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Background Studies comparing primary medical treatment of acromegaly with surgery are often non-randomized, and not stratified by illness severity. We prospectively compared primary medical therapy with pituitary surgery in patients with acromegaly. All patients had macroadenomas, at least one random human growth hormone (GH) level ≥12.5 ng/mL, elevated IGF-I levels and failure to suppress GH to <1 ng/mL during an oral glucose tolerance test (oGTT). Methods Forty-one patients from seven centers were randomized to primary treatment with octreotide LAR, 30 mg every 4 weeks × 3 months (ARM A, N = 15), or pituitary surgery (ARM B, N = 26) using a 1:2 randomization design. Patients cured by surgery (defined as nadir GH during oGTT <1 ng/mL and normal IGF-I) received no subsequent treatment. Those not cured surgically were then treated with octreotide LAR (SubArm B1) for 3 months. Results Only one of the 15 patients in ARM A (6.7%) had normalization of both GH and IGF-I. In contrast, 13/26 patients had normalization of both GH and IGF-I after surgery alone (50%). Of the remaining 13 patients who did not normalize with surgery alone, treatment with octreotide LAR resulted in a normal nadir GH and normal serum IGF-I in 7 (53.9%). In total, 20/26 in ARM B (76.9%) experienced normalization of defined biochemical acromegaly parameters. Conclusions Pituitary surgery alone was more effective than primary medical treatment (p = 0.006), and the combination of surgery followed by medical therapy was even more effective (p < 0.0001). Subjects treated with medical therapy after surgical debulking had a significant improvement in response rate compared to matched subjects treated with primary medical therapy.

A somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce GH secretion for the treatment of pituitary adenomas. To determine pharmacokinetics, safety, and tolerability and to monitor hormonal changes after single and multiple subcutaneous BIM23B065 administrations. Randomized, double-blind, placebo-controlled, parallel-group design with five single and three 13-day multiple ascending-dose cohorts. A total of 63 healthy male white volunteers were enrolled (47 active, 16 placebo). Pharmacokinetics, GH, prolactin (PRL), IGF-1, GH after GHRH administration, and general clinical safety criteria. The maximum dosage of BIM23B065 administered in this study was 1.5 mg. BIM23B065 reduced the mean GH concentrations after 8 and 13 days of treatment. A decrease in GH release after GHRH administration indicated inhibition of the hypothalamic-pituitary-somatotropic axis. IGF-1 was not altered after single doses but showed a significant change from baseline after multiple dosing. PRL secretion was reduced in all subjects who were treated. Orthostatic hypotension and injection site reactions were commonly observed at high dosages. A 6-day uptitration period was included to successfully lower the cardiovascular effects in the multiple ascending dose part of the study. Proof of pharmacology of BIM23B065 was shown by a reduction in GH, IGF-1, and PRL concentrations in healthy male volunteers, supporting activity of the somatostatin analog and dopamine agonist moieties. The safety and tolerability of the higher dosing regions was limited mainly by orthostatic hypotension.

Acromegaly is a chronic debilitating disorder resulting from excessive secretion of growth hormone and a resulting increase in the production of insulin-like growth factor I (IGF-I). It is usually caused by somatotroph adenomas of the pituitary gland. The goal of treatment is to reverse the effects of the hypersecretion of growth hormone and normalize production of IGF-I. Effective treatment ameliorates the symptoms and signs of the disease and lowers the mortality rate. The current treatments for acromegaly are surgical removal of the adenoma, radiation therapy, and drug treatment. Among patients treated surgically, only 60 percent of patients overall and less . . .

