The clinical and biochemical spectrum of ectopic acromegaly.

Ectopic acromegaly is a rare condition caused by extrapituitary central or peripheral neuroendocrine tumours (NET) that hypersecrete GH or, more commonly, GHRH. It affects less than 1% of acromegaly patients and a misdiagnosis of classic acromegaly can lead to an inappropriate pituitary surgery. Four types of ectopic acromegaly have been described: 1) Central ectopic GH-secretion: Careful cross-sectional imaging is required to exclude ectopic pituitary adenomas. 2) Peripheral GH secretion: Extremely rare. 3) Central ectopic GHRH secretion: Sellar gangliocytomas immunohistochemically positive for GHRH are found after pituitary surgery. 4) Peripheral GHRH secretion: The most common type of ectopic acromegaly is due to peripheral GHRH-secreting NETs. Tumours are large and usually located in the lungs or pancreas. Pituitary hyperplasia resulting from chronic GHRH stimulation is difficult to detect or can be misinterpreted as pituitary adenoma in the MRI. Measurement of serum GHRH levels is a specific and useful diagnostic tool. Surgery of GHRH-secreting NETs is often curative.

Hipofisitis primaria: diagnóstico y tratamiento. estudio multicéntrico / Primary hypophysitis: diagnosis and treatment multi-center study

Resumen Introducción : La hipofisitis es una enfermedad in frecuente que plantea un desafío en el diagnóstico y tratamiento. El objetivo de este estudio multicéntrico y retrospectivo fue describir: a) características de pa cientes con hipofisitis primaria (HP), b) métodos diag nósticos, y c) tratamientos realizados. Además, evaluar: a) presentación clínica, b) bioquímica, c) radiológica, d) oftalmológica al diagnóstico y evolución según el tratamiento recibido. Métodos : Estudio retrospectivo donde se estudiaron 28 pacientes (23 mujeres/5 varones) con HP, edad pro medio de 38±11.1 años. Resultados . Los síntomas fueron: cefalea: 68%, po liuria-polidipsia: 50% y alteraciones visuales: 48%. El examen de laboratorio inicial informó disfunción ade nohipofisaria en 71% de los pacientes, siendo el eje gonadal el más afectado. Los hallazgos radiológicos más frecuentes fueron: lesión simétrica:78.5%, aumento homogéneo post contraste: 78.5% y engrosamiento de tallo:70%. En 4/23 mujeres (17%) se relacionó con em barazos o puerperio La conducta inicial fue expectante (CE) en 14 pacientes, cirugía de resección/descompresión en 8 y tratamiento con inmunosupresores en 6. Quince pacientes tuvieron confirmación histológica, 9 resulta ron hipofisitis linfocitaria, 5 hipofisitis por IgG4 y una xantomatosa. Trece fueron diagnosticados por criterios clínicos establecidos. El tamaño de la lesión disminuyó en 43% de pacientes con CE, 62.5% con cirugía y 50% con inmunosupresores. Los síntomas compresivos mejora ron en los 3 grupos, con escaso efecto sobre la función adenohipofisaria, sin resolución de la diabetes insípida. Discusión : En pacientes sin síntomas compresivos adoptamos CE. En aquellos pacientes sin certeza diag nóstica o con síntomas compresivos graves, se optó por cirugía transesfenoidal.

