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INTRODUCTION: Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. OBJECTIVE: To identify methylation signatures in ACPs regarding clinical presentation and outcome. METHODS: Clinical and pathology data were collected from 35 ACP patients (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multi-dimensional scaling. Statistical associations between clusters and clinical features were achieved using Fisher's test and global biological process interpretations were aided by Gene Ontology enrichment analyses. RESULTS: Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = 0.0006), hypomethylated in CpG Island (CGI), non-CGI sites, and globally (P < 0.001), and associated with greater tumor size (24.1 vs 9.5cm3, P = 0.04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell-adhesion, cytoskeleton organization, and cytokine binding, and also cell-type specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. CONCLUSION: Two clusters of ACP patients were consistently revealed by unsupervised machine learning methods, being one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment.
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PURPOSE: People living with the human immunodeficiency virus (PLWH) developed higher life expectancy along with chronic bone disease over the past years. Our purpose is to evaluate bone mineral density, bone microarchitecture and fractures in young PLWH and understand the disease's contribution to bone derangements and fracture risk. METHODS: Eighty-one HIV-infected and 54 control young (20-50 years) male and female subjects were enrolled in this study. Methods for patient evaluation included DXA-VFA (dual energy X-rays and vertebral fracture assessment), HR-pQCT (high resolution peripheral quantitative computed tomography), biochemistry and FRAX. RESULTS: Fifty participants from each group completed all exams. Median age was 40 (25-49) vs. 36.5 (22-50) for the HIV and control groups, respectively (p 0.120). Ethnicity, body mass index, serum phosphorus, 25-hydroxyvitamin D, PTH and CTX were similar between groups, although ALP and OC suggested higher bone turnover in PLWH. VFA identified morphometric vertebral fractures in 12% of PLWH. PLWH had lower values for lumbar spine areal BMD and Z score, volumetric BMD, trabecular bone fraction (BV/TV) and trabecular number measured at the distal tibia by HR-pQCT; as a consequence, trabecular separation and heterogeneity were higher (all p < 0.05). The FRAX-estimated risk for hip and major osteoporotic fractures was statistically higher in PLWH (p < 0.001). CONCLUSION: Our results confirm severe bone impairment and fractures associated with HIV in young patients. Thus, we developed a screening protocol for young PLWH to detect bone fragility, reduce skeletal disease progression and morbimortality, decrease fracture risk, and increase quality of life.
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Infecções por HIV , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Humanos , Masculino , Feminino , Adulto , Densidade Óssea , HIV , Qualidade de Vida , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Infecções por HIV/complicações , Absorciometria de Fóton , Rádio (Anatomia)RESUMO
Endogenous Cushing's syndrome results from excess glucocorticoid secretion, which leads to a myriad of clinical manifestations, comorbidities, and increased mortality despite treatment. Molecular mechanisms and genetic alterations associated with different causes of Cushing's syndrome have been described in the last decade. Imaging modalities and biochemical testing have evolved; however, both the diagnosis and management of Cushing's syndrome remain challenging. Surgery is the preferred treatment for all causes, but medical therapy has markedly advanced, with new drug options becoming available. Nevertheless, several comorbidities remain even after patient remission, which can affect quality of life. Accurate and timely diagnosis and treatment are essential for mitigating chronic complications of excess glucocorticoids and improving patient quality of life. In this Seminar, we aim to update several important aspects of diagnosis, complications, and treatment of endogenous Cushing's syndrome of all causes.
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Síndrome de Cushing , Humanos , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/terapia , Qualidade de Vida , Glucocorticoides/uso terapêuticoRESUMO
Pasireotide long-acting release is effective in achieving biochemical control and reducing tumour volume in patients with acromegaly inadequately controlled by first-line therapy. As part of a long-term, real-world study at our centre, 20 of 50 patients receiving pasireotide benefited from a reduction in pasireotide dose. Pasireotide reduced insulin-like growth factor I (IGF-I) levels to below the upper limit of the normal range, with some patients responding within 1-3 months of treatment (n=11) and others after ≥4 months (n=9). Following pasireotide dose reduction, IGF-I levels showed a mild increase but remained within the normal range after a median of 39 months in the early responders and 17 months in the late responders. Glucose and glycated haemoglobin levels decreased following dose reduction. Identifying patients who may benefit from a reduction in pasireotide dose warrants further research as it may improve the management of pasireotide-associated hyperglycaemia in susceptible patients.