At present, there is no approved medical treatment option for patients with non-functioning pituitary adenoma. A number of open-label studies suggest that treatment with somatostatin analogues may prevent tumour progression. In vivo somatostatin receptor imaging using Ga-DOTATATE PET (PET, positron emission tomography) could help in preselecting patients potentially responsive to treatment. Our aim is to investigate the effect of the somatostatin analogue lanreotide as compared with placebo on tumour size in patients with a Ga-DOTATATE PET-positive non-functioning pituitary macroadenoma (NFMA). The GALANT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients with a suprasellar extending NFMA. Included patients undergo a Ga-DOTATATE PET/CT of the head and tracer uptake is assessed after coregistration with pituitary MRI. Forty-four patients with a Ga-DOTATATE PET-positive NFMA are randomised in a 1:1 ratio between lanreotide 120 mg or placebo, both administered as subcutaneous injections every 28 days for 72 weeks. The primary outcome is the change in cranio-caudal tumour diameter on pituitary MRI after treatment. Secondary outcomes are change in tumour volume, time to tumour progression, change in quality of life and number of adverse events. Final results are expected in the second half of 2021. The study protocol has been approved by the Medical Research Ethics Committee of the Academic Medical Centre (AMC) of the Amsterdam University Medical Centres and by the Dutch competent authority. It is an investigator-initiated study with financial support by Ipsen Farmaceutica BV. The AMC, as sponsor, remains owner of all data. Results will be submitted for publication in a peer-reviewed journal. NL5136 (Netherlands Trial Register); pre-recruitment.

INTRODUCTION: Long-acting repeatable (LAR) octreotide i.m. is a potent, synthetic somatostatin analogue (SSA) that requires less frequent dosing and offers quality of life (QoL) benefits in acromegaly patients compared to its shorter-acting predecessor. This study investigated the efficacy and safety of high-dose Sandostatin® LAR® as monotherapy or in combination with pegvisomant or cabergoline in acromegalic patients with pituitary adenomas following previous failure of conventional SSA treatment. MATERIAL AND METHODS: After three months of high-dose Sandostatin® LAR® monotherapy (40 mg), patients who achieved biochemical control (n = 7) continued to receive the same treatment for an additional four months, whereas uncontrolled patients were randomised to receive high-dose Sandostatin® LAR® in combination with pegvisomant (n = 31) or cabergoline (n = 32). Outcomes included biochemical response at eight months, QoL, and safety. RESULTS: After three months, 3 of 68 (4.4%) evaluable patients achieved a biochemical control (BC) as assessed by levels of growth hormone and insulin-like growth factor-1. At eight months, 4 of 67 (6.0%) patients achieved BC, including one receiving monotherapy and three receiving Sandostatin® LAR® plus cabergoline. Partial response rate, improvements in acromegaly signs and symptoms, and changes in QoL were similar for all three groups. All treatments were well tolerated with a slight excess of adverse events in the combination arms. There were no deaths or serious adverse events leading to treatment discontinuation. CONCLUSION: These data demonstrate that high-dose Sandostatin® LAR® as monotherapy or in combination with pegvisomant or cabergoline is a feasible salvage option in patients with pituitary adenomas not adequately controlled on conventional SSA regimens.

Genetic analysis has shown the presence of activating BRAF mutations in 94% of papillary craniopharyngiomas. A phase 2 study showed partial response or better in 15 of 16 previously untreated patients.

Background Papillary craniopharyngiomas harbor the BRAF V600E mutation, which paves the way for using BRAF inhibitor molecules to treat tumors refractory to standard therapies. Single case reports confirmed the efficacy of targeted therapy. However, most reports were limited by the short follow-up. We describe the long-term course of a patient treated with dual-agent BRAF and MEK inhibitors and review the available literature. Case report A 75-year-old male patient had recurrence of a papillary craniopharyngioma after transsphenoidal surgery and Gamma Knife radiosurgery. Review of the pathologic specimen confirmed the presence of the BRAF V600E mutation. Because of the few therapeutic options, we decided to initiate BRAF/MEK inhibitor combined therapy for six months. Rapid reduction of the tumor occurred, but three months after quitting combined medical therapy the tumor recurred. BRAF/MEK inhibitor therapy was resumed and the tumor again showed a marked reduction. The second course was maintained for 20 months and the tumor showed another recurrence within three months, which, again, responded to a third course of targeted therapy. Conclusions Our study confirms the excellent response of papillary craniopharyngioma to combined BRAF and MEK inhibitors. However, rapid tumor recurrence is the rule when medical therapy is stopped. Resistance to a second and third course of targeted therapy did not occur, suggesting that tumor mutations affecting the response to drugs seems an uncommon event in papillary craniopharyngioma. The exact role of targeted therapy in the treatment algorithm of papillary craniopharyngiomas has still to be refined.

