The median PFS in the high MVR group (≥0.058) was significantly shorter than that in the low MVR group (P=0.002). Multivariate analysis revealed that high MVR was an independent negative predictor of PFS (hazard ratio, 3.21 [95% CI: 1.18–8.76], P=0.022). High MVR may critically affect EGFR-TKI resistance in patients with NSCLC and EGFR mutations.

Purpose Microvessel density plays an essential role in tumor development. However, whether a tumor microenvironment, abundant in microvessels, affects epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) efficacy in patients with non-small cell lung cancer (NSCLC) and EGFR mutations remains unclear. We aimed to investigate the impact of tumor microvessels on EGFR-TKI efficacy in patients with NSCLC and EGFR mutations. Methods We retrospectively studied the data of 40 post-operative patients with recurrent NSCLC and EGFR mutations who received EGFR-TKIs as a first-line treatment at Kumamoto University Hospital between January 2010 and February 2021. Tumor sections were retrieved from the tissue registry and analyzed for CD34-positive microvessels using immunohistochemical techniques. The microvascular area ratio (MVR), which is the CD34-positive microvascular area compared to the total tumor area, was measured using StrataQuest. The predictive value of MVR on treatment outcome, assessed via progression-free survival (PFS), was evaluated using a multivariate Cox proportional hazard model. Results The median MVR and PFS values of EGFR-TKI were 0.058 (range, 0.013–0.094) and 610 d (range, 102–2807 d), respectively. The median PFS in the high MVR group (≥ 0.058) was significantly shorter than that in the low MVR group (P = 0.002). Multivariate analysis revealed that high MVR was an independent negative predictor of PFS (hazard ratio, 3.21 [95% CI: 1.18–8.76], P = 0.022). Conclusions High MVR may critically affect EGFR-TKI resistance in patients with NSCLC and EGFR mutations.

Despite the success of cancer immunotherapies such as programmed cell death–1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator–activated receptor–γ coactivator 1α/peroxisome proliferator–activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase 1 trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced non–small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through up-regulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.

The mutation status of tumor tissue DNA (n = 389) of resected stage II‐III non‐squamous non–small‐cell lung cancer (Ns‐NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG‐TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation‐positive status had a significantly shorter recurrence‐free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22‐2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30‐2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15‐2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II‐III Ns‐NSCLC patients. This result supports a role for mandatory molecular diagnosis of early‐stage Ns‐NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum‐based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237)., Mutation status of stage II‐III Ns‐NSCLC (n = 389) was analyzed using targeted deep sequencing. Patients with an EGFR mutation‐positive status had a significantly shorter recurrence‐free survival (RFS). Both the pathological stage and EGFR mutation status were independent prognostic factors for RFS.

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I–IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer.

Background Lymphovascular invasion (LVI), which includes vascular or lymphatic invasions, is a representative prognostic factor even in patients with resected stage IA non-small cell lung cancer (NSCLC). Because tegafur-uracil is effective on cancers with LVI, we conducted a multi-center single-arm phase II study to estimate the efficacy of adjuvant tegafur-uracil in patients with LVI-positive stage IA NSCLC. Methods Patients with completely resected LVI-positive stage IA NSCLC were registered. LVI was diagnosed by consensus of two of three pathologists. Adjuvant chemotherapy consisted of 2 years of oral tegafur-uracil at 250 mg/m2/day. Fifty-five patients from 7 institutions were enrolled from June 2007 to September 2012. Results Among the 52 eligible patients, 36 (69.2%) completed the treatment course. There were 39 male and 13 female patients. The observation period was calculated as 562 to 3107 days using the reverse Kaplan-Meier method. The 5-year overall and relapse free survival rates were 94.2 and 88.5% respectively, which were significantly better than that of any other studies conducted on patients with LVI-positive stage IA NSCLC. Notably, the overall survival rate was 15% better than that of our prior retrospective study. The retrospective analysis of stage IA NSCLC patients who had received an operation in the same period revealed that the 5-year overall survival rate of the LVI positive group was 73.6% when adjuvant chemotherapy was not applied. Among 55 safety analysis sets, 4 cases of grade 3 hepatic function disorder (9.1%) and 5 cases of grade 2 anorexia (10.9%) were most frequently observed. No grade 4 adverse effects were encountered. Conclusion A 2-year course of oral tegafur-uracil administration is feasible and might have a significant benefit in the adjuvant treatment of LVI-positive stage IA NSCLC. Trial registration UMIN identifier: UMIN000005921; Date of enrolment of the first participant to the trial: 19 June 2007; Date of registration: 5 July 2011 (retrospectively registered).

