Search

A role for long non-coding RNAs (lncRNAs) in endocrine cancer pathogenesis is emerging. However, knowledge regarding their expression pattern, correlation with known genetic defects, and clinical implications in parathyroid tumors is still unclear. Here, we profiled 90 known lncRNAs in a first series of normal (PaN = 2), adenomatous (PAd = 12), and carcinomatous (PCa = 4) parathyroid glands and we confirmed deregulation of 11 lncRNAs using an independent cohort of patients (PaN = 4; PAd = 26; PCa = 9). Expression of lncRNAs was correlated with cytogenetic aberrations, status of genes multiple endocrine neoplasia 1 (MEN1) and cell division cycle 73 (CDC73), or clinical features. Globally, lncRNAs discriminate according to tissue histology. BC200 consistently identifies parathyroid cancers from adenomas and atypical adenomas. Loss-of-heterozygosity (LOH) at chromosomes 1, 11, 15, 21, and 22 significantly impacts expression of lncRNAs in PAds. Silencing of the key parathyroid gene MEN1 modulates the expression of six lncRNAs in primary PAds-derived cultures. Analogous levels of lncRNAs are measured in PAds with the mutation in the MEN1 gene compared with PAds with wild-type MEN1. Similarly, carcinomas with mutated CDC73 differ from PCas with wild-type protein in terms of expression of lncRNAs. PCas harboring CDC73 mutations overexpress BC200 compared to wild-type carcinomas. Overall, these findings shed light on deregulation of lncRNAs in human parathyroid tumors and propose that circuits between lncRNAs and the oncosuppressors MEN1 or CDC73 may have a role in parathyroid tumorigenesis as epigenetic modulators. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Objectives: Systolic anterior motion (SAM) can be an insidious complication after mitral repair. Predicting SAM represents a challenge, even for very experienced mitral valve surgeons. The goal of this pilot work was to illustrate for the first time, a computational software able to calculate and prevent SAM during mitral repair., Methods: Using MATLAB graphical user interface, a clinical software to predict SAM, we tested the performances of the software on 136 patients with degenerative mitral valves undergoing repair with standard techniques. A combination of 6 key echocardiographic parameters was used to calculate the SAM risk score. The discriminative performance of the model was assessed by the area under the receiver-operating characteristic curve. The receiver-operating characteristic was used to divide patients into low, medium and high risk for SAM. Simulation of virtual mitral repair (posterior leaflet resection and mitral ring annuloplasty) was also tested to reduce the risk of SAM., Results: The incidence of SAM was 8.1%; 73% were detected as high risk by the software. The area under the receiver-operating characteristic model discriminant performance was 0.87 (95% confidence interval: 0.78-0.95). Simulating a posterior leaflet resection with the leaflet length fixed at 15 mm, the estimated SAM risk was updated, and all patients were then classified at low risk., Conclusions: This software is the first computational model designed to predict SAM during mitral repair to show excellent discrimination. This software has the potential to predict SAM risk preoperatively and, after a virtual step-by-step mitral repair simulation, depending on the technique adopted, to always achieve a low-risk SAM profile., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To report the long-term results of the clover technique for the treatment of complex forms of tricuspid regurgitation (TR)., Methods: Ninety-six consecutive patients (mean age 60 ± 16.4, left ventricular ejection fraction 58 ± 8.8%) with severe or moderately-severe TR due to important leaflets prolapse/flail (81 patients), tethering (13 patients) or mixed (2 patients) lesions underwent clover repair combined with annuloplasty. The aetiology of TR was degenerative in 74 cases (77.1%), post-traumatic in 9 (9.4%) and secondary to dilated cardiomyopathy in 13 (13.5%). All patients but 3 (96.8%) underwent ring (59 patients, 61.5%) or suture (34 patients, 35.4%) annuloplasty. Concomitant procedures (mainly mitral surgery) were performed in 82 patients (85.4%)., Results: Hospital mortality was 7.2%. At hospital discharge 92 (95.8%) patients had no or mild TR. Follow-up was 98% complete (median 9 years, interquartile range 5.1; 10.9). At 12 years the overall survival was 71.6 ± 7.22% and the cumulative incidence function of cardiac death with non-cardiac death as competing risk 16 ± 4.1% [95% confidence interval (95% CI) 9.5-25.7]. At 12 years the cumulative incidence function of TR ≥ 3+ and TR ≥ 2+ with death as competing risk were 1.2 ± 1.2% (95% CI 0.1-5.8) and 28 ± 7.7% (95% CI 14.3-43.5), respectively. Preoperative left ventricular