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Cancer Science Jun 2022Theranostics is a term coined by combining the words "therapeutics" and "diagnostics," referring to single chemical entities developed to deliver therapy and diagnosis... (Review)
Review
Theranostics is a term coined by combining the words "therapeutics" and "diagnostics," referring to single chemical entities developed to deliver therapy and diagnosis simultaneously. Neuroendocrine tumors are rare cancers that occur in various organs of the body, and they express neuroendocrine factors such as chromogranin A and somatostatin receptor. Somatostatin analogs bind to somatostatin receptor, and when combined with diagnostic radionuclides, such as gamma-emitters, are utilized for diagnosis of neuroendocrine tumor. Somatostatin receptor scintigraphy when combined with therapeutic radionuclides, such as beta-emitters, are effective in treating neuroendocrine tumor as peptide receptor radionuclide therapy. Somatostatin receptor scintigraphy and peptide receptor radionuclide therapy are some of the most frequently used and successful theranostics for neuroendocrine tumor. In Japan, radiopharmaceuticals are regulated under a complex law system, creating a significant drug lag, which is a major public concern. It took nearly 10 years to obtain the approval for somatostatin receptor scintigraphy and peptide receptor radionuclide therapy use by the Japanese government. In 2021, Lu-DOTATATE (Lutathera), a drug for peptide receptor radionuclide therapy, was covered by insurance in Japan. In this review, we summarize the history of the development of neuroendocrine tumor theranostics and theranostics in general, as therapeutic treatment for cancer in the future. Furthermore, we briefly address the Japanese point of view regarding the development of new radiopharmaceuticals.
Topics: Humans; Neuroendocrine Tumors; Positron-Emission Tomography; Precision Medicine; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin
PubMed: 35271754
DOI: 10.1111/cas.15327 -
Radiographics : a Review Publication of... 2015Gallium 68 ((68)Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE, GaTate) positron emission tomography (PET)/computed tomography...
Gallium 68 ((68)Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE, GaTate) positron emission tomography (PET)/computed tomography (CT) is an imaging technique for detecting and characterizing neuroendocrine tumors (NETs). GaTate, a somatostatin analog, has recently been accorded orphan drug status by the U.S. Food and Drug Administration, thereby increasing interest in and availability of this radiotracer. GaTate PET/CT allows whole-body imaging of cell surface expression of somatostatin receptors (SSTRs) and is rapidly evolving as the new imaging standard of reference for the detection and characterization of NETs. The authors discuss the normal appearance at GaTate PET/CT and the utility of this modality in a variety of these tumors, including gastrointestinal, pancreatic, and bronchial NETs as well as pheochromocytoma, paraganglioma, meningioma, and oncogenic osteomalacia. In addition, they discuss potential causes of false-positive findings, including pancreatic uncinate process activity, inflammation, osteoblastic activity, and splenosis. They also highlight the complementary role of 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) PET/CT, including the advantages of using both GaTate PET/CT and FDG PET/CT to evaluate sites of well- and poorly differentiated disease. The use of GaTate PET/CT together with FDG PET/CT allows identification of tumor heterogeneity, which provides prognostic information and can be pivotal in guiding biopsy. It also allows optimal patient management, including theranostic application of peptide receptor radionuclide therapy, and the restaging of patients following therapy.
Topics: Humans; Image Interpretation, Computer-Assisted; Multimodal Imaging; Neuroendocrine Tumors; Organometallic Compounds; Positron-Emission Tomography; Receptors, Somatostatin; Tomography, X-Ray Computed
PubMed: 25763733
DOI: 10.1148/rg.352140164 -
Frontiers in Endocrinology 2022Molecular therapeutic targets in growth hormone (GH)-secreting adenomas range from well-characterized surface receptors that recognize approved drugs, to surface and... (Review)
Review
Molecular therapeutic targets in growth hormone (GH)-secreting adenomas range from well-characterized surface receptors that recognize approved drugs, to surface and intracellular markers that are potential candidates for new drug development. Currently available medical therapies for patients with acromegaly bind to somatostatin receptors, GH receptor, or dopamine receptors, and lead to attainment of disease control in most patients. The degree of control is variable: however, correlates with both disease aggressiveness and tumor factors that predict treatment response including somatostatin receptor subtype expression, granulation pattern, kinases and their receptors, and other markers of proliferation. A better understanding of the mechanisms underlying these molecular markers and their relationship to outcomes holds promise for expanding treatment options as well as a more personalized approach to treating patients with acromegaly.