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CONTEXT: Acromegaly is a rare, chronic, debilitating disorder caused by prolonged hypersecretion of growth hormone (GH) and overproduction of insulin-like growth factor I (IGF-I). Medical therapies, including the somatostatin receptor ligand (SRL) pasireotide, are frequently used to restore biochemical control. OBJECTIVE: As patients often receive therapy over prolonged periods, long-term data from real-life settings are needed. METHODS: A retrospective analysis was performed using a prospectively maintained database of all patients with acromegaly from our primary care center who were enrolled in clinical studies with pasireotide (first visit November 2008). The main outcome measures were safety and biochemical control (age-adjusted IGF-I ≤ upper limit of normal). RESULTS: Patients (n = 50) entered 4 parental studies and 30 continued in the rollover; at data cutoff (June 2022), 27 were still receiving pasireotide. Overall, median (range) exposure was 58 (3-137) months. Normal IGF-I was achieved in 54%, and acromegaly symptoms and quality of life were improved with treatment. No predictors of pasireotide response were identified; however, controlled patients had smaller tumors and lower GH at baseline. Tumor volume reduction occurred in 63% of evaluable patients (n = 10/16). Most patients presented hyperglycemic events, including 63.2% of patients with normal glucose before treatment. Older patients and those with higher IGF-I, glucose, and HbA1c at baseline had higher glucose and HbA1c during pasireotide treatment. CONCLUSION: Pasireotide provided clinical benefit and was well tolerated for more than 11 years of treatment in acromegaly patients, most of whom were resistant to first-generation SRLs.
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Acromegalia , Adenoma , Hormônio do Crescimento Humano , Humanos , Acromegalia/tratamento farmacológico , Acromegalia/etiologia , Fator de Crescimento Insulin-Like I/metabolismo , Hemoglobinas Glicadas , Estudos Retrospectivos , Qualidade de Vida , Resultado do Tratamento , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento/uso terapêutico , Glucose , Adenoma/complicações , Adenoma/tratamento farmacológicoRESUMO
Acromegaly is a chronic systemic disease caused in the vast majority of cases by growth hormone (GH)-secreting adenoma, with surgery being the first-line treatment. When a cure is not attained with surgery, first-generation somatostatin receptor ligands (fg-SRLs) are the most common medication prescribed. Predictors of response to fg-SRLs have been studied; however, they cannot fully predict the response to fg-SRL. MicroRNAs are small RNAs, the main role of which is messenger RNA (mRNA) post-transcriptional regulation. This study aimed to identify the microRNAs involved in resistance to treatment with fg-SRLs in acromegaly. Ten patients with acromegaly undergoing treatment with fg-SRLs were selected to undergo miRNA sequencing: five controlled and five uncontrolled with treatment. Bioinformatic analysis was performed to detect differentially expressed miRNAs. Then, the same 10 samples were used for validation by qPCR and an additional 22 samples were analyzed, totaling 32 samples. e We found 59 differentially expressed miRNAs in the first analysis. miR-181a-5p and miR-181b-5p were downregulated, and miR-383-5p was upregulated in the uncontrolled group. Receiver operating characteristic (ROC) curve analysis of miR-383-5p showed an NPV of 84.3% and a PPV of 84.5%. In summary, miR-181a-5p, miR-181b-5p, and miR-383-5p are biomarkers of response to fg-SRLs, and they can be used individually or included in prediction models as tools to guide clinical decisions.
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Acromegalia , MicroRNAs , Humanos , Acromegalia/genética , Receptores de Somatostatina/genética , MicroRNAs/genética , MicroRNAs/uso terapêuticoRESUMO
First-line treatment for Cushing´s disease is transsphenoidal surgery. But in cases of persistent or recurrent disease after surgery, contraindications to surgery, severe hypercortisolism control before surgery, or for patients waiting for radiotherapy effects, medical therapy may be indicated. Pituitary-directed agents include cabergoline and pasireotide. Both drugs present similar potential for biochemical control and pasireotide has additionally been proved to reduce tumor volume. Moreover, pasireotide was evaluated in high quality studies. In respect to safety, both drugs are well tolerated and safe, but special attention should be given for cardiac valve disease and psychiatric disorder for cabergoline, and hyperglycemia for pasireotide.
