Marleen Melis - Profile on Academia.edu (original) (raw)
Papers by Marleen Melis
Graefe's Archive for Clinical and Experimental Ophthalmology, 2008
From Outside to Inside? Dose-Dependent Renal Tubular Damage After High-Dose Peptide Receptor Radionuclide Therapy in Rats Measured with In Vivo 99mTc-DMSA-SPECT and Molecular Imaging
Cancer Biotherapy and Radiopharmaceuticals, Feb 1, 2007
In peptide receptor radionuclide therapy (PRRT), the dose-limiting organ is, most often, the kidn... more In peptide receptor radionuclide therapy (PRRT), the dose-limiting organ is, most often, the kidney. However, the precise mechanism as well as the exact localization of kidney damage during PRRT have not been fully elucidated. We studied renal damage in rats after therapy with different amounts of [(177)Lu-DOTA(0), Tyr(3)]octreotate and investigated (99m)Tc-DMSA (dimercaptosuccinic acid) as a tool to quantify renal damage after PRRT. Twenty-nine (29) rats were divided into 3 groups and injected with either 0, 278, or 555 MBq [(177)Lu-DOTA(0), Tyr(3) ]octreotate, leading to approximately 0, 46, and 92 Gy to the renal cortex. More than 100 days after therapy, kidney damage was investigated using (99m)Tc-DMSA single-photon emission computed tomography (SPECT) autoradiography, histology, and blood analyses. In vivo SPECT with (99m)Tc-DMSA resulted in high-resolution (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1.6-mm) images. The (99m)Tc-DMSA uptake in the rat kidneys was inversely related with the earlier injected activity of [(177)Lu-DOTA(0), Tyr(3)]octreotate and correlated inversely with serum creatinine values. Renal ex vivo autoradiograms showed a dose-dependent distribution pattern of (99m)Tc-DMSA. (99m)Tc-DMSA SPECT could distinguish between the rats that were injected with 278 or 555 MBq [(177)Lu-DOTA(0), Tyr(3) ]octreotate, whereas histologic damage grading of the kidneys was nearly identical for these 2 groups. Histologic analyses indicated that lower amounts of injected radioactivity caused damage mainly in the proximal tubules, whereas as well the distal tubules were damaged after high-dose radioactivity. Renal damage in rats after PRRT appeared to start in a dose-dependent manner in the proximal tubules and continued to the more distal tubules with increasing amounts of injected activity. In vivo SPECT measurement of (99m)Tc-DMSA uptake was highly accurate to grade renal tubular damage after PRRT.
Optimisation of combination of peptide receptor radionuclide therapy (PRRT) and temozolomide therapy using SPECT/CT and MRI in mice
Poster: "ECR 2014 / B-0523 / Optimisation of combination of peptide receptor radionuclide th... more Poster: "ECR 2014 / B-0523 / Optimisation of combination of peptide receptor radionuclide therapy (PRRT) and temozolomide therapy using SPECT/CT and MRI in mice" by: "S. M. Bison, J. C. Haeck, S. J. Koelewijn, M. Melis, M. R. Bernsen, M. de Jong; Rotterdam/NL"
Megalin is essential for the kidney uptake of In-111-labeled peptides: Studies in megalin-deficient mice
The Journal of Nuclear Medicine, May 1, 2010
Determination of the beta-cell mass by SPECT imaging with In-111-DTPA-Exendin-3 in rats
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2009
Breast cancer imaging using radiolabelled somatostatin analogues
Nuclear Medicine and Biology, 2016
Imaging and therapy using radiolabelled somatostatin analogues are methods successfully used in p... more Imaging and therapy using radiolabelled somatostatin analogues are methods successfully used in patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumours. Since these techniques were first introduced, many improvements have been made. SSTR expression has also been reported on breast cancer (BC). Currently mammography, magnetic resonance imaging and ultrasound are the most frequent methods used for BC imaging. Since SSTR expression on BC was demonstrated, clinical studies examining the feasibility of visualizing primary BC using SSTR radioligands have been performed. However, to date SSTR-mediated nuclear imaging is not used clinically in BC patients. The aim of this review is to assess whether recent improvements made within nuclear medicine may enable SSTR-mediated imaging to play a role in BC management. For this we critically analysed results of past studies and discussed the potential of the improvements made within nuclear medicine on SSTR-mediated nuclear imaging of BC. Seven databases were searched for publications on BC imaging with SSTR radioligands. The papers found were analysed by 3 individual observers to identify whether the studies met the pre-set inclusion criteria defined as studies in which nuclear imaging using radiolabelled SST analogues was performed in patients with breast lesions. Twenty-four papers were selected for this review including studies on SSTR-mediated nuclear imaging in BC, neuroendocrine BC and other breast lesions. The analysed studies were heterogeneous with respect to the imaging method, imaging protocol, patient groups and the radiolabelled SST analogues used. Despite the fact that the analysed studies were heterogeneous, sensitivity for primary BC ranged from 36-100%. In a subset of the studies LN lesions were visualized, but sensitivity was lower compared to that for primary tumours. A part of the studies included benign lesions and specificity ranged from 22-100%. Furthermore, false negatives and false positives were reported. In the majority of the studies scan outcome was not associated with BC subtype.
