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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

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.

Yoshimasa Shiraishi,1 Takayuki Shimose,2 Yuko Tsuchiya-Kawano,3 Hidenobu Ishii,4 Haruko Daga,5 Kentaro Ito,6 Koichi Saruwatari,7 Isamu Okamoto1 1Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 2Department of Statistics and Data Center, Clinical Research Support Center Kyushu, Fukuoka, Japan; 3Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan; 4Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan; 5Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan; 6Respiratory Center, Matsusaka Municipal Hospital, Mie, Japan; 7Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanCorrespondence: Isamu Okamoto, Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan, Tel +81-92-642-5378, Fax +81-92-642-5390, Email okamoto.isamu.290@m.kyushu-u.ac.jpBackground: The standard of care for extensive-stage small cell lung cancer (ES-SCLC) is an immune checkpoint inhibitor (ICI) combined with platinum-etoposide (PE) chemotherapy. At initial diagnosis, about 25% of ES-SCLC patients have brain metastases, which are associated with a poor prognosis. The decision as to whether to treat brain metastases with local therapies such as surgery or radiotherapy before initiation of systemic chemoimmunotherapy is based on symptoms due to the brain lesions and the general condition of the patient. Subset analysis of the CASPIAN study showed that combination therapy with PE plus durvalumab (MEDI4736) is promising for ES-SCLC with brain metastases. However, data required in daily clinical practice, such as intracranial response rate and duration of intracranial response, are insufficient for such patients.Patients and Methods: We have designed a single-arm phase II trial of durvalumab plus PE for patients aged ≥ 20 years with chemotherapy-naïve ES-SCLC and at least one brain metastasis ≥ 5 mm in size that has not been previously treated. Patients receive durvalumab intravenously combined with four cycles of PE. Enrollment of 50 patients over 2 years at 25 oncology facilities in Japan is planned. The primary endpoint is intracranial response rate.Conclusion: This is the first prospective study to evaluate the effects of an ICI with PE specifically in ES-SCLC patients with brain metastases. If it demonstrates intracranial efficacy, this regimen will be a potential treatment option for such individuals, and radiation therapy or surgery for brain metastases can be avoided or postponed.Keywords: immune checkpoint inhibitor, PD-L1, intracranial metastasis, intracranial response rate, platinum-etoposide

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.

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.

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.

BACKGROUND/AIM The optimal treatment strategy for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) has not yet been fully determined. The aim of this study was to investigate the optimal management of EGFR-mutant NSCLC patients with BM. PATIENTS AND METHODS A multicenter retrospective study was performed on the clinical outcomes of 81 advanced/recurrent EGFR-mutant NSCLC patients with BM treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) (gefitinib n=52 or erlotinib n=29). RESULTS Among the 81 patients, 30 patients received upfront cranial radiotherapy (CRT) and 51 did not. The multivariate cox analyses revealed that the use of erlotinib and upfront CRT were independent predictive factors for overall survival (OS) (erlotinib: HR 0.21; 95% CI, 0.10-0.48; p

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.

Gut dysbiosis caused by antibiotics impairs response to immune checkpoint blockade (ICB). Gut microbiota is becoming an attractive therapeutic target for cancer. The

Introduction The impact of immune checkpoint blockade on immunity in cancer patients is not completely elucidated due to the complexity of the immune network. Recent studies have revealed a significant role of programed cell death‐ligand 2 (PD‐L2) in negatively controlling the production of CD4+ T helper type 2 (Th2) cytokines and airway hypersensitiveness, suggesting hypo‐responsive Th2 cells via the PD‐1/PD‐L2 inhibitory pathway in lung could be reawaken by PD‐1 blockade therapy. Methods We describe the first report of acute eosinophilic pneumonia (AEP), which is known as Th2‐associated pulmonary disease, triggered by nivolumab, an anti‐PD‐1 antibody, in an advanced non‐small cell lung cancer patient. Based on the current case report and literature, the present study proposes a potential mechanism of the onset of AEP as an immune‐related adverse event (irAE). Results A 62‐year‐old man was diagnosed with lung adenocarcinoma and nivolumab was selected as the third‐line regimen. After three cycles of nivolumab treatment, chest computed tomography revealed pulmonary infiltrates in both lungs. The patient was diagnosed with AEP based on the diagnostic criteria for AEP. Nivolumab was suspended and the patient was started on oral prednisolone. His symptoms and radiological findings had rapidly improved. Conclusions Given the increasing frequency of the use of anti‐PD‐1 antibodies, clinicians should be aware of the risk of AEP as a potential irAE. This study may improve our understanding of the pathophysiology underlying Th2‐associated irAEs and AEP.

