Publications by authors named "Mônica Gadelha"

152 Publications

GH and IGF-I levels and tumor shrinkage in response to first generation somatostatin receptor ligands in acromegaly: a comparative study between two reference centers for pituitary diseases in Brazil.

Endocrine 2021 Oct 26;74(1):146-154. Epub 2021 May 26.

SEMPR, Serviço de Endocrinologia e Metabologia do Hospital de Clínicas, Departamento de Clínica Médica, Universidade Federal do Paraná, Curitiba, Brazil.

Purpose: To compare biochemical and tumor response rates between two reference centers for pituitary diseases in Brazil after primary and adjuvant therapy with somatostatin receptor ligands (SRL) in acromegaly.

Methods: Patients were classified as non-responders (NR), partial responders (PR), and full responders (FR) to 12-month SRL therapy according to: [criteria A] normal IGF-I and random GH (rGH) < 1 ng/mL (FR); ≥ 50% decrease of IGF-I and/or rGH (PR); < 50% decrease of IGF-I and rGH (NR); [criteria B] normal IGF-I (FR); ≥ 50% decrease of IGF-I (PR); < 50% decrease of IGF-I (NR). Tumor shrinkage <20% defined poor responders (tPR) and ≥ 20% good responders (tGR).

Results: We studied 219 acromegaly patients (59% women, age 43.1 ± 13.9 years; 73 from Center I and 146 from Center II). After SRL therapy, the proportion of FR, PR, and NR by criteria A and B was 30.2 vs 49.1%, 52.8 vs 21.2% and 17 vs 29.7%, respectively (p < 0.001). Considering criteria A or B separately, there was no difference in the proportion of FR, PR and NR between two centers. However, when comparing criteria A and B, the Center I showed a difference of 30.9% in classification of FR in relation to 13.2% observed in Center II (p = 0.006). tGR were 51.4% of patients, with no differences between the centers.

Conclusions: IGF-I alone significantly increased positive response rates to SRLs, whereas the inclusion of rGH levels into therapeutic decision might lead to a significant increment on the costs of acromegaly management.
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http://dx.doi.org/10.1007/s12020-021-02766-2DOI Listing
October 2021

Identification of mutant K-RAS in pituitary macroadenoma.

Pituitary 2021 Oct 5;24(5):746-753. Epub 2021 May 5.

Laboratório de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer, Rua do Rezende156-Centro, Rio de Janeiro, 20231-092, Brazil.

Purpose: RAS genes are among the most frequently mutated genes in cancer, where their mutation frequency varies according to the distinct RAS isoforms and tumour types. Despite occurring more prevalent in malignant tumours, RAS mutations were also observed in few benign tumours. Pituitary adenomas are examples of benign tumours which vary in size and aggressiveness. The present study was performed to investigate, via liquid biopsy and tissue analysis, the presence of K-RAS mutations in a pituitary macroadenoma.

Methods: Molecular analysis was performed to investigate K-RAS mutations using the droplet digital PCR (ddPCR) method by evaluating both plasma (liquid biopsy) and the solid tumour of a patient diagnosed with a giant clinically non-functioning pituitary tumour.

Results: The patient underwent surgical resection due to visual loss, and the histopathological analysis showed a gonadotrophic pituitary macroadenoma. The molecular analysis revealed the presence of mutant K-RAS both in the plasma and in the tumour tissue which, to our knowledge, has not been previously reported in the literature.

Conclusion: Our findings highlight the exceptional capacity of the digital PCR in detecting low frequency mutations (below 1%), since we detected, for the first time, K-RAS mutations in pituitary macroadenoma. The potential impact of K-RAS mutations in these tumours should be further investigated.
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http://dx.doi.org/10.1007/s11102-021-01151-6DOI Listing
October 2021

Apoplexy in sporadic pituitary adenomas: a single referral center experience and mutation analysis.

Arch Endocrinol Metab 2021 Apr 27. Epub 2021 Apr 27.

Centro de Pesquisas em Neuroendocrinologia/Seção de Endocrinologia, Faculdade de Medicina e Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil,

Objective: To analyze the clinical, laboratory, and radiological findings and management of patients with clinical pituitary apoplexy and to screen for aryl hydrocarbon receptor-interacting protein () mutations.

Methods: The clinical findings were collected from the medical records of consecutive sporadic pituitary adenoma patients with clinical apoplexy. Possible precipitating factors, laboratory data, magnetic resonance imaging (MRI) findings and treatment were also analyzed. Peripheral blood samples were obtained for DNA extraction from leukocytes, and the entire coding region was sequenced.