Megalin is essential for the kidney uptake of In-111-labeled peptides: Studies in megalin-deficient mice
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2010
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2009
This review focuses on the present status of kidney protection during peptide receptor radionucli... more This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/ cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the reninangiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower renal retention may be developed. Furthermore, knowledge on kidney protection from radiolabelled somatostatin analogues may be expanded to other peptides.
Qual Life Res, 2010
En ook voor andere vrouwen, zoals mijn grootmoeders, die niet de kans hebben gekregen of genomen ... more En ook voor andere vrouwen, zoals mijn grootmoeders, die niet de kans hebben gekregen of genomen hun talenten te ontplooien Radiopeptides for targeted tumour therapy and the kidney Contents Chapter 1 General introduction 1.1 Introduction and outline of the thesis 1.2 Kidney protection during peptide receptor radionuclide therapy Chapter 2 Renal retention of radiolabelled peptides; role of megalin 2.1 Renal uptake and retention of radiolabelled somatostatin, bombesin, neurotensin, minigastrin and CCK analogues: species and gender differences 2.2 Localisation and mechanism of renal retention of radiolabelled somatostatin analogues 2.3 Megalin is essential for renal proximal tubule reabsorption of 111 In-DTPA-octreotide 2.4 Renal uptake of different radiolabelled peptides is mediated by megalin-SPECT and biodistribution studies in megalin-deficient mice Chapter 3 Reduction of renal uptake of radiolabelled octreotate and kidney protection 3.1 Dose-response effect of Gelofusine on renal retention of radiolabelled octreotate in rats with CA20948 tumours 3.2 Kidney protection by amifostine during peptide receptor radionuclide therapy (PRRT) in tumor-bearing rats; indications for two mechanisms Chapter 4 Micro-SPECT to monitor renal function after renal retention of radiopeptides 4.1 From outside to inside? Dose-dependent renal tubular damage after high-dose peptide receptor radionuclide therapy in rats measured with in vivo 99m Tc-DMSA-SPECT and molecular imaging. 4.2 Dynamic and static micro-SPECT in rats to monitor renal function after 177 Lu-labelled octreotate radionuclide therapy
Radiolabelled bombesin analogs in preclinical studies
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2007
EJNMMI research, 2015
Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine... more Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine tumours (NET) comprise somatostatin-analogue lutetium-177-labelled octreotate ((177)Lu-TATE) treatment, also referred to as peptide receptor radionuclide therapy (PRRT), and temozolomide (TMZ) treatment. Their combination might result in additive effects. Using MRI and SPECT/CT, we studied tumour characteristics and therapeutic responses after different (combined) administration schemes in a murine tumour model in order to identify the optimal treatment schedule for PRRT plus TMZ. We performed molecular imaging studies in mice bearing SSTR-expressing H69 (humane small cell lung cancer) tumours after single intravenous (i.v.) administration of 30 MBq (177)Lu-TATE or TMZ (oral 50 mg/kg daily for 14 days). Tumour perfusion was evaluated weekly by dynamic contrast-enhanced MRI (DCE-MRI), whereas tumour uptake of (111)In-octreotide was quantified using SPECT/CT until day 39 after treatment. ...
Clinical nuclear medicine, Jan 12, 2015
Radiolabeled somatostatin (SST) analogs, used to visualize and treat SST receptor (SSTR)-expressi... more Radiolabeled somatostatin (SST) analogs, used to visualize and treat SST receptor (SSTR)-expressing neuroendocrine tumors, also accumulate in the spleen. There is a high interpatient variation and no significant radiation-induced splenic toxicity; however, an absorbed dose-related reduction in spleen size was detected. However, the exact localization of radioactivity and the role of SST receptors in splenic retention are unknown. Therefore, we performed ex vivo micro-SPECT of the isolated spleen from a patient with a pancreatic neoplasm after 1 GBq (27 mCi) Lu-DOTATATE administration, followed by autoradiography and immunohistochemistry. Ex vivo autoradiography demonstrated convincingly that most radioactivity accumulated in red pulp.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 6, 2015
Imaging and therapy using radioligands targeting receptors overexpressed on tumor cells is succes... more Imaging and therapy using radioligands targeting receptors overexpressed on tumor cells is successfully applied in neuroendocrine tumor patients. Since expression of the gastrin releasing peptide receptor (GRPR), somatostatin receptor 2 (SSTR2) and chemokine C-X-C motif receptor 4 (CXCR4) has been demonstrated in breast cancer, targeting these receptors using radioligands might offer new imaging and therapeutic opportunities for breast cancer patients. The aim of this study was to correlate messenger RNA (mRNA) expression of GRPR, SSTR2 and CXCR4 with clinico-pathological and biological factors, with prognosis and prediction to therapy response, to identify specific breast cancer patient groups suited for the application of radioligands targeting the receptors. First, we studied GRPR and SSTR2 expression in 13 clinical breast cancer specimens by in vitro autoradiography and correlated this with corresponding mRNA levels to investigate whether mRNA levels reliably represent cell surf...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2007
Ex vivo autoradiographs of healthy kidney tissue from patients who received (111)In-DTPA-octreoti... more 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. 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 the beta-emitter (90)...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2007
Human prostate cancers (PC) overexpress gastrin-releasing peptide (GRP) receptors. This observati... more Human prostate cancers (PC) overexpress gastrin-releasing peptide (GRP) receptors. This observation suggests that GRP receptors may be used as new visualization and treatment modalities for these tumors. Radiolabeled GRP receptor-targeting analogs of GRP and bombesin (BN) have successfully been developed for these purposes. Expression of GRP receptors in human prostate tumors is, however, primarily evaluated in early stages of tumor development and information on expression in the more progressive prostate tumors is uncertain. To evaluate GRP receptor expression in all stages of PC, we investigated GRP receptor expression using a panel of 12 established human PC xenograft models representing the different stages of human PC and the effect of antiandrogen treatment (castration). Human PC xenografts were grown in male nude mice, and GRP receptor density in the tumors was evaluated using displacement receptor autoradiography with the universal BN receptor analog (125)I-[D-Tyr(6),beta-A...
