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1.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670622

RESUMEN

The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1(MEN1), while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61, CTGF, and WNT5A, and this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Glándulas Paratiroides/metabolismo , Neoplasias de las Paratiroides/genética , Receptores Sensibles al Calcio/genética , Factores de Transcripción/genética , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Amidas/farmacología , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Neoplasias de las Paratiroides/metabolismo , Fenetilaminas/farmacología , Propilaminas/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Piridinas/farmacología , Interferencia de ARN , Receptores Sensibles al Calcio/agonistas , Receptores Sensibles al Calcio/metabolismo , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Señalizadoras YAP , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo
2.
Front Endocrinol (Lausanne) ; 14: 1205785, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37361526

RESUMEN

We report the case of a paediatric female patient affected by Bannayan-Riley-Ruvalcaba syndrome (BRRS) and congenital hypothyroidism (CH) with homozygous mutation of the TPO gene. She underwent total thyroidectomy at the age of seven years because of the development of a multinodular goiter. BRRS patients present an increased risk of benign and malignant thyroid disease since childhood because of inactivating mutation of PTEN, an onco-suppressor gene. Instead, homozygous mutations in the TPO gene can be associated with severe forms of hypothyroidism with goiter; previous studies have described cases of follicular and papillary thyroid cancer in CH patients with TPO mutation despite a perfectly controlled thyroid function with Levothyroxine therapy. To our knowledge, this is the first case that describes the possible synergic role of coexisting mutation of both TPO and PTEN in the development of multinodular goiter underlining the importance of a tailored surveillance program in these patients, especially during childhood.


Asunto(s)
Hipotiroidismo Congénito , Bocio , Síndrome de Hamartoma Múltiple , Neoplasias de la Tiroides , Humanos , Niño , Femenino , Síndrome de Hamartoma Múltiple/complicaciones , Síndrome de Hamartoma Múltiple/genética , Síndrome de Hamartoma Múltiple/patología , Hipotiroidismo Congénito/complicaciones , Hipotiroidismo Congénito/genética , Mutación , Bocio/complicaciones , Bocio/genética , Bocio/cirugía , Fosfohidrolasa PTEN/genética
3.
Pediatr Surg Int ; 28(6): 609-14, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22543510

RESUMEN

PURPOSE: The optimal treatment for pediatric Graves' disease (GD) is controversial. Antithyroid drugs are often used initially, but they are associated with a high failure rate. Therefore alternative therapies have become important. In the present study, we analyze our institution's experience regarding the safety and efficacy of thyroid surgery among pediatric patients with GD. METHODS: This is a retrospective chart review of 27 pediatric patients (age ≤ 18 years) with GD who underwent thyroid surgery between 1991 and 2009 at a single academic Institution. We recorded preoperative, intraoperative, and short-term postoperative data. RESULTS: All 27 patients were initially treated with thionamides. The high rate of hyperthyroidism relapse after discontinuation of medical treatment, age < 5 years, adverse reaction to medical therapy, severe ophthalmopathy, and patient preference justified the final decision to proceed with surgery as definitive therapy. All patients underwent total thyroidectomy. We had no mortality; surgical complications were rare: 4 (14.8 %) cases of transient hypocalcemia, 1 (3.7 %) of permanent hypocalcemia, 3 (11.1 %) of transient RLN neuropraxia, and 2 (7 %) of keloid scar. No bleeding, permanent RLN palsy or relapse hyperthyroidism were reported. CONCLUSIONS: Surgical therapy for pediatric GD performed by experienced thyroid surgeons is a safe, definitive and cost-effective treatment.


