Alessandro Fraternali

Validation of 68Ge/68Ga generator processing by chemical purification for routine clinical application of 68Ga-DOTATOC

INTRODUCTION Imaging of somatostatin receptor expressing tumours has been greatly enhanced by the use of (68)Ga-DOTATOC and PET/CT. METHODS In this work, a purification method for the (68)Ge/(68)Ga generator eluate and a method to produce (68)Ga-DOTATOC suitable for clinical use were evaluated. The generator eluate was purified and concentrated on a cation-exchange cartridge in HCl/acetone media. The efficacy of this procedure in eliminating metal impurities from the (68)Ga solution was investigated by ICP-MS. The radiotracer quality was evaluated by radio-TLC, GC and gamma-ray spectrometry. RESULTS (68)Ga-DOTATOC preparations (n=33) were carried out with a mean synthesis yield of 59.3+/-2.8% (not corrected for decay) and a batch activity ranging from 555 to 296 MBq. The radiochemical and radionuclidic purity were >98% and 99.9999%, respectively. With this purification process, >95% of the Fe(III), Zn(II) and Mn(II) were eliminated from the solution. CONCLUSIONS (68)Ga-DOTATOC produced with this method can be efficiently used in nuclear medicine departments for PET evaluations.

Ga-68 DOTATOC PET, endoscopic ultrasonography, and multidetector CT in the diagnosis of duodenopancreatic neuroendocrine tumors: a single-centre retrospective study.

Purpose: In this report, we compared endoscopic ultrasonography (EUS), multidetector CT (MDCT), and Ga-68 DOTATOC PET/CT in patients with neuroendocrine tumors (NETs). We report our experience with use of these methods in patients suspected to have duodenopancreatic primitive NET. Methods: Nineteen consecutive patients (mean age, 56; 21–80), who underwent both Ga-68 DOTATOC PET/CT and EUS between March 2007 and November 2008 were retrospectively included in the study (16 underwent MDCT). Suspicion of NET was confirmed by EUS-FNA and/or surgery. Operative characteristics of PET, EUS, and MDCT were compared. Results: Twenty-three neuroendocrine lesions were diagnosed in 13/19 patients. EUS, PET, and MDCT correctly identified as affected 13/13 (100%), 12/13 (92%), and 10/11 (91%) patients, respectively. On a lesion basis, EUS, PET, and MDCT identified correctly as NETs 22/23 (96%), 20/23 (87%), and 13/18 (72%) lesions (P = 0.08 EUS vs. CT). Both on a patient and on a lesion basis, specificity was 67%, 83%, and 80% for EUS, PET, and MDCT, respectively. Conclusions: EUS, Ga-68 DOTATOC PET, and MDCT seem to have comparable accuracy in diagnosis of duodenopancreatic NET and their combination may allow an optimal preoperative diagnosis.

Differentiated Thyroid Cancer: A New Perspective with Radiolabeled Somatostatin Analogues for Imaging and Treatment of Patients

BACKGROUND The expression of somatostatin receptors (SSTR) in thyroid cells may offer the possibility to identify metastatic lesions and to select patients for peptide receptor radionuclide therapy (PRRT). We investigated (68)Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) to select patients with progressive differentiated thyroid cancer (DTC) for PRRT as well as treatment response and toxicity in treated patients. METHODS We enrolled 41 patients with progressive radioiodine-negative DTC (24 women and 17 men; mean age=54.3 years, median=59 years, range=19-78 years). In all patients, [(18)F]FDG-PET/CT was performed to determine recurrent disease with enhanced glucose metabolism, and (68)Ga-DOTATOC PET/CT was used to identify SSTR expression. Dosimetric evaluation was performed with (111)In-DOTATOC scintigraphy. Eleven patients were treated with PRRT receiving a fractionated injection of 1.5-3.7 GBq (90)Y-DOTATOC/administration. Serial (68)Ga-DOTATOC PET/CT scans were performed in all treated patients to evaluate treatment response. Parameters provided by (68)Ga-DOTATOC PET/CT were analyzed as potential therapeutic predictors to differentiate responding from nonresponding. In all treated patients, adverse events and toxicity were recorded. RESULTS (68)Ga-DOTATOC PET/CT were positive in 24/41 of radioiodine-negative DTC patients. Based on the high expression of SSTR detected by (68)Ga-DOTATOC PET/CT, 13 patients were suitable for PRRT. Two out of 13 patients were not treated due to the lack of fulfillment of other study inclusion criteria. PRRT induced disease control in 7/11 patients (two partial response and five stabilization) with a duration of response of 3.5-11.5 months. Objective response was associated with symptoms relief. Functional volume (FV) over time obtained by PET/CT was the only parameter demonstrating a significant difference between lesions responding and nonresponding to PRRT (p=0.001). Main PRRT adverse events were nausea, asthenia, and transient hematologic toxicity. One patient experienced permanent renal toxicity. CONCLUSIONS In our series, SSTR imaging provided positive results in more than half of the cases with radioiodine-negative DTC, and about one third of patients were eligible for PRRT. (68)Ga-DOTATOC PET/CT seems a reliable tool both for patient selection and evaluation of treatment response. In our experience, FV determination over time seems to represent a reliable parameter to determine tumor response to PRRT, although further investigations are needed to better define its role.

