Whole-body PET Research Articles

Whole-body PET Imaging of T-cell Response to Glioblastoma.

Immunotherapy is a promising approach for many oncological malignancies, including glioblastoma, however, there are currently no available tools or biomarkers to accurately assess whole-body immune responses in patients with glioblastoma treated with immunotherapy. Here, the utility of OX40, a costimulatory molecule mainly expressed on activated effector T cells known to play an important role in eliminating cancer cells, was evaluated as a PET imaging biomarker to quantify and track response to immunotherapy. A subcutaneous vaccination approach of CpG oligodeoxynucleotide, OX40 mAb, and tumor lysate at a remote site in a murine orthotopic glioma model was developed to induce activation of T cells distantly while monitoring their distribution in stimulated lymphoid organs with respect to observed therapeutic effects. To detect OX40-positive T cells, we utilized our in-house-developed 89Zr-DFO-OX40 mAb and in vivo PET/CT imaging. ImmunoPET with 89Zr-DFO-OX40 mAb revealed strong OX40-positive responses with high specificity, not only in the nearest lymph node from vaccinated area (mean, 20.8%ID/cc) but also in the spleen (16.7%ID/cc) and the tumor draining lymph node (11.4%ID/cc). When the tumor was small (<106 p/sec/cm2/sr in bioluminescence imaging), a high number of responders and percentage shrinkage in tumor signal was indicated after only a single cycle of vaccination. The results highlight the promise of clinically translating cancer vaccination as a potential glioma therapy, as well as the benefits of monitoring efficacy of these treatments using immunoPET imaging of T-cell activation.

Bone Metastases Are Measurable: The Role of Whole-Body MRI and Positron Emission Tomography.

Metastatic tumor deposits in bone marrow elicit differential bone responses that vary with the type of malignancy. This results in either sclerotic, lytic, or mixed bone lesions, which can change in morphology due to treatment effects and/or secondary bone remodeling. Hence, morphological imaging is regarded unsuitable for response assessment of bone metastases and in the current Response Evaluation Criteria In Solid Tumors 1.1 (RECIST1.1) guideline bone metastases are deemed unmeasurable. Nevertheless, the advent of functional and molecular imaging modalities such as whole-body magnetic resonance imaging (WB-MRI) and positron emission tomography (PET) has improved the ability for follow-up of bone metastases, regardless of their morphology. Both these modalities not only have improved sensitivity for visual detection of bone lesions, but also allow for objective measurements of bone lesion characteristics. WB-MRI provides a global assessment of skeletal metastases and for a one-step “all-organ” approach of metastatic disease. Novel MRI techniques include diffusion-weighted imaging (DWI) targeting highly cellular lesions, dynamic contrast-enhanced MRI (DCE-MRI) for quantitative assessment of bone lesion vascularization, and multiparametric MRI (mpMRI) combining anatomical and functional sequences. Recommendations for a homogenization of MRI image acquisitions and generalizable response criteria have been developed. For PET, many metabolic and molecular radiotracers are available, some targeting tumor characteristics not confined to cancer type (e.g. 18F-FDG) while other targeted radiotracers target specific molecular characteristics, such as prostate specific membrane antigen (PSMA) ligands for prostate cancer. Supporting data on quantitative PET analysis regarding repeatability, reproducibility, and harmonization of PET/CT system performance is available. Bone metastases detected on PET and MRI can be quantitatively assessed using validated methodologies, both on a whole-body and individual lesion basis. Both have the advantage of covering not only bone lesions but visceral and nodal lesions as well. Hybrid imaging, combining PET with MRI, may provide complementary parameters on the morphologic, functional, metabolic and molecular level of bone metastases in one examination. For clinical implementation of measuring bone metastases in response assessment using WB-MRI and PET, current RECIST1.1 guidelines need to be adapted. This review summarizes available data and insights into imaging of bone metastases using MRI and PET.

