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There are only a few experimental studies which have investigated effects of glucose alone, and glucose in combination with insulin/insulin-like growth factors (IGF) on the growth of colon cancer. In the present study, we studied in vitro in human colorectal cancer cells originating from four Dukes’ stages of colorectal cancer the effects of glucose, insulin and IGFs on proliferation, migration, cell cycle progression and gene expression of the IGF system. Growth of colon cancer cells originating from a Dukes’ stage A was glucose-dependent, whereas growth of cancer cells from Dukes’ stage B, C and D was glucose-independent. Stimulatory effects of insulin and IGFs on cell growth were observed only in colon cancer cells originating from Dukes’ stage C and D. IGF-II stimulated migration in Dukes’ stage B cells only. The growth stimulatory effects in Dukes’ stage C and D colorectal cancer cells were accompanied by G2/M arrest and associated with an increased IGF-IR/IGF-II receptor ratio. In conclusion, our in vitro data suggest that the stimulating effects of glucose, IGFs and insulin on proliferation differ between colorectal cancer cells from early and late Dukes’ stages. Stimulatory effects of glucose on proliferation appear predominantly present in stage Dukes’ stage A colorectal cancer cells, while in contrast growth factor-mediated stimulation of cell proliferation is more pronounced in Dukes’ late stage (metastasized) colorectal cancer cells. Moreover, our study suggests that a stringent glucose control may be important to control tumor growth in early stages of colorectal cancer, while inhibition of the endocrine actions of the IGFs and insulin become more important in the late (metastasized) stages of colorectal cancer to restrain growth of colon cancer cells.

Serotonin, a biologically active amine, is related to carcinoid syndrome in functioning neuroendocrine tumors (NETs). Telotristat ethyl is a novel inhibitor of the tryptophan hydroxylase (TPH), a key enzyme in the production of serotonin. While its use in patients with carcinoid syndrome and uncontrolled diarrhea under somatostatin analogs (SSAs) has been recently approved, in vitro data evaluating its effectiveness are lacking. For this reason, we aimed to evaluate the effect of telotristat as monotherapy, and in combination with SSAs, on proliferation and secretion in a NET cell line model. The human pancreatic NET cell lines BON-1/QGP-1 were used as 2D and 3D cultured models; somatostatin receptor and TPH mRNA expression, as well as the potential autocrine effect of serotonin on tumor cell proliferation using a 3D culture system were evaluated. Telotristat decreased serotonin production in a dose-dependent manner at a clinically feasible concentration, without affecting cell proliferation. Its combination with pasireotide, but not with octreotide, had an additive inhibitory effect on serotonin secretion. The effect of telotristat was slightly less potent, when BON-1 cells were co-treated with octreotide. Octreotide and pasireotide had no effect on the expression of TPH. Telotristat did not have an effect on mRNA expression of somatostatin receptor subtypes. Finally, we showed that serotonin did not have an autocrine effect on NET cell proliferation on the 3D cell model. These results suggest that telotristat is an effective drug for serotonin inhibition, but the effectiveness of its combination with SST2 (somatostatin receptor subtype 2)-preferring SSA should be evaluated in more detail.

CONTEXT: Patients with adrenocortical carcinoma (ACC) often fail mitotane treatment and deal with severe toxicity, marking the relevance of predictive parameters for treatment outcome. OBJECTIVE: Determine the effects of mitotane in primary ACC cultures, and correlate sensitivity with patient and tumor characteristics. METHODS: In 32 primary ACC cultures, the effects of mitotane on cell growth and cortisol production were determined. RRM1, SOAT1, and CYP2W1 expression were assessed using reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: The median percentage cell amount inhibition in primary ACC cultures at 50 µM mitotane was 57%. Seven patients were classified as nonresponders, 14 as partial responders, and 11 as responders. The mean median effective concentration (EC50) value of mitotane for inhibition of cell amount in responders was 14.2 µM (95% CI, 11.3-17.9), in partial responders 41.6 µM (95% CI, 33.5-51.8), and could not be calculated in nonresponders. The percentage cortisol-producing ACC was 14%, 43%, and 73% for nonresponders, partial responders, and responders (P = 0.068). Mitotane inhibited cortisol production with a mean EC50 of 1.4 µM (95% CI, 0.9-2.1), which was considerably lower than the EC50

