Inhomogeneous Activity Distributions Research Articles

Toward a Patient-Specific Traceable Quantification of SPECT/CT-Based Radiopharmaceutical Distributions.

Quantitative SPECT/CT imaging is currently the state of the art for peritherapeutic monitoring of radiopharmaceutical distributions. Because of poor resolution, however, the verification of SPECT/CT-based activity distributions is of particular importance. Because of the lack of a ground truth in patient measurements, phantoms are commonly used as a substitute for clinical validation of quantitative SPECT/CT. Because of the time-consuming and erroneous preparation of multicompartment phantoms, such as for the kidney, the usually very complex internal activity distributions are typically replaced by 1- or 2-compartment models. To provide a simplified solution for generating inhomogeneous activity distributions, this work presents a methodology for designing single-compartment phantoms that mimic inhomogeneous spatial activity distributions by using internal filling structures of different volume fractions. Methods: A series of phantoms with different filling structures was designed, 3-dimensionally printed, and measured. After assessing the feasibility of the presented approach in a simple geometry, a set of three patient-specific kidney phantoms was designed on the basis of the contrast-enhanced CT scan of a patient with metastatic castration-resistant prostate cancer. Internal gyroid structures of different wall thicknesses were used in the renal medulla and cortex to reproduce the inhomogeneous activity distribution observed in a peritherapeutic SPECT/CT acquisition 24 h after injection of 177Lu-labeled prostate-specific membrane antigen (apparent activity concentration ratios of 1:1, 1:3.5, and 1:7.5). After 3-dimensional printing, SPECT/CT experiments were performed and the results were compared with the patient data for different reconstruction settings (iterations, subsets, and postfiltering). Results: Good agreement was found between phantom designs and fabricated phantoms (based on high-resolution CT). No internal filling structures were visible in any of the SPECT images, indicating a sufficiently small feature size. Although good visual and quantitative agreement was achieved for certain combinations of filling structure and reconstruction, a histogram analysis indicated an even more complex activity distribution in the patient than represented by the two compartments assumed in our model. Conclusion: The proposed methodology provides patient-specific phantoms mimicking inhomogeneous activity distributions while using a single stock solution, thus simplifying the filling process and reducing uncertainties in the activity determination. This method enables an unprecedented possibility for patient-specific evaluation of radiopharmaceutical uptake, reducing uncertainties in internal dosimetry and individualized treatments.

A gel tumour phantom for assessment of the accuracy of manual and automatic delineation of gross tumour volume from FDG-PET/CT

Introduction. Our primary aim was to make a phantom for PET that could mimic a highly irregular tumour and provide true tumour contours. The secondary aim was to use the phantom to assess the accuracy of different methods for delineation of tumour volume from the PET images. Material and methods. An empty mould was produced on the basis of a contrast enhanced computed tomography (CT) study of a patient with a squamous cell carcinoma in the head and neck region. The mould was filled with a homogeneous fast-settling gel that contained both 18F for positron emission tomography (PET) and an iodine contrast agent. This phantom (mould and gel) was scanned on a PET/CT scanner. A series of reference tumour contours were obtained from the CT images in the PET/CT. Tumour delineation based on the PET images was achieved manually, by isoSUV thresholding, and by a recently developed three-dimensional (3D) Difference of Gaussians algorithm (DoG). Average distances between the PET-derived and reference contours were assessed by a 3D distance transform. Results. The manual, thresholding and DoG delineation methods resulted in volumes that were 146%, 86% and 100% of the reference volume, respectively, and average distance deviations from the reference surface were 1.57 mm, 1.48 mm and 1.0, mm, respectively. Discussion. Manual drawing as well as isoSUV determination of tumour contours in geometrically irregular tumours may be unreliable. The DoG method may contribute to more correct delineation of the tumour. Although the present phantom had a homogeneous distribution of activity, it may also provide useful knowledge in the case of inhomogeneous activity distributions. Conclusion. The geometric irregular tumour phantom with its inherent reference contours was an important tool for testing of different delineation methods and for teaching delineation.

