Magnetic resonance imaging as a predictor of therapeutic response to pasireotide in acromegaly.

OBJECTIVE: Hyperintensity signal in T2-weighted magnetic resonance imaging (MRI) has been related to better therapeutic response during pasireotide treatment in acromegaly. The aim of the study was to evaluate T2 MRI signal intensity and its relation with pasireotide therapeutic effectiveness in real-life clinical practice. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective multicentre study including acromegaly patients treated with pasireotide. Adenoma T2-weighted MRI signal at diagnosis was qualitatively classified as iso-hyperintense or hypointense. Insulin-like growth factor (IGF-I), growth hormone (GH) and tumour volume reduction were assessed after 6 and 12 months of treatment and its effectiveness evaluated according to baseline MRI signal. Hormonal response was considered 'complete' when normalization of IGF-I levels was achieved. Significant tumour shrinkage was defined as a volume reduction of ≥25% from baseline. RESULTS: Eighty-one patients were included (48% women, 50 ± 1.5 years); 93% had previously received somatostatin receptor ligands (SRLs) treatment. MRI signal was hypointense in 25 (31%) and hyperintense in 56 (69%) cases. At 12 months of follow-up, 42/73 cases (58%) showed normalization of IGF-I and 37% both GH and IGF-I. MRI signal intensity was not associated with hormonal control. 19/51 cases (37%) presented a significant tumour volume shrinkage, 16 (41%) from the hyperintense group and 3 (25%) from the hypointense. CONCLUSIONS: T2-signal hyperintensity was more frequently observed in pasireotide treated patients. Almost 60% of SRLs resistant patients showed a complete normalization of IGF-I after 1 year of pasireotide treatment, regardless of the MRI signal. There was also no difference in the percentage tumour shrinkage over basal residual volume between the two groups.

Male pituitary-gonadal axis dysfunction in post-acute COVID-19 syndrome-Prevalence and associated factors: A Mediterranean case series.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 through angiotensin-converting enzyme 2 receptor can harm testes function. The objectives were to analyse the prevalence of low serum testosterone (LT) and impaired fertility potential (Leydig and Sertoli cells dysfunction, respectively) in coronavirus disease 2019 (COVID-19) male survivors and to evaluate acute infection-related associated factors. Also, we explore its association with post-acute COVID-19 syndrome (PCS) and quality of life (QOL). MATERIALS AND METHODS: Male adults recovered from polymerase chain reaction-confirmed COVID-19 were offered a structured evaluation 8-12 weeks after recovery. The main outcome measure(s) were as follows: LT, defined as total testosterone (TT) < 2 ng/ml or if TT levels 2-4 ng/ml as calculated free testosterone < 6.36 ng/dl; Sertoli cell dysfunction was defined as inhibin-B < 89 pg/ml. Secondary outcome-associated factors were analysed by multiple logistic regression (odds ratio; 95% confidence interval [CI]). QOL was evaluated by SF-36 v.2. RESULTS: One hundred and forty-three patients were evaluated at a median (interquartile range) of 77 days (72-83) after disease onset; 72% of them recovered from severe pneumonia. LT was detected in 41 patients (28.7%; 95% CI: 21.8-36.5). Low levels of inhibin-B were detected in 25 patients (18.1%; 95% CI: 12.5-25.3). After multivariate adjustment, obesity and hypokalaemia were associated with LT, whereas age more than 65 was an independent predictor of Sertoli cell dysfunction. LT or Sertoli cell dysfunction was not associated with PCS. Patients with LT had a lower score in four domains of QOL. CONCLUSIONS: Prevalence of male LT and impaired fertility potential in COVID-19 survivors is high in the medium term. Traditional risk factors and severity markers for COVID-19 could be predictive.

Molecular determinants of enhanced response to somatostatin receptor ligands after debulking in large GH-producing adenomas.

