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Julie Bolcaen

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My main research interest lies in the field of nuclear medicine and radiation science, bringing cancer treatment and molecular imaging together. Since may 2019, I am a Post Doctoral scientist at the Radiobiology lab of iThemba Laboratory for Accelerator Based Sciences (iThemba LABS) in South-Africa. During my PhD I performed research at the Nuclear Medicine department and the INFINITY lab of Ghent University in Belgium. My PhD focussed on PET imaging of glioblastoma.

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Chatchote Thitaram

Chiang Mai University

Margarida Mourão

Ramesh R Bhonde

Dr. D.Y.Patil Medical College, Pimpri Pune

cristina Januario

Gabriela Mastromonaco

T.C. Haliç Üniversitesi

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Papers by Julie Bolcaen

Establishment of Primary Adult Skin Fibroblast Cell Lines from African Savanna Elephants (Loxodonta africana)

Animals

Following population declines of the African savanna elephant (Loxodonta africana) across the Afr... more Following population declines of the African savanna elephant (Loxodonta africana) across the African continent, the establishment of primary cell lines of endangered wildlife species is paramount for the preservation of their genetic resources. In addition, it allows molecular and functional studies on the cancer suppression mechanisms of elephants, which have previously been linked to a redundancy of tumor suppressor gene TP53. This methodology describes the establishment of primary elephant dermal fibroblast (EDF) cell lines from skin punch biopsy samples (diameter: ±4 mm) of African savanna elephants (n = 4, 14–35 years). The applied tissue collection technique is minimally invasive and paves the way for future remote biopsy darting. On average, the first explant outgrowth was observed after 15.75 ± 6.30 days. The average doubling time (Td) was 93.02 ± 16.94 h and 52.39 ± 0.46 h at passage 1 and 4, respectively. Metaphase spreads confirmed the diploid number of 56 chromosomes. T...

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

Cancers

Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains chal... more Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these...

Use of 18F-fluoromethylcholine PET in early treatment response assessment in glioblastoma patients

In vitro and in vivo evaluation of the LAT1 PET tracer 2-[18F]FELP in comparison to [18F]FET and [18F]FDG

Assessment of therapy response and differentiation between tumor recurrence and therapy-related effects in high-grade glioma using PET and MRI