Fully automated identification of brain abnormality from whole-body FDG-PET imaging using deep learning-based brain extraction and statistical parametric mapping

BackgroundThe whole brain is often covered in [18F]Fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) in oncology patients, but the covered brain abnormality is typically screened by visual interpretation without quantitative analysis in clinical practice. In this study, we aimed to develop a fully automated quantitative interpretation pipeline of brain volume from an oncology PET image.MethodWe retrospectively collected 500 oncologic [18F]FDG-PET scans for training and validation of the automated brain extractor. We trained the model for extracting brain volume with two manually drawn bounding boxes on maximal intensity projection images. ResNet-50, a 2-D convolutional neural network (CNN), was used for the model training. The brain volume was automatically extracted using the CNN model and spatially normalized. For validation of the trained model and an application of this automated analytic method, we enrolled 24 subjects with small cell lung cancer (SCLC) and performed voxel-wise two-sample T test for automatic detection of metastatic lesions.ResultThe deep learning-based brain extractor successfully identified the existence of whole-brain volume, with an accuracy of 98% for the validation set. The performance of extracting the brain measured by the intersection-over-union of 3-D bounding boxes was 72.9 ± 12.5% for the validation set. As an example of the application to automatically identify brain abnormality, this approach successfully identified the metastatic lesions in three of the four cases of SCLC patients with brain metastasis.ConclusionBased on the deep learning-based model, extraction of the brain volume from whole-body PET was successfully performed. We suggest this fully automated approach could be used for the quantitative analysis of brain metabolic patterns to identify abnormalities during clinical interpretation of oncologic PET studies.

Primary breast CD20-positive extranodal NK/T cell lymphoma with stomach involvement: a case report and literature review

BackgroundWe present a unique case of primary breast CD20-positive extranodal NK/T cell lymphoma with stomach involvement in a young Chinese female patient.Case presentationThe patient presented with a mass in her right breast that rapidly increased in size over approximately 2 months. Upper gastrointestinal endoscopy showed a giant serpentine ulcer in the stomach. Biopsy was performed, and microscopic inspection revealed that the fibrous tissue was diffusely involved by medium to large abnormal lymphocytes. The cytoplasm was low to moderate. The tumor cells had irregular nuclei and inconspicuous nucleoli. The lymphoid cells were strongly immunoreactive to CD20, CD3, CD4, CD56, TIA-1, EBER, and Ki-67 (90%). Epstein-Barr virus genomes were also found in tumor cells by in situ hybridization. A whole-body positron emission tomography (PET)-CT scan revealed intense FDG uptake in the right breast and greater curvature of the stomach. Monoclonal rearrangements of the T cell receptor (TCR-γ) and immunoglobulin heavy chain (IgH) were identified by genetic analysis. Whole-genome next-generation sequencing was performed, and up to 12 gene mutations, including a frameshift mutation in exon 4 of the BCOR (G97Rfs*87; 44.3%) gene and a base substitution mutation (Q61H 17.6%) in exon 3 of the KRAS gene, were detected. Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using the database for annotation, visualization, and integrated discovery, which showed that rare primary breast CD20-positive extranodal NK/T cell lymphoma had a unique genetic background compared with diffuse large B cell lymphoma and extranodal NK/T cell lymphoma without CD20 expression. The patient received four cycles of the modified SMILE regimen. The second whole-body PET-CT scan revealed that the right breast mass was significantly smaller than before; additionally, FDG uptake in the stomach wall disappeared.ConclusionsSystemic examination, extensive immunohistochemistry, and molecular profiling are essential for an accurate diagnosis. More similar cases are required to clarify the biological pathways and even the potential molecular mechanisms of rare lymphomas, which may help direct further treatment.

Prognostic Value of Whole-Body PET Volumetric Parameters Extracted from 68Ga-DOTATOC PET/CT in Well-Differentiated Neuroendocrine Tumors

Our objective was to evaluate the prognostic value of somatostatin receptor tumor burden on 68Ga-DOTATOC PET/CT in patients with well-differentiated (WD) neuroendocrine tumors (NETs). Methods: We retrospectively analyzed the 68Ga-DOTATOC PET/CT scans of 84 patients with histologically confirmed WD NETs (51 grade 1, 30 grade 2, and 3 grade 3). For each PET/CT scan, all 68Ga-DOTATOC-avid lesions were independently segmented by 2 operators using a customized threshold based on the healthy liver SUVmax (LIFEx, version 5.1). Somatostatin receptor-expressing tumor volume (SRETV) and total lesion somatostatin receptor expression (TLSRE = SRETV × SUVmean) were extracted for each lesion, and then whole-body SRETV and TLSRE (SRETVwb and TLSREwb, respectively) were defined as the sum of SRETV and TLSRE, respectively, for all segmented lesions in each patient. Time to progression (TTP) was defined as the combination of disease-free survival in patients undergoing curative surgery (n = 10) and progression-free survival for patients with unresectable or metastatic disease (n = 74). TTP and overall survival were calculated by Kaplan-Meier analysis, log-rank testing, and the Cox proportional-hazards regression model. Results: After a median follow-up of 15.5 mo, disease progression was confirmed in 35 patients (41.7%) and 14 patients died. A higher SRETVwb (>39.1 cm3) and TLSREwb (>306.8 g) correlated significantly with a shorter median TTP (12 mo vs. not reached; P < 0.001). In multivariate analysis, SRETVwb (P = 0.005) was the only independent predictor of TTP regardless of histopathologic grade and TNM staging. Conclusion: According to our results, SRETVwb and TLSREwb extracted from 68Ga-DOTATOC PET/CT could predict TTP or overall survival and might have important clinical utility in the management of patients with WD NETs.