Abstract Introduction : Primary hypophysitis (PH) is a rare disease that represents a challenge among differential diagnosis and management. Our aim was to describe clinical characteristics, diagnostic criteria and different treatment outcomes in patients with PH. Multicentric, retrospective study. Clinical presentation, endocrine function, magnetic resonance imaging findings, visual field defects at diagnosis and treatment outcomes were recorded. Methods : Twenty-eight patients (23 women), with PH were included. Median age: 37. Results : The most frequent symptoms: headache: 68%, polyuria-polydipsia: 50% and visual disturbances: 48%. At diagnosis, anterior pituitary deficiency was present in 71%, being hypogonadotrophic hypogonad ism the most frequent manifestation. The radiological findings: symmetric lesion: 78.5%, homogeneous en hancement: 78.5% and pituitary stalk thickening: 70%. Association with pregnancy or puerperium was found in 4/23 women (17%). Fourteen patients did not receive any treatment ("wait and see" group), 8 underwent surgery for mass reduction or resection and 6 were treated with immunosuppression therapy. Among 15 patients with histopathological diagnosis, 9 were lymphocytic hypophysitis, 5 IgG4 related hypophysitis and 1 xanthomatous hypophysitis. Thirteen were di agnosed by established clinical criteria. Mass reduction was observed in 43% of "wait and see group" patients, 62.5% of operated patients and 50% with immuno suppression therapy. Compressive symptoms showed improvement in the 3 groups, with modest effect on anterior pituitary function, diabetes insipidus did not resolve in any patients. Discussion : In patients without severe compressive symptoms, we adopted a "wait and see" approach. In patients with uncertain diagnosis of PH or severe com pressive symptoms, transsphenoidal surgery was the best option.

[Primary hypophysitis: diagnosis and treatment multicenter study]. / Hipofisitis primaria: diagnóstico y tratamiento. Estudio multicéntrico.

INTRODUCTION: Primary hypophysitis (PH) is a rare disease that represents a challenge among differential diagnosis and management. Our aim was to describe clinical characteristics, diagnostic criteria and different treatment outcomes in patients with PH. Multicentric, retrospective study. Clinical presentation, endocrine function, magnetic resonance imaging findings, visual field defects at diagnosis and treatment outcomes were recorded. METHODS: Twenty-eight patients (23 women), with PH were included. Median age: 37. RESULTS: The most frequent symptoms: headache: 68%, polyuria-polydipsia: 50% and visual disturbances: 48%. At diagnosis, anterior pituitary deficiency was present in 71%, being hypogonadotrophic hypogonadism the most frequent manifestation. The radiological findings: symmetric lesion: 78.5%, homogeneous enhancement: 78.5% and pituitary stalk thickening: 70%. Association with pregnancy or puerperium was found in 4/23 women (17%). Fourteen patients did not receive any treatment ("wait and see" group), 8 underwent surgery for mass reduction or resection and 6 were treated with immunosuppression therapy. Among 15 patients with histopathological diagnosis, 9 were lymphocytic hypophysitis, 5 IgG4 related hypophysitis and 1 xanthomatous hypophysitis. Thirteen were diagnosed by established clinical criteria. Mass reduction was observed in 43% of "wait and see group" patients, 62.5% of operated patients and 50% with immunosuppression therapy. Compressive symptoms showed improvement in the 3 groups, with modest effect on anterior pituitary function, diabetes insipidus did not resolve in any patients. DISCUSSION: In patients without severe compressive symptoms, we adopted a "wait and see" approach. In patients with uncertain diagnosis of PH or severe compressive symptoms, transsphenoidal surgery was the best option.

Introducción: La hipofisitis es una enfermedad infrecuente que plantea un desafío en el diagnóstico y tratamiento. El objetivo de este estudio multicéntrico y retrospectivo fue describir: a) características de pacientes con hipofisitis primaria (HP), b) métodos diagnósticos, y c) tratamientos realizados. Además, evaluar: a) presentación clínica, b) bioquímica, c) radiológica, d) oftalmológica al diagnóstico y evolución según el tratamiento recibido. Métodos: Estudio retrospectivo donde se estudiaron 28 pacientes (23 mujeres/5 varones) con HP, edad promedio de 38±11.1 años. Resultados. Los síntomas fueron: cefalea: 68%, poliuria- polidipsia: 50% y alteraciones visuales: 48%. El examen de laboratorio inicial informó disfunción adenohipofisaria en 71% de los pacientes, siendo el eje gonadal el más afectado. Los hallazgos radiológicos más frecuentes fueron: lesión simétrica:78.5%, aumento homogéneo post contraste: 78.5% y engrosamiento de tallo:70%. En 4/23 mujeres (17%) se relacionó con embarazos o puerperio La conducta inicial fue expectante (CE) en 14 pacientes, cirugía de resección/descompresión en 8 y tratamiento con inmunosupresores en 6. Quince pacientes tuvieron confirmación histológica, 9 resultaron hipofisitis linfocitaria, 5 hipofisitis por IgG4 y una xantomatosa. Trece fueron diagnosticados por criterios clínicos establecidos. El tamaño de la lesión disminuyó en 43% de pacientes con CE, 62.5% con cirugía y 50% con inmunosupresores. Los síntomas compresivos mejoraron en los 3 grupos, con escaso efecto sobre la función adenohipofisaria, sin resolución de la diabetes insípida. Discusión: En pacientes sin síntomas compresivos adoptamos CE. En aquellos pacientes sin certeza diagnóstica o con síntomas compresivos graves, se optó por cirugía transesfenoidal.

