Recurrent adamantinomatous craniopharyngiomas show MAPK pathway activation, clonal evolution and rare TP53-loss-mediated malignant progression.

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children's Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.

Identification of Succinate Dehydrogenase Gene Variant Carriers by Blood Biomarkers.

Background: Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase genes (SDHx) are at risk of developing tumors, including paragangliomas, gastrointestinal stromal tumors, and renal cell carcinomas. Early tumor detection is paramount for improved clinical outcome. Blood-based biomarkers could aid in identifying individuals with PVs early and provide functional evidence in patients with variants of unknown significance. Methods: Blood plasma, urine, peripheral blood mononuclear cells, and erythrocytes from patients with and without SDHx PVs were investigated for central carbon metabolites. These were measured by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy and included among others, succinate, fumarate, α-ketoglutarate, and lactate. Results: Plasma succinate to fumarate ratios effectively distinguished tumor-bearing and asymptomatic patients with and without SDHx PV with promising diagnostic performance (areas under the receiver operating characteristic curve 0.86-0.95), although higher levels were noted in individuals with SDHB PV. Metabolites in urine and in peripheral blood mononuclear cell extracts were largely similar between groups. Erythrocytes showed strong metabolic alterations in patients with SDHx PV compared to controls, with 8 of 13 low-molecular organic acids being significantly different (P < .05). The lactate-α-ketoglutarate-ratio of erythrocytes identified individuals with SDHx PV equally well as plasma, with a sensitivity and specificity of 92% (AUC 0.97). Conclusion: Blood biomarkers have been underutilized for identifying carriers of SDHx PV or to validate variants of unknown significance. Our findings advocate for further investigation into a combined approach involving plasma and erythrocytes for future diagnostic strategies.

Adverse skeletal related events in patients with bone-metastatic pheochromocytoma/paraganglioma.

Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications. Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset. In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled. SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0-246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309-0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410-0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877-0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396-0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405-0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274-0.718]; P = .001) were associated with a reduced risk of death. SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome.

Pregnancy and acromegaly: clinical outcomes of retrospectively analysed data from the German acromegaly registry.

CONTEXT: Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child. OBJECTIVE: To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly. DESIGN & METHODS: Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry. RESULTS: 87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications. CONCLUSION: Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.

The effect of coping strategies on health-related quality of life in acromegaly patients.

PURPOSE: Patients with acromegaly oftentimes exhibit a reduced physical and psychological health-related quality of life (HRQoL). Maladaptive coping styles are associated with poor HRQoL in a number of diseases and patients with pituitary adenomas in general exhibit less effective coping styles than healthy controls. This study aimed to assess coping strategies in acromegaly patients in order to explore leverage points for the improvement of HRQoL. METHODS: In this cross-sectional study, we administered self-report surveys for coping strategies and HRQoL (Short Form SF-36, Freiburg questionnaire on coping with illness, FKV-LIS) in patients with acromegaly. These were set into relation with a variety of health variables. RESULTS: About half of the 106 patients (44.3% female) with a mean age of 56.4 ± 1.3 years showed impaired physical and psychological HRQoL on average 11.2 years after the initial diagnosis. Body mass index, age at survey date and concomitant radiotherapy explained 27.8% of the variance of physical HRQoL, while depressive coping added an additional 9.2%. Depressive coping style and trivialization and wishful thinking were pivotal predictors of an impaired psychological HRQoL with a total explained variance of 51.6%, whereas patient health variables did not affect psychological HRQoL. CONCLUSION: Our results show that maladaptive coping styles have a substantial negative impact on psychological HRQoL in patients with acromegaly, whereas physical HRQoL is influenced to a lesser extent. Specialized training programs aimed at improving coping strategies could reduce long-term disease burden and increase HRQoL in the affected patients.

