Dosimetry of a Novel 111Indium-Labeled Anti-P-Cadherin Monoclonal Antibody (FF-21101) in Non-Human Primates.

P-cadherin is associated with a wide range of tumor types, making it an attractive therapeutic target. FF-21101 is a human-mouse chimeric monoclonal antibody (mAb) directed against human P-cadherin, which has been radioconjugated with indium-111 (111In) utilizing a DOTA chelator. We investigated the biodistribution of FF-21101(111In) in cynomolgus macaques and extrapolated the results to estimate internal radiation doses of 111In- and yttrium-90 (90Y)-FF-21101 for targeted radioimmunotherapy in humans. Whole-body planar and SPECT imaging were performed at 0, 2, 24, 48, 72, 96, and 120 h post-injection, using a dual-head gamma camera. Volumes of interest of identifiable source organs of radioactivity were defined on aligned reference CT and serial SPECT images. Organs with the highest estimated dose values (mSv/MBq) for FF-21101(111In) were the lungs (0.840), spleen (0.816), liver (0.751), kidneys (0.629), and heart wall (0.451); and for FF-21101(90Y) dose values were: lungs (10.49), spleen (8.21), kidneys (5.92), liver (5.46), and heart wall (2.61). FF-21101(111In) exhibits favorable biodistribution in cynomolgus macaques and estimated human dosimetric characteristics. Data obtained in this study were used to support the filing of an investigational new drug application with the FDA for a Phase I clinical trial.

Sequential Targeting of Retinoblastoma and DNA Synthesis Pathways Is a Therapeutic Strategy for Sarcomas That Can Be Monitored in Real Time.

Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell-cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1,043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective two-step sequential combination strategy was developed. Abemaciclib was used first to prime Rb-positive sarcoma cells to reversibly arrest in G1 phase. Upon drug removal, cells synchronously traversed to S phase, where a second treatment with S-phase targeted agents (gemcitabine or Wee1 kinase inhibitor) mediated a synergistic response by inducing DNA damage. The response to treatment could be noninvasively monitored using real-time positron emission tomography imaging and serum thymidine kinase activity. Collectively, these results show that a novel, sequential treatment strategy with a CDK4/6 inhibitor followed by a DNA-damaging agent was effective, resulting in synergistic tumor cell killing. This approach can be readily translated into a clinical trial with noninvasive functional imaging and serum biomarkers as indicators of response and cell cycling. SIGNIFICANCE: An innovative sequential therapeutic strategy targeting Rb, followed by treatment with agents that perturb DNA synthesis pathways, results in synergistic killing of Rb-positive sarcomas that can be noninvasively monitored.

The potential of biology-guided radiation therapy in thoracic cancer: A preliminary treatment planning study.

Purpose: We investigated the feasibility of biology-guided radiotherapy (BgRT), a technique that utilizes real-time positron emission imaging to minimize tumor motion uncertainties, to spare nearby organs at risk. Methods: Volumetric modulated arc therapy (VMAT), intensity-modulated proton (IMPT) therapy, and BgRT plans were created for a paratracheal node recurrence (case 1; 60 Gy in 10 fractions) and a primary peripheral left upper lobe adenocarcinoma (case 2; 50 Gy in four fractions). Results: For case 1, BgRT produced lower bronchus V40 values compared to VMAT and IMPT. For case 2, total lung V20 was lower in the BgRT case compared to VMAT and IMPT. Conclusions: BgRT has the potential to reduce the radiation dose to proximal critical structures but requires further detailed investigation.

Impact of low injected activity on data driven respiratory gating for PET/CT imaging with continuous bed motion.

