Management of pediatric papillary thyroid cancer.

Papillary thyroid carcinoma (PTC) originates from the follicular cell of the thyroid gland. PTC is a rare cancer and usually develops in pre-existing thyroid nodules, which are not common in children. PTC is often multifocal and bilateral. Low-risk subtypes such as classic PTC and follicular variant account for the majority of PTC, while high-risk histologic subtypes such as tall cell variant, diffuse sclerosing variant and poorly differentiated thyroid cancer occur more rarely in children. It is worth noting that the size of the thyroid in children is smaller compared to that of adults. Therefore, the size criteria used for tumor staging as well as the diagnosis of papillary microcarcinoma in adults, do not apply to children. Family history of thyroid cancer, exposure to external radiation, iodine deficiency, and autoimmune thyroid diseases as well as some genetic syndromes increase the risk of its occurrence.

Inhibition of calcitriol inactivating enzyme CYP24A1 gene expression by flavonoids in hepatocellular carcinoma cells under normoxia and hypoxia.

A vast number of epidemiological, preclinical and in vitro experimental data strongly indicate the anticancer potential of calcitriol, the biologically active form of vitamin D. However, for the implementation of a vitamin D based cancer therapy the increased deactivation of calcitriol in cancer cells by overexpressed CYP24A1 hydroxylase should be suppressed. Inhibition of this enzyme expression or activity nowadays is considered as important aspect of anticancer therapeutic strategies. Herein, we investigated the impact of genistein, biochanin A, formonentin and kaempferol on the expression of the CYP24A1 gene induced by calcitriol in hepatocellular cancer cells Huh7 under normoxia (21%O2) or hypoxia (1%O2). We demonstrate that calcitriol induces CYP24A1 under normoxia and hypoxia, but this induction is significantly more potent under hypoxia, the typical microenvironment of solid tumors. In the presence of isoflavones genistein, biochanin A and formononetin, this induction is abrogated to the control levels under normoxia, while under hypoxia there is some differentiation in suppression efficacy between these compounds with genistein ≥ biochanin > formononetin. At the same time, kaempferol turned out to be completely ineffective in the suppression of CYP24A1 gene expression.

Results of a prospective multicenter neuroendocrine tumor registry reporting on clinicopathologic characteristics of Greek patients.

BACKGROUND: The rare incidence of neuroendocrine neoplasms (NENs) has contributed to a paucity of large epidemiologic studies of patients with this condition. We investigated the occurrence and clinicopathologic features of NENs in Greece. METHODS: Between October 2010 and November 2012 we collected data on 246 newly diagnosed patients from a broad-based multi-institutional registry that comprises eight academic and hospital sites in Greece. The WHO 2010 pathologic classification and the 7th AJCC Staging system was applied in all cases. RESULTS: Of all patients 94 % had a sporadic and 6 % a multiple endocrine neoplasia tumor; 63.4 % were gastroenteropancreatic-(GEP)-NENs, 17.9 % Head & Neck NENs, 9.8 % NENs of Unknown Primary, 6.5 % Lung NENs and 2.4 % Pheochromocytomas. Gastric and pancreatic NENs were the most common primary sites. Poorly differentiated neuroendocrine carcinomas (NEC) were 9.3 %, all sporadic. Fifteen percent of patients were asymptomatic at presentation, 24 % had a first symptom of the disease related to endocrine syndrome and 61 % had symptoms related to locally advanced or metastatic disease. Metastatic disease was established in 25 % of tumors most frequently in the GEP NEN group. Findings are presented according to Ki-67 distribution. MRI had a higher diagnostic positive yield than Octreoscan. Somatostatin analogs, lanreotide and octreotide acetate, were prescribed at 38.5 & 61.5 % of NEN patients respectively and were found to be equally effective at providing symptomatic relief. CONCLUSIONS: This is to our knowledge the first study of a Greek tumor registry and one of the few European Registries providing information regarding clinicopathologic characteristics and therapies in patients with neuroendocrine tumors of various origin sites, beyond GEP NENs.

SERUM ADIPONECTIN AND INSULIN-LIKE GROWTH FACTOR 1 IN PREDOMINANTLY FEMALE PATIENTS WITH THYROID CANCER: ASSOCIATION WITH THE HISTOLOGIC CHARACTERISTICS OF THE TUMOR.

