PET and PET/CT with <sup>68</sup>Gallium-Labeled Somatostatin Analogues in Non GEP-NETs Tumors

Sollini, Martina; Erba, Paola Anna; Fraternali, Alessandro; Casali, Massimiliano; Di Paolo, Maria Liberata; Froio, Armando; Frasoldati, Andrea; Versari, Annibale

doi:https://doi.org/10.1155/2014/194123

The Scientific World Journal

On this page

Abstract Introduction Conclusion References Copyright Related Articles

Review Article | Open Access

Volume 2014 | Article ID 194123 | https://doi.org/10.1155/2014/194123

PET and PET/CT with ⁶⁸Gallium-Labeled Somatostatin Analogues in Non GEP-NETs Tumors

Martina Sollini,¹Paola Anna Erba,²Alessandro Fraternali,¹Massimiliano Casali,¹Maria Liberata Di Paolo,¹Armando Froio,¹Andrea Frasoldati,³and Annibale Versari¹

Academic Editor: H. P. Easwaran, H.-J. Biersack, J. Yu

Received31 Aug 2013

Accepted30 Oct 2013

Published13 Feb 2014

Abstract

Somatostatin (SST) is a 28-amino-acid cyclic neuropeptide mainly secreted by neurons and endocrine cells. A major interest for SST receptors (SSTR) as target for in vivo diagnostic and therapeutic purposes was born since a series of stable synthetic SST-analouges PET became available, being the native somatostatin non feasible for clinical use due to the very low metabolic stability. The rationale for the employment of SST-analogues to image cancer is both based on the expression of SSTR by tumor and on the high affinity of these compounds for SSTR. The primary indication of SST-analogues imaging is for neuroendocrine tumors (NETs), which usually express a high density of SSTR, so they can be effectively targeted and visualized with radiolabeled SST-analogues in vivo. Particularly, SST-analogues imaging has been widely employed in gastroenteropancreatic (GEP) NETs. Nevertheless, a variety of tumors other than NETs expresses SSTR thus SST-analogues imaging can also be used in these tumors, particularly if treatment with radiolabeled therapeutic SST-analouges PET is being considered. The aim of this paper is to provide a concise overview of the role of positron emission tomography/computed tomography (PET/CT) with ⁶⁸Ga-radiolabeled SST-analouges PET in tumors other than GEP-NETs.

1. Introduction

Scintigraphy with radiolabeled somatostatin (SST) analogues, first labeled with ¹²³I and subsequently with ¹¹¹In and , has proven useful in diagnosing SST-receptor- (SSTR-) positive tumors with a reported detection rate of 50–100% [1–12]. Although SSTR scintigraphy shows high efficacy for whole-body imaging, there are some limitations in organs with higher physiological uptake (e.g., liver) and in terms of detection of small lesions due to the suboptimal physical resolution of the isotopes used [13, 14]. More recently, the development of SST-analogues radiolabeled with ⁶⁸Ga for positron emission tomography (PET) imaging such as [⁶⁸Ga-DOTA⁰-Tyr³]octreotide (⁶⁸Ga-DOTATOC, ⁶⁸Ga-edotreotide), [⁶⁸Ga-DOTA⁰-¹NaI³]octreotide (⁶⁸Ga-DOTANOC), and [⁶⁸Ga-DOTA⁰-Tyr³]octreotate (⁶⁸Ga-DOTATATE) has brought clear advantages compared to radiolabeled SST-analogues scintigraphy offering a higher spatial resolution and improving pharmacokinetics [15–17]. Although ⁶⁸Ga-DOTATOC, ⁶⁸Ga-DOTANOC, and ⁶⁸Ga-DOTATATE can all bind to SSTR subtype 2, they have different affinity profiles for the other SSTR subtypes [18]. In particular, ⁶⁸Ga-DOTANOC also shows a good affinity for SSTR subtypes 3 and 5, ⁶⁸Ga-DOTATOC also binds to SSTR5 (although with lower affinity than DOTANOC), while ⁶⁸Ga-DOTATATE has a predominant affinity for SSTR2 [19]. More recently, has been evaluated the ⁶⁸Ga-labeled DOTA-lanreotide (DOTALAN) for which has been reported a high affinity to the SSTR subtypes 2–5 [20, 21] although other data confirmed a high affinity only for SSTR subtypes 3 and 5 [22]. The dosimetric data measured for the whole body and for specific organs using ⁶⁸Ga-DOTATATE [23] have been published recently. Although the organ doses and effective doses for ⁶⁸Ga-DOTATATE, and ⁶⁸Ga-DOTATOC are similar (though ⁶⁸Ga-DOTATOC is slightly lower), the reported dosimetry of ⁶⁸Ga-DOTANOC is the lowest [23–25]. Importantly, the effective dose per megabecquerel for ⁶⁸Ga-labeled SST-analogues is approximately 3–5 times lower than for ¹¹¹In-DTPA-octreotide resulting in an additional advantage of PET tracers compared to radiolabeled SST-analogues scintigraphy [23, 26].

Finally, there was no observed toxicity, immediate or delayed, during the followup (1 year), for ⁶⁸Ga-DOTATATE demonstrating that this radiopharmaceutical is safe and both organ-specific and effective dose exposures are acceptable [23].

The primary indication of radiolabeled SST-analogues imaging is for neuroendocrine tumors (NETs), a heterogeneous group of neoplasms that arise from endocrine cells within glands (adrenal medulla, pituitary, and parathyroid) or from endocrine islets in thyroid, pancreas, or respiratory/gastrointestinal tract, which usually express a high density of SSTR. However radiolabeled SST-analogues can also be used in the imaging of inflammatory granulomatous and autoimmune conditions as well as non NETs although they cannot be considered as the first-choice functional imaging modality in the management of these patients, except for the determination of SSTR status [27–30]. Table 1 summarizes the different SSTR subtypes expressed by each tumor considered.

The aim of this paper is to provide a concise overview of the role of positron emission tomography/computed tomography (PET/CT) with ⁶⁸Ga-labeled SST-analogues in tumors other than GEP-NETs (Tables 2 and 3).

2. Sympathoadrenal System Tumors

The use of ⁶⁸Ga-labeled SST-analogues PET and PET/CT paraganglioma (Figure 1) and phaeochromocytoma (Figure 2) remains small, consisting mainly of case reports and small series.

Fanti et al. [31] evaluated the role of ⁶⁸Ga-DOTANOC in 14 patients with NET including 3 cases of paragangliomas. All paragangliomas were detected with ⁶⁸Ga-DOTANOC and were strongly positive. Mittal et al. [32] retrospectively evaluated 145 patients including phaeochromocytoma () and paraganglioma () with ⁶⁸Ga-DOTATATE PET/CT. PET/CT was positive in only 1 patient affected by paraganglioma. Several authors have reported the higher diagnostic performances of ⁶⁸Ga-DOTATATE PET/CT compared to ¹²³I-MIBG scintigraphy in phaeochromocytoma and paraganglioma [33–35]. Kroiss et al. [36] reported a higher sensitivity for lesion detection of ⁶⁸Ga-DOTATOC PET/CT in metastatic phaeochromocytoma patients () compared to ¹²³I-MIBG scan (92% and 63%, resp.). More recently, Maurice et al. [37] reported similar results in 15 patients with phaeochromocytoma () or paragangliomas () evaluated with ⁶⁸Ga-DOTATATE PET/CT and ¹²³I-MIBG single photon emission computed tomography (SPECT). Utilizing ¹²³I-MIBG scintigraphy as gold standard, ⁶⁸Ga-DOTATATE had a sensitivity of 80% and a positive predictive value of 62%. The greatest discordance was in head and neck lesions, with the lesions in 4 patients being picked up by ⁶⁸Ga-DOTATATE and missed by ¹²³I-MIBG. On a per-lesion analysis, ⁶⁸Ga-DOTATATE was superior to ¹²³I-MIBG in detecting lesions in all anatomical locations (particularly bone lesions). Very recently, Sharma et al. [38] studied 26 patients with known or suspected head and neck paragangliomas by ⁶⁸Ga-DOTANOC PET/CT and compared PET/CT findings to ¹²³I-MIBG scintigraphy and CT/MRI results. ⁶⁸Ga-DOTANOC PET/CT was positive in all patients and it was able to detect more lesions () compared to ¹²³I-MIBG alone or combined with CT/MRI ( and , resp.). ⁶⁸Ga-DOTANOC PET/CT has also been compared to CT for the evaluation of bone metastases in patients with NET including patients with paraganglioma (), being more accurate than CT for the early identification of bone lesions [31].

Hofman et al. [39] compared ⁶⁸Ga-DOTATATE PET/CT to ¹¹¹In-octreotide imaging (SPECT or SPECT/CT) in a series of oncological patients including phaeochromocytoma () in order to identify the management impact of incremental diagnostic information obtained from PET/CT compared with conventional staging. ⁶⁸Ga-DOTATATE PET/CT provided additional diagnostic information in a large proportion of patients with consequent high management impact. This impact included directing patients to curative surgery by identifying the primary site and directing patients with multiple metastases to systemic therapy.