Asunto(s)
Enfermedad de Graves/cirugía , Adolescente , Niño , Preescolar , Femenino , Enfermedad de Graves/diagnóstico , Humanos , Lactante , Masculino , Estudios Retrospectivos , Resultado del Tratamiento
4.
Endocrine ; 75(3): 823-828, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34755316

RESUMEN

INTRODUCTION: Hürthle cells are modified follicular thyroid cells, whose development and proliferation have been related to different stimuli inducing cellular stress. Most thyroid aspirates containing Hürthle cells are classified as indeterminate, although the specific risk of malignancy for this subtype of atypia remains unclear. The aim of our study was to assess if the presence of Hürthle cells in indeterminate thyroid nodules correlates with the risk of malignancy. We further evaluated if this risk can be modified by the presence of an underlying Hashimoto's thyroiditis. MATERIALS AND METHODS: We retrospectively analyzed all indeterminate thyroid nodules that were surgically treated at our institution between January 2010 and March 2019. For each nodule, we inferred the presence of Hürthle cells in the cytological report. Cytological findings were then correlated with histological reports. RESULTS: 354 indeterminate thyroid nodules were included in the study. The rate of malignancy resulted significantly lower in nodules exhibiting Hürthle cells compared to those negative for this cellular pattern (11.4% vs 22.5%, p = 0.01). Although there was no difference in the rate of malignancy in the whole population according to the presence or absence of Hashimoto's thyroiditis (21.5 vs 18.5%, p = 0.63), the significantly lower prevalence of malignant lesions in nodules with Hürthle cells was confirmed only in the presence of a histologically documented Hashimoto's thyroiditis (6.2% vs 32%, p = 0.005). CONCLUSIONS: The finding of Hürthle cells in indeterminate thyroid nodules is associated with a low risk of malignancy in patients with an underlying Hashimoto's thyroiditis. The clinical management of these lesions may therefore be more conservative.


Asunto(s)
Enfermedad de Hashimoto , Neoplasias de la Tiroides , Nódulo Tiroideo , Tiroiditis Autoinmune , Enfermedad de Hashimoto/patología , Humanos , Células Oxífilas/patología , Estudios Retrospectivos , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/patología , Tiroiditis Autoinmune/complicaciones , Tiroiditis Autoinmune/epidemiología
5.
Int J Endocrinol ; 2021: 8820364, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33688344

RESUMEN

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system changed the age cutoff for risk stratification of differentiated thyroid carcinoma (DTC), downgrading patients between 45 and 54 years to stage I or II. The aim of our study was to assess cancer-specific survival (CSS) in patients aged 45-54 years, in order to document the prognostic capability of the last edition of the staging system. METHODS: We retrospectively reviewed the medical records of 172 patients that from January 1st, 2005, to May 31st, 2017, were diagnosed at our institution with DTC when aged 45-54 years. We restaged patients according to the 8th edition of the staging system and estimated CSS. RESULTS: 101 out of 172 patients (58.7%) were reallocated to a lower stage. Of the 101 downstaged patients, 88 (88.9%) showed a high or intermediate American Thyroid Association (ATA) risk of recurrence. We recorded no cancer-specific deaths. CONCLUSIONS: Risk of cancer-specific mortality in patients aged 45-54 years with DTC is low, supporting the prognostic capability of the 8th edition of the staging system. However, we recommend to consider carefully the significant proportion of patients at intermediate or high risk of recurrence in this group of patients.

6.
Endocr Relat Cancer ; 28(1): 53-63, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33151903

RESUMEN

Tumors of the parathyroid glands are highly vascularized and display a microRNA (miRNA) profile divergent from normal parathyroid glands (PaNs). Angiogenic miRNAs, namely miR-126-3p, miR-126-5p, and miR-296-5p, have been found downregulated in parathyroid tumors. Here, we show that miR-126-3p expression levels are reduced in parathyroid adenomas (PAds; n = 12) compared with PaNs (n = 4). In situ hybridization (ISH) of miR-126-3p and miR-296-5p in 10 PAds show that miR-126-3p is expressed by endothelial cells lining the walls of great vessels and by cells within the thin stroma surrounding acinar structures. At variance, miR-296-5p was detectable in most PAd epithelial cells. Combining ISH for miR-126-3p with immunohistochemistry for the endothelial and mesenchymal markers CD34, CD31 and α-smooth muscle actin (αSMA), we could identify that miR-126-3p is localized in the αSMA-positive thin stroma. Further, miR-126-3p-expressing cells are enriched in the CD34-positive stromal cells surrounding epithelial cell acinar structures, a cellular pattern consistent with tumor-associated myofibroblasts (TAMs). In line with this, CD34-positive cells, sorted by FACS from PAds tissues, express miR-126-3p at higher levels than CD34-negative cells, suggesting that miR-126-3p downregulation promotes the endothelial-to-αSMA+ mesenchymal transition. In human mesenchymal stem cells derived from bone marrow (hBM-MSCs), a model of TAMs, the co-culture with PAds-derived cells for 5 days decreases miR-126-3p, while it increases VEGFA expression. At variance, adrenomedullin (ADM) expression is unaffected. Finally, overexpression of the miR-126-3p mimic in both hBM-MSCs and PAds-derived explants downregulates VEGFA expression levels. In conclusion, miR-126-3p is expressed by both endothelial cells and TAMs in PAds, and its downregulation promotes neoangiogenesis, possibly through VEGFA overexpression.


