Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

BACKGROUND: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). OBJECTIVE: To evaluate current management of new cases of CS with a focus on VTE and thromboprophylaxis. DESIGN AND METHODS: A survey was conducted within those that report in electronic reporting tool (e-REC) of The European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 until July 2022. RESULTS: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%) and 12 patients ectopic CS (5.4%). The mean follow-up period post CS diagnosis was 15 months (range 3-30). Cortisol lowering medications were initiated in 38% of patients. One hundred and fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular weight-heparins were used in 96% of cases. VTE was reported in 6 patients (2.7%), of which 1 was fatal: 2 long before CS diagnosis, 2 between diagnosis and surgery and 2 post-operatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. CONCLUSIONS: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage and half of the VTE cases even occurred during this stage despite thromboprophylaxis Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed.

The thrombotic risk in Cushing's syndrome-questions, answers, and the algorithm to consider in its assessment: part I-thrombotic risk not related to surgery.

Introduction: Recently, it has been reported that there is a great diversity in strategies used for thromboprophylaxis in patients with Cushing's syndrome (CS). An aim of this review was to discuss these practices in light of the existing data on the thrombotic risk in patients with CS and guidelines for medically ill patients. Methods: The four relevant topics and questions on thrombotic risk in CS were identified. The current guidelines on prevention and diagnosis of venous thromboembolism (VTE) were reviewed for the answers. An algorithm to consider in the assessment of the thrombotic risk in patients with CS was proposed. Results: To address both generic and CS-specific risk factors for VTE, the algorithm includes the stepwise approach consisting of Padua Score, urine free cortisol, and CS-VTE score, with no indication for routine thrombophilia testing in the prediction of an index VTE episode. Having confirmed VTE, selected patients require thrombophilia testing to aid the duration of anticoagulant treatment. The separate part of the algorithm is devoted to patients with ectopic adrenocorticotropic hormone syndrome in whom exclusion of VTE precedes introducing routine thromboprophylaxis to prevent VTE. The cancer-related VTE also prompts thromboprophylaxis, with the possible vessel invasion. The algorithm presents a unifactorial and multifactorial approach to exclude high-bleeding risks and safely introduce thromboprophylaxis with low-molecular-weight heparin. Summary: Our article is the first to present an algorithm to consider in the thrombotic risk assessment among patients with Cushing's syndrome as a starting point for a broader discussion in the environment. A plethora of factors affect the VTE risk in patients with CS, but no studies have conclusively evaluated the best thromboprophylaxis strategy so far. Future studies are needed to set standards of care.

Evaluation of bone-related mechanical properties in female patients with long-term remission of Cushing's syndrome using quantitative computed tomography-based finite element analysis.

BACKGROUND: Hypercortisolism in Cushing's syndrome (CS) is associated with bone loss, skeletal fragility, and altered bone quality. No studies evaluated bone geometric and strain-stress values in CS patients after remission thus far. PATIENTS AND METHODS: Thirty-two women with CS in remission (mean age [±SD] 51 ± 11; body mass index [BMI], 27 ± 4 kg/m2; mean time of remission, 120 ± 90 months) and 32 age-, BMI-, and gonadal status-matched female controls. Quantitative computed tomography (QCT) was used to assess volumetric bone mineral density (vBMD) and buckling ratio, cross-sectional area, and average cortical thickness at the level of the proximal femur. Finite element (FE) models were generated from QCT to calculate strain and stress values (maximum principal strain [MPE], maximum strain energy density [SED], maximum Von Mises [VM], and maximum principal stress [MPS]). Areal BMD (aBMD) and trabecular bone score (TBS) were assessed by dual-energy X-ray absorptiometry (2D DXA). RESULTS: Trabecular vBMD at total hip and trochanter were lower in CS as compared with controls (P < .05). Average cortical thickness was lower, and buckling ratio was greater in CS vs controls (P < .01). All strain and stress values were higher in CS patients vs controls (P < .05). 2D DXA-derived measures were similar between patients and controls (P > .05). Prior hypercortisolism predicted both VM (ß .30, P = .014) and MPS (ß .30, P = .015), after adjusting for age, BMI, menopause, delay to diagnosis, and duration of remission. CONCLUSIONS: Women with prior hypercortisolism have reduced trabecular vBMD and impaired bone geometrical and mechanical properties, which may contribute to an elevated fracture risk despite long-term remission.

