Молекулярная визуализация нейроэндокринных опухолей при соматостатин-рецепторной сцинтиграфии (ОФЭКТ/КТ) c 99mTc-тектротидом

1993). The initial management of NET comprises surgical excision of the primary tumour (aimed at reducing as much as possible of the tumour mass); additionally, in patients who are not cured by surgery alone, medical therapy is used for the control of symptoms and humoral syndromes with agents such as somatostatin analogues and/or a-interferon. Specific therapy with radiopharmaceuticals using radio-labelled substances such as meta-iodobenzylguanidine (MIBG) or somatostatin analogues appears promising for some tumours which show diagnostic uptake, and is the first-line systemic management for sensitive cases. Hepatic artery ligation and/or chemoembolization is also used in patients with excessive hepatic tumour load and uncontrollable symptoms. The control of tumour growth with chemotherapeutic agents is currently mainly reserved for patients with recurrent and/or progressive disease and where other therapeutic modalities have failed. Chemotherapy may be particularly helpful for selected cases of advanced NET, especially pancreatic or poorly differentiated NET. This review deals with the general role of chemotherapy in the management of malignant NET, its integration with other modes of therapy, and the specific protocols which have been used. Histological classification and differentiation of NET

Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1–5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000–2009 with keywords ‘somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary’ and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.

Introduction: Neuroendocrine tumors (NETs) are epithelial tumors that arise from neuroendocrine cells of the digestive system. Within the digestive system, the majority occur in small intestine (45%). Diagnosis is usually made accidentally during a routine workup or from the patient experiencing symptoms from the tumor. We report a difficult-to-diagnose unsuspected NET of the ileum in a young, otherwise healthy individual. Case Description/Methods: A 57-year-old female with a history of hypertension and hyperlipidemia presented to the emergency department with multiple episodes of dark stools one day prior to admission. A CT angiogram showed high density fluid in the small bowel with no active bleeding. Overnight, the patient had a near syncopal episode. A repeat CT angiogram showed active bleeding within the small intestine. However, on angiogram, no active bleeding was noted. The following day, an MR enterography showed thickening of the segment of the small intestine that had shown active bleeding on the repeat CT angiogram. During laparoscopy, the surgeon identified what felt to be a tumor in the distal ileum. Pathology revealed a well-differentiated neuroendocrine tumor (Figure 1). Discussion: NETs are the most common type of small bowel neoplasms. They are divided into duodenal NETs and distal NETs of the jejunum and ileum. Lymph node metastasis occurs in about 60% of cases of duodenal NET. Liver metastasis occurs in less than 10% of duodenal NET cases and about 20% of cases of distal NET of the jejunum and ileum. The stage of the disease has a large impact on prognosis. The 10-year survival rate is 95% for patients with localized NETs and 10% for those with distant metastasis. Distal NETs of the jejunum and ileum have a poorer prognosis because of their tendency to metastasize. The annual incidence of NETs has increased over the past five years to forty to fifty cases per million, largely due to better diagnostic tools. For duodenal NETs, upper gastrointestinal endoscopy with biopsy is the most sensitive diagnostic test. Several genetic markers are being evaluated as diagnostic tools. Treatment depends on the size of the NET. Small (≤ 1 cm) duodenal NETs can be resected endoscopically. Larger duodenal NETs (≥ 2 cm) or lymph node metastasis should be treated surgically. Systemic chemotherapy is not recommended for well-differentiated NETs. In conclusion, this case describes difficulties in diagnosing NETs of the ileum and highlights the need for improvements in diagnosis and management of NETs.Figure 1.: Ulcerated submucosal mass in distal small bowel measuring 2.8x1.8 cm.