The author and promotors give the authorization to consult and to copy parts of this thesis for p... more The author and promotors give the authorization to consult and to copy parts of this thesis for personal use only. Any other use is limited by the Laws of Copyright, especially concerning the obligation to refer to the source whenever results are cited from this thesis. De auteur en promotoren geven de toestemming dit proefschrift voor raadpleging ter beschikking te stellen en delen ervan te kopiëren voor persoonlijk gebruik. Elk ander gebruik valt onder de beperking van het auteursrecht, in het bijzonder tot de verplichting de bron te vermelden bij het aanhalen van resultaten uit deze thesis. Gent, March 2017, Julie Bolcaen Ook bedankt aan de collega's van MEDISIP voor de hulp bij meer technische vraagstukken. Bedankt Prof. Roel Vanholen, Stijn, Carmen en Karen om te geloven in het project in verband met de textuuranalyse en me te helpen bij het maken van de software en interpretatie van de resultaten. Ik geloof sterk in het slagen van het radiomics project in de toekomst. Mijn thesisstudenten Kelly en Josephine zou ik ook graag bedanken voor hun hulp bij de experimenten. Ik heb geluk gehad met gedreven studenten zoals jullie. PART II: THERAPY-RESPONSE ASSESSMENT OF HIGH-GRADE GLIOMA A. From MacDonald Criteria to RANO criteria B. Therapy related side effects Radiation necrosis Radiation necrosis vs tumor recurrence C. Limitations of the RANO criteria DSC-MRI MR-spectroscopy PART II: PET IN NEURO-ONCOLOGY A. PET B. Image-degrading effect in PET C. PET tracers in neuro-oncology 18 F-Fluorodeoxyglucose [ 18 F-FDG] 18 F-Fluoroethyltyrosine [ 18 F-FET] 18 F-Fluoromethylcholine [ 18 F-FCho] Hypoxia-PET 18 F-fluorothymidine [ 18 F-FLT] PART III: IMAGE ANALYSIS OF PET AND MRI A. Semi-quantitative image analysis PET DCE-MRI B. Quantitative image analysis Kinetic modeling in PET Graphical analysis in PET Patlak plot or Patlak/Gjedde plot Logan plot Kinetic modeling in DCE-MRI Model selection criteria PART IV: SPECIFICS OF SMALL ANIMAL PET AND MRI A. Small animal PET B. Small animal MRI C. Data analysis in small animal imaging REFERENCES Chapter 3. Scope and aims A. Therapy response assessment in GB as early as possible using PET and MRI Question 1 Are we able to assess therapy response in glioblastoma patients post-treatment using 18 F-FCho PET and MRI according to the RANO criteria? Question 2 Are we able to assess the effect of therapy in a rat model of GB using PET and MRI? B. Differentiation between radiation necrosis and tumor recurrence using PET and MRI Question 3 Are 18 F-FCho, 18 F-FET and 18 F-FDG PET able to discriminate between recurrent glioblastoma and radiation necrosis in rats? Question 4 Is in-vivo DCE-MRI able to discriminate between glioblastoma and radiation necrosis in rats? Chapter 4. Therapy response assessment in GB patients using 18 F-FCho PET and MRI according to the RANO criteria. INTRODUCTION MATERIALS AND METHODS Patients and treatments Response assessment PET imaging with 18 F-FCho Semi-quantitative PET analysis Magnetic resonance imaging Statistical analysis RESULTS Response evaluation Semi-quantitative PET analysis DISCUSSION REFERENCES Chapter 5. Assessment of the effect of therapy in a rat model of GB using PET and MRI List of abbreviations 1C1i One Compartment and One input function 2C1i Two Compartment and One input function 3C2i Three Compartments and Two input functions 2D Two

F-18 fluoromethylcholine (F-18 FCho) PET for the prediction of response according to the RANO criteria in glioblastoma patients

In Vivo DCE-MRI for the Discrimination Between Glioblastoma and Radiation Necrosis in Rats

Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging, Jan 16, 2017

In this study, the potential of semiquantitative and quantitative analysis of dynamic contrast-en... more In this study, the potential of semiquantitative and quantitative analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) was investigated to differentiate glioblastoma (GB) from radiation necrosis (RN) in rats. F98 GB growth was seen on MRI 8-23 days post-inoculation (n = 15). RN lesions developed 6-8 months post-irradiation (n = 10). DCE-MRI was acquired using a fast low-angle shot (FLASH) sequence. Regions of interest (ROIs) encompassed peripheral contrast enhancement in GB (n = 15) and RN (n = 10) as well as central necrosis within these lesions (GB (n = 4), RN (n = 3)). Dynamic contrast-enhanced time series, obtained from the DCE-MRI data, were fitted to determine four function variables (amplitude A, offset from zero C, wash-in rate k, and wash-out rate D) as well as maximal intensity (ImaxF) and time to peak (TTPF). Secondly, maps of semiquantitative and quantitative parameters (extended Tofts model) were created using Olea Sphere (O). Semiquantitative DC...

P07.22 Kinetic modeling and graphical analysis of 18F-fluoromethylcholine (FCho), 18F-fluoroethyltyrosine (FET) and 18F-fluorodeoxyglucose (FDG) PET for the discrimination between high-grade glioma and radiation necrosis in rats

