Asunto(s)
Neoplasias de la Corteza Suprarrenal , Neoplasias de las Glándulas Suprarrenales , Carcinoma Corticosuprarrenal , Feocromocitoma , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/epidemiología , Neoplasias de la Corteza Suprarrenal/terapia , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/terapia , Carcinoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/epidemiología , Carcinoma Corticosuprarrenal/terapia , Estudios de Seguimiento , Humanos , Feocromocitoma/diagnóstico , Feocromocitoma/epidemiología , Feocromocitoma/terapiaRESUMEN
BACKGROUND: Wnt/ß-catenin signaling pathway activation plays an important role in adrenocortical tumorigenesis, but is only in part related to ß-catenin activating somatic mutations. Recently, genetic alteration in AXIN2, a key component of the Wnt/ß-catenin signaling pathway, has been described in adrenocortical tumors and specifically in adrenocortical carcinoma (ACC). AIM: To assess frequency and consequences of AXIN genes alteration on a large cohort of ACC. PATIENTS AND METHODS: Forty-nine adult sporadic ACC, with expression data available, in addition to both ACC cell lines H295 and H295R were studied. AXIN2 exon 8 hot-spot sequencing was performed on the entire cohort. AXIN1 entire coding region was studied on the 8 ACC with nuclear ß-catenin staining. RESULTS: The previously described AXIN2 in-frame heterozygous 12bp deletion c2013_2024del12 was found in 1 of the 49 ACC studied (2%), in a tumor with pSer45del activating CTNNB1 mutation and nuclear ß-catenin staining. This heterozygous deletion was also found in the patient's germline DNA, extracted from peripheral blood leukocytes. This genetic alteration was also present in H295 and H295R cell lines. The single-nucleotide polymorphism rs35415678 was found with an allele frequency similar to those found in reference populations. No correlation between AXIN2 expression, AXIN2 genetic variant or nuclear ß- catenin staining was observed. No AXIN1 alterations were found in the 8 ACC studied. CONCLUSIONS: AXIN genes do not play a major role in ACC tumorigenesis and Wnt/ß-catenin signaling pathway activation. AXIN2 germline variant c2013_2024del12 is likely to be a non-pathogenic polymorphism.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Proteína Axina/genética , Vía de Señalización Wnt/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Humanos , Masculino , Persona de Mediana Edad , TranscriptomaRESUMEN
Objective Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis. Many publications in ACC report on risk factors for a poor outcome; one risk factor studied is hormonal hypersecretion (cortisol, sex-hormones, steroid precursors or aldosterone). The aim of this systematic review was to study the association between hormonal secretion and recurrence or mortality in ACC. Design Systematic review and meta-analysis. We searched PubMed, EMBASE and The Cochrane library (January 2018) for cohort studies examining the association between hormonal secretion on overall or recurrence-free survival in ACC. Methods A random-effects model meta-analysis was performed to obtain a weighted relative risk comparing cortisol-secreting and/or androgen-secreting ACCs to non-secreting tumours regarding overall and recurrence-free survival. Risk of bias assessment was performed for all studies included. Results Nineteen publications were included representing a total of 3814 patients. Most studies were generally considered low/intermediate risk of bias. Meta-analysis showed higher mortality risk for cortisol-secreting ACCs, weighted relative risk 1.71 (95% CI: 1.18-2.47) combining studies that adjusted for tumour stage; also a higher recurrence risk was found for cortisol producing ACCs, relative risk 1.43 (95% CI: 1.18-1.73). Androgen secretion was not clearly associated with survival (RR: 0.82, 95% CI: 0.60-1.12). Conclusion This systematic review and meta-analysis show that cortisol-secreting ACCs are associated with a worse overall survival; future research is needed to establish whether this association points to negative effects of cortisol action, whether it signifies a more aggressive ACC subtype or whether cortisol is merely a prognostic marker.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/sangre , Neoplasias de la Corteza Suprarrenal/mortalidad , Carcinoma Corticosuprarrenal/sangre , Carcinoma Corticosuprarrenal/mortalidad , Hidrocortisona/sangre , Neoplasias de la Corteza Suprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/diagnóstico , Estudios de Cohortes , Humanos , Hidrocortisona/metabolismo , Tasa de Supervivencia/tendenciasRESUMEN
