Oliver S. Grosser

Predictive Value of Intratumoral 99mTc-Macroaggregated Albumin Uptake in Patients with Colorectal Liver Metastases Scheduled for Radioembolization with 90Y-Microspheres

90Y radioembolization is a promising therapy for patients with primary and secondary liver malignancies. Pretherapeutic assessment consists of hepatic angiography and 99mTc-macroaggregated albumin (99mTc-MAA) perfusion scintigraphy to estimate the liver-to-lung shunt and exclude extrahepatic 99mTc-MAA deposition. However, the predictive value of intratumoral 99mTc-MAA uptake remains unclear. Methods: One hundred four patients with chemotherapy-refractory liver-dominant metastatic colorectal cancer were treated with 90Y radioembolization between December 2006 and December 2010. All of the patients underwent angiographic assessment and perfusion scintigraphy with 99mTc-MAA before lobar 90Y radioembolization. For inclusion, patients must have undergone pretherapeutic and follow-up MR imaging (6 wk and 3 mo after radioembolization, respectively). The degree of intratumoral 99mTc-MAA uptake was rated, and liver metastases were classified according to changes in tumor diameter on both an individual and a patient basis using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Response at both time points, MAA uptake, and catheter position were then statistically analyzed in a linear and generalized linear mixed model at a significance level of 0.05 (P value). Results: Sixty-six patients with a total of 435 colorectal liver metastases (mean number of lesions ± SD, 6.6 ± 2.8; mean lesion size ± SD, 33.8 ± 21.2 mm; lesion size range, 10–154 mm) were included in this analysis. According to the patient-based analysis, 3 patients had partial response, 49 stable disease, and 6 progressive disease after 6 wk. After 3 mo, 5 patients showed partial response, 26 stable disease, and 17 progressive disease. There was no association of patient-based tumor response with overall 99mTc-MAA uptake (P = 0.172) or with catheter position (P = 0.6456). Furthermore, an interaction effect of 99mTc-MAA uptake and catheter position in relation to tumor response was not found (P = 0.512). Moreover, in lesion-based analysis according to RECIST 1.1 there was no association of tumor response with degree of 99mTc-MAA uptake, catheter position, or interaction of 99mTc-MAA uptake and catheter position (P = 0.339, 0.593, and 0.658, respectively). Conclusion: Response to 90Y radioembolization was found to be independent of the degree of 99mTc-MAA uptake. Therefore, therapy should not be withheld from patients with colorectal liver metastases lacking intratumoral 99mTc-MAA accumulation.

SPECT-imaging of activity-dependent changes in regional cerebral blood flow induced by electrical and optogenetic self-stimulation in mice

Electrical and optogenetic methods for brain stimulation are widely used in rodents for manipulating behavior and analyzing functional connectivities in neuronal circuits. High-resolution in vivo imaging of the global, brain-wide, activation patterns induced by these stimulations has remained challenging, in particular in awake behaving mice. We here mapped brain activation patterns in awake, intracranially self-stimulating mice using a novel protocol for single-photon emission computed tomography (SPECT) imaging of regional cerebral blood flow (rCBF). Mice were implanted with either electrodes for electrical stimulation of the medial forebrain bundle (mfb-microstim) or with optical fibers for blue-light stimulation of channelrhodopsin-2 expressing neurons in the ventral tegmental area (vta-optostim). After training for self-stimulation by current or light application, respectively, mice were implanted with jugular vein catheters and intravenously injected with the flow tracer 99m-technetium hexamethylpropyleneamine oxime (99mTc-HMPAO) during seven to ten minutes of intracranial self-stimulation or ongoing behavior without stimulation. The 99mTc-brain distributions were mapped in anesthetized animals after stimulation using multipinhole SPECT. Upon self-stimulation rCBF strongly increased at the electrode tip in mfb-microstim mice. In vta-optostim mice peak activations were found outside the stimulation site. Partly overlapping brain-wide networks of activations and deactivations were found in both groups. When testing all self-stimulating mice against all controls highly significant activations were found in the rostromedial nucleus accumbens shell. SPECT-imaging of rCBF using intravenous tracer-injection during ongoing behavior is a new tool for imaging regional brain activation patterns in awake behaving rodents providing higher spatial and temporal resolutions than 18F-2-fluoro-2-dexoyglucose positron emission tomography.