BACKGROUND/AIM The impact of interstitial lung disease (ILD) on the clinical outcome of patients with small-cell lung cancer (SCLC) is not fully understood. The aim of this study was to investigate the impact of ILD on treatment and survival outcomes of SCLC patients. PATIENTS AND METHODS A retrospective analysis was performed on the clinical outcomes of SCLC patients, treated with chemotherapy, with or without ILD ([ILD group (n=16) and non-ILD group (n=51)]. RESULTS Median PFS and OS were significantly shorter in the ILD group than in the non-ILD group (median PFS, 184 vs. 290 days, p=0.008; median OS, 236 vs. 691 days, p

PD-1 blockade therapy activates T cells by blocking the interaction between PD-1 and PD-L1 and promotes IFN-γ and Th1 cytokine production. In turn, IFN-γ and Th1 cytokines produced by activated T cells promote TF synthesis in monocytes/macrophages, which results in hypercoagulability leading to thrombosis.

Introduction Lung cancer mimicking organizing pneumonia (LCOP) is a novel radiological entity of lung adenocarcinoma that could be misdiagnosed as inflammatory lesions. However, the characteristic biological and genetic features of LCOP are not fully clarified. Materials and methods We used thin-section CT images to select cases of (LCOP) among surgically resected lung adenocarcinoma patients. We compared the clinicopathological characteristics and the immunophenotypes of LCOP (n = 44) and other lepidic-predominant adenocarcinomas (non-LCOP, n = 56). We also analyzed the genomic mutation features of LCOP (n = 4) by whole-exome sequencing (WES). Results All LCOP lesions were lepidic-predominant invasive adenocarcinoma. Patients with LCOP had significantly superior recurrence-free survival, compared to non-LCOP patients (95.5% and 74.4%; P = 0.006, respectively). Vascular invasion and lymph node metastasis were less frequent in LCOP than in non-LCOP patients (P = 0.001 and P = 0.03, respectively). The cancer cell expression levels of aggressiveness-related molecules, including ezrin, ALDH-1, laminin-5 were similar between LCOP and non-LCOP. On the contrary, the number of tumor promoting stromal cells, i.e., podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor associated macrophages, was significantly lower in LOCP (P = 0.021 and P = 0.037, respectively). WES revealed that ABCB1, DNAH3, MSI2, and SLITRK2 were specifically mutated in LCOP. Conclusions Our results indicate that LCOP is characterized by fewer tumor-promoting stromal cells, which may contribute to the better prognosis of LCOP patients. Moreover, recognition of specific somatic mutations of LCOP patients may provide information regarding the development and progression of this type of lung cancer.

Background: Acute exacerbation (AE) of interstitial pneumonia disease (ILD) in lung cancer (LC) patients with ILD could be one of the lethal adverse effect related to chemotherapy. The purpose of this study was to determine if the result of 18F-FDG PET/CT before chemotherapy could predict onset of chemotherapy-related AE-ILD in LC patients with ILD. Methods: Between April 2006 and March 2018, 33 patients with LC and ILD performed 18F-FDG PET/CT and treated with chemotherapy in Kumamoto University Hospital. The SUVmax of interstitial lesion was measured to quantify the background ILD activity. A prediction model chemotherapy-related AE of ILD was developed using a logistic regression and ROC curve analysis. Results: Among 33 patients, 7 experienced AE of ILD (AE group) and 26 did not (non-AE group), the SUVmax of contralateral interstitial lesion in AE group was significantly higher than that in non-AE group (median SUVmax 2.22 vs. 1.80, P = 0.041). An univariable logistic regression analysis showed that the SUVmax of contralateral interstitial lesion had potential to be associated with chemotherapy-related AE of ILD (odds ratio, 8.683; 95% confidence interval [CI], 0.88–85.83; P = 0.064). The AUC of the SUVmax for predicting chemotherapy-related AE of ILD was 0.780 (95% CI: 0.579-0.982, P = 0.025). The optimal cut-off value for SUVmax was 2.005. Sensitivity and specificity value for this cut-off point were 0.857 and 0.769, respectively. Conclusions: The SUVmax of contralateral interstitial lesion in 18F-FDG PET/CT might be useful to predict chemotherapy-related AE of ILD in LC with ILD.

