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Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades it is known that cholecystokinine-2 receptor (CCK2R) is a promising target for the treatment of MTC with radiolabeled minigastrin analogues. Unfortunately, kidney toxicity precluded their therapeutic application so far. In 6 consecutive patients we evaluated with advanced 3D dosimetry whether improved minigastrin analogue 177Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received two injections of about 1 GBq (~80 µg) 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random cross-over sequence in order to evaluate biodistribution, pharmacokinetics as well as tumor- and organ dosimetry. ECG, blood count and blood chemistry were measured up to 12 weeks after administration of 177Lu-PP-F11N to assess safety. Results: In all patients 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach and kidneys. Altogether 13 tumors were eligible for dosimetry. The median (interquartile range = IQR) absorbed dose for tumors, stomach, kidneys and bone marrow was 0.88 Gy/GBq (0.85-1.04), 0.42 (0.25-1.01), 0.11 (0.07-0.13) and 0.028 (0.026-0.034). These resulted in a median (IQR) tumor-to-kidney dose ratio of 11.6 (8.11-14.4) without SG and 13.0 (10.2-18.6) with SG, which were not significantly different (P = 1.0). The median (IQR) tumor-to-stomach dose ratio was 3.34 (1.14-4.7). Adverse reactions (mainly hypotension, flushing and hypokalemia) were self-limiting and not higher than grade 1. Conclusion:177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With little kidney and bone marrow radiation dose 177Lu-PP-F11N shows promising biodistribution. The dose limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.

In this work we investigate the usage of deep learning techniques on SPECT data solving a multi-organ segmentation problem. We extract projections from 21 Lu-177 MELP SPECT scans and obtain the corresponding ground truth labels from the accompanied CT scans by forward-projection of 3D CT organ segmentations. We train a U-Net to predict the area of the kidney, spleen, liver, and background seen in the projection data, using a weighted dice loss between prediction and target labels to account for class imbalance. With our method we achieved a mean dice coefficient of 72 % on the test set, encouraging us to perform further experiments using the U-Net.

It has been long known that denoising of Single Photon Emission Computed Tomography (SPECT) projection data from multi channel collimators harbors the danger that features are filtered away as distinction between noise and signal in the 2D projection image does not consider the tomographic information (see Vija, Yahil et al.). We investigate if an approach using Neural Networks can overcome the past issues, by training a U-Net on Monte Carlo Simulations of the XCAT phantom. Although error metrics indicate improvement of signal statistics, we observe a loss of image features after the reconstruction. We show that when using OSEM reconstruction without denoising in projection domain, these features can be preserved.

Single Photon Emitted Computed Tomography (SPECT) is characterized by low photon counts which results in a high degree of image noise. In this work, we demonstrate the feasibility of applying deep learning-based image denoising networks to this imaging modality. We propose a four-layered U-Net for denoising of SPECT images that was trained using data obtained from Monte Carlo simulations of XCAT phantoms. Our proposed network was able to increase image quality by a factor of 14.15 dB as measured with PSNR.

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog (177)Lu-DOTA-(d-Glu)(6)-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH(2) ((177)Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 μg) of (177)Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of (177)Lu-PP-F11N to assess safety. Results: In all patients, (177)Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85–1.04), 0.42 (IQR: 0.25–1.01), 0.11 (IQR: 0.07–0.13), and 0.028 (IQR: 0.026–0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11–14.4) without SG and 13.0 (IQR: 10.2–18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14–4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: (177)Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, (177)Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of (177)Lu-PP-F11N.

Background We investigated the clinical performance of a quantitative multi-modal SPECT/CT reconstruction platform for yielding radioactivity concentrations of bone imaging with 99mTc-methylene diphosphonate (MDP) or 99mTc-dicarboxypropane diphosphonate (DPD). The novel reconstruction incorporates CT-derived tissue information while preserving the delineation of tissue boundaries. We assessed image-based reader concordance and confidence, and determined lesion classification and SUV thresholds from ROC analysis. Methods Seventy-two cancer patients were scanned at three US and two German clinical sites, each contributing two experienced board-certified nuclear medicine physicians as readers. We compared four variants of the reconstructed data resulting from the Flash3D (F3D) and the xSPECT Bone™ (xB) iterative reconstruction methods and presented images to the readers with and without a fused CT, resulting in four combinations. We used an all-or-none approach for inclusion, compiling results only when a reader completed all reads in a subset. After the final read, we conducted a “surrogate truth” reading, presenting all data to each reader. For any remaining discordant lesions, we conducted a consensus read. We next undertook ROC analysis to determine SUV thresholds for differentiating benign and lesional uptake. Results On a five-point rating scale of image quality, xB was deemed better by almost two points in resolution and one point better in overall acceptance compared to F3D. The absolute agreement of the rendered decision between the nine readers was significantly higher with CT information either inside the reconstruction (xB, xBCT) or simply through image fusion (F3DCT): 0.70 (xBCT), 0.67 (F3DCT), 0.64 (xB), and 0.46 (F3D). The confidence level to characterize the lesion was significantly higher (3.03x w/o CT, 1.32x w/CT) for xB than for F3D. There was high correlation between xB and F3D scores for lesion detection and classification, but lesion detection confidence was 41% higher w/o CT, and 21% higher w/CT for xB compared to F3D. Without CT, xB had 6.6% higher sensitivity, 7.1% higher specificity, and 6.9% greater AUC compared to F3D, and similarly with CT-fusion. The overall SUV-criterion (SUVc) of xB (12) exceeded that for xSPECT Quant™ (xQ; 9), an approach not using the tissue delineation of xB. SUV critical numbers depended on lesion volume and location. For non-joint lesions > 6 ml, the AUC for xQ and xB was 94%, with SUVc > 9.28 (xQ) or > 9.68 (xB); for non-joint lesions ≤ 6 ml, AUCs were 81% (xQ) and 88% (xB), and SUVc > 8.2 (xQ) or > 9.1 (xB). For joint lesions, the AUC was 80% (xQ) and 83% (xB), with SUVc > 8.61 (xQ) or > 13.4 (xB). Conclusion The incorporation of high-resolution CT-based tissue delineation in SPECT reconstruction (xSPECT Bone) provides better resolution and detects smaller lesions (6 ml), and the CT component facilitates lesion characterization. Our approach increases confidence, concordance, and accuracy for readers with a wide range of experience. The xB method retained high reading accuracy, despite the unfamiliar image presentation, having greatest impact for smaller lesions, and better localization of foci relative to bone anatomy. The quantitative assessment yielded an SUV-threshold for sensitively distinguishing benign and malignant lesions. Ongoing efforts shall establish clinically usable protocols and SUV thresholds for decision-making based on quantitative SPECT.

Introduction: Despite the introduction of new molecular targeted therapies, there is still an unmet need for an effective systemic therapy for advanced medullary thyroid carcinoma (MTC). As MTC expresses cholecystokinine-2 (CCK-2) receptors at a high incidence and density, targeting the CCK-2 receptor with radiolabelled gastrin analogues is a potential approach for radionuclide therapy. Unfortunately, kidney and bone marrow toxicity precluded therapeutic applications of CCK-2 receptor specific radiotracers until now. The aim of this prospective study is the feasibility testing of targeting CCK-2 receptors with the novel gastrin analogue [177Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nleu-Asp-PheNH2] (177Lu-PP-F11N) in six patients with advanced MTC (ClinicalTrials.gov: NCT02088645). Subjects and Methods: Six patients received two injections of 1 GBq 177Lu-PP-F11N, one injection with and the other without Physiogel (Gelofusin = plasma expander for nephroprotection) infusion. Planar scintigraphy and SPECT/CT scans were performed at several time points for up to 72 h post injection in order to calculate tumour- and organ doses using 3D voxel- and MIRD based dosimetry (Dosimetry Research Tool v5.2, Siemens Medical Solutions, USA). Blood samples were taken for bone marrow dose calculations. ECG, blood count and blood chemistry were measured up to 12 weeks after the second administration of 177Lu-PP-F11N in order to evaluate adverse events. Results: Adverse reactions (mainly hypotension, flushing and hypokalemia) were self-limiting and not higher than grade 1, according to CTCAE version 4.03. In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, in the kidneys, stomach and the colon. Altogether, 14 tumours were eligible for dosimetry. The median (range) radiation dose for tumours, kidneys and bone marrow was 0.88 Gy/GBq (0.69-2.85), 0.090 (0.045-0.115) and 0.010 (0.008-0.016). These resulted in median tumour-to-kidney dose ratios of 12.8 (6.0-52.4) (without Physiogel) and 12.4 (6.4-29.8) (with Physiogel), which was not significantly different. The median tumour-to-bone marrow dose ratio was 87.9 (52.8-316.4). Discussion/Conclusion: The administration of the novel CCK-2 receptor ligand 177Lu-PP-F11N was safe in all six examined patients. Visualization of metastasized/recurrent disease in all patients provides evidence that CCK-2 receptor targeting with 177Lu-PP-F11N is feasible in patients with MTC. The dosimetry results indicate tumour doses that could enable radionuclide therapy. Dosimetry results for kidneys and bone marrow revealed low organ doses, as well as excellent tumour-to-kidney and tumour-to-bone marrow ratios. Further studies will be necessary to evaluate the theranostic potential of 177Lu-PP-F11N in patients with CCK-2 receptor expressing tumours.