Neuro-Oncology, 2016

not on corresponding normal cells. mHsp70 is rapidly internalized into tumor cells and thus targe... more not on corresponding normal cells. mHsp70 is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. In the presented study we conjugated the Hsp70-specific antibody (cmHsp70.1) which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor-specific targeting before and after ionizing irradiation. MATERIALS AND METHODS: Synthesized superparamagnetic iron oxide nanoparticles covered with anti-Hsp70 cmHsp70.1 antibodies (cmHsp70.1-SPIONs) were characterized using transmission electron microscopy (TEM), dynamic light scattering, NMR relaxometry. Cellular interactions of the cmHsp70.1-SPIONs conjugates with tumor cell lines (i.e., U87, LN229, C6, K562, HeLa) were assessed using confocal microscopy, flow cytometry and TEM. Brain tumor targeting was analyzed in the orthotopic C6 glioma model in rats, human U87 and LN229 gliomas in nu/nu mice. Following intravenous administration retention of the nanoparticles in the tumor site was assessed using high-field 11.0 T magnetic resonance imaging (MRI) with subsequent histological assay. Biodistribution studies of the SPIONs were performed by NLR-M2 measurements. Combination of the nanoparticle targeting with radiotherapy of the brain tumors was performed at small animal radiation research platform (SARRP) (Xstrahl Inc., UK) using single of fractionated irradiation. RESULTS: In vitro experiments demonstrated the selectivity of cmHsp70.1-SPION conjugates to free and mHsp70 in different tumor cell types (U87, LN229, C6 glioblastoma, K562 leukemia, HeLa cervix carcinoma) in a dose-dependent manner. High-resolution MRI on T2-weighted images showed the retention of the conjugates in C6 glioma model in rats, and U87 and LN229 humna orthotopic glioma models in nu/nu mice. Accumulation of cmHsp70.1-SPION nanoparticles in the glioma resulted in nearly 2-fold drop of T2* values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M2 measurements showed a 7-fold increase in the tumor-to-background (normal brain) uptake ratio of cmHsp70.1-SPIONs conjugates in glioma-bearing animals in comparison to SPIONs. Accumulation within Hsp70-positive glioma was enhanced after a single dose (10 Gy) of ionizing radiation. Application of the fractionated radiotherapy further improved the retention of cmHsp70.1-SPI-ONs. CONCLUSIONS: Elevated accumulation of the functionalized magnetic nanoparticles in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents in brain tumors.

Marshalling the Potential of Auger Electron Radiopharmaceutical Therapy

Journal of Nuclear Medicine

Introducing HDAC-Targeting Radiopharmaceuticals for Glioblastoma Imaging and Therapy

Pharmaceuticals

Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, rad... more Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA repair, cell proliferation, differentiation, apoptosis and cell cycle, HDAC inhibitors have gained a lot of attention in the last decade as anti-cancer agents. Despite their known underlying mechanism, their therapeutic activity is not well-defined. In this review, an extensive overview is given of the current status of HDAC inhibitors for GB therapy, followed by an overview of current HDAC-targeting radiopharmaceuticals. Imaging HDAC expression or activity could provide key insights regarding the role of HDAC enzymes in gliomagenesis, thus identifying patients likely to benefit from HDACi-targeted therapy.

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

Pharmaceuticals

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate an... more Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, b...

Immunological Changes During Space Travel: A Ground-Based Evaluation of the Impact of Neutron Dose Rate on Plasma Cytokine Levels in Human Whole Blood Cultures

Frontiers in Physics, 2020

A better understanding of the combined impact of different space stressors on human health is urg... more A better understanding of the combined impact of different space stressors on human health is urgently warranted, considering the upcoming long-duration missions beyond lower Earth orbit. Therefore, a growing number of particle accelerator facilities implement ground-based set-ups to study the effect of simulated space radiation with simulated psychological or physical stressors. The immune system is highly sensitive to these types of stressors and limited information is currently available on the impact of the complex space radiation environment on the astronauts' immune function. This pilot study presents a first step in the implementation of a ground-based set-up with neutron irradiation, which is considered to be an important secondary component in space radiation fields. The effect of dose rate on immune alterations was studied using the in vitro cytokine release assay. Whole blood samples (n = 8) were exposed to 0.125 or 1 Gy of neutron irradiation (fluence-weighted averag...