Topics: Humans; Acromegaly; Adenoma; Receptors, Somatostatin; Growth Hormone-Secreting Pituitary Adenoma; Pituitary Neoplasms
PubMed: 36545335
DOI: 10.3389/fendo.2022.1068061 -
The Journal of Clinical Endocrinology... Sep 2023Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk....
CONTEXT
Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors.
OBJECTIVE
Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs.
METHODS
Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs.
RESULTS
Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx).
CONCLUSION
SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs.
Topics: Humans; Adrenal Gland Neoplasms; Neoplasms, Second Primary; Paraganglioma; Pheochromocytoma; Receptors, Somatostatin; Retrospective Studies; Succinate Dehydrogenase
PubMed: 36946182
DOI: 10.1210/clinem/dgad166 -
Pituitary Feb 2017Acromegaly, a rare disease due to growth hormone (GH) hypersecretion by a pituitary adenoma, is associated with severe comorbidity and premature death if not adequately... (Review)
Review
Acromegaly, a rare disease due to growth hormone (GH) hypersecretion by a pituitary adenoma, is associated with severe comorbidity and premature death if not adequately treated. The usual first-line treatment is surgery. Various drugs, including somatostatin receptor ligands, dopamine agonists and GH receptor antagonists, are now available for use if surgery fails to suppress GH/IGF-I hypersecretion. Cabergoline, now the preferred dopamine agonist for treating hyperprolactinemia, is also used off-label for treating acromegaly. Cabergoline monotherapy is reported to normalize IGF-I levels in more than one-third of patients with acromegaly. When a somatostatin receptor ligand proves ineffective, cabergoline add-on therapy normalizes the IGF-I level in 40-50% of patients. Finally, when combined with the GH receptor antagonist pegvisomant in patients with mild uncontrolled disease, cabergoline helps to achieve normal IGF-I levels while avoiding the need for high-dose pegvisomant. Cabergoline is also inexpensive and well tolerated; in particular, it does not appear to promote heart valve disease.
Topics: Acromegaly; Cabergoline; Dopamine Agonists; Ergolines; Human Growth Hormone; Humans; Pituitary Neoplasms; Receptors, Somatostatin
PubMed: 28025719
DOI: 10.1007/s11102-016-0782-6 -
PET Clinics Jul 2021Several studies have demonstrated the effectiveness of somatostatin receptor (SSTR)-targeted imaging for diagnosis, staging, evaluating the possibility of treatment with... (Review)
Review
Several studies have demonstrated the effectiveness of somatostatin receptor (SSTR)-targeted imaging for diagnosis, staging, evaluating the possibility of treatment with cold somatostatin analogs, as well peptide receptor radionuclide therapy (PRRT), and evaluation of treatment response. PET with Ga-labeled somatostatin analogs provides excellent sensitivity and specificity for diagnosing and staging neuroendocrine tumors (NETs). Metabolic imaging with PET with fludeoxyglucose F/computed tomography (CT) complements the molecular imaging with Ga-SSTR PET/CT toward a personalized therapy in NET patients. The documented response rate of PRRT in NET summing up complete response, partial response, minor response, and stable disease is 70% to 80%.
Topics: Humans; Neuroendocrine Tumors; Organometallic Compounds; Positron Emission Tomography Computed Tomography; Receptors, Somatostatin; Tomography, X-Ray Computed
PubMed: 34053580
DOI: 10.1016/j.cpet.2021.03.001 -
The Journal of Clinical Endocrinology... Jun 2022The key for molecular imaging is the use of a radiotracer with a radioactive and a functional component. While the functional component targets a specific feature of the... (Review)
Review
The key for molecular imaging is the use of a radiotracer with a radioactive and a functional component. While the functional component targets a specific feature of the tumor, the radioactive component makes the target visible. Neuroendocrine neoplasms (NEN) are a diverse group of rare tumors that arise from neuroendocrine cells found mainly in the gastroenteropancreatic system, lung, thyroid, and adrenal glands. They are characterized by the expression of specific hormone receptors on the tumor cell surface, which makes them ideal targets for radiolabeled peptides. The most commonly expressed hormone receptors on NEN cells are the somatostatin receptors. They can be targeted for molecular imaging with various radiolabeled somatostatin analogs, but also with somatostatin antagonists, which have shown improved imaging quality. 18F-DOPA imaging has become a second-line imaging modality in NENs, with the exception of the evaluation of advanced medullary thyroid carcinoma. Alternatives for NENs with insufficient somatostatin receptor expression due to poor differentiation involve targeting glucose metabolism, which can also be used for prognosis. For the localization of the often-small insulinoma, glucagon-like peptide-1 (GLP-1) receptor imaging has become the new standard. Other alternatives involve metaiodobenzylguanidine and the molecular target C-X-C motif chemokine receptor-4. In addition, new radiopeptides targeting the fibroblast activation protein, the glucose-dependent insulinotropic polypeptide receptor and cholecystokinin-2 receptors have been identified in NENs and await further evaluation. This mini-review aims to provide an overview of the major molecular imaging modalities currently used in the field of NENs, and also to provide an outlook on future developments.
