Lymphoscintigraphy in the Time of COVID-19: Effect of Molybdenum-99 Shortage on Feasibility of Sentinel Node Mapping.

Background: In the current study, we reported our experience on sentinel node mapping of breast cancer patients during the extreme shortage of Mo99-Tc99m generators using Tc-99m phytate. Methods and Results: During the period from March 7, 2019, to April 18, 2020, due to disruption of molybdenum supply chain, we used low specific activity Tc-99m pertechnetate elute (0.5-2 mCi of 99mTcO4 in 5 mL) for each kit preparation. Two or three intradermal periareolar injections were done for each patient (0.02-0.1 mCi/0.2 mL for each injection). Immediately following injection, dynamic lymphoscintigraphy was done. Surgery was done the same day of injection and the axillary sentinel node was sought using a gamma probe. Overall, 35 patients were included in the study. The specific activity of the Tc-99m elute (in 5 mL) used for kit preparation was 2 mCi/10 mg in four, 1.5 mCi/10 mg in eight, 1.25 mCi/10 mg in eight, 1 mCi/10 mg in three, 0.75 mCi/10 mg in five, and 0.5 mCi/10 mg of 99mTc-Phytate in seven patients. For the first four groups of patients, we used two 0.2 mL injections, while in the latter two groups, three 0.2 mL injections were used. At least one sentinel node was detected in all patients but three in whom axilla was involved. Conclusion: Sentinel node biopsy can be achieved with low specific activity of Tc-99m elute at the time of Mo99-Tc-99m generator shortage. If special personal protection is used, sentinel node mapping can be done in nuclear medicine departments with excellent results despite the COVID-19 pandemic and disruption of generator shipment.

Supply and Clinical Application of Actinium-225 and Bismuth-213.

The recent development of 225Ac-PSMA617 for therapy of prostate cancer has strikingly demonstrated the clinical potential of targeted alpha therapy. Further promising applications of the alpha emitters 225Actinium and its daughter nuclide 213Bismuth include the therapy of brain tumors, bladder cancer, neuroendocrine tumors, and leukemia. This paper will provide a brief overview on the current status of the clinical development of compounds labelled with 225Ac or 213Bi and describe the various production routes that are in place or are under development to meet the increasing demand for these radionuclides.

Production and Clinical Applications of Radiopharmaceuticals and Medical Radioisotopes in Iran.

During past 3 decades, nuclear medicine has flourished as vibrant and independent medical specialty in Iran. Since that time, more than 200 nuclear physicians have been trained and now practicing in nearly 158 centers throughout the country. In the same period, Tc-99m generators and variety of cold kits for conventional nuclear medicine were locally produced for the first time. Local production has continued to mature in robust manner while fulfilling international standards. To meet the ever-growing demand at the national level and with international achievements in mind, work for production of other Tc-99m-based peptides such as ubiquicidin, bombesin, octreotide, and more recently a kit formulation for Tc-99m TRODAT-1 for clinical use was introduced. Other than the Tehran Research Reactor, the oldest facility active in production of medical radioisotopes, there is one commercial and three hospital-based cyclotrons currently operational in the country. I-131 has been one of the oldest radioisotope produced in Iran and traditionally used for treatment of thyrotoxicosis and differentiated thyroid carcinoma. Since 2009, (131)I-meta-iodobenzylguanidine has been locally available for diagnostic applications. Gallium-67 citrate, thallium-201 thallous chloride, and Indium-111 in the form of DTPA and Oxine are among the early cyclotron-produced tracers available in Iran for about 2 decades. Rb-81/Kr-81m generator has been available for pulmonary ventilation studies since 1996. Experimental production of PET radiopharmaceuticals began in 1998. This work has culminated with development and optimization of the high-scale production line of (18)F-FDG shortly after installation of PET/CT scanner in 2012. In the field of therapy, other than the use of old timers such as I-131 and different forms of P-32, there has been quite a significant advancement in production and application of therapeutic radiopharmaceuticals in recent years. Application of (131)I-meta-iodobenzylguanidine for treatment of neuroblastoma, pheochromocytoma, and other neuroendocrine tumors has been steadily increasing in major academic university hospitals. Also (153)Sm-EDTMP, (177)Lu-EDTMP, (90)Y-citrate, (90)Y-hydroxyapatite colloid, (188/186)Re-sulfur colloid, and (188/186)Re-HEDP have been locally developed and now routinely available for bone pain palliation and radiosynovectomy. Cu-64 has been available to the nuclear medicine community for some time. With recent reports in diagnostic and therapeutic applications of this agent especially in the field of oncology, we anticipate an expansion in production and availability. The initiation of the production line for gallium-68 generator is one of the latest exciting developments. We are proud that Iran would be joining the club of few nations with production lines for this type of generator. There are also quite a number of SPECT and PET tracers at research and preclinical stage of development preliminarily introduced for possible future clinical applications. Availability of fluorine-18 tracers and gallium-68 generators would no doubt allow rapid dissemination of PET/CT practices in various parts of our large country even far from a cyclotron facility. Also, local production and availability of therapeutic radiopharmaceuticals are going to open exciting horizons in the field of nuclear medicine therapy. Given the available manpower, local infrastructure of SPECT imaging, and rapidly growing population, the production of Tc-99m generators and cold kit would continue to flourish in Iran.

