Faculty Bibliography

OBJECTIVE:To evaluate which tests are performed to diagnose hypercortisolism in patients included in the European Registry on Cushing's syndrome (ERCUSYN), and to examine if their use differs from the current guidelines. PATIENTS AND METHODS:We analyzed data on the diagnostic tests performed in 1341 patients with Cushing's syndrome (CS) who have been entered into the ERCUSYN database between January 1, 2000 and January 31, 2016 from 57 centers in 26 European countries. Sixty-seven percent had pituitary-dependent CS (PIT-CS), 24% had adrenal-dependent CS (ADR-CS), 6% had CS from an ectopic source (ECT-CS) and 3% were classified as having CS from other causes (OTH-CS). RESULTS: < 0.05). CONCLUSIONS:Use of diagnostic tests for CS varies across Europe and partly differs from the currently available guidelines. It would seem pertinent that a European consensus be established to determine the best diagnostic approach to CS, taking into account specific inter-country differences with regard to the availability of diagnostic tools.

Peptide receptor radionuclide therapy (PRRT) with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-DOTATATE) is a treatment with good results in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEPNETs). However, there are some pitfalls that should be taken into consideration when evaluating the treatment response after PRRT. 354 Dutch patients with GEPNETs who were treated with ¹⁷⁷Lu-DOTATATE between March 2000 and December 2011 were retrospectively selected. Liver function parameters and chromogranin A were measured before each therapy and in follow-up. Anatomical imaging was performed before therapy and in follow-up. An increase in aminotransferases by ≥20% compared to baseline was observed in 83 of 351 patients (24%). In patients with an objective response (OR) and stable disease (SD) this increase was observed in 71/297 (24%) and in patients with progressive disease (PD) it was observed in 12/54 patients (22%). An increase in chromogranin A by ≥20% compared to baseline was observed in 76 patients (29%). This was present in 34% of patients who eventually had PD and 27% of patients who had OR/SD. In 70% of patients this tumour marker returned to baseline levels after therapy. An increase in liver enzymes and chromogranin A is not uncommon after PRRT. In the vast majority of patients this will resolve in follow-up. Clinicians should be aware that these changes may occur due to radiation-induced inflammation or disease progression and that repeated measurements over time are necessary to differentiate between the two.

PURPOSE/OBJECTIVE:: To develop a clinical prediction model to predict a clinically relevant adrenal disorder for patients with adrenal incidentaloma. MATERIALS AND METHODS/METHODS:: This retrospective study is approved by the institutional review board, with waiver of informed consent. Natural language processing is used for filtering of adrenal incidentaloma cases in all thoracic and abdominal CT reports from 2010 till 2012. A total of 635 patients are identified. Stepwise logistic regression is used to construct the prediction model. The model predicts if a patient is at risk for malignancy or hormonal hyperfunction of the adrenal gland at the moment of initial presentation, thus generates a predicted probability for every individual patient. The prediction model is evaluated on its usefulness in clinical practice using decision curve analysis (DCA) based on different threshold probabilities. For patients whose predicted probability is lower than the predetermined threshold probability, further workup could be omitted. RESULTS:: A prediction model is successfully developed, with an area under the curve (AUC) of 0.78. Results of the DCA indicate that up to 11% of patients with an adrenal incidentaloma can be avoided from unnecessary workup, with a sensitivity of 100% and specificity of 11%. CONCLUSION/CONCLUSIONS:: A prediction model can accurately predict if an adrenal incidentaloma patient is at risk for malignancy or hormonal hyperfunction of the adrenal gland based on initial imaging features and patient demographics. However, with most adrenal incidentalomas labeled as nonfunctional adrenocortical adenomas requiring no further treatment, it is likely that more patients could be omitting from unnecessary diagnostics.

Cushing's syndrome is a rare disease that results from prolonged exposure to supraphysiological levels of glucocorticoids. Severe and rapidly progressive cases are often, but not exclusively, attributable to ectopic ACTH secretion. Extreme hypercortisolism usually has florid metabolic consequences and is associated with an increased infectious and thrombotic risk. The authors report on a case of a 51-year-old male that presented with severe Cushing's syndrome secondary to an ACTH-secreting pituitary macroadenoma, whose diagnostic workup was affected by concurrent subclinical multifocal pulmonary infectious nodules. The case is noteworthy for the atypically severe presentation of Cushing's disease, and it should remind the clinician of the possible infectious and thrombotic complications associated with Cushing's syndrome.

OBJECTIVE:To determine if urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion is of prognostic value for overall survival (OS) in patients with a gastrointestinal neuroendocrine tumour (NET) and to compare the prognostic value with patient characteristics, ENETS/WHO grading, ENETS TNM staging and biomarkers. DESIGN AND METHODS/METHODS:Data was collected from patients with a gastrointestinal NET or a NET with gastrointestinal metastases and available 5-HIAA excretion in 24-h urine samples. Laboratory results were stratified for urinary 5-HIAA and chromogranin A (CgA): <2× upper limit of normal (ULN), 2-10× ULN, or >10× ULN. For neuron-specific enolase (NSE), this was the reference range or >1× ULN. OS was compared using Kaplan-Meier and log-rank tests, and hazard ratios were calculated using Cox regression for univariate and multivariate analyses. RESULTS:A total of 371 patients were included, 46.6% female with a mean age of 59.9 years. OS was shortest in patients with urinary 5-HIAA excretion >10× ULN vs reference range (median 83 months vs 141 months, P = 0.002). In univariate analysis, urinary 5-HIAA excretion >10× ULN was a negative predictor (HR 1.62, 95% CI: 1.09-2.39). However, in multivariate analysis, only age (HR 1.04, 95% CI: 1.01-1.08), grade 3 disease (HR 5.09, 95% CI: 2.20-11.79), NSE >1× ULN (HR 2.36, 95% CI: 1.34-4.14) and CgA >10× ULN (HR 3.61, 95% CI: 1.56-8.34) remained as the predictors. CONCLUSION/CONCLUSIONS:Urinary 5-HIAA excretion >10× ULN is a negative predictor for OS. However, when added to other biomarkers and grading, it is no longer a predictor for OS. Therefore, it should only be determined to assess carcinoid syndrome and not for prognostic value.

Purpose To present an updated prevalence estimate for incidental findings on brain magnetic resonance (MR) images and provide information on clinical relevance, including natural course, over a period of up to 9 years. Materials and Methods This study was approved by the institutional review board and all participants gave informed consent. In a prospective population-based setting, structural brain MR imaging was performed in 5800 participants (mean age, 64.9 years; 3194 women [55.1%]). Trained reviewers recorded abnormalities, which were subsequently evaluated by neuroradiologists. The prevalence with 95% confidence interval (CI) of incidental findings was determined, and clinical management of findings that required the attention of a medical specialist was followed. Follow-up imaging in the study context provided information on the natural course of findings that were not referred. Results In 549 of 5800 participants (9.5% [95% CI: 8.7%, 10.3%]), incidental findings were found, of which meningiomas (143 of 5800; 2.5% [95% CI: 2.1%, 2.9%]) and cerebral aneurysms (134 of 5800; 2.3% [95% CI: 2.0%, 2.7%]) were most common. A total of 188 participants were referred to medical specialists for incidental findings (3.2% [95% CI: 2.8%, 3.7%]). Of these, 144 (76.6% [95% CI: 70.1%, 82.1%]) either underwent a wait-and-see policy or were discharged after the initial clinical visit. The majority of meningiomas and virtually all aneurysms not referred or referred but untreated remained stable in size during follow-up. Conclusion Incidental findings at brain MR imaging that necessitate further diagnostic evaluation occur in over 3% of the general middle-aged and elderly population, but are mostly without direct clinical consequences. ^© RSNA, 2016.

OBJECTIVE:To evaluate the association between Cushing syndrome and hypercoagulability in children. STUDY DESIGN:A prospective, observational study was performed of 54 patients with Cushing syndrome, 15.1 ± 3.9 years, treated at the National Institutes of Health Clinical Center. Coagulation profiles were taken before and 6-12 months after surgery and compared with18 normocortisolemic children, 13.7 ± 3.6 years. RESULTS:At baseline, patients with Cushing syndrome had greater levels of the procoagulant factor VIII (FVIII) vs controls (145 IU/dL ± 84 vs 99 ± 47, P = .04); 6-12 months after surgery, FVIII levels decreased to 111 ± 47, P = .05. Patients with Cushing syndrome had greater levels of the antifibrinolytic α2-antiplasmin, 96 ± 17% vs 82 ± 26%, P = .015. After surgery, antifibrinolytic α2-antiplasmin levels decreased to 82 ± 24%, P < .001. Anticoagulants were greater in patients with Cushing syndrome vs controls at baseline, including protein C (138 ± 41% vs 84 ± 25%, P < .001), protein S (94 ± 19% vs 74 ± 19%, P = .001), and antithrombin III (96 ± 18% vs 77 ± 13%, P < .0001). The 24-hour urinary free cortisol levels correlated positively with FVIII levels, r = 0.43, P = .004. CONCLUSION:Children with Cushing syndrome had elevated procoagulants, antifibrinolytics, and anticoagulants at baseline compared with controls; normalization of coagulation measures was seen after surgical cure. Despite the increase in anticoagulants, hypercortisolemia is associated with a hypercoagulable state in children, as is the case in adults. This finding has potential implications for prevention of venous thromboembolism in children with Cushing syndrome. TRIAL REGISTRATION:ClinicalTrials.gov:NCT00001595.

To date, the value of fasting plasma acylated ghrelin (AG) and unacylated ghrelin (UAG) as potential novel biomarkers in patients with neuroendocrine tumors (NETs) is unknown. The aims of this study are to (i) compare fasting AG and UAG levels between nonobese, nondiabetic NET patients (N=28) and age- (±3 years) and sex-matched nonobese, nondiabetic controls (N=28); and (ii) study the relationship between AG, UAG, and AG/UAG ratios and biochemical (chromogranin-A (CgA) and neuron-specific enolase (NSE) levels) and clinical parameters (age at diagnosis, sex, primary tumor location, carcinoid syndrome, ENETS TNM classification, Ki-67 proliferation index, grading, prior incomplete surgery) in NET patients. Fasting venous blood samples (N=56) were collected and directly stabilized with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride after withdrawal. Plasma AG and UAG levels were determined by ELISA. Expression of ghrelin was examined in tumor tissue by immunohistochemistry. There were no significant differences between NET patients and controls in AG (median: 62.5 pg/mL, IQR: 33.1-112.8 vs median: 57.2pg/mL, IQR: 26.7-128.3, P=0.66) and UAG in levels (median: 76.6pg/mL, IQR: 35.23-121.7 vs median: 64.9, IQR: 27.5-93.1, P=0.44). No significant correlations were found between AG, UAG, and AG/UAG ratios versus biochemical and clinical parameters in NET patients with the exception of age at diagnosis (AG: ρ= -0.47, P=0.012; AG/UAG ratio: ρ= -0.50, P=0.007) and baseline chromogranin-A levels (AG/UAG ratio: ρ= -0.44, P=0.019). In our view, fasting plasma acylated and unacylated ghrelin appear to have no value as diagnostic biomarkers in the clinical follow-up of patients with NETs.

OBJECTIVE:The high expression of somatostatin receptor subtype 2 (SSTR2 also known as sst2) usually present in growth hormone (GH)-secreting adenomas is the rationale for therapy with somatostatin analogs (SSAs) in acromegaly. Although SSTR2 expression is a good predictor for biochemical response to SSA treatment, we still face tumors resistant to SSAs despite high SSTR2 expression. Recently, beta-arrestins (β-arrestins) have been highlighted as key players in the regulation of SSTR2 function. DESIGN/METHODS:To investigate whether β-arrestins might be useful predictors of responsiveness to long-term SSA treatment in acromegaly, we retrospectively evaluated 35 patients with acromegaly who underwent adenomectomy in two referral centers in The Netherlands. METHODS:β-arrestin mRNA levels were evaluated in adenoma samples, together with SSTR2 (and SSTR5) mRNA and protein expression. Biochemical response to long-term SSA treatment (median 12 months) was assessed in 32 patients. RESULTS:β-arrestin 1 and 2 mRNA was significantly lower in adenoma tissues from patients who achieved insulin-like growth factor 1 normalization (P = 0.024 and P = 0.047) and complete biochemical control (P = 0.047 and P = 0.039). The SSTR2 mRNA was higher in SSA responder patients compared with the resistant ones (P = 0.026). This difference was more evident when analyzing the SSTR2/β-arrestin 1 and SSTR2/β-arrestin 2 ratio (P = 0.011 and P = 0.010). β-arrestin 1 and 2 expression showed a significant trend of higher median values from full responders, partial responders to resistant patients (P = 0.045 and P = 0.021, respectively). Interestingly, SSTR2 protein expression showed a strong inverse correlation with both β-arrestin 1 and 2 mRNA (ρ = -0.69, P = 0.0011 and ρ = -0.67, P = 0.0016). CONCLUSIONS:Low β-arrestin expression and high SSTR2/β-arrestin ratio correlate with the responsiveness to long-term treatment with SSAs in patients with acromegaly.