Topics: Carcinoma, Neuroendocrine; Humans; Molecular Imaging; Neuroendocrine Tumors; Receptors, Somatostatin; Somatostatin
PubMed: 35380158
DOI: 10.1210/clinem/dgac207 -
Journal of Nuclear Medicine : Official... Sep 2017The molecular imaging and treatment of neuroendocrine tumors (NETs) with radiolabeled somatostatin analogs represent a milestone in the development of theranostic... (Review)
Review
The molecular imaging and treatment of neuroendocrine tumors (NETs) with radiolabeled somatostatin analogs represent a milestone in the development of theranostic compounds. Whole-body scintigraphy with In-pentetreotide has revolutionized the diagnosis and staging of NETs and the evaluation of treatment outcomes. At present, diagnostic accuracy with positron-emitting radionuclides is greater than 90%. Peptide receptor radionuclide therapy (PRRT) has become a well-accepted treatment for patients with well-differentiated inoperable or metastatic NETs and disease progression after first-line treatment. Disease control rates (complete or partial remission or stable disease in patients with formerly progressive disease) of up to 95%, with a low incidence of long-term hematologic and renal toxicity, have been reported. In a recently published randomized trial, compared with intensified treatment of midgut NETs with long-acting and repeatable octreotide, PRRT reduced the hazard of disease progression and death by 79%. Upcoming developments in PRRT include the use of somatostatin receptor antagonists and α-emitting radionuclides, which may further enhance treatment outcomes.
Topics: Animals; Diagnostic Imaging; Drug Discovery; Humans; Molecular Targeted Therapy; Receptors, Somatostatin; Safety
PubMed: 28864613
DOI: 10.2967/jnumed.117.191015 -
Abdominal Radiology (New York) Dec 2022Advanced molecular imaging has come to play an integral role in the management of gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Somatostatin receptor... (Review)
Review
Advanced molecular imaging has come to play an integral role in the management of gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Somatostatin receptor (SSTR) PET has now emerged as the reference standard for the evaluation of NENs and is particularly critical in the context of peptide receptor radionuclide therapy (PRRT) eligibility. SSTR PET/MRI with liver-specific contrast agent has a strong potential for one-stop-shop multiparametric evaluation of GEP-NENs. F-FDG is a complementary radiotracer to SSTR, especially in the context of high-grade neuroendocrine neoplasms. Knowledge gaps in quantitative evaluation of molecular imaging studies and their role in assessment of response to PRRT and combination therapies are active research areas. Novel radiotracers have the potential to overcome existing limitations in the molecular imaging of GEP-NENs. The purpose of this article is to provide an overview of the current trends, pitfalls, and recent advancements of molecular imaging for GEP-NENs.
Topics: Humans; Positron Emission Tomography Computed Tomography; Neuroendocrine Tumors; Receptors, Somatostatin; Positron-Emission Tomography; Magnetic Resonance Imaging; Pancreatic Neoplasms
PubMed: 35426497
DOI: 10.1007/s00261-022-03516-2 -
Abdominal Radiology (New York) Dec 2023Molecular imaging plays a vital role in the management of neuroendocrine neoplasms (NENs). Somatostatin receptor (SSTR) PET is critical for evaluating NENs, ascertaining... (Review)
Review
Molecular imaging plays a vital role in the management of neuroendocrine neoplasms (NENs). Somatostatin receptor (SSTR) PET is critical for evaluating NENs, ascertaining peptide receptor radionuclide therapy (PRRT) eligibility, and treatment response. SSTR-PET/MRI can provide a one-stop-shop multiparametric evaluation of NENs. The acquisition of complementary imaging information in PET/MRI has distinct advantages over PET/CT and MR imaging acquisitions. The purpose of this manuscript is to provide a comprehensive overview of PET/MRI and a current review of recent PET/MRI advances in the diagnosis, staging, treatment, and surveillance of NENs.
Topics: Humans; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Receptors, Somatostatin; Magnetic Resonance Imaging; Neuroendocrine Tumors
PubMed: 36525051
DOI: 10.1007/s00261-022-03757-1