Development of a classifier for [18F]fluorodeoxyglucose extravasation severity using semi-quantitative readings from topically applied detectors.

BACKGROUND: Radiotracer extravasations, caused largely by faulty tracer injections, can occur in up to 23% of 18F-fluorodeoxyglucose (FDG) PET/CT scans and negatively impact radiological review and tracer quantification. Conventional radiological assessment of extravasation severity on PET has limited performance (e.g., extravasations frequently resolve before scanning) and practical drawbacks. In this study, we develop a new topical detector-based FDG extravasation severity classifier, calibrated from semi-quantitative PET measurements, and assess its performance on human subjects. METHODS: A retrospective study examined patients whose FDG injections had been monitored as part of their standard workup for PET/CT imaging. Topical uncollimated gamma ray detectors were applied proximal to the injection site and on the same location on the opposing arm, and readings were acquired continuously during radiotracer uptake. Patients were imaged with their arms in the PET field of view and total extravasation activity quantified from static PET images through a volume of interest approach. The image-derived activities were considered ground truth and used to calibrate and assess quantification of topical detector readings extrapolated to the start of PET imaging. The classifier utilizes the calibrated detector readings to produce four extravasation severity classes: none, minor, moderate, and severe. In a blinded study, a radiologist qualitatively labeled PET images for extravasation severity using the same classifications. The radiologist's interpretations and topical detector classifications were compared to the ground truth PET results. RESULTS: Linear regression of log-transformed image-derived versus topical detector tracer extravasation activity estimates showed a strong correlation (R2 = 0.75). A total of 24 subject scans were cross-validated with the quantitatively based classifier through a leave-one-out methodology. For binary classification (none vs. extravasated), the topical detector classifier had the highest overall diagnostic performance for identifying extravasations. Specificity, sensitivity, accuracy, and positive predictive value were 100.0%, 80.0%, 95.8%, and 100.0%, respectively, for the topical detector classifier and 31.6%, 100.0%, 45.8%, and 27.8%, respectively, for the radiological analysis. The topical detector classifier, with an optimal detection threshold, produced a significantly higher Matthews correlation coefficient (MCC) than the radiological analysis (0.87 vs. 0.30). CONCLUSIONS: The topical detector binary classifier, calibrated using quantitative static PET measurements, significantly improves extravasation detection compared to qualitative image analysis.

Prostate-Specific Membrane Antigen as Target for Neuroimaging of Central Nervous System Tumors.

Introduction: Positron emission tomography (PET) imaging with prostate-specific membrane antigen- (PSMA-) binding tracers has been found incidentally to demonstrate uptake in CNS tumors. Following the encouraging findings of several such case reports, there is a growing interest in the potential application of PSMA-targeted PET imaging for diagnostics, theranostics, and monitoring of CNS tumors. This is a systematic literature review on PSMA-binding tracers in CNS tumors. Methods: A PubMed search was conducted, including preclinical and clinical reports. One hundred and twelve records were identified, and after screening, 56 were included in the final report. Results: Tissue studies demonstrated PSMA expression in tumor vascular endothelial cells, without expression in normal brain tissue, though the extent and intensity of staining varied by anti-PSMA antibody and methodology. Most included studies reported on gliomas, which showed strong PSMA ligand uptake and more favorable tumor to background ratios than other PET tracers. There are also case reports demonstrating PSMA ligand uptake in prostate cancer brain metastases, nonprostate cancer brain metastases, and meningiomas. We also review the properties of the various PSMA-binding radiotracers available. Therapeutic and theranostic applications of PSMA-binding tracers have been studied, including labeled alpha- and beta-ray emitting isotopes, as well as PSMA targeting in directing MRI-guided focused ultrasound. Conclusions: There is a potential application for PSMA-targeted PET in neuro-oncology as a combination of diagnostic and therapeutic use, as a theranostic modality for managing CNS tumors. Further research is needed regarding the mechanism(s) of PSMA expression in CNS tumors and its differential performance by tumor type.

Detection of Excess Presence of 99m Tc-MDP Near Injection Site-A Case Report.

Nuclear medicine extravasations and prolonged venous stasis may cause poor quality and quantification errors that can affect image interpretation and patient management. Radiopharmaceutical remaining near the administration site means that some portion of the radioactivity is not circulating as required for the prescribed uptake period. This case describes how detection of excess presence of 99mTc-MDP near the injection site enabled the technologist to apply mitigation tactics early in the uptake process. It also suggests that detecting an extravasation or stasis early in the injection process can be important for image interpretation and minimizing radiation dose to tissue.

The Scientific and Clinical Case for Reviewing Diagnostic Radiopharmaceutical Extravasation Long-Standing Assumptions.

