Personalized medicine in acromegaly: The ACROFAST study.

Medical treatment of acromegaly is currently performed through a trial-error approach using first generation somatostatin receptor ligands (fgSRLs) as first-line drugs, with an effectiveness of about 50%, and subsequent drugs are indicated through clinical judgment. Some biomarkers can predict fgSRLs response. Here we report the results of the ACROFAST study, a clinical trial in which a protocol based on predictive biomarkers of fgSRLs was evaluated. METHODS AND SUBJECTS: prospective trial (21 university hospitals) comparing the effectiveness and time-to control of two treatment protocols during 12 months: A) A personalized protocol in which first option were fgSRLs as monotherapy or in combination with pegvisomant or, pegvisomant as monotherapy depending on the short Acute Octreotide Test (sAOT) results, tumor T2 Magnetic Resonance (MRI) signal or immunostaining for E-cadherin and, B) A control group with treatment always started by fgSRLs and the other drugs included after demonstrating inadequate control. RESULTS: Eighty-five patients participated; 45 in the personalized and 40 in the control group. More patients in the personalized protocol achieved hormonal control compared to those in the control group (78% vs 53%, p < 0.05). Survival analysis revealed a hazard ratio for achieving hormonal control adjusted by age and sex of 2.53 (CI 1.30-4.80). Patients from personalized arm were controlled in a shorter period of time (p = 0.01). CONCLUSION: Personalized medicine is feasible using a relatively simple protocol and allows a higher number of patients achieving control in a shorter period of time.

One-Stage Vs. Two-Step One Anastomosis Duodenal Switch (OADS/SADI-S): A Safety and Efficacy Single-Center Propensity-Score Matched Analysis.

INTRODUCTION: One Anastomosis Duodenal Switch (OADS/SADI-S) is used both as a one stage and a second-step procedure, either planned or revisional after a failed sleeve gastrectomy. However, there is lack of adjusted comparative evidence validating its use. MATERIAL AND METHODS: Propensity-score matched comparison between patients submitted to one-stage vs. two-step OADS, adjusted by age, gender, and initial body mass index (BMI). RESULTS: One hundred ninety-five patients (130 one-stage and 65 two-step OADS) were included, with mean initial BMI 52.4 kg/m2. Overall complication rate was 6.6% in the short-term (3.3% Clavien-Dindo ≥ III), and 7.3% in the long-term, with no differences between groups. Follow-up at 1 and 3 years was 83.6% and 61.5%. After one-stage OADS, total weight loss was 36.6 ± 8.2% at 1 year and 30.4 ± 10.3% at 3 years, vs. 30.2 ± 9.4% and 25.6 ± 10.2% after two-steps OADS (p = 0.021). Resolution rates of diabetes mellitus, hypertension, dyslipidemia, and obstructive sleep apnea were 86.4%, 80.4%, 78.0%, and 73.3%, with no differences between groups. CONCLUSION: One-stage OADS is a safe and effective bariatric technique for patients with grade III and IV obesity. The two-step strategy does not reduce postoperative risks and may compromise weight loss results at mid-term.

Does the Prevalence of Obesity in the Different Regions of Spain Influence the Attitudes, Perception, and Barriers to Its Treatment?

INTRODUCTION: The differences in the prevalence of obesity between the various regions of Spain, partly attributed to socioeconomic differences, may influence the approach to this disease. The aim of this study was to compare differences in attitudes, perception, and barriers to the treatment of obesity between people with obesity (PwO) and health care professionals (HCPs), between the different regions of Spain. METHODS: Sub-analysis of the ACTION-IO Spain study, which included 1,500 PwO and 306 HCP, was performed to identify differences in PwQ and HCPs belonging to regions with high prevalence of obesity (>16%, n = 9 regions, high prevalence of obesity [HPO] group) and low prevalence of obesity (<16%, n = 8 regions, low prevalence of obesity [LPO] group) (self-reported data), according to the 2017 National Health Survey of Spain. STATISTICS: comparison of proportions (χ2). RESULTS: A total of 746 PwO belonged to HPO and 754 to LPO group. The PwO in HPO group were younger, had lower income, a lower level of higher education, higher unemployment rate, and fewer comorbidities. Obesity was considered a chronic disease to a higher extent in HPO compared to LPO group (62 vs. 56%), but this difference was not statistically significant. The PwO in HPO group discussed less with the HCPs about their excess weight (57 vs. 70%), did not feel motivated to lose weight in a higher percentage (26 vs. 18%), and felt less emotionally supported (16 vs. 24%). In HPO group, the preference for unhealthy food (51 vs. 36%), and the costs of healthy eating, anti-obesity drugs and bariatric surgery were perceived barriers to losing weight. A higher proportion of PwO in HPO group considered that exercise (58 vs. 40%) was more effective for achieving weight loss. In contrast, LPO group considered diet more effective (48 vs. 32%). HCPs in HPO group felt more motivated to treat obesity (83 vs. 68%) and a higher proportion (14 vs. 5%) identified the economic burden as one of the main reasons why PwO do not start conversations to lose weight. CONCLUSIONS: There is less concern and conversation about excess weight in PwO in regions with a higher prevalence of obesity, with socioeconomic limitations being one of the main perceived barriers to treatment.

