In-vivo inhibition of neutral endopeptidase 1 results in higher absorbed tumor doses of [177Lu]Lu-PP-F11N in humans: the lumed phase 0b study.

BACKGROUND: A new generation of radiolabeled minigastrin analogs delivers low radiation doses to kidneys and are considered relatively stable due to less enzymatic degradation. Nevertheless, relatively low tumor radiation doses in patients indicate limited stability in humans. We aimed at evaluating the effect of sacubitril, an inhibitor of the neutral endopeptidase 1, on the stability and absorbed doses to tumors and organs by the cholecystokinin-2 receptor agonist [177Lu]Lu-PP-F11N in patients. In this prospective phase 0 study eight consecutive patients with advanced medullary thyroid carcinoma and a current somatostatin receptor subtype 2 PET/CT scan were included. Patients received two short infusions of ~ 1 GBq [177Lu]Lu-PP-F11N in an interval of ~ 4 weeks with and without Entresto® pretreatment in an open-label, randomized cross-over order. Entresto® was given at a single oral dose, containing 48.6 mg sacubitril. Adverse events were graded and quantitative SPECT/CT and blood sampling were performed. Absorbed doses to tumors and relevant organs were calculated. RESULTS: Pretreatment with Entresto® showed no additional toxicity and increased the stability of [177Lu]Lu-PP-FF11N in blood significantly (p < 0.001). Median tumor-absorbed doses were 2.6-fold higher after Entresto® pretreatment (0.74 vs. 0.28 Gy/GBq, P = 0.03). At the same time, an increase of absorbed doses to stomach, kidneys and bone marrow was observed, resulting in a tumor-to-organ absorbed dose ratio not significantly different with and without Entresto®. CONCLUSIONS: Premedication with Entresto® results in a relevant stabilization of [177Lu]Lu-PP-FF11N and consecutively increases radiation doses in tumors and organs. Trial registration clinicaltrails.gov, NCT03647657. Registered 20 August 2018.

Radiolabeled Somatostatin Receptor Antagonist Versus Agonist for Peptide Receptor Radionuclide Therapy in Patients with Therapy-Resistant Meningioma: PROMENADE Phase 0 Study.

Our primary aim was to compare the therapeutic index (tumor-to-bone marrow and tumor-to-kidney absorbed-dose ratios) of the new radiolabeled somatostatin receptor antagonist [177Lu]Lu-DOTA-JR11 with the established radiolabeled somatostatin receptor agonist [177Lu]Lu-DOTATOC in the same patients with progressive, standard therapy-refractory meningioma. Methods: In this prospective, single-center, open-label phase 0 study (NCT04997317), 6 consecutive patients were included: 3 men and 3 women (mean age, 63.5 y). Patients received 6.9-7.3 GBq (standard injected radioactivity) of [177Lu]Lu-DOTATOC followed by 3.3-4.9 GBq (2 GBq/m2 × body surface area) of [177Lu]Lu-DOTA-JR11 at an interval of 10 ± 1 wk. In total, 1 [177Lu]Lu-DOTATOC and 2-3 [177Lu]Lu-DOTA-JR11 treatment cycles were performed. Quantitative SPECT/CT was done at approximately 24, 48, and 168 h after injection of both radiopharmaceuticals to calculate meningioma and organ absorbed doses as well as tumor-to-organ absorbed-dose ratios (3-dimensional segmentation approach for meningioma, kidneys, liver, bone marrow, and spleen). Results: The median of the meningioma absorbed dose of 1 treatment cycle was 3.4 Gy (range, 0.8-10.2 Gy) for [177Lu]Lu-DOTATOC and 11.5 Gy (range, 4.7-22.7 Gy) for [177Lu]Lu-DOTA-JR11. The median bone marrow and kidney absorbed doses after 1 treatment cycle were 0.11 Gy (range, 0.05-0.17 Gy) and 2.7 Gy (range, 1.3-5.3 Gy) for [177Lu]Lu-DOTATOC and 0.29 Gy (range, 0.16-0.39 Gy) and 3.3 Gy (range, 1.6-5.9 Gy) for [177Lu]Lu-DOTA-JR11, resulting in a 1.4 (range, 0.9-1.9) times higher median tumor-to-bone marrow absorbed-dose ratio and a 2.9 (range, 2.0-4.8) times higher median tumor-to-kidney absorbed-dose ratio with [177Lu]Lu-DOTA-JR11. According to the Common Terminology Criteria for Adverse Events version 5.0, 2 patients developed reversible grade 2 lymphopenia after 1 cycle of [177Lu]Lu-DOTATOC. Afterward, 2 patients developed reversible grade 3 lymphopenia and 1 patient developed reversible grade 3 lymphopenia and neutropenia after 2-3 cycles of [177Lu]Lu-DOTA-JR11. No grade 4 or 5 adverse events were observed at 15 mo or more after the start of therapy. The disease control rate was 83% (95% CI, 53%-100%) at 12 mo or more after inclusion. Conclusion: Treatment with 1 cycle of [177Lu]Lu-DOTA-JR11 showed 2.2-5.7 times higher meningioma absorbed doses and a favorable therapeutic index compared with [177Lu]Lu-DOTATOC after injection of 1.4-2.1 times lower activities. The first efficacy results demonstrated a high disease control rate with an acceptable safety profile in the standard therapy for refractory meningioma patients. Therefore, larger studies with [177Lu]Lu-DOTA-JR11 are warranted in meningioma patients.