Adrenocortical carcinomas (ACCs) are rare tumors with scant treatment options for which new treatments are required. The mTOR pathway mediates the intracellular signals of several growth factors, including the insulin-like growth factors (IGFs), and therefore represents a potential attractive pathway for the treatment of several malignancies including ACCs. Several mTOR inhibitors, including sirolimus, temsirolimus and everolimus, have been clinically developed. This review summarizes the results of the studies evaluating the expression of the mTOR pathway components in ACCs, the effects of the mTOR inhibitors alone or in combination with other drugs in preclinical models of ACCs and the early experience with the use of these compounds in the clinical setting. The mTOR pathway seems a potential target for treatment of patients with ACC, but further investigation is still required to define the potential role of mTOR inhibitors alone or in combination with other drugs in the treatment of ACC patients.

Pancreatic Neuroendocrine Neoplasms (pNEN) are rare tumors which treatment still represent an important clinical problem, due to the paucity of medical treatments. Due to tumor complexity, techniques as 3D cultures are important to study drug activity in a more realistic model. This study aims to compare three different 3D culture methods in order to understand which one can be considered the best option in terms of experimental easiness and reproducibility in studying the efficacy of a target drug on pNEN. The BON1 cell line was used as a pNEN model and the well-known Receptor Tyrosine Kinase inhibitor Sunitinib was used in order to better investigate the different features of each method. The investigated methods are: (1) 96-well hanging drop plates (HD plates), (2) 24-well plates with a cell-repellent surface, and (3) ultra-low attachment 96-well plates with clear round bottom (ULA plates). The evaluated parameters during the study were: cell seeding, easiness in spheroids formation, morphology, culture maintenance, medium change, spheroids monitoring, picture quality, spheroid perimeter measurement reproducibility error, possibility to perform assays into the seeding plate, overall time of the experiment. Moreover, we investigated how culture methods can influence experimental outcomes evaluating perimeter changes, cell viability and immunohistochemistry of spheroids treated with different Sunitinib concentrations. Results showed that each method has weak and strong points but, considering the easiness of spheroids maintenance and reproducibility results, ULA plates method appears to be the best approach to culture BON1 spheroids and, therefore, to study pNEN.

Human aging is currently defined as a physiological decline of biological functions in the body with a continual adaptation to internal and external damaging. The endocrine system plays a major role in orchestrating cellular interactions, metabolism, growth, and aging. Several in vivo studies from worms to mice showed that downregulated activity of the GH/IGF-1/insulin pathway could be beneficial for the extension of human life span, whereas results are contradictory in humans. In the present review, we discuss the potential role of the IGF-1 system in modulation of longevity, hypothesizing that the endocrine and metabolic adaptation observed in centenarians and in mammals during caloric restriction may be a physiological strategy for extending lifespan through a slower cell growing/metabolism, a better physiologic reserve capacity, a shift of cellular metabolism from cell proliferation to repair activities and a decrease in accumulation of senescent cells. Therefore, understanding of the link between IGF-1/insulin system and longevity may have future clinical applications in promoting healthy aging and in Rehabilitation Medicine.