An Automated Microscopic Scoring Method for the γ-H2AX Foci Assay in Human Peripheral Blood Lymphocytes

Journal of Visualized Experiments, 2021

Ionizing radiation is a potent inducer of DNA damage and a well-documented carcinogen. Biological... more Ionizing radiation is a potent inducer of DNA damage and a well-documented carcinogen. Biological dosimetry comprises the detection of biological effects induced by exposure to ionizing radiation to make an individual dose assessment. This is pertinent in the framework of radiation emergencies, where health assessments and planning of clinical treatment for exposed victims are critical. Since DNA double strand breaks (DSB) are considered to be the most lethal form of radiation-induced DNA damage, this protocol presents a method to detect DNA DSB in blood samples. The methodology is based on the detection of a fluorescent labelled phosphorylated DNA repair protein, namely, γ-H2AX. The use of an automated microscopy platform to score the number of γ-H2AX foci per cell allows a standardized analysis with a significant decrease in the turnaround time. Therefore, the γ-H2AX assay has the potential to be one of the fastest and sensitive assays for biological dosimetry. In this protocol, whole blood samples from healthy adult volunteers will be processed and irradiated in vitro in order to illustrate the usage of the automated and sensitive γ-H2AX foci assay for biodosimetry applications. An automated slide scanning system and analysis platform with an integrated fluorescence microscope is used, which allows the fast, automatic scoring of DNA DSB with a reduced degree of bias.

An Automated Microscopic Scoring Method for the γ-H2AX Foci Assay in Human Peripheral Blood Lymphocytes

Journal of Visualized Experiments

Ionizing radiation is a potent inducer of DNA damage and a well-documented carcinogen. Biological... more Ionizing radiation is a potent inducer of DNA damage and a well-documented carcinogen. Biological dosimetry comprises the detection of biological effects induced by exposure to ionizing radiation to make an individual dose assessment. This is pertinent in the framework of radiation emergencies, where health assessments and planning of clinical treatment for exposed victims are critical. Since DNA double strand breaks (DSB) are considered to be the most lethal form of radiation-induced DNA damage, this protocol presents a method to detect DNA DSB in blood samples. The methodology is based on the detection of a fluorescent labelled phosphorylated DNA repair protein, namely, γ-H2AX. The use of an automated microscopy platform to score the number of γ-H2AX foci per cell allows a standardized analysis with a significant decrease in the turnaround time. Therefore, the γ-H2AX assay has the potential to be one of the fastest and sensitive assays for biological dosimetry. In this protocol, whole blood samples from healthy adult volunteers will be processed and irradiated in vitro in order to illustrate the usage of the automated and sensitive γ-H2AX foci assay for biodosimetry applications. An automated slide scanning system and analysis platform with an integrated fluorescence microscope is used, which allows the fast, automatic scoring of DNA DSB with a reduced degree of bias.

Molecular MRI in preclinical research

In vivo magnetic resonance imaging of acute radiation induced inflammation using ICAM1 targeted micron-sized particles of iron oxide (ICAM-MPIO)

The Path Toward PET-Guided Radiation Therapy for Glioblastoma in Laboratory Animals: A Mini Review

Frontiers in Medicine, 2019

Glioblastoma is the most aggressive and malignant primary brain tumor in adults. Despite the curr... more Glioblastoma is the most aggressive and malignant primary brain tumor in adults. Despite the current state-of-the-art treatment, which consists of maximal surgical resection followed by radiation therapy, concomitant, and adjuvant chemotherapy, progression remains rapid due to aggressive tumor characteristics. Several new therapeutic targets have been investigated using chemotherapeutics and targeted molecular drugs, however, the intrinsic resistance to induced cell death of brain cells impede the effectiveness of systemic therapies. Also, the unique immune environment of the central nervous system imposes challenges for immune-based therapeutics. Therefore, it is important to consider other approaches to treat these tumors. There is a well-known dose-response relationship for glioblastoma with increased survival with increasing doses, but this effect seems to cap around 60 Gy, due to increased toxicity to the normal brain. Currently, radiation treatment planning of glioblastoma patients relies on CT and MRI that does not visualize the heterogeneous nature of the tumor, and consequently, a homogenous dose is delivered to the entire tumor. Metabolic imaging, such as positron-emission tomography, allows to visualize the heterogeneous tumor environment. Using these metabolic imaging techniques, an approach called dose painting can be used to deliver a higher dose to the tumor regions with high malignancy and/or radiation resistance. Preclinical studies are required for evaluating the benefits of novel radiation treatment strategies, such as PET-based dose painting. The aim of this review is to give a brief overview of promising PET tracers that can be evaluated in laboratory animals to bridge the gap between PET-based dose painting in glioblastoma patients.

