Effectiveness of Combined First-Line Medical Treatment in Acromegaly with Prolactin Co-secretion.

OBJECTIVE: To compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin co-secreting PA (GH&PRL-PA). DESIGN: Retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least six months of first-line medical treatment. METHODS: Baseline characteristics, first-line medical treatment strategies, and outcomes were analysed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality. RESULTS: Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs. 51.9 ± 12.7 years; p < 0.01) and harboring more frequently macroadenomas (89.7% vs. 72.1%, p = 0.03). First generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs. 15.2%; p < 0.01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs. 55.1%, p = 0.04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline. CONCLUSION: In GH&PRL-PA the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first line medical treatment in combination with fgSRLs in these subgroups of patients.

Differences between GH and PRL co-secreting and GH-secreting pituitary adenomas. A series of 604 cases.

PURPOSE: To evaluate differences in clinical presentation and in surgical outcomes between growth hormone-secreting pituitary adenomas (GH-PAs) and GH and prolactin co-secreting pituitary adenomas (GH&PRL-PAs). METHODS: Multicenter retrospective study of 604 patients with acromegaly submitted to pituitary surgery. Patients were classified into two groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal and IHC for GH and PRL was positive or PRL levels were >100ng/and PRL IHC was not available (n=130) and b) GH-PAs who did not meet the previously mentioned criteria (n=474). RESULTS: GH&PRL-PAs represented 21.5% (n=130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P<0.001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs. 77.4%, P=0.001) and tended to be more invasive (33.6% vs. 24.7%, P=0.057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (OR 2.8, 95% CI 1.83-4.38). IGF-1 upper limit of normality (ULN) levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [IQR 1.73-3.29] vs. 2.7 [IQR 1.91-3.67], P=0.023). There were no differences in the immediate (41.1% vs 43.3%, P=0.659) or long-term post-surgical acromegaly biochemical cure rate (53.5% vs. 53.1%, P=0.936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs. 2.4%, P=0.011) in GH&PRL-PAs patients. CONCLUSIONS: GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.

Is adrenal venous sampling always necessary to differentiate between unilateral and bilateral primary aldosteronism? Lesson from the SPAIN-ALDO register.

PURPOSE: To evaluate whether the clinical, biochemical and radiological features of patients with primary aldosteronism (PA) can predict both main subtypes of PA. METHODS: A retrospective multicenter study of PA patients followed in 27 Spanish tertiary hospitals (SPAIN-ALDO Register). Only patients with confirmed unilateral or bilateral PA based on adrenal venous sampling (AVS) and/or postsurgical biochemical cure after adrenalectomy were included. Supervised regression techniques were used for model development. RESULTS: 328 patients [270 unilateral PA (UPA), 58 bilateral PA (BPA)] were included. The area under the curve (AUC) for aldosterone/potassium ratio and aldosterone responses following saline infusion test were 0.602 [95%CI 0.520 to 0.684] and 0.574 [95% CI 0.446-0.701], respectively, to differentiate UPA from BPA. The AUC was 0.825 [95% 0.764-0.886] when the prediction model with seven parameters - comorbidities (dyslipidemia, cerebrovascular disease, sleep apnea syndrome [SAS]), systolic blood pressure (SBP), plasma aldosterone levels (PAC), hypokalemia and unilateral adrenal nodule >1 cm and normal contralateral adrenal gland on CT/MRI - was used. In patients without comorbidities, hypokalemia, SBP > 160 mmHg, PAC > 40 ng/dL, and unilateral adrenal lesions were associated with a likelihood of having a UPA of 98.5%. The chance of BPA was higher in individuals with comorbidities, SBP < 140 mmHg, normokalemia, low PAC levels, and no adrenal tumors on the CT/MRI (91.5%). CONCLUSION: A combination of high PAC, SBP > 160 mmHg, low serum potassium, a unilateral adrenal nodule>1 cm and no comorbidities could predict a UPA with a 98.5% accuracy.

Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications on cardiometabolic profile and on surgical outcomes.

Purpose: The aim of this study was to evaluate the prevalence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) and its implications on cardiometabolic and surgical outcomes. Methods: This is a retrospective multicenter study of PA patients who underwent 1 mg dexamethasone-suppression test (DST) during diagnostic workup in 21 Spanish tertiary hospitals. ACS was defined as a cortisol post-DST >1.8 µg/dL (confirmed ACS if >5 µg/dL and possible ACS if 1.8-5 µg/dL) in the absence of specific clinical features of hypercortisolism. The cardiometabolic profile was compared with a control group with ACS without PA (ACS group) matched for age and DST levels. Results: The prevalence of ACS in the global cohort of patients with PA (n = 176) was 29% (ACS-PA; n = 51). Ten patients had confirmed ACS and 41 possible ACS. The cardiometabolic profile of ACS-PA and PA-only patients was similar, except for older age and larger tumor size of the adrenal lesion in the ACS-PA group. When comparing the ACS-PA group (n = 51) and the ACS group (n = 78), the prevalence of hypertension (OR 7.7 (2.64-22.32)) and cardiovascular events (OR 5.0 (2.29-11.07)) was higher in ACS-PA patients than in ACS patients. The coexistence of ACS in patients with PA did not affect the surgical outcomes, the proportion of biochemical cure and clinical cure being similar between ACS-PA and PA-only groups. Conclusion: Co-secretion of cortisol and aldosterone affects almost one-third of patients with PA. Its occurrence is more frequent in patients with larger tumors and advanced age. However, the cardiometabolic and surgical outcomes of patients with ACS-PA and PA-only are similar.

Effect of Obesity on Clinical Characteristics of Primary Aldosteronism Patients at Diagnosis and Postsurgical Response.

CONTEXT: Patients with obesity have an overactivated renin-angiotensin-aldosterone system (RAAS) that is associated with essential hypertension. However, the influence of obesity in primary aldosteronism (PA) is unknown. OBJECTIVE: We analyzed the effect of obesity on the characteristics of PA, and the association between obesity and RAAS components. METHODS: A retrospective study was conducted of the Spanish PA Registry (SPAIN-ALDO Registry), which included patients with PA seen at 20 tertiary centers between 2018 and 2022. Differences between patients with and without obesity were analyzed. RESULTS: A total of 415 patients were included; 189 (45.5%) with obesity. Median age was 55 years (range, 47.3-65.2 years) and 240 (58.4%) were male. Compared to those without obesity, patients with obesity had higher rates of diabetes mellitus, chronic kidney disease, obstructive apnea syndrome, left ventricular hypertrophy, prior cardiovascular events, higher means of systolic blood pressure, and required more antihypertensive drugs. Patients with PA and obesity also had higher values of serum glucose, glycated hemoglobin A1c, creatinine, uric acid, and triglycerides, and lower levels of high-density lipoprotein cholesterol. Levels of blood aldosterone (PAC) and renin were similar between patients with and without obesity. Body mass index was not correlated with PAC nor renin. The rates of adrenal lesions on imaging studies, as well as the rates of unilateral disease assessed by adrenal vein sampling or I-6ß-iodomethyl-19-norcholesterol scintigraphy, were similar between groups. CONCLUSION: Obesity in PA patients involves a worse cardiometabolic profile, and need for more antihypertensive drugs but similar PAC and renin levels, and rates of adrenal lesions and lateral disease than patients without obesity. However, obesity implicates a lower rate of hypertension cure after adrenalectomy.

Efficacy of [177Lu]Lu-DOTATATE in metastatic neuroendocrine neoplasms of different locations: data from the SEPTRALU study.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [177Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of 177Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282). RESULTS: The sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7-not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8-28.1) in pancreatic, and 17.6 months (14.4-33.1) in bronchopulmonary NENs. [177Lu]Lu-DOTATATE exhibited scant severe toxicity. CONCLUSION: This study confirms the efficacy and safety of [177Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs.

Predictive model of hypertension resolution after adrenalectomy in primary aldosteronism: the SPAIN-ALDO score.

PURPOSE: To develop a predictive model of hypertension resolution after adrenalectomy in patients with primary aldosteronism (PA), based on their presurgical characteristics. METHODS: A retrospective multicenter study of PA patients in follow-up in 20 Spanish tertiary hospitals between 2018 and 2021 was performed (SPAIN-ALDO Register). Clinical response postadrenalectomy was classified according to the primary aldosteronism surgical outcome (PASO) consensus criteria. The predictive model was developed using a multivariate logistic regression model with the estimation of all possible equations. RESULTS: A total of 146 patients (54.8% females; mean age of 51.5 ± 10.9 years) with PA who underwent unilateral adrenalectomy were included. After a mean follow-up of 29.1 ±â€Š30.43 months after surgery, hypertension cure was obtained in 37.7% ( n  = 55) of the patients. The predictive model with the highest diagnostic accuracy to predict hypertension cure combined the variables female sex, use of two or fewer antihypertensive medications, hypertension grade 1, without type 2 diabetes and nonobesity. The area under the receiver operating characteristic curve of this model was 0.841 [0.769-0.914]. Based on this model, the group of patients with a higher probability of cure (80.4%) were those without type 2 diabetes, BMI <30 kg/m 2 , female sex, hypertension grade 1 and who use two or fewer antihypertensives. Our predictive model offered a slightly higher diagnostic accuracy than Wachtel's (area under the curve [AUC]: 0.809), Utsumi's (AUC: 0.804) and Zarnegar's (AUC: 0.796) models and was similar than the Burello's (AUC: 0.833) model. CONCLUSION: Female sex, use of two or fewer antihypertensive medications, hypertension grade 1, no type 2 diabetes and nonobesity may predict hypertension cure after adrenalectomy in patients with PA. Our score provides a potential tool to guide preoperative patient counseling.

Adrenal venous sampling in primary aldosteronism: Experience of a Spanish multicentric study (Results from the SPAIN-ALDO Register).

OBJECTIVE: The aim of this study was to evaluate the rate of adrenal venous sampling (AVS) performance in patients with primary aldosteronism (PA), the main reasons for its non-performance, and the success and complications rate of this procedure in Spain. Moreover, the concordance between CT/MRI and AVS for PA subtyping was evaluated. METHODS: A retrospective multicenter study of PA patient follow-up in 20 Spanish tertiary hospitals between 2018-2021 was performed (SPAIN-ALDO Register). RESULTS: Of the 440 patients with PA included in the study, 153 underwent AVS (34.8%). The main reasons for not performing AVS were: patient rejection to the procedure, low catheterization rate in the center and unilateral disease based on CT/MRI. The overall success rate was 44.4% (the left adrenal vein was properly canulated in 77.8% and the right adrenal vein in 48.4%). Only 3 patients experienced minor complications. In the 45 patients with unilateral disease according to AVS, CT/MRI indicated bilateral disease or normal adrenal glands in 17. In the 23 patients with bilateral disease, CT/MRI indicated unilateral disease in 14. However, no significant differences were observed in biochemical response (P = 0.051) and hypertension resolution (P = 0.150) between patients who underwent surgery based on CT/MRI results and those who underwent surgery based on AVS results. CONCLUSION: In our setting, AVS is still an underused technique in patients with PA. The low experience and success rate in AVS partially justify these results. More training for providers and patients needs to be done to include appropriate well performed AVS in the diagnosis algorithm of PA.

Differences in the presentation and evolution of primary aldosteronism in elderly (≥65 years) and young patients (<65 years).

Objective: To compare the presentation and evolution of primary aldosteronism (PA) in the elderly (≥65 years) and young patients (<65 years). Methods: A retrospective multicenter study was performed in 20 Spanish hospitals of PA patients in follow-up between 2018 and 2021. Results: Three hundred fifty-two patients with PA <65 years and 88 patients ≥65 years were included. Older PA patients had a two-fold higher prevalence of type 2 diabetes, dyslipidemia, and cerebrovascular disease, but these differences disappeared after adjusting for hypertension duration. At diagnosis, diastolic blood pressure was lower than in young patients (83.3 ± 11.54 vs 91.6 ± 14.46 mmHg, P < 0.0001). No differences in the rate of overall correct cannulation (56.5% vs 42.3%, P = 0.206) or the diagnosis of unilaterality (76.9% vs 62.5%, P = 0.325) in the adrenal venous sampling (AVS) was observed between the elderly and young groups. However, there was a lower proportion of PA patients who underwent adrenalectomy in the elderly group than in the younger group (22.7% (n = 20) vs 37.5% (n = 132), P = 0.009). Nevertheless, no differences in the rate of postsurgical biochemical (100% (n = 14) vs 92.8% (n = 90), P = 0.299) and hypertension cure (38.6% (n = 51) vs 25.0% (n = 5), P = 0.239) were observed between both groups. Conclusion: Older patients with PA have a worse cardiometabolic profile than young patients with PA that it is related to a longer duration of hypertension. However, the results of the AVS, and adrenalectomy are similar in both groups. Therefore, the management of elderly patients with PA should be based not only on age, but rather on the overall medical, physical, social, and mental characteristics of the patients.

Efficacy and safety of 177Lu­DOTATATE in patients with advanced pancreatic neuroendocrine tumours: data from the NETTER-R international, retrospective study.

PURPOSE: NETTER-R aimed to determine the efficacy, safety and tolerability of 177Lu-DOTATATE in patients with progressive, advanced pancreatic neuroendocrine tumours (panNETs) using retrospective real-world data from multiple sites. METHODS: This international study retrospectively included patients with panNETs treated with 177Lu-DOTATATE. The primary endpoint was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included overall survival (OS), safety and tumour response. RESULTS: In total, 110 patients with panNETs were studied; 65.5% received a cumulative dose of 177Lu-DOTATATE 29.6 GBq ± 10% (median: 7.4 GBq). In 62 patients with available RECIST v1.1 tumour response, the median PFS was 24.8 months (95% confidence interval [CI]: 17.5-34.5), and the objective response rate was 40.3% (95% CI: 28.1-53.6); all responses were partial. With a median follow up of 24.5 months (range: 2.0-123.4 months) after the first cycle of 177Lu-DOTATATE, the median OS in the full analysis set (n = 110) was 41.4 months (95% CI: 28.6-50.2). PFS (hazard ratio [HR]: 3.672; p = 0.0009) and OS (HR: 3.360; p < 0.0001) were longer in patients who received no chemotherapy prior to 177Lu-DOTATATE than those who did. No treatment-emergent adverse events (TEAEs) led to treatment discontinuation. Grade 3 anaemia, lymphopenia and thrombocytopenia occurred in 0.9%, 5.4% and 0.9% of patients, respectively. No acute leukaemia or myelodysplastic syndrome was reported. Six patients (5.5%) had renal TEAEs. All renal grade ≥ 3 events were transient and did not lead to treatment modification. CONCLUSIONS: These results reinforce the role of 177Lu-DOTATATE for the treatment of patients with advanced, somatostatin receptor-positive panNETs.

External Validity of Somatostatin Analogs Trials in Advanced Neuroendocrine Neoplasms: The GETNE-TRASGU Study.

INTRODUCTION: Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs. METHODS: We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs. RESULTS: The dataset contained 535 patients with a median age of 62 years (range: 26-89). The median Ki-67% was 4 (range: 0-20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1-32.0) for octreotide versus 30.1 months (95% CI: 23.1-38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71-1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively. CONCLUSION: Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs.

Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study.

PURPOSE: Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS: We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS: We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION: The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

Control glucemico en pacientes hospitalizados no criticos / Glycemic control in non-critial hospitalized patients

Conocer la prevalencia de hiperglucemia en pacientes ingresados, el grado de control glucemico, la tasa de hipoglucemias y el tratamiento utilizado. Material y métodos Estudio observacional de corte transversal. Resultados De 691 pacientes, 185 (26,7%) tenían (..) (AU)

Objectives: To assess in hospitalized patients the prevalence of hyperglycemia, degree of glycemiccontrol, rate of hypoglycemia, and treatment used. Patients and (..) (AU)

[Glycemic control in non-critical hospitalized patients]. / Control glucémico en pacientes hospitalizados no críticos.

OBJECTIVES: To assess in hospitalized patients the prevalence of hyperglycemia, degree of glycemic control, rate of hypoglycemia, and treatment used. PATIENTS AND METHODS: A prospective, observational study. RESULTS: Hyperglycemia was found in 185 (26.7%) of 691 patients, of whom 85% had been diagnosed with diabetes and 15% had no diabetes. Preprandial mean blood glucose was 169 mg/dL (95% CI 160-177). Control goals were achieved by 34.5% of patients (blood glucose ≤140 mg/dL). In 121 patients only sliding-scale regular insulin was used, while 64 patients received both basal and regular insulin. The mean daily insulin dose used was 19.5 units. Oral antidiabetics were given to 11.4% of patients. Thirteen patients (7%) experienced hypoglycemia (< 70 mg/dL), none of them severe. CONCLUSIONS: Glycemic control is not adequate in hospitalized patients, probably because of overuse of sliding scales and the low insulin doses used.