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AIM: To investigate the impact of pituitary surgery on glucose metabolism and to identify predictors of remission of diabetes after pituitary surgery in patients with acromegaly. METHODS: A national multicenter retrospective study of patients with acromegaly undergoing transsphenoidal surgery for the first time at 33 tertiary Spanish hospitals (ACRO-SPAIN study) was performed. Surgical remission of acromegaly was evaluated according to the 2000 and 2010 criteria. RESULTS: A total of 604 acromegaly patients were included in the study with a total median follow up of 91 months (interquartile range [IQR] 45-163). At the acromegaly diagnosis, 23.8% of the patients had diabetes mellitus (DM) with a median glycated hemoglobin (HbA1c) of 6.9% (IQR 6.4-7.9) [51.9 mmol/mol (IQR 46.4-62.8)]. In the multivariate analysis, older age (odds ratio [OR] 1.02, 95% CI 1.00-1.05), dyslipidemia (OR 5.25, 95% CI 2.81 to 9.79), arthropathy (OR 1.39, 95% CI 2.82 to 9.79), and higher IGF-I levels (OR 1.30, 95% CI 1.05 to 1.60) were associated with a greater prevalence of DM. At the last follow-up visit after surgery, 21.1% of the DM patients (56.7% of them with surgical remission of acromegaly) experienced diabetes remission. The cure rate of DM was more common in older patients (hazard ratio [HR] 1.77, 95% CI 1.31 to 2.43), when surgical cure was achieved (HR 2.10, 95% CI 1.01 to 4.37) and when anterior pituitary function was not affected after surgery (HR 3.38, 95% CI 1.17 to 9.75). CONCLUSION: Glucose metabolism improved in patients with acromegaly after surgery and 21% of the diabetic patients experienced diabetes remission; being more frequent in patients of older age, and those who experienced surgical cure and those with preserved anterior pituitary function after surgery.
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INTRODUCTION: It is estimated that 30-40% of patients with apparently sporadic pheochromocytomas (PHEOs) have an inherited predisposition syndrome. The aim of our study was to develop a predictive model of hereditary PHEO based on the clinical, hormonal, and radiological features present at the diagnosis of patients with PHEOs. METHODS: A retrospective multicenter cohort study of patients with PHEOs with available genetic study from 18 tertiary hospitals. Clinical, biochemical, and radiological features were used to build a multivariate logistic regression model. The estimation of all possible equations was used to select the model with the best diagnostic accuracy (lower Akaike index). RESULTS: A total of 245 patients were included: 169 (69.0%) patients with sporadic PHEOs and 76 (31%) with hereditary PHEOs. The parsimonious predictive model with the highest diagnostic accuracy for the prediction of hereditary PHEO combined the variables age, non-cardiovascular disease, urinary norepinephrine levels, and tumor size. The area under the ROC curve of this model was 0.800 (0.705-0.887). Based on the predictive model, the probability of hereditary PHEO in patients older than 60 years with cardiovascular disease, high levels of urinary norepinephrine and unilateral PHEOs >60 mm was <2%. And if the age was above 80 years, lower than 1%. The probability of sporadic PHEO linearly increased with age (MH Test for linear Trend: χ2 (1) = 30.05; p < 0.001). CONCLUSION: In certain populations such as old patients with cardiovascular disease, with high levels of urinary norepinephrine and large tumors in which the probability of hereditary PHEO is very low, genetic testing could be avoided in the absence of specific suspicion.