ejection fraction (hazard ratio 0.9, CI 0.9-1, P  = 0.05) and previous cardiac surgery (hazard ratio 2.7, 95% CI 1-7.1, P  = 0.03) were predictors of recurrent TR ≥ 2+ at univariable but not at multivariable analysis., Conclusions: Complex forms of TR due to severe prolapse or tethering of the leaflets can be effectively treated with the clover technique with very satisfactory long-term results and extremely low recurrence of severe TR., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: A single MitraClip implant is often considered enough to achieve adequate mitral regurgitation (MR) reduction. The aim of this study was to compare MR recurrence in patients with an initial optimal result treated with a single clip versus those treated with two clips., Methods: From October 2008 to May 2016, 322 patients were treated with the MitraClip procedure at our institution. We retrospectively selected all patients treated for functional MR (FMR) and degenerative MR (DMR) aetiologies with residual MR ≤1+, excluding patients who required >2 clips. FMR and DMR were analysed separately., Results: In FMR, a single clip was used in 45 patients and 2 clips in 99 patients. The single clip group had smaller coaptation depth (1.1 ± 0.3 vs 1.3 ± 0.3 mm, P  = 0.022) and jet extension (10.5 ± 2.1 vs 13.0 ± 3.6 mm, P  = 0.026) as well as left ventricular end-diastolic diameter (64.4 ± 7.3 vs 69.0 ± 7.9 mm, P  = 0.001). Freedom from MR ≥ 3+ after 4 years was 71.9 ± 8.9% in patients receiving a single clip vs 88.0 ± 5.2% in those receiving 2 clips, single clip use being an independent predictor of MR recurrence (HR 3.48, CI 1.24-9.81, P  = 0.018). In DMR, a single clip was deployed in 24 patients and 2 clips in 30 patients. The single clip group had a smaller flail gap (3.6 ± 0.7 vs 6.8 ± 2.5, P  = 0.002). Freedom from MR ≥ 3+ after 2 years was 82.5 ± 8% in patients with a single clip vs 100% in those with 2 clips, P  = 0.014. The residual mitral area was reduced in patients with 2 clips compared with those with single clip, both in FMR ( P  = 0.015) and DMR ( P  = 0.039), but it was not associated with increased death rate during the follow-up period (all P  > 0.05)., Conclusions: Despite favourable anatomical characteristics and an optimal initial result, implantation of a single clip was associated with an increased recurrence of MR compared with that of 2 clips, both in FMR and in DMR. Caution should be exercised with the implantation of a single clip., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To evaluate whether the adoption of a right minithoracotomy operative approach had an impact on the long-term results of edge-to-edge (EE) repair compared to conventional sternotomy in patients with Barlow's disease and bileaflet prolapse., Methods: We assessed the long-term results of 104 patients with Barlow's disease treated with a minimally invasive EE technique. An equal number of patients had a conventional median sternotomy EE repair for the same disease and were used as a control group. The inverse probability of treatment weighting was used to create comparable distributions of the covariates that were significantly different at baseline in the two groups. We performed a comparative analysis of the groups., Results: No hospital deaths were observed. Follow-up was 99.5% complete (median 11.3 years). The cumulative incidence function (CIF) of cardiac death at 12 years, with noncardiac death as a competing risk, showed no difference between the two groups ( P  = 0.87). At 12 years, the CIF of recurrent MR ≥ 3+, with death as the competing risk, was 7% in the sternotomy group and 5% in the minimally invasive group ( P  = 0.30), and the CIF of recurrence of MR ≥ 2+ was 15 and 14%, respectively ( P  = 0.63). The type of surgical approach was not a predictor of cardiac death, reoperation, recurrent MR ≥ 3+ or recurrent MR ≥ 2+., Conclusions: A minimally invasive approach does not have a negative impact on the effectiveness and long-term durability of the EE repair for bileaflet prolapse in Barlow's disease. Long-term outcomes are excellent, and valvular performance remains stable over time with no evidence of mitral stenosis., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and it is often poorly tolerated because of loss of atrial contraction and reduced filling time with rapid ventricular rates. Restoring sinus rhythm is of great clinical benefit to HCM patients. Very few data exist regarding surgical ablation of concomitant AF in this setting. The aim of this study was to evaluate the mid-term outcome of surgical AF ablation in patients who underwent cardiac surgery due to HCM., Methods: Thirty-one consecutive patients with primary HCM and drug-refractory symptomatic AF underwent surgical ablation with concomitant septal myectomy (77%) and/or mitral valve