["Technetium crisis" -  causes, possible solutions and consequences for planar scintigraphy and SPECT diagnostics]. / "Techneciová krize" -  príciny, mozná resení a dopad na dia-gnostiku planární scintigrafií a SPECT.

Nuclear medicine is an important field of nuclear medicine, especially thanks to its role in in vivo imaging of important processes in human organism. An overwhelming majority of nuclear medicine examinations comprises of planar scintigraphy and single photon emission computed tomography, for decades relying on the labeling by metastable technetium nuclide (99mTc), used with a great diversity of ligands for various applications. Nuclear medicine departments utilize commercially available molybdenum technetium generators, being able to elute the nuclide at any time and prepare the radiopharmaceutical. The mother nuclide, molybdenum-99 (99Mo), is produced in just a handful of places around the world. The production places are without exception research nuclear reactors working far past their life expectancy. A concurrent temporary shutdown of two of them in the year 2009 caused a critical worldwide shortage of 99mTc. An unavoidable permanent shutdown of part of these capacities in the second decade of the 21st century will cause the second, and this time rather permanent "technetium crisis". The article focuses on history, present, potential future and possible solutions in regard to SPECT diagnostics.

Options to meet the future global demand of radionuclides for radionuclide therapy.

Nuclear medicine continues to represent one of the important modalities for cancer management. While diagnostic nuclear medicine for cancer management is fairly well established, therapeutic strategies using radionuclides are yet to be utilized to their full potential. Even if 1% of the patients undergoing diagnostic nuclear medicine procedures can benefit from subsequent nuclear therapeutic intervention, the radionuclide requirement for nuclear therapeutics would be expected to be in the multi-million Curie levels. Meeting the demand for such high levels of therapeutic radionuclides at an affordable price is an important task for the success of radionuclide therapy. Although different types of particle emitters (beta, alpha, Auger electron etc.) have been evaluated for treating a wide variety of diseases, the use of ß⁻ emitting radionuclides is most feasible owing to their ease of production and availability. Several ß⁻ emitting radionuclides have been successfully used to treat different kind of diseases. However, many of these radionuclides are not suitable to meet the projected demand owing to the non-availability with sufficiently high specific activity and adequate quantity because of high production costs, relatively short half-lives etc. This article describes the advantages and disadvantages for broader uses of some of the well known therapeutic radionuclides. In addition, radioisotopes which are expected to have the potential to meet the growing demand of therapeutic radionuclides are also discussed.

Paving the way to personalized medicine: production of some promising theragnostic radionuclides at Brookhaven National Laboratory.

This article reintroduces and reinforces our proposed paradigm that involves specific individual "dual-purpose" radionuclides or radionuclide pairs with emissions suitable for both imaging and therapy and which, when molecularly (selectively) targeted using appropriate carriers, would allow pretherapy low-dose imaging as well as higher-dose therapy in the same patient. We have made an attempt to sort out and organize a number of such theragnostic radionuclides and radionuclide pairs that may thus potentially bring us closer to the age-long dream of personalized medicine for performing tailored low-dose molecular imaging (single-photon emission computed tomography/computed tomography or positron emission tomography/CT) to provide the necessary pretherapy information on biodistribution, dosimetry, the limiting or critical organ or tissue, the maximum tolerated dose, and so forth, followed by performing higher-dose targeted molecular therapy in the same patient with the same radiopharmaceutical. Beginning in the 1980s, our work at Brookhaven National Laboratory with such a "dual-purpose" radionuclide, tin-117m, convinced us that it is arguably one of the most promising theragnostic radionuclides, and we have continued to concentrate on this effort. Our results with this radionuclide are therefore covered in somewhat greater detail in this publication. A major problem that continues to be addressed, but remains yet to be fully resolved, is the lack of availability, in sufficient quantities, of a majority of the best candidate theragnostic radionuclides in a no-carrier-added form. A brief description of the recently developed new or modified methods at Brookhaven National Laboratory for the production of 5 theragnostic radionuclide/radionuclide pair items, whose nuclear, physical, and chemical characteristics seem to show great promise for personalized cancer and other therapies, is provided.

A review of ion sources for medical accelerators (invited).

There are two major medical applications of ion accelerators. One is a production of short-lived isotopes for radionuclide imaging with positron emission tomography and single photon emission computer tomography. Generally, a combination of a source for negative ions (usually H- and/or D-) and a cyclotron is used; this system is well established and distributed over the world. Other important medical application is charged-particle radiotherapy, where the accelerated ion beam itself is being used for patient treatment. Two distinctly different methods are being applied: either with protons or with heavy-ions (mostly carbon ions). Proton radiotherapy for deep-seated tumors has become widespread since the 1990s. The energy and intensity are typically over 200 MeV and several 10(10) pps, respectively. Cyclotrons as well as synchrotrons are utilized. The ion source for the cyclotron is generally similar to the type for production of radioisotopes. For a synchrotron, one applies a positive ion source in combination with an injector linac. Carbon ion radiotherapy awakens a worldwide interest. About 6000 cancer patients have already been treated with carbon beams from the Heavy Ion Medical Accelerator in Chiba at the National Institute of Radiological Sciences in Japan. These clinical results have clearly verified the advantages of carbon ions. Heidelberg Ion Therapy Center and Gunma University Heavy Ion Medical Center have been successfully launched. Several new facilities are under commissioning or construction. The beam energy is adjusted to the depth of tumors. It is usually between 140 and 430 MeV∕u. Although the beam intensity depends on the irradiation method, it is typically several 10(8) or 10(9) pps. Synchrotrons are only utilized for carbon ion radiotherapy. An ECR ion source supplies multi-charged carbon ions for this requirement. Some other medical applications with ion beams attract developer's interests. For example, the several types of accelerators are under development for the boron neutron capture therapy. This treatment is conventionally demonstrated by a nuclear reactor, but it is strongly expected to replace the reactor by the accelerator. We report status of ion source for medical application and such scope for further developments.

Questionnaire survey of hospitals in Saitama Prefecture regarding the shortage of 99mTc-labeled radiopharmaceuticals and 99Mo/99mTc generators.

OBJECTIVE AND METHODS: A questionnaire survey was conducted at all 32 hospitals in Saitama Prefecture to investigate the current difficult situation in terms of nuclear medicine management in the face of the (99m)Tc shortage due to insufficient supply, and 29 hospitals (90.6%) replied. RESULTS: Of the 29, 15 (51.7%) reported a reduction in the number of nuclear medicine studies performed due to the shortage of supply, although the reduction was small. The decrease per month was less than 20 studies in 73% of the institutions. Of the nuclear medicine studies that involve the use of (99m)Tc, the studies whose reduction in number most seriously affected patient management were, in decreasing order: (99m)Tc-MAA lung perfusion scans, (99m)Tc-MAG(3), (99m)Tc-DTPA, or (99m)Tc-DMSA renoscans, (99m)Tc-MDP bone scans, (99m)Tc-HMPAO or ECD brain SPECT studies, (99m)Tc-MIBI or tetrofosmin myocardial SPECT studies, (99m)Tc-radiocolloid sentinel lymphoscintigraphy, (99m)Tc-HSA-D or pyrophosphate bleeding scans, (99m)Tc-GSA hepatic function reserve scans, and (99m)Tc-MIBI parathyroid scans. The reduction is probably ascribable to factors such as cancellations of emergency studies, absence of substitute studies, sequential studies using the same radiopharmaceutical, and higher cost of the syringe-type products than the vial-type products. Substitutes for (99m)Tc studies were performed at 52% (15/29) of the institutions. Myocardial perfusion imaging with (201)Tl chloride was the most common substitute study. CONCLUSIONS: The results of this survey suggested the several procedures to resolve the issues related to the shortage. The staffs at all institutions except one gave the impression that their nuclear medicine ordering systems had been greatly affected by the shortage of supply. This adverse circumstance, however, may provide a good opportunity to educate the public about nuclear medicine studies that use (99m)Tc and SPECT, with which citizen are now unfamiliar.

Radioimmunoimaging with longer-lived positron-emitting radionuclides: potentials and challenges.