Background: For progressive metastatic medullary thyroid carcinoma (MTC), the available treatment options with tyrosine kinase inhibitors result in grade 3–4 adverse events in a large number of patients. Peptide Receptor Radionuclide Therapy (PRRT), which has also been suggested to be a useful treatment for MTC, is usually well tolerated, but evidence on its effectivity is very limited. Methods: Retrospective evaluation of treatment effects of PRRT in a highly selected group of MTC patients, with progressive disease or refractory symptoms. In addition, a retrospective evaluation of uptake on historical 111InDTPA-octreotide scans was performed in patients with detectable tumor size > 1 cm. Results: Over the last 17 years, 10 MTC patients were treated with PRRT. Four out of 10 patients showed stable disease at first follow-up (8 months after start of therapy) whereas the other 6 were progressive. Patients with stable disease were characterized by a combination of both a high uptake on 111In-DTPA-octreotide scan (uptake grade ≥ 3) and a positive somatostatin receptor type 2a (SSTR2a) expression of the tumor by immunohistochemistry. Retrospective evaluation of historical 111In-DTPA-octreotide scans of 35 non-treated MTC patients revealed low uptake (uptake grade 1) in the vast majority of patients 31/35 (89%) with intermediate uptake (uptake grade 2) in the remaining 4/35 (11%). Conclusions: PRRT using 177Lu-octreotate could be considered as a treatment in those patients with high uptake on 111In-DTPA-octreotide scan (uptake grade 3) and positive SSTR2a expression in tumor histology. Since this high uptake was present in a very limited number of patients, this treatment is only suitable in a selected group of MTC patients. Keywords: Thyroid cancer, medullary, Peptide receptor radionuclide therapy, Lutetium, Receptors, somatostatin

Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and

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Medullary thyroid cancer (MTC) is a tumor highly resistant to chemo- and radiotherapy. Drug resistance can be induced by epigenetic changes such as aberrant DNA methylation. To overcome drug resistance, we explored a promising approach based on the use of 5-aza-2'-deoxycytidine (AZA), a demethylating agent, in combination with the mTOR inhibitor everolimus in MTC cells (MZ-CRC-1 and TT). This combined treatment showed a strong synergistic antiproliferative activity through the induction of apoptosis. The effect of everolimus and/or AZA on genome-wide expression profiling was evaluated by Illumina BeadChip in MZ-CRC-1 cells. An innovative bioinformatic pipeline identified four potential molecular pathways implicated in the synergy between AZA and everolimus: PI3K-Akt signaling, the neurotrophin pathway, ECM/receptor interaction, and focal adhesion. Among these, the neurotrophin signaling pathway was most directly involved in apoptosis, through the overexpression of NGFR and Bax genes. The increased expression of genes involved in the NGFR-MAPK10-TP53-Bax/Bcl2 pathway during incubation with AZA plus everolimus was validated by western blotting in MZ-CRC-1 cells. Interestingly, addition of a neutralizing anti-NGFR antibody inhibited the synergistic cytotoxic activity between AZA and everolimus. These results open a new therapeutic scenario for MTC and potentially other neuroendocrine tumors, where therapy with mTOR inhibitors is currently approved.

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Item does not contain fulltext, Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors.

Objective: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to the

Objective/methods: Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-Analog pasireotide, the dopamine-Agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-Angiotensin- aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone. Results: Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction. Conclusions: The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.

Item does not contain fulltext, OBJECTIVE/METHODS: Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone. RESULTS: Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction. CONCLUSIONS: The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.

1 december 2013, Item does not contain fulltext, Cushing's disease (CD) is associated with severely impaired quality of life (QoL). Moreover, the physiological cortisol diurnal rhythm (CDR) is disturbed in CD. QoL can improve after successful surgery, the primary treatment for CD. We evaluated the effects of medical treatment on QoL and CDR. In 17 patients, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline and the adrenal-blocking agent ketoconazole. After 80 days, 15/17 (88%) patients had reached normal urinary free cortisol excretion (UFC). Subsequently, patients continued medical therapy or underwent surgery. UFC, plasma and salivary CDR and QoL-related parameters (assessed using 5 questionnaires: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index-20, RAND-36, CushingQoL) were measured. At baseline, 5/17 patients had preserved CDR. In 6/12 patients with disturbed baseline CDR, recovery was observed, but without any correlation with QoL. QoL was significantly impaired according to 18/20 subscales in CD patients compared to literature-derived controls. According to the RAND-36 questionnaire, patients reported more pain at day 80 (p < 0.05), which might reflect steroid-withdrawal. Generally, QoL did not improve or deteriorate after 80 days. CushingQoL scores seemed to improve after 1 year of remission in three patients that continued medical therapy (p = 0.11). CDR can recover during successful pituitary- and adrenal-targeted medical therapy. Patients with CD have impaired QoL compared to controls. Despite the occurrence of side-effects, QoL does not deteriorate after short-term biochemical remission induced by medical therapy, but might improve after sustained control of hypercortisolism.