In Vivo Enzyme Inhibition Improves the Targeting of [177Lu]DOTA-GRP(13–27) in GRPR-Positive Tumors in Mice
Cancer Biotherapy and Radiopharmaceuticals, 2014
Gastrin-releasing peptide receptors (GRPR) and GRP-derived analogs have attracted attention due t... more Gastrin-releasing peptide receptors (GRPR) and GRP-derived analogs have attracted attention due to high receptor expression in frequently occurring human neoplasia. The authors recently synthesized a series of GRPR-affine peptide analogs based on the 27-mer GRP and derivatized with the DOTA chelator at the N-terminus for (111)In-labeling. In this study, the authors evaluated the most promising from these series, DOTA-GRP(13-27), after radiolabeling with (177)Lu for future therapeutic applications. In addition, to improve in vivo stability of the peptide against in vivo degradation by the protease neutral endopeptidase (NEP), the authors coinjected [(177)Lu]DOTA-GRP(13-27) with the potent NEP inhibitor phosphoramidon (PA). The authors also aimed at reducing renal uptake by coadministration of lysine. In vivo stability studies were performed in Swiss albino mice. Biodistribution studies were conducted in NMRI nu/nu mice bearing prostate cancer (PC)-3 xenografts. Ex vivo autoradiography was performed using frozen sections from PC-3 xenografts and kidneys. Coadministration of PA significantly increased the percentage of intact radiopeptide in the mouse circulation. From biodistribution and ex vivo autoradiography studies, coadministration of both lysine and PA with [(177)Lu]DOTA-GRP(13-27) appeared to induce a clear improvement of tumor uptake as well as lower levels of renal radioactivity, causing a promising ninefold increase in tumor/kidney ratios.
Journal of Nuclear Medicine, 2012
Megalin-mediated renal retention of radiolabeled somatostatin analogs may lead to nephrotoxicity ... more Megalin-mediated renal retention of radiolabeled somatostatin analogs may lead to nephrotoxicity during peptide receptor radionuclide therapy (PRRT). The cytoprotective agent amifostine protected rats from long-term nephrotoxicity after PRRT with 177 Lu-DOTA,Tyr 3-octreotate. This study describes the direct effect of amifostine on kidney and tumor uptake of 111 In-DOTA,Tyr 3-octreotate. Methods: In vivo biodistribution studies were performed using CA20948 tumor-bearing rats, with or without amifostine coadministration, via several routes. In vitro uptake was studied in somatostatin receptor-expressing CA20948 and megalin or cubilin receptor-expressing BN-16 cells, in the absence or presence of amifostine or its active metabolite WR-1065. Results: Coadministration of amifostine decreased renal uptake of radiolabeled octreotate in vivo, whereas tumor uptake was not affected. In agreement, amifostine and WR-1065 coincubation reduced uptake in BN-16 but not in CA20948 cells. Conclusion: Amifostine may provide renal protection during PRRT using somatostatin analogs, both by mitigation of radiation damage and the currently observed reduction of absorbed kidney radiation dose.
