RESUMEN
BACKGROUND: Although surgery is the primary treatment for ampullary cancer (AC), the benefit of adjuvant chemotherapy (CTx) has not yet been confirmed. METHODS: AC patients who were administered 5-fluorouracil(FU)/leucovorin(LV)-based CTx after curative intent surgery between 2011 and 2019 were included. Prognosis was compared between the observation (OB) and CTx groups after propensity score matching (PSM) using perioperative variables to control differences in patient characteristics. RESULTS: Before PSM, of 475 patients, those in the CTx group (n = 281) had worse 5-year overall survival (OS) (82.1% vs. 78.5%, p = 0.017) and worse 5-year recurrence-free survival (RFS) (54.9% vs. 75.7%, p < 0.001) than those in the OB group (n = 194). In addition, the CTx group had a higher rate of poor prognostic factors such as a high T stage (p < 0.001), node metastasis (p < 0.001), and poor differentiation (p < 0.001). After PSM, perioperative outcomes were comparable. In addition, there were no significant differences in OS (hazard ratio [HR], 1.085; 95% confidence interval [CI], 0.688-1.710; p = 0.726) or RFS (HR, 0.883; 95% CI, 0.613 1.272; p = 0.505) between the CTx (n = 123) and OB (n = 123) groups even after stratification by TNM stage. Intestinal subtype showed better 5-year OS (83.7% vs 33.2%, p = 0.015) and RFS (46.5% vs 24.9%, p = 0.035) rate compared with pancreatobiliary/mixed subtype. CONCLUSION: Patients who received adjuvant chemotherapy based on 5-FU/LV showed comparable oncologic outcomes to patients in the OB group even after stratification by tumor stage. The patients with intestinal subtype showed oncologic benefit for adjuvant 5-FU/LV CTx compared with pancreatobiliary or mixed subtypes.
Asunto(s)
Ampolla Hepatopancreática , Neoplasias del Conducto Colédoco , Ampolla Hepatopancreática/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Neoplasias del Conducto Colédoco/tratamiento farmacológico , Neoplasias del Conducto Colédoco/cirugía , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Estadificación de Neoplasias , Puntaje de PropensiónRESUMEN
In patients with advanced-stage cancer, cancer-associated anorexia affects treatment success and patient survival. However, the underlying mechanism is poorly understood. Here, we show that Dilp8, a Drosophila homologue of mammalian insulin-like 3 peptide (INSL3), is secreted from tumour tissues and induces anorexia through the Lgr3 receptor in the brain. Activated Dilp8-Lgr3 signalling upregulated anorexigenic nucleobinding 1 (NUCB1) and downregulated orexigenic short neuropeptide F (sNPF) and NPF expression in the brain. In the cancer condition, the protein expression of Lgr3 and NUCB1 was significantly upregulated in neurons expressing sNPF and NPF. INSL3 levels were increased in tumour-implanted mice and INSL3-treated mouse hypothalamic cells showed Nucb2 upregulation and Npy downregulation. Food consumption was significantly reduced in intracerebrospinal INSL3-injected mice. In patients with pancreatic cancer, higher serum INSL3 levels increased anorexia. These results indicate that tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals.
Asunto(s)
Anorexia/metabolismo , Encéfalo/metabolismo , Proteínas de Drosophila/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias/metabolismo , Neuropéptidos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Secuencia de Aminoácidos , Animales , Anorexia/etiología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Neoplasias del Ojo/patología , Conducta Alimentaria , Humanos , Hipotálamo/metabolismo , Insulina/sangre , Insulina/química , Insulina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/química , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones Endogámicos C57BL , Neoplasias/complicaciones , Neuronas/metabolismo , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/complicaciones , Proteínas/química , Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de SeñalRESUMEN
Pancreatic cancer has a high rate of local recurrence and poor prognosis even with adjuvant chemotherapy after curative resection. The aim of this study was to investigate if local drug delivery combined with low dose systemic chemotherapy can increase the therapeutic effect of chemotherapy while reducing systemic toxicities. Poly-L-lactic acid-based 5-FU releasing patch was fabricated by electrospinning, and its tumour killing effects were first confirmed in vitro. The 5-FU patch directly adhered to the tumour in subcutaneous and orthotopic murine models, and induced a significant decrease in tumour size. Systemic gemcitabine treatment group, 5-FU drug releasing patch group, and systemic gemcitabine plus 5-FU patch group were compared by tumour size measurement, non-invasive bio-imaging, and histology in subcutaneous models. Combination of local drug patch and systemic chemotherapy led to increased tumour suppression effects that lasted longer, as well as increased survival rate. Histology revealed higher degree of apoptosis in the combined group. Systemic toxicity was recovered within 7 days after the treatment in all mice. Conclusively, local drug delivery using biocompatible polymer patch significantly inhibited tumour growth, and combination with systemic chemotherapy was more effective than single systemic chemotherapy.