RESUMO
PURPOSE: Neoadjuvant therapy (NAT) is increasingly used to improve the prognosis of patients with borderline resectable pancreatic cancer (BRPC) albeit with little evidence of its advantage over upfront surgical resection. We analyzed the prognostic impact of NAT on patients with BRPC in a multicenter retrospective study. METHODS: Medical data of 165 consecutive patients who underwent treatment for BRPC between January 2010 and December 2014 were collected from ten institutions. We defined BRPC according to the National Comprehensive Cancer Network guidelines, and subclassified patients according to venous invasion alone (BR-PV) and arterial invasion (BR-A). RESULTS: The rates of NAT administration and resection were 35% and 79%, respectively. There were no significant differences in resection rates and prognoses between patients in the BR-PV and BR-A subgroups. NAT did not have a significant impact on prognosis according to intention-to-treat analysis. However, in patients who underwent surgical resection, NAT was independently associated with longer overall survival (OS). The median OS of patients who underwent resection after NAT (53.7 months) was significantly longer than that of patients who underwent upfront (17.8 months) or no resection (14.9 months). The rates of superior mesenteric or portal vein invasion, lymphatic invasion, venous invasion, and lymph node metastasis were significantly lower in patients who underwent resection after NAT than in those who underwent upfront resection despite similar baseline clinical profiles. CONCLUSIONS: Resection after NAT in patients with BRPC is associated with longer OS and lower rates of both invasion to the surrounding tissues and lymph node metastasis.
Assuntos
Adenocarcinoma/terapia , Terapia Neoadjuvante , Neoplasias Pancreáticas/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Terapia Combinada , Humanos , Metástase Linfática , Invasividade Neoplásica , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
The tumor suppressor gene p53 encodes a transcription factor that regulates various cellular functions, including DNA repair, apoptosis and cell cycle progression. Approximately half of all human cancers carry mutations in p53 that lead to loss of tumor suppressor function or gain of functions that promote the cancer phenotype. Thus, targeting mutant p53 as an anticancer therapy has attracted considerable attention. In the current study, a small-molecule screen identified andrographlide (ANDRO) as a mutant p53 suppressor. The effects of ANDRO, a small molecule isolated from the Chinese herb Andrographis paniculata, on tumor cells carrying wild-type or mutant p53 were examined. ANDRO suppressed expression of mutant p53, induced expression of the cyclin-dependent kinase inhibitor p21 and pro-apoptotic proteins genes, and inhibited the growth of cancer cells harboring mutant p53. ANDRO also induced expression of the heat-shock protein (Hsp70) and increased binding between Hsp70 and mutant p53 protein, thus promoting proteasomal degradation of p53. These results provide novel insights into the mechanisms regulating the function of mutant p53 and suggest that activation of Hsp70 may be a new strategy for the treatment of cancers harboring mutant p53.
Assuntos
Diterpenos/administração & dosagem , Proteínas de Choque Térmico HSP70/genética , Mutação , Neoplasias Experimentais/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Andrographis/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Células HCT116 , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Camundongos , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Extratos Vegetais/química , Proteólise , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Among several chemotherapeutic agents, 5-fluorouracil (5-FU) has been widely used as a key drug in adjuvant chemotherapy for gastric cancer. However, no reliable marker, which predicts the response to 5-FU in an adjuvant setting, has been identified. Hypoxia-induced drug resistance, via upregulation of HIF-1alpha, is a major obstacle in the development of effective cancer therapy. However, few clinical studies have so far assessed the relationship between the HIF-1alpha expression and the chemo-resistance of gastric cancer patients in an adjuvant setting. We established 2 HIF-1alpha knockdown gastric cancer cell lines in order to clarify the role of HIF-1alpha in chemo-resistance against 5-FU. Furthermore, expression of HIF-1alpha was immunohistochemically assessed in 91 resected specimens. Sixty-four of 91 patients received 5-FU adjuvant chemotherapy after surgery. HIF-1alpha expression was associated with the significantly shorter relapse-free survival and disease-specific survival in the 64 patients of adjuvant group (p = 0.026, 0.014, respectively), but not in the 27 of surgery group. Multivariate analysis showed that HIF-1alpha was an independent risk factor for relapse in 64 patients in the adjuvant group (p = 0.029). In conclusion, the current study confirmed, for the first time that HIF-1alpha expression is an independent risk factor for relapse in high-risk gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy. A favorable effect of 5-FU might therefore be expected in patients that do not express HIF-1alpha, whereas, other types of chemotherapy or additional treatments, such as HIF-1alpha inhibitors, should be considered in patients that do express HIF-1alpha.