Pituitary Apoplexy After a Single Dose of Long-Acting Octreotide

Pituitary apoplexy (PA) is a rare and potentially life-threatening syndrome resulting from an acute infarction or hemorrhage of the pituitary gland. Although the pathogenesis is not fully understood, some predisposing factors such as pituitary stimulation tests, diabetes mellitus, anticoagulant or antiplatelet aggregation therapy, head trauma, and high blood pressure may play a role in its pathophysiology. Octreotide is the mainstay of medical treatment for acromegaly. The majority of reported complications of octreotide therapy are gastrointestinal. We report the case of a 51-year-old acromegalic woman who developed pituitary apoplexy within the context of high blood pressure and a single dose of long-acting octreotide. Our data suggest that the combination of hypertension and octreotide therapy enhances the risk of pituitary apoplexy.

Resistance to octreotide LAR in acromegalic patients with high SSTR2 expression: analysis of AIP expression

We present here the clinical and molecular data of two patients with acromegaly treated with octreotide LAR after non-curative surgery, and who presented different responses to therapy. Somatostatin receptor type 2 and 5 (SSTR2 and SSTR5), and aryl hydrocarbon receptor-interacting protein (AIP) expression levels were analyzed by qPCR. In both cases, high SSTR2 and low SSTR5 expression levels were detected; however, only one of the patients achieved disease control after octreotide LAR therapy. When we analyzed AIP expression levels of both cases, the patient whose disease was controlled after therapy exhibited AIP expression levels that were two times higher than the patient whose disease was still active. These two cases illustrate that, although the currently available somatostatin analogs bind preferentially to SSTR2, some patients are not responsive to therapy despite high expression of this receptor. This difference could be explained by differences in post-receptor signaling pathways, including the recently described involvement of AIP. Arq Bras Endocrinol Metab. 2012;56(8):501-6

Internalized somatostatin receptor subtype 2 in neuroendocrine tumors of octreotide-treated patients

Somatostatin receptor subtype 2 (sst(2)) is widely expressed in neuroendocrine tumors and can be visualized immunohistochemically at the cell membrane for diagnostic purposes. Recently, it has been demonstrated in animal sst(2) tumor models in vivo that somatostatin analog treatment was able to induce a complete internalization of the tumor sst(2).

Novel octreotide dicarba-analogues with high affinity and different selectivity for somatostatin receptors

A limited set of novel octreotide dicarba-analogues with non-native aromatic side chains in positions 7 and/or 10 were synthesized. Their affinity toward the ssts1-5 was determined. Derivative 4 exhibited a pan-somatostatin activity, except sst4, and derivative 8 exhibited high affinity and selectivity toward sst5. Actually, compound 8 has similar sst5 affinity (IC50 4.9 nM) to SRIF-28 and octreotide. Structure-activity relationships suggest that the Z geometry of the double-bond bridge is that preferred by the receptors. The NMR study on the conformations of these compounds in SDS(-d25) micelles solution shows that all these analogues have the pharmacophore beta-turn spanning Xaa7-D-Trp8-Lys9-Yaa10 residues. Notably, the correlation between conformation families and affinity data strongly indicates that the sst5 selectivity is favored by a helical conformation involving the C-terminus triad, while a pan-SRIF mimic activity is based mainly on a conformational equilibrium between extended and folded conformational states.

Phosphorylation of sst2 receptors in neuroendocrine tumors after octreotide treatment of patients