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Cabergolina , Hipersecreção Hipofisária de ACTH , Somatostatina , Humanos , Cabergolina/uso terapêutico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/patologia , Hipófise/patologia , Somatostatina/uso terapêuticoRESUMO
Objectives: To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations. Design: Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions. Methods: Clinicopathological features were retrieved from the patient's charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths. Results: Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297-0.597vs 0.607, IQR: 0.445-0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs. Conclusions: CTNNB1: mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/ß-catenin pathway and telomere biology in the pathogenesis of aCPs.
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Craniofaringioma , Telômero , beta Catenina , Adolescente , Criança , Craniofaringioma/genética , Estudos Transversais , Humanos , Mutação , Estudos Retrospectivos , Telômero/ultraestrutura , Via de Sinalização Wnt , beta Catenina/genéticaRESUMO
Cystic lesions arising in the sellar region are not uncommon and encompass cystic pituitary adenomas, Rathke cleft cysts, craniopharyngiomas, and arachnoid cysts. Their clinical presentation may be similar, including headache, visual field defects, and anterior pituitary hormone deficits, which makes differential diagnosis challenging. On the other hand, imaging features may indicate certain pathologies. In this approach to the patient, we describe the case of a patient who presented with right temporal hemianopsia and a sellar/suprasellar cystic lesion, which was determined to be Rathke cleft cyst. We discuss the imaging characteristics that may suggest a particular diagnosis between Rathke cleft cyst, cystic pituitary adenoma, craniopharyngioma, and arachnoid cyst and propose a flowchart for aiding in the imaging differential diagnosis.
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Adenoma , Cistos do Sistema Nervoso Central , Craniofaringioma , Neoplasias Hipofisárias , Adenoma/diagnóstico , Adenoma/patologia , Cistos do Sistema Nervoso Central/diagnóstico , Craniofaringioma/diagnóstico , Craniofaringioma/patologia , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética/métodos , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/patologiaRESUMO
Currently, the first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot, and nasal octreotide, may improve patients' adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as paltusotine, somatropin, ONO-5788, and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.
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Acromegalia/tratamento farmacológico , Antineoplásicos Hormonais/administração & dosagem , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Receptores de Somatostatina/metabolismo , Acromegalia/sangue , Acromegalia/etiologia , Antineoplásicos Hormonais/efeitos adversos , Biomarcadores Tumorais/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos , Octreotida/administração & dosagem , Octreotida/efeitos adversos , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/efeitos adversos , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Somatostatina/análogos & derivados , Resultado do TratamentoRESUMO
Pituitary adenomas (PAs) represent the most frequently found lesions in the sellar region; however, several other lesions may be encountered in this region, such as meningiomas, craniopharyngiomas, and aneurysms. High-quality imaging is fundamental for diagnosis, characterization, and guidance of treatment planning of PAs. Sellar magnetic resonance imaging (MRI) is considered the imaging modality of choice for the evaluation of lesions in the sella turcica. The sellar MRI standard protocol includes coronal and sagittal T1-weighted spin-echo sequencing with and without gadolinium-based contrast agent and coronal T2-weighted (T2w) fast-spin echo sequencing. A systematic MRI approach to the pituitary region generally provides information that includes the size and shape of the PA, the presence of cysts or hemorrhage within the tumor, its relationship with the optic pathways and surrounding structures, potential cavernous sinus invasion, sphenoid sinus pneumatization type, and differential diagnosis with other sellar lesions. The standard protocol is sufficient for the evaluation of most cases; however, some advanced techniques (susceptibility imaging, diffusion-weighted imaging, 3D T2w high-resolution sequences, magnetic resonance elastography, perfusion-weighted imaging) may render additional information, which may be important for some cases. In this "approach to the patient" manuscript, we will discuss the use of standard and advanced MRI sequences in the diagnosis and characterization of PAs, including MRI features associated with treatment response that may aid in presurgical evaluation and planning, and red flags that may point to an alternative diagnosis.
