Contribution of molecular analysis to the typification of the non-functioning pituitary adenomas.

AIM: The WHO Classification of Tumours of Endocrine Organs considers the inmunohistochemical characterization of pituitary adenomas (PA) as mandatory for patient diagnosis. Recent advances in the knowledge of the molecular patterns of these tumours could complement this classification with gene expression profiling. METHODS: Within the context of the Spanish Molecular Registry of Pituitary Adenomas (REMAH), a multicentre clinical-basic research project, we analysed the molecular phenotype of 142 PAs with complete IHC and clinical information. Gene expression levels of all pituitary hormones, type 1 corticotrophin-releasing hormone receptor, dopamine receptors and arginine vasopressin receptor 1b were measured by quantitative real-time polymerase chain reaction. In addition, we used three housekeeping genes for normalization and a pool of nine healthy pituitary glands from autopsies as calibration reference standard. RESULTS: Based on the clinically functioning PA (FPA: somatotroph, corticotroph, thyrotroph and lactotroph adenomas), we established the interquartile range of relative expression for all genes studied in each PA subtype. That allowed molecularly the different PA subtypes, including the clinically non-functioning PA (NFPA). Afterwards, we estimated the concordance of the molecular and immunohistochemical classification with clinical diagnosis in FPA and between them in NFPA. The kappa values were higher in molecular than in immunohistochemical classification in FPA and showed a bad concordance in all NFPA subtypes. CONCLUSIONS: According to these results, the molecular characterization of the PA complements the IHC analysis, allowing a better typification of the NFPA.

Severe sleep apnea–hypopnea syndrome is related to left ventricle dysfunction and hypertrophy in acromegalic patients / El síndrome de apnea-hipoventilación del sueño grave se asocia a disfunción del ventrículo izquierdo e hipertrofía cardíaca en pacientes acromegálicos

OBJECTIVE: To assess whether sleep apnea-hypopnea syndrome (SAHS) is a risk factor for development of acromegalic cardiomyopathy. METHODS: A descriptive, cross-sectional study of 32 patients with acromegaly (15 categorized as non-controlled-NCA and 17 as controlled-CA) compared to 20 matched controls (by sex, age, and BMI) referred to the pulmonology department for suspected SAHS. Polysomnography, echocardiography (M-mode, 2-dimensional, and Doppler), and 12-lead electrocardiography were performed in all participants. Development of cardiac morbidity (ischemia heart disease or heart failure) was evaluated after 7 years. RESULTS: SAHS was diagnosed in 81.3% of patients with acromegaly and 85% of controls. Mild SAHS was more common in CA than in NCA patients (31.3% vs. 0%, p = 0.048). There was a trend to greater prevalence of left ventricular diastolic dysfunction (LVDD) in acromegalic patients as compared to controls (58.1% vs. 30%, p = 0.05). Presence of severe SAHS in patients with acromegaly was related to greater risk of LVDD (90.9% vs. 40%, p = 0.008; OR 2.3 [1.3-4.0]), LV hypertrophy (55.6% vs. 10.5%,p = 0.02; OR 5.3 [1.3-22.2]), and cardiac events (87.5% vs. 35.6%; p = 0.01; OR 7.53 [1.07-53.24]). CONCLUSION: SAHS is highly prevalent in patients with acromegaly. Only in these patients was severe SAHS associated to hypertrophy, LV diastolic dysfunction, and cardiac events