Results: Thirty-five patients with pituitary adenoma were included, and 23 (67%) had non-functioning pituitary adenomas. Headache was observed in 31 (89%) patients. No clear precipitating factor was identified. Hypopituitarism was observed in 14 (40%) patients. MRI from 20 patients was analyzed, and 10 (50%) maintained a hyperintense signal in MRI performed more than three weeks after pituitary apoplexy (PA). Surgery was performed in ten (28%) patients, and 25 (72%) were treated conservatively with good outcomes. No mutation was found in this cohort.

Conclusion: Patients with stable neuroophthalmological impairments can be treated conservatively if no significant visual loss is present. Our radiological findings suggest that hematoma absorption lasts more than that observed in other parts of the brain. Additionally, our study suggests no benefits of mutation screening in sporadic patients with apoplexy.
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http://dx.doi.org/10.20945/2359-3997000000358DOI Listing
April 2021

Management of hypopituitarism: a perspective from the Brazilian Society of Endocrinology and Metabolism.

Arch Endocrinol Metab 2021 Feb 24. Epub 2021 Feb 24.

Unidade de Neuroendocrinologia, Laboratório de Endocrinologia Celular e Molecular LIM-25, Divisão de Endocrinologia e Metabolismo, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.

Hypopituitarism is a disorder characterized by insufficient secretion of one or more pituitary hormones. New etiologies of hypopituitarism have been recently described, including head trauma, cerebral hemorrhage, and drug-induced hypophysitis. The investigation of patients with these new disorders, in addition to advances in diagnosis and treatment of hypopituitarism, has increased the prevalence of this condition. Pituitary hormone deficiencies can induce significant clinical changes with consequent increased morbidity and mortality rates, while hormone replacement based on current guidelines protects these patients. In this review, we will first discuss the different etiologies of hypopituitarism and then address one by one the clinical aspects, diagnostic evaluation, and therapeutic options for deficiencies of TSH, ACTH, gonadotropin, and GH. Finally, we will detail the hormonal interactions that occur during replacement of pituitary hormones.
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http://dx.doi.org/10.20945/2359-3997000000335DOI Listing
February 2021

Cyclic ACTH-secreting thymic carcinoid: a case report and review of the literature.

Arch Endocrinol Metab 2021 Apr 12. Epub 2021 Apr 12.

Unidade de Medicina Interna e Serviço de Endocrinologia, Faculdade de Medicina e Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil,

Cyclic Cushing's syndrome (CS) due to thymic carcinoid is a rare disorder. We report a case of cyclic CS due to ectopic adrenocorticotropic hormone (ACTH)-secreting atypical thymic carcinoid tumor and reviewed similar cases published in the literature. Our patient had hypercortisolemia lasting approximately one month, followed by normal cortisol secretion, with relapse one year later. Histopathology revealed an atypical ACTH-positive thymic carcinoid. Ectopic CS can be derived from atypical thymic carcinoids, which can be aggressive tumors with early relapse, suggesting that this type of tumor probably needs aggressive treatment.
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http://dx.doi.org/10.20945/2359-3997000000346DOI Listing
April 2021

New and emerging pharmacological treatment options for acromegaly.

Expert Opin Pharmacother 2021 Aug 8;22(12):1615-1623. Epub 2021 Apr 8.

Neuroendocrinology Research Center/Endocrinology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

: Transsphenoidal surgery is the first-line treatment for acromegaly, but even in referral centers, approximately 50% of patients are not cured, and adjuvant pharmacological treatment is necessary. Widely used therapies encompass different drug classes, such as injectable somatostatin receptor ligands (SRLs), oral dopamine agonists and injectable growth hormone receptor antagonists, but approximately 40% of patients still have disease activity in real-life practice. Therefore, there is a need for new medical therapies to allow disease control in a larger proportion of patients, increase quality of life, reduce morbidity and mortality and improve treatment adherence in acromegaly.: In this review, the authors cover new and emerging drugs under development or drugs recently approved for the treatment of acromegaly.: Disease control is essential to reduce morbidity and mortality in acromegaly but is still not achieved in a significant proportion of patients or takes a long time to be achieved with currently available options and treatment algorithms. Therefore, the development of new drugs as well as the establishment of biomarkers of disease control to allow precision medicine will improve treatment and outcomes in acromegaly.
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http://dx.doi.org/10.1080/14656566.2021.1908998DOI Listing
August 2021

Machine Learning-based Prediction Model for Treatment of Acromegaly With First-generation Somatostatin Receptor Ligands.

J Clin Endocrinol Metab 2021 Jun;106(7):2047-2056

Endocrine Unit and Neuroendocrinology Research Center, Medical School and Hospital Universitário Clementino Fraga Filho-Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

Context: Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly.

Objective: To develop a prediction model of therapeutic response of acromegaly to fg-SRL.

Methods: Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP).

Results: A total of 153 patients were analyzed. Controlled patients were older (P = .002), had lower GH at diagnosis (P = .01), had lower pretreatment GH and IGF-I (P < .001), and more frequently harbored tumors that were densely granulated (P = .014) or highly expressed SST2 (P < .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%.

