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Background A cisplatin plus irinotecan (CPT‐11) regimen is used for patients with extensive disease small cell lung cancer (ED‐SCLC). Amrubicin (AMR) is primarily used for relapsed SCLC. The HOT1401/NJLCG1401 trial, an open‐label randomized phase II trial, was designed to assess the benefit of maintenance therapy in patients with ED‐SCLC who responded to induction therapy. Methods Patients with histologically‐ or cytologically‐confirmed ED‐SCLC were included and were treated with an induction therapy of four cycles of cisplatin (60 mg/m2 on day 1) plus CPT‐11 (60 mg/m2 on days 1, 8, and 15) every four weeks. After induction therapy, patients who had nonprogressive disease were randomized to receive either maintenance CPT‐11 (60 mg/m2 on days 1 and 8) every three weeks, or AMR (35 mg/m2 on days 1–3) every three weeks. Results A total of 34 patients were enrolled; 20 patients had progressive disease or received incomplete induction chemotherapy. Finally, 14 patients were randomly assigned to receive CPT‐11 (n = 7) or AMR (n = 7). This study was terminated prematurely because of low patient accrual. The overall objective response rate was 73%, the median PFS was 5.7 months (95% confidence interval [CI]: 3.6–11.8), and the median overall survival was 20.1 months (95% CI: 13.7–not reached). No statistically significant difference in progression‐free survival (PFS) were noted between patients treated with CPT‐11 and those treated with AMR. There were no treatment‐related deaths in this study. Conclusions Maintenance therapy with CPT‐11 or AMR after induction therapy might be effective in some patients., There were some patients who achieved long disease control. Maintenance therapy with CPT‐11 or AMR after induction therapy could have potential for treating ED‐SCLC.

Introduction Despite the extensive use of the combination of cytotoxic chemotherapy and programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors for cancer treatment, the incidence and characteristics of pneumonitis caused by this combination therapy have not been examined in clinical settings. Methods We conducted a 36-centre, retrospective cohort study in patients with chemo-naive advanced non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed and pembrolizumab between December 2018 and June 2019. Results The study comprised 299 patients. The most frequent grade ≥3 non-hematologic adverse event was pneumonitis. There were 37 patients (12.4%, 95% CI 8.9–16.7) with all-grade pneumonitis and 10 (3.3%, 95% CI 1.6–6.1) with grade ≥3 pneumonitis. Of these, 21 (7.0%, 95% CI 4.4–10.5) and 9 patients (3.0%, 95% CI 1.4–5.6) developed all-grade and grade ≥3 pneumonitis within 90 days after initiating the combination therapy, respectively. The median time to treatment failure and progression-free survival was 5.9 (95% CI 5.0–6.8) and 7.5 (95% CI 6.5–8.7) months, respectively. In the survival analysis after adjusting for immortal time bias, pneumonitis was independently associated with shorter progression-free survival (HR 1.99, 95% CI 1.07–3.69, P = 0.03) and overall survival (HR 3.03, 95% CI 1.12–8.20, P = 0.03). Conclusions Treatment-related pneumonitis occurred at a higher rate in the real-world population than that reported previously; it led to worse survival outcomes. Pneumonitis requires more attention. Additional studies are required to improve the safety of this combination therapy. Trial registration number UMIN000038084

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 Nivolumab is known to demonstrate superior overall survival compared with docetaxel in pretreated non‐small cell lung cancer (NSCLC) patients. Programmed death‐ligand 1 (PD‐L1) expression is reported to predict the outcome of treatment by nivolumab in lung cancer patients. However, the significance of the morphological characteristics of chest computed tomography (CT) as predictors of nivolumab efficacy for advanced NSCLC patients remains unknown. Methods We performed a multicenter retrospective trial from April 2013 to March 2017, to assess the significance of CT morphological characteristics as predictors of nivolumab efficacy for advanced NSCLC patients. A total of 78 NSCLC patients pretreated with nivolumab were enrolled. A chest radiologist used chest CT to assess the following morphological characteristics of each patient's main tumor and intrathoracic status prior to nivolumab treatment; interstitial septal thickening, peritumoral ground‐glass opacity, spiculated margin, air bronchogram, cavity or necrosis, adjacent organ invasion, bulky lymph node, and accumulation of small lymph nodes. Logistic regression and Cox proportional hazards regression models were used to analyze outcomes. Results A total of 60 (77%) patients were male and 72 (92%) had a performance status (PS) of 0 or 1. The objective response rates of male patients and heavy smokers were significantly higher than those of female patients and light or never smokers, respectively. Multivariate analysis identified light or never smoking, poor PS, histological type of squamous cell carcinoma, and interstitial septal thickening as independent negative predictors of progression free survival (PFS). Conclusions Interstitial septal thickening was a significant and independent predictor of PFS in NSCLC patients treated with nivolumab. Key points Significant findings of the study Interstitial septal thickening is an independent predictor of progression free survival in non‐small lung cancer patients treated with nivolumab. What this study adds The current study reveals the significance of morphological characteristics obtained via chest computed tomography as a predictor of nivolumab efficacy for advanced non‐small cell lung cancer patients., Interstitial septal thickening is an independent predictor of progression‐free survival in non‐small lung cancer patients treated with nivolumab.

