Blue Earth Diagnostics (United Kingdom)

32 Background: PET-based radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA) have become the mainstay of prostate cancer imaging; however, high urinary radioactivity from these primarily renally cleared compounds may obscure tumors in the prostate and peri-ureteric regions. We conducted the first intra-patient comparator study to assess the urinary radioactivity of two 18 F-labelled PSMA-PET radiopharmaceuticals, 18 F-piflufolastat and 18 F-flotufolastat. Methods: This multicenter, prospective, intra-patient comparator study (NCT06604442) enrolled men ≥ 18 years with low PSA (≤ 0.5 ng/mL) biochemical recurrence of prostate cancer ≥ 6 months after radical prostatectomy with undetectable PSA post-surgery, scheduled for a standard-of-care (SoC) 18 F-piflufolastat PET. Patients had a SoC PET/CT after IV 18 F-piflufolastat (target dose 333 MBq), and a second PET/CT 1–10 days later after IV 18 F-flotufolastat (target dose 296 MBq), both scans started approximately 60 min after administration and used the same scanner. The primary endpoint was the difference in urinary bladder radioactivity (mean standardized uptake value [SUV mean ]) between 18 F-piflufolastat PET and 18 F-flotufolastat PET. Secondary endpoints included patient and region-level detection rates (DR) for each radiopharmaceutical. Images were interpreted by two blinded central readers, with a third to resolve disagreements, allowing majority read results. Results: Between Oct 2024 and Jun 2025, 55 patients (mean PSA, 0.28 [range 0.09–0.50] ng/mL) were included in the primary efficacy analysis. Median bladder SUV mean was significantly higher with 18 F-piflufolastat (29.0; interquartile range [IQR], 18.9–40.8) than 18 F-flotufolastat (10.9; IQR, 6.0–18.5) with a median difference of 15.1 (IQR, 8.5–27.0; p<0.001 [Wilcoxon signed-rank test]). The patient-level DR was 27.3% (15/55) for 18 F-piflufolastat and 45.5% (25/55) for 18 F-flotufolastat (majority read). Among the 21 patients with very low PSA levels (≤ 0.2 ng/mL), 38.1% had a positive 18 F-piflufolastat scan compared with 52.4% for 18 F-flotufolastat scans (majority read). Regional and sub-regional DRs are shown in the table. Conclusions: In this intra-patient study, 18 F-flotufolastat showed significantly lower urinary radioactivity, and a higher overall DR than 18 F-piflufolastat indicating it may offer improved image assessment in regions close to the bladder. Clinical trial information: NCT06604442 . Region 18 F-Piflufolastat DR* n (%)N=55 18 F-Flotufolastat DR*n (%)N=55 Prostate bed 6 (10.9) 10 (18.2) Vesicourethral anastomosis 1 (1.8) 4 (7.3) Retrovesical 2 (3.6) 2 (3.6) Remnant seminal vesicles/ lateral surgical margin 2 (3.6) 4 (7.3) Pelvic lymph nodes 8 (14.5) 9 (16.4) Majority read. *≥ 1 PET positive lesion.

ABSTRACT PURPOSE The first long-term safety data with a 212 Pb-labelled radiopharmaceutical reported significant renal adverse events after more than two years of follow-up. Understanding the pharmacokinetic drivers of dose delivery for alpha emitting radioligand therapy (RLT) will be critical to optimizing molecules. We aimed to model and compare the dosimetry and therapeutic index (TI) of a single pharmaceutical, rhPSMA-10.1, when labeled with either 225 Ac or 212 Pb, using human pharmacokinetic data. METHODS Dosimetry data from a Phase 1 trial of 177 Lu-rhPSMA-10.1 in 13 mCRPC patients was used to generate time–activity curves for tumors and select organs-at-risk. These curves were used to model the dosimetry of 225 Ac-rhPSMA-10.1 and 212 Pb-rhPSMA-10.1 by substituting the physical half-life and decay properties of 177 Lu with those of the alpha-emitters. Absorbed doses and TIs were calculated. The potential impact of daughter radionuclide translocation on organ doses and TIs was also modeled. RESULTS To deliver 5Gy (RBE5) absorbed dose to tumors, a ∼29-fold higher administered activity of 212 Pb was required compared to 225 Ac (131 MBq versus 4.6 MBq, respectively). At this tumor dose, the activity of 212 Pb resulted in 2.5-fold and 2.2-fold higher absorbed doses to the kidneys and salivary glands, respectively, compared with 225 Ac. Consequently, 225 Ac demonstrated a substantially improved TI, with a ∼3-fold higher tumor:kidney dose ratio (9.85 versus 3.36) and a ∼2.2-fold higher tumor:salivary gland ratio (15.9 versus. 7.1). Even when modeling a worst-case scenario for daughter translocation, 225 Ac maintained a superior TI. Importantly, based on the pharmacokinetics of this drug, to achieve 120Gy (RBE5) absorbed dose to tumors would require the delivery of 12.1Gy (RBE5) and 35.7Gy (RBE5) to the kidneys for 225 Ac and 212 Pb respectively. Modeling daughter translocation, these values become 39.1Gy (RBE5) and 114.3Gy (RBE5) respectively which may help to explain recently reported safety data from 212 Pb-labelled RLT. CONCLUSIONS The physical half-life of 225 Ac is better suited to the pharmacokinetic profile of rhPSMA-10.1 than the shorter half-life of 212 Pb. This results in substantially enhanced TI for 225 Ac-rhPSMA-10.1, permitting the delivery of markedly lower absorbed doses to organs-at-risk for a fixed tumor dose. Importantly, labelling with 212 Pb may lead to very high renal absorbed radiation doses driven predominantly by demetallation. GRAPHICAL ABSTRACT