A specific gut microbiota signature is associated with an enhanced GLP-1 and GLP-2 secretion and improved metabolic control in patients with type 2 diabetes after metabolic Roux-en-Y gastric bypass.

Objective: To determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement. Materials and methods: Prospective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota. Results: Thirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m2, HbA1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P<0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P<0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients. Conclusions: Patients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature.

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.

Exploring the influence of circulating endocannabinoids and nucleus accumbens functional connectivity on anorexia nervosa severity.

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by a harmful persistence of self-imposed starvation resulting in significant weight loss. Research suggests that alterations in the nucleus accumbens (NAcc) and circulating endocannabinoids (eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), may contribute to increased severity and maladaptive behaviors in AN, warranting an examination of the interplay between central reward circuitry and eCBs. For this purpose, we assessed NAcc functional connectivity and circulating AEA and 2-AG concentrations in 18 individuals with AN and 18 healthy controls (HC) to test associations between circulating eCBs, NAcc functional connectivity, and AN severity, as defined by body mass index (BMI). Decreased connectivity was observed between the NAcc and the right insula (NAcc-insula; pFWE < 0.001) and the left supplementary motor area (NAcc-SMA; pFWE < 0.001) in the AN group compared to HC. Reduced NAcc-insula functional connectivity mediated the association between AEA concentrations and BMI in the AN group. However, in HC, NAcc-SMA functional connectivity had a mediating role between AEA concentrations and BMI. Although no significant differences in eCBs concentrations were observed between the groups, our findings provide insights into how the interaction between eCBs and NAcc functional connectivity influences AN severity. Altered NAcc-insula and NAcc-SMA connectivity in AN may impair the integration of interoceptive, somatosensory, and motor planning information related to reward stimuli. Furthermore, the distinct associations between eCBs concentrations and NAcc functional connectivity in AN and HC could have clinical implications for weight maintenance, with eCBs being a potential target for AN treatment.

Dynamic fronto-amygdalar interactions underlying emotion-regulation deficits in women at higher weight.

OBJECTIVE: The regulation of negative emotions entails the modulation of subcortical regions, such as the amygdala, by prefrontal regions. There is preliminary evidence suggesting that individuals at higher weight may present with hypoactivity in prefrontal regulatory systems during emotional regulation, although the directionality of these pathways has not been tested. In this study, we compared fronto-amygdalar effective connectivity during cognitive reappraisal as a function of BMI in 48 adult women with obesity and 54 control participants. METHODS: Dynamic causal modeling and parametric empirical Bayes were used to map effective connectivity between the dorsomedial prefrontal cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, and the amygdala. RESULTS: Difficulty in Emotion Regulation Scale scores were higher in the obesity group compared with control participants (p < 0.001). A top-down cortical model best explained our functional magnetic resonance imaging data (posterior probability = 86%). Participants at higher BMI were less effective at inhibiting activity in the amygdala via the orbitofrontal cortex and dorsomedial prefrontal cortex during reappraisal compared with those at lower BMI. In contrast, increased excitatory modulation of dorsolateral prefrontal cortex-to-amygdalar connectivity was found in participants at lower BMI. CONCLUSIONS: These findings support a framework involving alterations in fronto-amygdalar connectivity contributing to difficulties in regulating negative affect in individuals at higher weight.