repair/replacement (39%). Follow-up was 97% complete with a median of 6.4 years [3.8-9.1]., Results: Hospital mortality was 6% and the overall survival at 7 years was 87 ± 6.1%. No stroke and thromboembolic events were documented at follow-up. The arrhythmia-free survival off antiarrhythmic drugs was 82 ± 7.3% at 1 year and 52 ± 10.2% at 6 years. The 1- and 6-year arrhythmia control (maintenance of sinus rhythm with or without antiarrhythmic drugs) was 96 ± 3.5 and 80 ± 8.1%, respectively. The recurrent arrhythmia was AF in all patients. No predictors of AF recurrence were detected., Conclusions: Concomitant surgical ablation of AF is a reasonable treatment option for drug refractory AF in patients with HCM undergoing surgical myectomy and/or mitral valve surgery. However, chronic antiarrhythmic drugs are needed to achieve a satisfactory mid-term arrhythmia control., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Thyroid cancer is highly prevalent in women during the fertile age, which suggests a possible impact of hormonal and reproductive factors., Methods: We studied the expression of estrogen receptor α (ERα or ESR1) and progesterone receptor (PR or PGR) in 182 female and male patients with papillary thyroid cancer and correlated it to clinical and molecular features., Results: ERα and PR expression was found in 66.5 and 75.8% of patients respectively and was significantly correlated with larger tumor size and with a non-incidental diagnosis. Moreover, a trend toward a higher prevalence of local metastases was observed in ER- and PR-expressing tumors, which possibly indicates a more aggressive behavior. Interestingly, the occurrence of the 'receptor conversion' phenomenon, which has already been reported to have a negative prognostic effect in breast cancer, was demonstrated for the first time in thyroid tumors. Indeed, almost all of the ERα-positive primary tumors analyzed had ERα-negative metastatic lymph nodes. At the genetic analyses, BRAF(V600E) mutation was detected in 23.2% of the tumors and had a higher prevalence in larger tumors and in those with a stronger ERα or PR staining., Conclusions: The whole of the findings reported in the present study argue for an association between ERα and PR sex hormone receptor expression and a more aggressive presentation. Although no impact on outcome was found, the evaluation of ERα and PR receptor expression could add insights into the biological behavior of tumors and could modify the follow-up, particularly in fertile women affected with persistent disease., (© 2015 European Society of Endocrinology.)

Context: Hypercalciuria is frequently found in primary hyperparathyroidism (1HPT) and, although it generally normalizes after successful parathyroidectomy, may persist in some patients. The factors associated with persistent calcium renal leak (cRL) have not been clarified., Objective: The purpose of this study was to determine the prevalence of cRL in our 1HPT population and investigate cRL-related factors., Design: This was a retrospective longitudinal study., Setting: The study was conducted in an outpatient setting., Patients/intervention: The participants were 95 patients with 1HPT successfully operated on who had a normal estimated glomerular filtration rate., Main Outcome Measures: The biochemical parameters of calcium metabolism and bone mineral density (BMD) measured by dual-X-ray absorptiometry before and 24 months after surgery were assessed. All histological findings were recorded., Results: The prevalence of hypercalciuria before and after surgery was 74% and 32%, respectively. Before, surgery patients with cRL showed lower calcium and higher phosphate levels than those without cRL (10.9 ± 0.6 vs 11.4 ± 0.8 mg/dL [2.7 ± 0.2 vs 2.8 ± 0.2 mmol/L], P = .01 and 2.6 ± 0.5 vs 2.4 ± 0.4 mg/dL [0.84 ± 0.2 vs 0.77 ± 0.1 mmol/L], P = .04, respectively), whereas 24-h calciuria levels and the prevalence of 1HPT complications (osteoporosis, renal stones, and hypertension) were comparable. After surgery, serum calcium, phosphate, and PTH levels were comparable between patients with and without cRL. The prevalence of the histological finding of parathyroid hyperplasia was higher in patients with cRL (50%) than in patients without cRL (22%) (P = .01). The presence of cRL was independently associated with presurgery hypercalciuria (odds ratio, 4.71; 95% confidence interval, 1.18-18.8; P = .03) and parathyroid hyperplasia (odds ratio, 3.52; 95% confidence interval, 1.31-9.43; P = .01). Only patients without cRL had improved BMD at the spine (P = .04), total femur (P = .01), and femoral neck (P = .01)., Conclusions: cRL is present in 30% of patients with 1HPT after successful surgery, and it is associated with parathyroid hyperplasia before surgery and the lack of improvement in BMD after surgery.