New fluoroethyl phenylalanine analogues as potential LAT1-targeting PET tracers for glioblastoma

Scientific Reports, 2019

The use of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) as a positron emission tomography (PET) t... more The use of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) as a positron emission tomography (PET) tracer for brain tumor imaging might have some limitations because of the relatively low affinity for the L-type amino acid transporter 1 (LAT1). To assess the stereospecificity and evaluate the influence of aromatic ring modification of phenylalanine LAT1 targeting tracers, six different fluoroalkylated phenylalanine analogues were synthesized. After in vitro Ki determination, the most promising compound, 2-[18F]-2-fluoroethyl-l-phenylalanine (2-[18F]FELP), was selected for further evaluation and in vitro comparison with [18F]FET. Subsequently, 2-[18F]FELP was assessed in vivo and compared with [18F]FET and [18F]FDG in a F98 glioblastoma rat model. 2-[18F]FELP showed improved in vitro characteristics over [18F]FET, especially when the affinity and specificity for system L is concerned. Based on our results, 2-[18F]FELP is a promising new PET tracer for brain tumor imaging.

Kinetic Modeling and Graphical Analysis of 18F-Fluoromethylcholine (FCho), 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET for the Fiscrimination between High-Grade Glioma and Radiation Necrosis in Rats

PloS one, 2016

Discrimination between glioblastoma (GB) and radiation necrosis (RN) post-irradiation remains cha... more Discrimination between glioblastoma (GB) and radiation necrosis (RN) post-irradiation remains challenging but has a large impact on further treatment and prognosis. In this study, the uptake mechanisms of 18F-fluorodeoxyglucose (18F-FDG), 18F-fluoroethyltyrosine (18F-FET) and 18F-fluoromethylcholine (18F-FCho) positron emission tomography (PET) tracers were investigated in a F98 GB and RN rat model applying kinetic modeling (KM) and graphical analysis (GA) to clarify our previous results. Dynamic 18F-FDG (GB n = 6 and RN n = 5), 18F-FET (GB n = 5 and RN n = 5) and 18F-FCho PET (GB n = 5 and RN n = 5) were acquired with continuous arterial blood sampling. Arterial input function (AIF) corrections, KM and GA were performed. The influx rate (Ki) of 18F-FDG uptake described by a 2-compartmental model (CM) or using Patlak GA, showed more trapping (k3) in GB (0.07 min-1) compared to RN (0.04 min-1) (p = 0.017). K1 of 18F-FET was significantly higher in GB (0.06 ml/ccm/min) compared to RN ...

P16.04 * Use of 18F-FLUOROMETHYLCHOLINE Pet in Early Treatment Response Assessment in Glioblastoma Patients

Neuro-Oncology, 2014

Establishment of Primary Adult Skin Fibroblast Cell Lines from African Savanna Elephants (Loxodonta africana)

Animals

Following population declines of the African savanna elephant (Loxodonta africana) across the Afr... more Following population declines of the African savanna elephant (Loxodonta africana) across the African continent, the establishment of primary cell lines of endangered wildlife species is paramount for the preservation of their genetic resources. In addition, it allows molecular and functional studies on the cancer suppression mechanisms of elephants, which have previously been linked to a redundancy of tumor suppressor gene TP53. This methodology describes the establishment of primary elephant dermal fibroblast (EDF) cell lines from skin punch biopsy samples (diameter: ±4 mm) of African savanna elephants (n = 4, 14–35 years). The applied tissue collection technique is minimally invasive and paves the way for future remote biopsy darting. On average, the first explant outgrowth was observed after 15.75 ± 6.30 days. The average doubling time (Td) was 93.02 ± 16.94 h and 52.39 ± 0.46 h at passage 1 and 4, respectively. Metaphase spreads confirmed the diploid number of 56 chromosomes. T...

