Pegvisomant in acromegaly: a multicenter real-life study in Argentina

ABSTRACT Objective To describe the long term safety and efficacy of pegvisomant (PEGV), and the predictors of treatment response in patients with acromegaly in the real life setting. Subjects and methods We retrospectively reviewed the clinical, hormonal and radiological data of acromegalic patients treated with PEGV in 17 Argentine centers. Results Seventy-five patients (age range 22-77, 51 females) with acromegaly have been treated with PEGV for up to 118 months (median 27 months). Before PEGV, 97.3% of patients had been treated with medical therapy, surgery and/or radiotherapy, two patients had no previous treatment. At that time, all patients had an IGF-1 above the upper normal limit (ULN) (mean 2.4 x ULN ± 0.98, range 1.25-7). At diagnosis of acromegaly 84% presented macroadenomas, prior to PEGV only 23,5% of patients remained with tumor remnant > 1 cm, the remaining showed normal or less than 1 cm images. Disease control (IGF-1 ≤ 1.2 x ULN) was achieved in 62.9% of patients with a mean dose of 11.8 mg/day. Thirty-four patients (45%) received PEGV monotherapy, while 41 (55%) received combined therapy with either somatostatin analogues and/or cabergoline. Adverse events related to PEGV were: local injection site reaction in 5.3%, elevated liver enzymes in 9.3%, and tumor size growth in 9.8%. Pre-PEGV IGF-I level was the only predictor of treatment response: 2.1 x ULN vs 2.8 x ULN in controlled and uncontrolled patients respectively (p < 0.001). Conclusion this long term experience indicates PEGV treatment was highly effective and safe in our series of Argentine patients with acromegaly refractory to standard therapies. Arch Endocrinol Metab. 2019;63(4):320-7

Prolactinomas: evolution after menopause

ABSTRACT Objetive The aim was to assess the evolution of tumor size and prolactin (PRL) levels in patients with micro and macroprolactinomas diagnosed and treated with dopamine agonists during fertile age, and the effects of suspension of drugs after menopause. Retrospective study, 29 patients with prolactinomas, 22 microadenomas and 7 macroadenomas, diagnosed during their fertile age were studied in their menopause; treatment was stopped in this period. Age at menopause was 49 ± 3.6 years. The average time of treatment was 135 ± 79 months. The time of follow-up after treatment suspension was 4 to 192 months. Results Pre-treatment PRL levels in micro and macroadenomas were 119 ± 57 ng/mL and 258 ± 225 ng/mL, respectively. During menopause after treatment suspension, and at the latest follow-up: in microadenomas PRL levels were 23 ± 13 ng/mL and 16 ± 5.7 ng/mL, respectively; in macroadenomas, PRL levels were 20 ± 6.6 ng/mL 5t5and 25 ± 18 ng/mL, respectively. In menopause after treatment suspension, the microadenomas had disappeared in 9/22 and had decreased in 13/22. In the group of patients whose tumor had decreased, in the latest follow-up, tumors disappeared in 7/13 and remained unchanged in 6/13. In macroadenomas, after treatment suspension 3/7 had disappeared, 3/7 decreased and 1/7 remained unchanged. In the latest control in the 3 patients whose tumor decreased, disappeared in 1/3, decreased in 1/3 and there was no change in the remaining. Conclusions Normal PRL levels and sustained reduction or disappearance of adenomas were achieved in most of patients, probably due to the decrease of estrogen levels. Dopamine agonists might be stopped after menopause in patients with prolactinomas.

