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Hypoxia plays a critical role in tumor biology, influencing cancer progression, treatment resistance, and patient prognosis. While 18-Fluorine fluoredeoxyglucose ([18F]F-FDG) PET imaging has been the standard for metabolic assessment, its limitations in accurately depicting hypoxic tumor regions necessitate the exploration of non-FDG hypoxia tracers. This review aims to evaluate emerging non-FDG radiotracers, such as nitroimidazole derivatives, copper-based agents, gallium-based agents and other innovative compounds, highlighting their mechanisms of action, biodistribution, and clinical applications. We will discuss the advantages and challenges associated with hypoxia imaging, as well as recent advancements in imaging techniques that enhance the assessment of tumor hypoxia. By synthesizing current research, this review seeks to provide insights into the potential of non-FDG hypoxia tracers for improving cancer diagnosis, treatment planning, and monitoring, ultimately contributing to more personalized and effective cancer care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Following on from the 2015 Lancet Oncology Commission on expanding global access to radiotherapy, Radiotherapy and theranostics: a Lancet Oncology Commission was created to assess the access and availability of radiotherapy to date and to address the important issue of access to the promising field of theranostics at a global level. A marked disparity in the availability of radiotherapy machines between high-income countries and low-income and middle-income countries (LMICs) has been identified previously and remains a major problem. The availability of a suitably trained and credentialled workforce has also been highlighted as a major limiting factor to effective implementation of radiotherapy, particularly in LMICs. We investigated initiatives that could mitigate these issues in radiotherapy, such as extended treatment hours, hypofractionation protocols, and new technologies. The broad implementation of hypofractionation techniques compared with conventional radiotherapy in prostate cancer and breast cancer was projected to provide radiotherapy for an additional 2·2 million patients (0·8 million patients with prostate cancer and 1·4 million patients with breast cancer) with existing resources, highlighting the importance of implementing new technologies in LMICs. A global survey undertaken for this Commission revealed that use of radiopharmaceutical therapy-other than 131 I-was highly variable in high-income countries and LMICs, with supply chains, workforces, and regulatory issues affecting access and availability. The capacity for radioisotope production was highlighted as a key issue, and training and credentialling of health professionals involved in theranostics is required to ensure equitable access and availability for patient treatment. New initiatives-such as the International Atomic Energy Agency's Rays of Hope programme-and interest by international development banks in investing in radiotherapy should be supported by health-care systems and governments, and extended to accelerate the momentum generated by recognising global disparities in access to radiotherapy. In this Commission, we propose actions and investments that could enhance access to radiotherapy and theranostics worldwide, particularly in LMICs, to realise health and economic benefits and reduce the burden of cancer by accessing these treatments., Competing Interests: Declaration of interests HH serves (unpaid) on an external advisory board of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, on the International Advisory Board of the University of Vienna, on the Scientific Committee of the German Cancer Research Center (DKFZ), on the Board of Trustees of the DKFZ, and on the advisory board of The Lancet Oncology; is remunerated for serving on the Board of Directors of Ion Beam Applications; receives stock options for serving on the Board of Directors of iCAD; and reports research funding to their institution (Memorial Sloan-Kettering Center Support Grant/Core Grant P30 CA008748) from the National Institutes of Health (NIH)–National Cancer Institute (NCI). AA reports funding to their institution from the National Institute for Health and Care Research (NIHR) and the NIH. GB reports research funding to their institution from the Science and Technology Facilities Council UK and reports travel support from International Council Expert Corps. MD reports research funding to their institution from Science and Technology Facilities Council UK and reports travel support from International Council Expert Corps. TE reports honoraria from the University of Washington and the Japanese Society for Radiation Oncology (JASTRO) and reports receiving travel support to attend meetings from JASTRO, the Turkish Society for Radiation Oncology, and the American Society for Radiation Oncology (ASTRO). SGr reports receiving grants from the NCI; reports consulting fees from Lumonus and the Sustainable Dialogue on Peaceful Uses; and has stock options in Harbinger Health. KH reports research funding to their institution from Novartis and Sofie Biosciences; reports consulting fees from Advanced Accelerator Applications, Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curiun, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien Munchen, Janssen, Merck, Molecular Partners, Nvision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Telix, Theragnostics, and Ymabs; reports honoraria for lectures from PeerVoice; serves on paid advisory boards for Fusion and GE Healthcare; reports travel support from Janssen; and has stock options from Sofie Biosciences, Pharma15, Nvision, Convergent, Aktis Oncology, and AdvanCell. MSH reports research funding to their institution from the Prostate Cancer Foundation, the US Department of Defence, Movember, and the Peter MacCallum Foundation; reports clinical trial funding to their institution from Bayer and Isotopia; reports clinical trial support to their institution from the Australian Nuclear Science and Technology Organisation; reports consulting fees from Merck Sharp & Dohme and Novartis; reports speaker fees from Janssen and AstraZeneca; reports fees to their institution for serving on the advisory board on Novartis; reports unremunerated participation in the Scientific Committee at the Australian Friends of Sheba; and is supported by a National Health and Medical Research Council (NHMRC) Investigator grant. DJ reports royalties from Elekta Oncology System, Precision X-ray System, and Modus Medical; reports license of technology to iRT; reports board membership on Break Through Cancer; reports being an advisor to ACS BrightEdge; and is a founder and stockholder in Nanovista. JK reports participation on a data safety monitoring board and advisory board from Novartis (personal fees) and reports lecture honoraria from Monrol. JSL reports research support from Clarity Pharmaceuticals and Avid Radiopharmaceuticals; has acted as an adviser of Alpha-9 Theranostics, Clarity Pharmaceuticals, Earli, Evergreen Theragnostics, Suba Therapeutics, Inhibrx, Precirix, Solve, Goldman Sachs, TPG Capital, Curie Therapeutics, NextTech Invest, and Telix Pharmaceuticals; is secretary/treasurer of the Society of Nuclear Medicine and Molecular Imaging (SNMMI); holds equity in Curie Therapeutics, Summit Biomedical Imaging, Telix Pharmaceuticals, and Evergreen Theragnostics; and is supported by NIH R35 CA232130. YL reports funding to their institution for the European Society for Radiotherapy and Oncology (ESTRO) Chair on Health Economics in Radiation Oncology (HERO)–Value-Based Radiation Oncology, for a proton beam project from the Research Foundation Flanders (FWO)–Applied Biomedical Research with a Primary Finality, and for the ARCHERY trial; reports unpaid positions on advisory boards for the HALT trial and PROSECCA trial; is a member of the ESTRO Scientific Council and the Belgian Board of Oncology; is co-chair of the ESTRO-HERO project; and is principal investigator of the E2-Radiate trial, a joint project of ESTRO, and the European Organisation for Research and Treatment of Cancer (EORTC). JRP reports being an unpaid chair of the American Association of Physicists in Medicine (AAPM) International Council. AAR received consulting fees from Novartis; received honoraria for lectures from the European Society for Medical Oncology, Sociedade Brasileira de Mastologia, and Instituto Oncoclinicas; received financial support for attending meetings from ASTRO, Congresso Gramado, and Congresso Oncolinicas; reports an unpaid leadership position at the Sociedade Brasileira de Radioterapia; and has stock and stock options in Grupo Oncoclinicas. MMS reports research funding to their institution from Aktis, Point Biopharma, and Telix Pharmaceuticals; reports speaker honoraria from Novartis, Ion Beam Applications, and Johnson and Johnson; and holds positions in the Africa Health Research Institute and Adcock. VV holds positions as editor of the Journal of Clinical Oncology/Global Oncology and Translational Oncology and is a member of the board for City Cancer Challenge. RLW reports research funding to their institution from Siemens Healthineers, White Rabbit AI, Fusion, Perspective Therapeutics, Rayze, and Bayer; provides consulting services to Voximetry, Molecular Targeting Technologies (MTT), Perspective, Siemens, Abdera, and Seno; reports speaker payment from Hamad Health Qatar; reports travel support from Rayze and Hamad Health Qatar; has stock options in Voximetry and MTT; is a stockholder in Clarity Pharmaceuticals; participates on advisory boards for Perspective and Fusion; is a member of the SNMMI Mars Shot Board; and was a past president of SNMMI. JSY reports funding to their institution from the NIH, the IVY Foundation, and the Falk Research Medical Trust; reports honoraria from the University of Maryland and the Dana Farber/Harvard Cancer Center; and holds an unpaid position in the Clinical Advisory Council at the American Brain Tumor Association. AMS reports trial funding to their institution from EMD Serono, ITM, Telix Pharmaceuticals, AVID Radiopharmaceuticals, Fusion Pharmaceuticals, and Cyclotek; reports research funding to their institution from Medimmune, Antengene, Humanigen, and Telix Pharmaceuticals; is on advisory boards of Imagion and ImmunOs; reports unpaid board membership of the Australian and New Zealand Society of Nuclear Medicine and the World Federation of Nuclear Medicine and Biology; and is supported by a NHMRC Investigator grant (number 1177837). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The diagnostic work-up of patients with fever of unknown origin (FUO) begins with a thorough history and physical examination, complete blood count with differential, chest x-ray, urinalysis and culture, electrolyte panel, liver enzymes, erythrocyte sedimentation rate, and C-reactive protein level. Additional imaging procedures, including nuclear medicine tests, are generally used as second-line procedures, with 18 F-FDG PET and PET/CT assuming increasingly important roles in the diagnostic work-up. The Society of Nuclear Medicine and Molecular Imaging, the Infectious Diseases Society of America, and the American College of Nuclear Medicine convened an autonomous expert work group to comprehensively review the published literature for nuclear imaging in adults and children with FUO and establish appropriate use criteria (AUC). This process was performed in accordance with the Protecting Access to Medicare Act of 2014, which requires that all referring physicians consult AUC by using a clinical decision support mechanism before ordering advanced diagnostic imaging services. The complete findings and discussions of the work group were published on January 8, 2023, and are available at https://www.snmmi.org/ClinicalPractice/content.aspx?ItemNumber=15666 The AUC in the final document are intended to assist referring health care providers in appropriate use of nuclear medicine imaging procedures in patients with FUO. The work group noted limitations in the current literature on nuclear medicine imaging for FUO, with the need for well-designed prospective multicenter investigations. Consensus findings from published data and expert opinions were used to create recommendations in common clinical scenarios for adults and children. Included in the complete document is a discussion of inflammation of unknown origin (IUO), a recently described entity. In view of the fact that the criteria for FUO and IUO are similar (except for fever > 38.3°C [100.9°F]) and that the most common etiologies of these 2 entities are similar, it is the expert opinion of the work group that the recommendations for nuclear medicine imaging of FUO are also applicable to IUO. These recommendations are included in the full guidance document. This summary reviews rationale, methodology, and main findings and refers the reader to the complete AUC document., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Gallium-68 has gained substantial momentum since 2003 as a versatile radiometal that is extremely useful for application in the development of novel oncology targeting diagnostic radiopharmaceuticals. It is available through both generator produced radioactivity and via cyclotron production methods and can therefore be implemented in either small- or large-scale production facilities. It can also be implemented within different spectrum of infrastructure settings with relative ease. Whilst many of the radiopharmaceuticals are being development and investigated, which is summarized in this manuscript, [ 68 Ga]Ga-SSTR2 and [ 68 Ga]Ga-PSMA has prominence in current clinical guidelines. The novel tracer [ 68 Ga]Ga-FAPi has also gained significant interest in the clinical context. A comparison of the labelling strategies followed to incorporate gallium-68 and fluorine-18 into the same molecular targeting constructs clearly demonstrate that gallium-68 complexation is the most convenient approach. Recently, cold kit based starting products are available to make the small-scale production of gallium-68 radiopharmaceuticals even more efficient when combined with generator produced gallium-68. The regulatory aspects is currently changing to support the implementation of gallium-68 and other diagnostic radiopharmaceuticals, simplifying the translation towards clinical use. Overall, the development of gallium-68 based radiopharmaceuticals is not only rapidly changing the landscape of diagnosis in oncology, but this growth also promotes innovation and progress in new applications of therapeutic radiometals such as lutetium-177 and actinium-225., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Janke Kleynhans reports financial support was provided by Research Foundation Flanders. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The ability of bacteria to recycle exogenous amino acid-based peptides and amino sugars for peptidoglycan biosynthesis was extensively investigated using optical imaging. In particular, fluorescent AeK-NBD was effectively utilized to study the peptidoglycan recycling pathway in Gram-negative bacteria. Based on these promising results, we were inspired to develop the radioactive AeK conjugate [ 68 Ga]Ga-DOTA-AeK for the in vivo localization of bacterial infection using PET/CT. An easy-to-implement radiolabeling procedure for DOTA-AeK with [ 68 Ga]GaCI 3 followed by solid-phase purification was successfully established to obtain [ 68 Ga]Ga-DOTA-AeK with a radiochemical purity of ≥95%. [ 68 Ga]Ga-DOTA-AeK showed good stability over time with less protein binding under physiological conditions. The bacterial incorporation of [ 68 Ga]Ga-DOTA-AeK and its fluorescent Aek-NBD analog were investigated in live and heat-killed Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ). Unfortunately, no conclusive in vitro intracellular uptake of [ 68 Ga]Ga-DOTA-AeK was observed for E. coli or S. aureus live and heat-killed bacterial strains ( p > 0.05). In contrast, AeK-NBD showed significantly higher intracellular incorporation in live bacteria compared to the heat-killed control ( p < 0.05). Preliminary biodistribution studies of [ 68 Ga]Ga-DOTA-AeK in a dual-model of chronic infection and inflammation revealed limited localization at the infection site with non-specific accumulation in response to inflammatory markers. Finally, our study demonstrates proof that the intracellular incorporation of AeK is necessary for successful bacteria-specific imaging using PET/CT. Therefore, Ga-68 was not a suitable radioisotope for tracing the bacterial uptake of AeK tripeptide, as it required chelation with a bulky metal chelator such as DOTA, which may have limited its active membrane transportation. An alternative for optimization is to explore diverse chemical structures of AeK that would allow for radiolabeling with 18 F or 11 C.

