SSTR2 Expression Research Articles

D Atherosclerotic inflammation imaging using 68ga-dotatate pet vs. 18f-fdg pet: a prospective clinical sudy with molecular and histological validation

BackgroundInflammation drives atherosclerotic plaque rupture underlying most clinical events. While inflammation can be measured using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), 18F-FDG lacks cell-specificity and is unreliable for coronary imaging...

Pituicytoma-An outlook on possible targeted therapies.

Pituicytoma is a rare neoplasm of the sella region. Tumor resection is the primary treatment option, but remains subtotal due to excessive bleeding in many cases. The search for alternative or additional treatment regimens is necessary. We aimed to determine the receptor expression of pituicytoma to find alternatives or supplements to surgical therapy in the use of targeted therapies. Pituicytoma samples were collected from three institutions between 2006 and 2015 and were stained for vascular endothelial growth factors (VEGF), thyroid transcription factor (TTF1), and somatostatin receptors (SSTR 2/3/5). The stains were classified from 0=no staining to +++=strong staining. A complementary retrospective analysis of the patient charts regarding sex, age, and primary symptoms, pituitary function, and perioperative complications was performed. Ten samples were analyzed; mean patient age was 57.8years SD 16.3years. Seven samples were acquired from male patients (one relapse) and three from female. All tumors stained strongly positive (+++) for VEGF-R. Six samples stained positive for TTF1. As for somatostatin receptors, three samples were slightly positive for SSTR 2; seven were negative. SSTR 3 was + in one, three were ++, three were +++, and three were 0. SSTR 5 stained +++ in 1, ++ in 5, + in 1, and 0 in three patients. Pituicytomas were generally positive for VEGFR and showed regular expression of SSTR 3 and 5 indicating a possible treatment option through targeted therapies in cases where resection remains insufficient. Further research is necessary as to whether tumor growth can be inhibited using these pathways.

68Ga-DOTATATE PET/CT to predict response to peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumours (NETs).

4093 Background: PRRT represents a step change in NET management, significantly improving survival. However, objective response to PRRT, approximately 20%, is poor. There are no predictive biomarkers of response. Uptake on 68Ga-DOTATATE PET/CT imaging is used to assess patient suitability for PRRT, highlighting the presence of somatostatin receptors (SSTR) to which PRRT selectively binds. We hypothesise that the density of SSTRs, as defined by a minimum SUV uptake, predicts for response to PRRT. Methods: 54 patients underwent PRRT. Modified PERCIST assessment was performed: up to 2 target lesions per organ were identified and volume of interest drawn. Maximum 5 targets were counted. Average SUV (SUVave) was calculated by dividing sum of SUVmax of target lesions by number of lesions. Response was determined by RECIST 1.1. Ki67 and SSTR2 expression were assessed on tumour samples and compared with SUVave. Results: Response to PRRT: partial response (PR) 26%, stable disease (SD) 40% progressive disease (PD) 12%. Response to PRRT predicted progression free survival (PFS) with patients experiencing PR having a PFS 2.5x that of those with SD, and almost 20x as long as PD. Using ROC curve analysis, SUVave of 21.6 predicted for tumour response with high sensitivity (0.74) and specificity (1.0), p = 0.15, 95% CI 0.71-3.96. No association between baseline SUVave and SSTR2 or Ki-67 was observed. SUVave > 21.6 was an independent predictor of clinical outcome. Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study.

Targeted radiopeptide therapy Re188-P2045 to treat neuroendocrine lung cancer.

