Papers by Mark Konijnenberg
European Journal of Nuclear Medicine and Molecular Imaging, 2021
Executive SummaryWith an increasing variety of radiopharmaceuticals for diagnostic or therapeutic... more Executive SummaryWith an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarker...
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Journal of Nuclear Medicine and Radiation Sciences
Currently, radiolabeled DOTA-[Tyr3]-octreotate (DOTA-TATE) is most commonly used in the clinic to... more Currently, radiolabeled DOTA-[Tyr3]-octreotate (DOTA-TATE) is most commonly used in the clinic to image and treat neuroendocrine tumors. To further improve tumor uptake, and thus treatment, the amount of radiotracer that can accumulate in the tumor might be increased by prolonging the blood circulation time of the radiotracer. To achieve this, we designed Albutate-1, with both DOTA and an albumin-binding domain coupled to TATE via a suitable linker. The aim of this study was to determine the characteristics of the novel radiotracer Albutate-1. A competition binding assay was performed using [111In]In-DOTA-TATE on fresh-frozen SSTR2+ tumor sections. In vitro cell-uptake and internalization of [111In]In-Albutate-1 and [111In]In-DOTA-TATE were determined. The stability of [177Lu]Lu-Albutate-1 was tested. A biodistribution study was performed to provide tumor and organ uptake of [177Lu]Lu-Albutate-1. The biodistribution data was used to determine time-activity curves and the radiation d...
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EJNMMI Research
Background The role of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography/co... more Background The role of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in children is still expanding. Dedicated paediatric dosage regimens are needed to keep the radiation dose as low as reasonably achievable and reduce the risk of radiation-induced carcinogenesis. The aim of this study is to investigate the relation between patient-dependent parameters and [18F]FDG PET image quality in order to propose a dedicated paediatric dose regimen. Methods In this retrospective analysis, 102 children and 85 adults were included that underwent a diagnostic [18F]FDG PET/CT scan. The image quality of the PET scans was measured by the signal-to-noise ratio (SNR) in the liver. The SNR liver was normalized (SNRnorm) for administered activity and acquisition time to apply curve fitting with body weight, body length, body mass index, body weight/body length and body surface area. Curve fitting was performed with two power fits, a nonlinear two-pa...
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Journal of Nuclear Medicine
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Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2004
UNLABELLED The therapeutic effects of peptide receptor-based radionuclide therapy are extensively... more UNLABELLED The therapeutic effects of peptide receptor-based radionuclide therapy are extensively being investigated in rats bearing tumors. Both the dose to the tumor and the therapy-limiting dose to normal tissues, such as kidneys and bone marrow, are of interest for these preclinical studies. The aim of this work was to develop a generalized computational model for internal dosimetry in rats. METHODS Mature rats were dissected and the relative positions, dimensions, and weights of all of their major organs were measured. A mathematic model was set up for the rat body and its internal organs to enable Monte Carlo radiation transport calculations to determine estimates for both tumor and organ self-doses as cross-organ doses for (90)Y, (111)In, and (177)Lu. The organs and body were mostly of ellipsoid shape with the axes given as the measured length, width, and height normalized to values that, together with the measured weights, are consistent with the recommended soft-tissue and ...
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Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2021
Rationale: To build a refined dosimetry model for [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE... more Rationale: To build a refined dosimetry model for [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vivo experiments enabling the correlation of absorbed dose with double strand breaks (DSBs) induction and cell death. Methods: Somatostatin receptor type-2 (SSTR2) expression of NCI-H69 xenografted mice, injected with 177Lu-DOTATATE, was imaged at 0, 2, 5, 11 days. This was used as input to reconstruct realistic 3 dimensional heterogeneous activity distributions and tissue geometries of both cancer and heathy cells. The resulting volumetric absorbed dose rate distributions were calculated using GATE Monte Carlo code and compared to homogenous dose rate distributions. The absorbed dose (0-2 days) on µm-scale sections was correlated with DSBs induction, measured by γH2AX foci. Moreover, the absorbed dose on larger mm-scale sections delivered over the whole treatment (0-14 days) was correlated to the modelled in vivo survival to determine the radiosensitivity parameters α and β for com...