Peptide receptor radionuclide therapy (PRRT) is an established treatment for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) expressing somatostatin receptors (SSTR). Despite robust trial and real-world data, heterogeneity persists regarding patient selection, therapeutic sequencing, and follow-up strategies. A Delphi consensus was conducted by the Galician Multidisciplinary Group on Neuroendocrine and Endocrine Tumors (GGNET). Ten experts in oncology, endocrinology, nuclear medicine, and radiology participated. 29 clinical statements were developed after a systematic review and rated using a 4-point Likert scale. Consensus was defined as ≥ 70% agreement. Consensus (defined a priori as ≥ 70% agreement) was achieved for all statements although the level of agreement varied across domains. PRRT was endorsed for patients with unresectable or metastatic, progressive, well-differentiated GEP-NETs (grades 1-3, Ki-67 ≤ 55%) with confirmed SSTR expression. SSTR-targeted imaging (PET or scintigraphy) was considered mandatory for eligibility, with PET identified as the preferred modality. [18F]-FDG-PET was recommended selectively as a complementary prognostic tool in higher-grade tumors, rapid progression, or discordant imaging. Multidisciplinary tumor board review was universally supported. Guidance was provided on treatment administration, including standard dosing, renal protection, hematologic monitoring, and individualized risk assessment. Routine interim imaging was not recommended. Structured follow-up with CT/MRI was endorsed, with indication-driven use of SSTR or FDG-PET and limited routine value of non-specific biomarkers. Functional biomarkers, such as 5-HIAA and peptide hormones, retained utility in functioning tumors. This Delphi consensus provides pragmatic, multidisciplinary, and evidence-informed guidance to harmonize routine clinical practice in the use of PRRT for well-differentiated, SSTR-positive NETs. The proposed statements and the algorithm aim to harmonize practice across centers, reduce variability in care, enhance safety, and ultimately improve patient outcomes.

Somatostatin (SS) and dopamine (DA) receptors have been highlighted as two critical regulators in the negative control of hormonal secretion in a wide group of human endocrine tumors. Both families of receptors belong to the superfamily of G protein-coupled receptors and share a number of structural and functional characteristics. Because of the generally reported high expression of somatostatin receptors (SSTRs) in neuroendocrine tumors (NET), somatostatin analogs (SSA) have a pronounced role in the medical therapy for this class of tumors, especially pituitary adenomas and well-differentiated gastroenteropancreatic NET (GEP NET). Moreover, NET express not only SSTR but also frequently dopamine receptors (DRs), and DA agonists targeting the D(2) receptor (D(2)) have been demonstrated to be effective in controlling hormone secretion and cell proliferation in in vivo and in vitro studies. The treatment with SSAs combined with DA agonists has already been demonstrated efficacious in a subgroup of patients with GH-secreting pituitary adenomas and few reported cases of carcinoids. The recent availability of new selective and universal SSA and DA agonists, as well as the chimeric SS/DA compounds, may shed new light on the potential role of SSTR and D(2) as combined targets for biotherapy in NET. This review provides an overview of the latest studies evaluating the expression of SSTR and DR in NET, focusing on their co-expression and the possible clinical implications of such co-expression. Moreover, the most recent insights in SSTR and D(2) pathophysiology and the future perspectives for treatment with SSA, DA agonists, and SS/DA chimeric compounds are discussed.

Next-Generation Sequencing Identified a Novel Crizotinib-Sensitive PLB1-ALK Rearrangement in Lung Large-Cell Neuroendocrine Carcinoma

Introduction: Neuroendocrine and pituitary tumors are uncommon tumors that develop from cells of the (neuro-)endocrine system. They can secrete hormones, leading to typical symptoms and syndromes. The cornerstone of antisecretory treatment for neuroendocrine and growth hormone-secreting pituitary tumors consists of somatostatin analogs, which target the somatostatin receptors that are expressed on the tumor cell membrane. Somatostatin analogs activate the second messenger pathways that inhibit hormone secretion and may also delay tumor growth.Areas covered: Recent developments in the field of somatostatin analogs and promising new angles in neuroendocrine tumor treatment are discussed. The recently approved somatostatin analog pasireotide and promising new analogs KE108 and somatoprim are reviewed. Further, innovative developments in the field of receptor manipulation, such as epigenetic manipulation and viral somatostatin receptor subtype-2 expression vectors, are discussed, as well as oncolytic viruses specifically targeting neuroendocrine tumor cells.Expert opinion: In addition to the development of novel somatostatin analogs and refining treatment with existing somatostatin analogs, alternative treatments targeting the somatostatin receptors that aim at increasing the number of somatostatin receptors should be explored as well, thereby broadening treatment perspectives and increasing options for prolonging survival.