Long-acting somatostatin analogs are frequently used as adjuvant treatment of acromegaly patients after noncurative surgery. This sudy aims to compare the efficacy of octreotide long-acting release (OCT) and lanreotide Autogel (LAN) in acromegaly patients. Sixty-eight patients not cured by transsphenoidal endoscopic or microscopic pituitary surgery between 2003 and 2009 were retrospectively analyzed (25 men; 43 women; mean age 41.1 ± 10.9 years [range 18–65 years]). The patients were assigned randomly to OCT (n = 36) and LAN (n = 32) groups. Evaluations included insulin-like growth factor I (IGF-I) and growth hormone (GH) after oral glucose tolerance test (OGTT) 3, 6, 12 and 18 months after starting medical treatment; pituitary magnetic resonance imaging was performed before treatment and after 3 and 12 months. Patients achieving IGF-I levels within the age and gender normal range and GH level <1 μg/l following OGTT were considered a ‘biochemical cure’. Mean IGF-I and GH values and tumor volumes (cm 3 ) in the LAN and OCT groups were similar in the post-operative period before initiation of medical treatment. A statistically significant decrease in GH and IGF-I levels was obtained for both treatment groups at each follow-up visit compared to the previous value. Tumor shrinkage after 12 months of treatment was statistically significant in both groups but the percentage tumor shrinkage (28.5% vs. 34.9%, P  = 0.166) and rate of patients achieving biochemical cure (63.9 and 78.1%, P  = 0.454) were similar between OCT and LAN groups, respectively. OCT and LAN treatment options have similar efficacy for ensuring biochemical cure and tumor shrinkage in acromegaly patients who had noncurative surgery.

There are five subtypes of somatostatin receptors (SST1‐5), which are expressed in several types of solid neoplasms, neuroendocrine tumors, and pituitary adenomas. Most commonly, SST2 and SST5, are of interest regarding diagnostic, treatment, and prognostic purposes. In this article the basic biological characteristics of SST are briefly reviewed, and focus given to the immunohistochemical evaluation of SST2 and SST5 in growth hormone (GH)‐secreting pituitary tumors, and their quantification as predictors of response to treatment with somatostatin receptor ligands (SRL), the mainstay of the pharmacological therapy available for these tumors. Although many different scoring systems for SST2 immunohistochemistry showing correlation with SRL response have been reported, among which the immunoreactivity score (IRS) has been the most consistently used, a universally validated immunohistochemical technique and scoring scheme is lacking. Efforts should be made on collaborative multicenter studies aiming at validating homogeneous immunostaining protocols and a scoring system for SST2 and SST5 expression, to help clinicians to define the optimal therapeutic strategy for the patients with somatotroph tumors. This article reviews the major biological characteristics of somatostatin receptors (SST2 and SST5) in anterior pituitary tumors, and the immunohistochemical evaluation of their expression as predictors of response to pharmacological therapy with SST ligands.

Acromegaly usually occurs owing to a growth-hormone-secreting adenoma in the pituitary gland, which leads to metabolic and anatomical changes in the patient. This Expert Consensus Document outlines the current recommendations for the treatment of acromegaly as determined by the Acromegaly Consensus Group in March 2013. In March 2013, the Acromegaly Consensus Group met to revise and update guidelines for the medical treatment of acromegaly. The meeting comprised experts skilled in the medical management of acromegaly. The group considered treatment goals covering biochemical, clinical and tumour volume outcomes, and the place in guidelines of somatostatin receptor ligands, growth hormone receptor antagonists and dopamine agonists, and alternative modalities for treatment including combination therapy and novel treatments. This document represents the conclusions of the workshop consensus.