Voxel-level dosimetry of 177Lu-octreotate : from phantoms to patients

In radionuclide therapy, the patient is injected with relatively high amounts of therapeutic radiopharmaceutical which localises to target tissue and emits ionising radiation. Unfortunately, a perfectly targeting radiopharmaceutical has not been discovered and part of the radiopharmaceutical accumulates to healthy tissues, which are also thus irradiated. In order to ensure safe use, the absorbed dose of radiation-sensitive organs must be monitored. The focus of this thesis is on patient specific dosimetry of lutetium-177 (Lu-177) labelled somatostatin analogue Lu-177-DOTA-Tyr3-octreotate (Lu-177-DOTATATE) treatments and development of internal dosimetry software. Lu-177-DOTATATE is a radiopharmaceutical that binds to somatostatin receptors and is used to treat patients with metastatic neuroendocrine tumours. Recent studies have shown significant treatment outcome improvements with Lu-177-DOTATATE when compared to previously used somatostatin analogue treatments. However, the kidneys are the healthy organ which receives the highest amount of radiation dose from Lu-177-DOTATATE treatments and could be the organ that limits the number of treatments a patient can tolerate. In addition, absorbed dose to kidneys varies highly from patient to patient and thus patient specific dosimetry is recommended. Despite many years of dosimetry research and the existence of several published scientific dosimetry tools, there is no clinically validated kidney dosimetry software for Lu-177-DOTATATE treatments. The aim of this thesis was to study quantification accuracy of Lu-177 radionuclide using SPECT/CT imaging and to study mean absorbed doses to kidneys and dose distribution characteristics of Lu-177-DOTATATE. A streamlined voxel level absorbed dose software for clinical practice was developed and validated for kidney dosimetry of Lu-177-DOTATATE treatments. The effect of reconstruction methods on Lu-177 quantification accuracy was studied using an anthropomorphic phantom with known Lu-177 sources. Acquired data were reconstructed using different image compensation methods and results were compared with known source activities in the phantom. It was found that Monte Carlo simulation based scatter compensation and SPECT detector response compensation improved Lu-177 quantification accuracy considerably. Similar findings were also observed with data from patients treated with Lu-177-DOTATATE. A Monte Carlo simulation study was carried out to investigate absorbed dose distribution of Lu-177. Two main findings were that electrons emitted by Lu-177 can be assumed to absorb locally when the resolution of the imaging system is taken into account and the photon cross-irradiation can contribute significantly to total absorbed dose especially in the vicinity of highly active volumes. Using Lu-177-DOTATATE patient data, two different kidney absorbed dose calculation methods were compared. Comparing the mean kidney absorbed dose with the estimated maximum absorbed dose, it was observed that Lu-177-DOTATATE accumulates unevenly to kidney causing significantly heterogeneous dose distribution within kidneys. In addition, a simplified imaging protocol was found to be adequate for dosimetry purposes and was later adopted clinical practice. Combining previous findings new voxel level dosimetry software was developed. The