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Nancy D Perrier, Andrew Arnold, Jessica Costa-Guda, Naifa L Busaidy, Ha Nguyen, Hubert H Chuang, and Maria Luisa Brandi

This report summarizes published data on parathyroid cancer, with the inclusion of topics discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27–29 March 2019, Houston, TX, USA. An expert panel on parathyroid cancer was constituted by the Steering Committee to address key questions in the field. The objectives were to recap open forum discussion of interested parties from multiple disciplines. The expert panel met in a closed session to consult on the data to be highlighted on the evidence-based results and on the future directions. Preceding the Conference, members of the expert panel conducted an extensive literature search. All presentations were based upon the best peer-reviewed information taking into account the historical and current literature. Questions were developed by the expert panel on parathyroid carcinoma. A comprehensive literature search for relevant studies was undertaken. This report represents the expert panel’s synthesis of the conference material placed in a context designed to be relevant to clinicians and those engaged in cutting-edge studies of parathyroid carcinoma. This document not only provides a summary of our current knowledge but also places recent advances in its management into a context that should enhance future advances in our understanding of parathyroid carcinoma.

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F Lumachi, P Zucchetta, S Varotto, F Polistina, G Favia, and D D'Amico

In primary hyperparathyroidism (pHPT), parathyroidectomy is the treatment of choice, but anatomic variations of ectopic glands may cause surgical failure. Reliable preoperative noninvasive localization procedures would have a positive impact on the operative time and increase recovery rate. We retrospectively evaluated 186 patients with pHPT who were studied before successful parathyroidectomy by double tracer scintigraphy (99mTc-pertechnetate+201TI chloride or 99mTc-pertechnetate +99mTc-sestamibi, 160 patients), ultrasonography (148 patients) and computerized tomography (CT) scan (92 patients). During bilateral neck exploration, 159 (85.5%) single adenomas, 6 (3.2%) parathyroid carcinomas, and 3 (1.6%) double adenomas were found. Moreover, 18 (9.7%) patients had diffuse chief cells parathyroid hyperplasia. Removed parathyroid glands were in ectopic sites in 41 (22.0%) cases, mainly localized in the upper mediastinum or behind the esophagus. The overall sensitivity was 83.5 and 85.2% for 99mTc-pertechnetate+201TI chloride and 99mTc-pertechnetate+99mTc-sestamibi scintigraphy respectively, 80.4% for CT scan and 81.1% for ultrasonography. In patients with ectopic glands, sensitivity was 81.2, 79.5, 73.3 and 81.6% respectively. In 36 out of 41 patients with ectopic glands in whom the removed parathyroids were correctly localized, mean operative time was 95 min, and in 5 patients without preoperative localization it was 260 min. In conclusion, in pHPT, preoperative localization of an enlarged parathyroid is helpful, especially in ectopic adenomas and in anatomic variations in location, and it has been proved to reduce operative time and morbidity rate.

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Inga-Lena Nilsson, Jan Zedenius, Li Yin, and Anders Ekbom

In order to evaluate the link between primary hyperparathyroidism (pHPT) and malignancies, cases subjected to parathyroid adenomectomy (PTX) during 1958–1997 in Sweden were identified by analyzing the National Swedish Cancer Registry. To minimize the influence of confounding by detection, cases with malignant disease diagnosed before or at the same time as pHPT or during the first year after PTX were excluded. Altogether 9782 cases (7642♀) were included and followed for up to 40 years. Thus, the study comprises 89 571 person-years of observation. The incidence of malignancies was compared with that in the Swedish population standardized for age, sex, and calendar year. An increased overall incidence of cancer was demonstrated in both genders (standardized incidence ratio (SIR) 1.43, 95% confidence interval (CI) 1.35–1.52). This remain unchanged beyond 15 years after PTX. Breast cancer contributed a quarter of the cancer incidence in women (SIR 1.44, 95% CI 1.25–1.62). An increased risk of kidney (SIR 2.40, 95% CI 1.72–3.25), colonic (SIR 1.46, 95% CI 1.19–1.77), and squamous cell skin cancer (SIR 2.79, 95% CI 2.25–3.43) was found in both genders. The risk of endocrine and pancreas cancer was increased in the minority of patients who had their PTX before the age of 40. We conclude that pHPT is associated with an increased risk of developing malignancies that persists even after PTX. This suggests a causal disassociation with the biochemical derangements caused by parathyroid adenoma, while potentially common etiological mechanisms may include genetic predisposition or acquired disability to withstand environmental influence.

