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1.
Medicine (Baltimore) ; 98(43): e17418, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651844

RESUMO

RATIONALE: Primary aldosteronism (PA) comprises 2 main subtypes: unilateral aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism or named as bilateral adrenal hyperplasia (BAH). An accurate discrimination between APA and BAH is crucial because the former is treated with adrenalectomy (ADX) and the latter is primarily by aldosterone antagonists. We report a case of idiopathic hyperaldosteronism characterized by BAH. PATIENT CONCERNS: A 46-year-old woman had experienced a paroxysmal elevation of blood pressure for the past 2 months, along with an intermittent headache and mild occipital swelling and pain. DIAGNOSES: We performed clinical, laboratory, and imaging tests, as well as bilateral adrenal vein sampling (AVS) on this patient. Specifically, computed tomography scan and magnetic resonance imaging were used to characterize the properties of bilateral adrenal adenoma. Additionally, bilateral AVS was performed to distinguish unilateral from bilateral adrenal abnormality in this patient. INTERVENTIONS: After oral administration of aldosterone antagonists, her blood pressure and potassium levels returned to normal ranges and her condition improved. OUTCOMES: Following differential diagnosis, screening, functional tests, a variety of imaging studies, and bilateral adrenal vein sampling (AVS) typing, she was finally diagnosed with idiopathic hyperaldosteronism. LESSONS: For PA patients with lack of typical hypertension and hypokalemia performance, early identification and accurate diagnosis are of great significance for improving the prognosis of BAH. AVS plays an important role in the classification of PA subtype, especially for the cases with bilateral lesions. In regard to patients with rare bilateral adrenocortical adenoma-type aldosteronism, AVS plays a key role in choosing the appropriate treatment regimen.


Assuntos
Adenoma/complicações , Neoplasias das Glândulas Suprarrenais/complicações , Hiperaldosteronismo/diagnóstico , Adenoma/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Diagnóstico Diferencial , Feminino , Humanos , Hiperaldosteronismo/tratamento farmacológico , Hiperaldosteronismo/etiologia , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico
2.
Integr Cancer Ther ; 18: 1534735419866908, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31416372

RESUMO

The Standardized Cultured Extract of Lentinula edodes Mycelia (also known as Active Hexose Correlated Compound, AHCC) and Wasabia japonica (Wasabi) are natural nutritional supplements known for their immunomodulatory and anticancer potential. The aim of this study was to evaluate the combinatorial effect of the bioactive immunomodulatory compound (BAIC), obtained by combining Wasabi and AHCC, on human breast (MCF-7) and pancreatic (Panc02) adenocarcinoma cell lines. Data obtained revealed that BAIC determines a striking decline in cancer cell growth at minimal concentrations compared with the use of Wasabi and AHCC as single agents. A significant increase in the G0/G1 subpopulation together with a marked augmentation in the percentage of apoptotic cells was demonstrated by flow cytometry, together with a significant upregulation in the expression of genes associated to the apoptotic cascade in both cell lines. The inhibitory role BAIC plays in mammospheres formation from MCF-7-derived cancer stem cells was shown with a marked reduction in size and number. Interestingly, when BAIC was exposed to monocytic cells, no cytotoxic effects were observed. A monocytes-to-macrophages differentiation was rather observed with the concomitant acquisition of an anti-inflammatory phenotype. Taken together, our findings suggest that BAIC could be used as a potential integration of standard chemotherapy treatments because of the improved inhibitory activity on cancer cell proliferation and reduced potential adverse effects.


Assuntos
Adenoma/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Fatores Imunológicos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Medicina Integrativa/métodos , Células MCF-7 , Macrófagos/efeitos dos fármacos , Oncologia/métodos , Monócitos/efeitos dos fármacos
3.
Arch Endocrinol Metab ; 63(4): 328-336, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365632

