Claudio Malizia

Incidence of Increased 68Ga-DOTANOC Uptake in the Pancreatic Head in a Large Series of Extrapancreatic NET Patients Studied with Sequential PET/CT

The aim of our retrospective study was to assess the incidence of increased uptake of 68Ga-DOTANOC in the head of the pancreas among a large population of patients with extrapancreatic neuroendocrine tumors studied with serial 68Ga-DOTANOC PET/CT. Methods: Patients who had undergone at least two 68Ga-DOTANOC PET/CT studies over time were included. Uptake in the head of the pancreas was measured and compared with uptake in normal liver parenchyma (target-to-liver ratio). Patients were followed up for 6–24 mo. Results: We reviewed 245 studies performed on 100 patients and classified the pancreatic uptake as either diffuse or focal. Twenty-three patients (66 scans) showed diffuse uptake; 8 patients (16 scans) showed focal uptake. None of these 31 patients had negative findings on their subsequent scans, and vice versa. During follow-up, localization of neuroendocrine tumors in the pancreas was not suspected in any patient. Conclusion: Focal and diffuse uptake of 68Ga-DOTANOC in the head of the pancreas occurred, respectively, in 23% and 8% of the patients. The main finding of our study was that increased pancreatic uptake was stable over time.

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.

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.

Overview and Perspectives on Automation Strategies in 68 Ga Radiopharmaceutical Preparations

The renaissance of (68)Ga radiopharmacy has led to great advances in automation technology. The availability of a highly efficient, reliable, long-lived (68)Ge/(68)Ga generator system along with a well-established coordination chemistry based on bifunctional chelating agents have been the bases of this development in (68)Ga radiopharmacy. Syntheses of (68)Ga peptides were originally performed by manual or semiautomated systems, but increasing clinical demand, radioprotection, and regulatory issues have driven extensive automation of their production process. Several automated systems, based on different post-processing of the (68)Ga generator eluate, on different engineering, and on fixed tubing or disposable cassette approaches, have been developed and are discussed in this chapter. Since automatic systems for preparation of radiopharmaceuticals should comply with qualification and validation protocols established by regulations such as current Good Manufacturing Practices (cGMP) and local regulations, some regulatory issues and the more relevant qualification protocols are also discussed.

11C-choline PET/CT scan in patients with prostate cancer treated with intermittent ADT: a sequential PET/CT study.

Aim The purpose of this preliminary study was to evaluate the usefulness of 11C-choline PET/CT in patients with recurrent prostate cancer and hormone-sensitive disease treated with intermittent antiandrogen therapy scheme. Patients and Methods We retrospectively evaluated 10 patients after radical prostatectomy (n = 8) or external beam radiotherapy (n = 2) as primary therapy, studied with sequential 11C-choline PET/CT. The first PET/CT (PET1) was performed during antiandrogen therapy (ADT) and the second PET/CT (PET2) was performed after therapy interruption. Only patients with negative results at PET1 were included in the study. At the time of PET1, all patients were under ADT from at least 6 months (mean PSA 0.54 ng/mL). At the time of PET2, all patients had completed ADT for a mean period of 7 months. 11C-Choline PET/CT findings were validated by a follow-up of at least 12 months or histological confirmation in case of local relapse. Results PET2 has been able to detect the site of recurrences in all cases. At the time of PET2, mean PSA was 3.88 ng/mL; mean PSAdt was 2.46 months; and mean PSAvel was 6.94 ng/mL/year. Four out of 10 patients showed a single lesion, 5 out of 10 patients showed 2 lesions and 1 patient showed multiple lymph-node lesions. Conclusion When performed during ADT interruption, 11C-choline PET/CT has been able to detect the site of recurrence in patients with increasing PSA values. In this context, 11C-choline PET/CT may help to assess the burden of disease or to change the therapeutic approach using more aggressive and addressed therapies like guided RT or salvage lymph-node dissection.

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.

Effective production of 65Zn with a PET cyclotron

Cyclotrons dedicated to the production of PET radiopharmaceuticals for clinical use can be a resource also for research in other fields of science. In the present study we assessed the feasibility of (65)Zn production via the (65)Cu(p,n)(65)Zn reaction using a 16.5 MeV GE-PETtrace biomedical cyclotron. The radioisotope (65)Zn (t(1/2)=244.26 zd; decay mode: EC 98.3%, β(+) 1.7%) has a wide range of applications, especially in botany and agriculture; its long half life allows storage and delivery to research centers without a cyclotron on site. Natural copper foils (thickness: 100 μm; purity: >99.9%) were irradiated in a solid target station developed in our institution. The EXFOR and IAEA cross sections databases were carefully studied to optimize the irradiation setup in order to maximize the yield of the radionuclide of interest and minimize the production of isotopic impurities. We performed production runs at 20 μA for 30 min. Activity was measured using a calibrated HPGe gamma ray detector and an ionization chamber radionuclide activity meter. These measures showed the presence of two main contaminants: (63)Zn (t(1/2)=38.47 min) and (64)Cu (t(1/2)=12.7h); we produced (65)Zn with a saturation yield of (1.06 ± 0.07) GBq/μA (E(p)=12.65→10.48 MeV). The irradiated target was dissolved in 1 ml of 6N HNO(3) at the temperature of 90°C and then purified through anion exchange chromatography with BIO RAD AG 1×8 resin. The radionuclidic purity of the final solution of (65)Zn in HCl 0.005 N, expressed in activity, resulted superior to (99.921 ± 0.003) %.

Use of 65Zn as a tracer for the assessment of purification in the 68Ga-DOTANOC synthesis.

In the last years (68)Ga has got into the focus of researchers and clinicians especially for radio-labeling of biomolecules; an important characteristic of this positron emitting isotope is its availability via the (68)Ge/(68)Ga generator system: the long-lived (68)Ge (t1/2=270.8 d) produces the short-lived (68)Ga (t1/2=67.63 min) which decays to stable (68)Zn. (68)Ge breakthrough compromises (68)Ga radionuclidic purity, while (68)Zn might affect the specific activity of the radiopharmaceutical. In this paper we investigated the weight of these impurities in (68)Ga-DOTANOC synthesis. (65)Zn (t1/2=244.26d; decay mode: EC 98.3%, β(+) 1.7%) was used as a radiotracer of stable (68)Zn; samples of the purification columns, wastes and product were recovered and measured with a calibrated HPGe gamma-ray spectrometry system. The results showed that (68)Zn competes with (68)Ga in labeling DOTANOC with a (95±2)% labeling yield; they also proved the effectiveness of the STRATA X-C cationic post-processing of the generator eluate in lowering the amount of this impurity to less than 1%. Moreover this approach, along with the purification of the final product through a STRATA X cartridge, effectively removes (68)Ge breakthrough providing a (68)Ga-DOTANOC radionuclidic purity of (99.9999986±0.0000006)%, superior to 99.9% required by the Pharmacopoeia Monograph on (68)Ga Edotreotide injection.