Conclusion: We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.
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http://dx.doi.org/10.1210/clinem/dgab125DOI Listing
June 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

Misinterpretation of viral load in COVID-19 clinical outcomes.

Virus Res 2021 04 13;296:198340. Epub 2021 Feb 13.

Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, RJ, Brazil; Neuroendocrinology Research Center, Endocrinology Division, - Medical School and Hospital Universitário Clementino Fraga Filho - Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Knowledge of viral load is essential to formulate strategies for antiviral treatment, vaccination, and epidemiological control of COVID-19. Moreover, identification of patients with high viral loads can also be useful to understand risk factors such as age, comorbidities, severity of symptoms and hypoxia, to decide on the need for hospitalization. Several ongoing studies are analyzing viral load in different types of samples and evaluating its relationship with clinical outcomes and viral transmission pathways. However, in a great number of emerging studies, cycle threshold (Ct) values alone are often used as viral load indicators, which may be a mistake. In this study, we compared tracheal aspirate with nasopharyngeal swab samples obtained from critically ill COVID-19 patients and here we report how the raw Ct can lead to misinterpretation of results. Furthermore, based on analysis of nasopharyngeal swab samples we propose a method to reduce evaluation errors that could occur from using raw Ct data. Based on these findings, we show the impact that normalization of Ct values has on interpretation of SARS-CoV-2 viral load from different biological samples.
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http://dx.doi.org/10.1016/j.virusres.2021.198340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881726PMC
April 2021

Effect of Convalescent Plasma in Critically Ill Patients With COVID-19: An Observational Study.

Front Med (Lausanne) 2021 28;8:630982. Epub 2021 Jan 28.

Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO), Rio de Janeiro, Brazil.

Convalescent plasma is a potential therapeutic option for critically ill patients with coronavirus disease 19 (COVID-19), yet its efficacy remains to be determined. The aim was to investigate the effects of convalescent plasma (CP) in critically ill patients with COVID-19. This was a single-center prospective observational study conducted in Rio de Janeiro, Brazil, from March 17th to May 30th, with final follow-up on June 30th. We included 113 laboratory-confirmed COVID-19 patients with respiratory failure. Primary outcomes were time to clinical improvement and survival within 28 days. Secondary outcomes included behavior of biomarkers and viral loads. Kaplan-Meier analyses and Cox proportional-hazards regression using propensity score with inverse-probability weighing were performed. 41 patients received CP and 72 received standard of care (SOC). Median age was 61 years (IQR 48-68), disease duration was 10 days (IQR 6-13), and 86% were mechanically ventilated. At least 29 out of 41CP-recipients had baseline IgG titers ≥ 1:1,080. Clinical improvement within 28 days occurred in 19 (46%) CP-treated patients, as compared to 23 (32%) in the SOC group [adjusted hazard ratio (aHR) 0.91 (0.49-1.69)]. There was no significant change in 28-day mortality (CP 49% vs. SOC 56%; aHR 0.90 [0.52-1.57]). Biomarker assessment revealed reduced inflammatory activity and increased lymphocyte count after CP. In this study, CP was not associated with clinical improvement or increase in 28-day survival. However, our study may have been underpowered and included patients with high IgG titers and life-threatening disease. The study protocol was retrospectively registered at the Brazilian Registry of Clinical Trials (ReBEC) with the identification RBR-4vm3yy (http://www.ensaiosclinicos.gov.br).
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http://dx.doi.org/10.3389/fmed.2021.630982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876445PMC
January 2021

Glucocorticoid use in patients with adrenal insufficiency following administration of the COVID-19 vaccine: a pituitary society statement.

Pituitary 2021 Apr 10;24(2):143-145. Epub 2021 Feb 10.

Neuroendocrinology Research Center/Endocrinology Section, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Purpose: Side effects of the coronavirus disease 2019 (COVID-19) vaccines include pain at the injection site, fatigue, headache, myalgias, arthralgias, chills, and fever, all of which can be early indicators of an increased need for glucocorticoid replacement in patients with adrenal insufficiency. The Pituitary Society surveyed its membership to understand planned approaches to glucocorticoid management in patients with adrenal insufficiency who will receive a COVID-19 vaccine.

Methods: Members were asked to complete up to 3 questions regarding their planned approach for use of glucocorticoid replacement in patients with proven adrenal insufficiency.

Results: Surveys were sent to 273 members and 103 responded. Thirty-six percent plan to recommend that patients automatically increase glucocorticoid dosage with administration of the first vaccine injection. Of these, 84% plan to increase glucocorticoid dose on the day of vaccination, and 49% plan to increase glucocorticoid dose prior to vaccination. Of the 64% who do not plan to recommend automatic glucocorticoid dose increase with vaccine administration, 88% plan to increase the dose if the patient develops a fever, and 47% plan to increase the dose if myalgias and arthralgias occur.

