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Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1–73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9–23.9) months. The median overall survival was not reached (95% confidence interval 24.6–not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

Background Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Although several ICI options are available, the treatment regimen for NSCLC with large tumors (large NSCLC) is controversial and the efficacy of anti-CTLA4 antibody is unclear. We thus investigated potential biomarkers for CTLA-4 blockade. Methods We examined the correlation between tumor diameter and treatment duration in advanced NSCLC patients treated with anti-PD-1 antibody in our institution. In addition, we evaluated the ratio of tumor-infiltrating CD8+ T cells and regulatory T (Treg) cells in small and large NSCLC using immunohistochemical staining. Finally, we investigated the efficacy of treatment containing anti-CTLA4 antibody against large NSCLC. Results We found a negative correlation between tumor diameter and treatment duration in patients treated with anti-PD-1 antibody. Immunohistochemical staining revealed that Treg cell infiltration was significantly higher in large NSCLC tumors than in small tumors. We obtained a remarkable tumor reduction in patients with large NSCLC with an ICI regimen including anti-CTLA4 antibody. Conclusions Anti-PD-1 antibody might be less effective for large NSCLC due to the infiltration of Treg cells. Therefore, for large NSCLC, it might be appropriate to select a treatment with anti-CTLA4 antibody, which is expected to deplete Treg cells via antibody-dependent cellular cytotoxicity activity.

Objectives Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1’s clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). Methods We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). Results In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P Conclusion A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.

Background Immune checkpoint inhibitors (ICIs) have provided more options in the treatment of lung cancer. However, ICIs can cause several unfavorable reactions generally referred to as immune-related adverse effects. Case presentation In this report, we present the case of a 52-year-old woman with successful regression of pleomorphic carcinoma of the lung following nivolumab therapy. She developed purpura fulminans (PF) ultimately resulting in amputation of both lower extremities. Blood tests revealed thrombocytopenia with increased serum soluble IL-2 receptor, ferritin, and triglyceride levels suggesting hemophagocytic lymphohistiocytosis (HLH). In addition, serum A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 activity was decreased, suggesting thrombotic thrombocytopenic purpura (TTP). Further detailed analysis revealed severe hypercytokinemia including increased levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, and G-CSF. Conclusion The severe systemic inflammatory reaction and impaired peripheral circulation in this patient was attributed to excessive immunological effect induced by nivolumab resulting in cytokine release syndrome (CRS). This is the first report of a patient with multiple pathological conditions including HLH, TTP-like condition, and PF presumably arising from ICI-induced CRS. Further accumulating thoroughly investigated cases would lead to better understanding of the disease and development of reliable cancer immunotherapy.

Objectives: Limited information is available on the appropriate treatment duration of immune checkpoint inhibitors (ICIs). We aimed to identify candidates who would benefit from ICI discontinuation after one year of treatment for metastatic non-small cell lung cancer (NSCLC). Materials and methods: This retrospective multi-institutional observational study examined medical records of all consecutive patients with advanced or recurrent NSCLC, who started ICI monotherapy at 15 institutions in Japan between December 2015 and December 2017. Patients who received initial ICI therapy for >1 year without progressive disease were defined as the long-term treatment (LT) group; others were defined as the non -longterm treatment (NLT) group. Primary outcomes included the prognostic factors in the LT group, whereas secondary outcomes included efficacy of ICI rechallenge, safety, and survival outcomes in the overall population. Results: In total, 676 patients were enrolled, and 114 (16.9 %) were assigned to the LT group. The median time interval from the start of initial ICI administration to data cutoff was 34.3 months (range, 24.1 & ndash;47.8); thus, all surviving patients were followed-up for at least 2 years from the start of initial ICI. Median progression-free survival (PFS) was longer in the LT than in the NLT group (33.6 months vs. 2.7 months; p < 0.001). On multivariate analysis, significantly better PFS was associated with smoking (hazard ratio [HR]=0.36, p = 0.04), and complete response (CR; HR=uncomputable, p < 0.001) in the LT group. Thirty-seven patients (5.5 %) received ICI rechallenge, including 10 in the LT group. Among patients receiving rechallenge treatment, the median PFS was 2.2 months, with no difference between the LT and NLT groups. Conclusions: In the LT group, smoking and achieving CR were significantly associated with better PFS. Since rechallenge treatment was not effective, careful consideration is required for discontinuing ICI. However, these prognostic factors are helpful in considering candidates for ICI discontinuation. Trial Registration: UMIN ID, UMIN000041403

OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)–NR] vs 13.2 months [9.1–17.2], p = .024; OS, NR [95% CI, NR–NR] vs 29.8 months [21.3–38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.