Clinical and outcome comparison of genetically positive vs. negative patients in a large cohort of suspected familial hypocalciuric hypercalcemia.

OBJECTIVE: Biochemical suspicion of familial hypocalciuric hypercalcemia (FHH) might provide with a negative (FHH-negative) or positive (FHH-positive) genetic result. Understanding the differences between both groups may refine the identification of those with a positive genetic evaluation, aid management decisions and prospective surveillance. We aimed to compare FHH-positive and FHH-negative patients, and to identify predictive variables for FHH-positive cases. DESIGN: Retrospective, national multi-centre study of patients with suspected FHH and genetic testing of the CASR, AP2S1 and GNA11 genes. METHODS: Clinical, biochemical, radiological and treatment data were collected. We established a prediction model for the identification of FHH-positive cases by logistic regression analysis and area under the ROC curve (AUROC) was estimated. RESULTS: We included 66 index cases, of which 30 (45.5%) had a pathogenic variant. FHH-positive cases were younger (p = 0.029), reported more frequently a positive family history (p < 0.001), presented higher magnesium (p < 0.001) and lower parathormone levels (p < 0.001) and were less often treated for hypercalcemia (p = 0.017) in comparison to FHH-negative cases. Magnesium levels showed the highest AUROC (0.825, 95%CI: 0.709-0.941). The multivariate analysis revealed that family history and magnesium levels were independent predictors of a positive genetic result. The predictive model showed an AUROC of 0.909 (95%CI: 0.826-0.991). CONCLUSIONS: The combination of magnesium and a positive family history offered a good diagnostic accuracy to predict a positive genetic result. Therefore, the inclusion of magnesium measurement in the routine evaluation of patients with suspected FHH might provide insight into the identification of a positive genetic result of any of the CaSR-related genes.

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.

Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly.

Introduction: We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) . Methods: A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered responders and those whose IGF1 was ≥3SDS, were considered non-responders. The 2 hours GH value (GH2h) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively. Results: In all, 30 patients were responders and 17 were non-responders. GH2h was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH2h = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH2h = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH2h than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01). Conclusion: The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly.

Gut microbial dysbiosis in patients with Cushing's disease in long-term remission. Relationship with cardiometabolic risk.

Background: Patients with Cushing's disease (CD) in remission maintain an increased cardiovascular risk. Impaired characteristics of gut microbiome (dysbiosis) have been associated with several cardiometabolic risk factors. Methods: Twenty-eight female non-diabetic patients with CD in remission with a mean ± SD) age of 51 ± 9 years, mean ( ± SD) BMI, 26 ± 4, median (IQR) duration of remission, 11(4) years and 24 gender-, age, BMI-matched controls were included. The V4 region of the bacterial 16S rDNA was PCR amplified and sequenced to analyse microbial alpha diversity (Chao 1 index, observed number of species, Shannon index) and beta diversity analysis through the Principal Coordinates Analysis (PCoA) of weighted and unweighted UniFrac distances. Inter-group difference in microbiome composition was analysed using MaAsLin2. Results: The Chao 1 index was lower in CD as compared with controls (Kruskal-Wallis test, q = 0.002), indicating lower microbial richness in the former. Beta diversity analysis showed that faecal samples from CS patients clustered together and separated from the controls (Adonis test, p<0.05). Collinsella, a genus form of the Actinobacteria phylum was present in CD patients only, whereas Sutterella, a genus from Proteobacteria phylum, was scarcely detectable/undetectable in CD patients as well as Lachnospira, a genus of the Lachnospiraceae family of the Firmicutes phylum. In CS, the Chao 1 index was associated with fibrinogen levels and inversely correlated with both triglyceride concentrations and the HOMA-IR index (p<0.05). Conclusions: Patients with CS in remission have gut microbial dysbiosis which may be one of the mechanisms whereby cardiometabolic dysfunctions persist after "cure".

Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors.

Introduction: Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas. Methods: We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes. Results: We found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas. Conclusion: NF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET.

Mortality in Acromegaly Diagnosed in Older Individuals in Spain Is Higher in Women Compared to the General Spanish Population.

