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PURPOSE: The aims of the study were to evaluate the performance and robustness of [18F]fluorocholine PET/CT in detecting hyperfunctioning parathyroid glands in MEN1-related primary hyperparathyroidism (pHPT) at different stages of their disease. METHODS: Retrospective French multicenter study including patients with MEN1 pHPT who underwent [18F]fluorocholine PET/CT at initial diagnosis or for evaluation of persistent/recurrent disease. PET/CT were independently reviewed by two readers in a blinded manner. The assessment of PET/CT on a per-patient basis was assessed using a comprehensive set of criteria that considered pathological findings or agreement with alternative diagnostic methods in non-operated patients. The secondary objectives included the analysis of the performance of PET/CT at a per-lesion level, with reference to a pathological Gold Standard, and examining its interobserver reproducibility. RESULTS: A total of 71 MEN1 patients were included (73 PET/CT) in the study. At the per-patient level (entire cohort), [18F]fluorocholine PET/CT sensitivity ranged from 98.5 to 100% among the different readers. An average of 1.77 glands per PET was described, with 2.35 glands at the initial diagnosis (n = 23) and 1.5 in previously operated cases (n = 50). PET/CT detected more lesions than conventional imaging work-up (neck ultrasound and/or scintigraphy). At the per-lesion level (41 operated patients), sensitivity ranged across different readers from 84.4 to 87%, and specificity ranged from 94.7 to 98.8%. At initial diagnosis, all patients that exhibited 3 or more abnormal glands on PET underwent subtotal parathyroidectomy while 7 out of 13 patients with 1 or 2 gland abnormalities on PET underwent less than subtotal parathyroidectomy. Finally, the degree of inter-observer agreement was high. CONCLUSION: [18F]fluorocholine PET/CT is a reliable and robust imaging modality for the evaluation of MEN1-related pHPT and could guide surgeons in achieving the optimal benefit-risk ratio. This study gives a great impetus for its adoption as a primary diagnostic tool in this context.
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Colina/análogos & derivados , Hiperparatireoidismo Primário , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Hiperparatireoidismo Primário/diagnóstico por imagem , Hiperparatireoidismo Primário/cirurgia , Estudos Retrospectivos , Reprodutibilidade dos Testes , Glândulas ParatireoidesRESUMO
Background: Anaplastic thyroid carcinoma (ATC) is a rare and frequently fatal type of thyroid cancer. The degree of heterogeneity in survival rates for ATC is incompletely studied. This study evaluated the factors associated with overall survival (OS) of patients with ATC using multicenter real-world data from a national tertiary care center network in France. Methods: In this multicenter, retrospective cohort study, all patients with ATC diagnosed between 2010 and 2020 were identified from the national database of the French ENDOCAN-TUTHYREF network. Factors associated with OS were examined in multivariable analyses using Cox proportional hazards models. Results: The study included 360 patients. Of these, 220 (61%) were female and the median age was 72 years (interquartile range: 62-80). The percentages of patients with pure and mixed (synchronously-transformed) ATC (p-ATC and st-ATC) were 62.5% and 26.7%, respectively. The median OS was 6.8 months [confidence interval, CI: 5.5-8.1]: not reached for stage IVa, 11.4 months [8.2-17.8] for IVb, and 4.6 months [3.5-5.7] for IVc. Surgery, radiation therapy to the neck, chemotherapy, and best supportive care were administered to 69 (19.2%), 214 (59.4%), 254 (70.6%), and 66 (18.3%) patients, respectively. In a multivariable analysis, including stage IVb-IVc patients, significantly higher OS was observed in patients with Eastern Cooperative Oncology Group performance-status of 0-1 (hazard ratio [HR], 0.6; [CI, 0.4-0.9], p < 0.02), stage IVb [HR, 0.5; CI, 0.4-0.8, p < 0.001], and multimodal treatment (surgery and chemoradiotherapy) [HR, 0.07; CI, 0.04-0.1, p < 0.001]. Variables associated with significantly worse OS included: p-ATC (vs. st-ATC) [HR, 1.83; CI, 1.33-2.51, p = 0.001] and a neutrophil-to-lymphocyte ratio (NLR) >5.05 [HR, 2.05, CI, 1.39-3.05, p < 0.001]. Conclusions: Factors independently associated with improved OS in ATC included: European Cooperative Oncology Group performance status, disease stage, multimodality treatment, synchronously transformed ATC, and lower NLR. Long-term OS was observed in selected patients with ATC who underwent multimodal treatment.