High-throughput screening of caterpillars as a platform to study host-microbe interactions and enteric immunity.

Mammalian models of human disease are expensive and subject to ethical restrictions. Here, we present an independent platform for high-throughput screening, using larvae of the tobacco hornworm Manduca sexta, combining diagnostic imaging modalities for a comprehensive characterization of aberrant phenotypes. For validation, we use bacterial/chemical-induced gut inflammation to generate a colitis-like phenotype and identify significant alterations in morphology, tissue properties, and intermediary metabolism, which aggravate with disease progression and can be rescued by antimicrobial treatment. In independent experiments, activation of the highly conserved NADPH oxidase DUOX, a key mediator of gut inflammation, leads to similar, dose-dependent alterations, which can be attenuated by pharmacological interventions. Furthermore, the developed platform could differentiate pathogens from mutualistic gastrointestinal bacteria broadening the scope of applications also to microbiomics and host-pathogen interactions. Overall, larvae-based screening can complement mammals in preclinical studies to explore innate immunity and host-pathogen interactions, thus representing a substantial contribution to improve mammalian welfare.

EARL compliance measurements on the biograph vision Quadra PET/CT system with a long axial field of view.

BACKGROUND: Our aim was to determine sets of reconstruction parameters for the Biograph Vision Quadra (Siemens Healthineers) PET/CT system that result in quantitative images compliant with the European Association of Nuclear Medicine Research Ltd. (EARL) criteria. Using the Biograph Vision 600 (Siemens Healthineers) PET/CT technology but extending the axial field of view to 106 cm, gives the Vision Quadra currently an around fivefold higher sensitivity over the Vision 600 with otherwise comparable spatial resolution. Therefore, we also investigated how the number of incident positron decays-i.e., exposure-affects EARL compliance. This will allow estimating a minimal acquisition time or a minimal applied dose in clinical scans while retaining data comparability. METHODS: We measured activity recovery curves on a NEMA IEC body phantom filled with an aqueous 18F solution and a sphere to background ratio of 10-1 according to the latest EARL guidelines. Reconstructing 3570 image sets with varying OSEM PSF iterations, post-reconstruction Gaussian filter full width at half maximum (FWHM), and varying exposure from 59 kDecays/ml (= 3 s frame duration) to 59.2 MDecays/ml (= 1 h), allowed us to determine sets of parameters to achieve compliance with the current EARL 1 and EARL 2 standards. Recovery coefficients (RCs) were calculated for the metrics RCmax, RCmean, and RCpeak, and the respective recovery curves were analyzed for monotonicity. The background's coefficient of variation (COV) was also calculated. RESULTS: Using 6 iterations, 5 subsets and 7.8 mm Gauss filtering resulted in optimal EARL1 compliance and recovery curve monotonicity in all analyzed frames, except in the 3 s frames. Most robust EARL2 compliance and monotonicity were achieved with 2 iterations, 5 subsets, and 3.6 mm Gauss FWHM in frames with durations between 30 s and 10 min. RCpeak only impeded EARL2 compliance in the 10 s and 3 s frames. CONCLUSIONS: While EARL1 compliance was robust over most exposure ranges, EARL2 compliance required exposures between 1.2 MDecays/ml to 11.5 MDecays/ml. The Biograph Vision Quadra's high sensitivity makes frames as short as 10 s feasible for comparable quantitative images. Lowering EARL2 RCmax limits closer to unity would possibly even permit shorter frames.

