IAEA activities on 67Cu, 186Re, 47Sc Theranostic radionuclides and Radiopharmaceuticals

Despite interesting properties, the use of 67Cu, 186Re and 47Sc theranostic radionuclides in preclinical studies and clinical trials is curtailed by their limited availability due to a lack of widely established production methods. An IAEA Coordinated Research Project (CRP) was initiated to identify important technical issues related to the production and quality control of these emerging radionuclides and related radiopharmaceuticals, based on the request from IAEA Member States. The international team worked on targetry, separation, quality control and radiopharmaceutical aspects of the radionuclides obtained from research reactors and cyclotrons leading to preparation of a standard recommendations for all Member States. The CRP was initiated in 2016 with fourteen participants from thirteen Member States from four continents. Extraordinary results on the production, quality control and preclinical evaluation of selected radionuclides were reported in this project that was finalized in 2020. The outcomes, outputs and results of this project achieved by participating Member States are described in this minireview

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Cyclotron Produced Radionuclides: Emerging Positron Emitters for Medical Applications: 64Cu and 124I

1.1.BACKGROUNDThe application of radionuclides in medicine has undergone significant growth in the last two decades, with the availability of a large number of cyclotrons exclusively dedicated to their production contributing to this growth, The widespread use of positron emission tomography (PET) in oncology and the rapid dissemination of PET--computed tomography (PET -CT) cameras throughout the world have revolutionized nuclear medicine. The rapidly growing fleet of modern cameras and the progress in molecular imaging signify that clinical PET will grow beyond present state of the art 2-[18F] fluoro-2-deoxy-D-glucose(18F-FDG) imaging in diagnosis and staging in oncology, New 18F tracers will certainly drive some of this expansion, but there is a growing understanding that many physiological and biological uptake mechanisms in humans are slow when compared to the short half-life of 18F. An abundant positron emission and long half-life are in general not favoured for nuclear physics reasons, however a handful of such isotopes have been explored and reported on by researchers in the past. Among these, only two at present deserve to be raised to the level of being called \u27emerging PET isotopes\u27: 64Cu and 124I. A third isotope, 89Zr, might deserve to be added to this category, and could prove to be ideally suited for future use in PET labelled antibodies. New radiopharmaceuticals which can be routinely used for diagnosis or for evaluation of cancer therapy would be valuable additions to the arsenal available to the nuclear medicine physician. There is great potential forproduction and development of new radiopharmaceuticals using PET radionuclides other than 18F and 11C at most of the present day medical cyclotron facilities with cyclotrons in the energy range of 10-20 MeV. Cyclotron time is usually available for research, but there are several other factors to be addressed in the development and use of new radiopharmaceuticals. More than 30 potentially useful cyclotron produced positron emitting radionuclides havebeen reported, and 64CU and 1241 in particular have received considerable attention. Because of low positron energy, low abundance of gamma radiation, suitable half-life and favourable coordination chemistry, these radionuclidesare attracting widespread interest. There are two major challenges in wider production of these PET tracers:(1) The targets for the production of these radionuclides are not widely available or are considered too difficult to use.(2) The separation of the radionuclide from the target material requires ion exchange chromatography or thermal diffusion and the labelling efficiency of the resultant nuclide needs to be further developed.There is a need to evaluate and compare the emerging radionuclides as imaging agents. The most widespread medical applications of these non-standard PET radionuclides are in oncology for labelling of proteins, particularlyimmunoglobulins (antibodies to tumour specific antigens), and of small peptides which recognize receptors expressed on tumours. Some examples of applications would be:(a) As diagnostic PET imaging agents (with greater biological specificity than 18F_FDG). Such a diagnostic tracer, for example, would differentiate between malignant tumours and benign conditions such as sarcoidosis.This currently is a problem when using 18F-FDG, which mimics increased anaerobic glucose metabolism in tumours but also inflammatory processes.(b) To identifY patients with specific tumour phenotypes for novel targeted therapies (e.g. antibody therapies).(c) To provide improved dosimetry of therapeutic radionuclides based upon improved quantitation of tumour and normal tissue (organ) distribution using PET instrumentation. In particular, the use of PET radionuclides with a longer half-life than 18F, such as 1241 or 64Cu, provides information required for optimal organ and tumour dosimetry.Even though interest in the use of these radionuclides for clinical application is steadily increasing, support from the (radio)pharmaceutical industry is rather limited. The major reason is that large scale production for provision of a sufficient number of customers is technically not achievable, whereas local, small scale production, on the other hand, is economically not very attractive. In this respect, the IAEA\u27s role in fostering streamlined research and production· capacities in Member States is of great importance to further develop this field and in general for these health care applications where short lived radionuclides are being used

Therapeutic Radiopharmaceuticals Labelled with Copper-67, Rhenium-186 and Scandium-47 (IAEA-TECDOC-1945)

Theranostic radiopharmaceuticals have shown tremendous capabilities in the last decade in the treatment and diagnosis of human diseases via nuclear medicine procedures. In particular, the use of radiometals has experienced a great increase as a result of the development of relevant production technologies. This publication presents the outcome of an IAEA coordinated research project (CRP) focusing on the production, quality control and radiopharmaceutical aspects of three key radionuclides, 67CU, 186Re and 47Sc, which have been selected based on their theranostic potential and their dual production routes. The publication was compiled using inputs from experts in the field as well as presenting the overall results of the CRP. It contains separate sections for each radionuclide including: nuclear data and information on targetry, irradiation, chemical separation, quality control as well as sample radiopharmaceutical production. The findings and considerations will be of use to scientists and technologists interested in translating research reactor and cyclotron based radioisotope production into practice, as well as to post graduate students in the field