The kinome, cyclins and cyclin-dependent kinases of pituitary adenomas, a look into the gene expression profile among tumors from different lineages.

BACKGROUND: Pituitary adenomas (PA) are the second most common intracranial tumors and are classified according to hormone they produce, and the transcription factors they express. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. METHODS: Here we performed transcriptome and proteome analysis of tumors derived from POU1F1 (GH-, TSH-, and PRL-tumors, N = 16), NR5A1 (gonadotropes and null cells adenomas, n = 17) and TBX19 (ACTH-tumors, n = 6) lineages as well as from silent ACTH-tumors (n = 3) to determine expression of kinases, cyclins, CDKs and CDK inhibitors. RESULTS: The expression profiles of genes encoding kinases were distinctive for each of the three PA lineage: NR5A1-derived tumors showed upregulation of ETNK2 and PIK3C2G and alterations in MAPK, ErbB and RAS signaling, POU1F1-derived adenomas showed upregulation of PIP5K1B and NEK10 and alterations in phosphatidylinositol, insulin and phospholipase D signaling pathways and TBX19-derived adenomas showed upregulation of MERTK and STK17B and alterations in VEGFA-VEGFR, EGF-EGFR and Insulin signaling pathways. In contrast, the expression of the different genes encoding cyclins, CDK and CDK inhibitors among NR5A1-, POU1F1- and TBX19-adenomas showed only subtle differences. CDK9 and CDK18 were upregulated in NR5A1-adenomas, whereas CDK4 and CDK7 were upregulated in POUF1-adenomas. CONCLUSIONS: The kinome of PA clusters these lesions into three distinct groups according to the transcription factor that drives their terminal differentiation. And these complexes could be harnessed as molecular therapy targets.

Proteomic and Transcriptomic Analysis Identify Spliceosome as a Significant Component of the Molecular Machinery in the Pituitary Tumors Derived from POU1F1- and NR5A1-Cell Lineages.

BACKGROUND: Pituitary adenomas (PA) are the second most common tumor in the central nervous system and have low counts of mutated genes. Splicing occurs in 95% of the coding RNA. There is scarce information about the spliceosome and mRNA-isoforms in PA, and therefore we carried out proteomic and transcriptomic analysis to identify spliceosome components and mRNA isoforms in PA. METHODS: Proteomic profile analysis was carried out by nano-HPLC and mass spectrometry with a quadrupole time-of-flight mass spectrometer. The mRNA isoforms and transcriptomic profiles were carried out by microarray technology. With proteins and mRNA information we carried out Gene Ontology and exon level analysis to identify splicing-related events. RESULTS: Approximately 2000 proteins were identified in pituitary tumors. Spliceosome proteins such as SRSF1, U2AF1 and RBM42 among others were found in PA. These results were validated at mRNA level, which showed up-regulation of spliceosome genes in PA. Spliceosome-related genes segregate and categorize PA tumor subtypes. The PA showed alterations in CDK18 and THY1 mRNA isoforms which could be tumor specific. CONCLUSIONS: Spliceosome components are significant constituents of the PA molecular machinery and could be used as molecular markers and therapeutic targets. Splicing-related genes and mRNA-isoforms profiles characterize tumor subtypes.

Transcriptome and methylome analysis reveals three cellular origins of pituitary tumors.

Pituitary adenomas (PA) are the second most common intracranial tumors. These neoplasms are classified according to the hormone they produce. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. The present transcriptomic and methylomic analysis of PA revealed that they segregate into three molecular clusters according to the transcription factor driving their terminal differentiation. First cluster, driven by NR5A1, consists of clinically non-functioning PA (CNFPA), comprising gonadotrophinomas and null cell; the second cluster consists of clinically evident ACTH adenomas and silent corticotroph adenomas, driven by TBX19; and the third, POU1F1-driven TSH-, PRL- and GH-adenomas, segregated together. Genes such as CACNA2D4, EPHA4 and SLIT1, were upregulated in each of these three clusters, respectively. Pathway enrichment analysis revealed specific alterations of these clusters: calcium signaling pathway in CNFPA; renin-angiotensin system for ACTH-adenomas and fatty acid metabolism for the TSH-, PRL-, GH-cluster. Non-tumoral pituitary scRNAseq data confirmed that this clustering also occurs in normal cytodifferentiation. Deconvolution analysis identify potential mononuclear cell infiltrate in PA consists of dendritic, NK and mast cells. Our results are consistent with a divergent origin of PA, which segregate into three clusters that depend on the specific transcription factors driving late pituitary cytodifferentiation.

Molecular alterations in non-functioning pituitary adenomas.

