Advances in Molecular Imaging and Radionuclide Therapy of Neuroendocrine Tumors

Neuroendocrine neoplasms make up a heterogeneous group of tumors with inter-patient and intra-patient variabilities. Molecular imaging can help to identify and characterize neuroendocrine tumors (NETs). Furthermore, imaging and treatment with novel theranostics agents offers a new, tailored approach to managing NETs. Recent advances in the management of NETs aim to enhance the effectiveness of targeted treatment with either modifications of known substances or the development of new substances with better targeting features. There have been several attempts to increase the detectability of NET lesions via positron emission tomography (PET) imaging and improvements in pretreatment planning using dosimetry. Especially notable is PET imaging with the radionuclide Copper-64. Increasing interest is also being paid to theranostics of grade 3 and purely differentiated NETs, for example, via targeting of the C-X-C motif chemokine receptor 4 (CXCR4). The aim of this review is to summarize the most relevant recent studies, which present promising new agents in molecular imaging and therapy for NETs, novel combination therapies and new applications of existing molecular imaging modalities in nuclear medicine.

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Unparalleled and revolutionary impact of PET imaging on research and day to day practice of medicine

Bio-Algorithms and Med-Systems ◽

10.1515/bams-2021-0186 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Abass Alavi ◽

Thomas J. Werner ◽

Ewa Ł. Stępień ◽

Pawel Moskal

Keyword(s):

Molecular Imaging ◽

Pet Imaging ◽

Imaging Techniques ◽

The Body ◽

Therapeutic Interventions ◽

University Of Pennsylvania ◽

Positron Emission ◽

Practice Of Medicine ◽

Pet Instrumentation ◽

Total Body

Abstract Positron emission tomography (PET) imaging is the most quantitative modality for assessing disease activity at the molecular and cellular levels, and therefore, it allows monitoring its course and determining the efficacy of various therapeutic interventions. In this scientific communication, we describe the unparalleled and revolutionary impact of PET imaging on research and day to day practice of medicine. We emphasize the critical importance of the development and synthesis of novel radiotracers (starting from the enormous impact of F-Fluorodeouxyglucose (FDG) introduced by investigators at the University of Pennsylvania (PENN)) and PET instrumentation. These innovations have led to the total-body PET systems enabling dynamic and parametric molecular imaging of all organs in the body simultaneously. We also present our perspectives for future development of molecular imaging by multiphoton PET systems that will enable users to extract substantial information (owing to the evolving role of positronium imaging) about the related molecular and biological bases of various disorders, which are unachievable by the current PET imaging techniques.

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The Spectrum of Neuroendocrine Tumors: Histologic Classification, Unique Features and Areas of Overlap

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2015.35.92 ◽

2015 ◽

pp. 92-103 ◽

Cited By ~ 22

Author(s):

David S. Klimstra ◽

Himisha Beltran ◽

Rogerio Lilenbaum ◽

Emily Bergsland

Keyword(s):

Neuroendocrine Tumors ◽

Prostate Gland ◽

Neuroendocrine Differentiation ◽

Large Cell ◽

Genetic Alterations ◽

Neuroendocrine Cells ◽

Neuroendocrine Neoplasms ◽

Platinum Based Chemotherapy ◽

Well Differentiated ◽

Grade 3

Neuroendocrine neoplasms are diverse in terms of sites of origin, functional status, and degrees of aggressiveness. This review will introduce some of the common features of neuroendocrine neoplasms and will explore the differences in pathology, classification, biology, and clinical management between tumors of different anatomic sites, specifically, the lung, pancreas, and prostate. Despite sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype in most organs, well-differentiated neuroendocrine tumors (WD-NETs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) are two very different families of neoplasms. WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades), closely resemble non-neoplastic neuroendocrine cells, and demonstrate production of neurosecretory proteins, such as chromogranin A. They arise in the lungs and throughout the gastrointestinal tract and pancreas, but WD-NETs of the prostate gland are uncommon. Surgical resection is the mainstay of therapy, but treatment of unresectable disease depends on the site of origin. In contrast, PD-NECs (grade 3, small cell or large cell) of all sites often demonstrate alterations in P53 and Rb, exhibit an aggressive clinical course, and are treated with platinum-based chemotherapy. Only WD-NETs arise in patients with inherited neuroendocrine neoplasia syndromes (e.g., multiple endocrine neoplasia type 1), and some common genetic alterations are site-specific (e.g., TMPRSS2-ERG gene rearrangement in PD-NECs arising in the prostate gland). Advances in our understanding of the molecular basis of NETs should lead to new diagnostic and therapeutic strategies and is an area of active investigation.

