scholarly journals Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
K. Lithgow ◽  
H. Venkataraman ◽  
S. Hughes ◽  
H. Shah ◽  
J. Kemp-Blake ◽  
...  
Keyword(s):  
Primary Tumour ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Treatment Strategies ◽  
Biological Behavior ◽  
Queen Elizabeth Hospital ◽  
Neuroendocrine Neoplasms ◽  
Single Centre ◽  
Net G3 ◽  
Well Differentiated

AbstractNeuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

scholarly journals The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

2021 ◽  
Author(s):  
Andreas Venizelos ◽  
Hege Elvebakken ◽  
Aurel Perren ◽  
Oleksii Nikolaienko ◽  
Wei Deng ◽  
...  
Keyword(s):  
Copy Number ◽  
Primary Tumour ◽  
Treatment Strategies ◽  
Morphological Differentiation ◽  
Molecular Characteristics ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Braf Mutations ◽  
Molecular Features ◽  
Net G3

High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on sequencing of 360 cancer related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). 8/152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicates a high potential for better personalized treatments.

Pasireotide in the treatment of neuroendocrine tumors: a review of the literature

2018 ◽  
Vol 25 (6) ◽  
pp. R351-R364 ◽  
Author(s):  
Giovanni Vitale ◽  
Alessandra Dicitore ◽  
Concetta Sciammarella ◽  
Sergio Di Molfetta ◽  
Manila Rubino ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Clinical Relevance ◽  
State Of The Art ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Future Perspectives ◽  
Review Of The Literature ◽  
Antiproliferative Effects ◽  
High Affinity ◽  
Well Differentiated

Somatostatin analogs have an important role in the medical therapy of neuroendocrine tumors (NETs). Octreotide and lanreotide, both somatostatin analogs binding with high affinity for the somatostatin receptor (SSTR)2, can control symptoms in functional NETs. In addition, these compounds, because of their antiproliferative effects, can stabilize growth of well-differentiated NETs. Pasireotide is a novel multireceptor-targeted somatostatin analog with high affinity for SSTR1, 2, 3, and 5. This review provides an overview of the state of the art of pasireotide in the treatment of NETs, with the aim of addressing clinical relevance and future perspectives for this molecule in the management of NETs.

scholarly journals Imaging of Pancreatic Neuroendocrine Neoplasms

2021 ◽  
Vol 18 (17) ◽  
pp. 8895
Author(s):  
Giuditta Chiti ◽  
Giulia Grazzini ◽  
Diletta Cozzi ◽  
Ginevra Danti ◽  
Benedetta Matteuzzi ◽  
...  
Keyword(s):  
Functional Imaging ◽  
Imaging Techniques ◽  
Therapy Monitoring ◽  
Somatostatin Receptor ◽  
World Health ◽  
Biological Behavior ◽  
Pancreatic Tumors ◽  
Neuroendocrine Neoplasms ◽  
Imaging Features ◽  
Pancreatic Neuroendocrine Neoplasms

Pancreatic neuroendocrine neoplasms (panNENs) represent the second most common pancreatic tumors. They are a heterogeneous group of neoplasms with varying clinical expression and biological behavior, from indolent to aggressive ones. PanNENs can be functioning or non-functioning in accordance with their ability or not to produce metabolically active hormones. They are histopathologically classified according to the 2017 World Health Organization (WHO) classification system. Although the final diagnosis of neuroendocrine tumor relies on histologic examination of biopsy or surgical specimens, both morphologic and functional imaging are crucial for patient care. Morphologic imaging with ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) is used for initial evaluation and staging of disease, as well as surveillance and therapy monitoring. Functional imaging techniques with somatostatin receptor scintigraphy (SRS) and positron emission tomography (PET) are used for functional and metabolic assessment that is helpful for therapy management and post-therapeutic re-staging. This article reviews the morphological and functional imaging modalities now available and the imaging features of panNENs. Finally, future imaging challenges, such as radiomics analysis, are illustrated.

scholarly journals Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)

2018 ◽  
Vol 108 (1) ◽  
pp. 54-62 ◽  
Author(s):  
Halfdan Sorbye ◽  
Eric Baudin ◽  
Ivan Borbath ◽  
Martyn Caplin ◽  
Jie Chen ◽  
...  
Keyword(s):  
Patient Group ◽  
Unmet Needs ◽  
Proliferation Rate ◽  
Pancreatic Tumors ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
High Grade ◽  
Primary Tumor Site ◽  
Net G3 ◽  
Well Differentiated

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1 to G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinomas (NEC). Recently, a new subgroup of well-differentiated high-grade pancreatic tumors (NET G3) has been defined. The GEP NEN G3 group consisting of both NEC and NET G3 has recently been shown to be a quite heterogeneous patient group concerning prognosis and treatment benefit, depending on factors such as the primary tumor site, differentiation, proliferation rate, and molecular alterations. In this review we discuss the existing data on diagnostics, treatment, and biomarkers in this patient group, the unmet needs, and the future perspectives.

Genomic Profiles and Current Therapeutic Agents in Neuroendocrine Neoplasms

2020 ◽  
Vol 21 (4) ◽  
pp. 389-405
Author(s):  
Akihiro Ohmoto ◽  
Chigusa Morizane
Keyword(s):  
Current Knowledge ◽  
Treatment Strategies ◽  
Phase Iii ◽  
World Health ◽  
Standards Of Care ◽  
Neuroendocrine Neoplasms ◽  
Targeted Agents ◽  
Poorly Differentiated ◽  
Molecular Targeted Agents ◽  
Well Differentiated

Neuroendocrine neoplasms (NENs) are rare tumors that mainly occur in the gastroenteropancreatic (GEP) tract and lungs. According to the current World Health Organization classification for GEP-NENs and lung NENs, treatment strategies differ for well-differentiated and poorly differentiated subtypes. For well-differentiated GEP-NENs, somatostatin analogues (SSA), peptide receptor radionuclide therapy, and molecular-targeted agents are approved as the standards of care based on phase III clinical trial data. Promising data regarding the use of everolimus and the novel SSA pasireotide for lung NENs are emerging, though additional studies are required to confirm these effects. For poorly differentiated tumors from the GEP tract and lung, a platinum-based cytotoxic regimen is widely used. Genomic analysis has recently revealed a diverse pattern of primary organ-dependent mutations, and the use of traditional treatment strategies versus organ-specific strategies is currently under discussion. In addition, clinical trials for several molecular-targeted agents and immune checkpoint inhibitors for the treatment of NENs are currently underway. Accumulating genomic information is expected to contribute to the development of novel therapies for other organ-derived NENs or poorly differentiated neuroendocrine carcinomas (NECs). Here, we provide an updated overview of the current knowledge regarding genomic profiles and representative agents for NENs and highlight the prospects for future investigations.

scholarly journals Current best practice in the management of neuroendocrine tumors

2018 ◽  
Vol 10 ◽  
pp. 204201881880469 ◽  
Author(s):  
Marina Tsoli ◽  
Eleftherios Chatzellis ◽  
Anna Koumarianou ◽  
Dionysia Kolomodi ◽  
Gregory Kaltsas
Keyword(s):  
Best Practice ◽  
Treatment Options ◽  
Somatostatin Analogs ◽  
Response To Therapy ◽  
Biological Behavior ◽  
Neuroendocrine Neoplasms ◽  
Number Of Factors ◽  
Long Acting ◽  
Initiation Sequence ◽  
Degree Of Differentiation

Neuroendocrine neoplasms are rare tumors that display marked heterogeneity with varying natural history, biological behavior, response to therapy and prognosis. Their management is complex, particularly as a number of them may be associated with a secretory syndrome and involve a variety of options. A number of factors such as proliferation rate, degree of differentiation, functionality and extent of the disease are mostly utilized to tailor treatment accordingly, ideally in the context of a multidisciplinary team. In addition, a number of relevant scientific societies have published therapeutic guidelines in an attempt to direct and promote evidence-based treatment. Surgery remains the treatment of choice with an intention to cure while it may also be recommended in some cases of metastatic disease and difficult to control secretory syndromes. Long-acting somatostatin analogs constitute the main treatment for the majority of functioning tumors, whereas specific evolving agents such as telotristat may be used for the control of carcinoid syndrome and related sequelae. In patients with advanced disease not amenable to surgical resection, treatment options include locoregional therapies, long-acting somatostatin analogs, molecular targeted agents, radionuclides, chemotherapy and recently immunotherapy, alone or in combination. However, the ideal time of treatment initiation, sequence of administration of different therapies and identification of robust prognostic markers to select the most appropriate treatment for each individual patient still need to be defined.

scholarly journals How I treat neuroendocrine tumours

ESMO Open ◽  
2020 ◽  
Vol 5 (4) ◽  
pp. e000811
Author(s):  
Barbara Kiesewetter ◽  
Markus Raderer
Keyword(s):  
Neuroendocrine Tumours ◽  
Kinase Inhibitor ◽  
Primary Tumour ◽  
Somatostatin Receptor ◽  
Treatment Strategies ◽  
Somatostatin Analogues ◽  
Receptor Expression ◽  
Minor Role ◽  
Endocrine Activity ◽  
Therapeutic Concepts