Neuroendocrine (NE) tumors include a diverse spectrum of hormone-secreting neoplasms that arise from the endocrine and nervous systems. Current chemo- and radio- therapies have marginal curative benefits. The goal of this study was to develop an innovative antibody-drug conjugate (ADC) to effectively treat NE tumors (NETs). First, we confirmed that somatostatin receptor 2 (SSTR2) is an ideal cancer cell surface target by analyzing 38 patient-derived NET tissues, 33 normal organs, and 3 NET cell lines. Then, we developed a new monoclonal antibody (mAb, IgG1 and kappa) to target two extracellular domains of SSTR2, which showed strong and specific surface binding to NETs. The ADC was constructed by conjugating the anti-SSTR2 mAb and antimitotic monomethyl auristatin E. In vitro evaluations indicated that the ADC can effectively bind, internalize, release payload, and kill NET cells. Finally, the ADC was evaluated in vivo using a NET xenograft mouse model to assess cancer-specific targeting, tolerated dosage, pharmacokinetics, and anti-tumor efficacy. The anti-SSTR2 ADC exclusively targeted and killed NET cells with minimal toxicity and high stability in vivo. This study demonstrates that the anti-SSTR2 ADC has a high therapeutic potential for NET therapy.

Some subtypes of somatostatin receptors (SSTRs) are overexpressed in neuroendocrine tumors (NETs). 177Lu-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-D-Phel-Tyr3-Thr8-octreotide (DOTATATE) is a somatostatin analogue that can be combined with somatostatin receptor specifically, which plays an important role not only in early diagnosis, clinical staging, treatment guiding, recurrence detection and metastasis of NETs, but also in the targeted radionuclide therapy of tumors. The side effect of peptide receptor radionuclide therapy is relatively mild, which is of great clinical significance for prolonging patients′ survival, improving symptoms and the quality of life. Key words: Neuroendocrine tumors; DOTATATE; Lutetium; Trends

Somatostatin receptor 2 in 10 different types of human non-neoplastic gastrointestinal neuroendocrine cells

Neuroendocrine tumors (NET) of the gastrointestinal tract are rare and constitute 0.5-1% of all human malignancies. Based on their endocrine secretion, they are functional active or inactive. They are further classified into fore-, mid-, or hindgut tumors. The recently published WHO-classification grouped the tumors according to their tumor size, angioinvasion and Ki-67 index. NET are mainly diagnosed in an advanced tumor stadium because of the paucity of symptoms or when symptoms occur due to endocrine hypersecretion. NET are diagnosed serologically by their hormone secretion and by measuring Chromogranin A levels. They are further detected by CT, MRI or endoscopy including endoscopic ultrasound. Many NET have somatostatin receptors on their surface and can be diagnosed by somatostatin receptor scintigrafy with high sensitivity and specificity. Only by surgery NET can be cured. Because many tumors are diagnosed late, medical options are of utmost importance. Symptom control can be established by somatostatin analogues and interferon-ot. Diazoxid can further inhibit insulin secretion, proton pump inhibitors are the therapy of choice for acid hypersecretion in Zollinger-Ellison syndrome. Advanced neuroendocrine cancers can be treated with chemotherapy. Recently, radio receptor therapy with 90Y-DOTA Octreotid and 177Lu-DOTA Octreotate was established in advanced neuroendocrine cancers and is further evaluated in studies. Net of the gastrointestinal tract should be treated in a multidisciplinary approach with gastroenterologists, surgeons and experts in nuclear medicine. An overview about epidemiology, clinical features, diagnostic methods and therapy of NET of the gastrointestinal tract will is provided in this article.

This review deals with the analysis of up-to-date concepts of the human neuroendocrine tumors (NETs) of the digestive system, which are a heterogeneous group of epithelial neoplasms arising from the diffuse neuroendocrine system of the gastrointestinal tract and pancreas. The review summarizes the information about the specifics of the recent histological classifications and criteria of diagnosis the different types of neuroendocrine neoplasms accounting histological and immunohistochemical parameters. In the light of these criteria, current issues of the nomenclature, as well as systems of grading and staging are discussed. Well-differentiated NETs generally present characteristic histopathological features with nests, trabecular or gland-like formations, low mitotic activity and Ki-67 labeling indices and are mostly classified as either G1 or G2 NET. In contrast, poorly differentiated neuroendocrine carcinomas have diffuse growth pattern, high-grade nuclear atypia and cellular proliferation, necrosis. They are always classified as G3 and further subclassified into small-cell or large-cell types based on their histological features. Immunohistochemistry is a powerful tool in confirming neuroendocrine differentiation of tumor cells by the expression of chromogranin A and/or synaptophysin. The grade (G) is based on the proliferative activity of the tumor assessed by the mitotic rate or by Ki-67 immunohistochemistry. Several markers are useful in the identification of a primary organ of NETs in metastatic lesions are also discussed. NETs represent challenging neoplasms in terms of clinical management and prognosis assessment. Morphology alone and immunophenotypic features have no specific predictive implications. Ki-67 has been proven the only significant prognostic marker and can predict response to therapy. Additionally, data on key signaling pathways and potential predictive molecular markers involved in the development of neuroendocrine tumors of the gastrointestinal tract and pancreas are presented in this review. New molecular targeted therapies have become available in patients with NETs. Somatostatin receptors (SSTRs) are expressed by these tumors and show high affinity for somatostatin analogues. Immunohistochemical positive staining, especially of the subtype SSTR 2А, has been shown to be well associated with therapeutic response to somatostatin analogue therapy. Detecting the expression of SSTRs helps to predict not only the efficacy of treatment but also the prognosis in NETs. The PI3K/AKT/mTOR signaling pathway plays a crucial role in development of neuroendocrine neoplasms and is targeted by specific inhibitors. However, the exact cellular molecules, which may help predict response, their expression levels and prognostic values are still to be defined. Determining specific prognostic and predictive molecular markers in NETs can significantly improve biological and morphological characterization of individual neuroendocrine neoplasms and identification of patients that may benefit from targeted therapy.

Somatostatin, cortistatin and their receptors in tumours

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.

Somatostatin receptor targeting is considered the standard nuclear medicine technique for visualization of neuroendocrine tumors (NET). Since not all NETs over-express somatostatin receptors, the search for novel targets, visualizing these NETs, is ongoing. Many NETs, expressing low somatostatin receptor levels, express glucose-dependent insulinotropic polypeptide (GIP) receptors (GIPR). Here, we evaluated the performance of [Lys37(DTPA)]N-acetyl-GIP1-42, a newly synthesized GIP analogue to investigate whether NET imaging via GIPR targeting is feasible. Therefore, [Lys37(DTPA)]N-acetyl-GIP1-42 was radiolabeled with 111In with specific activity up to 1.2 TBq/µmol and both in vitro and in vivo receptor targeting properties were examined. In vitro, [Lys37(111In-DTPA)]N-acetyl-GIP1-42 showed receptor-mediated binding to BHK-GIPR positive cells, NES2Y cells and isolated islets. In vivo, both NES2Y and GIPR-transfected BHK tumors were visualized on SPECT/CT. Furthermore, co-administration of an excess unlabeled GIP1-42 lowered tracer uptake from 0.7 ± 0.2%ID/g to 0.6 ± 0.01%ID/g (p = 0.78) in NES2Y tumors and significantly lowered tracer uptake from 3.3 ± 0.8 to 0.8 ± 0.2%ID/g (p = 0.0001) in GIPR-transfected BHK tumors. In conclusion, [Lys37(111In-DTPA)]N-acetyl-GIP1-42 shows receptor-mediated binding in various models. Furthermore, both GIPR-transfected BHK tumors and NES2Y tumors were visible on SPECT/CT using this tracer. Therefore, [Lys37(111In-DTPA)]N-acetyl-GIP1-42 SPECT seems promising for visualization of somatostatin receptor negative NETs.