Clinical and pathological features of intraductal papillary neoplasm of the biliary tract and gallbladder.

BACKGROUND: Intraductal papillary neoplasms of the biliary tract (IPNB) and intracholecystic papillary neoplasms (ICPN) are rare tumours characterized by intraluminal papillary growth that can be associated with invasive carcinoma. Their natural history remains poorly understood. This study examines clinicopathological features and outcomes. METHODS: Patients who underwent surgery for IPNB/ICPN (2008-2014) were identified. Descriptive statistics and survival data were generated. RESULTS: Of 23 patients with IPNB/ICPN, 10 were male, and the mean age was 68 years. The most common presentations were abdominal pain (n = 10) and jaundice (n = 9). Tumour locations were: intrahepatic (n = 5), hilar (n = 3), the extrahepatic bile duct (n = 8) and the gallbladder (n = 7). Invasive cancer was found in 20/23 patients. Epithelial subtypes included pancreatobiliary (n = 15), intestinal (n = 7) and gastric (n = 1). The median follow-up was 30 months. The 5-year overall (OS) and disease-free survivals (DFS) were 51% and 57%, respectively. Decreased OS (P = 0.09) and DFS (P = 0.05) were seen in patients with tumours expressing MUC1 on immunohistochemistry (IHC). CONCLUSION: IPNB/ICPN are rare precursor lesions that can affect the entire biliary epithelium. At pathology, the majority of patients have invasive carcinoma, thus warranting a radical resection. Patients with tumours expressing MUC1 appear to have worse OS and DFSs.

Src promotes delta opioid receptor (DOR) desensitization by interfering with receptor recycling.

Abstract An important limitation in the clinical use of opiates is progressive loss of analgesic efficacy over time. Development of analgesic tolerance is tightly linked to receptor desensitization. In the case of delta opioid receptors (DOR), desensitization is especially swift because receptors are rapidly internalized and are poorly recycled to the membrane. In the present study, we investigated whether Src activity contributed to this sorting pattern and to functional desensitization of DORs. A first series of experiments demonstrated that agonist binding activates Src and destabilizes a constitutive complex formed by the spontaneous association of DORs with the kinase. Src contribution to DOR desensitization was then established by showing that pre-treatment with Src inhibitor PP2 (20 microM; 1 hr) or transfection of a dominant negative Src mutant preserved DOR signalling following sustained exposure to an agonist. This protection was afforded without interfering with endocytosis, but suboptimal internalization interfered with PP2 ability to preserve DOR signalling, suggesting a post-endocytic site of action for the kinase. This assumption was confirmed by demonstrating that Src inhibition by PP2 or its silencing by siRNA increased membrane recovery of internalized DORs and was further corroborated by showing that inhibition of recycling by monensin or dominant negative Rab11 (Rab11S25N) abolished the ability of Src blockers to prevent desensitization. Finally, Src inhibitors accelerated recovery of DOR-Galphal3 coupling after desensitization. Taken together, these results indicate that Src dynamically regulates DOR recycling and by doing so contributes to desensitization of these receptors.

Internalization and Src activity regulate the time course of ERK activation by delta opioid receptor ligands.

The present study showed that delta opioid receptor (deltaOR) ligands Tyr-Ticpsi [CH(2)-NH]Cha-Phe-OH (TICP) and ICI174864 behaved as inverse agonists in the cyclase pathway but induced agonist responses in the ERK cascade. Unlike ligands that behaved as agonists in both pathways, and whose stimulation of ERK was marked but transient (10 min), ERK activation by ICI174864 and TICP was moderate and sustained, lasting for more than 1 h in the case of TICP. Biochemical experiments showed that duration of ERK activation by agonists and "dual efficacy ligands" was inversely correlated with their ability to trigger receptor phosphorylation and degradation. Thus, although TICP stabilized deltaORs in a conformation that did not incorporate (32)P, was not a substrate for tyrosine kinase Src, and was not down-regulated following prolonged exposure to the drug, the conformation stabilized by D-Pen-2,5-enkephalin (DPDPE) incorporated (32)P, was phosphorylated by Src, and suffered degradation within the first 2 h of treatment. Inhibition of endocytosis by sucrose prolonged ERK activation by DPDPE increasing the decay half-life of the response to values that resembled those of dual efficacy ligands (from a 2-min decay t((1/2)) increased to 12 min). Src inhibitor PP2 also prolonged ERK stimulation by DPDPE. It did so by maintaining a sustained activation of the kinase at approximately 20% of maximum following an initial rapid reduction in the response. These results show that specific kinetics of ERK activation by agonists and dual efficacy ligands are determined, at least in part, by the differential ability of the two types of drugs to trigger mechanisms regulating deltaOR responsiveness.