In conclusion, in case of negative ¹²³I-MIBG scan in patients with a high pretest probability of phaeochromocytoma or paraganglioma, ⁶⁸Ga-labeled SST-analogues PET or PET/CT should be considered as the next investigation. Additionally, ⁶⁸Ga-labeled SST-analogues PET/CT should be considered in the staging of patients in whom metastatic spread, particularly to the bone, is suspected.

3. Lung Tumors

⁶⁸Ga-SST-analogues PET and PET/CT have been evaluated in all types of lung tumor (Figures 3 and 4). Hofmann et al. [15] compared the diagnostic values of ¹¹¹In-octreotide scintigraphy and ⁶⁸Ga-DOTATOC PET to morphologic imaging in 8 patients with metastatic carcinoid tumors including 2 bronchial carcinoids. ⁶⁸Ga-DOTATOC PET was superior to ¹¹¹In-octreotide scintigraphy in the identification of tumor lesions (overall sensitivity of 100% versus 85%). Similarly, Koukouraki et al. [40] used ⁶⁸Ga-DOTATOC PET to evaluate 15 cases of carcinoid tumors, including 2 cases of pulmonary carcinoids, reporting an overall sensitivity of 92%. Gabriel et al. [41] used ⁶⁸Ga-DOTATOC PET to evaluate 84 patients with NET, including 5 patients with bronchial carcinoids, and reported results higher than those obtained with radiolabeled SST-analogues SPECT or CT. Ambrosini et al. [42] compared ⁶⁸Ga-DOTANOC PET/CT to CT scan in 11 patients with bronchial carcinoids. There were no false-positive findings at PET/CT, and ⁶⁸Ga-DOTANOC PET/CT detected more lesions than CT (37 versus 21). On a clinical basis, ⁶⁸Ga-DOTANOC PET/CT provided additional information in 82% of patients changing the clinical management in 33% of cases. Kayani et al. [43] compared the performance of ⁶⁸Ga-DOTATATE PET/CT to [¹⁸F]FDG-PET/CT in the detection of pulmonary NET and correlated the PET radiotracer uptake to tumor grade on histology (11 typical carcinoids, 2 atypical carcinoids, 1 large cell neuroendocrine tumor, 1 small cell neuroendocrine carcinoma, 1 non-small cell lung cancer with neuroendocrine differentiation, and 2 cases of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia). All typical carcinoids showed high ⁶⁸Ga-DOTATATE uptake , but 4/11 showed negative or faint [¹⁸F]FDG uptake , while atypical carcinoids showed high uptake of [¹⁸F]FDG , but 3/5 showed only faint accumulation of ⁶⁸Ga-DOTATATE . Neither case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia showed ⁶⁸Ga-DOTATATE or [¹⁸F]FDG uptake. No false-positive results were observed on ⁶⁸Ga-DOTATATE PET/CT, while [¹⁸F]FDG-PET/CT was false-positive in 3 cases due to inflammation. Kumar et al. [44] compared ⁶⁸Ga-DOTATATE and [¹⁸F]FDG PET/CT in 7 patients with bronchial mass detected by CT (carcinoid tumors, ; inflammatory myofibroblastic tumor, ; mucoepidermoid carcinoma, ; hamartoma, ; synovial cell sarcoma, ). The typical carcinoids had mild [¹⁸F]FDG uptake and high ⁶⁸Ga-DOTATOC uptake. Atypical carcinoid had moderate [¹⁸F]FDG uptake and high ⁶⁸Ga-DOTATOC uptake. Inflammatory myofibroblastic tumor and mucoepidermoid carcinoma were positive on [¹⁸F]FDG-PET/CT (high and moderate uptake, resp.) and both were negative using ⁶⁸Ga-DOTATOC PET/CT. Hamartoma showed no uptake on either [¹⁸F]FDG or ⁶⁸Ga-DOTATOC PET/CT scans. Synovial cell sarcoma showed moderate [¹⁸F]FDG uptake and mild focal ⁶⁸Ga-DOTATOC uptake. More recently, Jindal et al. [45] reported similar results in 20 patients with pulmonary carcinoids (13 typical and 7 atypical). In this series all the atypical carcinoids revealed higher uptake on the [¹⁸F]FDG-PET/CT than that in typical carcinoids while was significantly higher in typical carcinoids () compared with atypical carcinoids () on ⁶⁸Ga-DOTATOC PET/CT. Jindal et al. [46] in a retrospective analysis of patients with primary pulmonary carcinoid () who underwent ⁶⁸Ga-DOTATOC PET/CT reported a detection rate of 95%. Putzer et al. [47] compared ⁶⁸Ga-DOTALAN to ⁶⁸Ga-DOTATOC PET in 53 patients with cancer including NET of the lung (), SCLC (), and bronchial carcinoid (). Results showed that ⁶⁸Ga-DOTATOC has a clear advantage over ⁶⁸Ga-DOTALAN in detection and staging of this series of NETs.

⁶⁸Ga-SST-analogues PET/CT has also been compared to CT and bone scintigraphy for the evaluation of bone metastases in patients with lung NET being more accurate than CT and bone scintigraphy for the early identification of bone lesions [48, 49]. Finally, ⁶⁸Ga-DOTATATE PET/CT has also been evaluated to predict progression-free survival and clinical outcome after peptide radioreceptor therapy (PRRT) in a series of patients with well-differentiated NET including 4 cases with lung NET. Results showed that patients with a decline in tumor-to-spleen SUV ratio () after finishing the first cycle of PRRT had a significant longer time to progression than patients without favorable changes, suggesting that this parameter has a potential role in the early prediction of outcome in patients with well-differentiated NET [50].

Dimitrakopoulou-Strauss et al. [51] compared SSTR expression assessed by ⁶⁸Ga-DOTATOC PET to tumor viability assessed by [¹⁸F]FDG-PET in 9 patients with NSCLC. Moderately enhanced ⁶⁸Ga-DOTATOC uptake was noted in 7/9 primary tumors (mean for ⁶⁸Ga-DOTATOC and 5.683 for [¹⁸F]FDG) but none of the 8 metastases which were positive on [¹⁸F]FDG-PET showed any ⁶⁸Ga-DOTATOC uptake. These findings suggest a loss of the SSTR expression in metastases as compared with the NSCLC primary tumors.

Recently, we evaluated the performances of PET/CT with ⁶⁸Ga-labeled SST-analogues in 24 patients with progressive extensive SCLC, to select patients for subsequent PRRT and compared ⁶⁸Ga-labeled SST-analogues PET/CT results to contrast-enhanced CT findings. PET/CT was positive in 83% of patients and concordant to CT findings for all the sites of disease in 37.5% of cases [52].

In conclusion, the degree of uptake and different uptake patterns on [¹⁸F]FDG and ⁶⁸Ga-SST-analogues PET or PET/CT may be helpful in differentiating between typical and atypical carcinoids. ⁶⁸Ga-SST-analogues PET/CT may be useful also to stage disease in lung cancer and to select patients for the best treatment option, including PRRT.

4. Brain Neuroepithelial Tissue Tumors

The overexpression of SSTR has been reported in most high grade gliomas and it may be an interesting target for PRRT. ⁶⁸Ga-DOTATOC PET showed SSTR expression (unpublished data from Innsbruck Medical University) in the majority of patients with brain tumors (89%) including glioma (), medulloblastoma (), anaplastic astrocytoma (), and glioblastoma () with a different degree of radiotracer uptake (faint = 37%, medium = 21%, and intense = 31%) [53]. Mittal et al. [32] retrospectively evaluated 145 patients including neuroblastoma () with ⁶⁸Ga-DOTATATE PET/CT with different purposes (initial staging, ; disease recurrence detection and response evaluation, each). In all the patients evaluated PET/CT was positive and in 5/6 cases in which ⁶⁸Ga-DOTATATE PET/CT was performed as initial stage it was able to detect metastatic site of disease. Kroiss et al. [36] compared ⁶⁸Ga-DOTATOC PET/CT to ¹²³I-MIBG scan in a series of patients including neuroblastoma () reporting the superiority of PET/CT compared to scintigraphy (sensitivity of 97% and 91%, resp.). ⁶⁸Ga-radiolabeled SST-analogues PET/CT has been also used to select patients for PRRT (neuroblastoma, ; glioma, ) [54, 55] and to evaluate treatment response combined with other imaging modalities [54].