Performance Characteristics of the Biograph Vision Quadra PET/CT System with a Long Axial Field of View Using the NEMA NU 2-2018 Standard.

Our purpose was to evaluate the performance of the Biograph Vision Quadra PET/CT system. This new system is based on the Biograph Vision 600, using the same silicon photomultiplier-based detectors with 3.2 × 3.2 × 20 mm lutetium-oxoorthosilicate crystals. The 32 detector rings of the Quadra provide a 4-fold larger axial field of view (AFOV) of 106 cm, enabling imaging of major organs in 1 bed position. Methods: The physical performance of the scanner was evaluated according to the National Electrical Manufacturers Association NU 2-2018 standard, with additional experiments to characterize energy resolution. Image quality was assessed with foreground-to-background ratios of 4:1 and 8:1. Additionally, a clinical 18F-FDG PET study was reconstructed with varying frame durations. In all experiments, data were acquired using the maximum ring distance of 322 crystals (MRD 322), whereas image reconstructions could be performed with a maximum ring distance of only 85 crystals (MRD 85). Results: The spatial resolution at full width at half maximum in the radial, tangential, and axial directions was 3.3, 3.4, and 3.8 mm, respectively. The sensitivity was 83 cps/kBq for MRD 85 and 176 cps/kBq for MRD 322. The noise-equivalent count rates (NECRs) at peak were 1,613 kcps for MRD 85 and 2,956 kcps for MRD 322, both at 27.49 kBq/mL. The respective scatter fractions at peak NECR equaled 36% and 37%. The time-of-flight resolution at peak NECR was 228 ps for MRD 85 and 230 ps for MRD 322. Image contrast recovery ranged from 69.6% to 86.9% for 4:1 contrast ratios and from 77.7% to 92.6% for 8:1 contrast ratios reconstructed using point-spread function time of flight with 8 iterations and 5 subsets. Thirty-second frames provided readable lesion detectability and acceptable noise levels in clinical images. Conclusion: The Biograph Vision Quadra PET/CT device has spatial and time resolution similar to those of the Biograph Vision 600 but exhibits improved sensitivity and NECR because of its extended AFOV. The reported spatial resolution, time resolution, and sensitivity make it a competitive new device in the class of PET scanners with an extended AFOV.

3D printing of radioactive phantoms for nuclear medicine imaging.

BACKGROUND: For multicenter clinical studies, PET/CT and SPECT/CT scanners need to be validated to ensure comparability between various scanner types and brands. This validation is usually performed using hollow phantoms filled with radioactive liquids. In recent years, 3D printing technology has gained increasing popularity for manufacturing of phantoms, as it is cost-efficient and allows preparation of phantoms of almost any shape. So far, however, direct 3D printing with radioactive building materials has not yet been reported. The aim of this work was to develop a procedure for preparation of 99mTc-containing building materials and demonstrate successful application of this material for 3D printing of several test objects. METHOD: The desired activity of a [99mTc]pertechnetate solution eluted from a 99Mo/99mTc-generator was added to the liquid 3D building material, followed by a minute amount of trioctylphosphine. The resulting two-phase mixture was thoroughly mixed. Following separation of the phases and chemical removal of traces of water, the radioactive building material was diluted with the required volume of non-radioactive building material and directly used for 3D printing. RESULTS: Using our optimized extraction protocol with trioctylphosphine as complex-forming phase transfer agent, technetium-99m was efficiently transferred from the aqueous 99Mo/99mTc-generator eluate into the organic liquid resin monomer. The observed radioactivity concentration ratio between the organic phase and the water phase was > 2000:1. The radioactivity was homogeneously distributed in the liquid resin monomer. We did not note differences in the 3D printing behavior of the radiolabeled and the unlabeled organic liquid resin monomers. Radio-TLC and SPECT studies showed homogenous 2D and 3D distribution of radioactivity throughout the printed phantoms. The radioactivity was stably bound in the resin, apart from a small amount of surface-extractable radioactivity under harsh conditions (ethanol at 50 °C). CONCLUSIONS: 3D printing of radioactive phantoms using 99mTc-containing building materials is feasible. Compared to the classical fillable phantoms, 3D printing with radioactive building materials allows manufacturing of phantoms without cold walls and in almost any shape. Related procedures with longer-lived radionuclides will enable production of phantoms for scanner validation and quality control.