Somatostatin analogues, which are used to treat neuroendocrine tumors, target the high levels of somatostatin receptor subtype 2 (SSTR1; alias sst2) expressed in these cancers. However, some tumors are resistant to somatostatin analogues, and it is unknown whether the defect lies in sst2 activation or downstream signaling events. Because sst2 phosphorylation occurs rapidly after receptor activation, we examined whether sst2 is phosphorylated in neuroendocrine tumors. The sst2 receptor phosphorylation was evaluated by IHC and Western blot analysis with the new Ra-1124 antibody specific for the sst2 receptor phosphorylated at Ser341/343 in receptor-positive neuroendocrine tumors obtained from 10 octreotide-treated and 7 octreotide-naïve patients. The specificity, time course, and subcellular localization of sst2 receptor phosphorylation were examined in human embryo kinase-sst2 cell cultures by immunofluorescence and confocal microscopy. All seven octreotide-naïve tumors displayed exclusively nonphosphorylated cell surface sst2 expression. In contrast, 9 of the 10 octreotide-treated tumors contained phosphorylated sst2 that was predominantly internalized. Western blot analysis confirmed the IHC data. Octreotide treatment of human embryo kinase-sst2 cells in culture demonstrated that phosphorylated sst2 was localized at the plasma membrane after 10 seconds of stimulation and was subsequently internalized into endocytic vesicles. These data show, for the first time to our knowledge, that phosphorylated sst2 is present in most gastrointestinal neuroendocrine tumors from patients treated with octreotide but that a striking variability exists in the subcellular distribution of phosphorylated receptors among such tumors.

Increased uptake of 111In-octreotide in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by an uncontrolled accumulation and activation of lung fibroblasts. A modulation of fibroblast activation has been observed in various systems with octreotide, a synthetic somatostatin analog with strong affinity for the somatostatin receptor subtype 2 (sst2). One aim of our study was to evaluate the expression of somatostatin receptors in the lungs of patients with IPF. A second aim was to evaluate the relationship between 111In-octreotide uptake and the effect of pulmonary fibrosis as assessed by lung function tests and parameters and by radiologic findings. METHODS: We investigated 11 patients with IPF, 6 patients with pulmonary fibrosis associated with systemic sclerosis (SSc), and 19 patients with disease not of the lung (control patients). The expression of somatostatin receptors was evaluated in vivo using 111In-octreotide scintigraphy. We evaluated the relationship between 111In-octreotide uptake and the activity of pulmonary fibrosis as assessed by lung function tests, bronchoalveolar lavage (BAL) cellularity, and high-resolution CT (HRCT) of the chest. Planar images and thoracic SPECT (24 h) were performed after injection of 222 MBq of 111In-octreotide. Lung uptake was quantified using the lung-to-background ratio (L/B). In addition, the expression of sst2 was evaluated in vitro, in frozen lung-tissue samples using autoradiography, and in human cultures of lung fibroblasts using a ligand-binding assay. RESULTS: Compared with lung uptake in control patients (median L/B, 1.25; range, 1.14-1.49), lung uptake was increased in all 11 IPF patients (median L/B, 2.63; range, 1.59-3.13; P < 0.001) and in 4 of 6 SSc patients (median L/B, 1.68; range, 1.42-2.16). The L/B was lower in SSc patients than in IPF patients (P = 0.011). Increased uptake correlated with the alteration of lung function (carbon monoxide diffusing capacity [rho = -0.655; P = 0.038], diffusing capacity for carbon monoxide and alveolar volume ratio [rho = -0.627; P = 0.047], vital capacity [rho = -0.609; P = 0.054], and total lung capacity [rho = -0.598; P = 0.058]) and with the intensity of alveolitis (total BAL cellularity [rho = 0.756; P = 0.045], neutrophil counts [rho = 0.738; P = 0.05]), and HRCT fibrosis score (rho = 0.673; P = 0.007). Autoradiography suggested that vascular structures were a prominent binding site. Lung fibroblasts expressed somatostatin receptors in vitro as measured by binding assay. CONCLUSION: Our preliminary results identified an increased expression of sst2 in (mainly idiopathic) pulmonary fibrosis. Lung uptake correlates with the alteration of lung function and with the intensity of alveolitis.