5. Meningioma

Several authors have investigated the role of ⁶⁸Ga-labeled SST-analogues PET/CT in patients with intracranial meningioma. Virtually, all patients with meningioma present ⁶⁸Ga-labeled SST-analogues uptake (Figure 5). Afshar-Oromieh et al. [56] compared diagnostic accuracy of ⁶⁸Ga-DOTATOC PET/CT to brain contrast-enhanced MRI in a large series of meningioma patients before radiotherapy. In the 134 patients investigated by both modalities, 190 meningiomas were detected by ⁶⁸Ga-DOTATOC PET/CT and 171 by contrast-enhanced MRI. With the knowledge of the PET/CT data, MRI scans were reinvestigated, leading to the detection of 4 of the 19 incidental meningiomas, resulting in an overall detection rate of 92% of the meningioma lesions that have been found by PET/CT. Milker-Zabel et al. [57] compared the planning target volume outlined on CT and contrast-enhanced MRI to the planning target volume outlined on ⁶⁸Ga-DOTATOC PET. Patients were treated according to the planning target volume defined with CT, MRI, and PET. The planning target volume defined with CT, MRI, and PET was somewhat larger than the volume detectable in MRI/CT (median 57.2 cc and 49.6 cc, resp.). In all patients ⁶⁸Ga-DOTATOC PET delivered additional information concerning tumor extension and the planning target volume was significantly modified based on ⁶⁸Ga-DOTATOC PET data in 73% of the cases. Similarly, Gehler et al. [58] defined the gross tumor volume by MRI, CT, and ⁶⁸Ga-DOTATOC PET/CT in 26 patients with meningioma. Initial gross tumor volume definition was only based on radiological data and was secondarily integrated with ⁶⁸Ga-DOTATOC PET/CT information. ⁶⁸Ga-DOTATOC PET/CT provided additional information concerning tumor extension in 65% of patients (especially for skull base manifestations and recurrent disease after surgery) and modified the planning target volume in more than half of patients. Nyuyki et al. [59] investigated the potential value of ⁶⁸Ga-DOTATOC PET/CT in the definition of the gross tumor volume in 42 meningioma patients before radiotherapy. ⁶⁸Ga-DOTATOC PET/CT findings were compared to CT and MRI. Results showed that ⁶⁸Ga-DOTATOC PET/CT enabled delineation of SSTR-positive meningiomas and provided additional information compared to both CT and MRI regarding the planning of stereotactic radiotherapy (particularly for the detection of osseous infiltration). Additionally, in a subgroup of patients with multiple meningiomas, ⁶⁸Ga-DOTATOC PET/CT was able to identify more lesions compared to CT or MRI (19 versus 10, resp.). Similarly, Graf et al. [60] retrospectively compared ⁶⁸Ga-DOTATOC PET/CT to MRI and CT in the delineation of infracranial extension of skull base meningiomas in 16 patients subsequently treated with fractionated stereotactic radiotherapy. The mean infracranial volume delineable in PET was somewhat larger than the volume detectable in MRI/CT ( cm³ and cm³, resp.). However, authors have concluded that ⁶⁸Ga-DOTATOC PET/CT may be useful for planning fractionated stereotactic radiation when used in addition to conventional imaging modalities often inconclusive in the skull base region. Henze et al. [61, 62] characterized meningioma with dynamic ⁶⁸Ga-DOTATOC PET in order to evaluate kinetic parameters reporting a good correlation with MRI and CT findings and a significant difference of radiotracer uptake between meningioma and reference tissue (mean SUV = 10.5 and 1.3, resp.) suggesting a possible role of ⁶⁸Ga-DOTATOC PET/CT in monitoring meningioma SSTR expression after radiotherapy. Recently, Hänscheid et al. [63] evaluated the predictive role of ⁶⁸Ga-labeled SST-analogues PET to assess tumor radionuclide uptake in PRRT of meningioma. Results showed a strong correlation between and PRRT radionuclide tumor retention in the voxels with the highest uptake suggesting a potential role of ⁶⁸Ga-labeled SST-analogues PET to estimate the PRRT achievable dose. Therefore ⁶⁸Ga-labeled SST-analogues PET/CT may provide additional information in patients with uncertain or equivocal results using MRI or could help to confirm a diagnosis of meningioma based on MRI or may help to confirm MRI-based diagnosis of meningioma in cases of biopsy limitations. Finally, ⁶⁸Ga-labeled SST-analogues PET or PET/CT may be useful to delineate the target volume for fractionated stereotactic radiotherapy.

6. Medullary Thyroid Cancer

Although studies investigating larger and more homogeneous patient populations are needed to better elucidate the potential diagnostic role of new PET tracers for the assessment of recurrent medullary thyroid carcinoma (MTC), the preliminary published data seem to suggest that the diagnostic role of ⁶⁸Ga-SST-analogues appears to be controversial (Figure 6). In fact, well-differentiated tumors show a variable and often low SSTR subtype cell expression. Of course, the evidence of a high uptake of ⁶⁸Ga-labeled SST-analogues could be used to accurately define the tumor biology “map” and therefore may be potentially helpful in selecting the most appropriate therapeutic option. Conry et al. [64] compared the sensitivity of ⁶⁸Ga-DOTATATE PET/CT to [¹⁸F]FDG-PET/CT in a series of 18 patients with recurrent MTC. Although the overall detection rate for both procedures was comparable (positive results in 72% and 77% of the cases for ⁶⁸Ga-DOTATATE and [¹⁸F]FDG, resp.), on a region-based analysis [¹⁸F]FDG-PET identified more metastatic lesions than ⁶⁸Ga-DOTATATE PET/CT (28 versus 23, resp.). Treglia et al. [65] retrospectively compared PET/CT with ⁶⁸Ga-DOTATATE, [¹⁸F]FDG, and [¹⁸F]DOPA in 18 patients with residual/recurrent MTC suspected on the basis of elevated serum calcitonin levels. Results showed statistically different sensitivity values between [¹⁸F]DOPA and [¹⁸F]FDG-PET/CT (72% and 17%, resp.) and between [¹⁸F]DOPA and ⁶⁸Ga-DOTATATE PET/CT (72% and 33%, resp.). Miederer et al. [66] compared a score of SSTR2 immunoistochemistry with the in vivo SUV of preoperative or prebiopsy ⁶⁸Ga-DOTATOC PET/CT in a small series of patients including 2 patients with metastases from MTC. In these patients who were negative on immunohistochemistry PET/CT showed a moderate ⁶⁸Ga-DOTATOC uptake ( and 6.8). Koukouraki et al. [67] evaluating the pharmacokinetics of ⁶⁸Ga-DOTATOC in series of patients with metastatic NET reported the lowest ⁶⁸Ga-DOTATOC uptake in the patient with MTC. In another series of patients, including one case of MTC, Koukouraki et al. [40] compared ⁶⁸Ga-DOTATOC to [¹⁸F]FDG PET results. In this case ⁶⁸Ga-DOTATOC PET showed 50% of lesions evident at [¹⁸F]FDG-PET. Very recently, Putzer et al. [47] compared ⁶⁸Ga-DOTALAN to ⁶⁸Ga-DOTATOC PET in 53 patients with cancer including 8 patients with MTC. In this series of NETs ⁶⁸Ga-DOTATOC PET showed a clear advantage over ⁶⁸Ga-DOTALAN PET in both lesion detection and staging.

7. Differentiated Thyroid Carcinoma

Although papillary, follicular, and anaplastic thyroid cancers and also Hürthle-cell carcinomas do not belong to the group of traditional NET, ⁶⁸Ga-SST-analogues PET and PET/CT may be positive in many patients (Figure 7) and could provide, especially in negative radioiodine cases, new therapeutic options. Mittal et al. [32] retrospectively evaluated 145 patients including differentiated thyroid carcinoma (DTC) patients presenting thyroglobulin-elevated negative iodine scan () with ⁶⁸Ga-DOTATATE PET/CT. In all patients evaluated, PET/CT was positive (cervical nodes, ; remnant and cervical nodes, ; thyroid bed soft tissue nodule, ). Middendorp et al. [68] compared ⁶⁸Ga-DOTATOC PET/CT to [¹⁸F]FDG-PET/CT in 17 patients with recurrent DTC. Both PET tracers consistently detected metastases in 12 patients. [¹⁸F]FDG-PET/CT has been reported more sensitive compared to ⁶⁸Ga-DOTATOC PET/CT in the detection of radioiodine negative lesions (64% versus 31%) but not in radioiodine positive lesions (48% versus 46%). On a lesion-by-lesion basis, only 2% of lesions were visible using ⁶⁸Ga-DOTATOC PET/CT. Gabriel et al. [69] reported the usefulness of ⁶⁸Ga-SST analogues PET/CT to identify patients with thyroid cancer with radioiodine negative metastases () suitable for PRRT. Similarly, our group used ⁶⁸Ga-DOTATOC PET/CT to select patients with radioiodine negative metastatic DTC () for PRRT [70].

8. Thymic Malignancies

Few data are available about the role of ⁶⁸Ga-SST-analogues PET in thymic malignancies [40, 48, 66, 67, 71–73].