Journal of Nuclear Medicine, 2010
High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with b-p... more High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with b-particle-emitting radiolabeled somatostatin analogs will lead to renal failure several months after treatment, urging the coinfusion of the cationic amino acids lysine and arginine to reduce the renal radiation dose. In rat PRRT studies, renal protection by the coadministration of lysine was confirmed by histologic examination of kidney specimens indicating nephrotoxicity. In the current study, we investigated dedicated small-animal SPECT/CT renal imaging in rats to monitor renal function in vivo during follow-up of PRRT, with and without lysine. Methods: The following 3 groups of rats were imaged using a multipinhole SPECT/CT camera: controls (group 1) and rats at more than 90 d after therapy with 460 MBq (15 mg) of 177 Lu-DOTA-Tyr 3-octreotate without (group 2) or with (group 3) a 400-mg/kg lysine coinjection as kidney protection (n $ 6 per group). At 90 and 140 d after therapy, static kidney scintigraphy was performed at 2 h after injection of 25 MBq of 99m Tc-dimercaptosuccinic acid (99m Tc-DMSA). In addition, dynamic dual-isotope renography was performed using 50 MBq of 111 In-diethylenetriaminepentaacetic acid (111 In-DTPA) and 50 MBq of 99m Tc-mercaptoacetyltriglycine (99m Tc-MAG3) at 100-120 d after therapy. Results: 111 In-DTPA and 99m Tc-MAG3 studies revealed a time-activity pattern comparable to those in patients, with a peak at 2-6 min followed by a decline of renal radioactivity. Reduced 111 In-DTPA, 99m Tc-MAG3, and 99m Tc-DMSA uptake indicated renal damage in group 2, whereas group 3 showed only a decrease of 99m Tc-MAG3 peak activity. These results indicating nephrotoxicity in group 2 and renal protection in group 3 correlated with levels of urinary protein and serum creatinine and urea and were confirmed by renal histology. Conclusion: Quantitative dynamic dual-isotope imaging using both 111 In-DTPA and 99m Tc-MAG3 and static 99m Tc-DMSA imaging in rats is feasible using small-animal SPECT, enabling longitudinal monitoring of renal function. 99m Tc-MAG3 renography, especially, appears to be a more sensitive marker of tubular function after PRRT than serum chemistry or 99m Tc-DMSA scintigraphy.
![Research paper thumbnail of Effect of Interferon- Treatment on [68Ga-DOTA,Tyr3,Thre8]Octreotide Uptake in CA20948 Tumors: A Small-Animal PET Study](https://attachments.academia-assets.com/110785590/thumbnails/1.jpg)
](Journal of Nuclear Medicine, 2011
In peptide receptor radionuclide therapy of neuroendocrine tumors, improvements have been made by... more In peptide receptor radionuclide therapy of neuroendocrine tumors, improvements have been made by increasing the affinity for receptors and by protecting critical organs (e.g., kidneys). However, tumor parameters involved in radiopeptide uptake are still under investigation. Interferon-a (IFNa) is used as biotherapy for neuroendocrine tumors. Several mechanisms of action are described, but the potential effect of IFNa on tumor uptake of labeled peptide has not been studied in vivo yet. Methods: Twenty-six male CA20948 tumor-bearing Lewis rats were imaged before and during IFNa treatment using quantitative small-animal PET with [ 68 Ga-DOTA,Tyr 3 ,Thre 8 ]octreotide. Imaging was performed at days 0, 3, and 7. Animals were divided into 3 groups according to the treatment: control (injected daily with saline), half (4 d of IFNa treatment from day 0 to day 3, then saline), and full (7 d of IFNa). A daily dose of IFNa (1.5 mIU) was administered subcutaneously. Quantitative PET results are expressed as percentage injected dose per cm 3 and normalized to baseline (day 0) values. Tumor size was monitored by PET and caliper measurements. Results: Gross tumor uptake and tumor volumes increased in all groups over the 7-d period. On day 3, mean 6 SD ratios to day 0 were 1.2 6 0.2, 1.3 6 0.5, and 1.2 6 0.4, respectively, for control, half, and full groups. On day 7, respective values were 1.1 6 0.2, 1.3 6 0.6, and 1.5 6 0.4. At day 3, a comparison among groups showed no statistically significant difference. At day 7, the full group showed a significantly higher ratio in activity concentration than the control group (P 5 0.021). A good correlation was found between tumor volumes assessed by small-animal PET and caliper measurements (R 5 0.89, P , 0.0001). Conclusion: As expected, over a period of 7 d, both tumor volumes and radiopeptide uptake increased in all animals. However, the activity concentration increased significantly more at day 7 in animals treated for 7 d with IFNa, compared with controls. This is the first, to our knowledge, in vivo indication that IFNa is able to increase tumor uptake of the labeled analog in a small-animal model of neuroendocrine tumors. The mechanisms underlying this effect (flow, vascular permeability, receptor upregulation) remain unknown and need to be further investigated.
Journal of Leukocyte Biology, 2010
Mouse histiocytosis sarcoma virus infection induces a heterogeneous disease with characteristics ... more Mouse histiocytosis sarcoma virus infection induces a heterogeneous disease with characteristics of Mφ/DC neoplasms involving Langerin+ DC, Mφ, and precursors. Neoplastic diseases of macrophages (Mφ) and dendritic cells (DC), collectively called histiocytoses, are relatively rare. The etiology of most forms of histiocytosis is poorly understood, and the development of animal models is crucial for further research in this field. Previously, an animal model for malignant histiocytosis (MH), involving transformed histiocytic cells, has been generated by infecting mice with malignant histiocytosis sarcoma virus (MHSV). However, increased insight into the heterogeneity of Mφ and DC, and the associated reappraisal of human proliferative diseases involving these cells inspired us to re-evaluate the mouse model. We analyzed spleen, bone marrow, and lymph nodes of susceptible mice at various time points after infection. From day 11 onwards, a heterogeneous population of cells, consisting of ...
