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Background Thymic malignancies are a model of rare cancer. However, little clinical data is available based on the large database. We aimed to clarify the prognostic factors, particularly the metastatic sites, for thymic malignancies using one of the largest, representative, multi-institutional databases, the NEJ023 database. Patients and Methods Patients with Stage IVA/IVB or recurrent thymic carcinoma were enrolled between 1995 and 2014. Clinicopathologic information was evaluated, and the patients were subdivided according to the metastatic organs of involvement (serosal dissemination, liver, lymph node, pulmonary, and bone metastasis). A Kaplan-Meier analysis and multivariate Cox regression were used to evaluate survival. Results Two hundred and seventy-nine patients with metastases and a predominantly squamous histology (66.7%) were included. Most patients (53.0%) had serosal dissemination, whereas 26.5%, 21.9%, 19.7%, and 15.8% had pulmonary, lymph node, bone and liver metastases, respectively. Over a median follow-up time of 21.5 months, the median overall survival (mOS) was 30.7 months. When the subjects were grouped according to involved metastatic sites, patients with more than 3 involved metastatic organs had the worst survival outcome. Among patients with isolated involvement, those with bone metastasis had the poorest survival, followed by patients with liver metastasis. Subjects with hypoalbuminemia also had poor survival outcomes. When patients treated with platinum and anthracycline-containing pharmacotherapy were compared with those treated with platinum and non-anthracycline-containing pharmacotherapy, no significant difference was observed. Bone metastasis (P = 0.0005), liver metastasis (P = 0.047), and hypoalbuminemia (P = 0.0021) were identified as prognostic factors in a multivariate analysis. Conclusion The site of metastatic involvement affects the survival outcomes of patients with thymic carcinoma, and this result may reflect the sensitivity of metastatic sites to pharmacotherapy. As a next step, controlling liver metastasis with pharmacotherapy could help to improve the prognosis of patients with thymic carcinoma.

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.

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.

// 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.

// 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 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.

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.

Objective: Platinum-free regimens can represent an alternative for advanced non-small cell lung cancer (NSCLC) if similar efficacy is provided with better tolerability. This study evaluated the efficacy and safety of combined irinotecan and S-1 for chemotherapy-naïve advanced NSCLC. Methods: Chemotherapy consisted of 4-week cycles of intravenous irinotecan (100 mg/m2, days 1 and 15) and oral S-1 (80 mg/m2, days 1–14). The primary endpoint was response rate, while secondary endpoints were overall survival, progression-free survival (PFS), and safety. Results: A total of 112 cycles was administered to 40 patients (median 3 cycles; range 1–6 cycles). Twelve patients showed partial response and 17 patients had stable disease, representing a response rate of 30% and a disease control rate of 72.5%. Median survival time and median PFS were 16.1 and 4.8 months, respectively. Hematological toxicities of grade 3 or 4 were neutropenia (32.5%) and anemia (5.0%). The most common nonhematological toxicities of grade 3 or 4 included diarrhea (15.0%) and anorexia (17.5%). Patients homo- or heterozygous for UGTA1A*6 tended to show a higher incidence of grade 3 diarrhea (p = 0.055). Conclusion: The combination of irinotecan and S-1 offers good efficacy and tolerability for previously untreated advanced NSCLC.

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).

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

1983年より1998年までに当科に入院した原発性肺癌755例, 762病変を年齢によって40歳以下, 41～50歳, 51～60歳, 61～70歳, 71～80歳, 81歳以上の6群に分i類し, 各グループの臨床的特徴について検討した.組織型では若年齢であるほど腺癌の比率が高く, 高年齢になるほど扁平上皮癌の比率が増加していた.この傾向は男性, 喫煙者群において明らかであったが, 女性, 非喫煙群では年齢とは無関係に腺癌の比率が高かった.発見動機iでは40歳以下において有症状受診例が約76%と高く, 81歳以上では他疾患治療中の症例が多く見られた (p