Radiolabeled Somatostatin Analogues Therapy in Advanced Neuroendocrine Tumors: A Single Centre Experience

The aim of this study was to assess the efficacy of PRRT in patients with advanced neuroendocrine tumors (NETs). Patients and Methods. From January 2007 to August 2011, we enrolled 65 patients (m/f 38/27; mean age 65 years, range 33–83) with advanced NETs having enhanced SSTR expression, treated with PRRT. The enhanced expression of SSTR was assessed using 68Ga-DOTATOC/DOTATATE PET/CT. Among all the enrolled patients, 6 of them were excluded from the present analysis since they voluntarily interrupted treatment. Mean activity/cycle of 2.6 GBq (90Y-DOTATOC/DOTATATE) or 6.0 GBq (177Lu-DOTATOC/DOTATATE) was administrated intravenously (max 9 cycles). Results. Complete response (CR) was found in 1/59 (2%) patients, partial remission (PR) in 24/59 (40.5%) patients, stable disease (SD) in 24/59 (40.5%), and progression (PD) in 10/59 (17%) patients. The overall tumor response rate (CR + PR) was 42.5%. In 40.5% of patients, the disease could be stabilized. Overall, 49 out of 59 patients had no tumor progression (83%). Twelve patients out of 59 (20%) had grade 2-3 hematological side effects including anemia, thrombocytopenia, and leukopenia. Long-term nephrotoxicity was observed in 3 patients (2 moderate, 1 severe). Conclusions. PRRT is a promising perspective for patients with advanced NETs.

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

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.

Development of a simple kit-based method for preparation of pharmaceutical-grade 68Ga-DOTATOC

IntroductionThe use of germanium-68 (68Ge)/gallium-68 (68Ga) generators is still limited when compared with the 99Mo/99mTc counterpart, mainly because of the absence of commercial kits and a kit-based method for preparing 68Ga-labelled radiopharmaceuticals in a reliable way. The present study aimed to develop and optimize a reliable direct labelling of DOTATOC with 68Ga through a kit-based approach. Materials and methodsA fraction of the eluate of two different 68Ge/68Ga generators was directly injected into a vial prefilled with precursor, buffer and scavenger (the prototype of a potential lyophilized kit). The vial was directly warmed to 100°C and then buffered with a 1.5 mol/l sodium ascorbate solution. The parameters influencing the reaction were studied and optimized. The efficacy of the method in terms of incorporation yield and quality of the final radiotracer was compared with preparations performed with two commercial automatic synthesizers by applying the tests prescribed in the European Pharmacopeia monograph for 68Ga-DOTATOC. ResultsUnder optimal conditions, the overall radiochemical yields of the kit-based process were 73±4 and 69±3% not decay-corrected for the IGG100 and itG generator, respectively. The radiochemical purity was 95±3% and the preparations were compliant with all specifications given in the pharmacopoeia monograph. ConclusionThe feasibility of a kit-based approach for the preparation of 68Ga-DOTATOC was proved and a first home-made version of a putative lyophilized kit was proposed.

The impact of 18F-deoxyglucose positron emission tomography on tumor staging, treatment strategy and treatment planning for radiotherapy in a department of radiation oncology

Aims and Background The study analyzed the potential contribution of positron emission tomography (PET) in patient selection for radiotherapy and in radiation therapy planning. Methods Eighty-seven patients with a histological cancer diagnosis were accrued for the study from December 2000 to December 2001. Demographic characteristics included a median age of 54 years and male/female ratio of 51/36. All patients staged by conventional workup who were candidates for radiotherapy had PET imaging and were allocated to a conventional “pre/post-PET stage”. The treatment protocol and the shape and/or size of the portals was directly related to PET results. We examined 26 lung cancers, 15 gastrointestinal tumors, 22 genitourinary cancers and 24 hematologic malignancies. Results In the lung cancer group, the stage was modified in 10/26 patients (38.5%) by PET, with a change in management in 13 (50%) and a change in radiotherapy planning in 6 (23.1%). In the hematological group, stage was modified by PET in 8/24 cases (33.3%), with a change in treatment strategy in 9 (37.5%) and a change in radiotherapy planning in 3 (12.5%). In the gastrointestinal group, the stage was modified by PET in 2/15 cases (13.4%), with a change inn treatment strategy in 4 (26.7%) and a change in the decision for radiotherapy in 8 (no radiotherapy in 53.3%). In the mixed group (genitourinary, breast and other), the stage was modified by PET in 6/22 cases (27.3%), with a change in treatment strategy in 11 (50%) and a very low rate of change in radiotherapy planning. Conclusions PET contributed to a modification of stage in 26/87 patients (30%), to a changing in treatment strategy in 37/87 (42.5%), and to a substantial change of the shape and/or size of radiotherapy portals in 13/43 (30%) who underwent radiotherapy.

Somatostatin receptor positron emission tomography/computed tomography imaging in Merkel cell carcinoma

Merkel cell carcinoma (MCC) is an uncommon aggressive primary cutaneous carcinoma with neuroendocrine differentiation. However, literature data about the use of somatostatin receptor positron emission tomography/computed tomography (PET/CT) imaging in MCC are limited and its role is not clearly stated.