Ron Receptor Tyrosine Kinase Activation Confers Resistance to Tamoxifen in Breast Cancer Cell Lines1

Although tamoxifen treatment is associated with improved survival in patients with estrogen receptor (ER)-positive breast tumors, resistance remains an important clinical obstacle. Signaling through growth factor signaling pathways, in particular through receptor tyrosine kinases, has been demonstrated to confer tamoxifen resistance in an estradiol-independent manner. The Ron receptor tyrosine kinase, a member of the c-Met family of receptors, is expressed in a number of human epithelial tumors, and elevated expression of Ron is associated with poor prognosis in women with breast cancer. In this report, we evaluated the role of Ron receptor activation in conferring resistance to tamoxifen in human and murine breast cancer cell lines. Activation of Ron by its ligand, hepatocyte growth factor-like protein (HGFL) was associated with partial rescue from tamoxifen-induced growth inhibition in Ron-expressing cell lines. Western analysis revealed that treatment of the T47D human breast cancer cell line with tamoxifen and HGFL was associated with increased phosphorylation of mitogen-activated protein kinase (MAPK) 1/2 and phosphorylation of serine residue 118 of ER. Expression of ER-dependent genes was increased in cells treated with tamoxifen and HGFL by quantitative reverse transcription-polymerase chain reaction. All of these effects were inhibited by treatment with either a Ron-neutralizing antibody or a MEK1 inhibitor, suggesting the specificity of the effect to Ron, and the involvement of the MAPK 1/2 signaling pathway. In summary, these results illustrate a novel connection between the Ron receptor tyrosine kinase and an important mechanism of tamoxifen resistance in breast cancer

A comparison of pancreaticoduodenectomy and duodenum-preserving head resection for the treatment of chronic pancreatitis

AbstractBackgroundFor chronic pancreatitis, European prospective trials have concluded that duodenum-preserving head resections (DPHR) are associated with less morbidity and similar pain relief and quality of life (QoL) outcomes compared with pancreaticoduodenectomy (PD). However, DPHR procedures are seldom performed in North America.MethodsPatients undergoing PD or DPHR for unremitting pain secondary to chronic pancreatitis were retrospectively identified. Quality of life was assessed cross-sectionally using the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ-C30) and pancreatic cancer-specific supplemental module (QLQ-PAN26).ResultsEighty-one patients underwent either a Whipple PD (n= 59) or a DPHR (Bern, Beger or Frey procedure, n= 22) for the treatment of pain caused by chronic pancreatitis over a 5-year period. The characteristics of patients undergoing DPHR and PD procedures were similar. Duration of procedure (360min vs. 245min), duration of hospital stay (12.0 days vs. 9.5 days) and estimated blood loss (535ml vs. 214ml) were all significantly less for DPHR patients (P < 0.05). Thirty-day morbidity and mortality, postoperative pain relief and QoL scores did not differ significantly between groups.ConclusionsDuodenum-preserving head resection is equally as effective as PD in relieving pain and improving QoL in chronic pancreatitis patients, and involves a shorter hospital stay and less blood loss

A Multicenter Analysis of Distal Pancreatectomy for Adenocarcinoma: Is Laparoscopic Resection Appropriate?

As compared with open distal pancreatectomy (ODP), laparoscopic distal pancreatectomy (LDP) affords improved perioperative outcomes. The role of LDP for patients with pancreatic ductal adenocarcinoma (PDAC) is not defined. Records from patients undergoing distal pancreatectomy (DP) for PDAC from 2000 to 2008 from 9 academic medical centers were reviewed. Short-term (node harvest and margin status) and long-term (survival) cancer outcomes were assessed. A 3:1 matched analysis was performed for ODP and LDP cases using age, American Society of Anesthesiologists (ASA) class, and tumor size. There were 212 patients who underwent DP for PDAC; 23 (11%) of these were approached laparoscopically. For all 212 patients, 56 (26%) had positive margins. The mean number of nodes (± SD) examined was 12.6 ±8.4 and 114 patients (54%) had at least 1 positive node. Median overall survival was 16 months. In the matched analysis there were no significant differences in positive margin rates, number of nodes examined, number of patients with at least 1 positive node, or overall survival. Logistic regression for all 212 patients demonstrated that advanced age, larger tumors, positive margins, and node positive disease were independently associated with worse survival; however, method of resection (ODP vs. LDP) was not. Hospital stay was 2 days shorter in the matched comparison, which approached significance (LDP, 7.4 days vs. ODP, 9.4 days, p = 0.06). LDP provides similar short- and long-term oncologic outcomes as compared with OD, with potentially shorter hospital stay. These results suggest that LDP is an acceptable approach for resection of PDAC of the left pancreas in selected patients