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Neoplasias de las Glándulas Suprarrenales , Feocromocitoma , Humanos , Anciano de 80 o más Años , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/patología , Estudios de Cohortes , Pruebas Genéticas , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , NorepinefrinaRESUMEN
PURPOSE: To compare the clinical, hormonal, and radiological presentation and surgical outcomes of patients with macroadenomas presenting with pituitary apoplexy and patients not presenting pituitary apoplexy. METHODS: Multicentre retrospective study of patients presenting with macroadenomas and pituitary apoplexy in three Spanish tertiary hospitals between 2008 and 2022. We selected as control group (non-pituitary apoplexy), patients with pituitary macroadenomas without apoplexy who underwent pituitary surgery between 2008 and 2020. RESULTS: A total of 60 patients with apoplexy and 185 without apoplexy were enrolled. Patients with pituitary apoplexy were more frequently men (70% vs. 48.1%, p = 0.003), had higher prevalence of hypertension (43.3% vs. 26.0%, p = 0.011) and of obesity (23.3% vs. 9.7%, P = 0.007), were under treatment with anticoagulants more commonly (11.7% vs. 4.3%, P = 0.039) and had larger (27.5 ± 11.03 vs. 23.6 ± 12.55 mm, p = 0.035) and invasive pituitary macroadenomas more frequently (85.7% vs. 44.3%, P < 0.001) than those without apoplexy. Surgical remission was more frequent in patients with pituitary apoplexy than those without apoplexy (OR 4.55, P < 0.001), but they developed new pituitary deficits (OR 13.29, P < 0.001) and permanent diabetes insipidus (OR 3.40, P = 0.022) more commonly. However, visual improvement (OR 6.52, p < 0.001) and complete pituitary function recovery (OR 2.37, P < 0.001) was more common in patients without apoplexy. CONCLUSION: Surgical resection is more common in patients presenting with pituitary apoplexy than those without apoplexy; however, visual improvement and complete recovery of pituitary function is more common in patients without apoplexy. The risk of new pituitary deficits and permanent diabetes insipidus is higher in patients with apoplexy than in those without it.
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Adenoma , Diabetes Insípida , Apoplejia Hipofisaria , Neoplasias Hipofisarias , Masculino , Humanos , Estudios Retrospectivos , Adenoma/diagnóstico por imagen , Adenoma/cirugía , Apoplejia Hipofisaria/cirugía , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Craniopharyngioma (CP) is a rare tumor in the elderly whose clinical features and prognosis are not well known in this population. AIM: To evaluate the clinicopathological features and therapeutic outcomes of CP diagnosed in the elderly. PATIENTS AND METHODS: This was a retrospective, multicenter, national study of CP patients diagnosed over the age of 65 years and surgically treated. RESULTS: From a total of 384 adult CP patients, we selected 53 (13.8%) patients (27 women [50.9%], mean age 72.3 ± 5.1 years [range 65-83 years]) diagnosed after the age of 65 years. The most common clinical symptoms were visual field defects (71.2%) followed by headache (45.3%). The maximum tumor diameter was 2.9 ± 1.1 cm. In most patients, the tumor was suprasellar (96.2%) and mixed (solid-cystic) (58.5%). The surgical approach most commonly used was transcranial surgery (52.8%), and more than half of the patients (54.7%) underwent subtotal resection (STR). Adamantinomatous CP and papillary CP were present in 51 and 45.1%, respectively, with mixed forms in the remaining. Surgery was accompanied by an improvement in visual field defects and in headaches; however, pituitary hormonal hypofunction increased, mainly at the expense of an increase in the prevalence of diabetes insipidus (DI) (from 3.9 to 69.2%). Near-total resection (NTR) was associated with a higher prevalence of DI compared with subtotal resection (87.5 vs. 53.6%, p = 0.008). Patients were followed for 46.7 ± 40.8 months. The mortality rate was 39.6% with a median survival time of 88 (95% CI: 57-118) months. DI at last visit was associated with a lower survival. CONCLUSION: CP diagnosed in the elderly shows a similar distribution by sex and histologic forms than that diagnosed at younger ages. At presentation, visual field alterations and headaches are the main clinical symptoms which improve substantially with surgery. However, surgery, mainly NTR, is accompanied by worsening of pituitary function, especially DI, which seems to be a predictor of mortality in this population.