1983年より1998年までに当科に入院した原発性肺癌患者755例, 762病変の組織型の変遷とその背景因子について検討した. 便宜的に前半8年間 (1983～1990: 1980年代) と後半8年間 (1991～1998: 1990年代) に分けて比較した. 1980年代と1990年代では, 原発性肺癌総患者数, 男女比, 喫煙率, 発見動機, 臨床病期, 治療法に大きな変化はなかったが, 平均年齢は1990年代が有意に低かった (平均1.5年, p

We assessed insulin sensitivity in women comparing the insulin tolerance test (ITT) with the intravenous glucose tolerance test with frequent sampling and computer modeling (FSIVGTT) and evaluated the effects of hormonal therapy in postmenopausal women using both methods.This prospective study tested 18 premenopausal women and ten postmenopausal women randomized to receive either estrogen alone or estrogen with a sequential progestin for 6 months at a menopause research clinic. All subjects received an ITT and an FSIVGTT within 48-72 hours of each other in random sequence. Postmenopausal women were then randomized to receive either 0.625 mg conjugated equine estrogen for 6 months or 0.625 mg conjugated equine estrogen with medroxyprogesterone acetate, 10 mg, for 10 days each month for 6 months. Both the ITT and the FSIVGTT were repeated following hormonal therapy at 2 and 6 months. Plasma insulin and glucose were measured; insulin sensitivity was calculated after the ITT (Kitt) and the FSIVGTT (Si) at each visit in each group.A close correlation was found between Kitt and Si values at initial testing in both pre- and postmenopausal women and following both types of hormonal therapy (r = 0.76 for all tests, P.001). A reduction in insulin sensitivity was observed in postmenopausal compared to premenopausal women; this occurred in five of ten postmenopausal women using the Kitt measurement and in four of ten women using Si. Estrogen replacement had a beneficial effect on insulin sensitivity. While Kitt increased by 24.2 +/- 9.6% (P.05), the increase in Si (6.7 +/- 18%) was not significant because of the variability with this measurement. An attenuation in insulin sensitivity was seen with added progestin. Kitt values decreased by 17.7 +/- 7.7% and Si values by 31.9 +/- 12%. Similar findings were noted at 2 and 6 months.The ITT and FSIVGTT provide quantitatively similar information regarding insulin sensitivity in healthy women. A mild degree of insulin resistance appears to be present in some healthy postmenopausal women. Estrogen appears to improve insulin sensitivity, while added progestin may attenuate this beneficial effect.

Following a three-week administration of alpha-interferon (IFN-α), a 62-year-old woman with chronic hepatitis C manifested fever and dyspnea and showed diffuse infiltrative opacities on chest roentgenograms. Her laboratory data included results of anemia with reticulocytosis, a decreased complement level and hepatitis with elevated ALP, LDH and γ-GTP, Because laboratory data also revealed a positive lymphocyte stimulation test for IFN-α, this cytokine was considered to be responsible for the development of interstitial pneumonia, hemolytic anemia and cholestatic liver dysfunction due to its immunomodulatory effects. Although these three disorders have been reported to develop singly after IFN-α therapy, this is the first report of a patient in whom these disorders occurred simultaneously.(Internal Medicine 33: 337-341, 1994)

