BACKGROUND In a phase 1–2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel–gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel–gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel–gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel–gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel–gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.)

Purpose: nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of secreted protein acidic and rich in cysteine (SPARC) levels with efficacy as an exploratory endpoint.Experimental Design: Patients with previously untreated MPC (N ¼ 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in pancreatic cancer mouse models in which SPARC was intact or deleted.Results: SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), from the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level [high (n ¼ 71) vs. low (n ¼ 185)] was not associated with overall survival (OS; HR, 1.019; P ¼ 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC was associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy.Conclusions: SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression.

LBA148 Background: nab-Paclitaxel (nab-P, 130 nm albumin-bound paclitaxel) provides tumor selective localization via transcytosis across the endothelium, potential tumor uptake via macropinocytosis, and improved pharmacokinetics vs cremophor-paclitaxel. In vitro, nab-P increased tumoral gemcitabine (G) levels, and in a phase I/II study in metastatic pancreatic cancer (mPC) nab-P + G showed promising activity. Methods: Patients (pts) with mPC were randomized to nab-P 125 mg/m2, followed by G 1000 mg/m2 on days 1, 8, and 15 every 4 weeks or G 1000 mg/m2 weekly for 7 weeks (cycle 1), then on days 1, 8, and 15 every 4 weeks (≥ cycle 2). For the primary endpoint of overall survival (OS), 608 events from 842 patients provided a power of 0.9 to detect a HR of 0.769 (2-side α = 0.049). Results: 861 pts received therapy. Baseline pt characteristics were well balanced. Median age was 63 years, Karnofsky performance status was 90-100 in 60% and ≤80 in 40% of pts, 43% had head of pancreas lesions, 84% had liver and 39% had lung metastases, and 52% of pts had CA19-9 ≥59 x ULN. Treatment duration was 4 vs 3 months in nab-P + G vs G. The relative protocol G dose was 75% vs 85% in nab-P + G vs G; nab-P dose was 81%. OS, progression-free survival (PFS), time to treatment failure (TTF), and overall response rate (ORR) were significantly improved in the nab-P + G arm (Table). Most common grade ≥3 AEs were neutropenia (38% vs 27%), fatigue (17% vs 7%), and neuropathy (17% vs 1%) in the nab-P + G vs G arms. Grade ≥3 neuropathy improved to grade ≤1 in 29 days. Febrile neutropenia was reported in 3% (nab-P + G) vs 1% (G) pts. Conclusions: In this multinational, multiinstitutional study, nab-P + G was well tolerated and superior to G with statistically significant and clinically meaningful results in all endpoints and across subgroups. Clinical trial information: NCT00844649. [Table: see text]

1. Cofilin 1 is overexpressed in HCC, especially in PVTT tissues. 2. Cofilin 1 is up-regulated in hypoxia condition and promotes HCC progression. 3. CFL1 binds to PLD1 and maintains PLD1 protein stability. 4. HIF-1α regulates CFL1 transcription and activates CFL1-PLD1-AKT axis in HCC.

Plasmonic noble metal nanocrystals with interior nanogaps have attracted great attention in surface-enhanced Raman scattering (SERS) applications due to the presence of built-in hotspots. Herein, we report a synthesis route to holey Au-Ag alloy nanoplates by controlled galvanic replacement with Ag nanoplates as the sacrificial template, a sulfite-coordinated Au(i) salt as the Au source, and polyvinylpyrrolidone (PVP) as the capping agent. PVP helps regulate the anisotropic growth of nanopores on the Ag nanoplates to afford a highly holey nanostructure, and the monovalent Au(i) salt plays a critical role in stabilizing these holey nanoplates by rapidly enriching Au in the alloy nanostructures. Numerical simulations and experimental results suggest that these holey Au-Ag alloy nanoplates possess enormous internal hotspots for high sensitivity in the SERS analysis, and high stability for excellent reliability of the analysis under many harsh conditions. We believe that this strategy is potentially applicable to the synthesis of many other types of plasmonic nanostructures with inherent nanogaps for many sensing and imaging applications.