Jean-Mathieu Beauregard

Dynamic 18F-FET PET in Newly Diagnosed Astrocytic Low-Grade Glioma Identifies High-Risk Patients

Because the clinical course of low-grade gliomas in the individual adult patient varies considerably and is unpredictable, we investigated the prognostic value of dynamic 18F-fluorethyltyrosine (18F-FET) PET in the early diagnosis of astrocytic low-grade glioma (World Health Organization grade II). Methods: Fifty-nine patients with newly diagnosed low-grade glioma and dynamic 18F-FET PET before histopathologic assessment were retrospectively investigated. 18F-FET PET analysis comprised a qualitative visual classification of lesions; assessment of the semiquantitative parameters maximal, mean, and total standardized uptake value as ratio to background and biologic tumor volume; and dynamic analysis of intratumoral 18F-FET uptake over time (increasing vs. decreasing time–activity curves). The correlation between PET parameters and progression-free survival, overall survival, and time to malignant transformation was investigated. Results: 18F-FET uptake greater than the background level was found in 34 of 59 tumors. Dynamic 18F-FET uptake analysis was available for 30 of these 34 patients. Increasing and decreasing time–activity curves were found in 18 and 12 patients, respectively. Neither the qualitative factor presence or absence of 18F-FET uptake nor any of the semiquantitative uptake parameters significantly influenced clinical outcome. In contrast, decreasing time–activity curves in the kinetic analysis were highly prognostic for shorter progression-free survival and time to malignant transformation (P < 0.001). Conclusion: Absence of 18F-FET uptake in newly diagnosed astrocytic low-grade glioma does not generally indicate an indolent disease course. Among the 18F-FET–positive gliomas, decreasing time–activity curves in dynamic 18F-FET PET constitute an unfavorable prognostic factor in astrocytic low-grade glioma and, by identifying high-risk patients, may ease treatment decisions.

Quantitative (177)Lu SPECT (QSPECT) imaging using a commercially available SPECT/CT system.

Abstract Purpose: The combination of single photon emission computed tomography (SPECT) and computer tomography (CT) that incorporates iterative reconstruction algorithms with attenuation and scatter correction should facilitate accurate non-invasive quantitative imaging. Quantitative SPECT (QSPECT) may improve diagnostic ability and could be useful for many applications including dosimetry assessment. Using 177Lu, we developed a QSPECT method using a commercially available SPECT/CT system. Methods: Serial SPECT of 177Lu sources (89–12,400 MBq) were acquired with multiple contiguous energy windows along with a co-registered CT, and were reconstructed using an iterative algorithm with attenuation and scatter correction. Camera sensitivity (based on reconstructed SPECT count rate) and dead-time (based on wide-energy spectrum count rate) were resolved by non-linear curve fit. Utilizing these parameters, a SPECT dataset can be converted to a QSPECT dataset allowing quantitation in Becquerels per cubic centimetre or standardized uptake value (SUV). Validation QSPECT/CT studies were performed on a 177Lu cylindrical phantom (7 studies) and on 5 patients (6 studies) who were administered a therapeutic dose of [177Lu]octreotate. Results: The QSPECT sensitivity was 1.08 × 10−5 ± 0.02 × 10−5 s−1 Bq−1. The paralyzing dead-time constant was 0.78 ± 0.03 µs. The measured total activity with QSPECT deviated from the calibrated activity by 5.6 ± 1.9% and 2.6 ± 1.8%, respectively, in phantom and patients. Dead-time count loss up to 11.7% was observed in patient studies. Conclusion: QSPECT has high accuracy both in our phantom model and in clinical practice following [177Lu]octreotate therapy. This has the potential to yield more accurate dosimetry estimates than planar imaging and facilitate therapeutic response assessment. Validating this method with other radionuclides could open the way for many other research and clinical applications.