OBJECTIVE: Large somatotrophic adenomas depict poor response to somatostatin receptor ligands (SRLs). Debulking has shown to enhance SRLs effect in some but not all cases and tumour volume reduction has been proposed as the main predictor of response. No biological studies have been performed so far in this matter. We aimed to identify molecular markers of response to SRLs after surgical debulking in GH-secreting adenomas. DESIGN: We performed a multicenter retrospective study. PATIENTS: 24 patients bearing large GH-producing tumours. MEASUREMENTS: Clinical data and SRLs response both before and after surgical debulking were collected, and 21 molecular biomarkers of SRLs response were studied in tumour samples by gene expression. RESULTS: From the 21 molecular markers studied, only two of them predicted enhanced SRLs response after surgery. Tumours with improved response to SRLs after surgical debulking showed lower levels of Ki-67 (MKI67, FC = 0.17 and P = .008) and higher levels of RAR-related orphan receptor C (RORC) (FC = 3.1 and P Ë‚ .001). When a cut-off of no detectable expression was used for Ki-67, the model provided a sensitivity of 100% and a specificity of 52.6% with an area under the curve of 65.8%. Using a cut-off of 2 units of relative expression of RORC, the prediction model showed 100% of sensitivity and specificity. CONCLUSIONS: High levels of RORC and low levels of Ki-67 identify improved SRLs response after surgical debulking in large somatotropic adenomas. To determine their expression would facilitate medical treatment decision-making after surgery.

High Irisin levels in nondiabetic HIV-infected males are associated with insulin resistance, nonalcoholic fatty liver disease, and subclinical atherosclerosis.

OBJECTIVE: HIV infection is associated with an increased risk of cardiovascular disease. Irisin is a miokyne secreted by skeletal muscle, which may influence insulin homeostasis, nonalcoholic fatty liver disease (NAFLD) and atherosclerosis. Our objective was to evaluate the relationships between serum irisin, insulin homeostasis, NAFLD and subclinical atherosclerosis in HIV-infected males. DESIGN: Cross-sectional study in a cohort of HIV-infected patients. PATIENTS: Inclusion criteria: men older than 18 years; antiretroviral therapy (ART) -naïve or on effective ART (<50 HIV-1 RNA copies/mL) without changes in the previous 6 months; no diabetes or hepatitis C. MEASUREMENTS: Irisin was measured by enzymatic immunoassay (Phoenix Pharmaceuticals), insulin sensitivity by homeostasis model assessment of insulin resistance (HOMA-IR), as well as the 2-hour continuous infusion of glucose with model assessment (CIGMA-HOMA). Hepatic steatosis was measured by 1-H magnetic resonance spectroscopy, subclinical atherosclerosis by evaluation of carotid intima-media thickness (C-IMT), measured by Ultrasonography. RESULTS: Eight nine men (age 42.0 ± 8.3 years, duration of HIV infection 7.9 ± 5.6 years, CD4 count 547 ± 279 cells/mL) were included. Circulating irisin was positively related to HOMA-IR and CIGMA-HOMA, hepatic triglyceride content, and to VAT/SAT ratio. Higher irisin concentrations were associated with higher C-IMT, although this association did not persist in multivariate analysis. Lipodystrophy and a higher baseline PAI-1 concentration were independently associated with C-IMT. CONCLUSIONS: In male HIV patients without diabetes, higher irisin concentrations are positively associated with insulin resistance, NAFLD and subclinical atherosclerosis. However, waist-hip-ratio is the main determinant of insulin resistance, and PAI-1 and lipodystrophy were the strongest determinants of IMT in this population.

Characterization of Artifact Influence on the Classification of Glucose Time Series Using Sample Entropy Statistics.

This paper analyses the performance of SampEn and one of its derivatives, Fuzzy Entropy (FuzzyEn), in the context of artifacted blood glucose time series classification. This is a difficult and practically unexplored framework, where the availability of more sensitive and reliable measures could be of great clinical impact. Although the advent of new blood glucose monitoring technologies may reduce the incidence of the problems stated above, incorrect device or sensor manipulation, patient adherence, sensor detachment, time constraints, adoption barriers or affordability can still result in relatively short and artifacted records, as the ones analyzed in this paper or in other similar works. This study is aimed at characterizing the changes induced by such artifacts, enabling the arrangement of countermeasures in advance when possible. Despite the presence of these disturbances, results demonstrate that SampEn and FuzzyEn are sufficiently robust to achieve a significant classification performance, using records obtained from patients with duodenal-jejunal exclusion. The classification results, in terms of area under the ROC of up to 0.9, with several tests yielding AUC values also greater than 0.8, and in terms of a leave-one-out average classification accuracy of 80%, confirm the potential of these measures in this context despite the presence of artifacts, with SampEn having slightly better performance than FuzzyEn.