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Envejecimiento , Craneofaringioma , Neoplasias Hipofisarias , Anciano , Anciano de 80 o más Años , Craneofaringioma/diagnóstico , Craneofaringioma/mortalidad , Craneofaringioma/patología , Craneofaringioma/terapia , Femenino , Humanos , Masculino , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/mortalidad , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/terapia , Estudios Retrospectivos , España/epidemiologíaRESUMEN
The clinical characteristics of patients with postoperative hypoparathyroidism who recover parathyroid function more than 12 months after surgery have not been studied. We aimed to evaluate whether the intensity of replacement therapy with calcium and calcitriol is related to the late recovery of parathyroid function. We compared the demographic, surgical, pathological, and analytical features of two groups of patients: cases, i. e., late recovery patients (those who recover parathyroid function>1 year after thyroidectomy, n=40), and controls, i. e., patients with permanent hypoparathyroidism (n=260). Replacement therapy with calcium and calcitriol was evaluated at discharge of surgery, 3-6 months, 12 months, and last visit. No significant differences were found in clinical, surgical, pathological, or analytical characteristics between cases and controls. The proportion of cases who required treatment with calcium plus calcitriol at 12 months was significantly lower than that found in controls (p<0.001). Furthermore, daily calcium and calcitriol doses in controls were significantly higher than those in cases at 3-6 months (p=0.014 and p=0.004, respectively) and at 12 months (p<0.001 and p=0.043, respectively). In several models of logistic regression analysis therapy with calcium and calcitriol at 12 months was negatively related to late recovery of parathyroid function. Although delayed recuperation of parathyroid function after total thyroidectomy is uncommon (13%), follow-up beyond 12 months is necessary in patients with postoperative hypoparathyroidism, especially in those whose needs of treatment with Ca and calcitriol are reducing over time.
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Hipoparatiroidismo/rehabilitación , Glándulas Paratiroides/fisiopatología , Tiroidectomía/efectos adversos , Adulto , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Hipoparatiroidismo/etiología , Hipoparatiroidismo/fisiopatología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/fisiopatología , Complicaciones Posoperatorias/rehabilitación , Recuperación de la Función/fisiología , Estudios Retrospectivos , España , Tiroidectomía/rehabilitación , Factores de TiempoRESUMEN
It is critical to identify biomarkers and functional networks associated with aggressive thyroid cancer to anticipate disease progression and facilitate personalized patient management. We performed miRNome sequencing of 46 thyroid tumors enriched with advanced disease patients with a median follow-up of 96 months. MiRNome profiles correlated with tumor-specific histopathological and molecular features, such as stromal cell infiltration and tumor driver mutation. Differential expression analysis revealed a consistent hsa-miR-139-5p downexpression in primary carcinomas from patients with recurrent/metastatic disease compared to disease-free patients, sustained in paired local metastases and validated in publicly available thyroid cancer series. Exogenous expression of hsa-miR-139-5p significantly reduced migration and proliferation of anaplastic thyroid cancer cells. Proteomic analysis indicated RICTOR, SMAD2/3 and HNRNPF as putative hsa-miR-139-5p targets in our cell system. Abundance of HNRNPF mRNA, encoding an alternative splicing factor involved in cryptic exon inclusion/exclusion, inversely correlated with hsa-miR-139-5p expression in human tumors. RNA sequencing analysis revealed 174 splicing events differentially regulated upon HNRNPF repression in our cell system, affecting genes involved in RTK/RAS/MAPK and PI3K/AKT/MTOR signaling cascades among others. These results point at the hsa-miR-139-5p/HNRNPF axis as a novel regulatory mechanism associated with the modulation of major thyroid cancer signaling pathways and tumor virulence.