CONTEXT: There are no data on mortality of acromegaly diagnosed in older individuals. OBJECTIVE: This work aimed to compare clinical characteristics, growth hormone-related comorbidities, therapeutic approaches, and mortality rate of patients diagnosed before or after 2010 and to assess overall mortality rate compared with the general Spanish population. METHODS: A retrospective evaluation was conducted among Spanish tertiary care centers of 118 patients diagnosed with acromegaly at age 65 or older. Kaplan-Meier curves were constructed to trace survival, and Cox proportional hazard models were used to assess the risk factors associated with mortality. We also compared mortality with that of the Spanish population by using age- and sex-adjusted standardized mortality ratios (SMRs). RESULTS: No differences were found in first-line treatment or biochemical control, between both periods except for faster biochemical control after 2010. Twenty-nine (24.6%) patients died, without differences between groups, and had a median of follow-up 8.6 years (103, [72.3] months). Overall SMR was 1.02 (95% CI, 0.57-1.54), (0.60; 95% CI, 0.35-1.06) for men and (1.80; 95% CI, 1.07-2.94) for women. The most common cause of death was cardiovascular disease (CVD). CONCLUSION: The mortality in patients with acromegaly diagnosed in older individuals was no different between both periods, and there was no overall SMR difference compared with the general Spanish population. However, the SMR was higher in women. As CVD is the leading cause of mortality, it seems advisable to initiate an intense CVD protective treatment as soon as acromegaly is diagnosed, particularly in women, in addition to tight acromegaly control to prevent excess mortality.

Cushing's syndrome in the elderly: data from the European Registry on Cushing's syndrome.

OBJECTIVE: To evaluate whether age-related differences exist in clinical characteristics, diagnostic approach, and management strategies in patients with Cushing's syndrome (CS) included in the European Registry on Cushing's Syndrome (ERCUSYN). DESIGN: Cohort study. METHODS: We analyzed 1791 patients with CS, of whom 1234 (69%) had pituitary-dependent CS (PIT-CS), 450 (25%) adrenal-dependent CS (ADR-CS), and 107 (6%) had an ectopic source (ECT-CS). According to the WHO criteria, 1616 patients (90.2%) were classified as younger (<65 years old) and 175 (9.8%) as older (≥65 years old). RESULTS: Older patients were more frequently males and had a lower Body Mass Index (BMI) and waist circumference when compared with the younger. Older patients also had a lower prevalence of skin alterations, depression, hair loss, hirsutism, and reduced libido, but a higher prevalence of muscle weakness, diabetes, hypertension, cardiovascular disease, venous thromboembolism, and bone fractures than younger patients, regardless of sex (P < .01 for all comparisons). Measurement of urinary free cortisol supported the diagnosis of CS less frequently in older patients when compared with the younger (P < .05). An extrasellar macroadenoma (macrocorticotropinoma with extrasellar extension) was more common in older PIT-CS patients than in the younger (P < .01). Older PIT-CS patients more frequently received cortisol-lowering medications and radiotherapy as a first-line treatment, whereas surgery was the preferred approach in the younger (P < .01 for all comparisons). When transsphenoidal surgery was performed, the remission rate was lower in the elderly when compared with their younger counterpart (P < .05). CONCLUSIONS: Older CS patients lack several typical symptoms of hypercortisolism, present with more comorbidities regardless of sex, and are more often conservatively treated.

PRESTO 2: An International Survey to Evaluate Patients' Injection Experiences with the Latest Devices/Formulations of Long-Acting Somatostatin Analog Therapies for Neuroendocrine Tumors or Acromegaly.