Background: The patient benefit from a diagnostic nuclear medicine procedure far outweighs the associated radiation risk. This benefit/risk ratio assumes a properly administered radiopharmaceutical. However, a significant diagnostic radiopharmaceutical extravasation can confound the procedure in many ways. We identified three current extravasation hypotheses espoused by medical societies, advisory committees, and hundreds of individual members of the nuclear medicine community: diagnostic extravasations do not cause harm, do not result in high absorbed dose to tissue, and require complex dosimetry methods that are not readily available in nuclear medicine centers. We tested these hypotheses against a framework of current knowledge, recent developments, and original research. We conducted a literature review, searched regulatory databases, examined five clinical cases of extravasated patients, and performed dosimetry on those extravasations to test these globally accepted hypotheses. Results: A literature review found 58 peer-reviewed documents suggesting patient harm. Adverse event/vigilance report database reviews for extravasations were conducted and revealed 38 adverse events which listed diagnostic radiopharmaceutical extravasation as a factor, despite a regulatory exemption for required reporting. In our own case material, assessment of care was evaluated for five extravasated patients who underwent repeat imaging. Findings reflected results of literature review and included mis- or non-identification of lesions, underestimation of Standardized Uptake Values (SUVs) by 19-73%, classification of scans as non-diagnostic, and the need to repeat imaging with the associated additional radiation exposure, inconvenience, or delays in care. Dosimetry was performed for the same five cases of diagnostic radiopharmaceutical extravasation. Absorbed doses to 5 cm3 of tissue were between 1.1 and 8.7 Gy, and shallow dose equivalent for 10 cm2 of skin was as high as 4.2 Sv. Conclusions: Our findings suggest that significant extravasations can or have caused patient harm and can irradiate patients' tissue with doses that exceed medical event reporting limits and deterministic effect thresholds. Therefore, diagnostic radiopharmaceutical injections should be monitored, and dosimetry of extravasated tissue should be performed in certain cases where thresholds are thought to have been exceeded. Process improvement efforts should be implemented to reduce the frequency of extravasation in nuclear medicine.

Comparison of maximum likelihood and conventional PET scatter scaling methods for 18 F-FDG and 68 Ga-DOTATATE PET/CT.

PURPOSE: We aim to quantify differences between a new maximum likelihood (ML) background scaling (MLBS) algorithm and two conventional scatter scaling methods for clinical PET/CT. A common source of reduced image quantification with conventional scatter corrections is attributed to erroneous scaling of the initial scatter estimate to match acquired scattered events in the sinogram. MLBS may have performance advantages over conventional methods by using all available data intersecting the subject. METHODS: A retrospective analysis was performed on subjects injected with 18 F-FDG (N = 71) and 68 Ga-DOTATATE (N = 11) and imaged using time-of-flight (TOF) PET/CT. The scatter distribution was estimated with single scatter simulation approaches. Conventional scaling algorithms included (a) tail fitted background scaling (TFBS), which scales the scatter to "tails" outside the emission support, and (b) absolute scatter correction (ABS), which utilizes the simulated scatter distribution with no scaling applied. MLBS consisted of an alternating iterative reconstruction with a TOF-based ML activity image update allowing negative values (NEG-ML) and nested loop ML scatter scaling estimation. Scatter corrections were compared using reconstructed images as follows: (a) normalized relative difference images were generated and used for voxel-wise analysis, (b) liver and suspected lesion ROIs were drawn to compute mean SUVs, and (c) a qualitative analysis of overall diagnostic image quality, impact of artifacts, and lesion conspicuity was performed. Absolute quantification and normalized relative differences were also assessed with an 18 F-FDG phantom study. RESULTS: For human subjects 18 F-FDG data, Bland-Altman plots demonstrated that the largest normalized voxel-wise differences were observed close to the lower limit (SUV = 1.0). MLBS reconstructions trended towards higher scatter fractions compared to TFBS and ABS images, with median voxel differences across all subjects for TFBS-MLBS measured at 1.7% and 7.6% for 18 F-FDG and 68 Ga-DOTATATE, respectively. For mean SUV analysis, there was a high degree of correlation between the scatter corrections. For 18 F-FDG, ABS scatter correction reconstructions trended towards higher liver mean SUVs relative to MLBS. The qualitative image analysis revealed no significant differences between TFBS and MLBS image reconstructions. For a uniformly filled relatively large 37 cm diameter phantom, MLBS produced the lowest bias in absolute quantification, while normalized voxel-wise differences showed a trend in scatter correction performance consistent with the human subjects study. CONCLUSIONS: For 18 F-FDG, MLBS is at least a valid substitute to TFBS, providing reconstructed image performance comparable to TFBS in most subjects but exhibiting quantitative differences in cases where TFBS is typically prone to inaccuracies (e.g., due to patient motion and CT-based attenuation map truncation). Particularly for low contrast regions, quantification differs for ABS compared to MLBS and TFBS, and caution should be taken when utilizing ABS for decision-making based on quantitative metrics.

Patient-specific Extravasation Dosimetry Using Uptake Probe Measurements.

ABSTRACT: Extravasation is a common problem in radiopharmaceutical administration and can result in significant radiation dose to underlying tissue and skin. The resulting radiation effects are rarely studied and should be more fully evaluated to guide patient care and meet regulatory obligations. The purpose of this work was to show that a dedicated radiopharmaceutical injection monitoring system can help clinicians characterize extravasations for calculating tissue and skin doses. We employed a commercially available radiopharmaceutical injection monitoring system to identify suspected extravasation of 18F-fluorodeoxyglucose and 99mTc-methylene diphosphonate in 26 patients and to characterize their rates of biological clearance. We calculated the self-dose to infiltrated tissue using Monte Carlo simulation and standard MIRD dosimetry methods, and we used VARSKIN software to calculate the shallow dose equivalent to the epithelial basal-cell layer of overlying skin. For 26 patients, injection-site count rate data were used to characterize extravasation clearance. For each, the absorbed dose was calculated using representative tissue geometries. Resulting tissue-absorbed doses ranged from 0.6 to 11.2 Gy, and the shallow dose equivalent to a 10 cm2 area of adjacent skin in these patients ranged from about 0.1 to 5.4 Sv. Extravasated injections of radiopharmaceuticals can result in unintentional doses that exceed well-established radiation protection and regulatory limits; they should be identified and characterized. An external injection monitoring system may help to promptly identify and characterize extravasations and improve dosimetry calculations. Patient-specific characterization can help clinicians determine extravasation severity and whether the patient should be followed for adverse tissue reactions that may present later in time.

Assessing and Reducing Positron Emission Tomography/Computed Tomography Radiotracer Infiltrations: Lessons in Quality Improvement and Sustainability.

PURPOSE: Accurate administration of radiotracer dose is essential to positron emission tomography (PET) image quality and quantification. Misadministration (infiltration) of the dose can affect PET/computed tomography results and lead to unnecessary or inappropriate treatments and procedures. Quality control efforts ensure accuracy of the administered dose; however, they fail to ensure complete delivery of the dose into the patient's circulation. We used new technology to assess and improve infiltration rates and evaluate sustainability. METHODS: Injection quality was measured, improved, and sustained during our participation in a multicenter quality improvement project using Define, Measure, Analyze, Improve, Control methodology. Five technologists monitored injection quality in the Measure and Improve phases. After seven new technologists joined the team in the Control phase, infiltration rates were recalculated, controlling for technologist- and patient-level correlations, and comparisons were made between these two groups of technologists. RESULTS: In the Measure phase, five technologists monitored 263 injections (13.3% infiltration rate). Nonantecubital fossa injections had a higher probability of infiltration than antecubital fossa injections. After implementing a quality improvement plan (QIP), the same technologists monitored 278 injections in the Improve phase (2.9% infiltration rate). The 78% decrease in infiltration rate was significant (P < .001) as was the decrease in nonantecubital fossa infiltrations (P = .0025). In the Control phase, 12 technologists monitored 1,240 injections (3.1% infiltration rate). The seven new technologists had significantly higher rates of infiltration (P = .017). CONCLUSION: A QIP can significantly improve and sustain injection quality; however, ongoing monitoring is needed as new technologists join the team.

Quality Improvement Initiatives to Assess and Improve PET/CT Injection Infiltration Rates at Multiple Centers.

PET/CT radiotracer infiltration is not uncommon and is often outside the imaging field of view. Infiltration can negatively affect image quality, image quantification, and patient management. Until recently, there has not been a simple way to routinely practice PET radiopharmaceutical administration quality control and quality assurance. Our objectives were to quantify infiltration rates, determine associative factors for infiltration, and assess whether rates could be reduced at multiple centers and then sustained. Methods: A "design, measure, analyze, improve, and control" quality improvement methodology requiring novel technology was used to try to improve PET/CT injection quality. Teams were educated on the importance of quality injections. Baseline infiltration rates were measured, center-specific associative factors were analyzed, team meetings were held, improvement plans were established and executed, and rates remeasured. To ensure that injection-quality gains were retained, real-time feedback and ongoing monitoring were used. Sustainability was assessed. Results: Seven centers and 56 technologists provided data on 5,541 injections. The centers' aggregated baseline infiltration rate was 6.2% (range, 2%-16%). On the basis of their specific associative factors, 4 centers developed improvement plans and reduced their aggregated infiltration rate from 8.9% to 4.6% (P < 0.0001). Ongoing injection monitoring showed sustainability. Significant variation was found in center- and technologist-level infiltration rates (P < 0.0001 and P = 0.0020, respectively). Conclusion: A quality improvement approach with new technology can help centers measure infiltration rates, determine associative factors, implement interventions, and improve and sustain injection quality. Because PET/CT images help guide patient management, the monitoring and improvement of radiotracer injection quality are important.

Impact of an 18F-FDG PET/CT Radiotracer Injection Infiltration on Patient Management-A Case Report.

Major management decisions in patients with solid tumors and lymphomas are often based on 18F-fluorodeoxyglucose (18F-FDG) PET/CT. The misadministration of 18F-FDG outside the systemic circulation can have an adverse impact on this test's sensitivity (1) and is not uncommon (2-7). This report describes how an 18F-FDG misadministration led to a repeat PET/CT study, resulting in the visualization of distant metastases that changed the original treatment plan. The findings suggest that routine injection monitoring is indicated whenever sensitivity is critical, and support claims that infiltrations can confound interpretation of semi-quantitative PET outcome measures in patients who are followed longitudinally (2).