Data driven respiratory gating (DDG) in positron emission tomography (PET) imaging extracts respiratory waveforms from the acquired PET data obviating the need for dedicated external devices. DDG performance, however, degrades with decreasing detected number of coincidence counts. In this paper, we assess the clinical impact of reducing injected activity on a new DDG algorithm designed for PET data acquired with continuous bed motion (CBM_DDG) by evaluating CBM_DDG waveforms, tumor quantification, and physician's perception of motion blur in resultant images. Forty patients were imaged on a Siemens mCT scanner in CBM mode. Reduced injected activity was simulated by generating list mode datasets with 50% and 25% of the original data (100%). CBM_DDG waveforms were compared to that of the original data over the range between the aortic arch and the center of the right kidney using the Pearson correlation coefficient (PCC). Tumor quantification was assessed by comparing the maximum standardized uptake value (SUVmax) and peak SUV (SUVpeak) of reconstructed images from the various list mode datasets using elastic motion deblurring (EMDB) reconstruction. Perceived motion blur was assessed by three radiologists of one lesion per patient on a continuous scale from no motion blur (0) to significant motion blur (3). The mean PCC of the 50% and 25% dataset waveforms was 0.74 ± 0.18 and 0.59 ± 0.25, respectively. In comparison to the 100% datasets, the mean SUVmax increased by 2.25% (p = 0.11) for the 50% datasets and by 3.91% (p = 0.16) for the 25% datasets, while SUVpeak changes were within ±0.25%. Radiologist evaluations of motion blur showed negligible changes with average values of 0.21, 0.3, and 0.28 for the 100%, 50%, and 25% datasets. Decreased injected activities degrades the resultant CBM_DDG respiratory waveforms; however this decrease has minimal impact on quantification and perceived image motion blur.

Delayed FDG PET Provides Superior Glioblastoma Conspicuity Compared to Conventional Image Timing.

Background: Glioblastomas are malignant, often incurable brain tumors. Reliable discrimination between recurrent disease and treatment changes is a significant challenge. Prior work has suggested glioblastoma FDG PET conspicuity is improved at delayed time points vs. conventional imaging times. This study aimed to determine the ideal FDG imaging time point in a population of untreated glioblastomas in preparation for future trials involving the non-invasive assessment of true progression vs. pseudoprogression in glioblastoma. Methods: Sixteen pre-treatment adults with suspected glioblastoma received FDG PET at 1, 5, and 8 h post-FDG injection within the 3 days prior to surgery. Maximum standard uptake values were measured at each timepoint for the central enhancing component of the lesion and the contralateral normal-appearing brain. Results: Sixteen patients (nine male) had pathology confirmed IDH-wildtype, glioblastoma. Our results revealed statistically significant improvements in the maximum standardized uptake values and subjective conspicuity of glioblastomas at later time points compared to the conventional (1 h time point). The tumor to background ratio at 1, 5, and 8 h was 1.4 ± 0.4, 1.8 ± 0.5, and 2.1 ± 0.6, respectively. This was statistically significant for the 5 h time point over the 1 h time point (p > 0.001), the 8 h time point over the 1 h time point (p = 0.026), and the 8 h time point over the 5 h time point (p = 0.036). Conclusions: Our findings demonstrate that delayed imaging time point provides superior conspicuity of glioblastoma compared to conventional imaging. Further research based on these results may translate into improvements in the determination of true progression from pseudoprogression.

Phase I Study of P-cadherin-targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors.

PURPOSE: 90Y-FF-21101 is an Yttrium-90-conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. PATIENTS AND METHODS: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5-25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. RESULTS: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. CONCLUSIONS: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.

What scans we will read: imaging instrumentation trends in clinical oncology.

