OLINDA/EXM 2-The Next-generation Personal Computer Software for Internal Dose Assessment in Nuclear Medicine.

ABSTRACT: The OLINDA/EXM version 2.0 personal computer code was created as an upgrade to the widely used OLINDA/EXM 1.0 and 1.1 codes. This paper documents the upgrades that were implemented. New decay data and anthropomorphic and biokinetic models were implemented in the software, and the software alpha and beta tested. Agreement of doses between the OLINDA/EXM codes 1 and 2 was very good. Use of the new anthropomorphic and biokinetic models results in understandable differences between the codes. Previous models were retained in the new code, and those results were identical to those in the previous code. OLINDA/EXM 2.0 represents an upgrade from version 1, with new modeling data recommended by the international community. It standardizes internal dose calculations for dose assessments in clinical trials with radiopharmaceuticals, theoretical calculations for existing pharmaceuticals, teaching, and other purposes.

Comparison of absorbed dose extrapolation methods for mouse-to-human translation of radiolabelled macromolecules.

BACKGROUND: Extrapolation of human absorbed doses (ADs) from biodistribution experiments on laboratory animals is used to predict the efficacy and toxicity profiles of new radiopharmaceuticals. Comparative studies between available animal-to-human dosimetry extrapolation methods are missing. We compared five computational methods for mice-to-human AD extrapolations, using two different radiopharmaceuticals, namely [111In]CHX-DTPA-scFv78-Fc and [68Ga]NODAGA-RGDyK. Human organ-specific time-integrated activity coefficients (TIACs) were derived from biodistribution studies previously conducted in our centre. The five computational methods adopted are based on simple direct application of mice TIACs to human organs (M1), relative mass scaling (M2), metabolic time scaling (M3), combined mass and time scaling (M4), and organ-specific allometric scaling (M5), respectively. For [68Ga]NODAGA-RGDyK, these methods for mice-to-human extrapolations were tested against the ADs obtained on patients, previously published by our group. Lastly, an average [68Ga]NODAGA-RGDyK-specific allometric parameter αnew was calculated from the organ-specific biological half-lives in mouse and humans and retrospectively applied to M3 and M4 to assess differences in human AD predictions with the α = 0.25 recommended by previous studies. RESULTS: For both radiopharmaceuticals, the five extrapolation methods showed significantly different AD results (p < 0.0001). In general, organ ADs obtained with M3 were higher than those obtained with the other methods. For [68Ga]NODAGA-RGDyK, no significant differences were found between ADs calculated with M3 and those obtained directly on human subjects (H) (p = 0.99; average M3/H AD ratio = 1.03). All other methods for dose extrapolations resulted in ADs significantly different from those calculated directly on humans (all p ≤ 0.0001). Organ-specific allometric parameters calculated using combined experimental [68Ga]NODAGA-RGDyK mice and human biodistribution data varied significantly. ADs calculated with M3 and M4 after the application of αnew = 0.17 were significantly different from those obtained by the application of α = 0.25 (both p < 0.001). CONCLUSIONS: Available methods for mouse-to-human dosimetry extrapolations provided significantly different results in two different experimental models. For [68Ga]NODAGA-RGDyK, the best approximation of human dosimetry was shown by M3, applying a metabolic scaling to the mouse organ TIACs. The accuracy of more refined extrapolation algorithms adopting model-specific metabolic scaling parameters should be further investigated.

RADAR Guide: Standard Methods for Calculating Radiation Doses for Radiopharmaceuticals, Part 2-Data Analysis and Dosimetry.

This paper presents standardized methods for performing dose calculations for radiopharmaceuticals. Various steps in the process are outlined, with some specific examples given. Special models for calculating time-activity integrals (urinary bladder, intestines) are also reviewed. This article can be used as a template for designing and executing kinetic studies for calculating radiation dose estimates from animal or human data.

RADAR Guide: Standard Methods for Calculating Radiation Doses for Radiopharmaceuticals, Part 1-Collection of Data for Radiopharmaceutical Dosimetry.

This paper presents standardized methods for collecting data to be used in performing dose calculations for radiopharmaceuticals. Various steps in the process are outlined, with some specific examples given. This document can be used as a template for designing and executing kinetic studies for calculating radiation dose estimates, from animal or human data.

Oral Administration of 99mTechnetium-Labeled Heparin in Eosinophilic Esophagitis.