Objectives Few reports have explored clinical biomarkers, including those identified by targeted exome sequencing (TES) of surgically resected small-cell lung cancer (SCLC) and correlation with patient survival. Patients and methods We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC who had undergone surgery and analysed nonsynonymous somatic gene mutation profiles by TES of 26 cancer-related genes using next-generation sequencing (NGS) and web databases (UMIN Registration No. 000010117). Results We detected 38 nonsynonymous somatic tumor protein p53 (TP53) mutations in 43 (54.4%) patients. Among these TP53 lesions, we identified clinically relevant mutations including those encoding Y220C, R248W, R249M, M237I, and R273L substitutions in the p53 protein. These mutations have been reported to be associated with certain clinical outcomes or biology in other types of malignancies but not in SCLC. Moreover, nonsynonymous somatic mutations of TP53 were positively associated with relapse-free survival (RFS) (median, 17.33 months [95% confidence interval (CI), 3.86–30.79] in a mutation-positive group vs 10.39 months (6.96–13.82) in a mutation-negative group, p = 0.042). Multivariate analysis revealed that nonsynonymous somatic TP53 mutation was an independent factor of prolongation of RFS (hazard ratio: 0.51, 95% CI: 0.29–0.89, p = 0.019) but not overall survival (OS). Conclusion These data suggested that TES may play a critical role for promoting reverse-translational studies, including investigations of the biology of TP53 mutations in different stages of SCLC. Accumulation of the data using cancer panels with a broader range of genes, including TP53, is expected to be useful for future clinical applications for patients with SCLC., Bioinformatics; Genetics; Cancer research; Respiratory system; Clinical genetics; Surgery; Oncology; Clinical research; Small-cell lung cancer; Mutation; Next-generation sequencing; TP53.

Background: This study evaluated the efficacy and safety of switch maintenance erlotinib and bevacizumab after induction therapy with carboplatin/pemetrexed/bevacizumab for non-squamous non-small cell lung cancer (NSCLC) with wild-type EGFR. Methods: Enrolled patients had treatment-naive, advanced non-squamous NSCLC with wild-type EGFR. Carboplatin [area under the curve (AUC) 5.0], pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) were administered on day 1 every 3 weeks for 4-6 cycles. Maintenance therapy with erlotinib (150 mg/body) on day 1 through 21 plus bevacizumab on day 1 every 3 weeks was continued until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), toxicity, and quality of life (QOL). Results: Fifty-one patients were enrolled between September 2011 and June 2014. The median number of cycles for induction and maintenance therapy was 4 (range 1-6) and 4 (range 1-20). Twenty-nine patients (58%) received maintenance therapy. The 6-month PFS rate was 59.5% [95% confidence interval (CI) 45.0-72.6%]. The ORR was 48.0% (95% CI 34.8-61.5%), and disease control rate was 86.0% (95% CI 73.8-93.0%). The median PFS and OS were 6.5 months (95% CI 5.8-7.2 months) and 21.4 months (95% CI 15.9-26.9 months), respectively. Although grades ≥ 3 adverse events were observed in 33 patients (66.0%), most were hematologic; there was no febrile neutropenia. QOL was maintained throughout treatment. Conclusions: Carboplatin/pemetrexed/bevacizumab followed by erlotinib and bevacizumab maintenance showed modest efficacy and was well tolerated in non-squamous NSCLC patients with wild-type EGFR.

// Hajime Kikuchi 1 , Jun Sakakibara-Konishi 1 , Megumi Furuta 1 , Hiroshi Yokouchi 2 , Hiroshi Nishihara 3 , Shigeo Yamazaki 4 , Hidetaka Uramoto 5, 6 , Fumihiro Tanaka 5 , Masao Harada 7 , Kenji Akie 8 , Fumiko Sugaya 9 , Yuka Fujita 10 , Kei Takamura 11 , Tetsuya Kojima 12 , Toshiyuki Harada 13 , Mitsunori Higuchi 14, 15 , Osamu Honjo 9, 16 , Yoshinori Minami 17 , Naomi Watanabe 18 , Satoshi Oizumi 1, 7 , Hiroyuki Suzuki 15 , Takashi Ishida 2, 19 , Hirotoshi Dosaka-Akita 20 , Hiroshi Isobe 12 , Mitsuru Munakata 2 , Masaharu Nishimura 6 1 Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan 2 Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan 3 Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 4 Department of Thoracic Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan 5 Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu, Japan 6 Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Japan 7 Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan 8 Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan 9 Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan 10 Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan 11 Department of Medicine, Obihiro Kosei Hospital, Obihiro, Japan 12 Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan 13 Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan 14 Department of Thoracic Surgery, Fukushima Red Cross Hospital, Fukushima, Japan 15 Department of Thoracic Surgery, Fukushima Medical University, Fukushima, Japan 16 Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo, Japan 17 Respiratory Center, Asahikawa Medical University, Asahikawa, Japan 18 Department of Internal Medicine, Sunagawa City Medical Center, Sunagawa, Japan 19 Clinical Oncology Center, Fukushima Medical University Hospital, Fukushima, Japan 20 Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Correspondence to: Jun Sakakibara-Konishi, email: konishj@med.hokudai.ac.jp Keywords: small cell lung cancer, Notch1, Numb, immunohistochemistry, surgery Received: August 04, 2016 Accepted: December 12, 2016 Published: January 02, 2017 ABSTRACT Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.

Introduction: Corticosteroids are used to treat immune-related adverse events (irAEs) associated with nivolumab. However, patients with non-small-cell lung cancer who are administered corticosteroids before the initiation of nivolumab treatment are commonly excluded from clinical trials. The appropriate timing for corticosteroid administration in relation to nivolumab treatment, effects of corticosteroids on the efficacy of nivolumab, and resulting adverse events are not clearly understood. In this study, the effects of differences in the timing of corticosteroid administration on nivolumab efficacy and the resulting adverse events were examined. Methods: A retrospective study was conducted with 109 patients who were treated with nivolumab at Sapporo Minami-Sanjo Hospital between December 2015 and March 2018. Results: Of the 109 patients treated with nivolumab, 12 patients were administered corticosteroids before the first cycle of nivolumab (pre-CS), and 33 patients were administered corticosteroids after the first cycle of nivolumab (post-CS). These 2 groups were compared with the control group comprising 64 patients who were not administered corticosteroids (non-CS). The objective response rate in the post-CS group was significantly higher than that in the non-CS group, and the disease control rate in the pre-CS group was significantly lower than that in the non-CS group. The overall survival time and progression-free survival time in the pre-CS group were significantly shorter than those observed in the non-CS group; however, these did not differ from those in the post-CS group. Conclusions: These results suggest that corticosteroids administered to patients with non-small-cell lung cancer after initiation of nivolumab treatment did not affect the disease prognosis. Thus, corticosteroids can be administered immediately for rapid treatment of irAEs.

