Genetic and Molecular Biomarkers in Aggressive Pheochromocytomas and Paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neoplasms producing catecholamines that occur as hereditary syndromes in 25-40% of cases. To date, PPGLs are no longer classified as benign and malignant tumors since any lesion could theoretically metastasize, even if it occurs only in a minority of cases (approximately 10-30%). Over the last decades, several attempts were made to develop a scoring system able to predict the risk of aggressive behavior at diagnosis, including the risk of metastases and disease recurrence; unfortunately, none of the available scores is able to accurately predict the risk of aggressive behavior, even including clinical, biochemical, and histopathological features. Thus, life-long follow-up is required in PPGL patients. Some recent studies focusing on genetic and molecular markers (involved in hypoxia regulation, gene transcription, cellular growth, differentiation, signaling pathways, and apoptosis) seem to indicate they are promising prognostic factors, even though their clinical significance needs to be further evaluated. The most involved pathways in PPGLs with aggressive behavior are represented by Krebs cycle alterations caused by succinate dehydrogenase subunits (SDHx), especially when caused by SDHB mutations, and by fumarate hydratase mutations that lead to the activation of hypoxia pathways and DNA hypermethylation, suggesting a common pathway in tumorigenesis. Conversely, PPGLs showing mutations in the kinase cascade (cluster 2) tend to display less aggressive behavior. Finally, establishing pathways of tumorigenesis is also fundamental to developing new drugs targeted to specific pathways and improving the survival of patients with metastatic disease. Unfortunately, the rarity of these tumors and the scarce number of cases enrolled in the available studies represents an obstacle to validating the role of molecular markers as reliable predictors of aggressiveness.

Tumor Grade and Molecular Characteristics Associated with Survival in Sporadic Medullary Thyroid Carcinoma.

Background: The International Medullary Thyroid Carcinoma Grading System (IMTCGS) divides medullary thyroid carcinoma (MTC) into two categories, high- and low-grade tumors, which has a profound impact on patient outcomes. The aim of this study was to explore the association between IMTCGS grading, clinical data, and molecular status in sporadic MTC. Methods: A retrospective cohort study was performed on consecutive sporadic MTCs from patients undergoing initial surgery between January 2000 and January 2022 at the Padua Endocrine Surgery Unit. Clinical, pathological, and follow-up data were collected, tumors were graded, and somatic mutations of RET and RAS genes were analyzed. Patient outcomes were based on Ct levels and MTC-related deaths. Survival analyses were carried out employing the Kaplan-Meier method and the log-rank test. A Cox proportional hazard regression model was employed for multivariable survival analysis with the following covariates: somatic RET mutation, MTC stage at diagnosis, sex, age at diagnosis, and IMTCGS grade. Results: We included 141 consecutive sporadic MTCs. The median follow-up was 80.0 months (interquartile ranges: 41.5-122.5 months). Seventeen patients (12.1%) died from disease-related causes. 107/141 (76.9%) were classified as low-grade tumors, 32/141 (23.1%) as high-grade. Patients carrying a RET mutation had more aggressive features and shorter disease-specific survival (DSS) (p = 0.001) and were more frequently classified high-grade than low-grade MTC (p < 0.001). At multivariable survival analysis, only IMTCGS grading was independently associated with DSS (hazard ratio 8.8 [confidence interval: 2.7-28.3], p = 0.005). RET mutations, in particular RET-M918T, were more frequent in high-grade than in low-grade MTC (68.8% vs. 29.4% mutated in RET, 46.9% vs. 12.7% mutated in RET-M918T; p < 0.001). None of the high-grade tumors was mutated in the RAS gene, but the mutation was present in 11.8% of low-grade tumors. Conclusions: IMTCGS grading was associated with DSS independently of other clinical, pathological, and molecular factors. Moreover, MTC grading was associated with RET and RAS patterns, which explains, at least in part, the molecular basis of the aggressive behavior of high-grade MTC.

Water and Electrolyte Content in Salt-Dependent HYpertension in the SKIn (WHYSKI): Effect of Surgical Cure of Primary Aldosteronism.