Radiolabelled puromycin analogues will allow the quantification of protein synthesis through nuclear medicine-based imaging. A particularly useful application could be the non-invasive longitudinal visualisation of mycobacterial activity through direct quantification of puromycin binding. This study assesses the value of [ 68 Ga]Ga-DOTA-puromycin in the visualisation of mycobacteria through positron emission tomography combined with magnetic resonance imaging (µPET/MRI). The radiopharmaceutical was produced by previously published and validated methods. [ 68 Ga]Ga-DOTA-Puromycin imaging was performed on severe immunodeficient mice infected with Bacille Calmette-Guérin-derived M. Bovis (BCG). Acute and chronic infection stages were examined by µPET/MRI. A follow-up group of animals acted as controls (animals bearing S. aureus-derived infection and sterile inflammation) to assess tracer selectivity. [ 68 Ga]Ga-DOTA-puromycin-µPET/MRI images revealed the acute, widespread infection within the right upper shoulder and armpit. Also, [ 68 Ga]Ga-DOTA-puromycin signal sensitivity measured after a 12-week period was lower than that of [ 18 F]FDG-PET in the same animals. A suitable correlation between normalised uptake values (NUV) and gold standard histopathological analysis confirms accurate tracer accumulation in viable bacteria. The radiopharmaceutical showed infection selectivity over inflammation but accumulated in both M. Bovis and S. Aureus, lacking pathogen specificity. Overall, [ 68 Ga]Ga-DOTA-puromycin exhibits potential as a tool for non-invasive protein synthesis visualization, albeit without pathogen selectivity., (© 2024. The Author(s).)