Background Pleomorphic carcinoma of the lung is a malignant epithelial tumor that contains carcinomatous and sarcomatoid components. Due to its rarity, few studies have been reported, and its clinical and pathological characteristics remain unclear. Method We retrospectively investigated 22 cases of pleomorphic carcinoma of the lung. Results Fifteen cases were diagnosed by surgical resection, 4 by autopsy, and 3 by transbronchial biopsy. Nineteen patients were male and 3 were female, and their mean age at diagnosis was 68.3 years (±10.1). Eighteen were current- or ex-smokers with substantial smoking histories (mean 46.4 pack-years). Sixteen patients had symptoms: hemoptysis and cough were commonly seen. Chest computed tomography (CT) findings revealed that the tumors were quite large (mean diameter 45.3 ± 21.9 mm; range 14–110 mm), and 21 tumors were peripherally located. Positron emission tomography with 18-fluorodeoxy-glucose (FDG-PET) was performed in 12 patients, and the Standardized Uptake Value (SUV) tended to be high (9.44 ± 4.98). In the 15 patients who underwent surgical resection, recurrence was common; systemic metastases were also frequently found. Patients who had received surgical treatment with proper follow-up care survived longer than those who did not undergo surgery. Responses to chemotherapy were generally poor, although 1 patient exhibited partial response to gefitinib. Conclusions Pulmonary pleomorphic carcinoma has strong malignant potential with frequent distant metastases, as has already been reported. However, this study demonstrated that surgical treatment and appropriate follow-up therapy might result in better prognoses.

Combination chemotherapy comprising amrubicin and vinorelbine as a second-line therapy for advanced non-small cell lung cancer (NSCLC) has not been fully evaluated. To determine the maximum tolerated dose (MTD) and recommended dose (RD), the present phase I study examined patients with advanced NSCLC.The subjects were nine patients with histologically confirmed advanced NSCLC, Eastern Cooperative Oncology Group performance status 0-1, prior platinum-based first-line chemotherapy, and measurable or evaluable lesions. Treatment consisted of five dose levels, with amrubicin 35-45 mg/m2 administered as a 5-min intravenous infusion on days 1-3 and vinorelbine 15-25 mg/m2 given as a 1-h intravenous infusion on days 1 and 8, every 3 weeks.All patients had received carboplatin and paclitaxel as first-line therapy. Dose-limiting toxicity (DLT) was seen in two of six patients (febrile neutropenia and deep vein thrombosis ) at level 1, allowing us to conduct level 2. At level 2, all three patients experienced DLT (leucopeniaor =4 days in one patient; febrile neutropenia in three patients; and infection in two patients), and this level was determined as the MTD. Subsequently, level 1 (amrubicin 35 mg/m2 and vinorelbine 15 mg/m2) was defined as the RD. Responses in the nine patients included a partial response in one patient and stable disease in four patients.As second-line therapy, the RD of the combination of amrubicin and vinorelbine is 35 mg/m2 and 15 mg/m2, respectively. Further study should proceed to clarify the efficacy of this regimen.

Two cases of pleural involvement of dialysis-related amyloidosis (DRA) with pleural effusion are presented. DRA is one of the most important complications in longterm dialysis patients and 2-microglobulin is the principal protein component of DRA, but pleural deposition of 2-microglobulin amyloid has not yet been reported. To the best of the authors’ knowledge, this is the first case report of pleural involvement of DRA presenting with pleural effusion. This case study suggests that pleural involvement of DRA should be considered when exudative pleural effusion is observed in patients undergoing longterm dialysis. (Internal Medicine 44: 628–631, 2005)

While papillary serous adenocarcinomas are histocytologically common in primary peritoneal carcinomas, clear cell carcinomas are rare. We report a new regimen for the treatment of recurrent clear cell carcinomas of the peritoneum. A 45-year-old woman was referred to our hospital and underwent optimal debulking surgery. Thirty-two months after the operation, lymph node swelling and elevation of serum CA19-9 were detected and recurrence was diagnosed. Paclitaxel (175 mg/m(2)) in a 3-hour and carboplatin (300 mg/m(2)) in a 1-hour infusion were repeated at three-week intervals. After completion of four courses, abdominal CT and serum CA19-9 were undertaken and results compared. Lymph node swelling was significantly decreased and the serum CA19-9 level was decreased to within a normal range. Paclitaxel and carboplatin combination chemotherapy may be effective in preventing the recurrence of peritoneal carcinomas.