RESUMO

OBJECTIVE: Investigate the therapeutic response of acromegaly patients to pegvisomant (PEGV) in a real-life, Brazilian multicenter study. SUBJECTS AND METHODS: Characteristics of acromegaly patients treated with PEGV were reviewed at diagnosis, just before and during treatment. All patients with at least two IGF-I measurements on PEGV were included. Efficacy was defined as any normal IGF-I measurement during treatment. Safety data were reviewed. Predictors of response were determined by comparing controlled versus uncontrolled patients. RESULTS: 109 patients [61 women; median age at diagnosis 34 years; 95.3% macroadenomas] from 10 Brazilian centers were studied. Previous treatment included surgery (89%), radiotherapy (34%), somatostatin receptor ligands (99%), and cabergoline (67%). Before PEGV, median levels of GH, IGF-I and IGF-I % of upper limit of normal were 4.3 µg/L, 613 ng/mL, and 209%, respectively. Pre-diabetes/diabetes was present in 48.6% and tumor remnant in 71% of patients. Initial dose was 10 mg/day in all except 4 cases, maximum dose was 30 mg/day, and median exposure time was 30.5 months. PEGV was used as monotherapy in 11% of cases. Normal IGF-I levels was obtained in 74.1% of patients. Glycemic control improved in 56.6% of patients with pre-diabetes/diabetes. Exposure time, pre-treatment GH and IGF-I levels were predictors of response. Tumor enlargement occurred in 6.5% and elevation of liver enzymes in 9.2%. PEGV was discontinued in 6 patients and 3 deaths unrelated to the drug were reported. CONCLUSIONS: In a real-life scenario, PEGV is a highly effective and safe treatment for acromegaly patients not controlled with other therapies.


Assuntos
Acromegalia/tratamento farmacológico , Cabergolina/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Receptores de Somatostatina/uso terapêutico , Adenoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Brasil , Cabergolina/administração & dosagem , Criança , Quimioterapia Combinada , Feminino , Hormônio do Crescimento/sangue , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Receptores de Somatostatina/administração & dosagem , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
4.
BMJ Case Rep ; 12(7)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308184

RESUMO

McCune Albright syndromeis a rare disorder that presents with multiple endocrine abnormalities. We report the case of a 24-year-old woman who presented with right lower limb pain, with no preceding trauma or fracture. On examination she was noted to have coarsened facial features, acral enlargement, bitemporal hemianopia, galactorrhoea and multiple café-au-lait macules. She gave history of precocious puberty, having attained menarche at 7 years of age. Biochemical investigations revealed hyperprolactinaemia, with unsuppressed growth hormone levels following a glucose load and subclinical hyperthyroidism. Technetium-99m methylene diphosphonate bone scan showed polyostotic fibrous dysplasia, MRI of the brain showed a pituitary macroadenoma. Thus she was diagnosed to have McCune Albright syndrome with multiple endocrine manifestations. She was treated with parenteral zoledronate for her bony lesions and initiated on cabergoline for plurihormonal pituitary macroadenoma. She is planned to be on close follow-up to assess for clinical improvement and appearance of other manifestations.


Assuntos
Displasia Fibrosa Poliostótica/diagnóstico , Dor Musculoesquelética/etiologia , Adenoma/complicações , Adenoma/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Cabergolina/uso terapêutico , Diagnóstico Diferencial , Agonistas de Dopamina/uso terapêutico , Feminino , Displasia Fibrosa Poliostótica/tratamento farmacológico , Humanos , Hipertireoidismo/complicações , Perna (Membro) , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/tratamento farmacológico , Doenças Raras , Adulto Jovem , Ácido Zoledrônico/uso terapêutico
5.
Medicine (Baltimore) ; 98(23): e16000, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169743

RESUMO

RATIONALE: Mixed adenoneuroendocrine carcinoma (MANEC) is a rare neoplasm, and consensus on the treatment is unavailable. PATIENT CONCERN: A 60-year-old Chinese man presented with obstructive symptoms while eating and paroxysmal stomach pain for more than a month. DIAGNOSIS: MANEC was diagnosed based on clinical manifestations, imaging findings, and pathological examinations. INTERVENTIONS: The patient underwent radical gastrectomy and received XELOX adjuvant chemotherapy (oxaliplatin 200 mg day 1 + capecitabine 1.5 g twice a day) after surgery. OUTCOMES: After 4 cycles of XELOX adjuvant chemotherapy were administered, abdominal computerized tomography and liver magnetic resonance showed liver metastasis. LESSONS: The therapy of gastric MANEC is based on surgical operation, and adjuvant chemotherapy program has an important influence on its prognosis. Therefore, further studying the effectiveness of XELOX adjuvant chemotherapy for gastric MANEC is necessary.