Graefe's Archive for Clinical and Experimental Ophthalmology, 2008
From Outside to Inside? Dose-Dependent Renal Tubular Damage After High-Dose Peptide Receptor Radionuclide Therapy in Rats Measured with In Vivo 99mTc-DMSA-SPECT and Molecular Imaging
Cancer Biotherapy and Radiopharmaceuticals, Feb 1, 2007
In peptide receptor radionuclide therapy (PRRT), the dose-limiting organ is, most often, the kidn... more In peptide receptor radionuclide therapy (PRRT), the dose-limiting organ is, most often, the kidney. However, the precise mechanism as well as the exact localization of kidney damage during PRRT have not been fully elucidated. We studied renal damage in rats after therapy with different amounts of [(177)Lu-DOTA(0), Tyr(3)]octreotate and investigated (99m)Tc-DMSA (dimercaptosuccinic acid) as a tool to quantify renal damage after PRRT. Twenty-nine (29) rats were divided into 3 groups and injected with either 0, 278, or 555 MBq [(177)Lu-DOTA(0), Tyr(3) ]octreotate, leading to approximately 0, 46, and 92 Gy to the renal cortex. More than 100 days after therapy, kidney damage was investigated using (99m)Tc-DMSA single-photon emission computed tomography (SPECT) autoradiography, histology, and blood analyses. In vivo SPECT with (99m)Tc-DMSA resulted in high-resolution (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1.6-mm) images. The (99m)Tc-DMSA uptake in the rat kidneys was inversely related with the earlier injected activity of [(177)Lu-DOTA(0), Tyr(3)]octreotate and correlated inversely with serum creatinine values. Renal ex vivo autoradiograms showed a dose-dependent distribution pattern of (99m)Tc-DMSA. (99m)Tc-DMSA SPECT could distinguish between the rats that were injected with 278 or 555 MBq [(177)Lu-DOTA(0), Tyr(3) ]octreotate, whereas histologic damage grading of the kidneys was nearly identical for these 2 groups. Histologic analyses indicated that lower amounts of injected radioactivity caused damage mainly in the proximal tubules, whereas as well the distal tubules were damaged after high-dose radioactivity. Renal damage in rats after PRRT appeared to start in a dose-dependent manner in the proximal tubules and continued to the more distal tubules with increasing amounts of injected activity. In vivo SPECT measurement of (99m)Tc-DMSA uptake was highly accurate to grade renal tubular damage after PRRT.
Optimisation of combination of peptide receptor radionuclide therapy (PRRT) and temozolomide therapy using SPECT/CT and MRI in mice
Poster: "ECR 2014 / B-0523 / Optimisation of combination of peptide receptor radionuclide th... more Poster: "ECR 2014 / B-0523 / Optimisation of combination of peptide receptor radionuclide therapy (PRRT) and temozolomide therapy using SPECT/CT and MRI in mice" by: "S. M. Bison, J. C. Haeck, S. J. Koelewijn, M. Melis, M. R. Bernsen, M. de Jong; Rotterdam/NL"
Megalin is essential for the kidney uptake of In-111-labeled peptides: Studies in megalin-deficient mice
The Journal of Nuclear Medicine, May 1, 2010
Determination of the beta-cell mass by SPECT imaging with In-111-DTPA-Exendin-3 in rats
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2009
Breast cancer imaging using radiolabelled somatostatin analogues
Nuclear Medicine and Biology, 2016
Imaging and therapy using radiolabelled somatostatin analogues are methods successfully used in p... more Imaging and therapy using radiolabelled somatostatin analogues are methods successfully used in patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumours. Since these techniques were first introduced, many improvements have been made. SSTR expression has also been reported on breast cancer (BC). Currently mammography, magnetic resonance imaging and ultrasound are the most frequent methods used for BC imaging. Since SSTR expression on BC was demonstrated, clinical studies examining the feasibility of visualizing primary BC using SSTR radioligands have been performed. However, to date SSTR-mediated nuclear imaging is not used clinically in BC patients. The aim of this review is to assess whether recent improvements made within nuclear medicine may enable SSTR-mediated imaging to play a role in BC management. For this we critically analysed results of past studies and discussed the potential of the improvements made within nuclear medicine on SSTR-mediated nuclear imaging of BC. Seven databases were searched for publications on BC imaging with SSTR radioligands. The papers found were analysed by 3 individual observers to identify whether the studies met the pre-set inclusion criteria defined as studies in which nuclear imaging using radiolabelled SST analogues was performed in patients with breast lesions. Twenty-four papers were selected for this review including studies on SSTR-mediated nuclear imaging in BC, neuroendocrine BC and other breast lesions. The analysed studies were heterogeneous with respect to the imaging method, imaging protocol, patient groups and the radiolabelled SST analogues used. Despite the fact that the analysed studies were heterogeneous, sensitivity for primary BC ranged from 36-100%. In a subset of the studies LN lesions were visualized, but sensitivity was lower compared to that for primary tumours. A part of the studies included benign lesions and specificity ranged from 22-100%. Furthermore, false negatives and false positives were reported. In the majority of the studies scan outcome was not associated with BC subtype.
