RESUMEN
BACKGROUND: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.
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Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Neoplasias Pancreáticas/sangre , Proteínas Proto-Oncogénicas p21(ras)/sangre , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante/métodos , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Humanos , Biopsia Líquida , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirugía , Pronóstico , GemcitabinaRESUMEN
INTRODUCTION: The atypical antipsychotic (APs) drugs have become the most widely used agents to treat a variety of psychoses because of their superiority with regard to safety and tolerability profile compared to conventional/'typical' APs. AREAS COVERED: We aimed at providing a synthesis of most current evidence about the safety and tolerability profile of the most clinically used atypical APs so far marketed. Qualitative synthesis followed an electronic search made inquiring of the following databases: MEDLINE, Embase, PsycINFO and the Cochrane Library from inception until January 2016, combining free terms and MESH headings for the topics of psychiatric disorders and all atypical APs as following: ((safety OR adverse events OR side effects) AND (aripiprazole OR asenapine OR quetiapine OR olanzapine OR risperidone OR paliperidone OR ziprasidone OR lurasidone OR clozapine OR amisulpride OR iloperidone)). EXPERT OPINION: A critical issue in the treatment with atypical APs is represented by their metabolic side effect profile (e.g. weight gain, lipid and glycaemic imbalance, risk of diabetes mellitus and diabetic ketoacidosis) which may limit their use in particular clinical samples. Electrolyte imbalance, ECG abnormalities and cardiovascular adverse effects may recommend a careful baseline and periodic assessments.
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Antipsicóticos/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Metabólicas/inducido químicamente , Enfermedades Cardiovasculares/fisiopatología , Electrocardiografía , Humanos , Enfermedades Metabólicas/fisiopatología , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
Homer proteins are linked to both dopamine and glutamate neurotransmission and are putatively involved in the mechanisms of action of psychoactive drugs. In the present study, we evaluated the effects of compounds differently impacting dopaminergic neurotransmission on the transcripts of different Homer isoforms in rat forebrain by means of in situ hybridization histochemistry. Animals were treated with the typical antipsychotic haloperidol 0.8 mg/kg, the atypical antipsychotic clozapine 15 mg/kg, the dopamine partial agonist aripiprazole 12 mg/kg and 30 mg/kg and the dopamine transporter inhibitor GBR12909 30 mg/kg in acute and chronic paradigms. Homer 1a and ania-3 were induced in the caudate-putamen by acute administration of aripiprazole 12 mg/kg, while aripiprazole 30 mg/kg had no significant effects. Furthermore, acute haloperidol and GBR12909 induced both the splice variants of Homer 1 in the caudate-putamen. In the nucleus accumbens, aripiprazole 30 mg/kg and clozapine increased Homer 1a and ania-3 transcripts in the shell, whereas haloperidol induced expression of both isoforms in core and shell. Aripiprazole 30 mg/kg increased Homer 1a in the frontal cortex. Homer 1 splice variants were both up-regulated by GBR12909 in the frontal cortex, whereas GBR12909 induced only ania-3 in the parietal cortex. In the chronic paradigm, results showed a significant induction of Homer 1a and ania-3 in the striatum by haloperidol and aripiprazole. The constitutive Homer 2 isoform was overexpressed in the lateral septum by chronic administration of haloperidol and clozapine. In the cortex the expression of Homer 1a and ania-3 was down-regulated by chronic clozapine and aripiprazole. These results may indicate a differential modulation of Homer genes by compounds differently regulating dopaminergic neurotransmission in discrete regions of the rat forebrain and suggest that Homer could be a molecular marker of the involvement of the glutamatergic postsynaptic density in antipsychotic mechanisms of action.
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Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Dopaminérgicos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Animales , Encéfalo/anatomía & histología , Proteínas Portadoras/genética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Proteínas de Andamiaje Homer , Hibridación in Situ , Masculino , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Radiografía , Ratas , Ratas Sprague-DawleyRESUMEN
The authors report the results of a study of 25 patients with Raynaud's phenomenon (primary, posttraumatic, and secondary to diffuse connective tissue diseases) treated with regional intravenous injections of guanethidine or ketanserin. These two drugs were chosen because of the different etiopathologic profiles of the conditions. All the patients showed a substantial clinical improvement with a remission of trophic lesions. Conditions secondary to connective tissue disorders did not demonstrate much improvement based on instrumental data alone, possibly because of the intrinsic limitations of the techniques used for evaluating peripheral blood flow. This specific type of pharmaceutical treatment appeared to be especially suitable for this disease owing to a combination of therapeutic efficacy and a substantial reduction in the total dosage for each patient.