1293 Hibernoma: Rare Case of An Intense 18F-FDG Uptake Mediastinal Lesion Mimicking Thymic Carcinoma

Abstract Hibernoma is a rare benign neoplasia derived from remnants of brown adipose tissue. Here, we describe an unusual case of mediastinal hibernoma which radiologically mimicked a thymic malignancy. The patients had presented with chest pain, associated with palpitations and dizziness suggestive of cardiac pathology. Investigation of coronary anatomy by CT scan, incompletely revealed the presence of the lesion situated in the region of the thymus gland, 48 mm x 94 mm. The mass was smooth walled with evidence of invasion of local structures. Whole-body positron-emission tomography (PET) demonstrated the mass had a very high uptake, SUV 55.2. The mass was excised by total thymectomy through a sternotomy. Histopathological analysis revealed it to be fibro-fatty in nature. Light microscopy demonstrated the presence of large multi-vacuolated cells, with appearances typical of brown fat, a hibernoma. This is one of only 7 reported cases. Its findings highlight the importance of careful interpretation of PET studies in hibernoma cases. We propose hibernoma should be included as a differential diagnosis of growing mediastinal masses.

Hist-P-05 - A rare primary subcutaneous panniculitis-like T-cell lymphoma with scalp involvement associated with lupus panniculitis

Hist-P-05 - A rare primary subcutaneous panniculitis-like T-cell lymphoma with scalp involvement associated with lupus panniculitis

MAGIC OF ADVANCED IMAGING AND IMMUNOTHERAPY IN CARDIAC SARCOIDOSIS

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: This case report emphasizes the role of advanced imaging and immunotherapy in the diagnosis and management of cardiac sarcoidosis (CS). CASE PRESENTATION: A 52-year-old healthy male presented with near-syncope for 5 days. He had a blood pressure of 164/67 mmHg and a heart rate of 43 bpm. Electrocardiogram revealed complete-heart-block (CHB) with a ventricular rate of 38/min. Troponin T and electrolytes were normal, and Lyme's serology was negative. Echocardiogram was normal. Cardiac magnetic resonance imaging (CMR) revealed late gadolinium enhancement (LGE) affecting the mid inferior segment at the right ventricle (RV) insertion site (Figure 1). A cardiac and whole-body 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan showed focal areas of increased FDG uptake in the LV involving mid and basal anteroseptal segments, mid inferoseptal segment, basal inferolateral, and basal inferior segments with normal perfusion (Figure 2). The scan also revealed hypermetabolic bilateral hilar and mediastinal lymphadenopathy. A diagnosis of CS was made. An Implantable-Cardioverter-defibrillator (ICD) was placed and the patient was discharged on 40mg of prednisone and 20mg of leflunomide. Within 4 months, he went from 100% RV pacing to 0%. Eventually, the corticosteroid was tapered off. At follow-up after 1.5 years, RV pacing remained 0% on Leflunomide 20mg. DISCUSSION: One should always suspect CS in young patients with high-grade AV block. During the workup of CHB (Figure 3), the 2017 Japanese Circulation Society Working Group Criteria for diagnosing CS was followed (1). The patient had 2 characteristic findings strongly suggestive of sarcoidosis: (a) hilar lymphadenopathy and (b) significant tracer accumulation in the myocardium and hilar lymph nodes on FDG-PET scan. He also met 2 major criteria strongly suggestive of CS: (a) LGE on CMR and (b) abnormal myocardial FDG uptake. These findings, per the criteria, establish the clinical diagnosis of CS. The mainstay of treatment for CS is corticosteroids +/- steroid-sparing agents to decrease intra-cardiac inflammation (1). CHB patients with CS have a high risk of ventricular arrhythmias, hence should receive ICD (2). The addition of antimetabolite adjuvants is more effective than corticosteroids alone (3). They may reduce the total time of glucocorticoid therapy and keep patients in remission. CONCLUSIONS: Clinical diagnosis of CS can be established with FDG-PET imaging and CMR. CS patients with advanced heart block should receive ICD. Corticosteroids are the mainstay of treatment. Immunotherapy is an effective adjunct that can help taper the glucocorticoids and keep patients in remission. Early introduction of these agents should be considered in these patients. REFERENCE #1: 1. Trivieri MG et al. Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review. J Am Coll Cardiol 2020;76:1878-1901 REFERENCE #2: 2. Nordenswan H-K et al. Outcome of Cardiac Sarcoidosis Presenting With High-Grade Atrioventricular Block. Circulation: Arrhythmia and Electrophysiology 2018;11:e006145 REFERENCE #3: 3. Nagai S, Yokomatsu et al. Treatment with methotrexate and low-dose corticosteroids in sarcoidosis patients with cardiac lesions. Intern Med 2014;53:427-33. DISCLOSURES: No relevant relationships by Roy Chung, source=Web Response No relevant relationships by Sachin Kumar, source=Web Response No relevant relationships by Raunak Nair, source=Web Response

S1935 Anorectal Melanoma: A Rare but Potentially Fatal Cause of Rectal Bleeding

Introduction: Rectal bleeding is a common complaint with many relatively benign causes including hemorrhoids, anal fissures, and colonic diverticula. However, there are more insidious causes of rectal bleeding that can potentially prove to be fatal without early intervention, including colon cancer. Here, we present one rare but potentially deadly cause of rectal bleeding. Case description/methods: A 63-year-old female presents with 1 month history of recurrent painless hematochezia. Prior to presentation, she had 3 episodes large volume bright red blood per rectum. Screening colonoscopy completed 3 years earlier was negative. On presentation the patient was hemodynamically stable, but severely anemic with hemoglobin of 6 g/dl. Digital rectal exam revealed a large anterior anal mass. Further evaluation with colonoscopy revealed a bleeding 2 cm submucosal mass in the anal canal, extending distal to the dentate line, which bled easily with pressure and fibrovascular in appearance. The mass was too friable to biopsy at the time of colonoscopy. She underwent trans-anal resection of the anal mass. Histopathology revealed nodular mucosal malignant melanoma, epithelioid type. Immunohistochemical studies were positive for SOX-10 and Melan A, and negative for cytokeratin AE, CD45, chromogranin, synaptophysin, BRAF. Whole-body PET scan revealed 1.1 cm perirectal lymph node involvement without evidence of distant metastasis. Follow up MRI revealed six suspicious meso-rectal lymph nodes. Eventually, the patient underwent abdominoperineal resection (APR). Histopathology following APR revealed 3 tumor deposits, with negative surgical margin, 7/16 lymph nodes involvement. Patient is following oncology for adjuvant chemotherapy. Discussion: Anorectal melanoma (ARM) is rare, having fewer than 700 cases reported in the literature. Patients with anorectal melanoma typically present with rectal bleeding, anorectal pain, and change in bowel habits. The gold standard for diagnosis is immunohistochemistry. Treatment strategies include surgery with or without immunotherapy. Unfortunately, recurrence and mortality rate are high, with a 5-year survival rate of less than 20% and a median survival of less than 2 years. In summary, ARM is a rare and aggressive variant of mucosal melanoma which is often associated with diagnosis at advanced stage, high metastatic potential, and high mortality. It is imperative that a high index of suspicion be maintained to mitigate the high burden of late diagnoses and advanced disease.Figure 1.: Figure 1A. 4.3 x 3.5 cm mass anterior to a large sigmoid diverticulum with Hounsfield units of 22-36 (red arrow). Hounsfield units of lipomas range from 30 to 70. Figure 1B. 4 cm pedunculated polyp 20 cm from the anal verge. Figure 1C. Microscopy depicting submucosal mass with mature white adipose tissue (red arrow).

Whole-body PET tracking of a d-dodecapeptide and its radiotheranostic potential for PD-L1 overexpressing tumors

Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [64Cu]DPA and investigated the tumor engagement of [64Cu/68Ga]DPA in mouse models. Our results revealed that intact [64Cu/68Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [64Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.

Biodistribution of 18F-FES in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant (G1T48), a Novel Selective ER Degrader.

