Association between PD-L1 expression and initial brain metastasis in patients with non-small cell lung cancer and its clinical implications.

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.

The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer.

The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P = 0.009) and protein (P < 0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (Δ126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (> 90%; P < 0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P < 0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.

RASSF1A and ERCC1 expression levels might be predictive of prognosis in advanced, recurrent, and metastatic squamous cell carcinoma of the head and neck treated with docetaxel and cisplatin.

BACKGROUND: The purpose of this study was to test the hypothesis that the immunohistochemical expression of ERCC1 and RASSF1A would predict both response to and survival after docetaxel and cisplatin combination chemotherapy in inoperable or recurrent head and neck squamous cell carcinoma. PATIENTS AND METHODS: A total of 54 patients were treated with frontline systemic chemotherapy composed of docetaxel (60 mg/m(2)) and cisplatin (65 mg/m(2)), every 3 weeks for up to 6 cycles. The expression levels of ERCC1 and RASSF1A were evaluated in the available 36 prechemotherapy samples. RESULTS: The overall objective response rate was 35% (complete remission 12% and partial remission 23%). The median progression-free survival and overall survival (OS) times were 5.0 months (95% confidence interval (CI), 3.7-6.4 months) and 24.2 months (95% CI, 3.5-45.0 months), respectively. The status of low ERCC1 and high RASSF1A expression was an independent favorable prognostic factor for OS in multivariate analysis (p = 0.043; hazard ratio, 7.224; 95% CI, 1.060-49.217). Toxicities were comparable with those of previously reported trials. CONCLUSIONS: Less intensive doses of cisplatin and docetaxel are active but not effective in reducing toxicity. Also, both ERCC1 and RASSF1A might be useful prognostic markers in this regimen.

Roles of AKT1 and AKT2 in non-small cell lung cancer cell survival, growth, and migration.

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.

Application of the Epstein criteria for prediction of clinically insignificant prostate cancer in Korean men.

OBJECTIVE: To investigate the rate of pathologically confirmed unfavourable prostate cancers among Korean men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer. PATIENTS AND METHODS: This was a retrospective study of 131 Korean men who underwent radical prostatectomy (RP) for clinically insignificant prostate cancer as defined by contemporary Epstein criteria. We assessed the percentage of unfavourable prostate cancer (pathological Gleason sum > or = 7 and/or extraprostatic extension [EPE]) among these men and tried to identify useful predictors for such unfavourable tumour profiles using uni- and multivariate analyses. RESULTS: Among 131 men with clinically insignificant prostate cancer, 40 (30.5%) had pathological Gleason > or = 7 tumours after RP. Of these 40 men, four (3.1%) also had EPE on examination of RP specimen. All those who did not have Gleason score upgrading after RP had organ-confined disease from examination of RP specimen. Overall, 40 (30.5%) of the 131 men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer before RP had pathologically unfavourable disease. Among our patients, no significant preoperative predictor of pathologically unfavourable disease was identified using uni- and multivariate analyses. CONCLUSION: Our results showed that a significant proportion of contemporary Korean patients who meet all the conditions of the contemporary Epstein criteria for prediction of clinically insignificant prostate cancer might actually harbour prostate cancer with unfavourable pathological features. Such findings should be considered when treatment options are contemplated based upon the Epstein criteria among Asian patients.

Pituitary tumor transforming gene binding factor: a novel transforming gene in thyroid tumorigenesis.

CONTEXT: There are currently no clear markers for the detection of differentiated thyroid cancer and its recurrence. Pituitary tumor transforming gene (PTTG) is a protooncogene implicated in the pathogenesis of multiple tumor types, which stimulates fibroblast growth factor-2 secretion via PTTG binding factor (PBF). OBJECTIVE: The aim of this study was to ascertain whether PBF expression is associated with thyroid cancer outcome. DESIGN: PBF expression was measured at the mRNA and protein level. Tissue was collected during surgery, with normal samples being taken from the contralateral lobe. In vitro studies ascertained the ability of PBF to transform cells and form tumors in nude mice and its subcellular localization. SETTING: The study was conducted at a primary care/referral center. PATIENTS: Thyroid tumors were collected from a series of 27 patients undergoing surgical excision of papillary and follicular thyroid tumors. INTERVENTION: No intervention was conducted. MAIN OUTCOME MEASURE: The expression of PBF in thyroid cancers compared with normal thyroid, hypothesized before the investigation to be raised in tumors, was the main outcome measure. RESULTS: PBF mRNA expression was higher in differentiated thyroid carcinomas than in normal thyroid (P < 0.001; n = 27) and was independently associated with tumor recurrence (P = 0.002; R(2) = 0.49). PTTG was able to up-regulate PBF mRNA expression in vitro (P < 0.001; n = 12), and stable overexpression of PBF in NIH3T3 cells resulted in significant colony formation (P < 0.001; n = 12). In vivo, stable sc overexpression of PBF induced tumor formation in athymic nude mice. CONCLUSIONS: PBF is an additional prognostic indicator in differentiated thyroid cancer that is transforming in vitro and tumorigenic in vivo.