Diagnosis of exocrine pancreatic insufficiency in chronic pancreatitis: 13C-Mixed Triglyceride Breath Test versus Fecal Elastase.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is indicated in case of clinically relevant exocrine pancreatic insufficiency (EPI). Clinical trials addressing PERT have used the coefficient of fat absorption (CFA) to define EPI but this test is cumbersome to perform. Our aim was to compare two easier-to-perform tests to detect clinically relevant EPI: Fecal Elastase-1 (FE-1) and 13C-Mixed Triglyceride Breath Test (TGBT). METHODS: We prospectively included 54 patients with chronic pancreatitis (CP), 24.1% operated, 29.6% had EPI. EPI was defined as a CFA <93%. The sensitivity (Se), specificity (Sp), positive (PPV) and negative (NPV) predictive values for different cut-offs of FE-1 and TGBT were calculated. RESULTS: The area under the ROC curve for FE-1/TGBT was 0.861/0.876 for the global sample, 0.842/0.794 for non-operated patients and 0.917/1 for operated patients respectively. Se, Sp, PPV and NPV for a cut-off of FE-1 <200 µg/g were 93.8%, 63.2%, 51.7% and 96% respectively. The best cut-off point for FE-1 was 84 µg/g, which yielded an 87.5% Se, 81.6% Sp, 66.7% PPV and 93.9% NPV. The same parameters for a TGBT <29% were 81.3%, 84.2%, 68.4% and 91.4% respectively. The best cut-off point for TGBT was <23%, which yielded an 81.3% Se, 94.7% Sp, 86.7% PPV and 92.3% NPV. Diabetes was associated to decreased FE-1 levels, even in multivariate analysis. CONCLUSIONS: FE-1 and TGBT showed similar results for the diagnosis of EPI in CP. In non-operated CP patients, TGBT does not offer any advantage to FE-1 but in operated CP patients TGBT seems a more accurate test.

Escape and lipodystrophy in acromegaly during pegvisomant therapy, a retrospective multicentre Spanish study.

BACKGROUND: Pegvisomant is an effective treatment for acromegaly. OBJECTIVE: To investigate escape (loss of biochemical control in patients previously controlled) and lipodystrophy in acromegalic patients treated with pegvisomant and to evaluate possible associations with clinical features. PATIENTS AND METHODS: Multicentre retrospective study involving 19 Spanish centres. RESULTS: Ninety-seven patients were included (59% women, mean age at diagnosis 42 ± 13 years, 80% macroadenomas); mean follow-up on pegvisomant was 5 ± 2·5 years, and 89 (92%) achieved normal IGF-1. Escape was reported in 30/89 (34%) of responders, after a mean treatment duration of 25 ± 21 months. The mean initial dose of pegvisomant was 11 ± 5 mg/day, and mean dose at escape was 14 ± 7 mg/day. Most patients (26/30, 87%) achieved control with dose increase (57%), additional medical treatment (3%) or both (27%). Mean new dose that controlled IGF-1 after escape was 20 ± 7 mg/day. Treatments associated were somatostatin analogues (SSA in 47%), cabergoline (CAB in 47%) and both (6%). Lipodystrophy was observed in 15 patients (13 females), mild in six, moderate in six, severe in three and persistent in four. Among patients with lipodystrophy, three escaped and three were nonresponders to pegvisomant. Four patients discontinued the drug, and four had dose reductions because of lipodystrophy. It tended to be more frequent in females (P = 0·06) and in patients treated with triple association SSA+CAB+PEG (P = 0·018). No relationship between escape and clinical variables was found, except prior CAB (P = 0·04) and metformin treatment (0·02) and grade of lipodystrophy (P = 0·02). CONCLUSIONS: A significant proportion of patients treated with pegvisomant escaped (34%); however, the majority (87%) was easily controlled with either dose increase, further medical treatment or both. Lipodystrophy developed in 15%, mostly females, and influenced the response to treatment.

A discrete choice experiment to understand preferences of patients with type 2 diabetes about the attributes of GLP1 receptor agonists in Spain.

