Naomi Watanabe

Nucleolar organizer regions in precancerous and cancerous lesions of the bronchus.

Using a silver staining technique, nucleolar organizer region‐associated proteins (Ag‐NOR) were studied in paraffin sections of five specimens of normal bronchial epithelium, eight of atypical squamous metaplasia, five of carcinoma in situ, and seven of microinvasive squamous cell carcinoma. The mean number of Ag‐NOR in the nucleus were normal epithelium 1.2 ± 0.1 (mean ± SD), atypical squamous metaplasia (borderline lesion) 2.2 ± 0.5, carcinoma in situ 3.8 ± 0.6, and microinvasive squamous cell carcinoma 4.8 ± 1.1. There was a highly significant difference between the Ag‐NOR numbers in the atypical squamous metaplasia and those in the carcinoma in situ (P < 0.01). The Ag‐NOR staining is a useful technique for the differential diagnosis of difficult borderline lesions in the bronchial epithelium.

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.

Clinical Evaluation of Serum Laminin P1 and 7S Collagen in Lung Cancer Patients.

健常者19例, 肺癌患者59例 (腺癌32例, 扁平上皮癌14例, 小細胞癌13例), 転移性肺腫瘍7例について, 血清ラミニンP1, 7Sコラーゲン濃度を測定した.小細胞癌患者のみで健常者より血清ラミニンP1, 7Sコラーゲン値ともに平均値が有意に増加し, 陽性率も高かった.腺癌, 扁平上皮癌患者では, 病期進行例で高値例を認めた.更に小細胞癌で治療によって測定値の変化を認め, 治療モニターとして有用となる可能性が考えられた.

Cytodiagnostic significance of AgNORs in body cavity fluids.

胸水・腹水などの体腔液細胞診で悪性細胞か否かの診断が困難な異型細胞に遭遇することがある.このような細胞の鑑別のため, 疑陽性と判定された異型細胞のSilver-bindingnucleolarorganizer regions (AgNORs) について検討した.同じく疑陽性と判定された異型細胞でも, 悪性体腔液中の異型細胞では核内AgNORs平均個数 (mean±SD) は3.4±0.7であり, 非悪性体腔液中にみられた異型細胞での2.0±0.6に比べて有意に高値であった (P<0.01).特に核内AgNORs平均個数が3以上のときは, その体腔液が悪性である可能性がきわめて高かった.また, 疑陽性と判定された悪性胸水では, 多くが胸水CEA・核内AgNORs平均個数とも高値であるが, 前者が正常, 後者が高値の例もあった.体腔液に疑陽性と判定された異型細胞がみられた場合, 核内AgNORsの計測は体腔液の良性・悪性の鑑別に有用であった.