Assuntos
Adenoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Neuroendócrino/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Tumor Misto Maligno/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
6.
Endocr Pract ; 25(8): 846-853, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31070948

RESUMO

Objective: Adrenal incidentalomas are increasingly detected with the widespread use of thoracic and abdominal imaging. The most common secretory syndrome in adrenal nodules is autonomous cortisol secretion (ACS). Recent data show that even mild cortisol excess is associated with adverse outcomes. The glucocorticoid receptor antagonist mifepristone has been used in patients with overt Cushing syndrome and hyperglycemia. The purpose of our study was to determine the effect of mifepristone on metabolic parameters in patients with ACS and concomitant prediabetes or diabetes. Methods: Eight patients with either unilateral or bilateral adrenal nodules with ACS were included in the study. Fasting laboratory tests including glucose and insulin levels to calculate homeostatic model assessment for insulin resistance (HOMA-IR) were performed at baseline and again after either 3 months (3 patients) or 6 months (5 patients) on mifepristone 300 mg daily treatment. Patients also completed several validated surveys on mood and quality of life at baseline and follow-up. Results: There were significant reductions in fasting glucose measurements and insulin resistance as measured by HOMA-IR in the 6 of 8 study patients in whom these measurements were available (P = .03). Conclusion: This pilot study demonstrates that mifepristone treatment of ACS is associated with a significant decrease in fasting glucose and insulin resistance as measured by HOMA-IR scores. Mifepristone treatment of ACS may be considered as a medical option for patients with ACS due to adrenal adenomas with concomitant abnormal glucose parameters in whom surgical removal is not being considered. Abbreviations: ACS = autonomous cortisol secretion; ACTH = adrenocorticotropic hormone; AI = adrenal incidentaloma; DHEAS = dehydroepiandrosterone sulfate; GR = glucocorticoid receptor; HbA1c = hemoglobin A1c; HOMA-IR = homeostatic model assessment for insulin resistance; ODT = overnight dexamethasone suppression test; QoL = quality of life; STAI = state trait anxiety inventory; TSH = thyroid stimulating hormone; UFC = urinary free cortisol.


Assuntos
Adenoma , Neoplasias das Glândulas Suprarrenais , Mifepristona/uso terapêutico , Adenoma/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Humanos , Hidrocortisona , Projetos Piloto , Qualidade de Vida
7.
Endocr J ; 66(6): 515-522, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30880293

RESUMO

Cushing's disease is almost always caused by hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. A mutation in the deubiquitinase gene USP8 has been found in human ACTH-producing pituitary adenoma cells. This mutational hotspot hyperactivates USP8, rescuing epidermal growth factor receptor (EGFR) from lysosomal degradation and ensuring its sustained signaling in Cushing's disease. An EGFR inhibitor would be an effective anti-tumor agent in EGFR-related tumors. We investigated the effect of a potent dual tyrosine kinase inhibitor, lapatinib, on ACTH production and cell proliferation in AtT-20 mouse corticotroph tumor cells. Lapatinib decreased proopiomelanocortin (Pomc) mRNA levels and ACTH levels in AtT-20 cells and also inhibited cell proliferation, induced apoptosis, and decreased pituitary tumor-transforming gene 1 (Pttg1), a hallmark of pituitary tumors, mRNA levels. KSN/Slc nude mice were subcutaneously inoculated with AtT-20 cells. After 1 week, the mice were randomized either to control or lapatinib groups. The inhibitor decreased the tumor weight of AtT-20 allografts in vivo versus control mice. Lapatinib also significantly decreased Pomc and Pttg1 mRNA levels in the tumor and plasma ACTH and corticosterone levels in vivo. Thus, lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells. An EGFR-targeting therapy could be an important treatment for Cushing's disease.


Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Corticotrofos/efeitos dos fármacos , Lapatinib/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Adenoma Hipofisário Secretor de ACT/tratamento farmacológico , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/tratamento farmacológico , Adenoma/patologia , Hormônio Adrenocorticotrópico/sangue , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Corticosterona/sangue , Corticotrofos/metabolismo , Corticotrofos/patologia , Lapatinib/uso terapêutico , Camundongos , Camundongos Nus , Transplante de Neoplasias , Inibidores de Proteínas Quinases/uso terapêutico
8.
Neurosurgery ; 84(3): 616-623, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30767017

RESUMO

BACKGROUND: Accurate assessment of the need for glucocorticoid therapy is essential after transsphenoidal surgery (TSS) for pituitary tumors. Agreement on the best test to use in the early postoperative setting is lacking. OBJECTIVE: To examine recovery room (RR) cortisol as a predictor of long-term need for glucocorticoids. METHODS: We conducted a retrospective cohort study of 149 patients who underwent TSS for pituitary tumors between January 2007 and December 2014. Pathological tumor diagnoses were confirmed. Endocrinologists assessed the need for glucocorticoid supplementation within 6 to 8 wk after TSS. We extracted data on preoperative, RR, and day 1 to 3 post-TSS morning serum cortisol (MSC). We reported areas under the receiver operating characteristic curve (AUC) and diagnostic measures for different cortisol measures. We also conducted a logistic regression to identify the most predictive variables. RESULTS: Eighteen patients required glucocorticoid supplementation at follow-up. RR cortisol was the most accurate measurement in the early postoperative period (AUC [95% confidence interval (CI)], .92 [.85-.99]; P < .001), followed by day 1, 2, and 3 post-TSS MSC, respectively. A threshold RR cortisol of 744.0 nmol/L (26.97 µg/dL) had 90.9% sensitivity and 73.7% specificity for detecting patients in the hypocortisolism group, while 757.5 nmol/L (27.46 µg/dL) had 100% and 70.0%, respectively. The logistic regression identified RR cortisol as the sole significant predictor (odds ratio [CI], .36[.18-.71] for every 100 nmol/L increase; P = .0033). CONCLUSION: The RR cortisol is accurate in predicting long-term glucocorticoid supplementation and may be the best early postoperative measure. Future larger studies should validate these findings and derive optimal RR cortisol threshold values.


Assuntos
Adenoma/sangue , Glucocorticoides/administração & dosagem , Hidrocortisona/sangue , Neoplasias Hipofisárias/sangue , Sala de Recuperação/tendências , Adenoma/tratamento farmacológico , Adenoma/cirurgia , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/cirurgia , Valor Preditivo dos Testes , Estudos Retrospectivos , Seio Esfenoidal/cirurgia
9.
Minerva Endocrinol ; 44(2): 109-128, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30650942

RESUMO

Acromegaly is a chronic systemic disease mainly caused by a growth hormone (GH)-secreting pituitary neuroendocrine tumor (PitNETs), which is associated with many health complications and increased mortality when not adequately treated. Transsphenoidal surgery is considered the treatment of choice in GH-secreting PitNETs, but patients in whom surgery cannot be considered or with persistent disease after surgery require medical therapy. Treatment with available synthetic somatostatin analogues (SSAs) is considered the mainstay in the medical management of acromegaly which exert their beneficial effects through the binding to a family of G-protein coupled receptors encoded by 5 genes (SSTR1-5). However, although it has been demonstrated that the SST1-5 receptors are physically present in tumor cells, SSAs are in many cases ineffective (i.e. approximately 10-30% of patients with GH-secreting PitNET are unresponsive to SSAs), suggesting that other cellular/molecular determinants could be essential for the response to the pharmacological treatment in patients with GH-secreting PitNETs. Therefore, the scrutiny of these determinants might be used for the identification of subgroups of patients in whom an appropriate pharmacological treatment can be successfully employed (responders vs. non-responders). In this review, we will describe some of the existing, classical and novel, genetic and molecular determinants involved in the response of patients with GH-secreting PitNETs to the available therapeutic treatments, as well as new molecular/therapeutic approaches that could be potentially useful for the treatment of GH-secreting PitNETs.


