Framework for radiation pneumonitis risk stratification based on anatomic and perfused lung dosimetry.

PURPOSE: To design and apply a framework for predicting symptomatic radiation pneumonitis in patients undergoing thoracic radiation, using both pretreatment anatomic and perfused lung dose-volume parameters. MATERIALS AND METHODS: Radiation treatment planning CT scans were coregistered with pretreatment [99mTc]MAA perfusion SPECT/CT scans of 20 patients who underwent definitive thoracic radiation. Clinical radiation pneumonitis was defined as grade ≥ 2 (CTCAE v4 grading system). Anatomic lung dose-volume parameters were collected from the treatment planning scans. Perfusion dose-volume parameters were calculated from pretreatment SPECT/CT scans. Equivalent doses in 2 Gy per fraction were calculated in the lung to account for differences in treatment regimens and spatial variations in lung dose (EQD2lung). RESULTS: Anatomic lung dosimetric parameters (MLD) and functional lung dosimetric parameters (pMLD70%) were identified as candidate predictors of grade ≥ 2 radiation pneumonitis (AUC > 0.93, p < 0.01). Pairing of an anatomic and functional dosimetric parameter (e. g., MLD and pMLD70%) may further improve prediction accuracy. Not all individuals with high anatomic lung dose (MLD > 13.6 GyEQD2lung, 19.3 Gy for patients receiving 60 Gy in 30 fractions) developed radiation pneumonitis, but all individuals who also had high mean dose to perfused lung (pMLD70% > 13.3 GyEQD2) developed radiation pneumonitis. CONCLUSIONS: The preliminary application of this framework revealed differences between anatomic and perfused lung dosimetry in this limited patient cohort. The addition of perfused lung parameters may help risk stratify patients for radiation pneumonitis, especially in treatment plans with high anatomic mean lung dose. Further investigations are warranted.

Morphology supporting function: attenuation correction for SPECT/CT, PET/CT, and PET/MR imaging.

Both SPECT, and in particular PET, are unique in medical imaging for their high sensitivity and direct link to a physical quantity, i.e. radiotracer concentration. This gives PET and SPECT imaging unique capabilities for accurately monitoring disease activity for the purposes of clinical management or therapy development. However, to achieve a direct quantitative connection between the underlying radiotracer concentration and the reconstructed image values several confounding physical effects have to be estimated, notably photon attenuation and scatter. With the advent of dual-modality SPECT/CT, PET/CT, and PET/MR scanners, the complementary CT or MR image data can enable these corrections, although there are unique challenges for each combination. This review covers the basic physics underlying photon attenuation and scatter and summarizes technical considerations for multimodal imaging with regard to PET and SPECT quantification and methods to address the challenges for each multimodal combination.

Depth of Interaction Calibration and Capabilities in 2×2 Discrete Crystal Arrays and Digital Silicon Photomultipliers.

Digital silicon photomultiplers (dSiPMs) have potential in the advancement of PET detectors. Their advantages include decreased dark counts through selective microcell activation, fast timing, and flexibility configuring event triggering and collection. Further improvements in PET image resolution are possible when photon depth of interaction (DOI) is available, as this reduces parallax error caused by mispositioning events at the peripheral field of view. These improvements are desirable in smaller ring diameter PET systems, such as whole body PET/MRI. In this study we quantify the DOI capabilities of a unique crystal array design (termed dual light sharing arrays or DLSA) that takes advantage of the 2-by-2-pixel die readout logic of a PDPC dSiPM (Philips Digital Photon Counting 3200) device by Philips Medical Systems. The DLSA is comprised of a 2×2 array of 4×4×22 mm3 LYSO crystals; inter-crystal surfaces were optically coupled in part with high-index optical adhesive and optically isolated in complimentary parts with mirror-film reflector such that light sharing was depth-dependent and different along two axes. The DLSA was mounted to one die of a PDPC and its depth-dependent response to 511-keV gamma rays was calibrated using a coincidence-collimated beam from both side and entrance surfaces. Entrance surface DOI calibration was performed through an iterative application of maximum likelihood calculations based on the signal ratio in crystals adjacent to the crystal of interaction. Results showed timing resolutions of 350-370 ps and energy resolutions of 10-12% while achieving a DOI position estimation of 6-7 mm FWHM. Significant improvements in depth estimation error were found when using maximum likelihood estimation and 3-4 depth bins. Furthermore, similar calibration results were obtained for both side-surface and entrance-surface illumination methods, which suggest that PET system calibrations may be easily performed using a monoenergetic flood source with entrance surface illumination.