Context: Calcitonin (CT) measurement is crucial to the early diagnosis and the follow-up of medullary thyroid cancer (MTC). If the evaluation of stimulated CT levels is required, a provocative test can be performed, being the high-dose Ca test recently reintroduced in clinical practice., Objective: Our objective was to identify gender-specific thresholds for MTC diagnosis in a large series of patients who underwent the Ca test., Patients and Methods: A total of 91 patients (49 females and 42 males) underwent the Ca test (calcium gluconate, 25 mg/kg) before thyroidectomy and both basal CT (bCT) and stimulated CT (sCT) were compared with histological results by receiver operating characteristic plot analyses. To evaluate possible side effects of Ca administration, cardiac function has been extensively studied., Results: bCT levels were found to harbor the same accuracy as sCT in the preoperative diagnosis of MTC. The best Ca thresholds for the identification of MTC were >26 and >68 for bCT and >79 and >544 pg/mL for sCT in females and males, respectively. The high tolerability and safety of the Ca test was demonstrated and advice offered to be followed before and during the test., Conclusions: Gender-specific bCT and sCT cutoffs for the identification of C-cell hyperplasia and/or MTC have been defined. The bCT and sCT were found to have a similar accuracy, indicating that serum CT assays with improved functional sensitivity may likely decrease the relevance of the stimulation test in several conditions. Finally, systematic cardiac monitoring confirms the safety of the Ca test.

Context: The evaluation of basal calcitonin (bCT) and stimulated calcitonin (sCT) can be used for the diagnosis and follow-up of medullary thyroid cancer (MTC)., Objective: The aim of this study was to evaluate the reliability of high-calcium (Ca) test and to identify gender-specific thresholds for MTC diagnosis., Patients: Patients with MTC in remission (n=24) or in persistence (n=18), RET gene mutations carriers (n=14), patients with nodular goiter (n=69), and healthy volunteers (n=16) were submitted to pentagastrin and Ca (25 mg/kg) tests., Results: In all groups, the levels of calcitonin (CT) stimulated by either pentagastrin or Ca were significantly correlated. The prevalence of both C-cell hyperplasia (CCH) and MTC in women and men paralleled the increasing basal and peak CT levels in a gender-specific manner. Receiver operating characteristic plot analyses showed that the best levels of bCT to separate normal and CCH cases from MTC patients were above 18.7 pg/ml in females and above 68 pg/ml in males. Furthermore, Ca sCT above 184 pg/ml in females and above 1620 pg/ml in males had the highest accuracy to distinguish normal and CCH cases from patients with MTC. At the C-cell immunohistochemical examination, Ca sCT below 50 pg/ml corresponded to a mean number of 30 cells per 10 fields, whereas higher sCT associated with a mean number of 400 cells per 10 fields, often displaying a diffuse and nodular distribution pattern., Conclusions: High-dose Ca test is a potent and well-tolerated procedure that can be applied worldwide at a low cost. Reference ranges for Ca sCT levels in different groups of patients and CT thresholds to diagnose CCH/MTC have been identified.