clinical feasibility of the proposed software was tested with digital phantom simulations and reanalysing patient data from Lu-177-DOTATATE treatments. The software was found to be reliable and to speed up and simplify the dosimetry workflow.Lutetium-177 (Lu-177) -oktreotaattihoito on tehokas hoitomenetelmä levinneisiin neuroendokriinisiin kasvaimiin. Suonensisäisesti annettava Lu-177 -isotoopilla leimattu oktreotaatti sitoutuu kasvaimien pinnalla ilmeneviin somatostatiinireseptoreihin ja Lu-177:n emittoima elektronisäteily tuhoaa syöpäsolukkoa. Paikallisesti ionisoivan elektronisäteilyn lisäksi Lu-177 emittoi myös gammasäteilyä, joka voidaan kuvantaa gammakameralla potilaan ulkopuolelta. Oktreotaatti sitoutuu pieninä määrinä myös terveisiin kudoksiin. Sitoutumaton lääke erittyy munuaisten kautta virtsaan, minkä seurauksena munuaiset voivat saada hoidoista suuren säteilyannoksen. Tämä voi johtaa munuaisten vajaatoimintaan. Munuaisiin kertyvän radiolääkkeen määrä vaihtelee suuresti potilaiden välillä, minkä vuoksi munuaisiin kohdistuvaa säderasitusta tulee seurata potilaskohtaisesti. Tämän väitöskirjan tavoite oli kehittää annoslaskentaohjelma radionuklidihoitoihin keskittyen Lu-177 -oktreotaattihoitoihin. Työssä tutkittiin Lu-177 -aktiivisuuden määrityksen tarkkuutta SPECT-TT-kuvauksilla ja eri kuvarekonstruktiomenetelmien vaikutusta aktiivisuuden määrityksen suorituskykyyn. Monte Carlo -simuloinneilla tutkittiin Lu-177:n elektroni- ja gammasäteilyn annosjakaumia. Kliinisesti käytössä olevilla annoslaskentamenetelmillä vertailtiin Lu-177 -oktreotaattihoidettujen potilaiden munuaisannoksia ja annosten vaihtelua hoitokertojen välillä. Yhdistämällä näiden töiden tulokset kehitettiin uusi potilaan yksilöllisiin SPECT-TT-kuviin perustuva annoslaskentaohjelma. Työssä osoitettiin, että kuvarekonstruktiossa käytettävillä kompensaatiomenetelmillä on huomattava vaikutus Lu-177:n aktiivisuuden määrityksen tarkkuuteen etenkin pienten kohteiden kohdalla. Tarkimmat tulokset saavutettiin yhdistämällä kuvarekonstruktioon vaimennuskorjaus, sirontakorjaus ja kollimaattori-detektori-vastemallinnus. Monte Carlo -simulointien avulla havaittiin elektronisäteilyn kantaman olevan häviävän pieni verrattuna gammakameran erotuskykyyn. Tämän takia SPECT-kuviin perustuvassa Lu-177:n annoslaskennassa voidaankin olettaa elektronien absorboituvan paikallisesti. Toisaalta simuloinneissa havaittiin, että hyvin aktiivisista lähteistä aiheutuu suuri gammasäteilyannos, joka tulisi ottaa huomioon annoslaskennassa. Lu-177 -oktreotaattihoidettujen potilaiden munuaisten säteilyannokset vaihtelivat suuresti. Potilaskuvista määritetyistä annosjakaumista havaittiin, että munuaisten keskimääräinen annos ja maksimiannos erosivat toisistaan tilastollisesti merkitsevästi. Radionuklidihoitojen annoslaskenta on monivaiheinen prosessi, jossa SPECT-kuvaus- ja rekonstruktiomenetelmät ovat keskeisessä asemassa. Tämän lisäksi annoslaskenta- ja analyysimenetelmien tulee olla käyttötarkoitukseen validoituja. Väitöskirjassa esitetty annoslaskentaohjelma mahdollistaa potilaan yksilöllisiin SPECT-TT-kuviin perustuvan annoslaskennan. Ohjelma validoitiin Lu-177 -oktreotaattihoitojen munuaisannoksen määrittämiseen, mutta sen kehittäminen muiden radionuklidien annoslaskentaan on mahdollista. Ohjelmiston kehitys on tehty yhteistyössä HERMES Medical Solution -yrityksen kanssa ja ohjelma tulee kaupallisesti saataville