Towards guidelines to harmonize textural features in PET: Haralick textural features vary with image noise, but exposure-invariant domains enable comparable PET radiomics.

PURPOSE: Image texture is increasingly used to discriminate tissues and lesions in PET/CT. For quantification or in computer-aided diagnosis, textural feature analysis must produce robust and comparable values. Because statistical feature values depend on image count statistics, we investigated in depth the stability of Haralick features values as functions of acquisition duration, and for common image resolutions and reconstructions. METHODS: A homogeneous cylindrical phantom containing 9.6 kBq/ml Ge-68 was repeatedly imaged on a Siemens Biograph mCT, with acquisition durations ranging from three seconds to three hours. Images with 1.5, 2, and 4 mm isometrically spaced voxels were reconstructed with filtered back-projection (FBP), ordered subset expectation maximization (OSEM), and the Siemens TrueX algorithm. We analysed Haralick features derived from differently quantized (3 to 8-bit) grey level co-occurrence matrices (GLCMs) as functions of exposure E, which we defined as the product of activity concentration in a volume of interest (VOI) and acquisition duration. The VOI was a 50 mm wide cube at the centre of the phantom. Feature stability was defined for df/dE → 0. RESULTS: The most stable feature values occurred in low resolution FBPs, whereas some feature values from 1.5 mm TrueX reconstructions ranged over two orders of magnitude. Within the same reconstructions, most feature value-exposure curves reached stable plateaus at similar exposures, regardless of GLCM quantization. With 8-bit GLCM, median time to stability was 16 s and 22 s for FBPs, 18 s and 125 s for OSEM, and 23 s, 45 s, and 76 s for PSF reconstructions, with longer durations for higher resolutions. Stable exposures coincided in OSEM and TrueX reconstructions with image noise distributions converging to a Gaussian. In FBP, the occurrence of stable values coincided the disappearance of negatives image values in the VOI. CONCLUSIONS: Haralick feature values depend strongly on exposure, but invariance exists within defined domains of exposure. Here, we present an easily replicable procedure to identify said stable exposure domains, where image noise does not substantially add to textural feature values. Only by imaging at predetermined feature-invariant exposure levels and by adjusting exposure to expected activity concentrations, can textural features have a quantitative use in PET/CT. The necessary exposure levels are attainable by modern PET/CT systems in clinical routine.

A novel single-crystal & single-pass source for polarisation- and colour-entangled photon pairs.

We demonstrate a new generation mechanism for polarisation- and colour-entangled photon pairs. In our approach we tailor the phase-matching of a periodically poled KTP crystal such that two downconversion processes take place simultaneously. Relying on this effect, our source emits entangled bipartite photon states, emerging intrinsically from a single, unidirectionally pumped crystal with uniform poling period. Its property of being maximally compact and luminous at the same time makes our source unique compared to existing photon-entanglement sources and is therefore of high practical significance in quantum information experiments.

Technical Note: Transconvolution based equalization of positron energy effects for the use of 68 Ge/68 Ga phantoms in determining 18 F PET recovery.

PURPOSE: Avoiding measurement variability from 18 F phantom preparation by using 68 Ge/68 Ga phantoms for the determination of 18 F recovery curves (RC) in clinical quality assurance measurements and for PET/CT site qualification in multicentre clinical trials. METHODS: RCs were obtained from PET/CT measurements of seven differently sized phantom spheres filled either with 18 F or with 68 Ga. RCs for the respective other isotope were then determined by two different methods: In the first method, images were convolved with positron range transconvolution functions derived from positron annihilation distributions found in literature. This method generated recasted images matching images using the respective other isotope. In the second method, the PET/CT system's isotope independent (intrinsic) point spread function was determined from said phantom measurements and convolved with numerical representations simulating hot spheres filled with the respective other isotope. These simulations included the isotope specific positron annihilation distributions. Recovered activity concentrations were compared between recasted images, simulated images, and the originally acquired images. RESULTS: 18 F and 68 Ga recovery was successfully determined from image acquisitions of the respective opposite isotope as well as from the simulations. 68 Ga RCs derived from 18 F data had a normalized root-mean-square deviation (NRMSD) from real 68 Ga measurements of 0.019% when using the first method and of 0.008% when using the second method. 18 F RCs derived from 68 Ga data had a NRMSD from real 18 F measurements of 0.036% when using the first method and of 0.038% when using the second method. CONCLUSIONS: Applying the principles of transconvolution, 18 F RCs can be recalculated from 68 Ga phantom measurements with excellent accuracy. The maximal additionally introduced error was below 0.4% of the error currently accepted for RCs in the site qualification of multicentre clinical trials by the EARL program of the European Association of Nuclear Medicine (EANM). Therefore, our methods legitimately allow for the use of long-lived solid state 68 Ge/68 Ga phantoms instead of manually prepared 18 F phantoms to characterize comparability of 18 F measurements across different imaging sites or of longitudinal 18 F measurements at a single PET/CT system.