Context: In patients with adrenal incidentalomas, subclinical hypercortisolism (SH) is associated with an increased prevalence of the metabolic syndrome. The effect of surgical/conservative approach is debated., Objective: The objective of the study was to determine the effect of the surgical and conservative approaches on the metabolic syndrome in patients with adrenal incidentalomas., Design: This was a retrospective longitudinal study (18-48 months follow-up)., Setting: The study was conducted on an in- and outpatient basis., Patients: One hundred eight patients with adrenal incidentalomas were studied for the presence of SH, which was diagnosed in the presence of more than two of the following: urinary free cortisol greater than 70 microg per 24 h (193 nmol per 24 h), cortisol after 1 mg dexamethasone suppression test greater than 3.0 microg/dl (83 nmol/liter), ACTH less than 10 pg/ml (2.2 pmol/liter)., Interventions: Surgery was performed in 25 patients with SH (group TrSH+) and 30 without SH (group TrSH-), whereas the conservative approach was chosen by 16 patients with SH (group UntrSH+) and 37 without SH (group UntrSH-)., Main Outcome Measures: During the follow-up, the improvement/worsening of body weight, blood pressure, or glucose and cholesterol levels was defined in the presence of a greater than 5% weight decrease/increase and following the European Society of Cardiology or the Adult Treatment Panel III criteria, respectively., Results: In group TrSH+, weight, blood pressure, and glucose levels improved (32, 56, and 48%, respectively) more frequently than in group UntrSH+ (12.5%, P = 0.05; 0.0%, P < 0.0001; 0.0%, P = 0.001; and 0.0%, P = 0.0014, respectively). In group UntrSH+, blood pressure, glucose, and low-density lipoprotein levels worsened more frequently (50.0, 37.5, and 50.0%, respectively) than in group TrSH+ (0.0%, P < 0.0001; 0.0%, P = 0.001; and 20.0%, P = 0.05, respectively)., Conclusions: Regarding the various components of the metabolic syndrome, in patients with adrenal incidentalomas and SH, surgery is beneficial.

Objective: Few data are available regarding the need of steroid substitutive therapy after unilateral adrenalectomy for adrenal incidentaloma (AI). It is unknown whether, before surgery, the hypothalamic-pituitary-adrenal (HPA) axis secretion parameters can predict post-surgical hypocortisolism., Aim: This study aimed to evaluate whether, in AI patients undergoing unilateral adrenalectomy, post-surgical hypocortisolism could be predicted by the parameters of HPA axis function., Design: Prospective, multicenter., Methods: A total of 60 patients underwent surgical removal of AI (surgical indication: 29 subclinical hypercortisolism (SH); 31 AI dimension). Before surgery, SH was diagnosed in patients presenting at least three criteria out of urinary free cortisol (UFC) levels>60 microg/24 h, cortisol after 1-mg dexamethasone suppression test (1 mg-DST)>3.0 microg/dl, ACTH levels<10 pg/ml, midnight serum cortisol (MSC)>5.4 microg/dl. Two months after surgery, HPA axis function was assessed by low dose ACTH stimulation test or insulin tolerance test when needed: 39 patients were affected (Group B) and 21 were not affected (Group A) with hypocortisolism. The accuracy in predicting hypocortisolism of pre-surgical HPA axis parameters or their combinations was evaluated., Results: The presence of >2 alterations among 1 mg-DST>5.0 microg/dl, ACTH<10 pg/ml, elevated UFC and MSC has the highest odds ratio (OR) for predicting post-surgical hypocortisolism (OR 10.45, 95% confidence interval, CI 2.54-42.95, P=0.001). Post-surgical hypocortisolism was predicted with 100% probability by elevated UFC plus MSC levels, but not ruled out even in the presence of the normality of all HPA axis parameters., Conclusion: Post-surgical hypocortisolism cannot be pre-surgically ruled out. A steroid substitutive therapy is indicated after unilateral adrenalectomy for SH or size of the adenoma.

Objective: Pregnancy represents a favorable condition for the development of thyroid nodules, likely due to the secretion of hormones with stimulatory activity. In particular, differentiated thyroid cancer (DTC) represents the second most frequent tumor among those diagnosed during pregnancy. However, few and discordant data are available about the impact of pregnancy on tumor outcome., Methods: A total of 123 women with DTC were divided into three groups according to the timing of tumor diagnosis (group 1, at least 1 year after the delivery; group 2, during pregnancy or in the first year after delivery; and group 3, before pregnancy or nulliparity) and evaluated according to the international guidelines. Furthermore, immunohistochemical studies of estrogen receptor alpha (ERalpha) were performed in 38 papillary thyroid cancer tissues from the three groups., Results: Thyroid cancer diagnosed during pregnancy was associated with a poorer prognosis compared to tumors developed in nongravidic periods (P<0.0001). Accordingly, at the stepwise logistic regression analysis, the diagnosis of DTC during pregnancy or in the first year post partum was the most significant indicator of persistent disease (P=0.001). Interestingly, ERalpha expression significantly differed among tumors of the three groups, being detected in 31% of group 1, in 87.5% of group 2, and in 0% of group 3 (P=0.01)., Conclusions: Present data indicate that pregnancy has a negative impact on the outcome of thyroid cancer. The presence of ERalpha in the majority of tumors diagnosed during pregnancy indicates that the poorer outcome of these cases could be related to the estrogen-mediated growth stimulus.

Objective: Primary hyperparathyroidism (PHPT) is often complicated by kidney stones. Hypercalciuria and urine oxalate excretion are considered risk factors for urolithiasis in PHPT as well as in idiopathic stone-formers. Recently, the anion-exchanger SLC26A6 has been involved in the oxalate metabolism., Design and Methods: We tested the hypothesis that the 206M polymorphic variant of SLC26A6 gene might contribute to the risk of kidney stones in PHPT. DNA samples from 145 PHPT patients and 129 age- and sex-matched healthy subjects were genotyped., Results: The homozygous 206V genotype was the most frequent both in PHPT patients and controls (79.3 and 74.4%), while heterozygosity for the 206M allele was detected in 20.0 and 23.3% respectively. The homozygous 206M genotype was extremely rare, occurring in 0.7 and 2.3% of PHPT and healthy subjects respectively. In the PHPT cohort, the prevalence of urolithiasis did not differ between the V/V and V/M+M/M groups and urine oxalate excretions did not correlate with the genotype. Considering the subset of PHPT stone formers (n=74), calciuria was lower in V/M+M/M patients with respect to V/V stone-formers (4.40+/-1.88 vs 5.92+/-2.62 mg/kg per 24 h; mean+/-s.d., P=0.034). Finally, the SLC26A6 206M alleles were significantly related to the presence of hypertension (73.3 vs 47.8%), showing an OR of 4.8., Conclusions: Though the SLC26A6 206M polymorphism did not correlate with kidney stone development in PHPT patients, PHPT stone-formers harbouring the M allele had a lower hypercalciuria. This observation and the high prevalence of hypertension associated with the 206M polymorphism need further investigation.

The calcium-sensing receptor (CaR) activation has recently been shown to modulate the ERK1 and ERK2 cascade in different cell lines. The present study investigated this pathway in human normal and tumoral parathyroid cells. In cells from normal parathyroids and almost all hyperplasia increasing extracellular calcium concentrations (Ca(o)(2+)) induced a significant activation of ERK1 and -2, the percent stimulation over basal activity (at 0.5 mM Ca(o)(2+)) being 545 +/- 140 and 800 +/- 205 in normal cells and 290 +/- 71 and 350 +/- 73 in hyperplasia at 1 and 2 mM Ca(o)(2+), respectively. This effect was mediated by CaR because it was mimicked by the receptor agonist gadolinium and neomycin. Basal and Ca(o)(2+)-stimulated ERK1 and -2 activity was nearly abolished by the PKC inhibitor calphostin C, and PKA changes did not affect ERK1 and -2 activity. PI3K blockade by wortmannin, known to prevent G protein betagamma subunit effect on ERK1 and -2, induced a 30% reduction of the Ca(o)(2+)-stimulated ERK1 and -2 activity. Adenomatous cells showed high PKC-dependent ERK1 and -2 activity in resting conditions that was unresponsive to high Ca(o)(2+). A role of MAPK on PTH secretion was suggested by the finding that PD98059, a specific MEK inhibitor, abolished the inhibitory effect of 1.5 mM Ca(o)(2+) on PTH release from normal parathyroid cells. In conclusion, these data first demonstrate that CaR activation, through the PKC pathway and, to a lesser extent, PI3K, increases ERK1 and -2 activity in normal parathyroid cells and this cascade seems to be involved in the modulation of PTH secretion by Ca(o)(2+). Interestingly, this signaling pathway is disrupted in parathyroid tumors.