Brain imaging reveals neuronal circuitry underlying the crow's perception of human faces.

Crows pay close attention to people and can remember specific faces for several years after a single encounter. In mammals, including humans, faces are evaluated by an integrated neural system involving the sensory cortex, limbic system, and striatum. Here we test the hypothesis that birds use a similar system by providing an imaging analysis of an awake, wild animal's brain as it performs an adaptive, complex cognitive task. We show that in vivo imaging of crow brain activity during exposure to familiar human faces previously associated with either capture (threatening) or caretaking (caring) activated several brain regions that allow birds to discriminate, associate, and remember visual stimuli, including the rostral hyperpallium, nidopallium, mesopallium, and lateral striatum. Perception of threatening faces activated circuitry including amygdalar, thalamic, and brainstem regions, known in humans and other vertebrates to be related to emotion, motivation, and conditioned fear learning. In contrast, perception of caring faces activated motivation and striatal regions. In our experiments and in nature, when perceiving a threatening face, crows froze and fixed their gaze (decreased blink rate), which was associated with activation of brain regions known in birds to regulate perception, attention, fear, and escape behavior. These findings indicate that, similar to humans, crows use sophisticated visual sensory systems to recognize faces and modulate behavioral responses by integrating visual information with expectation and emotion. Our approach has wide applicability and potential to improve our understanding of the neural basis for animal behavior.

Light-Sharing Interface for dMiCE Detectors Using Sub-Surface Laser Engraving.

We have previously reported on dMiCE, a method of resolving depth or interaction (DOI) in a pair of discrete crystals by encoding light sharing properties as a function of depth in the interface of a crystal-element pair. A challenge for this method is the cost and repeatability of interface treatment for each crystal pair. In this work, we report our preliminary results on using sub-surface laser engraving (SSLE) as a means of forming this depth-dependent interface in a dMiCE detector. A surplus first-generation SSLE system was used to create a partially reflective layer 100-microns thick at the boundary between two halves of a 1.4-by-2.9-by-20 mm3 LYSO crystal. The boundary of these paired crystal elements was positioned between two 3-mm wide Silicon photomultiplier arrays. The responses of these two photodetectors were acquired for an ensemble of 511-keV photons collimated to interact at a fixed depth in just one crystal element. Interaction position was then varied to measure detector response as a function of depth, which was then used to maximum-likelihood positions. Despite use of sub-optimal SSLE processing we found an average DOI resolution of 3.4 mm for front-sided readout and 3.9 mm for back-sided readout while obtaining energy resolutions on the order of 10%. We expect DOI resolution can be improved significantly by optimizing the SSLE process and pattern.

PET imaging of Oatp-mediated hepatobiliary transport of [(11)C] rosuvastatin in the rat.

UNLABELLED: A novel positron emission tomography (PET) tracer, [(11)C]-rosuvastatin (RSV), was developed to dynamically and noninvasively measure hepatobiliary transport and tissue distribution of [(11)C]-RSV in rats. METHODS: Male Sprague-Dawley rats were administered either an Oatp inhibitor, rifampin (RIF, 40 mg/kg iv bolus plus 1.85 mg/min/kg iv infusion, n = 3), or the corresponding vehicle (saline, n = 3) for at least 90 min. Then, while these infusions were ongoing, the animals received [(11)C]-rosuvastatin (∼1 mCi/30 s, iv infusion). After [(11)C]-RSV administration, the lower abdominal region of the rats was imaged for 90 min. Time-activity curves for liver, intestine, and kidney were obtained and corrected for vascular content prior to noncompartmental and compartmental (five-compartment model) analysis. RESULTS: The majority of the [(11)C]-RSV dose was distributed into the liver. In the presence of RIF, the area under the [(11)C]-RSV radioactivity blood concentration-time profile (AUC0-90 min) was increased by ∼3-fold. Relative to the control animals, RIF reduced the distribution of [(11)C]-RSV radioactivity into the liver and kidney (tissue AUC0-15 min/blood AUC0-15 min) by 54% and 73% respectively. Compartmental modeling showed that RIF decreased CLBL, CLLI, CLBK, and CLK0 but had no effect on CLLB, where B, L, I, K, and 0 represent blood, liver, intestine, kidney, and irreversible loss. CONCLUSION: [(11)C]-RSV can be used to dynamically and noninvasively quantify hepatobiliary transport and hepatic concentration of the drug, in the absence and presence of drug interactions, in rats and could be used for the same purpose in humans.