OBJECTIVE: Insulin-like growth factor (IGF)-1 and adiponectin have been proposed to contribute to the pathogenesis of different malignancies. However, data regarding their association with histologic characteristics of thyroid cancer are scarce. The main aims of the present study were the comparative evaluation of IGF-1, IGF-binding protein 3 (BP3), and adiponectin serum levels between different histologic types of thyroid cancer, as well as within specific histologic characteristics of the tumors. METHODS: A total of 179 thyroid cancer patients (126 [70.4%] women) were recruited. A total of 129 (72.1%) had papillary thyroid carcinoma (including variants), 26 had follicular thyroid carcinoma (14.5%), and 24 had medullary thyroid carcinoma (13.4%). Parameters from history, physical examination, and thyroid histology were selected. Serum adiponectin, IGF-1, and IGF-BP3 were measured in fasting morning samples. RESULTS: IGF-1, IGF-BP3, and adiponectin levels were similar among different histologic types of thyroid carcinoma, with a trend towards higher IGF-1 and IGF-BP3 levels in patients with intrathyroid invasion, compared to those without. In addition, ratios of IGF-1 to adiponectin (P = .012) and IGF-1 to (adiponectin × IGF-BP3) (P = .003), as well as type 2 diabetes (P = .001), were positively associated with tumor size. CONCLUSION: Although IGF-1, IGF-BP3, and adiponectin were not separately different between groups or within specific histologic lesions, when they were combined to produce IGF-1 to adiponectin and IGF-1 to (adiponectin × IGF-BP3) ratios, they were independently associated with tumor size. Future prospective studies are needed to evaluate whether these ratios could serve as prognostic markers of thyroid tumor aggressiveness.

Papillary thyroid carcinomas in patients under 21 years of age: clinical and histologic characteristics of tumors ≤10 mm.

OBJECTIVE: To compare clinical and histologic characteristics of papillary thyroid carcinomas (PTCs) ≤10 mm in patients ≤21 years old with larger ones and with microcarcinomas in adults. STUDY DESIGN: Retrospective study of patients with PTC diagnosed between 1983 and 2012. Medical records were reviewed and information about age, sex, tumor size, intra/extrathyroid extension, lymph node, and distant metastases were collected. RESULTS: Patients ≤21 years old (n = 93) and adults (n = 1235) with PTC were identified. Among the former, 34 had PTC ≤10 mm (37.4%) and among the latter, 584 had papillary thyroid microcarcinoma (PTM) (47.3%), P = .082. Patients with tumors ≤10 mm less frequently had extrathyroidal extension and lymph node metastases compared with larger tumors (8.8% vs 33.3%, P = .017, and 60.0% vs 95.2%, P = .001, respectively). The percentage of PTC ≤10 mm increased with age (7.1%, 32.0%, and 48.1% in age groups ≤15, 15-18, and >18 to ≤21 years old, respectively; P = .016). Mean tumor size was larger (6.8 ± 2.7 vs 5.8 ± 2.8 mm, P = .030), and lymph nodes metastases were more frequent (41.2% vs 18.6%, P = .003) in patients ≤21 years of age compared with adults with PTM. The frequency of multifocal cancers decreased between 1983-1992, 1993-2002, and 2003-2012 (66.7%, 53.6%, and 27.1%, respectively, P = .019). CONCLUSIONS: The frequency of PTC ≤10 mm is low in children, increases in adolescents, and reaches that of adults at 18-21 years of age. Mean tumor size is larger and metastases to regional lymph nodes more frequent in comparison with PTM in adults. Whether their treatment and follow-up could be based on guidelines used for PTM in adults is questionable.

