68Ga-labeled Somatostatin Analogs Research Articles

Preclinical Study of a Dual-Target Molecular Probe Labeled with 68Ga Targeting SSTR2 and FAP

Objective: Currently, 68Ga-labeled somatostatin analogs (SSAs) are the most commonly used imaging agents for patients with neuroendocrine tumors (NETs) in clinical practice, demonstrating good results in tumor diagnosis. For applications in peptide receptor radionuclide therapy (PRRT), targeted drugs should have high tumor uptake and prolonged tumor retention time. To enhance the uptake and retention of tracers in NETs, our goal is to design a 68Ga-labeled heterodimer for optimizing pharmacokinetics and assess whether this form is more efficacious than its monomeric equivalents. Methods: Using the somatostatin analog TATE and quinoline-based compound FAPI-46 as raw materials, we designed and synthesized 68Ga-labeled TATE-46. The labeling efficiency and stability were verified by Radio-HPLC. The receptor binding properties and tumor targeting were examined both in vitro and in vivo by using NCI-H727 (SSTR2/FAP, positive) and Mc38 (SSTR2/FAP, negative) cell lines and tumor-bearing mouse models. Preclinical evaluation was performed through cell uptake, pharmacokinetics, Micro PET, and biodistribution studies, and the results were compared with [68Ga]Ga-DOTA-TATE and [68Ga]Ga -FAPI-46. Immunohistochemistry and HE staining were performed on tumor tissues from tumor-bearing mice for further validation. Results: [68Ga]Ga-TATE-46 showed comparable SSTR2 and FAP targeting ability to monomeric TATE and FAPI-46 in cell uptake and PET imaging studies. [68Ga]Ga-TATE-46 exhibited significantly higher uptake in NCI-H727 (SSTR2/FAP, positive) tumors compared to [68Ga]Ga-DOTA-TATE (p < 0.001) and [68Ga]Ga-FAPI-46 (p < 0.001). No increased uptake of [68Ga]Ga-TATE-46 was observed in MC38 tumors (SSTR2/FAP, negative). Additionally, excess DOTA-TATE and/or unlabeled FAPI-46 significantly blocked the uptake of [68Ga]Ga-TATE-46 in NCI-H727 tumors (p < 0.001), confirming its dual-receptor targeting characteristics. The ex vivo biodistribution, immunofluorescence and immunohistochemistry results were in line with the in vivo imaging findings. Conclusion: Compared with 68Ga-labeled FAPI-46 and DOTA-TATE mono-specific tracers, the dual-target tracer [68Ga]Ga-TATE-46 improves tumor uptake, extends tumor retention, and enhances pharmacokinetics. It is an effective probe for non-invasive detection of tumors expressing FAP and SSTR2, and it is worth further studying its application in the expression of sstr2 and FAP-related tumors.

Cutting-Edge Imaging of Cardiac Metastases from Neuroendocrine Tumors: Lesson from a Case Series

With the increasing availability of high-performance medical imaging for the management of patients with neuroendocrine tumors (NETs), a progressive growth of asymptomatic and incidentally detected cardiac metastases (CMs) has been observed in the recent years. In clinical practice, CMs of NENs are often incidentally detected by whole-body 68Ga-labeled somatostatin analogs or 18F-fluorodihydroxyphenylalanine positron emission tomography/computed tomography, and afterwards accurately characterized by cardiac magnetic resonance (CMR) and/or gated cardiac computed tomography when CMR is contraindicated or not available. The interpreting physician should familiarize with the main imaging features of CM, a finding that may be encountered in NETs patients more than previously thought. Herein, we present a case series of four patients with CMs from small-intestine NETs highlighting strengths and weaknesses of a multimodality imaging approach in clinical practice.

