Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients.

BACKGROUND: Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source. METHODS: The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB. RESULTS: Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10(-4) and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS. CONCLUSIONS: We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.

Acute renal failure when exenatide is co-administered with diuretics and angiotensin II blockers.

Case (description) the patient is a 20 years old male smoker, who was diagnosed with type 2 diabetes mellitus in 2006. Due to the inadequate response to the previously established treatment, the pharmacotherapy was modified by introducing exenatide (up to 10 µg, twice daily) instead of insulin glargine, but maintaining the treatment with the diuretic and angiotensin II receptor antagonist drugs. Two months later, the patient exhibited a very important intolerance to exenatide (continuous nausea, vomiting, and dehydration), finally leading to ischemic acute renal failure. When the angiotensin II receptor antagonist and exenatide were suspended, a very rapid recovery of renal function was observed. Conclusion ischemic acute renal failure is supposed to be the consequence of the extracellular volume contraction caused by exenatide (the result of continuous nausea and vomiting). This adverse effect could be caused by the co-administration of diuretics and angiotensin II receptor antagonists.

PheoSeq: A Targeted Next-Generation Sequencing Assay for Pheochromocytoma and Paraganglioma Diagnostics.

Genetic diagnosis is recommended for all pheochromocytoma and paraganglioma (PPGL) cases, as driver mutations are identified in approximately 80% of the cases. As the list of related genes expands, genetic diagnosis becomes more time-consuming, and targeted next-generation sequencing (NGS) has emerged as a cost-effective tool. This study aimed to optimize targeted NGS in PPGL genetic diagnostics. A workflow based on two customized targeted NGS assays was validated to study the 18 main PPGL genes in germline and frozen tumor DNA, with one of them specifically directed toward formalin-fixed paraffin-embedded tissue. The series involved 453 unrelated PPGL patients, of whom 30 had known mutations and were used as controls. Partial screening using Sanger had been performed in 275 patients. NGS results were complemented with the study of gross deletions. NGS assay showed a sensitivity ≥99.4%, regardless of DNA source. We identified 45 variants of unknown significance and 89 pathogenic mutations, the latter being germline in 29 (7.2%) and somatic in 58 (31.7%) of the 183 tumors studied. In 37 patients previously studied by Sanger sequencing, the causal mutation could be identified. We demonstrated that both assays are an efficient and accurate alternative to conventional sequencing. Their application facilitates the study of minor PPGL genes, and enables genetic diagnoses in patients with incongruent or missing clinical data, who would otherwise be missed.

[The figure of a nurse educator improves HbA1c levels and lipid profile in patients with type 1 diabetes]. / La figura de la enfermera educadora hospitalaria mejora la HbA1c y el perfil lipídico de los pacientes con diabetes tipo 1.

Diabetes education has proved to be an essential tool in the care of patients with type 1 diabetes mellitus. To perform this educational task, the VII Area Murcia East Diabetes Unit, incorporated nurses in advanced diabetes education in the Hospital General Universitario Reina Sofía of Murcia. We carried out a retrospective study, which assessed the performance of these nurses by evaluating the type 1 diabetic patients attending inquiries between 2007 and 2011. We analyzed a total of 179 medical records, of patients with type 1 diabetes mellitus over 11 years, with 103 (52.3%) males and 94 (47.7%) women. Patients had a mean age 38.25 ± 14.02 years and a mean duration of diabetes of 16.22 ± 11.73 years. The initial mean value of HbA1c was 8.49 ± 2.04%. Only 37 (16.2%) of the 197 patients were under 25 at the start of the study. The results showed that the decrease in HbA1c (-0.57 ± 1.80%) was significant after 6 months (p = 0.002) from the first query, reaching values of 7.86 ± 1.39% and remained from that time. Insulin doses were stable throughout the study.