1 december 2013, Item does not contain fulltext, Context: Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D2R) and somatostatin receptor subtype 5 (sst5). The sst2 expression is relatively low, likely resulting from downregulating effects of high cortisol levels. This may explain why the sst2-preferring somatostatin analog octreotide, compared with the multi-receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease. Objective: Our objective was to compare sst and D2R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion. Patients and Design: Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11; mean duration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles. Main Outcome Measures: We evaluated receptor mRNA and protein expression levels and effects of octreotide, pasireotide, and cabergoline on ACTH secretion by cultured human corticotroph adenoma cells. Results: The sst2 mRNA expression in group 2 was 10-fold higher than in group 1 (P < .01), even comparable to that in somatotroph adenomas. There were no statistically significant differences in sst5 and D2R mRNA expression or in sst2, sst5, and D2R protein expression between both groups of corticotroph adenomas. In responders, octreotide (n = 2 out of 4; -30.5% +/- 10.4%) was less potent than pasireotide (n = 5 out of 6; -47.0% +/- 4.2%) and cabergoline (n = 3 out of 4; -41.9% +/- 3.1%) with respect to inhibition of ACTH secretion by adenomas from group 2. Conclusions: After achieving normocortisolism induced by medical therapy, cortisol-mediated sst2 downregulation on corticotroph adenomas appears to be a reversible process at the mRNA but not at the protein level. Octreotide remains less potent than pasireotide and cabergoline with resp

Context: Somatostatin receptor subtype 2 (sst2A) protein expression has been demonstrated to positively correlate with somatostatin analog treatment outcome in GH-secreting adenomas. Recently, a new rabbit monoclonal anti-sst2A antibody (clone UMB-1) has been validated as a reliable method to selectively detect sst2A protein levels in formalin-fixed tissues. Objective: The aim of the study was to establish whether the evaluation of sst2A protein levels, assessed with a routine reproducible immunohistochemistry protocol using UMB-1 antibody, may predict the successful adjuvant therapy with somatostatin analogs in acromegalic patients. Design, Setting, and Patients: Thirty-six acromegalic patients from our referral hospital were evaluated retrospectively. Sst2A expression analysis was performed by immunohistochemistry in 25 patients and by quantitative RT-PCR in 26 patients. Sst2A immunoreactivity was evaluated using an immunoreactivity score (IRS), which takes into account both the percentage of positive cells and staining intensity. Interventions: Patients with persistent disease after surgery (n = 26) were treated with somatostatin analogs for a median duration of 6 months. Main Outcome Measure: GH and IGF-I levels were measured before and after postoperative treatment. Results: Sst2A IRS showed a significant positive correlation with both GH (P = 0.039) and IGF-I (P = 0.001) suppression by octreotide. Sst2A IRS was negatively associated with IGF-I levels reached after treatment (P = 0.001), and patients that achieved IGF-I normalization showed significantly higher sst2A IRS compared to the group that was not normalized (P = 0.002). A sst2A IRS of at least 5 showed a sensitivity of 86% and a specificity of 91% in predicting IGF-I normalization during adjuvant octreotide treatment. Conclusion: Sst2A IRS with the anti-sst2A antibody UMB-1 represents a valid tool in