We examined whether fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (Thirty-three patients with lung cancer and ILD who underwentAmong the 33 patients, 7 experienced AE-ILD. The SUVThe SUV

Background Acute exacerbation of interstitial lung disease (AE-ILD) is the most serious complication in lung cancer patients with pre-existing ILD receiving chemotherapy. The role of vascular endothelial growth factor (VEGF) in pathogenesis of AE-ILD is conflicting. The influence of bevacizumab (Bev), a monoclonal antibody against VEGF, on lung cancer patients with pre-existing ILD remains unclear. We examined the effect of Bev on reducing AE-ILD risk in non-squamous non-small cell lung cancer (NSCLC) patients receiving chemotherapy. Methods We analysed incidence of AE-ILD and outcomes of 48 patients with advanced non-squamous NSCLC with ILD who received first-line chemotherapy with (Bev group, n = 17) and without (non-Bev group, n = 31) Bev between July 2011 and July 2016. Gray’s test, which was competing risk analysis during the study period, was performed for both groups. Results The most common regimen used for first-line chemotherapy was the combination of carboplatin plus pemetrexed (PEM) in both groups. The incidences of chemotherapy-related AE-ILD 120 days after first-line chemotherapy initiation were significantly lower in the Bev than in the non-Bev groups (0% vs. 22.6%, p = 0.037, Gray’s test). However, there were no differences in development of progressive disease of lung cancer and other events as the competing risk factors of AE-ILD between the two groups. Only patients receiving PEM-containing regimens also showed a significant difference in the incidence of AE-ILD between the two groups (p = 0.044). The overall-cumulative incidence of AE-ILD during the first-line and subsequent chemotherapy was 29.2% (14 of the 48). The median progression-free survival was significantly longer in the Bev than in the non-Bev groups (8.0 vs. 4.3 months, p = 0.026). Conclusions The addition of Bev to chemotherapy regimens may reduce the risk of chemotherapy-related AE-ILD in patients with lung cancer. Electronic supplementary material The online version of this article (10.1186/s12890-019-0838-2) contains supplementary material, which is available to authorized users.

There is little information on the clinical outcome of patients with small-cell lung cancer (SCLC) treated with third-line chemotherapy. The purpose of this study was to clarify the prognostic factors of SCLC patients receiving third-line chemotherapy.Between November 2001 and October 2011, 202 of 648 consecutive SCLC patients at the National Cancer Center Hospital East received third-line chemotherapy. Multivariate Cox regression analysis was performed to identify the prognostic factors for overall survival after third-line chemotherapy.The demographics of the 202 patients were as follows: median age 66 years, 83% male, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2, and 3 values of 22, 122, 49, and 9, respectively. Median time to treatment failure after second-line chemotherapy (TTF2) was 4.5 months (TTF2 ≥ 5/5 months, 82/120). The median overall survival after third-line chemotherapy was 5.1 months. Multivariate Cox regression analysis showed that PS 0-1 (hazard ratio, 0.38; 95% confidence interval, 0.27-0.54; P .001) and TTF2 ≥ 5 months (hazard ratio, 0.57; 95% confidence interval, 0.41-0.79; P .001) were independent prognostic factors. TTF2 threshold of 5 months was determined on the basis of concordance probability adjusted by PS.PS 0-1 and TTF2 ≥ 5 months were associated with a favorable prognosis among SCLC patients receiving third-line chemotherapy. These 2 factors might be helpful for the selection of candidates for third-line chemotherapy and for patient stratification when conducting future clinical trials in the third-line setting.