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F Lumachi, M Ermani, F Marino, A Poletti, SMM Basso, M Iacobone, and G Favia

The aim of this study was to evaluate the usefulness of DNA flow cytometry to determine tumor nuclear DNA index (DI), and nucleolar organizer region protein counts visualized by the argyrophil (AgNOR) technique, in confirming diagnosis and predicting clinical outcome of patients with parathyroid carcinoma (PC). We reviewed paraffin-embedded tissue sections, from 15 patients (median age 63 years, range 30–68 years) with PC who died of the disease, which were randomly compared with tissue sections from 15 age- and sex-matched patients with parathyroid adenoma (PA). The proliferative activity in parathyroid tumours as detected by DI and AgNOR counts was evaluated in all specimens. Both DI (1.37 ± 0.33 vs 1.0 ± 0.1) and AgNOR (3.01 ± 0.31 vs 1.54 ± 0.35) counts were higher (P < 0.001) (Student’s t-test) in patients with PC than in those with PA. Diploid (DI = 1), aneuploid (DI>1) and hypoploid (DI<1) neoplasms were found in 11 (PC = 4, PA = 7), 14 (PC = 11, PA = 3) and five (PC = 0, PA = 5) patients respectively. The average postoperative survival in patients with PC was 46.9 ± 37.4 months (range 21–146 months). The survivals of patients with aneuploid (n = 11) and diploid (n = 4) PC were 74.0 ± 58.1 and 34.1 ± 18.4 months (P=0.21) respectively. There was a significant relationship between DI and AgNOR counts (R=0.69, P < 0.01), but no correlation was found between survival and both DI (Rho = 0.17, P = 0.55) and AgNOR counts (Rho = 0.26, P = 0.35). Moreover, there was no correlation (P = NS) between the main preoperative biochemical parameters and survival. In conclusion, DI and AgNOR are useful in confirming the diagnosis of PC, but they are of little value in predicting the clinical outcome of patients with PC.

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Joanna Grey and Kym Winter

Multiple endocrine neoplasia type 2 (MEN2) refers to the autosomal-dominant neuroendocrine tumour syndromes, MEN type 2A (MEN2A) and MEN type 2B (MEN2B). They are typified by the development of medullary thyroid cancer (MTC), phaeochromocytoma and parathyroid hyperplasia in MEN2A and MTC, phaeochromocytomas, ganglioneuromatosis and skeletal abnormalities in MEN2B. The aggressiveness of MTC is variable according to genotype, and although it is still the major cause of mortality in both conditions, prognosis has improved dramatically in those diagnosed and treated at a young age thanks to predictive genetic testing. Nevertheless, metastatic MTC, ganglioneuromatosis and a variety of other negative clinical and psychosocial impacts on quality of life and/or prognosis in MEN2 persist. In the absence, at the time of writing, of any large-scale research into quality of life specifically in MEN2, this review includes data from patient surveys and anonymised patient anecdotes from the records of the Association for Multiple Endocrine Neoplasia Disorders (AMEND), for whom the authors work. We recommend that these patients are cared for only in centres of expertise able to provide expert diagnosis, treatment and continuity of care, including psychological and transition support. Only in this way can the clinical advances of the last two and half decades be built upon further to ensure that the care of these complex, lifelong patients can be considered truly holistic.

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Tomoko Sekiya, Marcello D Bronstein, Katiuscia Benfini, Viviane C Longuini, Raquel S Jallad, Marcio C Machado, Tatiana D Goncalves, Luciana H Osaki, Leonardo Higashi, Jose Viana-Jr, Claudio Kater, Misu Lee, Sara Molatore, Guilherme Francisco, Roger Chammas, Michel S Naslavsky, David Schlesinger, Patricia Gama, Yeda A O Duarte, Maria Lucia Lebrão, Mayana Zatz, Osorio Meirelles, Bernardo Liberman, Maria Candida B V Fragoso, Sergio P A Toledo, Natalia S Pellegata, and Rodrigo A Toledo

Abstract

Germline mutations in p27 kip1 are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.01), particularly for those with ACTH-secreting pituitary adenomas (P=0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.

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S Takahashi, M Hakuta, K Aiba, Y Ito, N Horikoshi, M Miura, K Hatake, and E Ogata

Parathyroid hormone (PTH) and PTH-related protein/peptide (PTHrP) bind to the same PTH/PTHrP receptor and stimulate osteoblasts to secrete pro-inflammatory cytokines like interleukin (IL)-6. In patients with primary hyperparathyroidism, elevation of plasma levels of tumor necrosis factor (TNF)-alpha and IL-6 was also described. We, therefore, postulated that PTHrP secreted from cancer cells stimulates the secretion of cytokines and causes increases in their blood levels. Blood concentrations of several cytokines (TNF-alpha, IL-1beta, IL-5, IL-6, IL-8, IL-11 and IL-12) in cancer-bearing patients with or without elevation of blood PTHrP were measured by ELISA. The patients with high plasma PTHrP levels (n=29, intact PTHrP: 8.5 +/- 1.4 pmol/l, normal: <1.1) had higher serum type 1 collagen C-telopeptide (ICTP). Twenty of the patients were hypercalcemic. Plasma concentrations of TNF-alpha, IL-6 and IL-8 were significantly increased in patients with high PTHrP, in either the presence or absence of hypercalcemia. The concentrations of TNF-alpha and IL-6 were also significantly correlated with those of PTHrP. Our observations indicate that high plasma levels of PTHrP in cancer-bearing patients contribute not only to the development of hypercalcemia, but also to the development of the syndrome caused by an excess of pro-inflammatory cytokines.

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Rachel S van Leeuwaarde, Joanne M de Laat, Carolina R C Pieterman, Koen Dreijerink, Menno R Vriens, and Gerlof D Valk

Multiple endocrine neoplasia type 1 is a rare autosomal inherited disorder associated with a high risk for patients to simultaneously develop tumors of the parathyroid glands, duodenopancreatic neuroendocrine tumors and tumors of the anterior pituitary gland. Early identification of MEN1 in patients enables presymptomatic screening of manifestations, which makes timely interventions possible with the intention to prevent morbidity and mortality. Causes of death nowadays have shifted toward local or metastatic progression of malignant neuroendocrine tumors. In early cohorts, complications like peptic ulcers in gastrinoma, renal failure in hyperparathyroidism, hypoglycemia and acute hypercalcemia were the primary causes of early mortality. Improved medical treatments of these complications led to a significantly improved life expectancy. The MEN1 landscape is still evolving, considering the finding of breast cancer as a new MEN1-related manifestation and ongoing publications on follow-up and medical care for patients with MEN1. This review aims at summarizing the most recent insights into the follow-up and medical care for patients with MEN1 and identifying the gaps for future research.

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Anna Angelousi, Krystallenia I Alexandraki, George Kyriakopoulos, Marina Tsoli, Dimitrios Thomas, Gregory Kaltsas, and Ashley Grossman

Endocrine organs are metastatic targets for several primary cancers, either through direct extension from nearby tumour cells or dissemination via the venous, arterial and lymphatic routes. Although any endocrine tissue can be affected, most clinically relevant metastases involve the pituitary and adrenal glands with the commonest manifestations being diabetes insipidus and adrenal insufficiency respectively. The most common primary tumours metastasing to the adrenals include melanomas, breast and lung carcinomas, which may lead to adrenal insufficiency in the presence of bilateral adrenal involvement. Breast and lung cancers are the most common primaries metastasing to the pituitary, leading to pituitary dysfunction in approximately 30% of cases. The thyroid gland can be affected by renal, colorectal, lung and breast carcinomas, and melanomas, but has rarely been associated with thyroid dysfunction. Pancreatic metastasis can lead to exo-/endocrine insufficiency with renal carcinoma being the most common primary. Most parathyroid metastases originate from breast and lung carcinomas and melanoma. Breast and colorectal cancers are the most frequent ovarian metastases; prostate cancer commonly affects the testes. In the presence of endocrine deficiencies, glucocorticoid replacement for adrenal and pituitary involvement can be life saving. As most metastases to endocrine organs develop in the context of disseminated disease, surgical resection or other local therapies should only be considered to ameliorate symptoms and reduce tumour volume. Although few consensus statements can be made regarding the management of metastases to endocrine tissues because of the heterogeneity of the variable therapies, it is important that clinicians are aware of their presence in diagnosis.

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Chiara Verdelli, Irene Forno, Annamaria Morotti, Pasquale Creo, Vito Guarnieri, Alfredo Scillitani, Filomena Cetani, Leonardo Vicentini, Gianni Balza, Edoardo Beretta, Stefano Ferrero, Valentina Vaira, and Sabrina Corbetta

Parathyroid tumors deregulate microRNAs belonging to the two clusters on the chromosome 19, the C19MC and miR-371-373 clusters. Here, we report that the embryonic miR-372 is aberrantly expressed in half of parathyroid adenomas (PAds) in most of atypical adenomas and carcinomas (n = 15). Through in situ hybridization, we identified that miR-372-positive parathyroid tumor cells were scattered throughout the tumor parenchyma. In PAd-derived cells, ectopic miR-372 inhibited the expression of its targets CDKN1A/p21 and LATS2 at both mRNA and protein levels. Although the viability of parathyroid cells was not affected by miR-372 overexpression, the miRNA blunted camptothecin-induced apoptosis in primary PAd-derived cultures. miR-372 overexpression in parathyroid tumor cells increased parathormone (PTH) mRNA levels, and it positively correlated in vivo with circulating PTH levels. Conversely, the parathyroid-specific genes TBX1 and GCM2 were not affected by miR-372 mimic transfection. Finally, miR-372 dampened the Wnt pathway in parathyroid tumor cells through DKK1 upregulation. In conclusion, miR-372 is a novel mechanism exploited by a subset of parathyroid tumor cells to partially decrease sensitivity to apoptosis, to increase PTH synthesis and to deregulate Wnt signaling.