INTRODUCTION: Real-world data evaluating patients' injection experiences using the latest devices/formulations of the long-acting (LA) somatostatin analogs (SSAs) lanreotide Autogel/Depot (LAN; Somatuline®) and octreotide LA release (OCT; Sandostatin®) are limited. METHODS: PRESTO 2 was a 2020/2021 e-survey comparing injection experience of adults with neuroendocrine tumors (NETs) or acromegaly treated with LAN prefilled syringe versus OCT syringe for > 3 months in Canada, Ireland, the UK and the USA (planned sample size, 304). PRIMARY ENDPOINT: the proportion of patients with injection-site pain lasting > 2 days after their most recent injection, analyzed using a multivariate logistic regression model. Secondary endpoints included interference with daily life due to injection-site pain and technical injection problems in patients with current SSA use for ≥ 6 months. RESULTS: There were 304 respondents (acromegaly, n = 85; NETs, n = 219; LAN, n = 168; OCT, n = 136; 69.2% female; mean age, 59.6 years). Fewer patients had injection-site pain lasting > 2 days after the most recent injection with LAN (6.0%) than OCT (22.8%); the odds of pain lasting > 2 days were significantly lower for LAN than OCT, adjusted for disease subgroup and occurrence of injection-site reactions (odds ratio [95% confidence interval]: 0.13 [0.06-0.30]; p < 0.0001). Injection-site pain interfered with daily life "a little bit" or "quite a bit" in 37.2% and 3.8% (LAN) versus 52.5% and 7.5% (OCT) of patients, respectively. Among patients with ≥ 6 months' experience with current SSA (92.4% of patients), technical injection problems never occurred in 76.8% (LAN) and 42.9% (OCT) of patients. CONCLUSIONS: Compared with OCT, significantly fewer patients using LAN had injection-site pain lasting > 2 days after their most recent injection. Also, fewer LAN-treated patients experienced technical problems during injection. These findings demonstrate the importance of injection modality for overall LA SSA injection experience for patients with acromegaly or NETs.

Patients with neuroendocrine tumors or acromegaly often receive long-term monthly treatment with somatostatin analogs. These injectable drugs stop the body from making an excess of certain hormones. Understanding patients' experiences of these injections helps to provide better care. The PRESTO 2 online study surveyed 304 patients in Canada, Ireland, the UK and the USA with neuroendocrine tumors or acromegaly who were being treated with a somatostatin analog, either lanreotide Autogel/Depot (LAN) or octreotide long-acting release (OCT). The survey asked about injection experience, including injection-site pain lasting > 2 days and how it affected patients' lives, anxiety before injections and technical problems during injections (like syringe blockages). The survey showed fewer patients receiving LAN than OCT had injection-site pain that lasted > 2 days, and fewer said that the pain interfered with their daily lives. There were fewer technical injection problems with LAN than with OCT. However, more patients receiving LAN than OCT felt anxious before their injection. In some countries (including Canada, Ireland and the UK, but not the USA), the patient (or family member/friend) can inject LAN if they are on a stable dose, their doctor agrees, and they received training. A nurse/doctor must inject OCT. In PRESTO 2, about 40% of non-US patients who were eligible injected themselves (or were helped by a family member/friend). This may explain why more patients reported anxiety in the LAN group. PRESTO 2 provides important insights into patients' experiences of receiving somatostatin analogs and helps identify areas for improving patient care.

The effect of mindfulness therapy in acromegaly, a pilot study.

BACKGROUND: Patients with acromegaly have often several comorbidities, including decreased quality of life, mood alterations and chronic pain. Mindfulness is effective at improving mood, quality of life and pain management; however, there is no data available on its effect in patients with acromegaly. OBJECTIVE: We aimed at evaluating changes in quality of life, mood, pain, sleep, self-compassion, life satisfaction, blood pressure and heart rate after a mindfulness program. DESIGN AND PATIENTS: This was a randomized, multicentre, international clinical trial (Barcelona-BCN and Bergamo-BG) of 60 patients, 30 per centre. MEASUREMENTS: The intervention group participated in an 8-week face-to-face group program; the control group followed normal clinical routine. In BG, patients performed a classic Mindfulness Based Stress Reduction program; in BCN they performed an adapted program including elements of mindfulness and compassion with a greater focus on daily life. RESULTS: In the BCN intervention group there was an increase in night-time hours in bed (p = 0.05) after the program. In both centres there was a trend to a reduction of the time to start sleeping (p = 0.06 BCN, p = 0.07 BG). In BCN, the intervention group reduced the pain score compared to the control group (p = .02), and an improvement in self-compassion was found (p = .04). In both centres, heart rate decreased significantly in the intervention group during a single 2-hour session. This was evidenced at the first and the last program session (BCN p = .013 and p = .009; BG < 0.001 and p = .04). A training effect was found in BG, where heart rate fell more in the last session than in the first (p = 002). CONCLUSIONS: We have demonstrated for the first time the value of a mindfulness program in patients with acromegaly, analysing possible effects and advantages, and clarifying the usefulness of a specific protocol for the disease.