Technical Note: Determination of individual thyroid clearance effective half-life with a common handheld electronic dosimeter.

PURPOSE: To determine the thyroid clearance effective half-life T with a common handheld electronic dosimeter (ED) in patients undergoing radioiodine treatment for hyperthyroidism. METHODS: Dose rates from 12 inpatients were measured daily with an ED and with a clinical uptake counter. The ED was attached to the patient with two different setups, one using a cervical collar and another employing a neck strap. Estimation of T was performed by linear regression analysis of the log of both the ED and the uptake counter measurements versus time. The latter provided the reference data. RESULTS: Based on repeated neck strap dose rate measurements, individual Ts were determined with clinically required accuracy. The mean difference from the reference method equaled to -0.09 ± 0.35 days. CONCLUSIONS: Determination of individual T is feasible with a common handheld ED using the simple and easy to instruct neck strap measurement setup. This simple method complements stationary uptake counter measurements and thus may improve the accuracy of radioiodine treatment planning by adding an individual T for dose calculation.

Isotope independent determination of PET/CT modulation transfer functions from phantom measurements on spheres.

PURPOSE: A PET/CT system's imaging capabilities are best described by its point spread function (PSF) in the spatial domain or equivalently by its modulation transfer function (MTF) in the spatial frequency domain. Knowing PSFs or MTFs is a prerequisite for many numerical methods attempting to improve resolution and to reduce the partial volume effect. In PET/CT, the observed PSF is a convolution of the system's intrinsic imaging capabilities including image reconstruction (PSF0) and the positron range function (PRF) of the imaged ß+ emitting isotope. A PRF describes the non-Gaussian distribution of ß+ annihilation events around a hypothetical point source. The main aim was to introduce a new method for determining a PET/CT system's intrinsic MTF (MTF0) from phantom measurements of hot spheres independently of the ß+ emitting isotope used for image acquisition. Secondary aim was to examine non-Gaussian and nonlinear MTFs of a modern iterative reconstruction algorithm. METHODS: PET/CT images of seven phantom spheres with volumes ranging from 0.25 to 16 ml and filled either with 18F or with 68Ga were acquired and reconstructed using filtered back projection (FBP). MTFs were modeled with linear splines. The spline fit iteratively minimized the mean squared error between the acquired PET/CT image and a convolution of the thereof derived PSF with a numerical representation of the imaged hot phantom sphere. For determining MTF0, the numerical sphere representations were convolved with a PRF, simulating a fill with either 18F or 68Ga. The MTFs determined by this so-called MTF fit method were compared with MTFs derived from point source measurements and also compared with MTFs derived with a previously published PSF fit method. The MTF fit method was additionally applied to images reconstructed by a vendor iterative algorithm with PSF recovery (Siemens TrueX). RESULTS: The MTF fit method was able to determine 18F and 68Ga dependent MTFs and MTF0 from FBP reconstructed images. Root-mean-square deviation between fit determined MTFs and point source determined MTFs ranged from 0.023 to 0.039. MTFs from Siemens TrueX reconstructions varied with size of the imaged sphere. CONCLUSIONS: MTF0 can be determined regardless of the imaged isotope, when using existing PRF models for the MTF fit method presented. The method proves that modern iterative PET/CT reconstruction algorithms have nonlinear imaging properties. This behaviour is not accessible by point source measurements. MTFs resulting from these clinically applied algorithms need to be estimated from objects of similar geometry to those intended for clinical imaging.

Analysis of relation between hypoxia PET imaging and tissue-based biomarkers during head and neck radiochemotherapy.

BACKGROUND: Tumor hypoxia is associated with poor prognosis and outcome and can be visualized using 18F-MISO-positron emission tomography (PET) imaging. The goal of this study was to evaluate the correlation between biological markers and biological imaging in a group of patients in whom a correlation between biological imaging and outcome has previously been demonstrated. MATERIAL AND METHODS: In a prospective pilot project, 16 patients with locally advanced cancer of the head and neck underwent 18F-MISO-PET scans before and during primary radiochemotherapy in addition to 18F-FDG-PET and computed tomography (CT). Tumor biopsies were stained for three tissue-based markers (Ku80, CAIX, CD44); in addition, human papillomavirus (HPV) status was assessed. H-scores of marker expression were generated and the results were correlated with the biological imaging and clinical outcome. RESULTS: No statistically significant correlation was established between the H-scores for Ku80, CD44 and CAIX or between any of the H-scores and the imaging variables (tumor volume on 18F-FDG-PET in ml, hypoxic subvolume as assessed by 18F-MISO-PET in ml, and SUVmax tumor/SUVmean muscle during the 18F-MISO-PET). A statistically significant negative correlation was found between CD44 H-score and HPV status (p = .004). Cox regression analysis for overall survival and recurrence-free survival showed one significant result for CAIX being associated with improved overall survival [hazard ratio 0.96 (0.93-1.00), p = .047]. CONCLUSION: Expression of Ku80, CAIX and CD44 as assessed by immunohistochemistry of tumor biopsies were not correlated to one another or the biological imaging data. However, there was a significant influence of CAIX on overall survival and between CD44 and HPV.

Radiation exposure levels of routine SPECT/CT imaging protocols.

AIMS: To assess incremental and total patient exposure from clinical SPECT/CT imaging by means of effective dose estimations with regards to different protocols and SPECT/CT systems. MATERIALS AND METHODS: Consecutive patient exposure levels were documented prospectively from SPECT/CT operations at three European imaging centers. Documentation included the volume-weighted computed tomography (CT) dose index, the CT dose length product (DLP) and the amount of applied radiopharmaceutical. SPECT/CT examinations were categorized regionally into head, neck, myocardium, thorax, abdomen, extremities and whole-body. Effective dose from the CT (EDCT) was estimated from the DLP using gender specific conversion factors. EDSPECT was estimated from the injected activity levels and corresponding conversion factors (ICRP 106). RESULTS: This study included 678 SPECT/CT examinations. EDCT per indication and EDSPECT per tracer ranged from 0.01mSv to 7.4mSv and from 1.1mSv to 12.2mSv, respectively. In general, EDSPECT contributed most to overall patient exposure. Total EDSPECT/CT averaged across all protocol categories was 6.7mSv. CONCLUSION: Total patient exposure from clinical SPECT/CT is 7mSv on average. Individual dose levels vary with the clinical indication and on-site protocol parameters.

Modelling parametric down-conversion yielding spectrally pure photon pairs.

Pair creation by spontaneous parametric down-conversion (SPDC) has become a reliable source for single-photon states, used in many kinds of quantum information experiments and applications. In order to be spectrally pure, the two photons within a generated pair should be as frequency-uncorrelated as possible. For this purpose most experiments use narrow bandpass filters, having to put up with a drastic decrease in count rates. This article elaborates (theoretically and by numerical evaluation) the alternative method to engineer a setup such that the SPDC-generated quantum states are intrinsically pure. Using pulsed pump lasers and periodically poled crystals this approach makes bandpass filtering obsolete and allows for significantly higher output intensities and therefore count rates in the detectors. After numerically scanning all common wavelength regimes, polarisation configurations and three different non-linear crystals, we present a broad variety of setups which allow for an implementation of this method.

Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome.

PURPOSE: The aim was to assess changes of tumour hypoxia during primary radiochemotherapy (RCT) for head and neck cancer (HNC) and to evaluate their relationship with treatment outcome. MATERIAL AND METHODS: Hypoxia was assessed by FMISO-PET in weeks 0, 2 and 5 of RCT. The tumour volume (TV) was determined using FDG-PET/MRI/CT co-registered images. The level of hypoxia was quantified on FMISO-PET as TBRmax (SUVmaxTV/SUVmean background). The hypoxic subvolume (HSV) was defined as TV that showed FMISO uptake ⩾1.4 times blood pool activity. RESULTS: Sixteen consecutive patients (T3-4, N+, M0) were included (mean follow-up 31, median 44months). Mean TBRmax decreased significantly (p<0.05) from 1.94 to 1.57 (week 2) and 1.27 (week 5). Mean HSV in week 2 and week 5 (HSV2=5.8ml, HSV3=0.3ml) were significantly (p<0.05) smaller than at baseline (HSV1=15.8ml). Kaplan-Meier plots of local recurrence free survival stratified at the median TBRmax showed superior local control for less hypoxic tumours, the difference being significant at baseline and after 2weeks (p=0.031, p=0.016). CONCLUSIONS: FMISO-PET documented that in most HNC reoxygenation starts early during RCT and is correlated with better outcome.