Predictive factors that influence the course of medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid cancer (MTC) is an infrequent form of thyroid cancer. We aimed to examine how gender and histological characteristics influence the rate of recurrence/persistent disease, distant metastases and survival and also to define specific characteristics of MTC microcarcinomas. METHODS: The medical records of 85 patients with MTC were reviewed. The following characteristics were recorded: year of diagnosis, age at diagnosis, sex, tumor size, number of tumor foci, lymph node metastases, thyroid capsule and vascular invasion, infiltration of thyroid parenchyma and extrathyroid extension, and distant metastases. RESULTS: During follow-up (mean 78.8 months), persistent disease occurred in 40 patients, local recurrences in 5 and distant metastases in 32 patients. Local and distant disease appeared more frequently in patients with larger tumors (p < 0.005) and lymph node metastases (p < 0.01). In addition, patients with invasive tumors had local and distant disease more frequently. The percentage of males who had persistent disease and/or local recurrence was significantly higher than the percentage of males who did not (p < 0.05). Similar results were observed for distant disease (p < 0.01). Independent predictors of recurrence and persistent disease was the presence of lymph node metastases at diagnosis (risk ratio 11.66) and of distant metastases were the presence of lymph node metastases at diagnosis (risk ratio 17.42) and the presence of vascular invasion (risk ratio 2.41). Fifteen patients died due to MTC during follow-up (17.6 %). Patients who died were more frequently males, and had thyroid capsule invasion, extrathyroidal extension, vascular invasion and metastatic disease. CONCLUSIONS: Male sex, tumor size and invasive characteristics of the tumor are negative predictive factors for evolution of MTC.

Thyroid cancer after in vitro fertilization: a retrospective, non-consecutive case-series analysis.

Although a firm association between fertility treatment and thyroid cancer has not been established, the widespread use of IVF, as a substantial reservoir of subclinical thyroid cancer disease and evidence suggesting an estrogen-dependent behavior may render thyroid cancer patients after IVF a distinct subpopulation of particular interest. Thus, a retrospective, non-consecutive case-series analysis of patients with history of thyroid cancer after in vitro fertilization was conducted. Twelve female patients with thyroid cancer who had previously undergone IVF treatment were identified within the cohort of thyroid cancer patients followed in our institution. All cases of thyroid cancer were papillary thyroid carcinoma (PTC) on histology and median tumor size (25th and 75th percentile) was 12 mm (7 and 17 mm). Thyroid cancer was diagnosed after a median of 4 years (2 and 6 years) from the last IVF cycle and at the time of diagnosis lymph node metastases were present in five patients (42%) and distant metastases where seen in four of them. Collectively, these data suggest that an aggressive pattern of PTC might be present in this distinct subpopulation. This preliminary observation may be explained, at least in part, by the delay in the diagnosis.

Mixed corticomedullary adrenal carcinoma.

Truly mixed corticomedullary tumors (MCMTs) are extremely rare and present as a single tumor mass composed of an intimately admixed population of both adrenal cortical cells and pheochromocytes. The current study describes the first case of a mixed corticomedullary adrenal carcinoma. In addition, we also review the published data on MCMTs to determine their clinical features, biochemical characteristics, pathological findings, and management. In order to compose this review, a search of the international literature for MCMTs was conducted. Fifteen related articles were found. The clinical and pathological information was obtained for all reported cases. MCMTs were found almost exclusively in females. In the vast majority of patients, the symptoms were related to the tumor's hormone hypersecretion. Hypertension and diabetes were present in 80 and 40 % of cases, respectively. Cushing's syndrome was reported in eight cases (53.33 %). A final diagnosis was made in all cases after surgery based on the pathological results. As of the writing of this article, all published cases of MCMTs had benign clinical behavior, with no instances of metastasis or death due to the tumor. MCMTs are currently considered to be benign tumors. Ours is the first case of malignant MCMT reported in the literature. The potential for malignancy should therefore be considered for these tumors.

Parathyroid involvement in thyroid cancer: an unforeseen event.

BACKGROUND: Parathyroid metastatic disease from thyroid cancer has not been studied extensively, mainly due to the need for parathyroid preservation during thyroid surgery. METHODS: We reviewed files from 1,770 patients with thyroid cancer followed up in our department and 10 patients with parathyroid metastases (0.5%) were identified. Patient and tumor characteristics were recorded. RESULTS: Six out of ten patients had metastases from papillary thyroid cancer, three from follicular thyroid cancer and one from anaplastic thyroid cancer. In nine patients parathyroid infiltration from thyroid cancer was found in direct contact with the thyroid cancer, and in one patient metastatic foci were observed not in continuity with the thyroid cancer. CONCLUSIONS: Parathyroid involvement, although infrequent, may occur in thyroid cancer independently of patient age and tumor size. The clinical significance of such event is not clear. The influence on disease outcome remains to be elucidated.

A Real-world Multicenter Prospective Study of Everolimus in Pancreatic Neuroendocrine Tumors: The 'PROTOR' Study.