OBJECTIVE: To determine if heparin labeled with 99mTechnetium (99mTc) could be an imaging probe to detect eosinophil-related inflammation in eosinophilic esophagitis and to determine the biodistribution and radiation dosimetry of 99mTc-heparin oral administration using image-based dosimetry models with esophageal modeling. METHODS: Freshly prepared 99mTc-heparin was administered orally to 5 research subjects. Radioactivity was measured by whole-body scintigraphy and single-photon emission computed tomography during the 24 hours postadministration. Following imaging, endoscopic examination was performed. The biodistribution of esophageal radioactivity was compared with endoscopic findings, eosinophil counts in biopsy tissues, and immunostaining for eosinophil granule major basic protein-1 (eMBP1). These studies were conducted from July 1, 2013, until April 22, 2017. RESULTS: Oral administration of 99mTc-heparin was well tolerated in all 5 subjects. The entire esophagus could be visualized dynamically during oral administration. Bound esophageal radioactivity marked areas of inflammation as judged by endoscopy scores, by eosinophils per high power field and by localization of eMBP1 using immunostaining. Ninety percent of the radioactivity did not bind to the esophagus and passed through the gastrointestinal tract. CONCLUSION: The biodistribution of ingested 99mTc-heparin is almost exclusively localized to the gastrointestinal tract. Radiation exposure was highest in the lower gastrointestinal tract and was comparable with other orally administered diagnostic radiopharmaceuticals. The use of swallowed 99mTc-heparin may aid in assessing eosinophil-related inflammation in the esophagus.

NANETS/SNMMI Procedure Standard for Somatostatin Receptor-Based Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE.

With the recent approval of 177Lu-DOTATATE for use in gastroenteropancreatic neuroendocrine tumors, access to peptide receptor radionuclide therapy is increasing. Representatives from the North American Neuroendocrine Tumor Society and the Society of Nuclear Medicine and Molecular Imaging collaborated to develop a practical consensus guideline for the administration of 177Lu-DOTATATE. In this paper, we discuss patient screening, maintenance somatostatin analog therapy requirements, treatment location and room preparation, drug administration, and patient release as well as strategies for radiation safety, toxicity monitoring, management of potential complications, and follow-up. Controversies regarding the role of radiation dosimetry are discussed as well. This document is designed to provide practical guidance on how to safely treat patients with this therapy.

Dose calculation of radioactive nanoparticles: first considerations for the Design of Theranostic Agents.

The use of radioactive nanoparticles as imaging and therapeutic agents is increasing globally. Indeed, the use of these nanoparticles as perfect theranostic agent is highly anticipated in the pharmaceutical market. Among the radioactive nanoparticles, liposomes, solid lipid nanoparticles and polymeric nanoparticles are the most studied. However little information among adverse reactions, absorbed dose and correct dose to achieve the theranostic goal in a translational application is available. We developed a radioactive polymeric nanoparticle and calculated the absorbed dose in animal model (Wistar rats) using the OLINDA/EXM program. The results showed that some nanoparticle were uptake in five organs and minor elimination through the gastrointestinal and urinary pathways. The data corroborates the safe use in terms of blood-brain barrier and did not show high uptake by liver. The dosimetry data support the safe use of radioactive nanoparticles as theranostic agent. Graphical abstract ᅟ.

RADAR Dose Estimate Report: A Compendium of Radiopharmaceutical Dose Estimates Based on OLINDA/EXM Version 2.0.

A compendium of about 100 radiopharmaceuticals, based on the OLINDA/EXM version 2.0 software, is presented. A new generation of voxel-based, realistic human computational phantoms developed by the RADAR committee of the Society of Nuclear Medicine and Molecular Imaging, based on 2007 recommendations of the International Commission on Radiological Protection, was used to develop the dose estimates, and the most recent biokinetic models were used as well. These estimates will be made available in electronic form and can be modified and updated as models are changed and as new radiopharmaceuticals are added.

New Fetal Radiation Doses for 18F-FDG Based on Human Data.

Current standard values of fetal dosimetry deriving from 18F-FDG injection in pregnant women are estimated from animal data. The present communication offers a revision of fetal dosimetry values calculated from recently published human data, in which fetal 18F-FDG uptake was directly observed in vivo. The final doses were obtained from the observed time-integrated activity coefficients and a new generation of anthropomorphic voxel-based pregnancy phantoms.

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib.

Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Here we prepare both 11C- and 18F-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep 11C-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability.

Radiation dose and risks to fetus from nuclear medicine procedures.

This article discusses issues regarding administration of radiopharmaceuticals to pregnant women. Standardized dose estimates and possible biological effects on the unborn child are presented. Current and future mathematical models (phantoms) are discussed. Standardized dose estimates for pregnant women at several stages of gestation based on the current generation of phantoms are given. Issues related to administration of radioiodines, particularly 131I-NaI, are presented. Iodine concentrates in the fetal thyroid and therefore can give very high doses, even resulting in complete destruction of the fetal thyroid. Strategies for preventing unwanted administrations of radiopharmaceuticals to these patients, and for strategies for mitigating radiation doses, should an unwanted administration occur, are discussed.

Realistic phantoms to characterize dosimetry in pediatric CT.

BACKGROUND: The estimation of organ doses and effective doses for children receiving CT examinations is of high interest. Newer, more realistic anthropomorphic body models can provide information on individual organ doses and improved estimates of effective dose. MATERIALS AND METHODS: Previously developed body models representing 50th-percentile individuals at reference ages (newborn, 1, 5, 10 and 15 years) were modified to represent 10th, 25th, 75th and 90th height percentiles for both genders and an expanded range of ages (3, 8 and 13 years). We calculated doses for 80 pediatric reference phantoms from simulated chest-abdomen-pelvis exams on a model of a Philips Brilliance 64 CT scanner. Individual organ and effective doses were normalized to dose-length product (DLP) and fit as a function of body diameter. RESULTS: We calculated organ and effective doses for 80 reference phantoms and plotted them against body diameter. The data were well fit with an exponential function. We found DLP-normalized organ dose to correlate strongly with body diameter (R2>0.95 for most organs). Similarly, we found a very strong correlation with body diameter for DLP-normalized effective dose (R2>0.99). Our results were compared to other studies and we found average agreement of approximately 10%. CONCLUSION: We provide organ and effective doses for a total of 80 reference phantoms representing normal-stature children ranging in age and body size. This information will be valuable in replacing the types of vendor-reported doses available. These data will also permit the recording and tracking of individual patient doses. Moreover, this comprehensive dose database will facilitate patient matching and the ability to predict patient-individualized dose prior to examination.

New Fetal Dose Estimates from 18F-FDG Administered During Pregnancy: Standardization of Dose Calculations and Estimations with Voxel-Based Anthropomorphic Phantoms.

Data from the literature show that the fetal absorbed dose from 18F-FDG administration to the pregnant mother ranges from 0.5E-2 to 4E-2 mGy/MBq. These figures were, however, obtained using different quantification techniques and with basic geometric anthropomorphic phantoms. The aim of this study was to refine the fetal dose estimates of published as well as new cases using realistic voxel-based phantoms. METHODS: The 18F-FDG doses to the fetus (n = 19; 5-34 wk of pregnancy) were calculated with new voxel-based anthropomorphic phantoms of the pregnant woman. The image-derived fetal time-integrated activity values were combined with those of the mothers' organs from the International Commission on Radiological Protection publication 106 and the dynamic bladder model with a 1-h bladder-voiding interval. The dose to the uterus was used as a proxy for early pregnancy (up to 10 wk). The time-integrated activities were entered into OLINDA/EXM 1.1 to derive the dose with the classic anthropomorphic phantoms of pregnant women, then into OLINDA/EXM 2.0 to assess the dose using new voxel-based phantoms. RESULTS: The average fetal doses (mGy/MBq) with OLINDA/EXM 2.0 were 2.5E-02 in early pregnancy, 1.3E-02 in the late part of the first trimester, 8.5E-03 in the second trimester, and 5.1E-03 in the third trimester. The differences compared with the doses calculated with OLINDA/EXM 1.1 were +7%, +70%, +35%, and -8%, respectively. CONCLUSION: Except in late pregnancy, the doses estimated with realistic voxelwise anthropomorphic phantoms are higher than the doses derived from old geometric phantoms. The doses remain, however, well below the threshold for any deterministic effects. Thus, pregnancy is not an absolute contraindication of a clinically justified 18F-FDG PET scan.

[(124)I]FIAU: Human dosimetry and infection imaging in patients with suspected prosthetic joint infection.

INTRODUCTION: Fialuridine (FIAU) is a nucleoside analog that is a substrate for bacterial thymidine kinase (TK). Once phosphorylated by TK, [(124)I]FIAU becomes trapped within bacteria and can be detected with positron emission tomography/computed tomography (PET/CT). [(124)I]FIAU PET/CT has been shown to detect bacteria in patients with musculoskeletal bacterial infections. Accurate diagnosis of prosthetic joint infections (PJIs) has proven challenging because of the lack of a well-validated reference. In the current study, we assessed biodistribution and dosimetry of [(124)I]FIAU, and investigated whether [(124)I]FIAU PET/CT can diagnose PJIs with acceptable accuracy. METHODS: To assess biodistribution and dosimetry, six subjects with suspected hip or knee PJI and six healthy subjects underwent serial PET/CT after being dosed with 74MBq (2mCi) [(124)I]FIAU intravenously (IV). Estimated radiation doses were calculated with the OLINDA/EXM software. To determine accuracy of [(124)I]FIAU, 22 subjects with suspected hip or knee PJI were scanned at 2-6 and 24-30h post IV injection of 185MBq (5mCi) [(124)I]FIAU. Images were interpreted by a single reader blinded to clinical information. Representative cases were reviewed by 3 additional readers. The utility of [(124)I]FIAU to detect PJIs was assessed based on the correlation of the patient's infection status with imaging results as determined by an independent adjudication board (IAB). RESULTS: The kidney, liver, spleen, and urinary bladder received the highest radiation doses of [(124)I]FIAU. The effective dose was 0.16 to 0.20mSv/MBq and doses to most organs ranged from 0.11 to 0.76mGy/MBq. PET image quality obtained from PJI patients was confounded by metal artifacts from the prostheses and pronounced FIAU uptake in muscle. Consequently, a correlation with infection status and imaging results could not be established. CONCLUSIONS: [(124)I]FIAU was well-tolerated in healthy volunteers and subjects with suspected PJI, and had acceptable dosimetry. However, the utility of [(124)I]FIAU for the clinical detection of PJIs is limited by poor image quality and low specificity.