New European guidelines for the management of adrenal incidentalomas were recently released. One of the most novel recommendations is to stop following patients when they present a typical, small and non-secreting adenoma. We report here the case of a 71-year-old man with such an adenoma, who developed an adrenocortical carcinoma (ACC) fourteen years later, with subsequent metastases and death. Clinically, he had a normal blood pressure and no sign of hormonal hypersecretion. The hormonal work-up showed no hormone excess: urinary free cortisol level was normal, the diurnal cortisol rhythm was respected and urinary catecholamine metabolites levels were normal. Computed tomography (CT) scan showed a homogeneous lesion, with a low density. The lesion remained unchanged during the five years of follow-up. Eight years after the last CT, a large right heterogeneous adrenal mass was incidentally discovered during an ultrasound examination. On CT scan, it was a 6 cm heterogeneous tumor. On hormonal work-up, there was no secretion. The patient was operated of an adrenalectomy, and the histology described an ACC with a Weiss score at 8, with no benign contingent. To our knowledge, this is the first case of an ACC occurring in a patient with prior adrenal imaging showing a typical benign adenoma.
Asunto(s)
Adenoma/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/diagnóstico por imagen , Carcinoma Corticosuprarrenal/diagnóstico por imagen , Síndromes Mielodisplásicos/fisiopatología , Adenoma/etiología , Adenoma/patología , Neoplasias de las Glándulas Suprarrenales/etiología , Neoplasias de las Glándulas Suprarrenales/patología , Glándulas Suprarrenales/patología , Glándulas Suprarrenales/cirugía , Adrenalectomía , Carcinoma Corticosuprarrenal/etiología , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/cirugía , Anciano , Europa (Continente) , Resultado Fatal , Francia , Humanos , Hallazgos Incidentales , Masculino , Clasificación del Tumor , Estadificación de Neoplasias , Guías de Práctica Clínica como Asunto , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
The isolated, in vitro whole brain of guinea-pig was used to assess some of the main physiological and pharmacological properties of the vestibulo-ocular pathways in this species. Extracellular and intracellular recordings were obtained from the vestibular, abducens and oculomotor nuclei, as well as from the abducens and oculomotor nerves, while inputs from the vestibular afferents, the visual pathways and the spinal cord were activated. The three main types of medial vestibular nucleus neurons (A, B and B+LTS), previously described on slices, were also identified in the isolated brain. They had similar membrane properties in both preparations. Eighty-five per cent of cells recorded in the vestibular nucleus responded with monosynaptic, excitatory postsynaptic potentials (latency 1.05-1.9 ms) to stimulation of the ipsilateral vestibular nerve, and were thus identified as second-order vestibular neurons. In addition, stimulation of the contralateral vestibular afferents revealed in most cases a disynaptic or trisynaptic, commissural inhibition. Second-order vestibular neurons displayed in the isolated brain a high degree of variability of their spontaneous activity, as in alert guinea-pigs. Type A neurons always exhibited a regular firing, while type B and B+LTS cells could have very irregular patterns of spontaneous discharge. Thus, type A and type B neurons might correspond, respectively, to the tonic and phasic vestibular neurons described in vivo. The regularity of spontaneous discharge was positively correlated with the amplitude of spike after hyperpolarization, and there was a trend for irregular neurons to be excited from ipsilateral vestibular afferents at shorter latencies than regular units. Synaptic activation could trigger subthreshold plateau potentials and low-threshold spikes in some of the second-order vestibular neurons. As a second step, the pharmacology of the synaptic transmission between primary vestibular afferents and second-order neurons was assessed using specific antagonists of the glutamatergic receptors. Both the synaptic field potentials and excitatory postsynaptic potentials elicited in the medial vestibular nucleus by single shock stimulation of the ipsilateral