Objectives Patients with concomitant advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are excluded from most clinical chemotherapy trials because of the high risk of exacerbating the latter condition. This study prospectively investigated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in patients with both advanced NSCLC and ILD. Patients and methods The enrolled patients had treatment-naive, advanced NSCLC with ILD. Patients received 100 mg/m2 nab-paclitaxel weekly and carboplatin at an area under the concentration-time curve of 6 once every 3 weeks for 4–6 cycles. The primary endpoint was the overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Results Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had adenocarcinoma, 15 (41.7%) had squamous cell carcinoma (Sq), and 5 (13.9%) had non-small cell carcinoma. The median number of cycles administered were 4 (range: 1–6). The ORR was 55.6% (95% confidence interval [CI]: 39.6–70.5). The median PFS and OS were 5.3 months (95% CI: 3.9–8.2) and 15.4 months (95% CI: 9.4–18.7), respectively. A greater proportion of patients with Sq experienced improvements than did those with non-Sq: ORRs, 66.7% (95% CI: 41.7–84.8) vs. 47.6% (95% CI: 28.3–67.6) (P = 0.254); median PFS, 8.2 months (95% CI: 4.0–10.2) vs. 4.1 months (95% CI: 3.3–5.4) (HR, 0.60 [95% CI, 0.30–1.20]; P = 0.15); and median OS, 16.8 months (95% CI: 9.8–not reached) vs. 11.9 months (95% CI: 7.3–17.4) (HR, 0.56 [95% CI, 0.24–1.28]; P = 0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and 1 patient (2.8%) died. Conclusion Weekly nab-paclitaxel combined with carboplatin showed favorable efficacy with acceptable toxicity in patients with both advanced NSCLC and ILD.

Background Delta-like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete-scute homolog-1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early-stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. Materials and Methods We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. Results Seventy-seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3-high expression (≥75%) was observed in 44 samples (47%). Sixty-one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease. Conclusion DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC. Implications for Practice This article examines the relationship between delta-like protein 3 (DLL3) and achaete-scute homolog-1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early-stage SCLC, including with Rova-T.

Introduction YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study. Methods The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest). Results The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab—groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths. Conclusions The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated.

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: Decorin is a small leucine-rich repeat proteoglycan that plays a critical role in collagen fibrillogenesis, and regulates inflammation, wound healing and angiogenesis. In idiopathic pulmonary fibrosis (IPF), decorin is expressed in fibrotic lesions; furthermore, intratracheal gene transfer of decorin has been demonstrated to inhibit bleomycin-induced pulmonary fibrosis. Although these results suggest the critical role of decorin in pulmonary fibrosis, the role of decorin in the acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) has not been clarified in detail. Thus, the goal of this study was to determine the role of decorin in AE-IIP. Methods: We retrospectively analyzed AE-IIP patients who had been admitted to our hospital. First, serum decorin levels were compared among patients with AE-IIP, patients with stable idiopathic interstitial pneumonia (SD-IIP), and healthy subjects. Next, the relationship between serum decorin levels and clinical parameters was analyzed in AE-IIP patients. Finally, the association between serum decorin levels and prognosis was evaluated in AE-IIP patients. IIP was divided into IPF and non-IPF, according to the published guidelines. Results: The serum decorin levels of AE-IIP patients were significantly lower than those of both healthy subjects and SD-IIP patients. Serum decorin levels were not related with the clinical parameters and prognosis, when all IIP patients were analyzed. In IPF patients, serum decorin levels had a significant correlation with oxygenation, and IPF patients with low serum decorin levels had a significantly higher survival rate than those with high serum decorin levels. Conclusions: Serum decorin levels are a potential prognostic biomarker in AE-IPF.

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.