// Hiroshi Yokouchi 1 , Hiroshi Nishihara 2 , Toshiyuki Harada 3 , Takashi Ishida 1,4 , Shigeo Yamazaki 5 , Hajime Kikuchi 6 , Satoshi Oizumi 6,7 , Hidetaka Uramoto 8,9 , Fumihiro Tanaka 8 , Masao Harada 7 , Kenji Akie 10 , Fumiko Sugaya 11 , Yuka Fujita 12 , Kei Takamura 13 , Tetsuya Kojima 14 , Mitsunori Higuchi 15,16 , Osamu Honjo 11,17 , Yoshinori Minami 18 , Naomi Watanabe 19 , Aya Goto 20 , Hiroyuki Suzuki 16 , Hirotoshi Dosaka-Akita 21 , Hiroshi Isobe 14 , Masaharu Nishimura 6 and Mitsuru Munakata 1 1 Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan 2 Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 3 Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan 4 Clinical Oncology Center, Fukushima Medical University Hospital, Fukushima, Japan 5 Department of Thoracic Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan 6 First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan 7 Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan 8 Second Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu, Japan 9 Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Japan 10 Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan 11 Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan 12 Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan 13 First Department of Medicine, Obihiro Kosei Hospital, Obihiro, Japan 14 Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan 15 Department of Thoracic Surgery, Fukushima Red Cross Hospital, Fukushima, Japan 16 Department of Thoracic Surgery, Fukushima Medical University, Fukushima, Japan 17 Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo, Japan 18 Respiratory Center, Asahikawa Medical University, Asahikawa, Japan 19 Department of Internal Medicine, Sunagawa City Medical Center, Sunagawa, Japan 20 Center for Integrated Science and Humanities, Fukushima Medical University, Fukushima, Japan 21 Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Correspondence to: Hiroshi Yokouchi, email: // Keywords : small-cell lung cancer, surgery, MED12, c-kit, immunohistochemistry Received : June 13, 2016 Accepted : December 01, 2016 Published : December 31, 2016 Abstract The limited number of available treatments for patients with small-cell lung cancer (SCLC) has prompted us to further investigate the biology of SCLC by molecular profiling. We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-βRII) by immunohistochemistry (IHC). Of the 125 evaluable samples, all tumors expressed MED12, and 123 samples (98.4%) expressed TGF-βRII. MED12 was highly expressed in the nucleus in 92% of the positive samples while TGF-βRII was highly expressed in the cytoplasm in 55% of the positive samples. High c-kit expression was an independent favorable prognostic marker confirmed by multivariate analysis (hazard ratio: 0.543, 95% confidence interval: 0.310–0.953, p = 0.033). Both the relapse free-survival and overall survival of patients who underwent adjuvant chemotherapy were statistically longer in those with high c-kit expression (n = 38) than those with intermediate, low, or no c-kit expression ( n = 19) (not reached vs 11.6 months, p = 0.021; not reached vs 25.9 months, p = 0.028). IHC for c-kit may offer a prognostic marker for early-stage SCLC, and the results for MED12 and TGF-βRII may suggest the biological characteristics of SCLC. Further investigation of the roles of their related molecules in early stage SCLC is required.

Background Since osimertinib significantly prolonged progression free survival compared with conventional EGFR-TKI and was well-tolerated, it was approved in August 2018 as the primary treatment in EGFR mutation positive non-small cell lung cancer. In this study, we compared the safety of osimertinib administration after the primary and secondary treatments. Method 73 patients with non-small cell lung cancer who received osimertinib from March 2016 to February 2019 were investigated after the follow-up and the adverse events were compared between the first-line treatment (1stOsi) group and the previously treated T790M positive (≥2ndOsi) group. Adverse events were assessed with CTCAE v4.0. Result The median age of the 1stOsi group (n = 23) was 74 years, male: 6 (26%) / female: 17 (74%), the median age of ≥ 2ndOsi group (n = 50) was 70 years, male: 15 (30%) / female 35 (70%). When comparing 1stOsi group with ≥2ndOsi group, significant difference was found between stomatitis [8 (35%) vs 7 (14%), P = 0.04], fatigue [0 (0%) vs 8 (16%), P = 0.04], thrombocytopenia [6 (26%) vs 26 (52%), P = 0.04], anemia [7 (30%) vs 29 (58%), P = 0.03]. Significant difference was observed in adverse events of Grade 3≤ tended to be more frequent in ≥ 2ndOsi group than in 1stOsi group (30% vs 52%, P = 0.08). Discussion From the results, it was found that the administration of osimertinib as the primary treatment showed more frequent rash and stomatitis oral, and the frequency of bone marrow suppression was less frequent as compared with the secondary treatment. In addition, no new adverse event profile is developed and the extent is also mild, so we can deal with the conventional patient education.