Radioimmunoimaging and therapy has been an area of interest for several decades. Steady progress has been made toward clinical translation of radiolabeled monoclonal antibodies for diagnosis and treatment of diseases. Tremendous advances have been made in imaging technologies such as positron emission tomography (PET). However, these advances have so far eluded routine translation into clinical radioimmunoimaging applications due to the mismatch between the short half-lives of routinely used positron-emitting radionuclides such as (18)F versus the pharmacokinetics of most intact monoclonal antibodies of interest. The lack of suitable positron-emitting radionuclides that match the pharmacokinetics of intact antibodies has generated interest in exploring the use of longer-lived positron emitters that are more suitable for radioimmunoimaging and dosimetry applications with intact monoclonal antibodies. In this review, we examine the opportunities and challenges of radioimmunoimaging with select longer-lived positron-emitting radionuclides such as (124)I, (89)Zr, and (86)Y with respect to radionuclide production, ease of radiolabeling intact antibodies, imaging characteristics, radiation dosimetry, and clinical translation potential.

A limiting factor for the progress of radionuclide-based cancer diagnostics and therapy--availability of suitable radionuclides.

Advances in diagnostics and targeted radionuclide therapy of haematological and neuroendocrine tumours have raised hope for improved radionuclide therapy of other forms of disseminated tumours. New molecular target structures are characterized and this stimulates the efforts to develop new radiolabelled targeting agents. There is also improved understanding of factors of importance for choice of appropriate radionuclides. The choice is determined by physical, chemical, biological, and economic factors, such as a character of emitted radiation, physical half-life, labelling chemistry, chemical stability of the label, intracellular retention time, and fate of radiocatabolites and availability of the radionuclide. There is actually limited availability of suitable radionuclides and this is a limiting factor for further progress in the field and this is the focus in this article. The probably most promising therapeutic radionuclide, 211At, requires regional production and distribution centres with dedicated cyclotrons. Such centres are, with a few exceptions in the world, lacking today. They can be designed to also produce beta- and Augeremitters of therapeutic interest. Furthermore, emerging satellite PET scanners will in the near future demand long-lived positron emitters for diagnostics with macromolecular radiopharmaceuticals, and these can also be produced at such centres. To secure continued development and to meet the foreseen requirements for radionuclide availability from the medical community it is necessary to establish specialized cyclotron centres for radionuclide production.

[Radionuclide therapy--a possible way toward an improved treatment of cancer. The obstacle is the shortage of commercially available radionuclides for clinical use]. / Radionuklidterapi--möjlig väg mot bättre behandling av cancer. Hindret är bristen på kommersiellt tillgängliga nuklider i kliniken.

About one third of all cancer develops into a spread disease that is difficult to treat. Radioimmunotherapy has during the last years proven to be of help when other therapy modalities fail in e.g. lymphomas. The development in this area is fast mainly due to substantial improvements in molecular biology and in our increasing understanding of specific receptor expressions in cancer cells. However, radionuclides used today, 131I and 90Y, are not optimal in that sense that they emit radiation mainly suitable to treat the bulk tumor and not the single cell and micrometastases present in spread disease. The article stresses the importance that radionuclides with more suitable emission of particles like 177Lu and 211At are made available for clinical research and routine.

Delivery and collection of radioactive packages to and from UK hospital nuclear medicine departments.

Under radiation protection legislation in the UK, employers have a duty to maintain appropriate records to account for radioactive materials in their possession and to ensure security of these materials. This applies to radioactive packages, containing items such as technetium generators, which are regularly delivered to hospital nuclear medicine departments. It also applies to the collection of packages, such as those containing used generators for return to the supplier. This article has been written by the professional bodies representing nuclear medicine in the UK in order to provide guidance to hospitals on appropriate procedures that will comply with the legislation. General principles, which should be met by any acceptable protocol, are stated, and practical guidance on how these may be implemented is given. Some example scenarios are outlined.

Production and supply of high specific activity radioisotopes for radiotherapy applications

High specific activity radioisotopes such as Lu-177, Pm-149, Ho-166 and Rh-105 can be produced by indirect methods involving neutron irradiation of isotopically enriched (e.g. Ru-104) targets producing parent radioisotopes that beta decay to form the desired daughter radioisotopes. For example, Lu-177 can be produced by direct (n, gamma) irradiation of Lu-176. However, only about 20 percent of the Lu-176 atoms are converted to Lu-177 and the long-lived impurity Lu-177m (half-life = 160 days) is also produced in small quantities. Direct irradiation of Yb-176 results in the production of Yb-177 (half-life = 1.9 hr) that beta decays to form Lu-177, with the further advantage that this route of production avoids long-lived Lu-177m. Chemical separation of the Lu-177 from the Yb target results in a high specific activity Lu-177 that can then be used for radiotherapy. Separation of Rh-105 from irradiated Ru-104 targets is also being investigated by volatilization of the Ru