Neuroendocrine tumours (NETs) constitute a heterogeneous group of neoplasms characterised by variable endocrine activity and somatostatin receptor expression, with the latter allowing the use of targeted therapeutic concepts. Currently accepted treatment strategies for advanced well-differentiated NET include somatostatin analogues octreotide and lanreotide, peptide receptor radionuclide therapy using radiolabelled somatostatin analogues, mammalian target of Rapamycin inhibitor everolimus, tyrosine kinase inhibitor sunitinib, interferon alpha and classical cytostatic, such as streptozotocin-based and temozolomide-based treatment. Indication, use and approval of these treatments differ based on primary tumour origin, grading and symptomatic burden and require an optimised multidisciplinary cooperation of medical oncologists, endocrinologists and nuclear medicine specialists. Interestingly, hot topics in oncology including immunotherapy and use of next-generation-sequencing techniques currently play a minor role for the treatment of NETs. The recent revision of the WHO classification including the recognition of the novel NET G3 category allows for potentially more tailored treatment strategies in the near future. However, this new entity also poses a therapeutic challenge as only limited data are currently available. The present article aims to provide an overview on our personal treatment concepts for advanced NETs with a focus on tumours of gastroenteropancreatic origin.

scholarly journals Radiotheranostics of neuroendocrine neoplasms: quo vadis

2021 ◽  
Vol 49 ◽  
Author(s):  
P. O. Rumyantsev
Keyword(s):  
Neuroendocrine Tumors ◽  
Single Photon ◽  
Somatostatin Receptor ◽  
Photon Emission ◽  
Biological Behavior ◽  
Neuroendocrine Neoplasms ◽  
Emission Computed Tomography ◽  
Positron Emission ◽  
Specific Receptors ◽  
Quo Vadis

Neuroendocrine neoplasms are grouped based on their neuroendocrine origin and represented by a  heterogeneous tumor cluster with various malignancy potentials and types of biological behavior. These tumors can localize anywhere, but most commonly within the gastrointestinal tract. The ability of tumor cells to express specific receptors and particulars of their metabolism make it possible to successfully use molecular visualization (single-photon emission computed tomography /positron emission tomography) and radiotargeted therapy for diagnosis and treatment of patients with neuroendocrine tumors. In clinical practice, somatostatin receptor (receptors type 2) radiotheranostics has been used most widely. Improvement of diagnostic and therapeutic characteristics of new radioligands, discovery of new receptor and metabolic targets, widening of the medical isotope spectrum and development of new theranostic pairs open wide horizons for radiotheranostics as an integral field in modern biomedicine. The paper summarizes the worldwide experience, highlights the state-of-the-art and future development of radiotheranostics of neuroendocrine tumors. 

scholarly journals Somatostatin Receptors and Analogs in Pheochromocytoma and Paraganglioma: Old Players in a New Precision Medicine World

2021 ◽  
Vol 12 ◽  
Author(s):  
Mayank Patel ◽  
Isabel Tena ◽  
Abhishek Jha ◽  
David Taieb ◽  
Karel Pacak
Keyword(s):  
Neuroendocrine Tumors ◽  
Somatostatin Receptor ◽  
Hormone Secretion ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
Rare Condition ◽  
Receptor Imaging ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Well Differentiated ◽  
Succinate Dehydrogenase Subunit B

Neuroendocrine tumors overexpress somatostatin receptors, which serve as important and unique therapeutic targets for well-differentiated advanced disease. This overexpression is a well-established finding in gastroenteropancreatic neuroendocrine tumors which has guided new medical therapies in the administration of somatostatin analogs, both “cold”, particularly octreotide and lanreotide, and “hot” analogs, chelated to radiolabeled isotopes. The binding of these analogs to somatostatin receptors effectively suppresses excess hormone secretion and tumor cell proliferation, leading to stabilization, and in some cases, tumor shrinkage. Radioisotope-labeled somatostatin analogs are utilized for both tumor localization and peptide radionuclide therapy, with 68Ga-DOTATATE and 177Lu-DOTATATE respectively. Benign and malignant pheochromocytomas and paragangliomas also overexpress somatostatin receptors, irrespective of embryological origin. The pattern of somatostatin receptor overexpression is more prominent in succinate dehydrogenase subunit B gene mutation, which is more aggressive than other subgroups of this disease. While the Food and Drug Administration has approved the use of 68Ga-DOTATATE as a radiopharmaceutical for somatostatin receptor imaging, the use of its radiotherapeutic counterpart still needs approval beyond gastroenteropancreatic neuroendocrine tumors. Thus, patients with pheochromocytoma and paraganglioma, especially those with inoperable or metastatic diseases, depend on the clinical trials of somatostatin analogs. The review summarizes the advances in the utilization of somatostatin receptor for diagnostic and therapeutic approaches in the neuroendocrine tumor subset of pheochromocytoma and paraganglioma; we hope to provide a positive perspective in using these receptors as targets for treatment in this rare condition.

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