Induction therapy induces degenerative changes of various degrees in both cancerous and non-cancerous cells of non-small cell lung cancer (NSCLC). The effect of induction therapy on histological characteristics, in particular the ratio of residual cancer cells to non-cancerous components, is unknown. Seventy-four NSCLC patients treated with induction therapy followed by surgery were enrolled. Residual cancer cells were identified using anti-pan-cytokeratin antibody (AE1/AE3). We analyzed and quantified the following three factors via digital image analysis; (1) the tumor area containing cancer cells and non-cancerous components (TA), (2) the total area of AE1/AE3 positive cancer cells (TACC), (3) the percentage of TACC to TA (%TACC). These factors were also analyzed in a matched control group (surgery alone, n = 80). The median TACC of the induction therapy group was significantly lower than that of the control group (p

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.

Tumor microenvironment critically affects cancer progression. This study aimed to identify differences in microenvironments of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations by histological subtypes.The study cohort included 214 lung adenocarcinomas harboring EGFR mutations. We analyzed clinicopathological characteristics of lepidic (LPA), papillary (PPA), acinar (APA), and solid-predominant adenocarcinoma (SPA) subtypes, and examined expression levels of EGFR, E-cadherin, ezrin, laminin-5, ALDH1, and PD-L1 in cancer cells, and of CD34, CD204, podoplanin (PDPN), and FoxP3 in stromal cells in 4 subtypes (n=20 each).SPA displayed significantly more frequent lymph node metastasis, lymphovascular invasion, and worse prognosis than the other subtypes. Ezrin expression levels in SPA were also significantly higher than in LPA, PPA, or APA (P0.05, all). Laminin-5 and PD-L1 expression levels in SPA were significantly higher than in LPA (P0.01 for both) and PPA (P0.01 for both) and tended to be higher than in APA (laminin-5: P=0.096, PD-L1: P=0.081). Furthermore, SPA displayed higher levels of PDPN (+) cancer-associated fibroblasts (P0.01) and CD204 (+) tumor-associated macrophages (P0.05) than the other subtypes.Compared with other predominant subtypes with EGFR mutations, the microenvironment of SPA with EGFR mutations is characterized by cancer cells with higher invasive and immune evasion potential and more abundant stromal cells with tumor-promoting functions, which would contribute to the more aggressive behavior of SPA.

Histological vascular invasion (VI) by tumors is a risk factor for recurrence after surgical resection. However, VI features vary histologically. The aim of this study was to identify characteristic VI features that are associated with recurrence in squamous cell carcinoma (SCC) of the lung.We enrolled 149 patients with pathological stage I primary lung SCC in this study and examined whether the presence, frequency, and size of VI were associated with recurrence. We also evaluated immunophenotypes of carcinoma cells and stromal cells within VI areas.Of the 149 patients, 58 had tumors with VI. The presence of VI was significantly correlated with shorter recurrence-free survival (RFS) (P = 0.018). Although VI frequency was not associated with RFS, larger VI size (425 µm) was significantly correlated with shorter RFS (P = 0.003). Carcinoma cells within larger VI areas expressed significantly higher levels of podoplanin, cancer stem cell marker (P = 0.039); higher numbers of CD34(+) microvessels (P = 0.009), CD204(+) macrophages (P = 0.026), and α-SMA(+) myofibroblasts (P = 0.056) were present within larger VI areas than within smaller VI ones.Our results indicate that larger VI areas are a predictor for recurrence in lung SCC; also, within the larger blood vessel, cancer stem cells and abundant stromal cells can create a more favorable microenvironment for tumor metastasis.

Background: EGFR signaling maintains aerobic glycolysis, but the molecular mechanism is still undefined. Results: Drug inhibition studies reveal that downstream signaling via the PI3K pathway is critical for glucose transport and metabolism. Conclusion: The PI3K signaling regulates key metabolic activities in EGFR-mutant lung adenocarcinoma. Significance: These data may guide the development of chemotherapeutic options, including targeting of the PI3K pathway and glucose transporter machinery., Oncogenic epidermal growth factor receptor (EGFR) signaling plays an important role in regulating global metabolic pathways, including aerobic glycolysis, the pentose phosphate pathway (PPP), and pyrimidine biosynthesis. However, the molecular mechanism by which EGFR signaling regulates cancer cell metabolism is still unclear. To elucidate how EGFR signaling is linked to metabolic activity, we investigated the involvement of the RAS/MEK/ERK and PI3K/AKT/mammalian target of rapamycin (mTOR) pathways on metabolic alteration in lung adenocarcinoma (LAD) cell lines with activating EGFR mutations. Although MEK inhibition did not alter lactate production and the extracellular acidification rate, PI3K/mTOR inhibitors significantly suppressed glycolysis in EGFR-mutant LAD cells. Moreover, a comprehensive metabolomics analysis revealed that the levels of glucose 6-phosphate and 6-phosphogluconate as early metabolites in glycolysis and PPP were decreased after inhibition of the PI3K/AKT/mTOR pathway, suggesting a link between PI3K signaling and the proper function of glucose transporters or hexokinases in glycolysis. Indeed, PI3K/mTOR inhibition effectively suppressed membrane localization of facilitative glucose transporter 1 (GLUT1), which, instead, accumulated in the cytoplasm. Finally, aerobic glycolysis and cell proliferation were down-regulated when GLUT1 gene expression was suppressed by RNAi. Taken together, these results suggest that PI3K/AKT/mTOR signaling is indispensable for the regulation of aerobic glycolysis in EGFR-mutated LAD cells.

