Optimized radiological alert thresholds based on device-dosimetric information to predict peak skin dose between 2 and 4 Gy during vascular fluoroscopically guided intervention.

OBJECTIVES: To provide radiologists and physicists with methodological tools to improve patient management after vascular fluoroscopically guided intervention (FGI) by providing optimized thresholds (OT) values that could be used as a surrogate to the thresholds classically proposed by the National Council on Radiation Protection (NCRP) or could be useful to adapt their own substantial radiation dose levels (SRDL) values. METHODS: PSD of 2000-4000 mGy after FGI were calculated for 258 patients with dedicated software. Overall, the kerma and KAP 3D-ROC curves were used to assess the sensitivity (SEN) and specificity (SPE) of NCRP thresholds and OT for each PSD. Kiviat diagram and density curves were plotted for the best SEN/SPE pair of 3D-ROC curves and compared to the NCRP thresholds. RESULTS: OT for both kerma and KAP generating the best SEN/SPE couple for PSD of 2000-4000 mGy were obtained. The SEN/SPE couple of each OT was always better than that obtained using NCRP ones. The best OT among all those calculated providing the highest SEN/SPE values for kerma (3020.5 mGy) and KAP (741.02 Gy.cm2) were obtained when PSD was equal to 3300 mGy. CONCLUSIONS: We have calculated OT in terms of kerma and KAP based on 3D-ROC curves analysis and peak skin dose calculations that can be obtained to better predict high skin dose. The use of OT that predicted PSD greater than 3000 mGy is likely to improve patient follow-up. The methodology developed in this work could be adapted to other institutions in order to better define their own SRDL. KEY POINTS: • Optimized dose thresholds in terms of kerma and KAP based on 3D-ROC curves analysis and peak skin dose calculations between 2000 and 4000 mGy can be obtained to better predict high skin dose. • Patients receiving a peak skin dose between 2000 and 4000 mGy have their follow-up enhanced by using the optimized thresholds instead of the NCRP thresholds. • The best-optimized thresholds, corresponding to 3020.5 mGy and 741.02 Gy.cm2 for kerma and KAP respectively can be used instead of NRCP ones to trigger patient follow-up after fluoroscopically guided vascular interventions.

Phase I study of [131I] ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol.

BACKGROUND: Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT). [131I]ICF01012 presents a highly favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of [131I]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma. METHODS: The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of [131I]ICF01012 (185 MBq at D0) to select patients who might benefit from [131I]ICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with [131I]ICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m2, or 1600 MBq/m2, or 2700 MBq/m2 or 4000 MBq/m2 of [131I]ICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of [131I]ICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of [131I]ICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part. DISCUSSION: This study is a first-in-human trial evaluating the [131I]ICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the [131I]ICF01012 to select the patients who may benefit from a therapeutic dose of [131I]ICF01012, with at least one tumor lesion with [131I]ICF01012 uptake and an acceptable AD to healthy organ. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03784625 . Registered on December 24, 2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17.

Optimized radiological alert thresholds based on device dosimetric information and peak skin dose in vascular fluoroscopically guided intervention.

OBJECTIVES: The National Council on Radiation Protection (NCRP) report no. 168 recommended that during fluoroscopically guided interventions (FGIs), each patient should be monitored when one of the following thresholds is reached: an air kerma > 5 Gy, a kerma area product (KAP) > 500 Gy.cm2, a fluoroscopy time > 60 min, or a peak skin dose (PSD) > 3 Gy. Whereas PSD is the most accurate metric regarding the prevention of radiological risks, it remains the most difficult parameter to assess. We aimed to evaluate the relevance of the other, more accessible metrics and propose new optimized threshold (OT) for improved patient follow-up. METHODS: Overall, 108 patients who underwent FGI in which at least one NCRP threshold was reached and PSD was measured were considered. The correlation between all metrics was assessed using principal component analysis (PCA). ROC curves and the sensitivity/specificity of both NCRP and OT to predict PSD > 3 Gy were evaluated. RESULTS: The PCA shows that FGI can be decomposed with two components based on time and dose variables. Only KAP and kerma were correlated with PSD. The overall sensitivity and specificity of the new OT regarding KAP (67.6/93.0), kerma (97.3/81.7), and time (62.2/62.0) were better compared with NCRP thresholds (97.3/16.9, 40.5/95.4, and 21.6/74.7). CONCLUSIONS: This study shows that fluoroscopy time is not a relevant metric when used to predict PSDs > 3 Gy. By adapting KAP and kerma thresholds to predict PSD over 3 Gy, patient follow-ups following vascular FGI can be improved. KEY POINTS: • In vascular fluoroscopically guided interventions, principal component analysis demonstrates that between fluoroscopy time, KAP, and kerma, only the two last were correlated to the peak skin dose. • Optimized thresholds replacing NRCP ones obtained with ROC curves analysis were 85,451 µGy.cm2, 2938 mGy, and 41 min for KAP, kerma, and fluoroscopy time respectively. • Improvements to trigger patient follow-up after vascular fluoroscopically guided interventions may be obtained by using the optimized thresholds.