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Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Feminino , Idoso , Masculino , Carcinoma Anaplásico da Tireoide/patologia , Estudos Retrospectivos , Tireoidectomia , Neoplasias da Glândula Tireoide/patologia , Terapia Combinada , PrognósticoRESUMO
BACKGROUND: Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT-JT have a 15-20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients. CASE REPORT: Here are report two atypical cases of HPT-JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first-line panel by Next-Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT-JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait. CONCLUSION: In view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis.
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Fibroma , Hiperparatireoidismo Primário , Neoplasias Maxilomandibulares , Humanos , Feminino , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/patologia , Proteínas Supressoras de Tumor/genética , Neoplasias Maxilomandibulares/genética , Neoplasias Maxilomandibulares/patologia , Fibroma/genéticaRESUMO
CONTEXT: Despite the growing evidence of the clinical value of somatostatin receptor (SSTR) positron emission tomography (PET) in the evaluation of neuroendocrine tumors (NETs), its role remains to be clarified at different time points in the journey of patients with multiple endocrine neoplasia type 1 (MEN1). The rarity of the disease is however a significant impediment to prospective clinical trials. OBJECTIVE: The goals of the study were to assess the indications and value of SSTR PET/computed tomography (CT) in patients with MEN1. METHODS: We retrospectively included patients from 7 French expert centers for whom data on SSTR PET/CT and morphological imaging performed at the same period were available. Detection rates of PET study were analyzed. RESULTS: One hundred and 8 patients were included. SSTR PET/CT was performed at screening (n = 33), staging (n = 34), restaging (n = 37), and for peptide receptor targeted radiotherapy selection (n = 4). PET detected positive pancreatic lesions in 91% of cases at screening, with results comparable with magnetic resonance imaging but superior to CT (P = .049). Metastases (mostly lymph node [LN]) were present at the screening phase in 28% of cases, possibly due to the suboptimal value of screening morphological imaging in the assessment of nodal metastases and/or a long delay between imaging studies. SSTR PET/CT was considered superior or complementary to the reference standard in the assessment of LN or distant metastases in the vast majority of cases and regardless of the clinical scenario. CONCLUSION: This study shows the potential added value of SSTR PET in the assessment of MEN1-associated NETs and provides great impetus toward its implementation in the evaluation of patients with MEN1.
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Neoplasia Endócrina Múltipla Tipo 1 , Tumores Neuroendócrinos , Humanos , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico por imagem , Tumores Neuroendócrinos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Receptores de Somatostatina , Estudos RetrospectivosRESUMO
BACKGROUND: Idiopathic central precocious puberty (ICPP) is supposed to be non-existent in a context of testicular destruction that is typically present in Klinefelter syndrome (KS). Herein, we describe a rare case of ICPP in a Klinefelter patient (47,XXY) with 2 maternal X chromosomes. Moreover, we highlight the differences in gonadotropin levels in comparison to males with ICPP and a normal karyotype. CASE PRESENTATION: An 8 years old boy with a history of cryptorchidism was evaluated for precocious puberty (Tanner staging: P2/G3). Both testes measured 25x35mm. His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml), luteinizing hormone [LH (3.5 UI/l)] and follicle stimulating hormone [FSH (7.7 UI/l)] levels. Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively. Brain magnetic resonance imaging (MRI) was normal. No MKRN3 mutation was detected. He was treated for ICPP for two years. During puberty, he suffered from hypergonadotropic hypogonadism leading to the diagnosis of KS (47,XXY karyotype). Chromosomal analysis by fluorescent multiplex polymerase chain reaction (PCR) using X chromosome microsatellite markers identified 2 maternal X chromosomes. Analysing 8 cases of KS developing ICPP (our reported case and 7 other published cases) revealed that these KS patients with ICPP have higher LH and FSH levels during ICPP episode than in ICPP patients with a normal karyotype (ICPP with KS vs ICPP with a normal karyotype: LH levels 9.4 ± 12 vs 1.1 ± 0.6 UI/l; FSH levels 23.1 ± 38.5 vs 2.7 ± 1.5 UI/l). Furthermore, their response to gonadotropin-releasing hormone (GnRH) stimulation is characterized by excessive LH and FSH secretion (LH levels post-GnRH: 58 ± 48 vs 15.5 ± 0.8 UI/l; FSH levels post-GnRH: 49.1 ± 62.1 vs 5.7 ± 3.9 UI/l). CONCLUSIONS: ICPP in boys is extremely rare. The pathophysiology of ICPP in KS is unknown. However, maternal X supplementary chromosome and early testicular destruction may play a significant role in the initiation of ICPP, in part explaining the relative "overrepresentation of ICPP in KS. Thus, karyotype analysis could be considered for boys suffering from ICPP, especially if testicular size is smaller or gonadotropins are significantly elevated.