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Adenoma , Neoplasias Meníngeas , Doenças da Hipófise , Neoplasias Hipofisárias , Adenoma/diagnóstico por imagem , Adenoma/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Doenças da Hipófise/patologia , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/patologia , Sela Túrcica/patologiaRESUMO
INTRODUCTION: Non-functioning pituitary adenomas (NFPAs) are clinically silent tumors and the second most common pituitary adenoma. Surgery is the mainstay of treatment as there is, as yet, no effective medical treatment. AREAS COVERED: We present current knowledge on the clinical diagnosis, histopathological classification, molecular data, and management strategies in NFPA. EXPERT OPINION: NFPA is a heterogeneous group of tumors, in respect to their origin and clinical course. In recent years, research on pathology and molecular biology have advanced our knowledge of NFPA pathogenesis. NFPA exhibit, in the majority of cases, an indolent behavior, with satisfactory response to treatment. In aggressive cases, multimodal management is needed; however, even this approach may be insufficient, so the development of new treatments is warranted for better management. In this setting, the understanding of the mechanisms involved in the genesis and progression of NFPA is crucial for the identification and development of directed treatments with higher chances of response.
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Adenoma , Neoplasias Hipofisárias , Adenoma/diagnóstico , Adenoma/terapia , Humanos , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/terapia , Resultado do TratamentoRESUMO
Hyperprolactinemia, defined by a level of serum prolactin above the standard upper limit of normal range, is a common finding in clinical practice and prolactinomas are the main pathological cause. Prolactinomas lead to signs and symptoms of hormone oversecretion, such as galactorrhea and hypogonadism, as well as symptoms of mass effect, including visual impairment, headaches and intracranial hypertension. Diagnosis involves prolactin measurement and sellar imaging, but several pitfalls are involved in this evaluation, which may difficult the proper management. Treatment is medical in the majority of cases, consisting of dopamine agonists, which present high response rates, with a very favorable safety profile. Major adverse effects that should be monitored consist of cardiac valvulopathy and impulse control disorders. Other treatment options include surgery and radiotherapy. Temozolomide may be used for aggressive or malignant carcinomas. Finally, pregnancy outcomes are similar to general population even when dopamine agonist treatment is maintained.
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Neoplasias Hipofisárias , Prolactinoma , Antineoplásicos Alquilantes/uso terapêutico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/diagnóstico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Agonistas de Dopamina/uso terapêutico , Feminino , Galactorreia/etiologia , Humanos , Hiperprolactinemia/etiologia , Hipogonadismo/etiologia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/terapia , Gravidez , Prolactina/sangue , Prolactinoma/complicações , Prolactinoma/diagnóstico , Prolactinoma/epidemiologia , Prolactinoma/terapia , Sela Túrcica/diagnóstico por imagem , Temozolomida/uso terapêuticoRESUMO
BACKGROUND: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. METHODS: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. RESULTS: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. CONCLUSIONS: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.
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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 (AIP) 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 AIP 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 AIP 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 AIP mutation screening in sporadic patients with apoplexy.
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Adenoma , Apoplexia Hipofisária , Neoplasias Hipofisárias , Adenoma/diagnóstico por imagem , Adenoma/genética , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Apoplexia Hipofisária/etiologia , Apoplexia Hipofisária/genética , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/genética , Encaminhamento e ConsultaRESUMO
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 (Pâ =â .002), had lower GH at diagnosis (Pâ =â .01), had lower pretreatment GH and IGF-I (Pâ <â .001), and more frequently harbored tumors that were densely granulated (Pâ =â .014) or highly expressed SST2 (Pâ <â .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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Acromegalia/tratamento farmacológico , Regras de Decisão Clínica , Monitoramento de Medicamentos/métodos , Aprendizado de Máquina , Receptores de Somatostatina/administração & dosagem , Acromegalia/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Queratinas , Ligantes , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Receptores de Somatostatina/sangue , Resultado do Tratamento , Adulto JovemRESUMO
Filamin-A (FLNA) plays a crucial role in somatostatin receptor (sst) subtype-2 signaling in somatotropinomas. Our objective was to investigate the in vivo association between FLNA and sst2 expression, sst5 expression, dopamine receptor subtype-2 (D2) expression, somatostatin receptor ligand (SRL) responsiveness and tumor invasiveness in somatotropinomas. Quantitative real-time PCR was used to evaluate the absolute mRNA copy numbers of FLNA/sst2/sst5/D2 in 96 somatotropinomas. FLNA, sst2 and sst5 protein expression levels were also evaluated using immunohistochemistry. The Knosp-Steiner criteria were used to evaluate tumor invasiveness. Median FLNA, sst2, sst5 and D2 copy numbers were 4,244, 731, 156 and 3,989, respectively. Thirty-one of the 35 available tumors (89%) were immune positive for FLNA in the cytoplasm and membrane but not in the nucleus. FLNA and sst5 expression were positively correlated at the mRNA and protein levels (p < 0.001 and p = 0.033, respectively). FLNA was positively correlated with sst2 mRNA in patients who were responsive to SRL (p = 0.014, R = 0.659). No association was found between FLNA and tumor invasiveness. Our findings show that in somatotropinomas FLNA expression positively correlated with in vivo sst5 and D2 expression. Notably, FLNA was only correlated with sst2 in patients who were controlled with SRL. FLNA was not associated with tumor invasiveness.