Molecular imaging of pancreatic neoplasms

Pancreatic ductal adenocarcinomas (PDACs) derive from the exocrine pancreas and account for the majority of pancreatic tumors (95%). It is the seventh leading cause of cancer-related deaths and shows one of the worst prognoses in oncology with a 5-year survival rate of 9%. Pancreatic neuroendocrine tumors (pNETs) derive from the endocrine part of the pancreas. Well-differentiated pNETs are characterized by slow tumor growth and good life expectancy. In all pancreatic tumor entities, imaging plays a key role. Hybrid imaging modalities (PET/CT and PET/MRI) combine functional and structural data and may reflect a more accurate assessment of disease spread which directs subsequent treatment planning and patient management. A comprehensive search strategy was used based on PubMed and SCOPUS databases from 1999 to date. FDG PET/CT in PDAC shows high sensitivity and specificity in evaluation of T- and M-staging but lesser sensitivity of N-staging. In restaging, metabolic changes occur earlier than morphological changes in tumor size and can be assessed by molecular imaging which can act as a predictor of prognosis. 68Ga-labeled somatostatin analogs (SSAs) are the gold standard in imaging of well-differentiated pNETs. In poorly differentiated pNETs, FDG is the radiotracer of choice. PET/MRI may have added value due to higher soft-tissue contrast. However, more prospective studies comparing PET/CT and PET/MRI systems are needed. FDG PET/CT plays a key role in PDAC in staging, restaging as well as disease monitoring during follow-up. Functional imaging with 68Ga-labeled SSA is the gold standard in imaging of well-differentiated pNETs.

Importance of PET with 68Ga-Labeled Somatostatin Analogs.

Neuroendocrine tumors (NETs) still represent a diagnostic challenge because their clinical presentation is often nonspecific and usually occurs late in the disease, when metastases are already present ([1][1]). Imaging modalities such as CT, MRI, and transabdominal ultrasound are fundamental for

Biodistribution and first clinical results of 18F-SiFAlin-TATE PET: a novel 18F-labeled somatostatin analog for imaging of neuroendocrine tumors.

PET/CT using 68Ga-labeled somatostatin analogs (SSA) targeting somatostatin receptors (SSR) on the cell surface of well-differentiated neuroendocrine tumors (NET) represents the clinical reference standard for imaging. However, economic and logistic challenges of the 68Ge/68Ga generator-based approach have disadvantages over 18F-labeled compounds. Here, we present the first in-human data of 18F-SiFAlin-TATE, a novel 18F-labeled, SSR-targeting peptide. The aim was to compare the intra-individual biodistribution, tumor uptake, and image quality of 18F-SiFAlin-TATE to the clinical reference standard 68Ga-DOTA-TOC. Thirteen patients with NET staged with both 68Ga-DOTA-TOC and 18F-SiFAlin-TATE PET/CT have been included in this retrospective analysis. We compared the biodistribution in normal organs and tumor uptake of NET lesions by SUVmean and SUVmax measurement for tracers. Additionally mean and max tumor-to-liver (TLR) and tumor-to-spleen ratios (TSR) have been calculated by division of SUVmean and SUVmax of tumor lesions by the SUVmean of the liver and spleen, respectively. Additionally, image quality was visually rated by 5 blinded readers and an intra-class correlation (ICC) analysis on inter-observer agreement has been performed. Compared with 68Ga-DOTA-TOC, the biodistribution of 18F-SiFAlin-TATE showed somewhat higher, however, statistically not significant higher uptake in the liver, spleen, and adrenal glands. Significantly higher uptake was observed in the kidneys. Tumor uptake was higher in most tumor lesions with significantly higher uptake in common metastatic sites of NET including the liver (SUVmax 18.8 ± 8.4 vs. 12.8 ± 5.6; p < 0.001), lymph nodes (SUVmax 23.8 ± 20.7 vs. 17.4 ± 16.1; p < 0.001) and bone (SUVmax 16.0 ± 10.1 vs. 10.3 ± 5.7; p < 0.01) for 18F-SiFAlin-TATE. The high tumor uptake resulted in favorable TLR and TSR, comparable with that of 68Ga-DOTA-TOC. The ICC analysis on the inter-observer agreement on image quality was substantial and almost perfect. Image quality was rated as excellent in most cases in both 68Ga-DOTA-TOC and 18F-SiFAlin-TATE PET. The favorable characteristics of 18F-SiFAlin-TATE with a high image quality, the kit-like labeling procedure, and the promising clinical performance enable improved logistics and diagnostic possibilities for PET imaging of NET. Our first clinical results warrant further systematic studies investigating the clinical use of 18F-SiFAlin-TATE in NET patients.