The uncommon mutations in the EGFR (the epithelial growth factor receptor) gene include a heterogeneous group of genomic alterations within exons 18-21. The clinical response of patients with such mutations to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment, however, remains unclear. We herein report a case of advanced lung adenocarcinoma harboring complex exon 18 G719X (Gly719Xaa) and exon 20 S768I (Ser768Ile) mutations. The patient started to receive afatinib and has exhibited good response without progression for 12 months. Second-generation EGFR-TKIs might be an optimal treatment option for non-small cell lung cancers harboring these types of rare EGFR mutation.

Background Cisplatin is a key drug in lung cancer therapy. However, cisplatin is also well known to induce gastrointestinal disorders, such as chemotherapy-induced nausea and vomiting, anorexia, and weight loss. These symptoms sometimes affect patients’ quality of life and make continuation of chemotherapy difficult. Anorexia is a cause of concern for patients with cancer because a persistent loss of appetite progresses to cancer cachexia. Although evidence-based management for chemotherapy has recently been established, there is room for improvement. Methods/design This placebo-controlled, double-blind, randomized trial will aim to determine the efficacy of the traditional Japanese Kampo medicine rikkunshito (TJ-43) for preventing anorexia caused by cisplatin-including chemotherapy in patients with lung cancer. Patients with lung cancer who plan to receive cisplatin-including chemotherapy will be recruited. Patients who provide written consent will be randomly allocated to receive either TJ-43 (arm A) or placebo (arm B) for one course of chemotherapy (21 or 28 consecutive days). Investigators and patients will be masked to the treatment assignment throughout the trial. The primary endpoint will be evaluated as the change in dietary intake from day 0 (the day before the start of chemotherapy) to day 7 of cisplatin-including chemotherapy. The two arms of the trial will comprise 30 patients each. From November 2014, a total of 60 patients will be recruited, and recruitment for the study is planned to be complete by October 2017. Discussion This trial is designed to examine the efficacy of rikkunshito (TJ-43) for reducing anorexia and maintaining food intake caused by cisplatin-including chemotherapy in patients with lung cancer. Trial registration Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC CTI), trial registration: JAPIC CTI-142747. Registered on 15 December 2014; the RICH trial. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2227-6) contains supplementary material, which is available to authorized users.

Purpose Amrubicin is one of the most active chemotherapeutic drugs for small cell lung cancer (SCLC). Previous studies reported its effectiveness and severe hematological toxicity. However, the efficacy of amrubicin monotherapy in elderly patients with SCLC has not been described. The objective of this study was to investigate the feasibility of amrubicin monotherapy in elderly patients and its efficacy for relapsed SCLC. Methods A retrospective cohort study design was used. We retrospectively evaluated the clinical effects and adverse events of amrubicin treatment in elderly (≥70 years) SCLC patients with relapsed SCLC. Results Between November 2003 and September 2015, 86 patients (aged ≥70 years) received amrubicin monotherapy for relapsed SCLC at four institutions. There were 42 cases of sensitive relapse (S) and 44 of refractory relapse (R). S cases with median age of 75 years (range 70–85 years) and R cases with median age of 74 years (range 70–84 years) were included in our analysis. The median number of treatment cycles was three (range 1–9), and the response rate was 33.7% (40.5% in the S and 27.2% in the R cases). Median progression-free survival time was 4.0 months in the S and 2.7 months in the R patients (p = 0.013). Median survival time from the start of amrubicin therapy was 7.6 months in the S and 5.5 months in the R cases (p = 0.26). The frequencies of grade ≥3 hematological toxicities were as follows: leukopenia, 60.4%; neutropenia, 74.4%; anemia, 11.6%; thrombocytopenia, 16.2%; and febrile neutropenia, 17.4%. Treatment-related death was observed in one patient. Conclusion Although hematological toxicities, particularly neutropenia, were severe, amrubicin showed favorable efficacy, not only in the S but also in the R cases, as shown in previous studies. Amrubicin could be a preferable standard treatment in elderly patients with relapsed SCLC. These results warrant further evaluation of amrubicin in elderly patients with relapsed SCLC by a prospective trial. Electronic supplementary material The online version of this article (doi:10.1007/s00280-017-3403-9) contains supplementary material, which is available to authorized users.

// 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.