Oncological diseases account for a significant portion of the burden on public healthcare systems with associated costs driven primarily by complex and long-lasting therapies. Through the visualization of patient-specific morphology and functional-molecular pathways, cancerous tissue can be detected and characterized non-invasively, so as to provide referring oncologists with essential information to support therapy management decisions. Following the onset of stand-alone anatomical and functional imaging, we witness a push towards integrating molecular image information through various methods, including anato-metabolic imaging (e.g., PET/CT), advanced MRI, optical or ultrasound imaging.This perspective paper highlights a number of key technological and methodological advances in imaging instrumentation related to anatomical, functional, molecular medicine and hybrid imaging, that is understood as the hardware-based combination of complementary anatomical and molecular imaging. These include novel detector technologies for ionizing radiation used in CT and nuclear medicine imaging, and novel system developments in MRI and optical as well as opto-acoustic imaging. We will also highlight new data processing methods for improved non-invasive tissue characterization. Following a general introduction to the role of imaging in oncology patient management we introduce imaging methods with well-defined clinical applications and potential for clinical translation. For each modality, we report first on the status quo and, then point to perceived technological and methodological advances in a subsequent status go section. Considering the breadth and dynamics of these developments, this perspective ends with a critical reflection on where the authors, with the majority of them being imaging experts with a background in physics and engineering, believe imaging methods will be in a few years from now.Overall, methodological and technological medical imaging advances are geared towards increased image contrast, the derivation of reproducible quantitative parameters, an increase in volume sensitivity and a reduction in overall examination time. To ensure full translation to the clinic, this progress in technologies and instrumentation is complemented by advances in relevant acquisition and image-processing protocols and improved data analysis. To this end, we should accept diagnostic images as "data", and - through the wider adoption of advanced analysis, including machine learning approaches and a "big data" concept - move to the next stage of non-invasive tumour phenotyping. The scans we will be reading in 10 years from now will likely be composed of highly diverse multi-dimensional data from multiple sources, which mandate the use of advanced and interactive visualization and analysis platforms powered by Artificial Intelligence (AI) for real-time data handling by cross-specialty clinical experts with a domain knowledge that will need to go beyond that of plain imaging.

Improved Alignment of PET and CT Images in Whole-Body PET/CT in Cases of Respiratory Motion During CT.

Respiratory motion during the CT and PET parts of a PET/CT scan leads to imperfect alignment of anatomic features seen by the 2 modalities. In this work, we concentrate on the effects of motion during CT. We propose a novel approach for improving the alignment. Methods: Respiratory waveform data were gathered during the CT and PET parts of 28 PET/CT scans of cancer patients with 40 lesions up to 3 cm in size in the lung or upper abdomen. PET list-mode data were reconstructed by 3 reconstruction methods: PET/static (the standard method with no motion correction); PET/ex (a method that calculates a range of expiratory amplitudes from the lowest one to the highest one); and PET/matched (a novel method that uses both waveforms). The 3 methods were compared. The distance between tumor positions in PET and CT were characterized in visual interpretation by physicians as well as quantitatively. Tumor SUVs (SUVmax and SUVpeak) were determined relative to SUV based on the static method. Image noise was evaluated in the liver and compared with PET/static. Results: In visual interpretation, the rate of good alignment was 13 of 21, 13 of 23, and 18 of 21 for the PET/static, PET/ex, and PET/matched methods, respectively, and the mean PET/CT distances were 3.5, 5.1, and 2.8 mm. In visual comparison with PET/ex, the rate of good alignment was increased in 1 of 10 and 7 of 10 cases for PET/static and PET/matched, respectively. SUVmax was on average 21% higher than PET/static when either PET/ex or PET/matched was used. SUVpeak was 12% higher. Image noise in the liver was 15% higher than PET/static for the PET/ex method, and 40% higher for PET/matched; that is, noise was much lower than in gated PET. Conclusion: Acquiring respiratory waveforms both in PET (as in the current state of the art) and in CT (an unusual key step in this approach) has the potential to improve the alignment of PET and CT images. A proposed method for using this information was tested. Improved alignment was demonstrated.

Characterization of continuous bed motion effects on patient breathing and respiratory motion correction in PET/CT imaging.

Continuous bed motion (CBM) was recently introduced as an alternative to step-and-shoot (SS) mode for PET/CT data acquisition. In CBM, the patient is continuously advanced into the scanner at a preset speed, whereas in SS, the patient is imaged in overlapping bed positions. Previous investigations have shown that patients preferred CBM over SS for PET data acquisition. In this study, we investigated the effect of CBM versus SS on patient breathing and respiratory motion correction. One hundred patients referred for PET/CT were scanned using a Siemens mCT scanner. Patient respiratory waveforms were recorded using an Anzai system and analyzed using four methods: Methods 1 and 2 measured the coefficient of variation (COV) of the respiratory cycle duration (RCD) and amplitude (RCA). Method 3 measured the respiratory frequency signal prominence (RSP) and method 4 measured the width of the HDChest optimal gate (OG) window when using a 35% duty cycle. Waveform analysis was performed over the abdominothoracic region which exhibited the greatest respiratory motion and the results were compared between CBM and SS. Respiratory motion correction was assessed by comparing the ratios of SUVmax, SUVpeak, and CNR of focal FDG uptake, as well as Radiologists' visual assessment of corresponding image quality of motion corrected and uncorrected images for both acquisition modes. The respiratory waveforms analysis showed that the RCD and RCA COV were 3.7% and 33.3% lower for CBM compared to SS, respectively, while the RSP and OG were 30.5% and 2.0% higher, respectively. Image analysis on the other hand showed that SUVmax, SUVpeak, and CNR were 8.5%, 4.5%, and 3.4% higher for SS compared to CBM, respectively, while the Radiologists' visual comparison showed similar image quality between acquisition modes. However, none of the results showed statistically significant differences between SS and CBM, suggesting that motion correction is not impacted by acquisition mode.

Mechanism-Specific Pharmacodynamics of a Novel Complex-I Inhibitor Quantified by Imaging Reversal of Consumptive Hypoxia with [18F]FAZA PET In Vivo.

Tumors lack a well-regulated vascular supply of O2 and often fail to balance O2 supply and demand. Net O2 tension within many tumors may not only depend on O2 delivery but also depend strongly on O2 demand. Thus, tumor O2 consumption rates may influence tumor hypoxia up to true anoxia. Recent reports have shown that many human tumors in vivo depend primarily on oxidative phosphorylation (OxPhos), not glycolysis, for energy generation, providing a driver for consumptive hypoxia and an exploitable vulnerability. In this regard, IACS-010759 is a novel high affinity inhibitor of OxPhos targeting mitochondrial complex-I that has recently completed a Phase-I clinical trial in leukemia. However, in solid tumors, the effective translation of OxPhos inhibitors requires methods to monitor pharmacodynamics in vivo. Herein, 18F-fluoroazomycin arabinoside ([18F]FAZA), a 2-nitroimidazole-based hypoxia PET imaging agent, was combined with a rigorous test-retest imaging method for non-invasive quantification of the reversal of consumptive hypoxia in vivo as a mechanism-specific pharmacodynamic (PD) biomarker of target engagement for IACS-010759. Neither cell death nor loss of perfusion could account for the IACS-010759-induced decrease in [18F]FAZA retention. Notably, in an OxPhos-reliant melanoma tumor, a titration curve using [18F]FAZA PET retention in vivo yielded an IC50 for IACS-010759 (1.4 mg/kg) equivalent to analysis ex vivo. Pilot [18F]FAZA PET scans of a patient with grade IV glioblastoma yielded highly reproducible, high-contrast images of hypoxia in vivo as validated by CA-IX and GLUT-1 IHC ex vivo. Thus, [18F]FAZA PET imaging provided direct evidence for the presence of consumptive hypoxia in vivo, the capacity for targeted reversal of consumptive hypoxia through the inhibition of OxPhos, and a highly-coupled mechanism-specific PD biomarker ready for translation.

Effects of alterations in positron emission tomography imaging parameters on radiomics features.