Fatal outcome of a young woman with papillary thyroid carcinoma and graves' disease: possible implication of "cross-signalling" mechanism / Desfecho Fatal de uma Paciente com Carcinoma Papilífero de Tiróide e Doença de Graves: possível Implicação do Mecanismo de Sinalização Cruzada

A 29 yrs-old patient was referred to our hospital due to generalized convulsions. She had hyperthyroidism treated with methimazole. Her MRI showed 4 metastatic lesions in the brain. She had a goiter with a "cold" nodule and a palpable ipsilateral lymph node. The FNAB disclosed a papillary thyroid carcinoma. Under 5 mg of MMI treatment, she had a subclinical hyperthyroidism and TRAb were 47.8 percent (n.v. < 10 percent). The CT scan also showed lung metastasis. She underwent a total thyroidectomy with a modified neck dissection and she received an accumulated radioiodine dose of 700 mCi during the following two years. She died from the consequences of multiple metastatic lesions. Studies were performed in DNA extracted from paraffin-embedded tissue from the tumor, the metastatic lymph node and the non-tumoral thyroid. The genetic analysis of tumoral DNA revealed point mutations in two different genes: the wild type CAA at codon 61 of N-RAS mutated to CAT, replacing glycine by histidine (G61H) and the normal GCC sequence at codon 623 of the TSHR gene was replaced by TCC, changing the alanine by serine (A623S). In the non-tumoral tissue no mutations were found. In vitro studies showed a constitutive activation of the TSHR. It is very probable that this activating mutation of the TSHR is unable to reach the end point of the PKA cascade in the tumoral tissue. One possibility that could explain this is the presence of a cross-signaling mechanism generating a deviation of the TSH receptor cascade to the more proliferative one involving the MAPKinase, giving perhaps a more aggressive behavior of this papillary thyroid cancer.

Paciente de 29 anos foi encaminhada ao Hospital de Clínicas por causa de convulsões generalizadas. Apresentava hipertiroidismo tratado com metimazol (MMI). A ressonância magnética mostrava quatro lesões metastáticas cerebrais. Possuía bócio com nódulo frio e linfonodo palpável ipsilateral. Usando 5 mg de MMI, a paciente apresentava hipertiroidismo subclínico e TRAb = 47,8 por cento (normal < 10 por cento). A tomografia computadorizada também mostrava metástases pulmonares. A paciente foi submetida a tiroidectomia total com dissecção cervical modificada e recebeu dose acumulada de radioiodo de 700 mCi durante o período de dois anos. Foi analisado o DNA extraído de tecido emblocado em parafina do tumor, do linfonodo metastático e de tecido tiroidiano não-tumoral. Foram encontradas mutações pontuais em dois genes: uma substituição do genótipo selvagem CAA no códon 61 de /N-RAS/ por CAT, substituindo a glicina pela histidina (G61H) e uma substituição da seqüência normal GCC no códon 623 do gene TSHR por TCC, trocando a alanina pela serina (A623S). Não foram encontradas mutações no tecido não-tumoral. Estudos in vitro mostraram ativação constitutiva de TSHR. Já que esta mutação ativadora de TSHR foi incapaz de atingir o final da cascata PKA no tecido tumoral, sugere-se que um mecanismo de cross-signaling possa explicar o desvio da cascata do receptor de TSH para outra mais proliferativa, envolvendo MAPKinase e levando ao comportamento mais agressivo deste câncer papilífero.

Effect of hypercortisolism control on high blood pressure in Cushing's syndrome / Efecto del control del hipercortisolismo sobre la hipertensión arterial en el síndrome de Cushing

Many hypertensive patients affected by endogenous Cushing's syndrome (CS) persist with high blood pressure (HBP) despite good control of cortisol excess. We assessed the effect of preoperative ketoconazole administration and of definitive treatment of CS on arterial hypertension and analysed the factors involved in the persistence of hypertension. We assessed retrospectively 71 patients with CS and HBP (60 women, 11 men; 50 pituitary, 21 adrenal) successfully treated by surgery and/or radiotherapy; 19 of them received ketoconazole (KNZ) before surgery. After treatment, patients were divided into those with persistent high blood pressure (PHBP) and those with normal blood pressure (NBP). As possible predictive factors for PHBP we analysed age, duration and family history of HBP, pre-treatment 24 hour urinary free cortisol (24h-UFC) and body mass index (BMI). HBP normalized in 53 out of 71 patients (74.6%), regardless of the origin of Cushing's syndrome. PHBP patients were older (p=0.003), had longer duration (p=0.007) and higher systolic blood pressure before treatment (p=0.046) than NBP patients. Thirteen out of 19 patients (68.4%) treated with ketoconazole, normalized their hypertension and remained normotensive after successful surgery. Five patients became normotensive only after surgery. In conclusion: a) blood pressure levels normalized in most patients after remission of CS; b) ketoconazole was effective for the control of HBP, and seems to be a good indicator of post-surgical outcome, and c) higher age at presentation, longer duration of hypertension and higher systolic blood pressure figures before treatment negatively influence normalization of blood pressure after resolution of Cushing's syndrome.