Conclusions: Most clinicians plan to maintain the current glucocorticoid dose with vaccine administration. The vast majority plan and to increase glucocorticoid dose in case of fever, and just under half in case of arthralgias and myalgias. These survey results offer suggested management guidance for glucocorticoid management in patients with adrenal insufficiency.
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http://dx.doi.org/10.1007/s11102-021-01130-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872824PMC
April 2021

The Glittre Activities of Daily Living Test in patients with acromegaly: Associations with hand function and health-related quality of life.

J Back Musculoskelet Rehabil 2021 ;34(3):441-451

Rehabilitation Sciences, Augusto Motta University Center (UNISUAM), Rio de Janeiro, Brazil.

Background: Musculoskeletal disorders in acromegaly compromise upper and lower limb activity. Corresponding changes can be better assessed by a functional capacity test incorporating multitasking, such as the Glittre Activities of Daily Living Test (GA-T).

Objectives: To evaluate functional capacity in adults with acromegaly using the GA-T and to correlate functional capacity with hand function and health-related quality of life.

Methods: The GA-T was applied to 36 patients with acromegaly and an equal number of healthy individuals. Additionally, participants completed the Acromegaly Quality of Life (AcroQoL) questionnaire and underwent a chronic pain assessment using a map of the human body, a hand function evaluation using the Cochin Hand Functional Scale (CHFS), and a handgrip strength test.

Results: Relative to the comparison group, patients with acromegaly required more time to perform the GA-T, showed worse hand function, and reported that squatting to accomplish shelving tasks was the major difficulty. GA-T time was correlated with the AcroQoL global score, handgrip strength, and the CHFS (rs=-0.487, p= 0.002; rs=-0.369, p= 0.026; rs= 0.538, p= 0.0007, respectively).

Conclusions: Patients with acromegaly exhibited a reduced functional capacity as assessed by the GA-T. Additionally, an association was identified between the total GA-T time and both hand function and quality of life.
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http://dx.doi.org/10.3233/BMR-200089DOI Listing
July 2021

Risk factors and management of pasireotide-associated hyperglycemia in acromegaly.

Endocr Connect 2020 Dec;9(12):1178-1190

Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.

Pasireotide, a multireceptor-targeted somatostatin analog with highest affinity for somatostatin receptor subtype (SST) 5, has demonstrated superior efficacy over the SST2-preferential somatostatin analogs octreotide and lanreotide. The safety profile is similar to those of octreotide and lanreotide, except for a higher frequency and degree of hyperglycemia. This analysis investigated baseline characteristics and occurrence and management of hyperglycemia during pasireotide treatment in patients with acromegaly treated in two prospective clinical studies, SOM230C2305 (C2305) and SOM230C2402 (C2402; PAOLA). One hundred and seventy-eight patients naïve to medical therapy at baseline (C2305) and 125 uncontrolled on first-generation somatostatin analogs at baseline (C2402) received long-acting pasireotide in these studies. Of patients treated with pasireotide in studies C2305 and C2402, respectively, 75.3 (134/178) and 65.6% (82/125) developed hyperglycemia or experienced worsening of existing hyperglycemia. Occurrence of hyperglycemia during pasireotide treatment was less frequent in patients with lower age (<40 years, C2402; <30 years, C2305), normal glucose tolerance, and no history of hypertension or dyslipidemia at baseline. Thirteen (4%) patients discontinued pasireotide because of hyperglycemia-related adverse events. Metformin alone or in combination with other oral antidiabetic medications controlled elevations in glucose levels in most pasireotide-treated patients; 78% of C2305 patients and 73 (pasireotide 40 mg) and 60% (pasireotide 60 mg) of C2402 patients achieved the ADA/EASD goal of HbA1c <7% (<53 mmol/mol) at the end of the core phase. Not all patients develop hyperglycemia, and it is reversible upon pasireotide withdrawal. Close monitoring, patient education and prompt action remain key elements in addressing hyperglycemia during pasireotide treatment.
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http://dx.doi.org/10.1530/EC-20-0361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774766PMC
December 2020

Novel therapies for acromegaly.

Endocr Connect 2020 Dec;9(12):R274-R285

Neuroendocrinology Research Center/Endocrinology Division - Medical School and Hospital Universitário Clementino Fraga Filho - Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Acromegaly is a systemic disease associated with increased morbidity and mortality. Most of these comorbidities can be prevented or delayed with adequate disease treatment. Although three modalities of treatment (surgery, medical treatment, and radiotherapy) are available and new drugs were approved in the last decades, there are still some patients that maintain disease activity despite treatment. Therefore, there is a need for novel therapies for acromegaly and for that purpose new formulations of currently used drugs and also new drugs are currently under study. In this review, we summarize the novel therapies for acromegaly.
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http://dx.doi.org/10.1530/EC-20-0433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774757PMC
December 2020

Telomerase expression in clinically non-functioning pituitary adenomas.