Ectopic insulinoma: a systematic review.

Knowledge of ectopic insulinomas comes from single cases. We performed a systematic review through PubMed, Web of Science, Embase, eLibrary and ScienceDirect of all cases reported in the last four decades. We also describe one unreported patient. From 28 patients with ectopic insulinoma, 78.6% were female and mean age was 55.7 ± 19.2 years. Hypoglycaemia was the first symptom in 85.7% while 14.3% complained of abdominal pain or genital symptoms. Median tumour diameter was 27.5 [15-52.5] mm and it was localised by CT (73.1%), MRI (88.9%), [68Ga]Ga-DOTA-exedin-4 PET/CT (100%), 68Ga-labelled-DOTA-conjugated somatostatin analogue PET/TC (100%), somatostatin receptor scintigraphy (40%) and endoscopic ultrasound (50%). Ectopic insulinomas were located at duodenum (n = 3), jejunum (n = 2), and one respectively at stomach, liver, appendix, rectum, mesentery, ligament of Treitz, gastrosplenic ligament, hepatoduodenal ligament and splenic hilum. Seven insulinomas were affecting the female reproductive organs: ovary (n = 5), cervix (n = 2) and remaining tumours were at retroperitoneum (n = 3), kidney (n = 2), spleen (n = 1) and pelvis (n = 1). 89.3% underwent surgery (66.7% surgery vs. 33.3% laparoscopy) and 16% underwent an ineffective pancreatectomy. 85.7% had localized disease at diagnosis and 14.3% developed distant metastasis. Median follow-up time was 14.5 [4.5-35.5] months and mortality was reported in 28.6% with median time until death of 60 [5-144] months. In conclusion, ectopic insulinomas are presented as hypoglycaemia with female preponderance. Functional imaging [68Ga]Ga-DOTA-exedin-4 PET/CT and 68Ga-labelled-DOTA-conjugated somatostatin analogue PET/TC have very high sensitivity. Clinicians should be alert to the possibility of extra-pancreatic insulinomas when classic diagnostic tests and intraoperative pancreas exploration failed to locate the tumour.

Association of anandamide and 2-arachidonoylglycerol concentrations with clinical features and body mass index in eating disorders and obesity.

BACKGROUND: Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) play a pivotal role in stimulating motivational behavior toward food and energy metabolism. Aberrant functioning of the endocannabinoid system has been observed in extreme weight conditions (EWCs), suggesting it may influence pathophysiology. Then, we aimed to analyze fasting AEA and 2-AG plasma concentrations among individuals with EWC (i.e., anorexia nervosa [AN] and obesity with and without eating disorders [EDs]) compared with healthy controls (HCs), and its association with clinical variables and body mass index (BMI). METHODS: The sample included 113 adult women. Fifty-seven belonged to the obesity group, 37 without EDs (OB-ED) and 20 with ED (OB+ED classified within the binge spectrum disorders), 27 individuals from the AN group, and 29 from the HC group. Peripheral blood samples, several clinical variables, and BMI were evaluated. RESULTS: Unlike 2-AG, AEA concentrations showed significant differences between groups (p < 0.001). Increased AEA was observed in the OB-ED and OB+ED compared with both HC and AN group, respectively. Likewise, AEA was differentially associated with emotional dysregulation, general psychopathology, food addiction, and BMI in all clinical groups. CONCLUSIONS: These results support the interaction between biological and clinical factors contributing to delineating vulnerability pathways in EWC that could help fit personalized therapeutic approaches.

SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression.

Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its receptor SUCNR1. Adipocyte-specific deletion of Sucnr1 influences metabolic health according to nutritional status. Adipocyte Sucnr1 deficiency impairs leptin response to feeding, whereas oral succinate mimics nutrient-related leptin dynamics via SUCNR1. SUCNR1 activation controls leptin expression via the circadian clock in an AMPK/JNK-C/EBPα-dependent manner. Although the anti-lipolytic role of SUCNR1 prevails in obesity, its function as a regulator of leptin signaling contributes to the metabolically favorable phenotype in adipocyte-specific Sucnr1 knockout mice under standard dietary conditions. Obesity-associated hyperleptinemia in humans is linked to SUCNR1 overexpression in adipocytes, which emerges as the major predictor of adipose tissue leptin expression. Our study establishes the succinate/SUCNR1 axis as a metabolite-sensing pathway mediating nutrient-related leptin dynamics to control whole-body homeostasis.