Megalin is essential for the kidney uptake of In-111-labeled peptides: Studies in megalin-deficient mice
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2010
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2009
This review focuses on the present status of kidney protection during peptide receptor radionucli... more This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/ cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the reninangiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower renal retention may be developed. Furthermore, knowledge on kidney protection from radiolabelled somatostatin analogues may be expanded to other peptides.
Qual Life Res, 2010
En ook voor andere vrouwen, zoals mijn grootmoeders, die niet de kans hebben gekregen of genomen ... more En ook voor andere vrouwen, zoals mijn grootmoeders, die niet de kans hebben gekregen of genomen hun talenten te ontplooien Radiopeptides for targeted tumour therapy and the kidney Contents Chapter 1 General introduction 1.1 Introduction and outline of the thesis 1.2 Kidney protection during peptide receptor radionuclide therapy Chapter 2 Renal retention of radiolabelled peptides; role of megalin 2.1 Renal uptake and retention of radiolabelled somatostatin, bombesin, neurotensin, minigastrin and CCK analogues: species and gender differences 2.2 Localisation and mechanism of renal retention of radiolabelled somatostatin analogues 2.3 Megalin is essential for renal proximal tubule reabsorption of 111 In-DTPA-octreotide 2.4 Renal uptake of different radiolabelled peptides is mediated by megalin-SPECT and biodistribution studies in megalin-deficient mice Chapter 3 Reduction of renal uptake of radiolabelled octreotate and kidney protection 3.1 Dose-response effect of Gelofusine on renal retention of radiolabelled octreotate in rats with CA20948 tumours 3.2 Kidney protection by amifostine during peptide receptor radionuclide therapy (PRRT) in tumor-bearing rats; indications for two mechanisms Chapter 4 Micro-SPECT to monitor renal function after renal retention of radiopeptides 4.1 From outside to inside? Dose-dependent renal tubular damage after high-dose peptide receptor radionuclide therapy in rats measured with in vivo 99m Tc-DMSA-SPECT and molecular imaging. 4.2 Dynamic and static micro-SPECT in rats to monitor renal function after 177 Lu-labelled octreotate radionuclide therapy
Radiolabelled bombesin analogs in preclinical studies
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2007
EJNMMI research, 2015
Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine... more Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine tumours (NET) comprise somatostatin-analogue lutetium-177-labelled octreotate ((177)Lu-TATE) treatment, also referred to as peptide receptor radionuclide therapy (PRRT), and temozolomide (TMZ) treatment. Their combination might result in additive effects. Using MRI and SPECT/CT, we studied tumour characteristics and therapeutic responses after different (combined) administration schemes in a murine tumour model in order to identify the optimal treatment schedule for PRRT plus TMZ. We performed molecular imaging studies in mice bearing SSTR-expressing H69 (humane small cell lung cancer) tumours after single intravenous (i.v.) administration of 30 MBq (177)Lu-TATE or TMZ (oral 50 mg/kg daily for 14 days). Tumour perfusion was evaluated weekly by dynamic contrast-enhanced MRI (DCE-MRI), whereas tumour uptake of (111)In-octreotide was quantified using SPECT/CT until day 39 after treatment. ...
Clinical nuclear medicine, Jan 12, 2015
Radiolabeled somatostatin (SST) analogs, used to visualize and treat SST receptor (SSTR)-expressi... more Radiolabeled somatostatin (SST) analogs, used to visualize and treat SST receptor (SSTR)-expressing neuroendocrine tumors, also accumulate in the spleen. There is a high interpatient variation and no significant radiation-induced splenic toxicity; however, an absorbed dose-related reduction in spleen size was detected. However, the exact localization of radioactivity and the role of SST receptors in splenic retention are unknown. Therefore, we performed ex vivo micro-SPECT of the isolated spleen from a patient with a pancreatic neoplasm after 1 GBq (27 mCi) Lu-DOTATATE administration, followed by autoradiography and immunohistochemistry. Ex vivo autoradiography demonstrated convincingly that most radioactivity accumulated in red pulp.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 6, 2015
Imaging and therapy using radioligands targeting receptors overexpressed on tumor cells is succes... more Imaging and therapy using radioligands targeting receptors overexpressed on tumor cells is successfully applied in neuroendocrine tumor patients. Since expression of the gastrin releasing peptide receptor (GRPR), somatostatin receptor 2 (SSTR2) and chemokine C-X-C motif receptor 4 (CXCR4) has been demonstrated in breast cancer, targeting these receptors using radioligands might offer new imaging and therapeutic opportunities for breast cancer patients. The aim of this study was to correlate messenger RNA (mRNA) expression of GRPR, SSTR2 and CXCR4 with clinico-pathological and biological factors, with prognosis and prediction to therapy response, to identify specific breast cancer patient groups suited for the application of radioligands targeting the receptors. First, we studied GRPR and SSTR2 expression in 13 clinical breast cancer specimens by in vitro autoradiography and correlated this with corresponding mRNA levels to investigate whether mRNA levels reliably represent cell surf...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2007
Ex vivo autoradiographs of healthy kidney tissue from patients who received (111)In-DTPA-octreoti... more 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. 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 the beta-emitter (90)...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2007
Human prostate cancers (PC) overexpress gastrin-releasing peptide (GRP) receptors. This observati... more Human prostate cancers (PC) overexpress gastrin-releasing peptide (GRP) receptors. This observation suggests that GRP receptors may be used as new visualization and treatment modalities for these tumors. Radiolabeled GRP receptor-targeting analogs of GRP and bombesin (BN) have successfully been developed for these purposes. Expression of GRP receptors in human prostate tumors is, however, primarily evaluated in early stages of tumor development and information on expression in the more progressive prostate tumors is uncertain. To evaluate GRP receptor expression in all stages of PC, we investigated GRP receptor expression using a panel of 12 established human PC xenograft models representing the different stages of human PC and the effect of antiandrogen treatment (castration). Human PC xenografts were grown in male nude mice, and GRP receptor density in the tumors was evaluated using displacement receptor autoradiography with the universal BN receptor analog (125)I-[D-Tyr(6),beta-A...