vestibular nerve were largely or, sometimes, totally blocked by 6-cyano-7-nitroquinoxaline-2,3-dione, indicating a dominating role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated glutamatergic transmission. The remaining component of the responses was completely or partially suppressed by DL-2-amino-5-phosphonovaleric acid in 35% of the cases, suggesting a concomitant, moderate involvement of N-methyl-D-asparate receptors. In addition, a synaptic response resistant to both antagonists, but sensitive to a zero Ca2+/high Mg(2+)-containing solution, was often observed. Finally, recordings from abducens and oculomotor complexes confirmed the existence in the guinea-pig of strong bilateral, disynaptic excitatory and inhibitory inputs from vestibular afferents to motoneurons of extraocular muscles, which contribute to generation of the vestibulo-ocular reflex. The functional integrity of vestibular-related pathways in the isolated brain was additionally checked by stimulation of the spinal cord and optic tract. Stimulation of the spinal cord evoked, in addition to antidromic responses in the vestibular nucleus, short-latency synaptic responses in both the vestibular nucleus and abducens motoneurons, suggesting possible recruitment of spinal afferents. Activation of visual pathways at the level of the optic chiasm often induced long latency responses in the various structures under study. These results demonstrate that the in vitro isolated brain can be readily used for detailed, functional studies of the neuronal networks underlying gaze and posture control.
Asunto(s)
Encéfalo/fisiología , Vías Nerviosas/fisiología , Núcleos Vestibulares/fisiología , Animales , Estimulación Eléctrica , Femenino , Cobayas , Técnicas In Vitro , Masculino , Potenciales de la Membrana/fisiologíaAsunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Perfilación de la Expresión Génica , Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/clasificación , Neoplasias de la Corteza Suprarrenal/mortalidad , Neoplasias de la Corteza Suprarrenal/patología , ADN de Neoplasias/genética , Humanos , Metástasis de la Neoplasia , Transcripción GenéticaRESUMEN
Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Local and distant recurrences occur in a subset of tumors classified as 'aggressive' ACC (aACC), as opposed to 'non-aggressive' ACC (naACC). In this study, we investigated whether tissue and serum microRNAs (miRNAs) are predictive of ACC prognosis. Tissue miRNA expression profiles were determined using microarrays in a test series of six adrenocortical adenomas (ACAs), six naACCs, and six aACCs. Eight miRNAs were selected for further validation by quantitative RT-PCR (ten ACAs, nine naACCs, nine aACCs, and three normal adrenals). Serum levels of five miRNAs were measured in samples from 56 subjects (19 healthy controls (HC), 14 ACA, nine naACC, and 14 aACC patients). MiR-195 and miR-335 levels were significantly decreased in both tumor and serum samples of ACC patients relative to ACA patients or HC. MiR-139-5p and miR-376a levels were significantly increased in aACC compared with naACC patients in tumor samples only. Tissue miR-483-5p was markedly upregulated in a majority of ACC compared with ACA patients or HC, but most importantly, serum miR-483-5p was detected only in aACC patients. High circulating levels of miR-483-5p or low circulating levels of miR-195 were associated with both shorter recurrence-free survival (P=0.0004 and P=0.0014 respectively) and shorter overall survival (P=0.0005 and P=0.0086 respectively). In conclusion, this study reports for the first time that circulating miR-483-5p and miR-195 are promising noninvasive biomarkers with a highly specific prognostic value for the clinical outcome of ACC patients.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/metabolismo , MicroARNs/metabolismo , Adolescente , Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Adulto JovenRESUMEN
Transcriptome studies of adrenocortical tumors have shown clear differences between adenomas and carcinomas and identified two subgroups of carcinomas with different prognoses. This review focuses on how transcriptomes have enriched our knowledge about genes previously identified by classical candidate gene approaches, uncovered novel genes relevant to adrenocortical tumor biology, helped to identify and understand specific pathway alterations, and advanced the overall translational relevance of this field of research.