Miederer et al. [66] compared a score of SSTR2 immunoistochemistry with the in vivo SUV of preoperative or pre-biopsy ⁶⁸Ga-DOTATOC PET/CT in a small series of patients including one case of thymoma. In this patient who was negative on immunohistochemistry, PET/CT showed a faint ⁶⁸Ga-DOTATOC uptake (). Dutta et al. [72] investigated 3 patients with thymic carcinoid tumors by ⁶⁸Ga-DOTATOC PET/CT but none of these tumors showed radiotracer uptake. Koukouraki et al. [40] compared ⁶⁸Ga-DOTATOC PET to [¹⁸F]FDG-PET in a series of patients including one case of carcinoid of thymus in which the disease was correctly addressed by both PET radiotracers. We reported a series of 39 patients with metastatic thymic malignancies evaluated by ⁶⁸Ga-SST-analogues PET/CT and [¹⁸F]FDG-PET/CT. ⁶⁸Ga-SST-analogues PET/CT and [¹⁸F]FDG-PET/CT were concordant in 43% of cases (both positive in 36% of cases and both negative in 8% of patients); in 52% of patients [¹⁸F]FDG-PET/CT was positive and ⁶⁸Ga-SST-analogues PET/CT was negative while in the remaining 5% of cases ⁶⁸Ga-SST-analogues PET/CT was positive and [¹⁸F]FDG-PET/CT was negative. In a per-lesion analysis, all lesions shown by contrast enhanced CT scan, which was considered the gold standard, were detected in 20% and 43% of cases using ⁶⁸Ga-SST-analogues and [¹⁸F]FDG, respectively; in the remaining cases we observed at least one measurable CT lesion without either ⁶⁸Ga-SST-analogues or [¹⁸F]FDG uptake. In this series of thymic neoplasms at restaging a predominant [¹⁸F]FDG positivity was observed compared to ⁶⁸Ga-SST-analogues at PET/CT suggesting a relative loss of SSTR expression during thymic malignancies progression and a subsequent increasing of biological aggressiveness [73] (Figure 8).

9. Merkel Cell Carcinoma

Merkel cell tumors are aggressive neoplasms that often metastasize and, despite therapy, the disease-related death rate is high. Ultrastructurally and immunocytochemically, the majority of these tumors have neuroendocrine characteristics. Establishing the extent of the disease may ensure an optimal choice of treatment for these tumors; however, due to the rarity of these tumors, few cases have been evaluated by ⁶⁸Ga-labeled SST-analogues PET/CT. Nevertheless, available data showed the usefulness of ⁶⁸Ga-labeled SST-analogues PET/CT to stage and restage patients with Merkel cell carcinoma, and also to identify patients suitable for PRRT and to evaluate treatment response [48, 67, 74–77].

10. Breast Cancer

In breast cancer differentiated tumors express more SSTR2 than undifferentiated ones, and estrogens positively affect SSTR2 expression; additionally, the research of new factors that could allow a more accurate prognosis of the existing disease and that could improve traditional treatment strategies remains critical [29]. However no sufficient data are available about the role of ⁶⁸Ga-SST-analogues PET or PET/CT in this clinical setting (Figure 9). Elgeti et al. [78] retrospectively analyzed ⁶⁸Ga-DOTATOC PET/CT performed for staging purpose in 33 women with NET. In 6/33 patients ⁶⁸Ga-DOTATOC PET/CT revealed the presence of a breast lesion classified as suspected in 4/6 cases. In 2 cases the suspected breast lesion was diagnosed as NET metastases while in the remaining 2 cases it was diagnosed as primary breast cancer resulting in a change of therapeutic management. Primary breast cancer presented a lower ⁶⁸Ga-DOTATOC uptake compared to concomitant abdominal NET lesions. In this small series of patients ⁶⁸Ga-DOTATOC PET/CT not only improved NET staging but also increased the chance to detect SSTR-positive breast cancer. In the case of breast lesions, authors suggested further diagnostic characterization since the confirmation of a secondary tumor impact on therapeutic management of patients.

11. Colorectal Cancer

Some data suggest that SSTR2 gene expression in colorectal cancer might be related to a more favorable outcome [79]. However no sufficient data are available about the role of ⁶⁸Ga-SST-analogues PET/CT in this clinical setting [80, 81]. Desai et al. [81] reported the usefulness of molecular imaging using different PET radiotracers in order to understand NET biology and subsequently to determine the best treatment option. In this case a different tumor pattern of [¹⁸F]FDG and ⁶⁸Ga-DOTATATE uptake was shown by PET examinations within the liver, resulting in synchronous colorectal cancer and pancreatic NET liver metastases.

12. Melanoma

Few cases have been reported in the literature about the role of ⁶⁸Ga-labeled SST-analogues PET/CT in melanoma patients [48, 82].

Brogsitter et al. [82] compared ⁶⁸Ga-DOTATOC PET/CT to [¹⁸F]FDG-PET/CT in 18 patients with metastatic melanoma. ⁶⁸Ga-DOTATOC PET/CT was positive in 61% of the investigated patients; however, on a lesion-by-lesion basis, only 22% of [¹⁸F]FDG-positive metastases were seen with ⁶⁸Ga-DOTATOC PET/CT. Further, ⁶⁸Ga-DOTATOC uptake was only faint (mean , range 1.2–4.2) compared to [¹⁸F]FDG (mean , range 2.3–115). The exact impact of ⁶⁸Ga-SST-analogues PET/CT on staging and management of melanoma patient remains to be determined.

13. Prostate Cancer

Few cases have been reported in the literature about the role of ⁶⁸Ga-labeled SST-analogues PET/CT in prostate cancer patients [31, 41, 48, 49, 83–85]. Luboldt et al. [84] assessed SSTR expression in 20 patients with advanced prostate cancer to potentially guide SSTR-mediated therapies. On a side-by-side analysis only 30% of bone scintigraphy-positive metastases were seen with ⁶⁸Ga-DOTATOC PET/CT. The authors concluded by suggesting further studies with different SST-analogues with a higher affinity for SSTR1 and SSTR4 (expressed by prostate cancer), not adequately addressed with DOTATOC. The only case reported in the literature using ⁶⁸Ga-DOTATATE showed intense radiotracer uptake in bone metastases, confirming bone scan results and suggesting a potential role of ⁶⁸Ga-DOTATATE PET/CT to guide SSTR-mediated therapies also in this clinical setting [85].

14. Mesenchymal Tumors

Despite the promising results only few cases have been reported in the literature about the use of ⁶⁸Ga-labeled SST-analogues PET/CT to evaluate tumor-induced osteomalacia (phosphaturic mesenchymal tumors) [32, 39, 86–88]. In the two larger series of patients ( and , resp.) with suspicious tumor-induced osteomalacia, PET/CT demonstrated high ⁶⁸Ga-DOTATATE uptake and localized the tumor in 75–100% of the cases evaluated [32, 88].

In this clinical setting ⁶⁸Ga-DOTATATE PET/CT may represent the first step functional imaging to identify the site of disease but further studies are needed to confirm these preliminary results.

15. Lymphoma

The use of ⁶⁸Ga-labeled SST-analogues PET/CT in lymphoma is limited to sporadic cases [31, 80] (Figure 10).

16. Conclusion and General Remarks

The use of ⁶⁸Ga-labeled SST-analogues PET/CT in phaeochromocytoma and paraganglioma remains small, consisting mainly of case reports and small series. The diagnostic accuracy of ⁶⁸Ga-SST-analogues PET/CT is superior to ¹³¹I-MIBG; thus, in the case of negative ¹²³I-MIBG scan in patients with a high pretest probability of phaeochromocytoma or paraganglioma, ⁶⁸Ga-labeled SST-analogues PET/CT should be considered. Additionally, ⁶⁸Ga-labeled SST-analogues PET/CT should be considered in the staging of patients in whom metastatic spread, particularly to the bone, is suspected.

Although limited experience exists in NCSCL and SCLC, ⁶⁸Ga-SST-analogues PET or PET/CT has been evaluated in all types of lung tumor. Particularly, the degree of uptake and the different uptake patterns on [¹⁸F]FDG and ⁶⁸Ga-SST-analogues PET or PET/CT may be helpful to differentiate typical from atypical carcinoids. ⁶⁸Ga-SST-analogues PET/CT may be useful also to stage lung cancer (especially for the early identification of bone lesions) and to select patients for the best treatment option, including PRRT.

Some interesting studies on radiolabeled SST-analogues PET/CT in patients with brain neuroepithelial tumors (either for staging, treatment selection, or response evaluation) are reported in the literature.

⁶⁸Ga-labeled SST-analogues PET/CT has been widely used in patients with intracranial meningioma. ⁶⁸Ga-labeled SST-analogues PET/CT provides additional information in patients with uncertain or equivocal results at MRI and helps to confirm a diagnosis of meningioma based on MRI or to confirm MRI-based diagnosis of meningioma in cases of biopsy limitations. Finally, ⁶⁸Ga-labeled SST-analogues PET or PET/CT may be useful to delineate the target volume for fractionated stereotactic radiotherapy.

Although studies investigating larger and more homogeneous patient populations are needed to better elucidate the potential diagnostic role of radiolabeled SST-analogues for the assessment of recurrent MTC, the preliminary published data suggest a controversial role of ⁶⁸Ga-SST-analogues since well-differentiated tumors show a variable and often low SSTR subtype cell expression.