OBJECTIVE: To determine the preferences regarding injection, medication frequency and complexity of GLP1 receptor agonists among patients with type 2 diabetes, treatment-naïve for such drugs in Spain. Additionally, patients' willingness to pay according to these attributes was evaluated. METHODS: A discrete-choice experiment survey designed to evaluate patients' preferences over three attributes discriminating by age, sex and patients experience with previous injectable treatment was fulfilled by patients. The resulting model was analyzed using a conditional (fixed-effects) logistic regression. RESULTS: A total of 180 patients (63.35 ± 11.49 years, 63.28% men, 48.41% with previous cardiovascular disease, 54.69% with a time of evolution of diabetes >10 years) recruited from 5 health care centers in Spain completed the survey. Patients viewed positively weekly injections (vs daily injections), but rated negatively a complex preparation of the dose (vs simple preparation). Whereas naïve patients for injectable medications did not consider administration timing of importance, no naïve patients considered it relevant. No relevant differences were observed according to age or gender. Patients were willing to pay 83.25€for a "no preparation required" dose. No naïve and naïve patients were willing to pay 34.61€ and 14.35€; p = 0.000, to change daily injection for a weekly injection. CONCLUSIONS: Patients highly valued the avoidance of injections, with weekly dosing clearly preferred over daily dosing, as well as reducing the treatment complexity. These findings may provide a better understanding of what patients prefer and value in their treatment and provide guidance for clinicians making therapeutic decisions regarding treatments of patients with type 2 diabetes.

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.

Integrative clinical, hormonal, and molecular data associate with invasiveness in acromegaly: REMAH study.

INTRODUCTION: Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management. OBJECTIVES: The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression. METHODS: Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables. RESULTS: Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs). CONCLUSIONS: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.

Changes in acromegaly treatment over four decades in Spain: analysis of the Spanish Acromegaly Registry (REA).

Since 1997 there is an online National Registry of acromegalic patients in Spain (REA). We aimed to study changes in acromegaly treatment and outcomes over the last four decades in Spain. In REA clinical and biochemical data are collected at diagnosis and updated every one to 2 years. We analyzed the first treatment received and the different treatments administered according to decade of diagnosis of acromegaly: prior to 1980, 1980-1989, 1990-1999 and 2000-2009. Surgical cure rates according to pretreatment with long-acting somatostatin receptor ligands (SRLs) were also analyzed. 1,658 patients were included of which 698 had accurate follow-up data. Treatment of acromegaly changed over time. Surgery was the main treatment option (83.8 %) and medical treatment was widely used (74.7 %) both maintained over decades, while radiation therapy declined (62.8, 61.6, 42.2 and 11.9 % over decades, p < 0.001). First treatment type also changed: surgery was the first line option up until the last decade in which medical treatment was preferred (p < 0.001). Radiotherapy was barely used as first treatment. Treatment combinations changed over time (p < 0.001). The most common treatment combination (surgery plus medical therapy), was received by 24.4, 16.4, 25.3 and 56.5 % of patients over decades. Medical treatment alone was performed in 7.3, 6, 7.2 and 14.7 % over decades. Type of medical treatment also changed, SRLs becoming the first medical treatment modality in the last decades, whereas dopamine agonist use declined (p < 0.001). Surgical cure rates improved over decades (21, 21, 36 and 38 %, p = 0.002) and were not influenced by SRL pre-surgical use. Acromegaly treatment has changed in Spain in the last four decades. Surgery has been the main treatment option for decades; however, medical therapy has replaced surgery as first line in the last decade and radiotherapy rates have clearly declined. SRLs are the most used medical treatment.

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.

The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

Long-term Safety of Growth Hormone in Adults With Growth Hormone Deficiency: Overview of 15 809 GH-Treated Patients.

CONTEXT: Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. OBJECTIVE: We aimed to evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. METHODS: The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin [somatropin]; Pfizer, NY) and followed through routine clinical practice. Adverse events (AEs) and clinical characteristics (eg, lipid profile, glucose) were collected. RESULTS: A cohort of 15 809 GH-treated patients were analyzed (mean follow-up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitary/hypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. A total of 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiac/vascular disorders, 48 by cerebrovascular disorders). Overall, de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92; 95% CI, 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathic/congenital GHD (0.64; 0.43-0.91), but similar in those with pituitary/hypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipids/fasting blood glucose levels. CONCLUSION: These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice.