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OBJECTIVE: The dental and periodontal impact of GH/IGF-1 hypersecretion has been poorly investigated until now. Our aim is to precisely describe the oro-dental state of acromegalic patients and to study the impact of GH/IGF-1 hypersecretion on patients' reported oral health-related quality of life (OHRQoL). METHODS: After collecting characteristics of their disease, acromegalic patients answered the GOHAI questionnaire assessing their OHRQoL, the AcroQoL questionnaire and then benefited from a complete stomatological and radiological examination (orthopantomogram systematically, retro-alveolar radiography or Cone Beam CT if necessary). RESULTS: In total, 29 patients aged 59.1 ± 16.0 years were included. The average DMFT index (sum of Decayed, Missing and Filled Teeth per patient) was 19.0 ± 7.8. 16/29 patients had a gingivitis and 18/29 a mild to moderate chronic periodontitis, but no case of severe chronic periodontitis was found, probably because the frequency of a protective thick gingival biotype was increased (9/29). No case of generalized gingival hypertrophy or diffuse hypercementosis was observed. According to the Add-GOHAI score, only 8/26 patients had a satisfactory OHRQoL. This parameter was correlated to the acromegaly-specific quality of life according to the AcroQoL score. Interestingly, 11/29 patients had bulky oral bony outgrowths (OBO), such as large maxillary or mandibular tori and multiple vestibular exostosis. CONCLUSIONS: The unsatisfactory OHRQoL reported by acromegalic patients contrasts with a rather good objective oro-dental state and annual oral examination seems relevant in this population. Finally, we report that huge OBO could be helpful signposts for the diagnosis of acromegaly.
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Introduction: Loco regional persistence or recurrence of differentiated thyroid cancer (DTC) is frequent despite initial thyroidectomy and radioactive iodine therapy (RAI). The aim of this study was to analyze the impact of a complementary adjuvant RAI (Ad-RAI) on disease recurrence following re-operation on patients with locally persistent or recurrent DTC. Patients and Methods: A retrospective study of 85 patients with DTC was conducted. All patients were initially treated with total thyroidectomy and RAI, and re-operated for a locally persistent or recurrent disease. Propensity score was calculated to predict the impact of Ad-RAI on survival after reoperation, and to reduce the bias of the limited sample size and the prognostic tests. Results: 49 (58%) patients were re-treated with Ad-RAI after re-operation while 36 (42%) were only followed up. Disease recurrence after re-treatment (re-operation ± Ad-RAI) was detected in 31 patients (36.5%). In multivariate analysis, age >55 years (HR: 3.9 [1.6; 9.5]; p < 0.00001) was the main poor prognostic factor for recurrence-free survival. Three parameters independently influenced the decision to administer ad-RAI: low number of previous RAI administrations, Nx before re-operation, and pTg > 30 µg/l. These parameters were incorporated in the Propensity score calculation. If ad-RAI tended to improve recurrence-free survival (median survival 17.4 vs. 10.9 months), adjustment using the Propensity score removed any difference between the groups (p = 0.54), confirming the limited value of ad-RAI. Conclusion: In patients with locally persistent or recurrent DTC, age is the main independent prognostic factor. Adjuvant RAI does not improve recurrence-free survival of DTC patients.