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Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/genética , MicroARNs/metabolismo , Neoplasias de la Tiroides/genética , Adulto , Anciano , Anciano de 80 o más Años , Empalme Alternativo/genética , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/metabolismo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Transducción de Señal/genética , Tasa de Supervivencia , Glándula Tiroides/patología , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patologíaRESUMEN
AIM: The ACROPRAXIS program aims to describe the management of acromegaly in Spain and provide guidance. METHODS: Ninety-three endocrinologists were organized into 13 panels to discuss the practical issues in managing acromegaly. Based on the key learnings, an online Delphi survey with 62 statements was performed, so those statements achieving consensus could be used as guidance. Statements were rated on a 9-point scale (9, full agreement; consensus > 66.6% of response in the same tertile). RESULTS: Ninety-two endocrinologists (98.8%) answered two rounds of the survey (mean age 47.6 years; 59.8% women; median 18.5 years of experience). Consensus was achieved for 49 (79%) statements. DIAGNOSIS: The levels of insulin-like growth factor I (IGFI) is the preferred screening test. If IGFI levels 1-1.3 ULN, the test is repeated and growth hormone (GH) after oral glucose tolerance test (OGTT) is assessed. A pituitary magnetic resonance is performed after biochemical diagnosis. TREATMENT: Surgery is the first treatment choice for patients with microadenoma or macroadenoma with/without optical pathway compression. Pre-surgical somatostatin analogues (SSA) are indicated when surgery is delayed and/or to reduce anaesthesia-associated risks. After unsuccessful surgery, reintervention is performed if the residual tumor is resectable, while if non-resectable, SSA are administered. Follow-up First biochemical and clinical controls are performed 1-3 months after surgery. Disease remission is considered if random GH levels are < 1 µg/L or OGTT is < 1 or ≤ 0.4 µg/L, depending on the assay's sensitivity. CONCLUSION: Current clinical management for acromegaly is homogeneous across Spain and generally follows clinical guidelines.
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Acromegalia/diagnóstico , Acromegalia/cirugía , Acromegalia/tratamiento farmacológico , Acromegalia/epidemiología , Adolescente , Adulto , Niño , Endocrinólogos , Femenino , Prueba de Tolerancia a la Glucosa , Hormona del Crecimiento/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , España/epidemiología , Adulto JovenRESUMEN
Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin analogs have also shown to be useful in the treatment of other endocrine diseases (congenital hyperinsulinism, Graves' orbitopathy, diabetic retinopathy, diabetic macular edema), non-endocrine tumors (breast, colon, prostate, lung, and hepatocellular), and digestive diseases (chronic refractory diarrhea, hepatorenal polycystosis, gastrointestinal hemorrhage, dumping syndrome, and intestinal fistula).
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Antineoplásicos Hormonales/uso terapéutico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Neoplasias Intestinales/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Somatostatina/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/patología , Oftalmopatía de Graves/tratamiento farmacológico , Oftalmopatía de Graves/patología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Neoplasias Intestinales/genética , Neoplasias Intestinales/patología , Edema Macular/tratamiento farmacológico , Edema Macular/patología , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/patología , Somatostatina/análogos & derivados , Somatostatina/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
OBJECTIVES: We aimed to compare the effectiveness of contrast-enhanced ultrasound (CEUS), technetium Tc 99m methoxyisobutylisonitrile (99m Tc-MIBI) single-photon emission computed tomographic (SPECT) scintigraphy, and high-resolution ultrasound (US) in the detection of a pathologic parathyroid gland in patients with primary hyperparathyroidism (pHPT). METHODS: Twenty-nine consecutive patients with pHPT were prospectively enrolled and underwent preoperative imaging with 99m Tc-MIBI SPECT scintigraphy, high-resolution US, and CEUS and subsequent parathyroidectomy. Contrast-enhanced US examinations were performed by an experienced examiner who was blinded to the results of scintigraphy and high-resolution US. The diagnostic performance of all of the imaging tests was analyzed in comparison with the pathologic anatomic findings. All investigations were performed at La Paz University Hospital. RESULTS: In the 29 patients (22 female and 7 male), a total of 31 parathyroid adenomas were detected: single lesions in 27 patients and a double lesion in 2 patients. Contrast-enhanced US revealed sensitivity of 66.7% (95% confidence interval [CI], 46%-82.7%) for detection of single adenomas in comparison with 77.8 % (95% CI, 57.3%-90.6) for 99m Tc-MIBI SPECT scintigraphy and 51.8% (95% CI, 32.3%-70.8%) for high-resolution US (P = .100). With CEUS, double adenomas could be detected in both cases (sensitivity, 100%); however, scintigraphy and high-resolution US did not detect any cases of double adenomas. In addition, CEUS allowed the differentiation of lymphatic nodes from parathyroid glands in 2 patients. No side effects were observed for CEUS. CONCLUSIONS: In our study, CEUS facilitated the detection and diagnosis of double adenomas compared with high-resolution US and 99m Tc-MIBI SPECT scintigraphy. Additionally, CEUS was useful in the differentiation between parathyroid adenomas and lymph nodes.