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The Journal of Nuclear Medicine, 2014
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Background The role of 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG) positron emission tomograph... more Background The role of 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG) positron emission tomography/computed tomography (PET/CT) in children is still expanding. Dedicated paediatric dosage regimens are needed to keep the radiation dose as low as reasonably achievable and reduce the risk of radiation-induced carcinogenesis. The aim of this study is to investigate the relation between patient-dependent parameters and [ 18 F]FDG PET image quality in order to propose a dedicated paediatric dose regimen. Methods In this retrospective analysis, 102 children and 85 adults were included that underwent a diagnostic [ 18 F]FDG PET/CT scan. The image quality of the PET scans was measured by the signal-to-noise ratio (SNR) in the liver. The SNR liver was normalized (SNRnorm) for administered activity and acquisition time to apply curve fitting with body weight, body length, body mass index, body weight/body length and body surface area. Curve fitting was performed with two power fits, a nonlinea...
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UNLABELLED Ex vivo autoradiographs of healthy kidney tissue from patients who received (111)In-DT... more UNLABELLED Ex vivo autoradiographs of healthy kidney tissue from patients who received (111)In-DTPA-octreotide (DTPA is diethylenetriaminepentaacetic acid) before nephrectomy showed very heterogeneous radioactivity patterns in the kidneys. The consequences of the reported inhomogeneities have been evaluated for radionuclide therapy with (90)Y- DOTA-Tyr(3)-octreotide (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), (177)Lu-DOTA-Tyr(3)-octreotate, and (111)In-DTPA-octreotide by calculating dose distributions and dose-volume histograms (DVHs) for the kidneys. METHODS Monte Carlo radiation transport calculations were performed by using the MCNP code version 5. The autoradiography data were used in a 2-dimensional model of the kidney tissue sections. A voxel structure inside the MIRD Pamphlet 19 multiregion kidney model was developed to generate a 3-dimensional representation of the autoradiographs. Dose distributions were calculated for th...
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EJNMMI Physics
The aim of this standard operational procedure is to standardize the methodology employed for the... more The aim of this standard operational procedure is to standardize the methodology employed for the evaluation of pre- and post-treatment absorbed dose calculations in 90Y microsphere liver radioembolization. Basic assumptions include the permanent trapping of microspheres, the local energy deposition method for voxel dosimetry, and the patient–relative calibration method for activity quantification.The identity of 99mTc albumin macro-aggregates (MAA) and 90Y microsphere biodistribution is also assumed. The large observed discrepancies in some patients between 99mTc-MAA predictions and actual 90Y microsphere distributions for lesions is discussed. Absorbed dose predictions to whole non-tumoural liver are considered more reliable and the basic predictors of toxicity. Treatment planning based on mean absorbed dose delivered to the whole non-tumoural liver is advised, except in super-selective treatments.Given the potential mismatch between MAA simulation and actual therapy, absorbed dos...
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Polish Archives of Internal Medicine
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EJNMMI Physics
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European journal of nuclear medicine and molecular imaging, Jan 14, 2018
A framework is proposed for modelling the uncertainty in the measurement processes constituting t... more A framework is proposed for modelling the uncertainty in the measurement processes constituting the dosimetry chain that are involved in internal absorbed dose calculations. The starting point is the basic model for absorbed dose in a site of interest as the product of the cumulated activity and a dose factor. In turn, the cumulated activity is given by the area under a time-activity curve derived from a time sequence of activity values. Each activity value is obtained in terms of a count rate, a calibration factor and a recovery coefficient (a correction for partial volume effects). The method to determine the recovery coefficient and the dose factor, both of which are dependent on the size of the volume of interest (VOI), are described. Consideration is given to propagating estimates of the quantities concerned and their associated uncertainties through the dosimetry chain to obtain an estimate of mean absorbed dose in the VOI and its associated uncertainty. This approach is demon...
