Current Management of Head and Neck Paragangliomas: A Multicenter Series With Long-Term Follow-Up.

OBJECTIVE, STUDY DESIGN, SETTING, METHODS: To improve our knowledge about head and neck paragangliomas (HN-PGL), the clinical characteristics of all the patients with HN-PGL included in the Spanish Registry were analyzed, as well as the treatment modalities and their outcomes. RESULTS: A total of 202 patients, 67.8% women, aged 53.1 ± 17.4, with 264 HN-PGL, from 16 Spanish hospitals, were included. Tumors were located in the carotid body in 61%, jugular bulb in 20.5%, tympanic area in 10.2%, and along the vagal nerve in 6.4%. Multiple tumors developed in 20.8% and metastatic disease in 4%. A genetic study was done in 64.4% and showed a pathogenic variant in SDHx in 50%. These patients were younger, with no sex predominance, and had more multiple and metastatic tumors. Tumors were treated by surgery in 134 patients, radiotherapy in 33, and other treatments in 20, and were observed without active treatment in 41 patients, who were older, more often asymptomatic, and had smaller tumors. Tumors treated with radiotherapy were larger and more often in locations other than the carotid body. After a median follow-up of 80 months (interquartile range: 41-136), 6.9% had died; among the survivors, 48.4% were disease-free, 42.1% stable, and 9.4% had progressed. The rate of sequelae was similar among patients submitted to surgery, radiotherapy, or observation. We could not identify any prognostic factor for progression. CONCLUSION: Most HN-PGL are localized slow-growing tumors. Long-term survival is high, even in case of metastasis. Although surgery is the most common treatment, radiotherapy and active surveillance are safe approaches.

Long term outcomes of pituitary adenomas in Multiple Endocrine Neoplasia type 1: a nationwide study.

Introduction: Historically, Multiple Endocrine Neoplasia type 1 (MEN1)-related pituitary adenomas (PAs) were considered more aggressive and treatment-resistant than sporadic PAs. However, recent studies suggest similarities in their behavior. This study aimed to evaluate the long-term outcomes of MEN1 PAs and identify predictive factors. Methods: Nationwide multicenter retrospective cohort study of MEN1-related PAs with a minimum 1-year follow-up, collecting patient demographics, germline MEN1 pathogenic variants (PV), PA size, secretory profile, radiological characteristics, treatments, and outcomes. Results: We analyzed 84 PAs, 69%in females and 31% in males (P<0.001), diagnosed at a mean age of 35.2±14.9 years, mostly through screening (60.7%). Median follow-up was 9 years (IQR:4-16). Prolactin-secreting PAs (PRLomas) (53.5%) and microadenomas (65.5%) were most common. Dopamine agonist treatment was first line for 16 macroPRLomas and 25 microPRLomas, 60.9% of them achieved PRL normalization. There was no significant association observed with tumor size, sex, treatment duration or MEN1 PV. The risk of progression from micro-PA to invasive macro-PA was 7.2% (4/55), after 8 years (IQR:4-13), all of them were microPRLomas. Kaplan-Meier estimation curve showed significantly higher progression probability in microPRLomas than in other microadenomas subtypes (P=0.017) or microNFPAs (P=0.032). No differences were found between sex, age, or germline MEN1 PV. Conclusion: MEN1-related micro-PAs have a low risk of progressing to invasive macro-PAs, regardless of sex, age at diagnosis, or MEN1 germline PV. The risk is higher for microPRLomas over the long term. Therefore, long-term surveillance with reduced frequency, rather than intensive short-term monitoring, may be appropriate for patients with MEN1-related PAs.

Pre-Surgery Cortisol Levels as Biomarker of Evolution after Bariatric Surgery: Weight Loss and Weight Regain.