Ectopic extrarenal renin-producing tumor is a rare disease with approximately 30 case reports in English literature. We herein present the first case of renin-producing germ cell tumors in the pineal apparatus and mediastinum. A 26-year-old man who had undergone craniotomy for the treatment of pineal tumor was found to have hypertension at a regular visit postoperatively. Laboratory findings revealed high plasma levels of renin activity and that of aldosterone concentration. Chest computed tomography demonstrated a large tumor in the mediastinum. The pathological findings revealed the mediastinal germ cell tumor positive for renin. The present case suggests that for young patients presenting with hypertension with a mediastinal tumor, the possibility of a renin-producing tumor should be considered.

// 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.

We recently reported an increase in dicentric chromosome (DIC) formation after a single computed tomography (CT) scan (5.78–60.27 mSv: mean 24.24 mSv) and we recommended analysis of 2000 metaphase cells stained with Giemsa and centromere-FISH for dicentric chromosome assay (DCA) in cases of low-dose radiation exposure. In the present study, we analyzed the frequency of chromosome translocations using stored Carnoy's-fixed lymphocyte specimens from the previous study; these specimens were from 12 patients who were subject to chromosome painting of Chromosomes 1, 2 and 4. Chromosomes 1, 2 and 4 were analyzed in ∼5000 cells, which is equivalent to the whole-genome analysis of almost 2000 cells. The frequency of chromosome translocation was higher than the number of DICs formed, both before and after CT scanning. The frequency of chromosome translocations tended to be higher, but not significantly higher, in patients with a treatment history compared with patients without such a history. However, in contrast to the results for DIC formation, the frequency of translocations detected before and after the CT scan did not differ significantly. Therefore, analysis of chromosome translocation may not be a suitable assay for detecting chromosome aberrations in cases of low-dose radiation exposure from a CT scan. A significant increase in the frequency of chromosome translocations was not likely to be detected due to the high baseline before the CT scan; the high and variable frequency of translocations was probably due to multiple confounding factors in adults.

The herbal medicine rikkunshito has the potential to improve chemotherapy-induced nausea and vomiting (CINV) by stimulating ghrelin secretion. We aimed to evaluate the efficacy and safety of rikkunshito in preventing CINV for patients with lung cancer. Two separate prospective, randomized, phase II parallel design studies were conducted in patients with lung cancer. Fifty-eight and sixty-two patients scheduled to receive highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), respectively, were randomized 1:1 to receive either standard antiemetic therapy in accordance with international guidelines (S group) or standard antiemetic therapy plus oral rikkunshito (R group). The primary endpoint was overall complete response (CR)—that is, no emesis and rescue medication in the first 120 h post-chemotherapy. Secondary endpoints included CR in the acute (0–24 h) and delayed (>24–120 h) phases and safety. Fifty-seven patients (S group, 28; R group, 29) receiving HEC and sixty-two patients (S group, 30; R group, 32) receiving MEC with comparable characteristics were evaluated. The CR rates were similar across the S and R groups for the HEC study in the overall (67.9% vs. 62.1%), acute (96.4% vs. 89.6%), and delayed (67.9% vs. 62.1%) phases, respectively, and for the MEC study in the overall (83.3% vs. 84.4%), acute (100% vs. 100%), and delayed (83.3% vs. 84.4%) phases, respectively. No severe adverse events were observed. Although rikkunshito was well tolerated, it did not demonstrate an additional preventative effect against CINV in lung cancer patients receiving HEC or MEC.Clinical Trial Registry Information: This study is registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry1, identification numbers UMIN 000014239 and UMIN 000014240.

