Severe hypothyroidism as a trigger for Brugada-type ECG abnormalities: a case report and literature review

SUMMARY Brugada syndrome (BrS) is an inherited disorder that can cause ventricular fibrillation and sudden cardiac death in individuals with otherwise structurally normal hearts. Several provoking factors are known to potentially unmask or exacerbate a typical Brugada ECG pattern in predisposed subjects. Hypothyroidism has been suggested as one of these triggers, but the exact mechanisms underlying this relationship remain poorly understood. Moreover, the severity of thyroid dysfunction beyond which a Brugada-type ECG alteration might be triggered is still unclear. We report the case of a 33-year-old male who displayed a Brugada type 1 ECG pattern and was diagnosed with severe hypothyroidism (TSH > 100 mU/L with undetectable levels of fT4 and fT3). Hormonal replacement therapy with levothyroxine was initiated at increasing doses; serial biochemical and ECG controls were performed, initially every 3 weeks up to 15 weeks and afterward every 3 months. The regression of typical Brugada ECG waveforms could be seen at an early stage, when the patient was still taking a low dose of levothyroxine (37.5 µg/day, i.e., one-fourth of his final requirements of 150 µg/day), and laboratory tests still showed a marked alteration of thyroid hormonal parameters. Hypothyroidism may act as a trigger for Brugada-type ECG abnormalities, but a very severe alteration of the hormonal parameters is necessary to prompt these alterations. In our case, the initiation of replacement therapy with levothyroxine rapidly reversed the ECG modifications, even at a low subtherapeutic dose.

Pathophysiology and Management of Glycemic Alterations before and after Surgery for Pheochromocytoma and Paraganglioma.

Glycemic alterations are frequent in patients with pheochromocytoma and paraganglioma (PPGL), but the real incidence of secondary diabetes mellitus (DM) is uncertain, because prospective multicenter studies on this topic are lacking in the literature. The main pathophysiological mechanisms of glucose homeostasis alterations in PPGL, related to catecholamine hypersecretion, are impaired insulin and glucagon-like peptide type 1 (GLP-1) secretion and increased insulin resistance. Moreover, it has been reported that different pathways leading to glucose intolerance may be related to the secretory phenotype of the chromaffin tumor. Predictive factors for the development of glucose intolerance in PPGL patients are a higher age at diagnosis, the need for a higher number of anti-hypertensive drugs, and the presence of secreting neoplasms. Tumor resection is strongly related to the resolution of DM in PPGL patients, with a significant improvement of glycemic control in most cases. We can hypothesize a different personalized therapeutic approach based on the secretory phenotype. The adrenergic phenotype is more closely related to reduced insulin secretion, so insulin therapy may be required. On the other hand, the noradrenergic phenotype mainly acts by increasing insulin resistance and, therefore, insulin-sensitizing antidiabetic agents can find a greater application. Regarding GLP-1 receptor agonists, the data suggest a possible promising therapeutic effect, based on the assumption that GLP-1 secretion is impaired in patients with PPGL. The principal predictors of remission of glycemic alterations after surgery for PPGL are a lower preoperative body mass index (BMI), a larger tumor, higher preoperative catecholamine levels, and a shorter duration of the disease (under three years). Otherwise, after resection of PPGL, hypoglycemia can occur as the result of an excessive rebound of preoperative hyperinsulinemia. It is a rare, but potentially severe complication reported in a lot of case reports and a few small retrospective studies. Higher 24-h urinary metanephrine levels, longer operative times and larger tumors are predictive factors for hypoglycemia in this setting. In conclusion, alterations of carbohydrate metabolism are clinically relevant manifestations of PPGL before and after surgery, but there is the need to conduct multicenter prospective studies to obtain an adequate sample size, and to allow the creation of shared strategies for the clinical management of these potentially severe manifestations of PPGL.