Incidentalomas o no incidentalomas: ¿cuál es la relevancia de los adenomas hipofisarios en el adulto? / Incidentalomas or Non-Incidentalomas: What is the Relevance of Pituitary Adenomas in the Adult?

Introducción: desde el punto de vista anatómico, los adenomas hipofisarios (AH) se observan en el 10% de la población. Son en su mayoría pequeños y no funcionantes. La mayoría de los incidentalomas descubiertos en estudios de imágenes con alta resolución pedidos en situaciones clínicas frecuentes, como el traumatismo craneoencefálico, el accidente cerebrovascular y las demencias, corresponden a AH indolentes. Nos preguntamos cuál es la relevancia clínica de los adenomas hipofisarios. Desarrollo: los AH clínicamente relevantes son tumores en su mayoría benignos que conllevan, en diferentes proporciones, aumento en la morbilidad y/o mortalidad de los pacientes por mecanismos relacionados con la hipersecreción hormonal, la insuficiencia hormonal y/o los efectos de masa ocupante. La prevalencia de los AH clínicamente relevantes es mayor de la que se suponía hace 20 años. Afecta aproximadamente a 1/1000 habitantes. Los más prevalentes son los prolactinomas y los adenomas no funcionantes. La acromegalia, la enfermedad de Cushing y los tumores agresivos se traducen en pacientes complejos con mayor morbimortalidad. El diagnóstico temprano y el tratamiento multimodal proveen una razonable mejoría de la sobrevida. El estudio epidemiológico de los AH clínicamente relevantes es importante para la estimación del impacto en los sistemas de salud. Conclusiones: los estudios por imágenes de mejor resolución continuarán señalando incidentalomas hipofisarios. Una evaluación cuidadosa de los pacientes podrá identificar aquellos AH clínicamente relevantes. (AU)

Introduction: from the anatomical point of view, pituitary adenomas (HA) are observed in 10% of the population. They are mostly small and non-functioning. Most incidentalomas discovered in high-resolution imaging studies ordered in frequent clinical situations, such as head trauma, stroke and dementia, correspond to indolent HA. We wonder what is the clinical relevance of pituitary adenomas. Development: clinically relevant HAs are mostly benign tumors that lead, in different degrees, to an increased morbidity and/or mortality in patients by mechanisms related to hormone hypersecretion, hormone insufficiency and/or occupying mass effects. The prevalence of clinically relevant HA is higher from what was assumed 20 years ago. It affects approximately 1/1000 of the population. The most prevalent are prolactinomas and non-functioning adenomas. Acromegaly, Cushing's disease and aggressive tumors make for complex patients with increased morbidity and mortality. Early diagnosis and multimodal treatment provide a reasonable improvement in survival. Epidemiological study of clinically relevant HAs is important for estimating the impact on health systems. Conclusions: Higher-resolution imaging studies will continue to highlight pituitary incidentalomas. Careful evaluation of patients will identify clinically relevant HAs. (AU)

Pituitary MRI Features in Acromegaly Resulting From Ectopic GHRH Secretion From a Neuroendocrine Tumor: Analysis of 30 Cases.