Pilot study of humanized glypican-3-targeted zirconium-89 immuno-positron emission tomography for hepatocellular carcinoma.

Purpose: Glypican-3 (GPC3)-targeted radioisotope immuno-positron emission tomography (immunoPET) may lead to earlier and more accurate diagnosis of hepatocellular carcinoma (HCC), thus facilitating curative treatment, decreasing early recurrence, and enhancing patient survival. We previously demonstrated reliable HCC detection using a zirconium-89-labeled murine anti-GPC3 antibody (89Zr-αGPC3M) for immunoPET. This study evaluated the efficacy of the humanized antibody successor (αGPC3H) to further clinical translation of a GPC3-based theranostic for HCC. Methods: In vitro αGPC3 binding to HepG2 cells was assessed by flow cytometry. In vivo 89Zr-αGPC3H and 89Zr-αGPC3M tumor uptake was evaluated by PET/CT and biodistribution studies in an orthotopic xenograft mouse model of HCC. Results: αGPC3H maintained binding to GPC3 in vitro and 89Zr-αGPC3H immunoPET identified liver tumors in vivo. PET/CT and biodistribution analyses demonstrated high 89Zr-αGPC3H tumor uptake and tumor-to-liver ratios, with no difference between groups. Conclusion: Humanized αGPC3 successfully targeted GPC3 in vitro and in vivo. 89Zr-αGPC3H immunoPET had comparable tumor detection to 89Zr-αGPC3M, with highly specific tumor uptake, making it a promising strategy to improve HCC detection.

PDE3 and PDE4 isozyme-selective inhibitors are both required for synergistic activation of brown adipose tissue.

Brown adipose tissue (BAT) is a highly thermogenic organ that converts lipids and glucose into heat. Many of the metabolic and gene transcriptional hallmarks of BAT activation, namely increased lipolysis, uncoupling protein-1 (UCP1) mRNA, and glucose uptake, are regulated by the adrenergic second messenger, cAMP. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the breakdown of cAMP, thereby regulating the magnitude and duration of this signaling molecule. In the absence of adrenergic stimulus, we found that it required a combination of a PDE3 and a PDE4 inhibitor to fully induce UCP1 mRNA and lipolysis in brown adipocytes, whereas neither PDE inhibitor alone had any substantial effect under basal conditions. Under submaximal ß-adrenoceptor stimulation of brown adipocytes, a PDE3 inhibitor alone could potentiate induction of UCP1 mRNA, whereas a PDE4 inhibitor alone could augment lipolysis, indicating differential roles for each of these two PDEs. Neither induction of UCP1 nor lipolysis was altered by inhibition of PDE1, PDE2, or PDE8A. Finally, when injected into mice, the combination of PDE3 and PDE4 inhibitors stimulated glucose uptake in BAT under thermoneutral and fasted conditions, a response that was further potentiated by the global ablation of PDE8A. Taken together, these data reveal that multiple PDEs work in concert to regulate three of the important pathways leading to BAT activation, a finding that may provide an improved conceptual basis for the development of therapies for obesity-related diseases.

Distinct neural circuits underlie assessment of a diversity of natural dangers by American crows.

Social animals encountering natural dangers face decisions such as whether to freeze, flee or harass the threat. The American crow, Corvus brachyrhynchos, conspicuously mobs dangers. We used positron emission tomography to test the hypothesis that distinct neuronal substrates underlie the crow's consistent behavioural response to different dangers. We found that crows activated brain regions associated with attention and arousal (nucleus isthmo-opticus/locus coeruleus), and with motor response (arcopallium), as they fixed their gaze on a threat. However, despite this consistent behavioural and neural response, the sight of a person who previously captured the crow, a person holding a dead crow and a taxidermy-mounted hawk activated distinct forebrain regions (amygdala, hippocampus and portion of the caudal nidopallium, respectively). We suggest that aspects of mobbing behaviour are guided by unique neural circuits that respond to differences in mental processing-learning, memory formation and multisensory discrimination-required to appropriately nuance a risky behaviour to specific dangers.

Effects of Detector Thickness on Geometric Sensitivity and Event Positioning Errors in the Rectangular PET/X Scanner.

We used simulations to investigate the relationship between sensitivity and spatial resolution as a function of crystal thickness in a rectangular PET scanner intended for quantitative assessment of breast cancers. The system had two 20 × 15-cm2 and two 10 × 15-cm2 flat detectors forming a box, with the larger detectors separated by 4 or 8 cm. Depth-of-interaction (DOI) resolution was modeled as a function of crystal thickness based on prior measurements. Spatial resolution was evaluated independent of image reconstruction by deriving and validating a surrogate metric from list-mode data (dFWHM). When increasing crystal thickness from 5 to 40 mm, and without using DOI information, the dFWHM for a centered point source increased from 0.72 to 1.6 mm. Including DOI information improved dFWHM by 12% and 27% for 5- and 40-mm-thick crystals, respectively. For a point source in the corner of the FOV, use of DOI information improved dFWHM by 20% (5-mm crystal) and 44% (40-mm crystal). Sensitivity was 7.7% for 10-mm-thick crystals (8-cm object). Increasing crystal thickness on the smaller side detectors from 10 to 20 mm (keeping 10-mm crystals on the larger detectors) boosted sensitivity by 24% (relative) and degraded dFWHM by only ~3%/8% with/without DOI information. The benefits of measuring DOI must be evaluated in terms of the intended clinical task of assessing tracer uptake in small lesions. Increasing crystal thickness on the smaller side detectors provides substantial sensitivity increase with minimal accompanying loss in resolution.

Timing, Energy, and 3-D Spatial Resolution of the BING PET Detector Module.

We evaluated the 3D spatial, energy, and timing resolution of the Brain (or Breast)-Initiative Next-Generation (BING) PET detector. The BING detector is an array of 1-mm-thick slats of LYSO scintillator with lapped specular-reflective faces (15-mm by 52-mm) that are stacked together and oriented with their long-narrow edges normal to the imaging field of view. Interaction positions are determined from the signals of silicon-photomultiplier (SiPM) arrays placed on the entrance (top) and exit (bottom) faces. The SiPM arrays are offset to determine the slat of interaction (SOI) without requiring any optical light sharing between slats. Maximum likelihood 2D location within the SOI is determined using the sensor signals. Interaction time is determined with a modified first-optical-photon pickoff method. Performance of the BING detector was measured as a function of position using a sideways coincidence-collimated beam. Slats were accurately identified, with an effective tangential detector resolution of 1 mm. Average resolutions (and ranges) are: 0.96 mm (0.85 mm to 1.11 mm) for lateral (axial) detector resolution, 1.6 mm (1.0 mm to 2.1 mm) for depth resolution, 13.6% (12.7% to 16.0%) for energy resolution, and 317 ps (241 ps to 404 ps) for coincidence timing resolution. Initial spatial and timing resolution results demonstrated that the BING detector can be effective in a small field-of view (e.g., brain or breast) PET system.

Timing, Energy, and Spatial Characterization of Highly Sampled Monolithic PET Detectors with Different Thicknesses.

The HyPET project proposes a hybrid dedicated TOF-PET for prostate imaging, with pixelated detector blocks in the front layer and monolithic blocks in the back layer. In this work, four detector configurations have been experimentally evaluated for the rear detector layer. The detector configuration consists of LYSO monolithic blocks with the same size (25.4 mm × 25.4 mm) but different thicknesses (5, 7.5, 10, and 15 mm) coupled to the same SiPM array. Each detector configuration has been experimentally characterized in terms of time, energy and spatial resolution by scanning the crystal surface using a fan beam in steps of 0.25 mm. Regarding spatial resolution, the interaction position was estimated using a Neural Network technique. All resolutions except energy, which remains nearly constant at 17% for all cases, show better values for the 5 mm detector thickness. We have achieved spatial resolution values of FWHM of 1.02 ± 0.10, 1.19 ± 0.13, 1.53 ± 0.17, 2.33 ± 0.55 mm, for the 5, 7.5, 10, and 15 mm blocks, respectively. The detector time resolution obtained was 275 ± 26, 291 ± 21, 344 ± 48, and 433 ± 45 ps respectively, using the energy weighted average method for the time stamps.

Glypican-3 targeted positron emission tomography detects sub-centimeter tumors in a xenograft model of hepatocellular carcinoma.

BACKGROUND: Early intrahepatic recurrence is common after surgical resection of hepatocellular carcinoma (HCC) and leads to increased morbidity and mortality. Insensitive and nonspecific diagnostic imaging contributes to EIR and results in missed treatment opportunities. In addition, novel modalities are needed to identify targets amenable for targeted molecular therapy. In this study, we evaluated a zirconium-89 radiolabeled glypican-3 (GPC3) targeting antibody conjugate (89Zr-αGPC3) for use in positron emission tomography (PET) for detection of small, GPC3+ HCC in an orthotopic murine model. Athymic nu/J mice received hepG2, a GPC3+ human HCC cell line, into the hepatic subcapsular space. Tumor-bearing mice were imaged by PET/computerized tomography (CT) 4 days after tail vein injection of 89Zr-αGPC3. Livers were then excised for the tumors to be identified, measured, bisected, and then serially sectioned at 500 µm increments. Sensitivity and specificity of PET/CT for 89Zr-αGPC3-avid tumors were assessed using tumor confirmation on histologic sections as the gold standard. RESULTS: In tumor-bearing mice, 89Zr-αGPC3 avidly accumulated in the tumor within four hours of injection with ongoing accumulation over time. There was minimal off-target deposition and rapid bloodstream clearance. Thirty-eight of 43 animals had an identifiable tumor on histologic analysis. 89Zr-αGPC3 immuno-PET detected all 38 histologically confirmed tumors with a sensitivity of 100%, with the smallest tumor detected measuring 330 µm in diameter. Tumor-to-liver ratios of 89Zr-αGPC3 uptake were high, creating excellent spatial resolution for ease of tumor detection on PET/CT. Two of five tumors that were observed on PET/CT were not identified on histologic analysis, yielding a specificity of 60%. CONCLUSIONS: 89Zr-αGPC3 avidly accumulated in GPC3+ tumors with minimal off-target sequestration. 89Zr-αGPC3 immuno-PET yielded a sensitivity of 100% and detected sub-millimeter tumors. This technology may improve diagnostic sensitivity of small HCC and select GPC3+ tumors for targeted therapy. Human trials are warranted to assess its impact.

An Online Repository for Pre-Clinical Imaging Protocols (PIPs).

Providing method descriptions that are more detailed than currently available in typical peer reviewed journals has been identified as an actionable area for improvement. In the biochemical and cell biology space, this need has been met through the creation of new journals focused on detailed protocols and materials sourcing. However, this format is not well suited for capturing instrument validation, detailed imaging protocols, and extensive statistical analysis. Furthermore, the need for additional information must be counterbalanced by the additional time burden placed upon researchers who may be already overtasked. To address these competing issues, this white paper describes protocol templates for positron emission tomography (PET), X-ray computed tomography (CT), and magnetic resonance imaging (MRI) that can be leveraged by the broad community of quantitative imaging experts to write and self-publish protocols in protocols.io. Similar to the Structured Transparent Accessible Reproducible (STAR) or Journal of Visualized Experiments (JoVE) articles, authors are encouraged to publish peer reviewed papers and then to submit more detailed experimental protocols using this template to the online resource. Such protocols should be easy to use, readily accessible, readily searchable, considered open access, enable community feedback, editable, and citable by the author.

Impact of Analog IC Impairments in SiPM Interface Electronics.

The recent realization of Silicon Photomultiplier (SiPM) devices as solid-state detectors for Positron Emission Tomography holds the promise of improving image resolution, integrating a significant portion of the interface electronics, and potentially lowering the power consumption. Our lab has previously reported on novel board-level readout electronics for an 8×8 silicon photomultiplier (SiPM) array featuring row/column summation technique to reduce the hardware requirements for signal processing and is currently working on taking the next step by implementing a monolithic CMOS chip which is based on the row-column architecture. To date, relatively little modeling has been done to understand the impact of analog non-idealities associated with the front-end electronics, on SiPM-based PET systems. This paper focuses on various analog impairments associated with PET scanner readout electronics. Matlab was used as a simulation platform to model the noise, linearity and signal bandwidth of the frontend electronics with the measured SiPM pulses as the input.

Use of Cramer-Rao Lower Bound for Performance Evaluation of Different Monolithic Crystal PET Detector Designs.

We have previously reported on continuous miniature crystal element (cMiCE) PET detectors that provide depth of interaction (DOI) positioning capability. A key component of the design is the use of a statistics-based positioning (SBP) method for 3D event positioning. The Cramer-Rao lower bound (CRLB) expresses limits on the estimate variances for a set of deterministic parameters. We examine the CRLB as a useful metric to evaluate the performance of our SBP algorithm and to quickly compare the best possible resolution when investigating new detector designs.In this work, the CRLB is first reported based upon experimental results from a cMiCE detector using a 50×50×15-mm(3) LYSO crystal readout by a 64-channel PMT (Hamamatsu H8500) on the exit surface of the crystal. The X/Y resolution is relatively close to the CRLB, while the DOI resolution is more than double the CRLB even after correcting for beam diameter and finite X (i.e., reference DOI position) resolution of the detector. The positioning performance of the cMiCE detector with the same design was also evaluated through simulation. Similar with the experimental results, the difference between the CRLB and measured spatial resolution is bigger in DOI direction than in X/Y direction.Another simulation study was conducted to investigate what causes the difference between the measured spatial resolution and the CRLB. The cMiCE detector with novel sensor-on-entrance-surface (SES) design was modeled as a 49.2×49.2×15-mm(3) LYSO crystal readout by a 12×12 array of 3.8×3.8-mm(2) silicon photomultiplier (SiPM) elements with 4.1-mm center-to-center spacing on the entrance surface of the crystal. The results show that there are two main causes to account for the differences between the spatial resolution and the CRLB. First, Compton scatter in the crystal degrades the spatial resolution. The DOI resolution is degraded more than the X/Y resolution since small angle scatter is preferred. Second, our maximum likelihood (ML) clustering algorithm also has limitations when developing 3D look up tables during detector calibration.

Performance Characteristics of a Dual-Sided Position-Sensitive Sparse-Sensor Detector for Gamma-ray Imaging.

Purpose: We characterize the performance of a dualsided position-sensitive sparse sensor (DS-PS3) array detector for positron emission tomography (PET). The DS-PS3 detector is designed as a high performance, cost effective PET detector for organ-specific imaging systems (e.g., brain, breast, etc.). Methods: Two sparse 4-by-4 arrays of silicon photomultipliers (18.5% SiPM fill-factor) coupled through segmented light guide are used to readout a 15-by-15 array of 2-mm-pitch, 20-mm-long LSYO crystals. Uniform flood data were used for crystal identification, depth determination, and position-dependent energy resolution. Intrinsic-spatial and depth-of-interaction (DOI) resolutions were determined by stepping a collimated gamma-ray source over the front and side, respectively. Results: We measured an average intrinsic spatial resolution of 2.14 ± 0.07 mm full width at half maximum (FWHM). DOI FWHM resolution varied from 2.2 mm for crystals over sensors to 5.3 mm for crystals between sensors. Average DOI resolution was 3.6 ± 0.8 mm FHWM. Average energy resolution for the detector module was 16.6% with a range of 11.3% to 25.8%. Conclusions: We have demonstrated use of a dual-sided sparse sensor arrays to enable low-cost high-performance decoding of three-dimensional positioning within a PET detector using an 18.5% sensor fill-factor.

Radiation and immune checkpoint inhibitor-mediated pneumonitis risk stratification in patients with locally advanced non-small cell lung cancer: role of functional lung radiomics?

BACKGROUND: Patients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC. METHODS: Patients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [99mTc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout. RESULTS: Thirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69-12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59-0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65-0.88]) or shape feature classes (c-index 0.79 [0.66-0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59-0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R2 = 0.84-1.00), representing surrogates rather than independent predictors of pneumonitis risk. CONCLUSIONS: In patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.

Prognostic Value of Early Fluorodeoxyglucose-Positron Emission Tomography Response Imaging and Peripheral Immunologic Biomarkers: Substudy of a Phase II Trial of Risk-Adaptive Chemoradiation for Unresectable Non-Small Cell Lung Cancer.

Purpose: We sought to examine the prognostic value of fluorodeoxyglucose-positron emission tomography (PET) imaging during chemoradiation for unresectable non-small cell lung cancer for survival and hypothesized that tumor PET response is correlated with peripheral T-cell function. Methods and Materials: Forty-five patients with American Joint Committee on Cancer version 7 stage IIB-IIIB non-small cell lung cancer enrolled in a phase II trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). Fluorodeoxyglucose-PET was performed before treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactorial radiologic interpretation. PET responders received 60 Gy in 30 fractions, while nonresponders received concomitant boosts to 74 Gy in 30 fractions. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor sequencing, and plasma cytokine analysis were performed. Results: Median follow-up was 18.8 months, 1-year overall survival (OS) 82%, 1-year progression-free survival 53%, and 1-year locoregional control 88%. Higher midtreatment PET total lesion glycolysis was detrimental to OS (1 year 87% vs 63%, P < .001), progression-free survival (1 year 60% vs 26%, P = .044), and locoregional control (1 year 94% vs 65%, P = .012), even after adjustment for clinical/treatment factors. Twenty-nine of 45 patients (64%) were classified as PET responders based on a priori definition. Higher tumor programmed death-ligand 1 expression was correlated with response on PET (P = .017). Higher T-cell receptor richness and clone distribution slope were associated with improved OS (P = .018-0.035); clone distribution slope was correlated with PET response (P = .031). Conclusions: Midchemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral T-cell biomarkers.

DOI-based reconstruction algorithms for a compact breast PET scanner.

PURPOSE: The authors discuss the design and evaluate the performance of combined event estimation and image reconstruction algorithms designed for a proposed high-resolution rectangular breast PET scanner (PETX). The PETX scanner will be capable of measuring the depth of interaction by utilizing detector modules composed of depth-of-interaction microcrystal element (dMiCE) crystal pairs. This design allows a unique combination of event estimation and fast projection methods. METHODS: The authors implemented a Monte Carlo simulator to model the PETX system using only true coincident events. The performance of the dMiCE crystal pairs was determined experimentally over a range of depths of interaction. This distribution was used to simulate the noisy dMiCE detector signals and to estimate the line of response for each decay. Three different statistical methods were implemented to determine photon event positioning. Images were reconstructed from these line of response estimators with the exact planogram frequency distance rebinning algorithm, which is an exact analytical reconstruction algorithm for planar systems. Reconstructed images were analyzed with contrast, noise, and spatial resolution metrics. RESULTS: The authors' simulations demonstrate the ability for the PETX system to produce quantitatively accurate images from true coincident events with a contrast recovery coefficient of greater than 0.8 for 5 mm spheres at the axial center of the scanner and a spatial resolution (FWHM) of 3 mm throughout most of the imaging field of view. CONCLUSIONS: The authors' proposed positioning and reconstruction algorithms for the PETX system show the potential for creating high-quality, high-resolution, and quantitatively accurate images within a clinically feasible reconstruction time.