A retrospective study on the association between urine metanephrines and cardiometabolic risk in patients with nonfunctioning adrenal incidentaloma.

Several studies argued that cardiovascular evaluation of patients with nonfunctioning adrenal incidentaloma is of particular importance. Therefore, we aimed to evaluate the possibility of stratifying the cardiometabolic risk using metanephrine levels in this setting of patients. A retrospective cross-sectional study was designed, collecting data of metanephrine values in 828 patients with nonfunctioning adrenal incidentaloma, referred to our Division within the University of Turin between 2007 and 2021. The univariate analysis showed associations between urine metanephrines and cardiometabolic variables/parameters, particularly considering the noradrenaline metabolite. At the univariate regression, normetanephrine was associated with metabolic syndrome (OR = 1.13, p = 0.002), hypertensive cardiomyopathy (OR = 1.09, p = 0.026), microalbuminuria (OR = 1.14, p = 0.024), and eGFR < 60 mL/min/1.73 m2 (OR = 1.11, p = 0.013), while metanephrine was associated with microalbuminuria (OR = 1.50, p = 0.008). At multivariate regression, considering all major cardiovascular risk factors as possible confounders, normetanephrine retained a significant association with metabolic syndrome (OR = 1.10, p = 0.037). Moreover, metanephrine retained a significant association with the presence of microalbuminuria (OR = 1.66, p = 0.003). The present study showed a further role for metanephrines in the cardiovascular risk stratification of patients with nonfunctioning adrenal incidentaloma. Individuals with high levels of these indirect markers of sympathetic activity should be carefully monitored and may benefit from an aggressive treatment to reduce their additional cardiometabolic burden.

Clinical and Pathological Tools for Predicting Recurrence and/or Metastasis in Patients with Pheochromocytoma and Paraganglioma.

Pheochromocytomas and paragangliomas are endocrine tumors belonging to the family of neural crest cell-derived neoplasms. They have an extremely variable clinical course, characterized by a non-negligible percentage of relapse and/or metastasis after radical surgery. To date, there are no reliable methods to predict the metastatic potential of these neoplasms, despite several clinical, molecular, and histopathological factors that have been extensively studied in the literature as predictors of the recurrence and/or metastasis in these neoplasms with different performances and results. In this review, we aimed to discuss and analyze the most important clinical and histopathological tools for predicting recurrence risk in patients affected by pheochromocytomas or paragangliomas. Thus, we compared the main available predictive models, exploring their applications in stratifying patients' risks. In conclusion, we underlined the importance of simple and validated tools to better define disease aggressiveness and establish tailored patients' treatments and follow-ups.

The metabolic phenotype of patients with primary aldosteronism: impact of subtype and sex - a multicenter-study of 3566 Caucasian and Asian subjects.

Background: Accumulating evidence suggests that primary aldosteronism (PA) is associated with several features of the metabolic syndrome, in particular with obesity, type 2 diabetes mellitus, and dyslipidemia. Whether these manifestations are primarily linked to aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) remains unclear. The aim of the present study was to investigate differences in metabolic parameters between APA and IHA patients and to assess the impact of treatment on these clinical characteristics. Methods: We conducted a retrospective multicenter study including 3566 patients with APA or IHA of Caucasian and Asian origin. We compared the prevalence of metabolic disorders between APA and IHA patients at the time of diagnosis and 1-year post-intervention, with special references to sex differences. Furthermore, correlations between metabolic parameters and plasma aldosterone, renin, or plasma cortisol levels after 1 mg dexamethasone (DST) were performed. Results: As expected, APA patients were characterized by higher plasma aldosterone and lower serum potassium levels. Only female IHA patients demonstrated significantly worse metabolic parameters than age-matched female APA patients, which were associated with lower cortisol levels upon DST. One-year post-intervention, female adrenalectomized patients showed deterioration of their lipid profile, when compared to patients treated with mineralocorticoid receptor antagonists. Plasma aldosterone levels negatively correlated with the BMI only in APA patients. Conclusions: Metabolic alterations appear more prominent in women with IHA. Although IHA patients have worse metabolic profiles, a correlation with cortisol autonomy is documented only in APAs, suggesting an uncoupling of cortisol action from metabolic traits in IHA patients.