Muchos pacientes con síndrome de Cushing (SC) permanecen hipertensos a pesar del control del exceso glucocorticoideo. Investigamos el efecto de la administración de ketoconazol (KNZ) y del tratamiento definitivo del SC sobre la hipertensión arterial (HTA), analizando su relación con diversos factores. Evaluamos 71 pacientes con SC e HTA (60 mujeres, 11 varones; 50 pituitarios, 21 adrenales) exitosamente tratados por cirugía y/o radioterapia; 19 de ellos recibieron KNZ antes de cirugía. Luego del tratamiento, fueron divididos en pacientes con HTA persistente (HTAP) y normal (HTAN). Como posibles factores predictivos de HTAP se analizaron edad, duración, historia familiar de HTA, cortisol libre urinario de 24 hs pre-tratamiento e índice de masa corporal. La HTA normalizó en 53/71 pacientes (74.6%) independientemente del origen del síndrome de Cushing. Los pacientes con HTAP fueron de mayor edad (p=0.003), con mayor duración previa (p=0.007) y valores mayores de presión arterial sistólica antes de tratamiento (p=0.046) que aquellos con HTAN. Trece de 19 pacientes (68.4 %) tratados con ketoconazol normalizaron su tensión arterial y se mantuvieron normotensos luego de cirugía exitosa. Cinco pacientes se tornaron normotensos solo después de cirugía. En conclusión: a) la HTA se normalizó en la mayoría de pacientes luego de remisión del SC, b) el ketoconazol fue efectivo para el control tensional y aparenta ser indicador de la evolución pos-quirúrgica, y c) mayor edad, duración más prolongada de la HTA y valores más altos de presión sistólica influencian negativamente la normalización de la presión arterial luego de resolución del síndrome de Cushing.

Ketoconazole therapy: an efficacious alternative to achieve eucortisolism in patients with Cushing's syndrome

El síndrome de Cushing (SC) es un trastorno grave que requiere frecuentemente tratamiento medicamentoso. Cincuenta y cuatro pacientes (44 mujeres, 10 varones) de 14-63 años de edad con SC, recibieron ketoconazol (KTZ) previo a cirugía (n=27), como complemento luego de cirugía y/o radioterapia (n=16), o como tratamiento primario (n=11). La dosis de mantenimiento fue de 600 (500 - 600) mg/día (mediana-IC95) durante 15 días a 13 años. Los signos clínicos, hepatograma y cortisol libre urinario (CLU) fueron evaluados antes y durante tratamiento con KNZ. El CLU cayó a valores normales o subnormales en 85% de los pacientes, 5 a 150 días luego de iniciar el tratamiento; aún sin normalizar, el CLU disminuyó a 12-48% de los valores pre-tratamiento en el resto de los pacientes acompañándose de mejoría de los signos clínicos. Los efectos colaterales fueron: insuficiencia adrenal (18.5%), toxicidad hepática reversible (11%), "rash" cutáneo (5.5%) e intolerancia gástrica (3.7%); en 11% de los pacientes se observó un fenómeno de "escape". Veinticuatro pacientes (44.4%) fueron tratados por períodos prolongados, de uno a trece años. Este estudio confirma que el KTZ constituye un tratamiento eficaz y generalmente bien tolerado del SC, en particular: a) como preparación para cirugía b) en casos de hipercortisolismo residual luego de cirugía o en espera de resultados de radioterapia, c) como una alternativa razonable en pacientes con SC de origen desconocido y, d) como tratamiento crónico en casos de hipercortisolismo no resuelto luego de fracaso de las terapéuticas habituales.

