Prostate-specific Membrane Antigen: Alpha-labeled Radiopharmaceuticals.

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.

Advances in Radioligand Theranostics in Oncology.

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 (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-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 177Lu-DOTATATE and 177Lu-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.

Imaging Molecular Targets and Metabolic Pathways in Breast Cancer for Improved Clinical Management: Current Practice and Future Perspectives.

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 [18F]FDG and [18F]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.

Insights into Peptidoglycan-Targeting Radiotracers for Imaging Bacterial Infections: Updates, Challenges, and Future Perspectives.

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.

Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study.

BACKGROUND: Actinium-225 (225Ac) 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 225Ac-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 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) 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 225Ac-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, 177Lu-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 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-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: 225Ac-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.

Prognostic Value of PSMA PET/CT in Prostate Cancer.

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.

Correlation between [68Ga]Ga-FAPI-46 PET Imaging and HIF-1α Immunohistochemical Analysis in Cervical Cancer: Proof-of-Concept.

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). [68Ga]Ga-FAPI PET imaging has been demonstrated in various cancer types. We hypothesized that [68Ga]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 [68Ga]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 cm3, 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.

Recent Innovations and Nano-Delivery of Actinium-225: A Narrative Review.

The actinium-225 (225Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the 225Ac 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 225Ac 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 225Ac 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 225Ac is discussed. Quality control measures in the preparation of 225Ac-conjugates are also highlighted.

Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi8,Met(O2)11]-Substance P.

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-[Thi8,Met(O2)11]-SP (DOTA-[Thi8,Met(O2)11]SP), in the theranostic pair [68Ga]Ga-/ [213Bi]Bi-DOTA-[Thi8,Met(O2)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-[Thi8,Met(O2)11]SP was examined using inositol phosphate accumulation assay in HEK293-T cells expressing NK1R, NK2R, NK3R or MRGPRX2. DOTA-[Thi8,Met(O2)11]SP had similar efficacy and potency as native SP at NK1R, but displayed greater NK1R selectivity. DOTA-[Thi8,Met(O2)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-[Thi8,Met(O2)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.

Imaging of Invasive Fungal Infections- The Role of PET/CT.

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.

Molecular Imaging of Tuberculosis.

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.

68 Ga-nitroimidazole PET/CT imaging of hypoxia in tuberculosis: A case series.

Tuberculosis (TB) lesions in humans have been proven to be severely hypoxic with hypoxia leading to latency and dormancy of disease. Dormant TB lesions become less susceptible to standard TB treatment regimens with varying responses to treatment but may have increased susceptibility to nitroimidazole drugs. This in turn implies that positron emission tomography / computed tomography (PET/CT) imaging with radiolabelled nitroimidazoles may identify patients who will benefit from treatment with antimicrobial agents that are active against anaerobic bacteria. This case series aims to highlight the hypoxic uptake and retention of a novel 68 Ga-labelled hypoxia-seeking agent in TB lesions at different time points during anti-TB therapy using PET/CT imaging. Patients with confirmed TB underwent whole-body PET/CT after administration of a 68 Ga-nitroimidazole derivative at baseline and follow-up. Images were analysed both qualitatively and semi-quantitatively. Hypoxic uptake and change in uptake over time were analysed using lesion-to-muscle ratio (LMR) and lesion-to-blood ratio (LBR). 68 Ga-nitroimidazole avid lesions were demonstrated most frequently in the upper lobes of the lung. Low-grade hypoxic uptake was visualised in areas of consolidation, cavitation, nodules and lymph nodes. From baseline to follow-up imaging, the LMR increased with persistent hypoxic load despite morphologic improvement. This case series highlights the dynamic hypoxic microenvironment in TB lesions. From these initial data, it appears that 68 Ga-nitroimidazole is a promising candidate for monitoring hypoxic load in patients diagnosed with TB. Such imaging could identify patients who would benefit from individualised therapy targeting other mechanisms in the TB microenvironment with the intention to predict or improve treatment response.

[68Ga]Ga-NODAGAZOL uptake in atherosclerotic plaques correlates with the cardiovascular risk profile of patients.

OBJECTIVES: This study aimed to determine the correlation of [68Ga]Ga-NODAGAZOL 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 [68Ga] Ga-NODAGAZOL. 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 [68Ga]Ga-NODAGAZOL and the number of atherogenic risk factors which translates to the risk of atherosclerosis and cardiovascular risk factors.

PET/CT features of a novel gallium-68 labelled hypoxia seeking agent in patients diagnosed with tuberculosis: a proof-of-concept study.

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.

68Ga-PSMA-11 PET/CT Initial Staging in Black and White South African Males with ISUP Grade Group 1 and 2 Prostate Adenocarcinoma.

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. 68Gallium prostate specific membrane antigen (68Ga-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 68Ga-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.

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma.

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.

Hematologic toxicity profile and efficacy of [225Ac]Ac-PSMA-617 α-radioligand therapy of patients with extensive skeletal metastases of castration-resistant prostate cancer.

PURPOSE: Actinium-225-labeled prostate-specific membrane antigen ([225Ac]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 [225Ac]Ac-PSMA-617 therapy in patients with extensive skeletal metastases of mCRPC. METHODS: We retrospectively reviewed the medical record of patients treated with [225Ac]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: [225Ac]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 [225Ac]Ac-PSMA-617 therapy.

Cardiovascular disturbances in COVID-19: an updated review of the pathophysiology and clinical evidence of cardiovascular damage induced by SARS-CoV-2.

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.

The Use of 18F-FDG PET/CT Metabolic Parameters in Predicting Overall Survival in Patients Undergoing Restaging for Malignant Melanoma.

Malignant melanoma is one of the more aggressive cancers in the skin, with an increasing incidence every year. Melanoma has a better prognosis if diagnosed early and survival tends to decrease once the disease has metastasized. Positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) has been used extensively over the past two decades in staging and assessing responses to therapy in patients with melanoma. Metabolic PET parameters have been demonstrated to be independent prognostic factors for progression-free survival (PFS) and overall survival (OS) in different malignancies, melanoma included. In our study, we evaluated the metabolic parameters of 18F-FDG PET/CT (flourodeoxyglucose positron emission tomography/computed tomography) in predicting the overall survival in patients with malignant melanoma who presented for restaging. Metabolic PET parameters (maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG)) of the primary tumor, as well as whole-body MTV and TLG of the metastatic disease, were measured. Survival curves for OS were constructed and mortality rates were determined using the different PET variables. Forty-nine patients who presented for a PET/CT restaging in melanoma were included in this study. We found that non-survivors had significantly higher median MTV (11.86 cm3 vs. 5.68 cm3; p-value = 0.022), TLG (3125 vs. 14; p-value = 0.0357), whole-body MTV (53.9 cm3 vs. 14.4 cm3; p-value = 0.0076) and whole-body TLG (963.4 vs. 114.6; p-value = 0.0056). This demonstrated that high MTV and TLG values of the primary tumor and whole-body TLG as quantified by 18F-FDG PET/CT were prognostic factors for overall survival. The findings may potentially guide clinicians in decision making and identifying patients with a poorer prognosis.