Background Non-small cell lung cancer (NSCLC) is characterized by a high incidence of brain metastasis (BM) and the prognosis of NSCLC patients with BM is poor. Previous study demonstrated four prognostic factors, which were age, poor PS, presence of extracranial metastases (ECM), and number of BM, in NSCLC patients with BM. This study aimed to identify prognostic factors and clarify the survival in NSCLC patients with BM at the time of a diagnosis. Methods A total of 566 NSCLC patients with BM from 15 institutions between January 2008 and December 2014. Among them, 176 patients had driver mutation, such as EGFR mutation and ALK-rearrangement, and 390 patients did not. This retrospective study focused on the 390 NSCLC patients without driver mutation, and identified clinical prognostic factors using Cox proportional hazards model. Moreover, we validated the disease specific Graded prognostic assessment (DS-GPA) in this cohort. Results Median OS was 7.6 months, respectively (95% confidence interval [CI]; 6.5-8.7, data cut-off; December 2018). Multivariate analyses demonstrated the following independent prognostic factors; gender male (P = 0.001), age > 64 years (P = 0.009), poor PS (P Conclusions Prognosis of NSCLC patients with EGFR, ALK negative and BM is poor. In addition to the known prognostic factors such as DS-GPA, this study shown that male, T factor, N factor, and histological type of non-adenocarcinoma, had a prognostic role in NSCLC patients with driver mutation negative and BM. Clinical trial identification UMIN000030313, 08/12/2017. Legal entity responsible for the study Hokkaido Lung Cancer Clinical Study Group Trial: HOT. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses.To explore novel severe asthma phenotypes by cluster analysis when including smoking patients with asthma.We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters.Five clinical clusters, including two characterized by low forced expiratory volume in 1 second/forced vital capacity, were identified. When characteristics of smoking subjects in these two clusters were compared, there were marked differences between the two groups: one had high levels of circulating eosinophils, high immunoglobulin E levels, and a high sinus score, and the other was characterized by low levels of the same parameters. Sputum analysis revealed intriguing differences of cytokine/chemokine pattern in these two groups. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 3 years later.This study reveals two distinct phenotypes with potentially different biological pathways contributing to fixed airflow limitation in cigarette smokers with severe asthma.

This phase II study evaluated the response rate (RR) and safety of combination therapy with carboplatin (CBDCA) and pemetrexed (PEM) in Japanese patients with non-squamous non-small cell lung cancer (non-sq NSCLC). Further, the relationship between therapy efficacy/toxicity and genetic polymorphisms associated with PEM metabolism was analyzed. Forty-one patients received CBDCA at a dose targeting an area under the concentration–time curve of 5 mg/mL × min and PEM of 500 mg/m2 on day 1 every 3 weeks. Single-nucleotide polymorphisms of the thymidylate synthase (TYMS) coding gene, the variable number of tandem repeat (VNTR) in the TYMS, and the methylenetetrahydrofolate reductase (MTHFR) coding gene were analyzed. The overall RR was 36.6 %. Median progression-free survival and median survival time were 4.7 months [95 % confidence interval (CI) 3.9–5.6 months] and 16.2 months (95 % CI 6.1–26.2 months), respectively. Epidermal growth factor receptor gene mutations were detected in 6 patients (14.6 %). The VNTR in the TYMS significantly correlated with anemia (p = 0.047) and thrombocytopenia (p = 0.038). This combination therapy was effective and tolerable in patients with advanced non-sq NSCLC. The VNTR in the TYMS appears to be a predictive factor for anemia and thrombocytopenia in patients treated with this regimen.

Several American and Japanese guidelines recommend surgery for patients with c-stage I small-cell lung cancer (SCLC), whereas the European Society of Medical Oncology (ESMO) guidelines recommend surgery for patients with not only c-stage I but also c-stage II (T2N1) SCLC. In addition, previous studies identified various factors other than clinical stage that are related to survival in these patients. Thus, further validation and examination of the association of clinical stage and other clinical variables with survival are required for establishing practical management of early-stage SCLC.We reviewed the clinical courses of 156 SCLC patients who had undergone surgery at 17 institutions between January 2003 and January 2013.Clinical stages (tumor-node-metastasis [TNM] version 7) of the 156 patients were 98 cases in IA, 14 in IB, 16 in IIA, 7 in IIB, 18 in IIIA, and 3 in IIIB. Median overall survival (OS) was 33.3 months (95% confidence interval: 20.9-45.8). Multivariate analysis revealed that OS was longer in patients either at c-stage II and under, with a maximum tumor diameter of20mm, with preoperative diagnosis, without a history or presence of other types of cancer, or who underwent prophylactic cranial irradiation (PCI).These results indicate that a history or presence of other types of cancer might be a major decisive factor for surgery. Patients with c-stages I and II (c-T2N1) can be considered for surgery, and PCI may be useful in patients undergoing surgery in a practical setting, partly supporting the ESMO guidelines.(1).

