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e14576 Background: To determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could differentiate between responding and non-responding locally advanced esophageal squamous cell carcinoma (ESCC) early in the course of neoadjuvant chemoradiotherapy (CRT). Methods: Patients (pts) with T3 or N1M0-1a (AJCC, 6th Ed) ESCC first received a 21-D cycle of induction chemo (paclitaxel 70 mg/m2 D 1, 8; cisplatin 30 mg/m2 D 1, 8; fluorouracil 2000 and leucovorin 300 mg/m2 24-hr D 1, 8). This was followed by concurrent CRT (paclitaxel 35 mg/m2 1-hr D 1, 4 /wk, cisplatin 15 mg/m2 1-hr D 2, 5/wk, and radiotherapy 2 Gy D 1-5 /wk) (Lin CC, et al. Ann Oncol 18:93,2007). When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated. In pts for whom esophagectomy was not feasible, concurrent CRT was continued to a dose of ≥60 Gy. Serial FDG-PETs were performed before and 14 days after start of induction chemo. Pathologic response (PR) was defined as no or microscopic residual disease. PET response was measured using the standardized uptake value (SUV). Receiver operating characteristic (ROC) analysis was used to evaluate the ability of SUV in distinguishing between PR and non-PR. Results: Of 65 pts (M:F = 60:5, median age 55, range 39-71) with locally advanced (M0:M1a = 58:7) ESCC enrolled from March 2008 to December 2011, 40 pts underwent esophagectomy and 26 pts were pathologic responders. The median SUV decrease 14 days after the start of therapy was 75.8% for pathologic responders and 30.1% for non-responders (p

Background We previously found that GADD45b, which is associated with cellular stress response and apoptosis regulation, contributes to sorafenib resistance in HCC cells. The present study explored the role of GADD45γ, another GADD45 family protein, in HCC treatment. Methods HCC cell lines tested included Huh-7, HepG2, Hep3B, Huh-7R, HepG2R, the latter two sorafenib-resistant cell lines established by continuously exposure of Huh-7 and HepG2 cells to sorafenib. GADD45γ expression was examined by quantitative real-time PCR (qRT-PCR) and western blotting. Control of GADD45γ transcription was examined by luciferase reporter assay using a series of reporter plasmids with deletions or site-directed mutants of the 5′-flanking region of GADD45γ promoter. Apoptosis was analyzed by flow cytometry and western blotting. Expression of GADD45γ in human HCC tumor tissues was measured by qRT-PCR and immunohistochemistry. Results GADD45γ mRNA and protein levels were increased after sorafenib independent of cellular MEK/ERK activity. GADD45γ induction was more prominent in sorafenib-sensitive HCC cells (Huh-7 and HepG2, IC50 6-7 µM) than in sorafenib-resistant HCC cells (Hep3B, Huh-7R and HepG2R, IC50 12-15 µM). Knockdown of GADD45γ expression partially abrogated the pro-apoptotic effects of sorafenib in sorafenib-sensitive cells but not sorafenib-resistant cells. The region -449/ - 82 in the 5′-flanking region of GADD45γ promoter was found crucial for GADD45 gamma induction by sorafenib. Decreased GADD45γ expression in HCC tumor tissue was associated with worse overall survival in patients who underwent surgery for HCC. Conclusions Induction of GADD45γ expression contributes to sorafenib-induced apoptosis in HCC cells. The role of GADD45γ as a predictive biomarker for sorafenib sensitivity in HCC warrants further exploration. (Supported by grants NSC-100-2325-B-002 -042, NSC 100-2314-B-002 -058-MY3, DOH100-TD-B-111-001, and NHRI-EX101-9911BC.)