Background Cisplatin plus irinotecan (PI) regimen is used for patients with extensive disease (ED)-SCLC. Amrubicin is mainly used for relapsed SCLC. HOT1401/NJLCG1401 trial, open-label randomized phase II trials was designed to assess the benefit of maintenance therapy in patients with ED-SCLC who responded induction therapy. Methods Eligible patients were aged 20-74 years; had histologically or cytologically confirmed, ED-SCLC. After induction therapy PI (P: 60mg/m2 on day 1, I: 60mg/m2 on days 1, 8, 15, every 4 weeks for 4 cycles), patients who attained CR, PR and SD were randomized to either maintenance irinotecan (I: 60mg/m2 on days 1, 8, every 3 weeks) or amrubicin (A: 35 mg/m2 on days 1-3 every 3 weeks). The primary endpoint is 6-months PFS rate. Results A total of 34 patients were enrolled from 2014 to 2017. Twenty patients had disease progression or incomplete of induction chemotherapy, finally 14 (41.1%) patients were randomly assigned to receive irinotecan (n = 7) and amrubicin (n = 7). This study was terminated prematurely because of low patient accrual. Of the evaluable patients (n = 34) the overall objective response rate was 73%, median progression free survival was 5.7 months (95% CI: 3.6 -11.8), and median overall survival was 20.1 months (95% CI: 13.7-NR). Six months PFS rate was 47 % (95%CI: 31.4-63.2). Sub group analysis showed the patients receive maintenance group showed longer PFS and OS than those without (15.8 months and 3.5 months, respectively p Conclusions Maintenance therapy of irinotecan or amrubicin after induction therapy was well tolerated. Some patients might be effective for maintenance therapy. Clinical trial identification UMIN 000013882. Legal entity responsible for the study HOT/NJLCG. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Objective Carboplatin-based regimens are the standard regimens for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, the efficacies of these regimens are unsatisfactory. We previously identified carboplatin plus irinotecan (CI) and carboplatin plus amrubicin (CA) as promising new carboplatin-based regimens. Accordingly, we conducted a randomized phase II study to identify the appropriate regimen for future phase III trials. Materials and methods Chemotherapy-naive patients with ES-SCLC were randomly assigned to receive 4–6 cycles of carboplatin [area under the curve (AUC) 5.0, day 1] plus irinotecan (70 mg/m2, days 1 and 8) every 3 weeks (CI arm) or carboplatin (AUC 4.0, day 1) plus amrubicin (35 mg/m2, days 1–3) every 3 weeks (CA arm). The primary endpoint was the overall response rate (ORR). The secondary endpoints were the progression-free survival (PFS), overall survival (OS) and toxicity. Results Between December 2009 and March 2013, 71 patients were enrolled. One patient in each arm did not receive any protocol treatment due to rapid disease progression. The characteristics of the treated patients were as follows: median age, 70 years (range 51–84 years); proportion of males, 84%. The ORRs were 79% and 89% in the CI and CA arms, respectively. The median PFS values were 5.1 and 6.2 months in the CI and CA arms, respectively [CA; hazard ratio (HR) = 0.59, 95% confidence interval (CI): 0.35–0.98, P = 0.042]. The grade 3 or higher toxicity severities were neutropenia (CI, 53% and CA, 89%), anemia (CI, 26% and CA, 20%), thrombocytopenia (CI, 18% and CA, 14%), and febrile neutropenia (CI, 12% and CA, 29%). No treatment-related deaths were observed. Conclusion CA was numerically more effective than CI, with acceptable toxicity, in chemo-naive ES-SCLC patients. CA could be selected for future phase III trials.

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.

Background Because of the high risk of exacerbation of ILD, patients with concomitant advanced NSCLC and ILD have been excluded from most clinical trials of chemotherapy, despite around 10% of all NSCLC cases. This study prospectively evaluated the efficacy and safety of nab-paclitaxel in combination with CBDCA in advanced NSCLC patients with ILD. Methods Enrolled patients had treatment-naive, advanced NSCLC with ILD. Patients received 100 mg/m2nabPTX weekly and CBDCA at area under the concentration-time curve (AUC) 6 once every 3 weeks for 4-6 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS) and overall survival (OS). Results Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had an adenocarcinoma, followed by 15 (41.7%) squamous cell carcinoma, and 5 (13.9%) non-small cell carcinoma. The median number of cycles administered were 4 (range: 1-6). The ORR was 55.6% (95% confidence interval [CI]: 39.6-70.5). The median PFS and OS were 5.3 months (95% CI: 3.9-8.2) and 15.4 months (95% CI: 9.4-18.7). There was no significant difference between two groups, however, numerically better treatment outcomes were observed in the Sq group: the ORR was 66.7% (95% CI: 41.7–84.8) in the Sq group compared with 47.6% (95% CI: 28.3–67.6) in the Non-Sq group (P = 0.254); median PFS was 8.2 months (95% CI: 4.0–10.2) in the Sq group vs. 4.1 months (95% CI: 3.3-5.4) in the Non-Sq group (HR, 0.60 [95% CI, 0.30–1.20]; p = 0.15); median OS was 16.8 months (95% CI: 9.8–not reached) in the Sq group vs. 11.9 months (95% CI: 7.3-17.4) in the Non-Sq group (HR, 0.56 [95% CI, 0.24–1.28]; p = 0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and one patient (2.8%) died. After the protocol treatment, 24 patients (66.7%) underwent second-line therapy. Most preferred regimen were S-1 (n = 12, 50%), followed by vinorelbine (n = 4, 16.7%) and docetaxel (n = 3, 12.5%). Conclusions This is the first prospective phase II trial of weekly nabPTX in combination with CBDCA in advanced NSCLC patients with ILD. This treatment showed favorable efficacy and was well tolerated. Clinical trial identification UMIN000012901. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure T. Harada: Honoraria (institution): GlaxoSmithKline K.K.; Honoraria (institution): Hisamitsu Pharmaceutical Co.,Inc; Honoraria (institution): Boehrnger INgelheim. S. Oizumi: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Chugai Pharmaceutical Co.; Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Eli Lilly. Y. Fujita: Honoraria (institution): Eli Lilly; Honoraria (institution): Chugai Pharma; Honoraria (institution): Taiho Pharmaceutical; Honoraria (institution): Pfizer; Honoraria (institution): Hisamitsu Pharmaceutical; Honoraria (institution): Novartis; Honoraria (institution): Ono Pharmaceutical. All other authors have declared no conflicts of interest.