Recent advances in the imaging of pheochromocytomas and paragangliomas

Pheochromocytoma and paraganglioma (PPGL) belong to the family of neural crest cell-derived neoplasms, and can be widely distributed throughout the body. Over the past few years, with respect to these tumors, precision medicine has offered the promise of improved patient care. Through tumor visualization and identification of molecular signatures, nuclear medicine is capable of playing a key role in PPGL precision medicine. 68Ga-labeled somatostatin analogs were found to improve the detection and staging of head and neck paragangliomas, SDHx-related PPGLs and metastatic PPGLs regardless of genetic background. For PPGLs associated with increased kinase signaling or HIF2A mutations, 18F-fluorodihydroxyphenylalanine appears to be the most informative radiopharmaceutical. This review emphasizes the current theranostic approaches and future perspective related to PPGL imaging options.

The NETPET Score: Combining FDG and Somatostatin Receptor Imaging for Optimal Management of Patients with Metastatic Well-Differentiated Neuroendocrine Tumors

Neuroendocrine tumors (NET) are often metastatic at the time of diagnosis. Metastatic well-differentiated (G1/G2) NET may display a wide range of behaviors, ranging from indolent to aggressive, even within apparently homogeneous categories. Thus, selecting the optimal treatment strategy is a challenging task. Somatostatin receptor imaging (SRI) is the standard molecular imaging technique for well-differentiated NET. When performed with 68Ga-labeled somatostatin analogs (SRI-PET), it offers exquisite sensitivity for disease staging. SRI is also a prerequisite for using targeted radionuclide therapy (e.g. 177Lu-DOTATATE). 18F-FDG imaging has traditionally been reserved for staging poorly-differentiated G3 neuroendocrine carcinomas. However, recent data showed that FDG imaging has prognostic value in patients with well-differentiated NET: high uptake was associated with an increased risk of early progression while low uptake suggested an indolent tumor.In this issue of the Journal, Chan and colleagues propose a grading system where the results from the combined reading of SRI-PET and FDG-PET are reported as a single parameter, the “NETPET” score. While the scoring system still needs validation, it is clear that time has come to think about FDG and SRI in metastatic NET not as competitors but as complementary imaging modalities. Dual-tracer imaging can be viewed as a way to characterize disease phenotype in the whole-body. Moving from the prognostic value of dual-tracer imaging to a tool that allows for individualized management would require prospective trials. This editorial will argue that dual-tracer FDG-PET and SRI-PET might influence management of patients with well-differentiated metastatic NET and help selecting between different therapy options.

Influence of PET/CT 68Ga somatostatin receptor imaging on proceeding with patients, who were previously diagnosed with 99mTc-EDDA/HYNIC-TOC SPECT.

The aim of this study was the assessment of utility of somatostatin receptor scintigraphy (SRS) by SPECT imaging using 99mTc-EDDA/HYNIC-Tyr3-octreotide (99mTc-EDDA/HYNIC-TOC) in patients with neuroendocrine neoplasm (NEN) or suspected NEN, referred to Nuclear Medicine Dept. of Voivodship Specialty Center in Rzeszow. The selected group of patients was referred also to 68Ga PET/CT. The posed question was the ratio of patients for whom PET/CT with 68Ga would change their management. The distribution of somatostatin receptors was imaged using 99mTc-EDDA/HYNIC-TOC in 61 planar and SPECT studies between 13/05/2010 and 04/02/2013 in Nuclear Medicine Dept. of Voivodship Specialty Center in Rzeszow. The patient age was within a range of 17-80, with the average age of 57.6. The average age of women (65% of patients over-all) was 55.6 and the average age of men (35% of patients overall) was 61.4. In 46 participants (75% of the study group), that underwent SRS, NEN was documented using pathology tests. Selected patients were referred to PET/CT with 68Ga labeled somatostatin analogs, DOTATATE or DOTANOC. This study group consisted of 14 female and 10 male participants with age range of 35-77 and average age of 55.5 years. Patients were classified into 3 groups, as follows: detection - referral due to clinical symptoms and/or biochemical markers (CgA-Chromogranin A, IAA-indoleacetic acid) with the aim of primary diagnosis, staging - referral with the aim of assessment of tumor spread, and follow-up - assessment of the therapy. Out of 61 patients, 24 underwent both 99mTc-EDDA/HYNIC-Tyr3-octreotide SPECT and 68Ga PET/CT. The result of PET/CT was used as a basis for further evaluation. Therefore, the patients were divided into groups; true positive TP (confirmed presence of tissue somatostatin receptors with 68Ga PET/CT) and TN (68Ga PET/CT did not detect any changes and the results were comparable and had the same influence on treatment protocol). In case of SPECT, the results were assigned as follows: TP, TN (in cases where the results were confirmed by 68Ga PET/CT), FP (patient's scintigraphy demonstrated focal change by SPECT but not PET/CT) and FN (99mTc-EDDA/HYNIC-Tyr3-octreotide SPECT failed to demonstrate any abnormalities; however, the treatment protocol was changed after PET/CT). The accuracy of SPECT diagnosis was found to be as high as 91.6%. Only in 8.4% of patients the additional PET/CT with 68Ga-labeled somatostatin analog changed the treatment protocol.