Ejection fraction in myocardial perfusion imaging assessed with a dynamic phantom : comparison between IQ-SPECT and LEHR

BACKGROUND: Developments in single photon emission tomography instrumentation and reconstruction methods present a potential for decreasing acquisition times. One of such recent options for myocardial perfusion imaging (MPI) is IQ-SPECT. This study was motivated by the inconsistency in the reported ejection fraction (EF) and left ventricular (LV) volume results between IQ-SPECT and more conventional low-energy high-resolution (LEHR) collimation protocols. IQ-SPECT and LEHR quantitative results were compared while the equivalent number of iterations (EI) was varied. The end-diastolic (EDV) and end-systolic volumes (ESV) and the derived EF values were investigated. A dynamic heart phantom was used to produce repeatable ESVs, EDVs and EFs. Phantom performance was verified by comparing the set EF values to those measured from a gated multi-slice X-ray computed tomography (CT) scan (EF(True)). The phantom with an EF setting of 45, 55, 65 and 70% was imaged with both IQ-SPECT and LEHR protocols. The data were reconstructed with different EI, and two commonly used clinical myocardium delineation software were used to evaluate the LV volumes. RESULTS: The CT verification showed that the phantom EF settings were repeatable and accurate with the EF(True) being within 1% point from the manufacture’s nominal value. Depending on EI both MPI protocols can be made to produce correct EF estimates, but IQ-SPECT protocol produced on average 41 and 42% smaller EDV and ESV when compared to the phantom’s volumes, while LEHR protocol underestimated volumes by 24 and 21%, respectively. The volume results were largely similar between the delineation methods used. CONCLUSIONS: The reconstruction parameters can greatly affect the volume estimates obtained from perfusion studies. IQ-SPECT produces systematically smaller LV volumes than the conventional LEHR MPI protocol. The volume estimates are also software dependent.Peer reviewe

Quantitative accuracy of Lu-177 SPECT reconstruction using different compensation methods : phantom and patient studies

Background: In targeted radionuclide therapy (TRT), accurate quantification using SPECT/CT images is important for optimizing radiation dose delivered to both the tumour and healthy tissue. Quantitative SPECT images are regularly reconstructed using the ordered subset expectation maximization (OSEM) algorithm with various compensation methods such as attenuation (A), scatter (S) and detector and collimator response (R). In this study, different combinations of the compensation methods are applied during OSEM reconstruction and the effect on the Lu-177 quantification accuracy is studied in an anthropomorphic torso phantom. In addition, the phantom results are reflected to (177) Lu-DOTA-Tyr3-octreotate (Lu-177-DOTATATE)-treated patient data and kidney absorbed dose estimates. Methods: The torso phantom was imaged with nine various sized (0.4-104.4 cm(3)) spherical inserts, filled with known Lu-177 activity ranging from 0.5 to 105.5 MBq. Images were reconstructed using OSEM algorithm using A, AR and ARS compensation method combinations. The compensation method combinations were compared by calculating the concentration recovery coefficient (cRC) for each insert. In addition, ten Lu-177-DOTATATE-treated patient's post-therapy dosimetry acquisitions were reconstructed, and the absorbed dose to kidneys was estimated. Results: cRC values depend on the insert size for all compensation methods. AR and ARS produced significantly higher cRC values than attenuation correction alone. There were no cRC value differences between the methods for the smallest 1-cm-diameter insert, cRC being 0.18. However, the collimator and detector response compensation method (R) made the 1.3-cm-diameter insert clearly visible and improved cRC estimate from 0.19 to 0.43. ARS produced slightly higher cRC values for small- and medium-sized inserts than AR. On the patient data, a similar trend could be seen. AR and ARS produced higher kidney activities than using attenuation correction alone; the total absorbed doses to the right and left kidneys were on average 15 and 20 % higher for AR and 19 and 25 % higher for ARS, respectively. The effective half-life decay estimated from time-activity curves however showed no notable difference between the compensation methods. Conclusions: The highest cRC values were achieved by applying ARS compensation during reconstruction. The results were notably higher than those using attenuation correction alone. Similarly, higher activity estimates and thus higher absorbed dose estimates were found in patient data when all compensation methods were applied. ARS improved cRC especially in small-sized sources, and it thus might aid tumour dosimetry for Lu-177 PRRT treatments.Peer reviewe

Marker-controlled Watershed with Deep Edge Emphasis and Optimized H-minima Transform for Automatic Segmentation of Densely Cultivated 3D Cell Nuclei

