No abstract

Context.— Preoperative neoadjuvant therapy has been increasingly used to treat patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant therapy often induces extensive fibrosis in tumor, adjacent pancreatic parenchyma, and peripancreatic tissue. Histopathologic evaluations and histologic tumor response grading (HTRG) of posttherapy pancreatectomy specimens are very difficult and challenging. Studies on prognostic significance of posttherapy pathologic staging, optimal system for HTRG, and other pathologic parameters in treated PDAC patients are limited. Objective.— This review is to provide a timely update of the prognostic values of posttherapy pathologic staging, HTRG, and other pathologic parameters in PDAC patients who received neoadjuvant therapy and pancreas resection. Data Sources.— Systemic review of major studies on pathologic evaluation and its clinicopathologic implications in treated PDAC patients. Conclusions.— Systemic pathologic examination, histologic tumor regression grading, pathologic evaluation of the margins, tumor involvement of superior mesenteric vein/portal vein, accurate pathologic staging, and reporting of posttherapy pancreatectomy specimens provide highly valuable prognostic information for postoperative patient care. Our findings suggest for the first time that tumor size of 1.0 cm, instead of 2.0 cm, is a better cutoff for ypT2 in PDAC patients. The newly proposed 3-tier MD Anderson HTRG system not only has proved to be an independent prognostic marker for PDAC patients who received neoadjuvant therapy and pancreatectomy, but also improves interobserver agreement among pathologists in evaluation of tumor response. This grading system should be considered in future editions of the College of American Pathologists protocol for PDAC.

This easy-to-use nomogram may accurately predict survival at 1 and 3 years for individual HCC patients beyond the Milan criteria, and provide quantitative survival advantage of SR over TACE.

Oncogenic receptor tyrosine kinase (RTK) signaling through the Ras-Raf-Mek-Erk (Ras-MAPK) pathway is implicated in a wide array of carcinomas, including those of the breast. The cyclin-dependent kinases (CDKs) are implicated in regulating proliferative and survival signaling downstream of this pathway. Here, we show that CDK inhibitors exhibit an order of magnitude greater cytotoxic potency than a suite of inhibitors targeting RTK and Ras-MAPK signaling in cell lines representative of clinically recognized breast cancer (BC) subtypes. Drug combination studies show that the pan-CDK inhibitor, flavopiridol (FPD), synergistically potentiated cytotoxicity induced by the Raf inhibitor, sorafenib (SFN). This synergy was most pronounced at sub-EC50 SFN concentrations in MDA-MB-231 (KRAS-G13D and BRAF-G464V mutations), MDA-MB-468 [epidermal growth factor receptor (EGFR) overexpression], and SKBR3 [ErbB2/EGFR2 (HER-2) overexpression] cells but not in hormone-dependent MCF-7 and T47D cells. Potentiation of SFN cytotoxicity by FPD correlated with enhanced apoptosis, suppression of retinoblastoma (Rb) signaling, and reduced Mcl-1 expression. SFN and FPD were also tested in an MDA-MB-231 mammary fat pad engraftment model of tumorigenesis. Mice treated with both drugs exhibited reduced primary tumor growth rates and metastatic tumor load in the lungs compared to treatment with either drug alone, and this correlated with greater reductions in Rb signaling and Mcl-1 expression in resected tumors. These findings support the development of CDK and Raf co-targeting strategies in EGFR/HER-2-overexpressing or RAS/RAF mutant BCs.