Corticotroph tumor progression after bilateral adrenalectomy: data from ERCUSYN.

Corticotroph tumor progression after bilateral adrenalectomy/Nelson's syndrome (CTP-BADX/NS) is a severe complication of bilateral adrenalectomy (BADX). The aim of our study was to investigate the prevalence, presentation and outcome of CTP-BADX/NS in patients with Cushing's disease (CD) included in the European Registry on Cushing's Syndrome (ERCUSYN). We examined data on 1045 CD patients and identified 85 (8%) who underwent BADX. Of these, 73 (86%) had follow-up data available. The median duration of follow-up since BADX to the last visit/death was 7 years (IQR 2-9 years). Thirty-three patients (45%) experienced CTP-BADX/NS after 3 years (1.5-6) since BADX. Cumulative progression-free survival was 73% at 3 years, 66% at 5 years and 46% at 10 years. CTP-BADX/NS patients more frequently had a visible tumor at diagnosis of CD than patients without CTP-BADX/NS (P < 0.05). Twenty-seven CTP-BADX/NS patients underwent surgery, 48% radiotherapy and 27% received medical therapy. The median time since diagnosis of CTP-BADX/NS to the last follow-up visit was 2 years (IQR, 1-5). Control of tumor progression was not achieved in 16 of 33 (48%) patients, of whom 8 (50%) died after a mean of 4 years. Maximum adenoma size at diagnosis of CD was associated with further tumor growth in CTP-BADX/NS despite treatment (P = 0.033). Diagnosis of CTP-BADX/NS, older age, greater UFC levels at diagnosis of CD and initial treatment predicted mortality. In conclusion, CTP-BADX/NS was reported in 45% of the ERCUSYN patients who underwent BADX, and control of tumor growth was reached in half of them. Future studies are needed to establish effective strategies for prevention and treatment.

Factors associated with therapeutic response in acromegaly diagnosed in the elderly in Spain.

Context: Some reports suggest that acromegaly in elderly patients has a more benign clinical behavior and could have a better response to first-generation long-acting somatostatin receptor ligands (SRL). However, there is no specific therapeutic protocol for this special subgroup of patients. Objective: This study aimed at identifying predictors of response to SRL in elderly patients. Design: Multicentric retrospective nationwide study of patients diagnosed with acromegaly at or over the age of 65 years. Results: One-hundred and eighteen patients (34 men, 84 women, mean age at diagnosis 71.7 ± 5.4 years old) were included. Basal insulin-like growth factor type 1 (IGF-1) above the upper limit of normal (ULN) and growth hormone (GH) levels (mean ± SD) were 2.7 ± 1.4 and 11.0 ± 11.9 ng/ml, respectively. The mean maximal tumor diameter was 12.3 ± 6.4 mm, and up to 68.6% were macroadenoma. Seventy-two out of 118 patients (61.0%) underwent surgery as primary treatment. One-third of patients required first-line medical treatment due to a rejection of surgical treatment or non-suitability because of high surgical risk. After first-line surgery, 45/72 (63.9%) were in disease remission, and 16/34 (46.7%) of those treated with SRL had controlled disease. Patients with basal GH at diagnosis ≤6 ng/ml had lower IGF-1 levels and had smaller tumors, and more patients in this group reached control with SRL (72.7% vs. 33.3%; p < 0.04) [OR: 21.3, IC: 95% (2.4-91.1)], while male patients had a worse response [OR: 0.09, IC 95% (0.01-0.75)]. The predictive model curve obtained for SRL response showed an AUC of 0.82 CI (0.71-0.94). Conclusions: The most frequent phenotype in newly diagnosed acromegaly in the elderly includes small adenomas and moderately high IGF-1 levels. GH at diagnosis ≤6 ng/ml and female gender, but not age per se, were associated with a greater chance of response to SRL.

Patient journey experiences may contribute to improve healthcare for patients with rare endocrine diseases.