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

Cancers

Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains chal... more Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these...

Use of 18F-fluoromethylcholine PET in early treatment response assessment in glioblastoma patients

In vitro and in vivo evaluation of the LAT1 PET tracer 2-[18F]FELP in comparison to [18F]FET and [18F]FDG

Assessment of therapy response and differentiation between tumor recurrence and therapy-related effects in high-grade glioma using PET and MRI

The author and promotors give the authorization to consult and to copy parts of this thesis for p... more The author and promotors give the authorization to consult and to copy parts of this thesis for personal use only. Any other use is limited by the Laws of Copyright, especially concerning the obligation to refer to the source whenever results are cited from this thesis. De auteur en promotoren geven de toestemming dit proefschrift voor raadpleging ter beschikking te stellen en delen ervan te kopiëren voor persoonlijk gebruik. Elk ander gebruik valt onder de beperking van het auteursrecht, in het bijzonder tot de verplichting de bron te vermelden bij het aanhalen van resultaten uit deze thesis. Gent, March 2017, Julie Bolcaen Ook bedankt aan de collega's van MEDISIP voor de hulp bij meer technische vraagstukken. Bedankt Prof. Roel Vanholen, Stijn, Carmen en Karen om te geloven in het project in verband met de textuuranalyse en me te helpen bij het maken van de software en interpretatie van de resultaten. Ik geloof sterk in het slagen van het radiomics project in de toekomst. Mijn thesisstudenten Kelly en Josephine zou ik ook graag bedanken voor hun hulp bij de experimenten. Ik heb geluk gehad met gedreven studenten zoals jullie. PART II: THERAPY-RESPONSE ASSESSMENT OF HIGH-GRADE GLIOMA A. From MacDonald Criteria to RANO criteria B. Therapy related side effects Radiation necrosis Radiation necrosis vs tumor recurrence C. Limitations of the RANO criteria DSC-MRI MR-spectroscopy PART II: PET IN NEURO-ONCOLOGY A. PET B. Image-degrading effect in PET C. PET tracers in neuro-oncology 18 F-Fluorodeoxyglucose [ 18 F-FDG] 18 F-Fluoroethyltyrosine [ 18 F-FET] 18 F-Fluoromethylcholine [ 18 F-FCho] Hypoxia-PET 18 F-fluorothymidine [ 18 F-FLT] PART III: IMAGE ANALYSIS OF PET AND MRI A. Semi-quantitative image analysis PET DCE-MRI B. Quantitative image analysis Kinetic modeling in PET Graphical analysis in PET Patlak plot or Patlak/Gjedde plot Logan plot Kinetic modeling in DCE-MRI Model selection criteria PART IV: SPECIFICS OF SMALL ANIMAL PET AND MRI A. Small animal PET B. Small animal MRI C. Data analysis in small animal imaging REFERENCES Chapter 3. Scope and aims A. Therapy response assessment in GB as early as possible using PET and MRI Question 1 Are we able to assess therapy response in glioblastoma patients post-treatment using 18 F-FCho PET and MRI according to the RANO criteria? Question 2 Are we able to assess the effect of therapy in a rat model of GB using PET and MRI? B. Differentiation between radiation necrosis and tumor recurrence using PET and MRI Question 3 Are 18 F-FCho, 18 F-FET and 18 F-FDG PET able to discriminate between recurrent glioblastoma and radiation necrosis in rats? Question 4 Is in-vivo DCE-MRI able to discriminate between glioblastoma and radiation necrosis in rats? Chapter 4. Therapy response assessment in GB patients using 18 F-FCho PET and MRI according to the RANO criteria. INTRODUCTION MATERIALS AND METHODS Patients and treatments Response assessment PET imaging with 18 F-FCho Semi-quantitative PET analysis Magnetic resonance imaging Statistical analysis RESULTS Response evaluation Semi-quantitative PET analysis DISCUSSION REFERENCES Chapter 5. Assessment of the effect of therapy in a rat model of GB using PET and MRI List of abbreviations 1C1i One Compartment and One input function 2C1i Two Compartment and One input function 3C2i Three Compartments and Two input functions 2D Two

