Long-Term Prognosis After Segmentectomy for cT1 N0 M0 Non-Small Cell Lung Cancer.

BACKGROUND: Prognosis beyond 5 years after segmentectomy for non-small cell lung cancer (NSCLC) has not been well studied. METHODS: This study is a retrospective analysis of a previous prospective cohort study of patients with peripheral cT1 N0 M0 NSCLC who underwent segmentectomy between 2005 and 2009. Exclusion criteria were right middle lobe tumors, multiple tumors in same lobe, patients having considerable risk for segmentectomy, and patients requesting lobectomy rather than segmentectomy. The median follow-up period was 108 months. Study outcomes included overall survival, recurrence-free probability, and local recurrence. RESULTS: Of 179 patients with cT1 N0 M0 who were treated by segmentectomy, clinical T stages were Tis in 57 patients, T1mi or T1a in 34, T1b in 57, and T1c in 31. All tumors were pathologic N0 tumors. The 10-year recurrence-free probability rates in each clinical stage were 100% in Tis, 97% in T1mi or T1a, 90% in T1b, and 69% in T1c, which were significantly lower in advanced T stages (p < 0.001). Fourteen patients (8%) experienced recurrences after segmentectomy; these were local in 8 patients (five recurrences at the surgical margin and three in the preserved lobe) and nonlocal in 6 patients. Six of the eight local recurrences developed more than 5 years after segmentectomy. All eight local recurrences were treated by local therapy, resulting in 6 patients surviving without disease at 55 months of median follow-up after the additional treatments. CONCLUSIONS: Although segmentectomy may be a viable curative option for treating T1 N0 M0 NSCLC, monitoring for local recurrence should be continued beyond 5 years after segmentectomy to avoid missing opportunities to effect a cure.

Pathobiology of Notch2 in lung cancer.

Notch signalling has been reported to be involved in initiation, progression, and suppression in various types of cancer. The pathological significance of Notch1 has been well studied in lung cancer, but that of Notch2 remains unclear. An immunohistochemical study was performed to clarify the expression of NOTCH2 in non-neoplastic lung tissues and lung cancers in comparison with Clara (Club) cell 10 kDa protein (CC10), and western blotting analysis was performed to detect NOTCH2 in human cancer cell lines. A Notch2 gene knockdown experiment was carried out to reveal the function of Notch2. Transient transfection of the intracellular domain of the Notch2 (N2ICD) gene was used. In addition, the relationship of the expressions of Notch1, 2, and 3 was studied. Immunohistochemical study of lung tissues revealed that NOTCH2 was detected in bronchiolar epithelial cells and was often colocalised with CC10, and that adenocarcinoma tissues were more positively stained than those of squamous cell carcinoma and small cell carcinoma. In human lung cancer cell lines, expression of NOTCH2 was similar to that of NOTCH1, and preferentially detected in non-small cell lung carcinoma (NSCLC) cell lines. Knockdown of the Notch2 gene in NSCLC cell lines showed no remarkable changes in expression of molecules associated with cell differentiation, proliferation, apoptosis, and motility, and the seemingly unvalued effects of Notch2 gene knockdown could be masked by concomitant Notch1 activation, as indicated by an increase in the intracellular domain of NOTCH1. Additionally, transient transfection of the N2ICD gene induced CC10 expression in an adenocarcinoma cell line. The present study revealed that Notch2 is important in Club cell differentiation in normal lungs and adenocarcinoma. Notch2 is regulated mutually with Notch1, and the balance of the expression of Notch receptors could determine the biological behaviours of lung cancer cells.

Correlation between histone acetylation and expression of Notch1 in human lung carcinoma and its possible role in combined small-cell lung carcinoma.

Combined small-cell lung carcinoma (cSCLC) is composed of small-cell lung carcinoma (SCLC) admixed with non-small-cell lung carcinoma (NSCLC). Evaluating the molecular differences between SCLC and NSCLC could lead to a better understanding of the pathogenesis of such neoplasms. Therefore, in this study, we investigated the correlation between histone acetylation and Notch1 expression in lung carcinoma. Using chromatin immunoprecipitation (ChIP) assay, we measured the level of acetylated histone H3 around the promoter region of Notch1 in SCLC and NSCLC cells. We then treated SCLC cells with trichostatin A (TSA) and characterized the level of histone H3 acetylation at Notch1. In addition, TSA-treated cells were injected into immune-compromised mice, for analysis of the ex vivo tumor xenograft phenotype. The level of acetylated histone H3 surrounding the Notch1 promoter was lower in lung cancer cells not expressing Notch1. Tumors originated from TSA-treated SCLC cells occasionally formed an epithelial-like glandular arrangement of cells; with Notch1 expression and decreased expression of neuroendocrine (NE) markers. Histone deacetylation around the promoter region of Notch1 inhibits Notch1 protein expression in SCLC and the restoration of Notch1 expression in SCLC leads to the concurrent appearance of epithelial-like areas within the SCLC, which could provide a possible mechanism for histogenesis of cSCLC.

Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer.

Insulinoma-associated protein 1 (INSM1) is expressed exclusively in embryonic developing neuroendocrine (NE) tissues. INSM1 gene expression is specific for small-cell lung cancer (SCLC), along with achaete-scute homolog-like 1 (ASCL1) and several NE molecules, such as chromogranin A, synaptophysin, and neural cell adhesion molecule 1. However, the underlying biological role of INSM1 in lung cancer remains largely unknown. We first showed that surgically resected SCLC samples specifically expressed INSM1. Forced expression of the INSM1 gene in adenocarcinoma cell lines (H358 and H1975) induced the expression of ASCL1, brain-2 (BRN2), chromogranin A, synaptophysin, and neural cell adhesion molecule 1; in contrast, knockdown of the INSM1 gene by siRNA in SCLC (H69 and H889) decreased their expression. However, forced/knockdown expression of ASCL1 and BRN2 did not affect INSM1 expression. A chromatin immunoprecipitation study revealed that INSM1 bound to the promoter region of the ASCL1 gene. A xenotransplantation assay using tet-on INSM1 gene-transfected adenocarcinoma cell lines demonstrated that INSM1 induced NE differentiation and growth inhibition. Furthermore, we found that INSM1 was not expressed in non-small-cell lung cancer and some SCLC cell lines expressing Notch1-Hes1. By forced/knockdown expression of Notch1 or Hes1 genes, we revealed that Notch1-Hes1 signaling suppressed INSM1, as well as ASCL1 and BRN2. INSM1, expressed exclusively in SCLC, is a crucial regulator of NE differentiation in SCLCs, and is regulated by the Notch1-Hes1 signaling pathway.