Ectopic growth hormone-releasing hormone secretion by a metastatic bronchial carcinoid tumor: a case with a non hypophysial intracranial tumor that shrank during long acting octreotide treatment

Ectopic acromegaly represents less than 1% of the reported cases of acromegaly. Although clinical improvement is common after treatment with somatostatin (SMS) analogs, the biochemical response and tumor size of the growth hormone-releasing hormone (GHRH)-producing tumor and its metastases are less predictable. Subject A 36-year-old male was referred because of a 3-year history of acromegaly related symptoms. He had undergone lung surgery in 1987 for a "benign" carcinoid tumor. Endocrine evaluation confirmed acromegaly Plasma IGF-1: 984 ng/ml (63-380), GH: 49.8 ng/ml (<5). MRI showed a large mass in the left cerebellopontine angle and diffuse pituitary hyperplasia. Pulmonary, liver and bone metastases were shown by chest and abdominal CT scans. Ectopic GHRH secretion was suspected. Methods Measurement of circulating GHRH levels by fluorescence immunoassay levels and immunohistochemical study of the primary lung tumor and metastatic tissue with anti-GHRH and anti-somatostatin receptor type 2 (sst2A) antibodies. Results Basal plasma GHRH: 4654 pg/ml (<100). Pathological study of liver and bone biopsy material and lung tissue removed 19 years earlier was consistent with an atypical carcinoid producing GHRH and exhibiting sst2A receptor expression. Treatment with octreotide LAR 20-40 mg q. month resulted in normalization of plasma IGF-1 levels. Circulating GHRH levels decreased dramatically. The size of the left prepontine cistern mass, with SMS receptors shown by a radiolabeled pentetreotide scan, decreased by 80% after 18 months of therapy. Total regression of pituitary enlargement was also observed. No changes were observed in lung and liver metastases. After 24 months of therapy the patient is asymptomatic and living a full and active life.

Preventive effects of octreotide (SMS 201-995) on diabetic ketogenesis during insulin withdrawal

1. Exogenous somatostatin inhibits glucagon secretion and prevents ketoacidosis in diabetic patients, but has the therapeutic disadvantage of requiring continuous intravenous infusion to exhibit these effects. 2. Consequently, we examined the effect of subcutaneous administration of the long-acting somatostatin analogue octreotide (SMS 201-995) on early ketogenesis in diabetic ketoacidosis. On two separate occasions insulin was withdrawn over a period of 9 h from seven type I diabetic patients. On the second occasion the patients were given 50 micrograms octreotide s.c. before the insulin withdrawal and every 3 h during insulin withdrawal. 3. Differences in integrated free fatty acid responses (4706 +/- 1227 mumol l-1 h vs 3026 +/- 835 mumol l-1 h, AUC, P = NS) were not significant, but the peak increments of acetoacetate (1413 +/- 354 mumol l-1 vs 612 +/- 176 mumol l-1, P less than 0.05), beta-hydroxybutyrate (2180 +/- 475 mumol l-1 vs 922 +/- 246 mumol l-1, P less than 0.01) and the decrements in plasma bicarbonate (-8 +/- 1 mumol l-1 vs -4 +/- 1 mumol l-1, P less than 0.05) and pH (-0.07 +/- 0.01 vs -0.03 +/- 0.01, P less than 0.05) were significantly less with octreotide. 4. At the same time peak increments of glucagon were lower with octreotide treatment (329 +/- 206 pg ml-1 vs 39 +/- 30 pg ml-1, P less than 0.05). 5. We conclude that, despite accelerated lipolysis and provision of substrate for ketogenesis during insulin withdrawal, this somatostatin analogue significantly reduces ketogenesis resulting from insulin deprivation, probably secondary to decreasing glucagon secretion. This drug may be useful in short term prophylactic treatment of diabetic patients during periods of increased risk for ketoacidosis.

Ring size in octreotide amide modulates differently agonist versus antagonist binding affinity and selectivity

H-DPhe (2)-c[Cys (3)-Phe (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Thr (15)-NH2 (1) (a somatostatin agonist, SRIF numbering) and H-Cpa (2)-c[DCys (3)-Tyr (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Nal (15)-NH2 (4) (a somatostatin antagonist) are based on the structure of octreotide that binds to three somatostatin receptor subtypes (sst 2/3/5) with significant binding affinity. Analogues of 1 and 4 were synthesized with norcysteine (Ncy), homocysteine (Hcy), or D-homocysteine (DHcy) at positions 3 and/or 14. Introducing Ncy at positions 3 and 14 constrained the backbone flexibility, resulting in loss of binding affinity at all sst s. The introduction of Hcy at positions 3 and 14 improved selectivity for sst 2 as a result of significant loss of binding affinity at the other sst s. Substitution by DHcy at position 3 in the antagonist scaffold (5), on the other hand, resulted in a significant loss of binding affinity at sst 2 and sst 3 as compared to the different affinities of the parent compound (4). The 3D NMR structures of the analogues in dimethylsulfoxide are consistent with the observed binding affinities.