Medical Therapy of Endogenous Cushing's Syndrome with Steroidogenesis Inhibitors: Treatment Rationale, Available Drugs, and Therapeutic Effects.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by a glucocorticoid excess. If inadequately treated, hypercortisolism can lead to increased morbidity and mortality. Surgical removal of the underlying tumor is the first-line treatment but is sometimes not feasible or even contraindicated. Additionally, in cases with severe CS, rapid control of hypercortisolism may be required. In these scenarios, steroidogenesis inhibitors represent a therapeutic alternative to surgery. Over the last years, the knowledge of the broad therapeutic effects of steroidogenesis inhibitors per se and the number of available drugs have increased. However, large comparative studies are still lacking. Accordingly, the decision on which drug to be used in a certain patient or clinical setting may be difficult. This review aims to summarize the main characteristics of steroidogenesis inhibitors.

Diagnosis and management of urinary bladder paragangliomas: A Sino-American-European retrospective observational study.

OBJECTIVE: Paragangliomas of the urinary bladder (UBPGLs) are rare neuroendocrine tumours and pose a diagnostic and surgical challenge. It remains unclear what factors contribute to a timely presurgical diagnosis. The purpose of this study is to identify factors contributing to missing the diagnosis of UBPGLs before surgery. DESIGN, PATIENTS AND MEASUREMENTS: A total of 73 patients from 11 centres in China, and 51 patients from 6 centres in Europe and 1 center in the United States were included. Clinical, surgical and genetic data were collected and compared in patients diagnosed before versus after surgery. Logistic regression analysis was used to identify clinical factors associated with initiation of presurgical biochemical testing. RESULTS: Among all patients, only 47.6% were diagnosed before surgery. These patients were younger (34.0 vs. 54.0 years, p < .001), had larger tumours (2.9 vs. 1.8 cm, p < .001), and more had a SDHB pathogenic variant (54.7% vs. 11.9%, p < .001) than those diagnosed after surgery. Patients with presurgical diagnosis presented with more micturition spells (39.7% vs. 15.9%, p = .003), hypertension (50.0% vs. 31.7%, p = .041) and catecholamine-related symptoms (37.9% vs. 17.5%, p = .012). Multivariable logistic analysis revealed that presence of younger age (<35 years, odds ratio [OR] = 6.47, p = .013), micturition spells (OR = 6.79, p = .007), hypertension (OR = 3.98, p = .011), and sweating (OR = 41.72, p = .013) increased the probability of initiating presurgical biochemical testing. CONCLUSIONS: Most patients with UBPGL are diagnosed after surgery. Young age, hypertension, micturition spells and sweating are clues in assisting to initiate early biochemical testing and thus may establish a timely presurgical diagnosis.

Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. METHODS: FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. FINDINGS: From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock. INTERPRETATION: This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. FUNDING: French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.

Adrenal Crisis - Definition, Prevention and Treatment: Results from a Delphi Survey.

Based on recent data, a total number of about 29 000 patients with adrenal insufficiency can be calculated for Germany, and about 1500 fatalities due to adrenal crises have to be expected within the next decade. Management of adrenal crises is still unsatisfactory. The objectives of this study were to establish consensus for diagnostic criteria, prevention strategies, and treatment recommendations for adrenal crises. The study was conducted from January 2022 to April 2023, using Delphi technique. Four rounds of questionnaires were sent to 45 experts, selected by a coordinating group on behalf of the adrenal section of the German Society of Endocrinology. The survey was implemented online using the REDCap web application. Responses were captured anonymously. During the Delphi process the expert panel developed diagnostic criteria to identify patients likely to have an adrenal crisis. Education about adrenal insufficiency among patients as well as non-endocrine medical personnel were regarded as highly important. It was suggested that recommendations for the management of adrenal insufficiency have to be simplified and made widely available. This study provides pragmatic strategies to identify and treat patients prone to adrenal crisis, thereby highlighting the need for an improved management of patients with adrenal insufficiency.

High prevalence of venous thrombotic events in Cushing's syndrome: data from ERCUSYN and details in relation to surgery.

