Local recurrence and metastatic disease in pheochromocytomas and sympathetic paragangliomas.

Purpose: To evaluate the rate of recurrence among patients with pheochromocytomas and sympathetic paragangliomas (PGLs; together PPGLs) and to identify predictors of recurrence (local recurrence and/or metastatic disease). Methods: This retrospective multicenter study included information of 303 patients with PPGLs in follow-up in 19 Spanish tertiary hospitals. Recurrent disease was defined by the development of local recurrence and/or metastatic disease after initial complete surgical resection. Results: A total of 303 patients with PPGLs that underwent 311 resections were included (288 pheochromocytomas and 15 sympathetic PGLs). After a median follow-up of 4.8 years (range 1-19), 24 patients (7.9%) had recurrent disease (3 local recurrence, 17 metastatic disease and 4 local recurrence followed by metastatic disease). The median time from the diagnosis of the PPGL to the recurrence was of 11.2 months (range 0.5-174) and recurrent disease cases distributed uniformly during the follow-up period. The presence of a pathogenic variant in SDHB gene (hazard ratio [HR] 13.3, 95% CI 4.20-41.92), higher urinary normetanephrine levels (HR 1.02 per each increase in standard deviation, 95% CI 1.01-1.03) and a larger tumor size (HR 1.01 per each increase in mm, 95% CI 1.00-1.02) were independently associated with disease recurrence. Conclusion: The recurrence of PPGLs occurred more frequently in patients with SDHB mutations, with larger tumors and with higher urinary normetanephrine levels. Since PPGL recurrence may occur at any time after the initial PPGL diagnosis is performed, we recommend performing a strict follow-up in all patients with PPGLs, especially in those patients with a higher risk of recurrent disease.

An Integrated CT and MRI Imaging Model to Differentiate between Adrenal Adenomas and Pheochromocytomas.

PURPOSE: to perform an external validation of our predictive model to rule out pheochromocytoma (PHEO) based on unenhanced CT in a cohort of patients with PHEOs and adenomas who underwent adrenalectomy. METHODS: The predictive model was previously developed in a retrospective cohort of 1131 patients presenting with adrenal lesions. In the present study, we performed an external validation of the model in another cohort of 214 patients with available histopathological results. RESULTS: For the external validation, 115 patients with PHEOs and 99 with adenomas were included. Our previously described predictive model combining the variables of high lipid content and tumor size in unenhanced CT (AUC-ROC: 0.961) had a lower diagnostic accuracy in our current study population for the prediction of PHEO (AUC: 0.750). However, when we excluded atypical adenomas (with Hounsfield units (HU) > 10, n = 39), the diagnostic accuracy increased to 87.4%. In addition, in the whole cohort (including atypical adenomas), when MRI information was included in the model, the diagnostic accuracy increased to up to 85% when the variables tumor size, high lipid content in an unenhanced CT scan, and hyperintensity in the T2 sequence in MRI were included. The probability of PHEO was <0.3% for adrenal lesions <20 mm with >10 HU and without hyperintensity in T2. CONCLUSION: Our study confirms that our predictive model combining tumor size and lipid content has high reliability for the prediction of PHEO when atypical adrenal lesions are excluded. However, for atypical adrenal lesions with >10 HU in an unenhanced CT scan, MRI information is necessary for a proper exclusion of the PHEO diagnosis.

Genetic Study in Pheochromocytoma: Is It Possible to Stratify the Risk of Hereditary Pheochromocytoma?

INTRODUCTION: It is estimated that 30-40% of patients with apparently sporadic pheochromocytomas (PHEOs) have an inherited predisposition syndrome. The aim of our study was to develop a predictive model of hereditary PHEO based on the clinical, hormonal, and radiological features present at the diagnosis of patients with PHEOs. METHODS: A retrospective multicenter cohort study of patients with PHEOs with available genetic study from 18 tertiary hospitals. Clinical, biochemical, and radiological features were used to build a multivariate logistic regression model. The estimation of all possible equations was used to select the model with the best diagnostic accuracy (lower Akaike index). RESULTS: A total of 245 patients were included: 169 (69.0%) patients with sporadic PHEOs and 76 (31%) with hereditary PHEOs. The parsimonious predictive model with the highest diagnostic accuracy for the prediction of hereditary PHEO combined the variables age, non-cardiovascular disease, urinary norepinephrine levels, and tumor size. The area under the ROC curve of this model was 0.800 (0.705-0.887). Based on the predictive model, the probability of hereditary PHEO in patients older than 60 years with cardiovascular disease, high levels of urinary norepinephrine and unilateral PHEOs >60 mm was <2%. And if the age was above 80 years, lower than 1%. The probability of sporadic PHEO linearly increased with age (MH Test for linear Trend: χ2 (1) = 30.05; p < 0.001). CONCLUSION: In certain populations such as old patients with cardiovascular disease, with high levels of urinary norepinephrine and large tumors in which the probability of hereditary PHEO is very low, genetic testing could be avoided in the absence of specific suspicion.