e20016 Background: : Despite the recent success of checkpoint inhibitors, there continues to be a significant medical need for lung cancer therapies that can be directed to the patients most likely to respond. Somatostatin receptor subtype 2 (SSTR2) is the most widely up-regulated subtype in both small and non-small cell lung cancers and is also expressed in tumoral (but not mature) blood vessels. Peptide targeted radiotherapy has advantages over traditional targeted therapies in that targeted tumor cells as well as surrounding cancer cells and supporting stroma are selectively killed. This study was conducted to determine the ability of Rhenium Re 188 P2045, a radiolabeled somatostatin analog specific for SSTR2 to both image (to select the most appropriate patients) and treat lung cancer patients who over-express somatostatin receptors. Methods: In an open label, single arm study, refractory lung cancer patients to standard of care therapy were identified by image analysis using Rhenium Re 188 P2045, a radiolabeled somatostatin analog. 25 Patients received the imaging dose of 10uCi of Re188 and 265ng of peptide by intravenous injection. Three patients were selected based on high SSTR expression levels to receive 30uCi of Re188 P2045 as a therapeutic dose 14 days after imaging. Patients were followed for 8 weeks post treatment. Results: The imaging study revealed a high density of expression of the somatostatin receptor in the lungs of patients. Patients in the imaging and therapeutic treatment groups reported no adverse advents or signs of toxicity. The image analysis using Re188 P2045 was compared to CT images and demonstrated accurate detection of lung tumor lesions. The images obtained using Re188 P2045 were of sufficiently high quality to enable identification of receptor expression at the tumor site as shown in Figures 1&2. Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach and this highly targeted patient therapy may significantly improve treatment of tumors that over express somatostatin receptor.

SSTR-Mediated Imaging in Breast Cancer: Is There a Role for Radiolabeled Somatostatin Receptor Antagonists?

Recent studies have shown enhanced tumor targeting by novel somatostatin receptor (SSTR) antagonists compared with clinically widely used agonists. However, these results have been obtained mostly in neuroendocrine tumors, and only limited data are available for cancer types with lower SSTR expression, including breast cancer (BC). To date, two studies have reported higher binding of the antagonist than the agonist in BC, but in both studies only a limited number of cases were evaluated. In this preclinical study, we further investigated whether the application of an SSTR antagonist can improve SSTR-mediated BC imaging in a large panel of BC specimens. We also generated an in vivo BC mouse model and performed SPECT/MRI and biodistribution studies. Methods: Binding of 111In-DOTA-Tyr3-octreotate (SSTR agonist) and 111In-DOTA-JR11 (SSTR antagonist) to 40 human BC specimens was compared using in vitro autoradiography. SSTR2 immunostaining was performed to confirm SSTR2 expression of the tumor cells. Furthermore, binding of the radiolabeled SSTR agonist and antagonist was analyzed in tissue material from 6 patient-derived xenografts. One patient-derived xenograft, the estrogen receptor-positive model T126, was chosen to generate in vivo mouse models containing orthotopic breast tumors for in vivo SPECT/MRI and biodistribution studies after injection with 177Lu-DOTA-Tyr3-octreotate or 177Lu-DOTA-JR11. Results:111In-DOTA-JR11 binding to human BC tissue was significantly higher than 111In-DOTA-Tyr3-octreotate binding (P < 0.001). The median ratio of antagonist binding versus agonist binding was 3.39 (interquartile range, 2-5). SSTR2 immunostaining confirmed SSTR2 expression on the tumor cells. SPECT/MRI of the mouse model found better tumor visualization with the antagonist. This result was in line with the significantly higher tumor uptake of the radiolabeled antagonist than of the agonist as measured in biodistribution studies 285 min after radiotracer injection (percentage injected dose per gram of tissue: 1.92 ± 0.43 vs. 0.90 ± 0.17; P = 0.002). Conclusion: SSTR antagonists are promising candidates for BC imaging.

Clinical Importance of Somatostatin Receptor 2 (SSTR2) and Somatostatin Receptor 5 (SSTR5) Expression in Thyrotropin-Producing Pituitary Adenoma (TSHoma).

BackgroundThyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism. Somatostatin analogs have proved to be effective for inhibiting pituitary hormones secretion, working via interactions with somatostatin receptors (SSTRs). Moreover, antiproliferative activity of somatostatin analog is now demonstrated in several studies. In the present study, we determined the relative predominance of SSTR2 and SSTR5 subtypes among the different types of adenomas, especially TSHoma, and investigated the relationship between efficacy of short-term octreotide (OCT) treatment and SSTR expression.Material/MethodsSerum hormone determinations and histological findings in resected tissue resulted in 5 diagnoses: 16 TSHomas, 8 acromegaly, 3 prolactinomas, 3 corticotropinomas, 4 clinically nonfunctioning adenomas (NFPAs), and 4 normal pituitary specimens. IHC was performed on formalin-fixed and paraffin-embedded tissue in tissue microarrays.ResultsIHC of SSTR subtypes in the different cohorts showed SSTR2 staining intensity scores higher than SSTR5 in TSHoma, acromegaly and prolactinoma, whereas the expression of SSTR5 was stronger than SSTR2 in corticotropinoma and NFPA. SSTR2 and SSTR5 expressions were significantly higher in TSHoma than in other pituitary adenomas. OCT treatment for a median of 8.4 days (range: 3–18 days) and with a total median dose of 1.9 mg (range: 0.9–4.2 mg) showed a significant decrease of thyroid hormone levels (TSH [μIU/ml] in all patients. Patients with low SSTR5 expression presented a significantly higher TSH suppression rate (P values <0.05).ConclusionsThe present data confirm that somatostatin analogs should be considered as a medical alternative to surgical treatment, especially in patients with TSHoma, and short-term response to OCT therapy may be related to the expression of SSTR5.

Short-term Preoperative Octreotide for Thyrotropin-secreting Pituitary Adenoma.

Background:Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism. Somatostatin (SST) analogs work by interacting with somatostatin receptors (SSTRs). This study aimed to evaluate short-term preoperative octreotide (OCT) use in TSHoma patients and to investigate SSTR2 and SSTR5 expression and observe structural changes in tumor tissue.Methods:We reviewed records and samples from eight TSHoma patients treated between July 2012 and July 2015. We tested immunohistochemically for SSTR2/5 expression and examined TSHoma cells for morphological changes. Signed rank sum test was used to compare the efficacy of short-term preoperative OCT treatment.Results:OCT treatment (median time: 7.9 days, range: 3–16 days; median total dose: 1.8 mg, range: 0.9–4.2 mg) led to significant decrease in all patients’ thyroid hormone levels (FT3 [nmol/L]: 8.33 [7.02, 12.29] to 4.67 [3.52, 5.37] [P = 0.008]; FT4 [pmol/L]: 25.36 [21.34, 28.99] to 16.66 [14.88, 21.49] [P = 0.016]; and TSH [μU/ml]: 5.80 [4.37, 6.78] to 0.57 [0.19, 1.24] [P = 0.008]). All the eight tumor specimens expressed high SSTR2 protein levels; 5/8 expressed high SSTR5, but 3/8 that expressed low SSTR5 presented a significantly higher TSH suppression rate (P = 0.036). Electron microscopy showed subcellular level impairments, including clumped nuclear chromatin and reduced cytoplasmic volume. Golgi complexes were observed in the OCT-treated TSHoma specimens.Conclusions:OCT can control hormone levels and damage the ultrastructure of tumor cells and organelles. Short-term response to OCT may be related to SSTR5 expression. Preoperative SST analog treatment for TSHoma could be considered as a combination therapy.

Upregulated Expression of SSTR3 is Involved in Neuronal Apoptosis After Intracerebral Hemorrhage in Adult Rats.

