Preoperative imaging characteristics predict poor survival and inadequate resection for left-sided pancreatic adenocarcinoma: a multi-institutional analysis.

BACKGROUND: Optimal treatment of pancreatic ductal adenocarcinoma of the neck, body and tail (PDAC-NBT) necessitates R0 surgical resection. Preoperative radiographic identification of patients likely to achieve successful oncologic resection remains difficult. This study seeks to identify preoperative imaging characteristics predictive of non-R0 resections or impaired survival for PDAC-NBT. METHODS: Patients at five high-volume centers who underwent resection for PDAC-NBT were retrospectively analyzed. The most immediate preoperative cross-sectional scan was assessed along with outcome measures of overall survival and margin status. RESULTS: 330 patients were treated between 2001 and 2016. Margin status included 247 R0 (78.2%), 67 R1 (21.2%), and 2 R2 (0.6%). A non-R0 resection predicted worse survival (p = 0.0002). On preoperative imaging, patients with tumors greater than 20 mm, tumor attenuation greater than 70 Hounsfield units, or who demonstrated pancreatic atrophy and/or calcifications also had worse survival (p = 0.010, p = 0.036, p = 0.025 respectively). Patients with tumors interfacing with the splenic artery or vein or extending posteriorly achieved fewer R0 resections (p = 0.0006, p = 0.0004, p = 0.001, respectively). CONCLUSION: Preoperative cross-sectional imaging can identify tumor characteristics associated with poor survival and non-R0 resection. Further investigation is needed to identify the appropriate surgical and treatment modifications necessary to clinically benefit this subset of patients.

A pyridazine series of alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety.

The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.

Discovery of imidazo[1,2-b][1,2,4]triazines as GABA(A) alpha2/3 subtype selective agonists for the treatment of anxiety.

The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.

Imidazo[1,2-a]pyrimidines as functionally selective GABA(A) ligands.

Imidazo[1,2-a]pyrimidines are GABA(A) receptor benzodiazepine binding site ligands which can exhibit functional selectivity for the alpha(3) subtype over the alpha(1) subtype. SAR studies to optimize this functional selectivity are described.

Imidazo[1,2-b][1,2,4]triazines as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety.

Imidazo[1,2-a]pyrimidines and imidazo[1,2-b][1,2,4]triazines are ligands for the benzodiazepine binding site of GABA(A) receptors that are functionally selective for the alpha2/alpha3 subtypes over the alpha1 subtype. SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are described.