Background The segmentation of 3D cell nuclei is essential in many tasks, such as targeted molecular radiotherapies (MRT) for metastatic tumours, toxicity screening, and the observation of proliferating cells. In recent years, one popular method for automatic segmentation of nuclei has been deep learning enhanced marker-controlled watershed transform. In this method, convolutional neural networks (CNNs) have been used to create nuclei masks and markers, and the watershed algorithm for the instance segmentation. We studied whether this method could be improved for the segmentation of densely cultivated 3D nuclei via developing multiple system configurations in which we studied the effect of edge emphasizing CNNs, and optimized H-minima transform for mask and marker generation, respectively. Results The dataset used for training and evaluation consisted of twelve in vitro cultivated densely packed 3D human carcinoma cell spheroids imaged using a confocal microscope. With this dataset, the evaluation was performed using a cross-validation scheme. In addition, four independent datasets were used for evaluation. The datasets were resampled near isotropic for our experiments. The baseline deep learning enhanced marker-controlled watershed obtained an average of 0.69 Panoptic Quality (PQ) and 0.66 Aggregated Jaccard Index (AJI) over the twelve spheroids. Using a system configuration, which was otherwise the same but used 3D-based edge emphasizing CNNs and optimized H-minima transform, the scores increased to 0.76 and 0.77, respectively. When using the independent datasets for evaluation, the best performing system configuration was shown to outperform or equal the baseline and a set of well-known cell segmentation approaches. Conclusions The use of edge emphasizing U-Nets and optimized H-minima transform can improve the marker-controlled watershed transform for segmentation of densely cultivated 3D cell nuclei. A novel dataset of twelve spheroids was introduced to the public.Peer reviewe

Phantom and clinical evaluation of the effect of full Monte Carlo collimator modelling in post-SIRT yttrium-90 Bremsstrahlung SPECT imaging

Background: Post-therapy SPECT/CT imaging of Y-90 microspheres delivered to hepatic malignancies is difficult, owing to the continuous, high-energy Bremsstrahlung spectrum emitted by Y-90. This study aimed to evaluate the utility of a commercially available software package (HybridRecon, Hermes Medical Solutions AB) which incorporates full Monte Carlo collimator modelling. Analysis of image quality was performed on both phantom and clinical images in order to ultimately provide a recommendation of an optimum reconstruction for post-therapy Y-90 microsphere SPECT/CT imaging. A 3D-printed anthropomorphic liver phantom was filled with Y-90 with a sphere-to-background ratio of 4:1 and imaged on a GE Discovery 670 SPECT/CT camera. Datasets were reconstructed using ordered-subsets expectation maximization (OSEM) 1-7 iterations in order to identify the optimal OSEM reconstruction (5 iterations, 15 subsets). Quantitative analysis was subsequently carried out on phantom datasets obtained using four reconstruction algorithms: the default OSEM protocol (2 iterations, 10 subsets) and the optimised OSEM protocol, both with and without full Monte Carlo collimator modelling. The quantitative metrics contrast recovery (CR) and background variability (BV) were calculated. The four algorithms were then used to retrospectively reconstruct 10 selective internal radiation therapy (SIRT) patient datasets which were subsequently blind scored for image quality by a consultant radiologist. Results: The optimised OSEM reconstruction (5 iterations, 15 subsets with full MC collimator modelling) increased the CR by 42% (p <0.001) compared to the default OSEM protocol (2 iterations, 10 subsets). The use of full Monte Carlo collimator modelling was shown to further improve CR by 14% (30 mm sphere, CR = 90%, p <0.05). The consultant radiologist had a significant preference for the optimised OSEM over the default OSEM protocol (p <0. 001), with the optimised OSEM being the favoured reconstruction in every one of the 10 clinical cases presented. Conclusions: OSEM (5 iterations, 15 subsets) with full Monte Carlo collimator modelling is quantitatively the optimal image reconstruction for post-SIRT 90Y Bremsstrahlung SPECT/CT imaging. The use of full Monte Carlo collimator modelling for correction of image-degrading effects significantly increases contrast recovery without degrading clinical image quality.Peer reviewe