Assuntos
Acromegalia/tratamento farmacológico , Acromegalia/genética , Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos , Neoplasias Hipofisárias/complicações
10.
Expert Rev Endocrinol Metab ; 14(1): 35-42, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30595057

RESUMO

INTRODUCTION: Acromegaly requires a multimodal treatment approach that includes surgery by an expert pituitary neurosurgeon, pharmacological treatment with one or more of the available drugs and radiation therapy. These treatment alternatives are not mutually exclusive but rather complement each other when properly indicated in the individual patient. In this review, we summarize and analyze the available data concerning the choice of the surgical approach (microscopy vs. endoscopy) and the interactions between medical treatment with somatostatin analogs and pituitary surgery. AREAS COVERED: Technical aspects, complications and outcome of transsphenoidal surgery (TSS); Advantages and disadvantages of the microscopic and endoscopic approaches; Safety and efficacy of somatostatin analogs (SSA); Primary pharmacological therapy versus primary TSS; Benefits of the preoperative treatment with SSA; and the effect of surgical tumor debulking in the therapeutic response to SSA. EXPERT COMMENTARY: Continuing efforts at improving surgical techniques and at generating more efficacious pharmacological therapies for acromegaly are likely to improve the outcome of these patients. However, an integral approach of the patient aimed not only at achieving biochemical criteria of cure but also at treating the individual comorbidities is mandatory to improve the quality of life of these patients and to reduce their mortality rate.


Assuntos
Acromegalia/tratamento farmacológico , Acromegalia/cirurgia , Terapia Combinada/efeitos adversos , Somatostatina/análogos & derivados , Acromegalia/sangue , Acromegalia/radioterapia , Adenoma/sangue , Adenoma/tratamento farmacológico , Adenoma/radioterapia , Adenoma/cirurgia , Terapia Combinada/métodos , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Procedimentos Cirúrgicos de Citorredução/métodos , Endoscopia/efeitos adversos , Hormônio do Crescimento Humano/sangue , Humanos , Peptídeos Cíclicos/uso terapêutico , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/radioterapia , Neoplasias Hipofisárias/cirurgia , Cuidados Pré-Operatórios , Qualidade de Vida , Somatostatina/uso terapêutico , Resultado do Tratamento
11.
Minerva Endocrinol ; 44(2): 129-136, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30531694

RESUMO

Acromegaly is mainly due to the somatotroph pituitary neuroendocrine tumors (PitNET)s. These have been subtyped into densely granulated (DG) and sparsely granulated (SG) tumors, which differ in clinical, histological and biological characteristics and in response to somatostatin analogs (SA)s. The variable remission rate after surgical resection, as first line treatment, has increased interest in identifying pathological markers to better predict the response to medical treatment. Several techniques have shown somatotroph tumors to express somatostatin receptors (SSTR)s, and mainly SSTR2 and SSTR5. The molecular methods appear to give contradictory results, are expansive and cannot be routinely performed. Immunohistochemistry, while being the most powerful technique, requires optimal fixation and the use of monoclonal antibodies against at least SSTR2 and SSTR5. Almost all somatotroph tumors express SSTR2 or SSTR5, and, in great majority, at a high level. More importantly, the type of SSTR, the level of expression, and the response to SA treatment appear well correlated. Indeed, a significantly higher expression of SSTR2 in DG compared to in SG tumors likely explains the better response of DG tumors to the normalization of growth hormone and insulin-like growth factor-1 under SA. However, a reproducible scoring and a cut-off from which the SA efficacy can be reliably predicted, remain to be found. In conclusion, the SSTR expression profile and morphological subtypes of the somatotroph tumor may help predict the response to medical treatment. Such pathological profiling could become a useful decision-making tool for clinicians in the context of a multidisciplinary approach, after surgery failure.