Radiomics studies require large patient cohorts, which often include patients imaged using different imaging protocols. We aimed to determine the impact of variability in imaging protocol parameters and interscanner variability using a phantom that produced feature values similar to those of patients. Positron emission tomography (PET) scans of a Hoffman brain phantom were acquired on GE Discovery 710, Siemens mCT, and Philips Vereos scanners. A standard-protocol scan was acquired on each machine, and then each parameter that could be changed was altered individually. The phantom was contoured with 10 regions of interest (ROIs). Values for 45 features with 2 different preprocessing techniques were extracted for each image. To determine the impact of each parameter on the reliability of each radiomics feature, the intraclass correlation coefficient (ICC) was calculated with the ROIs as the subjects and the parameter values as the raters. For interscanner comparisons, we compared the standard deviation of each radiomics feature value from the standard-protocol images to the standard deviation of the same radiomics feature from PET scans of 224 patients with non-small cell lung cancer. When the pixel size was resampled prior to feature extraction, all features had good reliability (ICC > 0.75) for the field of view and matrix size. The time per bed position had excellent reliability (ICC > 0.9) on all features. When the filter cutoff was restricted to values below 6 mm, all features had good reliability. Similarly, when subsets and iterations were restricted to reasonable values used in clinics, almost all features had good reliability. The average ratio of the standard deviation of features on the phantom scans to that of the NSCLC patient scans was 0.73 using fixed-bin-width preprocessing and 0.92 using 64-level preprocessing. Most radiomics feature values had at least good reliability when imaging protocol parameters were within clinically used ranges. However, interscanner variability was about equal to interpatient variability; therefore, caution must be used when combining patients scanned on equipment from different vendors in radiomics data sets.

Radiomics features of the primary tumor fail to improve prediction of overall survival in large cohorts of CT- and PET-imaged head and neck cancer patients.

Radiomics studies require many patients in order to power them, thus patients are often combined from different institutions and using different imaging protocols. Various studies have shown that imaging protocols affect radiomics feature values. We examined whether using data from cohorts with controlled imaging protocols improved patient outcome models. We retrospectively reviewed 726 CT and 686 PET images from head and neck cancer patients, who were divided into training or independent testing cohorts. For each patient, radiomics features with different preprocessing were calculated and two clinical variables-HPV status and tumor volume-were also included. A Cox proportional hazards model was built on the training data by using bootstrapped Lasso regression to predict overall survival. The effect of controlled imaging protocols on model performance was evaluated by subsetting the original training and independent testing cohorts to include only patients whose images were obtained using the same imaging protocol and vendor. Tumor volume, HPV status, and two radiomics covariates were selected for the CT model, resulting in an AUC of 0.72. However, volume alone produced a higher AUC, whereas adding radiomics features reduced the AUC. HPV status and one radiomics feature were selected as covariates for the PET model, resulting in an AUC of 0.59, but neither covariate was significantly associated with survival. Limiting the training and independent testing to patients with the same imaging protocol reduced the AUC for CT patients to 0.55, and no covariates were selected for PET patients. Radiomics features were not consistently associated with survival in CT or PET images of head and neck patients, even within patients with the same imaging protocol.

Task Group 174 Report: Utilization of [18 F]Fluorodeoxyglucose Positron Emission Tomography ([18 F]FDG-PET) in Radiation Therapy.

The use of positron emission tomography (PET) in radiation therapy (RT) is rapidly increasing in the areas of staging, segmentation, treatment planning, and response assessment. The most common radiotracer is 18 F-fluorodeoxyglucose ([18 F]FDG), a glucose analog with demonstrated efficacy in cancer diagnosis and staging. However, diagnosis and RT planning are different endeavors with unique requirements, and very little literature is available for guiding physicists and clinicians in the utilization of [18 F]FDG-PET in RT. The two goals of this report are to educate and provide recommendations. The report provides background and education on current PET imaging systems, PET tracers, intensity quantification, and current utilization in RT (staging, segmentation, image registration, treatment planning, and therapy response assessment). Recommendations are provided on acceptance testing, annual and monthly quality assurance, scanning protocols to ensure consistency between interpatient scans and intrapatient longitudinal scans, reporting of patient and scan parameters in literature, requirements for incorporation of [18 F]FDG-PET in treatment planning systems, and image registration. The recommendations provided here are minimum requirements and are not meant to cover all aspects of the use of [18 F]FDG-PET for RT.

Impact of free-breathing CT on quantitative measurements of static and quiescent period-gated PET Images.