From SGAP-Model to SGAP-Score: A Simplified Predictive Tool for Post-Surgical Recurrence of Pheochromocytoma.

A reliable prediction of the recurrence risk of pheochromocytoma after radical surgery would be a key element for the tailoring/personalization of post-surgical follow-up. Recently, our group developed a multivariable continuous model that quantifies this risk based on genetic, histopathological, and clinical data. The aim of the present study was to simplify this tool to a discrete score for easier clinical use. Data from our previous study were retrieved, which encompassed 177 radically operated pheochromocytoma patients; supervised regression and machine-learning techniques were used for score development. After Cox regression, the variables independently associated with recurrence were tumor size, positive genetic testing, age, and PASS. In order to derive a simpler scoring system, continuous variables were dichotomized, using > 50 mm for tumor size, ≤ 35 years for age, and ≥ 3 for PASS as cut-points. A novel prognostic score was created on an 8-point scale by assigning 1 point for tumor size > 50 mm, 3 points for positive genetic testing, 1 point for age ≤ 35 years, and 3 points for PASS ≥ 3; its predictive performance, as assessed using Somers' D, was equal to 0.577 and was significantly higher than the performance of any of the four dichotomized predictors alone. In conclusion, this simple scoring system may be of value as an easy-to-use tool to stratify recurrence risk and tailor post-surgical follow-up in radically operated pheochromocytoma patients.

Development and internal validation of a predictive model for the estimation of pheochromocytoma recurrence risk after radical surgery.

Objective: Various features have been identified as predictors of relapse after complete resection of pheochromocytoma, but a comprehensive multivariable model for recurrence risk prediction is lacking. The aim of this study was to develop and internally validate an integrated predictive model for post-surgical recurrence of pheochromocytoma. Methods: The present research retrospectively enrolled 177 patients affected by pheochromocytoma and submitted to radical surgery from 1990 to 2016, in nine referral centers for adrenal diseases. Cox regression analysis was adopted for model development, and a bootstrapping procedure was used for internal validation. Results: Variables independently associated with recurrence were tumor size (hazard ratio (HR): 1.01, 95% CI: 1.00-1.02), positive genetic testing (HR: 5.14, 95% CI: 2.10-12.55), age (HR: 0.97, 95% CI: 0.94-0.99), and Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) (HR: 1.16, 95% CI: 1.04-1.29). The predictive performance of the overall model, evaluated by Somers' D, was equal to 0.594, and was significantly higher than the ones of any single predictor alone (P = 0.002 compared to tumor size; P = 0.004 compared to genetic testing; P = 0.048 compared to age; P = 0.006 compared to PASS). Internal validation by bootstrapping techniques estimated an optimistic bias of 6.3%, which reassured about a small tendency towards overfit. Conclusions: We proposed a multivariable model for the prediction of post-surgical recurrence of pheochromocytoma, derived by the integration of genetic, histopathological, and clinical data. This predictive tool may be of value for a comprehensive tailoring of post-surgical follow-up in radically operated pheochromocytoma patients.

The Accuracy of Simple and Adjusted Aldosterone Indices for Assessing Selectivity and Lateralization of Adrenal Vein Sampling in the Diagnosis of Primary Aldosteronism Subtypes.

OBJECTIVE: This study aimed to evaluate the reliability of simple and corrected aldosterone indices for assessing the selectivity and lateralization of adrenal vein sampling (AVS) in patients with primary aldosteronism. METHODS: Data of all consecutive patients with primary aldosteronism who underwent AVS for subtype diagnosis, followed at two Italian referral centers, were analyzed retrospectively. RESULTS: AVS achieved bilateral selectivity in 112/144 patients. Unilateral disease was diagnosed in 60 cases (53.6%) and idiopathic hyperaldosteronism in 52 individuals (46.4%). The aldosterone index (aldosterone ratio between an adrenal vein and the inferior vena cava) showed a high accuracy in predicting selectivity, compared to a cortisol selectivity index of 1.1, and a moderate accuracy, compared to cortisol cut-offs of 2 and 3. The simple aldosterone index showed a moderate accuracy in predicting ipsi/contralateral aldosterone hypersecretion, while lesion side- and hypokalemia-corrected aldosterone index revealed a significant improvement in predicting ipsi/contralateral disease. Moreover, the comparative aldosterone index (aldosterone ratio in the dominant vs the non-dominant adrenal vein) revealed a high accuracy in predicting unilateral primary aldosteronism. For an immediate clinical application of our results, the adjusted cut-offs were calculated, according to the Youden's criterion and to a pre-established specificity of 90%, for all possible combinations of lesion side at imaging and presence/absence of hypokalemia. CONCLUSIONS: This study demonstrated the diagnostic accuracy of simple and clinical-/imaging-corrected aldosterone indices for adrenal vein sampling in subtype diagnosis of primary aldosteronism and suggests the potential application of these tools to select patients for adrenalectomy when standard indices cannot be performed.

A Multicenter Epidemiological Study on Second Malignancy in Non-Syndromic Pheochromocytoma/Paraganglioma Patients in Italy.

No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46-15.71) in males and 13.21 (95% CI 7.52-21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15-5.44, p = 0.021 for 50-59 vs. <50-year category; HR 3.46, 95% CI 1.67-7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10-0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.

"Never Trust to General Impressions, My Boy, but Concentrate Yourself upon Details": An Unusual and Challenging Presentation of Pheochromocytoma.

We present the case of a 45-year-old woman admitted to our unit with acute heart failure and cardiogenic shock, requiring an intra-aortic balloon pump insertion and inotropes and vasopressors infusion. Despite such treatment, the patient developed multi organ failure and intravascular disseminated coagulation with haemolysis. The initial diagnosis of acute myocarditis was subsequently denied by the finding of bilateral adrenal masses by MRI scan, and urine and plasma metanephrines measurements confirmed a pheochromocytoma (PCC). Genetic analysis revealed a mutation in the neurofibromatosis type 1 (NF1) gene, and an accurate physical examination drew attention to small cafè-au-lait spots, usually associated with this syndrome. PCC diagnosis should be promptly considered in patients presenting with unexplained acute heart failure and cardiogenic shock of unknown origin, considering its life-threatening complications and the good prognosis after radical surgery.

Predictor Analysis in Radiofrequency Ablation of Benign Thyroid Nodules: A Single Center Experience.