Objectives: This study was designed to determine the recommended dose of carboplatin and pemetrexed for elderly (≥70-year-old) chemotherapy-naïve patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of pemetrexed. Methods: The patients were treated with 4-6 cycles of carboplatin plus a fixed dose of pemetrexed (500 mg/m2) every 3 weeks; the dose of carboplatin was escalated [from area under the curve (AUC) 4 to AUC 6]. To examine the pharmacokinetics of pemetrexed, blood samples were collected before and after pemetrexed infusion, and the blood levels of pemetrexed were measured by liquid chromatography-mass spectrometry. Results: Grade 3 infection as a dose-limiting toxicity was observed at a carboplatin dose of AUC 6. We therefore determined a carboplatin dose of AUC 5 and a pemetrexed dose of 500 mg/m2 as the recommended doses from this study. The pharmacokinetic study showed a significant inverse correlation between the AUC of pemetrexed and the creatinine clearance. Conclusions: For elderly chemotherapy-naïve patients with advanced nonsquamous NSCLC, the combination of carboplatin AUC 5 plus pemetrexed 500 mg/m2 is recommended as a promising regimen; however, a reduction of the pemetrexed dose may be required for patients with renal dysfunction because of the high risk of hematotoxicities. © 2014 S. Karger AG, Basel

Background: Anti-programmed cell death 1 (PD-1) monoclonal antibodies (Abs) unleash an immune response to cancer. However, a disruption of the immune checkpoint function by blocking PD-1/PD-ligand 1(PD-L1) signaling may trigger myasthenia gravis (MG) as a life-threatening immune-related adverse event. MG is a neuromuscular disease and is closely associated with being positive for anti-acetylcholine receptor (anti-AChR) Abs, which are high specific and diagnostic Abs for MG. Methods: A 72-year-old man was diagnosed with chemotherapy-refractory lung squamous cell carcinoma and nivolumab was selected as the third-line regimen. We describe the first report of an anti-AChR Ab-seropositive lung cancer patient achieving a durable complete response (CR) to an anti-PD-1 antibody therapy. To further explore this case, we performed multiplex immunofluorescence analysis on a pretreatment tumor. Results: The patient achieved a durable CR without developing MG. However, the levels of anti-AChR Abs were elevated during two years of anti-PD-1 antibody therapy. The tumor of the subclinical MG patient had high PD-L1 expression and an infiltrated⁻inflamed tumor immune microenvironment. Conclusions: This study suggests that immune checkpoint inhibitors can be safely used and provide the benefits for advanced cancer patients with immunologically ‘hot’ tumor even if anti-AChR Abs are positive. Although careful monitoring clinical manifestation in consultation with neurologist is needed, immune checkpoint inhibitors should be considered as a treatment option for asymptomatic anti-AChR Ab-seropositive cancer patients.

