Hajime Kikuchi

(5S,7R,10R)-selin-4(14)-en-5α-ol, a sesquiterpene alcohol from the red alga Laurencia nipponica☆

Abstract A new sesquiterpene alcohol isolated from the red alga Laurencia nipponica has been characterized as (5 S ,7 R ,10 R )-selin-4(14)-en-5α-ol by spectral and chemical methods.

The absolute configuration of cycloeudesmol from the red alga Laurencia nipponica Yamada

Abstract The absolute configuration of cycloeudesmol, isolated from the red alga Laurencia nipponica Yamada and Chondria oppositiclada Dawson, is determined by the crystallographic study.

Expression of Notch1 and Numb in small cell lung cancer

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.

Prognostic impact of clinical variables on surgically resected small-cell lung cancer: Results of a retrospective multicenter analysis (FIGHT002A and HOT1301A)

OBJECTIVES 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. PATIENTS AND METHODS We reviewed the clinical courses of 156 SCLC patients who had undergone surgery at 17 institutions between January 2003 and January 2013. RESULTS 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 of <20mm, with preoperative diagnosis, without a history or presence of other types of cancer, or who underwent prophylactic cranial irradiation (PCI). CONCLUSION 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).

Immunohistochemical profiling of receptor tyrosine kinases, MED12, and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker

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.

Numb has distinct function in lung adenocarcinoma and squamous cell carcinoma

Some reports suggest that Numb is a potential tumor suppressor. However, its role in non-small cell lung cancer remains unclear. Non-small cell lung cancer comprises two major histological subtypes, adenocarcinoma and squamous cell carcinoma. To investigate the role of Numb in tumorigenesis of lung adenocarcinoma and squamous cell carcinoma, we firstly performed loss-of-function and gain-of-function assays. Moreover, Numb expression was investigated in surgically resected lung adenocarcinoma and squamous cell carcinoma tissues by immunohistochemistry and correlations with prognosis were analyzed. Numb suppressed the proliferation, migration, and invasion of adenocarcinoma cells and inhibited Notch signaling and epithelial-mesenchymal transition in vitro. Numb overexpression also inhibited subcutaneous adenocarcinoma tumor growth. In contrast, Numb promoted the proliferation, migration, and invasion of squamous cell carcinoma cells, but did not induce any consistent changes in Notch signaling. High Numb expression was associated with favorable prognosis in patients with lung adenocarcinoma, but not in those with squamous cell carcinoma. Collectively, our data demonstrate that Numb plays distinct roles in lung adenocarcinoma and squamous cell carcinoma. In lung adenocarcinoma, Numb impairs tumor growth and inhibits the Notch pathway and epithelial-mesenchymal transition, whereas in lung squamous cell carcinoma it may promote proliferation.

Successful Application of Edoxaban in the Treatment of Venous Thromboembolism Recurrence in a Patient with Non-small Cell Lung Cancer after Tumor Shrinkage

This report describes the case of a 66-year-old man with non-small cell lung cancer and venous thromboembolism (VTE). Unfractionated heparin (UFH) was initially used to control VTE before chemotherapy. However, switching UFH to warfarin or edoxaban, a novel oral anticoagulant (NOAC), failed. Chemotherapy was then administered to control the tumor which was thought to have been the main cause of VTE, which had been treated by UFH. After tumor shrinkage was achieved by chemotherapy, we were able to successfully switch from UFH to edoxaban. Controlling the tumor size and activity enabled the use of edoxaban as maintenance therapy for VTE.

Abstract 1172: Expression of notch1, numb, and musashi1 in non-small cell lung cancer

Background: Deregulation of Notch pathway is associated with carcinogenesis, and Notch signaling is identified as tumor activator in non-small cell lung cancer(NSCLC). The function of Musashi1 has been found to activate Notch signaling through the translational repression of Numb, which represses an intracellular Notch signaling. In NSCLC, the association between Numb or Musashi1 expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1, Numb, and Musashi1 in NSCLC. Methods: A total of 135 surgically resected NSCLCs were immunohistochemically assessed for Notch1, Numb, and Musashi1 expression. Only cytoplasm and nuclear staining was considered in the evaluation of activated Notch1 expression. The immunoscores were determined, and then its correlation with either the clinicopathological variables or the survival outcomes was analyzed. Results: Immunohistochemical reactivity for Numb, and Musashi1 was detected in the cytoplasm and nuclear of the tumor cells. Notch1 expression was associated with several clinicopathological factors, including pathological histology (p = 0.002), and differentiation of tumor (p = 0.024). Numb expression was also associated with several clinicopathological factors, including sex (p = 0.037), smoking habit (p = 0.033), pathological histology (p = 0.002), and differentiation of tumor (p = 0.015). No correlations were noted between Musashi1 expression and any of the variables. Analysis of cellular biological expression demonstrated a link between low Numb expression and high Notch expression. Multivariate Cox regression analysis showed that positive Numb expression was an independent favorable prognostic factor. Conclusions: We demonstrate that Numb expression was associated with better prognosis in NSCLC. Numb might have the function as tumor suppressor in NSCLC. Citation Format: Hajime Kikuchi, Jun Sakakibara-Konishi, Yasuyuki Ikezawa, Taichi Takashina, Hidenori Mizugaki, Eiki Kikuchi, Junko Kikuchi, Naofumi Shinagawa, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura. Expression of notch1, numb, and musashi1 in non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1172.

1465PUPDATED DATA ON CLINICAL AND MOLECULAR PROFILE OF SURGICALLY RESECTED SMALL CELL LUNG CANCER: INTERGROUP STUDY WITH FIGHT002 AND HOT1301

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