Background: Bariatric surgery (BS) is effective for achieving significant weight loss. However, weight regain (WR) is an emerging problem. Objective: To assess the prognostic value of morning serum cortisol, a 1 mg dexamethasone suppression test (DST), 24 h urinary free cortisol (UFC) and late-night salivary cortisol (LNSC) in a cohort of patients with severe obesity (pwSO) undergoing BS in terms of weight loss and WR. Methods: Patients scheduled for BS underwent the following procedures at baseline, 12 months and 24 months after BS: medical history, anthropometric data, blood analysis and cortisol tests. We evaluated total weight loss (TWL) ≥ 30% at 1 year and WR after 2 years as an increase of ≥10% of the maximum weight lost. Results: In total, 142 subjects were included; 101 (71.1%) were females and the mean age was 45.9 ± 9.2 years. Up to 76.8% of subjects achieved ≥30% TWL, without statistically significant differences in DST results or morning serum cortisol, UFC or LNSC levels. However, a higher pre-surgery morning serum cortisol level was a significant predictor of a WR ≥ 10% (cortisol 17.8 [IQR 13.1-18.5] vs. 12.0 [IQR 8.8-15.8] µg/dL; p < 0.01); OR of 1.216 (95% CI 1.069-1.384); AUC [0.761, CI: (0.616-0.906); p < 0.01]. A cut-off value of cortisol > 13.0 µg/dL was predictive of a WR ≥ 10% (sensitivity 0.71; specificity 0.63). Conclusions: No cortisol test was useful in predicting weight loss; however, the pre-surgery morning serum cortisol level was able to predict a WR ≥ 10% in a cohort of pwSO 2 years after BS. A cut-off value of cortisol > 13 µg/dL might be an easy tool to identify patients at higher risk of WR, enabling healthcare providers to implement tailored, long-term strategies to minimize this outcome.

Impact of primary aldosteronism on kidney function: results from the SPAIN-ALDO registry.

AIM: To evaluate the impact of aldosterone excess on renal function in individuals with primary aldosteronism and to compare its evolution after surgery or mineralocorticoid receptor antagonist (MRA) treatment. METHODS: A multicentre, retrospective cohort study of primary aldosteronism patients in follow-up in 36 Spanish tertiary hospitals, who underwent specific treatment for primary aldosteronism (MRA or adrenalectomy). RESULTS: A total of 789 patients with primary aldosteronism were included, with a median age of 57.5 years and 41.8% being women. At primary aldosteronism diagnosis, the prevalence of chronic kidney disease (CKD) was 10.7% ( n  = 84), with 75% of cases classified as state 3a ( n  = 63). Primary aldosteronism patients with CKD had a longer duration of hypertension, a higher prevalence of type 2 diabetes, dyslipidaemia, cardiovascular events, hypokalaemia, and albuminuria. Unilateral adrenalectomy was performed in 41.8% of cases ( n  = 330), and 459 patients were treated with MRA. After a median follow-up of 30.7 months (range 13.3-68.4), there was a significant decline in the estimated glomerular filtration rate (eGFR) in operated patients and those receiving MRA. During follow-up, 24.4% of patients with CKD at the time of primary aldosteronism diagnosis had normalized renal function, and 39% of those with albuminuria had albuminuria remission. There were no differences in renal function or albuminuria regression between the two therapy groups. However, development of albuminuria was less common in operated than in medically treated patients (0 vs. 6.0%, P  = 0.009). CONCLUSION: CKD affects around 10% of the patients with primary aldosteronism, with a higher risk in individuals with long-term hypertension, type 2 diabetes, dyslipidaemia, cardiovascular events, hypokalaemia, and albuminuria. At short-term, both MRA and surgical treatment lead to a reduction of renal function, but adrenalectomy led to higher renal protection.

Genetic testing for primary aldosteronism in SPAIN: Results from the SPAIN-ALDO Registry and review of the literature.