Cushing's syndrome (CS) is a serious condition requiring drug management in diverse clinical settings. Fifty four patients (44 females, 10 males) with CS, aged 14-63, received ketoconazole (KTZ) prior to surgery (n= 27), as complementary therapy after surgery and/or radiotherapy (n= 16), or as primary treatment (n= 11). It was given at a 600 (500 - 600) mg/day (median - CI95) maintenance dose for periods ranging from 15 days to 13 years. Clinical signs, hepatic enzymes and urinary free cortisol (UFC) were evaluated before and during KTZ treatment. UFC normalised or decreased to subnormal values in 85% of the patients, in 5 to 150 days after starting treatment; although failing to normalise, UFC decreased to 12-48% of pre-treatment values in the remaining patients. Clinical signs improved throughout. Side effects were adrenal insufficiency (18.5%), reversible hepatic toxicity (11%), allergic skin rash (5.5%) and gastric intolerance (3.7%); in 11% of patients, an "escape phenomenon" was observed. Twenty-four out of the total (44.4%) were treated for prolonged periods, from one up to 13 years. In conclusion, this study confirms that KTZ is an effective and generally well tolerated treatment for CS particularly: a) shortly before surgery, b) because of persistent hypercortisolism after surgery or awaiting the results of radiotherapy, c) as a reasonable option in patients with CS of unknown aetiology and, d) as long-term therapy in any case of unsolved hypercortisolism after failure of current treatments.

Adenoma paratiroideo ectopico mediastinal: diagnostico por sonda de deteccion gamma y reseccion por videotoracoscopia / Ectopic mediastinal parathyroid adenoma: detection with a radioisotopic probe and resolution with videothoracoscopy

Presentamos el caso de una mujer de 66 años con diagnóstico de hiperparatiroidismo primariopor adenoma paratiroideo ectópico mediastinal realizado por gammagrafía paratiroidea con 99mtcmetoxi-isobutil-isonitrito (Tc99-MIBI). Fue intervenida exitosamente mediante la técnica de videotoracoscopia.Durante el procedimiento se utilizó la medición de parathormona y a los 10 minutos de extirpado el adenoma seobtuvo un descenso mayor del 50% del basal. La sonda de detección gamma no fue efectiva in situ por la superposicióndel radioisótopo con el miocardio pero confirmó la radioactividad dentro del quirófano una vez extirpadoel adenoma. La paciente normalizó los valores de calcemia y parathormona en el postoperatorio y permaneciónormocalcémica luego de 9 meses de seguimiento. En nuestro caso, la localización prequirúrgica y elmonitoreo de parathormona intraoperatoria fueron de gran utilidad para el éxito quirúrgico, la sonda detectora marcada con Tc99-MIBI no fue efectiva in situ pero confirmó la radioactividad una vez extirpado el adenoma. El tratamiento quirúrgico endoscópico por videotoracoscopia fue bien tolerado, menos doloroso que la toracotomía y acortó el tiempo de internación

We report a 66 years old woman with a diagnosis of primary Hyperparathyroidism. Localization to mediastinum was obtained with parathyroid scintigraphy using 99mtc-methoxyisobutyl-isonitrite (Tc99-MIBI). The patient was successfully operated upon by means of a videothora-coscopicapproach. During the procedure serum parathormone was measured before and 10 minutes after adenomectomy,showing a more than 50% reduction from the basal level. An attempt to detect the precise site of the adenomawith a Tc99-MIBI probe was unsuccessful because of its proximity to the myocardium, but radioactivity was confirmed on the surgical specimen after resection. The patient’s calcemia and parathormone levels became normalduring the postoperative course and she remains normocalcemic 9 months after the procedure. In our case,preoperative localization and intraoperative parathormone measurements were both very useful for confirming surgical success; the intraoperative localization with a radioactive probe was not useful, but radioactivity was confirmedafter resection on the surgical specimen. The endoscopic surgical procedure with videothoracoscopy waswell tolerated, less painful than a thoracotomy, and it shortened the hospitalization period