Octreotide treatment of patients with hepatocellular carcinoma--a retrospective single centre controlled study

BACKGROUND: Studies of treatment with octreotide of patients with hepatocellular carcinoma (HCC) gave conflicting results. We analyzed retrospectively the survival of our patients treated with octreotide monotherapy and compared it to stage-matched patients who received either TACE, multimodal therapy or palliative care. METHODS: 95 patients seen at the department of Gastroenterology and Hepatology, Medical University of Vienna with HCC in BCLC stage A or B, who received either TACE, multimodal therapy, long-acting octreotide or palliative care were reviewed for this retrospective study. RESULTS: Survival rates of patients with BCLC stage B and any "active" treatment (long-acting octreotide, TACE or multimodal therapy) were significantly higher (22.4, 22.0, 35.5 months) compared to patients who received palliative care only (2.9 months). Survival rates of patients with BCLC stage A and "active" treatment (31.4, 37.3, 40.2 months) compared to patients who received only palliative care (15.1 months) did not show statistically significant differences. Octreotide monotherapy showed a similar outcome compared to patients who received TACE or multimodal therapy. CONCLUSION: Survival under octreotide treatment was not different compared to TACE or multimodal therapy and might be a therapeutic option for patients with HCC.

Radiolabelled somatostatin analogue scintigraphy in oncology

Somatostatin analogue scintigraphy represents a new technique employing radiolabelled peptides to detect specific receptor-bearing lesions. 111Indium diethylenetriaminopentaacetic acid-linked octreotide (111In-DTPA-D-Phe1 octreotide), also known as [111In]pentetreotide or OctreoScan, is now established in the management of patients with neuroendocrine gastrointestinal tract and pancreatic tumours, and has proved effective in localizing disease sites in lung, breast and medullary thyroid carcinomas, lymphomas, meningiomas and others. In these conditions (a) the imaging of all disease sites at a single sitting (in a proportion of patients) thereby making further investigations unnecessary, (b) the localization of otherwise unexpected metastatic deposits and (c) the detection of residual disease not found by other means suggest that [111In]pentetreotide may be a useful adjunct in the diagnostic evaluation of patients with somatostatin receptor-bearing tumours.

A metastatic neuroendocrine anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome : assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with 111In-pentetreotide

Extrapulmonary small cell and small cell neuroendocrine tumors of unknown primary site are, in general, aggressive neoplasms with a short median survival. Like small cell lung cancer (SCLC), they often are responsive to chemotherapy and radiotherapy. Small cell lung cancer and well differentiated neuroendocrine carcinomas of the gastrointestinal tract and pancreas tend to express somatostatin receptors. These tumors may be localized in patients by scintigraphic imaging using radiolabeled somatostatin analogues. A patient with an anaplastic neuroendocrine small cell tumor arising on a background of multiple endocrine neoplasia type 1 syndrome is reported. The patient had a known large pancreatic gastrinoma and previously treated parathyroid adenopathy. At presentation, there was small cell cancer throughout the liver and skeleton. Imaging with a radiolabeled somatostatin analogue, 111In- pentetreotide (Mallinckrodt Medical B. V., Petten, Holland), revealed all sites of disease detected by routine biochemical and radiologic methods. After six cycles of chemotherapy with doxorubicin, cyclophosphamide, and etoposide, there was almost complete clearance of the metastatic disease. 111In-pentetreotide scintigraphy revealed uptake consistent with small areas of residual disease in the liver, the abdomen (in mesenteric lymph nodes), and posterior thorax (in a rib). The primary gastrinoma present before the onset of the anaplastic small cell cancer showed no evidence of response to the treatment. The patient remained well for 1 year and then relapsed with brain, lung, liver, and skeletal metastases. Despite an initial response to salvage radiotherapy and chemotherapy with carboplatin and dacarbazine, the patient died 6 months later.