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BACKGROUND: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription. METHODS: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis. RESULTS: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC. CONCLUSIONS: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness.
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Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Fator de Transcrição E2F1/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Proteínas de Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Imunoprecipitação da Cromatina , Biologia Computacional , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Humanos , Indóis/farmacologia , Camundongos Knockout , Análise Multivariada , Modelos de Riscos Proporcionais , Ribonucleosídeo Difosfato Redutase/antagonistas & inibidores , Ribonucleosídeo Difosfato Redutase/genética , Securina/genéticaRESUMO
INTRODUCTION: Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied. OBJECTIVE: The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND METHODS: This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI. RESULTS: According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 µg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30µg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30µg/l or ≥55 years with pre-ablation sTg <30 µg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30µg/l) representing 3% of the cohort. CONCLUSION: Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 µg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 µg/l have the worst survival rate.
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Radioisótopos do Iodo/administração & dosagem , Tireoglobulina/sangue , Neoplasias da Glândula Tireoide/mortalidade , Tireoidectomia , Adulto , Fatores Etários , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Período Pré-Operatório , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Medição de Risco/métodos , Taxa de Sobrevida , Glândula Tireoide/patologia , Glândula Tireoide/efeitos da radiação , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/terapia , Resultado do TratamentoRESUMO
SUMOylation is a highly conserved and dynamic post-translational mechanism primarily affecting nuclear programs for adapting organisms to stressful challenges. Alteration of SUMOylation cycles leads to severe developmental and homeostatic defects and malignancy, but signals coordinating SUMOylation are still unidentified. The adrenal cortex is a zonated endocrine gland that controls body homeostasis and stress response. Here, we show that in human and in mouse adrenals, SUMOylation follows a decreasing centripetal gradient that mirrors cortical differentiation flow and delimits highly and weakly SUMOylated steroidogenic compartments, overlapping glomerulosa, and fasciculata zones. Activation of PKA signaling by acute hormonal treatment, mouse genetic engineering, or in Carney complex results in repression of small ubiquitin-like modifier (SUMO) conjugation in the inner cortex by coordinating expression of SUMO pathway inducers and repressors. Conversely, genetic activation of canonical wingless-related integration site signaling maintains high SUMOylation potential in the outer neoplastic cortex. Thus, SUMOylation is tightly regulated by signaling pathways that orchestrate adrenal zonation and diseases.-Dumontet, T., Sahut-Barnola, I., Dufour, D., Lefrançois-Martinez, A.-M., Berthon, A., Montanier, N., Ragazzon, B., Djari, C., Pointud, J.-C., Roucher-Boulez, F., Batisse-Lignier, M., Tauveron, I., Bertherat, J., Val, P., Martinez, A. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex.