Seasonal Temperature Changes Do Not Affect Cardiac Glucose Metabolism

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Multicellular dosimetric chain for molecular radiotherapy exemplified with dose simulations on 3D cell spheroids

Purpose: Absorbed radiation dose-response relationships are not clear in molecular radiotherapy (MRT). Here, we propose a voxel-based dose calculation system for multicellular dosimetry in MRT. We applied confocal microscope images of a spherical cell aggregate i.e. a spheroid, to examine the computation of dose distribution within a tissue from the distribution of radiopharmaceuticals. Methods: A confocal microscope Z-stack of a human hepatocellular carcinoma HepG2 spheroid was segmented using a support-vector machine algorithm and a watershed function. Heterogeneity in activity uptake was simulated by selecting a varying amount of the cell nuclei to contain In-111, I-125, or Lu-177. Absorbed dose simulations were carried out using vxlPen, a software application based on the Monte Carlo code PENELOPE. Results: We developed a schema for radiopharmaceutical dosimetry. The schema utilizes a partially supervised segmentation method for cell-level image data together with a novel main program for voxel-based radiation dose simulations. We observed that for 177Lu, radiation cross-fire enabled full dose coverage even if the radiopharmaceutical had accumulated to only 60% of the spheroid cells. This effect was not found with 111In and 125I. Using these Auger/internal conversion electron emitters seemed to guarantee that only the cells with a high enough activity uptake will accumulate a lethal amount of dose, while neighboring cells are spared. Conclusions: We computed absorbed radiation dose distributions in a 3D-cultured cell spheroid with a novel multicellular dosimetric chain. Combined with pharmacological studies in different tissue models, our cell-level dosimetric calculation method can clarify dose-response relationships for radiopharmaceuticals used in MRT. (C) 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Convolutional neural networks for detection of transthyretin amyloidosis in 2D scintigraphy images

Background Transthyretin amyloidosis (ATTR) is a progressive disease which can be diagnosed non-invasively using bone avid [Tc-99m]-labeled radiotracers. Thus, ATTR is also an occasional incidental finding on bone scintigraphy. In this study, we trained convolutional neural networks (CNN) to automatically detect and classify ATTR from scintigraphy images. The study population consisted of 1334 patients who underwent [Tc-99m]-labeled hydroxymethylene diphosphonate (HMDP) scintigraphy and were visually graded using Perugini grades (grades 0-3). A total of 47 patients had visual grade >= 2 which was considered positive for ATTR. Two custom-made CNN architectures were trained to discriminate between the four Perugini grades of cardiac uptake. The classification performance was compared to four state-of-the-art CNN models. Results Our CNN models performed better than, or equally well as, the state-of-the-art models in detection and classification of cardiac uptake. Both models achieved area under the curve (AUC) >= 0.85 in the four-class Perugini grade classification. Accuracy was good in detection of negative vs. positive ATTR patients (grade = 2, AUC > 0.88) and high-grade cardiac uptake vs. other patients (grade < 3 vs. grade 3, AUC = 0.94). Maximum activation maps demonstrated that the automated deep learning models were focused on detecting the myocardium and not extracardiac features. Conclusion Automated convolutional neural networks can accurately detect and classify different grades of cardiac uptake on bone scintigraphy. The CNN models are focused on clinically relevant image features. Automated screening of bone scintigraphy images using CNN could improve the early diagnosis of ATTR.Peer reviewe