Purpose: To confirm the efficacy of ultrasound (US) guided radiofrequency ablation (RFA) in the treatment of benign thyroid nodules, we evaluated as primary outcome the technical efficacy and clinical success in a single center dataset. The secondary outcome was to find a correlation between nodules' pre-treatment features and volume reduction rate (VRR) ≥75% at 12 months after RFA and during follow-up period. Methods: This retrospective study included 119 consecutive patients (99 females, 20 males, 51.5 ± 14.4 years) with benign thyroid nodules treated in our hospital between October 2014 and December 2018 with a mean follow-up of 26.8 months (range 3-48). Clinical and US features before and after RFA were evaluated by a US examination at 1, 3, 6, 12 months and annually thereafter up to 48 months. Results: The median pre-treatment volume was 22.4 ml; after RFA we observed a statistically significant volume reduction from the first month (11.7 ml) to the last follow-up (p < 0.001 for all follow-up times). The median VRR was 47.1, 55.3, 61.2, 67.6, 72.8, 71.3, and 62.9% at 1, 3, 6, 12, 24, 36, and 48 months of follow-up respectively, showing a progressive significant improvement up to 24 months (VRRs 1 vs 3 months, 3 vs 6 months and 6 vs 12 months p < 0.001, 12 vs 24 months p = 0.05) while no differences at 24 vs 36 and 36 vs 48 months were observed. Symptoms improved significantly (complete resolution 64.35%, partial resolution 35.65%), and neck circumference was reduced as compared to pre-treatment (p < 0.001). Lower pre-treatment neck circumference (37.5 vs 36.0 cm, p = 0.01) was a positive predictor of VRR ≥75% at 12 months. Macrocystic echostructure (HR 2.48, p 0.046) and pre-treatment volume >22.4 ml (HR 0.54, p 0.036) were found to be independent positive and negative predictors of VRR ≥75% respectively. One-month post RFA VRR ≥50% represented the best positive predictor of technical success. Conclusions: This study confirmed the efficacy of RFA in the treatment of benign thyroid nodules. In particular we show that by selecting macrocystic nodules smaller than 22.4 ml better long-term response can be achieved, which is predicted by an early shrinkage of the nodule.

A Simplified Ultrasonographic Score for the Prediction of Cytologically Suspicious Thyroid Nodules.

PURPOSE: The major aim of ultrasound (US)-based risk stratification systems is to reduce unnecessary thyroid biopsies without losing the ability to recognize nodules with clinically significant malignancy. Each of the classic suspicious features of a thyroid nodule detected on US scan (hypoechoic pattern, microcalcifications, irregular margin, taller than wide shape, irregular vascularization) is significantly independently associated with the probability of malignancy, but none of them has good diagnostic accuracy. Thus, we evaluated the predictive value of a binary score simply based on the combination of these US features, regardless of the specific predictive value of each US feature, against the outcome of suspected malignancy at cytological diagnosis (TIR3 to TIR5 categories by SIAPEC-IAP [TIR+]). MATERIALS AND METHODS: 1009 thyroid nodules from 1081 patients were considered. The US features of suspicion of all nodules were categorized in 5 binary scores (U1 to U5), each including from 1 to 5 of those features. RESULTS: U2 (at least 2 US suspicious features) was the most balanced predictor of TIR+ (PPV 0.48, NPV 0.93, LR+ 3.05 and LR- 0.24). Weighting the predictivity of the single features did not improve the estimate. Using U2 as the criterion to send nodules to FNAC would have reduced the number of biopsies by 60 % (604 patients) and the false negatives would have only accounted for 41 cases out of 237 TIR+ (17 %) with 39 cases of TIR3 and 2 cases of TIR4, including only 6 malignant nodules on histological examination. U2 performed much better than the ATA recommendations for detecting those nodules, resulting in TIR+ at cytology. CONCLUSION: This simple and reproducible sonographic score based on 2 US features of suspicion of malignancy has quite a good performance with respect to identifying thyroid lesions categorized by cytology as medium-high risk of malignancy and could allow us to reduce cytology costs for low-risk nodules.

The Cut-off Limits of Growth Hormone Response to the Insulin Tolerance Test Related to Body Mass Index for the Diagnosis of Adult Growth Hormone Deficiency.

