| 1. |
- Ambrosini, Valentina, et al.
(författare)
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Consensus on molecular imaging and theranostics in neuroendocrine neoplasms
- 2021
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 146, s. 56-73
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Forskningsöversikt (refereegranskat)abstract
- Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing 68gallium-labelled somatostatin analogue ([68Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing 18fluorine-fluoro-2-deoxyglucose ([18F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[68Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [68Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [18F]FDG and [68Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies.
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| 2. |
- Bodei, Lisa, et al.
(författare)
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Molecular profiling of neuroendocrine tumours to predict response and toxicity to peptide receptor radionuclide therapy
- 2020
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Ingår i: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 21:9, s. E431-E443
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Forskningsöversikt (refereegranskat)abstract
- Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be evaluated (eg, ATM and DAXX) are limited to pancreatic NETs and are most likely not informative. Assays that are transcriptomic or based on genes are effective in the prediction of radiotherapy response in other cancers. A blood-based assay for eight genes (the PRRT prediction quotient [PPQ]) has an overall accuracy of 95% for predicting responses to PRRT in NETs. No molecular markers exist that can predict the toxicity of PRRT. Candidate molecular targets include seven single nucleotide polymorphisms (SNPs) that are susceptible to radiation. Transcriptomic evaluations of blood and a combination of gene expression and specific SNPs, assessed by machine learning with algorithms that are tumour-specific, might yield molecular tools to enhance the efficacy and safety of PRRT.
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| 3. |
- Castano, J. P., et al.
(författare)
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Gastrointestinal neuroendocrine tumors (NETs) : new diagnostic and therapeutic challenges
- 2014
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Ingår i: Cancer Metastasis Review. - : Springer Science and Business Media LLC. - 0167-7659 .- 1573-7233. ; 33:1, s. 353-359
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Forskningsöversikt (refereegranskat)abstract
- This paper summarizes the current understanding of the biology of somatostatin receptor (sst), role of immunotherapy in neuroendocrine tumor (NET), new agents for PPRT, and methods to assess response and clinical benefit in NET. One of the most interesting aspects of sst biology is the recent discovery of truncated variants of the sst5 receptor subtype with unique tissue distribution and response to somatostatin (SST). These truncated receptors are associated with bad patient prognosis, decreased response to SST analogs, and may be new targets for diagnoses and treatment. IFN remains a cost-effective agent, particularly in classic mid gut carcinoids, and there is interest to continue examining immunotherapy's in this disease. PRRT remains a key strategy for treatment and imaging. In addition to the classic agents, there are a series of new agents targeting other receptors such as the incretin receptors (GLP-1R; GIPR) and other G-protein coupled receptors with great potential. With regards to therapy monitoring, the most commonly used criteria are Response Criteria Evaluation in Solid Tumors (RECIST). However, for different reasons, these criteria are not very useful in NET. Incorporation of other criteria such as Choi as well as functional imaging assessment with PET would be of great interest in this area.
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| 4. |
- Culler, Michael D., et al.
(författare)
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Somatostatin analogs for the treatment of neuroendocrine tumors
- 2011
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Ingår i: Cancer Metastasis Review. - : Springer Science and Business Media LLC. - 0167-7659 .- 1573-7233. ; 30:1, s. 9-17
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Forskningsöversikt (refereegranskat)abstract
- Somatostatin is an important regulator of endocrine and exocrine secretion, affecting the release of many hormones. The effects of somatostatin are mediated through its interaction with one of five somatostatin receptors. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express multiple somatostatin receptors, making them excellent potential therapeutic targets. Many trials have shown that treatment with somatostatin analogs is associated with disease stabilization and prolonged survival. More recently, somatostatin analogs have been shown to have antiproliferative effects, thus broadening the scope of their uses. In this review, we update the current data on the treatment of GEP-NETs with somatostatin analogs, with particular emphasis on the results of the PROMID study. In addition, we discuss the current state of knowledge of novel therapies against GEP-NETs, including the use of somatostatin analogs with broader receptor binding profiles, chimeric somatostatin-dopamine molecules, combinations of somatostatin analogs with other active chemotherapy agents, and peptide receptor-targeted radionuclide therapy.
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| 5. |
- Essand, Magnus, et al.