Measurements of standardized uptake values (SUV) can vary due to many causes, including respiratory motion. Various methodologies have been introduced to correct for motion in PET, with quiescent-period-gated (QPG) PET being the most popular approach. QPG has been shown to improve PET image quantification compared to static-whole-body (SWB) PET. However, to achieve this improvement, QPG PET requires CT attenuation correction data that matches the QPG PET data. In this paper we investigated the effect of using free-breathing CT for attenuation correction of QPG PET on SUVmax and SUVpeak and compared the results to those of SWB PET. 34 lesions in 27 patients were included. All patients were injected with F-18 FDG. 4D-CT datasets representing all possible phases of respiration that could result from a free-breathing CT were acquired. The 4D-CT datasets were used for attenuation correction of the QPG and SWB PET data. Percentage change in the SUVmax and SUVpeak range was calculated for the reconstructions and compared between QPG and SWB PET. The mean percentage change in the lesion SUVmax and SUVpeak ranges were 19.1% (p  = 0.0178) and 25.2% (p  = 0.0002) higher for QPG compared to SWB, respectively. The maximum percent change in SUVmax and SUVpeak ranges were 58.5% and 59.0% for QPG, respectively compared to 46.1% and 45.3% for SWB, respectively. The highest SUVmax and SUVpeak measurements corresponded to the CT phase that matched the QPG phase. Utilizing free-breathing CT for attenuation correction can lead to large changes in quantification due to misalignment with PET data. This misalignment has a large quantitative impact on QPG PET as compared to SWB PET. When interpreting quantitative changes in lesions, it is critical to consider the influences of free-breathing CT-based attenuation correction.

A PET Radiomics Model to Predict Refractory Mediastinal Hodgkin Lymphoma.

First-order radiomic features, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), are associated with disease progression in early-stage classical Hodgkin lymphoma (HL). We hypothesized that a model incorporating first- and second-order radiomic features would more accurately predict outcome than MTV or TLG alone. We assessed whether radiomic features extracted from baseline PET scans predicted relapsed or refractory disease status in a cohort of 251 patients with stage I-II HL who were managed at a tertiary cancer center. Models were developed and tested using a machine-learning algorithm. Features extracted from mediastinal sites were highly predictive of primary refractory disease. A model incorporating 5 of the most predictive features had an area under the curve (AUC) of 95.2% and total error rate of 1.8%. By comparison, the AUC was 78% for both MTV and TLG and was 65% for maximum standardize uptake value (SUVmax). Furthermore, among the patients with refractory mediastinal disease, our model distinguished those who were successfully salvaged from those who ultimately died of HL. We conclude that our PET radiomic model may improve upfront stratification of early-stage HL patients with mediastinal disease and thus contribute to risk-adapted, individualized management.

Dose volume histogram-based optimization of image reconstruction parameters for quantitative 90 Y-PET imaging.

PURPOSE: 90 Y-microsphere radioembolization or selective internal radiation therapy is increasingly being used as a treatment option for tumors that are not candidates for surgery and external beam radiation therapy. Recently, volumetric 90 Y-dosimetry techniques have been implemented to explore tumor dose-response on the basis of 3D 90 Y-activity distribution from PET imaging. Despite being a theranostic study, the optimization of quantitative 90 Y-PET image reconstruction still uses the mean activity concentration recovery coefficient (RC) as the objective function, which is more relevant to diagnostic and detection tasks than is to dosimetry. The aim of this study was to optimize 90 Y-PET image reconstruction by minimizing errors in volumetric dosimetry via the dose volume histogram (DVH). We propose a joint optimization of the number of equivalent iterations (the product of the iterations and subsets) and the postreconstruction filtration (FWHM) to improve the accuracy of voxel-level 90 Y dosimetry. METHODS: A modified NEMA IEC phantom was used to emulate clinically relevant 90 Y-PET imaging conditions through various combinations of acquisition durations, activity concentrations, sphere-to-background ratios, and sphere diameters. PET data were acquired in list mode for 300 min in a single-bed position; we then rebinned the list mode PET data to 60, 45, 30, 15, and 5 min per bed, with 10 different realizations. Errors in the DVH were calculated as root mean square errors (RMSE) of the differences in the image-based DVH and the expected DVH. The new optimization approach was tested in a phantom study, and the results were compared with the more commonly used objective function of the mean activity concentration RC. RESULTS: In a wide range of clinically relevant imaging conditions, using 36 equivalent iterations with a 5.2-mm filtration resulted in decreased systematic errors in volumetric 90 Y dosimetry, quantified as image-based DVH, in 90 Y-PET images reconstructed using the ordered subset expectation maximization (OSEM) iterative reconstruction algorithm with time of flight (TOF) and point spread function (PSF) modeling. Our proposed objective function of minimizing errors in DVH, which allows for joint optimization of 90 Y-PET iterations and filtration for volumetric quantification of the 90 Y dose, was shown to be superior to conventional RC-based optimization approaches for image-based absorbed dose quantification. CONCLUSION: Our proposed objective function of minimizing errors in DVH, which allows for joint optimization of iterations and filtration to reduce errors in the PET-based volumetric quantification 90 Y dose, is relevant to dosimetry in therapy procedures. The proposed optimization method using DVH as the objective function could be applied to any imaging modality used to assess voxel-level quantitative information.

A measurement of the attenuation of radiation from F-18 by a PET/MR scanner.

The attenuation of 511 keV photons by the structure of a PET/MR scanner was measured prior to energizing the magnet. The exposure rate from a source of fluorine-18 was measured in air and, with the source placed at the isocenter of the instrument, at various points outside of the scanner. In an arc from 45 to 135 degrees relative to the long axis of the scanner and at a distance of 1.5 m from the isocenter, the attenuation by the scanner is at least 5.6 half-value layers from the MR component alone and at least 6.6 half-value layers with the PET insert installed. This information could inform better design of the radiation shielding for PET/MR scanners.

Evaluation of a novel elastic respiratory motion correction algorithm on quantification and image quality in abdomino-thoracic PET/CT.

Our aim is to evaluate in phantom and patient studies a recently developed elastic motion debluring (EMDB) technique which makes use of all the acquired PET data and compare its performance to other conventional techniques such as phase based gating (PBG) and HDChest (HDC) both of which use fractions of the acquired data. Comparisons were made with respect to static whole-body (SWB) images with no motion correction. Methods: A phantom simulating respiratory motion of the thorax with lung lesions (5 spheres with ID=10- 28 mm) was scanned with 0, 1, 2, and 3 cm motion. Four reconstructions were performed: SWB, PBG, HDC, and EMDB. For PBG, the average (PBGave) and maximum bin (PBGmax) were used. To compare the reconstructions, the ratios of SUVmax (RSmax), SUVpeak (RSpeak), and CNR (RCNR) were calculated with respect to SWB. Additionally, 46 patients with lung or liver tumors < 3 cm diameter were also studied. Measurements of SUVmax, SUVpeak, and contrast-to-noise ratio (CNR) were made for 46 lung and 19 liver lesions. To evaluate image noise, the SUV standard deviation was measured in healthy lung and liver tissue and in the phantom background. Finally, subjective image quality of patient exams was scored on a 5 point scale by four radiologists. Results: In the phantom, EMDB increased SUVmax/SUVpeak over SWB but to a lesser extent than the other reconstruction methodologies. The RCNR for EMDB however was higher than all other reconstructions (0.68 EMDB > 0.54 HDC > 0.41 PBGmax > 0.31 PBGave). Similar results were seen in patient studies. The SUVmax/SUVpeak were higher by 19.3/11.1% EMDB, 21.6/13.9% HDC, 22.8/12.8% PBGave, and 45.6/26.8% PBGmax compared to SWB. Lung/liver noise increased EMDB (3/15%), HDC (35/56%), PBGave (100/170%), and PBGmax (146/219%). CNR increased in lung/liver tumors only for EMDB (18/13%), and decreased for HDC (-14/-23%), PBGave (-39/-63%), and PBGmax (-18/-46%). Average radiologist scores of image quality were SWB (4.0 ± 0.8) > EMDB (3.7 ± 1.0) > HDC (3.1 ± 1.0) > PBG (1.5 ± 0.7). Conclusion: The EMDB algorithm had the least increase in image noise, improved lesion CNR, and had the highest overall image quality score.

Positron emission tomography-computed tomography predictors of progression after DA-R-EPOCH for PMBCL.

Dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) has produced good outcomes in primary mediastinal B-cell lymphoma (PMBCL), but predictors of resistance to this treatment are unclear. We investigated whether [18F]fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) findings could identify patients with PMBCL who would not respond completely to DA-R-EPOCH. We performed a retrospective analysis of 65 patients with newly diagnosed stage I to IV PMBCL treated at 2 tertiary cancer centers who had PET-CT scans available before and after frontline therapy with DA-R-EPOCH. Pretreatment variables assessed included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Optimal cutoff points for progression-free survival (PFS) were determined by a machine learning approach. Univariate and multivariable models were constructed to assess associations between radiographic variables and PFS. At a median follow-up of 36.6 months (95% confidence interval, 28.1-45.1), 2-year PFS and overall survival rates for the 65 patients were 81.4% and 98.4%, respectively. Machine learning-derived thresholds for baseline MTV and TLG were associated with inferior PFS (elevated MTV: hazard ratio [HR], 11.5; P = .019; elevated TLG: HR, 8.99; P = .005); other pretreatment clinical factors, including International Prognostic Index and bulky (>10 cm) disease, were not. On multivariable analysis, only TLG retained statistical significance (P = .049). Univariate analysis of posttreatment variables revealed that residual CT tumor volume, maximum standardized uptake value, and Deauville score were associated with PFS; a Deauville score of 5 remained significant on multivariable analysis (P = .006). A model combining baseline TLG and end-of-therapy Deauville score identified patients at increased risk of progression.

Multimodal Imaging of Pathologic Response to Chemoradiation in Esophageal Cancer.

PURPOSE: To examine the value of early changes in quantitative diffusion-weighted imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for discriminating complete pathologic response (pCR) to chemoradiation in esophageal cancer. METHODS AND MATERIALS: Twenty esophageal cancer patients treated with chemoradiation followed by surgery were prospectively enrolled. Patients underwent magnetic resonance imaging and FDG-PET/CT scans at baseline, interim (2 weeks after chemoradiation start), and first follow-up. On the basis of pathologic findings at surgery, patients were categorized into tumor regression groups (TRG1, TRG2, and TRG3+). Distributions of summary statistics in apparent diffusion coefficient (ADC) and FDG-PET at baseline and relative changes at interim and follow-up scans were compared between pCR/TRG1 and non-pCR/TRG2+ groups and across readers. Receiver operating characteristics were evaluated for summary measures to characterize discrimination of pCR from non-pCR. RESULTS: Relative changes in tumor volume ADC (ΔADC) mean and 25th and 10th percentiles from baseline to interim were able to completely discriminate (area under the curve = 1, P < .0011) between pCR and non-pCR (thresholds = 27.7%, 29.2%, and 32.1%, respectively) and were found to have high interreader reliability (95% limits of agreement of 1.001, 0.944, and 0.940, respectively). Relative change in total lesion glycolysis (TLG) from baseline to interim was significantly different among pCR and non-pCR groups (P=.0117) and yielded an area under the curve of 0.947 (95% confidence interval 0.8505-1.043). An optimal threshold of 59% decrease in TLG provided optimal sensitivity (specificity) of 1.000 (0.867). Changes in ADC summary measures were negatively correlated with that of TLG (Spearman, -0.495, P=.027). CONCLUSIONS: Quantitative volume ΔADC and TLG during treatment may serve as early imaging biomarkers for discriminating pathologic response to chemoradiation in esophageal cancer. Validation of these data in larger, prospective, multicenter studies is essential.