Assuntos
Adenoma/tratamento farmacológico , Adenoma/patologia , Biomarcadores/análise , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Acromegalia/tratamento farmacológico , Acromegalia/patologia , Animais , Humanos , Valor Preditivo dos Testes , Prognóstico , Receptores de Somatostatina/genética
12.
J Clin Endocrinol Metab ; 104(3): 925-933, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535260

RESUMO

Context: The most frequent cause of endogenous hypercortisolism is Cushing disease (CD), a devastating condition associated with severe comorbidities and high mortality. Effective tumor-targeting therapeutics are limited. Design: Search in PubMed with key words "corticotroph" and "Cushing's disease" plus the name of the mentioned therapeutic agent and in associated references of the obtained papers. Additionally, potential therapeutics were obtained from ClinicalTrials.gov with a search for "Cushing disease." Results: At present, the tumor-targeted pharmacological therapy of CD is concentrated on dopamine agonists (cabergoline) and somatostatin analogs (pasireotide) with varying efficacy, escape from response, and considerable side effects. Preclinical studies on corticotroph pathophysiology have brought forward potential drugs such as retinoic acid, silibinin, and roscovitine, whose efficacy and safety remain to be determined. Conclusions: For many patients with CD, effective tumor-targeted pharmacological therapy is still lacking. Coordinated efforts are pivotal in establishing efficacy and safety of novel therapeutics in this rare but devastating disease.


Assuntos
Adenoma Hipofisário Secretor de ACT/tratamento farmacológico , Adenoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Corticotrofos/efeitos dos fármacos , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/complicações , Adenoma/patologia , Antineoplásicos/farmacologia , Cabergolina/farmacologia , Cabergolina/uso terapêutico , Ensaios Clínicos como Assunto , Corticotrofos/patologia , Humanos , Hipersecreção Hipofisária de ACTH/etiologia , Hipersecreção Hipofisária de ACTH/patologia , Roscovitina/farmacologia , Roscovitina/uso terapêutico , Silibina/farmacologia , Silibina/uso terapêutico , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Resultado do Tratamento , Tretinoína/farmacologia , Tretinoína/uso terapêutico
13.
J Steroid Biochem Mol Biol ; 187: 88-96, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30439415

RESUMO

Although the molecular mechanisms underlying the formation of pituitary adenomas are largely unknown, it is clear that estrogen plays a key role in the pathogenesis of pituitary adenomas. Though this is exemplified by an investigation of fulvestrant in the pituitary adenoma cell line GH3, no systematic studies on the effects of selective estrogen receptor modulators (SERMs) on functional properties of pituitary adenoma cell lines to modulate cell migration, cell invasion, and cell survival are available. Here we analyzed the effects of fulvestrant and three SERMs, bazedoxifene, clomifene, and raloxifene, on pituitary adenomas cell lines AtT20, TtT/GF, and GH3. In cell survival assays, clomifene was shown to be the most potent compound in all three cell lines with IC50 values ranging between 2, 6, and 10 µM, respectively, depending on the cell type. Raloxifene and bazedoxifene were also effective but to a lower extent. Also, all SERMs affected migratory and invasive behavior of pituitary adenoma cells. Mechanistically, treatment of cells with SERMs caused cell apoptosis, as demonstrated by Caspase 3/7 activity and western blot assays. In addition, western blots demonstrate activation of p53 in TtT/GF cells and loss of ERK1/2 activation in AtT20 cells. In contrast, fulvestrant was only effective in GH3 cells. Thus, the general applicability of SERMs for pituitary adenoma cells might be promising in clinical applications for the treatment of pituitary adenomas.


Assuntos
Adenoma/tratamento farmacológico , Antagonistas do Receptor de Estrogênio/farmacologia , Fulvestranto/farmacologia , Invasividade Neoplásica/prevenção & controle , Neoplasias Hipofisárias/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Adenoma/metabolismo , Adenoma/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Invasividade Neoplásica/patologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia
14.
Mol Carcinog ; 58(4): 511-523, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30499618

RESUMO

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFß1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFß1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFß1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFß1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFß1 alone, and TGFα relative to TGFß1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.