PURPOSE: To determine the rate of genetic testing for familial hyperaldosteronism (FH) in the SPAIN-ALDO Registry and to describe the clinical characteristics of patients with FH. In addition, a literature review of reports of FH cases was performed. METHODS: A retrospective multicenter study of primary aldosteronism (PA) in patients followed in 35 Spanish tertiary hospitals (SPAIN-ALDO Registry). RESULTS: Twenty-five of the 855 patients (3%) with PA included in the registry underwent genetic testing for FH, with complete results available in only 24 patients. However, we found that there were 57 patients who met the criteria for performing a genetic study of PA. Only 8 out of these 57 patients were genetically tested (14.0%), while the reasons to perform a genetic study in the remaining 9 genetically studied cases were quite heterogeneous. A positive result for FH was found only in one case for FH type III (KCNJ5 pathogenic variant). A systematic review of the literature was performed and identified a total of 25 articles reporting 246 patients with FH type I; 12 articles reporting 72 patients with FH type II; 14 articles reporting 29 cases of FH type III and 3 articles reporting 12 patients with FH type IV. CONCLUSION: The genetic study of familial hyperaldosteronism is often scarce in real-world clinical practice, as 86% of patients with criteria to undergo genetic study were not evaluated in our cohort. Nevertheless, FH is an uncommon cause of PA, representing only 0.2% of cases in the SPAIN-ALDO Registry, although its prevalence may be as high as 4% among suspected cases might be studied.

Clinical Significance of T2-Weighted Sequence Intensity on Magnetic Resonance Imaging in Clinically Non-Functioning Pituitary Adenomas.

BACKGROUND: Little is known about the relationship between signal intensity patterns on T2-weighted magnetic resonance imaging (MRI) in non-functioning pituitary adenomas (NFPAs). OBJECTIVE: In this study, the clinical, hormonal, histological features, and therapeutic responses were evaluated according to the T2 signal intensity in NFPAs. METHODS: This retrospective and multicenter study included a group of 166 NFPA patients (93 men, 56%, mean age 58.5 ±14.8 yr). RESULTS: Approximately half of the tumors (n=84, 50.6%) were hyperintense, while 34.3% (n=57) and 15.1% (n=25) were iso- and hypointense, respectively. The median maximum tumor diameter of the isointense group [16 (13-25) mm] was significantly lower than that of the hyperintense [23 (16.6-29.7) mm] group (p=0.003). Similarly, the tumor volume of the isointense group [1,523 (618-5,226) mm3] was significantly lower than that of the hyperintense [4,012 (2,506-8,320) mm3] group (p=0.002). Chiasmatic compression occurred less frequently in tumors with isointense signal characteristics (38.6%) compared to tumors with hypointense (68%) and hyperintense (65.5%) signal characteristics (p=0.003). Invasive adenomas (p=0.001) and the degree of cavernous sinus invasion (p<0.001) were more frequent in the hyperintense adenoma group compared to the remaining groups. Plurihormonal tumors and silent lactotroph adenomas were more frequent in the isointense tumor group. CONCLUSION: In conclusion, hyperintensity on T2-weighted MRI in NFPAs is associated with larger and more invasive tumors compared to isointense NFPAs.

Diagnostic Accuracy of Adrenal Iodine-131 6-Beta-Iodomethyl-19-Norcholesterol Scintigraphy for the Subtyping of Primary Aldosteronism.

PURPOSE: To evaluate the diagnostic accuracy of the 131I-6ß-iodomethyl-19-norcholesterol (NP-59) adrenal scintigraphy for the subtyping diagnosis of primary aldosteronism (PA), considering as gold standard for the diagnosis of unilateral PA (UPA), either the results of the adrenal venous sampling (AVS) or the outcome after adrenalectomy. METHODS: A retrospective multicenter study was performed on PA patients from 14 Spanish tertiary hospitals who underwent NP-59 scintigraphy with an available subtyping diagnosis. Patients were classified as UPA if biochemical cure was achieved after adrenalectomy or/and if an AVS lateralization index > 4 with ACTH stimulation or >2 without ACTH stimulation was observed. Patients were classified as having bilateral PA (BPA) if the AVS lateralization index was ≤4 with ACTH or ≤2 without ACTH stimulation or if there was evidence of bilateral adrenal nodules >1 cm in each adrenal gland detected by CT/MRI. RESULTS: A total of 86 patients with PA were included (70.9% (n = 61) with UPA and 29.1% (n = 25) with BPA). Based on the NP-59 scintigraphy results, 16 patients showed normal suppressed adrenal gland uptake, and in the other 70 cases, PA was considered unilateral in 49 patients (70%) and bilateral in 21 (30%). Based on 59-scintigraphy results, 10.4% of the patients with unilateral uptake had BPA, and 27.3% of the cases with bilateral uptake had UPA. The AUC of the ROC curve of the NP-59 scintigraphy for PA subtyping was 0.812 [0.707-0.916]. Based on the results of the CT/MRI and NP-59 scintigraphy, only 6.7% of the patients with unilateral uptake had BPA, and 24% of the cases with bilateral uptake had UPA. The AUC of the ROC curve of the model combining CT/MRI and 59-scintigraphy results for subtyping PA was 0.869 [0.782-0.957]. CONCLUSION: The results of NP-59 scintigraphy in association with the information provided by the CT/MRI may be useful for PA subtyping. However, their diagnostic accuracy is only moderate. Therefore, it should be considered a second-line diagnostic tool when AVS is not an option.

