Pathologic Tumor Regression is Associated With Improved Survival in Pancreatic Cancer.

OBJECTIVES: The advent of effective chemotherapy regimens has increased the use of neoadjuvant multiagent chemotherapy in pancreatic cancer. However, the effect of tumor downstaging with neoadjuvant treatment on survival is unclear. METHODS: Retrospective study included all resected patients with pancreatic adenocarcinoma who underwent neoadjuvant chemotherapy with FOLFIRINOX or gemcitabine/Abraxane. Downstaging was quantified using (1) difference between presenting AJCC clinical and final pathologic stage and (2) College of American Pathologists (CAP) Tumor Regression Grading Schema. RESULTS: Eighty-seven patients met inclusion criteria. FOLFIRINOX was the most common regimen, 63.2% vs 21.8%. Change in regimen occurred in 15% of patients. Downstaging based on a difference in AJCC stage group occurred in only 4.6%. In contrast, 45.2% were classified as downstaged by the CAP Tumor Regression of 0-2. Downstaging was similar for FOLFIRINOX gemcitabine/Abraxane (64.7 vs 53.6, P = .12) using the CAP criteria. On univariate analysis, treatment regimen (gemcitabine/Abraxane vs FOLFIRINOX, median survival 27 vs 29 mo; HR 1.57, P = .2) had similar survival. Downstaging by the AJCC stage was not associated with improved survival (HR 1.51, P = .4). However, there was a survival benefit for those downstaged by the CAP Tumor Regression Grading Schema, the median survival of 41 mo vs 25 mo; HR 3.05, P = .009. Improved survival 3.32 (1.35-8.16), P = .009) was maintained on multivariate analysis. CONCLUSION: Survival is significantly improved in those downstaged, as assessed by the CAP Tumor Regression Schema. Downstaging is an important prognostic variable that can help with joint decision making for clinicians and patients.

Antimicrobial agent triclosan suppresses mast cell signaling via phospholipase D inhibition.

Humans are exposed to the antimicrobial agent triclosan (TCS) through use of TCS-containing products. Exposed tissues contain mast cells, which are involved in numerous biological functions and diseases by secreting various chemical mediators through a process termed degranulation. We previously demonstrated that TCS inhibits both Ca2+ influx into antigen-stimulated mast cells and subsequent degranulation. To determine the mechanism linking the TCS cytosolic Ca2+ depression to inhibited degranulation, we investigated the effects of TCS on crucial signaling enzymes activated downstream of the Ca2+ rise: protein kinase C (PKC; activated by Ca2+ and reactive oxygen species [ROS]) and phospholipase D (PLD). We found that TCS strongly inhibits PLD activity within 15 minutes post-antigen, a key mechanism of TCS mast cell inhibition. In addition, experiments using fluorescent constructs and confocal microscopy indicate that TCS delays antigen-induced translocations of PKCßII, PKCδ and PKC substrate myristoylated alanine-rich C-kinase. Surprisingly, TCS does not inhibit PKC activity or overall ability to translocate, and TCS actually increases PKC activity by 45 minutes post-antigen; these results are explained by the timing of both TCS inhibition of cytosolic Ca2+ (~15+ minutes post-antigen) and TCS stimulation of ROS (~45 minutes post-antigen). These findings demonstrate that it is incorrect to assume that all Ca2+ -dependent processes will be synchronously inhibited when cytosolic Ca2+ is inhibited by a toxicant or drug. The results offer molecular predictions of the effects of TCS on other mammalian cell types, which share these crucial signal transduction elements and provide biochemical information that may underlie recent epidemiological findings implicating TCS in human health problems.