In Vivo Enzyme Inhibition Improves the Targeting of [177Lu]DOTA-GRP(13–27) in GRPR-Positive Tumors in Mice
Cancer Biotherapy and Radiopharmaceuticals, 2014
Gastrin-releasing peptide receptors (GRPR) and GRP-derived analogs have attracted attention due t... more Gastrin-releasing peptide receptors (GRPR) and GRP-derived analogs have attracted attention due to high receptor expression in frequently occurring human neoplasia. The authors recently synthesized a series of GRPR-affine peptide analogs based on the 27-mer GRP and derivatized with the DOTA chelator at the N-terminus for (111)In-labeling. In this study, the authors evaluated the most promising from these series, DOTA-GRP(13-27), after radiolabeling with (177)Lu for future therapeutic applications. In addition, to improve in vivo stability of the peptide against in vivo degradation by the protease neutral endopeptidase (NEP), the authors coinjected [(177)Lu]DOTA-GRP(13-27) with the potent NEP inhibitor phosphoramidon (PA). The authors also aimed at reducing renal uptake by coadministration of lysine. In vivo stability studies were performed in Swiss albino mice. Biodistribution studies were conducted in NMRI nu/nu mice bearing prostate cancer (PC)-3 xenografts. Ex vivo autoradiography was performed using frozen sections from PC-3 xenografts and kidneys. Coadministration of PA significantly increased the percentage of intact radiopeptide in the mouse circulation. From biodistribution and ex vivo autoradiography studies, coadministration of both lysine and PA with [(177)Lu]DOTA-GRP(13-27) appeared to induce a clear improvement of tumor uptake as well as lower levels of renal radioactivity, causing a promising ninefold increase in tumor/kidney ratios.
Journal of Nuclear Medicine, 2012
Megalin-mediated renal retention of radiolabeled somatostatin analogs may lead to nephrotoxicity ... more Megalin-mediated renal retention of radiolabeled somatostatin analogs may lead to nephrotoxicity during peptide receptor radionuclide therapy (PRRT). The cytoprotective agent amifostine protected rats from long-term nephrotoxicity after PRRT with 177 Lu-DOTA,Tyr 3-octreotate. This study describes the direct effect of amifostine on kidney and tumor uptake of 111 In-DOTA,Tyr 3-octreotate. Methods: In vivo biodistribution studies were performed using CA20948 tumor-bearing rats, with or without amifostine coadministration, via several routes. In vitro uptake was studied in somatostatin receptor-expressing CA20948 and megalin or cubilin receptor-expressing BN-16 cells, in the absence or presence of amifostine or its active metabolite WR-1065. Results: Coadministration of amifostine decreased renal uptake of radiolabeled octreotate in vivo, whereas tumor uptake was not affected. In agreement, amifostine and WR-1065 coincubation reduced uptake in BN-16 but not in CA20948 cells. Conclusion: Amifostine may provide renal protection during PRRT using somatostatin analogs, both by mitigation of radiation damage and the currently observed reduction of absorbed kidney radiation dose.