Clinical SPECT routine uses tedious manual image evaluation using simplistic region of interest statistical analysis without taking the quantification aspect into account. We introduce a software framework for quantitative analysis of 3D/4D SPECT·CT Tc-99m bone scintigraphy data that incorporates automatic analysis and osseous tissue healthiness classification based on a patient database annotated by an experienced physician. The usage workflow of our framework starts with the input of SPECT and CT data registered on each other. Using CT information we segment osseous tissue also in the co-registered SPECT dataset. Patient weight, injected dose and system calibration factor are read out of the input datasets in order to estimate tracer activity concentration (AC) in kBq/ml and standardized uptake value (SUV). Support vector machine method is used to classify tissue based on the reference patient database that contains quantitative data for normal and abnormal tissue. Evaluation of the framework was done on patient data acquired 3 hours post injection on a SPECT/CT Symbia T6 system using protocol for quantitative estimation of tracer activity. The acquired projection data was reconstructed using Ordered Subset Expectation Maximization with 3D resolution recovery (OSEM-3D) with attenuation and scatter correction. Data analysis showed a significant correlation between AC and bone density measured in Hounsfield Units (HU) for both male and female patients. The proposed methods demonstrate the ability to automatically quantify and distinguish abnormal tissue from healthy one and to increase physicians' diagnostic confidence.

Background Routine single-photon emission computed tomography (SPECT) currently lacks quantitative information on regional activity concentration (ACC) of the injected tracer (e.g. kBq/ml). Furthermore, little is known on the skeletal absolute concentration of 99mTc-DPD after intravenous injection in bone scintigraphy. The aim of this study is to determine ACC in the healthy lumbar vertebrae of patients using a recently published quantitative SPECT/computed tomography (CT) protocol. Methods Lumbar vertebrae ACC estimates were performed in 50 female patients (mean age 69.88 ± 13.73 years) who had been administered 562.84 ± 102.33 MBq of 99mTc-DPD and had undergone SPECT acquisition 4 h after the injection. The SPECT/CT system was calibrated against a well counter. Images were reconstructed with Flash3D. ACC and CT tissue density were measured in volumes of interest drawn over the spongious bone tissue of the three lower lumbar vertebral bodies when these exhibited no focal CT or SPECT pathology. Results Average ACC measured in the normal spongious bone tissue was 48.15 ± 13.66 kBq/ml (95% confidence interval (CI) 45.81 to 50.50 kBq/ml). This corresponds to a mean standardised uptake value (SUV) of (5.91 ± 1.54) (95% CI (5.64 to 6.17) SUV). SUV correlated significantly with Hounsfield units (HU) (r = 0.678, p < 0.0001). Significant negative correlations were observed between age and HU (r = −0.650, p < 0.0001) and between age and SUV (r = −0.385, p < 0.0001). Conclusions The SUVs determined for 99mTc-DPD uptake 4 h post injection are in the same range as those reported for [18F]fluoride in positron emission tomography. The strong correlation of SUV with bone CT density underlines the physiological significance of this variable. Our data suggest further investigation of the potential value of ACC measurement in the diagnosis of pathological conditions such as osteoporosis or in following up osseous metastases under therapy.