16α-18F-fluoro-17β-estradiol (18F-FES) is a PET tracer characterizing the expression of the estrogen receptor (ER). Because therapy can interfere with the kinetics and biodistribution of 18F-FES, the aim of this study was to describe the biodistribution of 18F-FES in patients with metastatic ER-positive (ER+) breast cancer undergoing treatment with rintodestrant (G1T48), a novel selective ER degrader. Methods: Eight patients underwent 18F-FES PET/CT imaging at baseline, 4-6 wk during treatment with rintodestrant (interim), and after treatment. After intravenous administration of 200 MBq (±10%) of 18F-FES, a 50-min dynamic PET/CT scan of the thorax was obtained, followed by a whole-body PET/CT scan 60 min after injection. Blood samples were drawn for measuring whole blood and plasma activity concentration and the parent fraction of 18F-FES. Volumes of interest were placed in the aorta ascendens and in healthy tissues on both dynamic and whole-body PET scans. SUVs and target-to-blood ratios (TBRs) were calculated. Areas under the curve (AUCs) of input functions and time-activity curves were calculated as a measure of uptake in different regions. Results:18F-FES concentration in whole blood (and plasma) significantly (P < 0.05) increased at interim with median AUCs of 96.6, 116.6, and 110.3 at baseline, interim, and after treatment, respectively. In ER-expressing tissues, that is, the uterus and the pituitary gland, both SUV and TBR showed high 18F-FES uptake at baseline, followed by a decrease in uptake at interim (uterus: SUV -50.6% and TBR -58.5%; pituitary gland: SUV -39.0% and TBR -48.3%), which tended to return to baseline values after treatment (uterus: SUV -21.5% and TBR -37.9%; pituitary gland: SUV -14.2% and TBR -26.0%, compared with baseline). In other healthy tissues, tracer uptake remained stable over the 3 time points. Conclusion: The biodistribution of 18F-FES is altered in blood and in ER-expressing healthy tissues during therapy with rintodestrant. This indicates that rintodestrant alters the kinetics of the tracer, possibly affecting interpretation and quantification of 18F-FES uptake. Of note, 6 d or more after treatment with rintodestrant ended, the biodistribution returned to baseline values, consistent with recovery of ER availability after washout of the drug.

Low-count whole-body PET with deep learning in a multicenter and externally validated study

More widespread use of positron emission tomography (PET) imaging is limited by its high cost and radiation dose. Reductions in PET scan time or radiotracer dosage typically degrade diagnostic image quality (DIQ). Deep-learning-based reconstruction may improve DIQ, but such methods have not been clinically evaluated in a realistic multicenter, multivendor environment. In this study, we evaluated the performance and generalizability of a deep-learning-based image-quality enhancement algorithm applied to fourfold reduced-count whole-body PET in a realistic clinical oncologic imaging environment with multiple blinded readers, institutions, and scanner types. We demonstrate that the low-count-enhanced scans were noninferior to the standard scans in DIQ (p < 0.05) and overall diagnostic confidence (p < 0.001) independent of the underlying PET scanner used. Lesion detection for the low-count-enhanced scans had a high patient-level sensitivity of 0.94 (0.83–0.99) and specificity of 0.98 (0.95–0.99). Interscan kappa agreement of 0.85 was comparable to intrareader (0.88) and pairwise inter-reader agreements (maximum of 0.72). SUV quantification was comparable in the reference regions and lesions (lowest p-value=0.59) and had high correlation (lowest CCC = 0.94). Thus, we demonstrated that deep learning can be used to restore diagnostic image quality and maintain SUV accuracy for fourfold reduced-count PET scans, with interscan variations in lesion depiction, lower than intra- and interreader variations. This method generalized to an external validation set of clinical patients from multiple institutions and scanner types. Overall, this method may enable either dose or exam-duration reduction, increasing safety and lowering the cost of PET imaging.

Comparison between dynamic whole-body FDG-PET and early-delayed imaging for the assessment of motion in focal uptake in colorectal area.

Serial changes of focal uptake in whole-body dynamic positron emission tomography (PET) imaging were assessed and compared with those in early-delayed imaging to differentiate pathological uptake from physiological uptake in the colorectal area, based on the change in uptake shape. In 60 patients with at least 1 pathologically diagnosed colorectal cancer or adenoma, a serial 3min dynamic whole-body PET/computed tomography imaging was performed four times around 60min after the administration of 18F-fluorodeoxyglucose (FDG) to create a conventional (early) image by summation. Delayed imaging was performed separately at 110min after FDG administration. High focal uptake lesions in the colorectal area were visually assessed as "changed" or "unchanged" on serial dynamic imaging and early-delayed imaging, based on the alteration in uptake shape over time. These criteria on the images were used to differentiate pathological uptake from physiological uptake. In this study, 334 lesions with high focal FDG uptake were observed. Among 73 histologically proven pathological FDG uptakes, no change was observed in 69 on serial dynamic imaging and 72 on early-delayed imaging (sensitivity of 95 vs. 99%, respectively; ns). In contrast, out of 261 physiological FDG uptakes, a change in uptake shape was seen in 159 on dynamic PET imaging and 66 on early-delayed imaging (specificity of 61 vs. 25%, respectively; p < 0.01). High and similar negative predictive values for identifying pathological uptake were obtained by both methods (98 vs 99%, respectively). Thus, the overall accuracy for differentiating pathological from physiological FDG uptake based on change in uptake shape tended to be higher on serial dynamic imaging (68%) than on early-delayed imaging (41%; p < 0.01). Dynamic whole-body FDG imaging enables differentiation of pathological uptake from physiological uptake based on the serial changes in uptake shape in the colorectal area. It may provide greater diagnostic value than early-delayed PET imaging. Thus, this technique holds a promise for minimizing the need for delayed imaging.

Assessing the Functional Redundancy between P-gp and BCRP in Controlling the Brain Distribution and Biliary Excretion of Dual Substrates with PET Imaging in Mice.

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are co-localized at the blood–brain barrier, where they display functional redundancy to restrict the brain distribution of dual P-gp/BCRP substrate drugs. We used positron emission tomography (PET) with the metabolically stable P-gp/BCRP substrates [11C]tariquidar, [11C]erlotinib, and [11C]elacridar to assess whether a similar functional redundancy as at the BBB exists in the liver, where both transporters mediate the biliary excretion of drugs. Wild-type, Abcb1a/b(−/−), Abcg2(−/−), and Abcb1a/b(−/−)Abcg2(−/−) mice underwent dynamic whole-body PET scans after i.v. injection of either [11C]tariquidar, [11C]erlotinib, or [11C]elacridar. Brain uptake of all three radiotracers was markedly higher in Abcb1a/b(−/−)Abcg2(−/−) mice than in wild-type mice, while only moderately changed in Abcb1a/b(−/−) and Abcg2(−/−) mice. The transfer of radioactivity from liver to excreted bile was significantly lower in Abcb1a/b(−/−)Abcg2(−/−) mice and almost unchanged in Abcb1a/b(−/−) and Abcg2(−/−) mice (with the exception of [11C]erlotinib, for which biliary excretion was also significantly reduced in Abcg2(−/−) mice). Our data provide evidence for redundancy between P-gp and BCRP in controlling both the brain distribution and biliary excretion of dual P-gp/BCRP substrates and highlight the utility of PET as an upcoming tool to assess the effect of transporters on drug disposition at a whole-body level.

First clinical assessment of [18F]MC225, a novel fluorine-18 labelled PET tracer for measuring functional P-glycoprotein at the blood-brain barrier.

5-(1-(2-[18F]fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen ([18F]MC225) is a selective substrate for P-glycoprotein (P-gp), possessing suitable properties for measuring overexpression of P-gp in the brain. This is the first-in-human study to examine safety, radiation dosimetry and P-gp function at the blood-brain barrier (BBB) of [18F]MC225 in healthy subjects. [18F]MC225 biodistribution and dosimetry were determined in 3 healthy male subjects, using serial 2h and intermittent 4 and 6h whole-body PET scans acquired after [18F]MC225 injection. Dynamic [18F]MC225 brain PET (90min) was obtained in 5 healthy male subjects. Arterial blood was sampled at various time intervals during scanning and the fraction of unchanged [18F]MC225 in plasma was determined. T1-weighted MRI was performed for anatomical coregistration. Total distribution volume (VT) was estimated using 1- and 2-tissue-compartment models (1-TCM and 2-TCM, respectively). VT was also estimated using the Logan graphical method (Logan plot) (t* = 20min). Surrogate parameters without blood sampling (area-under the curve [AUC] of regional time-activity curves [TACs] and negative slope of calculated TACs) were compared with the VT values. No serious adverse events occurred throughout the study period. Although biodistribution implied hepatobiliary excretion, secretion of radioactivity from liver to small intestine through the gallbladder was very slow. Total renal excreted radioactivity recovered during 6h after injection was < 2%ID. Absorbed dose was the highest in the pancreas (mean ± SD, 203 ± 45μGy/MBq) followed by the liver (83 ± 11μGy/MBq). Mean effective dose with and without urination was 17 ± 1 μSv/MBq. [18F]MC225 readily entered the brain, distributing homogeneously in grey matter regions. 2-TCM provided lower Akaike information criterion scores than did 1-TCM. VT estimated by Logan plot was well correlated with that of 2-TCM (r2 > 0.9). AUCs of TACs were positively correlated with VT (2-TCM) values (r2: AUC0-60min = 0.61, AUC0-30min = 0.62, AUC30-60min = 0.59, p < 0.0001). Negative slope of SUV TACs was negatively correlated with VT (2-TCM) values (r2 = 0.53, p < 0.0001). This initial evaluation indicated that [18F]MC225 is a suitable and safe PET tracer for measuring P-gp function at the BBB.

High-resolution monolithic LYSO detector with 6-layer depth-of-interaction for clinical PET

The system spatial resolution of whole-body positron emission tomography (PET) is limited to around 2 mm due to positron physics and the large diameter of the bore. To stay below this ‘physics’-limit a scintillation detector with an intrinsic spatial resolution of around 1.3 mm is needed. Currently used detector technology consists of arrays of 2.6–5 mm segmented scintillator pixels which are the dominant factor contributing to the system resolution. Pixelated detectors using smaller pixels exist but face major drawbacks in sensitivity, timing, energy resolution and cost. Monolithic continuous detectors, where the spatial resolution is determined by the shape of the light distribution on the photodetector array, are a promising alternative. Without having the drawbacks of pixelated detectors, monolithic ones can also provide depth-of-interaction (DOI) information. In this work we present a monolithic detector design aiming to serve high-resolution clinical PET systems while maintaining high sensitivity. A 50 × 50 × 16 mm3 Lutetium–Yttrium oxyorthosilicate scintillation crystal with silicon photomultiplier (SiPM) backside readout is calibrated in singles mode by a collimated beam obtaining a reference dataset for the event positioning. A mean nearest neighbour (MNN) algorithm and an artificial neural network for positioning are compared. The targeted intrinsic detector resolution of 1.3 mm needed to reach a 2 mm resolution on system level was accomplished with both algorithms. The neural network achieved a mean spatial resolution of 1.14 mm FWHM for the whole detector and 1.02 mm in the centre (30 × 30 mm2). The MNN algorithm performed slightly worse with 1.17 mm for the whole detector and 1.13 mm in the centre. The intrinsic DOI information will also result in uniform system spatial resolution over the full field of view.

The Role of Positron Emission Tomography in Bariatric Surgery Research: a Review.

Bariatric surgery, initially understood as restricting or bypassing the amount of food that reaches the stomach to reduce food intake and/or increase malabsorption of food to promote weight loss, is now recognized to also affect incretin signaling in the gut and promote improvements in system-wide metabolism. Positron emission tomography (PET) is an imaging technique whereby patients are injected with picomolar concentrations of radioactive molecules, below the threshold of having physiological effects, to measure spatial distributions of blood flow, metabolism, receptor, and enzyme pharmacology. Recent advances in both whole-body PET imaging and radioligand development will allow for novel research that may help clarify the roles of peripheral and central receptor/enzyme systems in treating obesity with bariatric surgery.

Primary pulmonary epithelioid sarcoma: a case report

BackgroundEpithelioid sarcoma most frequently occurs in the dermal or subcutaneous area of the distal extremities. To date, there have been three cases of primary pulmonary epithelioid sarcoma reported. We report a case of epithelioid sarcoma that is considered a primary lung tumor.Case presentationA 65-year-old asymptomatic Asian male patient underwent chest radiography during a routine health examination, and an abnormal mass was detected. His past medical history was unremarkable. He smoked 40 cigarettes every day and had slightly obstructive impairment on spirometry. He worked as an employee of a company and had no history of asbestos exposure. He underwent partial resection of the right lung by thoracoscopy. A histological examination of the tumor revealed a cellular nodule of epithelioid and spindle-shaped cells. Some of the tumor cells displayed rhabdoid features and reticular arrangement in a myxomatous stroma. Immunohistochemically, the tumor cells were positive for vimentin, smooth muscle actin (SMA), CD34, and epithelial membrane antigen (EMA); loss of the BAF47/INI1 protein in the tumor cells was also confirmed. A diagnosis of epithelioid sarcoma was established. Careful screening by whole-body positron emission tomography for another primary lesion after surgery did not detect any possible lesion. He had no cutaneous disease.ConclusionTo our knowledge, this is the fourth case of a proximal-type epithelioid sarcoma considered as a primary lung tumor.

UPAR PET/CT for Prognostication and Response Assessment in Patients with Metastatic Castration-Resistant Prostate Cancer Undergoing Radium-223 Therapy: A Prospective Phase II Study.

The aim of this Phase II study was to investigate the potential for response assessment and prognostication of positron emission tomography (PET) using the ligand 68Ga-NOTA-AE105 targeting the urokinase-type plasminogen activator receptor (uPAR) in patients receiving Radium-223-dichloride therapy (223RaCl2). A combined whole-body uPAR PET and computed tomography (CT) was performed before initiation of 223RaCl2 and after two cycles of therapy. Standardized uptake value (SUV) in selected bone metastases was measured and the lesion with the highest SUVmax was considered the index lesion. Clinical outcomes were overall survival (OS), radiographic progression free survival (rPFS) and occurrence of symptomatic skeletal event (SSE). A total of 17 patients were included and 14 patients completed both baseline and follow-up uPAR-PET/CT. Baseline SUVmax of the index lesion was associated with OS; hazard ratio 2.51 (95% CI: 1.01–6.28, p = 0.05) per unit increase in SUVmax. No association between changes in SUVmax from baseline to follow-up and OS, progression during therapy, or rPFS was found. Baseline SUVmax was a significant predictor of SSE with receiver operating characteristics (ROC) area under the curve (AUC) = 0.81 (95% CI: 0.58–1.00, p = 0.034). A cut-off for tumor SUVmax could be established with an odds ratio of 14.0 (95% CI: 1.14–172.6, p = 0.023) for occurrence of SSE within 12 months. Although based on a small number of patients, uPAR-PET SUVmax in bone metastases was predictive for OS and risk of SSE in mCRPC patients receiving 223RaCl2. However, a relatively low uptake of the uPAR ligand in bone metastases impedes visual evaluation and requires another modality for lesion delineation.

Performance comparison of a dedicated total breast PET system with a clinical whole-body PET system: a simulation study

This paper presents a novel PET geometry for breast cancer imaging. The scanner consists of a ‘stadium’ (a rectangle with two semi-circles on opposite sides) shaped ring, along with anterior and posterior panels to provide high sensitivity and high spatial resolution for an imaging field-of-view (FOV) that include both breasts, mediastinum and axilla. We simulated this total-breast PET system using GATE and reconstructed the coincidence events using a GPU-based list-mode image reconstruction implementing maximum likelihood expectation-maximization (ML-EM) algorithm. The rear-panel is made up of a single layer of LSO crystals (3.2 × 3.2 × 20 mm3 each), while the ‘stadium’-shaped elongated ring and the anterior panel are made with dual-layered LSO crystals (1.6 × 1.6 × 6 mm3 each). The energy resolution and coincidence resolving time of all detectors are assumed to be 12% and 250 ps full-width-at-half-maximum, respectively. Various sized simulated lesions (4, 5, 6 mm) having 4:1, 5:1, and 6:1 lesion-to-background radioactivity concentration ratios, mimicking different biological uptakes, were strategically located throughout a volumetric torso phantom. We compared system sensitivity and lesion detectability of the dedicated total-breast PET system to a state-of-the-art clinical whole-body PET scanner. The mean sensitivity of the total-breast PET system is 3.21 times greater than that of a whole-body PET scanner in the breast regions. The total-breast PET system also provides better contrast-recovery coefficients for lesions of all sizes and lesion-to-background ratios in the breast when compared to a reference clinical whole-body PET scanner. Receiver operating characteristics (ROC) study shows the area under the ROC curve is 0.948 and 0.924 for the total-breast system and the whole-body PET scanner, respectively, in the detection of 4 mm diameter lesions with 4:1 lesion-to-background ratio. This study demonstrates our novel geometry can provide an imaging FOV larger than conventional PEM systems to simultaneously image both breasts, chest wall and axillae with significantly improved lesion detectability in the breasts when compared to a whole-body PET scanner.