Prevalencia de disfunción tiroidea primaria en pacientes con pénfigo vulgar / Prevalence of primary thyroid disorders in patients with pemphigus vulgaris

Introducción. Los pénfigos representan un grupo de enfermedades autoinmunes caracterizadas por la formación de ampollas. Dentro de este grupo, el pénfigo vulgar es la forma clínica más frecuente. Por otro lado, la patología tiroidea tiene elevada prevalencia en la práctica médica y está asociada con un amplio rango de trastornos cutáneos. Hay publicaciones aisladas de la asociación entre patología tiroidea y pénfigo vulgar. Por esta razón, se decidió establecer la prevalencia de disfunción tiroidea primaria y autoinmunidad tiroidea en pacientes con pénfigo vulgar. Objetivos. (i) Determinar la prevalencia de disfunción tiroidea primaria y autoinmunidad tiroidea en pacientes con pénfigo vulgar. (ii) Relacionar los hallazgos con lo referido en la bibliografía. Material y métodos. Se efectuó un estudio observacional, transversal, prospectivo y controlado, entre marzo del 2002 y marzo del 2004, en 28 pacientes con diagnóstico de pénfigo vulgar que concurrieron a la Sección Ampollares de la División Dermatología y fueron evaluados posteriormente por endocrinólogos de la División Endocrinología, en el Hospital de Clínicas José de San Martín. La evaluación tiroidea fue realizada en 28 pacientes consecutivos con pénfigo vulgar y 40 voluntarios sanos (controles) apareados por sexo y edad, y consistió en palpación tiroidea, prueba de funcionalidad tiroidea mediante dosaje en sangre de las hormonas T3, T4, TSH, y prueba de autoinmunidad tiroidea mediante dosaje en sangre de anticuerpos antiperoxidasa...

Diagnostico por imagenes en la enfermedad de Cushing y su correlacion con la evolucion postquirurgica / Image diagnosis in Cushing's disease and its correlation with postsurgical evolution

El objetivo de este trabajo es evaluar la sensibilidad (S) de la tomografía computada (TC) y la resonancia magnética nuclear (RMN) para visualizar un adenoma pituitario en pacientes con enfermedad de Cushing (EC) y correlacionar los hallazgos con la evolución postquirúrgica. Se estudiaron en forma retrospectiva los hallazgos por imágenes de 44 pacientes con EC. Se evaluaron 23 TC y 29 RMN obtenidas previamente a la cirugía hipofisiaria. Se los clasificó como curados o no curados según los criterios bioquímicos y clínicos y la evolución postquirúrgica. De las 23 TC, 13 evidenciaron adenoma y 10 fueron negativas, con una S de 56.5 por ciento. Para la RMN la S fue mayor (86.0 por ciento; P: 0.037, con correción de Yates) con 25 imágenes positivas y 4 negativas de las 29 realizadas. De los 44 casos estudiados 31 (70.5 por ciento, IC 0.70 + 0.13) curaron (27 total, 4 parcial): 23 tenían diagnóstico prequirúrgico por TC y/o RMN. Trece pacientes persistieron con EC con bioquímica de hipercortisolismo. En 11 de ellos se había localizado el adenoma antes de la cirugía. El diagnóstico de enfermedad de Cushing fue confirmado por histología en 33 casos, no lográndose evidenciar tejido tumoral en los 11 restantes. La tasa de remisión fue significativamente mayor en el grupo con confirmación anatomo-patológica, 82 por ciento vs 36 por ciento respectivamente (P< 0.0078). En conclusión: 1) la RMN tendría mayor S que la TC para la localización de un adenoma en la enfermedad de Cushing (P: 0.0373, luego de correción de Yates), confirmando los datos de la literatura; 2) no se halló correlación entre ausencia de imagen y falta de curación; 3) la tasa de remisión es significativamente mayor en los casos con verificación histológica del adenoma pituitario.