Radiopharmaceuticals for somatostatin receptor imaging.

The aim of this review is to summarize the developments and briefly characterize the somatostatin analogs which are currently used for somatostatin receptor imaging in clinical routine or in early phase clinical trials. Somatostatin (sst) receptor targeting with radiolabeled peptides has become an integral part in nuclear oncology during the last 20 years. This integration process has been initiated in Europe with the introduction to the market of 111In-DTPA-DPhe1-octreotide [111In-pentetreotide]. Introducing 99mTc in somatostatin receptor targeting radiopeptides resulted in much better image quality, higher sensitivity of tumor detection and lower mean effective dose for the examined patient. The next generation are 68Ga labeled somatostatin analogs. Due to the spatial resolution of PET technique and increasing number of PET scanners, the PET or PET/CT technique became very important in somatostatin receptor imaging. Until up to a couple of years ago the analogs of somatostatin were constructed aiming at their agonistic behavior, expecting that their internalization with the receptor acti-vated by the radiolabeled ligand and its retention within the tumor cell are crucial for efficient imaging and therapy. Recently it has been shown that the antagonists recognize more binding sites at the tumor cell membrane and hence offer an improved diagnostic efficacy, especially when the density of sst receptors is low. This approach may in future improve diagnostic value of somatostatin receptor imaging techniques. The developments in tracer design are followed by the improvements in imaging techniques. The new SPECT scanners offer resolution close to that of PET, which might open a new era for 99mTc and other SPECT radiotracers.

Nuclear imaging of neuroendocrine tumors with unknown primary: why, when and how?

Neuroendocrine tumors (NETs) with unknown primary (CUP-NET) are associated with a poor prognosis (10-year survival 22%), grade 1 and 2 NETs having a more favorable outcome than grade 3 (also called carcinoma). There is evidence that an effort should be made to localize the primary tumor even in the presence of metastasis because resection of the primary tumor(s) may improve disease-free and overall survival, and because the choice of chemotherapeutic agent depends on the location of the primary tumor. Localization of the tumors remains challenging and often relies on a combination of radiological, endoscopic and functional imaging. The functional imaging protocol for evaluation of these patients has historically relied on somatostatin receptor scintigraphy (SRS). However, the sensitivity and specificity of SRS may be unsatisfactory, especially for NETs of midgut origin. Newer PET radiotracers such as (68)Ga-labeled somatostatin analogs ((68)Ga-DOTA-SSTa) and (18)F-DOPA have shown promise. In direct comparisons between (68)Ga-DOTA-SSTa PET/CT and (99m)Tc-HYNIC-octreotide/(111)In-pentetreotide SPECT(/CT), (68)Ga-DOTA-SSTa performed better than other techniques, giving a compelling reason for switching from SPECT/CT to PET/CT imaging. (18)F-DOPA performs better than SRS and CT in well-differentiated NETs of the small intestine. For detecting pancreatic NETs, the high background uptake of (18)F-DOPA by the normal exocrine pancreas can be somewhat overcome by pretreatment with carbidopa. We have suggested a protocol in which SRS is replaced by one of the two agents (preferably with (68)Ga-DOTA-SSTa, alternatively (18)F-DOPA) as first-line nuclear tracer for detection of CUP-NET in patients with well-differentiated NETs and (18)F-FDG PET/CT may be an additional diagnostic test for poorly differentiated tumors and for prognostication. In the near future, it is expected that patients with CUP-NET will benefit from newly developed PET approaches (radiopharmaceuticals) and intraoperative PET imaging.

