MET and ERBB2 are coexpressed in ERBB2+ breast cancer and contribute to innate resistance.

UNLABELLED: Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2(+) tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET(-)/ERBB2(+), MET(+)/ERBB2(-), and MET(+)/ERBB2(+). In a MET(+)/ERBB2(+) breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2(+) breast cancers express MET and contain MET(+)/ERBB2(+) subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance. IMPLICATIONS: ERBB2(+) breast cancers with MET(+)/ERBB2(+) subpopulations may have an innate resistance to ERBB2 inhibition and may benefit from combined MET and ERBB2 inhibition.

A double-blinded, prospective randomized controlled trial of intraperitoneal bupivacaine in laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Intraperitoneal local anesthetics have been investigated in several laparoscopic procedures that demonstrate improved postoperative pain control and reduced length of hospital stay. No published studies to date address the effectiveness of IP local anesthetics in laparoscopic gastric bypass patients (LRYGB). STUDY DESIGN: Between October 2004 and March 2005, 133 patients were prospectively studied to evaluate the efficacy of IP bupivacaine (IPB) in LRYGB. Patients were randomized to receive either bupivacaine (study group) or saline (control group), which was administered over the esophageal hiatus before dissection and bypass. All procedures were performed in a University-affiliated community-based hospital by three experienced laparoscopic gastric bypass surgeons. Outcomes variables included postoperative pain and narcotic use, length of stay, antiemetic use, cost, and pulmonary function. RESULTS: There were 65 patients within the study group and 68 control patients, with equivalent patient demographics (p > 0.05). A statistically significant decrease in oral narcotic (hydrocodone/acetaminophen, Lortab Elixir, UCB) use was seen in the experimental group relative to the control group (23.8 +/- 2.2 mL versus 33.7 +/- 3.0 mL). Material cost was greater by $0.36 per patient in the study group. All other outcomes variables (ie, length of stay, postoperative IV narcotic use, incentive spirometer volumes, visual analog pain scale, and antiemetic use) showed no considerable differences. CONCLUSIONS: IPB use during LRYGB revealed a statistically significant difference only in postoperative oral narcotic use. Possibly, the IPB can limit or prevent peritoneal irritation and reduce the need for longer narcotic use. Clinical significance was not demonstrated by our outcomes variables.