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Córtex Suprarrenal/metabolismo , Hormônio Adrenocorticotrópico/farmacologia , Processamento de Proteína Pós-Traducional/fisiologia , Sumoilação/fisiologia , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/ultraestrutura , Neoplasias do Córtex Suprarrenal/patologia , Hormônio Adrenocorticotrópico/administração & dosagem , Animais , Complexo de Carney/metabolismo , Linhagem Celular Tumoral , Colforsina/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Cicloeximida/farmacologia , Dactinomicina/farmacologia , Preparações de Ação Retardada , Dexametasona/análogos & derivados , Dexametasona/farmacologia , Feminino , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas de Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sumoilação/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/fisiologia , Zona Fasciculada/efeitos dos fármacos , Zona Fasciculada/metabolismo , Zona Glomerulosa/efeitos dos fármacos , Zona Glomerulosa/metabolismo , beta Catenina/deficiência , beta Catenina/genéticaRESUMO
CONTEXT: Despite its good prognosis, differentiated thyroid cancer (DTC) is characterized by high rates of disease persistence and recurrence. Estimation of long-term remission (excellent response) thanks to specific parameters could help to individualize the active surveillance schedule. OBJECTIVE: Evaluation of the ability of stimulated thyroglobulin (Tg) and Tg reduction index (TRI) to predict long-term remission in patients with DTC managed by thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND INTERVENTIONS: Observational retrospective study of 1093 patients treated for DTC between 1995 and 2010. Preablation stimulated thyroglobulin (presTg) was measured under thyroid hormone withdrawal just before RAI. Recombinant human TSH-stimulated thyroglobulin (sTg) was measured at first evaluation of the initial management 6 to 12 months after RAI. TRI was calculated based on pre-Tg and sTg. RESULTS: After univariate and multivariate analyses, lymph node invasion (N1, OR = 2.08; 95% CI, 1.19 to 3.64), presTg (OR = 4.04; 95% CI, 2.56 to 6.38), sTg (OR = 2.62; 95% CI, 2.05 to 3.34), and TRI (OR = 0.43; 95% CI, 0.21 to 0.88) were identified as independent prognostic factors influencing the rate of disease persistence or recurrence after the initial management. Receiver operating characteristic analysis identified presTg cutoff (<10 µg/L) to predict excellent response, with a negative predictive value of 94%, and validated for higher stages (T3/T4, N1). Furthermore, sTg <1 µg/L predicts excellent response. TRI >60% for the entire cohort and 62.5% for locally advanced disease (T3/T4, N1) was sensitive predictor for excellent response. CONCLUSION: This study identifies presTg, sTg, and TRI as highly sensitive predictors of excellent response in patients with DTC and subsequently disease-free status. The cutoff of such parameters is also adapted for patients with higher tumor stages (T3/T4, N1).
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Ablação por Radiofrequência , Tireoglobulina/sangue , Hormônios Tireóideos/sangue , Neoplasias da Glândula Tireoide/sangue , Tireoidectomia , Adulto , Protocolos Antineoplásicos , Terapia Combinada , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Indução de Remissão , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/terapia , Resultado do TratamentoRESUMO
INTRODUCTION: Insulin infusion is recommended during management of diabetic patients in critical care units to rapidly achieve glycaemic stability and reduce the mortality. The application of an easy-to-use standardized protocol, compatible with the workload is preferred. Glycaemic target must quickly be reached, therefore static algorithms should be replaced by dynamic ones. The dynamic algorithm seems closer to the physiological situation and appreciates insulin sensitivity. However, the protocol must meet both safety and efficiency requirements. Indeed, apprehension from hypoglycaemia is the main deadlock with the dynamic algorithms, thus their application remains limited. In contrary to the critical care units, to date, no prospective study evaluated a dynamic algorithm of insulin infusion in non-critically ill patients. AIM: This study primarily aimed to evaluate the efficacy of a dynamic algorithm of intravenous insulin therapy in non-critically-ill patients, and addressed its safety and feasibility in different departments of our university hospital. METHODS: A "before-after" study was conducted in five hospital departments (endocrinology and four "non-expert" units) comparing a dynamic algorithm (during the "after" period-P2) to the static protocol (the "before" period-P1). Static protocol is based on determining insulin infusion according to an instant blood glycaemia (BG) level at a given time. In the dynamic algorithm, insulin infusion rate is determined according to the rate of change of the BG (the previous and actual BG under a specific insulin infusion rate). Additionally, two distinct glycaemic targets were defined according to the patients' profile: 100-180 mg/dl (5.5-10 mmol/l) for vigorous patients and 140-220 mg/dl (7.8-12.2 mmol/l) for frail ones. Different BG measurements for each patient were collected and recorded in a specific database (e-CRF) in order to analyse the rates of hypo- and hyperglycaemia. A satisfaction survey was also performed. A study approval was obtained from the institutional revision board before starting the study. RESULTS: Over 8 months, 72 and 66 patients during P1 and P2 were respectively included. The dynamic algorithm was more efficient, with reduced time to control hyperglycaemia (P1 vs P2:8.3 vs 5.3 hours; HR: 2.02 [1.27; 3.21]; p<0.01), increased the number of in-target BG measurements (P1 vs P2: 37.0% vs 41.8%; p<0.05), and reduced the glycaemic variability related to each patient (P1 vs P2, %CV: 40.9 vs 38.2;p<0.05, Index Correlation Class:0.30 vs 0.14; p<0.05). In patients after the first event of hypoglycemia after having started the infusion, new events were lower (P1 vs P2: 19.4 vs 11.4; p<0.001) thanks to an earlier reaction to hypoglycaemia (8.3% during P1 vs 44.3% during P2; p = 0.004). With the dynamic algorithm, the percentage of recurrence of mild hypoglycaemia was significantly lower in frail patients (20.5% vs 10.2%; p<0.001), and in patients managed in the non-expert units (18 vs 7.1%, p<0.001). The %CV was significantly improved in frail patients (36.9%). Mean BG measurements for each patient/day were 5.5±1.1 during P1 and 6.0±1.6 during P2 (p = 0.6). The threat from hypoglycaemia and the difficulty in using dynamic algorithm are barriers for nurses' adherence. CONCLUSIONS: This dynamic algorithm for non-critically-ill patients is more efficient and safe than the static protocol, and adapted for frail patients and non-expert units.