Inhomogeneous activity distribution of 177Lu-DOTA0-Tyr3-octreotate and effects on somatostatin receptor expression in human carcinoid GOT1 tumors in nude mice

The aim of this study was to investigate the activity distribution in neouroendocrine tumors after diagnostic, or therapeutic, amounts of [(177)Lu-DOTA(0)-Tyr(3)]-octreotate and to investigate how the activity distribution influences the absorbed dose. Furthermore, the activity distribution of a second administration of radiolabeled octreotate was studied. Nude mice with subcutaneously grown human midgut carcinoid (GOT1) were injected intravenously with different amounts of (177)Lu-octreotate. At different time points thereafter (4 h to 13 days), a second injection of [(111)In-DOTA(0)-Tyr(3)]-octreotate was given to estimate the somatostatin receptor (sstr) expression. The activity distribution in the tumors was then determined. Monte Carlo simulations with PENELOPE were performed for dosimetry. Fifty-one out of 58 investigated tumors showed a lower activity concentration in the peripheral part than in the central part of the tumor. The amount of activity injected, or time after administration, did neither influence the relative activity nor the sstr distribution in the tumor. After an initial down-regulation (at 4-24 h), there was an up-regulation of sstr (1.5-2 times, at 7-14 days). Monte Carlo simulations demonstrated an inhomogeneous absorbed dose distribution in the tumor using (177)Lu, with twice as high absorbed dose centrally than peripherally. The high activity concentration centrally and the up-regulation of sstr demonstrated will facilitate fractionated therapy using radiolabeled somatostatin analogues if similar results will be obtained also in patients. The inhomogeneous activity distribution in the tumor has to be taken into account when the absorbed dose distribution in tumor is calculated.

Editorial [Hot Topic: Targeted Alpha Therapy – Part I (Guest Editor: Jorgen Elgqvist)

The possibility of pinpointing biological targets, and thereby potentially targeting and eradicating small tumors or even single cancer cells, is a tantalizing concept that has been discussed since the magic-bullet concept was first presented by Paul Erlich in the beginning of the 20th century in connection with his work on tissue staining for histological examinations and the work by Kohler and Milstein on antibody production published in 1975. This concept now seems feasible through the use of highly specific targeting constructs, chemical labeling of radioactive substances to these targeting constructs that results in high specific activities, radioimmunocomplexes with good stability even after injection, and the use of radionuclides emitting alpha( α)-particles having exceedingly high ionizing density and, therefore, a high probability of killing cells along its track in tissue. The short range of the emitted α-particles makes them even more interesting by minimizing unwanted irradiation of normal tissue surrounding the targeted cancer cells of interest, assuming high specificity of the targeting construct and good stability of the chemical bonds between the targeting construct and the α-particle emitter. Targeted Alpha Therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to the biological target, is gaining more attention as new targets, targeting constructs, chemical labeling techniques, and α-particle emitters are, respectively, identified, constructed, developed, and made available. Results and improvements are now being published at an increasing rate and the number of conceivable applications is expanding, especially in the field of cancer treatment. Therefore, it is of utmost importance to provide an overview of the overall progress in the research field of TAT on a regular basis. However, problems such as limited or delayed diffusion of the α-radioimmunocomplex and inhomogeneous activity distributions in the targeted tumors, resulting in inhomogeneous absorbed dose distributions, are challenges that need to be addressed. These challenges need to be overcome before TAT becomes a standard treatment for diseases such as micrometastatic cancer. Hopefully, when enough funding will be provided and, hence, more treatment strategies of TAT will reach the clinical level the importance to conduct controlled, randomized trials with sufficient patient numbers, enabling statistical significance to occur must be emphasized in order to be able to properly compare and evaluate different approaches. In this issue, of the two hot-topic issues for targeted alpha therapy, articles discuss the recent developments in radionuclide availability, biomolecular targeting, labeling chemistry, and dosimetry for the most promising α-particle emitters. In the first article, Zalutsky et al. discuss the possibilities and limitations of using the promising α-particle emitter, 211At, and emphasize the need for funding new cyclotrons and prioritizing beam-times of already existing cyclotrons to improve the availability of 211At. Haddad et al. describe the status of the ARRONAX project through which a number of important nuclear medicine radionuclides will be produced, including some of those suitable for TAT. Relevant targeting constructs and their associated antigens used today and candidates for use in the future are discussed by Olafsen et al. in the third article. The next article, by Scott Wilbur, discusses chemical and radiochemical issues of radiolabeling using α-particle emitting radionuclides, e.g. factors that are important in selecting chelation or bonding reagents during the development of α-particle emitting radiopharmaceuticals. Lindegren at al. continue the discussion of chemical considerations in the following article, but focuses on pre-targeting techniques, which will hopefully enhance both the activity distribution in the targeted tumor and the tumor-to-normal tissue absorbed dose ratio. The two final articles discuss different aspects of the dosimetry related to α-particles. The article by Sgouros et al. discusses how knowledge of the microscopic distribution of α-particle emitters is necessary to perform correct dosimetry, as well as the importance of the translation of activity distributions obtained in pre-clinical studies to the human situation, which requires micro-scale models of the source-target geometry at human dimensions according to the authors. Chouin et al. focus in the following article on the microdosimetry of α-particles. The authors present basic concepts and some applications of the microdosimetry for TAT, and conclude microdosimetry should only be considered when alternative approaches fail to provide an account of a given biological endpoint. The intention of this particular hot-topic issue is to present an up-to-date overview of key areas in the research field of TAT, i.e. radionuclides available, targeting constructs, labeling chemistry, and dosimetry. This issue will hopefully be followed by similar ones jointly produced by contributions from the research community active in the field, of which most researchers are participating in these two particular issues, i.e. Targeted Alpha Therapy - Part I and II.