Histological vascular invasion (VI) is major predictor of recurrence after surgery for several cancer types. We previously reported that VI with abundant stromal cell infiltrates was a negative prognostic factor in lung adenocarcinoma. This study examined whether stromal cell infiltrates within VI are associated with prognosis in high-grade neuroendocrine carcinoma (HGNEC) of the lung. We investigated the relationship between the frequency and density of VI and recurrence-free survival (RFS) of 60 resected HGNEC patients without adjuvant chemotherapy. We examined prognostic effects of CD204 (+) macrophages, CD34 (+) microvessels and α-smooth muscle actin (+) myofibroblasts within VI. Correlation between expressions of stem cell-related molecules (ALDH-1, Notch 1, CD44) and epithelial–mesenchymal transition-related molecules (E-cadherin, S100A4) in cancer cells within VI and RFS was also analyzed. Among 60 cases, 51 cases showed VI. Although the presence of VI was a significant predictor for worse RFS (P = 0.04), the frequency and density of VI were not correlated with RFS. The number of CD204 (+) macrophage, CD34 (+) microvessels and α-smooth muscle actin (+) myofibroblasts within VI did not influence on the RFS. On the contrary, cases with higher Notch 1 expression in cancer cells in the VI displayed significantly shorter RFS than lower expression group (7.6 vs. 29.4 months, P = 0.02). The current study revealed the presence of stromal cells within VI was not significant predictor for recurrence in HGNEC. This suggests that in HGNEC, unlike adenocarcinoma, intravascular stromal cells are not major contributors to metastasis.

e20559 Background: Biomarkers predicting the efficacy and toxicity of bevacizumab (Bev) have not yet been established. Therefore we conducted this pharmacokinetic study to elucidate the role of plasma concentration of Bev as a biomarker to predict outcome in the treatment of patients with lung cancer. Methods: This multicenter prospective pharmacokinetic study was conducted among nine centers in Kumamoto Prefecture, Japan. Patients with non-squamous non-small cell lung cancer who were treated using tri-weekly Bev (15mg/kg) with platinum-doublet chemotherapy were enrolled. Plasma samples were collected from all patients before the administration of every dose of Bev until disease progression or treatment discontinuation owing to toxicity. Plasma concentrations of Bev were analyzed via nano-surface and molecular-orientation limited proteolysis coupled with liquid chromatography-mass spectrometry. Results: Between July 2010 and May 2014, 30 patients were enrolled in this study. Majority of the patients received pemetrexed with cisplatin or carboplatin (24 patients, 80%) and others received paclitaxel with carboplatin. The trough concentrations of Bev after first administration (day 22) were 63.19 ± 19.57 μg/mL. Trough concentrations gradually increased until the six cycle of Bev and reached a steady state. Plasma concentrations of Bev did not decrease until disease progression in patients with a long treatment period. Higher mean plasma concentrations of Bev correlated with female sex (p = 0.034) and high serum albumin levels (p = 0.034). Patients who received pemetrexed had higher mean concentrations of Bev (p = 0.038) than those who received paclitaxel. The response rate and progression-free survival did not correlate with the plasma concentration of Bev. Proteinuria (≥Grade 2) correlated with higher concentrations of Bev. Conclusions: Our study demonstrated that various types of chemotherapy influenced the concentrations of Bev, and a higher concentration of Bev may predict the incidence of proteinuria. In addition, clearance of Bev did not change after long treatment period until disease progression. Clinical trial information: 000007630.

In order to improve the lubricity and wear resistance of aluminum anodic oxide films, it is necessary to ensure the film layers are dense to prevent cracking, and to harden the films as well as reduce the shear stress of the film surfaces. From this view point, lubricious, hard anodic oxide films have been studied in the past, but fully satisfactory results have yet to be realized. In this paper, we report on our study of the re-anodizing of anodic oxide film in an aqueous solution of (NH)MoS. Molybdenum sulfide and compounds filled the 20-nm diameter pores of the film, creating internal stress which compressed the film, suppressing the occurrence of cracks and reducing the friction coefficient.

A study on color and far-infrared emissivity of anodic oxide film of strip cast Al–Mn based alloy was conducted. Sulfuric anodized film of strip cast Al–2.0%Mn alloy containing fine Al6Mn precipitates reveals black color. These precipitates do not oxidized during anodizing and exist as metallic Al6Mn phase in anodic film. A superior far-infrared emissivity was recognized on the black anodic film of strip cast Al–1.8%Mn alloy. The anodic film has very complex structure with irregular pore as the result of Al6Mn precipitates. Film hardness and resistance to heat crack was found also superior. A good radiation property of the black anodized film was confirmed. Application of far-infrared radiation contributes to effective heating and to saving energy.