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (panNETs) are rare neoplasms with challenging disease management. We aimed to evaluate the progression-free survival (PFS) and overall response rate (ORR) in chemotherapy-naïve patients with unresectable or metastatic Grade (G) 1-2 panNETs treated with everolimus in the routine care in Greece. PATIENTS AND METHODS: This was a multicenter, prospective, observational study. Eligible patients were recently (≤4 weeks) initiated on treatment with everolimus and were followed for up to 48 months. RESULTS: Nineteen eligible patients (mean age 55.1 years) were enrolled. All patients had metastatic disease and 84.2% had G2 panNET. Everolimus was initiated in combination with somatostatin analogues in 84.2% of the patients. The mean everolimus treatment duration was 21.5 months. The median Kaplan-Meier-estimated PFS was 20.4 months (95% confidence interval=14.1-41.5). The ORR was 27.8%. The rate of everolimus-related adverse events was 84.2% (Grade ≥3: 31.6%). CONCLUSION: Everolimus displayed clinical benefit and a predictable safety profile in pancreatic neuroendocrine tumors.

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino.

The corticotropin releasing factor system in cancer: expression and pathophysiological implications.

Malignant tumors express multiple factors that have some role in the regulating networks supporting their ectopic growth. Recently, increased interest has been developing in the expression and biological role of the neuropeptides and receptors of the corticotropin releasing factor (CRF) system, the principal neuroendocrine mediator of the stress response, especially in the light of several R&D programs for small molecule antagonists that could present some anticancer therapeutic benefit. In the present article, we review the literature suggesting that the CRF system could be involved in the regulation of human cancer development. Potential implication in growth, metastasis, angiogenesis, or immune parameters via activation of locally expressed receptors could be clinically exploited by presenting targets of new therapeutic approaches.

[Therapeutic approach of differentiated thyroid carcinoma in children and adolescents].

Diferentiated thyroid cancer is uncommon in children and adolescents. It presents as a solitary thyroid nodule, as multinodular goiter, or as a neck mass that is noted accidentally by the patient, the family or by the physician. Surgery is the treatment of choice and most of the specialists consider that total thyroidectomy with central cervical lymph nodes dissection must be applied in all patients. Some specialists prefer a more conservative surgical treatment in order to avoid complications. Postoperatively, ablation treatment with iodine-131, for the eradication of the remaining normal or malignant thyroid tissue is indicated in the majority of patients. Thyroid hormone is administered for life. Follow-up is continued for many years.

Obesity and COVID-19: A jigsaw puzzle with still missing pieces.

Apart from posing various mechanical and medical issues compromising general health, obesity is a major factor for respiratory tract infections, due to specific inflammation and immunological compromise. The burden of obesity on morbidity and mortality of SARS-CoV-2 infection/COVID-19 is considerable. Herein, we aimed to search the literature and present to the readers pathophysiologic pathways that may associate obesity and COVID-19. We present potential mechanisms, which might partly explain why patients with obesity are more prone to suffer from respiratory infections in the context of COVID-19. Better understanding of these pathways could eventually guide management strategies and therapies for COVID-19 in the future.

Sialadenitis as a complication of radioiodine therapy in patients with thyroid cancer: where do we stand?

PURPOSE: This study aims to elaborate on the current knowledge concerning the mechanism, frequency, clinical manifestations, diagnostic procedures, prevention, and management of radioactive iodine (RAI)-induced sialadenitis in patients receiving treatment for differentiated thyroid cancer (DTC). METHODS: A review of the literature was carried out through the " www.ncbi.nlm.nih.gov/pubmed " database focusing on the results of the past decade. RESULTS: The high concentration of RAI in the salivary glands results in high beta radiation exposure of the striated duct cells and stem cells. This exposure leads to acute and/or chronic sialadenitis with obstructive symptoms and progressive loss of salivary gland function and xerostomia, with severe impact on patients' quality of life. No standard diagnostic method has been established. As far as prevention is concerned, many approaches have been proposed, such as sialogogues, local massage, vitamin E, and amifostine administration. Although there is no unanimity as to their effectiveness, the use of sialogogues is recommended. Treatment includes conservative drug therapy and sialendoscopy when necessary. CONCLUSION: RAI-induced sialadenitis has a major impact on patients' quality of life. Due to the good prognosis of DTC, the reduction of sialadenitis and its prognosis, prevention, and treatment constitute a priority for the overall treatment of these patients. Further studies that will establish a coherent treatment protocol for this condition are necessary.