BACKGROUND: Clinically non-functioning Pituitary Adenomas (NFPA) are among the most common neoplasms of the sellar region. They usually present with compressive symptoms such as headache and visual field defects and not infrequently, are found incidentally. NFPA are classified as gonadotropinomas, null cell adenomas, according to their immunohistochemical phenotype. The molecular alterations responsible for the development of these lesions are incompletely understood, and there is scarce information regarding the molecular alterations and markers. OBJECTIVE: We carried out an in-silico analysis aimed at identifying the molecular alterations in NFPA and to discover new molecular markers. METHODS: Twenty-three microarray libraries were analyzed. Fourteen correspond to NFPA and 9 to control tissue gland. They were analyzed using Partek Genomic Suite to identify differentially expressed genes and WebGestalt and Metascape to understand the meaning behind the gene lists. RESULTS: Pituitary adenomas showed a markedly different transcriptome compared to the non-tumoral gland, regardless of their putative immunophenotype. Genes related to calcium metabolism such as CACNA2D4, immune-related CXCR4, and stem cell-related KLF8 and PITX2 were altered. CONCLUSIONS: Differentially expressed calcium metabolism and immune-related genes in NFPA represent attractive molecular markers and potential therapeutic targets.

Generalización de la gestión por procesos como plataforma de trabajo de apoyo a la mejora de organizaciones de salud / Generalization of business process management as a framework supporting health care improvement / Generalização da gestão por processos como uma plataforma de trabalho de apoio à melhoria de organizações de saúde

Resumen El Sistema Nacional de Salud Cubano se plantea como reto el perfeccionamiento de la gestión de sus instituciones, para lo cual considera objetivos medulares: fomentar la creatividad y la innovación, impulsar la formación permanente, buscar la eficiencia, estudiar buenas prácticas internacionales y propiciar una constante evaluación de los procesos. Estos propósitos son comunes a enfoques gerenciales frecuentemente adoptados por las organizaciones que buscan calidad, eficiencia, eficacia y mejor servicio al cliente. Este trabajo busca ilustrar los resultados de experiencias de gestión por procesos como plataforma de trabajo que impulsa la mejora de los servicios de salud. Para ello muestra la inserción de un procedimiento, resultado del estudio bibliográfico de setenta propuestas metodológicas. Se toman cinco hospitales de una provincia cubana para probar la utilidad de los instrumentos y luego se aprecian los avances en el servicio y el desempeño hospitalario, así como la extensión del estudio a otros hospitales del territorio.

Abstract Cuban National System faces an important challenge, which is to consolidate the improvement programs of their institutions; consequently, there are considered key objectives like: fostering creativity and innovation; promoting continuous training; and ensuring the efficiency seeking, the application of best practices and permanent processes evaluation. These objectives are commonly assumed when organizations adopted managerial approaches based on quality, efficiency, effectiveness and service to clients. Hence, this paper shows the results of experiences in business process management, being conceived as a work setting of improvement in health institutions. To seek such goal, it is conducted a bibliography study of 70 methodological procedures, resulting in a new approach that is applied to five hospitals in a Cuban province in order to prove its efficacy for performance improvement, which is illustrated by progress being obtained in service and processes functioning with consequent extension to other hospital of the province.

Resumo O Sistema Nacional de Saúde cubano confronta o desafio de melhorar a gestão das suas instituições, para o qual são considerados como objetivos centrais a promoção da criatividade e da inovação, a promoção da aprendizagem permanente, a busca da eficiência, o estudo das melhores práticas internacionais e uma avaliação constante dos processos. Estes efeitos são comuns a abordagens de gestão, muitas vezes adoptadas pelas organizações que buscam qualidade, eficiência, eficácia e melhor atendimento ao cliente. Este trabalho procura ilustrar os resultados de experiências de gestão de processos como uma plataforma de trabalho que impulsiona a melhoria dos serviços de saúde, traves da inserção de um procedimento, resultado da revisão de literatura de setenta propostas metodológicas. Cinco hospitais de uma província cubana são tomados para testar a utilidade dos instrumentos, depois sao avaliados os avances no serviço e o desempenho hospitalar, e finalmente é apresentada a extensão do estudo para outros hospitais da região.

AIP mutations in young patients with acromegaly and the Tampico Giant: the Mexican experience.