Asunto(s)
MicroARNs/metabolismo , Neoplasias de las Paratiroides/irrigación sanguínea , Anciano , Femenino , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neoplasias de las Paratiroides/genética , Neoplasias de las Paratiroides/metabolismo
7.
Hepatogastroenterology ; 50(54): 1948-52, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-14696439

RESUMEN

BACKGROUND/AIMS: The impact of histologic type and surgical strategy on survival of patients with cancer of the esophagogastric junction is debated. Thus, we evaluated the relationship between cancer histologic type (adenocarcinoma vs. squamous cell carcinoma) on long-term survival and the results of two different surgical techniques on outcome. METHODOLOGY: Two hundred and one patients with neoplasm of the esophagogastric junction were prospectively observed, and 133 patients (66%) underwent operation with curative intent. The results of two resective techniques, total gastrectomy with a thoraco-abdominal approach and total gastrectomy with a trans-hiatal approach were also compared in a subgroup with Siewert's type II and III cancer. RESULTS: Seventy-seven patients had an adenocarcinoma and 56 a squamous cell carcinoma. The 5-year proportion of survival was 35% in the adenocarcinoma group versus 40% in the squamous group (log-rank = 0.92), and the mean length of survival was 35 +/- 3 months and 34 +/- 5 months, respectively. The overall incidence of postoperative morbidity and the length of hospital stay were both significantly lower in the trans-hiatal group than in the thoraco-abdominal group (31% vs. 51%; p = 0.04; and 15.6 days vs. 23.2 days; p = 0.02 respectively), while the 5-year patient survival was 37% thoraco-abdominal approach and 42% in the trans-hiatal approach (log-rank = 0.62). CONCLUSIONS: In the present population, histologic type of the esophagogastric cancer was not a determinant factor for long-term survival. The transhiatal approach resulted in a better postoperative outcome without compromising surgical radicality and patient survival.


Asunto(s)
Adenocarcinoma/cirugía , Carcinoma de Células Escamosas/cirugía , Neoplasias Esofágicas/cirugía , Unión Esofagogástrica/cirugía , Gastrectomía/métodos , Neoplasias Gástricas/cirugía , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Anastomosis en-Y de Roux , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Femenino , Humanos , Italia , Tiempo de Internación , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tasa de Supervivencia
8.
Int J Surg Pathol ; 20(5): 500-6, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22180528

RESUMEN

This study reports a case of plasma cell granuloma of the thyroid gland in a 47-year-old woman, presenting with a right subhyoid mass and a previous diagnosis of Hashimoto thyroiditis dating back to 1988, which was made on a subtotal thyroidectomy. Plasma cell granuloma preferentially involves the lung, with only 18 cases of thyroid gland involvement having been reported to date in the English literature. Thyroid plasma cell granuloma preferentially affects women and classically shows a prominent plasma cell infiltrate embedded in a variable degree of fibrous stroma: only 2 of the reported cases exhibited the morphologic features of inflammatory myofibroblastic tumor. These morphologic features may raise problems in the differential diagnosis with other plasma cell-rich disorders, including infectious diseases and auto(dys)immune conditions, including the recently described "IgG4-related sclerosing disease." In view of these considerations, a contemporary diagnostic approach to thyroid plasma cell granuloma is therefore discussed here.


Asunto(s)
Granuloma de Células Plasmáticas/diagnóstico , Células Plasmáticas/patología , Enfermedades de la Tiroides/diagnóstico , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Enfermedades Transmisibles/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Inmunoglobulina G/inmunología , Persona de Mediana Edad
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