RESUMO
BACKGROUND: Lugol solution is often administered to patients with Graves' disease before surgery. The aim is to reduce thyroid vascularization and surgical morbidity, but its real effectiveness remains controversial. The present study was designed to evaluate the effects of preoperative Lugol solution on thyroid vascularization and surgical morbidity in patients with Graves' disease undergoing total thyroidectomy. METHODS: Fifty-six patients undergoing total thyroidectomy for Graves' disease were randomly assigned to receive 7 days of Lugol treatment (Lugol+ group, 29) or no Lugol treatment (LS- group, 27) before surgery in this single-centre and single-blinded trial. Preoperative hormone and colour Doppler ultrasonographic data for assessing thyroid vascularization were collected 8 days before surgery (T0) and on the day of surgery (T1). The primary outcome was intraoperative and postoperative blood loss. Secondary outcomes included duration of surgery, thyroid function, morbidity, vascularization, and microvessel density at final pathology. RESULTS: No differences in demographic, preoperative hormone or ultrasonographic data were found between LS+ and LS- groups at T0. At T1, free tri-iodothyronine (FT3) and free thyroxine (FT4) levels were significantly reduced compared with T0 values in the LS+ group, whereas no such variation was observed in the LS- group. No differences between T0 and T1 were found for ultrasonographic vascularization in either group, nor did the histological findings differ. There were no significant differences between the LS+ and LS- groups concerning intraoperative/postoperative blood loss (median 80.5 versus 94 ml respectively), duration of surgery (75 min in both groups) or postoperative morbidity. CONCLUSION: Lugol solution significantly reduces FT3 and FT4 levels in patients undergoing surgery for Graves' disease, but does not decrease intraoperative/postoperative blood loss, thyroid vascularization, duration of surgery or postoperative morbidity. REGISTRATION NUMBER: NCT05784792 (https://www.clinicaltrials.gov).
Assuntos
Doença de Graves , Iodetos , Glândula Tireoide , Tireoidectomia , Humanos , Tireoidectomia/métodos , Doença de Graves/cirurgia , Feminino , Masculino , Adulto , Método Simples-Cego , Pessoa de Meia-Idade , Glândula Tireoide/cirurgia , Glândula Tireoide/irrigação sanguínea , Iodetos/administração & dosagem , Iodetos/uso terapêutico , Cuidados Pré-Operatórios/métodos , Perda Sanguínea Cirúrgica/prevenção & controle , Duração da Cirurgia , Ultrassonografia Doppler em Cores , Resultado do Tratamento , Tiroxina/uso terapêutico , Tiroxina/sangueRESUMO
Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue.
Assuntos
Receptores de Mineralocorticoides , Neoplasias da Glândula Tireoide , Animais , Humanos , Ratos , Aldosterona/farmacologia , Técnicas de Cultura de Células , Mineralocorticoides , Receptores de Mineralocorticoides/genética , Câncer Papilífero da TireoideRESUMO
BACKGROUND: Neuroendocrine neoplasms (NENs) represent a heterogeneous class of rare tumors with increasing incidence. They are characterized by the ability to secrete peptide hormones and biogenic amines but other reliable biomarkers are lacking, making diagnosis and identification of the primary site very challenging. While in some NENs, such as the pancreatic ones, next generation sequencing technologies allowed the identification of new molecular hallmarks, our knowledge of the molecular profile of NENs from other anatomical sites is still poor. METHODS: Starting from the concept that NENs from different organs may be clinically and genetically correlated, we applied a multi-omics approach by combining multigene panel testing, CGH-array, transcriptome and miRNome profiling and computational analyses, with the aim to highlight common molecular and functional signatures of gastroenteropancreatic (GEP)-NENs and medullary thyroid carcinomas (MTCs) that could aid diagnosis, prognosis and therapy. RESULTS: By comparing genomic and transcriptional profiles, ATM-dependent signaling emerged among the most significant pathways at multiple levels, involving gene variations and miRNA-mediated regulation, thus representing a novel putative druggable pathway in these cancer types. Moreover, a set of circulating miRNAs was also selected as possible diagnostic/prognostic biomarkers useful for clinical management of NENs. CONCLUSIONS: These findings depict a complex molecular and functional landscape of NENs, shedding light on novel therapeutic targets and disease biomarkers to be exploited.
