Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools in the treatment algorithm of neuroendocrine tumors (NETs). Octreotide and lanreotide are the first-generation SRLs developed and show a preferential binding affinity to somatostatin receptor (SST) subtype 2, while pasireotide, which is a second-generation SRL, has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). A number of studies demonstrated that first-generation and second-generation SRLs show distinct functional properties, besides the mere receptor affinity. Therefore, the aim of the present review is to critically review the current evidence on the biological effects of SRLs in pituitary adenomas and neuroendocrine tumors, by mainly focusing on the differences between first-generation and second-generation ligands.

Neuronal plasticity produces changes in excitability, synaptic transmission, and network architecture in response to external stimuli. Network adaptation to environmental conditions takes place in time scales ranging from few seconds to days, and modulates the entire network dynamics. To study the network response to defined long-term experimental protocols, we setup a system that combines optical and electrophysiological tools embedded in a cell incubator. Primary hippocampal neurons transduced with lentiviruses expressing channelrhodopsin-2/H134R were subjected to various photostimulation protocols in a time window in the order of days. To monitor the effects of light-induced gating of network activity, stimulated transduced neurons were simultaneously recorded using multi-electrode arrays (MEAs). The developed experimental model allows discerning short-term, long-lasting, and adaptive plasticity responses of the same neuronal network to distinct stimulation frequencies applied over different temporal windows.

Background Pasireotide is a second-generation somatostatin (SRIF) receptor ligand (SRL), approved for medical treatment of acromegaly and Cushing's disease (CD). The molecule is a stable cyclohexapeptide synthetized based on SRIF structure. Differently from first-generation SRLs (e.g. octreotide), preferentially binding somatostatin receptor (SST) subtype 2 (SST 2 ), pasireotide has high affinity for multiple SSTs (SST 5 > SST 2 > SST 3 > SST 1 ). Interestingly, early preclinical studies demonstrated that pasireotide shows distinct functional properties compared to SRIF and first-generation SRLs when binding SSTs. Methods We aimed to highlight the differential receptor-targeted action of pasireotide in the treatment of somatotroph and corticotroph adenomas, throughout the critical revision of preclinical studies carried out on acromegaly and CD models. Results Different authors demonstrated that the antisecretory effect of pasireotide in somatotroph adenoma cell cultures is comparable to that of the SST 2 -preferential agonist octreotide. Some reports even show a direct correlation between SST 2 mRNA expression and GH reduction after pasireotide treatment, thus laying for a predominant role of SST 2 in driving pasireotide efficacy in somatotropinomas in vitro. On the other hand, the inhibitory effect of pasireotide on ACTH secretion in corticotropinoma cells seems to be mainly mediated by SST 5 . Indeed, most reports show a higher potency and efficacy of pasireotide compared to SST 2 preferential agonists, while functional studies confirm the pivotal role of SST 5 targeting in corticotroph cells. Conclusions The analysis of preclinical studies carried out in somatotroph and corticoph adenomas points out that pasireotide shows a cell-specific activity, exerting its biological effects via different SSTs in the different adenoma histotypes.

Context Discordant GH and IGF-1 values are frequent in acromegaly. Objective To evaluate the impact of different GH cut-offs on discordance rate. To investigate whether the mean of consecutive GH measurements impact discordance rate when matched to the last available IGF-1 value. Design Retrospective study. Setting Referral centre for pituitary diseases. Patients Ninety acromegaly patients with at least three consecutive evaluations for GH and IGF-1 using the same assay in the same laboratory (median follow-up 13 years). Interventions Multimodal treatment of acromegaly. Main outcome measures Single fasting GH (GHf) and IGF-1 (IGF-1f). Mean of three GH measurements (GHm), collected during consecutive routine patients’ evaluations. Results At last evaluation GHf values were 1.99 ± 2.79 µg/L and age-adjusted IGF-1f 0.86 ± 0.44 xULN (mean ± SD). Discordance rate using GHf was 52.2% (cut-off 1 µg/L) and 35.6% (cut-off 2.5 µg/L) (p=0.025). “High GH” discordance was more common for GHf <1.0 µg/L, while “high IGF-1” was predominant for GHf <2.5 µg/L (p<0.0001). Using GHm mitigated the impact of GH cut-offs on discordance (GHm <1.0 µg/L: 43.3%; GHm <2.5 µg/L: 38.9%; p=0.265). At ROC curve analysis, both GHf and GHm were poor predictors of IGF-1f normalization (AUC=0.611 and AUC=0.645, respectively). The prevalence of disease-related comorbidities did not significantly differ between controlled, discordant, and active disease patients. Discussion GH/IGF-1 discordance strongly depends on GH cut-offs. The use of GHm lessen the impact of GH cut-offs. Measurement of fasting GH levels (both GHf and GHm) is a poor predictor of IGF-1f normalization in our cohort.

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