Gianfranco Cicoria

Prediction of 89Zr production using the Monte Carlo code FLUKA

The widely used Monte Carlo simulation code FLUKA has been utilized to prototype a solid target for the production of (89)Zr by irradiation of a metallic (89)Y target foil in a 16.5MeV proton biomedical cyclotron, through the reaction (89)Y(p, n)(89)Zr. Simulations were performed with and without an Al energy degrader. In the setup of the geometry of the target, state of the art support tools, like SimpleGeo, were used for accurate, detailed modeling. The results permitted a quick assessment of all possible radionuclidic contaminants and confirmed that the use of an energy degrader avoids production of the most important impurity, (88)Zr. The estimated value for the activity produced in one hour of irradiation at 20μA is 384 ± 42MBq; this is encouraging, indicating possible production of clinically significant amounts of activity with the relatively simple target setup adopted. Initial experimental tests gave results in excellent agreement with simulations, confirming the usefulness and accuracy of FLUKA as a tool for the design and optimization of targets for the production of PET radionuclides.

Automation synthesis modules review.

The introduction of (68)Ga labelled tracers has changed the diagnostic approach to neuroendocrine tumours and the availability of a reliable, long-lived (68)Ge/(68)Ga generator has been at the bases of the development of (68)Ga radiopharmacy. The huge increase in clinical demand, the impact of regulatory issues and a careful radioprotection of the operators have boosted for extensive automation of the production process. The development of automated systems for (68)Ga radiochemistry, different engineering and software strategies and post-processing of the eluate were discussed along with impact of automation with regulations.

Usefulness of 64Cu-ATSM in head and neck cancer: a preliminary prospective study.

Aims 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) is a hypoxia-avid, positron emitter radiotracer. The primary aim of this study is to assess the efficacy of pretherapy 64Cu-ATSM PET/CT as a prognostic factor of response to therapy. The secondary aims are to investigate if there is a difference between early and late PET/CT scans and if there is a difference between the biologic tumor volume (BTV) in radiotherapy treatment planning calculated between 64Cu-ATSM and 18F-FDG, and to assess if 64Cu-ATSM is a prognostic marker of disease progression. Methods Eleven patients with head and neck cancer treated with chemoradiotherapy were enrolled prospectively; both 64Cu-ATSM and 18F-FDG PET/CT scans before and after treatment were obtained. The 64Cu-ATSM scans were performed after 1 hour (early) and 16 hours (late). Results All patients had stage III or IV squamous cell head and neck cancer; 7 of 11 patients had nodal metastasis, and 22 cancer foci were detected with 64Cu-ATSM. SUVmax was 16.2 ± 7.9, and there was no significant SUVmax difference between early and late imaging. 18F-FDG SUVmax before therapy was 15.6 ± 9.4, whereas 18F-FDG SUVmax after therapy was 1.5 ± 1.2. Sensitivity and specificity values of 64Cu-ATSM calculated with receiver operating characteristic curves were 100% and 50% considering the SUVmax and 100% and 33% considering the volume, respectively. No difference has been found between the BTV contoured with 64Cu-ATSM and 18F-FDG. Conclusions The 64Cu-ATSM scans showed high sensitivity but low specificity in predicting neoadjuvant chemoradiotherapy response. No difference was noted between early and late scans. 18F-FDG and 64Cu-ATSM provided similar results about delineation of BTV.

Synthesis and quality control of 68Ga citrate for routine clinical PET.

Introduction and aimScintigraphic imaging of infection and inflammation with 67Ga-citrate is an established and powerful diagnostic tool in the management of patients with infectious or inflammatory diseases. 68Ga is a short-lived positron-emitting radionuclide (half-life 67.6 min, positron energy 2.92 MeV), which allows better imaging qualities than 67Ga using the high spatial resolution and the quantitative features of PET. The aim of this study was to develop a method of synthesis for 68Ga citrate with high and reproducible radiochemical yield using a commercial 68Ga-labelling module. The resultant 68Ga citrate would be suitable for use in the detection of infectious or inflammatory diseases in routine clinical practice. MethodsA simplified method of producing 68Ga citrate is described. Radiochemical purity, pyrogen testing were performed as per the standard protocols. ResultsAfter performing 10 syntheses of 68Ga citrate, the radiochemical yield was 64.1±6.0% (mean±standard deviation) with an average activity of 971.2±103.4 MBq available for labelling. Radiochemical purity determined by instant thin-layer chromatography-silica gel was higher than 98%. All the synthesized products were found to be sterile and pyrogen-free. In this study, the quality control step provided good and reproducible results. This is worth noting, especially in view of the stringent new rules adopted in most European countries for the in-house good manufacturing practice (GMP) synthesis of radiopharmaceuticals. ConclusionThe high radiochemical yield and purity showed that this method is a reliable tool for the production of 68Ga citrate to be used in the detection of inflammatory and infectious diseases using high resolution and qualitative PET.

Synthesis of oncological [11C]radiopharmaceuticals for clinical PET

Positron emission tomography (PET) is a nuclear medicine modality which provides quantitative images of biological processes in vivo at the molecular level. Several PET radiopharmaceuticals labeled with short-lived isotopes such as (18)F and (11)C were developed in order to trace specific cellular and molecular pathways with the aim of enhancing clinical applications. Among these [(11)C]radiopharmaceuticals are N-[(11)C]methyl-choline ([(11)C]choline), l-(S-methyl-[(11)C])methionine ([(11)C]methionine) and 1-[(11)C]acetate ([(11)C]acetate), which have gained an important role in oncology where the application of 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) is suboptimal. Nevertheless, the production of these radiopharmaceuticals did not reach the same level of standardization as for [(18)F]FDG synthesis. This review describes the most recent developments in the synthesis of the above-mentioned [(11)C]radiopharmaceuticals aiming to increase the availability and hence the use of [(11)C]choline, [(11)C]methionine and [(11)C]acetate in clinical practice.

Engineered porphyrin loaded core-shell nanoparticles for selective sonodynamic anticancer treatment

AIM Porphyrin-loaded core-shell nanoparticles have been engineered for use as in vivo sonosensitizing systems, radio-tracers or magnetic resonance (MR) imaging agents, which may be suitable for the selective treatment of solid tumors and imaging analyses. MATERIALS & METHODS Polymethyl methacrylate nanoparticles (PMMANPs) have been either loaded with meso-tetrakis (4-sulphonatophenyl) porphyrin (TPPS) for sonodynamic anticancer treatment, with (64)Cu-TPPS for positron emission tomography biodistribution studies or with Mn(III)-TPPS for MR tumor accumulation evaluation. RESULTS PMMANPs are easily functionalized with negatively charged molecules and show favorable biodistribution. In vivo TPPS-PMMANPs have demonstrated shock wave responsiveness in a Mat B III syngeneic rat breast cancer model as measured by MR analyses of pre- and post-treatment tumor volumes. CONCLUSION TPPS-PMMANPs are a multimodal system which can efficiently induce in vivo sonodynamic anticancer activity.

Prognostic Evaluation of Disease Outcome in Solid Tumors Investigated With 64Cu-ATSM PET/CT.

Purpose 64Cu-ATSM is a very promising PET radiopharmaceutical for tumor imaging of hypoxia. One of the advantages of this compound compared with other hypoxia-avid tracers is the high tumor-to-background signal offered, which guaranties facilitated tumor delineation. This study analyzes optimal semiquantitative and quantitative parameters obtained by 64Cu-ATSM PET/CT in the same cohort of patients with special focus on their correlation to disease outcome. Patients and Methods A prospective recruitment of 18 consecutive patients (M:F, 13:5; mean age, 60.7 years) with locally advanced non–small cell lung cancer (n = 7) or head and neck cancer (HNC) was performed. Each participant received 105 to 500 MBq of tracer according to body size and was scanned in a 3-dimensional mode PET/CT 60 minutes after tracer injection. PET images were reconstructed and visualized on a GE Advanced 4.6 workstation for the definition of semiquantitative and quantitative parameters: SUVmax, SUVratio-to-muscle, hypoxic tumor volume (HTV), and hypoxic burden (HB = HTV × SUVmean). These data were subsequently correlated to disease outcome, expressed in terms of progression-free survival calculated on a follow-up period with a median of 14.6 months. Results All patients showed a moderately to highly increased uptake of 64Cu-ATSM in tumor lesions, with a mean SUVmax of 5.2 (range, 1.9–8.3) and mean SUVratio of 4.4 (range, 1.6–6.8). In addition, a broad range of HTV and HB was defined as mean values of 99.3 cm3 (range, 2.5–453.7 cm3) and 301 (4.2–1134), respectively. Receiver operating characteristic analysis identified as reference cutoffs with respect to disease outcome with the following values: SUVmax >2.5 (AUC, 0.57; sensitivity, 88.9%; specificity, 50%), SUVratio ⩽4.4 (AUC, 0.60; sensitivity, 50; specificity, 83.3%), HTV >160.7 cm3 (AUC, 0.61; sensitivity, 55.6%; specificity, 75%), and HB >160.7 (AUC, 0.67; sensitivity, 58.3%; specificity, 83.3%). In our cohort, HB showed a statistically significant difference in terms of mean values on the analysis of variance test with respect to disease progression (P = 0.04). On univariate analysis, Cox regression confirmed these findings and showed a significant correlation to progression-free survival for HB (P = 0.05) and HTV (P = 0.02). Conclusions In our cohort, the definition of optimal semiquantitative and quantitative parameters on 64Cu-ATSM PET/CT seems feasible and in line with previously published data. However, when considering the prognostic role with respect to disease outcome, the more robust parameters are represented by HTV and HB.