Intrahepatic Activity Distribution in Radioembolization with Yttrium-90-Labeled Resin Microspheres Using the Body Surface Area Method--A Less than Perfect Model.

PURPOSE To retrospectively assess the influence of the parameters of the body surface area (BSA) method in hepatic radioembolization using yttrium-90-labeled microspheres on the determination of the prescribed activity. MATERIALS AND METHODS Data from 283 consecutive patients treated with radioembolization (BSA method) were included. For interindividual comparisons, activity concentrations (ACs; MBq/mL) were calculated for each liver. The impact of the BSA method parameters was assessed by analysis of variance and pairwise t test with Bonferroni-Holm correction. RESULTS Prescribed activity was 1.01-2.71 GBq, with BSA, liver volume (LV), tumor burden, and the liver-lung shunt reduction factor (LLS RF) being significant contributing factors to the AC (all P < .0001, analysis of variance). BSA and LV correlated only moderately (ρ = 0.46, P < .0001). Compared with base activity defined by the BSA (median = 1.67 GBq; range, 1.20-2.32 GBq), the activity contribution of tumor burden was small (median = 150 MBq; range, 3-800 MBq). Resulting activities were reduced according to LLS RF by 20% in 12.4% and by 40% in 3.5% of patients. AC was significantly (up to 56%) lower in association with larger LV than in small LV (LV < 1,500 mL vs ≥ 2,500 mL, P < .0001). CONCLUSIONS In the BSA model, BSA and LV showed only a moderate correlation, resulting in a significantly lower AC in patients with larger livers. Tumor burden percentage contributed little to the prescribed activity because the BSA model did not account for actual LVs and tumor volumes. These inaccuracies may potentially result in underdosage in patients with larger livers, especially if further LLS RF needs to be applied.

Comparative Evaluation of the Biodistribution Profiles of a Series of Nonpeptidic Neurotensin Receptor-1 Antagonists Reveals a Promising Candidate for Theranostic Applications

Neurotensin receptor-1 (NTR1) is a promising target for diagnostic imaging and targeted radionuclide therapy. The aim of this study was to evaluate the biodistribution profiles of a series of newly developed diarylpyrazole-based NTR1 antagonists regarding their suitability as diagnostic and potentially radiotherapeutic agents. Methods: 3BP-227, 3BP-228, and 3BP-483 were labeled with 111In and injected intravenously into NTR1-positive HT29 xenograft–bearing nude mice. At 3, 6, 12, and 24 h after administration, SPECT/CT images were acquired or mice were sacrificed for ex vivo determination of tissue-associated radioactivity. Results: High-contrast tumor visualization in SPECT/CT images was achieved using the 3 compounds of this study. Ex vivo biodistribution studies confirmed a high and persistent tumor uptake, peaking at 6 h after injection for 111In-3BP-227 (8.4 ± 3.1 percentage injected dose per gram [%ID/g]) and at 3 h after injection for 111In-3BP-228 (10.2 ± 5.3 %ID/g) and 111In-3BP-483 (1.9 ± 0.8 %ID/g). Tumor–to–normal-tissue ratios obtained with 111In-3BP-227 and 111In-3BP-228 were consistently greater than 1. Conclusion: On the basis of the superior biodistribution profile compared with previously reported radiolabeled NTR1 ligands, 111In-3BP-227 is an ideal candidate for further development as a theranostic tracer.

Optimization of SPECT-CT Hybrid Imaging Using Iterative Image Reconstruction for Low-Dose CT: A Phantom Study.