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Algoritmos , Cuidados Críticos/normas , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Idoso , Estudos Controlados Antes e Depois , Estado Terminal , Feminino , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Infusões Intravenosas , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Amiodarone, a benzofuranic iodine-rich pan-anti-arrhythmic drug, induces amiodarone-induced thyrotoxicosis (AIT) in 7-15% of patients. AIT is a major issue due to its typical severity and resistance to anti-thyroid measures, and to its negative impact on cardiac status. Classically, AIT is either an iodine-induced thyrotoxicosis in patients with abnormal thyroid (type 1), or due to acute thyroiditis in a "healthy" thyroid (type 2). Determination of the type of AIT is a diagnostic dilemma, as characteristics of both types may be present in some patients. As it is the main etiological factor in AIT, it is recommended that amiodarone treatment should be stopped; however, it may be the only anti-arrhythmic option, needing to be either continued or re-introduced to improve cardiovascular survival. Recently, a few studies demonstrated that amiodarone could be continued or re-introduced in patients with history of type-2 AIT. However, in the other patients, it is recommended that amiodarone treatment be interrupted, to improve response to thioamides and to alleviate the risk of AIT recurrence. In such patients, thyroidectomy is recommended once AIT is under control, allowing safe re-introduction of amiodarone.
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Amiodarona/efeitos adversos , Antiarrítmicos , Tireotoxicose/induzido quimicamente , Amiodarona/uso terapêutico , Humanos , Recidiva , Fatores de Risco , Taquicardia/tratamento farmacológico , Tioamidas/uso terapêutico , Tireoidectomia , Tireotoxicose/classificação , Tireotoxicose/terapiaRESUMO
Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.
Assuntos
Córtex Suprarrenal/enzimologia , Subunidade RIbeta da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Transdução de Sinais , Córtex Suprarrenal/metabolismo , Animais , Diferenciação Celular , Subunidade RIbeta da Proteína Quinase Dependente de AMP Cíclico/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esteroides/metabolismo , Zona Fasciculada/citologia , Zona Fasciculada/enzimologia , Zona Fasciculada/metabolismo , Zona Glomerulosa/citologia , Zona Glomerulosa/enzimologia , Zona Glomerulosa/metabolismoRESUMO
Amiodarone, a benzofuranic iodine-rich pan antiarrhythmic drug, is frequently associated with thyroid dysfunction. This side effect is heterogeneous and unpredicted, motivating regular evaluation of thyroid function tests. In contrary to hypothyroidism, amiodarone-induced thyrotoxicosis (AIT) is a challenging situation owing to the risk of deterioration of the general and cardiac status of such debilitating patients. Classically, AIT is either an iodine-induced thyrotoxicosis in patients with an abnormal thyroid (type I), or due to a subacute thyroiditis on a "healthy" thyroid (type II). Even if many studies tried to better identify the types of AIT, the diagnostic dilemma of type of AIT could be present, and many patients are treated by an association of antithyroid drugs (useful for type I AIT) with corticoids (useful for type II AIT). Being the main etiological factor in AIT, amiodarone is supposed to be stopped, but it could remain the only anti-arrhythmic option that is needed to be either continued or reintroduced to improve the cardiovascular survival. Recently, many studies demonstrated that amiodarone could be continued or reintroduced in patients with history of type II AIT. Nevertheless, in the other patients, amiodarone maintenance complicates the therapeutic response to the antithyroid drugs and increases the risk of AIT recurrence. Thus, amiodarone therapy is preferred to be interrupted. In such patients, thyroid ablation is recommended once AIT is under control.