Serum Follistatin Is Increased in Thyroid Cancer and Is Associated With Adverse Tumor Characteristics in Humans.

CONTEXT: Obesity and classical growth factors are associated with thyroid cancer (TC). However, less is known regarding novel hormones such as follistatins and activins. We hypothesized that serum follistatin but not activins would be increased in TC. OBJECTIVE: This work aimed to assess circulating levels of follistatins, activins, and growth factors in patients with a history of TC vs patients with nonmalignant thyroid diseases. METHODS: A hospital-based, unmatched case-control study was conducted with 170 thyroidectomized patients due to well-differentiated TC and 106 thyroidectomized patients without history of malignancy. Anthropometric, biochemical, and histological parameters were recorded. Serum samples were collected in the steady state 45 days after surgery. Multivariate models were used to adjust for baseline differences of the unmatched variables. Serum levels of follistatin (FST), follistatin like-3, activin A, activin B, bioactive insulin-like growth factor-1, and stanniocalcin-2 were assayed with novel, highly specific ELISA kits. RESULTS: In unmatched univariate models, TC patients had higher FST serum levels compared to cancer-free individuals, independently of histological subtype. In multivariate models adjusting for covariates, individuals in the highest tertile of FST levels were associated with an increased risk for the presence of any type of TC or specific histological subtypes, including papillary, follicular and Hürthle-cell carcinoma, and medullary TC. Higher postoperative FST concentrations were found in patients with vascular invasion and distant metastases and associated with TNM staging at diagnosis. CONCLUSION: FST serum levels are increased in TC patients and correlate with advanced tumor aggressiveness. Future longitudinal studies are needed to confirm and extend our observations.

Association of Vitamin D Receptor Gene Polymorphisms with Serum Vitamin D Levels in a Greek Rural Population (Velestino Study).

BACKGROUND/AIM: An alarming increase in vitamin D deficiency even in sunny regions highlights the need for a better understanding of the genetic background of the vitamin D endocrine system and the molecular mechanisms of gene polymorphisms of the vitamin D receptor (VDR). In this study, the serum levels of 25(OH)D3 were correlated with common VDR polymorphisms (ApaI, BsmI, FokI, and TaqI) in 98 subjects of a Greek homogeneous rural population. METHODS: 25(OH)D3 concentration was measured by ultra-HPLC, and the VDR gene polymorphisms were identified by quantitative real-time PCR followed by amplicon high-resolution melting analysis. RESULTS: Subjects carrying either the B BsmI (OR: 0.52, 95% CI: 0.27-0.99) or t TaqI (OR: 2.06, 95%: 1.06-3.99) allele presented twice the risk for developing vitamin D deficiency compared to the reference allele. Moreover, subjects carrying 1, 2, or all 3 of these genotypes (BB/Bb, Tt/tt, and FF) demonstrated 2-fold (OR: 2.04, 95% CI: 0.42-9.92), 3.6-fold (OR: 3.62, 95% CI: 1.07-12.2), and 7-fold (OR: 6.92, 95% CI: 1.68-28.5) increased risk for low 25(OH)D3 levels, respectively. CONCLUSIONS: Our findings reveal a cumulative effect of specific VDR gene polymorphisms that may regulate vitamin D concentrations explaining, in part, the paradox of vitamin D deficiency in sunny regions, with important implications for precision medicine.

Circulating and Tissue Expression Profile of MicroRNAs in Primary Hyperparathyroidism Caused by Sporadic Parathyroid Adenomas.