Endocrine 2021 04 22;72(1):208-215. Epub 2020 Oct 22.

Neuropathology and Molecular Genetics Laboratory - Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil.

Purpose: Non-functioning pituitary adenomas (NFPA) are benign tumors, however, some are agressive. We aimed to assess if human telomerase reverse transcriptase (hTERT) is present in NFPA and if it can be used as a marker of aggressiveness and proliferation.

Methods: Consecutive patients operated for NFPA whose fresh frozen tumors were available were included. We analyzed tumor's aggressiveness (based on radiological progression) and proliferation (based on Ki-67), as well as hTERT mRNA by quantitative real-time polymerase chain reaction (RT-qPCR).

Results: We included 109 samples from 86 patients followed for a median period of 60 months (5-120 months). Aggressive tumors were present in 66% cases and proliferative tumors in 47.7%. Seven (6.4%) samples expressed hTERT: 3 (42.8%) had aggressive and proliferative tumors, 2 (28.6%) only exhibited aggressiveness and the remaining 2 (28.6%) only proliferation. From the aggressive and proliferative tumors, 14% and 16%, respectively, expressed hTERT. From the non-aggressive and non-proliferative tumors, 9% and 6%, respectively, expressed hTERT.

Conclusion: hTERT expression is present in a minority of NFPA and does not seem to be related to aggressiveness or proliferation in NFPA.
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http://dx.doi.org/10.1007/s12020-020-02524-wDOI Listing
April 2021

A Pituitary Society update to acromegaly management guidelines.

Pituitary 2021 Feb 20;24(1):1-13. Epub 2020 Oct 20.

Pituitary Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 2015, Los Angeles, CA, 90048, USA.

Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize outcomes. Given significant novel recent advances in understanding acromegaly natural history and individualized therapies, the Pituitary Society invited acromegaly experts to critically review the current literature in the context of Endocrine Society guidelines and Acromegaly Consensus Group statements. This update focuses on how recent key advances affect treatment decision-making and outcomes, and also highlights the likely role of recently FDA-approved therapies as well as novel combination therapies within the treatment armamentarium.
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http://dx.doi.org/10.1007/s11102-020-01091-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864830PMC
February 2021

Multidisciplinary management of acromegaly: A consensus.

Rev Endocr Metab Disord 2020 12 10;21(4):667-678. Epub 2020 Sep 10.

Medical Research Unit in Endcrine Diseases, Hospital de Especialidades, Centro Médico Nacional, Siglo XXI, IMSS, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.
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http://dx.doi.org/10.1007/s11154-020-09588-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942783PMC
December 2020

Acromegaly: Update on Management and Long-Term Morbidities.

Endocrinol Metab Clin North Am 2020 09 15;49(3):475-486. Epub 2020 Jul 15.

Endocrinology Division, Neuroendocrinology Research Center, Medical School and Hospital Universitário Clementino Fraga Filho - Universidade Federal do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco, 255, 9° andar - Setor 9, Ilha do Fundão, Rio de Janeiro 21941-913, Brazil; Neuroendocrinology Division, Instituto Estadual do Cérebro Paulo Niemeyer, 156th Resende Street, Rio de Janeiro, RJ, Brazil; Neuropatology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil. Electronic address:

Acromegaly is a systemic disease associated with great morbidity and increased mortality if not adequately treated. In the past decades much improvement has been achieved in its treatment and in the knowledge of its comorbidities. We provide an update of acromegaly management with current recommendations. We also address long-term comorbidities emphasizing the changing face of the disease in more recent series, with a decrease of cardiovascular disease severity and an increased awareness of comorbidities like bone disease, manifested mainly as vertebral fractures and the change in the main cause of death (from cardiovascular disease to cancer in more recent series).
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http://dx.doi.org/10.1016/j.ecl.2020.05.007DOI Listing
September 2020

Cyclin A in nonfunctioning pituitary adenomas.

Endocrine 2020 11 3;70(2):380-387. Epub 2020 Jul 3.

Neuroendocrinology Research Center/ Endocrinology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Purpose: Assess cyclin A in nonfunctioning pituitary adenomas (NFPA) and compare its expression in non-invasive and non-proliferative tumors with invasive and proliferative tumors (12× higher risk of recurrence).

Methods: Quantitative real time polymerase chain reaction to analyze cyclin A using normal pituitary gland as reference. Fold change (FC) > 1 was considered as increased. Tumor invasion was based on Knosp criteria (grades 3-4 considered invasive) and proliferation on the presence of at least two of three criteria: Ki-67 ≥ 3%; mitoses > 2/10; positive p53. Both groups were compared with Mann-Whitney test considering p value < 0.05 as statistically significant.