Context: Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D2R) and somatostatin receptor subtype 5 (sst5). The sst2 expression is relatively low, likely resulting from downregulating effects of high cortisol levels. This may explain why the sst2-preferring somatostatin analog octreotide, compared with the multi-receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease. Objective: Our objective was to compare sst and D2R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion. Patients and Design: Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11;meanduration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles. Main Outcome Measures: We evaluated receptor mRNA and protein expression levels and effects of octreotide,pa

Context: Cushing's disease (CD) is associated with serious morbidity and, when suboptimallytreated, an increased mortality. Although surgery is the first-line treatment modality for CD, hypercortisolism persists or recurs in an important subset of patients. Considering the deleterious effects of uncontrolled CD, there is a clear need for effective medical therapy. Objective: Inthis review, wediscuss molecular targets for medical therapy, efficacy, and side effects of the currently used drugs to treat hypercortisolism and focus on recent developments resulting from translational and clinical studies. Evidence Acquisition: Selection of publications related to the study objective was performed via a PubMed search using relevant keywords and search terms. MainFindings: Medical therapy for CD can be classified into pituitary-directed, adrenal-blocking, and glucocorticoid receptor-antagonizing drugs. Recent studies demonstrate that somatostatinreceptor subtype 5 (sst5) and dopamine receptor subtype 2 (D2) are frequently (co-)expressed by corticotroph adenomas. Pituitary-directed therapy with pasireotide and cabergoline, targeting sst5 and D2, respectively, is successful in approximately 25-30% of patients. Adrenal-blocking drugs can be effective by inhibiting steroidogenic enzyme activity. Finally, the glucocorticoid receptor antagonist mifepristone induces clinical and metabolic improvement in the majority of patients. Each drug can have important side effects that may impair long-term treatment. Generally, patientswith moderate to severe hypercortisolism need combination therapy to normalize cortisol production. Conclusion: Medical therapy for CD can be targeted at different levels and should be tailored in each individual patient. Future studies should examine the optimal dose and combination of medical treatment modalities for CD. Copyright

Context: No relationship has been found between improvement in quality of life (QOL) and total IGF-I during GH therapy. Aim: Our aim was to investigate the relationship between IGF-I bioactivity and QOL in GH-deficient (GHD) patients receiving GH for 12 months. Methods: Of 106 GHD patients, 84 on GH treatment discontinued therapy 4 weeks before establishing baseline values and 22 were GH-naive. IGF-I bioactivity was determined by IGF-I kinase receptor activation assay, total IGF-I by immunoassay (Immulite), and QOL by the disease-specific Question on Life Satisfaction Hypopituitarism (QLS-H) module and by the general SF-36 questionnaire (SF-36Q). Results: IGF-I bioactivity increased after 6 months (-2.5 vs -1.9 SD, P < .001) and did not further increase after 12 months (-1.8 SD, P = .23); total IGF-I increased from -2.3 to -0.9 SD (P < .001) and to -0.6 SD (P < .005), respectively. QLS-H did not change over 12 months (-0.66 ± 0.16 to -0.56 ± 0.17 SD [P = .42] to -0.68 ± 0.17 SD [P = .22]). The mental component summary of the SF-36Q increased from 47.4 (38.7-52.8) to 50.2 (43.1-55.3) (P = .001) and did not further improve (49.4 [42.1-54.1], P = .19); the physical component summary did not change (47.5 [42.0-54.2] vs 47.0 [41.9-55.3], P = .91, vs 48.3 [39.9-55.4], P = .66). After 12 months, IGF-I bioactivity was related to QLS-H (r = 0.28, P = .01); total IGF-I was not (r = 0.10, P = .37). IGF-I bioactivity and total IGF-I were related to PCS (

Somatostatin receptors are an important target for medical treatment of pituitary and neuroendocrine tumors. To date, five somatostatin receptor (sst) subtypes have been identified. The currently available somatostatin analogues octreotide and lanreotide have predominantly affinity for sst2. Pasireotide is a sst multireceptor ligand with affinity for sst1 , sst2, sst3 and sst5 and this broader binding profile may translate into a higher efficacy with respect to suppression of hormone product