ANTECEDENTES Y OBJETIVO: La acromegalia se asocia con el síndrome de apnea-hipopnea del sueño (SAHS) y cambios a nivel cardíaco. Nuestro objetivo es evaluar si la presencia de SAHS es un factor de riesgo de desarrollo de cardiomiopatía acromegálica. MATERIAL Y MÉTODO: Estudio transversal descriptivo de 32 pacientes acromegálicos (15 clasificados como no-controlados-NCA- y 17 como controlados-CA-) comparados con 20 controles pareados (en sexo, edad e IMC) derivados al Servicio de Neumología por sospecha de SAHS. Se realizó polisomnografía, ecocardiografía (M-modo, 2-dimensiones, y Doppler) y electrocardiograma de 12-derivaciones a todos los participantes. Tras 7 años, se evaluó el desarrollo de morbilidad cardiológica (isquemia o insuficiencia cardíacas reportadas). RESULTADOS: 81,3% pacientes acromegálicos y 85% controles se diagnosticaron de SAHS. SAHS leve fue más frecuente en CA que NCA (31,3% vs. 0%, p = 0,048). Existía una tendencia a mayor prevalencia de disfunción diastólica del ventrículo izquierdo (DDVI) en los pacientes acromegálicos comparados con los controles (58,1% vs. 30%, p = 0,05). La presencia de SAHS grave en los pacientes acromegálicos se relacionó con mayor riesgo de DDVI (90,9% vs. 40%, p = 0,008; OR 2,3 [1,3-4,0]), hipertrofia del VI (55,6% vs. 10,5%, p = 0,02; OR 5,3 [1,3-22,2]) y eventos cardíacos (87,5% vs. 35,6%; p = 0.01; OR 7.53 [1.07-53.24]). CONCLUSIONES: SAHS es muy frecuente en los pacientes acromegálicos. Sólo en pacientes acromegálicos, el SAHS grave se asoció con hipertrofia, disfunción diastólica del VI y eventos cardíacos

Severe sleep apnea-hypopnea syndrome is related to left ventricle dysfunction and hypertrophy in acromegalic patients.

OBJECTIVE: To assess whether sleep apnea-hypopnea syndrome (SAHS) is a risk factor for development of acromegalic cardiomyopathy. METHODS: A descriptive, cross-sectional study of 32 patients with acromegaly (15 categorized as non-controlled-NCA and 17 as controlled-CA) compared to 20 matched controls (by sex, age, and BMI) referred to the pulmonology department for suspected SAHS. Polysomnography, echocardiography (M-mode, 2-dimensional, and Doppler), and 12-lead electrocardiography were performed in all participants. Development of cardiac morbidity (ischemia heart disease or heart failure) was evaluated after 7 years. RESULTS: SAHS was diagnosed in 81.3% of patients with acromegaly and 85% of controls. Mild SAHS was more common in CA than in NCA patients (31.3% vs. 0%, p=0.048). There was a trend to greater prevalence of left ventricular diastolic dysfunction (LVDD) in acromegalic patients as compared to controls (58.1% vs. 30%, p=0.05). Presence of severe SAHS in patients with acromegaly was related to greater risk of LVDD (90.9% vs. 40%, p=0.008; OR 2.3 [1.3-4.0]), LV hypertrophy (55.6% vs. 10.5%, p=0.02; OR 5.3 [1.3-22.2]), and cardiac events (87.5% vs. 35.6%; p=0.01; OR 7.53 [1.07-53.24]). CONCLUSION: SAHS is highly prevalent in patients with acromegaly. Only in these patients was severe SAHS associated to hypertrophy, LV diastolic dysfunction, and cardiac events.

Pituitary tumor transforming gene and insulin-like growth factor 1receptor expression and immunohistochemical measurement ofKi-67 as potential prognostic markers of pituitary tumorsaggressiveness

Introducción y objetivo La capacidad de predecir recurrencia en los adenomas hipofisarios (AH) tras la cirugía puede ser útil para determinar la frecuencia de seguimiento y la necesidad de tratamientos adyuvantes. El objetivo del presente estudio fue valorar la capacidad pronóstica de gen transformador de tumores hipofisarios (pituitary tumor transforming gene [PTTG]), del receptor del factor de crecimiento insulinoide 1 (insulin-like growth factor 1 receptor [IGF1R]) y de Ki-67. Material y métodos En este estudio retrospectivo determinamos el número de copias normalizadas de ARNm (Cnn) de PTTG e IGF1R mediante RT-PCR y el índice Ki-67 mediante inmunohistoquímica en 46 muestras de AH. Los datos clínicos, el subtipo histológico y las características radiológicas se recogieron para determinar asociaciones entre las variables y el comportamiento tumoral. Además, estudiamos la progresión de los restos tumorales y su asociación con los marcadores en 14 pacientes sin tratamiento adyuvante posquirúrgico seguidos durante 46 ± 36 meses. Resultados Los tumores extraselares mostraron una expresión de PTTG menor que los intraselares (0,065 [1.er-3.er cuartil: 0,000-0,089] Cnn frente a 0,135 [0,105–0,159] Cnn, p = 0,04). La expresión de IGF1R varió en función del subtipo histológico (p = 0,014), siendo mayor en los tumores que presentaron crecimiento de los restos mayor del 20% durante el seguimiento (10,69 ± 3,84 Cnn frente a 5,44 ± 3,55 Cnn, p = 0,014). Conclusiones Nuestros resultados indican que IGF1R, en mayor medida que PTTG, es un marcador molecular útil en el manejo de los AH. Ki-67 no mostró asociación con el comportamiento tumoral. Sin embargo, el potencial de estos marcadores debe ser establecido en futuros estudios con una metodología estandarizada y una muestra mayor (AU)