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Journal of Nuclear Medicine
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PloS one, 2017
Absorbed doses for α-emitters are different from those for β-emitters, as the high linear energy ... more Absorbed doses for α-emitters are different from those for β-emitters, as the high linear energy transfer (LET) nature of α-particles results in a very dense energy deposition over a relatively short path length near the point of emission. This highly localized and therefore high energy deposition can lead to enhanced cell-killing effects at absorbed doses that are non-lethal in low-LET type of exposure. Affinities of DOTA-DPhe1-Tyr3-octreotate (DOTATATE), 115In-DOTATATE, 175Lu-DOTATATE and 209Bi-DOTATATE were determined in the K562-SST2 cell line. Two other cell lines were used for radiation response assessment; BON and CA20948, with a low and high expression of somatostatin receptors, respectively. Cellular uptake kinetics of 111In-DOTATATE were determined in CA20948 cells. CA20948 and BON were irradiated with 137Cs, 177Lu-DTPA, 177Lu-DOTATATE, 213Bi-DTPA and 213Bi-DOTATATE. Absorbed doses were calculated using the MIRDcell dosimetry method for the specific binding and a Monte Car...
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EJNMMI research, 2016
Targeted alpha therapy (TAT) offers advantages over current β-emitting conjugates for peptide rec... more Targeted alpha therapy (TAT) offers advantages over current β-emitting conjugates for peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. PRRT with (177)Lu-DOTATATE or (90)Y-DOTATOC has shown dose-limiting nephrotoxicity due to radiopeptide retention in the proximal tubules. Pharmacological protection can reduce renal uptake of radiopeptides, e.g., positively charged amino acids, to saturate in the proximal tubules, thereby enabling higher radioactivity to be safely administered. The aim of this preclinical study was to evaluate the therapeutic effect of (213)Bi-DOTATATE with and without renal protection using L-lysine in mice. Tumor uptake and kinetics as a function of injected mass of peptide (range 0.03-3 nmol) were investigated using (111)In-DOTATATE. These results allowed estimation of the mean radiation absorbed tumor dose for (213)Bi-DOTATATE. Pharmacokinetics and dosimetry of (213)Bi-DOTATATE was determined in mice, in combination with renal protection. A ...
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Journal of Nuclear Medicine, 2016
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Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 8, 2016
Since overexpression of the gastrin releasing peptide receptor (GRPR) has been reported on variou... more Since overexpression of the gastrin releasing peptide receptor (GRPR) has been reported on various cancer types, e.g. prostate cancer and breast cancer, targeting this receptor with radioligands might have significant impact on staging and treatment of GRPR-expressing tumors. NeoBOMB1 is a novel DOTA-coupled GRPR antagonist with high affinity for GRPR and excellent in vivo stability. The purpose of this preclinical study was to further explore the use of NeoBOMB1 for theranostic application by determining the biodistribution of (68)Ga-NeoBOMB1 and (177)Lu-NeoBOMB1. PC-3 tumor-xenografted Balb c nu/nu mice were injected with either ~13 MBq/250 pmol (68)Ga-NeoBOMB1, or a low (~1 MBq/200 pmol) vs. high (~1 MBq/10 pmol) peptide amount of (177)Lu-NeoBOMB1 after which biodistribution and imaging studies were performed. At 6 time points (15, 30, 60, 2 h, 4 h and 6 h for (68)Ga-NeoBOMB1 and 1, 4, 24, 48, 96 and 168 h for (177)Lu-NeoBOMB1) post injection (p.i.) tumor and organ uptake was det...
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Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2014
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Papers by Mark Konijnenberg