RESUMO
PURPOSE: hENT1 is a transmembrane protein which acts as a nucleoside transporter and is the main mediator of Gemcitabine (GEM) uptake into human cells. In this retrospective study we compared GEM versus FOLFIRINOX in patients with metastatic pancreatic cancer in which hENT1 evaluation was available. METHODS: 149 patients affected by unresectable metastatic pancreatic cancer, treated in our institution from 2009 to 2013, have been screened for inclusion in this retrospective study. Seventy patients, treated with GEM or FOLFIRINOX in first-line therapy, fulfilled clinical inclusion criteria for survival analysis. Thirty-one patients were available and contained sufficient quality/quantity RNA for evaluation of hENT1 expression by RT-PCR. The primary endpoint was OS and the secondary endpoint was PFS. RESULTS: The survival analysis, carried out on 70 patients regardless of hENT1 expression, showed a statistically longer OS and PFS in the group treated with FOLFIRINOX compared to GEM. Within the exploratory analysis, which included 31 patients, no differences were found in hENT1 positive patients treated with FOLFIRINOX compared to GEM in terms of OS (8.5 vs 7 months, HR: 0.89; 95 % CI 0.3-2.5; p = 0.8) and PFS (5.5 vs 5 months, HR: 0.8, 95 % CI 0.2-2.2; p = 0.61). GEM-treated hENT1 positive patients showed a statistically significant improvement both of OS (8 vs 2 months; p = 0.0012) and PFS (5 vs 1 months; p = 0.0004) in comparison to GEM-treated hENT1 negative patients. CONCLUSIONS: In our exploratory analysis GEM seems as effective as FOLFIRINOX in terms of survival with a better safety profile in hENT1 positive metastatic pancreatic cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Capecitabina/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano , Leucovorina/administração & dosagem , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Gencitabina , Neoplasias PancreáticasRESUMO
Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by a progressive oral and ocular dryness that correlates poorly with the autoimmune damage of the glands. It has been proposed that a loss of homeostatic equilibrium in the glands is partly responsible for salivary dysfunction with acinar cells involved actively in the pathogenesis of SS. The non-obese diabetic (NOD) mouse model of Sjögren's syndrome develops secretory dysfunction and early loss of glandular homeostatic mechanisms, with mild infiltration of the glands. Based on the vasodilator, prosecretory and trophic effects of the vasoactive intestinal peptide (VIP) on acini as well as its anti-inflammatory properties we hypothesized that the local expression of VIP/vasoactive intestinal peptide receptor (VPAC) system in salivary glands could have a role in acinar cell apoptosis and macrophage function thus influencing gland homeostasis. Here we show a progressive decline of VIP expression in submandibular glands of NOD mice with no changes in VPAC receptor expression compared with normal mice. The deep loss of endogenous VIP was associated with a loss of acinar cells through apoptotic mechanisms that could be induced further by tumour necrosis factor (TNF)-α and reversed by VIP through a cyclic adenosine-5'-monophosphate (cAMP)/protein kinase A (PKA)-mediated pathway. The clearance of apoptotic acinar cells by macrophages was impaired for NOD macrophages but a shift from inflammatory to regulatory phenotype was induced in macrophages during phagocytosis of apoptotic acinar cells. These results support that the decline in endogenous VIP/VPAC local levels might influence the survival/apoptosis intracellular set point in NOD acinar cells and their clearance, thus contributing to gland homeostasis loss.