ABSTRACT
Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13C5-glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals (â¼7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.
Subject(s)
Acyltransferases/genetics , Adrenal Gland Neoplasms/genetics , Germ-Line Mutation , Paraganglioma/genetics , Pheochromocytoma/genetics , Adult , Basic Helix-Loop-Helix Transcription Factors/genetics , Carcinogenesis , Catalytic Domain , Citric Acid Cycle , DNA Methylation , Female , Gene Expression Profiling , Gene Expression Regulation , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Loss of Heterozygosity , Male , Middle AgedABSTRACT
El proceso de voluntades anticipadas permite a los pacientes dar a conocer sus preferencias. Método: estudio cualitativo de subgrupos homogéneos con pacientes con enfermedad renal crónica en programa de diálisis a través de entrevistas semiestructuradas, con el objetico de conocer su deseo de participar en la toma de decisiones sanitarias, en particular las relacionadas con el final de la vida. Resultados: de mayo a diciembre de 2012 se entrevistaron a catorce pacientes, con una mediana de edad de 66 años. Creen que reciben una información adecuada, pero reconocen que no se les habla sobre el final de la vida o la retirada de diálisis. Creen que los médicos no hablan de ello porque están centrados en otras cuestiones y no quieren entristecerles. Quieren participar en la toma de decisiones y expresar sus preferencias. En caso de deterioro neurológico severo preferirían suspender la diálisis y recibir tratamiento para no tener dolor, en su casa si es posible. Sería conveniente integrar los cuidados paliativos en la asistencia de los pacientes en diálisis (AU)
Advance Care Planning (ACP) helps communicate patients end-of-life care, particularly for older patients. Method: prospective qualitative study carried out on selected ESRD patients from a dialysis unit. The aim was to determine what was most important to the patient, if they wanted to participate in decision-making process and what degree of functional impairment they would consider intolerable. Two semi-structured interviews with each patient were performed, including their relatives. Results: from May to December 2012 fourteen patients with an average age of 66 years were interviewed. They believe that the information process is adecuate, but there is no information about the plan of care if a trasplant is not a real option. They would like to participate in decisions concerning their care and end-of-life. They would want to keep on with dialysis treatment while their quality of life continues to be acceptable for them. Respecting end-of-life care, dying without pain and to be cared for at home are the most important points for them. Patients think that doctors don ́t speak to them about end-of-life because they are focused on other aspects of care. Conclusion: although there are great opportunities to talk with ESRD patients about end-of-life care this is often not done. In cases with severe cognitive impairment they would prefer to withdraw dialysis. Then they wish to receive care at home to relieve suffering or pain. The best way to achieve this is by integrating palliative care into dialysis units (AU)
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Renal Dialysis/nursing , Renal Insufficiency/nursing , Withholding Treatment/statistics & numerical data , Withholding Treatment/trends , Palliative Care , Palliative Care/methods , Withholding Treatment/ethics , Withholding Treatment/standards , Withholding Treatment , Palliative Care/organization & administration , Palliative Care/trends , Indicators of Morbidity and MortalityABSTRACT
Con el objetivo de estudiar la frecuencia y las características de las calcificaciones mamarias de las enfermas en hemodiálisis, se investigaron 26 pacientes tratadas en nuestro hospital. Para ello, se realizaron mamografías en dos proyecciones de todas las pacientes. A una de ellas se le realizó una biopsia con aguja gruesa y un análisis histológico del material extraído. El 53,8% de las enfermas presentaban calcificaciones en las mamas, todas de características benignas. Se clasificaron en vasculares (64,28%), intersticiales (42,85%) y ductales (5,31%).En el 50% de los casos aparecían varias de ellas de forma simultánea. La presencia de calcificaciones intersticiales lo consideramos un hallazgo especialmente interesante, ya que no las detectamos en el grupo control. En el estudio, la frecuencia y el número de las calcificaciones se relacionan con la edad y con el tiempo en diálisis, no así con el producto calcio/fósforo ni con las cifras de PTH
Twenty-six patients treated at our hospital were studied to evaluate the frequency and characteristics of breast calcifications in patients undergoing hemodialysis. All patients underwent two-view mammography and one underwent core-needle biopsy. Breast calcifications were present in 53.8%; all calcifications had benign mammographic appearance. Calcifications were classified as vascular (64.28%), interstitial ( 42.85%), and ductal (5.31%).Calcifications were multiple in 50% of cases. We consider the presence of interstitial calcifications to be especially interesting, as none were detected in the control group. In this study, the frequency and number of calcifications correlated with age and time under dialysis but not with the calcium/phosphorous ratio or parathyroid hormone (PTH) values