OBJECTIVE: The aim of this study was to evaluate the prevalence of venous thromboembolism (VTE) in patients included in the European Registry on Cushing's syndrome (ERCUSYN), compare their clinical characteristics with those who did not develop VTE and identify risk factors for VTE. DESIGN: A retrospective observational cohort study. METHODS: Data extraction from the registry was taken on February, 7, 2022. At the time there were 2174 patients diagnosed with Cushing's syndrome (CS) and 95 VTEs were reported in the database. RESULTS: Of 95 VTE events 70 (74%) were in pituitary-dependent CS patients, 12 (12.5%) in adrenal-dependant CS, 10 (10.5%) in ectopic CS, and 3 (3%) in CS due to other causes. Sex, 24-hour urinary free cortisol (UFC) value at diagnosis, as well as the number of operations remained statistically significant predictors of VTE. Of patients who were treated with at least one surgery, 12 (13%) VTE occurred before and 80 (87%) after the surgery. Nearly half of these VTEs occurred within six months since the operation (36; 45%). Over half of the centers that reported VTE did not routinely anticoagulate CS patients. Anticoagulation schemes varied widely. CONCLUSION: Patients with CS have an elevated risk of developing VTE for an extended period of time. From ERCUSYN cohort patients have higher risk for VTE if they need multiple surgeries to treat CS, are males and have high UFC values at the diagnosis of CS. Since there is no agreement on thromboprohpylaxis, a protocol for VTE prevention that is widely adopted appears to be necessary for patients with CS.

Delineating endogenous Cushing's syndrome by GC-MS urinary steroid metabotyping.

BACKGROUND: Diagnosing Cushing's syndrome (CS) is highly complex. As the diagnostic potential of urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not yet been fully exploited, we studied a large cohort of patients with CS. METHODS: We quantified daily urinary excretion rates of 36 steroid hormone metabolites. Applying cluster analysis, we investigated a control group and 168 patients: 44 with Cushing's disease (CD) (70% female), 18 with unilateral cortisol-producing adrenal adenoma (83% female), 13 with primary bilateral macronodular adrenal hyperplasia (PBMAH) (77% female), and 93 ruled-out CS (73% female). FINDINGS: Cluster-Analysis delineated five urinary steroid metabotypes in CS. Metabotypes 1, 2 and 3 revealing average levels of cortisol and adrenal androgen metabolites included patients with exclusion of CS or and healthy controls. Metabotype 4 reflecting moderately elevated cortisol metabolites but decreased DHEA metabolites characterized the patients with unilateral adrenal CS and PBMAH. Metabotype 5 showing strong increases both in cortisol and DHEA metabolites, as well as overloaded enzymes of cortisol inactivation, was characteristic of CD patients. 11-oxygenated androgens were elevated in all patients with CS. The biomarkers THS, F, THF/THE, and (An + Et)/(11ß-OH-An + 11ß-OH-Et) correctly classified 97% of patients with CS and 95% of those without CS. An inverse relationship between 11-deoxygenated and 11-oxygenated androgens was typical for the ACTH independent (adrenal) forms of CS with an accuracy of 95%. INTERPRETATION: GC-MS based urinary steroid metabotyping allows excellent identification of patients with endogenous CS and differentiation of its subtypes. FUNDING: The study was funded by the Else Kröner-Fresenius-Stiftung and the Eva-Luise-und-Horst-Köhler-Stiftung.

Bilateral inferior petrosal sinus sampling: Procedural data from a German single-center study.

PURPOSE: To assess radiation exposure and diagnostic performance of bilateral inferior petrosal sinus sampling for the distinction of pituitary and ectopic adrenocorticotropin-dependent Cushing's syndrome. MATERIALS AND METHODS: Procedural data of bilateral inferior petrosal sinus procedures were retrospectively evaluated. The analysis included the patients' clinical and demographic data, procedural radiation exposure, and complication rates, sampling results, clinical course of the patients, and calculation of diagnostic performance data. RESULTS: The cases of 46 patients diagnosed with adrenocorticotropin-dependent Cushing's syndrome were evaluated. Bilateral inferior petrosal sinus sampling was successfully performed in 97.8 % of the cases. The overall median procedure-related fluoroscopy time was 7.8 min. (range 3.2-36.2 min.), and the median procedural dose area product was 11.9 Gy*cm2 (range 2.1-73.7 Gy*cm2). Radiation doses due to digital subtraction angiography series for visualization of the inferior petrosal sinus were 3.6 Gy*cm2 (range 1.0-18.1 Gy*cm2). Radiation doses due to fluoroscopy had a higher impact on the overall radiation exposure and were significantly influenced by the patients' habitus. The sensitivity, specificity, and positive and negative predictive values were 84 %, 100 %, 100 %, and 72 % before stimulation with corticotropin-releasing hormone, and 97 %, 100 %, 100 %, and 93 % after stimulation. Concordance between magnetic resonance imaging studies and bilateral inferior petrosal sinus sampling results was only found in 35.6 % of the cases. The periprocedural complication rate was 2.2 %, with one patient experiencing vasovagal syncope during catheterization. CONCLUSION: Bilateral inferior petrosal sinus sampling is a safe procedure with high technical success rates und excellent diagnostic performance. The procedure-related radiation exposure shows large variations and depends on the complexity of cannulation as well as the patients' habitus. Fluoroscopy accounted for the largest proportion of radiation exposure. Acquisition of digital subtraction angiography series for the verification of correct catheter placement appears justified. KEY POINTS: · Bilateral inferior petrosal sinus sampling with CRH stimulation provides high diagnostic performance in the distinction of pituitary and ectopic Cushing's syndrome.. · The associated radiation exposure is not negligible and is significantly influenced by the use of fluoroscopy and the patients' habitus.. · Digital subtraction angiography contributes less to the overall radiation dose and appears justified for the verification of correct catheter placement.. CITATION FORMAT: · Augustin A, Detomas M, Hartung V et al. Bilateral inferior petrosal sinus sampling: Procedural data from a German single-center study. Fortschr Röntgenstr 2023; 195: 1009 - 1017.

Bilateral inferior petrosal sinus sampling with human CRH stimulation in ACTH-dependent Cushing's syndrome: results from a retrospective multicenter study.

OBJECTIVE: Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as gold standard to differentiate between Cushing´s disease (CD) and ectopic Cushing's syndrome (ECS). However, published data e.g. on the diagnostic value of additional prolactin analysis is controversial. Thus, we evaluated the diagnostic performance of BIPSS with and without prolactin in a multicenter study. DESIGN AND METHODS: Retrospective study in 5 European reference centers. Patients with overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of BIPSS with human corticotropin-releasing hormone stimulation were eligible. Cut-offs for the inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and the normalized ACTH:prolactin IPS:P ratio were calculated via receiver operator characteristics analyses (reference: CD). RESULTS: 156 patients with BIPSS were identified. Of these, 120 patients (92 (77%) females; 106 (88%) CD, 14 (12%) ECS) had either histopathologically confirmed tumors or biochemical remission and/or adrenal insufficiency after surgery; only this subgroup was analyzed by ROC analysis. The optimal cut-offs for the ACTH IPS:P ratio were ≥1.9 at baseline (sensitivity 82.1% (95%CI 73.2-88.6), specificity 85.7% (95%CI 56.2-97.5), AUC 0.86) and ≥2.1 at 5 minutes post-CRH (sensitivity 91.3% (95%CI 83.6-95.7), specificity 92.9%(95%CI 64.1-99.6), AUC 0.96). A subgroup underwent additional prolactin analysis. An optimal cut-off of ≥1.4 was calculated for the normalized ACTH:prolactin IPS:P ratio (sensitivity 96.0% (95%CI 77.7-99.9), specificity 100% (95%CI 56.1-100), AUC 0.99). CONCLUSION: Our study confirms the high accuracy of BIPSS in the differential diagnosis of ACTH-dependent Cushing's syndrome and suggests that the simultaneous measurement of prolactin might further improve the diagnostic performance of this test.