The first alpha emitting radiopharmaceutical, 223 RaCl 2 , radium dichloride, was approved 10 years ago into the clinical armament of treating bone metastases in metastatic castration-resistant prostate cancer (mCRPC). In addition to this, the first beta-emitting radionuclide Lu-177 chelated with a prostate-specific membrane antigen (PSMA) compound, got last year its marketing approval for the third line treatment of mCRPC. Therefore, there is great excitement about combining alpha-emitters and prostate cancer targeting PSMA compounds. This review describes the clinical history of alpha-emitting PSMA in treating mCRPC. Here, we present the potential, current status, and opportunities for 225 Ac-PSMA therapy. The work reviews the basic concepts, current treatment outcome, and toxicity, and areas requiring further investigations such as dosimetric aspects in clinical studies covering more than 400 patients. In general, approximately two-thirds of the patients benefit from this third-line therapy. There is also successful evidence of using 225 Ac-PSMA in the second-line of prostate cancer management. The future potential of 225 Ac-PSMA therapy and targeted alpha therapy (TAT) of cancer in general is enormous. According to our overview the clinical experience with 225 Ac-PSMA therapy to date has shown great benefit and physicians dedicated to theragnostics are anxiously waiting for new applications. Hopefully, this review helps in deeper understanding of the strengths and limitations of TAT and may help in creating effective therapy protocols., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1842/coif). K.K. serves as an unpaid editorial board member of Annals of Translational Medicine from July 2023 to June 2025. The other authors have no conflicts of interest to declare., (2024 Annals of Translational Medicine. All rights reserved.)

Introduction: Nuclear medicine infection imaging is routinely performed with the use of leukocytes radiolabelled with technetium-99m hexamethylpropyleneamine oxime ([ 99m Tc]Tc-HMPAO) and single-photon emission computed tomography (SPECT). Positron emission tomography (PET) is more sensitive than SPECT and results in higher-quality images. Zirconium-89 ( 89 Zr) is a positron emitter with a half-life of 78.4 h, which translates to the biological half-life and slow biodistribution of intact cells and allows delayed PET imaging for more accurate biodistribution of the labelled leukocytes to infection foci. A first-in-human study with [ 89 Zr]Zr-oxine-leukocytes in four healthy volunteers was reported in 2022. Our first-in-human study utilising the cell surface labelling approach aimed to image infection in patients with the use of 89 Zr-labelled leukocytes, using p -isothiocyanatobenzyl-desferrioxamine B (Df-Bz-NCS) as a bifunctional chelating agent, and to compare the scan quality and biodistribution of [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes on PET images to SPECT images obtained with [ 99m Tc]Tc-HMPAO-labelled leukocytes., Methods: Leukocytes were isolated from whole-blood samples of eight patients with clinically and/or radiologically confirmed infection. Isolated leukocytes were labelled with [ 99m Tc]Tc-HMPAO according to standardised methods, and [ 89 Zr]Zr-Df-Bz-NCS according to our previously published radiolabelling method. Whole-body SPECT imaging was performed 2 and 18 h post injection of [ 99m Tc]Tc-HMPAO-labelled leukocytes, and whole-body PET/CT was performed 3 and 24 h post injection of [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes in seven patients., Results: Successful [ 89 Zr]Zr-Df-Bz-NCS-leukocyte labelling was achieved. High labelling efficiencies were obtained (81.7% ± 3.6%; n  = 8). A mean high viability of [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes was observed (88.98% ± 12.51%). The [ 89 Zr]Zr-Df-Bz-NCS-leukocyte labelling efficiency was not significantly affected by the white blood cell count of the patient. The performance of [ 99m Tc]Tc-HMPAO- and [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes, in terms of the ability to accurately detect infection, were similar in two out of seven patients, and [ 99m Tc]Tc-HMPAO-labelled leukocytes outperformed [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes in one patient with femoral osteomyelitis. However, in two cases of pulmonary pathology, [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes demonstrated improved pathological uptake. No skeletal activity was observed in any of the patients imaged with [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes, illustrating the in vivo stability of the radiolabel., Discussion: Although the [ 89 Zr]Zr-Df-Bz-NCS-leukocyte labelling aspect of this study was noteworthy, infection imaging did not yield convincingly positive results due to the pulmonary trapping of intravenously administered [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes., Competing Interests: TE and JZ were employed by The South African Nuclear Energy Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Kahts, Summers, Ndlela, Gutta, Nemutaduni, More, Parsoo, Ebenhan, Zeevaart, Aras and Sathekge.)

Novel prostate-specific membrane antigen (PSMA) ligands labeled with α-emitting radionuclides are sparking a growing interest in prostate cancer treatment. These targeted alpha therapies (TATs) have attractive physical properties that deem them effective in progressive metastatic castrate-resistant prostate cancer (mCRPC). Among the PSMA TAT radiopharmaceuticals, [225Ac]Ac-PSMA has been used extensively on a compassionate basis and is currently undergoing phase I trials. Notably, TAT has the potential to improve quality of life and has favorable antitumor activity and outcomes in multiple scenarios other than in mCRPC. In addition, resistance mechanisms to TAT may be amenable to combination therapies., Competing Interests: Disclosure Ethical approval and consent to participate: Although this is a review article, ethics approval and informed consent for the images used are available. Competing interests: The authors declare that they have no competing interests. Consent for publication: Informed patient consent for publication of [(68) Ga] Ga-DOTATATE PET/CT and [(68) Ga]Ga-PSMA-PET/CT images and other relevant information was obtained. Availability of data and materials: The articles quoted and referenced are available online as referenced. The images used for the review are available from the corresponding author on request. Funding: The authors declare that the review was conducted in the absence of any commercial or financial relationships., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP inhibitors hamper single-strand deoxyribonucleic acid (DNA) repair by trapping poly(ADP-ribose)polymerase (PARP) at sites of DNA damage, forming a non-functional "PARP enzyme-inhibitor complex" leading to cell cytotoxicity. The effect is more pronounced in the presence of PARP upregulation and homologous recombination (HR) deficiencies such as breast cancer-associated gene ( BRCA1/2 ). Hence, identifying HR-deficiencies by genomic analysis-for instance, BRCA1/2 used in triple-negative breast cancer-should be a part of the selection process for PARP inhibitor therapy. Published data suggest BRCA1/2 germline mutations do not consistently predict favorable responses to PARP inhibitors, suggesting that other factors beyond tumor mutation status may be at play. A variety of factors, including tumor heterogeneity in PARP expression and intrinsic and/or acquired resistance to PARP inhibitors, may be contributing factors. This justifies the use of an additional tool for appropriate patient selection, which is noninvasive, and capable of assessing whole-body in vivo PARP expression and evaluating PARP inhibitor pharmacokinetics as complementary to the currently available BRCA1/2 analysis. In this review, we discuss [ 18 F]Fluorine PARP inhibitor radiotracers and their potential in the imaging of PARP expression and PARP inhibitor pharmacokinetics. To provide context we also briefly discuss possible causes of PARP inhibitor resistance or ineffectiveness. The discussion focuses on TNBC, which is a tumor type where PARP inhibitors are used as part of the standard-of-care treatment strategy.

Preclinical studies are essential for effectively evaluating TAT radiopharmaceuticals. Given the current suboptimal supply chain of these radionuclides, animal studies must be refined to produce the most translatable TAT agents with the greatest clinical potential. Vector design is pivotal, emphasizing harmonious physical and biological characteristics among the vector, target, and radionuclide. The scarcity of alpha-emitting radionuclides remains a significant consideration. Actinium-225 and lead-212 appear as the most readily available radionuclides at this stage. Available animal models for researchers encompass xenografts, allografts, and PDX (patient-derived xenograft) models. Emerging strategies for imaging alpha-emitters are also briefly explored. Ultimately, preclinical research must address two critical aspects: (1) offering valuable insights into balancing safety and efficacy, and (2) providing guidance on the optimal dosing of the TAT agent., (© 2024. The Author(s).)

Aim: The integration of innovative radio-pharmaceutical agents targeting prostate-specific membrane antigen (PSMA) within nuclear medicine has transformed prostate cancer detection and management. This study aims to investigate the present landscape of [ 177 Lu]Lu-PSMA in prostate cancer, elucidating trends, global contributions, scholarly outlets, institutions, and thematic concentrations with an aim to inform forthcoming research endeavors., Methods: We systematically probed the Scopus repository for relevant [ 177 Lu]Lu-PSMA literature. An assessment of bibliometric and altmetric data was carried out. Finally, we assessed the correlation between the altmetric attention scores and the number of citations for the retrieved data., Results: Spanning January 2015 to July 2023, the study encompassed 466 articles concerning [ 177 Lu]Lu-PSMA therapy for prostate cancer. Predominant citation accolades gravitated towards metastatic castration-resistant prostate cancer investigations and assessments of [ 177 Lu]Lu-PSMA therapy's safety and efficacy. Further research encompassed adverse effects linked to [ 177 Lu]Lu-PSMA intervention, including xerostomia, thrombocytopenia, anemia, and fatigue. Germany emerged as the primary academic contributor, with The Journal of Nuclear Medicine dominating publications (n = 55). A moderate significant correlation was detected between the number of citations and altmetric attention scores ., Conclusion: The findings highlight the growing interest and advancements in the utilization of [ 177 Lu]Lu-PSMA therapy in prostate cancer and offer a comprehensive global perspective on future research directions., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Infections of the bones and joints, if misdiagnosed, may result in serious morbidity and even mortality. A prompt diagnosis followed by appropriate management may reduce the socioeconomic impact of bone and joint infections. Morphologic imaging such as ultrasound and plain radiographs form the first line investigations, however, in early infections findings may be negative or nonspecific. Nuclear medicine imaging techniques play a complementary role to morphologic imaging in the diagnosis of bone and joint infections. The availability of hybrid systems (SPECT/CT, SPECT/MRI, PET/CT or PET/MRI) offers improved specificity with ability to assess the extent of infection. Bone scans are useful as a gatekeeper wherein negative scans rule out sepsis with a good accuracy, however positive scans are nondiagnostic and more specific tracers should be considered. These include the use of labeled white blood cells and antigranulocyte antibodies. Various qualitative and quantitative interpretation criteria have been suggested to improve the specificity of the scans. PET has better image resolution and 18 F-FDG is the major tracer for PET imaging with applications in oncology and inflammatory/infective disorders. It has demonstrated improved sensitivity over the SPECT based tracers, however, still suffers from lack of specificity. 18 F-FDG PET has been used to monitor therapy in bone and joint infections. Other less studied, noncommercialized SPECT and PET tracers such as 111 In-Biotin, 99m Tc-Ubiquicidin, 18 F-Na-Fluoride, 18 F-labeled white blood cells and 124 I-Fialuridine to name a few have shown great promise, however, their role in various bone and joint infections has not been established. Hybrid imaging with PET or PET/MRI offers huge potential for improving diagnostics in infections of the joints and bones., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE ( 177 Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen ( 177 Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177 Lu-DOTATATE and 177 Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The unique structural architecture of the peptidoglycan allows for the stratification of bacteria as either Gram-negative or Gram-positive, which makes bacterial cells distinguishable from mammalian cells. This classification has received attention as a potential target for diagnostic and therapeutic purposes. Bacteria's ability to metabolically integrate peptidoglycan precursors during cell wall biosynthesis and recycling offers an opportunity to target and image pathogens in their biological state. This Review explores the peptidoglycan biosynthesis for bacteria-specific targeting for infection imaging. Current and potential radiolabeled peptidoglycan precursors for bacterial infection imaging, their development status, and their performance in vitro and/or in vivo are highlighted. We conclude by providing our thoughts on how to shape this area of research for future clinical translation.

Background: Actinium-225 ( 225 Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225 Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world., Methods: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225 Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 ( 177 Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival., Findings: Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225 Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177 Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225 Ac-PSMA RLT. All patients who received more than seven cycles of 225 Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded., Interpretation: 225 Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events., Funding: None., Competing Interests: Declaration of interests MMS reports grants or contracts from Novartis; payment or honoraria from Bayer, Johnson & Johnson, NTP, and Sanofi; support for attending meetings from the International Atomic Energy Agency; and receipt of equipment or materials from POINT Biopharma. ME reports grants or contracts from Blue Earth Diagnostics; royalties from patent on radiohybrid PSMA; consulting fees from Novartis, Point Biopharma, payment from Novartis; payment for expert testimony from Novartis, Bayer, Telix, and Blue Earth Diagnostics; support for attending meetings from Blue Earth Diagnostics; and patent ownership on radiohybrid PSMA. TH reports grants or contracts from Siemens. CK reports patent ownership. NPL reports contracts from Telix, Ipsen/Ariceum, and Clarity; receipt of educational material from Telix; support for attending meetings from Telix; participation on the advisory board of Telix; and family stock ownership at Clarity. ASi reports support for attending meetings from Telix International, Australia and participation on Data Safety Monitoring Borad for Telix International. RT reports payment or honoraria from Astella, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck, MSD, Novartis, Orion, Pfizer, Roche, and Sanofi; support for attending meetings from Bayer, Janssen, Orion, Pfizer, and Roche; participation on Data Safety Monitoring Board or Advisory Board of Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisei, EUSA, IPSEN, Janssen, Merck, MSD, Novartis, Orion, Pfizer, Philogen, Roche, and Sanofi; stock ownership at Bayer; and financial or non-financial interests at Thieme compliance and Elsevier. AM reports patents owning a patent for treatment of PSMA-expressing cancers. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Breast cancer is the most frequently diagnosed cancer and leading cause of cancer-related deaths worldwide. Timely decision-making that enables implementation of the most appropriate therapy or therapies is essential for achieving the best clinical outcomes in breast cancer. While clinicopathologic characteristics and immunohistochemistry have traditionally been used in decision-making, these clinical and laboratory parameters may be difficult to ascertain or be equivocal due to tumor heterogeneity. Tumor heterogeneity is described as a phenomenon characterized by spatial or temporal phenotypic variations in tumor characteristics. Spatial variations occur within tumor lesions or between lesions at a single time point while temporal variations are seen as tumor lesions evolve with time. Due to limitations associated with immunohistochemistry (which requires invasive biopsies), whole-body molecular imaging tools such as standard-of-care [ 18 F]FDG and [ 18 F]FES PET/CT are indispensable in addressing this conundrum. Despite their proven utility, these standard-of-care imaging methods are often unable to image a myriad of other molecular pathways associated with breast cancer. This has stimulated interest in the development of novel radiopharmaceuticals targeting other molecular pathways and processes. In this review, we discuss validated and potential roles of these standard-of-care and novel molecular approaches. These approaches' relationships with patient clinicopathologic and immunohistochemical characteristics as well as their influence on patient management will be discussed in greater detail. This paper will also introduce and discuss the potential utility of novel PARP inhibitor-based radiopharmaceuticals as non-invasive biomarkers of PARP expression/upregulation.