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PET Tracers for Clinical Imaging of Breast Cancer

Journal of Oncology ◽

10.1155/2012/710561 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Iván Peñuelas ◽

Inés Domínguez-Prado ◽

María J. García-Velloso ◽

Josep M. Martí-Climent ◽

Macarena Rodríguez-Fraile ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Imaging ◽

Pet Imaging ◽

Hormone Receptors ◽

Tumour Microenvironment ◽

Laboratory Animals ◽

Breast Cancer Imaging ◽

Positron Emission ◽

Transport Molecules ◽

Metabolic Phenomena

Molecular imaging of breast cancer has undoubtedly permitted a substantial development of the overall diagnostic accuracy of this malignancy in the last years. Accurate tumour staging, design of individually suited therapies, response evaluation, early detection of recurrence and distant lesions have also evolved in parallel with the development of novel molecular imaging approaches. In this context, positron emission tomography (PET) can be probably seen as the most interesting molecular imaging technology with straightforward clinical application for such purposes. Dozens of radiotracers for PET imaging of breast cancer have been tested in laboratory animals. However, in this review we shall focus mainly in the smaller group of PET radiopharmaceuticals that have lead through into the clinical setting. PET imaging can be used to target general metabolic phenomena related to tumoural transformation, including glucose metabolism and cell proliferation, but can also be directed to specific hormone receptors that are characteristic of the breast cancer cell. Many other receptors and transport molecules present in the tumour cells could also be of interest for imaging. Furthermore, molecules related with the tumour microenvironment, tumour induced angiogenesis or even hypoxia could also be used as molecular biomarkers for breast cancer imaging.

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Tumor size and perineural invasion predict outcome of gastric high grade neuroendocrine neoplasms

Endocrine Connections ◽

10.1530/ec-21-0017 ◽

2021 ◽

Author(s):

Qi Zhang ◽

Hongshan Wang ◽

Yanhong Xie ◽

Suming Huang ◽

Ke Chen ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Tumor Size ◽

Who Classification ◽

Perineural Invasion ◽

Radical Resection ◽

Neuroendocrine Neoplasms ◽

High Grade ◽

Ki67 Index ◽

Grade 3 ◽

Neuroendocrine Carcinomas

A new subcategory, grade 3 neuroendocrine tumors, is incorporated into the grading system of pancreatic neuroendocrine neoplasms in the 2017 WHO classification in order to differentiate grade 3 neuroendocrine tumors from neuroendocrine carcinomas. The 2019 WHO classification extends the concept of grade 3 neuroendocrine tumors to gastrointestinal high grade neuroendocrine neoplasms. However, there is still limited study focusing on the gastric grade 3 neuroendocrine tumors and gastric neuroendocrine carcinomas. We retrospectively enrolled 151 gastric high grade neuroendocrine neoplasms patients, who underwent radical resection from January 2007 to December 2015. Clinicopathologic and prognostic features were studied. The Surveillance, Epidemiology, and End Results database was used to verify the prognostic determinants found in Zhongshan cohort. Neuroendocrine carcinomas showed higher Ki67 index and higher mitotic count than grade 3 neuroendocrine tumors. We identified 109 (72.2%) patients of neuroendocrine carcinomas, 12 (7.9%) patients of grade 3 neuroendocrine tumors and 30 (19.9%) patients of mixed neuroendocrine non-neuroendocrine neoplasms. Although neuroendocrine carcinomas demonstrated higher Ki67 index (p=0.004) and mitoses (p=0.001) than grade 3 neuroendocrine tumors, their prognosis after radical resection did not demonstrate significant differences (p=0.709). Tumor size, perineural invasion and TNM stage were independent prognostic factors of gastric high grade neuroendocrine neoplasms.

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Well Differentiated Grade 3 Neuroendocrine Tumors of the Digestive Tract: A Narrative Review

Journal of Clinical Medicine ◽

10.3390/jcm9061677 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1677

Author(s):

Anna Pellat ◽

Romain Coriat

Keyword(s):

Digestive Tract ◽

Neuroendocrine Tumors ◽

Peptide Receptor Radionuclide Therapy ◽

Small Sample ◽

World Health ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Metastatic Setting ◽