Exploratory geographical analysis of hypoxic subvolumes using 18F-MISO-PET imaging in patients with head and neck cancer in the course of primary chemoradiotherapy.

BACKGROUND AND PURPOSE: Hypoxia in head and neck tumours is associated with poor prognosis and outcome, and can be visualized using (18)F-MISO-PET imaging; however, it is not clear whether the size and location of hypoxic subvolumes remain stable during therapy. In a pilot project, we conducted an exploratory analysis of persistent tumour hypoxia during treatment. MATERIALS AND METHODS: Sixteen patients with locally advanced head and neck tumours underwent consecutive (18)F-MISO-PET scans before and during primary chemoradiotherapy. The size, location and overlap of the hypoxic subvolumes were analysed using a semi-automatic algorithm based on a tumour to normal tissue ratio of 1.5. RESULTS: Quantitative evaluation showed tumour hypoxia in week 0 in 16 out of 16 and in week 2 in 5 out of 14 patients. For the five patients with persistent hypoxia, both increased and decreased hypoxic subvolumes could be observed. Mean hypoxic subvolume overlap was 55% of the hypoxic volume of the first scan and 72% of the hypoxic volume of the second scan. A stationary (in four out of five patients) and dynamic component (in three out of five patients) could be differentiated. CONCLUSION: In patients with persistent hypoxia after 2 weeks of treatment, the hypoxic subvolumes showed mostly a geographically relatively stable conformation.

Transconvolution and the virtual positron emission tomograph--a new method for cross calibration in quantitative PET∕CT imaging.

PURPOSE: Positron emission tomography (PET)∕computed tomography (CT) measurements on small lesions are impaired by the partial volume effect, which is intrinsically tied to the point spread function of the actual imaging system, including the reconstruction algorithms. The variability resulting from different point spread functions hinders the assessment of quantitative measurements in clinical routine and especially degrades comparability within multicenter trials. To improve quantitative comparability there is a need for methods to match different PET∕CT systems through elimination of this systemic variability. Consequently, a new method was developed and tested that transforms the image of an object as produced by one tomograph to another image of the same object as it would have been seen by a different tomograph. The proposed new method, termed Transconvolution, compensates for differing imaging properties of different tomographs and particularly aims at quantitative comparability of PET∕CT in the context of multicenter trials. METHODS: To solve the problem of image normalization, the theory of Transconvolution was mathematically established together with new methods to handle point spread functions of different PET∕CT systems. Knowing the point spread functions of two different imaging systems allows determining a Transconvolution function to convert one image into the other. This function is calculated by convolving one point spread function with the inverse of the other point spread function which, when adhering to certain boundary conditions such as the use of linear acquisition and image reconstruction methods, is a numerically accessible operation. For reliable measurement of such point spread functions characterizing different PET∕CT systems, a dedicated solid-state phantom incorporating (68)Ge∕(68)Ga filled spheres was developed. To iteratively determine and represent such point spread functions, exponential density functions in combination with a Gaussian distribution were introduced. Furthermore, simulation of a virtual PET system provided a standard imaging system with clearly defined properties to which the real PET systems were to be matched. A Hann window served as the modulation transfer function for the virtual PET. The Hann's apodization properties suppressed high spatial frequencies above a certain critical frequency, thereby fulfilling the above-mentioned boundary conditions. The determined point spread functions were subsequently used by the novel Transconvolution algorithm to match different PET∕CT systems onto the virtual PET system. Finally, the theoretically elaborated Transconvolution method was validated transforming phantom images acquired on two different PET systems to nearly identical data sets, as they would be imaged by the virtual PET system. RESULTS: The proposed Transconvolution method matched different PET∕CT-systems for an improved and reproducible determination of a normalized activity concentration. The highest difference in measured activity concentration between the two different PET systems of 18.2% was found in spheres of 2 ml volume. Transconvolution reduced this difference down to 1.6%. In addition to reestablishing comparability the new method with its parameterization of point spread functions allowed a full characterization of imaging properties of the examined tomographs. CONCLUSIONS: By matching different tomographs to a virtual standardized imaging system, Transconvolution opens a new comprehensive method for cross calibration in quantitative PET imaging. The use of a virtual PET system restores comparability between data sets from different PET systems by exerting a common, reproducible, and defined partial volume effect.