Results: Thirty-one patients with NFPA were included. Tumors were mainly of gonadotrophic origin (74.2%), followed by corticotrophic (19.4%) and lactotrophic (3.2%) origins and null-cell adenomas (3.2%). Median tumor diameter was 3.5 cm (1.8-8.0) and Ki-67 was 3.0% (0.3-11%). Sixteen patients had tumors classified as non-invasive and non-proliferative and 15 as invasive and proliferative. Median FC was 0.31 in all tumors (0.13-1.94). Cyclin A was not related to invasion or proliferation (FC 0.41 in non-invasive and non-proliferative tumors and FC 0.30 in invasive and proliferative tumors; p = 0.968). Four (12.9%) patients had tumors that exhibited increased cyclin A [median FC of 1.04 (1.02-1.94)]-three of gonadotrophic origin and one null-cell adenoma, with two tumors classified as non-invasive and non-proliferative and two tumors classified as invasive and proliferative. Median tumor diameter in these samples was 3.4 cm (2.4-3.6) and Ki-67 was 5.1% (2-11%).

Conclusions: Cyclin A was increased in a minority of NFPA and does not seem to be related to invasion or proliferation.
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http://dx.doi.org/10.1007/s12020-020-02402-5DOI Listing
November 2020

What is the potential function of microRNAs as biomarkers and therapeutic targets in COVID-19?

Infect Genet Evol 2020 11 8;85:104417. Epub 2020 Jun 8.

Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, RJ, Brazil; Neuroendocrinology Research Center/Endocrinology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19, a pandemic associated with substantial morbidity and mortality. Despite of this, no vaccine or approved drug is available to eradicate the virus. In this manuscript, we present an alternative study area that may contribute to development of diagnostic biomarkers and therapeutic targets for COVID-19. We analyzed sixty SARS-CoV-2 genomes to identify regions that could work as virus-encoded miRNA seed sponges and potentially bind to human miRNA seed sites and prevent interaction with their native targets thereby relieving native miRNA suppression. MicroRNAs (miRNAs) are evolutionally conserved single-stranded RNAs that regulate gene expression at the posttranscriptional level by disrupting translation. MiRNAs are key players in variety of biological processes that regulate differentiation, development and activation of immune cells in both innate and adaptive immunity. We find 34 miRNAs for positive-sense viral RNA and 45 miRNAs for negative-sense that can strongly bind to certain key SARS-CoV-2 genes. The disruption and dysfunction of miRNAs may perturb the immune response and stimulate the release of inflammatory cytokines altering the cellular response to viral infection. Previous studies demonstrate that miRNAs have the potential to be used as diagnostic and therapeutic biomarkers. Therefore, its discovery and validation are essential for improving the diagnosis of infection and clinical monitoring in COVID-19.
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http://dx.doi.org/10.1016/j.meegid.2020.104417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833518PMC
November 2020

Letter to the Editor: "Our Response to COVID-19 as Endocrinologists and Diabetologists".

J Clin Endocrinol Metab 2020 07;105(7)

Neuroendocrinology Research Center/Endocrinology Division - Medical School and Hospital Universitário Clementino Fraga Filho - Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

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http://dx.doi.org/10.1210/clinem/dgaa224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188172PMC
July 2020

Pasireotide for acromegaly: long-term outcomes from an extension to the Phase III PAOLA study.

Eur J Endocrinol 2020 Jun;182(6):583

Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Objective: In the Phase III PAOLA study (clinicaltrials.gov: NCT01137682), enrolled patients had uncontrolled acromegaly despite ≥6 months of octreotide/lanreotide treatment before study start. More patients achieved biochemical control with long-acting pasireotide versus continued treatment with octreotide/lanreotide (active control) at month 6. The current work assessed the extent of comorbidities at baseline and outcomes during a long-term extension.

Design/methods: Patients receiving pasireotide 40 or 60 mg at core study end could continue on the same dose in an extension phase if biochemically controlled or receive pasireotide 60 mg if uncontrolled. Uncontrolled patients on active control were switched to pasireotide 40 mg, with the dose increased at week 16 of the extension if still uncontrolled (crossover group). Efficacy and safety are reported to 304 weeks (~5.8 years) for patients randomized to pasireotide (core + extension), and 268 weeks for patients in the crossover group (extension only).

Results: Almost half (49.5%; 98/198) of patients had ≥3 comorbidities at core baseline. During the extension, 173 patients received pasireotide. Pasireotide effectively and consistently reduced GH and IGF-I levels for up to 5.8 years' treatment; 37.0% of patients achieved GH <1.0 µg/L and normal IGF-I at some point during the core or extension. Improvements were observed in key symptoms. The long-term safety profile was similar to that in the core study; 23/173 patients discontinued treatment because of adverse events.