Somatostatin which is a multifunctional growth hormone inhibitory neuropeptide shows diverse physiological effects, such as neurotransmission, cell growth, apoptosis, and endocrine signaling as well as exerts inhibitory effects on hormonal products and other secretory proteins. SSTR3 is a member of superfamily of somatostatin receptors (SSTR), which are G-protein-coupled plasma membrane receptors. Previous studies proved that SSTR3 regulates antiproliferative signaling and apoptosis in several cells. Here, we explored a potential role of SSTR3 in the regulation of neuronal apoptosis in the course of intracerebral hemorrhage (ICH). An ICH rat model was established and assessed by behavioral tests. We found SSTR3 was significantly upregulated surrounding the hematoma after ICH by Western blot and immunohistochemistry. Double immunofluorescence-manifested SSTR3 was strikingly increased in neurons, not astrocytes or microglia. Moreover, increasing SSTR3 level was found to be accompanied by the upregulation of p53, Bax, and active caspase-3 in vivo and in vitro studies. Furthermore, we detected that neuronal apoptosis marker active caspase-3 was co-localized with SSTR3 suggesting its potential role in neuronal apoptosis. In addition, in vitro study, revealed that SSTR3 knockdown specifically resulted in reducing neuronal apoptosis in PC12 cells, which further indicated that SSTR3 might exert its pro-apoptotic function on neuronal apoptosis. All our findings suggested that upregulated SSTR3 may be involved in neuronal apoptosis after ICH.

Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target

Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHL-HBs or those in frail patients are challenging problems. Therapies targeting oncologic and vascular endothelial growth factor (VEGF) pathways have failed to demonstrate tumor control. Our experience and previous reports on VHL-HB avidity to somatostatin analogues suggested somatostatin receptor (SSTR) expression in VHL-HBs, offering an alternative therapeutic strategy. We explored this possibility by demonstrating consistent histologic expression of SSTR1, 2a, 4, and 5 in VHL-HBs. We found that somatostatin analogue octreotide induces apoptosis in VHL-HB stromal cells in a dose-dependent fashion by BAX – caspase-3 pathway unrelated to canonical VHL pathway. When administered to a patient with unresectable symptomatic suprasellar hemangioblastoma, octreotide resulted in tumor volume reduction, symptom stabilization, and tumor cytopenia on repeat 68Ga-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy.

Somatostatin receptor expression indicates improved prognosis in gastroenteropancreatic neuroendocrine neoplasm, and octreotide long-acting release is effective and safe in Chinese patients with advanced gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is known to overexpress somatostatin receptors (SSTRs), most commonly SSTR2 and SSTR5. The expression of SSTRs on tumor cells forms the basis for somatostatin analog treatment of patients with NEN. The present study detected the expression of SSTR2 and SSTR5 in GEP-NEN and investigated the efficacy and safety of octreotide long-acting release (LAR) in the treatment of advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) in China. The present study reported that functionality of the pancreas, G1 and G2 grading, NET classification and Tumor-Node-Metastasis stages I and II were associated with higher SSTR2 positive expression. Similarly, SSTR5 was increased in pancreatic and well-differentiated tumors. SSTR2 and SSTR5 positive expression predicted improved survival in GEP-NEN patients. The median overall survival of patients treated with octreotide LAR was not reached. The median time to progression was 20.2 months, with the objective response rate being 5.6% and the stable disease rate being 79.6%. A total of 25.9% of the patients experienced adverse drug reactions. In conclusion, the present study demonstrated that SSTR2 and SSTR5 are heterogeneously expressed in GEP-NEN. Both markers may serve as potential prognostic factors. Octreotide LAR is effective and safe in the treatment of Chinese patients with advanced GEP-NET.

Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1

Background177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake.The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu-octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice.ResultsPriming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A.ConclusionsPriming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models.

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.

Expression of Somatostatin Receptor 2 in Somatotropinoma Correlated with the Short-Term Efficacy of Somatostatin Analogues.

The expression of somatostatin receptor subtypes (SSTRs) in pituitary growth hormone- (GH-) secreting adenomas may predict the response to somatostatin analogues (SSA). Our aim was to evaluate the value of the immunohistochemical (IHC) scores of 2 subtypes, SSTR2 and SSTR5, in predicting the short-term efficacy of SSA therapy in patients with active acromegaly. Ninety-three newly diagnosed acromegalic patients were included in our study. These patients were categorized into either a SSA-pretreated group (SA, n = 63) or a direct-surgery group (DS, n = 30), depending on whether or not presurgical SSA treatment was received. IHC analysis, using a 12-grade scoring system, with rabbit monoclonal antibodies against SSTR2 and SSTR5, was performed on all adenoma tissues. The reduction of GH, IGF-1, and tumor size after treatment with SSA for 3 months was measured. Compared with that in the DS group, SSTR2 expression was lower in the SA group. Additionally, in the SA group, SSTR2 expression was positively correlated with the reduction of IGF-1 and tumor volume. However, there was no correlation between the SSTR5 score and the efficacy of SSA. In conclusion, the protein expression of SSTR2, but not of SSTR5, is a valuable indicator in predicting biochemical and tumor size response to short-term SSA treatment in acromegalic patients.

Treatment of Gastroenteropancreatic Neuroendocrine Tumors with 177Lu-DOTA-TATE: Experience of the Portuguese Institute of Oncology in Porto

The purpose of this article is to report the experience of the Portuguese Institute of Oncology - Porto in the treatment of gastroenteropancreatic neuroendocrine tumors with 177Lu-DOTA-TATE, regarding the safety and efficacy of this treatment modality. A retrospective analysis of clinical reports of patients with gastroenteropancreatic neuroendocrine tumors undergoing treatment with 177Lu-DOTA-TATE between April 2011 and November 2013 was performed. Thirty six cases were reviewed and 30 completed all 3 cycles of 177Lu-DOTA-TATE (83.3%). In these patients it was registered: acute side effects in 8.9% of cycles; grade 3 CTCAE liver toxicity in 13.3% of patients (all with previous abnormal liver function); absence of significant renal or hematologic toxicity; symptomatic improvement in 71.4% of patients; median overall time to progression of 25.6 months; median overall survival from diagnosis of 121.7 months. Patients with higher expression of somatostatin receptors had longer progression-free survival and overall survival times (p < 0.05). Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE is an effective, safe and well-tolerated treatment, as evidenced in our study by the following findings: symptomatic improvement in most patients and increased time to disease progression and survival (especially in those with higher sstr expression), with acute and significant subacute/chronic side effects reported only in a minority of cases. Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE is a promising treatment for patients with gastroenteropancreatic neuroendocrine tumors, with demonstrated benefits in terms of safety and efficacy.

Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours.

Background:Neuroendocrine tumours (NET) overexpress somatostatin receptors (SSTR) that can be targeted for therapy. Somatostatin receptor expression is routinely measured by molecular imaging but the resolution is insufficient to define heterogeneity. We hypothesised that SSTR expression could be measured on circulating tumour cells (CTCs) and used to investigate heterogeneity of expression and track changes during therapy.Methods:MCF-7 cells were transfected with SSTR2 or 5 and spiked into donor blood for analysis by CellSearch. Optimum anti-SSTR antibody concentration and exposure time were determined, and flow cytometry was used to evaluate assay sensitivity. For clinical evaluation, blood was analysed by CellSearch, and SSTR2/5 immunohistochemistry was performed on matched tissue samples.Results:Flow cytometry confirmed CellSearch was sensitive and that detection of SSTR was unaffected by the presence of somatostatin analogue up to a concentration of 100 ng ml−l. Thirty-one NET patients were recruited: grade; G1 (29%), G2 (45%), G3 (13%), primary site; midgut (58%), pancreatic (39%). Overall, 87% had SSTR-positive tumours according to somatostatin receptor scintigraphy or 68-Ga-DOTATE PET/CT. Circulating tumour cells were detected in 21 out of 31 patients (68%), of which 33% had evidence of heterogeneous expression of either SSTR2 (n=5) or SSTR5 (n=2).Conclusions:Somatostatin receptors 2 and 5 are detectable on CTCs from NET patients and may be a useful biomarker for evaluating SSTR-targeted therapies and this is being prospectively evaluated in the Phase IV CALMNET trial (NCT02075606).

"Silent" thyrotropin (TSH) expression in acromegaly and clinically non-functioning pituitary adenomas.

The pituitary adenomas secreting thyrotropin (TSH) are considered the rarest type of hormonally active pituitary tumour. In spite of that, many cases are described in the literature. On the other hand, the observations of the co-expression of TSH with other pituitary hormones (mostly with growth hormone [GH]) and "silent" expression of TSH in clinically non-functioning pituitary adenomas (CNFPA) are rather scarce. Among 93 examined pituitary adenomas, 22 of them were diagnosed as active acromegaly and 71 as clinically non-functioning pituitary adenomas (CNFPA). All of them were immunostained with antibodies against pituitary hormones, including the anti-TSH antibody. TSH-immunopositive adenomas are immunostained also to detect somatostatin receptor subtypes (SSTR 1-5). TSH immunopositivity was found in 4.2% of CNFPA (3/71 tumours) and in 13.6% (3/22) cases of somatotropinomas manifesting as active acromegaly. All of the examined TSH-immunopositive adenomas expressed SSTR subtypes except SSTR4. The symptoms of hyperthyroidism were not observed in any of the acromegalic patients co-expressing TSH with GH. Our data confirm the relative rarity of TSH expression or co-expression of TSH in pituitary tumours. In most cases TSH is co-expressed with GH in patients with acromegaly and is not accompanied by hyperthyroidism. The "silent" expression of TSH may occur also, although rarely in CNFPA. The strong expression of SSTR in TSH-immunopositive CNFPA ("silent thyrotropinoma") indicates the possibility of the treatment of these tumours with somatostatin analogues. (Endokrynol Pol 2016; 67 (5): 515-518).

Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors.

Somatostatin receptors (SSTRs), products of gene superfamily SSTR1-5, are commonly expressed in neuroendocrine tumors (NETs). Somatostatin analogs (SSAs) bind to SSTRs and are used as therapeutic agents in patients with advanced NETs. We hypothesized that tumor SSTR expression status would be associated with clinical outcomes in NET. Expression of the 5 SSTRs was evaluated by immunohistochemistry, using tissue microarrays comprising 173 primary NETs, 24 matched metastases, and 22 metastatic NETs from 195 patients. Cox proportional hazards regression analysis was used to assess the association of SSTR expression status (high vs low) with clinical outcomes, adjusting for potential confounders. High expression of SSTR2 was associated with longer overall survival (OS) in the cohort overall (multivariate hazard ratio, 0.42; 95% confidence interval, 0.21-0.84; P = 0.013). In a subgroup of patients with metastatic small intestine NET treated with SSAs and evaluable for progression, SSTR2 expression was associated with both longer progression-free survival (PFS) and OS. No associations with PFS or OS were observed with expression of other SSTRs. Our study demonstrated that expression of SSTR2, but not other SSTRs, is associated with longer OS. In patients treated with SSAs, expression of SSTR2 is associated with longer PFS survival.

Связь экспрессии рецепторов соматостатина и лечения октреотидом гормонально-неактивных аденом гипофиза

Introduction. Neurosurgery, which is the treatment of choice of non-functioning pituitary adenomas (NFPA), is often incurative. It usually leaves tumour residue that can regrow in the future. There is no established management for the postoperative period of NFPA, however, some data suggest that somatostatin analogues (SSA) can be effective, especially regarding somatostatin receptors (SSTR) presence in NFPA. SSTR scintigraphy and immunohistochemistry are used to assess SSTR expression in NFPA. Aim: to analyse the outcome of SSA treatment in NFPA and to correlate it with the results of SSTR scintigraphy and immunohistochemistry. Material and methods. Twenty six NFPA patients after incomplete neurosurgery with positive results of scintigraphy and immunohistochemistry were included in the study. All patients were treated with octreotide LAR 20mg intramuscular every 4 weeks. The tumour size was evaluated in control magnetic resonance imaging after 2 years of SSA therapy. Results. Tumour size remained stable in the majority of NFPA. Adenoma size reduction was observed in 2 patients with strong expression of SSTR2 in both scintigraphy and immunohistochemistry. Increase of tumour size was noticed in 4 patients whose tumours were characterised not only by the presence of SSTR2 and SSTR5 but also by strong expression of SSTR1 in immunohistochemistry. Conclusions. Only strong expression of SSTR2 can predict patients response to SSA treatment in NFPA. However, strong expression of SSTR1 observed in some of NFPA gives hope that introduction of new broad spectrum SSA like pasireotide would be more effective, especially in tumour shrinkage.