Although aryl hydrocarbon receptor-interacting protein (AIP) mutations are rare in sporadic acromegaly, their prevalence among young patients is nonnegligible. The objectives of this study were to evaluate the frequency of AIP mutations in a cohort of Mexican patients with acromegaly with disease onset before the age of 30 and to search for molecular abnormalities in the AIP gene in teeth obtained from the "Tampico Giant". Peripheral blood DNA from 71 patients with acromegaly (51 females) with disease onset <30 years was analysed (median age of disease onset of 23 years) and correlated with clinical, biochemical and imaging characteristics. Sequencing was also carried out in DNA extracted from teeth of the Tampico Giant. Five patients (7 %) harboured heterozygous, germline mutations of the AIP gene. In two of them (a 9-year-old girl with gigantism and a young man with symptoms of GH excess since age 14) the c.910C>T (p.Arg304Ter), well-known truncating mutation was identified; in one of these two cases and her identical twin sister, the mutation proved to be a de novo event, since neither of their parents were found to be carriers. In the remaining three patients, new mutations were identified: a frameshift mutation (c.976_977insC, p.Gly326AfsTer), an in-frame deletion (c.872_877del, p.Val291_Leu292del) and a nonsense mutation (c.868A > T, p.Lys290Ter), which are predicted to be pathogenic based on in silico analysis. Patients with AIP mutations tended to have an earlier onset of acromegaly and harboured larger and more invasive tumours. A previously described genetic variant of unknown significance (c.869C > T, p.Ala299Val) was identified in DNA from the Tampico Giant. The prevalence of AIP mutations in young Mexican patients with acromegaly is similar to that of European cohorts. Our results support the need for genetic evaluation of patients with early onset acromegaly.

Acciones para reforzar los valores responsabilidad y humanismo en los futuros profesionales de la salud / Actions to reinforce the responsibility and humanism values in the future health professional

Fundamento: la educación en el trabajo es una forma organizativa fundamental del proceso pedagógico y de formación de valores humanos y revolucionarios. Objetivo: elaborar acciones para reforzar los valores responsabilidad y humanismo desde la educación en el trabajo en los futuros profesionales de la salud. Métodos: se realizó una investigación de tipo descriptiva con enfoque cualitativo en el Policlínico Universitario "Idalberto Revuelta Díaz" durante septiembre a diciembre del año 2014. Se utilizaron métodos teóricos: análisis-síntesis e inducción deducción, para los referentes teóricos del tema y dentro de los empíricos: el análisis documental, la observación y la encuesta en forma de entrevista a los médicos de la familia que actúan como docentes en sus escenarios de trabajo. Resultados: el análisis documental permitió corroborar la existencia de bibliografía digital e impresa actualizada en relación con los valores objeto de estudio, se comprobó que la mayoría de los docentes tienen carencias para desarrollarlos a través de la educación en el trabajo, ellos reconocen tener insuficiencias metodológicas para emprender esta tarea por falta de preparación pedagógica y poca accesibilidad a información, por lo que se elaboraron acciones para solucionar esas carencias. Conclusiones: las acciones propuestas son aplicables desde la educación en el trabajo y están sustentadas en la ejemplaridad del docente; fueron valoradas por un grupo de especialistas como pertinentes y factibles de aplicar y con fundamento científico pedagógico.

Background: the in-service training is a fundamental organizational form of the pedagogic process and the formation of human and revolutionary values. Objective: to elaborate actions to reinforce the responsibility and humanism values through the in-service training in the future health professional. Methods: it was carried out a descriptive research work within the qualitative approach in "Idalberto Revuelta Díaz" University Polyclinic from September to December 2014. Theoretical methods were used: analysis-synthesis and induction deduction, for the theoretical background of the topic and within the empiric ones: the documental analysis, the observation and the survey in interview form to General Practitioners who work as professors in their working scenarios. Results: the documental analysis allowed to corroborate the existence of updated digital and printed bibliography in connection with the object of study values, it was proven that most of the professors have deficiencies to develop them through the in-service training, they recognize to have methodological inadequacies to undertake this task due to deficiencies in the pedagogical preparation and little accessibility to information, for this reason actions were elaborated to solve those deficiencies. Conclusions: the proposed actions are applicable through the in-service training and they are sustained in the exemplariness of the professors; they were valued by a group of specialists as pertinent and feasible and with a pedagogic-scientific background.

[Current diagnosis and treatment of hyperprolactinemia]. / Diagnóstico y tratamiento actual de la hiperprolactinemia.