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Acromegalia/genética , Adenoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Filaminas/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Receptores de Dopamina D2/genética , Receptores de Somatostatina/genética , Acromegalia/etiologia , Acromegalia/metabolismo , Adenoma/complicações , Adenoma/genética , Adenoma/metabolismo , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Membrana Celular/genética , Membrana Celular/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Feminino , Filaminas/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/uso terapêutico , Receptores de Dopamina D2/metabolismo , Receptores de Somatostatina/metabolismo , Somatostatina/administração & dosagem , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Carga Tumoral , Adulto JovemRESUMO
BACKGROUND: Transsphenoidal surgery (TSS) is the cornerstone of acromegaly treatment, however there are no robust predictors of surgical outcome and remission can only be defined three months after surgery. PURPOSE: To analyze if biochemical, demographical, radiological, and immunohistochemical characteristics are predictors of surgical remission and investigate if immediate postoperative GH and IGF-I levels can help defining remission earlier. METHODS: Consecutive acromegaly patients submitted to TSS between 2013-2016 were evaluated. Remission criteria was defined as normal IGF-I and GH <1 mcg/L three months after surgery. Data of age, sex, GH and IGF-I levels, tumor volume, cavernous sinus invasion, T2-weighted signal, Ki-67, and granulation pattern were correlated with remission status. GH and IGF-I levels at 24, 48 h, and one week postoperative were evaluated as early criteria of remission. RESULTS: Sixty-nine patients were included (84% macroadenomas) and surgical remission was achieved in 45%. No difference between cured and not cured patients concerning age, gender, preoperative GH or IGF-I levels, tumor volume, T2-weighted signal, Ki-67 and tumor granularity was observed. Remission was obtained in 20 of 36 (56%) of the non-invasive tumors, and in 3 of 16 (19%) of the invasive tumors (p = 0.017). A GH <1.57 mcg/L 48 h after surgery was able to predict remission with 93% sensitivity and 86% specificity and an IGF-I < 231% ULNR one week after surgery predicted remission with 86% sensitivity and 93% specificity. CONCLUSION: Cavernous sinus invasion is the only preoperative predictor of surgical remission. GH at 48 h and IGF-I one week after surgery can define earlier not cured patients.
Assuntos
Acromegalia/cirurgia , Adenoma/cirurgia , Hormônio do Crescimento Humano/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Hipofisárias/cirurgia , Acromegalia/sangue , Adenoma/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/sangue , Período Pós-Operatório , Prognóstico , Indução de Remissão , Resultado do TratamentoRESUMO
BACKGROUND: Few studies evaluated the use of cabergoline (CAB) for acromegaly treatment in monotherapy or in combination with first-generation somatostatin receptor ligands (SRLs). AIM: To evaluate the efficacy, predictors of response and safety of CAB treatment in acromegaly both in monotherapy and in combination with SRLs. METHODS: We retrospectively collected demographic, biochemical, tumour and treatment data. Short-term disease control was defined as random GH level < 1.0 µg/L and normal age-matched IGF-I level after 3-6 months of treatment with the higher dose used. Long-term disease control was defined as maintenance of normal GH and IGF-I levels at the last visit (at least 9 months of treatment). RESULTS: Eighty-two patients were studied. The median total time of treatment in monotherapy or in combination with SRLs was 14 months (3-124) and 34 months (3-88), respectively. Short-term disease control was observed in 6 (21%) patients in the monotherapy group and in 20 (32%) in the combination group. Treatment escape was observed in 1 patient after 16 months of CAB monotherapy and in 6 (30%) patients with combination therapy (after a median of 38 months), resulting in long-term disease control of 18% and 23%, respectively. Hyperprolactinemia was a predictor of response to monotherapy and pretreatment GH level to combination treatment. CONCLUSION: We presented the results of the largest single-centre study with CAB in monotherapy and in combination with SRL. The efficacy of CAB in acromegaly seems to be lower than that of other drugs, and treatment escape may occur after a long-term follow-up.