The corellation between somatostatin receptors expression and octreotide treatment in non-functioning pituitary adenomas

Introduction. Neurosurgery, which is the treatment of choice of non-functioning pituitary adenomas (NFPA), is often incurative. It usually leaves tumour residue that can regrow in the future. There is no established management for the postoperative period of NFPA, however, some data suggest that somatostatin analogues (SSA) can be effective, especially regarding somatostatin receptors (SSTR) presence in NFPA. SSTR scintigraphy and immunohistochemistry are used to assess SSTR expression in NFPA.Aim: to analyse the outcome of SSA treatment in NFPA and to correlate it with the results of SSTR scintigraphy and immunohistochemistry.Material and methods. Twenty six NFPA patients after incomplete neurosurgery with positive results of scintigraphy and immunohistochemistry were included in the study. All patients were treated with octreotide LAR 20mg intramuscular every 4 weeks. The tumour size was evaluated in control magnetic resonance imaging after 2 years of SSA therapy.Results. Tumour size remained stable in the majority of NFPA. Adenoma size reduction was observed in 2 patients with strong expression of SSTR2 in both scintigraphy and immunohistochemistry. Increase of tumour size was noticed in 4 patients whose tumours were characterised not only by the presence of SSTR2 and SSTR5 but also by strong expression of SSTR1 in immunohistochemistry.Conclusions. Only strong expression of SSTR2 can predict patients response to SSA treatment in NFPA. However, strong expression of SSTR1 observed in some of NFPA gives hope that introduction of new broad spectrum SSA like pasireotide would be more effective, especially in tumour shrinkage.

P11.06 Expression of somatostatin receptors in meningiomas: Correlation of molecular PET-imaging and in-situ expression

AbstractSomatostatin receptors (SSTR) are expressed in the majority of meningiomas and represent the basis for somatostatin-analogue positron emission tomography (PET) such as 68Ga-DOTATOC. The high expression of SSTR in meningioma cells not only serves as a target for diagnosis, but also enables the development of specifically targeted therapy approaches. Therefore, the aim of this retrospective study was to confirm the correlation between 68Ga-DOTATOC-PET/CT and the expression intensity of the SSTR in surgically removed meningioma tissue evaluated by immunohistochemical analysis.Material and Methods:We identified 18 surgical specimens generated from histologically confirmed meningioma patients who underwent preoperative 68Ga-DOTATOC-PET/CT. Semi-quantitative assessment of tissue receptor expression of 6 different SSTR subtypes (SSTR1,2A,2B,3,4,5) was performed using the immunoreactive-score (IRS). 68Ga-DOTATOC-PET/CT scans were quantified, the maximal standard uptake value (SUVmax) was measured and the tumor-to-pituitary (SUVmax-T/P) as well as the tumor-to background-uptake ratios (SUVmax-T/B) were calculated.Results:All 18 tumor specimens were SSTR positive on immunohistochemistry. Tumor-specific 68Ga-DOTATOC uptake was detected in all patients with a median SUVmax of 12.3 (range 1.3–44.9). The IRS for SSTR2A, SSTR2B and SSTR5 correlated highly significant with the SUVmax on PET (p<0.001; p=0.001; p=0.012). SUVmax-T/P and SUVmax-T/B were correlated with SSTR2A reaching highly statistical significance (p=0.002; p<0.001).Conclusion:The highly significant correlation between SSTR2A and SUVmax as well as SUVmax-T/P and SUVmax-T/B on 68Ga-DOTATOC-PET/CT scans proofs somatostatin analogues as a valuable tool in the diagnosis of meningiomas. Furthermore, the significant correlation between SSTR imaging using 68Ga-DOTATOC-PET/CT with immunohistochemically analyzed SSTR expression provides SSTR as a potential target for meningioma specific therapy in patients not amenable to standard treatment modalities.