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Medios de Contraste , Hiperparatiroidismo Primario/diagnóstico por imagen , Aumento de la Imagen/métodos , Cuidados Preoperatorios/métodos , Ultrasonografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Organotecnecio , Glándulas Paratiroides/diagnóstico por imagen , Estudios Prospectivos , Radiofármacos , Sensibilidad y Especificidad , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
BACKGROUND: Efficacy of the GH-receptor antagonist pegvisomant (PEG) has differed between preclinical and observational studies mainly due to dose adjustment and IGF-I normalization criteria. An escape phenomenon has also been described, but its definition and underlying causes have not been fully established. OBJECTIVE: To re-evaluate the outcomes of long-term PEG in a series of previously published patients and analyse the escape phenomenon. METHODS: We reviewed all patients with acromegaly resistant to SSA in whom PEG was started as monotherapy, who had been included in a previous publication. We prospectively evaluated 64 (56·3% women) from six tertiary care referral hospitals in Spain, for whom data as of June 2014 were available. Escape to PEG was defined as confirmed loss of biochemical control (IGF-I >1·2xULN), after at least 6 months of previous control with a stable dose of PEG. RESULTS: Patients were followed up for 13·0 (5·9-34·8) years since diagnosis, and 9·0 (4·1-10·4) years since the first administration of PEG. Fifty-one (89·5%) patients had an adequate IGF-I control at the last follow-up visit, 9 of them without treatment. Tumour growth was reported in 6 of 64 cases (9·4%), none of whom had received prior radiotherapy (P = 0·011). Seven patients died during follow-up. We found 16 escapes in 10 patients (15·6%). We identified potential underlying causes in 9 cases (tumour regrowth, previous treatment modifications, concomitant menopause and change in testosterone administration). The reason was unknown in 7 escapes, which occurred in 6 patients (9·4%). All patients, except one, achieved subsequent biochemical control after treatment adjustment. CONCLUSIONS: We reassure the efficacy and safety of long-term PEG. An escape phenomenon may occur, but it can be overcome by adjusting therapy.
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Acromegalia/tratamiento farmacológico , Hormona de Crecimiento Humana/análogos & derivados , Acromegalia/metabolismo , Adulto , Anciano , Femenino , Estudios de Seguimiento , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Receptores de Somatotropina/antagonistas & inhibidores , Receptores de Somatotropina/metabolismo , España , Centros de Atención Terciaria , Factores de Tiempo , Resultado del TratamientoRESUMEN
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.