Assessment of Human Biodistribution and Dosimetry of 4-Fluoro-11β-Methoxy-16α-18F-Fluoroestradiol Using Serial Whole-Body PET/CT

4-Fluoro-11β-methoxy-16α-18F-fluoroestradiol (4FMFES) is a newly developed radiolabeled estradiol analog for PET imaging of estrogen receptors (ERs) that shows improved target-to-background ratios, compared with 16α-18F-fluoroestradiol (FES), in small-animal models. The aim of this study was to assess the biodistribution, dosimetry, and safety of 4FMFES in healthy women. Methods: Ten healthy subjects (6 pre- and 4 postmenopausal women) who had fasted were injected with 66–201 MBq of 4FMFES at a high effective specific activity (median, 251 GBq/μmol). During a 2-h period, each subject underwent 4 serial rapid PET acquisitions and 2 low-dose CT acquisitions on a PET/CT camera. Volumes of interest were drawn over source organs for each PET acquisition, allowing the calculation of time–activity curves, residence times, and radiation dosimetry estimates. Serial blood samples were obtained to measure blood and plasma activity clearance. 4FMFES safety was assessed by blood and urine analyses and vital-sign monitoring. Results: A 4FMFES injection was well tolerated in all subjects. The liver showed high uptake, and the hepatobiliary excretion was massive. Little urinary excretion occurred. Uterus uptake was visualized in all subjects and remained relatively constant over time (maximum and mean standardized uptake values at 60 min were 5.34 ± 3.32 and 2.68 ± 1.89, respectively). Background activity was low and decreased over time, resulting in an increasing uterus-to-background ratio (12.1 ± 2.2 at 60 min). The critical organ was the gallbladder (0.80 ± 0.51 mGy/MBq), followed by the upper large intestine (0.13 ± 0.04 mGy/MBq), small intestine (0.12 ± 0.04 mGy/MBq), and liver (0095 ± 0.019 mGy/MBq). For a typical 4FMFES dose of 185 MBq, the effective dose was calculated at 4.82 ± 0.70 mSv. Conclusion: 4FMFES is considered safe for use in humans, and its effective dose remains well within acceptable limits. The absorbed dose to the gallbladder was relatively high and could potentially be reduced by injecting 4FMFES in patients who had not fasted. 4FMFES showed a significant, potentially estrogen receptor–mediated uterus uptake in both pre- and postmenopausal subjects.

An automated voxelized dosimetry tool for radionuclide therapy based on serial quantitative SPECT/CT imaging

PURPOSE To create an accurate map of the distribution of radiation dose deposition in healthy and target tissues during radionuclide therapy. METHODS Serial quantitative SPECT∕CT images were acquired at 4, 24, and 72 h for 28 (177)Lu-octreotate peptide receptor radionuclide therapy (PRRT) administrations in 17 patients with advanced neuroendocrine tumors. Deformable image registration was combined with an in-house programming algorithm to interpolate pharmacokinetic uptake and clearance at a voxel level. The resultant cumulated activity image series are comprised of values representing the total number of decays within each voxels volume. For PRRT, cumulated activity was translated to absorbed dose based on Monte Carlo-determined voxel S-values at a combination of long and short ranges. These dosimetric image sets were compared for mean radiation absorbed dose to at-risk organs using a conventional MIRD protocol (OLINDA 1.1). RESULTS Absorbed dose values to solid organs (liver, kidneys, and spleen) were within 10% using both techniques. Dose estimates to marrow were greater using the voxelized protocol, attributed to the software incorporating crossfire effect from nearby tumor volumes. CONCLUSIONS The technique presented offers an efficient, automated tool for PRRT dosimetry based on serial post-therapy imaging. Following retrospective analysis, this method of high-resolution dosimetry may allow physicians to prescribe activity based on required dose to tumor volume or radiation limits to healthy tissue in individual patients.

Clinical Impact of a Second FDG-PET in Atypical/Unclear Dementia Syndromes.