Clinical course of patients with adrenal incidentalomas and cortisol autonomy: a German retrospective single center cohort study.

Background: Adrenal incidentalomas with cortisol autonomy are associated with increased cardiovascular morbidity and mortality. Specific data on the clinical and biochemical course of affected patients are lacking. Methods: Retrospective study from a tertiary referral centre in Germany. After exclusion of overt hormone excess, malignancy and glucocorticoid medication, patients with adrenal incidentalomas were stratified according to serum cortisol after 1 mg dexamethasone: autonomous cortisol secretion (ACS), >5.0; possible ACS (PACS), 1.9-5.0; non-functioning adenomas (NFA), ≤1.8 µg/dl. Results: A total of 260 patients were enrolled (147 women (56.5%), median follow-up 8.8 (2.0-20.8) years). At initial diagnosis, median age was 59.5 (20-82) years, and median tumour size was 27 (10-116) mm. Bilateral tumours were more prevalent in ACS (30.0%) and PACS (21.9%) than in NFA (8.1%). Over time, 40/124 (32.3%) patients had a shift of their hormonal secretion pattern (NFA to PACS/ACS, n=15/53; PACS to ACS, n=6/47; ACS to PACS, n=11/24; PACS to NFA, n=8/47). However, none of the patients developed overt Cushing's syndrome. Sixty-one patients underwent adrenalectomy (NFA, 17.9%; PACS, 24.0%; ACS, 39.0%). When non-operated patients with NFA were compared to PACS and ACS at last follow-up, arterial hypertension (65.3% vs. 81.9% and 92.0%; p<0.05), diabetes (23.8% vs. 35.6% and 40.0%; p<0.01), and thromboembolic events (PACS: HR 3.43, 95%-CI 0.89-13.29; ACS: HR 5.96, 95%-CI 1.33-26.63; p<0.05) were significantly less frequent, along with a trend towards a higher rate of cardiovascular events in case of cortisol autonomy (PACS: HR 2.23, 95%-CI 0.94-5.32; ACS: HR 2.60, 95%-CI 0.87-7.79; p=0.1). Twenty-five (12.6%) of the non-operated patients died, with higher overall mortality in PACS (HR 2.6, 95%-CI 1.0-4.7; p=0.083) and ACS (HR 4.7, 95%-CI 1.6-13.3; p<0.005) compared to NFA. In operated patients, prevalence of arterial hypertension decreased significantly (77.0% at diagnosis to 61.7% at last follow-up; p<0.05). The prevalence of cardiovascular events and mortality did not differ significantly between operated and non-operated patients, whereas thromboembolic events were significantly less frequent in the surgical treatment group. Conclusion: Our study confirms relevant cardiovascular morbidity in patients with adrenal incidentalomas (especially those with cortisol autonomy). These patients should therefore be monitored carefully, including adequate treatment of typical cardiovascular risk factors. Adrenalectomy was associated with a significantly decreased prevalence of hypertension. However, more than 30% of patients required reclassification according to repeated dexamethasone suppression tests. Thus, cortisol autonomy should ideally be confirmed before making any relevant treatment decision (e.g. adrenalectomy).

Glucocorticoid receptor polymorphism BclI with increased glucocorticoid sensitivity has a positive influence on quality of life in endogenous Cushing's syndrome in remission.

CONTEXT: Patients with endogenous Cushing's syndrome (CS) may suffer from a wide range of neuropsychiatric symptoms leading to impaired quality of life (QoL). OBJECTIVE: Glucocorticoid receptor (GR) polymorphisms are associated with increased (BclI and N363S) or decreased (A3669G and ER22/23EK) GR sensitivity. HYPOTHESIS: GR genotypes may modulate and affect QoL and recovery after remission differently via GR sensitivity. METHODS: 295 patients with endogenous CS (81 active, 214 in remission) from 3 centers of the German Cushing's Registry were included for the cross-sectional analysis. All subjects were assessed with three questionnaires (CushingQoL, Tuebingen CD-25, SF-36). For the longitudinal part, 120 patients of them were analyzed at baseline and after 1.5 ± 0.9 yrs of follow-up. DNA samples were obtained from peripheral blood leukocytes for GR genotyping. RESULTS: Patients in remission scored significantly better than patients with active CS in the CushingQoL questionnaire and in the SF-36 sub-categories physical and social functioning, role-physical, bodily pain, and vitality. In cross-sectional analysis, no differences in QoL between minor allele and wildtype carriers were detected for all polymorphisms in active or cured CS. In longitudinal analysis, however, carriers with BclI minor allele showed significant improvement in SF-36 sub-categories vitality (P = .038) and mental health (P = .013) compared to wildtype carriers (active CS at baseline vs. CS in remission at follow-up). The outcome of the two questionnaires CushingQoL and Tuebingen CD-25 improved significantly in both wildtype and minor allele carriers. CONCLUSION: BclI minor allele carriers initially had the lowest QoL but recovered better from impaired QoL than wildtype carriers.

The Population Comparison Index: An Intuitive Measure to Calibrate the Extent of Impairments in Patient Cohorts in Relation to Healthy and Diseased Populations.

We assume that a specific health constraint, e.g., a certain aspect of bodily function or quality of life that is measured by a variable X, is absent (or irrelevant) in a healthy reference population (Ref0), and it is materially present and precisely measured in a diseased reference population (Ref1). We further assume that some amount of this constraint of interest is suspected to be present in a population under study (SP). In order to quantify this issue, we propose the introduction of an intuitive measure, the population comparison index (PCI), that relates the mean value of X in population SP to the mean values of X in populations Ref0 and Ref1. This measure is defined as PCI[X] = (mean[X|SP] - mean[X|Ref0])/(mean[X|Ref1] - mean[X|Ref0]) × 100[%], where mean[X|.] is the average value of X in the respective group of individuals. For interpretation, PCI[X] ≈ 0 indicates that the values of X in the population SP are similar to those in population Ref0, and hence, the impairment measured by X is not materially present in the individuals in population SP. On the other hand, PCI[X] ≈ 100 means that the individuals in SP exhibit values of X comparable to those occurring in Ref1, i.e., the constraint of interest is equally present in populations SP and Ref1. A value of 0 < PCI[X] < 100 indicates that a certain percentage of the constraint is present in SP, and it is more than in Ref0 but less than in Ref1. A value of PCI[X] > 100 means that population SP is even more affected by the constraint than population Ref1.

Lack of sensitivity of diagnostic Cushing-scores in Germany: a multicenter validation.

OBJECTIVE: Endogenous Cushing's syndrome (CS) is a severe condition, often diagnosed at a late stage. To reduce mortality, early diagnosis plays an important role. Two screening tools for early identification of patients with CS have been developed in multicentric cohorts, but have not yet been validated in cohorts with different geographic backgrounds. DESIGN: We validated the Spanish score published by Leon-Justel et al. in 2016 and the Italian score by Parasiliti-Caprino et al. published in 2021 in our cohort. METHODS: In the multicentric German Cushing registry, patients with confirmed and expected but ruled out Cushing's syndrome are prospectively diagnosed and followed up. We validated both scores in a cohort of 458 subjects: 176 patients with confirmed CS and 282 patients with suspected, but finally excluded CS. RESULTS: Using the Spanish score, 17.5% of our patients with proven CS biochemical screening would not have been recommended. This concerned patients with pituitary CS (22%) and with adrenal CS (10%). On the contrary, only 14% of patients without CS would have received a recommendation for biochemical screening. Using the Italian score, 29% of patients with proven CS were classified into the low-risk classes not recommended for biochemical screening. This mostly affected patients with adrenal (31%) and pituitary CS (30%). About 12% of subjects without CS would have received a biochemical screening recommendation. CONCLUSIONS: Both scores had limited sensitivity and high specificity in a German validation cohort. Further research is necessary to develop a screening score, which is effective in different healthcare systems and ethnicities.