INTRODUCTION: The diagnosis of growth hormone deficiency (GHD) in adults is based on a reduced GH response to provocative tests, such as the insulin tolerance test (ITT) and the GH-releasing hormone (GHRH) + arginine (ARG) test. However, the cut-off limits of peak GH response in lean subjects are not reliable in obese patients; this is noteworthy since adult GHD is often associated with obesity. To date, there are no ITT cut-offs related to body mass index (BMI). OBJECTIVE: We aimed to evaluate the diagnostic cut-offs of GH response to the ITT in the function of BMI. METHODS: The GH response to the ITT was studied in 106 patients with a history of hypothalamic-pituitary disease, a mean age of 48.2 ± 12.4 years, and a mean BMI of 26.8 ± 6.1 kg/m2). Patients were divided into lean, overweight, and obese groups according to their BMI. The lack of GH response to GHRH + ARG test was considered the gold standard for the diagnosis of GHD. The best GH cut-off in the ITT, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using receiver-operating characteristics curve (ROC) analysis. RESULTS: The best GH cut-off in the ITT was 3.5 µg/L in lean subjects (SE 82.1%; SP 85.7%), 1.3 µg/L in overweight subjects (SE 74.1%; SP 85.7%), and 2.2 µg/L in obese subjects (SE 90.0%; SP 50.0%). The diagnostic accuracy was 97.2, 76.5, and 76.7%, respectively. CONCLUSIONS: Our data show that the ITT represents a reliable diagnostic tool for the diagnosis of adult GHD in lean subjects if an appropriate cut-off limit is assumed. Overweight and obesity strongly reduce the GH response to the ITT, GH BMI-related cut-off limits, and the diagnostic reliability of the test.

Prevalence of primary aldosteronism and association with cardiovascular complications in patients with resistant and refractory hypertension.

OBJECTIVES: To assess the prevalence of primary aldosteronism and its association with cardiometabolic complications in patients with resistant and refractory hypertension. METHODS: One hundred and ten consecutive patients with true resistant hypertension [insufficient blood pressure control despite appropriate lifestyle measures and treatment with at least three classes of antihypertensive medication, including a diuretic] and without previous cardiovascular events were screened for secondary hypertension. Refractory hypertension was diagnosed in case of uncontrolled blood pressure despite the use of at least five antihypertensive drugs. RESULTS: Primary aldosteronism was diagnosed in 32 cases (29.1%). The multivariate analysis showed that primary aldosteronism is a strong factor positively associated with left ventricular hypertrophy [odds ratio (OR) = 12.98, 95% confidence interval (CI) 3.82-60.88; P < 0.001], microalbuminuria (OR = 3.67, 95% CI 1.44-9.78; P = 0.007), carotid intima-media thickness at least 0.9 mm (OR = 2.69, 95% CI 1.02-7.82; P = 0.037), aortic ectasia (OR = 4.08, 95% CI 1,18-15.04; P = 0.027) and atrial fibrillation (OR 8.80, 95% CI 1.53-73.98; P = 0.022). Moreover, primary aldosteronism was independently associated with the presence of at least one (OR = 8.60, 95% CI 1.73-69.88; P = 0.018) and at least two types of organ damage (OR = 3.08, 95% CI 1.19-8.24; P = 0.022). Thirteen patients (11.8%) were affected by refractory hypertension. This group was characterized by significantly higher values of carotid intima-media thickness, higher rate of aldosterone-producing adenoma and atrial fibrillation, compared with the other individuals with resistant hypertension. CONCLUSION: The current study indicates that primary aldosteronism is a frequent cause of secondary hypertension and cardiovascular complications among patients with resistant and refractory hypertension, suggesting a crucial role of aldosterone in the pathogenesis of severe hypertensive phenotypes and cardiovascular disease.

Primary Pituitary Lymphoma As Rare Cause Of A Pituitary Mass And Hypopituitarism In Adulthood.