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the majority of prostate cancer (PCa). PSMA has an enzymatic function that makes metabolic substrates such as folate available for utilization by PCa cells. Intracellular folate availability drives aggressive tumor phenotype. PSMA expression is, therefore, a marker of aggressive tumor biology. The large extracellular domain of PSMA is available for targeting by diagnostic and therapeutic radionuclides, making it a suitable cellular epitope for theranostics. PET imaging of radiolabeled PSMA ligands has several prognostic utilities. In the prebiopsy setting, intense PSMA avidity in a prostate lesion correlate well with clinically significant PCa (csPCa) on histology. When used for staging, PSMA PET imaging outperforms conventional imaging for the accurate staging of primary PCa, and findings on imaging predict post-treatment outcomes. The biggest contribution of PSMA PET imaging to PCa management is in the biochemical recurrence setting, where it has emerged as the most sensitive imaging modality for the localization of PCa recurrence by helping to guide salvage therapy. PSMA PET obtained for localizing the site of recurrence is prognostic, such that a higher lesion number predicts a less favorable outcome to salvage radiotherapy or surgical intervention. Systemic therapy is given to patients with advanced PCa with distant metastasis. PSMA PET is useful for predicting response to treatments with chemotherapy, first- and second-line androgen deprivation therapies, and PSMA-targeted radioligand therapy. Artificial intelligence using machine learning algorithms allows for the mining of information from clinical images not visible to the human eyes. Artificial intelligence applied to PSMA PET images, therefore, holds great promise for prognostication in PCa management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is a major global health problem. Theragnostic is a term that refers to the integration of diagnostic and therapeutic modalities into a single system for personalized medicine. Theragnostic care in HCC involves the use of imaging techniques to diagnose the cancer and assess its characteristics, such as size, location, and extent of spread. Theragnostics involves the use of molecular and genetic tests to identify specific biomarkers that can help guide treatment decisions and, post-treatment, assess the dosimetry and localization of the treatment, thus guiding future treatment. This can be done through either positron emission tomography (PET) scanning or single photon emission tomography (SPECT) using radiolabeled tracers that target specific molecules expressed by HCC cells or radioembolization. This technique can help identify the location and extent of the cancer, as well as provide information on the tumor's metabolic activity and blood supply. In summary, theragnostics is an emerging field that holds promise for improving the diagnosis and treatment of HCC. By combining diagnostic and therapeutic modalities into a single system, theragnostics can help guide personalized treatment decisions and improve patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author MS declared that he was an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Nyakale, Aldous, Gutta, Khuzwayo, Harry and Sathekge.)

Tuberculosis (TB) remains the second leading cause of death globally from a single infectious agent, and there is a critical need to develop improved imaging biomarkers and aid rapid assessments of responses to therapy. We aimed to utilize radiomics, a rapidly developing image analysis tool, to develop a scoring system for this purpose. A chest X-ray radiomics score (RadScore) was developed by implementing a unique segmentation method, followed by feature extraction and parameter map construction. Signature parameter maps that showed a high correlation to lung pathology were consolidated into four frequency bins to obtain the RadScore. A clinical score (TBscore) and a radiological score (RLscore) were also developed based on existing scoring algorithms. The correlation between the change in the three scores, calculated from serial X-rays taken while patients received TB therapy, was evaluated using Spearman's correlation. Poor correlations were observed between the changes in the TBscore and the RLscore (0.09 ( p -value = 0.36)) and the TBscore and the RadScore (0.02 ( p -value = 0.86)). The changes in the RLscore and the RadScore had a much stronger correlation of 0.22, which is statistically significant ( p -value = 0.02). This shows that the developed RadScore has the potential to be a quantitative monitoring tool for responses to therapy.

Purpose: Accurate segmentation (separating diseased portions of the lung from normal appearing lung) is a challenge in radiomic studies of non-neoplastic diseases, such as pulmonary tuberculosis (PTB). In this study, we developed a segmentation method, applicable to chest X-rays (CXR), that can eliminate the need for precise disease delineation, and that is effective for constructing radiomic models for automatic PTB cavity classification., Methods: This retrospective study used a dataset of 266 posteroanterior CXR of patients diagnosed with laboratory confirmed PTB. The lungs were segmented using a U-net-based in-house automatic segmentation model. A secondary segmentation was developed using a sliding window, superimposed on the primary lung segmentation. Pyradiomics was used for feature extraction from every window which increased the dimensionality of the data, but this allowed us to accurately capture the spread of the features across the lung. Two separate measures (standard-deviation and variance) were used to consolidate the features. Pearson's correlation analysis (with a 0.8 cut-off value) was then applied for dimensionality reduction followed by the construction of Random Forest radiomic models., Results: Two almost identical radiomic signatures consisting of 10 texture features each (9 were the same plus 1 other feature) were identified using the two separate consolidation measures. Two well performing random forest models were constructed from these signatures. The standard-deviation model (AUC = 0.9444 (95% CI, 0.8762; 0.9814)) performed marginally better than the variance model (AUC = 0.9288 (95% CI, 0.9046; 0.9843))., Conclusion: The introduction of the secondary sliding window segmentation on CXR could eliminate the need for disease delineation in pulmonary radiomic studies, and it could improve the accuracy of CXR reporting currently regaining prominence as a high-volume screening tool as the developed radiomic models correctly classify cavities from normal CXR., (© 2023. The Author(s).)

It is important to constantly monitor developments in the preclinical imaging arena of infection. Firstly, novel radiopharmaceuticals with the correct characteristics must be identified to funnel into the clinic. Secondly, it must be evaluated if enough innovative research is being done and adequate resources are geared towards the development of radiopharmaceuticals that could feed into the Nuclear Medicine Clinic in the near future. It is proposed that the ideal infection imaging agent will involve PET combined with CT but more ideally MRI. The radiopharmaceuticals currently presented in preclinical literature have a wide selection of vectors and targets. Ionic formulations of PET-radionuclides such 64 CuCl 2 and 68 GaCl 2 are evaluated for bacterial infection imaging. Many small molecule based radiopharmaceuticals are being investigated with the most prominent targets being cell wall synthesis, maltodextrin transport (such as [ 18 F]F-maltotriose), siderophores (bacterial and fungal infections), the folate synthesis pathway (such as [ 18 F]F-PABA) and protein synthesis (radiolabelled puromycin). Mycobacterial specific antibiotics, antifungals and antiviral agents are also under investigation as infection imaging agents. Peptide based radiopharmaceuticals are developed for bacterial, fungal and viral infections. The radiopharmaceutical development could even react quickly enough on a pandemic to develop a SARS-CoV-2 imaging agent in a timely fashion ([ 64 Cu]Cu-NOTA-EK1). New immuno-PET agents for the imaging of viruses have recently been published, specifically for HIV persistence but also for SARS-CoV2. A very promising antifungal immuno-PET agent (hJ5F) is also considered. Future technologies could include the application of aptamers and bacteriophages and even going as far as the design of theranostic infection. Another possibility would be the application of nanobodies for immuno-PET applications. Standardization and optimization of the preclinical evaluation of radiopharmaceuticals could enhance clinical translation and reduce time spent in pursuing less than optimal candidates., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Breast cancer is a complex disease and constitutes the leading cause of cancer in women globally. Conventional treatment modalities include surgery, chemotherapy, radiation therapy, and hormonal therapy; all of these have their limitations and often result in significant side effects or toxicity. Targeted radionuclide therapy based on a theranostic approach has been successfully applied in several malignancies, such as prostate cancer, thyroid cancer, and neuro-endocrine tumours. Several studies have also highlighted the potential of theranostic applications in breast cancer., Aim: This review aims to provide an overview of the most promising current and future theranostic approaches in breast cancer., Discussion: The discussion includes pre-clinical as well as clinical data on some of the most successful targets used to date. Examples of potential theranostic approaches include those targeting the Human epidermal growth factor receptor 2 (HER2) expression, angiogenesis, aspects of the tumour microenvironment, Gastrin-releasing peptide receptor (GRPR), Prostate-specific membrane antigen (PSMA) and Chemokine receptor 4 (CXCR-4) expression. Several challenges to widespread clinical implementation remain, which include regulatory approval, access to the various radiopharmaceuticals and imaging technology, cost-effectiveness, and the absence of robust clinical data., Conclusion: Theranostic approaches have the potential to greatly improve diagnosis, treatment, and outcomes for patients with breast cancer. More research is needed to fully explore the potential of such approaches and to identify the best potential targets, considering feasibility, costs, efficacy, side effects and outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author MS declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Vorster, Hadebe and Sathekge.)

Hypoxia leads to changes in tumor microenvironment (upregulated CAFs) with resultant aggressiveness. A key factor in the physiological response to hypoxia is hypoxia-inducible factor-1alpha (HIF-1α). [ 68 Ga]Ga-FAPI PET imaging has been demonstrated in various cancer types. We hypothesized that [ 68 Ga]Ga-FAPI PET may be used as an indirect tracer for mapping hypoxia by correlating the image findings to pathological analysis of HIF-1α expression. The [ 68 Ga]Ga-FAPI PET/CT scans of women with cancer of the cervix were reviewed and the maximum and mean standardized uptake value (SUVmax and SUVmean) and FAPI tumor volume (FAPI-TV) were documented. Correlation analysis was performed between PET-derived parameters and immunohistochemical staining as well as between PET-derived parameters and the presence of metastasis. Ten women were included. All patients demonstrated tracer uptake in the primary site or region of the primary. All patients had lymph node metastases while only six patients had distant visceral or skeletal metastases. The mean SUVmax, SUVmean, and FAPI-TV was 18.89, 6.88, and 195.66 cm 3 , respectively. The average FAPI-TV for patients with additional sites of metastases was higher than those without. Immunohistochemistry revealed varying intensities of HIF-1α expression in all tested samples. There was a positive correlation between the presence of skeletal metastases and staining for HIF-1α (r=0.80;p=0.017). The presence of skeletal metastasis was correlated to the HIF-1⍺ staining (percentage distribution). Furthermore, the FAPI-TV was a better predictor of metastatic disease than the SUVmax.

The actinium-225 ( 225 Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the 225 Ac radionuclide presents multiple daughter nuclides in its decay chain, which can escape the targeted site, circulate in plasma, and cause toxicity in areas such as kidneys and renal tissues. Several ameliorative strategies have been devised to circumvent this issue, including nano-delivery. Alpha-emitting radionuclides and nanotechnology applications in nuclear medicine have culminated in major advancements that offer promising therapeutic possibilities for treating several cancers. Accordingly, the importance of nanomaterials in retaining the 225 Ac daughters from recoiling into unintended organs has been established. This review expounds on the advancements of targeted radionuclide therapy (TRT) as an alternative anticancer treatment. It discusses the recent developments in the preclinical and clinical investigations on 225 Ac as a prospective anticancer agent. Moreover, the rationale for using nanomaterials in improving the therapeutic efficacy of α-particles in targeted alpha therapy (TAT) with an emphasis on 225 Ac is discussed. Quality control measures in the preparation of 225 Ac-conjugates are also highlighted.

Radiopharmaceutical development hinges on the affinity and selectivity of the biological component for the intended target. An analogue of the neuropeptide Substance P (SP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi 8 ,Met(O 2 ) 11 ]-SP (DOTA-[Thi 8 ,Met(O 2 ) 11 ]SP), in the theranostic pair [ 68 Ga]Ga-/ [ 213 Bi]Bi-DOTA-[Thi 8 ,Met(O 2 ) 11 ]SP has shown promising clinical results in the treatment of inoperable glioblastoma. As the theranostic targeting component, modifications to SP that affect the selectivity of the resulting analogue for the intended target (neurokinin-1 receptor [NK1R]) could be detrimental to its therapeutic potential. In addition to other closely related tachykinin receptors (neurokinin-2 receptor [NK2R] and neurokinin-3 receptor [NK3R]), SP can activate a mast cell expressed receptor Mas-related G protein-coupled receptor subtype 2 (MRGPRX2), which has been implicated in allergic-type reactions. Therefore, activation of these receptors by SP analogues has severe implications for their therapeutic potential. Here, the receptor selectivity of DOTA-[Thi 8 ,Met(O 2 ) 11 ]SP was examined using inositol phosphate accumulation assay in HEK293-T cells expressing NK1R, NK2R, NK3R or MRGPRX2. DOTA-[Thi 8 ,Met(O 2 ) 11 ]SP had similar efficacy and potency as native SP at NK1R, but displayed greater NK1R selectivity. DOTA-[Thi 8 ,Met(O 2 ) 11 ]SP was unable to elicit significant activation of the other tachykinin receptors nor MRGPRX2 at high concentrations nor did it display antagonistic behaviour at these receptors. DOTA-[Thi 8 ,Met(O 2 ) 11 ]SP, therefore has high potency and selectivity for NK1R, supporting its potential for targeted theranostic use in glioblastoma multiforme and other conditions characterised by NK1R overexpression.

Despite the introduction of many novel diagnostic techniques and newer treatment agents, tuberculosis (TB) remains a major cause of death from an infectious disease worldwide. With about a quarter of humanity harboring Mycobacterium tuberculosis, the causative agent of TB, the current efforts geared towards reducing the scourge due to TB must be sustained. At the same time, newer alternative modalities for diagnosis and treatment response assessment are considered. Molecular imaging entails the use of radioactive probes that exploit molecular targets expressed by microbes or human cells for imaging using hybrid scanners that provide both anatomic and functional features of the disease being imaged. Fluorine-18 fluorodeoxyglucose (FDG) is the most investigated radioactive probe for TB imaging in research and clinical practice. When imaged with positron emission tomography interphase with computed tomography (PET/CT), FDG PET/CT performs better than sputum conversion for predicting treatment outcome. At the end of treatment, FDG PET/CT has demonstrated the unique ability to identify a subset of patients declared cured based on the current standard of care but who still harbor live bacilli capable of causing disease relapse after therapy discontinuation. Our understanding of the pathogenesis and evolution of TB has improved significantly in the last decade, owing to the introduction of FDG PET/CT in TB research. FDG is a non-specific probe as it targets the host inflammatory response to Mycobacterium tuberculosis, which is not specifically different in TB compared with other infectious conditions. Ongoing efforts are geared towards evaluating the utility of newer probes targeting different components of the TB granuloma, the hallmark of TB lesions, including hypoxia, neovascularization, and fibrosis, in TB management. The most exciting category of non-FDG PET probes developed for molecular imaging of TB appears to be radiolabeled anti-tuberculous drugs for use in studying the pharmacokinetic characteristics of the drugs. This allows for the non-invasive study of drug kinetics in different body compartments concurrently, providing an insight into the spatial heterogeneity of drug exposure in different TB lesions. The ability to repeat molecular imaging using radiolabeled anti-tuberculous agents also offers an opportunity to study the temporal changes in drug kinetics within the different lesions during treatment., (Published by Elsevier Inc.)

Over the last decades, the population at risk for invasive fungal disease (IFD) has increased because of medical therapy advances and diseases compromising patients' immune systems. The high morbidity and mortality associated with invasive fungal disease in the immunocompromised present the challenge of early diagnosis of the IFD and the need to closely monitor the infection during treatment. The definitive diagnosis of invasive fungal disease based on culture or histopathological methods often has reduced diagnostic accuracy in the immunocompromised and may be very invasive. Less invasive and indirect evidence of the fungal infection by serology and imaging has been used for the early diagnosis of fungal infection before definitive results are available or when the definitive methods of diagnosis are suboptimal. Imaging in invasive fungal disease is a non-invasive biomarker that helps in the early diagnosis of invasive fungal disease but helps follow-up the infection during treatment. Different imaging modalities are used in the workup to evaluate fungal disease. The different imaging modalities have advantages and disadvantages at different sites in the body and may complement each other in the management of IFD. Positron emission tomography integrated with computed tomography with [18F]Fluorodeoxyglucose (FDG PET/CT) has helped manage IFD. The combined functional data from PET and anatomical data from the CT from almost the whole body allows noninvasive evaluation of IFD and provides a semiquantitative means of assessing therapy. FDG PET/CT adds value to anatomic-based only imaging modalities. The nonspecificity of FDG uptake has led to the evaluation of other tracers in the assessment of IFD. However, these are mainly still at the preclinical level and are yet to be translated to humans. FDG PET/CT remains the most widely evaluated radionuclide-based imaging modality in IFD management. The limitations of FDG PET/CT must be well understood, and more extensive prospective studies in uniform populations are needed to validate its role in the management of IFD that can be international guidelines., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chemokine receptor CXCR4 is overexpressed in neoplasms and its expression is related to tumour invasion, metastasis and aggressiveness. 68 Ga-Pentixafor is used to non-invasively image the expression of CXCR4 in tumours and has been widely used in haematological malignancies. Recent evidence shows that therapies targeting CXCR4 can increase the chemosensitivity of the tumour as well as inhibit tumour metastasis and aggressiveness. 68 Ga-Pentixafor has shown promise as an elegant radiotracer to aid in the selection of patients whose tumours demonstrate CXCR4 overexpression and who therefore may benefit from novel therapies targeting CXCR4. In addition, its therapeutic partners 177 Lu- and 90 Y-Pentixather have been investigated in the treatment of patients with advanced haematological malignancies, and initial studies have shown a good treatment response in metabolically active lesions. 68 Ga-Pentixafor in solid tumours complements 18 F-FDG by providing prognostic information and selecting patients who may benefit from therapies targeting CXCR4. This review summarises the available literature on the potential applications of 68 Ga-Pentixafor in solid tumours.

Purpose: Actinium-225-labeled prostate-specific membrane antigen ([ 225 Ac]Ac-PSMA-617) is safe and effective in the treatment of metastatic castration-resistant prostate cancer (mCRPC). No study has specifically assessed its safety in patients with extensive skeletal metastases of mCRPC. We aimed to investigate the hematologic toxicity and efficacy of [ 225 Ac]Ac-PSMA-617 therapy in patients with extensive skeletal metastases of mCRPC., Methods: We retrospectively reviewed the medical record of patients treated with [ 225 Ac]Ac-PSMA-617 for mCRPC. We included patients with a superscan pattern of skeletal metastases and those with 20 or more multifocal sites of skeletal metastases on baseline [ 68  Ga]Ga-PSMA-11 PET/CT. We reviewed the levels of hemoglobin, white blood cell (WBC), and platelet prior to each cycle of treatment and determined the presence of impaired bone marrow function at baseline and the grade of toxicity in the hematologic parameters induced by treatment. We evaluated the predictors of hematologic toxicity using binary logistic regression analysis. We also determined the presence of renal dysfunction before or during treatment. We assessed response to treatment using prostate-specific antigen response and the progression-free survival (PFS) and overall survival (OS)., Results: A total of 106 patients were included. Skeletal metastasis was in the superscan pattern in 34 patients (32.1%) and multifocal in 72 patients (67.9%). The median treatment cycle was 4 (range = 1-9). Ninety-eight patients (92.5%) had abnormal baseline hematologic parameters. One patient had grade 4 thrombocytopenia. Grade 3 anemia, leukopenia, and thrombocytopenia were seen in 1 (0.9%), 3 (2.8%), and 2 (1.9%) patients, respectively. Age, the number of treatment cycles, and the presence of renal dysfunction were significant predictors of hematologic toxicity. Eighty-five patients (80.2%) achieved PSA response. The median PFS and OS of the study population were 14:00 (95%CI: 8.15-19.86) months and 15.0 (95%CI: 12.8-17.2) months, respectively., Conclusions: [ 225 Ac]Ac-PSMA-617 induces a good anti-tumor effect in about 80% of patients with extensive skeletal metastases of mCRPC with a rare incidence of severe hematologic toxicity. Age, number of treatment cycles, and the presence of renal dysfunction were significant risk factors for hematologic toxicity of [ 225 Ac]Ac-PSMA-617 therapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: This study aimed to determine the correlation of [ 68 Ga]Ga-NODAGA ZOL uptake in atherosclerotic plaques and the cardiovascular risk profile of patients imaged with positron emission tomography (PET), wherein quantification of uptake was determined by atherosclerotic plaque maximum target-to-background ratio (TBRmax). We also correlated uptake with a history of cardiovascular events., Methods: We included patients who underwent PET/CT imaging post-injection of [ 68 Ga] Ga-NODAGA ZOL . We documented the number of atherosclerotic plaques found in the major arteries on CT and the cardiovascular risks in each patient. We quantified the intensity of tracer uptake in atherosclerotic plaque in the major arteries using the maximum standardized uptake value (SUVmax). The SUVmax of the most tracer-avid plaque was documented as representative of the individual arterial bed. We determined background vascular tracer activity using the mean standardized uptake value (SUVmean) obtained from the lumen of the superior vena cava. The maximum target-to-background ratio (TBRmax) was calculated as a ratio of the SUVmax to the SUVmean. The TBRmax was correlated to the number of atherogenic risk factors and history of cardiovascular events., Results: Thirty-four patients (M: F 31:3; mean age ± SD: 63 ± 10.01 years) with ≥ 2 cardiovascular risk factors were included. Statistically significant correlation between TBRmax and the number of cardiovascular risk factors was noted in the right carotid (r = 0.50; p < 0.05); left carotid (r = 0. 649; p < 0.05); ascending aorta (r = 0.375; p < 0.05); aortic arch (r = 0.483; p < 0.05); thoracic aorta (r = 0.644; p < 0.05); left femoral (r = 0.552; p < 0.05) and right femoral arteries (r = 0.533; p < 0.05). TBRmax also demonstrated a positive correlation to history of cardiovascular event in the right carotid (U = 26.00; p < 0.05); left carotid (U = 11.00; p < 0.05); ascending aorta (U = 49.00; p < 0.05); aortic arch (U = 37.00; p < 0.05); thoracic aorta (U = 16.00; p < 0.05); left common iliac (U = 49.500; p < 0.05), right common iliac (U = 43.00; p < 0.05), left femoral (U = 40.500; p < 0.05) and right femoral (U = 37.500; p < 0.05)., Conclusion: In this cohort of patients, a positive correlation was noted between atherosclerotic plaque uptake of [ 68 Ga]Ga-NODAGA ZOL and the number of atherogenic risk factors which translates to the risk of atherosclerosis and cardiovascular risk factors., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Introduction: Positron emission tomography/computed tomography (PET/CT) in infection and inflammation has yielded promising results across a range of radiopharmaceuticals. In particular, PET/CT imaging of tuberculosis (TB) allows for a better understanding of this complex disease by providing insights into molecular processes within the TB microenvironment. TB lesions are hypoxic with research primarily focussed on cellular processes occurring under hypoxic stress. With the development of hypoxia seeking PET/CT radiopharmaceuticals, that can be labelled in-house using a germanium-68/gallium-68 (68Ge/68Ga) generator, a proof-of-concept for imaging hypoxia in TB is presented., Methods: Ten patients diagnosed with TB underwent whole-body PET/CT imaging, 60-90 min after intravenous administration of 74-185 MBq (2-5 mCi) 68Ga-nitroimidazole. No oral or intravenous contrast was administered. Images were visually and semiquantitatively assessed for abnormal 68Ga-uptake in the lungs., Results: A total of 28 lesions demonstrating hypoxic uptake were identified. Low- to moderate-uptake was seen in nodules, areas of consolidation and cavitation as well as effusions. The mean standard uptake value (SUVmean) of the lesions was 0.47 (IQR, 0.32-0.82) and SUVmax was 0.71 (IQR, 0.41-1.11). The lesion to muscle ratio (median, 1.70; IQR, 1.15-2.31) was higher than both the left ventricular and the aorta lesion to blood ratios., Conclusion: Moving towards the development of unique host-directed therapies (HDT), modulation of oxygen levels may improve therapeutic outcome by reprogramming TB lesions to overcome hypoxia. This proof-of-concept study suggests that hypoxia in TB lesions can be imaged and quantified using 68Ga-nitroimidazole PET/CT. Subsequently, hypoxic load can be estimated to inform personalised treatment plans of patients diagnosed with TB., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Prostate adenocarcinoma (PCa) is a leading cause of mortality. Black males with high-risk PCa have a poorer prognosis compared to white males. Patients with International Society of Urological Pathology (ISUP) Grade Group (GG) 1 and 2 PCa have little potential for metastases post radical prostatectomy. 68 Gallium prostate specific membrane antigen ( 68 Ga-PSMA) PET/CT imaging for metastatic PCa is superior to conventional imaging in staging high-risk PCa. No strong evidence is available to support imaging low-risk patients. We aimed to evaluate the value of 68 Ga-PSMA PET/CT in black and white South African (BSA and WSA) males with GG1 and 2 PCa at initial staging. We evaluated 25 WSA and 123 BSA males. The image findings were correlated with prostate specific antigen (PSA). PSA levels significantly correlated with both primary tumor and whole-body PSMA-tumor volume (PSMA-TV) and were higher in BSA males. No differences were noted in the occurrence of metastases; however, PSA, seminal vesicle invasion and black race predicted metastases. Our findings suggest higher PSMA expression and tumor burden in BSA with histologically low-risk PCa, and future research with immunohistochemistry evaluation will be essential to confirm these findings.

Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.

Aim: The prostate bed is one of the common sites of early recurrence of prostate cancer. The currently used PSMA ligands ( 68 Ga-PSMA-11 and 99m Tc-PSMA) undergo early urinary clearance resulting in interfering physiological activity within and surrounding the prostate. This can result in sites of cancer recurrence being obscured. 18 F-PSMA-1007 has an advantage of delayed urinary clearance thus the prostate region is reviewed without any interfering physiological activity. The aim of this study was to determine the diagnostic performance of 18 F-PSMA-1007 PET/CT in patients with early biochemical recurrence after definitive therapy., Methods: Forty-six Prostate cancer (mean age 66.7±7.5, range 48-87 years) presenting with biochemical recurrence (median PSA 1.6ng/ml, range 0.1-10.0) underwent non-contrast-enhanced 18 F-PSMA-1007 PET/CT. PET/CT findings were evaluated qualitatively and semiquantitatively (SUVmax) and compared to the results of histology, Gleason grade, and conventional imaging., Results: Twenty-four of the 46 (52.2%) patients demonstrated a site of recurrence on 18 F-PSMA-1007 PET/CT. Oligometastatic disease was detected in 15 (32.6%) of these patients. Of these 10 (37.5%) demonstrated intra-prostatic recurrence, lymph node disease was noted in 11 (45.8%) whilst two patients demonstrated skeletal metastases. The detection rates for PSA levels 0-<0.5, 0.5-<1, 1-2, >2 were 31.3%, 33.3%, 55.6% and 72.2% respectively. 7 (29.2%) of the positive patients had been described as negative or equivocal on conventional imaging. An optimal PSA cut-off level of 1.3ng/ml was found., Conclusion: 18 F-PSMA-1007 demonstrated good diagnostic performance detecting sites of recurrence. Its ability to detect sites of recurrence in the setting of early biochemical recurrence will have a significant impact on patient management., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Severe acute respiratory coronavirus-2 (SARS-Co-2) is the causative agent of coronavirus disease-2019 (COVID-19). COVID-19 is a disease with highly variable phenotypes, being asymptomatic in most patients. In symptomatic patients, disease manifestation is variable, ranging from mild disease to severe and critical illness requiring treatment in the intensive care unit. The presence of underlying cardiovascular morbidities was identified early in the evolution of the disease to be a critical determinant of the severe disease phenotype. SARS-CoV-2, though a primarily respiratory virus, also causes severe damage to the cardiovascular system, contributing significantly to morbidity and mortality seen in COVID-19. Evidence on the impact of cardiovascular disorders in disease manifestation and outcome of treatment is rapidly emerging. The cardiovascular system expresses the angiotensin-converting enzyme-2, the receptor used by SARS-CoV-2 for binding, making it vulnerable to infection by the virus. Systemic perturbations including the so-called cytokine storm also impact on the normal functioning of the cardiovascular system. Imaging plays a prominent role not only in the detection of cardiovascular damage induced by SARS-CoV-2 infection but in the follow-up of patients' clinical progress while on treatment and in identifying long-term sequelae of the disease., (© 2022. The Author(s).)