Assuntos
Carcinoma Neuroendócrino , Neoplasias Gastrointestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Carcinoma Neuroendócrino/genética , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/genética , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/patologia , PrognósticoRESUMO
OBJECTIVE: Alemtuzumab-induced autoimmune thyroid events (AIATEs) are the most common adverse effects observed in relapsing-remitting multiple sclerosis (RRMS) patients. This study aims to explore the clinical and biochemical characteristics of such AIATEs, and to examine the risk factors for their occurrence, particularly for the worst clinical phenotype of fluctuating Graves' disease (GD). DESIGN, PATIENTS, MEASUREMENTS: We retrospectively analysed a real-life single-centre consecutive series of 57 RRMS patients treated with alemtuzumab whose clinical and biochemical parameters were collected before starting the treatment and then monthly during their follow-up. RESULTS: AIATEs developed in 39% of patients a mean 17 months ± 11 after the first cycle of alemtuzumab. The most common AIATEs were GD (64%), followed by Hashimoto's thyroiditis with hypothyroidism (23%), TSH-receptor-antibody (TRAb)-positive hypothyroidism (9%), and silent thyroiditis (4%). GD showed a fluctuating course in 57% of cases. Baseline positivity for anti-thyroperoxidase antibodies, and higher absolute titers of anti-thyroglobulin and anti-thyroperoxidase antibodies correlated significantly with the risk of developing AIATEs, but TRAb positivity did not. Higher TRAb titers at the time of GD being diagnosed correlated strongly with a greater risk of the fluctuating GD phenotype. On ROC curve analysis, we found that a cut-off of 7.3 IU/L could be used to predict the risk of developing a fluctuating GD, with a positive predictive value of 100%. CONCLUSIONS: TRAb levels measured with commercial automatic methods at the time of a patient being diagnosed with alemtuzumab-induced GD emerged as a novel biomarker for predicting a fluctuating disease phenotype, with an influence on subsequent therapeutic decisions and patients' follow-up.
Assuntos
Doença de Graves , Hipotireoidismo , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Tireoidite , Alemtuzumab/efeitos adversos , Doença de Graves/diagnóstico , Humanos , Hipotireoidismo/induzido quimicamente , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Estudos RetrospectivosRESUMO
OBJECTIVES: The reported prevalence of TSH-receptor (TSHR) autoantibodies (TRAb) in patients with chronic thyroiditis (CT) range from 0 to 48%. The objective was to study the prevalence of TRAb in patients with CT and hypothyroidism and to correlate it with gender, age, thyroid dimensions, TSH levels, and autoimmune diseases. METHODS: The study comprised 245 patients with CT and hypothyroidism (median age 42 years, 193 females, 52 males) and 123 Italian healthy subjects matched for sex and age as controls. TRAb were tested with ELISA using a >2.5 IU/L cut off for positivity. TSHR blocking (TBAb) and TSHR stimulating autoantibodies (TSAb) were measured in 12 TRAb-positive patients using bioassays with Chinese hamster ovary (CHO) cells expressing wild-type or R255D-mutated TSHR. RESULTS: TRAb positivity was found in 32/245 (13.1%) patients and significantly correlated (p<0.05) with TSH levels. TRAb positivity was significantly higher in males vs. females (p=0.034), in females 16-45 years of age vs. >45 years of age (p<0.05) and in patients with reduced vs. normal/increased thyroid dimensions (p<0.05). Linear regression analysis showed a correlation between TRAb concentrations with age (p<0.05) and TRAb concentrations with TSH (p<0.01). In bioassay with TSHR-R255D all 12 patients tested were TBAb-positive while 33% were also TSAb-positive suggesting the presence of a mixture of TRAbs with different biological activities in some patients. CONCLUSIONS: TRAb have been found in patients with CT and hypothyroidism. A mixture of TBAb and TSAb was found in some patients and this may contribute to the pathogenesis of thyroid dysfunction during the course of the disease.