Hyperprolactinemia is a frequent neuroendocrinological condition that should be approached in an orderly and integral fashion, starting with a complete clinical history. Once physiological causes such as pregnancy, systemic disorders such as primary hypothyroidism and the use of drugs with dopamine antagonistic actions such as metochlopramide have been ruled out, the most common cause of hyperprolactinemia is a PRL-secreting pituitary adenoma or prolactinoma. Prolactinomas are usually classified as microprolactinomas (less than 1 cm) or macroprolactinomas (larger than 1 cm), which can either be confined or invasive. The hormonal consequence of hypeprolactinemia is hypogonadism; in women, this is manifested as amenorrhea/oligomenorreha, anovulation and galactorrhea, whereas in men the main complaints are a diminished libido and erectile dysfunction. Macroprolactinomas can also present with symptoms and signs resulting form mass effect of the tumor, such as headaches and visual field defects. Other structural causes of hyperprolactinemia include non-functioning pituitary adenomas and infiltrative disorders, which can interrupt the inhibitory, descending dopaminergic tone. The primary treatment of prolactinomas is pharmacological with dopamine agonists such as cabergoline.

La hiperprolactinemia es uno de los trastornos neuroendocrinológicos más frecuentes y su abordaje debe hacerse de manera ordenada e integral, partiendo de una historia clínica completa. Una vez excluidas las causas fisiológicas, como el embarazo, enfermedades sistémicas (como el hipotiroidismo primario) y el uso de fármacos con acción antidopaminérgica (como la metoclopramida), la causa más común de la hiperprolactinemia es la presencia de un adenoma hipofisario productor de prolactina (PRL) o prolactinoma. Los prolactinomas se clasifican por su tamaño en microprolactinomas (menores de 1 cm) y macroprolactinomas (mayores de 1 cm), los cuales a su vez pueden ser intraselares o invasivos. La consecuencia hormonal de la hiperprolactinemia es el hipogonadismo; en la mujer, esto se manifiesta como amenorrea/oligomenorrea, anovulación y galactorrea, mientras que en el hombre la manifestación consiste en la disminución de la libido y disfunción eréctil. En el caso de los macroprolactinomas, no es infrecuente encontrar síntomas y signos de efecto de masa como cefalea y alteraciones en los campos visuales. Otras causas estructurales de hiperprolactinemia son los adenomas no funcionantes y las enfermedades infiltrativas de la hipófisis, las cuales interrumpen el tono dopaminérgico descendente. El tratamiento primario de los prolactinomas es farmacológico, a base de agonistas dopaminérgicos, como la cabergolina.

Acciones para reforzar los valores responsabilidad y humanismo en los futuros profesionales de la salud / Actions to reinforce the responsibility and humanism values in the future health professional

Fundamento: la educación en el trabajo es una forma organizativa fundamental del proceso pedagógico y de formación de valores humanos y revolucionarios.Objetivo: elaborar acciones para reforzar los valores responsabilidad y humanismo desde la educación en el trabajo en los futuros profesionales de la salud. Métodos: se realizó una investigación de tipo descriptiva con enfoque cualitativo en el Policlínico Universitario Idalberto Revuelta Díaz durante septiembre a diciembre del año2014. Se utilizaron métodos teóricos: análisis-síntesis e inducción deducción, para los referentes teóricos del tema y dentro de los empíricos: el análisis documental, la observación y la encuesta en forma de entrevista a los médicos de la familia que actúan como docentes en sus escenarios de trabajo.Resultados: el análisis documental permitió corroborar la existencia de bibliografía digital e impresa actualizada en relación con los valores objeto de estudio, se comprobó que la mayoría de los docentes tienen carencias para desarrollarlos a través de la educación en el trabajo,ellos reconocen tener insuficiencias metodológicas para emprender esta tarea por falta de preparación pedagógica y poca accesibilidad a información, por lo que se elaboraron acciones para solucionar esas carencias.Conclusiones: las acciones propuestas son aplicables desde la educación en el trabajo y están sustentadas en la ejemplaridad del docente; fueron valoradas por un grupo de especialistas como pertinentes y factibles de aplicar y con fundamento científico pedagógico(AU)

Giant prolactinomas: are they really different from ordinary macroprolactinomas?