Well Differentiated ◽

Grade 3

The 2017 World Health Organization (WHO) classification of neuroendocrine neoplasms (NEN) of the digestive tract introduced a new category of tumors named well-differentiated grade 3 neuroendocrine tumors (NET G−3). These lesions show a number of mitosis, or a Ki−67 index higher than 20% with a well-differentiated morphology, therefore separating them from neuroendocrine carcinomas (NEC) which are poorly differentiated. It has become clear that NET G−3 show differences not only in morphology but also in genotype, clinical presentation, and treatment response. The incidence of digestive NET G−3 represents about one third of NEN G−3 with main tumor sites being the pancreas, the stomach and the colon. Treatment for NET G−3 is not yet standardized because of lack of data. In a non-metastatic setting, international guidelines recommend surgical resection, regardless of tumor grading. For metastatic lesion, chemotherapy is the main treatment with similar regimen as NET G−2. Sunitinib has also shown some positive results in a small sample of patients but this needs confirmation. Peptide receptor radionuclide therapy (PRRT) and immunotherapy could be future available treatments after ongoing studies. The goal of this review was to sum up the latest data on the epidemiology and management of digestive NET G−3.

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Molecular imaging-guided repair after acute myocardial infarction by targeting the chemokine receptor CXCR4

European Heart Journal ◽

10.1093/eurheartj/ehaa598 ◽

2020 ◽

Vol 41 (37) ◽

pp. 3564-3575 ◽

Cited By ~ 4

Author(s):

Annika Hess ◽

Thorsten Derlin ◽

Tobias Koenig ◽

Johanna Diekmann ◽

Alexander Wittneben ◽

...

Keyword(s):

Myocardial Infarction ◽

Positron Emission Tomography ◽

Flow Cytometry ◽

Molecular Imaging ◽

Functional Outcome ◽

Pet Imaging ◽

Contractile Function ◽

Cxcr4 Expression ◽

Emission Tomography ◽

Positron Emission

Abstract Aims Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction. Methods and results Mice (n = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P < 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P < 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (rpartial = −0.4, P = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up. Conclusion Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI.

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Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions

Cancers ◽

10.3390/cancers13102448 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2448

Author(s):

Anna Pellat ◽

Anne Ségolène Cottereau ◽

Lola-Jade Palmieri ◽

Philippe Soyer ◽

Ugo Marchese ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Functional Imaging ◽

World Health ◽

Neuroendocrine Neoplasms ◽

Tumor Site ◽

Ki 67 ◽

Future Directions ◽

Metastatic Setting ◽

Well Differentiated ◽

Grade 3

Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.

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Radiotheranostics of neuroendocrine neoplasms: quo vadis

Almanac of Clinical Medicine ◽

10.18786/2072-0505-2021-49-048 ◽

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.

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Distinctive detection of insulinoma using [18F]FB(ePEG12)12-exendin-4 PET/CT

Scientific Reports ◽

10.1038/s41598-021-94595-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Takaaki Murakami ◽

Hiroyuki Fujimoto ◽

Keita Hamamatsu ◽

Yuki Yamauchi ◽

Yuzo Kodama ◽

...

Keyword(s):

Pet Imaging ◽

Detection Sensitivity ◽

Neuroendocrine Neoplasms ◽

Mouse Tumor ◽

Post Injection ◽

Imaging Evaluation ◽

Insulinoma Cell ◽

Positron Emission ◽

Pet Ct

AbstractSpecifying the exact localization of insulinoma remains challenging due to the lack of insulinoma-specific imaging methods. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging, especially positron emission tomography (PET), has emerged. Although various radiolabeled GLP-1R agonist exendin-4-based probes with chemical modifications for PET imaging have been investigated, an optimal candidate probe and its scanning protocol remain a necessity. Thus, we investigated the utility of a novel exendin-4-based probe conjugated with polyethylene glycol (PEG) for [18F]FB(ePEG12)12-exendin-4 PET imaging for insulinoma detection. We utilized [18F]FB(ePEG12)12-exendin-4 PET/CT to visualize mouse tumor models, which were generated using rat insulinoma cell xenografts. The probe demonstrated high uptake value on the tumor as 37.1 ± 0.4%ID/g, with rapid kidney clearance. Additionally, we used Pdx1-Cre;Trp53R172H;Rbf/f mice, which developed endogenous insulinoma and glucagonoma, since they enabled differential imaging evaluation of our probe in functional pancreatic neuroendocrine neoplasms. In this model, our [18F]FB(ePEG12)12-exendin-4 PET/CT yielded favorable sensitivity and specificity for insulinoma detection. Sensitivity: 30-min post-injection 66.7%, 60-min post-injection 83.3%, combined 100% and specificity: 30-min post-injection 100%, 60-min post-injection 100%, combined 100%, which was corroborated by the results of in vitro time-based analysis of internalized probe accumulation. Accordingly, [18F]FB(ePEG12)12-exendin-4 is a promising PET imaging probe for visualizing insulinoma.

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