A pulmonary carcinoid tumor is a rare tumor that lacks a validated therapeutic approach for unresectable disease. Understanding the intersite tumor‐immune heterogeneity is essential to harness the immune system for cancer therapy. However, little is known about the tumor‐immune microenvironment (TIME). Here, we describe a patient who had heterogeneous TIME between primary and metastatic carcinoid tumors which differentially responded to chemoimmunotherapy. A 72‐year‐old man was diagnosed with an advanced pulmonary carcinoid tumor. CT‐guided biopsies of lung and scapular tumors confirmed typical carcinoid (PD‐L1, 1%–24%) and atypical carcinoid tumors (PD‐L1, negative), respectively. Although the primary lung carcinoid tumor showed a partial response, the scapular tumor was significantly enlarged after two cycles of anti‐PD‐L1 antibody therapy in combination with carboplatin plus etoposide. We performed quantitative pathology imaging analysis with fluorescent multiplex immunohistochemistry. CD8+ T cell infiltration was detected in the PD‐L1‐positive primary lung tumor nest; however, it was mostly restrained in the stroma in a PD‐L1‐negative metastatic scapular tumor. Treg infiltrations into both tumor nests and stroma were detected in the lung tumor, which were not detected in the metastatic scapular tumor. This study provides the first evidence of coexistence of heterogeneous TIME within a single individual with a pulmonary carcinoid tumor. This study may provide new insights into the mechanism of primary resistance to chemoimmunotherapy in pulmonary carcinoid tumors., We describe a patient who had heterogeneous TIME between primary and metastatic carcinoid tumors which differentially responded to chemoimmunotherapy. CD8+ T cell infiltration was detected in PD‐L1‐positive primary lung tumor nest, however, which was mostly restrained in the stroma in a PD‐L1‐negative metastatic scapular tumor. This study may provide new insights into the mechanism of primary resistance to chemoimmunotherapy in pulmonary carcinoid tumors.

Gut dysbiosis caused by antibiotics impairs response to immune checkpoint blockade (ICB). Gut microbiota is becoming an attractive therapeutic target for cancer. The Clostridium butyricum MIYAIRI 588 strain is a probiotic therapy used to improve symptoms related to antibiotic-induced dysbiosis in Japan. We hypothesized that probiotic Clostridium butyricum therapy (CBT) may affect the therapeutic efficacy of ICBs. We retrospectively evaluated 118 patients with advanced non–small cell lung cancer treated with ICBs at Kumamoto University Hospital (Kumamoto-shi, Kumamoto, Japan). Survival analysis comparing patients given CBT before and/or after ICB was conducted using univariate analyses and Cox proportional hazards regression models using propensity score. Propensity score analyses confirmed that probiotic CBT significantly prolonged progression-free survival (PFS) and overall survival (OS). Probiotic CBT significantly associated with longer PFS and OS even in patients who received antibiotic therapy. This study suggests that probiotic CBT may have a positive impact on therapeutic efficacy of ICB in patients with cancer. See articles by Hakozaki et al., p. 1243, and Peng et al., p. 1251

Anti-programmed cell death protein-1/ligand-1 (anti-PD-1/PD-L1) therapy is promising for patients with non-small-cell lung cancer (NSCLC); however, clinical trials have focused on patients with a performance status (PS) 0 or 1. This study aimed to evaluate the clinical outcomes and correlation between PD-L1 expression status and tumor response to anti-PD-1/PD-L1 therapy among NSCLC patients with poor PS (i.e., PS ≥ 2). In total, 130 patients with NSCLC and PS ≥ 2 treated with anti-PD-1/PD-L1 monotherapy at 12 institutions between January 2016 and August 2019 were retrospectively reviewed. PD-L1 expression status was divided into four groups

Radiation recall dermatitis (RRD) is an inflammatory reaction that occurs at previously irradiated skin regions after drug administration. We herein report a patient with non-small-cell lung cancer treated previously with thoracic radiotherapy who developed severe RRD induced by atezolizumab [anti-programmed death 1 ligand 1 (PD-L1) antibody]. Immunohistochemistry of the skin biopsy showed dermatitis with infiltration of CD8+ lymphocytes, suggesting that atezolizumab might provoke an immune-related inflammatory reaction at previously irradiated skin regions. When administering anti-PD-L1 antibody to patients who have undergone radiotherapy previously, physicians should carefully monitor the irradiated skin for the potential occurrence of RRD.

Background: Pembrolizumab (Pemb) is a key drug for the treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, there are limited data on Pemb use in older adults aged >75 years with NSCLC, especially in terms of pharmacokinetics (PK). Methods: This open-label multicenter observational study aimed to evaluate real-world data on the safety, efficacy, and blood concentrations of Pemb (both monotherapy and combination therapies) in older adults with NSCLC. Blood samples for PK analysis were collected immediately before Pemb administration. Quantitative Pemb concentrations were measured by liquid chromatography-mass spectrometry. Results: We enrolled 100 patients from July 2019 to September 2020; one patient was excluded due to stage migration. Patient characteristics were as follows: median age, 78 (75-87) years; male/female ratio, 70/29; performance status (PS) 0-1/2-3, 85/14; adenocarcinoma/squamous cell carcinoma/others, 62/25/12; stage I-III/IV/postoperative recurrence (TNM 7th edition), 9/60/30; PD-L1 TPS Conclusion: In older adults aged >75 years with NSCLC and low albumin levels and PS and a high number of metastatic organs, C1 trough of Pemb is reduced and not expected to prolong PFS and OS. Citation Format: Yoshiro Nakahara, Kageaki Watanabe, Yukio Hosomi, Yuta Yamanaka, Takayasu Kurata, Hidehito Horinouchi, Yuichiro Ohe, Tetsuhiko Asao, Sho Saeki, Yukari Tsubata, Yu Fujita, Jun Sakakibara Konishi, Hidenori Mizugaki, Mayu Ohuchi, Shigehiro Yagishita, Akinobu Hamada. Multicenter pharmacokinetic study of pembrolizumab for non-small cell lung cancer in older adults aged over 75 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2797.

A 69-year-old man with advanced non-small-cell lung cancer was treated with pembrolizumab for 4 months. Three months after pembrolizumab was discontinued, computed tomography showed enlargement of the pancreatic head, with hypoattenuating areas in the pancreatic head to body. On endoscopic ultrasonography, the entire pancreatic parenchyma was hypoechoic. Endoscopic retrograde cholangiopancreatography showed narrowing of the main pancreatic duct at the pancreatic head. Endoscopic ultrasound-guided fine-needle aspiration showed inflammatory cell infiltration in the stroma but no neoplastic lesions. CD8-positve T cells were dominant over CD4-positive T cells in the infiltrating lymphocytes, and the patient was diagnosed with pembrolizumab-induced pancreatitis.

The effect of radiotherapy during immunotherapy on immune-related adverse events (irAEs) is not fully understood. We herein report a 74-year-old woman diagnosed with lung adenocarcinoma with programmed death ligand 1 expression ≥50% and treated with pembrolizumab. She developed fatal immune thrombocytopenia associated with pembrolizumab immediately following radiotherapy. A flow cytometry analysis of peripheral blood detected an increased expression of PD-1 and Ki-67 in CD4+ and CD8+ T cells after radiotherapy, compared with pre-irradiation measurements. This case suggests that radiotherapy may evoke irAEs during treatment with anti-PD-1 antibodies, which physicians should consider when using radiotherapy in patients treated with these drugs.

We examined whether fluorine-18 2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) performed before chemotherapy could predict the onset of acute exacerbation of interstitial lung disease (AE-ILD) in patients with lung cancer and ILD treated with chemotherapy. Thirty-three patients with lung cancer and ILD who underwent 18F-FDG PET/CT and were treated with chemotherapy at Kumamoto University Hospital between April 2006 and March 2018 were retrospectively analyzed. The maximum standardized uptake value (SUVmax) of interstitial lesions was measured to quantify the background ILD activity. A prediction model of AE-ILD was developed using logistic regression analyses for the SUVmax, and receiver operating characteristic (ROC) curve analyses were conducted. Among the 33 patients, 7 experienced AE-ILD. The SUVmax of contralateral interstitial lesions was significantly higher in patients with vs. without AE-ILD (median SUVmax: 2.220 vs. 1.795, P = 0.025). Univariable logistic regression analyses showed that the SUVmax of contralateral interstitial lesions trended towards being significantly associated with the onset of AE-ILD [odds ratio: 8.683, 95% confidence interval (CI) 0.88–85.83, P = 0.064]. The area under the ROC curve of the SUVmax for predicting AE-ILD was 0.780 (95% CI 0.579–0.982, P = 0.025). The optimal cut-off value for SUVmax was 2.005, with sensitivity and specificity values of 0.857 and 0.769, respectively. The SUVmax of contralateral interstitial lesions in 18F-FDG PET/CT images might be useful for predicting the onset of AE-ILD in patients with lung cancer and ILD treated with chemotherapy.

Small cell lung cancer (SCLC) transformation of epidermal growth factor receptor (EGFR) mutant adenocarcinoma (ADC) during EGFR tyrosine kinase inhibitor (TKI) treatment is an example of a rare subset of acquired drug resistance. We herein report the case of a 75-year-old man treated with afatinib who was then diagnosed with SCLC transformation. After two years of successful treatment with afatinib, the tumor relapsed, and a re-biopsy revealed SCLC harboring EGFR exon 19 deletion. We encountered a case of transcriptional alteration, potentially important for SCLC transformation of EGFR mutant lung ADC, that was recognized via the expression of NOTCH, ASCL1 and RB1 on immunohistochemical staining.

Lung cancer patients have a high risk of cerebral infarction, but the clinical significance of cerebral infarction in advanced non-small cell lung cancer (NSCLC) remains unclear. This study aimed to comprehensively investigate the incidence, prognostic impact, and risk factors of cerebral infarction in patients with NSCLC.We retrospectively examined 710 consecutive patients with advanced or post-operative recurrent NSCLC treated between January 2010 and July 2020 at Kumamoto University Hospital. Cerebral infarction was diagnosed according to the detection of high-intensity lesions on diffusion-weighted magnetic resonance imaging regardless of the presence of neurological symptoms during the entire course from 3 months before NSCLC diagnosis. The prognostic impact and risk factors of cerebral infarction were evaluated based on propensity score matching (PSM) and multivariate logistic regression analysis.Cerebral infarction occurred in 36 patients (5%). Of them, 21 (58%) and 15 (42%) patients developed asymptomatic and symptomatic cerebral infarction, respectively. PSM analysis for survival showed that cerebral infarction was an independent prognostic factor (hazards ratio: 2.45, 95% confidence interval (CI): 1.24-4.85, P = 0.010). On multivariate logistic regression analysis, D-dimer (odds ratio [OR]: 1.09, 95% CI 1.05-1.14, P 0.001) and C-reactive protein (OR: 1.10, 95% CI 1.01-1.19, P = 0.023) levels were independent risk factors.Cerebral infarction occurred in 5% of NSCLC patients, and asymptomatic cerebral infarction was more frequent. Cerebral infarction was a negative prognostic factor and was associated with hyper-coagulation and inflammation. The high frequency of asymptomatic cerebral infarction and its risk in NSCLC patients with these conditions should be recognized.