OBJECTIVE: Differential diagnosis of nonadenomatous sellar masses causing hypopituitarism is still a challenge. Among these masses, growing evidence has demonstrated that primary pituitary lymphoma is a specific and emerging entity. The aim of our study was to describe our experience with a case of primary pituitary lymphoma and to perform a review of the available literature. METHODS: We searched relevant databases up to March 2020, identifying 36 suitable articles basing on inclusion criteria (primary pituitary lymphoma in adult immunocompetent subjects). Overall, 43 cases were included in the review, adding a new case diagnosed and treated in our hospital. Epidemiologic data, clinical presentation, hormonal status, radiologic findings, pathology, treatment, and outcome were extracted. RESULTS: Mean age at diagnosis was 58.9 years, without gender difference. Symptoms related to mass were common (52.3%), in particular cranial nerve palsy (70.5%), headache (56.8%), and alteration in visual field (40.9%). Impaired hormonal status was detected in 89.7% of patients; of them, 58.9% presented with anterior pituitary failure (partial or total), while 25.6% presented with panhypopituitarism. Overall, diabetes insipidus was present in 30.8% and hyperprolactinemia in 41.0% of patients. The majority of patients presented a radiologically invasive mass in the suprasellar region and cavernous sinus (65.9% and 40.9%, respectively) and histologic diagnosis of diffuse B-cell lymphoma (54.5%). CONCLUSION: The differential diagnosis of sellar and parasellar masses causing hypopituitarism should include primary pituitary lymphoma, even in absence of systemic symptoms or posterior pituitary dysfunction. The disease has a heterogeneous pattern, so a collaboration between endocrinologists, neuroradiologists, neurosurgeons, and hematologists is desirable.

Predictors of recurrence of pheochromocytoma and paraganglioma: a multicenter study in Piedmont, Italy.

The available data on the natural history of pheochromocytomas and paragangliomas after radical surgery are heterogeneous and discordant. The aim of our retrospective multicenter study was to find predictors of recurrence in patients with pheochromocytomas and sympathetic paragangliomas submitted to radical surgery in Piedmont (a region in northwest Italy). We collected data from 242 patients diagnosed between 1990 and 2016. Forty-two patients (17.4%) had disease recurrence. Multivariate analysis showed that genetic mutation (HR = 3.62; 95% CI 1.44-9.13; p = 0.006), younger age (HR = 0.97; 95% CI 0.95-0.99; p = 0.031) and larger tumor size (HR = 1.01; 95% CI 1.00-1.02; p = 0.015) were independently associated with a higher recurrence risk of pheochromocytoma and paraganglioma; in pheochromocytomas, genetic mutation (HR = 3.4; 95% CI 1.00-11.48; p = 0.049), younger age (HR = 0.97; 95% CI 0.94-0.99; p = 0.02), higher tumor size (HR = 1.01; 95% CI 1.00-1.03; p = 0.043) and PASS value (HR = 1.16; 95% CI 1.03-1.3; p = 0.011) were associated with recurrence. Moreover, tumor size was the only predictor of metastatic pheochromocytoma and paraganglioma (HR = 4.6; 95% CI 1.4-15.0; p = 0.012); tumor size (HR = 3.93; 95% CI 1.2-16.4; p = 0.026) and PASS value (HR = 1.27; 95% CI 1.06-1.53; p = 0.007) were predictors of metastatic pheochromocytoma. In conclusion, our findings suggest that the recurrence of pheochromocytoma and sympathetic paraganglioma develops more frequently in younger subjects, patients with a family history of chromaffin tissue neoplasms, mutations in susceptibility genes, larger tumors and higher values of PASS. We recommend genetic testing in all patients with PPGL and strict follow-up at least on an annual basis.

HLA DRB1*0415: a new possible genetic susceptibility factor for Hirata's disease.

CONTEXT: Hirata's disease (HD) is a rare autoimmune cause of hypoglycemia. Patients suffering from this condition have a genetic predisposition, determined by HLA DR4, with some differences in the worldwide population. In Caucasians HLA DRB1*0403 is the most frequent susceptibility background on which some drugs play as triggers. CASE DESCRIPTION: We reported the case of a woman with several hypoglycemic episodes, characterized by high insulin and c-peptide levels. Biochemical and morphological exams excluded a neuroendocrine tumor. HD was diagnosed according to insulin autoantibodies positivity and patient's history, particularly about drugs taken. The HLA analysis revealed DRB1*0415 allele. CONCLUSIONS: We found a potential new predisposing factor for HD, HLA DRB1*0415 allele, never described before as genetic background to insulin autoimmune syndrome in Caucasians.