Risk Factors, Radiological and Clinical Outcomes in Subclinical and Clinical Pituitary Apoplexy.

BACKGROUND: Pituitary apoplexy (PA) can be symptomatic, namely acute apoplexy (APA), or asymptomatic or subclinical (SPA). OBJECTIVE: To describe the clinical characteristics and evolution of the patients with APA compared to SPA Patients and methods: Retrospective, longitudinal database analysis. RESULTS: We identified 58 patients with PA, and 37 accomplished the inclusion criteria (17 men, median age 47.7 years). A total of 29 (78.4%) had APA (17 underwent surgery, and 12 were conservatively managed), and 8 (21.6%) had SPA. The presence of non-functioning pituitary adenoma (NFPA) odds ratio (OR): 29.36 (95% confidence interval (CI): 1.86-462.36) and the largest size OR 1.10 (95% CI: 1.01-1.2) elevated the risk of having surgery. Hypopituitarism developed in 35.1% without significant differences between APA and SPA. In non-surgical patients, adenoma volume shrunk spontaneously at one year magnetic resonance imaging (MRI), without statistical differences between the conservatively treated and SPA group. CONCLUSIONS: APA is more frequent in larger NFPAs, and this subset of patients has a higher risk of surgery. Hypopituitarism is quite frequent even in patients with SPA, and, therefore, long-term follow-up is mandatory. In the non-surgical group, the pituitary tumour shrinkage is clinically relevant after one year of PA. Consequently, surgery indication in NFPA should be delayed and reassessed if patients remain asymptomatic.

Effect of cabergoline on tumor remnant after surgery in nonfunctioning pituitary adenoma.

BACKGROUND: In recent years, dopamine agonists (DAs) have become an attractive therapeutic option to prevent both tumor growth and post-surgical tumor remnant growth in clinically non-functioning pituitary adenoma (NFPA). AIM: To analyze our experience on the effect of cabergoline (CAB) on tumor remnant after initial surgery in NFPA patients. PATIENTS AND METHODS: A retrospective and multicenter study of NFPA patients with tumor remnant after surgery treated with CAB was performed. RESULTS: From a total of 142 NFPA patients (79 men, 55.2%; mean age 57.2 ± 14.2 year) who underwent surgery, we selected 62/142 (43.7%) patients (32 men, 51.6%; mean age 59.3 ± 13.9 year) with tumor persistence (TP) after surgery. In 22/62 (35.5%) TP patients CAB was used (CAB group), while the rest of the patients (40/62, 64.5%) underwent active surveillance [observation (OBS) group)]. The maximum diameter of the tumor remnant did not change significantly in either the CAB group [11.5 (6.0-16.9) mm vs. 12.0 (7.0-15.0) mm, p = 0.85) or the OBS group [8.5 (6.0-13.7) mm vs. 9.0 (6.2-14.0) mm, p = 0.064) at the end of the follow-up [13 (10.5-17) vs. 77.5 (50.2-107.2) months, CAB vs. OBS group; p < 0.001]. At the end of the treatment period with CAB most of the patients (n = 20/22, 90.9%) showed no progression of the tumor remnant [stable disease, SD (n = 17/22, 77.2%) and partial response, PR (n = 3/22, 13.6%)], while 2/22 patients (9.1%) exhibited progression. Similar response rates were observed in the OBS group [SD (n = 32/40, 80%), PR (n = 2/40, 5%), and progression (n = 6/40, 15%)]. Although no statistically significant differences (p = 0.42) were found in these responses, the percentage of progression was 1.65 times higher in the OBS group compared to the CAB group. On the contrary, the percentage of PR was 2.72 times higher in the CAB group compared to the OBS group, despite a significantly shorter follow-up period in the CAB group. CONCLUSION: Although the present study showed no significant differences in the type of tumor response between the CAB and OBS groups of patients, the percentage of PR was higher and that of progression lower in the CAB group compared to the OBS group. This finding does not rule out a potential therapeutic benefit of CAB in the management of tumor remnant in patients with NFPA undergoing surgery.

Chronic pancreatitis for the clinician. Complications and special forms of the disease. Interdisciplinary position paper of the Catalan Society of Digestology (SCD) and the Catalan Pancreatic Society (SCPanc).

Chronic pancreatitis tends to develop a number of complications that may constitute the form of presentation of the disease. Some societies have issued guidelines for diagnosis and treatment of chronic pancreatitis complications, but the level of evidence for any topic is usually low and recommendations tend to be weak. We aimed at providing defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The goal was to propose defined terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 14 sections related to complications and special forms of chronic pancreatitis (early chronic, groove and autoimmune pancreatitis) were reviewed by 21 specialists from 6 different fields to generate 32 statements. Featured statements assert common bile duct stenosis does not require invasive treatment (endoscopic or surgical) unless cholestasis, cholangitis, lithiasis or other symptoms develop. Pancreatic duct strictures and calculi should be approached (after ruling out malignancy) if causing pain, pancreatitis, pseudocysts or other complications. Treatment of symptomatic pseudocysts must be individualized, considering associated main duct stenosis, vascular and pericystic complications. Higher risk conditions for pancreatic cancer are advance age, smoking, genetic background, recent diagnosis of chronic pancreatitis or diabetes, and appearance of new symptoms. Groove pancreatitis can initially be treated with conservative measures. Both prednisolone or rituximab can induce remission and maintenance of autoimmune pancreatitis. Internal fistula, vascular complications, bacterial overgrowth, osteoporosis and renal lithiasis require specific therapeutic approaches.

Chronic pancreatitis for the clinician. Part 2: Treatment and follow-up. Interdisciplinary Position Paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees. / Pancreatitis crónica para el clínico. Parte 2: Tratamiento y seguimiento. Documento de posicionamiento interdisciplinar de la Societat Catalana de Digestologia y la Societat Catalana de Pàncrees.

Chronic pancreatitis is associated with impaired quality of life, high incidence of comorbidities, serious complications and mortality. Healthcare costs are exorbitant. Some medical societies have developed guidelines for treatment based on scientific evidence, but the gathered level of evidence for any individual topic is usually low and, therefore, recommendations tend to be vague or weak. In the present position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 2 of these paper series discuss topics on treatment and follow-up. The therapeutic approach should include assessment of etiological factors, clinical manifestations and complications. The complexity of these patients advocates for detailed evaluation in multidisciplinary committees where conservative, endoscopic, interventional radiology or surgical options are weighed. Specialized multidisciplinary units of Pancreatology should be constituted. Indications for surgery are refractory pain, local complications, and suspicion of malignancy. Enzyme replacement therapy is indicated if evidence of exocrine insufficiency or after pancreatic surgery. Response should be evaluated by nutritional parameters and assessment of symptoms. A follow-up program should be planned for every patient with chronic pancreatitis.

Chronic pancreatitis for the clinician. Part 1: Etiology and diagnosis. Interdisciplinary position paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees. / Pancreatitis crónica para el clínico. Parte 1: etiología y diagnóstico. Documento de posicionamiento interdisciplinar de la Societat Catalana de Digestologia y la Societat Catalana de Pàncrees.

Chronic pancreatitis is a chronic fibroinflammatory disease of the pancreas with prevalence around 50 cases per 100,000 inhabitants. It appears to originate from diverse and yet mixed etiological factors. It shows highly variable presenting features, complication types and disease progression rates. Treatment options are as wide as the multiple personalized scenarios the disease might exhibit at a given time point. Some medical societies have developed guidelines for diagnosis and treatment based on scientific evidence. Although these efforts are to be acknowledged, the gathered level of evidence for any topic is usually low and, therefore, recommendations tend to be vague or weak. In the present series of position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on interdisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 1 of this paper series discusses topics on aetiology and diagnosis of chronic pancreatitis. Main clinical features are abdominal pain, exocrine and endocrine insufficiency and symptoms derived from complications. Some patients remain symptom-free. Diagnosis (definitive, probable or uncertain) should be based on objective data obtained from imaging, histology, or functional tests.

Shrinkage by the third month predicts long-term response of macroprolactinoma after cabergoline.

OBJECTIVE: Transsphenoidal surgery (TSS) is mainly indicated in prolactinomas when dopamine agonist treatment fails. However, there is no established early predictor of cabergoline (CBG) response. The present study was aimed to identify predictors of CBG resistance in order to select patients who may benefit from early TSS. DESIGN: Retrospective longitudinal study. METHODS: We reviewed the medical record of patients diagnosed with prolactinoma after 2010. Inclusion criteria: macroprolactinomas under CBG treatment with serial prolactin levels and MRI before treatment and 3 and 12 months afterwards. The main outcome was tumour size shrinkage ≥ 50% (using the two largest diameters in sagittal view) after 12 months of CBG (TS_50). The capacity of the most important clinical and biochemical variables in predicting the main outcome was examined. RESULTS: A total of 185 prolactinomas where included: 124 (67.0%) were microadenomas and 61 (33.0%) were macroadenomas of which 27 patients meet de inclusion criteria; median age (42.5 years; (IQR: 28.0)). The median follow-up was (67.5 months; (IQR: 30.2)). Ten patients (37.0%) underwent surgery after more than 1 year of CBG. The volume reduction at the first MRI (3-4 months) was the unique valuable predictor: (OR: 1.16 (95% CI: 1.02-1.32)) of TS_50. A tumour volume shrinkage of ≥ 30% in the first 3-4 months of CBG therapy predicts TS_50 with an AUC (0.95 (CI: 0.76-0.99)). CONCLUSION: Tumour shrinkage in the first 3-4 months after starting treatment with CBG is a good tool for predicting the long-term response and can help clinicians to take more appropriated and personalized decisions.

HOMA-IR in acromegaly: a systematic review and meta-analysis.

PURPOSE: This review is aimed at examining whether the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is higher in Caucasian, adult, treatment-naïve patients with acromegaly (ACRO) than in the reference population independently of diabetes presence and to evaluate the impact of treatment [surgery and somatostatin analogues (SSAs)] on its assessment. METHODS: We systematically reviewed in PubMed and Web of Science from July 1985 to December 2019, registered with the code number CRD42020148737. The inclusion criteria comprised studies conducted in Caucasian adult treatment-naïve patients with active ACRO in whom HOMA-IR or basal insulin and glucose were reported. Three reviewers screened eligible publications, extracted the outcomes, and assessed the risk of biases. RESULTS: Of 118 originally selected studies, 15 met the inclusion criteria. HOMA-IR was higher in ACRO than the reference population, with mean difference and (95% confidence intervals) of 2.04 (0.65-3.44), even in ACRO patients without diabetes, 1.89 (1.06-2.73). HOMA-IR significantly decreased after treatment with either surgery or SSAs - 2.53 (- 3.24- - 1.81) and - 2.30 (- 3.05- - 1.56); respectively. However, the reduction of HOMA-IR due to SSAs did not improve basal glucose. CONCLUSION: HOMA-IR in treatment-naïve ACRO patients is higher than in the reference population, even in patients without diabetes. This finding, confirms that insulin resistance is an early event in ACRO. Our results also suggest that HOMA-IR is not an adequate tool for assessing insulin resistance in those patients treated with SSAs.

MEN1-associated primary hyperparathyroidism in the Spanish Registry: clinical characterictics and surgical outcomes.

Primary hyperparathyroidism is the most frequent manifestation of multiple endocrine neoplasia type 1 (MEN1) syndrome. Bone and renal complications are common. Surgery is the treatment of choice, but the best timing for surgery is controversial and predictors of persistence and recurrence are not well known. Our study describes the clinical characteristics and the surgical outcomes, after surgery and in the long term, of the patients with MEN1 and primary hyperparathyroidism included in the Spanish Registry of Multiple Endocrine Neoplasia, Pheochromocytomas and Paragangliomas (REGMEN). Eighty-nine patients (49 men and 40 women, 34.2 ± 13 years old) were included. Sixty-four out of the 89 underwent surgery: a total parathyroidectomy was done in 13 patients, a subtotal parathyroidectomy in 34 and a less than subtotal parathyroidectomy in 15. Remission rates were higher after a total or a subtotal parathyroidectomy than after a less than subtotal (3/4 and 20/22 vs 7/12, P < 0.05), without significant differences in permanent hypoparathyroidism (1/5, 9/23 and 0/11, N.S.). After a median follow-up of 111 months, 20 of the 41 operated patients with long-term follow-up had persistent or recurrent hyperparathyroidism. We did not find differences in disease-free survival rates between different techniques, patients with or without permanent hypoparathyroidism and patients with different mutated exons, but a second surgery was more frequent after a less than subtotal parathyroidectomy.

Analysis of the PD-1/PD-L1 axis in human autoimmune thyroid disease: Insights into pathogenesis and clues to immunotherapy associated thyroid autoimmunity.

Autoimmune thyroid diseases (AITDs), i.e., Graves' disease (GD) and Hashimoto thyroiditis (HT), are the most prevalent organ-specific autoimmune diseases, but their pathogenesis is still incompletely understood. The PD-1/PD-L1 pathway is an important mechanism of peripheral tolerance that has not been investigated in AITDs. Here, we report the analysis of the expression of PD-1, PD-L1 and PD-L2 in PBMCs, infiltrating thyroid lymphocytes (ITLs) and in thyroid follicular cells (TFCs) in GD, HT and multinodular goiter (MNG) patients and healthy controls PBMCs (HC). By combining flow cytometry, tissue immunofluorescence and induction experiments on primary and thyroid cell line cultures, we show that: 1) while PD-1+ T cells are moderately expanded in PBMCs from GD vs HC, approximately half of T cells in the infiltrate are PD-1+ including some PD-1hi; 2) PD-L1, but not PD-L2, is expressed by 81% of GD glands and in 25% of non-autoimmune glands; 3) PD-L1, was expressed by TFCs in areas that also contain abundant PD-1 positive T cells but; 4) co-localization in TFCs indicated only partial overlap between the smaller areas of the PD-L1+ and the larger areas of HLA class II+ expression; 5) IFNγ is capable of inducing PD-L1 in >90% of TFCs in primary cultures and cell lines. Collectively these results indicate that the PD-1/PD-L1 axis is operative in AITD glands and may restrain the autoimmune response. Yet the discrepancy between easy induction in vitro and the limited expression in vivo (compared to HLA) suggests that PD-L1 expression in vivo is partially inhibited in GD and HT glands. In conclusions 1) the PD-1/PD-L1 pathway is activated in AITD glands but probably not to the extent to inhibit disease progression and 2) Thyroid autoimmunity arising after PD-1/PD-L1 blocking therapies in cancer patients may result from interfering PD-1/PD-L1 tolerance mechanism in thyroid with minimal (focal) thyroiditis. Finally acting on the PD-1/PD-L1 pathway could be a new approach to treat AITD and other organ-specific autoimmunity in the future.

Brown tumor of the jaw after pregnancy and lactation in a MEN1 patient.

Skeletal manifestations of primary hyperparathyroidism (pHPT) include brown tumors (BT), which are osteoclastic focal lesions often localized in the jaws. Brown tumors are a rare manifestation of pHTP in Europe and USA; however, they are frequent in developing countries, probably related to vitamin D deficiency and longer duration and severity of disease. In the majority of cases, the removal of the parathyroid adenoma is enough for the bone to remineralize, but other cases require surgery. Hyperparathyroidism in MEN1 develops early, and is multiglandular and the timing of surgery remains questionable. To our knowledge, there are no reports of BT in MEN 1 patients. We present a 29-year-old woman with MEN 1 who developed a brown tumor of the jaw 24 months after getting pregnant, while breastfeeding. Serum corrected calcium remained under 2.7 during gestation, and at that point reached a maximum of 2.82 mmol/L. Concomitant PTH was 196 pg/mL, vitamin D 13.7 ng/mL and alkaline phosphatase 150 IU/L. Bone mineral density showed osteopenia on spine and femoral neck (both T-scores = -1.6). Total parathyroidectomy was performed within two weeks, with a failed glandular graft autotransplantation, leading to permanent hypoparathyroidism. Two months after removal of parathyroid glands, the jaw tumor did not shrink; thus, finally it was successfully excised. We hypothesize that higher vitamin D and mineral requirements during maternity may have triggered an accelerated bone resorption followed by appearance of the jaw BT. We suggest to treat pHPT before planning a pregnancy in MEN1 women or otherwise supplement with vitamin D, although this approach may precipitate severe hypercalcemia. LEARNING POINTS: Brown tumors of the jaw can develop in MEN 1 patients with primary hyperparathyroidism at a young age (less than 30 years).Pregnancy and lactation might trigger brown tumors by increasing mineral and vitamin D requirements.Early parathyroidectomy is advisable in MEN 1 patients with primary hyperparathyroidism, at least before planning a pregnancy.Standard bone mineral density does not correlate with the risk of appearance of a brown tumor.Removal of parathyroid glands does not always lead to the shrinkage of the brown tumor, and surgical excision may be necessary.

Graves' disease TSHR-stimulating antibodies (TSAbs) induce the activation of immature thymocytes: a clue to the riddle of TSAbs generation?

Graves' disease (GD) is an autoimmune thyroid disease defined by the production of stimulating autoantibodies to the thyroid-stimulating hormone receptor (TSHR) (TSAbs) that induce a sustained state of hyperthyroidism in patients. We previously demonstrated that TSHR, the target of this autoimmune response, is also a key susceptibility gene for GD, probably acting through thymic-dependent central tolerance. We also showed that TSHR is, unexpectedly, expressed in thymocytes. In this report, we confirm the expression of TSHR in thymocytes by protein immunoblotting and quantitative PCR, and show that expression is confined to maturing thymocytes. Using functional assays, we show that thymic TSHR is functional and that TSAbs can stimulate thymocytes through this receptor. This new activity of TSAbs on thymocytes may: 1) explain GD-associated thymic enlargement (hyperplasia), and 2) suggest the provocative hypothesis that the continuous stimulation of thymocytes by TSAbs could lead to a vicious cycle of iterative improvement of the affinity and stimulating capability of initially low-affinity antibacterial (e.g., Yersinia) Abs cross-reactive with TSHR, eventually leading to TSAbs. This may help to fill one of the gaps in our present understanding of unusual characteristics of TSAbs.

RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation.

OBJECTIVE: Specific germline mutations in the RET proto-oncogene are correlated with clinical features in multiple endocrine neoplasia type 2A (MEN2A); however, data are scarce regarding differences in clinical profiles dependent on the type of nucleotide and amino acid substitution at the same codon. We aimed to analyse differences in clinical risk profiles and outcomes among different amino acids encoded by codon 634. DESIGN: The study was retrospective and multicentric. METHODS: We collected data included in the Spanish Online National Database from patients with MEN2A carrying a RET proto-oncogene mutation on codon 634. The mean follow-up time was 7.6±6.9 years (1-32). RESULTS: Patients (n=173) from 49 unrelated families were C634Y carriers, and 26 patients from eight different families had C634R mutation. We found higher penetrance of medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism (P<0.001, P=0.007 and P<0.001 respectively) in C634R carriers than in C634Y carriers. The Kaplan-Meier estimate of cumulative lymph node and distant metastases rates showed that these events occurred earlier in patients harbouring the C634R mutation (P<0.001). A multivariate adjusted Cox regression analysis indicated that the C634R mutation was an independent factor for persistent/recurrent disease (hazard ratio, 3.17; 95% CI: 1.66-6.03; P<0.001). CONCLUSIONS: Our results suggest that there could be clinical differences caused by different amino acid substitutions at codon 634; specifically, the C634R mutation was associated with a more aggressive MEN2A phenotype than the C634Y mutation.

Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens.

Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals.