The position of combined medical treatment in acromegaly

Advances in combination medical treatment have offer new perspectives for acromegaly patients with persistent disease activity despite receiving the available medical monotherapies. The outcomes of combination medical treatment may reflect both additive and synergistic effects. This review focuses on combination medical treatment and its current position in acromegaly, based on clinical studies evaluating the efficacy and safety of combined medical treatment(s) and our own experiences with combination therapy. Arch Endocrinol Metab. 2019;63(6):646-52

Soluble Klotho: a possible predictor of quality of life in acromegaly patients

Purpose: Although quality of life (QoL) is improved in patients with acromegaly after disease control, QoL correlates only weakly with traditional biomarkers. Our objective is to investigate a potential relation between the new serum biomarker soluble Klotho (sKlotho), GH and insulin-like growth factor 1 (IGF-

T2-signal intensity, SSTR expression, and somatostatin analogs efficacy predict response to pasireotide in acromegaly.

peer reviewed[en] OBJECTIVE: T2-signal intensity and somatostatin (SST) receptor expression are recognized predictors of therapy response in acromegaly. We investigated the relationship between these predictors and the hormonal and tumoral responses to long-acting pasireotide (PAS-LAR) therapy, which were also compared with responsiveness to first-generation somatostatin receptor ligands (SRLs). DESIGN: The PAPE study is a cohort study. METHODS: We included 45 acromegaly patients initially receiving SRLs, followed by combination therapy with pegvisomant, and finally PAS-LAR. We assessed tumor volume reduction (≥25% from baseline), IGF-1 levels (expressed as the upper limit of normal), and T2-weighted MRI signal and SST receptor expression of the adenoma. RESULTS: Patients with significant tumor shrinkage during PAS-LAR showed higher IGF-1 levels during PAS-LAR (mean (S.D.): 1.36 (0.53) vs 0.93 (0.43), P = 0.020), less IGF-1 reduction after first-generation SRLs (mean (S.D.): 0.55 (0.71) vs 1.25 (1.07), P = 0.028), and lower SST2 receptor expression (median (IQR): 2.0 (1.0-6.0) vs 12.0 (7.5-12.0), P = 0.040). Overall, T2-signal intensity ratio was increased compared with baseline (mean (S.D.): 1.39 (0.56) vs 1.25 (0.52), P = 0.017) and a higher T2-signal was associated with lower IGF-1 levels during PAS-LAR (β: -0.29, 95% CI: -0.56 to -0.01, P = 0.045). A subset of PAS-LAR treated patients with increased T2-signal intensity achieved greater reduction of IGF-1 (mean (S.D.): 0.80 (0.60) vs 0.45 (0.39), P = 0.016). CONCLUSIONS: Patients unresponsive to SRLs with a lower SST2 receptor expression are more prone to achieve tumor shrinkage during PAS-LAR. Surprisingly, tumor shrinkage is not accompanied by a biochemical response, which is accompanied with a higher T2-signal intensity

Multivariable Prediction Model for Biochemical Response to First-Generation Somatostatin Receptor Ligands in Acromegaly

CONTEXT: First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. OBJECTIVE: To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. DESIGN: Retrospective multicenter study. SETTING: Eight participating European centers. METHODS: We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. RESULTS: Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72-0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98-0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19-1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43-4.29), P = .0013; insulin therapy OR = 2.65, (1.02-6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01-1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94-0.99) year, P = .0070). Baseline IGF-1 and growth hormo

Excellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma.

peer reviewedProlactinomas are the most commonly encountered pituitary adenomas in the clinical setting. While most can be controlled by dopamine agonists, a subset of prolactinomas are dopamine-resistant and very aggressive. In such tumors, the treatment of choice is neurosurgery and radiotherapy, with or without temozolomide. Here, we report a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy , a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis, or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin (SST) receptor subtype 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis, or both in prolactinomas

Endocrine disorders are prominent clinical features in patients with primary antibody deficiencies

Background: Primary antibody deficiencies (PADs) and anterior pituitary dysfunction are both rare conditions. However, recent studies have remarkably reported the occurrence of anterior pituitary dysfunction in PAD patients. Methods: In this cross-sectional, single-center study we evaluated the prevalence of endocrine disorders in adult PAD patients. Our study focused on common variable immunodeficiency (CVID), immunoglobulin G (IgG) subclass deficiency (IgGSD), and specific anti-polysaccharide antibody deficiency (SPAD). We assessed hormone levels, performed provocative tests and genetic testing in a subset of patients by direct sequencing of the nuclear factor kappa beta subunit 2 (NFKB2) gene and primary immunodeficiency (PID) gene panel testing by whole exome sequencing (WES). Results: Our results demonstrated that one out of 24 IgGSD/SPAD patients had secondary hypothyroidism and three out of 9 men with IgGSD/SPAD had secondary hypogonadism. Premature ovarian failure was observed in four out of 9 women with CVID and primary testicular failure in one out of 15 men with CVID. In two out of 26 CVID patients we found partial adrenal insufficiency (AI) and in one out of 18 patients with IgGSD/SPAD secondary AI was found. Moreover, in one out of 23 patients with CVID and in two out of 17 patients with IgGSD/SPAD severe growth hormone deficiency (GHD) was found, while one patient with IgGSD/SPAD showed mild GHD. Combined endocrine disorders were detected in two women with CVID (either partial secondary AI or autoimmune thyroiditis with primary hypogonadism) and in three men with IgGSD/SPAD (two with either mild GHD or secondary hypothyroidism combined with secondary hypogonadism, and one man with secondary AI and severe GHD). Genetic testing in a subset of patients did not reveal pathogenic variants in NFKB2 or other known PID-associated genes. Conclusion: This is the first study to describe a high prevalence of both anterior pituitary and end-organ endocrine dysfunction in adult PAD patients. As these endocrine disorders may cause considerable health burden, assessment of endocrine axes should be considered in PAD patients

Acromegaly: Current and Emerging Treatment Options

This thesis investigates the therapeutic efficacy of somatostatin analogues and in particular pasireotide in acromegaly patients through analysis of large datasets from international multicenter cohorts and a large-scale phase IV study. She considers setting up a proof-of-concept study applying a ketogenic diet to acromegaly patients, a potential new treatment option, as her most notable contribution to this field of researc

Molecular genetic testing in the management of pituitary disease

Objective : Most pituitary tumours occur sporadically without a genetically identifiable germline abnormality, a small but increasing proportion present with a genetic defect that predisposes to pituitary tumour development, either isolated (e.g., aryl hydrocarbon receptor-interacting protein, AIP) or as part of a tumour-predisposing syndrome (e.g., multiple endocrine neoplasia (MEN) type 1, Carney complex, McCune-Albright syndrome or pituitary tumour and paraganglioma association). Genetic alterations in sporadic pituitary adenomas may include somatic mutations (e.g., GNAS, USP8). In this review, we take a practical approach: which genetic syndromes should be considered in case of different presentation, such as tumour type, family history, age of onset and additional clinical features of the patient. Design : Review of the recent literature in the field of genetics of pituitary tumours. Results : Genetic testing in the management of pituitary disease is recommended in a significant minority of the cases. Understanding the genetic basis of the disease helps to identify patients and at-risk family members, facilitates early diagnosis and therefore better long-term outcome and opens up new pathways leading to tumorigenesis. Conclusion: We provide a concise overview of the genetics of pituitary tumours and discuss the current challenges and implications of these genetic findings in clinical practice

Approach to the Patient With Treatment-resistant Acromegaly

Although most tumors in patients with acromegaly are benign and are cured or controlled by surgery and/or first-generation somatostatin receptor ligands therapy, some can behave more aggressively and are resistant to these standard therapies. Acromegaly, if left untreated, is a rare and chronic disorder, commonly caused by a GH-producing pituitary adenoma and is associated with significant comorbidities and an increased mortality. Transsphenoidal surgery is considered the mainstay of acromegaly management, but medical therapy has an increasingly important role. However, disease activity is not fully controlled in a significant number of patients treated with surgery and/or high-dose first-generation somatostatin receptor ligand monotherapy. In these circumstances, therefore, repeated surgery, second-line medical therapy, and radiotherapy, alone or combined as multimodal therapeutic strategies should be considered, in a patient-centered perspective