8559 Background: A variety of genetic analyses have been performed in small cell lung cancer (SCLC), however the clinical relevance of them remains unclear. We prospectively analyzed clinical samples of small-cell lung cancer using a nationwide genomic screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 (ver.1) or 161 (ver.3) cancer-related genes. Results: From July 2015 to January 2019, 707 SCLC patients had been enrolled. The median age was 68 years. 77% were male and 94% were smokers. Among 588 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 426 (72%) /194 (33%) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 21 (4%) /30 (5%) /9 (2%) of cases, respectively. This NGS analysis also showed that 32 (5%) of cases had well-known genetic alterations in receptor tyrosine kinase genes: 9 EGFR mutations, 9 KRAS mutations and 14 FGFR1 copy number gains. Mutations in the PI3K pathway were detected in 44 (7%) of the tumors. Among them, 8 cases enrolled in the investigator-initiated phase II study of gedatolisib (UMIN 000020585). Survival data was available in 463 patients receiving platinum-based chemotherapy. Multivariate analysis revealed that the presence of PIK3CA mutation (HR; 2.56; 95% CI 1.19 – 5.52; p = 0.016) and MYCN amplification (HR; 4.36; 95% CI 1.91 – 9.97; p < 0.001) were significantly associated with unfavorable survival. The frequency of amplifications in MYC family genes was higher in the samples obtained ≥ 90 days after the first-line platinum-based chemotherapy (18.1%) than in those < 90 days (8.1%, p = 0.01), suggesting MYC family amplification as one of the resistance mechanisms. Conclusions: This large-scale nationwide screening system is helpful for identifying therapeutically relevant genetic alterations, prognostic prediction, and exploring resistance mechanism in SCLC. Updated screening results will be presented at the 2019 ASCO Annual Meeting. Clinical trial information: UMIN000018656.

Idiopathic pulmonary fibrosis (IPF) often accompanies lung cancer, and life-threatening acute exacerbation (AE) of IPF (AE-IPF) is reported to occur in 20 % of IPF patients who undergo lung cancer surgery. Pirfenidone is an anti-fibrotic agent known to reduce disease progression in IPF patients. A phase II study was conducted to evaluate whether perioperative pirfenidone treatment could reduce the incidence of postoperative AE-IPF patients with lung cancer. Pirfenidone was orally administered to IPF patients who were candidates for lung cancer surgery; pirfenidone was dosed at 600 mg/day for the first 2 weeks, followed by 1200 mg/day. Surgery was performed after at least 2 weeks of 1200-mg/day administration. The primary endpoint was non–AE-IPF rate during postoperative days 0–30, compared to the null value of 80 %, and the secondary endpoint was safety. Radiologic and pathologic diagnoses of IPF and AE-IPF were confirmed by an independent review committee. From June 2012 to January 2014, 43 cases were enrolled, and 39 were eligible (full analysis set [FAS]). Both pirfenidone treatment and surgery were performed in 36 patients (per protocol set [PPS]). AE-IPF did not occur in 37/39 patients (94.9 % [95 % confidential interval: 82.7–99.4 %, p = 0.01]) in the FAS, and in 38/39 patients (97.2 % [95 % confidential interval: 85.5–99.9 %, p = 0.004] in the PPS. A grade 5 adverse event (death) occurred in 1 patient, after AE-IPF; no other grade 3–5 adverse events were observed. Perioperative pirfenidone treatment is safe, and is promising for reducing AE-IPF after lung cancer surgery in IPF patients. This clinical trial was registered with the University Hospital Medical Information Network (UMIN) on April 16th, 2012 (Registration Number: UMIN000007774 ).