CONTEXT: Ectopic acromegaly is a consequence of rare neuroendocrine tumors (NETs) that secrete GHRH. This abnormal GHRH secretion drives GH and IGF-1 excess, with a clinical presentation similar to classical pituitary acromegaly. Identifying the underlying cause for the GH hypersecretion in the setting of ectopic GHRH excess is, however, essential for proper management both of acromegaly and the NET. Owing to the rarity of NETs, the imaging characteristics of the pituitary in ectopic acromegaly have not been analyzed in depth in a large series. OBJECTIVE: Characterize pituitary magnetic resonance imaging (MRI) features at baseline and after NET treatment in patients with ectopic acromegaly. DESIGN: Multicenter, international, retrospective. SETTING: Tertiary referral pituitary centers. PATIENTS: Thirty ectopic acromegaly patients having GHRH hypersecretion. INTERVENTION: None. MAIN OUTCOME MEASURE: MRI characteristics of pituitary gland, particularly T2-weighted signal. RESULTS: In 30 patients with ectopic GHRH-induced acromegaly, we found that most patients had hyperplastic pituitaries. Hyperplasia was usually moderate but was occasionally subtle, with only small volume increases compared with normal ranges for age and sex. T2-weighted signal was hypointense in most patients, especially in those with hyperplastic pituitaries. After treatment of the NET, pituitary size diminished and T2-weighted signal tended to normalize. CONCLUSIONS: This comprehensive study of pituitary MRI characteristics in ectopic acromegaly underlines the utility of performing T2-weighted sequences in the MRI evaluation of patients with acromegaly as an additional tool that can help to establish the correct diagnosis.

Assessment of the utility of measuring Thyroglobulin mRNA levels by Quantitative Real-Time PCR in the follow-up of differentiated thyroid cancer patients.

INTRODUCTION: The determination of thyroglobulin levels by immunoassay and imaging studies is subject to interference by antithyroglobulin antibodies in up to 30% of cases, suggesting a need to find alternative methods for the follow-up of a significant number of thyroid cancer patients. OBJECTIVES: Assess the sensitivity, specificity, and predictive values of thyroglobulin messenger RNA levels measured by quantitative Real Time-PCR (qRT-PCR) in the blood of patients followed for differentiated thyroid cancer. METHODS: This is a prospective study of Tg-mRNA levels measured with qRT-PCR. A peripheral blood sample was taken in patients with excellent response (69) and with structural incomplete response to treatment (23). Results were analysed using the Unity Real-Time program and expressed as fg/µg RNA. A Receiver Operating Characteristic curve was constructed to assess Tg-mRNA cut-off values. RESULTS: Tg-mRNA levels were not significantly different between the group with excellent response [0.10 fg/µg RNA (0.08-0.17)] and the group with incomplete structural response [0.133 fg/µg RNA (0.07-0.33)] (P < .06). Test sensitivity was 69.6%, specificity was 59.4%, negative predictive value was 85.4% and positive predictive value 36.4% CONCLUSIONS: Our experience shows that this technique could be useful as a rule-out test in selected cases, but its low sensitivity and specificity preclude its usefulness as a first-line test.

[Erdheim-Chester disease: a rare histiocytosis with outstanding response to cobimetinib.] / Enfermedad de Erdheim-Chester: una rara histiocitosis con excelente respuesta a cobimetinib.

Introduction: Erdheim-Chester Disease (ECD) is a rare form of histiocytosis, characterized by xanthogranulomatous infiltration of multiple organs by lipid-laden histiocytes. It is considered a myeloid inflammatory clonal disorder that mainly affects men with a mean age of 55 years. Methods: We present the case of a 65-year-old man who consulted our Endocrinology Unit because of polyuria and polydipsia of 4 months of evolution, diagnosing central diabetes insipidus associated with pituitary infiltration. Physical examination showed skin lesions he has had for several years, that were papules-nodules in the anterior chest and xantelasma-like in the face and neck, with biopsy compatible with non-Langerhans histiocytosis. The genetic study of the skin biopsy showed the presence of a mutation in MAP2K1, confirming the ECD. Results: The patient started treatment with interferon alfa, but the response was incomplete and associated with severe intolerance, so given the findings of the genetic study, we decided to indicate treatment with cobimetinib, a potent and selective inhibitor of MEK. After 8 months of treatment, skin lesions have disappeared, as has the pituitary infiltration, with a remarkable improvement in his quality of life. Conclusions: We present a 65-year-old patient with a rare form of histiocytosis (ECD) who in turn presented an atypical form of ECD and, where the genetic study allowed us to confirm the diagnosis and use targeted therapy with cobimetinib with outstanding results.