Collimated scanning for large sample neutron activation analysis of inhomogeneous samples

A technique was developed for the identification of inhomogeneities in activity distribution and the correction of their effect on the interpretation of gamma spectrometry data in Large Sample Neutron Activation Analysis. The method was based on collimated gamma scanning using a germanium detector to obtain the activity pattern in the bulk sample and Monte Carlo simulations in order to correct the experimental data for the effect of the inhomogeneous activity distribution. The method was experimentally evaluated in the case of a large cylindrical reference sample of 2 L in volume containing quartz as matrix material and a known source of radioactivity and an excellent agreement was observed. The discussed technique improves the trueness of quantitative analysis of large samples with inhomogeneous activity distribution.

A fuzzy locally adaptive Bayesian segmentation approach for volume determination in PET.

Accurate volume estimation in positron emission tomography (PET) is crucial for different oncology applications. The objective of our study was to develop a new fuzzy locally adaptive Bayesian (FLAB) segmentation for automatic lesion volume delineation. FLAB was compared with a threshold approach as well as the previously proposed fuzzy hidden Markov chains (FHMC) and the fuzzy C-Means (FCM) algorithms. The performance of the algorithms was assessed on acquired datasets of the IEC phantom, covering a range of spherical lesion sizes (10-37 mm), contrast ratios (4:1 and 8:1), noise levels (1, 2, and 5 min acquisitions), and voxel sizes (8 and 64 mm(3)). In addition, the performance of the FLAB model was assessed on realistic nonuniform and nonspherical volumes simulated from patient lesions. Results show that FLAB performs better than the other methodologies, particularly for smaller objects. The volume error was 5%-15% for the different sphere sizes (down to 13 mm), contrast and image qualities considered, with a high reproducibility (variation < 4%). By comparison, the thresholding results were greatly dependent on image contrast and noise, whereas FCM results were less dependent on noise but consistently failed to segment lesions < 2 cm. In addition, FLAB performed consistently better for lesions < 2 cm in comparison to the FHMC algorithm. Finally the FLAB model provided errors less than 10% for nonspherical lesions with inhomogeneous activity distributions. Future developments will concentrate on an extension of FLAB in order to allow the segmentation of separate activity distribution regions within the same functional volume as well as a robustness study with respect to different scanners and reconstruction algorithms.

Effect of inhomogeneous activity distributions and airway geometry on cellular doses in radon lung dosimetry

The human tracheobronchial system has a very complex structure including cylindrical airway ducts connected by airway bifurcation units. The deposition of the inhaled aerosols within the airways exhibits a very inhomogeneous pattern. The formation of deposition hot spots near the carinal ridge has been confirmed by experimental and computational fluid and particle dynamics (CFPD) methods. In spite of these observations, current radon lung dosimetry models apply infinitely long cylinders as models of the airway system and assume uniform deposition of the inhaled radon progenies along the airway walls. The aim of this study is to investigate the effect of airway geometry and non-uniform activity distributions within bronchial bifurcations on cellular dose distributions. In order to answer these questions, the nuclear doses of the bronchial epithelium were calculated in three different irradiation situations. (1) First, CFPD methods were applied to calculate the distribution of the deposited alpha-emitting nuclides in a numerically constructed idealised airway bifurcation. (2) Second, the deposited radionuclides were randomly distributed along the surface of the above-mentioned geometry. (3) Finally, calculations were made in cylindrical geometries corresponding to the parent and daughter branches of the bifurcation geometry assuming random nuclide activity distribution. In all three models, the same 218Po and 214Po surface activities per tissue volumes were assumed. Two conclusions can be drawn from this analysis: (i) average nuclear doses are very similar in all three cases (minor differences can be attributed to differences in the linear energy transfer (LET) spectra) and (ii) dose distributions are significantly different in all three cases, with the highest doses at the carinal ridge in case 3.