Background Hybrid imaging combines nuclear medicine imaging such as single photon emission computed tomography (SPECT) or positron emission tomography (PET) with computed tomography (CT). Through this hybrid design, scanned patients accumulate radiation exposure from both applications. Imaging modalities have been the subject of long-term optimization efforts, focusing on diagnostic applications. It was the aim of this study to investigate the influence of an iterative CT image reconstruction algorithm (ASIR) on the image quality of the low-dose CT images. Methodology/Principal Findings Examinations were performed with a SPECT-CT scanner with standardized CT and SPECT-phantom geometries and CT protocols with systematically reduced X-ray tube currents. Analyses included image quality with respect to photon flux. Results were compared to the standard FBP reconstructed images. The general impact of the CT-based attenuation maps used during SPECT reconstruction was examined for two SPECT phantoms. Using ASIR for image reconstructions, image noise was reduced compared to FBP reconstructions for the same X-ray tube current. The Hounsfield unit (HU) values reconstructed by ASIR were correlated to the FBP HU values(R2 ≥ 0.88) and the contrast-to-noise ratio (CNR) was improved by ASIR. However, for a phantom with increased attenuation, the HU values shifted for low X-ray tube currents I ≤ 60 mA (p ≤ 0.04). In addition, the shift of the HU values was observed within the attenuation corrected SPECT images for very low X-ray tube currents (I ≤ 20 mA, p ≤ 0.001). Conclusion/Significance In general, the decrease in X-ray tube current up to 30 mA in combination with ASIR led to a reduction of CT-related radiation exposure without a significant decrease in image quality.

PET imaging with 11C-MDG, but not 18F-FDG, for proof of pharmacology of a sodium-dependent glucose cotransporter 2 inhibitor Ipragliflozin

lations based on 99mTc-MAA imaging, as reported with HCC,. . . should be seen critically.” This statement about HCC cannot be based on a study dealing with a different pathology and a different kind of microsphere. Metastases and HCC are different types of tumors (more peripheral vascularization in HCC and a higher proportion of small lesions in metastases). Results observed with one type of lesion cannot be extrapolated to the other. Ulrich et al. extend their conclusions from results obtained with resin spheres (SIR-Spheres) to glass spheres (TheraSphere; BTG), as if the two medical devices were identical. This is absolutely not the case from the dosimetric and biologic point of view (9). Activity per sphere is 50 times lower for the resin spheres than for the glass ones, requiring a 50 times higher number of particles to give the same mean absorbed dose, with a consequent increased real embolic effect. Because of this tremendous difference between the number of injected particles, we cannot agree about extrapolating results concerning the predictive value of 99mTc-MAA scintigraphy from resin to glass microspheres. The evidence on HCC treatment provided by the teams of Rennes (10) and Milan (2), both of which used glass spheres, in contradiction to what is reported by Ulrich et al., was not discussed adequately. In the first study (mean lesion size of 7.1 cm), 99mTc-MAA SPECT/CT was predictive of response with an accuracy of 90% (10). The lesion-absorbed dose was the only parameter associated not only with response but also with overall survival at multivariate analysis (10). Also, the second study found a dose–response relationship in HCC (2). Mean tumoral absorbed dose significantly correlated with the EASL response (Spearman r 5 0.60, P , 0.001). In conclusion, when reporting on the predictive value of 99mTcMAA scintigraphy in SIRT, one should pay attention to the type of microspheres, the quantification method for estimating the 99mTcMAA degree of perfusion, dosimetry issues, tumor type, lesion size, and the method of response assessment. At present, there is confirmed evidence that 99mTc-MAA SPECT–based dosimetry is predictive of response in HCC when glass microspheres are used. Published results with resin microspheres, especially in metastases, require additional studies to assess the predictive power of 99mTc-MAA scintigraphy. Conclusions from a methodologically weak study about the lack of predictive value of 99mTc-MAA uptake in liver metastases treated with resin microspheres should not be extrapolated to HCC treated with glass microspheres.

Software-assisted dosimetry in peptide receptor radionuclide therapy with 177Lutetium-DOTATATE for various imaging scenarios

In peptide receptor radionuclide therapy (PRRT) of patients with neuroendocrine neoplasias (NENs), intratherapeutic dosimetry is mandatory for organs at risk (e.g. kidneys) and tumours. We evaluated commercial dosimetry software (Dosimetry Toolkit) using varying imaging scenarios, based on planar and/or tomographic data, regarding the differences in calculated organ/tumour doses and the use for clinical routines. A total of 16 consecutive patients with NENs treated by PRRT with 177Lu-DOTATATE were retrospectively analysed. Single-photon emission computed tomography (SPECT)/low-dose computed tomography (CT) of the thorax and abdomen and whole body (WB) scintigraphy were acquired up to 7 days p.i. (at a maximum of five imaging time points). Different dosimetric scenarios were evaluated: (1) a multi-SPECT-CT scenario using SPECT/CT only; (2) a planar scenario using WB scintigraphy only; and (3) a hybrid scenario using WB scintigraphy in combination with a single SPECT/low-dose CT. Absorbed doses for the kidneys, liver, spleen, lungs, bladder wall and tumours were calculated and compared for the three different scenarios. The mean absorbed dose for the kidneys estimated by the multi-SPECT-CT, the planar and the hybrid scenario was 0.5 ± 0.2 Sv GBq-1, 0.8 ± 0.4 Sv GBq-1 and 0.6 ± 0.3 Sv GBq-1, respectively. The absorbed dose for the residual organs was estimated higher by the planar scenario compared to the multi-SPECT-CT or hybrid scenario. The mean absorbed tumour doses were 2.6 ± 1.5 Gy GBq-1 for the multi-SPECT-CT, 3.1 ± 2.2 Gy GBq-1 for the hybrid scenario and 5.3 ± 6.3 Gy GBq-1 for the planar scenario. SPECT-based dosimetry methods determined significantly lower kidney doses than the WB scintigraphy-based method. Dosimetry based completely on SPECT data is time-consuming and tedious. Approaches combining SPECT/CT and WB scintigraphy have the potential to ensure compromise between accuracy and user-friendliness.

Pharmacokinetics of 99mTc-MAA- and 99mTc-HSA-Microspheres Used in Preradioembolization Dosimetry: Influence on the Liver–Lung Shunt

Perfusion scintigraphy using 99mTc-labeled albumin aggregates is mandatory before hepatic radioembolization with 90Y-microspheres. As part of a prospective trial, the intrahepatic and intrapulmonary stability of 2 albumin compounds, 99mTc-MAA (macroaggregated serum albumin [MAA]) and 99mTc-HSA (human serum albumin [HSA]), was assessed. Methods: In 24 patients with metastatic colorectal cancer, biodistribution (liver, lung) and liver–lung shunt (LLS) of both tracers (12 patients each) were assessed by sequential planar scintigraphy (1, 5, and 24 h after injection). Results: Liver uptake of both albumin compounds decreased differently. Although initial LLSs at 1 h after injection were similar in both groups, MAA-LLS increased significantly from 1 (3.9%) to 5 h (7.7%) and 24 h (9.9%) after injection, respectively. HSA-LLS did not change significantly (1 to 5 h), indicating a steady state of pulmonary and intrahepatic degradation. Conclusion: Compared with 99mTc-MAA-microspheres, 99mTc-HSA-microspheres are likely more resistant to degradation over time, allowing a reliable LLS determination even at later time points.