Ileal neuroendocrine tumors and heart: not only valvular consequences.

Ileal neuroendocrine tumors (NETs) often progress slowly, but because of their generally nonspecific symptoms, they have often metastasized to local lymph nodes and to the liver by the time the patient presents. Biochemically, most of these patients have increased levels of whole blood serotonin, urinary 5-hydroxyindoleacetic acid, and chromogranin A. Imaging work-up generally comprises computed tomography or magnetic resonance imaging and somatostatin receptor scintigraphy, or in recent years positron emission tomography with 68Ga-labeled somatostatin analogs, allowing for detection of even sub-cm lesions. Carcinoid heart disease with affected leaflets, mainly to the right side of the heart, is a well-known complication and patients routinely undergo echocardiography to diagnose and monitor this. Multitasking surgery is currently recognized as first-line treatment for ileal NETs with metastases and carcinoid heart disease. Open heart surgery and valve replacement are advocated in patients with valvular disease and progressive heart failure. When valvulopathy in the tricuspid valve results in right-sided heart failure, a sequential approach, performing valve replacement first before intra-abdominal tumor-reductive procedures are conducted, reduces the risk of bleeding. Metastases to the myocardium from ileal NETs are seen in <1-4.3% of patients, depending partly on the imaging technique used, and are generally discovered in those affected with widespread disease. Systemic treatment with somatostatin analogs, and sometimes alpha interferon, is first-line medical therapy in metastatic disease to relieve hormonal symptoms and stabilize the tumor. This treatment is also indicated when heart metastases are detected, with the addition of diuretics and fluid restriction in cases of heart failure. Myocardial metastases are rarely treated by surgical resection.

Rare case of gall bladder neuroendocrine tumor: 18F-FDG and 68Ga-DOTANOC PET/CT findings

Neuroendocrine tumors (NETs) are rare neoplasms, which are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy. Radiolabeled metaiodobenzylguanidine (MIBG) was the first radiopharmaceutical used to specifically depict and localize catecholamine-secreting tumors (pheochromocytomas, paragangliomas, and neuroblastomas) and is still regarded as a first-choice imaging technique for diagnosis and follow-up; in patients with malignant disease, MIBG scintigraphy is an essential step to select patients for 131I-MIBG therapy. Scintigraphy with 111In- or 99mTc-labeled somatostatin analogs has become the main imaging technique for NETs, particularly those expressing a high density of somatostatin receptors, such as gastroenteropancreatic tumors; this procedure is used routinely for localizing the primary tumor, evaluating disease extension, monitoring the effect of treatment and for selecting patients for radioreceptor therapy. Since the recent development of hybrid machines, it has been possible to obtain images that simultaneously hold both anatomic (computed tomography [CT]) and functional (single-photon emission computed tomography [SPECT] or positron emission tomography [PET]) information, with great impact on diagnostic accuracy. Significant improvements have been made during the past few years with the development of highly specific radiopharmaceuticals for PET studies that reflect the different metabolic pathways of NETs, such as glucose metabolism (18F-fluorodeoxyglucose), the uptake of hormone precursors (11C-5-hydroxytryptophan, 11C- or 18F-dihydroxyphenylalanine, 18F-fluorodopamine), the expression of receptors (68Ga-labeled somatostatin analogs), as well as the synthesis, storage, and release of hormones (11C-hydroxyephedrine and others). Among these radiopharmaceuticals, 68Ga-labeled somatostatin analogs are increasingly used in specialized centers in Europe for PET and PET/CT imaging and show very promising results with high diagnostic sensitivity. New somatostatin analogs with different receptor affinity as well as other peptides are currently under investigation and will further improve our diagnostic and therapeutic capabilities in the future.