 INTRODUCTION: This study will test the hypothesis that primary aldosteronism (PA) involves alterations in Na+, K+, and water content in the skin that are corrected by adrenalectomy. AIM AND METHODS: In skin biopsies, we will measure the content of Na+, K+, water, by physical-chemical methods and the osmotic-stress-responsive transcription factor Tonicity-responsive Enhancer Binding Protein (TonEBP, NFAT5) mRNA copy number by droplet digital PCR, in sex-balanced cohorts of 18 -75-year-old consecutive consenting patients with unilateral and bilateral PA, primary (essential) hypertension, and normotension. Before surgery, the patients with unilateral PA will receive the mineralocorticoid receptor antagonist (MRA) canrenone at doses that correct hypokalemia and high blood pressure values. They will be reassessed in an identical way one month after surgical cure, while off MRA. PA patients not selected for adrenalectomy will similarly be assessed at diagnosis and follow-up while on stable MRA treatment. Since a pilot study showed a direct correlation of dry weight (DW) with skin electrolytes and water content and significant differences of biopsy DW between surgery and follow-up, meaningful comparison of the skin cations and water content and TonEBP mRNA copy number, between specimen obtained at different time points, will require DW- and total mRNA-adjustment, respectively. CONCLUSION: This study will provide novel information on the skin Na+, K+ and water content in PA, the paradigm of salt-dependent hypertension, and novel knowledge on the effect of surgical cure of hyperaldosteronism. The TonEBP-mediated regulation of Na+, K+ and water content in the skin will also be unveiled. TRAIL REGISTRY: Trial Registration number: NCT06090617. Date of Registration: 2023-10-19.

Total adrenalectomy versus subtotal adrenalectomy for bilateral pheochromocytoma: meta-analysis.

BACKGROUND: Bilateral pheochromocytomas are rare and often heritable. Total adrenalectomy leads to a definitive oncological cure, with subsequent definitive hypocortisolism. Subtotal adrenalectomy is a possible alternative. The aim of this study was to assess the effects of total adrenalectomy and subtotal adrenalectomy on bilateral pheochromocytoma in terms of post-surgical rate of recurrence, metastatic disease, and steroid dependence. METHODS: Systematic searches in the bibliographic databases PubMed, Embase, and Europe PMC were performed for 1945 to 1 June 2023. PRISMA guidelines were followed and the PICO strategy was applied to English-language studies comparing subtotal adrenalectomy with total adrenalectomy. A random-effects model was used to assess the different outcomes for studies with high heterogeneity. The Newcastle-Ottawa scale and the Risk Of Bias In Non-randomized Studies of Interventions ('ROBINS-I') tool were used to assess quality and risk of bias. RESULTS: From a total of 12 909 studies, 1202 patients (from 10 retrospective studies) were eligible for the meta-analysis. In six studies, including 1176 patients, the recurrence rate after subtotal adrenalectomy and total adrenalectomy was 14.1 versus 2.6 per cent respectively (OR 4.91, 95 per cent c.i. 1.30 to 18.54; P = 0.020; I2 72 per cent). In nine studies, including 1124 patients, the rate of post-surgical steroid dependence was 93.3 versus 11.6 per cent after total adrenalectomy and subtotal adrenalectomy respectively (OR 0.003, 95 per cent c.i. 0.0003 to 0.03; P < 0.00001; I2 66 per cent). Based on two studies, including 719 patients, no differences were evident regarding the occurrence of post-surgery metastatic disease. CONCLUSION: Subtotal adrenalectomy leads to less post-surgical primary adrenal insufficiency, but leads to a higher postoperative recurrence rate. Future prospective randomized studies, with clear eligibility criteria, are needed to confirm these results.

Long-Term Outcomes after Surgery for Pheochromocytoma and Sympathetic Paraganglioma.

BACKGROUND: The prognosis of pheochromocytoma and sympathetic paraganglioma (PHEO/sPGL) is difficult to predict at the time of diagnosis and long-term follow-up data are scarce, especially for apparently benign and sporadic variants. The aim of the study was to analyze the long-term outcomes in PHEO/sPGL patients. METHODS: A monocentric series of 170 patients who underwent surgery for PHEO/sPGL was analyzed. RESULTS: The study cohort included 91 female and 79 males with a median age of 48 years (range 6-83). The majority of PHEO/sPGL cases were considered apparently benign at the time of diagnosis; evident malignant behavior was found in 5% of cases. The overall 10-year risk of recurrence was 13%, but it rose up to 33% at 30 years. The risk of new tumor recurrence was higher in patients with hereditary tumors, but the risk was still significant in patients with apparently sporadic variants (20-year risk: 38% vs. 6.5%, respectively; p < 0.0001). The risk of metastatic recurrence was higher in patients with locally aggressive tumors at diagnosis, but the risk was present also in apparently benign variants (5-year risk: 100% vs. 1%, respectively; p < 0.0001). CONCLUSIONS: Lifelong follow-up is required not only for hereditary PHEO/sPGL but also for apparently benign and sporadic tumors at diagnosis because of the risk of long-term recurrent disease.

CT Texture Analysis of Adrenal Pheochromocytomas: A Pilot Study.

Radiomics is a promising research field that combines big data analysis (from tissue texture analysis) with clinical questions. We studied the application of CT texture analysis in adrenal pheochromocytomas (PCCs) to define the correlation between the extracted features and the secretory pattern, the histopathological data, and the natural history of the disease. A total of 17 patients affected by surgically removed PCCs were retrospectively enrolled. Before surgery, all patients underwent contrast-enhanced CT and complete endocrine evaluation (catecholamine secretion and genetic evaluation). The pheochromocytoma adrenal gland scaled score (PASS) was determined upon histopathological examination. After a resampling of all CT images, the PCCs were delineated using LifeX software in all three phases (unenhanced, arterial, and venous), and 58 texture parameters were extracted for each volume of interest. Using the Mann-Whitney test, the correlations between the hormonal hypersecretion, the malignancy score of the lesion (PASS > 4), and texture parameters were studied. The parameters DISCRETIZED_HUpeak and GLZLM_GLNU in the unenhanced phase and GLZLM_SZE, CONVENTIONAL_HUmean, CONVENTIONAL_HUQ3, DISCRETIZED_HUmean, DISCRETIZED_AUC_CSH, GLRLM_HGRE, and GLZLM_SZHGE in the venous phase were able to differentiate secreting PCCs (p < 0.01), and the parameters GLZLM_GLNU in the unenhanced phase and GLRLM_GLNU and GLRLM_RLNU in the venous differentiated tumors with low and high PASS. CT texture analysis of adrenal PCCs can be a useful tool for the early identification of secreting or malignant tumors.

The role of procalcitonin in the follow-up of medullary thyroid cancer.

Objective: Calcitonin (Ct) represents the most important biochemical marker of medullary thyroid cancer (MTC), but has certain limits. We analyzed the performance of procalcitonin (ProCt) in follow-up MTC patients. Methods: In this monocentric and retrospective study, we consecutively obtained ProCt and Ct values from all MTC patients that we visited during the period from April 2021 to May 2022. Patients were defined as having structural evidence of disease (29/90, 32.2%) irrespective of Ct values or, in its absence, as not evident disease (NED) if Ct was ≤10 ng/L (47/90, 52.2%), or minimal residual disease if Ct was >10 ng/L (14/90, 15.6%). Results: Ct and ProCt values were highly correlated (r = 0.883, P < 0.01). Median ProCt values differed between NED, minimal residual disease, and structural disease, being 0.04 ng/mL, 0.26 ng/mL, and 1.98 ng/mL, respectively (P < 0.01). ProCt was undetectable (<0.04 ng/mL) in 40/47 (85.1%) of NED patients, in 3/14 (21.4%) patients with minimal residual disease and in none of the patients with a structural disease (P < 0.01). Among the 11 patients with detectable but ≤10 ng/L Ct and undetectable ProCt values, none had a structural disease. The most accurate cut-off of ProCt to distinguish between the presence or absence of a structural disease was >0.12 ng/mL (P < 0.01, area under the curve: 0.963), with the following sensitivity, specificity, positive predictive value, and negative predictive value (NPV): 100%, 83.61%, 74.4%, and 100.0%. Conclusions: ProCt and Ct have a high correlation in MTC follow-up. ProCt may be useful as an adjunct to Ct, especially for its NPV concerning the structural disease.

Prophylactic and Early Thyroidectomy in RET Germline Mutation Carriers in Pediatric and Adult Population: Long-Term Outcomes of a Series of 63 Patients.