Three cases of benign pelvic tumors are presented (2 leiomyomas and 1 fibroma). All three tumors were suspected of being malignant neoplasms because they were visualized as heterogeneous high signal intensity on T2-weighted images, and thus they were difficult to diagnose preoperatively. One of the leiomyomas was located in the retroperitoneum and had been misdiagnosed as an ovarian tumor. All three tumors exhibited secondary myxoid changes, these changes may have been responsible for the high signal intensity on the T2-weighted MR images. Since benign tumors sometimes mimic malignant tumors on MR images, exploratory laparotomy is essential to make a definitive diagnosis.

Background Acute deterioration of ILD for unknown causes, sometimes called as acute exacerbation (AE), can occur at any point in the course of ILD. However, little is known about its incidence and prognostic significance in lung cancer pts with pre-existing ILD, who receive various treatments; chemotherapy, surgery, palliative radiotherapy, and best supportive care (BSC). Methods A total of 242 subjects (6.9% of all) were retrospectively identified to have pre-existing ILD by computed tomography (CT) from a sum of 3524 pts who had been hospitalized for lung cancer treatment at 8 institutions during 2004 to 2009. CT images of all the eligible pts were centrally reviewed. Univariate and multivariate analyses were performed using a Cox proportional hazard model to examine the potential role of any prognostic factors for overall survival (OS) from the initial lung cancer diagnosis. Results Pts' characteristics were: male/female = 217/25; median age (range) = 73 (42-98) yrs.; smoking status: ever/never = 223/19; Performance Status: 0/1/2/3/4 = 74/121/23/19/5; Stage I/II/III/IV = 48/10/98/86; Histology: adeno/squamous/large/NOS/small = 90/75/6/19/52; CT pattern: usual interstitial pneumonia (UIP)/non-UIP = 118/124; extent of normal lung on baseline CT: 10-50%/60-90% = 154/88; pre-existing emphysema: yes/no = 178/64. AE occurred in 71 of 242 pts (29%) overall; 56 of 147 pts (38%) with chemotherapy, 6 of 38 pts (16%) with surgery, 2 of 17 pts (12%) with palliative radiotherapy, and 5 of 36 pts (14%) with BSC alone, and chemotherapy was an independent risk factor for the occurrence of AE (P Conclusions The occurrence of AE is not rare in the lung cancer treatment, particularly during chemotherapy, and it is a factor for poor prognosis in pts with pre-existing ILD. Disclosure All authors have declared no conflicts of interest.

Objective To determine the effect of transdermal estrogen on insulin sensitivity in postmenopausal women and to compare this effect with changes observed with oral conjugated equine estrogens. Design Fourteen postmenopausal women were randomized to receive a transdermal E 2 patch, 0.1mg, for 25days each month (n=7) or transdermal E 2 with added medroxyprogesterone acetate (MPA), 10mg, from days 16 to 25 each month (n=7). An insulin tolerance test (ITT) was performed at baseline and between days 23 and 25 during the 2nd month of treatment to assess insulin sensitivity. Values for the disappearance of glucose (K itt ) were calculated and compared with values obtained from women receiving 1.25mg of oral equine estrogens (n=8). Setting University Clinical Research Center. Patients Healthy postmenopausal women not receiving hormonal replacement. Intervention Insulin tolerance tests before and after treatment. Main Outcome Measure Disappearance of glucose and insulin (K itt ) before and after treatment. Results Women receiving transdermal E 2 alone demonstrated improved insulin sensitivity. The K itt glucose values increased by 13.2%, compared with a 23.9% decrease in K itt values observed with 1.25mg of conjugated equine estrogen. The group treated with transdermal E 2 and MPA had a reduction in insulin sensitivity. Insulin clearance was enhanced only with transdermal estrogen and was significantly delayed (blunted clearance) with the addition of MPA to transdermal E 2 and with oral estrogen. Conclusion We previously demonstrated a bimodal effect of oral equine estrogens on insulin sensitivity with an improvement occurring with the lower dose of 0.625mg but with a deterioration with the dose of 1.25mg. Here we suggest that this effect may be related to a first-pass hepatic-portal effect in that transdermal E 2 (0.1mg), which may be equated more closely with the larger dose of oral estrogen (1.25mg), improved insulin sensitivity. Progestin, however, appeared to attenuate the beneficial effects of transdermal estrogen and may alter the clearance of insulin.