Neuroendocrine tumours: the role of imaging for diagnosis and therapy

In patients with neuroendocrine tumours (NETs), a combination of morphological imaging and nuclear medicine techniques is mandatory for primary tumour visualization, staging and evaluation of somatostatin receptor status. CT and MRI are well-suited for discerning small lesions that might escape detection by single photon emission tomography (SPECT) or PET, as well as for assessing the local invasiveness of the tumour or the response to therapy. Somatostatin receptor imaging, by (111)In-pentetreotide scintigraphy or PET with (68)Ga-labelled somatostatin analogues, frequently identifies additional lesions that are not visible on CT or MRI scans. Currently, somatostatin receptor scintigraphy with (111)In-pentetreotide is the more frequently available of the two techniques to determine somatostatin receptor expression and is needed to select patients for peptide receptor radionuclide therapy. In the future, because of its higher sensitivity, PET with (68)Ga-labelled somatostatin analogues is expected to replace somatostatin receptor scintigraphy. Whereas (18)F-FDG-PET is only used in high-grade neuroendocrine cancers, PET-CT with (18)F-dihydroxy-L-phenylalanine or (11)C-5-hydroxy-L-tryptophan is a useful problem-solving tool and could be considered for the evaluation of therapy response in the future. This article reviews the role of imaging for the diagnosis and management of intestinal and pancreatic NETs. Response evaluation and controversies in NET imaging will also be discussed.

Cost-effectiveness of 99mTc-MIBI in the evaluation of thyroid nodules for malignancy: a new lease of life for an old radiopharmaceutical?

In nuclear medicine practice, physicians are often confronted with the problem that formal registration of a specific radiopharmaceutical and the indications for its use are lacking (e.g. the modern Ga-labelled somatostatin analogues). If formal registration is available, this registration often only covers a few, specific and predominantly commercially interesting indications even when the radiopharmaceutical can be applied more broadly. A good example of the latter is the case of Tc-methoxyisobutylisonitrile (MIBI). MIBI was first described in the 1980s [1, 2]. Originally developed for myocardial perfusion scintigraphy for the detection and localization of coronary artery disease, it went on to eventually achieve registration not only for this indication, but also for the assessment of global ventricular function, scintimammography for the detection of suspected breast cancer when mammography is equivocal, inadequate or indeterminate, and localization of hyperfunctioning parathyroid tissue in patients with recurrent or persistent hyperparathyroidism, both primary and secondary, and in patients with primary hyperparathyroidism scheduled to undergo initial surgery of the parathyroid glands [3]. However, for many years it has been known that MIBI scintigraphy can also be used in the diagnostic work-up of scintigraphically cold and therefore suspicious thyroid nodules in combination with fine needle biopsy (FNB) [4–12]. As Wale et al. show in this edition of the European Journal of Nuclear Medicine and Molecular Imaging [13] and Treglia et al. showed recently in a comparable meta-analysis [14], in conjunction with prior Tc-pertechnetate thyroid scintigraphy MIBI scintigraphy can achieve a very high negative predictive value ranging from 88 % to 100 % with a mean of 97 %. Furthermore, the sensitivity of MIBI scintigraphy is similarly good with an aggregate value of 96%. This indicates that a negative MIBI scan will obviate the need to surgically remove the thyroid nodule for definitive histological clarification in the large majority of patients, as the risk of malignancy in such a nodule is very low. This of course does have economic implications. Considering that the risk of missing the diagnosis of thyroid cancer is low, and a large number of, in hindsight unnecessary, comparatively expensive surgical procedures can be avoided, it is not surprising that Wale et al. are able to show that the addition of MIBI scintigraphy leads to a considerable saving in costs per patient and per cancer diagnosed while not significantly affecting life expectancy [13]. Of course, the model used by Wale et al. is a theoretical one and any model requires simplification of the sometimes complex individual situations of different patients. For example, the authors did not directly assess the life expectancy of patients scanned with MIBI, but derived these data from unrelated survival analyses of patients with thyroid cancer. This and further notable limitations of the model are mainly due to the lack of data from prospective randomized controlled trials. F. A. Verburg : F. F. Behrendt : F. M. Mottaghy :A. Heinzel Department of Nuclear Medicine, RWTH Aachen University Hospital, Pauwelsstrase 30, 52074 Aachen, Germany