Journal of Nuclear Medicine, 2010
High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with b-p... more High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with b-particle-emitting radiolabeled somatostatin analogs will lead to renal failure several months after treatment, urging the coinfusion of the cationic amino acids lysine and arginine to reduce the renal radiation dose. In rat PRRT studies, renal protection by the coadministration of lysine was confirmed by histologic examination of kidney specimens indicating nephrotoxicity. In the current study, we investigated dedicated small-animal SPECT/CT renal imaging in rats to monitor renal function in vivo during follow-up of PRRT, with and without lysine. Methods: The following 3 groups of rats were imaged using a multipinhole SPECT/CT camera: controls (group 1) and rats at more than 90 d after therapy with 460 MBq (15 mg) of 177 Lu-DOTA-Tyr 3-octreotate without (group 2) or with (group 3) a 400-mg/kg lysine coinjection as kidney protection (n $ 6 per group). At 90 and 140 d after therapy, static kidney scintigraphy was performed at 2 h after injection of 25 MBq of 99m Tc-dimercaptosuccinic acid (99m Tc-DMSA). In addition, dynamic dual-isotope renography was performed using 50 MBq of 111 In-diethylenetriaminepentaacetic acid (111 In-DTPA) and 50 MBq of 99m Tc-mercaptoacetyltriglycine (99m Tc-MAG3) at 100-120 d after therapy. Results: 111 In-DTPA and 99m Tc-MAG3 studies revealed a time-activity pattern comparable to those in patients, with a peak at 2-6 min followed by a decline of renal radioactivity. Reduced 111 In-DTPA, 99m Tc-MAG3, and 99m Tc-DMSA uptake indicated renal damage in group 2, whereas group 3 showed only a decrease of 99m Tc-MAG3 peak activity. These results indicating nephrotoxicity in group 2 and renal protection in group 3 correlated with levels of urinary protein and serum creatinine and urea and were confirmed by renal histology. Conclusion: Quantitative dynamic dual-isotope imaging using both 111 In-DTPA and 99m Tc-MAG3 and static 99m Tc-DMSA imaging in rats is feasible using small-animal SPECT, enabling longitudinal monitoring of renal function. 99m Tc-MAG3 renography, especially, appears to be a more sensitive marker of tubular function after PRRT than serum chemistry or 99m Tc-DMSA scintigraphy.
Journal of Nuclear Medicine, 2011
In peptide receptor radionuclide therapy of neuroendocrine tumors, improvements have been made by... more In peptide receptor radionuclide therapy of neuroendocrine tumors, improvements have been made by increasing the affinity for receptors and by protecting critical organs (e.g., kidneys). However, tumor parameters involved in radiopeptide uptake are still under investigation. Interferon-a (IFNa) is used as biotherapy for neuroendocrine tumors. Several mechanisms of action are described, but the potential effect of IFNa on tumor uptake of labeled peptide has not been studied in vivo yet. Methods: Twenty-six male CA20948 tumor-bearing Lewis rats were imaged before and during IFNa treatment using quantitative small-animal PET with [ 68 Ga-DOTA,Tyr 3 ,Thre 8 ]octreotide. Imaging was performed at days 0, 3, and 7. Animals were divided into 3 groups according to the treatment: control (injected daily with saline), half (4 d of IFNa treatment from day 0 to day 3, then saline), and full (7 d of IFNa). A daily dose of IFNa (1.5 mIU) was administered subcutaneously. Quantitative PET results are expressed as percentage injected dose per cm 3 and normalized to baseline (day 0) values. Tumor size was monitored by PET and caliper measurements. Results: Gross tumor uptake and tumor volumes increased in all groups over the 7-d period. On day 3, mean 6 SD ratios to day 0 were 1.2 6 0.2, 1.3 6 0.5, and 1.2 6 0.4, respectively, for control, half, and full groups. On day 7, respective values were 1.1 6 0.2, 1.3 6 0.6, and 1.5 6 0.4. At day 3, a comparison among groups showed no statistically significant difference. At day 7, the full group showed a significantly higher ratio in activity concentration than the control group (P 5 0.021). A good correlation was found between tumor volumes assessed by small-animal PET and caliper measurements (R 5 0.89, P , 0.0001). Conclusion: As expected, over a period of 7 d, both tumor volumes and radiopeptide uptake increased in all animals. However, the activity concentration increased significantly more at day 7 in animals treated for 7 d with IFNa, compared with controls. This is the first, to our knowledge, in vivo indication that IFNa is able to increase tumor uptake of the labeled analog in a small-animal model of neuroendocrine tumors. The mechanisms underlying this effect (flow, vascular permeability, receptor upregulation) remain unknown and need to be further investigated.
Journal of Leukocyte Biology, 2010
Mouse histiocytosis sarcoma virus infection induces a heterogeneous disease with characteristics ... more Mouse histiocytosis sarcoma virus infection induces a heterogeneous disease with characteristics of Mφ/DC neoplasms involving Langerin+ DC, Mφ, and precursors. Neoplastic diseases of macrophages (Mφ) and dendritic cells (DC), collectively called histiocytoses, are relatively rare. The etiology of most forms of histiocytosis is poorly understood, and the development of animal models is crucial for further research in this field. Previously, an animal model for malignant histiocytosis (MH), involving transformed histiocytic cells, has been generated by infecting mice with malignant histiocytosis sarcoma virus (MHSV). However, increased insight into the heterogeneity of Mφ and DC, and the associated reappraisal of human proliferative diseases involving these cells inspired us to re-evaluate the mouse model. We analyzed spleen, bone marrow, and lymph nodes of susceptible mice at various time points after infection. From day 11 onwards, a heterogeneous population of cells, consisting of ...