Improvement of image quality and dose management in CT fluoroscopy by iterative 3D image reconstruction

AbstractObjectivesThe objective of this study was to assess the influence of an iterative CT reconstruction algorithm (IA), newly available for CT-fluoroscopy (CTF), on image noise, readers’ confidence and effective dose compared to filtered back projection (FBP).MethodsData from 165 patients (FBP/IA = 82/74) with CTF in the thorax, abdomen and pelvis were included. Noise was analysed in a large-diameter vessel. The impact of reconstruction and variables (e.g. X-ray tube current I) influencing noise and effective dose were analysed by ANOVA and a pairwise t-test with Bonferroni–Holm correction. Noise and readers’ confidence were evaluated by three readers.ResultsNoise was significantly influenced by reconstruction, I, body region and circumference (all p ≤ 0.0002). IA reduced the noise significantly compared to FBP (p = 0.02). The effect varied for body regions and circumferences (p ≤ 0.001). The effective dose was influenced by the reconstruction, body region, interventional procedure and I (all p ≤ 0.02). The inter-rater reliability for noise and readers’ confidence was good (W ≥ 0.75, p < 0.0001). Noise and readers’ confidence were significantly better in AIDR-3D compared to FBP (p ≤ 0.03). Generally, IA yielded a significant reduction of the median effective dose.ConclusionThe CTF reconstruction by IA showed a significant reduction in noise and effective dose while readers’ confidence increased.Key Points• CTF is performed for image guidance in interventional radiology. • Patient exposure was estimated from DLP documented by the CT. • Iterative CT reconstruction is appropriate to reduce image noise in CTF. • Using iterative CT reconstruction, the effective dose was significantly reduced in abdominal interventions.

Reply: Results Confounded by a Disregard for Basic Dose–Response Radiobiology

additional effort in accurately translating their visual descriptors of “low” versus “high” 99mTc-MAA implantation into absorbed radiation doses to tumor, their results cannot be verified. This is because inherent to the BSA method is the assumption of a fixed and favorable mean tumor–to–normal liver ratio for all patients (4,5)—an assumption that confounds their results. To illustrate this point, say we have patients A and B with advanced colorectal liver metastases, identical height (170 cm), identical body mass (65 kg), a negligible lung shunt (,1%), a 1kg lung mass, a 300-g tumor mass, and a 1,400-g nontumorous liver mass. Both A and B have good but slightly different mean tumor–to–normal liver ratios of 2.5 and 2.0, respectively. By visual scintigraphic appearance, both patients would be classified as “high” 99mTc-MAA implantation by the study of Ulrich et al. The BSA method will prescribe an identical 90Y activity of 1.73 GBq for both. However, tricompartmental MIRD macrodosimetry will show that A received a satisfactory mean tumor dose of 100 Gy whereas B received a suboptimal mean tumor dose of only 86 Gy. It follows—to no surprise—that A will have some treatment response whereas B will not, even though both been classified in the “high” group. It is common sense that 99mTc-MAA is an imperfect surrogate for 90Y microspheres. It is a tool, and the usefulness of any tool is only as good as its user and the complexity of the task at hand. To conduct a scientifically robust study on the predictive value of 99mTc-MAA yielding reproducible and radiobiologically meaningful results, one must have accurate means of, first, delineating artery-specific planning target volumes (e.g., catheterdirected CT angiography or, at minimum, cone-beam CT); second, determining technical success in accordance with the intended radiation therapy plan (e.g., 90Y time-of-flight PET/ CT or, at minimum, 90Y bremsstrahlung SPECT/CT); and third, quantifying the predictive radiation absorbed dose of technically successful cases by 99mTc-MAA SPECT/CT (5). Clinical validation of predicted radiation absorbed doses by 99mTc-MAA may be achieved either indirectly by follow-up diagnostic imaging (5) or directly by 90Y PET/CT quantification (subject of current research). In the discussion by Ulrich et al., they showed some awareness of the importance of the radiation absorbed dose and the tumor– to–normal liver ratio but did not explain why these were not factored into their analyses. Readers of their publication are advised to be cautious of their results and conclusions.