Assuntos
Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Tireotoxicose/induzido quimicamente , Tireotoxicose/terapia , Endocrinologia/métodos , Endocrinologia/normas , Humanos , Testes de Função Tireóidea , Tireoidectomia/estatística & dados numéricosAssuntos
Adenocarcinoma/secundário , Carcinoma Neuroendócrino/patologia , Neoplasia Endócrina Múltipla Tipo 2b/complicações , Neoplasias da Próstata/secundário , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adulto , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/genética , Mutação em Linhagem Germinativa , Humanos , Masculino , Neoplasia Endócrina Múltipla Tipo 2b/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2b/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Adulto JovemRESUMO
OBJECTIVES: Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival. DESIGN: Multicenter retrospective study by members of the French Society of Endocrinology. METHODS: Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment. RESULTS: The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success. DISCUSSION: Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.
Assuntos
Adenoma Hipofisário Secretor de ACT/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico , Carcinoma/tratamento farmacológico , Dacarbazina/análogos & derivados , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma Hipofisário Secretor de ACT/prevenção & controle , Adenoma Hipofisário Secretor de ACT/radioterapia , Adulto , Carcinoma/patologia , Carcinoma/prevenção & controle , Carcinoma/radioterapia , Quimiorradioterapia , Estudos de Coortes , Dacarbazina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , França , Humanos , Masculino , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/prevenção & controle , Neoplasias Hipofisárias/radioterapia , Padrões de Prática Médica , Prolactinoma/patologia , Prolactinoma/prevenção & controle , Prolactinoma/radioterapia , Estudos Retrospectivos , Análise de Sobrevida , Temozolomida , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiaçãoRESUMO
The risk of cancer is relatively higher in Graves' patients presenting simultaneously with thyroid nodules. Radioiodine (RAI) therapy recommended in high-risk differentiated thyroid carcinoma may be associated with worsening of a pre-existing Graves' orbitopathy (GO) or developing a new onset. The impact of RAI therapy in patients with differentiated thyroid cancer on the course of a pre-exisiting GO has not been specifically investigated.The aim of this study is to assess the influence of RAI treatment administered for differentiated thyroid cancer on the course of a pre-existing GO.This is a retrospective multicenter study including 35 patients from the University Hospital of Clermont-Ferrand (7 patients) and Lyon-Est (6 patients) in France and from a literature review published as case reports or studies (22 patients).Seven patients exhibited a worsened pre-existing GO after total thyroidectomy followed by RAI treatment for thyroid cancer. Older men, those who initially presented with a lower clinical score of GO before RAI therapy, received higher doses of I especially when prepared with recombinant thyroid-stimulating hormone, and/or not prepared with glucocorticoids during RAI are at a higher risk to worsen their GO.This study is the first and complete study collection. We describe worsening of GO in 20% of patients after RAI treatment for thyroid cancer and determine a pool of predictive factors.
Assuntos
Oftalmopatia de Graves/complicações , Radioisótopos do Iodo/uso terapêutico , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Adulto , Progressão da Doença , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates ß-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling.
Assuntos
Neoplasias das Glândulas Suprarrenais/etiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Via de Sinalização Wnt , Zona Fasciculada/metabolismo , Zona Glomerulosa/metabolismo , Animais , Carcinogênese , Diferenciação Celular , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Fosforilação , Zona Fasciculada/citologia , Zona Glomerulosa/citologia , beta Catenina/metabolismoRESUMO
Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely "functional," i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing's syndrome (hypercortisolism) or Conn's syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/ß-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/ß-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases.