ABSTRACT
BACKGROUND: Pleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM. METHODS: We analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA-drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up. RESULTS: While PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm2 had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm2 had a high risk of death (P=0.03) and a median survival time of 34 months. CONCLUSIONS: We shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM.
ABSTRACT
The objective of this study was to evaluate endoscopic ultrasound Trucut biopsy (TCB) specimens and compare these findings to fine needle aspiration (FNA) specimens for the diagnosis of neoplasia. FNA and TCB specimens were reviewed in blinded fashion by a cytopathologist from patients (N = 93) who had EUS-guided FNA and TCB specimens collected between July 2000 and January 2005. Specimens were categorized as nondiagnostic, negative, suspicious for stromal neoplasm, suspicious for malignancy, positive for stromal neoplasm, or positive for malignancy. Standard final diagnosis based on clinical and/or pathologic follow-up was available for 86 of 93 patients. The final diagnoses comprised malignancy (n = 55), stromal neoplasm (n = 19), and benign findings (n = 12). The combination of FNA and TCB results combined were significantly (P < 0.001) more sensitive that FNA alone for the detection of both malignancy (78% vs. 55%) and stromal neoplasia (79% vs. 19%) without a significant change in overall specificity (92% vs. 100%, P = 1.00). A positive FNA specimen with a negative/nondiagnostic TCB result was established in seven patients with malignancy. A positive TCB diagnosis with a negative/nondiagnostic FNA result was noted in five patients with malignancy. A suspicious FNA result was upgraded to positive in conjunction with TCB specimen evaluation in eight patients with malignancy. The results of this study suggest that TCB is a useful adjunctive technique when used in tandem with FNA for malignancy and stromal neoplasia detection. Additional data are needed to firmly establish practice guidelines for the use of EUS-guided TCB specimens in clinical practice.