Prophylactic and early thyroidectomy in RET germline mutation carriers allows the removal of the thyroid before medullary thyroid carcinoma (MTC) develops, or while it is still confined to the gland. This study was aimed to assess the clinicopathological features in RET carriers according to the age at surgery and the long-term outcomes after prophylactic and early thyroidectomy. A retrospective analysis of 63 operated asymptomatic RET carriers diagnosed after familial genetic screening was performed. Twenty-one RET carriers were operated at pediatric (<18 yrs) and 42 at adult (≥18 yrs) age. Serum preoperative calcitonin levels were significantly lower in pediatric compared to adult patients (p = 0.04); moreover, adult RET carriers had a greater frequency of microMTC at pathology (p = 0.009). Permanent postoperative morbidity occurred in 9.5% of patients, without differences between the two groups. Biochemical postoperative cure was achieved in all patients. At a median follow-up of 14 years, all C-cell hyperplasia patients are disease-free; conversely, biochemical, and structural recurrence of disease occurred in three adults and one pediatric patient with microMTC. The independent predictive factors of MTC were the age at surgery, the preoperative calcitonin level and the RET mutational risk profile (p < 0.02). In conclusion, prophylactic and early thyroidectomy are safe and effective procedures in achieving definitive cure in most RET carriers. However, since recurrences may occur at long-term in case of microMTC, thyroidectomy should be possibly performed earlier to prevent microMTC development.

The Overall Survival and Progression-Free Survival in Patients with Advanced Adrenocortical Cancer Is Increased after the Multidisciplinary Team Evaluation.

We aimed to evaluate the role of adrenal multidisciplinary team evaluation (MTE) in affecting the overall survival (OS) and progression-free survival (PFS) in patients with adrenocortical carcinoma (ACC). We included in a retrospective monocentric study 47 patients with ACC. We divided our cohort into group 1 (without adrenal-MTE discussion, ACC diagnosis from 2004 to 2012, n = 14) and group 2 (diagnosis and beginning of treatments after 2013, all discussed in the adrenal MTE, n = 33). OS was defined by the survival between the first and the last visit, while PFS as the time from the first visit to the progression of the disease. Kaplan−Meier curves were used to compare OS and PFS between Group 1 and Group 2. Group 1stages III−IV (n = 10) presented a shorter median OS than Group 2stages III−IV (25 patients, 4 vs. 31 months, p = 0.023). Likewise, the median PFS was lower in Group 1 as compared to Group 2 (2.9 vs. 17.2 months, p < 0.001). The gain in PFS (6 months) was also confirmed in stage III-IV patients (2.9 vs. 8.7 months, respectively, for Group 1 and Group 2, p = 0.02). Group 1 presented a median PFS of 4 months, while the median PFS of Group 2 was 14.7 months (p = 0.128). In conclusion, we found a significant gain in terms of survival in patients after the MTE discussion in 2013. Therefore, ACC patients should be referred to a tertiary center, ideally from the time of diagnosis, to promptly apply all available treatments, according to the single patient's clinical history and based on multidisciplinary management.

Aldosterone and cortisol synthesis regulation by angiotensin-(1-7) and angiotensin-converting enzyme 2 in the human adrenal cortex.

OBJECTIVE: The branch of the renin--angiotensin system constituting angiotensin-(1-7) [Ang-(1-7)], the Ang II type 2 receptor, the Mas receptors and the Ang-(1-7)-forming enzyme ACE-2, by counteracting the Ang II type 1 receptor (AT1R)-mediated effects, are held to be cardiovascular protective in several conditions. However, whether Ang-(1-7) and ACE-2 are detectable in human adrenocortical tissues and whether they affect aldosterone and cortisol biosynthesis was unknown. METHODS: We measured angiotensin peptides with liquid chromatography tandem-mass spectrometry and ACE-2 mRNA with digital droplet (dd)PCR in human aldosterone-producing adenoma (APA) and APA-adjacent tissue obtained from patients with primary aldosteronism. We also investigated the effects of Ang-(1-7) and the ACE-2 activator diminazene aceturate (DIZE) on aldosterone synthase (CYP11B2) and 11ß-hydroxylase (CYP11B1) gene expression, in the absence or presence of the AT1R antagonist irbesartan, or of the MasR antagonist A779. RESULTS: APA and APA-adjacent adrenocortical tissues express ACE-2 mRNA and contain detectable amounts of Ang II and Ang-(2-8), but not of Ang I, Ang-(1-5), Ang (3-8) and Ang-(1-7). Under unstimulated and Ang II- stimulated conditions Ang-(1-7) did not blunt CYP11B1 and CYP11B2 mRNA. At supraphysiological concentrations (10-4 mol/l), Ang-(1-7) stimulated both CYP11B1 and CYP11B2 mRNA via the AT1R. The ACE-2 activator DIZE increased by 1.5-fold ACE-2 mRNA but did not blunt Ang II- upregulated CYP11B1 and CYP11B2 expression. CONCLUSION: These results do not support the hypothesis that the ACE-2/Ang-(1-7)/MasR axis play a protective role by counteracting enhanced aldosterone secretion in humans.

Resolution of drug-resistant hypertension by adrenal vein sampling-guided adrenalectomy: a proof-of-concept study.

Drug-resistant hypertension (RH) is a very high-risk condition involving many hypertensive patients, in whom primary aldosteronism (PA) is commonly overlooked. Hence, we aimed at determining if (1) adrenal vein sampling (AVS) can identify PA in RH patients, who are challenging because of receiving multiple interfering drugs; (2) AVS-guided adrenalectomy can resolve high blood pressure (BP) resistance to treatment in these patients. Based on a pilot study we selected from 1016 consecutive patients referred to our Centre for 'difficult-to-treat' hypertension those with RH, for an observational prospective cohort study. We excluded those non-adherent to treatment (by therapeutic drug monitoring) and those with pseudo-RH (by 24-h BP monitoring), which left 110 patients who met the European Society of Cardiology/European Society of Hypertension (ESC/ESH) 2013 definition for RH. Of these patients, 77 were submitted to AVS, who showed unilateral PA in 27 (mean age 55 years; male/female 19/8). Therefore, these patients underwent AVS-guided laparoscopic unilateral adrenalectomy, which resolved RH in all: 20% were clinically cured in that they no longer needed any antihypertensive treatment; 96% were biochemically cured. Systolic and diastolic BP fell from 165/100 ± 26/14 mmHg at baseline, to 132/84 ± 14/9 mmHg at 6 months after surgery (P<10-4 for both) notwithstanding the fall of number and defined daily dose (DDD) of antihypertensive drugs required to achieve BP control (P<10-4 for both). A prominent regression of cardiac and renal damage was also observed. Thus, the present study shows the feasibility of identifying PA by AVS in RH patients, and of resolving high BP resistance to treatment in these patients by AVS-guided adrenalectomy.

PTH: Redefining Reference Ranges in a Healthy Population-The Role of Interfering Factors and the Type of Laboratory Assay.

Introduction. Parathyroid hormone (PTH) is a linear peptide constituted by 84 amino acids and active in its 1-84 form, but a wide range of PTH forms produced by its post-transcriptional modifications are present in blood. Many assays with different specificities are commercially available. The aim of our study was to compare a 2nd and 3rd generation in healthy population in order to better define the reference range in the healthy population residing in our region. Materials and Methods. 108 subjects (53 females and 55 males) referring to the transfusion donor were enrolled in the study centre in April 2016 and underwent PTH levels measurements with a 3rd generation kit (chemiluminescent immunoassay DiaSorin Liaison) and with a 2nd generation kit (immunoradiometric assay Total Intact PTH Assay (Coated Tube), Scantibodies). Also calcium, phosphate, creatinine, and 25OHD3 were measured. A questionnaire on lifestyle and dietary habits was obtained. RESULTS: The median PTH values obtained with the 2nd generation assay and the whole 3rd generation assay were 20.26 pg/ml and 23.11 pg/ml, respectively. Bland-Altman method showed substantial concordance between the two PTH assays, although with an overestimation of the 3rd generation method over the 2nd generation method. There was no correlation between 3rd generation PTH and 25OHD3 and creatinine. Calcium was negatively correlated with PTH only when measured with 3rd generation kit. CONCLUSIONS: On the basis of our data, obtained from healthy subjects, we can conclude that the reference range used by our laboratory was too narrow and was necessary to reestablish normal ranges according to our population. This is useful to avoid hyperparathyroidism misdiagnosis.

Long-Term Outcomes of Parathyroidectomy in Hyperparathyroidism-Jaw Tumor Syndrome: Analysis of Five Families with CDC73 Mutations.

BACKGROUND: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare disease caused by CDC73 germline mutations, with familial primary hyperparathyroidism (pHPT), ossifying jaw tumors, genito-urinary neoplasms. The present study was aimed at determining the long-term postoperative outcome of parathyroidectomy in HPT-JT. METHODS: A retrospective analysis of a single-center series of 20 patients from five unrelated HPT-JT families undergoing parathyroid surgery was performed. RESULTS: Pathology confirmed a single-gland involvement in 95% of cases at onset. Parathyroid carcinoma occurred in three patients undergoing en-bloc parathyroidectomy and thyroid lobectomy: parathyroid benign lesions in 17 patients undergoing subtotal parathyroidectomy for evident multiglandular involvement (n = 1) or selective parathyroidectomy for single-gland involvement (n = 16), during bilateral (n = 13) or targeted unilateral neck exploration (n = 7). At a median overall follow-up of 16 years (range 2.5-42), patients with parathyroid carcinoma had a persistent/recurrent disease in 66.6%; patients with benign lesions had recurrent pHPT in 23.5% after a prolonged disease-free period; recurrent benign pHPT occurred slightly more often in cases of discordant preoperative localization (60% vs 9%; p = 0.06). CONCLUSION: pHPT in HPT-JT is generally characterized by a benign and single-gland involvement, with a relatively increased risk of malignancy (15%). Parathyroid carcinoma needs extensive surgery because of high risk of permanent/recurrent disease (66.6%). In benign involvement, targeted unilateral exploration with selective parathyroidectomy may be effective in cases of concordant single-gland localization at preoperative localization imaging techniques. Bilateral neck exploration with subtotal parathyroidectomy might be preferred in cases of negative or discordant preoperative localization, because of the increased risk of multiglandular involvement and long-term recurrences (23.5%).

Surgical approaches and results of treatment for hereditary paragangliomas.

Paragangliomas (PGL) are rare neuroendocrine tumours; parasympathetic PGL are predominantly non-secreting and located at the skull base and neck, while sympathetic PGL are typically catecholamine-secreting and located at abdomino-pelvic level. Approximately 40% of PGL may be caused by germline mutations; hereditary variants should be suspected especially in case of positive family history, early onset, multifocal, or recurrent PGL. Significant genotype-phenotype correlation has been recognized, including syndromic presentation, location, multifocality and risk of malignancy. Surgical resection remains the only curative strategy, but the outcomes may be unsatisfactory because of surgical morbidity and recurrence rate. However, due to the rarity of the disease, most data derive from case-report or limited series. This paper was aimed to review the available literature on the epidemiology, diagnosis, clinical features, treatment of PGL in order to discuss the surgical approach and the results of treatment in hereditary PGL.

Effect of unilateral adrenalectomy on the quality of life of patients with lateralized primary aldosteronism.

BACKGROUND: Primary aldosteronism (PA) is associated with an increased prevalence of anxiety and depression. Subnormal quality of life (QoL) scores in PA patients may be improved after surgical treatment. The aim of the study was to assess the impact of surgery on health-related QoL and depression status of patients suffering from PA, comparing the results with a control group of patients undergoing surgery for non-secreting adrenal tumors. METHODS: Data on QoL and depression status were prospectively collected, from January 2014 to January 2017, before, early after surgery (at 1 month) and at late follow up (at least 6 months) in patients with unilateral PA and in a control group with non-secreting adrenal tumors submitted to unilateral laparoscopic adrenalectomy. QoL was assessed using the Short Form 36 (SF-36) Health Survey for Physical (PCS) and Mental Component (MCS); the depression status by a 20-item depression scale (DS) questionnaire. RESULTS: Twenty-six PA patients and 15 controls were recruited. Biochemical cure of the disease was achieved following surgery in all PA patients; hypertension was cured in 31% of cases and improved in the remaining 69% of cases. No morbidity occurred in both groups. There were no significant differences between PA patients and controls concerning demographics, preoperative PCS, MCS and DS values. In patients with PA, MCS values improved at early (42.72 ± 13.68 vs 51.56 ± 9.03, p = 0.0005) and late follow up (42.72 ± 13.68 vs 51.81 ± 7.04, p < 0.0001); also DS values improved at early (15.92 ± 11.98 vs 8.3 ± 8.8, p = 0.0002) and late follow up (15.92 ± 11.98 vs 4.57 ± 6.11, p < 0.0001). In PA patients PCS values significantly improved at late follow up (51.02 ± 8.04 vs 55.85 ± 5.1, p = 0.013). Also in controls an improvement of MCS and DS scores was found at early and late follow up compared to preoperative values, while no significant differences in PCS were found. CONCLUSIONS: Both PA and non-secreting adrenal tumors affect health-related QoL, worsening MCS and DS scores. Adrenalectomy is effective in curing PA, and improving MCS and DS scores at early and late follow-up, in patients with PA and non-secreting adrenal tumors. In PA patient surgery also significantly improves PCS at late follow up.

PTH Modulation by Aldosterone and Angiotensin II is Blunted in Hyperaldosteronism and Rescued by Adrenalectomy.

CONTEXT: Accumulating evidence suggests a link between adrenocortical zona glomerulosa and parathyroid gland through mechanisms that remain unexplored. OBJECTIVES: To test the hypothesis that in vivo angiotensin II blockade affects PTH secretion in patients with hypertension and that aldosterone and angiotensim II directly stimulate PTH secretion ex vivo. DESIGN AND SETTING: We investigated the changes of serum PTH levels induced by oral captopril (50 mg) administration in patients with primary essential hypertension (EH) and with primary aldosteronism (PA) caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA), the latter before and after adrenalectomy. We also exposed primary cultures of human parathyroid cells from patients with primary hyperparathyroidism to angiotensin II (10-7 M) and/or aldosterone (10-7 M). RESULTS: Captopril lowered PTH levels (in nanograms per liter) both in patients with EH (n = 63; 25.9 ± 8.3 baseline vs 24.4 ± 8.0 postcaptopril, P < 0.0001) and in patients with APA after adrenalectomy (n = 27; 26.3 ± 11.6 vs 24.0 ± 9.7 P = 0.021). However, it was ineffective in patients with full-blown PA caused by APA and BAH. In primary culture of human parathyroid cells, both aldosterone (P < 0.001) and angiotensin II (P = 0.002) markedly increased PTH secretion from baseline, by acting through mineralocorticoid receptor and angiotensin type 1 receptor, as these effects were abolished by canrenone and irbesartan, respectively. CONCLUSION: These results collectively suggest an implication of the renin-angiotensin-aldosterone system in PTH regulation in humans, at least in PTH-secreting cells obtained from parathyroid tumors. Moreover, they further support the concept that mild hyperparathyroidism is a feature of human PA that is correctable with adrenalectomy.

Cure and survival of sporadic medullary thyroid carcinoma following systematic preoperative calcitonin screening.

BACKGROUND: The improvement in outcome of sporadic medullary thyroid carcinoma (MTC) during the last decades remains controversial, even if a trend toward a better prognosis has been recently proposed. This study was aimed to determine the time trend cure and survival rates in sporadic MTC according to the use of systematic preoperative calcitonin screening. METHODS: Retrospective analysis of 178 sporadic MTC patients operated between 1980 and 2017 was performed. The impact of prognostic factors on cure and survival following the introduction of routine preoperative calcitonin screening in 2001 was evaluated according to the year of surgery. RESULTS: Since 2001, a significant decline of node-positive tumors (from 56.1 to 34.7%) and advanced stage at diagnosis (stage III/IV from 56.1 to 34.7%) occurred, with a concomitant significant increase in cure rate (64.5% vs 38.6%; p = 0.0012) and survival (p < 0.05). At univariate analysis, the cure was achieved more frequently in more recently operated patients (64.5% vs 38.6%; p = 0.0012), in disease staging I/II (86.5% vs 13.5%; p < 0.0001), in patients undergoing preoperative calcitonin screening (63.8% vs 23.5%; p < 0.0001) and in the absence of lymph node metastases (86.5% vs 13.5%; p < 0.0001). At multivariate analysis, only preoperative calcitonin screening and stage at diagnosis turned out to be significant independent prognostic factors for cure and survival. CONCLUSION: The outcome of sporadic MTC improved in the new millennium; diagnosis was achieved earlier, at a less advanced stage. Routine preoperative calcitonin screening may have contributed to improve cure and survival rates.