Giant prolactinomas (gPRLomas) are rare tumors of the lactotroph defined by an unusually large size (>4 cm) and serum PRL levels >1000 ng/mL. The purpose of this study is to characterize the clinical spectrum of gPRLomas comparing them with non-giant prolactinomas. This is a retrospective study at a large referral center. Data from patients harboring gPRLomas and macroprolactinomas were retrieved from medical records of the Prolactinoma Clinic. Analysis was focused on clinical, biochemical, and tumor volume characteristics, as well as on the response to treatment with dopamine agonists. Among 292 patients with prolactinomas followed between 2008 and 2015, 47 (16 %) met the diagnostic criteria for gPRLomas (42 males). The most common complaint was a visual field defect; headache was reported by 79 % and sexual dysfunction was present in over half of the patients. Median basal PRL level and tumor volume were 6667 ng/mL (3750-10,000) and 32 cm(3) (20-50), respectively; hypogonadotropic hypogonadism was documented in 87 %. Cabergoline treatment resulted in the normalization of PRL levels in 68 % and in the reduction of >50 % in tumor volume in 87 % of the gPRLoma patients. The composite goal of PRL normalization and >50 % tumor reduction was achieved by 55 % (n = 26) of patients with gPRL and by 66 % (n = 100) of patients with no giant macroprolactinomas (p = 0.19). Recovery of hypogonadism and improvement of visual fields defects occurred in 32 % and 68 % of the patients, respectively. Cabergoline treatment was equally effective in patients with gPRLoma and those with macroprolactinomas in regard of achieving treatment goals, although the median CBG dose was slightly higher in the gPRLoma group (2 vs. 1.5 mg/w). Six patients required surgery. Beyond their impressive dimensions and the huge amount of PRL they secrete, the clinical behavior of gPRLoma is not different from macroprolactinomas. These tumors are highly responsive to cabergoline treatment, and pituitary surgery is seldom required.

Octreotide LAR treatment of acromegaly in "real life": long-term outcome at a tertiary care center.

OBJECTIVE: To report our day-to day experience with the long-term use of octreotide LAR in the treatment of acromegaly. PATIENTS AND METHODS: Patients with acromegaly managed between 2003 and 2012 with octreotide LAR for a median of 27 months (interquartile ranges 12-60) and who had not received radiation therapy or concomitant treatment with cabergoline were retrospectively evaluated. Both primarily treated patients (n = 33) and patients who received octreotide after failed pituitary surgery (adjunctive treatment, n = 124) were included. Full biochemical response was defined as the achievement of a GH <2.5 ng/mL and an IGF-1 <1.2 times the upper limit of normal (× ULN); we also evaluated efficacy using a GH cut off of <1 ng/mL. RESULTS: Over 60% of the patients achieved a GH of <2.5 ng/mL. The combined GH (<2.5 ng/mL) and IGF-1 (<1.2 × ULN) target was achieved by 35.5 and 33.6% of the patients treated primarily and adjunctively, respectively; these figures dropped to 22.6 and 23% when using a GH target of <1 ng/mL. All patients reported a significant improvement in acromegalic symptoms. Lower pretreatment GH and IGF-1 levels were both associated with a higher probability of achieving the composite biochemical target. CONCLUSION: Currently recommended GH and IGF-1 targets are reached by <36% of patients treated with octreotide LAR in a day-to day practice context. Nevertheless, in most instances a clinical benefit and an improvement in biochemical markers can be clearly documented.

Successful mortality reduction and control of comorbidities in patients with acromegaly followed at a highly specialized multidisciplinary clinic.

CONTEXT: Acromegaly is usually due to the excessive secretion of GH by a pituitary adenoma. It is frequently accompanied by comorbidities that compromise quality of life and results in elevated mortality rates. OBJECTIVE: To evaluate mortality and morbidity in patients with acromegaly receiving multimodal care. SETTING: Tertiary care center. DESIGN, PATIENTS, AND METHODS: Retrospective evaluation of 442 patients (65.4% women; mean age, 43.5 ± 13.1 y) followed for a median of 6 years (interquartile range [IQR], 3-10). RESULTS: Twenty-two patients died during the study period (4.9%), representing a total standardized mortality ratio (SMR) of 0.72 (95% confidence interval [CI], 0.41-1.03). Standardized mortality ratios were 1.5 and 0.44 for patients whose last GH was above and below 2.5 ng/mL, respectively; 1.17 and 0.16 for those whose last GH was above and below 1 ng/mL, respectively; and 0.94 and 0.46 for those whose last IGF-1 was above and below 1.2 times the upper limit of normal (ULN), respectively. The prevalence of diabetes mellitus, hypertension, heart disease, and cancer was 30%, 35%, 8%, and 4.7%, respectively. The most common cause of death was cancer. On multivariate analysis, diabetes, heart disease, and cancer were related to a baseline GH > 10 ng/mL; the presence of cancer and the last IGF-1 were significant predictors of mortality. Survival decreased as the latest GH levels increased from < 1 ng/mL to > 5 ng/mL and as IGF-1 increased from < 1.2 to > 2 times the ULN. CONCLUSIONS: Mortality in acromegaly can be successfully reduced, provided patients are treated using a multimodal approach with careful management of comorbidities.

Persistence of Cushing's disease symptoms and comorbidities after surgical cure: a long-term, integral evaluation.

OBJECTIVES: Successful surgery does not always resolve all the clinical consequences of hypercortisolism in patients with Cushing's disease (CD). Our purpose was to integrally evaluate a group of CD patients cured by pituitary surgery and look for the persistence of CD symptoms, signs, and comorbidities. METHODS: We performed clinical and biochemical evaluations of 29 CD patients (2 males) cured by pituitary surgery. All patients underwent early (median 12 months) and late (median 58 months) postoperative evaluations. We sought information regarding hypercortisolism-related symptoms and signs, as well as metabolic, cardiovascular, reproductive, and psychologic comorbidities. RESULTS: The prevalence of obesity dropped from 72.4% at diagnosis to 31% at early evaluation but increased again to 44.8% at the late evaluation. Diabetes was present in 14 patients (48.3%) at diagnosis and persisted in 9 at the late evaluation. Hypertriglyceridemia was present in 58.6% and 55.1% of patients at diagnosis and at the late follow-up, respectively. The prevalence of hypercholesterolemia was 79.3% at diagnosis, decreased to 55.1% at the early evaluation, and increased to 65.5% at the late evaluation. Menstrual abnormalities were originally present in 15 of 20 women, and 8 of the 15 had recovered normal periods when seen at the last evaluation. Among the 24 patients with depression at diagnosis, 11 and 6 still exhibited mood abnormalities at the early and late evaluations, respectively. CONCLUSIONS: In a variable proportion of patients, the cardiovascular, metabolic, and emotional comorbidities of CD persist after long-term remission, irrespective of the initial degree of hypercortisolism.

Discontinuation of octreotide LAR after long term, successful treatment of patients with acromegaly: is it worth trying?

BACKGROUND: Somatostatin analogs (SA) have been used for over 25 years in the treatment of acromegaly. A major disadvantage is the need to continue therapy indefinitely. OBJECTIVE: To evaluate the feasibility of discontinuing therapy in well-controlled patients with acromegaly treated chronically with SA. DESIGN AND METHODS: Of the 205 subjects on octreotide LAR, we selected those who met the following criteria: two or more years of treatment, a stable dose and injection interval of 20  mg every 8 weeks or longer for the previous year, no history of radiation, no cabergoline for the previous 6 months, a GH <1.5  ng/ml, and an IGF1 <1.2×upper limit of normal (ULN). Octreotide LAR was stopped and both GH and IGF1 were measured monthly for 4 months; a glucose-suppressed GH value and magnetic resonance imaging were obtained at the 4th month, thereafter, basal GH and IGF1 were measured q. 3 months, for 12-18 months. Patients were removed from the study if GH or IGF1 rose to 1.5  ng/ml or 1.2×ULN respectively. RESULTS: Twelve patients (ten women, mean age 48±13 years) were studied. Seven patients (58.3%) relapsed biochemically within 1 year of having stopped the SA; two patients relapsed by GH and IGF1 criteria, the remaining five patients kept GH levels within target. Five patients (41.7%) remain in remission after 12 months of follow-up. Non-recurring patients were on longer injection intervals but no other characteristic was associated with a successful withdrawal. CONCLUSION: Withdrawal of SA is possible in a small but distinct subset of patients, particularly in those who are very well controlled on relatively low doses administered at long intervals.

Efficacy and safety of radiotherapy in acromegaly.

BACKGROUND AND AIMS: Transsphenoidal surgery remains the treatment of choice in acromegaly, yet 40-50% of patients require secondary forms of therapy such as radiation therapy (RT) and somatostatin analogues (SA). We undertook this study to evaluate the efficacy and safety of RT in acromegaly. METHODS: Forty patients with acromegaly treated with RT (mean dose, 52 Gy) after failed pituitary surgery between 1993 and 2007 were analyzed; all were clinically and biochemically active. Patients were evaluated with yearly hormonal measurements [basal and glucose-suppressed growth hormone (GH), IGF-1, thyroid-stimulating hormone (TSH), free T4, cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone or estradiol and prolactin (PRL)] and with magnetic resonance imaging every 2 years. RESULTS: Mean age of patients was 52.9 ± 12.1 years and 85% were female. All subjects had been followed for 1 year, 75% for 3 years, 70% for 5 years and 35% for 10 years. The median basal GH level fell from a baseline of 8.8 ng/mL to 2.27 ng/mL at 5 years (p = 0.001) and to 1.88 ng/mL at 10 years (p = 0.001). A GH <1 ng/mL was achieved by 46% and 57% of the patients at 5 and 10 years of follow-up, respectively. The proportion of patients achieving a normal IGF-1 was 36% at 5 years and 43% at 10 years. Before RT, hypothyroidism, hypocortisolism and hypogonadism were present in 44%, 26% and 74% of patients, respectively. After 5 years of follow-up (n = 28), these figures increased to 51%, 41% and 79% and over a third of the group had panhypopituitarism. One patient developed optic neuritis and another patient was diagnosed with a meningioma 10 years after RT. No cerebrovascular events or deaths occurred. CONCLUSIONS: RT is an effective, low-cost and reasonably safe means of controlling acromegalic activity, particularly useful in parts of the world where SA are not readily available.

Clinical and biochemical characteristics of acromegalic patients with different abnormalities in glucose metabolism.

To determine the prevalence of diabetes, glucose intolerance and impaired fasting glucose in Mexican patients with acromegaly and establish associations with clinical, anthropometric and biochemical variables. 257 patients with acromegaly were evaluated by a 75 g-oral glucose tolerance test with measurements of both GH and glucose (0, 30, 60, 90 120 min) as well as baseline IGF-1. Normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes (DM) were defined based on the 2003 ADA criteria. NGT, IFG, IGT and DM were found in 27.6, 8.9, 31.6 and 31.9% of the subjects, respectively; 42 of the DM patients were unaware of the diagnosis. Patients with diabetes were older than subjects in the other 3 categories (P = 0.001), and the proportion of women was significantly higher in the DM (74%) and IGT (68%) groups than in the NGT group (52%) (P = 0.004). Odds ratio for the development of DM was 3.29 (95% CI 3.28-3.3). GH and IGF-1 levels were comparable among the different groups. In a multivariable analysis DM was significantly associated with age, presence of a macroadenoma, disease duration and a basal GH > 30 µg/dl. DM and probably IGT are more prevalent in acromegaly than in the general Mexican population. DM was more frequent in females of all ages, in subjects with severely elevated GH concentrations, in patients with macroadenomas, and long-standing disease duration. The odds ratio for DM in our subjects with acromegaly is more than 3 times higher than in the general population.

[Treatment of acromegaly with octreotide LAR]. / Tratamiento de la acromegalia con octreotida LAR.

BACKGROUND: Treatment of acromegaly with somastostatin analogues, albeit highly effective, is not curative and its elevated cost represents a major disadvantage. Hereby we describe our Center's experience using a fixed, 20 mg q.4 weeks- dose of octreotide LAR. METHODS: 97 patients, 69 females, 71 with macroadenomas, treated with 20-mg im injections of octreotide LAR every 4 weeks, in 23 as primary therapy. No dose escalation was allowed. Patients were evaluated with GH and IGF-1 levels at 4 weeks after the third injection; thereafter, assessments occurred at 3 to 6 months intervals. In 27 unselected patients, evaluations were also performed 6 weeks after the SA injection. RESULTS: A GH concentration < 2.5 ng/mL was reached by 71%, 75% and 83% of patients at the 3rd , 6th and 12th months of follow up respectively, whereas over 30% achieved an IGF-1 index < or = 1.0 at each of these time points, and both biochemical goals were achieved by 30%, 33% and 32% of patients at the same time points. Biochemical success was the same for those patients treated primarily and those treated secondarily and prior radiation made no difference. A baseline GH level > 10 ng/mL was associated with a poor response. CONCLUSIONS: A biochemical control rate comparable with other published series it is feasible to reach with the treatment with a fixed dose of 20 mg.

Ectopic ACTH-secreting syndrome: a single center experience report with a high prevalence of occult tumor.

BACKGROUND: Differentiation between the two forms of ACTH-dependent Cushing's syndrome is a challenging task. Although the majority of these cases will be diagnosed as Cushing's disease secondary to an ACTH-secreting pituitary adenoma, 10-15% result from the ectopic ACTH secretion syndrome (EAS), which is usually due to neuroendocrine tumors. In the present study we report our experience with EAS in eight patients evaluated and treated during the past 10 years. METHODS: Our experience in the evaluation and management of EAS was retrospectively reviewed. The latter included a standard biochemical assessment (urinary free cortisol, low- and high-dose dexamethasone suppression tests), petrosal sinus sampling when indicated and imaging techniques such as pituitary MRI, total body CT and somatostatin receptor scintigraphy. RESULTS: The ectopic nature of the ACTH hypersecretion was confirmed with inferior petrosal sinus samplings in all cases. CT scanning localized a putative tumor in 6/8 patients, whereas octreotide scintigraphy was positive in only five. In all cases, the source was traced to the lungs. However, upon performing thoracotomy, a documented ACTH-secreting bronchial carcinoid tumor was found in only four patients. Thus, 4/8 patients with EAS remained "occult." All of these patients underwent adrenalectomy for hypercortisolism control. CONCLUSIONS: EAS is a rare cause of ACTH-dependent Cushing's syndrome. Truly "occult" tumors were frequent and these patients need to be under close surveillance for the detection of neuroendocrine tumors.