⁶⁸Ga-SST-analogues PET and PET/CT were positive in many patients with DTC providing, especially in negative radioiodine cases, new therapeutic options as PRRT. However, further studies comparing ⁶⁸Ga-SST-analogues to radioiodine scintigraphy and [¹⁸F]FDG-PET/CT in DTC are needed.

Limited disappointing experience exists regarding the role of ⁶⁸Ga-SST-analogues PET/CT in patients with thymic malignancies. In thymic neoplasms a predominant [¹⁸F]FDG positivity has been observed compared to ⁶⁸Ga-SST-analogues at PET/CT suggesting a relative loss of SSTR expression during thymic malignancy progression and subsequent increasing of biological aggressiveness.

Few but significant data are available about the role of ⁶⁸Ga-labeled SST-analogues PET/CT in Merkel cell carcinoma. ⁶⁸Ga-labeled SST-analogues PET/CT is useful to stage and restage patients, and also to select treatment for PRRT and to assess treatment response.

Although only few cases have been reported in the literature about the use of ⁶⁸Ga-labeled SST-analogues PET/CT in tumor-induced osteomalacia, ⁶⁸Ga-DOTATATE PET/CT may represent the first step functional imaging to identify mesenchymal tumors; however further studies are needed to confirm the promising preliminary results.

No sufficient data are available about the role of ⁶⁸Ga-SST-analogues PET or PET/CT in melanoma and breast, colorectal, and prostate cancers. The use of ⁶⁸Ga-labeled SST-analogues PET/CT in lymphoma is limited to sporadic cases with unfavorable results.

In conclusion, although these preliminary experiences suggest a possible role of ⁶⁸Ga-SST-analogues PET or PET/CT in many non GEP-NETs tumors, further studies are needed to confirm these promising results.

Conflict of Interests

All the authors declare that they have no conflict of interests.

References

J. C. Reubi, “Peptide receptors as molecular targets for cancer diagnosis and therapy,” Endocrine Reviews, vol. 24, no. 4, pp. 389–427, 2003.
View at: Publisher Site | Google Scholar
J. C. Reubi and B. Waser, “Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 30, no. 5, pp. 781–793, 2003.
View at: Google Scholar
E. Bombardieri, M. Maccauro, E. De Deckere, G. Savelli, and A. Chiti, “Nuclear medicine imaging of neuroendocrine tumours,” Annals of Oncology, vol. 12, no. 2, pp. S51–S61, 2001.
View at: Google Scholar
J. O. Olsen, R. V. Pozderac, G. Hinkle et al., “Somatostatin receptor imaging of neuroendocrine tumors with indium-111 pentetreotide (OctreoScan),” Seminars in Nuclear Medicine, vol. 25, no. 3, pp. 251–261, 1995.
View at: Google Scholar
V. Briganti, R. Sestini, C. Orlando et al., “Imaging of somatostatin receptors by indium-111-pentetreotide correlates with quantitative determination of somatostatin receptor type 2 gene expression in neuroblastoma tumors,” Clinical Cancer Research, vol. 3, no. 12, pp. 2385–2391, 1997.
View at: Google Scholar
A. Chiti, V. Briganti, S. Fanti, N. Monetti, R. Masi, and E. Bombardieri, “Results and potential of somatostatin receptor imaging in gastroenteropancreatic tract tumours,” Quarterly Journal of Nuclear Medicine, vol. 44, no. 1, pp. 42–49, 2000.
View at: Google Scholar
A. Chiti, S. Fanti, G. Savelli et al., “Comparison of somatostatin receptor imaging, computed tomography and ultrasound in the clinical management of neuroendocrine gastro-entero-pancreatic tumours,” European Journal of Nuclear Medicine, vol. 25, no. 10, pp. 1396–1403, 1998.
View at: Publisher Site | Google Scholar
E. P. Krenning, D. J. Kwekkeboom, W. H. Bakker et al., “Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients,” European Journal of Nuclear Medicine, vol. 20, no. 8, pp. 716–731, 1993.
View at: Google Scholar
E. Seregni, A. Chiti, and E. Bombardieri, “Radionuclide imaging of neuroendocrine tumours: biological basis and diagnostic results,” European Journal of Nuclear Medicine, vol. 25, no. 6, pp. 639–658, 1998.
View at: Publisher Site | Google Scholar
F. Jamar, R. Fiasse, N. Leners, and S. Pauwels, “Somatostatin receptor imaging with indium-111-pentetreotide in gastroenteropancreatic neuroendocrine tumors: safety, efficacy and impact on patient management,” Journal of Nuclear Medicine, vol. 36, no. 4, pp. 542–549, 1995.
View at: Google Scholar
R. Lebtahi, G. Cadiot, L. Sarda et al., “Clinical impact of somatostatin receptor scintigraphy in the management of patients with neuroendocrine gastroenteropancreatic tumors,” Journal of Nuclear Medicine, vol. 38, no. 6, pp. 853–858, 1997.
View at: Google Scholar
M. Bangard, M. Béhé, S. Guhlke et al., “Detection of somatostatin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide: first results in patients and comparison with 111In-DTPA-D-Phe1-octreotide,” European Journal of Nuclear Medicine, vol. 27, no. 6, pp. 628–637, 2000.
View at: Publisher Site | Google Scholar
J. Kowalski, M. Henze, J. Schuhmacher, H. R. Mäcke, M. Hofmann, and U. Haberkorn, “Evaluation of positron emission tomography imaging using [⁶⁸Ga]-DOTA-D Phe1-Tyr3- octreotidein comparison to [111In]-DTPAOC SPECT. First results in patients with neuroendocrine tumors,” Molecular Imaging and Biology, vol. 5, no. 1, pp. 42–48, 2003.
View at: Publisher Site | Google Scholar
I. Buchmann, M. Henze, S. Engelbrecht et al., “Comparison of ⁶⁸Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 34, no. 10, pp. 1617–1626, 2007.
View at: Publisher Site | Google Scholar
M. Hofmann, H. Maecke, A. R. Börner et al., “Biokinetics and imaging with the somatostatin receptor PET radioligand68Ga-DOTATOC: preliminary data,” European Journal of Nuclear Medicine, vol. 28, no. 12, pp. 1751–1757, 2001.
View at: Publisher Site | Google Scholar
D. Wild, J. S. Schmitt, M. Ginj et al., “DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 30, no. 10, pp. 1338–1347, 2003.
View at: Publisher Site | Google Scholar
V. Ambrosini, D. Campana, L. Bodei et al., “⁶⁸Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors,” Journal of Nuclear Medicine, vol. 51, no. 5, pp. 669–673, 2010.
View at: Google Scholar
P. Antunes, M. Ginj, H. Zhang et al., “Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?” European Journal of Nuclear Medicine and Molecular Imaging, vol. 34, no. 7, pp. 982–993, 2007.
View at: Publisher Site | Google Scholar
V. Ambrosini, D. Campana, P. Tomassetti, G. Grassetto, D. Rubello, and S. Fanti, “PET/CT with 68Gallium-DOTA-peptides in NET: an overview,” European Journal of Radiology, vol. 80, no. 2, pp. e116–e119, 2011.
View at: Publisher Site | Google Scholar
P. M. Smith-Jones, C. Bischof, M. Leimer et al., “DOTA-lanreotide: a novel somatostatin analog for tumor diagnosis and therapy,” Endocrinology, vol. 140, no. 11, pp. 5136–5148, 1999.
View at: Google Scholar
I. Virgolini, I. Szilvasi, A. Kurtaran et al., “Indium-111-DOTA-lanreotide: biodistribution, safety and radiation absorbed dose in tumor patients,” Journal of Nuclear Medicine, vol. 39, no. 11, pp. 1928–1936, 1998.
View at: Google Scholar
J. C. Reubi, J.-C. Schär, B. Waser et al., “Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use,” European Journal of Nuclear Medicine, vol. 27, no. 3, pp. 273–282, 2000.
View at: Google Scholar
R. C. Walker, G. T. Smith, E. Liu, B. Moore, J. Clanton, and M. Stabin, “Measured human dosimetry of ⁶⁸Ga-DOTATATE,” Journal of Nuclear Medicine, vol. 54, pp. 855–860, 2013.
View at: Google Scholar
H. Hartmann, K. Zöphel, R. Freudenberg et al., “Radiation exposure of patients during ⁶⁸Ga-DOTATOC PET/CT examinations,” NuklearMedizin, vol. 48, no. 5, pp. 201–207, 2009.
View at: Publisher Site | Google Scholar
C. Pettinato, A. Sarnelli, M. Di Donna et al., “⁶⁸Ga-DOTANOC: biodistribution and dosimetry in patients affected by neuroendocrine tumors,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 35, no. 1, pp. 72–79, 2008.
View at: Publisher Site | Google Scholar
E. P. Krenning, W. H. Bakker, P. P. M. Kooij et al., “Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide,” Journal of Nuclear Medicine, vol. 33, no. 5, pp. 652–658, 1992.
View at: Google Scholar
R. R. P. Warner, “Enteroendocrine tumors other than carcinoid: a review of clinically significant advances,” Gastroenterology, vol. 128, no. 6, pp. 1668–1684, 2005.
View at: Publisher Site | Google Scholar
G. L. Cascini, V. Cuccurullo, and L. Mansi, “The non tumour uptake of 111In-octreotide creates new clinical indications in benign diseases, but also in oncology,” Quarterly Journal of Nuclear Medicine and Molecular Imaging, vol. 54, no. 1, pp. 24–36, 2010.
View at: Google Scholar
M. C. Smith, M. Maggi, and C. Orlando, “Somatostatin receptors in non-endocrine tumours,” Digestive and Liver Disease, vol. 36, supplement 1, pp. S78–S85, 2004.
View at: Publisher Site | Google Scholar
I. Virgolini, V. Ambrosini, J. B. Bomanji et al., “Procedure guidelines for PET/CT tumour imaging with ⁶⁸Ga-DOTA-conjugated peptides: ⁶⁸Ga-DOTA-TOC, ⁶⁸Ga-DOTA-NOC, ⁶⁸Ga-DOTA-TATE,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 37, pp. 2004–2010, 2010.
View at: Publisher Site | Google Scholar
S. Fanti, V. Ambrosini, P. Tomassetti et al., “Evaluation of unusual neuroendocrine tumours by means of ⁶⁸Ga-DOTA-NOC PET,” Biomedicine and Pharmacotherapy, vol. 62, no. 10, pp. 667–671, 2008.
View at: Publisher Site | Google Scholar
B. R. Mittal, K. Agrawal, J. Shukla et al., “Ga-68 DOTATATE PET/CT in neuroendocrine tumors: initial experience,” Journal of Postgraduate Medicine Education and Research, vol. 47, pp. 1–6, 2013.
View at: Google Scholar
M. Naji, C. Zhao, S. J. Welsh et al., “⁶⁸Ga-DOTA-TATE PET vs.123I-MIBG in identifying malignant neural crest tumours,” Molecular Imaging and Biology, vol. 13, no. 4, pp. 769–775, 2011.
View at: Publisher Site | Google Scholar
Z. Win, L. Rahman, D. Towey, and A. Al-Nahhas, “⁶⁸Ga-DOTATATE PET imaging in neuroectodermal tumours,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 33, article S190, 2006.
View at: Google Scholar
Z. Win, A. Al-Nahhas, D. Towey et al., “⁶⁸Ga-DOTATATE PET in neuroectodermal tumours: first experience,” Nuclear Medicine Communications, vol. 28, no. 5, pp. 359–363, 2007.
View at: Publisher Site | Google Scholar
A. Kroiss, D. Putzer, C. Uprimny et al., “Functional imaging in phaeochromocytoma and neuroblastoma with ⁶⁸Ga-DOTA-Tyr3-octreotide positron emission tomography and 123I-metaiodobenzylguanidine,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 38, no. 5, pp. 865–873, 2011.
View at: Publisher Site | Google Scholar
J. B. Maurice, R. Troke, Z. Win et al., “A comparison of the performance of ⁶⁸Ga-DOTATATE PET/CT and ¹²³I-MIBG SPECT in the diagnosis and follow-up of phaeochromocytoma and paraganglioma,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 39, pp. 1266–1270, 2012.
View at: Publisher Site | Google Scholar
P. Sharma, A. Thakar, K. C. S. Suman et al., “⁶⁸Ga-DOTANOC PET/CT for baseline evaluation of patients with head and neck paraganglioma,” Journal of Nuclear Medicine, vol. 54, pp. 841–847, 2013.
View at: Google Scholar
M. S. Hofman, G. Kong, O. C. Neels, P. Eu, E. Hong, and R. J. Hicks, “High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours,” Journal of Medical Imaging and Radiation Oncology, vol. 56, no. 1, pp. 40–47, 2012.
View at: Publisher Site | Google Scholar
S. Koukouraki, L. G. Strauss, V. Georgoulias, M. Eisenhut, U. Haberkorn, and A. Dimitrakopoulou-Strauss, “Comparison of the pharmacokinetics of ⁶⁸Ga-DOTATOC and [18F]FDG in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 33, no. 10, pp. 1115–1122, 2006.
View at: Publisher Site | Google Scholar
M. Gabriel, C. Decristoforo, D. Kendler et al., “⁶⁸Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT,” Journal of Nuclear Medicine, vol. 48, no. 4, pp. 508–518, 2007.
View at: Publisher Site | Google Scholar
V. Ambrosini, P. Castellucci, D. Rubello et al., “⁶⁸Ga-DOTA-NOC: a new PET tracer for evaluating patients with bronchial carcinoid,” Nuclear Medicine Communications, vol. 30, no. 4, pp. 281–286, 2009.
View at: Publisher Site | Google Scholar
I. Kayani, B. G. Conry, A. M. Groves et al., “A comparison of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT in pulmonary neuroendocrine tumors,” Journal of Nuclear Medicine, vol. 50, no. 12, pp. 1927–1932, 2009.
View at: Publisher Site | Google Scholar
A. Kumar, T. Jindal, R. Dutta, and R. Kumar, “Functional imaging in differentiating bronchial masses: an initial experience with a combination of ¹⁸F-FDG PET-CT scan and ⁶⁸Ga DOTA-TOC PET-CT scan,” Annals of Nuclear Medicine, vol. 23, no. 8, pp. 745–751, 2009.
View at: Publisher Site | Google Scholar
T. Jindal, A. Kumar, B. Venkitaraman et al., “Evaluation of the role of [¹⁸F]FDG-PET/CT and [⁶⁸Ga]DOTATOC-PET/CT in differentiating typical and atypical pulmonary carcinoids,” Cancer Imaging, vol. 11, no. 1, pp. 70–75, 2011.
View at: Publisher Site | Google Scholar
T. Jindal, A. Kumar, B. Venkitaraman, R. Dutta, and R. Kumar, “Role of ⁶⁸Ga-DOTATOC PET/CT in the evaluation of primary pulmonary carcinoids,” Korean Journal of Internal Medicine, vol. 25, no. 4, pp. 386–391, 2010.
View at: Publisher Site | Google Scholar
D. Putzer, A. Kroiss, D. Waitz et al., “Somatostatin receptor PET in neuroendocrine tumours: ⁶⁸Ga-DOTA0, Tyr3-octreotide versus ⁶⁸Ga-DOTA0-lanreotide,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 40, pp. 364–372, 2013.
View at: Google Scholar
V. Ambrosini, C. Nanni, M. Zompatori et al., “⁶⁸Ga-DOTA-NOC PET/CT in comparison with CT for the detection of bone metastasis in patients with neuroendocrine tumours,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 37, no. 4, pp. 722–727, 2010.
View at: Publisher Site | Google Scholar
D. Putzer, M. Gabriel, B. Henninger et al., “Bone metastases in patients with neuroendocrine tumor: ⁶⁸Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphy,” Journal of Nuclear Medicine, vol. 50, no. 8, pp. 1214–1221, 2009.
View at: Publisher Site | Google Scholar
A. R. Haug, C. J. Auernhammer, B. Wängler et al., “⁶⁸Ga-DOTATATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors,” Journal of Nuclear Medicine, vol. 51, no. 9, pp. 1349–1356, 2010.
View at: Publisher Site | Google Scholar
A. Dimitrakopoulou-Strauss, V. Georgoulias, M. Eisenhut et al., “Quantitative assessment of SSTR2 expression in patients with non-small cell lung cancer using ⁶⁸Ga-DOTATOC PET and comparison with 18F-FDG PET,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 33, no. 7, pp. 823–830, 2006.
View at: Publisher Site | Google Scholar
M. Sollini, D. Farioli, A. Froio et al., “Brief report on the use of radiolabeled somatostatin analogs for the diagnosis and treatment of metastatic small-cell lung cancer patients,” Journal of Thoracic Oncology, vol. 8, pp. 1095–1101, 2013.
View at: Google Scholar
D. Waitz, D. Putzer, H. Kostron, and I. J. Virgolini, “Treatment of high-grade glioma with radiolabeled peptides,” Methods, vol. 55, no. 3, pp. 223–229, 2011.
View at: Publisher Site | Google Scholar
D. Heute, H. Kostron, E. Von Guggenberg et al., “Response of recurrent high-grade glioma to treatment with 90Y-DOTATOC,” Journal of Nuclear Medicine, vol. 51, no. 3, pp. 397–400, 2010.
View at: Publisher Site | Google Scholar
J. E. Gains, J. B. Bomanji, N. L. Fersht et al., “¹⁷⁷Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma,” Journal of Nuclear Medicine, vol. 52, no. 7, pp. 1041–1047, 2011.
View at: Publisher Site | Google Scholar
A. Afshar-Oromieh, F. L. Giesel, H. G. Linhart et al., “Detection of cranial meningiomas: comparison of Ga-DOTATOC PET/CT and contrast-enhanced MRI,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 39, pp. 1409–1415, 2012.
View at: Google Scholar
S. Milker-Zabel, A. Zabel-du Bois, M. Henze et al., “Improved target volume definition for fractionated stereotactic radiotherapy in patients with intracranial meningiomas by correlation of CT, MRI, and [⁶⁸Ga]-DOTATOC-PET,” International Journal of Radiation Oncology Biology Physics, vol. 65, no. 1, pp. 222–227, 2006.
View at: Publisher Site | Google Scholar
B. Gehler, F. Paulsen, M. T. Öksüz et al., “[⁶⁸Ga]-DOTATOC-PET/CT for meningioma IMRT treatment planning,” Radiation Oncology, vol. 4, no. 1, article 56, 2009.
View at: Publisher Site | Google Scholar
F. Nyuyki, M. Plotkin, R. Graf et al., “Potential impact of ⁶⁸Ga-DOTATOC PET/CT on stereotactic radiotherapy planning of meningiomas,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 37, no. 2, pp. 310–318, 2010.
View at: Publisher Site | Google Scholar
R. Graf, M. Plotkin, I. G. Steffen et al., “Magnetic resonance imaging, computed tomography, and ⁶⁸Ga-DOTATOC positron emission tomography for imaging skull base meningiomas with infracranial extension treated with stereotactic radiotherapy—a case series,” Head and Face Medicine, vol. 8, no. 1, article 1, 2012.
View at: Publisher Site | Google Scholar
M. Henze, J. Schuhmacher, P. Hipp et al., “PET imaging of somatostatin receptors using [⁶⁸GA]DOTA-D-Phe1-Tyr3-Octreotide: first results in patients with meningiomas,” Journal of Nuclear Medicine, vol. 42, no. 7, pp. 1053–1056, 2001.
View at: Google Scholar
M. Henze, A. Dimitrakopoulou-Strauss, S. Milker-Zabel et al., “Characterization of ⁶⁸Ga-DOTA-D-Phe1-Tyr 3-octreotide kinetics in patients with meningiomas,” Journal of Nuclear Medicine, vol. 46, no. 5, pp. 763–769, 2005.
View at: Google Scholar
H. Hänscheid, R. A. Sweeney, M. Flentje et al., “PET SUV correlates with radionuclide uptake in peptide receptor therapy in meningioma,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 39, pp. 1284–1288, 2012.
View at: Publisher Site | Google Scholar
B. G. Conry, N. D. Papathanasiou, V. Prakash et al., “Comparison of ⁶⁸Ga-DOTATATE and ¹⁸F- fluorodeoxyglucose PET/CT in the detection of recurrent medullary thyroid carcinoma,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 37, no. 1, pp. 49–57, 2010.
View at: Publisher Site | Google Scholar
G. Treglia, P. Castaldi, M. F. Villani et al., “Comparison of ¹⁸F-DOPA, ¹⁸F-FDG and ⁶⁸Ga-somatostatin analogue PET/CT in patients with recurrent medullary thyroid carcinoma,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 39, pp. 569–580, 2012.
View at: Publisher Site | Google Scholar
M. Miederer, S. Seidl, A. Buck et al., “Correlation of immunohistopathological expression of somatostatin receptor 2 with standardised uptake values in ⁶⁸Ga-DOTATOC PET/CT,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 36, no. 1, pp. 48–52, 2009.
View at: Publisher Site | Google Scholar
S. Koukouraki, L. G. Strauss, V. Georgoulias et al., “Evaluation of the pharmacokinetics of ⁶⁸Ga-DOTATOC in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 33, no. 4, pp. 460–466, 2006.
View at: Publisher Site | Google Scholar
M. Middendorp, I. Selkinski, C. Happel, W. T. Kranert, and F. Grünwald, “Comparison of positron emission tomography with [¹⁸F]FDG and [⁶⁸Ga]DOTATOC in recurrent differentiated thyroid cancer: preliminary data,” Quarterly Journal of Nuclear Medicine and Molecular Imaging, vol. 54, no. 1, pp. 76–83, 2010.
View at: Google Scholar
M. Gabriel, U. Andergassen, D. Putzer et al., “Individualized peptide-related-radionuclide-therapy concept using different radiolabelled somatostatin analogs in advanced cancer patients,” Quarterly Journal of Nuclear Medicine and Molecular Imaging, vol. 54, no. 1, pp. 92–99, 2010.
View at: Google Scholar
A. Versari, M. Sollini, A. Frasoldati et al., “Differentiated thyroid cancer: a new perspective with radiolabeled somatostatin analogues for imaging and treatment of patients,” Thyroid. In press.
View at: Google Scholar
J. Vasamiliette, P. Hohenberger, S. Schoenberg et al., “Treatment monitoring with ¹⁸F-FDG PET in metastatic thymoma after 90Y-Dotatoc and selective internal radiation treatment (SIRT),” Hellenic Journal of Nuclear Medicine, vol. 12, no. 3, pp. 271–309, 2009.
View at: Google Scholar
R. Dutta, A. Kumar, P. K. Julka et al., “Thymic neuroendocrine tumour (carcinoid): clinicopathological features of four patients with different presentation,” Interactive Cardiovascular and Thoracic Surgery, vol. 11, no. 6, pp. 732–736, 2010.
View at: Publisher Site | Google Scholar
A. Froio, M. Sollini, A. Fraternali et al., “Thymic neoplasms evaluation: role of ⁶⁸Ga-peptide and [18F]FDG PET/CT,” Journal of Nuclear Medicine, vol. 54, no. 5, supplement 1, article 1632, 2013.
View at: Google Scholar
C. Schneider, M. Schlaak, M. Bludau, B. Markiefka, and M. C. Schmidt, “⁶⁸Ga-DOTATATE-PET/CT positive metastatic lymph node in a 69-year-old woman with Merkel cell carcinoma,” Clinical Nuclear Medicine, vol. 37, pp. 1108–1111, 2012.
View at: Google Scholar
M. C. Schmidt, K. Uhrhan, B. Markiefka et al., “⁶⁸Ga-DotaTATE PET-CT followed by Peptide Receptor Radiotherapy in combination with capecitabine in two patients with Merkel Cell Carcinoma,” International Journal of Clinical and Experimental Medicine, vol. 5, pp. 363–366, 2012.
View at: Google Scholar
A. Salavati, V. Prasad, C.-P. Schneider, R. Herbst, and R. P. Baum, “Peptide receptor radionuclide therapy of Merkel cell carcinoma using 177lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: a potential novel treatment based on molecular pathology,” Annals of Nuclear Medicine, vol. 26, pp. 365–369, 2012.