Introduction and objective The ability to predict recurrence of pituitary adenoma (PA) after surgery may be helpful to determine follow-up frequency and the need for adjuvant treatment. The purpose of this study was to assess the prognostic capacity of pituitary tumor transforming gene (PTTG), insulin-like growth factor 1 receptor (IGF1R), and Ki-67. Materials and methods In this retrospective study, the normalized copy number (NCN) of PTIG and IGF1R mRNA was measured using RT-PCR, and the Ki-67 index was measured by immunohistochemistry in 46 PA samples. Clinical data, histological subtype, and radiographic characteristics were collected to assess associations between variables and tumor behavior. Progression of tumor remnants and its association to markers was also studied in 14 patients with no adjuvant treatment after surgery followed up for 46 ± 36 months. Results Extrasellar tumors had a lower PTTG expression as compared to sellar tumors (0.065 [1st–3rd quartile: 0.000–0.089] NCN vs. 0.135 [0.105–0.159] NCN, p = 0.04). IGF1R expression changed depending on histological subtype (p = 0.014), and was greater in tumor with remnant growth greater than 20% during follow-up (10.69 ± 3.84 NCN vs. 5.44 ± 3.55 NCN, p = 0.014). Conclusions Our results suggest that the IGF1R is a more helpful molecular marker than PTTG in PA management. Ki-67 showed no association to tumor behavior. However, the potential of these markers should be established in future studies with standardized methods and on larger samples(AU)

Pituitary tumor transforming gene and insulin-like growth factor 1 receptor expression and immunohistochemical measurement of Ki-67 as potential prognostic markers of pituitary tumors aggressiveness.

INTRODUCTION AND OBJECTIVE: The ability to predict recurrence of pituitary adenoma (PA) after surgery may be helpful to determine follow-up frequency and the need for adjuvant treatment. The purpose of this study was to assess the prognostic capacity of pituitary tumor transforming gene (PTTG), insulin-like growth factor 1 receptor (IGF1R), and Ki-67. MATERIALS AND METHODS: In this retrospective study, the normalized copy number (NCN) of PTIG and IGF1R mRNA was measured using RT-PCR, and the Ki-67 index was measured by immunohistochemistry in 46 PA samples. Clinical data, histological subtype, and radiographic characteristics were collected to assess associations between variables and tumor behavior. Progression of tumor remnants and its association to markers was also studied in 14 patients with no adjuvant treatment after surgery followed up for 46±36 months. RESULTS: Extrasellar tumors had a lower PTTG expression as compared to sellar tumors (0.065 [1st-3rd quartile: 0.000-0.089] NCN vs. 0.135 [0.105-0.159] NCN, p=0.04). IGF1R expression changed depending on histological subtype (p=0.014), and was greater in tumor with remnant growth greater than 20% during follow-up (10.69±3.84 NCN vs. 5.44±3.55 NCN, p=0.014). CONCLUSIONS: Our results suggest that the IGF1R is a more helpful molecular marker than PTTG in PA management. Ki-67 showed no association to tumor behavior. However, the potential of these markers should be established in future studies with standardized methods and on larger samples.

Over-expression of vascular endothelial growth factor in pituitary adenomas is associated with extrasellar growth and recurrence.