背景. 急速な腫瘍の増大を示した右肺上葉原発の多形癌を経験した. その臨床的, 病理学的特徴を検討し報告する. 症例. 66歳男性. 胃癌術後フォローアップ中の胸部CTにて腫瘤陰影を指摘された. 原発性肺癌が疑われたが, 気管支鏡下生検では確定診断を得られなかった. 陰影発見から2ヶ月半後のCTにおいて, 腫瘍は径2cmから7cmへと急激な増大を認めた. 骨シンチ等にて左大腿骨遠位端に異常所見がみられ骨転移を第一に疑ったが, 他の検査で異常は認められず局所コントロールの必要性を考慮し右肺上葉切除を行った. 切除標本病理検査で「多形癌」と診断された. 術後5ヶ月目に脳転移が出現し放射線治療を施行したが, 一時的な反応がみられたものの十分な効果は得られず, 照射8ヶ月後に脳転移巣を外科的に切除した. 現在のところ局所再発はみられておらず, 全身状態は良好で社会復帰ができている. 結論. 多形癌は悪性度の高い腫瘍であり手術適応には十分な検討が必要であるが, 症例によっては原発巣, 転移巣ともに外科的切除が, 局所コントロールや症状緩和などの点で有益かつ有効な治療手段となりうる可能性が示唆された.

Background: Notch signaling plays an important role in tumorigenesis. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. Methods: We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Results: Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC (hazard ratio = 0.503, P = 0.023). Conclusions: We demonstrate that Notch1 expression, but not Numb, is associated with prognosis in SCLC and may provide a novel prognostic marker of SCLC. Citation Format: Hajime Kikuchi, Jun Sakakibara-Konishi, Megumi Furuta, Hiroshi Yokouchi, Hiroshi Nishihara, Shigeo Yamazaki, Uramoto Hidetaka, Fumihiro Tanala, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Toshiyuki Harada, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Satoshi Oizumi, Hiroyuki Suzuki, Takashi Ishida, Hiotoshi Dosaka-Akita, Hiroshi Isobe, Mitsuru Munakata, Masaharu Nishimura. Expression of Notch1 and Numb in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4735. doi:10.1158/1538-7445.AM2017-4735

Aim: NCCN and Japanese guidelines suggest surgery for patients with c-stage I small-cell lung cancer (SCLC), and ESMO guidelines recommend surgery for patients with c-stage II (T1,2 N0,1). However, the clinical impact of surgery with other variables on patients with early stage SCLC has yet to be determined. Therefore, clarification of the clinical and molecular profile of surgically resected SCLC is required. We expanded the number of patients and updated the clinical data which had been presented at ASCO 2014 (abstract #7590). Methods: We reviewed the clinical courses of 156 patients with SCLC who had undergone surgery at 17 institutes from January 2003 to January 2013. 125 formalin-fixed paraffin-embedded tissue samples were subjected to immunohistochemistry using 8 antibodies and to next-generation sequencing (NGS) systems using MiSeq and TruSight Tumor Sequencing Panel (Illumina) loading 26 genes. (UMIN registration No. 000010116 /10117). Results: Median relapse-free survival (RFS) and overall survival (OS) were 15.6 (95%CI: 6.8-24.5), and 33.3 (20.9-45.8) months, respectively. Multivariate analysis revealed that OS was longer in patients without history of malignancy (HR: 0.459, 95%CI: 0.248-0.847, p=0.013), with preoperative diagnosis (HR: 0.529, 95%CI: 0.293-0.953, p=0.034), and with c-stage II and under (HR: 0.117, 95%CI: 0.047-0.288, p Conclusions: These results support the ESMO guidelines for the management of c-stage II small-cell lung cancer, and indicate that history of malignancy might be a major decisive factor for surgery. The results of immunohistochemistry assist us in gaining a better understandingof the biology of SCLC. Disclosure: All authors have declared no conflicts of interest.

7590 Background: NCCN and Japanese guidelines suggest surgery for patients with c-stage I small-cell lung cancer (SCLC). However, the clinical impact of surgery with other variables on patients wit...