Assuntos
Adenoma/metabolismo , Cálcio/administração & dosagem , Neoplasias Colorretais/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Fator de Crescimento Transformador alfa/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Vitamina D/administração & dosagem , Adenoma/tratamento farmacológico , Adenoma/patologia , Biomarcadores Tumorais , Estudos de Casos e Controles , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Reto/efeitos dos fármacos , Reto/metabolismo , Reto/patologia , Vitaminas/administração & dosagem
15.
Eur J Endocrinol ; 180(1): 1-9, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30400068

RESUMO

Objective To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery. Design A retrospective study in two large tertiary referral centers in The Netherlands. Methods Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit. Results In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006). Conclusions Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.


Assuntos
Acromegalia/cirurgia , Adenoma/cirurgia , Hipófise/cirurgia , Neoplasias Hipofisárias/cirurgia , Somatostatina/análogos & derivados , Acromegalia/tratamento farmacológico , Acromegalia/mortalidade , Adenoma/tratamento farmacológico , Adenoma/mortalidade , Adulto , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/mortalidade , Período Pós-Operatório , Estudos Retrospectivos , Taxa de Sobrevida
16.
Hormones (Athens) ; 18(2): 117-126, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30368687

RESUMO

Non-functioning pituitary adenomas (NFPAs) are the second most common variant of pituitary tumors. When symptomatic, primary therapy is surgery. Recurrence rates are high. Since many NFPAs express dopamine and somatostatin receptors, medical therapy has been used after surgery in order to prevent recurrence. So far, dopamine agonists have been more widely tested with some promise when introduced immediately after surgery but with less efficacy when introduced later upon tumor regrowth. Currently, the role of medical therapy to prevent tumor regrowth in NFPAs is limited by imprecisions as to final outcome and uncertainties concerning on patient selection, dosing, duration, and side effects.


Assuntos
Adenoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Adenoma/complicações , Adenoma/patologia , Adenoma/cirurgia , Quimioterapia Adjuvante/métodos , Terapia Combinada , Agonistas de Dopamina/uso terapêutico , Humanos , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/etiologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Receptores de Somatostatina/antagonistas & inibidores
17.
Am J Clin Oncol ; 42(2): 221-227, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30540568

RESUMO

BACKGROUND: Complete tumor removal by transsphenoidal surgery is usually difficult for large nonfunctioning pituitary adenomas (NFPAs). A validated medical treatment may be useful for their management. This study evaluates the clinical efficacy of the dopaminergic agonist cabergoline for residual NFPA. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomized, parallel, open-label clinical trial that compared cabergoline with nonintervention in patients with residual NFPA after transsphenoidal surgery over 2 years. The primary outcome was clinical efficacy (tumor reduction). The secondary outcome was the relationship between tumor dopamine D2 receptor (D2R) expression and clinical responsiveness. Tumor measurements and clinical evaluations were performed every 6 months. RESULTS: In total, 59 and 57 individuals were randomly assigned to the study and control groups, respectively. At the end of the study, residual tumor shrinkage, stabilization, and enlargement were observed in 28.8%, 66.1%, and 5.1% of patients, respectively, in the medical-therapy group and in 10.5%, 73.7%, and 15.8% of patients, respectively, in the control group (P=0.01). The progression-free survival rate was 23.2 and 20.8 months for the study and control groups, respectively (P=0.01). D2R was not associated with cabergoline responsiveness. No major side effects were related to cabergoline use. CONCLUSIONS: Cabergoline was an effective drug for treating residual NFPA, and its use was associated with a high rate of tumor shrinkage (ClinicalTrials.gov NCT03271918).


Assuntos
Adenoma/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Cabergolina/uso terapêutico , Neoplasia Residual/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Adenoma/metabolismo , Adenoma/patologia , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/metabolismo , Neoplasia Residual/patologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Prognóstico , Receptores de Dopamina D2/metabolismo , Taxa de Sobrevida
18.
Artigo em Inglês | MEDLINE | ID: mdl-30088454