Some pituitary adenomas (PA) demonstrate aggressive behavior with local invasion and recurrences. Angiogenesis is regarded as an essential step in the formation of solid tumors. The aim of this study is to find out whether angiogenic factors may have information about the aggressiveness of PA that could be useful in determining the frequency of follow-up and whether adjuvant therapy is necessary. In this retrospective descriptive study, we evaluated vascular endothelial growth factors (VEGF) and VEGF receptor (KDR) mRNA expression by RT-PCR analysis on 46 human PA samples. Clinical data, histological subtype and radiologic characteristics were studied to determine the associations between the variables and the pre-operative behavior of the tumor. In addition, we monitored 12 patients without adjuvant post-operative therapies over 46 months after surgery, determining progression of tumor remnants and its association with these markers. VEGF expression correlates with KDR expression (r = 0.40, p = 0.006). VEGF demonstrates different expression between histological subtypes (p = 0.036). The extension at magnetic resonance imaging showed that VEGF expression was related to suprasellar extension (p = 0.007), being expressed more on tumors with extrasellar growth than intrasellar ones (p = 0.008). Our results demonstrate a 27.5 times increased risk of extrasellar growth when VEGF expression exceeds 0.222 normalized copy number (NCN) (p = 0.002). Likewise, tumors with KDR greater than 0.750 NCN had less recurrence-free survival time (p = 0.032). Our results suggest that the expression of VEGF and its receptor could be a marker for poor outcome after partial tumor resection. These data should be considered in future studies evaluating angiogenic factors as therapeutic targets in patients with PA.

Effects of recombinant human growth hormone therapy in adults with Prader-Willi syndrome: a meta-analysis.

OBJECTIVE: Prader-Willi syndrome (PWS) is associated with GH deficiency, deleterious changes in body composition and function. As the effects of recombinant human GH (rhGH) in PWS adults have not been well established, we sought to conduct a meta-analysis of pertinent studies. DESIGN: Meta-analysis of studies examining the effects of rhGH therapy in PWS adults. PATIENTS: One hundred and thirty four PWS adults (75 men, 59 women). MEASUREMENTS: Literature searches, including publications (PubMed, EMBASE and the Cochrane Register), and abstracts presented at meetings through July 2011 describing studies of rhGH therapy in PWS adults; 8/1194 articles, describing unique cohorts, were included. Two authors independently extracted data and examined study quality. RESULTS: rhGH therapy for 12 months led to [weighted mean difference (95% CI)] decreased body fat [-2·91% (-3·90, -1·91)], visceral [-32·97 cm(2) (-55·67, -10·26)] and subcutaneous adiposity [-55·24 cm(2) (-89·05, -21·44)], and increased lean body mass (LBM) [2·41 Kg (1·32, 3·49)]. Similar changes in body fat [-2·89% (-4·69, -1·07)] and LBM [2·82 Kg (1·31, 4·33)] were found in longer studies. There were no changes in body mass index (BMI) or lipids. There was a small increase in fasting glucose [0·27 mmol/l (0·05, 0·49)] and trends towards higher fasting insulin [20·24 pmol/l (-0·55, 41·02)] and insulin resistance [HOMA: 0·60 (-0·04, 1·24)] after rhGH therapy for 12 months. CONCLUSIONS: In PWS adults, rhGH therapy led to decreased body adiposity and increased LBM without changes in BMI or lipids. There was a small increase in fasting glucose and trends towards higher insulin and insulin resistance.

Validation of the human chorionic gonadotropin immunoassay in cerebrospinal fluid for the diagnostic work-up of neurohypophyseal germinomas.

BACKGROUND: The measurement of human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) is useful for the differential diagnosis of suprasellar lesions. However, the concentrations that prove diagnostic for neurohypophyseal germinoma have not been well defined. In addition, the immunoassays used for such measurements are the same as those applied in serum, and few studies have been performed regarding the validation of such techniques in CSF. The present study aims to apply the Elecsys(®) hCG + ß immunoassay from Roche Diagnostics to measure hCG in CSF, as a useful tool in the diagnosis of neurohypophyseal germinomas in children and young adults. METHODS: Validation of the immunoassay involved calculation of the functional sensitivity and reference values for hCG in CSF in 35 controls in the absence of pregnancy, trophoblastic disease or tumour pathology. For the clinical application study, three patients diagnosed with neurohypophyseal germinoma have been reviewed. RESULTS: The functional sensitivity obtained was 0.4 IU/L. The reference values for hCG in CSF ranged from undetectable values to 0.7 IU/L. The hCG concentrations in CSF in the three studied patients, with confirmed diagnosis of neurohypophyseal germinoma, were 21.1, 32.6 and 23 IU/L, respectively. CONCLUSIONS: The Elecsys® hCG + ß immunoassay from Roche Diagnostics can be used to detect hCG in CSF with high precision. According to our results, CSF-hCG concentrations that exceed the established reference interval (undetectable values to 0.7 IU/L) in the presence of suprasellar lesions and hypophyseal stalk thickening must be considered pathological, establishing the need to exclude the presence of germinoma.

[Response to adjuvant therapy with potassium perchlorate in amiodarone-induced thyrotoxicosis: observations on three cases]. / A propósito de tres casos. Respuesta a la terapia adyuvante con perclorato potásico en la tirotoxicosis inducida por amiodarona.

INTRODUCTION: Amiodarone-induced thyrotoxicosis (AIT) is a common clinical disorder that may be life threatening and whose clinical manifestations and response to treatment may vary among patients. METHODS: We present three patients treated with amiodarone for atrial fibrillation who developed AIT at least 36 months after beginning the treatment. Thyrotoxicosis worsened the underlying cardiac disorders and was resistant to treatment based on the combination of dexamethasone 8-12 mg/day i.v., thioamides 45 mg/day p.o., beta blockers and potassium perchlorate at doses of 800 to 1000 mg per day p.o. Two of the patients attained sustained euthyroidism after 12 and 32 days of combined treatment, while the third required total thyroidectomy. CONCLUSION: The combination of thioamides with potassium perchlorate is an appropriate form of therapy for AIT in patients resistant to thioamides. The use of this combination should be evaluated in patients with mixed AIT or AIT of unclear etiology.

A propósito de tres casos. Respuesta a la terapia adyuvante con perclorato potásico en la tirotoxicosis inducida por amiodarona / Response to adjuvant therapy with potassium perchlorate in amiodarone-induced

Introducción La tiroiditis inducida por amiodarona (TIA) es una entidad clínica frecuente, con distintas formas de presentación, respuesta variable al tratamiento, y que puede ser potencialmente fatal. Métodos Se presentan tres pacientes con fibrilación auricular, que desarrollaron una TIA tras al menos 36 meses de exposición al fármaco. El hipertiroidismo asociado no respondió a la terapia farmacológica convencional, conllevando un empeoramiento franco de la cardiopatía de los pacientes, lo que motivó la indicación de tiroidectomía total, previa instauración de una terapia basada en la combinación de dexametasona 8-12mg/día iv, tionamidas 45mg/día vo, beta-bloqueantes, junto perclorato potásico 0,8-1g/día vo. Dos pacientes normalizaron las hormonas tiroideas periféricas tras 12 y 32 días de terapia combinada. Conclusión La combinación de tionamidas y perclorato potásico es una alternativa terapéutica eficaz en la TIA tipo I en pacientes refractarios a terapia convencional. Debe valorarse su empleo en pacientes con TIA mixta o etiología no aclarada (AU)

Introduction: Amiodarone-induced thyrotoxicosis (AIT) is a common clinical disorder that maybe life threatening and whose clinical manifestations and response to treatment may vary among patients. Methods: We present three patients treated with amiodarone for atrial fibrillation who developed AIT at least 36 months after beginning the treatment. Thyrotoxicosis worsened the underlying cardiac disorders and was resistant to treatment based on the combination of dexamethasone 8-12 mg/day i.v., thioamides 45 mg/day p.o., beta blockers and potassium perchlorate at doses of 800 to 1000 mg per day p.o. Two of the patients attained sustained euthyroidism after 12 and 32 days of combined treatment, while the third required total thyroidectomy. Conclusion: The combination of thioamides with potassium perchlorate is an appropriate formof therapy for AIT in patients resistant to thioamides. The use of this combination should be evaluated in patients with mixed AIT or AIT of unclear etiology (AU)

[Rol of pituitary tumour-transforming gene (PTTG) in the pituitary adenomas]. / Papel de pituitary tumour-transforming gene (PTTG) en los adenomas hipofisarios.