Introducción: La Enfermedad de Erdheim-Chester (ECD) es una rara forma de histiocitosis, caracterizada por la infiltración xantogranulomatosa de múltiples órganos por histiocitos cargados de lípidos. Se la considera un trastorno clonal inflamatorio mieloide que afecta principalmente a hombres con una edad media de 55 años. Métodos: Presentamos el caso de un hombre de 65 años que consultó a nuestro Servicio de Endocrinología por poliuria y polidipsia de 4 meses de evolución diagnosticándose diabetes insípida central asociada a infiltración hipofisaria. El paciente presentaba lesiones cutáneas pápulo-nodulares en tórax y xantelasma-símiles en cuello y cara de varios años de evolución, con biopsia compatible con histiocitosis no-Langerhans. El estudio genético de la biopsia cutánea detectó la mutación MAP2K1 confirmando la ECD. Resultados: El paciente inició tratamiento con interferón alfa con respuesta incompleta y mala tolerancia por lo que cambiamos el tratamiento a un inhibidor potente y selectivo de MEK, el cobimetinib. Tras 8 meses de tratamiento presenta desaparición de lesiones cutáneas y de la infiltración hipofisaria con notable mejoría de su calidad de vida. Conclusión: Presentamos el caso de un paciente adulto con una forma rara de histiocitosis (ECD) que a su vez presentó una forma atípica de ECD y, donde el estudio genético nos permitió confirmar el diagnóstico e introducir una terapia dirigida con cobimetinib con excelentes resultados.

[Adrenal crisis associated with modafinil use]. / Crisis adrenal asociada al uso de modafinilo.

Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treatment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembolism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose replacement in subjects receiving metabolism-inducing drugs.

La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser desencadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.

Crisis adrenal asociada al uso de modafinilo / Adrenal crisis associated with modafinil use

Resumen La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser des encadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.

Abstract Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treat ment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembo lism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose re placement in subjects receiving metabolism-inducing drugs.

Assessment of the utility of measuring Thyroglobulin mRNA levels by Quantitative Real-Time PCR in the follow-up of differentiated thyroid cancer patients. / Evaluación de la utilidad de medir los niveles de ARN mensajero de tiroglobulina por PCR cuantitativa en tiempo real para el seguimiento de pacientes con cáncer diferenciado de tiroides.

INTRODUCTION: The determination of thyroglobulin (Tg) levels by immunoassay is subject to interference by antithyroglobulin antibodies in up to 30% of cases, suggesting a need to find alternative methods for the follow-up of a significant number of thyroid cancer patients. OBJECTIVES: Assess the sensitivity, specificity, and predictive values of thyroglobulin messenger RNA (Tg-mRNA) levels measured by quantitative Real Time-PCR (qRT-PCR) in the blood of patients followed for differentiated thyroid cancer. METHODS: This is a prospective study of Tg-mRNA levels measured with qRT-PCR. A peripheral blood sample was taken in patients with excellent response (n=69) and with structural incomplete response to treatment (n=23). Results were analysed using the Unity Real-Time program and expressed as fg/µg RNA. A Receiver Operating Characteristic curve was constructed to establish Tg-mRNA cut-off values. RESULTS: Tg-mRNA levels were not significantly different between the group with excellent response [0.10fg/µg RNA (0.08-0.17)] and the group with incomplete structural response [0.133fg/µg RNA (0.07-0.33)] (p<0.06). Test sensitivity was 69.6%, specificity was 59.4%, negative predictive value was 85.4% and positive predictive value was 36.4%. CONCLUSIONS: Our experience shows that this technique could be useful as a rule-out test in selected cases, but its low sensitivity and specificity preclude its usefulness as a first-line test.

Increased risk of preneoplastic colonic lesions and colorectal carcinoma in acromegaly: multicenter case-control study.