Xanthogranuloma of the sellar region: a systematic review.

Knowledge of xanthogranuloma (XG) of the sellar region comes from short series or single cases. We performed a systematic review, using the PubMed, Web of Science, Embase, Scopus, eLibrary, and BIOSIS Preview databases, of all cases reported from 2000 to the present. We also describe one unreported patient treated in our institution. A search of the literature revealed that of 71 patients 50.7% were male and that mean age at diagnosis was 34.7 ± 19.2 years old. Median time from clinical onset until diagnosis was 7 (3-21) months. Hypopituitarism (70.4%), visual disorders (64.7%), headache (53.5%), and polyuria-polydipsia (28.2%) were the most common symptoms. On MRI, median tumor size was 20 (16-29) mm, while 71.8% were sellar/suprasellar and less frequently exclusively suprasellar (15.5%) or sellar (12.7%). On T1-weighted imaging, XG was hyperintense in 76.3% of patients, while it showed variable appearance on T2-weighted imaging. The tumor showed cystic features in 50.7%, gadolinium enhancement in 45.1%, and calcification in 22.5% of patients. All patients underwent surgery (77.4% transphenoidal approach and 18.3% craniotomy), with hypopituitarism (56.4%), diabetes insipidus (34.5%), and visual defects (7.3%) being the most common complications. Total/subtotal resection was achieved in 93.5%, while the tumor was partially removed in 6.6%. Median follow-up was 24 (6-55) months and no tumor recurrence or remnant growth was reported in 97.5% of cases. In conclusion, XG affects the younger population, manifested by hormonal deficit and mass effect symptoms. Surgery is safe and offers excellent outcomes, though hypopituitarism is frequent post-surgery. Tumor recurrence or remnant growth is rare and radiological surveillance is a good option for patients with remnant lesions.

Recommendations for the diagnosis and treatment of hypoglycaemia after bariatric surgery.

Postprandial hyperinsulinaemic hypoglycaemia is a common complication of bariatric surgery. Although in general its evolution is mild and self-limited, it can lead to neuroglycopaenia and compromise the patient's safety and quality of life. The aim of this document is to offer some recommendations to facilitate the clinical care of these complex patients, reviewing the aetiopathogenesis, its diagnosis and treatment that, sequentially, will include dietary and pharmacological measures and surgery in refractory cases. In the absence of high-quality studies, the diagnostic and therapeutic approach proposed is based on the consensus of experts of the Grupo de Obesidad de la Sociedad Española de Endocrinología y Nutrición [Obesity Group of the Spanish Society of Endocrinology and Nutrition], GOSEEN. Those undergoing bariatric surgery should be informed of the possibility of developing this complication.

A Clinical-Genetic Score for Predicting Weight Loss after Bariatric Surgery: The OBEGEN Study.

Around 30% of the patients that undergo bariatric surgery (BS) do not reach an appropriate weight loss. The OBEGEN study aimed to assess the added value of genetic testing to clinical variables in predicting weight loss after BS. A multicenter, retrospective, longitudinal, and observational study including 416 patients who underwent BS was conducted (Clinical.Trials.gov- NCT02405949). 50 single nucleotide polymorphisms (SNPs) from 39 genes were examined. Receiver Operating Characteristic (ROC) curve analysis were used to calculate sensitivity and specificity. Satisfactory response to BS was defined as at nadir excess weight loss >50%. A good predictive model of response [area under ROC of 0.845 (95% CI 0.805-0.880), p < 0.001; sensitivity 90.1%, specificity 65.5%] was obtained by combining three clinical variables (age, type of surgery, presence diabetes) and nine SNPs located in ADIPOQ, MC4R, IL6, PPARG, INSIG2, CNR1, ELOVL6, PLIN1 and BDNF genes. This predictive model showed a significant higher area under ROC than the clinical score (p = 0.0186). The OBEGEN study shows the key role of combining clinical variables with genetic testing to increase the predictability of the weight loss response after BS. This finding will permit us to implement a personalized medicine which will be associated with a more cost-effective clinical practice.