Metastatic Neuroendocrine Carcinoma Presenting as a “Superscan” on 68Ga-DOTANOC Somatostatin Receptor PET/CT

PET/CT imaging using Ga-labeled somatostatin analogs has become a popular noninvasive diagnostic modality in the workup of patients with neuroendocrine tumors. A 65-year-old man with pancreatic neuroendocrine tumor with confirmed liver metastases on conventional imaging underwent restaging Ga-DOTANOC PET/CT to monitor response to cold octreotide therapy. Previous PET/CT had shown presence of multiple liver and skeletal metastases along with a primary pancreatic tumor showing intense tracer uptake. The present PET/CT study showed an increase in number and uptake of the metastatic lesions suggestive of progressive disease resulting in the appearance of a superscan.

Comparison of 18F-FDG PET/CT and 111In Pentetreotide Scan for Detection of Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine neoplasm with propensity for nodal metastases. A few reports have presented imaging results with FDG PET/CT or 111In-pentetreotide (OctreoScan, OCT) indicating a higher sensitivity for FDG than OCT, but no reports have directly compared FDG to OCT in the same patients. We reviewed our experience in a limited number of patients who underwent both procedures. Patients with MCC who had FDG PET and OCT between 2000 and 2010 in our center were retrospectively reviewed. Patients were included if they had FDG PET/CT and OCT scan within a 2-month interval. For each eligible patient, we compared all abnormal lesions identified on either scan. The findings were verified by pathology or other imaging techniques up to a 4-month follow-up. A total of 9 patients met the selection criteria with 10 dual scans (1 was scanned twice). Three patients had no documented sites of disease at the time of imaging. One patient had negative findings on both FDG and OCT initially, but 1 year later developed FDG-positive OCT-negative disease. Five patients had metastatic disease at the time of imaging: 2 were negative on OCT and positive on FDG; the other 3 were positive on both scans but had more lesions on FDG. Our data on a small number of patients are in agreement with prior individual FDG or OCT reports and suggest that, overall, FDG PET/CT detects more MCC lesions and upgrades MCC stage compared with the OCT scan. Importantly, there were no lesions identified by OCT that were missed by PET. Thus, given the added resolution and sensitivity of PET, the use of OCT in MCC in the modern era is of limited value and it remains to be seen whether newer 68Ga-labeled somatostatin analogs will perform better than OCT.

Imaging of neuroendocrine tumors

The imaging needs in the individual neuroendocrine tumor (NET) patient are very diverse and the choice of method, or combination of techniques, depends on the characteristics of the particular type of NET and its presentation. The various morphological and functional imaging methods and important methodological aspects are described. The imaging requirements for the various NET subtypes are explained and typical NET image findings are described and illustrated. The choice of the optimum imaging techniques is not only a matter of sensitivity and specificity but must also be considered in the light of the local availability and expertise in the department. Familiarity with contrast-enhancement technique for computed tomography (CT) and magnetic resonance imaging (MRI) is important in the interpretation and understanding of the imaging results. MRI including diffusion weighted imaging (DWI) for oncological imaging has been reported to improve tumor visualization and reader confidence and is expected to similarly be beneficial for NET imaging. Positron emission tomography (PET) using 68Ga-labeled somatostatin analogs is in several aspects superior to somatostatin receptor scintigraphy using Octreoscan®. Molecular imaging problem-solving tools, when PET/CT using 68Ga-labeled somatostatin analogs fails, are PET/CT with 11C-5-HTP and 18F-DOPA.

