Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Primärer Hyperparathyreoidismus

Primary hyperparathyroidism is frequently an incidental finding in asymptomatic patients. Often the diagnosis of primary hyperparathyroidism is made in evaluation for osteoporosis, rarely in the context of hypercalcemic crisis, myopathy, kidney stones, nephrocalcinosis, and osteitis fibrosa. The most frequent cause for primary hyperparathyroidism is benign parathyroid adenoma, reminders have hyperplasia. Primary hyperparathyroidism is defined as hypercalcemia with inappropriately high parathyroid hormone levels. Surgery is the definitive treatment for patients with symptomatic primary hyperparathyroidism and asymptomatic patients, who meet one of the following criteria: serum calcium 60 ml/min) and presence of osteoporosis (T-score > – 2.5 or fracture). Parathyroidectomy should be performed by an experienced surgeon. As an alternative in inoperable patients or preoperatively in severe hypercalcemia cinacalcet successfully reduces calcium levels. In asymptomatic patients not meeting the above mentioned criteria serum calcium and creatinin levels should be measured once a year and DXA every two years, since 30 % of the patients with asymptomatic primary hyperparathyroidism are progressive

The Significance of 18F-Fluorocholine-PET/CT as Localizing Imaging Technique in Patients with Primary Hyperparathyroidism and Negative Conventional Imaging

ObjectiveThe essential prerequisite for focused parathyroidectomy in patients with primary hyperparathyroidism (pHPT) is proper localization of all autonomic tissue. Sensitivity of conventional imaging modalities (ultrasound, 99mTc-sestamibi scintigraphy/SPECT/CT) is influenced by different factors (i.e., size/weight and position of autonomic tissue) and decreases in the presence of a multinodular goiter. Therefore, a considerable percentage of pHPT patients have negative or equivocal localization studies before surgery. The aim of this study is to evaluate the utility of FCH-PET/CT for preoperative localization in patients with pHPT and negative/equivocal 99mTc-sestamibi scintigraphy/SPECT/CT and/or ultrasound.Methods and measurementsBetween 2014 and 2017, a total of 39 patients with pHPT and negative/equivocal conventional imaging were referred for FCH-PET/CT. In the analysis, we included those (n = 23) who had surgery and a histopathologic workup of the lesions.Results19 of 23 patients demonstrated no tracer uptake with 99mTc-sestamibi scintigraphy/SPECT/CT, 6 patients had an equivocal sonographic lesion, and multinodular goiter was present in 43% (10/23). In 21 of 23 patients, hyperfunctioning parathyroid tissue was identified correctly by FCH-PET/CT [21 true positive, 1 false negative, and 1 false positive; per-patient sensitivity 95.5% (95% confidence interval {CI}, 77.2–99.9)]. 29 lesions were resected [21 true positives, 3 false negatives, 1 false positive, and 4 true negatives; per-lesion sensitivity 87.5% (95% CI, 67.6–97.3)]. All patients were classified as having surgical success according to a decrease of intraoperative parathyroid hormone of ≥50% and normalization of postoperative serum calcium levels.ConclusionDespite a high prevalence of multinodular goiter, diagnostic accuracy of FCH-PET/CT in our patient group was excellent. Therefore, FCH-PET/CT is a promising new imaging tool in patients with pHPT and negative/equivocal results by conventional imaging techniques

Long-term outcome of profound hyponatremia: a prospective 12 months follow-up study

Hyponatremia is the most common electrolyte abnormality in hospitalized patients and given its impact on mortality and morbidity, a relevant medical condition. Nevertheless, little is known about factors influencing long-term outcome.; This is a prospective observational 12-month follow-up study of patients with profound hyponatremia (≤125 mmol/L) admitted to the emergency department of two tertiary care centers between 2011 and 2013. We analyzed the predictive value of clinical and laboratory parameters regarding the following outcomes: 1-year mortality, rehospitalization and recurrent profound hyponatremia.; Median (IQR) initial serum sodium (s-sodium) level of 281 included patients was 120 mmol/L (116-123). During the follow-up period, 58 (20.6%) patients died. The majority (56.2%) were rehospitalized at least once. Recurrent hyponatremia was observed in 42.7%, being profound in 16%. Underlying comorbidities, assessed by the Charlson Comorbidity Index, predicted 1-year mortality (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.25-1.64, P  120 mmol/L (14.8% and 27.8%, P  120 mmol/L.; Hyponatremia is associated with a substantial 1-year mortality, recurrence and rehospitalization rate. The positive correlation of s-sodium and mortality emphasizes the importance of the underlying disease, which determines the outcome besides hyponatremia itself

Evaluation of copeptin and commonly used laboratory parameters for the differential diagnosis of profound hyponatraemia in hospitalized patients: 'The Co-MED Study'

Hyponatraemia is common and its differential diagnosis is challenging. Commonly used diagnostic algorithms have limited diagnostic accuracy. Copeptin, the c-terminal portion of the precursor peptide of arginine vasopressin might help in the differential diagnosis of hyponatraemia.; Prospective multicentre observational study.; A total of 298 patients admitted with profound hypoosmolar hyponatraemia (Na < 125 mmol/l) were evaluated. Three experts uninvolved in the patients' care determined the aetiology of hyponatraemia after standardized diagnostic evaluation.; Hyponatraemia differential diagnoses were as follows: syndrome of inappropriate antidiuresis (SIAD), 106 patients (35·6%); 'diuretic-induced', 72 (24·2%); 'hypovolaemic', 59 (19·8%); 'hypervolaemic', 33 (11·1%); primary polydipsia (PP), 24 (8·1%); and cortisol deficiency, 4 (1·3%). Copeptin levels <3·9 pmol/l identified patients with PP with high specificity (91%). Further, copeptin levels >84 pmol/l were highly predictive for hypovolaemic hyponatraemia (specificity: 90%). Urinary sodium levels and copeptin/urinary sodium ratio in patients with SIAD were higher and lower as compared to other hyponatraemia aetiologies (P < 0·0001). However, the specificity to identify SIAD was moderate for both parameters (31% and 61%). Fractional uric acid excretion (FEUA ) and fractional urea excretion (FEurea ) were higher in patients with SIAD compared to other hyponatraemia aetiologies (both P < 0·0001). FEurea values >55% and FEUA values >12% had a specificity of 96% and 77% to detect patients with SIAD. These results remained similar after excluding patients taking diuretics.; Overall, there is only limited diagnostic utility of copeptin in the differential diagnosis of profound hyponatraemia. Very low copeptin levels are seen in patients with PP and highest copeptin levels in hypovolaemic hyponatraemia. To discriminate between SIAD and other hyponatraemia aetiologies, FEurea and FEUA levels are valuable irrespective of diuretics use

Corticosteroid treatment for community-acquired pneumonia--the STEP trial: study protocol for a randomized controlled trial

BACKGROUND Community-acquired pneumonia (CAP) is the third-leading infectious cause of death worldwide. The standard treatment of CAP has not changed for the past fifty years and its mortality and morbidity remain high despite adequate antimicrobial treatment. Systemic corticosteroids have anti-inflammatory effects and are therefore discussed as adjunct treatment for CAP. Available studies show controversial results, and the question about benefits and harms of adjunct corticosteroid therapy has not been conclusively resolved, particularly in the non-critical care setting. METHODS/DESIGN This randomized multicenter study compares a treatment with 7 days of prednisone 50 mg with placebo in adult patients hospitalized with CAP independent of severity. Patients are screened and enrolled within the first 36 hours of presentation after written informed consent is obtained. The primary endpoint will be time to clinical stability, which is assessed every 12 hours during hospitalization. Secondary endpoints will be, among others, all-cause mortality within 30 and 180 days, ICU stay, duration of antibiotic treatment, disease activity scores, side effects and complications, value of adrenal function testing and prognostic hormonal and inflammatory biomarkers to predict outcome and treatment response to corticosteroids. Eight hundred included patients will provide an 85% power for the intention-to-treat analysis of the primary endpoint. DISCUSSION This largest to date double-blind placebo-controlled multicenter trial investigates the effect of adjunct glucocorticoids in 800 patients with CAP requiring hospitalization. It aims to give conclusive answers about benefits and risks of corticosteroid treatment in CAP. The inclusion of less severe CAP patients will be expected to lead to a relatively low mortality rate and survival benefit might not be shown. However, our study has adequate power for the clinically relevant endpoint of clinical stability. Due to discontinuing glucocorticoids without tapering after seven days, we limit duration of glucocorticoid exposition, which may reduce possible side effects. TRIAL REGISTRATION 7 September 2009 on ClinicalTrials.gov: NCT00973154

Additional file 1: of Copeptin levels and commonly used laboratory parameters in hospitalised patients with severe hypernatraemia - the “Co-MED study”

Clinical diagnostic algorithm for the differential diagnosis of hypernatremia. (TIFF 143 kb

Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial

BACKGROUND Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. METHODS In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. FINDINGS From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. INTERPRETATION Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. FUNDING Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung