Quantitative SPECT/CT imaging of actinium-225 for targeted alpha therapy of glioblastomas.

BACKGROUND: A new, alternative option for patients with recurrent glioblastoma is targeted alpha therapy (TAT), in the form of a local administration of substance P (neurokinin type 1 receptor ligand, NK-1) labelled with 225Ac. The purpose of the study was to confirm the feasibility of quantitative SPECT imaging of 225Ac, in a model reproducing specific conditions of TAT. In particular, to present the SPECT calibration methodology used, as well as the results of validation measurements and their accuracy. Additionally, to discuss the specific problems related to high noise in the presented case. MATERIALS AND METHODS: All SPECT/CT scans were conducted using the Symbia T6 equipped with HE collimators, and acquired with multiple energy windows (three main windows: 440 keV, 218 keV, and 78 keV, with three lower scatter energy windows). A Jaszczak phantom with fillable cylindrical sources of various sizes was used to investigate quantitative SPECT/CT imaging characteristics. The planar sensitivity of the camera, an imaging calibration factor, and recovery coefficients were determined. Additionally, the 3D printed model of the glioblastoma tumour was developed and imaged to evaluate the accuracy of the proposed protocol. RESULTS: Using the imaging calibration factor and recovery coefficients obtained with the Jaszczak phantom, we were able to quantify the activity in a 3D-printed model of a glioblastoma tumour with uncertainty of no more than 10% and satisfying accuracy. CONCLUSIONS: It is feasible to perform quantitative 225Ac SPECT/CT imaging. However, there are still many more challenges that should be considered for further research on this topic (among others: accurate determination of ICF in the case of high background noise, better method of background estimation for recovery coefficient calculations, other methods for scatter correction than the dual-energy window scatter-compensation method used in this study).

Development of a multigenomic liquid biopsy (PROSTest) for prostate cancer in whole blood.

INTRODUCTION: We describe the development of a molecular assay from publicly available tumor tissue mRNA databases using machine learning and present preliminary evidence of functionality as a diagnostic and monitoring tool for prostate cancer (PCa) in whole blood. MATERIALS AND METHODS: We assessed 1055 PCas (public microarray data sets) to identify putative mRNA biomarkers. Specificity was confirmed against 32 different solid and hematological cancers from The Cancer Genome Atlas (n = 10,990). This defined a 27-gene panel which was validated by qPCR in 50 histologically confirmed PCa surgical specimens and matched blood. An ensemble classifier (Random Forest, Support Vector Machines, XGBoost) was trained in age-matched PCas (n = 294), and in 72 controls and 64 BPH. Classifier performance was validated in two independent sets (n = 263 PCas; n = 99 controls). We assessed the panel as a postoperative disease monitor in a radical prostatectomy cohort (RPC: n = 47). RESULTS: A PCa-specific 27-gene panel was identified. Matched blood and tumor gene expression levels were concordant (r = 0.72, p < 0.0001). The ensemble classifier ("PROSTest") was scaled 0%-100% and the industry-standard operating point of ≥50% used to define a PCa. Using this, the PROSTest exhibited an 85% sensitivity and 95% specificity for PCa versus controls. In two independent sets, the metrics were 92%-95% sensitivity and 100% specificity. In the RPCs (n = 47), PROSTest scores decreased from 72% ± 7% to 33% ± 16% (p < 0.0001, Mann-Whitney test). PROSTest was 26% ± 8% in 37 with normal postoperative PSA levels (<0.1 ng/mL). In 10 with elevated postoperative PSA, PROSTest was 60% ± 4%. CONCLUSION: A 27-gene whole blood signature for PCa is concordant with tissue mRNA levels. Measuring blood expression provides a minimally invasive genomic tool that may facilitate prostate cancer management.

Tumour-Induced Osteomalacia-A Long Way to the Diagnosis Facilitated by [68Ga]Ga-DOTATATE PET/CT.

Background: Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome. Detecting the primary tumour in TIO is challenging using conventional imaging methods. This study assesses the efficacy of [68Ga]Ga-DOTATATE PET/CT in identifying the primary tumour. Methods: Six patients with suspected TIO underwent [68Ga]Ga-DOTATATE PET/CT. The patients' clinical history and biochemical parameters were analysed. Results: [68Ga]Ga-DOTATATE PET/CT successfully identified primary tumours in four patients (femoral bones for two, iliac bone for one, subcutaneous tissue of pubic region for one). Tumour removal led to clinical and laboratory improvement. In one patient, PET/CT showed rib uptake, but the biopsy was negative. One patient showed no tumour lesions on PET/CT despite clinical evidence. Two patients had focal recurrence at the primary tumour site, detected by follow-up PET/CT. Conclusions: [68Ga]Ga-DOTATATE PET/CT is a valuable tool for detecting primary tumours in TIO, aiding in accurate diagnosis and guiding surgery, leading to improved outcomes. Further research is needed to validate these findings and explore [68Ga]Ga-DOTATATE PET/CT in other paraneoplastic syndromes.

Guardians of precision: advancing radiation protection, safety, and quality systems in nuclear medicine.

BACKGROUND: In the rapidly evolving field of nuclear medicine, the paramount importance of radiation protection, safety, and quality systems cannot be overstated. This document provides a comprehensive analysis of the intricate regulatory frameworks and guidelines, meticulously crafted and updated by national and international regulatory bodies to ensure the utmost safety and efficiency in the practice of nuclear medicine. METHODS: We explore the dynamic nature of these regulations, emphasizing their adaptability in accommodating technological advancements and the integration of nuclear medicine with other medical and scientific disciplines. RESULTS: Audits, both internal and external, are spotlighted for their pivotal role in assessing and ensuring compliance with established standards, promoting a culture of continuous improvement and excellence. We delve into the significant contributions of entities like the International Atomic Energy Agency (IAEA) and relevant professional societies in offering universally applicable guidelines that amalgamate the latest in scientific research, ethical considerations, and practical applicability. CONCLUSIONS: The document underscores the essence of international collaborations in pooling expertise, resources, and insights, fostering a global community of practice where knowledge and innovations are shared. Readers will gain an in-depth understanding of the practical applications, challenges, and opportunities presented by these regulatory frameworks and audit processes. The ultimate goal is to inspire and inform ongoing efforts to enhance safety, quality, and effectiveness in nuclear medicine globally.

European Association of Nuclear Medicine Focus 5: Consensus on Molecular Imaging and Theranostics in Prostate Cancer.

BACKGROUND: In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications. OBJECTIVE: We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa. DESIGN, SETTING, AND PARTICIPANTS: The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores. RESULTS AND LIMITATIONS: After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [177Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [223Ra]RaCl2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [18F]FDG and PSMA PET prior to [177Lu]Lu-PSMA therapy. CONCLUSIONS: There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community. PATIENT SUMMARY: There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide.

Comparison of Multiparametric MRI, [68Ga]Ga-PSMA-11 PET-CT, and Clinical Nomograms for Primary T and N Staging of Intermediate-to-High-Risk Prostate Cancer.

PURPOSE OF THE REPORT: Although multiparametric magnetic resonance imaging (mpMRI) is commonly used for the primary staging of prostate cancer, it may miss non-enlarged metastatic lymph nodes. Positron emission tomography-computed tomography targeting the prostate-specific membrane antigen (PSMA PET-CT) is a promising method to detect non-enlarged metastatic lymph nodes, but more data are needed. MATERIALS AND METHODS: In this single-center, prospective study, we enrolled patients with intermediate-to-high-risk prostate cancer scheduled for radical prostatectomy with pelvic node dissection. Before surgery, prostate imaging with mpMRI and PSMA PET-CT was used to assess lymph node involvement (LNI), extra-prostatic extension (EPE), and seminal vesicle involvement (SVI). Additionally, we used clinical nomograms to estimate the risk of these three outcomes. RESULTS: Of the 74 patients included, 61 (82%) had high-risk prostate cancer, and the rest had intermediate-risk cancer. Histopathology revealed LNI in 20 (27%) patients, SVI in 26 (35%), and EPE in 52 (70%). PSMA PET-CT performed better than mpMRI at detecting LNI (area under the curve (AUC, 95% confidence interval): 0.779 (0.665-0.893) vs. 0.655 (0.529-0.780)), but mpMRI was better at detecting SVI (AUC: 0.775 (0.672-0.878) vs. 0.585 (0.473-0.698)). The MSKCC nomogram performed well at detecting both LNI (AUC: 0.799 (0.680-0.918)) and SVI (0.772 (0.659-0.885)). However, when the nomogram was used to derive binary diagnoses, decision curve analyses showed that the MSKCC nomogram provided less net benefit than mpMRI and PSMA PET-CT for detecting SVI and LNI, respectively. CONCLUSIONS: mpMRI and [68Ga]Ga-PSMA-11 PET-CT are complementary techniques to be used in conjunction for the primary T and N staging of prostate cancer.

Long-Term Tumor Control Following Targeted Alpha Therapy (TAT) of Low-Grade Gliomas (LGGs): A New Treatment Paradigm?

The median survival time has been reported to vary between 5 and 8 years in low-grade (WHO grade 2) astrocytoma, and between 10 and 15 years for grade 2 oligodendroglioma. Targeted alpha therapy (TAT), using the modified peptide vector [213Bi]Bi/[225Ac]Ac-DOTA-substance P, has been developed to treat glioblastoma (GBM), a prevalent malignant brain tumor. In order to assess the risk of late neurotoxicity, assuming that reduced tumor cell proliferation and invasion should directly translate into good responses in low-grade gliomas (LGGs), a limited number of patients with diffuse invasive astrocytoma (n = 8) and oligodendroglioma (n = 3) were offered TAT. In two oligodendroglioma patients, TAT was applied as a second-line treatment for tumor progression, 10 years after targeted beta therapy using [90Y]Y-DOTA-substance P. The radiopharmaceutical was locally injected directly into the tumor via a stereotactic insertion of a capsule-catheter system. The activity used for radiolabeling was 2-2.5 GBq of Bismuth-213 and 17 to 35 MBq of Actinium-225, mostly applied in a single fraction. The recurrence-free survival times were in the range of 2 to 16 years (median 11 years) in low-grade astrocytoma (n = 8), in which TAT was administered following a biopsy or tumor debulking. Regarding oligodendroglioma, the recurrence-free survival time was 24 years in the first case treated, and 4 and 5 years in the two second-line cases. In conclusion, TAT leads to long-term tumor control in the majority of patients with LGG, and recurrence has so far not manifested in patients with low-grade (grade 2) astrocytomas who received TAT as a first-line therapy. We conclude that targeted alpha therapy has the potential to become a new treatment paradigm in LGG.

Prostate-specific membrane antigen expression in intracranial lesions - a review of the primary, metastatic, and nonneoplastic lesions.

Prostate-specific membrane antigen (PSMA) is a membrane protein originally discovered in prostate cancer cells. It is widely used at all stages of prostate cancer diagnosis. Several studies have highlighted its possible wide application in other cancers. This review discusses the potential use of positron emission tomography with labelled PSMA for the diagnosis or differentiation of intracranial lesions. Given the numerous reports on the usefulness of PSMA in the diagnosis of brain tumours of glial origin, the focus is on lesions of a different aetiology.

68 Ga-Prostate-Specific Membrane Antigen PET/CT in Imaging of Hemangiopericytoma.

ABSTRACT: Hemangiopericytoma is a mesenchymal neoplasm that derives from pericytes surrounding the capillaries presenting overexpression of PSMA, which can be a source of pitfall in 68 Ga-PSMA-11 PET/CT. We reported 2 cases with recurrent hemangiopericytoma grade III with high expression of 68 Ga-PSMA-11 in PET/CT. Based on the performed examination, one of them received targeted α-therapy with the IV injection of 225 Ac-PSMA-617.

A case of a patient with biochemical recurrence and inadequate results of suspected bone metastases in imaging methods - will [68Ga]Ga-PSMA-11 PET/CT give us an answer?

We present a case of a 79-year-old asymptomatic patient with prostate adenocarcinoma, Gleason score 9 (4 + 5), with the initial prostate-specific antigen (PSA) level of 17 ng/mL, treated with radiotherapy and hormonotherapy, who was diagnosed with the rapid growth of PSA levels up to 78.8 ng/mL. Due to suspected bone metastases, first, bone scintigraphy was performed. However, it showed only one intense "hot" lesion in the Th7 projection. This image was not consistent with a high level of PSA, for which reason a computed tomography (CT) scan was performed. It revealed lytic metastasis in Th7 and one more suspicious change in L2, which still was inconsistent with the patient's clinical picture. The patient was referred for [68Ga]Ga-PSMA-11 PET/CT. It showed an uncountable number of foci of increased marker accumulation in bones, mostly without visible change in CT examination. This case showed that the clinical results and suspicions of the advancement of a patient's disease are still the most important data in care and therapy planning.

European Association of Nuclear Medicine (EANM) Focus 4 consensus recommendations: molecular imaging and therapy in haematological tumours.

Given the paucity of high-certainty evidence, and differences in opinion on the use of nuclear medicine for hematological malignancies, we embarked on a consensus process involving key experts in this area. We aimed to assess consensus within a panel of experts on issues related to patient eligibility, imaging techniques, staging and response assessment, follow-up, and treatment decision-making, and to provide interim guidance by our expert consensus. We used a three-stage consensus process. First, we systematically reviewed and appraised the quality of existing evidence. Second, we generated a list of 153 statements based on the literature review to be agreed or disagreed with, with an additional statement added after the first round. Third, the 154 statements were scored by a panel of 26 experts purposively sampled from authors of published research on haematological tumours on a 1 (strongly disagree) to 9 (strongly agree) Likert scale in a two-round electronic Delphi review. The RAND and University of California Los Angeles appropriateness method was used for analysis. Between one and 14 systematic reviews were identified on each topic. All were rated as low to moderate quality. After two rounds of voting, there was consensus on 139 (90%) of 154 of the statements. There was consensus on most statements concerning the use of PET in non-Hodgkin and Hodgkin lymphoma. In multiple myeloma, more studies are required to define the optimal sequence for treatment assessment. Furthermore, nuclear medicine physicians and haematologists are awaiting consistent literature to introduce volumetric parameters, artificial intelligence, machine learning, and radiomics into routine practice.

Locoregional Treatment of Glioblastoma With Targeted α Therapy: [ 213 Bi]Bi-DOTA-Substance P Versus [ 225 Ac]Ac-DOTA-Substance P-Analysis of Influence Parameters.

BACKGROUND: Glioblastoma (GB) is the most malignant primary brain tumor. Therefore, introduction of new treatment options is critically important. The aim of this study was to assess local treatment with α emitters [ 213 Bi]Bi-DOTA-substance P (SP) and [ 225 Ac]Ac-DOTA-SP. METHODS: Treatment was performed as salvage therapy in patients with recurrent primary and secondary GB. [ 213 Bi]Bi-DOTA-SP with injected activity 1.85 GBq per cycle was used in 20 primary (48.2 ± 11.8 years old) and in 9 secondary (38.8 ± 10.8 years old) GB patients and [ 225 Ac]Ac-DOTA-SP in 15 primary (45.1 ± 9.9 years old) and in 6 secondary (37.8 ± 6.4 years old) GB patients with a dose escalation scheme (10, 20, and 30 MBq). RESULTS: Local treatment with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP was well tolerated with only few adverse effects. There was no statistically significant difference between [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP groups in survival parameters. For primary GB, survival parameters of patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows(in months): progression-free survival time, 2.7 versus 2.4; OS-d (overall survival from time of diagnosis to death from any cause), 23.6 versus 21.0; OS-t (overall survival from the start of treatment to death from any cause), 7.5 versus 5.0; and OS-r (overall survival from recurrence in primary tumors to death from any cause), 10.9 versus 12.0. Survival parameters of secondary GB patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows (in months): progression-free survival time, 5.8 versus 2.4; OS-d, 52.3 versus 65.0; OS-t, 16.4 versus 16.0; and OS-c (overall survival from conversion into secondary GB multiforme to death from any cause), 18.4 versus 36.0. CONCLUSIONS: The similarity results of 213 Bi or 225 Ac may suggest that the local treatment of brain tumors can be greatly simplified. The experience to date shows that local radioisotope treatment of brain tumors requires further dosimetry studies, taking into account the complexity of biological processes.

Nuclear medicine in the assessment and prevention of cancer therapy-related cardiotoxicity: prospects and proposal of use by the European Association of Nuclear Medicine (EANM).

Cardiotoxicity may present as (pulmonary) hypertension, acute and chronic coronary syndromes, venous thromboembolism, cardiomyopathies/heart failure, arrhythmia, valvular heart disease, peripheral arterial disease, and myocarditis. Many of these disease entities can be diagnosed by established cardiovascular diagnostic pathways. Nuclear medicine, however, has proven promising in the diagnosis of cardiomyopathies/heart failure, and peri- and myocarditis as well as arterial inflammation. This article first outlines the spectrum of cardiotoxic cancer therapies and the potential side effects. This will be complemented by the definition of cardiotoxicity using non-nuclear cardiovascular imaging (echocardiography, CMR) and biomarkers. Available nuclear imaging techniques are then presented and specific suggestions are made for their application and potential role in the diagnosis of cardiotoxicity.

68 Ga-Prostate-Specific Membrane Antigen PET/CT in Ovarian Tumors : Potential to Differentiate Benign and Malignant Tumors Before Surgery: A Preliminary Report.

PURPOSE OF THE REPORT: Ovarian cancer is usually diagnosed in an advanced stage of disease due to the absence of specific symptoms and a lack of sensitive diagnostic methods. Prostate-specific membrane antigen (PSMA) is expressed on prostate cancer cells but can be found in other tumors such as ovarian cancer.The aim of this pilot study was to evaluate the feasibility of using 68 Ga-PSMA-11 PET/CT in detection of ovarian neoplasm before surgical treatment. PATIENTS AND METHODS: Eight women with mean age of 56.0 ± 16.2 years were included in the study. All patients underwent transvaginal ultrasound followed by CT scan of the chest and abdomen as qualification for surgery. Within a 1-week interval, PET/CT was performed on a Siemens Biograph scanner, 60 minutes after injection of 2 MBq/kg 68 Ga-PSMA-11. RESULTS: In 3 cases (37.5%), the 68 Ga-PSMA-11 PET/CT was positive, whereas histological examination confirmed 2 serous ovarian cancer cases and 1 ovarian borderline tumor. The SUV max in the serous ovarian cancer was 8.7 and 4.1, and in the borderline ovarian tumor, it was 13.8. No correlation was found between antigen CA-125 level and 68 Ga-PSMA expression. Range of tumor SUV max was not correlated with stage of disease. The remaining 62.5% (5/8) were negative in 68 Ga-PSMA-11 PET/CT, and histopathology confirmed benign pelvic tumor. CONCLUSIONS: The initial experience supports the potential to use 68 Ga-PSMA-11 in ovarian cancer to differentiate malignant and benign tumors before surgery.This study was approved by the Ethical Committee of the Medical University of Warsaw (KB/2/A/2018).