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.

Quality of life evaluation in Mexican patients with severe obesity before and after bariatric surgery.

INTRODUCTION: In Mexico, neither the 36-item Short Form Health Survey (SF-36) nor the Bariatric Analysis and Reporting Outcome System (BAROS) instruments have been used to assess quality of life (QoL) before and after bariatric surgery (BS). OBJECTIVE: To describe changes in QoL using the SF-36 and BAROS questionnaires in patients with severe obesity before and after BS. METHODS: Clinical and anthropometric data of patients undergoing bariatric surgery between 2015 and 2016 were collected. Statistical significance was considered with a p-value < 0.05. RESULTS: 230 patients were analyzed, 98 before and 132 and after BS; most were females (81 %). Initial body mass index was 48 kg/m2 (44-53). SF-36-measured QoL showed an increase in the physical component score from 43 to 54.2 points (p < 0.001), and in the mental component, from 53.3 to 56.6 points after BS. With BAROS, 98.5 % showed good to excellent QoL results within the first three months after BS. CONCLUSION: When measured with the SF-36 and BAROS questionnaires, QoL of Mexican patients with severe obesity was found to improve after BS.

INTRODUCCIÓN: En México no se han utilizado los instrumentos Shorth Form 36 Items (SF-36) ni Baryatric Assesment Reporting Outcomes System (BAROS) para evaluar la calidad de vida (CV) antes y después de la cirugía bariátrica (CB). OBJETIVO: Describir los cambios en la CV con los cuestionarios SF-36 y BAROS, en pacientes con obesidad severa antes y después de la CB. MÉTODOS: Se recolectaron los datos clínicos y antropométricos de pacientes sometidos a cirugía baríatrica entre 2015 y 2016. Se consideró con significación estadística una p < 0.05. RESULTADOS: Se analizaron 230 pacientes, 98 y 132 antes y después de la CB; la mayoría fue del sexo femenino (81 %). El índice de masa corporal inicial fue de 48 kg/m2 (44-53). La CV medida con el SF-36 demostró un incremento en la puntuación del componente físico de 43 a 54.2 (p < 0.001) y en el componente mental, de 53.3 a 56.6 después de la CB. Con BAROS, en 98.5 % se registraron resultados buenos a excelentes en la CV en los primeros tres meses. CONCLUSIÓN: Al ser medida con los cuestionarios SF-36 y BAROS se definió que la CV de los pacientes mexicanos con obesidad severa mejora después de la CB.

Evaluación de la calidad de vida en pacientes mexicanos con obesidad severa antes y después de cirugía bariátrica / Quality of life evaluation in Mexican patients with severe obesity before and after bariatric surgery

Resumen Introducción: En México no se han utilizado los instrumentos Shorth Form 36 Items (SF-36) ni Baryatric Assesment Reporting Outcomes System (BAROS) para evaluar la calidad de vida (CV) antes y después de la cirugía bariátrica (CB). Objetivo: Describir los cambios en la CV con los cuestionarios SF-36 y BAROS, en pacientes con obesidad severa antes y después de la CB. Métodos: Se recolectaron los datos clínicos y antropométricos de pacientes sometidos a cirugía baríatrica entre 2015 y 2016. Se consideró con significación estadística una p < 0.05. Resultados: Se analizaron 230 pacientes, 98 y 132 antes y después de la CB; la mayoría fue del sexo femenino (81 %). El índice de masa corporal inicial fue de 48 kg/m2 (44-53). La CV medida con el SF-36 demostró un incremento en la puntuación del componente físico de 43 a 54.2 (p < 0.001) y en el componente mental, de 53.3 a 56.6 después de la CB. Con BAROS, en 98.5 % se registraron resultados buenos a excelentes en la CV en los primeros tres meses. Conclusión: Al ser medida con los cuestionarios SF-36 y BAROS se definió que la CV de los pacientes mexicanos con obesidad severa mejora después de la CB.

Abstract Introduction: In Mexico, neither the 36-item Short Form Health Survey (SF-36) nor the Bariatric Analysis and Reporting Outcome System (BAROS) instruments have been used to assess quality of life (QoL) before and after bariatric surgery (BS). Objective: To describe changes in QoL using the SF-36 and BAROS questionnaires in patients with severe obesity before and after BS. Methods: Clinical and anthropometric data of patients undergoing bariatric surgery between 2015 and 2016 were collected. Statistical significance was considered with a p-value < 0.05. Results: 230 patients were analyzed, 98 before and 132 and after BS; most were females (81 %). Initial body mass index was 48 kg/m2 (44-53). SF-36-measured QoL showed an increase in the physical component score from 43 to 54.2 points (p < 0.001), and in the mental component, from 53.3 to 56.6 points after BS. With BAROS, 98.5 % showed good to excellent QoL results within the first three months after BS. Conclusion: When measured with the SF-36 and BAROS questionnaires, QoL of Mexican patients with severe obesity was found to improve after BS.

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.

Erratum to "From ACTH-Dependent to ACTH-Independent Cushing's Syndrome from a Malignant Mixed Corticomedullary Adrenal Tumor: Potential Role of Embryonic Stem Cells".

[This corrects the article DOI: 10.1155/2020/4768281.].

High biochemical recurrence rate after withdrawal of cabergoline in prolactinomas: is it necessary to restart treatment?

PURPOSE: Treatment with dopamine agonists (DA) is highly effective in patients with prolactinomas. In selected patients, discontinuation of DA after several years of successful treatment is possible, however, hyperprolactinemia recurs in 60-80% of them. It is unclear what is the clinical significance of these recurrences and hence, whether or not reinitiation of therapy is necessary. OBJECTIVES: To evaluate the recurrence rate in prolactinoma patients after DA withdrawal and the necessity to restart treatment. METHODS: Patients with >2 years of treatment with cabergoline (CBG) who achieved normoprolactinemia and a > 50% reduction in tumor size were included. DA dose was down titrated until withdrawal. Basal tumor size, as well as PRL and gonadal steroid levels were recorded at diagnosis, at withdrawal of DA and every 3-6 months for 1-3 years. RESULTS: Fifty patients were included (38 women, 34 macroprolactinomas). After withdrawal, 34 (68%) presented recurrence of hyperprolactinemia. PRL levels <5 ng/mL at the time of withdrawal predicted remission (sensitivity 76%, specificity of 63%). CBG was restarted in eight patients (23%) because of the presence of hypogonadism. CBG was withheld in the remaining 26, based on the following arguments: (1) premenopausal women without biochemical hypogonadism, (54%); (2) asymptomatic men under 65 without biochemical hypogonadism (19%); (3) asymptomatic postmenopausal women (19%); (4) asymptomatic men over 65 (8%). After a median follow-up of 30 months, no increase in PRL levels or tumor growth was documented. CONCLUSIONS: Biochemical recurrence in prolactinomas is very frequent, however, in only a few of these patients reinitiation of DA is necessary.

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.

Are there really any predictive factors for a successful weight loss after bariatric surgery?

BACKGROUND: Currently, bariatric surgery is the most effective treatment for severe obesity and its metabolic complications; however, 15-35% of the patients that undergo bariatric surgery do not reach their goal for weight loss. The aim of this study was to determine the proportion of patients that didn't reach the goal of an excess weight loss of 50% or more during the first 12 months and determine the factors associated to this failure. METHODS: We obtained the demographic, anthropometric and biochemical information from 130 patients with severe obesity who underwent bariatric surgery in our institution between 2012 and 2017. We used self-reports of physical activity, caloric intake and diet composition. An unsuccessful weight loss was considered when the patient lost < 50% or more of the excess weight 12 months after surgery. We compared the characteristics between the successful and unsuccessful groups in order to find the factors associated with success. RESULTS: We included 130 patients (mean age 48 ± 9 years, 81.5% were women). One year after surgery, 26 (20%) had loss < 50% EBW. Unsuccessful surgery was associated with an older age, previous history of hypertension, abdominal surgery or depression/anxiety, also the number of comorbidities and unemployment affected the results. These patients loss enough weight to improve some of their comorbidities, but they are more prone to regain weight 2 years after surgery. CONCLUSIONS: A fifth of the patients undergoing bariatric surgery may not lose enough weight to be considered successful by current standards. Some patients may benefit from the surgery in the short term, but they are more likely to regain weight after 2 years. The factors influencing this result are still controversial but may be population-specific. Early detection of the patients that are more likely to fail is imperative to establish additional therapeutic strategies, without denying them the opportunity of surgery or waiting for weight re-gain to occur.

Tirotoxicosis inducida por amiodarona (TIA): un reto diagnóstico y terapéutico / Amiodarone-induced thyrotoxicosis (TIA): a diagnostic and therapeutic challenge

Resumen La tirotoxicosis inducida por amiodarona (TIA) se presenta en 5-12% de los pacientes tratados con ese medicamento, tiene el potencial de exacerbar una enfermedad cardiaca, lo que incrementa la morbilidad o mortalidad de los pacientes. Existen 2 tipos de TIA, con mecanismos fisiopatológicos diferentes; es importante distinguir entre ellos ya que el tratamiento es diferente. Sin embargo esta distinción en ocasiones es complicada. Se presenta el caso de una paciente de 81 años con antecedente de leucemia mieloide aguda, que cursó con aumento de volumen de cuello 48 h después de haber sido egresada por un cuadro de fibrilación auricular (FA) tratada con infusión de amiodarona. Bioquímicamente con tirotoxicosis y reaparición de la FA. Se sospechó de una TIA. Para enfocar el tratamiento es indispensable distinguir entre los 2 tipos de tirotoxicosis inducida por amiodarona. El ultrasonido Doppler y el gammagrama tiroideo pueden ser útiles para establecer el diagnóstico. Se deben considerar las comorbilidades de los pacientes, así como los efectos secundarios al momento de establecer el tratamiento.

Abstract Amiodarone induced thyrotoxicosis (AIT) appears on the 5-12% of patients, it potentially can exacerbate a cardiac illness, leading to an increase in the morbility/mortality of patients. Two types of AIT exist, each one with a different etiology. It is important to distinguish between them to be able to establish a treatment. However, sometimes it can be quite difficult. Case Report: An 81 year-old woman, with a history of acute myelod leukemia, showed up with thyroid enlargement at the ER. She was discharged 48 h earlier, after an atrial fibrillation (AF) episode which was controlled with amiodarone IV infusion. Because the biochemical diagnosis of thyrotoxicosis and reaparition of AF,an AIT was suspected. To be able of distinguishing between the two types of AIT is essential to establish a treatment. The use of a thyroid doppler sonography and a thyroid scintigraphy is helpful. The comorbidities of the patient and the possible side effects should be taken into account when deciding the treatment.