Imaging quality of an artificial intelligence denoising algorithm: validation in 68Ga PSMA-11 PET for patients with biochemical recurrence of prostate cancer.

BACKGROUND: 68 Ga-PSMA PET is the leading prostate cancer imaging technique, but the image quality remains noisy and could be further improved using an artificial intelligence-based denoising algorithm. To address this issue, we analyzed the overall quality of reprocessed images compared to standard reconstructions. We also analyzed the diagnostic performances of the different sequences and the impact of the algorithm on lesion intensity and background measures. METHODS: We retrospectively included 30 patients with biochemical recurrence of prostate cancer who had undergone 68 Ga-PSMA-11 PET-CT. We simulated images produced using only a quarter, half, three-quarters, or all of the acquired data material reprocessed using the SubtlePET® denoising algorithm. Three physicians with different levels of experience blindly analyzed every sequence and then used a 5-level Likert scale to assess the series. The binary criterion of lesion detectability was compared between series. We also compared lesion SUV, background uptake, and diagnostic performances of the series (sensitivity, specificity, accuracy). RESULTS: VPFX-derived series were classified differently but better than standard reconstructions (p < 0.001) using half the data. Q.Clear series were not classified differently using half the signal. Some series were noisy but had no significant effect on lesion detectability (p > 0.05). The SubtlePET® algorithm significantly decreased lesion SUV (p < 0.005) and increased liver background (p < 0.005) and had no substantial effect on the diagnostic performance of each reader. CONCLUSION: We show that the SubtlePET® can be used for 68 Ga-PSMA scans using half the signal with similar image quality to Q.Clear series and superior quality to VPFX series. However, it significantly modifies quantitative measurements and should not be used for comparative examinations if standard algorithm is applied during follow-up.

Assessment of 99mTc-NTP 15-5 uptake on cartilage, a new proteoglycan tracer: Study protocol for a phase I trial (CARSPECT).

Background: 99mTc-NTP 15-5 is a SPECT radiotracer targeting proteoglycans (PG), components of the cartilaginous extracellular matrix. Imaging of PGs would be useful for the early detection of cartilage disorders (osteoarthritis, arthritis and chondrosarcoma, Aromatase Inhibitor associated arthralgia (AIA) in breast cancer), and the follow-up of patients under treatment. According to preclinical study results, 99mTc-NTP 15-5, is a good candidate for a specific functional molecular imaging of joints. We intend to initiate a first in-human study to confirm and quantify 99mTc-NTP 15-5 uptake in healthy joints. Methods: As the clinical development of this radiotracer would be oriented toward the functional imaging of joint pathologies, we have chosen to include patients with healthy joints (unilateral osteoarthritis of the knee or breast cancer with indication of AI treatment). This phase I study will be an open-label, multicenter, dose-escalation trial of a radiopharmaceutical orientation to determine the recommended level of activity of 99mTc-NTP 15-5 to obtain the best joint tracer contrasts on images, without dose limiting toxicity (DLT). The secondary objectives will include the study of the pharmacology, biodistribution (using planar whole body and SPECT-CT acquisitions), toxicity, and dosimetry of this radiotracer. The dose escalation with 3 activity levels (5, 10, and 15 MBq/kg), will be conditioned by the absence at the previous level of DLT and of a visualized tracer accumulation on more than 80% of healthy joints as observed on scintigraphy performed at ≤ 2 h post-injection. Discussion: This first in-human phase I trial will be proof-of-concept of the relevance of 99mTc-NTP 15-5 as a cartilage tracer, with the determination of the optimal methodology (dose and acquisition time) to obtain the best contrast to provide a functional image of joints with SPECT-CT. Trial registration number: Clinicaltrials.gov: NCT04481230. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2020-000495-37.

Internal dosimetry of [99m Tc]NTP15-5 radiotracer for cartilage imaging in preclinical and clinical models using the GATE Monte Carlo platform.

PURPOSE: This study aims to perform dosimetry for [99m Tc]NTP15-5 radiotracer used in imaging of articular cartilage in rabbits and humans. The radiotracer (covered by a world patent WO 01/00621 A1) has been proposed in the previous years for the study of cartilage in osteoarthritis diseases. A sensitive imaging approach is essential to quantify osteoarthritis progression and monitor response to new therapies. [99m Tc]NTP15-5 binds to cartilage proteoglycans whose decreased content is associated to a loss of biomedical function of cartilage. We have implemented the whole dosimetry study concerning this new radiotracer for rabbits and humans using the GATE Monte Carlo platform. MATERIALS AND METHODS: Absorbed doses to critical organs are determined using the MIRD formalism. Biodistribution data are obtained by organ sampling, measuring the activity in organs for three rabbits sacrificed at various times postadministration, and by SPECT/CT imaging at different times after injection. Most important sources are cartilages (in knees and intervertebral discs), due to localization together with the liver and kidneys due to excretion of the agent. S-values are calculated from rabbit's CT scan and human CT scan using the GATE v8.0 Monte Carlo platform. Cumulated activity in humans is extrapolated from animals using the %kg-dose/g method. Particular attention is given to dose calculation in bones, bone marrow and organs at risk. RESULTS: The dosimetry performed in rabbits shows highest absorbed doses for liver and kidneys with respectively 22.5 and 43.8 µGy per MBq of injected activity. In humans, we found absorbed doses for a maximum injected activity of 15 MBq/kg, that is, 1050 MBq for an adult of 70 kgs of 9.03 mGy for kidneys and 4.16 mGy for knee cartilages. Effective dose is 2.69 µSv/MBq. CONCLUSIONS: The dosimetry profile of [99m Tc]NTP15-5 in the context of preclinical trials is of major importance in order to make sure that organs at risk are not overexposed. GATE provides all the capability needed to calculate dose profiles for internal dosimetry. The extrapolation of the dose for a human model is a first step towards clinical trials.

A compartmental model of mouse thrombopoiesis and erythropoiesis to predict bone marrow toxicity after internal irradiation.

UNLABELLED: In targeted radionuclide radiotherapy, the relationship between bone marrow (BM) toxicity and absorbed dose seems to be elusive. A compartmental model of mouse thrombopoiesis and erythropoiesis was set up to predict the depletion of hematopoietic cells as a function of the irradiation dose delivered to BM by injected radiopharmaceuticals. All simulated kinetics were compared with experimental toxicity for several stages of differentiation of the 2 hematopoietic lineages. METHODS: C57BL/6 mice were injected either with (18)FNa (37 and 60 MBq), a bone-seeking agent, or with saline. BM mean absorbed doses were calculated according to the MIRD formalism from small-animal PET/CT images. Hematologic toxicity was monitored over time, after (18)FNa injection, by studying BM progenitors and precursors in addition to blood cells. The compartmental model takes into account the pharmacokinetics of the compound, in addition to cellular kinetics and cell radiosensitivities for the 2 studied lineages. RESULTS: Because biodistribution studies showed an uptake of (18)FNa in bones, the skeleton was considered as the principal source organ of BM irradiation. The time-activity curve obtained from validated quantification of PET/CT images allowed for the calculation of mean absorbed doses to the whole BM of 2.1 and 3.4 Gy for (18)FNa injections of 37 and 60 MBq, respectively. Concerning hematologic toxicity, the model was in good agreement for the 2 absorbed doses with experimental measurements of cell depletion for platelets, progenitors, and precursors within the BM in terms of time to nadir, depletion intensity, and time to recovery. The same agreement was obtained for red blood cells and their precursors. Model predictions demonstrated that BM toxicity was in correlation with the mean absorbed dose as higher depletions at nadir and longer delays to recovery were noticed for 3.4 Gy than for 2.1 Gy. CONCLUSION: The developed compartmental model of thrombopoiesis and erythropoiesis in a BM toxicity context, after internal irradiation, allowed for the prediction of cell kinetics of BM progenitors, precursors, and mature blood cells in a dose-dependent manner. This model could therefore be used to predict hematologic toxicity in preclinical internal radiotherapy to study the dose-response relationship.