F-18 fluoromethylcholine (F-18 FCho) PET for the prediction of response according to the RANO criteria in glioblastoma patients

In Vivo DCE-MRI for the Discrimination Between Glioblastoma and Radiation Necrosis in Rats

Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging, Jan 16, 2017

In this study, the potential of semiquantitative and quantitative analysis of dynamic contrast-en... more In this study, the potential of semiquantitative and quantitative analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) was investigated to differentiate glioblastoma (GB) from radiation necrosis (RN) in rats. F98 GB growth was seen on MRI 8-23 days post-inoculation (n = 15). RN lesions developed 6-8 months post-irradiation (n = 10). DCE-MRI was acquired using a fast low-angle shot (FLASH) sequence. Regions of interest (ROIs) encompassed peripheral contrast enhancement in GB (n = 15) and RN (n = 10) as well as central necrosis within these lesions (GB (n = 4), RN (n = 3)). Dynamic contrast-enhanced time series, obtained from the DCE-MRI data, were fitted to determine four function variables (amplitude A, offset from zero C, wash-in rate k, and wash-out rate D) as well as maximal intensity (ImaxF) and time to peak (TTPF). Secondly, maps of semiquantitative and quantitative parameters (extended Tofts model) were created using Olea Sphere (O). Semiquantitative DC...

P07.22 Kinetic modeling and graphical analysis of 18F-fluoromethylcholine (FCho), 18F-fluoroethyltyrosine (FET) and 18F-fluorodeoxyglucose (FDG) PET for the discrimination between high-grade glioma and radiation necrosis in rats

Neuro-Oncology, 2016

not on corresponding normal cells. mHsp70 is rapidly internalized into tumor cells and thus targe... more not on corresponding normal cells. mHsp70 is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. In the presented study we conjugated the Hsp70-specific antibody (cmHsp70.1) which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor-specific targeting before and after ionizing irradiation. MATERIALS AND METHODS: Synthesized superparamagnetic iron oxide nanoparticles covered with anti-Hsp70 cmHsp70.1 antibodies (cmHsp70.1-SPIONs) were characterized using transmission electron microscopy (TEM), dynamic light scattering, NMR relaxometry. Cellular interactions of the cmHsp70.1-SPIONs conjugates with tumor cell lines (i.e., U87, LN229, C6, K562, HeLa) were assessed using confocal microscopy, flow cytometry and TEM. Brain tumor targeting was analyzed in the orthotopic C6 glioma model in rats, human U87 and LN229 gliomas in nu/nu mice. Following intravenous administration retention of the nanoparticles in the tumor site was assessed using high-field 11.0 T magnetic resonance imaging (MRI) with subsequent histological assay. Biodistribution studies of the SPIONs were performed by NLR-M2 measurements. Combination of the nanoparticle targeting with radiotherapy of the brain tumors was performed at small animal radiation research platform (SARRP) (Xstrahl Inc., UK) using single of fractionated irradiation. RESULTS: In vitro experiments demonstrated the selectivity of cmHsp70.1-SPION conjugates to free and mHsp70 in different tumor cell types (U87, LN229, C6 glioblastoma, K562 leukemia, HeLa cervix carcinoma) in a dose-dependent manner. High-resolution MRI on T2-weighted images showed the retention of the conjugates in C6 glioma model in rats, and U87 and LN229 humna orthotopic glioma models in nu/nu mice. Accumulation of cmHsp70.1-SPION nanoparticles in the glioma resulted in nearly 2-fold drop of T2* values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M2 measurements showed a 7-fold increase in the tumor-to-background (normal brain) uptake ratio of cmHsp70.1-SPIONs conjugates in glioma-bearing animals in comparison to SPIONs. Accumulation within Hsp70-positive glioma was enhanced after a single dose (10 Gy) of ionizing radiation. Application of the fractionated radiotherapy further improved the retention of cmHsp70.1-SPI-ONs. CONCLUSIONS: Elevated accumulation of the functionalized magnetic nanoparticles in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents in brain tumors.