We investigated the expression profile of selected microRNAs (miRs) in serum and tissue samples from patients with sporadic parathyroid adenomas (sPAs). This was a prospective, controlled cohort study. Forty patients with sPAs who had undergone parathyroidectomy (PTX) were included. MiR extraction was performed from (i) 40 formalin-fixed paraffin-embedded samples (FFPEs) of sPAs, (ii) 10 FFPEs of normal parathyroid tissue (NPT), (iii) serum samples of the 40 patients with sPAs (t1 = baseline; t2 = 2 months post-PTX), and (vi) serum samples of 10 healthy individuals (controls; t1 = baseline and t2 = 2 months later). Ten miRs were selected based on their interaction with genes related to parathyroid tumorigenesis (miR-17-5p, miR-24-3p, miR-29b-3p, miR-31-5p, miR-135b-5p, miR-186-5p, miR-195-5p, miR-330-3p, miR-483-3p, and miR-877-5p). At tissue level, the relative expression of miR-17-5p, miR-31-5p, miR-135b-5p, miR-186-5p, and miR-330-3p was significantly decreased (fold change [FC]: 0.17, FC: 0.03, FC: 0.01, FC: 0.10, FC: 0.10, respectively; all p values <0.001), and the expression of miR-24-3p and miR-29b-3p was significantly increased (FC: 12.4, p < 0.001; FC: 18.5, p = 0.011, respectively) in sPA compared with NPT samples. The relative expression of miR-135b-5p was also significantly decreased in the serum samples of patients compared with controls (FC: 0.7, p = 0.035). No significant differences were found in the serum samples of patients before and after PTX. MiRs that regulate genes linked to parathyroid tumors such as menin 1 (miR-24-3p, miR-29b-3p), cyclin D1 (miR-17-5p), calcium sensing receptor (miR-31-5p, miR-135b-5p), cyclin-dependent kinase inhibitors (miR-186-5p), and ß-catenin (miR-330-3p) were significantly deregulated in sPAs compared with NPT samples, suggesting a role for epigenetic changes in parathyroid tumorigenesis. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Benefits and Limitations of TKIs in Patients with Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have been used in patients with advanced medullary thyroid carcinoma (MTC); however, data on their effectiveness and safety are limited. The aim of this systematic review and meta-analysis was to document clinical response and toxicities of TKIs in advanced MTC. METHODS: We systematically searched major databases for articles or abstracts on TKI use in MTC patients until May 2018. Objective response (OR), defined as the sum of complete + partial response, expressed as percentage, was our primary endpoint, while disease stability, disease progression (DP), median progression-free survival (PFS), and drug discontinuation rate due to adverse events (AEs) were secondary endpoints. Pooled percentages, PFS time, and 95% CIs were reported. RESULTS: Thirty-three publications were finally included in the analysis: 1 phase IV, 2 phase III trials evaluating vandetanib and cabozantinib, respectively, 20 phase I or II studies, and the remaining 10 studies of retrospective-observational nature. OR was documented in 28.6% (95% CI 25.9-31.9) of patients. Stable disease was recorded in 46.2% (95% CI 43.3-49.1). Overall, DP was observed in 22.9% (95% CI 20.4-27.6). Grade 3 or more AEs occurred in 48.5% (95% CI 45.5-51.5) of patients, and drug discontinuation was reported in 44.7% (95% CI 41.7-47.6). In general, use of TKIs conferred a PFS of 23.3 months (95% CI 21.07-25.5). In particular, vandetanib induced an OR in 33.8% (95% CI 29.6-38.0) of patients and cabozantinib in 27.7% (95% CI 22.05-33.4). DP occurred in 23.7% (95% CI 19.9-27.6) with vandetanib use and in 22.6% (95% CI 17.4-27.9) in cabozantinib-treated patients. Sorafenib, the third most frequently studied drug, showed intermediate efficacy, but higher discontinuation rates. CONCLUSION: Treatment with TKIs in MTC patients with progressive disease is associated with a moderate therapeutic benefit, with achievement of either disease stability or partial response in 73%. The toxicity of these drugs is not negligible, but it is, nonetheless, manageable.

The hypothalamic-pituitary-adrenal axis in women with differentiated thyroid cancer.

INTRODUCTION: We studied the function of hypothalamic-pituitary-adrenal (HPA) axis in females with differentiated thyroid cancer (DTC) and its sequelae on metabolism and cardiovascular risk. METHODS AND RESULTS: Sixteen women were investigated with (1) morning, evening, and midnight cortisol and adrenocortophic hormone, (2) cortisol after overnight 1 mg dexamethasone suppression test, (3) cortisol after corticotropin releasing hormone test, (4) oral glucose tolerance test with glucose and insulin estimations, and (5) ultrasound for carotid intima media thickness. A matched control group underwent similar investigations. None of the parameters was significantly different between patients and controls. CONCLUSION: Females with DTC have normal HPA-axis function and similar insulin sensitivity and cardiovascular risk compared to controls.