Glycemic disorders in patients with pheochromocytomas and sympathetic paragangliomas.

The objective of our study was to determine the prevalence of glycemic disorders (diabetes mellitus and prediabetes) in patients with pheochromocytomas and sympathetic paragangliomas (PPGLs) and identify risk factors for their development and the likelihood of their resolution after surgery. A multicentric retrospective study of patients with PPGLs submitted to surgery between 2000 and 2021 in 17 Spanish hospitals was performed. Diabetes-specific data were collected at diagnosis, in the immediate- and long-term postsurgical follow-up. A total of 229 patients with PPGLs were included (218 with pheochromocytomas and 11 with sympathetic paragangliomas). Before surgery, glycemic disorders were diagnosed in 35.4% of the patients (n = 81): 54 with diabetes and 27 with prediabetes. The variables independently associated with a higher risk of glycemic disorders were sporadic PPGL (odds ratio (OR) = 3.26 (1.14-9.36)) and hypertension (OR = 3.14 (1.09-9.01)). A significant decrease in fasting plasma glucose and HbA1c levels was observed after surgery, in the short-term and long-term follow-up (P < 0.001). After a median follow-up of 48.5 months (range 3.3-168.9), after surgery, 52% of diabetic and 68% of prediabetic patients experienced a complete resolution. Lower body mass index (BMI) (P = 0.001), lower glucose levels (P = 0.047) and shorter duration of diabetes prior to surgery (P = 0.021) were associated with a higher probability of diabetes resolution. In conclusion, glycemic disorders in patients with PPGLs are present in more than a third of them at diagnosis. Sporadic PPGLs and hypertension are risk factors for their development. More than 50% of cases experience a complete resolution of the glycemic disorder after resection of the PPGLs.

Changes in Serum Creatinine Levels Can Help Distinguish Hypovolemic from Euvolemic Hyponatremia.

Background and Objectives: Differentiating between hypovolemic (HH) and euvolemic hyponatremia (EH) is crucial for correct diagnosis and therapy, but can be a challenge. We aim to ascertain whether changes in serum creatinine (SC) can be helpful in distinguishing HH from EH. Materials and Methods: Retrospective analysis of patients followed in a monographic hyponatremia outpatient clinic of a tertiary hospital during 1 January 2014−30 November 2019. SC changes during HH and EH from eunatremia were studied. The diagnostic accuracy of the SC change from eunatremia to hyponatremia (∆SC) was analyzed. Results: A total of 122 hyponatremic patients, median age 79 years (70−85), 46.7% women. In total, 70/122 patients had EH, 52/122 HH. During hyponatremia, median SC levels increased in the HH group: +0.18 mg/dL [0.09−0.39, p < 0.001], but decreased in the EH group: −0.07 mg/dL (−0.15−0.02, p < 0.001), as compared to SC in eunatremia. HH subjects presented a higher rate of a positive ∆SC than EH (90.4% vs. 25.7%, p < 0.001). EH subjects presented a higher rate of a negative/null ∆SC than HH (74.3% vs. 9.6%, p < 0.001). ROC curve analysis found an AUC of 0.908 (95%CI: 0.853 to 0.962, p < 0.001) for ∆SC%. A ∆SC% ≥ 10% had an OR of 29.0 (95%CI: 10.3 to 81.7, p < 0.001) for HH. A ∆SC% ≤ 3% had an OR of 68.3 (95%CI: 13.0 to 262.2, p < 0.001) for EH. Conclusions: The assessment of SC changes from eunatremia to hyponatremia can be useful in distinguishing between HH and EH.

Predictive model of pheochromocytoma based on the imaging features of the adrenal tumours.

The purpose of our study was to develop a predictive model to rule out pheochromocytoma among adrenal tumours, based on unenhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) features. We performed a retrospective multicentre study of 1131 patients presenting with adrenal lesions including 163 subjects with histological confirmation of pheochromocytoma (PHEO), and 968 patients showing no clinical suspicion of pheochromocytoma in whom plasma and/or urinary metanephrines and/or catecholamines were within reference ranges (non-PHEO). We found that tumour size was significantly larger in PHEO than non-PHEO lesions (44.3 ± 33.2 versus 20.6 ± 9.2 mm respectively; P < 0.001). Mean unenhanced CT attenuation was higher in PHEO (52.4 ± 43.1 versus 4.7 ± 17.9HU; P < 0.001). High lipid content in CT was more frequent among non-PHEO (83.6% versus 3.8% respectively; P < 0.001); and this feature alone had 83.6% sensitivity and 96.2% specificity to rule out pheochromocytoma with an area under the receiver operating characteristics curve (AUC-ROC) of 0.899. The combination of high lipid content and tumour size improved the diagnostic accuracy (AUC-ROC 0.961, sensitivity 88.1% and specificity 92.3%). The probability of having a pheochromocytoma was 0.1% for adrenal lesions smaller than 20 mm showing high lipid content in CT. Ninety percent of non-PHEO presented loss of signal in the "out of phase" MRI sequence compared to 39.0% of PHEO (P < 0.001), but the specificity of this feature for the diagnosis of non-PHEO lesions low. In conclusion, our study suggests that sparing biochemical screening for pheochromocytoma might be reasonable in patients with adrenal lesions smaller than 20 mm showing high lipid content in the CT scan, if there are no typical signs and symptoms of pheochromocytoma.

Surgical outcomes in the pheochromocytoma surgery. Results from the PHEO-RISK STUDY.

PURPOSE: To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery. METHODS: A retrospective study of pheochromocytomas submitted to surgery in ten Spanish hospitals between 2011 and 2021. Postoperative complications were classified according to Clavien-Dindo scale. RESULTS: One hundred and sixty-two surgeries (159 patients) were included. Preoperative antihypertensive blockade was performed in 95.1% of the patients, being doxazosin in monotherapy (43.8%) the most frequent regimen. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more frequently (49.4% vs 25.0%, P = 0.003) than patients treated with phenoxybenzamine, but no differences in the rate of intraoperative and postsurgical complications were observed. However, patients treated with phenoxybenzamine had a longer hospital stay (12.2 ± 11.16 vs 6.2 ± 6.82, P < 0.001) than those treated with doxazosin. Hypertension resolution was observed in 78.7% and biochemical cure in 96.6% of the patients. Thirty-one patients (19.1%) had postsurgical complications. Prolonged hypotension was the most common, in 9.9% (n = 16), followed by hypoglycaemia in six patients and acute renal failure in four patients. 13.0% of complications had a score ≥3 in the Clavien-Dindo scale. Postsurgical complications were more common in patients with diabetes, cerebrovascular disease, higher plasma glucose levels, higher urinary free metanephrine and norepinephrine, and with pheochromocytomas larger than 5 cm. CONCLUSION: Preoperative medical treatment and postsurgical monitoring of pheochromocytoma should be especially careful in patients with diabetes, cerebrovascular disease, higher levels of plasma glucose and urine free metanephrine and norepinephrine, and with pheochromocytomas >5 cm, due to the higher risk of postsurgical complications.

Risk factors for intraoperative complications in pheochromocytomas.

We aimed to identify presurgical and surgical risk factors for intraoperative complications in patients with pheochromocytomas. A retrospective study of patients with pheochromocytomas who underwent surgery in ten Spanish hospitals between 2011 and 2021 was performed. One hundred and sixty-two surgeries performed in 159 patients were included. The mean age was 51.6 ± 16.4 years old and 52.8% were women. Median tumour size was 40 mm (range 10-110). Laparoscopic adrenalectomy was performed in 148 patients and open adrenalectomy in 14 patients. Presurgical alpha- and beta-blockade was performed in 95.1% and 51.9% of the surgeries, respectively. 33.3% of the patients (n = 54) had one or more intraoperative complications. The most common complication was the hypertensive crisis in 21.0%, followed by prolonged hypotension in 20.0%, and hemodynamic instability in 10.5%. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more commonly than patients pre-treated with other antihypertensive drugs (51.1% vs 26.5%, P = 0.002). Intraoperative complications were more common in patients with higher levels of urine metanephrine (OR = 1.01 for each 100 µg/24 h, P = 0.026) and normetanephrine (OR = 1.00 for each 100 µg/24 h, P = 0.025), larger tumours (OR = 1.4 for each 10 mm, P < 0.001), presurgical blood pressure > 130/80 mmHg (OR = 2.25, P = 0.027), pre-treated with doxazosin (OR = 2.20, P = 0.023) and who had not received perioperative hydrocortisone (OR = 3.95, P = 0.008). In conclusion, intraoperative complications in pheochromocytoma surgery are common and can be potentially life-threatening. Higher metanephrine and normetanephrine levels, larger tumour size, insufficient blood pressure control before surgery, pre-treatment with doxazosin, and the lack of treatment with perioperative hydrocortisone are associated with higher risk of intraoperative complications.

Prognostic Impact of Hyponatremia and Hypernatremia in COVID-19 Pneumonia. A HOPE-COVID-19 (Health Outcome Predictive Evaluation for COVID-19) Registry Analysis.

Dysnatremia is associated with increased mortality in patients with community-acquired pneumonia. SARS-COV2 (Severe-acute-respiratory syndrome caused by Coronavirus-type 2) pneumonia can be fatal. The aim of this study was to ascertain whether admittance dysnatremia is associated with mortality, sepsis, or intensive therapy (IT) in patients hospitalized with SARS-COV2 pneumonia. This is a retrospective study of the HOPE-COVID-19 registry, with data collected from January 1th through April 31th, 2020. We selected all hospitalized adult patients with RT-PCR-confirmed SARS-COV2 pneumonia and a registered admission serum sodium level (SNa). Patients were classified as hyponatremic (SNa <135 mmol/L), eunatremic (SNa 135-145 mmol/L), or hypernatremic (SNa >145 mmol/L). Multivariable analyses were performed to elucidate independent relationships of admission hyponatremia and hypernatremia, with mortality, sepsis, or IT during hospitalization. Four thousand six hundred sixty-four patients were analyzed, median age 66 (52-77), 58% males. Death occurred in 988 (21.2%) patients, sepsis was diagnosed in 551 (12%) and IT in 838 (18.4%). Hyponatremia was present in 957/4,664 (20.5%) patients, and hypernatremia in 174/4,664 (3.7%). Both hyponatremia and hypernatremia were associated with mortality and sepsis. Only hyponatremia was associated with IT. In conclusion, hyponatremia and hypernatremia at admission are factors independently associated with mortality and sepsis in patients hospitalized with SARS-COV2 pneumonia. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04334291, NCT04334291.

SEEN guidelines for the management and prevention of acute adrenal insufficiency. / Guía para el manejo y la prevención de la insuficiencia suprarrenal aguda.

Acute adrenal insufficiency (AAI) is a potentially fatal medical emergency whose prevention and treatment should be known by all medical professionals. AAI is an underdiagnosed condition because of its non-specific symptoms, but its diagnosis and early treatment with glucocorticoids is vital. It may be triggered by a de novo deficiency in cortisol synthesis or occur secondarily to omission of hormone replacement therapy (corticosteroids) or inadequate adjustment of the dose required in stress situations in patients previously diagnosed with adrenal insufficiency. AAI prevention significantly decreases death from cardiovascular diseases and infections in patients with adrenal insufficiency, and also improves their quality of life. Adequate education of patients, relatives, and all healthcare professionals is therefore essential. Therefore, the Adrenal Disorders Group of the Neuroendocrinology Area of the Spanish Society of Endocrinology and Nutrition (SEEN) has prepared, at the proposal of the SEEN's board, a guideline for optimal management of acute adrenal insufficiency. The guideline is intended to provide practical recommendations for all healthcare professionals who may be involved in the diagnosis, treatment, and prevention of AAI. It is also intended to provide patients and their families with action guidelines for AAI management and prevention.

PheoSeq: A Targeted Next-Generation Sequencing Assay for Pheochromocytoma and Paraganglioma Diagnostics.

Genetic diagnosis is recommended for all pheochromocytoma and paraganglioma (PPGL) cases, as driver mutations are identified in approximately 80% of the cases. As the list of related genes expands, genetic diagnosis becomes more time-consuming, and targeted next-generation sequencing (NGS) has emerged as a cost-effective tool. This study aimed to optimize targeted NGS in PPGL genetic diagnostics. A workflow based on two customized targeted NGS assays was validated to study the 18 main PPGL genes in germline and frozen tumor DNA, with one of them specifically directed toward formalin-fixed paraffin-embedded tissue. The series involved 453 unrelated PPGL patients, of whom 30 had known mutations and were used as controls. Partial screening using Sanger had been performed in 275 patients. NGS results were complemented with the study of gross deletions. NGS assay showed a sensitivity ≥99.4%, regardless of DNA source. We identified 45 variants of unknown significance and 89 pathogenic mutations, the latter being germline in 29 (7.2%) and somatic in 58 (31.7%) of the 183 tumors studied. In 37 patients previously studied by Sanger sequencing, the causal mutation could be identified. We demonstrated that both assays are an efficient and accurate alternative to conventional sequencing. Their application facilitates the study of minor PPGL genes, and enables genetic diagnoses in patients with incongruent or missing clinical data, who would otherwise be missed.

Guidelines for the diagnosis and treatment of adrenal insufficiency in the adult.

Adrenal insufficiency (AI) is a disease characterized by a deficient production or action of glucocorticoids, with or without deficiency in mineral corticoids and/or adrenal androgens. It can result from disease intrinsic to the adrenal cortex (primary AI), from pituitary diseases that hamper the release of corticotropin (secondary AI) or from hypothalamic disorders that impair the secretion of the corticotropin-releasing hormone (tertiary AI). It is a disease with a low prevalence but its impact on the affected individual is very high as it can be life-threathening if not treated or lead to health problems if inadequately treated. However, currently there are no specific guidelines for the management of this disease. Therefore, at the proposal of the Spanish Society of Endocrinology and Nutrition (SEEN) board, a task-force under the Neuroendocrinology Knowledge Area of the SEEN was established, with the mandate of updating the diagnosis and treatment of AI. In fulfilment of this mandate the task-force has elaborated the present guide that, based on a comprehensive review of literature, is intended to provide an answer to questions related to the management of this disease. It is, therefore, an essentially practical document, mainly aimed at guiding the health professionals involved in the care of IA patients.

The exon 3-deleted growth hormone receptor is associated with better response to pegvisomant therapy in acromegaly.

CONTEXT: The deletion of exon 3 in the GH receptor (GHR) has been associated with a different biochemical picture and response to therapy in acromegaly. OBJECTIVE: The aim of the study was to determine whether or not the GHR genotype influences the efficacy of pegvisomant treatment. DESIGN AND SETTING: A cross-sectional study was conducted in six Spanish university hospitals. PATIENTS: Forty-four acromegalic patients with active disease and resistance to somatostatin analogs participated in the study. RESULTS: The prevalence of the full-length GHR and the exon 3-deleted GHR homozygous and heterozygous genotypes was 41, 2, and 57%, respectively. There were no differences in IGF-I or GH pre-pegvisomant levels related to GHR genotype. The exon 3-deleted patients required approximately 20% lower doses of pegvisomant per kilogram of weight (28 +/- 11 compared to 22 +/- 7 mg per kg of weight; P = 0.033) to normalize IGF-I. A stepwise multivariate linear regression analysis (R(2) = 0.27; P = 0.003) identified male gender (beta = -0.79; P = 0.03) and d3-GHR genotype (beta = -0.64; P = 0.007) as the only significant predictors of the dose of pegvisomant per kilogram of weight. In addition, d3-GHR carriers required fewer months for IGF-I normalization (P < 0.01). A stepwise multivariate linear regression analysis (R(2) = 0.40; P = 0.001) revealed that the only significant predictor of the time to IGF-I normalization was the dose of pegvisomant per kilogram of weight (beta = 0.451; P = 0.001). CONCLUSIONS: The exon 3 deletion in the GHR predicts an improved response to pegvisomant therapy in acromegaly.

Long-term treatment of acromegalic patients resistant to somatostatin analogues with the GH receptor antagonist pegvisomant: its efficacy in relation to gender and previous radiotherapy.

CONTEXT: Pegvisomant is an effective treatment for somatostatin analogue-resistant acromegaly, but the determinants defining the response to this treatment are largely unknown. OBJECTIVE: To investigate the efficacy of pegvisomant treatment in resistant acromegalic patients (e.g. serum IGF1 at least 1.25 x upper normal limit) in a clinical setting and the factors conditioning this response. DESIGN AND SETTING: A retrospective cross-sectional study performed in six Spanish University hospitals from 2004 to 2007. Patients Forty-four acromegalic patients (61.4% female, mean age: 49+/-14), 95% of whom had undergone pituitary surgery and 61% having received pituitary radiotherapy. The mean follow-up was 22.7+/-11.2 months. Main outcome measures IGF1 levels reflected treatment efficacy, and the influence of gender, age, weight, previous radiotherapy and duration of treatment was assessed. RESULTS: IGF1 normalisation was achieved in 84% of the patients. Male gender (P<0.05), previous irradiation (P<0.05) and the treatment duration (r=0.364, P<0.02) were associated with a better response to pegvisomant therapy. There was a significant decrease in HbA1c (P<0.001) and in the mean insulin dose (P<0.01) in acromegalic diabetic patients. Although 25% of patients experienced mild adverse events, pegvisomant was only withdrawn in four patients due to side effects (two cases of tumour growth, one liver dysfunction and one headache). CONCLUSIONS: Long-term pegvisomant is a very effective therapy in resistant acromegaly. Male gender and prior radiotherapy influence the therapeutic response rate.