Conclusions: In this patient population with a high burden of comorbid illness, pasireotide was well tolerated and efficacious, providing prolonged maintenance of biochemical control and improving symptoms.
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http://dx.doi.org/10.1530/EJE-19-0762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222286PMC
June 2020

Evaluation of the Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Inadequately Controlled With First-Generation Somatostatin Analogs.

Front Endocrinol (Lausanne) 2019 3;10:931. Epub 2020 Feb 3.

Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.

Acromegaly is a rare, serious endocrine disorder characterized by excess growth hormone (GH) secretion by a pituitary adenoma and overproduction of insulin-like growth factor I (IGF-I). Transsphenoidal surgery is the treatment of choice, although many patients require additional interventions. First-generation somatostatin analogs (SSAs) are the current standard of medical therapy; however, not all patients achieve control of GH and IGF-I. Outcomes from a Phase IIIb open-label study of patients with uncontrolled acromegaly on first-generation SSAs switching to pasireotide are reported. Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 μg/L from a five-point profile over 2 h, and IGF-I >1.3× upper limit of normal [ULN]) despite ≥3 months' treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be increased (maximum: 60 mg/28 days) after week 12 if biochemical control was not achieved, or decreased (minimum: 10 mg/28 days) for tolerability. Patients who completed 36 weeks' treatment could continue receiving pasireotide during an extension (weeks 36-72) when concomitant medication for acromegaly was permitted. Primary endpoint was proportion of patients with mGH <1 μg/L IGF-I 2.5 μg/L. For patients who entered the extension, 14.8% (95% CI: 8.1-23.9), 12.5% (95% CI: 6.4-21.3), 14.8% (95% CI: 8.1-23.9) and 11.4% (95% CI: 5.6-19.9) had mGH <1 μg/L and IGF-I
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http://dx.doi.org/10.3389/fendo.2019.00931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008501PMC
February 2020

Determinants of morbidities and mortality in acromegaly.

Arch Endocrinol Metab 2019 Nov-Dec;63(6):630-637

Centro de Pesquisa em Neuroendocrinologia, Divisão de Endocrinologia, Faculdade de Medicina e Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.

Acromegaly is a systemic disease associated with increased morbidity, presenting cardiovascular, metabolic, respiratory, neoplastic, endocrine, articular and bone complications. Most of these comorbidities can be prevented or delayed with adequate disease treatment and, more recent studies with the use of modern treatments of acromegaly, have shown a change in the severity and prevalence of these complications. In addition, acromegaly is associated with increased mortality, but recent studies (especially those published in the last decade) have shown a different scenario than older studies, with mortality no longer being increased in adequately controlled patients and a change in the main cause of death from cardiovascular disease to malignancy. In this review, we discuss this changing face of acromegaly summarizing current knowledge and evidence on morbimortality of the disease. Arch Endocrinol Metab. 2019;63(6):630-7.
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http://dx.doi.org/10.20945/2359-3997000000193DOI Listing
February 2020

Use of late-night salivary cortisol to monitor response to medical treatment in Cushing's disease.

Eur J Endocrinol 2020 Feb;182(2):207-217

Neuroendocrine Clinical Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: Monitoring of patients with Cushing's disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing's disease.

Design: Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing's disease (clinicaltrials.gov: NCT01374906).

Methods: Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time.

Results: At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman's correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN.

Conclusion: mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing's disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.
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http://dx.doi.org/10.1530/EJE-19-0695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003692PMC
February 2020

Collision sellar lesions: coexistence of pituitary adenoma and Rathke cleft cyst-a single-center experience.

Endocrine 2020 04 4;68(1):174-181. Epub 2019 Dec 4.

Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rua do Resende 156/Centro, Rio de Janeiro, 20231-092, Brazil.

Purpose: Collision sellar lesions represent the coexistence of distinct histopathological lesions found in the sella turcica. They are uncommon entities and have mainly been reported as pituitary adenoma (PA) associated to Rathke cleft cyst (RCC). Pre- and perioperative diagnosis is difficult, since most of the cases appear clinically, radiologically, and macroscopically as solitary cystic sellar lesion.

Methods: A retrospective study of histological reports from patients operated for PA from 2013 to 2018 in a single neurosurgery reference center was performed. Patients who also exhibited RCC in the histological sections were included. Clinical and biochemical data were collected from medical files. MRI scans and histopathological slides were also reviewed.

Results: Among 554 PA, five patients (0.9%) presented the association of PA and RCC. At diagnosis, patients had median age of 60 years (33-78) with, at least, one pituitary dysfunction, and visual field loss and/or headache. There was a female predominance (n = 3). All patients had nonfunctioning PA. MRI studies showed a predominantly cystic lesion and were unable to distinguish both lesions. The definitive diagnosis was made by histopathology.

