RESUMEN
The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. Determination of epigenetic modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as DNA methylation at RASSF1A are frequent findings in NETs of all origins and may be associated with worse prognosis. MicroRNA signatures and histone modifications have been identified which can differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic uncertainty. Historically, candidate gene-driven approaches have yielded limited insight into the epigenetics of NET. Recent progress has been facilitated by development of high-throughput tools including second-generation sequencing and arrays for analysis of the 'epigenome' of tumour and normal tissue, permitting unbiased approaches such as exome sequencing that identified mutations of chromatin-remodelling genes ATRX/DAXX in 44% of pancreatic NETs. Epigenetic changes are reversible and therefore represent an attractive therapeutic target; to date, clinical outcomes of epigenetic therapies in solid tumours have been disappointing; however, in vitro studies on NETs are promising and further clinical trials are required to determine utility of this class of novel agents. In this review, we perform a comprehensive evaluation of epigenetic changes found in NETs to date, including rare NETs such as phaeochromocytoma and adrenocortical tumours. We suggest priorities for future research and discuss potential clinical applications and novel therapies.
Asunto(s)
Tumores Neuroendocrinos/genética , Cromatina/metabolismo , Metilación de ADN , Epigénesis Genética , Neoplasias Gastrointestinales/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pancreáticas/genéticaRESUMEN
BACKGROUND: Capecitabine plus oxaliplatin (CAPOX) is an established treatment option in colorectal cancer, but can be associated with severe toxicities. METHODS: Following reporting of severe diarrhoea and dehydration with capecitabine 2000 mg m(-2) per day plus oxaliplatin every 3 weeks (CAPOX 2000) in 2006, we instituted a policy change to reduce capecitabine dose to 1700 mg m(-2) per day (CAPOX 1700). We undertook a retrospective analysis comparing toxicities encountered before and after this dose change. RESULTS: Of the 400 patients treated, no significant differences were seen between the CAPOX 2000 and CAPOX 1700 in grades 3 and 4 diarrhoea (21% vs 19%; P=0.80), stomatitis (0% vs 1%; P=0.50) or grades 2-4 hand foot syndrome (16% vs 11%; P=0.18). Grades 3 and 4 neutropenia (9.5% vs 3.5%; P=0.03) and all grades hyperbilirubinaemia (60% vs 40%; P<0.0001) were significantly reduced with CAPOX 1700. Rates of hospitalisation due to toxicities were not different between two groups (13% vs 11%; P=0.53). CONCLUSIONS: No clinically or statistically significant differences in gastrointestinal toxicities or hospitalisation rate were seen after reducing our routine capecitabine dose from CAPOX 2000 to CAPOX 1700.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Capecitabina , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Bronchial neuroendocrine tumours account for 1-2% of all lung cancers; they are thought to arise from the neuroendocrine cells located in the bronchial mucosa. The majority of the literature available comprises surgical series and there is a scarcity of data available for the management of patients with inoperable disease. We present a series of 45 patients referred to our institution from 1998 to 2006, with a mean follow-up of 54 months. Histological diagnosis from our department was available for 39 patients, with the remainder having had histological assessment performed previously. Typical carcinoid was present in 25 cases, atypical in 9 cases, large cell neuroendocrine carcinoma in 4 and 1 case of small cell lung carcinoma. All patients were staged at time of initial diagnosis with CT scan, in addition Octreoscans were performed when appropriate. Twenty-six of these 45 cases had unresectable disease, whilst the remainder were treated with surgical resection. Initial therapy with surgical resection was performed in 19 patients, 2 of whom had undergone neo-adjuvant chemotherapy. Recurrence occurred in 7 (36.8%), average duration of disease-free survival post-surgery was 61 months. Chemotherapy was first line therapy in five cases, four achieved disease stabilization and one case had progressive disease. Somatostatin analogues were used as first line therapy in six patients, for symptom control and anti-tumour effect. Peptide receptor radionuclide therapy, with Yttrium-90 DOTA-Octreotate, was given in two cases, both of whom achieved disease stabilization for 9-12 months respectively. There was a significant difference between Stage 4 and Stage 1 disease at presentation and survival. In conclusion curative surgical resection is treatment of choice, however, chemotherapy, somatostatin analogues and peptide receptor radionuclide therapy offers palliation improving both symptoms and mortality.