Implications of Heterogeneity of Epithelial-Mesenchymal States in Acromegaly Therapeutic Pharmacologic Response.

Acromegaly is caused by excess growth hormone (GH) produced by a pituitary tumor. First-generation somatostatin receptor ligands (SRLs) are the first-line treatment. Several studies have linked E-cadherin loss and epithelial-mesenchymal transition (EMT) with resistance to SRLs. Our aim was to study EMT and its relationship with SRLs resistance in GH-producing tumors. We analyzed the expression of EMT-related genes by RT-qPCR in 57 tumors. The postsurgical response to SRLs was categorized as complete response, partial response, or nonresponse if IGF-1 was normal, had decreased more than 30% without normalization, or neither of those, respectively. Most tumors showed a hybrid and variable EMT expression profile not specifically associated with SRL response instead of a defined epithelial or mesenchymal phenotype. However, high SNAI1 expression was related to invasive and SRL-nonresponsive tumors. RORC was overexpressed in tumors treated with SRLs before surgery, and this increased expression was more prominent in those cases that normalized postsurgical IGF-1 levels under SRL treatment. In conclusion, GH-producing tumors showed a heterogeneous expression pattern of EMT-related genes that would partly explain the heterogeneous response to SRLs. SNAI1 and RORC may be useful to predict response to SRLs and help medical treatment decision making.

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.

Integrative Clinical, Radiological, and Molecular Analysis for Predicting Remission and Recurrence of Cushing Disease.

CONTEXT: Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse. OBJECTIVES: This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas. METHODS: A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years' follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery. RESULTS: Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P < .001). CONCLUSION: This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas.

Recommendations on the pathological report of pituitary tumors. A consensus of experts of the Spanish Society of Endocrinology and Nutrition and the Spanish Society of Pathology.

Pituitary neuroendocrine tumors (PitNETs) constitute, together with other tumors of the sellar region, 15-25% of intracranial neoplasms. In 2017, the World Health Organization proposed a new classification of PitNETs. The main innovation with respect to the 2004 classification was the recommendation to include in the immunohistochemical evaluation of PitNETs the determination of the transcription factors of the 3 pituitary cell lineages: Pit-1, Tpit and SF-1. Additionally, other clinicopathological classifications with a predictive capacity of tumor behavior during follow-up were proposed. Given these changes, it is appropriate to adapt the knowledge generated during the last 15 years to the daily practice of the treatment and monitoring of PitNETs at the Centers of Excellence in Pituitary Pathology. This document includes the positioning of the Spanish Society of Endocrinology and Nutrition (SEEN) and the Spanish Society of Pathology (SEAP) on the classification and denomination of the PitNETs and the information that the pathologist should provide to the clinician to facilitate the treatment and monitoring of these tumors.

[Recommendations on the pathological report of pituitary tumors. A consensus of experts of the Spanish Society of Endocrinology and Nutrition and the Spanish Society of Pathology]. / Recomendaciones sobre el diagnóstico e informe anatomopatológico de los tumores neuroendocrinos hipofisarios. Consenso de expertos de la Sociedad Española de Endocrinologia y Nutrición y de la Sociedad Española de Anatomía Patológica.

Pituitary neuroendocrine tumors (PitNETs) constitute, together with other tumors of the sellar region, 15-25% of intracranial neoplasms. In 2017, the World Health Organization proposed a new classification of PitNETs. The main innovation with respect to the 2004 classification was the recommendation to include in the immunohistochemical evaluation of PitNETs the determination of the transcription factors of the 3 pituitary cell lineages: Pit-1, Tpit and SF-1. Additionally, other clinicopathological classifications with a predictive capacity of tumor behavior during follow-up were proposed. Given these changes, it is appropriate to adapt the knowledge generated during the last 15 years to the daily practice of the treatment and monitoring of PitNETs at the Centers of Excellence in Pituitary Pathology. This document includes the positioning of the Spanish Society of Endocrinology and Nutrition (SEEN) and the Spanish Society of Pathology (SEAP) on the classification and denomination of the PitNETs and the information that the pathologist should provide to the clinician to facilitate the treatment and monitoring of these tumors.