Diagnosis of atypical/unclear dementia is often difficult and this delays treatment initiation. Several authors have shown that beyond standard dementia workup, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) reduces the number of unclear diagnoses, leads to earlier treatment, and has a beneficial impact on families. However, it is not uncommon that the FDG-PET findings are equivocal in this setting. For those cases, a repeat FDG-PET may clarify the diagnosis and prevent treatment delay. We retrospectively assessed the clinical impact of a repeat FDG-PET in 59 patients with atypical/unclear dementia syndromes and inconclusive initial FDG-PET. Changes in primary diagnosis, diagnostic confidence, and management following the second FDG-PET were examined. Conducting a second FDG-PET reduced the number of unclear diagnoses from 80% to 34% , led to diagnostic change in 24% of cases, and treatment modification in 22% of patients. Overall, the clinical impact was higher when initial diagnostic confidence was low and the second FDG-PET repeated ≥12 months after the first one. In tertiary care memory clinic settings, when diagnostic incertitude persists despite extensive evaluation and an equivocal FDG-PET, repeating the FDG-PET 12 months later can greatly clarify the diagnosis and improve management.

Determination of gamma camera calibration factors for quantitation of therapeutic radioisotopes

BackgroundCamera calibration, which translates reconstructed count map into absolute activity map, is a prerequisite procedure for quantitative SPECT imaging. Both planar and tomographic scans using different phantom geometries have been proposed for the determination of the camera calibration factor (CF). However, there is no consensus on which approach is the best. The aim of this study is to evaluate all these calibration methods, compare their performance, and propose a practical and accurate calibration method for SPECT quantitation of therapeutic radioisotopes. Twenty-one phantom experiments (Siemens Symbia SPECT/CT) and 12 Monte Carlo simulations (GATE v6.1) using three therapy isotopes (131I, 177Lu, and 188Re) have been performed. The following phantom geometries were used: (1) planar scans of point source in air (PS), (2) tomographic scans of insert(s) filled with activity placed in non-radioactive water (HS + CB), (3) tomographic scans of hot insert(s) in radioactive water (HS + WB), and (4) tomographic scans of cylinders uniformly filled with activity (HC). Tomographic data were reconstructed using OSEM with CT-based attenuation correction and triple energy window (TEW) scatter correction, and CF was determined using total counts in the reconstructed image, while for planar scans, the photopeak counts, corrected for scatter and background with TEW, were used. Additionally, for simulated data, CF obtained from primary photons only was analyzed.ResultsFor phantom experiments, CF obtained from PS and HS + WB agreed to within 6% (below 3% if experiments performed on the same day are considered). However, CF from HS + CB exceeded those from PS by 4–12%. Similar trend was found in simulation studies. Analysis of CFs from primary photons helped us to understand this discrepancy. It was due to underestimation of scatter by the TEW method, further enhanced by attenuation correction. This effect becomes less important when the source is distributed over the entire phantom volume (HS + WB and HC).ConclusionsCamera CF could be determined using planar scans of a point source, provided that the scatter and background contributions are removed, for example using the clinically available TEW method. This approach is simple and yet provides CF with sufficient accuracy (~ 5%) to be used in clinics for radiotracer quantification.

Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy

Although intrapatient heterogeneity of prostate cancer (PCa) has recently been characterized via genomic and transcriptomic studies, the heterogeneity of systemic treatment responses has yet to be reported or imaged. Our objective was to evaluate the intrapatient intermetastasis response to systemic treatment among patients with metastatic PCa. We evaluated the metabolic response for each individual metastatic lesion (n=165) in 15 patients with metastatic PCa who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography before and at least 3 mo after initiation of a systemic therapy that did not change in that period. Intermetastasis heterogeneity was defined as opposite metabolic responses for at least two metastases from the same compartment (bone or soft tissue) between the two time points. We found intrapatient intermetastasis response heterogeneity in 40% of the cases in our retrospective series. Our results suggest that systemic therapies can induce heterogeneous responses among individual metastases in patients with PCa, supporting the polyclonal evolution of PCa in advanced disease. Molecular imaging may thus be useful in identifying clinical resistance early after therapy initiation and could also allow targeted biopsy of resistant clones for molecular analysis. PATIENT SUMMARY Systemic therapies can lead to heterogeneous responses in individual metastases of prostate cancer in a patient. Molecular imaging may be useful for identifying heterogeneity and could allow targeted biopsy for molecular analysis or therapy.

