Perioperative therapy for non-small cell lung cancer - Current status and future perspective -

　Lung cancer is the leading cause of cancer-related death. Surgery has been playing a pivotal role in the treatments with curative intent for non-small cell lung cancer (NSCLC). However, the outcome after surgery alone remains unsatisfactory. During the last two decades, several attempts have been made to improve the postoperative outcome. Metaanalysis demonstrated that adjuvant cisplatin-based chemotherapy achieved 4-5% of benefit in the 5-year survival as compared to surgery alone. Preoperative induction chemotherapy also yielded a 5% improvement of the 5-year survival rate, showing a similar efficacy with adjuvant chemotherapy. Induction chemoradiotherapy enhanced local control, whereas it was not associated with any survival benefit. Recently, the development of new drugs, such as tyrosine kinase inhibitors and immune checkpoint inhibitors, represents a major treatment advance for patients with lung cancer. Several attempts have been made to apply these drugs to perioperative treatments.　In this review, we sought to summarize the developments of perioperative therapy in the treatments of NSCLC, and discuss the future perspectives

Clinical significance of vascular endothelial growth factor and Delta-like ligand 4 in small pulmonary adenocarcinoma

Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. The notch ligand Delta-like ligand 4 (DLL4) is induced by VEGF and acts as a negative regulator of tumor angiogenesis by reducing the numbers of non-productive sprouting vessels. Several reports have shown the prognostic role of VEGF expression in non-small cell lung cancer. However, the correlation between VEGF and DLL4 expression and their clinical significance in non-small cell lung cancer remains unclear. The aim of this study was to analyze the correlation between the expression of VEGF/DLL4 and the clinicopathological background. Fifty-eight patients with lung adenocarcinomas measuring less than 3 cm in diameter who underwent surgical resection at Kawasaki Medical School Hospital from 2008 to 2010 were enrolled in this study. The expressions of VEGF, DLL4, CD31, and Ki-67 were analyzed using immunohistochemical staining. The tumor cells were VEGF-positive in 44 patients (75.9%) and DLL4-positive in 41 patients (70.7%). No statistically significant association was observed between the patients\u27 characteristics and VEGF/DLL4 expression. A high VEGF expression level tended to be associated with a high DLL4 expression level (P = 0.050, r = 0.258). The mean Ki-67 index was significantly lower in the patients with high VEGF expression (9.5 vs. 18.2, P = 0.011), but no significant difference was observed when patients were compared according to their DLL4 expression levels (11.8 vs. 11.0, P = 0.804). The mean Ki-67 index was higher in the VEGF_ DLL4_ patients than in the VEGFhigh DLL4high patients by a marginally significant difference (20.1 vs. 10.9 P = 0.056). The 3-year recurrence-free survival rates of the VEGF_/DLL4_ and the VEGF_/DLL4_ patients were 83.3% and 35.7%, respectively. The prognosis of the VEGF_/DLL4_ patients was significantly better than that of the VEGF_/DLL4_ patients (P = 0.032). To investigate the significance of the difference in tumor proliferation and prognosis between the VEGF_/DLL4_ and the VEGF_/DLL4_ patients, we evaluated the morphologic effect of VEGF/DLL4 expression on the intratumoral capillaries by counting the number of capillaries and calculating the luminal area (μm^2). No significant differences were seen between either the VEGF or DLL4 expression levels and the mean number of intratumoral capillaries or the luminal area (μm^2). In conclusion, VEGF_/DLL4_ patients with small pulmonary adenocarcinoma had a significantly poorer prognosis, although no significant difference in a morphological evaluation of the capillaries was seen between VEGF_/DLL4_ and VEGF_/DLL4_ patients

The biological Characteristics of Solid Components are Different between Part-Solid-Type and Solid-Type in Lung Adenocarcinoma

　Numerous studies have been conducted to determine the clinical significance of the ground-glass opacity and solid-components in lung adenocarcinomas, however, few biological analyses of the two components have been carried out. This study was aimed at clarifying the biological characteristics of solid components in part-solid-type and solid-type lung adenocarcinomas. Data of a total of 112 cases of cT1b/cN0M0 lung adenocarcinoma treated by surgical resection were analyzed. We compared clinicopathological characteristics and prognosis between part-solid-type and solid-type tumors. In addition, we performed immunohistochemical analysis to determine the Ki-67 labeling index (LI), programmed cell death-1 ligand 1 (PD-L1) expression status, and CD8-positive tumor-infiltrating T lymphocyte (CD8+ TIL) count for the solid component of each tumor. Five-year recurrence-free survival (RFS) risks were significantly worse for patients with solid-type tumor than for those with part-solidtype tumor (51.7% vs. 83.2%; p < 0.001). The percentages of lymphovascular invasion, lymph node metastasis, high Ki-67 LI, and high PD-L1 expression were higher in the patient group with solid-type tumors. Univariate analysis identified Ki-67 LI, PD-L1 expression status, and CD8+ TIL count were identified as predictors of RFS in the entire subject population. Separate analyses in the two groups identified only the Ki-67 LI as an independent predictor of the RFS in the group with part-solid-type tumors, whereas in the group with solid-type tumors, the PDL1 expression status and CD8+ TIL count were identified as independent predictors of the RFS. Clear differences in the biological characteristics of the solid-component were identified between part-solid-type and solid-type lung adenocarcinomas