Background/Objectives: To conduct a systematic review to evaluate the detection rates (DR) of the three FDA-approved PSMA-targeted radiopharmaceuticals in patients with recurrent prostate cancer. Methods: Two individuals systematically searched MEDLINE, ScienceDirect, and Cochrane Libraries (February 2025), and independently reviewed all results to identify studies reporting patient-level 68Ga-PSMA-11, 18F-DCFPyL, or 18F-flotufolastat DR in ≥100 evaluable patients with recurrent prostate cancer. Sample-weighted means (SWM) of extracted DR were calculated. Results: Of 5059 published articles, 37 met our inclusion criteria, reporting data from 8843 patients undergoing 68Ga-PSMA-11 (n = 27), 18F-DCFPyL (n = 8), or 18F-flotufolastat (n = 2) studies. Heterogeneity was noted across enrolled populations, particularly in prior treatments. 68Ga-PSMA-11 studies recruited patients with marginally higher median PSA than 18F-DCFPyL or 18F-flotufolastat studies (median PSA ranged from 0.1 to 10.7, 0.2-2.5, and 0.6-1.1, respectively). Reported overall DR ranged from 25 to 91% for 68Ga-PSMA-11, 49-86% for 18F-DCFPyL, and 73-83% for 18F-flotufolastat, with SWM of 71%, 66%, and 79%, respectively. Post-prostatectomy DR were reported in 18 articles, resulting in SWM DR of 58% for 68Ga-PSMA-11 (n = 12), 55% for 18F-DCFPyL (n = 4), and 76% for 18F-flotufolastat (n = 2). Among post-radiotherapy patients, SWM were 87% for 68Ga-PSMA-11 (n = 4), 90% for 18F-DCFPyL (n = 2), and 99% for 18F-flotufolastat (n = 1). SWM DR at PSA < 1 ng/mL were 53%, 42%, and 66% for 68Ga-PSMA-11 (n = 13), 18F-DCFPyL (n = 5), and 18F-flotufolastat (n = 2), respectively. Conclusions: Considerable heterogeneity exists across populations in studies of diagnostic PET radiopharmaceuticals. Despite a paucity of 18F-DCFPyL and 18F-flotufolastat studies compared with 68Ga-PSMA-11, the available data suggest that all three radiopharmaceuticals provide high overall DR in patients with biochemical recurrence of prostate cancer.

2001 Background: Differentiating radiation necrosis from tumor progression remains one of the most commonly encountered and clinically challenging scenarios after radiation therapy (RT) for brain metastases (BM). PURSUE (NCT04410367) evaluated the diagnostic performance of 18F-fluciclovine, an amino acid PET radiopharmaceutical, based on various lesion metrics, to establish image interpretation criteria (IIC) for suspected recurrent BM after RT. Methods: Patients with solid tumor BM were enrolled across 7 US sites if they had a previously irradiated ‘reference’ lesion equivocal on MRI for recurrence and were planned for craniotomy. 18F-Fluciclovine PET (185 MBq) took place &lt;42 days post-MRI and 1-21 days pre-craniotomy. The primary endpoint was the diagnostic performance (sensitivity, specificity, positive-, and negative-predictive value [PPV/NPV]) of different thresholds of lesion 18F-fluciclovine uptake on qualitative, visual reads vs central histopathological analysis. Lesion 18F-fluciclovine uptake was assessed qualitatively by 3 independent blinded readers who visually rated the uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid), or ‘marked’ (above parotid). Secondary endpoints included the diagnostic performance based on different thresholds of quantitative (e.g., lesion SUV) and dynamic measures of uptake. A committee, including 2 expert imaging physicians independent to PURSUE, reviewed all data in round-table meetings to establish the IIC, which were subsequently used to assess diagnostic performance. Results: All 23 reference lesions in 23 subjects underwent histopathological analysis, with 10 (43%) confirmed as recurrent tumor. The highest performing qualitative measure was ‘marked’, rendering a sensitivity of 92-100%, with variable specificity of 40-80% across readers. SUVmax was a reader-independent, high-performing quantitative metric on ROC analysis (AUC 0.87, SUVmax threshold 4.8 conferring a sensitivity of 80% and specificity of 85%). Dynamic measures did not provide added diagnostic value. After analyzing these metrics, the committee established IIC as: Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely. Application of the IIC resulted in a sensitivity of 80%, specificity of 77-85%, PPV of 73-80%, and NPV of 83-85% across the readers. Conclusions: This is the first prospective multicenter trial to evaluate PET characteristics of suspected recurrent BM after RT, verified by histopathology. Qualitative and quantitative IIC show 18F-fluciclovine to be a high-performing diagnostic tool. These IIC will help evaluate the diagnostic performance of 18F-fluciclovine PET in future trials. Clinical trial information: NCT04410367 .

Prostate Cancer: A Network Meta-Analysis of Randomized Trials." 3 The points they have raised reinforce our overarching drive for the above-mentioned study: Changes in practice substantiated by the use of lowerquality evidence can result in unintended consequences.We would like to underscore some fundamental principles in this reply.The goal of treatment is to help patients live better (quality) or longer (quantity).In localized prostate cancer (PCa), to improve overall survival (OS), treatment must reduce PCa-specific mortality (PCSM).The predominant cause of PCSM is a manifestation of the development of distant metastases (DMs).Thus, for an oncologic treatment to improve OS in men with localized PCa, in nearly all scenarios, the treatment must result in, at a minimum, a reduction in the risk of developing DMs.This concept is supported by the analysis performed by the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group, which demonstrated that the most suitable surrogate end point for OS in localized PCa is metastasisfree survival. 4,

This paper describes a method by which the Web Ontology Language (OWL) can be used to specify a highly structured health record, following internationally recognised standards such as ISO 13606 and HL7 CDA. The structured record is coded using schemes such as SNOMED, ICD or LOINC, with the coding applied statically, on the basis of the predefined structure, or dynamically, on the basis of data values entered in the health record. The highly structured, coded record can then be linked with external knowledge sources which are themselves coded using the Resource Description Framework. These methods have been used to implement dynamic decision support in the open source cityEHR health records system. The effectiveness of the decision support depends on the scope and quality of the clinical coding and the sophistication of the algorithm used to match the structured record with knowledge sources.

Development of novel therapies for CNS tumors requires reliable assessment of response and progression. This requirement has been particularly challenging in neuro-oncology for which contrast enhancement serves as an imperfect surrogate for tumor volume and is influenced by agents that affect vascular permeability, such as antiangiogenic therapies. In addition, most tumors have a nonenhancing component that can be difficult to accurately quantify. To improve the response assessment in neuro-oncology and to standardize the criteria that are used for different CNS tumors, the Response Assessment in Neuro-Oncology (RANO) working group was established. This multidisciplinary international working group consists of neuro-oncologists, medical oncologists, neuroradiologists, neurosurgeons, radiation oncologists, neuropsychologists, and experts in clinical outcomes assessments, working in collaboration with government and industry to enhance the interpretation of clinical trials. The RANO working group was originally created to update response criteria for high- and low-grade gliomas and to address such issues as pseudoresponse and nonenhancing tumor progression from antiangiogenic therapies, and pseudoprogression from radiochemotherapy. RANO has expanded to include working groups that are focused on other tumors, including brain metastases, leptomeningeal metastases, spine tumors, pediatric brain tumors, and meningiomas, as well as other clinical trial end points, such as clinical outcomes assessments, seizures, corticosteroid use, and positron emission tomography imaging. In an effort to standardize the measurement of neurologic function for clinical assessment, the Neurologic Assessment in Neuro-Oncology scale was drafted. Born out of a workshop conducted by the Jumpstarting Brain Tumor Drug Development Coalition and the US Food and Drug Administration, a standardized brain tumor imaging protocol now exists to reduce variability and improve reliability. Efforts by RANO have been widely accepted and are increasingly being used in neuro-oncology trials, although additional refinements will be needed.