View at: Publisher Site | Google Scholar
M. Epstude, K. Tornquist, C. Riklin et al., “Comparison of, (18)F-FDG PET/CT and (68)Ga-DOTATATE PET/CT imaging in metastasized merkel cell carcinoma,” Clinical Nuclear Medicine, vol. 38, pp. 283–284, 2013.
View at: Google Scholar
F. Elgeti, H. Amthauer, T. Denecke et al., “Incidental detection of breast cancer by ⁶⁸Ga-DOTATOC-PET/CT in women suffering from neuroendocrine tumours,” NuklearMedizin, vol. 47, no. 6, pp. 261–265, 2008.
View at: Publisher Site | Google Scholar
C. Casini Raggi, A. Calabrò, D. Renzi et al., “Quantitative evaluation of somatostatin receptor subtype 2 expression in sporadic colorectal tumor and in the corresponding normal mucosa,” Clinical Cancer Research, vol. 8, no. 2, pp. 419–427, 2002.
View at: Google Scholar
A. Haug, R. Cindea-Drimus, C. Auernhammer, G. Schmidt, P. Bartenstein, and M. Hacker, “⁶⁸Ga-DOTATATE PET/CT in the diagnosis of recurrent neuroendocrine tumors,” Journal of Nuclear Medicine, vol. 53, supplement 1, article 419, 2012.
View at: Google Scholar
K. Desai, J. Watkins, N. Woodward et al., “Use of molecular imaging to differentiate liver metastasis of colorectal cancer metastasis from neuroendocrine tumor origin,” Journal of Clinical Gastroenterology, vol. 45, no. 1, pp. e8–e11, 2011.
View at: Publisher Site | Google Scholar
C. Brogsitter, K. Zöphel, G. Wunderlich, E. Kämmerer, A. Stein, and J. Kotzerke, “Comparison between F-18 fluorodeoxyglucose and Ga-68 DOTATOC in metastasized melanoma,” Nuclear Medicine Communications, vol. 34, pp. 47–49, 2013.
View at: Google Scholar
M. Souvatzoglou, T. Maurer, U. Treiber, G. Weirich, B. J. Krause, and M. Essler, “⁶⁸Ga-DOTATOC-PET/CT detects neuroendocrine differentiation of prostate cancer metastases,” Nuklearmedizin, vol. 48, no. 5, pp. N52–N54, 2009.
View at: Google Scholar
W. Luboldt, K. Zöphel, G. Wunderlich, A. Abramyuk, H.-J. Luboldt, and J. Kotzerke, “Visualization of somatostatin receptors in prostate cancer and its bone metastases with Ga-68-DOTATOC PET/CT,” Molecular Imaging and Biology, vol. 12, no. 1, pp. 78–84, 2010.
View at: Publisher Site | Google Scholar
O. Alonso, J. P. Gambini, G. Lago, J. Gaudiano, A. Quagliata, and H. Engler, “In vivo visualization of somatostatin receptor expression with Ga-68-DOTA-TATE PET/CT in advanced metastatic prostate cancer,” Clinical Nuclear Medicine, vol. 36, no. 11, pp. 1063–1064, 2011.
View at: Google Scholar
C. Von Falck, T. Rodt, H. Rosenthal et al., “⁶⁸Ga-DOTANOC PET/CT for the detection of a mesenchymal tumor causing oncogenic osteomalacia,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 35, no. 5, article 1034, 2008.
View at: Publisher Site | Google Scholar
E. Woff, C. Garcia, L. Tant et al., “Imaging of tumour-induced osteomalacia using a gallium-68 labelled somatostatin analogue,” BMJ Case Reports, vol. 2010, Article ID bcr0220102750, 2010.
View at: Google Scholar
R. J. Clifton-Bligh, M. S. Hofman, E. Duncan et al., “Improving diagnosis of tumor-induced osteomalacia with Gallium-68 DOTATATE PET/CT,” The Journal of Clinical Endocrinology & Metabolism, vol. 98, pp. 687–694, 2013.
View at: Google Scholar
C. Mawrin, S. Schulz, S. U. Pauli et al., “Differential expression of sst1, sst2A, and sst3 somatostatin receptor proteins in low-grade and high-grade astrocytomas,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 1, pp. 13–19, 2004.
View at: Google Scholar
U. Kumar, S. I. Grigorakis, H. L. Watt et al., “Somatostatin receptors in primary human breast cancer: quantitative analysis of mRNA for subtypes 1–5 and correlation with receptor protein expression and tumor pathology,” Breast Cancer Research and Treatment, vol. 92, no. 2, pp. 175–186, 2005.
View at: Publisher Site | Google Scholar
C.-Z. Qiu, S.-Z. Zhu, Y.-Y. Wu, C. Wang, Z.-X. Huang, and J.-L. Qiu, “Relationship between somatostatin receptor subtype expression and clinicopathology, Ki-67, Bcl-2 and p53 in colorectal cancer,” World Journal of Gastroenterology, vol. 12, no. 13, pp. 2011–2015, 2006.
View at: Google Scholar
K. Pazaitou-Panayiotou, E. Tiensuu Janson, T. Koletsa et al., “Somatostatin receptor expression in non-medullary thyroid carcinomas,” Hormones (Athens), vol. 11, pp. 290–296, 2012.
View at: Google Scholar
K. Szepeshazi, A. V. Schally, A. Nagy, B. W. Wagner, A. M. Bajo, and G. Halmos, “Preclinical evaluation of therapeutic effects of targeted cytotoxic analogs of somatostatin and bombesin on human gastric carcinomas,” Cancer, vol. 98, no. 7, pp. 1401–1410, 2003.
View at: Publisher Site | Google Scholar
J. C. Reubi, B. Waser, J.-C. Schaer, and J. A. Laissue, “Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands,” European Journal of Nuclear Medicine, vol. 28, no. 7, pp. 836–846, 2001.
View at: Publisher Site | Google Scholar
G. Palmieri, L. Montella, C. Aiello et al., “Somatostatin analogues, a series of tissue transglutaminase inducers, as a new tool for therapy of mesenchimal tumors of the gastrointestinal tract,” Amino Acids, vol. 32, no. 3, pp. 395–400, 2007.
View at: Publisher Site | Google Scholar
T. Florio, L. Montella, A. Corsaro et al., “In vitro and in vivo expression of somatostatin receptors in intermediate and malignant soft tissue tumors,” Anticancer Research, vol. 23, no. 3, pp. 2465–2471, 2003.
View at: Google Scholar
M. Bläker, M. Schmitz, A. Gocht et al., “Differential expression of somatostatin receptor subtypes in hepatocellular carcinomas,” Journal of Hepatology, vol. 41, no. 1, pp. 112–118, 2004.
View at: Publisher Site | Google Scholar
V. A. S. H. Dalm, L. J. Hofland, C. M. Mooy et al., “Somatostatin receptors in malignant lymphomas: targets for radiotherapy?” Journal of Nuclear Medicine, vol. 45, no. 1, pp. 8–16, 2004.
View at: Google Scholar
S. S. Lum, W. S. Fletcher, M. S. O'Dorisio, R. W. Nance, R. F. Pommier, and M. Caprara, “Distribution and functional significance of somatostatin receptors in malignant melanoma,” World Journal of Surgery, vol. 25, no. 4, pp. 407–412, 2001.
View at: Publisher Site | Google Scholar
S. Arena, F. Barbieri, S. Thellung et al., “Expression of somatostatin receptor mRNA in human meningiomas and their implication in in vitro antiproliferative activity,” Journal of Neuro-Oncology, vol. 66, no. 1-2, pp. 155–166, 2004.
View at: Publisher Site | Google Scholar
M. Papotti, L. Macri, A. Pagani, F. Aloi, and G. Bussolati, “Quantitation of somatostatin receptor type 2 in neuroendocrine (Merkel cell) carcinoma of the skin by competitive RT-PCR,” Endocrine Pathology, vol. 10, no. 1, pp. 37–46, 1999.
View at: Google Scholar
M. C. Zatelli, F. Tagliati, J. E. Taylor, R. Rossi, M. D. Culler, and E. C. Degli Uberti, “Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line TT,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 5, pp. 2161–2169, 2001.
View at: Publisher Site | Google Scholar
E. Mato, X. Matías-Guiu, A. Chico et al., “Somatostatin and somatostatin receptor subtype gene expression in medullary thyroid carcinoma,” Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 7, pp. 2417–2420, 1998.
View at: Publisher Site | Google Scholar
D. Ferone, M. Arvigo, C. Semino et al., “Somatostatin and dopamine receptor expression in lung carcinoma cells and effects of chimeric somatostatin-dopamine molecules on cell proliferation,” American Journal of Physiology—Endocrinology and Metabolism, vol. 289, no. 6, pp. E1044–E1050, 2005.
View at: Publisher Site | Google Scholar
N. Dizeyi, L. Konrad, A. Bjartell et al., “Localization and mRNA expression of somatostatin receptor subtypes in human prostatic tissue and prostate cancer cell lines,” Urologic Oncology, vol. 7, no. 3, pp. 91–98, 2002.
View at: Publisher Site | Google Scholar
F. Kosari, J. M. A. Munz, C. D. Savci-Heijink et al., “Identification of prognostic biomarkers for prostate cancer,” Clinical Cancer Research, vol. 14, no. 6, pp. 1734–1743, 2008.
View at: Publisher Site | Google Scholar
A. Saveanu and P. Jaquet, “Somatostatin-dopamine ligands in the treatment of pituitary adenomas,” Reviews in Endocrine and Metabolic Disorders, vol. 10, no. 2, pp. 83–90, 2009.
View at: Publisher Site | Google Scholar
T. Tateno, M. Kato, Y. Tani, K. Oyama, S. Yamada, and Y. Hirata, “Differential expression of somatostatin and dopamine receptor subtype genes in adrenocorticotropin (ACTH)-secreting pituitary tumors and silent corticotroph adenomas,” Endocrine Journal, vol. 56, no. 4, pp. 579–584, 2009.
View at: Publisher Site | Google Scholar
A. Fusco, G. Gunz, P. Jaquet et al., “Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas,” European Journal of Endocrinology, vol. 158, no. 5, pp. 595–603, 2008.
View at: Publisher Site | Google Scholar
A. Yoshihara, O. Isozaki, N. Hizuka et al., “Expression of type 5 somatostatin receptor in TSH-secreting pituitary adenomas: a possible marker for predicting longterm response to octreotide therapy,” Endocrine Journal, vol. 54, no. 1, pp. 133–138, 2007.
View at: Publisher Site | Google Scholar
A. Saveanu, I. Morange-Ramos, G. Gunz, H. Dufour, A. Enjalbert, and P. Jaquet, “A luteinizing hormone-, alpha-subunit- and prolactin-secreting pituitary adenoma responsive to somatostatin analogs: in vivo and in vitro studies,” European Journal of Endocrinology, vol. 145, no. 1, pp. 35–41, 2001.
View at: Google Scholar
T. Florio, F. Barbieri, R. Spaziante et al., “Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: A Multi-Center Study,” Endocrine-Related Cancer, vol. 15, no. 2, pp. 583–596, 2008.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2014 Martina Sollini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

6923

Downloads

2588

Citations