(författare)
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Oncolytic Viruses for the Treatment of Neuroendocrine Tumors
- 2011
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 43:12, s. 877-883
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Forskningsöversikt (refereegranskat)abstract
- Oncolytic viruses are emerging as anticancer agents, and they have also shown great promise for use against neuroendocrine tumors. Many viruses have a natural tropism for replication in tumor cells. Others can be genetically engineered to selectively kill tumor cells. Viruses have some advantages as therapeutic agents over current cytotoxic drugs and small molecules. They replicate in tumor cells and thereby increase in number over time leading to increased dosage. They are immunogenic and can alter the immunosuppressive tumor microenvironment and activate immune effector cells. They have also been shown to be able to kill drug-resistant cancer stem cells. This article reviews the recent literature on oncolytic viruses used so far for neuroendocrine tumors and indicates important issues to focus on in the future.
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| 6. |
- Fazio, N, et al.
(författare)
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Interferon-{alpha} and somatostatin analog in patients with gastroenteropancreatic neuroendocrine carcinoma : single agent or combination?
- 2007
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 18:1, s. 13-19
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Forskningsöversikt (refereegranskat)abstract
- In most cases gastro-enteropancreatic neuroendocrine tumors grow slowly. Interferon-α and somatostatin analogs have shown symptomatic, biochemical, and, in a minority of cases, antiproliferative activity. Generally, they are proposed as single-agent therapy. However, based on in vitro and in vivo evidence, the combined use of these drugs was proposed in several non-randomized trials, indicating that there is an additive effect of the combination. Nevertheless, the three randomized trials published so far did not show a statistically significant survival benefit for the combination compared to the same agents alone, even though an advantage for the combination came out in all three studies. On the other hand, data from non-randomized trials would justify the sequential use of the two drugs or the combination after progression on single agent therapy. Therefore, at present the up-front combined use of interferon-α and somatostatin analog is not justified, whereas it could be indicated after progression to single-agent therapy. Further larger, international, prospective, randomized, multicentric clinical trials studying homogeneous populations would be necessary to give a final answer, but the rarity and heterogeneity of this malignancy does not assure that it will be possible.
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| 7. |
- Kidd, Mark, et al.
(författare)
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Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms.
- 2016
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Ingår i: Nature Reviews Clinical Oncology. - : Springer Science and Business Media LLC. - 1759-4774 .- 1759-4782. ; 13:11, s. 691-705
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Forskningsöversikt (refereegranskat)abstract
- Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) constitute a heterogeneous group of tumours associated with variable clinical presentations, growth rates, and prognoses. To improve the management of GEP-NENs, the WHO developed a classification system that enables tumours to be graded based on markers of cell proliferation in biopsy specimens. Indeed, histopathology has been a mainstay in the diagnosis of GEP-NENs, and the WHO grading system facilitates therapeutic decision-making; however, considerable intratumoural heterogeneity, predominantly comprising regional variations in proliferation rates, complicates the evaluation of tumour biology. The use of molecular imaging modalities to delineate the most-aggressive cell populations is becoming more widespread. In addition, molecular profiling is increasingly undertaken in the clinical setting, and genomic studies have revealed a number of chromosomal alterations in GEP-NENs, although the 'drivers' of neoplastic development have not been identified. Thus, our molecular understanding of GEP-NENs remains insufficient to inform on patient prognosis or selection for treatments, and the WHO classification continues to form the basis for management of this disease. Nevertheless, our increasing understanding of the molecular genetics and biology of GEP-NENs has begun to expose flaws in the WHO classification. We describe the current understanding of the molecular characteristics of GEP-NENs, and discuss how advances in molecular profiling measurements, including assays of circulating mRNAs, are likely to influence the management of these tumours.
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| 8. |
- Lindholm, Daniel P, et al.
(författare)
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Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors
- 2011
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 43:12, s. 832-837
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Forskningsöversikt (refereegranskat)abstract
- Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.
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| 9. |
- Malczewska, Anna, et al.