La educación diabetológica ha demostrado ser esencial en la atención del paciente diabético. Para realizar esta tarea educacional, la Unidad de Diabetes del Área VII Murcia Este, que incorporó a enfermeras especializadas en educación diabetológica avanzada en el Hospital General Universitario Reina Sofía de Murcia. Se realizó un estudio retrospectivo, donde se valoró la actuación de dichas enfermeras mediante la evaluación de los pacientes diabéticos tipo 1 que acudieron a sus consultas entre los años 2007 y 2011. Se analizaron un total de 179 historias clínicas de pacientes con diabetes mellitus tipo 1 (DM1) mayores de 11 años, siendo 103 (52.3 %) varones y 94 (47.7 %) mujeres. Los pacientes presentaban una edad media de 38.25 ± 14.02 años y un tiempo de duración de la diabetes medio de 16.22 ± 11.73 años. El valor de HbA1c inicial medio fue de 8.49 ± 2.04 %. De los 197 pacientes, solo 37 (16.2 %) eran menores de 25 años en el momento de acudir a consulta. Los resultados obtenidos demostraron que la disminución de la HbA1c (-0,57 ± 1,80 %) era significativa a los 6 meses (p: 0,002) de la primera consulta alcanzando valores de 7.86 ± 1.39 y manteniéndose a partir de ese momento. Las dosis de insulina fueron estables a lo largo del estudio.

Psychoeducative groups help control type 2 diabetes in a primary care setting.

INTRODUCTION: The purpose of this study is to measure the impact of a psychoeducational group intervention in diabetes using glycosylated haemoglobin (HbA1c), the body mass index (BMI) and cardiovascular risk factors (CVRF) compared with conventional educational measures provided individually. METHODS: A quasi-experimental study (pre/post-intervention) with a non-equivalent control group was conducted, including 72 type 2 individuals with diabetes (mean data: age 63.08 years, HbA1C 6.98%, BMI 30.48 kg/m2).The beneficial effect of psychoeducational group therapy in the study group (PGT) was compared with conventional diabetes education in the control group (CG). RESULTS: The PGT had a higher mean HbA1c reduction (-0.51 ± 1.7 vs. -0.06 ± 0.53%, p 0.003), met the objectives of optimal control of HbA1c to a higher degree (80% vs. 48%, p 0.005) and greater mean weight reduction (-1.93 ± 3.57 vs. 0.52 ± 1.73 kg, p 0002) than the CG.A significant improvement in total cholesterol, LDL cholesterol, triglycerides, systolic and diastolic blood pressure was achieved in PGT (all p < 0.05). CONCLUSIONS: PGT patients achieved a significant improvement in HbA1C, BMI and CVRF, and outperformed the conventional diabetes education group in achieving the optimal diabetes control objectives. Structural changes in the assistance programs should be considered to introduce these more efficient therapies for diabetes education in primary care.

Introducción: Los cambios en el estilo de vida mejoran el control de los diabéticos tipo 2, pero no sabemos cuales son las estrategias más eficientes para conseguir estos cambios. Hemos medido el impacto de una intervención psicoeducativa grupal en diabetes mediante hemoglobina glicosilada (HbA1c), índice de masa corporal (IMC) y factores de riesgo cardiovascular (FRCV). Métodos: Se trata de un ensayo clínico controlado, randomizado y multicéntrico, de 72 pacientes diabéticos tipo 2, edad media 63,08 AÑOs, 50% mujeres, HbA1c media 6.98% e IMC medio 30,48 kg/m2. Se comparó el efecto terapéutico de una intervención psicoeducativa grupal(GSE) con una educación diabetológica convencional (GC). Resultados: El GSE presentó una mayor reducción media de HbA1c, -0,51 ± 1,07 vs -0,06 ± 0,53% (p 0,003), un mayor grado de cumplimiento de los objetivos de control óptimo de HbA1c, 80% vs 48% (p 0,005) y una mayor reducción media de peso, -1,93 ± 3,57 vs 0,52 ± 1,73 kg (p 0,002), que el GC. También se objetivó una mejoría significativa de colesterol total, colesterol LDL, triglicéridos, tensión arterial sistólica y diastólica en GSE (todas las p < 0,05). Conclusiones: Los GSE de diabéticos tipo 2 consiguieron una mejoría significativa de HbA1c, IMC y FRCV, y superaron a la educación diabetológica convencional en el grado de cumplimiento de los objetivos de control óptimo de la diabetes. Debemos plantearnos cambios estructurales en nuestros programas asistenciales para introducir estos avances más eficientes en educación terapeútica de diabetes en atención primaria.