Biocompatibility of membranes with unrestricted somatic stem cells.

AIM: The biocompatibility of human osteoblasts (HOB) and human unrestricted somatic stem cells (USSCs) with membranes (BioGide®, GORE-TEX®, GENTA-FOIL resorb®, RESODONT®, BioMend®, BioMend® Extend™) was evaluated. MATERIALS AND METHODS: After osteogenic differentiation (dexamethasone, ascorbic acid and ß-glycerolphosphate) cells were seeded on membranes. On days 1, 3 and 7, attachment, proliferation, cell vitality, cytotoxicty and cell morphology were analyzed. RESULTS: Cells on BioGide® and RESODONT® exhibited significantly higher attachment (p<0.005) and proliferation (p<0.005). On BioMend® cells showed a significantly higher attachment compared to BioMend® Extend™ (p<0.005), whereas on BioMend® Extend™ cells had significantly higher proliferation (p<0.005). The vitality of cells was significantly better on BioGide® and RESODONT® (p<0.005). There were no significant differences between USSCs and HOBs. Scanning electron microscopy confirmed these results. CONCLUSION: BioGide® and RESODONT® had the best biocompatibility and are appropriate membranes for use in stem cell-derived regeneration of bone.

Is there an optimal scan time for 6-[F-18]fluoro-L-DOPA PET in pheochromocytomas and paragangliomas?

PURPOSE: To define the appropriate scan time for fluorine-18-labeled dihydroxyphenylalanine (F-18 DOPA) PET in oncological imaging of pheochromocytomas and paragangliomas. MATERIALS AND METHODS: F-18 DOPA PET examinations were performed in 9 patients with 7 pheochromocytomas and 4 head and neck paragangliomas using a dedicated PET scanner. The acquisition started with a dynamic single-bed scan in the tumor region over the first 60 minutes after tracer injection followed by a late time whole-body scan at approximately 130 minutes. Standard uptake values (SUVs) were calculated in tumors, surrounding background, and adjacent normal tissues of relevance. Furthermore, kinetic analysis was performed using a 2-compartment model with rate constants for uptake (K1'), release (k2'), metabolism (k3'), and reverse reaction (k4') for region of interest and pixel-wise analysis. RESULTS: All tumors show a marked increased F-18 DOPA uptake, which was visually detectable and distinguishable from the surrounding tissue. The SUV is significantly lower in neck paraganglioma compared with abdominal pheochromocytomas. Mean time-activity curves of F-18 DOPA in tumors show a rapid uptake of the tracer. Already 2 minutes after the injection, the activity in the tumor is beyond that of the blood pool. The average maximum value (SUVmean = 8.2) has already been reached after 20 minutes. Afterward, a very slight decrease of the tumor SUV starts, which still amounts to 80% of the maximum value after 132 minutes. Due to the continuous decrease of activity in the background tissue, the tumor-to-background ratio of SUVs shows a constant increase within the entire period of examination. The mean values of apparent kinetic constants obtained by region of interest analysis averaged over all tumors are as follows: K1' = 2.89 ± 2.56 min(-1), k2' = 2.59 ± 2.81 min(-1), k3' = 0.301 ± 0.395 min(-1), and k4' = 0.044 ± 0.043 min(-1). CONCLUSIONS: Pheochromocytoma and paraganglioma take up F-18 DOPA very quickly. At best, the acquisition for static clinical PET imaging of paraganglioma with F-18 DOPA can start at 20 minutes postinjection for maximum uptake in tumors. Separation of tumor, background, and adjacent normal tissues is feasible due to their differences in SUV values and kinetics. The kinetic analysis demonstrates an F-18 DOPA accumulation within the tumor due to considerable differences between the rate constants of uptake and metabolism. Second, in contradiction to healthy brain, paraganglionic tumors show a reversible F-18 DOPA metabolism.