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Background Brain metastases frequently occur in patients with non‐small cell lung cancer (NSCLC) resulting in a poor prognosis. Here, we investigated the association between PD‐L1 expression and brain metastasis in patients with NSCLC and its clinical significance. Methods A total of 270 patients diagnosed with metastatic NSCLC who underwent PD‐L1 testing on their tumor tissue between January 2017 and March 2019 were retrospectively reviewed. The VENTANA PD‐L1 (SP263) assay was used, and positive PD‐L1 expression was defined as staining in ≥1% of tumor cells. Results Positive PD‐L1 expression was observed in 181 (67.0%) patients, and 74 (27.4%) patients had brain metastasis at diagnosis. Synchronous brain metastases were more frequently observed in PD‐L1‐positive compared with PD‐L1‐negative patients (31.5% vs. 19.1%, p = 0.045). Multiple logistic regression analysis identified positive PD‐L1 expression (odds ratio [OR]: 2.24, p = 0.012) as an independent factor associated with synchronous brain metastasis, along with the histological subtype of nonsquamous cell carcinoma (OR: 2.84, p = 0.003). However, the incidence of central nervous system (CNS) progression was not associated with PD‐L1 positivity, with a two‐year cumulative CNS progression rate of 26.3% and 28.4% in PD‐L1‐positive and PD‐L1‐negative patients, respectively (log rank p = 0.944). Furthermore, positive PD‐L1 expression did not affect CNS progression or overall survival in patients with synchronous brain metastasis (long rank p = 0.513 and 0.592, respectively). Conclusions Initial brain metastases are common in NSCLC patients with positive PD‐L1 expression. Further studies are necessary to understand the relationship between early brain metastasis and cancer immunity., We investigated the association between PD‐L1 expression and brain metastasis in patients with non‐small cell lung cancer (NSCLC) and its clinical significance. Patients with tumors exhibiting positive PD‐L1 expression (TPS ≥ 1%) were found to have a higher frequency and risk of synchronous brain metastasis when diagnosed with advanced NSCLC. No prognostic impact of PD‐L1 expression was observed on either CNS progression in the entire cohort of patients or OS in patients presenting with synchronous brain metastasis.

Expression of HMGI(Y), a nucleoprotein that binds to A/T rich sequences in the minor groove of the DNA helix, is observable in neoplastically transformed cells but not in normal cells. We have analyzed HMGI(Y) expression in colorectal cancer and evaluated its clinicopathologic significance. HMGI(Y) mRNA was measured by CRT-PCR (competitive reverse transcription-polymerase chain reaction). Immunohistochemical staining for HMGI(Y), p53 and Ki-67 was performed in the same colon cancer tissues, and the results in colorectal tissues were similar to those of RT-PCR. HMGI(Y) expression evidenced by RT-PCR was observed in 63 of 64 (98.4%) colorectal cancer samples, and 2 of 5 (40%) adenomatous polyps, whereas 21 normal colon samples were negative (p

Although AKT ⁄ protein kinase B is constitutively active in nonsmall cell lung cancer (NSCLC) cells and is an attractive target for enhancing the cytotoxicity of therapeutic agents, the distinct roles of the AKT isoforms in NSCLC are largely unknown. In the present study, we investigated the roles of AKT1 and AKT2 in NSCLC cells using RNAi. The siRNA targeting of AKT1 or AKT2 effectively decreased protein levels of AKT1 and AKT2, respectively, in A549 and H460 cells. Cisplatin treatment of these cells increased apoptotic cell death compared with control. The siRNA-induced knockdown of AKT1 in H460 cells significantly decreased basal MEK⁄ ERK1 ⁄ 2 activity, resulting in nuclear factor-κB activation, whereas knockdown of AKT2 resulted in anti-apoptotic Bcl-2 family protein MCL-1 (MCL-1) cleavage, the collapse of mitochondrial membrane potential, cytochrome c release, and activation of the caspase cascade. Consequently, both siRNA treatments enhanced the chemosensitivity of H460 cells to cisplatin. However, neither AKT1 nor AKT2 siRNA treatment had any effect of p27 expression, and although both treatments tended to induced G₂ ⁄M phase arrest, the effect was not statistically significant. Treatment with AKT1 siRNA markedly decreased colony formation growth and migration, but AKT2 siRNA had no significant effects on these parameters. These data suggest that AKT1 and AKT2 both contribute to cell survival, albeit via different mechanisms, and that the effects on cell growth and migration are predominantly regulated by AKT1. These findings may aid in refining targeted strategies for the inhibition of AKT isoforms towards the sensitization of NSCLC cells to therapeutic agents.

Problem: Angiogenesis is the rate-limiting step in tumor progression and metastatic spread. Both promoters and inhibitors of angiogenesis have been implicated in thyroid tumorigenesis. We have reported PTTG overexpression in thyroid cancer, and PTTG upregulation of the angiogenic factors FGF-2 and VEGF. This study was conducted to investigate whether PTTG also transactivates other downstream angiogenic effectors. Methods: To investigate whether PTTG also transactivates other downstream angiogenic effectors, we used angiogenesis-specific cDNA arrays. Primary thyroid cells and PTTG-null HCT113 cells were transiently transfected with wild-type-PTTG. Angiogenic factors that demonstrated more than 2-fold changes in expression averaged over 3 cDNA consecutive arrays were selected for further investigation. Results: Thrombospondin-1 (TSP-1), an anti-angiogenic factor, showed a mean 2.7-fold downregulation in response to PTTG overexpression. Conversely, the pro-angiogenic factor ID3 showed a 3.8-fold induction. We subsequently validated these candidate genes using TaqMan RT-PCR. PTTG downregulated TSP-1 86% (P < 0.001) in primary thyroid cells and 73% (P < 0.05) in HCT113 cells compared to vector-only cells. By contrast, PTTG upregulated ID3 62% in primary thyroid cells (P = 0.0053), and transfection studies in FTC133 thyroid follicular cells further supported PTTG upregulation of ID3 (4.35-fold, P < 0.01). In addition, we validated our findings at the protein level. We next examined expression in our thyroid cancer cohort. In keeping with our in vitro data, TSP-1 was reduced in cancers compared to normal thyroids. ID3, however, was significantly raised in tumors compared to normal tissue (5.57 fold, P = 0.025). Conclusion: We conclude that PTTG promotion of angiogenesis may be via altered regulation of several genes with both pro-(ID3) and anti-angiogenic (TSP-1) properties. Significance: We have identified PTTG, ID3, and thrombospondin as potentially important anti-angiogenic targets. It is hoped that this will improve the future treatment of the more aggressive thyroid cancers that are associated with very poor prognosis. Support: None reported.