A Nordic survey of CT doses in hybrid PET/CT and SPECT/CT examinations

Background Computed tomography (CT) scans are routinely performed in positron emission tomography (PET) and single photon emission computed tomography (SPECT) examinations globally, yet few surveys have been conducted to gather national diagnostic reference level (NDRL) data for CT radiation doses in positron emission tomography/computed tomography (PET/CT) and single photon emission computed tomography/computed tomography (SPECT/CT). In this first Nordic-wide study of CT doses in hybrid imaging, Nordic NDRL CT doses are suggested for PET/CT and SPECT/CT examinations specific to the clinical purpose of CT, and the scope for optimisation is evaluated. Data on hybrid imaging CT exposures and clinical purpose of CT were gathered for 5 PET/CT and 8 SPECT/CT examinations via designed booklet. For each included dataset for a given facility and scanner type, the computed tomography dose index by volume (CTDIvol) and dose length product (DLP) was interpolated for a 75-kg person (referred to as CTDIvol,75kg and DLP75kg). Suggested NDRL (75th percentile) and achievable doses (50th percentile) were determined for CTDIvol,75kg and DLP75kg according to clinical purpose of CT. Differences in maximum and minimum doses (derived for a 75-kg patient) between facilities were also calculated for each examination and clinical purpose. Results Data were processed from 83 scanners from 43 facilities. Data were sufficient to suggest Nordic NDRL CT doses for the following: PET/CT oncology (localisation/characterisation, 15 systems); infection/inflammation (localisation/characterisation, 13 systems); brain (attenuation correction (AC) only, 11 systems); cardiac PET/CT and SPECT/CT (AC only, 30 systems); SPECT/CT lung (localisation/characterisation, 12 systems); bone (localisation/characterisation, 30 systems); and parathyroid (localisation/characterisation, 13 systems). Great variations in dose were seen for all aforementioned examinations. Greatest differences in DLP75kg for each examination, specific to clinical purpose, were as follows: SPECT/CT lung AC only (27.4); PET/CT and SPECT/CT cardiac AC only (19.6); infection/inflammation AC only (18.1); PET/CT brain localisation/characterisation (16.8); SPECT/CT bone localisation/characterisation (10.0); PET/CT oncology AC only (9.0); and SPECT/CT parathyroid localisation/characterisation (7.8). Conclusions Suggested Nordic NDRL CT doses are presented according to clinical purpose of CT for PET/CT oncology, infection/inflammation, brain, PET/CT and SPECT/CT cardiac, and SPECT/CT lung, bone, and parathyroid. The large variation in doses suggests great scope for optimisation in all 8 examinations.Peer reviewe

Pretargeted PET Imaging with a TCO-Conjugated Anti-CD44v6 Chimeric mAb U36 and [Zr-89]Zr-DFO-PEG(5)-Tz

The recent advances in the production of engineered antibodies have facilitated the development and application of tailored, target-specific antibodies. Positron emission tomography (PET) of these antibody-based drug candidates can help to better understand their in vivo behavior. In this study, we report an in vivo proof-ofconcept pretargeted immuno-PET study where we compare a pretargeting vs targeted approach using a new Zr-89-labeled tetrazine as a bio-orthogonal ligand in an inverse electron demand Diels-Alder (IEDDA) in vivo click reaction. A CD44v6-selective chimeric monoclonal U36 was selected as the targeting antibody because it has potential in immuno-PET imaging of head-and-neck squamous cell carcinoma (HNSCC). Zirconium-89 (t(1/2) = 78.41 h) was selected as the radionuclide of choice to be able to make a head-to-head comparison of the pretargeted and targeted approaches. [Zr-89]Zr-DFO-PEG S -Tz ([Zr-89]Zr-3) was synthesized and used in pretargeted PET imaging of HNSCC xenografts (VU-SCC-OE) at 24 and 48 h after administration of a trans-cyclooctene (TCO)-functionalized U36. The pretargeted approach resulted in lower absolute tumor uptake than the targeted approach (1.5 +/- 0.2 vs 17.1 +/- 3.0% ID/g at 72 h p.i. U36) but with comparable tumor-to-non-target tissue ratios and significantly lower absorbed doses. In conclusion, anti-CD44v6 monoclonal antibody U36 was successfully used for Zr-89-immuno-PET imaging of HNSCC xenograft tumors using both a targeted and pretargeted approach. The results not only support the utility of the pretargeted approach in immuno-PET imaging but also demonstrate the challenges in achieving optimal in vivo IEDDA reaction efficiencies in relation to antibody pharmacokinetics.Peer reviewe