Biochemical evaluation of disease activity after pituitary surgery in acromegaly: a critical analysis of patients who spontaneously change disease status.

BACKGROUND: The definition of biochemical cure in acromegaly involves both the normalization of IGF-1 and a glucose-suppressed GH level of < 1 ng/ml. These criteria were reached by several consensus meetings, although no evidence-based recommendations as to the optimal time to perform biochemical evaluations were made, nor was the fact that several patients may change biochemically upon long-term follow-up taken into consideration. OBJECTIVES: To identify and characterize biochemical changes in the follow-up of acromegaly. PATIENTS AND METHODS: One hundred and twenty-six acromegalic patients seen at a referral centre were followed prospectively (6-108 months) with regard to glucose-suppressed GH levels and IGF-1 concentrations. RESULTS: Eighty-nine patients did not change biochemical status, whereas in 37 (29.3%), one or more changes were identified, mostly during the first year. When glucose-suppressed GH values were discordant with the IGF-1 results, the likelihood of biochemical status modification was significantly greater than when such results were concordant [concordant 19.4%, discordant 57.6%, odds ratio (OR) = 5.6, 95% confidence interval (CI) = 2.3-13.3, P = 0.0001]. Among the changing patients, four out of the nine subjects initially considered as cured remained so at the last follow-up, whereas five became discordant; of the nine initially categorized as active, only three kept such a status at the last evaluation, whereas five became GH discordant and one achieved full biochemical criteria of cure; of 17 initially GH-discordant patients, seven remained so upon the last evaluation, whereas six became concordantly active and four concordantly cured. CONCLUSION: A significant proportion of acromegalic patients change biochemical status upon long-term follow-up after surgery. Most of these changes occur within the first postoperative year and are more likely to take place if the initial GH postglucose and IGF-1 levels are discordant.

GSPalpha mutations in Mexican patients with acromegaly: potential impact on long term prognosis.

OBJECTIVE: The frequency of activating mutations of the GSPalpha gene as the etiology of GH-secreting pituitary adenomas has been the subject of important ethnogenetic variability. Whereas up to 40% of Caucasian patients with acromegaly have tumors which harbor these somatic mutations, their prevalence among Asian populations is much lower. The correlation between the presence of these mutations and the clinical and biological behavior of these tumors has also been a matter of controversy. In the present study, we investigated the prevalence of GSPalpha mutations in GH-secreting tumors obtained from a genetically homogenous population of Mexican patients with acromegaly. We also sought to establish whether or not the presence of these mutations correlates in any way with the clinical or biochemical characteristics of the disease. STUDY DESIGN AND METHODS: Fifty eight GH-secreting pituitary adenomas were examined for the presence of point mutations in either codon 201 or 227 of the GSPalpha gene, using PCR and direct sequencing of DNA extracted from either fresh or paraffin-embedded tissues. Patients were prospectively followed clinically and biochemically for up to nine years after pituitary surgery. RESULTS: Heterozygous point mutations in exon 8 (codon 201) were found in 11 patients (19%), and no molecular alterations were evident in exon 9. The frequency and severity of the different clinical features of acromegaly did not differ between patients with and without GSPalpha mutations. Patients with and without mutations had pre-operative GH and IGF-I elevations of similar magnitude, and although microadenomas appeared to be more frequent among patients with GSPalpha mutations, this did not reach statistical significance. Upon short-term follow-up, biochemical cure (normal age- and gender-adjusted IGF-I and post-glucose GH below 1 ng/mL) was similarly achieved in both groups. After 3-9 years of post-operative follow up however, a significantly greater proportion of patients with the mutation achieved a "safe" basal GH value (100% vs 33%, p=0.001) as well a lower nadir post-glucose GH (0.53+/-0.5 vs 2.9+/-6.2 ng/mL, p=0.04) although the rate of IGF-1 normalization did not differ between the 2 groups. CONCLUSIONS: Our results show that the prevalence of GSPalpha mutations in Mexican patients with acromegaly is intermediate between that found in Asian and Caucasian populations. In this well-defined genetic population the presence of codon 201 mutations appeared to be associated with a greater probability of achieving a "safe" GH value upon long-term follow-up.