PURPOSE: Current international guidelines recommend colonoscopy in patients with acromegaly at the time of diagnosis, even though the risk of developing colorectal neoplasm is still controversial. The main objective of this Argentine multicenter study was to analyze through screening colonoscopy the presence of advanced neoplastic lesions considered as precancerous, in patients with acromegaly compared to a control group. METHODS: This is a case-control retrospective study. Full length colonoscopy of 70 acromegalic patients and 128 control subjects were studied. Polyps were classified into non pre-cancerous lesions and advance neoplastic lesions which included advanced adenomas (preneoplastic) and colorectal carcinomas. RESULTS: Thirty three out of 70 acromegalic patients and 32 out of 128 subjects controls presented polyps in the colonoscopy [47.1% vs 25%, p = 0.002, OR 2.68]. Non precancerous polyps were found in 11 (15.7%) and 23 (17.9%) (p = 0.690), while advanced neoplastic lesions were found in 22 (31.4%) and 9 (7.0%) (p = 0,0001 - OR: 6.06) patients and controls respectively. Advanced adenomas and colorectal carcinomas were found in 18 (27.3%) and 9 (7.0%) (p = 0,0006-OR: 4,57), and 4 (5.7%) and 0 (0.0%) p = 0.0063) of patients and controls respectively. The presence of insulin resistance was the only statistically significant associated factor among acromegalic patients with and without colonic polyps. CONCLUSIONS: Our findings show an increased risk of preneoplastic colonic lesions and colorectal carcinoma in patients with chronic and sustained GH excess compared to a control group. This supports the recommendation to perform screening colonoscopy at diagnosis of acromegaly.

Acromegaly and thyroid cancer: analysis of evolution in a series of patients.

BACKGROUND: Acromegaly is associated with higher morbidity and mortality mainly due to cardiovascular disease. Data on the incidence and evolution of thyroid cancer in acromegaly are controversial. Our objective was to describe the characteristics of a group of acromegalic patients with differentiated thyroid carcinoma (DTC) and analyze their evolution. METHODS: This is a retrospective multicenter study of 24 acromegalic patients with DTC. The AJCC Staging System 8th Edition was used for TNM staging, and the initial risk of recurrence (RR), initial response and response at the end of follow-up (RFU) were defined according to the 2015 ATA Guidelines. As a control group, 92 patients with DTC without acromegaly were randomly included. Statistical analyses were done using SPSS Statistics 20.0. RESULTS: Median age of patients at diagnosis of acromegaly was 49.5 years (range 12-69). The median delay in diagnosis of acromegaly was 3 years (range 0.5-23). Mean baseline IGF-1 level was 2.9 ± 1.1 ULN. Median age at DTC diagnosis was 51.5 years (18-69). At the moment of diagnosis of DTC, 58.3% of the patients had active acromegaly. Median time from DTC diagnosis to acromegaly control was 1.25 years (0.5-7). Mean DTC tumor diameter of the biggest lesion was 14.6 ± 9.2 mm, being multifocal in 37.5%. All tumors were papillary carcinomas, two cases being of an aggressive variety. Lymph node dissection was performed in 8 out of 24 patients and 62.5% had metastases. Only one patient had distant metastases. Radioiodine ablation was given to 87.5% of patients. Nineteen patients (79%) were stage I, four (17%) stage II and one (4%) stage IVb. Initial RR was low in 87% (21/24), intermediate in 9% (2/24) and high in 4% (1/24) patient. RFU was: 83% (19/23) patients with no evidence of disease, 9% (2/23) with indeterminate response, 4% (1/23) with biochemical incomplete response and 4% (1/23) with structural incomplete response, at a median time of FU of 36.5 months. When comparing RFU between acromegalics and controls no statistically significant differences were found. CONCLUSIONS: Patients with acromegaly and DTC mostly had a low initial RR. When compared with the control group, we found that DTC patients with acromegaly did not have a worse evolution.

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

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.