Conclusion: The association of PA and RCC is extremely rare. On MRI, they appear as a solid-cystic or cystic sellar tumors. RCC can rupture causing granulomatous reaction with cholesterol crystal formation, which can be mistaken for craniopharyngiomas during surgery. Therefore, collision sellar lesion must be included in the differential diagnosis of cystic sellar lesions. The definitive diagnosis is made by histological study.
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http://dx.doi.org/10.1007/s12020-019-02149-8DOI Listing
April 2020

Accuracy of microcystic aspect on T2-weighted MRI for the diagnosis of silent corticotroph adenomas.

Clin Endocrinol (Oxf) 2020 02 12;92(2):145-149. Epub 2019 Dec 12.

Neuroendocrinology Research Center/Endocrinology Section, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Introduction: A single study suggested that silent corticotropinomas (SCAs) have a different imaging phenotype, with microcystic aspect on T2-weighted sequence of magnetic resonance imaging (T2-MRI). This study only analysed manifest and silent corticotropinomas and nonfunctioning gonadotroph adenomas. Therefore, the prevalence of microcystic patterns of other tumours is not known.

Aim: To analyse frequency of microcystic patterns on T2-MRI in all subtypes of pituitary adenomas and determine accuracy of this radiological finding for diagnosing SCA.

Methods: Consecutive pituitary adenoma patients who underwent surgery between 2013 and 2016 at a single centre were included. T2-MRIs were evaluated by a radiologist and an endocrinologist blinded to histological diagnosis.

Results: A total of 143 patients (52% female) with median age of 49 years (14-80) were included. Clinically, there were 90 nonfunctioning pituitary adenomas (NFPAs), 32 somatotropinomas, 13 corticotropinomas, five prolactinomas and three TSH-secreting adenomas. Of the patients with NFPA, 12 (13%) were SCAs, 73 (79%) were gonadotropinomas and five (6%) were positive for prolactin (three) or TSH (two). A microcystic pattern was observed in 16 tumours (11%): one somatotropinoma, one corticotropinoma, seven SCAs and seven gonadotropinomas, and in no prolactinomas or TSH-secreting adenomas. It was more common in SCAs than in other tumours (58.3% vs 6.9%, respectively, P < .001) and had a sensitivity of 58%, a specificity of 93% and an accuracy of 90% to define an SCA.

Conclusion: Microcystic aspect on T2-MRI is able to define SCA with a good accuracy and can be a useful tool, considering the more aggressive behaviour of these tumours.
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http://dx.doi.org/10.1111/cen.14133DOI Listing
February 2020

A Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities: An Update.

J Clin Endocrinol Metab 2020 04;105(4)

Department of Medicine, CIBERER, Universidad Autónoma de Madrid, Madrid, Spain.

Objective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013.

Participants: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration.

Evidence: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities.

Consensus Process: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system.

Conclusions: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.
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http://dx.doi.org/10.1210/clinem/dgz096DOI Listing
April 2020

The effectiveness of a therapist-oriented home rehabilitation program for a patient with acromegaly: A case study.

J Bodyw Mov Ther 2019 Jul 28;23(3):634-642. Epub 2019 Jan 28.

Rehabilitation Sciences Post-graduate Program, Centro Universitário Augusto Motta (UNISUAM), Rio de Janeiro, Brazil; Post-graduate Program in Medical Sciences, School of Medical Sciences, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil. Electronic address:

Background: Acromegaly causes numerous functional limitations that negatively impact patients' performance of activities of daily living (ADLs) and contribute to the deterioration of health-related quality of life (HRQoL). Thus, the purpose of the present case study was to evaluate the effect of therapist-oriented home rehabilitation (TOHR) for a patient with acromegaly.

Case Description: We report the case of a 53-year-old man who was diagnosed with primary acromegaly 17 years ago. He complained of difficulties performing tasks that involved his hands, pain in the lower limbs, and fatigue when he climbed a few flights of stairs. Although he performed ADLs independently, he reported some difficulties or discomfort when performing them.

Intervention And Outcome: The patient underwent a booklet-guided physical exercise program that lasted two months (three times per week, 60 minutes per session). The activities included overall stretching, muscle strengthening, and endurance exercises, along with aerobic conditioning through functional circuit training. After two months of exercise, he reported improved HRQoL as assessed with the Acromegaly Quality of Life Questionnaire, with increases in quadriceps muscle strength and 6-min walking distance. However, none of these benefits remained when the patient was assessed after a 1-month washout period.

Conclusion: This study showed that patients with acromegaly may benefit markedly from TOHR, which could provide a novel therapeutic approach as an adjunct to hormone control therapy.
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http://dx.doi.org/10.1016/j.jbmt.2019.01.006DOI Listing
July 2019

Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features.

Cancers (Basel) 2019 09 26;11(10). Epub 2019 Sep 26.

Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain.

Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs.
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http://dx.doi.org/10.3390/cancers11101439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826715PMC
September 2019
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