Radiolabelling, quality control and radiochemical purity assessment of the Octreotide analogue 68Ga DOTA NOC

Somatostatin receptors 1-5 are over expressed in neuroendocrine tumours (NETs). 68Ga-labelled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-Nal3-Octreotide (DOTA NOC), a recent synthesized somatostatin analogue, shows high affinity for those receptors. Herein, modifications of a commercial module for the labelling of DOTA NOC with 68Ga, as well as the assessment of time course of the radiochemical purity variation are described. The evaluation of radiochemical stability was done by two different chromatographic methods: reversed-phase radio HPLC and fast TLC analysis. Labelled compound has been found radiochemically stable within 3h from the end of labelling (EOL) and radiochemical purity was always higher than 99%. After 73 labelling sessions the system showed great reproducibility and high radiochemical yield.

Some experimental studies on 89Zr production

Abstract The radionuclide 89Zr (T1/2=78.4ߙh) is particularly attractive for in vivo assessment of biochemical proesses characterized by biological half times in the order of several hours. In the present study we assessed the feasibility of 89Zr production via the 89Y(p,n)89Zr reaction. Irradiation tests were performed using a 16.5ߙMeV GE-PETtrace cyclotron. High purity (>99.9%) yttrium metallic foils (0.15ߙmm) were irradiated in a solid target station developed in our Institution. The literature cross section data of all the nuclear reactions possible in the energy range of interest were carefully studied to optimize the irradiation parameters. The irradiated target was dissolved in 1ߙN HCl and the activity of the sample was measured in a CRC-15 PET dose calibrator, setting different values for the calibration factor. The sample activity was then measured usin g a calibrated HPGe gamma ray detector. A comparison of the activity measurements allowed the evaluation of the calibration factor for the Capintec CRC-15 PET; for a 3ߙml syringe geometry, it was found 739±60. Saturation yields of 89Zr were found to be 1150±110ߙMBq/μA for a single 0.15ߙmm thick disc irradiation (Ep=12.6→11.2ߙMeV) and 2400±220ߙMBq/μA for irradiation of two discs of total thickness 0.3ߙmm (Ep=12.6→9.5MeV). Total produced activities in the range of 200–400ߙMBq (according to target thickness) were repeatedly and safely obtained by 60ߙmin bombardments at 20ߙμA. Analysis of gamma ray spectra of all the samples showed a very high radionuclidic purity (>99.9995%).

Generator Breakthrough and Radionuclidic Purification in Automated Synthesis of 68Ga-DOTANOC

68Ga labeled radiopharmaceuticals, like 68Ga-DOATNOC and other similar peptides, are gaining relevance in PET-CT, thanks to relatively easy local generator production, that do not requires an installed cyclotron. However, generator produced 68Ga is typically of suboptimal purity, mainly due to the breakthrough of the parent radionuclide 68Ge. Modern automated synthesis modules adopt both fractionation methods and purification methods in order to get rid of 68Ge breakthrough. Purification methods are mainly based on based on cationic prepurification even if anionic purification has been adopted as well. This work studies the efficacy of cationic prepurification using commercial STRATA-X-C, as well as distribution of the 68Ge contaminant during all steps of the synthesis of labeled peptides. Generator waste, STRATA-X-C purification cartridge, synthesis waste and the final product are quantitatively analyzed by means of high resolution gamma ray spectrometry. Our results show that current method of purification is highly effective; initial 68Ge breakthrough of the order of 1 kBq is decreased by a factor greater than 100, with removal of about 61% of the contaminant 68Ge in the first purification passage; this allow an efficient labeling, since removal of the remaining impurity happens during chelation in the reactor vessel. In conclusion, the synthesis with modular automated system resulted to reliably produce 68Ga-DOTANOC, with limited if any user intervention. 68Ge content in the final formulation results lower than 2x10(-7)%, avoiding unjustified patient irradiation due to radionuclidic impurities and satisfying quality prerequisites for radiopharmaceutical preparations.