RESUMO

BACKGROUND AND OBJECTIVE: Giant pituitary adenomas (GPAs) are benign tumours with a diameter ≥ 4 cm [1]. They can cause symptoms and signs due to the possible hyper-secretion of one or more pituitary hormones, and involvement of the surrounding structures whereas the compression of the pituitary itself can lead to hypopituitarism. METHODS: We report on a young woman with acromegaly due to an inoperable giant GH-secreting pituitary adenoma extending to right cavernous sinus, right orbital cavity, ethmoid, right maxillary sinus, sphenoid sinus, clivus and right temporal fossa, in which medical treatment with Octreotide- LAR was able to promptly relieve headache and bilateral hemianopsia due to optic chiasm involvement, improve acromegaly symptoms and, over the time, control tumor expansion, improving fertility and therefore allowing the patient to become pregnant. RESULTS: Octreotide-LAR therapy was withdrawn during pregnancy and the patient did not experience complications and gave birth to a healthy son. On magnetic resonance, the size of the tumor at the end of pregnancy and in the subsequent follow up was not increased. CONCLUSION: The history we report, therefore, confirms previous experiences reporting a possible favourable outcome of pregnancy in patients affected by acromegaly and adds further information about the behaviour of giant pituitary tumors in patients underwent pregnancy.


Assuntos
Adenoma/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Octreotida/uso terapêutico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Acromegalia/diagnóstico , Acromegalia/tratamento farmacológico , Acromegalia/etiologia , Acromegalia/patologia , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/patologia , Adulto , Antineoplásicos Hormonais/uso terapêutico , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Hemianopsia/diagnóstico , Hemianopsia/tratamento farmacológico , Hemianopsia/etiologia , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Síndromes de Compressão Nervosa/diagnóstico , Síndromes de Compressão Nervosa/tratamento farmacológico , Síndromes de Compressão Nervosa/etiologia , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Complicações Neoplásicas na Gravidez/patologia , Resultado da Gravidez , Carga Tumoral
19.
J Endocrinol Invest ; 42(4): 443-451, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30171531

RESUMO

PURPOSE: Somatostatin analogs (SSAs) are considered one of the most effective medical treatments for patients with growth hormone-secreting pituitary adenomas (GH-PAs). The postoperative electron microscopy (EM) pathological subtype and SSTR2 expression in the tumor are the most established predictors of patient response to SSA therapy. The aim of this study was to evaluate how will magnetic resonance spectroscopy (MRS) measurements before surgery predict the EM pathological subtypes and SSTR2 expression of tumors, and thereby serve as an indicator for the therapeutic sensitivity to SSAs of patients with GH-PAs. METHODS: Eighteen patients with GH pituitary macroadenomas who underwent transsphenoidal surgery were included in this retrospective study. The preoperative MRS data and T2 signal intensity were obtained from patients by 1.5 T MR spectroscopy of the sellar mass. The EM pathological subtypes of tumors were determined after surgery through examination of cell granulations. The expressions of somatostatin receptor 2 (SSTR2), SSTR5, P21, P27, and Ki-67 were evaluated by immunohistochemistry. RESULTS: The MRS parameters that were found to significantly predict the EM pathological subtypes of tumors, as calculated by the receiver operating characteristic curve, were the choline (Ch) value at 3140.5 MR units (sensitivity 69.2%, specificity 100%) and the choline/creatine (Ch/Cr) ratio at 1.27 (sensitivity 92.3%, specificity 100%). Further, the Ch/Cr ratio, but not other MRS data, was shown to negatively correlate with the expression of SSTR2 (P = 0.02). The Ch/Cr ratio was also found to positively correlate with the Ki-67 value (P < 0.05) and T2 signal (P < 0.05), but not with other factors that were examined in this study. Moreover, the Ch/Cr ratio could predict the EM pathological subtypes of tumors with an accuracy of 83.3% (5/6) for patients with an isointense T2 signal. CONCLUSION: The Ch/Cr ratio by MRS could effectively predict the tumor subtype and was significantly correlated with the expression of SSTR2, which was consistent with other predictors. It was also able to distinguish the patients with isointense T2 signals. Our results provide a potentially new and non-invasive method to predict the response to SSAs in patients with GH pituitary macroadenomas.


Assuntos
Adenoma/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Antagonistas de Hormônios/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Cuidados Pré-Operatórios , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Adenoma/tratamento farmacológico , Adenoma/metabolismo , Adenoma/cirurgia , Adulto , Idoso , Biomarcadores/análise , Feminino , Seguimentos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
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