Assuntos
Hipotireoidismo , Tireoidite , Adulto , Animais , Autoanticorpos , Células CHO , Cricetinae , Cricetulus , Feminino , Doença de Hashimoto , Humanos , Masculino , Receptores da Tireotropina , TireotropinaRESUMO
Pheochromocytoma (Pheo) is a tumor derived from chromaffin cells. It can be studied using 18F-dihydroxyphenylalanine (DOPA)-positron emission tomography (PET) due to its overexpression of L-type amino acid transporters (LAT1 and LAT2). The oncogenic pathways involved are still poorly understood. This study examined the relationship between 18F-DOPA-PET uptake and LAT1 expression, and we explored the role of miR-375 and putative target genes. A consecutive series of 58 Pheo patients were retrospectively analyzed, performing 18F-DOPA-PET in 32/58 patients. Real-time quantitative PCR was used to assess the expression of LAT1, LAT2, phenylethanolamine N-methyltransferase (PNMT), miR-375, and the major components of the Hippo and Wingless/Integrated pathways. Principal germline mutations associated with hereditary Pheo were also studied. Pheo tissues had significantly higher LAT1, LAT2, and PNMT mRNA levels than normal adrenal tissues. MiR-375 was strongly overexpressed. Yes-associated protein 1 and tankyrase 1 were upregulated, while beta-catenin, axin2, monocarboxylate transporter 8, and Frizzled 8 were downregulated. A positive relationship was found between 18F-DOPA-PET SUV mean and LAT1 gene expression and for 24 h-urinary norepinephrine and LAT1. This is the first experimental evidence of 18F-DOPA uptake correlating with LAT1 overexpression. We also demonstrated miR-375 overexpression and downregulated (Wnt) signaling and identified the Hippo pathway as a new potentially oncogenic feature of Pheo.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Transportador 1 de Aminoácidos Neutros Grandes/genética , MicroRNAs/genética , Feocromocitoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Di-Hidroxifenilalanina/administração & dosagem , Di-Hidroxifenilalanina/análogos & derivados , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/urina , Feniletanolamina N-Metiltransferase/genética , Feocromocitoma/genética , Feocromocitoma/patologia , Feocromocitoma/urina , Estudos Retrospectivos , Carga Tumoral , Regulação para Cima , Via de Sinalização WntRESUMO
PURPOSE OF REVIEW: MicroRNAs emerged as pivotal regulators of cell differentiation, growth, and cell death, suggesting their implication in tumorigenesis and prognosis of cancer. In the last decades, knowledge about the alterations of microRNAs in medullary thyroid cancer (MTC) is increasing. In this review, we try to summarize the most relevant findings regarding microRNA dysregulation in MTC. RECENT FINDINGS: A literature analysis was performed in MEDLINE for studies published up to August 2020. Comprehensively, at least 27 different microRNAs have been investigated in MTC showing evidence for overexpression or underexpression in comparison with normal thyroid tissue samples, healthy blood controls, or primary tumor site or hereditary form of MTC. We highlight the evidence in favor of a possible use of microRNAs for diagnosis, prognosis and treatment in MTC and their role in MTC pathogenesis. SUMMARY: This review reveals the emerging complexity of the molecular genetic and epigenetic panorama in MTC. Further studies are needed to confirm and refine the findings on microRNA expression pattern in MTC. Thus, in the future, microRNA analysis could enter in clinical practice and may pave the way to new risk-stratification tools and novel therapeutic approaches for MTC.
Assuntos
Carcinoma Neuroendócrino/genética , MicroRNAs/genética , Neoplasias da Glândula Tireoide/genética , Carcinogênese , Epigênese Genética , Humanos , MicroRNAs/biossíntese , PrognósticoRESUMO
BACKGROUND: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare disease caused by CDC73 germline mutations, with familial primary hyperparathyroidism (pHPT), ossifying jaw tumors, genito-urinary neoplasms. The present study was aimed at determining the long-term postoperative outcome of parathyroidectomy in HPT-JT. METHODS: A retrospective analysis of a single-center series of 20 patients from five unrelated HPT-JT families undergoing parathyroid surgery was performed. RESULTS: Pathology confirmed a single-gland involvement in 95% of cases at onset. Parathyroid carcinoma occurred in three patients undergoing en-bloc parathyroidectomy and thyroid lobectomy: parathyroid benign lesions in 17 patients undergoing subtotal parathyroidectomy for evident multiglandular involvement (n = 1) or selective parathyroidectomy for single-gland involvement (n = 16), during bilateral (n = 13) or targeted unilateral neck exploration (n = 7). At a median overall follow-up of 16 years (range 2.5-42), patients with parathyroid carcinoma had a persistent/recurrent disease in 66.6%; patients with benign lesions had recurrent pHPT in 23.5% after a prolonged disease-free period; recurrent benign pHPT occurred slightly more often in cases of discordant preoperative localization (60% vs 9%; p = 0.06). CONCLUSION: pHPT in HPT-JT is generally characterized by a benign and single-gland involvement, with a relatively increased risk of malignancy (15%). Parathyroid carcinoma needs extensive surgery because of high risk of permanent/recurrent disease (66.6%). In benign involvement, targeted unilateral exploration with selective parathyroidectomy may be effective in cases of concordant single-gland localization at preoperative localization imaging techniques. Bilateral neck exploration with subtotal parathyroidectomy might be preferred in cases of negative or discordant preoperative localization, because of the increased risk of multiglandular involvement and long-term recurrences (23.5%).
Assuntos
Mutação em Linhagem Germinativa , Hiperparatireoidismo Primário/cirurgia , Neoplasias Maxilomandibulares/cirurgia , Neoplasias das Paratireoides/cirurgia , Paratireoidectomia , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Hiperparatireoidismo Primário/genética , Neoplasias Maxilomandibulares/genética , Masculino , Pessoa de Meia-Idade , Neoplasias das Paratireoides/genética , Doenças Raras/genética , Doenças Raras/cirurgia , Estudos Retrospectivos , Adulto JovemRESUMO
Autoimmune Addison's disease (AAD) is a rare condition occurring either in isolation or associated with other autoimmune diseases as part of an autoimmune polyglandular syndrome (APS) type 1, 2 or 4. Multiple endocrine neoplasia (MEN) type 1, 2 or 4 is a hereditary autosomal dominant cancer syndrome. Medullary thyroid carcinoma and pheochromocytoma are neoplasms common to MEN-2a and MEN-2b. We describe a unique, complex case of a man resulted affected by both APS-2 and MEN-2a. The patient developed Hashimoto's thyroiditis, diabetes mellitus type 1 and AAD, despite testing negative for adrenal cortex autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21-OHAb). Moreover, he had also a family history for MEN-2a and he first developed medullay thyroid cancer, then bilateral pheochromocytoma on the adrenal substrate of an AAD. On adrenal histology we found complete bilateral cortical atrophy in the presence of a lymphocytic infiltration and fibrosis, confirming an ACA and 21-OHAb-negative AAD. This datum is the first documented in a living individual and confirms that the absence of autoantibodies is not incompatible with an autoimmune disease and confirms that AAD is a cell-mediated autoimmune disease limited to the adrenal cortex and sparing medullary. In the light of a literature review concerning the association between APS and MEN, this is the first proven case to be reported in humans. Finally, our findings suggest that adrenal medullary tumor can develop even on an adrenal gland with cortical atrophy due to autoimmune adrenalitis.
Assuntos
Neoplasias das Glândulas Suprarrenais/complicações , Neoplasia Endócrina Múltipla/complicações , Feocromocitoma/complicações , Poliendocrinopatias Autoimunes/complicações , Neoplasias das Glândulas Suprarrenais/imunologia , Adulto , Humanos , Masculino , Neoplasia Endócrina Múltipla/imunologia , Linhagem , Feocromocitoma/imunologia , Poliendocrinopatias Autoimunes/imunologiaRESUMO
BACKGROUND: The improvement in outcome of sporadic medullary thyroid carcinoma (MTC) during the last decades remains controversial, even if a trend toward a better prognosis has been recently proposed. This study was aimed to determine the time trend cure and survival rates in sporadic MTC according to the use of systematic preoperative calcitonin screening. METHODS: Retrospective analysis of 178 sporadic MTC patients operated between 1980 and 2017 was performed. The impact of prognostic factors on cure and survival following the introduction of routine preoperative calcitonin screening in 2001 was evaluated according to the year of surgery. RESULTS: Since 2001, a significant decline of node-positive tumors (from 56.1 to 34.7%) and advanced stage at diagnosis (stage III/IV from 56.1 to 34.7%) occurred, with a concomitant significant increase in cure rate (64.5% vs 38.6%; p = 0.0012) and survival (p < 0.05). At univariate analysis, the cure was achieved more frequently in more recently operated patients (64.5% vs 38.6%; p = 0.0012), in disease staging I/II (86.5% vs 13.5%; p < 0.0001), in patients undergoing preoperative calcitonin screening (63.8% vs 23.5%; p < 0.0001) and in the absence of lymph node metastases (86.5% vs 13.5%; p < 0.0001). At multivariate analysis, only preoperative calcitonin screening and stage at diagnosis turned out to be significant independent prognostic factors for cure and survival. CONCLUSION: The outcome of sporadic MTC improved in the new millennium; diagnosis was achieved earlier, at a less advanced stage. Routine preoperative calcitonin screening may have contributed to improve cure and survival rates.