Fluconazole treatment in severe ectopic Cushing syndrome

Summary: Severe Cushing syndrome (SCS) is considered an emergency that requires immediate treatment to lower serum cortisol levels. Fluconazole may be considered an alternative treatment in Cushing syndrome when ketoconazole is not tolerated or unavailable. We report a 39-year-old woman with a history of partial pancreaticoduodenectomy due to a periampullary neuroendocrine tumor with locoregional extension. Three years after surgery, she developed liver metastases and was started on 120 mg of lanreotide/month, despite which, liver metastases progressed in the following 6 months. The patient showed extreme fatigue, muscle weakness, delirium, moon face, hirsutism and severe proximal weakness. Laboratory tests showed anemia, hyperglycemia and severe hypokalemia. 24-h urinary free cortisol: 2152 nmol/day (reference range (RR): <276), morning serum cortisol 4883.4 nmol/L (RR: 138­690), ACTH 127.3 pmol/L (RR: 2.2­10). She was diagnosed with ectopic ACTH syndrome (EAS). On admission, she presented with acute upper gastrointestinal tract bleeding and hemodynamic instability. Intravenous fluconazole 400 mg/day was started. After 48 h, her mental state improved and morning cortisol decreased by 25%. The dose was titrated to 600 mg/day which resulted in a 55% decrease in cortisol levels in 1 week, but then had to be decreased to 400 mg/day because transaminase levels increased over 3 times the upper normal level. After 18 days of treatment, hemodynamic stability, lower cortisol levels and better overall clinical status enabled successful bilateral adrenalectomy. This case report shows that intravenous fluconazole effectively decreased cortisol levels in SCS due to EAS. Learning Points: Severe Cushing syndrome can be effectively treated with fluconazole to achieve a significant improvement of hypercortisolism prior to bilateral adrenalectomy. Intravenous fluconazole is an alternative treatment when ketoconazole is not tolerated and etomidate is not available. Fluconazole is well tolerated with mild side effects. Hepatotoxicity is usually mild and resolves after drug discontinuation.

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

Bilateral pheochromocytoma after kidney transplantation in neurofibromatosis type 1.

We present the case of a 25-year-old male with a history of neurofibromatosis type 1 and bilateral pheochromocytoma 4 years after kidney transplantation that was successfully treated with simultaneous bilateral posterior retroperitoneoscopic adrenalectomy. Learning points: Hypertensive patients with NF1 should always be screened for pheochromocytoma. Pheochromocytoma is rarely associated with transplantation, but it must be ruled out in patients with genetic susceptibility. Posterior retroperitoneoscopic adrenalectomy (PRA) allows more direct access to the adrenal glands, especially in patients with previous abdominal surgeries.

Síndrome de Turner: nuestra experiencia en la creación del Registro Institucional y de la Unidad Interdisciplinaria en el Hospital Italiano de Buenos Aires: un primer paso para el mejor seguimiento / Turner syndrome: our experience in the creation of the Registry Institutional and Interdisciplinary Unit at the Italian Hospital of Buenos Aires: a first step to the best follow-up

El síndrome de Turner (ST) resulta de la ausencia completa o parcial del segundo cromosoma sexual en fenotipos femeninos. Tiene una incidencia de 1:2000- 2500 nacidas vivas. Recién en la última década se ha puesto atención a la salud de las adultas con ST. La mortalidad es 3 veces superior respecto de la población general debido al riesgo de disección aórtica por anomalías cardiovasculares estructurales y aterosclerosis vinculada a hipertensión arterial, diabetes, dislipidemia y obesidad. También presentan elevada prevalencia de enfermedades autoinmunitarias. Objetivo: evaluar la calidad del seguimiento clínico de pacientes adultas con ST, comparando los controles de salud preconformación y posconformación del Registro y de la Unidad Interdisciplinaria. En el año 2017 fuimos convocados para integrar el Programa de Enfermedades Raras del Hospital Italiano de Buenos Aires. A partir de la creación del Registro Institucional y del equipo multidisciplinario obtuvimos mejoría significativa en los controles por las especialidades de cardiología, endocrinología y otorrinolaringología, en los controles bioquímicos del metabolismo lipídico, hidrocarbonado, hepatograma, TSH y anticuerpos para celiaquía e imágenes cardiovasculares y densitometría ósea. En conclusión, el seguimiento sistematizado e institucional, mediante el Registro y la creación de la Unidad Interdisciplinaria de Síndrome de Turner, permitió encontrar las falencias del sistema de atención y optimizar el seguimiento de esta población. (AU)

Turner syndrome (TS) results from the complete or partial absence of the second sex chromosome in female phenotypes. It has an incidence of 1: 2000-2500 girls born alive. Only in the last decade has been paid attention to the health of adults women with TS. Mortality is 3 times higher than in the general population due to the risk of aortic dissection cause to structural cardiovascular anomalies and atherosclerosis related to hypertension, diabetes, dyslipidemia and obesity. They also have a high prevalence of autoimmune diseases. Until nowadays in Argentina do not exist a national registry of this disease that complies with the international follow-up recommendations for these patients. We proposed to develop the institutional register at 2014 and a multidisciplinary team was created to care and follow up girls and women with TS during 2015. It was indexed to Italian Hospital of Buenos Aires' Rare Diseases Program since 2017. After the creation of the institutional registry and the multidisciplinary team we obtained a significant improvement in cardiology, endocrinology and otorhinolaryngology schedule visits, in lipids and hydrocarbon metabolism, liver, thyroid and celiac diseases biochemical controls and in the performance of cardiovascular MNR and bone densitometry. In conclusion, the systematized and institutional follow-up, through the registry and the creation of the Interdisciplinary Unit of Turner Syndrome, allowed us to find the flaws of the care system and to optimize the follow up of this population. (AU)

Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study.

BACKGROUND: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING: None.

[IgG4 related disease presenting as panhypopituitarism and perimacular scotoma]. / Panhipopituitarismo y escotoma perimacular como presentación de enfermedad relacionada a IgG4.

IgG4-related disease (IgG4-RD) is a recently described systemic entity of unknown origin. It predominantly affects older men and has distinctive histopathologic features as storiform fibrosis, obliterative phlebitis, dense lymphoplasmacytic infiltrate with immunostaining for IgG4, and it may be associated with elevated serum levels of IgG4. Although any organ can be affected, pituitary gland is rarely involved. We describe the case of a 36-year-old man who presented with headaches, impaired vision, panhypopituitarism with diabetes insipidus and an infiltrative lesion mainly of infundibulum and pituitary. We arrived at diagnosis of IgG4-RD by pituitary biopsy. A successful response to treatment with immunosuppressive doses of corticosteroids was achieved.

Panhipopituitarismo y escotoma perimacular como presentación de enfermedad relacionada a IgG4 / IgG4 related disease presenting as panhypopituitarism and perimacular scotoma

La enfermedad relacionada a IgG4 (IgG4-RD) constituye una entidad sistémica recientemente descrita, de causa desconocida. Afecta predominantemente a hombres mayores y presenta características histopatológicas distintivas, como fibrosis estoriforme, flebitis obliterante y denso infiltrado linfoplasmocitario con inmunomarcación para IgG4, pudiendo estar asociada a elevación sérica de dicha inmunoglobulina. Si bien cualquier órgano puede estar afectado, el compromiso de la hipófisis es infrecuente. Describimos el caso de un hombre de 36 años que se presentó con cefaleas, alteración del campo visual, panhipopituitarismo, diabetes insípida y una imagen que mostraba una lesión infiltrativa infundíbulo-panhipofisaria extendida. Arribamos al diagnóstico de IgG4-RD a través de biopsia hipofisaria. La respuesta al tratamiento con dosis inmunosupresoras de corticoides fue exitosa.

IgG4-related disease (IgG4-RD) is a recently described systemic entity of unknown origin. It predominantly affects older men and has distinctive histopathologic features as storiform fibrosis, obliterative phlebitis, dense lymphoplasmacytic infiltrate with immunostaining for IgG4, and it may be associated with elevated serum levels of IgG4. Although any organ can be affected, pituitary gland is rarely involved. We describe the case of a 36-year-old man who presented with headaches, impaired vision, panhypopituitarism with diabetes insipidus and an infiltrative lesion mainly of infundibulum and pituitary. We arrived at diagnosis of IgG4-RD by pituitary biopsy. A successful response to treatment with immunosuppressive doses of corticosteroids was achieved.