The pathogenesis of pituitary tumours is far to be understood. Pituitary transforming tumour gene (PTTG), a gen that induces aneuploidy, genetic instability, cellular proliferation and to stimulate angiogenesis, has been involved in neoplasic transformation and shown overexpressed in many neoplasm as lung, breast, endometrium, thyroid and colon malignant tumours. On the other hand, PTTG has been inconsistently studied in pituitary tumours. The majority of studies have been performed in animals and there is a great variability in the methods used in its determination. The goal of this review is to resume the role of PTTG in tumourogenesis and critically to revise the studies published in humans in order to advance in the knowledge of the pathogenesis of pituitary adenomas and to find clinical useful predictors of the behavior of these tumours.

Papel de pituitary tumour-transforming gene (PTTG) en los adenomas hipofisarios / Rol of Pituitary Tumour-Transforming Gene (PTTG) in the pituitary adenomas

El pituitary transforming tumour gene (PTTG) está involucrado en una gran variedad de mecanismos fisiológicos. Se ha descrito sobreexpresión proteínica de PTTG en múltiples neoplasias, como los tumores hipofisarios, la cual favorece la aneuploidía, la inestabilidad genética, la proliferación celular y la angiogénesis, todos ellos procesos clave en la transformación neoplásica. Los estudios llevados a cabo en adenomas hipofisarios indican su asociación con un mayor grado de infiltración y de recidivas. Actualmente se plantea su función potencial como diana terapéutica (AU)

The pathogenesis of pituitary tumours is far to be understood. Pituitary transforming tumour gene (PTTG), a gen that induces aneuploidy, genetic instability, cellular proliferation and to stimulate angiogenesis, has been involved in neoplasic transformation and shown overexpressed in many neoplasm as lung, breast, endometrium, thyroid and colon malignant tumours. On the other hand, PTTG has been inconsistently studied in pituitary tumours. The majority of studies have been performed in animals and there is a great variability in the methods used in its determination. The goal of this review is to resume the role of PTTG in tumourogenesis and critically to revise the studies published in humans in order to advance in the knowledge of the pathogenesis of pituitary adenomas and to find clinical useful predictors of the behavior of these tumours (AU)

Treatment of Graves' ophthalmopathy with high-dose intravenous methylprednisolone: a comparison of two dosing regimens.

RATIONALE AND OBJECTIVE: The treatment of active moderate-severe Graves' ophthalmopathy (GO) is based on the administration of highdose intravenous glucocorticoids. The present study compares the efficacy and safety of 2 different intravenous methylprednisolone (MTPiv) dosing regimens. MATERIAL AND METHODS: We carry a retrospective descriptive study with sequential sampling of 24 patients (83% females) presenting moderatesevere GO (EUGOGO criteria) and receiving treatment in our center between January 2006 and June 2008. We use 2 dosing regimens: regimen A (12 weeks): 6 doses of 0.5g/week followed by 6 doses of 0.25 g/week, for a cumulative dose of 4.5 g of MTPiv (n=13); and regimen B (16 weeks): 4 cycles of 15 mg/kg, followed by 4 cycles of 7.5mg/kg, for a cumulative dose of 90 mg/kg (range, 4.9-7.4 g) (n=11). Comparisons were made for safety (fasting glucose, cytolysis-cholestasis enzymes, lipid profile) and efficacy data (clinical improvement and recurrence). RESULTS: Mild-moderate liver cytolysis was recorded in four patients, one with associated moderate cholestasis and another with hyperglycemia, leading to treatment suspension - with no differences between the 2 treatment regimens. Percentage clinical improvement with regimen A was 92% (CI, 65-94%) versus 100% with regimen B (CI, 74-100%). The recurrence rate was 43% with regimen A and 63% with regimen B (p>0.05). None of the variables examined in the univariate logistic regression study were associated to a lesser treatment response or increased risk of recurrence of GO. CONCLUSIONS: The treatment of GO with MTPiv is safe and effective, with a lower recurrence rate when using dosing regimen A.

Glioblastoma multiforme y neoplasia endocrina múltiple tipo 2 A / Glioblastoma multiforme and multiple endocrine neoplasic type 2A

No disponible

No disponible