Assuntos
Calcitonina/sangue , Carcinoma Neuroendócrino/sangue , Carcinoma Neuroendócrino/cirurgia , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/cirurgia , Biomarcadores Tumorais/sangue , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/patologia , TireoidectomiaRESUMO
BACKGROUND: Curcumin has numerous properties and is used in many preclinical conditions, including cancer. It has low bioavailability, while its derivative EF24 shows enhanced solubility. However, its effects have never been explored in adrenocortical tumor cell models. The efficacy of EF24 alone or combined with mitotane (reference drug for adrenocortical cancer) was evaluated in two adrenocortical tumor cell lines, SW13 and H295R. METHOD AND RESULTS: EF24 reduced cell viability with an IC50 (half maximal inhibitory concentration) of 6.5 ± 2.4 µM and 4.9 ± 2.8 µM for SW13 and H295R cells, respectively. Combination index (EF24 associated with mitotane) suggested an additivity effect in both cell lines. Cell cycle analysis revealed an increase in subG0/G1 phase, while motility assay showed a decrease in migratory cell capacity, and similarly, clonogenic assay indicated that EF24 could reduce colony numbers. Furthermore, Wnt/ß-catenin, NF-κB, MAPK, and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with EF24 alone or combined with mitotane. In addition, intracellular reactive oxygen species levels increased in both cell lines. CONCLUSION: This work analyzed EF24 in adrenocortical tumor cell lines for the first time. These results suggest that EF24 could potentially impact on adrenocortical tumors, laying the foundation for further research in animal models.
Assuntos
Antineoplásicos/farmacologia , Compostos de Benzilideno/farmacologia , Curcumina/química , Curcumina/farmacologia , Mitotano/farmacologia , Piperidonas/farmacologia , Neoplasias do Córtex Suprarrenal , Animais , Antineoplásicos/química , Compostos de Benzilideno/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/análogos & derivados , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Camundongos , Estrutura Molecular , Piperidonas/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare C cells-derived tumor, with a hardly predictable long-term prognosis. This study was aimed to evaluate the predictive factors of cure and survival after surgery for MTC in a monocentric series. METHODS: A retrospective analysis of the long-term outcomes was assessed in 255 MTC patients operated between 1980 and 2015 at Padua University hospital. RESULTS: Sporadic MTC occurred in 65.1% and hereditary MTC in 34.9% of patients. At a median follow-up of 93 months (range 7-430), the cure rate was 56.8%. The overall 10-year survival was 84.4%, and MTC-related death rate was 15.3%. Patients who died because of MTC had a median age of 61 years (range 21-84) and were at stages III-IV in all cases; deaths occurred in 18% of sporadic MTC, 6% of MEN2a and 66.7% of MEN2b patients. None of the patients at stages I-II died because of the disease, but 17.7% had persistent/recurrent disease. Based on univariate analysis, age, gender, genetic variant, extent and year of surgery, tumor size, lymph-nodal metastases and tumor stage significantly affected cure and survival rates. At multivariate analysis, only patient- and tumor-related features (age, lymph-nodal status and stage) remained significant independent prognostic factors. CONCLUSIONS: Radical surgery is the only chance of definitive cure in MTC, but it is possible only at early stage; in advanced stages, even extensive surgery could not grant cure and prolonged survival. Stage, nodal metastases and age remain the main predictive factors for cure and survival.
Assuntos
Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/cirurgia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/cirurgia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Carcinoma Medular/congênito , Carcinoma Medular/mortalidade , Carcinoma Medular/cirurgia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/mortalidade , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores Sexuais , Taxa de Sobrevida , Adulto JovemRESUMO
New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies. Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells), 3 cell cultures of primary adrenocortical metastases (from lung cancer), and 4 primary adrenocortical tumor cell cultures. We also tested reversan, which is a P-gp inhibitor (a fundamental efflux pump that can extrude drugs), and we measured AK expression levels in 66 adrenocortical tumor tissue samples. Biomolecular and cellular tests were performed (such as MTT, thymidine assay, Wright's staining, cell cycle and apoptosis analysis, Western blot, qRT-PCR, and mutation analysis). Our results are the first to document AK overexpression in adrenocortical carcinoma as well as in H295R and SW13 cell lines, thus proving the efficacy of AKI against adrenal metastases and in the SW13 cancer cell model. We also demonstrated that reversan and AKI Vx-680 are useless in the H295R cell model, and therefore should not be considered as potential treatments for ACC. Serine/threonine AK inhibition, essentially with VX-680, could be a promising, specific therapeutic tool for eradicating metastases in adrenocortical tissue.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Adolescente , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/metabolismo , Adulto , Idoso , Aurora Quinases/genética , Aurora Quinases/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Células Tumorais Cultivadas , Adulto JovemRESUMO
Calcitonin (CT) is currently the most sensitive serological marker of C-cell disease [medullary thyroid carcinoma (MTC) and C-cell hyperplasia]. Starting with a report on a case that occurred at our institution, this review focuses on trying to explain the reasons behind the poor specificity and sensitivity of the various CT immunoassays. A 15-year-old patient was referred to our institution in May 2014 for moderately elevated CT levels. Thyroid ultrasonography (US) documented a colloidal goiter. Secondary causes of the hypercalcitoninemia (hyperCT) were ruled out. The mismatch between the clinical picture and the laboratory results prompted us to search for other reasons for the patient's high CT levels, so we applied the heterophilic blocking tube (HBT) procedure to the patient's sera before the CT assay. Using this pretreatment step, his serum CT concentration dropped to <1 ng/L, as measured at the same laboratory. Measuring plasma CT has an important role in screening for C-cell disease, but moderately elevated serum CT levels need to be placed in their clinical context, bearing in mind all the secondary causes of C-cell hyperplasia and the possibility of laboratory interference, before exposing patients to the risks and costs of further tests.
Assuntos
Calcitonina/sangue , Imunoensaio , Medições Luminescentes , Adolescente , Humanos , MasculinoRESUMO
BACKGROUND: Risk stratification in patients with papillary thyroid carcinoma (PTC) currently relies on postoperative parameters. Testing for BRAF mutations preoperatively may serve as a novel tool for identifying PTC patients at risk of persistence/recurrence after surgery. METHODS: The study involved 185 consecutive patients with a histological diagnosis of PTC and BRAF analysis performed on thyroid fine-needle aspiration biopsy (FNAB). We assessed BRAF status in FNAB specimens obtained before thyroidectomy for PTC, and examined its association with the clinicopathological characteristics identified postoperatively, and with outcome after a mean 55±15 months of follow-up. RESULTS: One hundred and fifteen of 185 (62%) PTCs carried a BRAF mutation. Univariate analysis showed that BRAF status correlated with the histological variant of PTC, cancer size, and stage at diagnosis, but not with gender, age, multifocality, or lymph node involvement. BRAF-mutated cases had a higher prevalence of persistent/recurrent disease by the end of the follow-up (11% vs. 8%), but this difference was not statistically significant. The Kaplan-Meier curve shows that among the patients with persistent/recurrent disease, BRAF-mutated patients needed a second treatment earlier than patients with BRAF wild-type, although the difference did not completely reach the statistical significance. CONCLUSIONS: Our study confirmed that preoperatively-identified BRAF mutation are associated with certain pathological features of PTC that correlate with prognosis. We speculate that it has a role in identifying PTCs that would generally be considered low-risk but that may reveal an aggressive behavior during their follow-up.
Assuntos
Carcinoma/diagnóstico , Carcinoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Tireoidectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Carcinoma/patologia , Carcinoma/cirurgia , Carcinoma Papilar , Análise Mutacional de DNA , DNA de Neoplasias/análise , DNA de Neoplasias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Adulto JovemRESUMO
PURPOSE: This survey aimed to assess iodine status in a female population at different ages, also investigating their eating habits. METHODS: We measured urinary iodine concentrations (UIC) in: 634 females at puberty and 361 fertile women in 246 of whom were considered also their children (134 daughters and 120 sons). All subjects completed a food frequency questionnaire. RESULTS: Median UIC decreased from childhood to adulthood (median UIC 107, 77 and 55 µg/l in the young girls, females at puberty and fertile women, respectively). Though using iodized salt improved iodine status in all groups, a significantly higher UIC was only noted in females at puberty. Milk consumption significantly increased UIC at all ages. In mother-child (both daughters and sons) pairs, the children's median UIC was nearly twice as high as their mothers' (UIC 115 vs. 57 µg/l). Milk consumption varied significantly: 56% of the mothers and 76% of their children drank milk regularly. The children (both daughters and sons) and mothers who drank milk had UIC ≥100 µg/l in 59 and 34% of cases, respectively, among the pairs who did not drink milk, 44% of the children and 19% of the mothers had UIC ≥100 µg/l. On statistical regression, 3.6% of the variability in the children's UIC depended on that of their mothers. CONCLUSIONS: Dietary iodine status declines from childhood to adulthood in females due to different eating habits. A mild iodine deficiency emerged in women of child-bearing age that could have consequences during pregnancy and lactation.
Assuntos
Alimentos Fortificados , Iodo/urina , Doenças da Glândula Tireoide/epidemiologia , Doenças da Glândula Tireoide/urina , Adolescente , Adulto , Animais , Criança , Estudos Transversais , Feminino , Humanos , Iodo/administração & dosagem , Iodo/deficiência , Itália/epidemiologia , Masculino , Leite , Atividade Motora , Estado Nutricional , Cloreto de Sódio na Dieta/administração & dosagem , Adulto JovemRESUMO
Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer-related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto-oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine-protein kinase B-Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET-mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen-activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Imidazóis/uso terapêutico , Piridinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Triazinas/uso terapêutico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Calcitonina/genética , Calcitonina/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Concentração Inibidora 50 , Modelos Biológicos , Proto-Oncogene Mas , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Triazinas/farmacologiaRESUMO
Mitogen-activated protein kinase (MAPK) pathway is often deregulated in adrenocortical tumors (ACT) but with no concrete data confirming alteration rate. The objective of this study was to evaluate genetic alterations in key components of MAPK pathway. We found one BRAF mutation (p.V600E) and four HRAS silent mutations. No alteration was found in NRAS, KRAS, EGFR genes. The patient carrying BRAF mutation was further characterized by investigating his biomolecular and clinico-pathological findings. Therefore, even if MAPK signaling is activated in ACT, our results suggest that genetic alterations do not seem to represent a frequent mechanism of ACT tumorigenesis.
Assuntos
Neoplasias do Córtex Suprarrenal/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Primary hyperparathyroidism (PHPT) is often found on routine blood tests, at a relatively asymptomatic stage. However many studies suggest different systemic effects related to PHPT, which could be enhanced by an abnormal cortisol release due to chronic stress of hyperparathyroidism. Being PHPT frequently found in the 6(th) to 7(th) decade of life, a careful and multifaceted approach should be taken. CASE PRESENTATION: We report the case of an elderly patient with symptomatic PHPT and incidental pulmonary embolism. He was treated with hydration, zoledronic acid, cinacalcet and high-dose unfractionated heparin. Parathyroid surgery was successfully performed, but patient's conditions suddenly worsened because of a transient thyrotoxicosis, probably induced by a previous exposure to iodine load and/or thyroid surgical manipulation. A short-term treatment with beta-blockers was introduced for symptomatic relief. The patient also presented a transient hypercortisolism with elevated ACTH, likely due to stress related not only to aging and hospitalization but also to PHPT, resolved only four months after parathyroid surgery. CONCLUSION: Chronic hyperparathyroidism has been linked with increased all-cause mortality. A functional chronic hypercortisolism could be established, enhancing PHPT related disorders. Only parathyroid surgery has been demonstrated to cure PHPT and complications related, showing similar outcome between older and younger patients. However, the management of post-operative period should be more careful in fragile patients. In particular, the early diagnosis and treatment of a transient post-operative thyrotoxicosis could improve recovery. Due to the increase in prevalence and the evidence of many related complications even in asymptomatic PHPT, expert opinion-based guidelines for surgical treatment of PHPT should be developed especially for elderly patients.
Assuntos
Síndrome de Cushing/etiologia , Hipercalcemia/etiologia , Hiperparatireoidismo Primário/complicações , Hipertireoidismo/etiologia , Paratireoidectomia , Idoso de 80 Anos ou mais , Conservadores da Densidade Óssea/uso terapêutico , Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Difosfonatos/uso terapêutico , Hidratação , Humanos , Hiperparatireoidismo Primário/terapia , Imidazóis/uso terapêutico , Masculino , Ácido ZoledrônicoRESUMO
BACKGROUND: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. METHODS: This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. FINDINGS: 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. INTERPRETATION: The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.