Patient journeys are instruments developed by EURORDIS, The Voice of Rare Disease Patients in Europe, to collect patients' experiences; they may identify gaps and areas deserving improvement, as well as elements positively considered by affected persons. As with other patient-reported experiences, they can complete the clinical evaluation and management of a specific disease, improving the often long diagnostic delay, therapy, patient education and access to knowledgeable multidisciplinary teams. This review discusses the utility of such patient-reported experience measures and summarises the experiences of patients with acromegaly, Addison's disease and congenital adrenal hyperplasia from different European countries. Despite rare endocrine diseases being varied and presenting differently, feelings of not having been taken seriously by health professionals, family and friends was a common patient complaint. Empathy and a positive patient-centred environment tend to improve clinical practice by creating a trustworthy and understanding atmosphere, where individual patient needs are considered. Offering access to adequate patient information on their disease, treatments and outcome helps to adapt to living with a chronic disease and what to expect in the future, contemplating the impact of a disease on patients' everyday life, not only clinical outcome but also social, financial, educational, family and leisure issues is desirable; this facilitates more realistic expectancies for patients and can even lead to a reduction in health costs. Patient empowerment with patient-centred approaches to these complex or chronic diseases should be contemplated more and more, not only for the benefit of those affected but also for the entire health system.

Impaired quality of life, but not cognition, is linked to a history of chronic hypercortisolism in patients with Cushing's disease in remission.

Context: Impaired cognition and altered quality of life (QoL) may persist despite long-term remission of Cushing's disease (CD). Persistent comorbidities and treatment modalities may account for cognitive impairments. Therefore, the role of hypercortisolism per se on cognitive sequelae remains debatable. Objective: To investigate whether memory and QoL are impaired after long-term remission of CD in patients with no confounding comorbidity. Design and Setting: Cross-sectional case-control study in two tertiary referral centers. Patients: 25 patients (44.5 ± 2.4 years) in remission from CD for 102.7 ± 19.3 Mo and 25 well-matched controls, without comorbidity or treatment liable to impair cognition. Main Outcome Measures: Hippocampus- and prefrontal cortex-dependent memory, including memory flexibility and working memory, were investigated using multiple tests including sensitive locally-developed computerized tasks. Depression and anxiety were evaluated with the MADRS and HADS questionnaires. QoL was evaluated with the SF-36 and CushingQoL questionnaires. The intensity of CD was assessed using mean urinary free cortisol and a score for clinical symptoms. Results: CD patients displayed similar performance to controls in all cognitive tests. In contrast, despite the absence of depression and a minimal residual clinical Cushing score, patients had worse QoL. Most of the SF36 subscales and the CushingQoL score were negatively associated only with the duration of exposure to hypercortisolism (p≤ 0.01 to 0.001). Conclusions: Persistent comorbidities can be a primary cause of long-lasting cognitive impairment and should be actively treated. Persistently altered QoL may reflect irreversible effects of hypercortisolism, highlighting the need to reduce its duration. Clinical Trial Registration number: https://clinicaltrials.gov, identifier NCT02603653.

Quality of life impairment after a diagnosis of Cushing's syndrome.

This brief review is devoted mainly to publications in the last 5 years dealing with health-related quality of life (QoL) after a diagnosis of endogenous hypercortisolism, due to pituitary-dependent Cushing's disease (CD) or any other cause of Cushing syndrome (CS). Despite improvement after treatment, persistent physical morbidity, neurocognitive problems like worse executive capacity and memory as well as stress intolerance, depressive symptoms and more anxiety, lead to long-term impairment of QoL.

Data mining analyses for precision medicine in acromegaly: a proof of concept.

Predicting which acromegaly patients could benefit from somatostatin receptor ligands (SRL) is a must for personalized medicine. Although many biomarkers linked to SRL response have been identified, there is no consensus criterion on how to assign this pharmacologic treatment according to biomarker levels. Our aim is to provide better predictive tools for an accurate acromegaly patient stratification regarding the ability to respond to SRL. We took advantage of a multicenter study of 71 acromegaly patients and we used advanced mathematical modelling to predict SRL response combining molecular and clinical information. Different models of patient stratification were obtained, with a much higher accuracy when the studied cohort is fragmented according to relevant clinical characteristics. Considering all the models, a patient stratification based on the extrasellar growth of the tumor, sex, age and the expression of E-cadherin, GHRL, IN1-GHRL, DRD2, SSTR5 and PEBP1 is proposed, with accuracies that stand between 71 to 95%. In conclusion, the use of data mining could be very useful for implementation of personalized medicine in acromegaly through an interdisciplinary work between computer science, mathematics, biology and medicine. This new methodology opens a door to more precise and personalized medicine for acromegaly patients.