Interaction of alpha particles at the cellular level--implications for the radiation weighting factor

Since low dose effects of alpha particles are produced by cellular hits in a relatively small fraction of exposed cells, the present study focuses on alpha particle interactions in bronchial epithelial cells following exposure to inhaled radon progeny. A computer code was developed for the calculation of microdosimetric spectra, dose and hit probabilities for alpha particles emitted from uniform and non-uniform source distributions in cylindrical and Y-shaped bronchial airway geometries. Activity accumulations at the dividing spur of bronchial airway bifurcations produce hot spots of cellular hits, indicating that a small fraction of cells located at such sites may receive substantially higher doses. While presently available data on in vitro transformation frequencies suggest that the relative biological effectiveness for alpha particles ranges from about 3 to 10, the effect of inhomogeneous activity distributions of radon progeny may slightly increase the radiation weighting factor relative to a uniform distribution. Thus a radiation weighting factor of about 10 may be more realistic than the current value of 20, at least for lung cancer risk following inhalation of short-lived radon progeny.

A model for dose estimation in therapy of liver with intraarterial microspheres

Therapy with intraarterial microspheres is a technique which involves incorporation of radioisotope-labelled microspheres into a capillary bed of tumour and normal tissue. Beta-emitters such as and are used for this purpose. This technique provides tumour to normal tissue (TNT) dose ratios in the range of 2 - 10 and demonstrates significant clinical benefit, which could potentially be increased with more accurate dose predictions and delivery. However, dose calculations in this modality face the difficulties associated with nonuniform and inhomogeneous activity distribution. Most of the dose calculations used clinically do not account for the nonuniformity and assume uniform activity distribution. This paper is devoted to the development of a model which would allow more accurate prediction of dose distributions from microspheres. The model calculates dose assuming that microspheres are aggregated into randomly distributed clusters, and using precomputed dose kernels for the clusters. The dose kernel due to a microsphere cluster was found by numerical integration of a point source dose kernel over the volume of the cluster. It is shown that a random distribution of clusters produces an intercluster distance distribution which agrees well with the one measured by Pillai et al in liver. Dose volume histograms (DVHs) predicted by the model agree closely with the results of Roberson et al for normal tissue and tumour. Dose distributions for different concentrations and types of radioisotope, as well as for tumours of different radii, have been calculated to demonstrate the model's possible applications.

Photon-absorbed fractions for cylindrical geometry: a TLD photon-absorbed fraction model.

The purpose of this study is to develop a mathematical model and calculate photon-absorbed fractions in a homogeneous nonradioactive cylinder placed inside off-center and outside a cylindrical homogeneous distribution of activity. In the second case, both the radioactive cylinder and the nonradioactive one are placed in a tissue-equivalent nonradioactive medium. The values of the photon-absorbed fractions are investigated for various geometrical configurations using water as the material filling the cylinders and the medium in between and an isotope commonly used in Nuclear Medicine, 99mTc. The calculations for off-center cylinders allows for modeling inhomogeneous distributions of activity within a tumor by placing several "cold" cylinders of various sizes in a radioactive finite cylinder. This three-dimensional model calculates photon-absorbed fractions for inhomogeneous activity distributions that can be used in quantitative nuclear medicine for self-absorption correction, thus introducing a more realistic correction than the one-dimensional corrections. These calculations are also used to model the response of a cylindrical TLD (thermoluminiscent dosimeter) placed inside a homogeneous radioactive cylinder and outside the homogeneous radioactive cylinder, in an absorbing nonradioactive surrounding medium. The purpose of these calculations is to evaluate the photon-absorbed fraction in the TLD as an instrument of measuring the time-integrated activity of a homogeneous radioactive source versus an inhomogeneous one. The dependence of the TLD-absorbed fraction on the position of the TLD with respect to the radioactive cylinder is investigated.

"Cold" thyroid nodules (author's transl)

Out of 541 thyroid operations during the past 6 years 419 were selected on the basis of standardised histology and evaluated statistically. 31 carcinomas were found. In 246 cases there was a cold nodule in the scintigram and in 88 cases an inhomogenous distribution of activity. Both of them clearly influenced the indication for operation. There were 24 carcinomas among the cold nodules and 4 among the inhomogeneous activity distributions. 64.5% were follicular, 29% papillary and 3.2% mixed; thus differentiated carcinomas outnumbered the other forms. 26 patients with carcinoma had a bilateral thyroidectomy, of these 5 had carcinomatous involvement of both thyroid lobes.