RESUMO
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.
Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/cirurgia , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
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.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Agonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A , Piridazinas/farmacologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/síntese química , Sítios de Ligação , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/síntese química , Humanos , Ligantes , Estrutura Molecular , Piridazinas/administração & dosagem , Piridazinas/síntese química , Ratos , Proteínas Recombinantes/agonistas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Ansiolíticos/síntese química , Agonistas de Receptores de GABA-A , Imidazóis/síntese química , Triazinas/síntese química , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Disponibilidade Biológica , Meia-Vida , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas de Patch-Clamp , Ensaio Radioligante , Ratos , Receptores de GABA-A/fisiologia , Saimiri , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologiaRESUMO
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.
Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Agonistas de Receptores de GABA-A , Imidazóis/farmacologia , Subunidades Proteicas/agonistas , Triazinas/farmacologia , Administração Oral , Animais , Ataxia/tratamento farmacológico , Sítios de Ligação , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Feminino , Agonistas GABAérgicos/farmacocinética , Agonistas GABAérgicos/farmacologia , Imidazóis/farmacocinética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Estrutura Molecular , Subunidades Proteicas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Saimiri , Relação Estrutura-Atividade , Triazinas/farmacocinéticaRESUMO
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.