(författare)
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An Assessment of Circulating Chromogranin A as a Biomarker of Bronchopulmonary Neuroendocrine Neoplasia : A Systematic Review and Meta-Analysis
- 2020
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 110:3-4, s. 198-216
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Forskningsöversikt (refereegranskat)abstract
- Background: Management of bronchopulmonary neuroendocrine neoplasia (NEN; pulmonary carcinoids [PCs], small-cell lung cancer [SCLC], and large cell neuroendocrine carcinoma) is hampered by the paucity of biomarkers. Chromogranin A (CgA), the default neuroendocrine tumor biomarker, has undergone wide assessment in gastroenteropancreatic neuroendocrine tumors.Objectives: To evaluate CgA in lung NEN, define its clinical utility as a biomarker, assess its diagnostic, prognostic, and predictive efficacy, as well as its accuracy in the identification of disease recurrence.Methods: A systematic review of PubMed was undertaken using the preferred reporting items for systematic reviews and meta-analyses guidelines. No language restrictions were applied. Overall, 33 original scientific papers and 3 case reports, which met inclusion criteria, were included in qualitative analysis, and meta-analysis thereafter. All studies, except 2, were retrospective. Meta-analysis statistical assessment by generic inverse variance methodology.Results: Ten different CgA assay types were reported, without consistency in the upper limit of normal (ULN). For PCs (n = 16 studies; median patient inclusion 21 [range 1-200, total: 591 patients]), the CgA diagnostic sensitivity was 34.5 +/- 2.7% with a specificity of 93.8 +/- 4.7. CgA metrics were not available separately for typical or atypical carcinoids. CgA >100 ng/mL (2.7 x ULN) and >600 ng/mL (ULN unspecified) were anecdotally prognostic for overall survival (n = 2 retrospective studies). No evidence was presented for predicting treatment response or identifying post-surgery residual disease. For SCLC (n = 19 studies; median patient inclusion 23 [range 5-251, total: 1,241 patients]), the mean diagnostic sensitivity was 59.9 +/- 6.8% and specificity 79.4 +/- 3.1. Extensive disease typically exhibited higher CgA levels (diagnostic accuracy: 61 +/- 2.5%). An elevated CgA was prognostic for overall survival (n = 4 retrospective studies). No prospective studies evaluating predictive benefit or prognostic utility were identified.Conclusion: The available data are scarce. An assessment of all published data showed that CgA exhibits major limitations as an effective and accurate biomarker for either PC or SCLC. Its utility especially for localized PC/limited SCLC (when surgery is potentially curative), is limited. The clinical value of CgA remains to be determined. This requires validated, well-constructed, multicenter, prospective, randomized studies. An assessment of all published data indicates that CgA does not exhibit the minimum required metrics to function as a clinically useful biomarker for lung NENs.
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| 10. |
- Malczewska, Anna, et al.
(författare)
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The clinical applications of a multigene liquid biopsy (NETest) in neuroendocrine tumors
- 2020
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Ingår i: Advances in Medical Sciences. - : Elsevier BV. - 1896-1126 .- 1898-4002. ; 65:1, s. 18-29
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Forskningsöversikt (refereegranskat)abstract
- Purpose: There are few effective biomarkers for neuroendocrine tumors. Precision oncology strategies have provided liquid biopsies for real-time and tailored decision-making. This has led to the development of the first neuroendocrine tumor liquid biopsy (the NETest). The NETest represents a transcriptomic signature of neuroendocrine tumor (NETs) that captures tumor biology and disease activity. The data have direct clinical application in terms of identifying residual disease, disease progress and the efficacy of treatment. In this overview we assess the available published information on the metrics and clinical efficacy of the NETest. Material and methods: Published data on the NETest have been collated and analyzed to understand the clinical application of this multianalyte biomarker in NETs. Results: NETest assay has been validated as a standardized and reproducible clinical laboratory measurement. It is not affected by demographic characteristics, or acid suppressive medication. Clinical utility of the NETest has been documented in gastroenteropancreatic, bronchopulmonary NETs, in paragangliomas and pheochromocytomas. The test facilitates accurate diagnosis of a NET disease, and real-time monitoring of the disease status (stable/progressive disease). It predicts aggressive tumor behavior, identifies operative tumor resection, and efficacy of the medical treatment (e.g. somatostatin analogues), or peptide receptor radionuclide therapy (PRRT). NETest metrics and clinical applications out-perform standard biomarkers like chromogranin A. Conclusions: The NETest exhibits clinically competent metrics as an effective biomarker for neuroendocrine tumors. Measurement of NET transcripts in blood is a significant advance in neuroendocrine tumor management and demonstrates that blood provides a viable source to identify and monitor tumor status.
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