We determined the independent effects of various doses of ethinyl estradiol used in oral contraceptives or norethindrone acetate, as well as their combination, on insulin sensitivity in normal women.Thirty-three normal ovulatory female volunteers were recruited for this study. Insulin tolerance tests were performed after carbohydrate loading to determine the kinetic disappearance of glucose and insulin. After initial testing the women were randomized into four groups: ethinyl estradiol 20 micrograms, 35 micrograms, and 50 micrograms and norethindrone 1 mg. Insulin tolerance tests were repeated after 1 month of treatment and again after a second month, when all ethinyl estradiol groups received the addition of norethindrone 1 mg to their doses of ethinyl estradiol. Plasma glucose and insulin were measured, and insulin sensitivity (K(itt) glucose) and the disappearance of insulin (K(itt) insulin) were calculated.All groups were comparable at baseline, and no significant changes in fasting glucose and insulin were evident with treatment. After ingestion of 50 micrograms ethinyl estradiol the K(itt) glucose value decreased significantly (p0.03) and ingestion of 20 micrograms and 35 micrograms showed individual changes, but as groups the changes were not statistically significant. All ethinyl estradiol groups combined had a significant decrease in K(itt) glucose (p0.01). Norethindrone 1 mg alone did not change K(itt) glucose values, and after the addition of norethindrone to ethinyl estradiol, K(itt) glucose values normalized. K(itt) insulin values were also lower with treatment but were lower with ethinyl estradiol plus norethindrone compared with ethinyl estradiol alone (p0.04), suggesting an attenuation of insulin clearance with the progestin.Ethinyl estradiol alone decreases insulin sensitivity, and this may occur at lower doses, but norethindrone 1 mg does not appear to do so. However, progestins may alter insulin clearance.In southern California, reproductive endocrinologists compared data on 3 normal ovulatory 19-42 year old women blindly randomized into 4 groups to determine the independent effect of ethinyl estradiol and norethindrone acetate, both of which are in oral contraceptives, on glucose tolerance and insulin sensitivity. They used the most simple and rapid of the alternatives to the oral glucose tolerance test--the insulin tolerance test. Women received either 20 mcg/day, 35 mcg/day, or 50 mcg/day of ethinyl estradiol or 1 mg/day of norethindrone acetate. For the 2nd month, all women using ethinyl estradiol also received 1 mg/day of norethindrone acetate. The women in all 4 groups had comparable plasma glucose and insulin values while fasting. Estrogen in the 3 contraceptive doses reduced insulin sensitivity (p 0.03). The effect was not significant at 20 mcg and 35 mcg ethinyl estradiol, but 22.2% and 14.3% of the women receiving 20 mcg and 35 mcg ethinyl estradiol, respectively, did experience some reduction in insulin sensitivity. One mg norethindrone acetate alone did not affect insulin sensitivity, but when it was administered with 50 mcg ethinyl estradiol, insulin sensitivity values returned close to normal. 35 mcg of ethinyl estradiol lowered insulin clearance values (19.17% min vs. 9.53%/min; p 0.03). Addition of 1 mg norethindrone acetate to all ethinyl estradiol groups resulted in even more of a reduction (10.58%/min vs. 8/81%/min; p 0.04), indicating that a progestin reduces insulin clearance. In conclusion, ethinyl estradiol, even at low doses, appears to decrease insulin sensitivity while progestins do not. Yet, progestin appear to affect insulin clearance.