Neuroradiological and Neuropathological Changes After 177Lu-Octreotate Peptide Receptor Radionuclide Therapy of Refractory Esthesioneuroblastoma

BACKGROUND AND IMPORTANCE Olfactory neuroblastoma, also known as esthesioneuroblastoma (ENB), is a malignant neoplasm with an unpredictable behavior. Currently, the widely accepted treatment is inductive chemotherapy, with or without surgery, followed by radiotherapy. Since data on genetics and molecular alterations of ENB are lacking, there is no standard molecularly targeted therapy. However, ENB commonly expresses the somatostatin receptor (SSTR) that is also expressed by neuroendocrine tumors. Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogues, such as 177Lu-octreotate, is an effective treatment for the latter. We present the complex neuroradiological and neuropathological changes associated with 177Lu-octreotate treatment of a patient with a highly treatment-resistant ENB. CLINICAL PRESENTATION A 60-yr-old male presented with an ENB that recurred after chemotherapy, surgery, stereotactic radiosurgery, and immunotherapy. Pathology revealed a Hyams grade 3 ENB and the tumor had metastasized to lymph nodes. Tumor SSTR expression was seen on 68Ga-octreotate positron emission tomography (PET)/computed tomography (CT), suggesting that PRRT may be an option. He received 4 cycles of 177Lu-octreotate over 6 mo, with a partial response of all lesions and symptomatic improvement. Four months after the last PRRT cycle, 2 of the lesions rapidly relapsed and were successfully resected. Three months later, 68Ga-octreotate PET/CT and magnetic resonance imaging indicate no progression of the disease. CONCLUSION We describe imaging changes associated with 177Lu-octreotate PRRT of relapsing ENB. To our knowledge, this is the first report describing neuropathological changes associated with this treatment. PRRT is a promising therapeutic option to improve the disease control, and potentially, the survival of patients with refractory ENB.

Potentiation of 177 Lu-octreotate peptide receptor radionuclide therapy of human neuroendocrine tumor cells by PARP inhibitor

For patients with inoperable neuroendocrine tumors (NETs) expressing somatostatin receptors, peptide receptor radionuclide therapy (PRRT) with 177Lu-[DOTA0-Tyr3]-octreotate (177Lu-octreotate) is one of the most promising targeted therapeutic options but it rarely achieves cure. Therefore, different approaches are being tested to increase the efficacy of 177Lu-octreotate PRRT in NET patients. Using the gastroenteropancreatic BON-1 and the bronchopulmonary NCI-H727 as NET cell models, here we report that pharmacological inhibitors of DNA repair-associated enzyme poly(ADP-ribose) polymerase-1 (PARPi) potentiate the cytotoxic effect of 177Lu-octreotate on 2D monolayer and 3D spheroid models of these two types of NET cells. PARPi mediates this effect by enhancing 177Lu-octreotate-induced cell cycle arrest and cell death. Thus, the use of PARPi may offer a novel option for improving the therapeutic efficacy of 177Lu-octreotate PRRT of NETs.

A CZT-based blood counter for quantitative molecular imaging

BackgroundRobust quantitative analysis in positron emission tomography (PET) and in single-photon emission computed tomography (SPECT) typically requires the time-activity curve as an input function for the pharmacokinetic modeling of tracer uptake. For this purpose, a new automated tool for the determination of blood activity as a function of time is presented.The device, compact enough to be used on the patient bed, relies on a peristaltic pump for continuous blood withdrawal at user-defined rates. Gamma detection is based on a 20 × 20 × 15 mm3 cadmium zinc telluride (CZT) detector, read by custom-made electronics and a field-programmable gate array-based signal processing unit. A graphical user interface (GUI) allows users to select parameters and easily perform acquisitions.ResultsThis paper presents the overall design of the device as well as the results related to the detector performance in terms of stability, sensitivity and energy resolution. Results from a patient study are also reported. The device achieved a sensitivity of 7.1 cps/(kBq/mL) and a minimum detectable activity of 2.5 kBq/ml for 18F. The gamma counter also demonstrated an excellent stability with a deviation in count rates inferior to 0.05% over 6 h. An energy resolution of 8% was achieved at 662 keV.ConclusionsThe patient study was conclusive and demonstrated that the compact gamma blood counter developed has the sensitivity and the stability required to conduct quantitative molecular imaging studies in PET and SPECT.