PET SUV correlates with radionuclide uptake in peptide receptor therapy in meningioma

To investigate whether the tumour uptake of radionuclide in peptide receptor radionuclide therapy (PRRT) of meningioma can be predicted by a PET scan with (68)Ga-labelled somatostatin analogue. In this pilot trial, 11 meningioma patients with a PET scan indicating somatostatin receptor expression received PRRT with 7.4 GBq (177)Lu-DOTATOC or (177)Lu-DOTATATE, followed by external beam radiotherapy. A second PET scan was scheduled for 3 months after therapy. During PRRT, multiple whole-body scans and a SPECT/CT scan of the head and neck region were acquired and used to determine the kinetics and dose in the voxel with the highest radionuclide uptake within the tumour. Maximum voxel dose and retention of activity 1 h after administration in PRRT were compared to the maximum standardized uptake values (SUV(max)) in the meningiomas from the PET scans before and after therapy. The median SUV(max) in the meningiomas was 13.7 (range 4.3 to 68.7), and the maximum fractional radionuclide uptake in voxels of size 0.11 cm³ was a median of 23.4 × 10(-6) (range 0.4 × 10(-6) to 68.3 × 10(-6)). A strong correlation was observed between SUV(max) and the PRRT radionuclide tumour retention in the voxels with the highest uptake (Spearman's rank test, P < 0.01). Excluding one patient who showed large differences in biokinetics between PET and PRRT and another patient with incomplete data, linear regression analysis indicated significant correlations between SUV(max) and the therapeutic uptake (r = 0.95) and between SUV(max) and the maximum voxel dose from PRRT (r = 0.76). Observed absolute deviations from the values expected from regression were a median of 5.6 × 10(-6) (maximum 9.3 × 10(-6)) for the voxel fractional radionuclide uptake and 0.40 Gy per GBq (maximum 0.85 Gy per GBq) (177)Lu for the voxel dose from PRRT. PET with (68)Ga-labelled somatostatin analogues allows the pretherapeutic assessment of tumour radionuclide uptake in PRRT of meningioma and an estimate of the achievable dose.

Radiopeptide Imaging and Therapy in the United States

Radiolabeled peptides targeted against receptors on the cell surface have been shown to be remarkably specific and effective in the diagnosis and therapy of malignant disease. Much of the early work in this field took place outside the United States, but in recent years the research effort within the United States has accelerated. Most of the initial studies in the United States focused on somatostatin receptor ligands. (111)In-pentetreotide was approved in 1994 and has been used extensively in the diagnosis and management of a wide variety of neuroendocrine tumors, particularly carcinoid. This work was extended to (99m)Tc-labeled analogs, and the most successful, (99m)Tc-depreotide, was approved in 1999. This agent was found to be accurate in the diagnosis of lung cancer, but it was not particularly successful because it was supplanted by (18)F-FDG imaging with positron tomography. More recently, studies with (68)Ga-labeled somatostatin analogs were initiated in the United States. This effort was delayed relative to that in other parts of the world because of difficulty in obtaining the necessary generators and regulatory uncertainty, both of which are less of a problem currently. Several ligands are being developed to image melanoma through targeting of the melanocyte-stimulating hormone receptor. Other ligands are being developed to use the arginine-glycine-aspartate oligopeptide to target angiogenesis and to use bombesin analogs to target the gastrin-releasing peptide receptor for the diagnosis and potential therapy of prostate cancer. Peptide dimers that target 2 receptors simultaneously are also being constructed, potentially increasing the selectivity of the approach significantly. Radiopeptide therapy has been explored with these ligands, initially with high-dose (111)In-pentetreotide. This step has been followed by U.S. participation in several trials with (90)Y-, (177)Lu-, and (188)Re-labeled analogs. Some of these agents are now available clinically outside the United States, and it is important to design and conduct the appropriate trials so that this therapy can be offered within the United States.

Apport de la tomographie par émission de positons dans les tumeurs endocrines digestives : choix du traceur

Digestive endocrine tumors represent a heterogeneous group of neoplasm sharing common characteristics such as their high density of peptide receptors, their ability to take up amino acids and decarboxylate them into biogenic amines and their low glycolytic activity. These features are used for nuclear imaging targeting. To date, somatostatin receptor scintigraphy is considered the “gold standard” imaging procedure of well-differentiated tumors. Despite the significant contribution of SPECT/CT, the use of positron emission tomography imaging (PET) is growing rapidly. Three PET imaging modalities are currently available: 68Ga-labeled somatostatin analogs PET, 18F-dihydroxyphenylalanine PET ( 18F-DOPA) and 18F-deoxyglucose PET ( 18F-FDG). This article focuses on the current targets of molecular imaging and highlights the potential clinical applications of new targets.