Circulating miRNA Expression Profiling in Primary Aldosteronism.

Objective: Primary aldosteronism is a major cause of secondary hypertension. Its two principal forms are bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) whose differentiation is clinically pivotal. There is a major clinical need for a reliable and easily accessible diagnostic biomarker for case identification and subtyping. Circulating microRNAs were shown to be useful as minimally invasive diagnostic markers. Our aim was to determine and compare the circulating microRNA expression profiles of adenoma and hyperplasia plasma samples, and to evaluate their applicability as minimally invasive markers. Methods: One hundred and twenty-three samples from primary aldosteronism patients were included. Next-generation sequencing was performed on 30 EDTA-anticoagulated plasma samples (discovery cohort). Significantly differently expressed miRNAs were validated by real-time reverse transcription-qPCR in an independent validation cohort (93 samples). Results: We have found relative overexpression of miR-30e-5p, miR-30d-5p, miR-223-3p, and miR-7-5p in hyperplasia compared to adenoma by next-generation sequencing. Validation by qRT-PCR confirmed significant overexpression of hsa-miR-30e-5p, hsa-miR-30d-5p, and hsa-miR-7-5p in hyperplasia samples. Regarding the microRNA expressional variations, adenoma is more heterogeneous at the miRNA level compared to hyperplasia. Conclusion: Three microRNAs were significantly overexpressed in hyperplasia samples compared to adenoma samples, but their sensitivity and specificity values are not good enough for introduction to clinical practice.

Progression of pituitary tumours: impact of GH secretory status and long-term GH replacement therapy.

BACKGROUND: Most patients treated for hypothalamic-pituitary tumours develop GH deficiency. Long-term GH replacement treatment in adults with a previous history of hypothalamic-pituitary tumour could represent a concern about increasing the risk of tumour enlargement or recurrence. PURPOSE: To assess the progression risk of hypothalamic-pituitary tumours according to the GH secretory status (normal GH secretion, non-treated and treated GH deficiency). and determine the predictors of neoplasm recurrence. METHODS: We retrospectively reviewed 309 patients with tumours of the hypothalamic-pituitary region (294 subjects underwent neurosurgery while 81 radiotherapy) who were followed for 9.9 ± 8.3 years. RESULTS: Out of 309 patients, 200 were affected by severe GH deficiency; 90 of these underwent GH therapy. The tumour progression rate did not differ among GH-sufficient, not-treated and treated GH-deficient patients (16.5%, 16.4%. and 10.0%, respectively). In a multivariate analysis, previous radiotherapy (HR 0.12, CI 0.03-0.52, p < 0.005) and residual tumour (HR 8.20, CI 2.38-28.29, p < 0.001) were independent predictors of recurrence. After controlling for multiple covariates, the tumour recurrence risk in GH-sufficient and GH-treated patients was similar to that observed in not-treated GH-deficient patients. CONCLUSIONS: With limitations of retrospective analysis, GH therapy is not associated with an increased progression rate of tumours of the hypotalamic-pituitary region during long follow-up, thus supporting the long-term safety of GH treatment. The only predictors of tumour recurrence appear to be the presence of residual disease and the lack of radiotherapy.

68Ga-DOTA-TOC PET/CT of von Hippel-Lindau Disease.

We present a rare case of a 42-year-old man with a long history of von Hippel-Lindau disease that was scanned with Ga-DOTA-TOC PET/CT for suspicion of disease relapse. Ga-DOTA-TOC imaging demonstrated increased DOTA-TOC uptake in pancreas tail and intramedullary and extramedullary spinal hemangioblastomas, only some of which have already been highlighted at MRI examination. This case illustrates the significant role the Ga-labeled somatostatin receptor analogs PET/CT in the management of the von Hippel-Lindau disease.