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Neoplasias de las Glándulas Suprarrenales/genética , Pruebas Genéticas , Mutación de Línea Germinal , Neoplasias de Cabeza y Cuello/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias Torácicas/genética , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Niño , Práctica Clínica Basada en la Evidencia , Femenino , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/diagnóstico , Humanos , Masculino , Mutación , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias Torácicas/diagnósticoRESUMEN
Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome-wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in four well-defined Southern European case-control collections contributing a total of 1,422 cases and 1,908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR = 1.64, p = 1.0 × 10(-22) , rs7037324: OR = 1.54, p = 1.2 × 10(-17) ). Moreover, the rare alleles of three SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR = 1.35, p = 1.2 × 10(-04) , OR = 1.26, p = 5.2 × 10(-04) and OR = 1.38, p = 5.9 × 10(-05) , respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR = 0.82, p = 2.0 × 10(-04) ). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease.
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Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 6/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Femenino , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , España , Adulto JovenRESUMEN
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Mutación , Paraganglioma Extraadrenal/complicaciones , Paraganglioma Extraadrenal/genética , Feocromocitoma/genética , Policitemia/complicaciones , Policitemia/genética , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/química , Aberraciones Cromosómicas , Cromosomas Humanos Par 2 , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hipoxia/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Dominios y Motivos de Interacción de Proteínas/genética , Adulto JovenRESUMEN
Medullary thyroid carcinoma accounts for 2% to 5% of thyroid malignancies, of which 75% are sporadic and the remaining 25% are hereditary and related to multiple endocrine neoplasia type 2 syndrome. Despite a genotype-phenotype correlation with specific germline RET mutations, knowledge of pathways specifically associated with each mutation and with non-RET-mutated sporadic MTC remains lacking. Gene expression patterns have provided a tool for identifying molecular events related to specific tumor types and to different clinical features that could help identify novel therapeutic targets. Using transcriptional profiling of 49 frozen MTC specimens classified as RET mutation, we identified PROM1, LOXL2, GFRA1, and DKK4 as related to RET(M918T) and GAL as related to RET(634) mutation. An independent series of 19 frozen and 23 formalin-fixed, paraffin-embedded (FFPE) MTCs was used for validation by RT-qPCR. Two tissue microarrays containing 69 MTCs were available for IHC assays. According to pathway enrichment analysis and gene ontology biological processes, genes associated with the MTC(M918T) group were involved mainly in proliferative, cell adhesion, and general malignant metastatic effects and with Wnt, Notch, NFκB, JAK/Stat, and MAPK signaling pathways. Assays based on silencing of PROM1 by siRNAs performed in the MZ-CRC-1 cell line, harboring RET(M918T), caused an increase in apoptotic nuclei, suggesting that PROM1 is necessary for survival of these cells. This is the first report of PROM1 overexpression among primary tumors.
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Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Neoplasias de la Tiroides/genética , Antígeno AC133 , Antígenos CD/metabolismo , Apoptosis/genética , Carcinoma Neuroendocrino , Línea Celular Tumoral , Análisis por Conglomerados , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Glicoproteínas/metabolismo , Humanos , Inmunohistoquímica , Patrón de Herencia/genética , Péptidos/metabolismo , ARN Interferente Pequeño/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Tiroides/patologíaRESUMEN
BACKGROUND: Pegvisomant is an effective treatment for acromegaly. OBJECTIVE: To investigate escape (loss of biochemical control in patients previously controlled) and lipodystrophy in acromegalic patients treated with pegvisomant and to evaluate possible associations with clinical features. PATIENTS AND METHODS: Multicentre retrospective study involving 19 Spanish centres. RESULTS: Ninety-seven patients were included (59% women, mean age at diagnosis 42 ± 13 years, 80% macroadenomas); mean follow-up on pegvisomant was 5 ± 2·5 years, and 89 (92%) achieved normal IGF-1. Escape was reported in 30/89 (34%) of responders, after a mean treatment duration of 25 ± 21 months. The mean initial dose of pegvisomant was 11 ± 5 mg/day, and mean dose at escape was 14 ± 7 mg/day. Most patients (26/30, 87%) achieved control with dose increase (57%), additional medical treatment (3%) or both (27%). Mean new dose that controlled IGF-1 after escape was 20 ± 7 mg/day. Treatments associated were somatostatin analogues (SSA in 47%), cabergoline (CAB in 47%) and both (6%). Lipodystrophy was observed in 15 patients (13 females), mild in six, moderate in six, severe in three and persistent in four. Among patients with lipodystrophy, three escaped and three were nonresponders to pegvisomant. Four patients discontinued the drug, and four had dose reductions because of lipodystrophy. It tended to be more frequent in females (P = 0·06) and in patients treated with triple association SSA+CAB+PEG (P = 0·018). No relationship between escape and clinical variables was found, except prior CAB (P = 0·04) and metformin treatment (0·02) and grade of lipodystrophy (P = 0·02). CONCLUSIONS: A significant proportion of patients treated with pegvisomant escaped (34%); however, the majority (87%) was easily controlled with either dose increase, further medical treatment or both. Lipodystrophy developed in 15%, mostly females, and influenced the response to treatment.
Asunto(s)
Adenoma/tratamiento farmacológico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/análogos & derivados , Lipodistrofia/inducido químicamente , Receptores de Somatotropina/antagonistas & inhibidores , Adenoma/metabolismo , Adulto , Antineoplásicos/uso terapéutico , Cabergolina , Quimioterapia Combinada , Ergolinas/uso terapéutico , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Inyecciones Subcutáneas , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Octreótido/uso terapéutico , Estudios Retrospectivos , España , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVE: Nodal metastases in the central compartment are frequent in papillary thyroid cancer (PTC). However, they are mostly micrometastases with no impact on survival and their relevance on the risk of locoregional relapse is controversial. There is no consensus regarding optimal management of the central neck in patients with PTC cN0. In our center, we do not perform prophylactic central neck dissection (pCND). The objective of this study is to review our long-term results and compare them with the most recent literature. PATIENTS AND METHODS: Retrospective review of patients with PTC who underwent total thyroidectomy (TT) without CND between 2005 and 2017. Primary result was disease-free survival in the neck (DFS). RESULTS: 321 patients were identified, mostly T1-T2 tumors (94.1%). Median follow-up was 90 months. DFS in the central compartment was excellent (96.1% at 10 year's follow-up). 19 patients had cervical recurrence, of which 15 underwent salvage surgery. On their last visit, including salvage surgery when appropriate, 77% of patients had excellent response, 18.7% had indeterminate response, 3.1% had biochemically incomplete response and 1.2% had morphologically incomplete response. Recurrent laryngeal nerve (RLN) paralysis after TT was transient in 4.7% of patients and permanent in 0.9% of patients. There were no RLN paralysis after salvage surgery. Permanent hypoparathyroidism occurred in 3.4% of patients. Only one patient had hypoparathyroidism after salvage surgery and it was permanent. CONCLUSIONS: Based on long-term results and low rate of complications associated with salvage surgery in our experience, we consider routine pCND is not justified.
Asunto(s)
Disección del Cuello , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Tiroidectomía , Humanos , Estudios Retrospectivos , Masculino , Femenino , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patología , Persona de Mediana Edad , Adulto , Cáncer Papilar Tiroideo/cirugía , Tiroidectomía/métodos , Anciano , Supervivencia sin Enfermedad , Recurrencia Local de Neoplasia , Adulto Joven , Metástasis Linfática , Resultado del Tratamiento , Adolescente , Terapia Recuperativa , Anciano de 80 o más Años , Carcinoma Papilar/cirugíaRESUMEN
PURPOSE: To identify clinical and radiological factors associated with a higher risk of developing a severe pituitary apoplexy (PA). METHODS: Multicenter retrospective study of patients presenting with clinical PA in three Spanish tertiary hospitals of Madrid between 2008 and 2022. We classified PA as severe when presenting with an altered level of consciousness (Glasgow Coma Scale (GCS) < 15) or visual involvement. RESULTS: A total of 71 PA cases were identified, of whom 80.28% (n = 57) were classified as severe PA. The median age was 60 (18 to 85 years old) and 67.6% (n = 48) were male. Most patients had macroadenomas, except for one patient with a microadenoma of 9 mm. Headache was the most common presenting symptom (90.1%) and anticoagulation was the most frequent predisposing risk factor, but it was not associated with a higher risk for severe PA (odds ratio [OR] 1.13 [0.21-5.90]). Severe cases were associated with male gender (OR 5.53 [1.59-19.27]), tumor size >20 mm (OR 17.67 [4.07-76.64]), and Knosp grade ≥2 (OR 9.6 [2.38-38.73]). In the multivariant analysis, the only variables associated with a higher risk for severe PA were tumor size and Knosp grade. Surgery was more common in severe PA than in non-severe (91.2% vs. 64.3%, P = 0.009). CONCLUSION: A tumor size >20 mm and cavernous sinus invasion are risk factors for developing a severe PA. These risk factors can stratify patients at a higher risk of a worse clinical picture, and subsequently, more need of decompressive surgery.
RESUMEN
Medical treatment of acromegaly is currently performed through a trial-error approach using first generation somatostatin receptor ligands (fgSRLs) as first-line drugs, with an effectiveness of about 50%, and subsequent drugs are indicated through clinical judgment. Some biomarkers can predict fgSRLs response. Here we report the results of the ACROFAST study, a clinical trial in which a protocol based on predictive biomarkers of fgSRLs was evaluated. METHODS AND SUBJECTS: prospective trial (21 university hospitals) comparing the effectiveness and time-to control of two treatment protocols during 12 months: A) A personalized protocol in which first option were fgSRLs as monotherapy or in combination with pegvisomant or, pegvisomant as monotherapy depending on the short Acute Octreotide Test (sAOT) results, tumor T2 Magnetic Resonance (MRI) signal or immunostaining for E-cadherin and, B) A control group with treatment always started by fgSRLs and the other drugs included after demonstrating inadequate control. RESULTS: Eighty-five patients participated; 45 in the personalized and 40 in the control group. More patients in the personalized protocol achieved hormonal control compared to those in the control group (78% vs 53%, p < 0.05). Survival analysis revealed a hazard ratio for achieving hormonal control adjusted by age and sex of 2.53 (CI 1.30-4.80). Patients from personalized arm were controlled in a shorter period of time (p = 0.01). CONCLUSION: Personalized medicine is feasible using a relatively simple protocol and allows a higher number of patients achieving control in a shorter period of time.
RESUMEN
PURPOSE: To evaluate differences in clinical presentation and in surgical outcomes between growth hormone-secreting pituitary adenomas (GH-PAs) and GH and prolactin co-secreting pituitary adenomas (GH&PRL-PAs). METHODS: Multicenter retrospective study of 604 patients with acromegaly submitted to pituitary surgery. Patients were classified into two groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal and IHC for GH and PRL was positive or PRL levels were >100ng/and PRL IHC was not available (n=130) and b) GH-PAs who did not meet the previously mentioned criteria (n=474). RESULTS: GH&PRL-PAs represented 21.5% (n=130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P<0.001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs. 77.4%, P=0.001) and tended to be more invasive (33.6% vs. 24.7%, P=0.057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (OR 2.8, 95% CI 1.83-4.38). IGF-1 upper limit of normality (ULN) levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [IQR 1.73-3.29] vs. 2.7 [IQR 1.91-3.67], P=0.023). There were no differences in the immediate (41.1% vs 43.3%, P=0.659) or long-term post-surgical acromegaly biochemical cure rate (53.5% vs. 53.1%, P=0.936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs. 2.4%, P=0.011) in GH&PRL-PAs patients. CONCLUSIONS: GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.