Marshalling the Potential of Auger Electron Radiopharmaceutical Therapy

Journal of Nuclear Medicine

Introducing HDAC-Targeting Radiopharmaceuticals for Glioblastoma Imaging and Therapy

Pharmaceuticals

Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, rad... more Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA repair, cell proliferation, differentiation, apoptosis and cell cycle, HDAC inhibitors have gained a lot of attention in the last decade as anti-cancer agents. Despite their known underlying mechanism, their therapeutic activity is not well-defined. In this review, an extensive overview is given of the current status of HDAC inhibitors for GB therapy, followed by an overview of current HDAC-targeting radiopharmaceuticals. Imaging HDAC expression or activity could provide key insights regarding the role of HDAC enzymes in gliomagenesis, thus identifying patients likely to benefit from HDACi-targeted therapy.

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

Pharmaceuticals

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate an... more Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, b...

Immunological Changes During Space Travel: A Ground-Based Evaluation of the Impact of Neutron Dose Rate on Plasma Cytokine Levels in Human Whole Blood Cultures

Frontiers in Physics, 2020

A better understanding of the combined impact of different space stressors on human health is urg... more A better understanding of the combined impact of different space stressors on human health is urgently warranted, considering the upcoming long-duration missions beyond lower Earth orbit. Therefore, a growing number of particle accelerator facilities implement ground-based set-ups to study the effect of simulated space radiation with simulated psychological or physical stressors. The immune system is highly sensitive to these types of stressors and limited information is currently available on the impact of the complex space radiation environment on the astronauts' immune function. This pilot study presents a first step in the implementation of a ground-based set-up with neutron irradiation, which is considered to be an important secondary component in space radiation fields. The effect of dose rate on immune alterations was studied using the in vitro cytokine release assay. Whole blood samples (n = 8) were exposed to 0.125 or 1 Gy of neutron irradiation (fluence-weighted averag...

An Automated Microscopic Scoring Method for the γ-H2AX Foci Assay in Human Peripheral Blood Lymphocytes

Journal of Visualized Experiments, 2021

Ionizing radiation is a potent inducer of DNA damage and a well-documented carcinogen. Biological... more Ionizing radiation is a potent inducer of DNA damage and a well-documented carcinogen. Biological dosimetry comprises the detection of biological effects induced by exposure to ionizing radiation to make an individual dose assessment. This is pertinent in the framework of radiation emergencies, where health assessments and planning of clinical treatment for exposed victims are critical. Since DNA double strand breaks (DSB) are considered to be the most lethal form of radiation-induced DNA damage, this protocol presents a method to detect DNA DSB in blood samples. The methodology is based on the detection of a fluorescent labelled phosphorylated DNA repair protein, namely, γ-H2AX. The use of an automated microscopy platform to score the number of γ-H2AX foci per cell allows a standardized analysis with a significant decrease in the turnaround time. Therefore, the γ-H2AX assay has the potential to be one of the fastest and sensitive assays for biological dosimetry. In this protocol, whole blood samples from healthy adult volunteers will be processed and irradiated in vitro in order to illustrate the usage of the automated and sensitive γ-H2AX foci assay for biodosimetry applications. An automated slide scanning system and analysis platform with an integrated fluorescence microscope is used, which allows the fast, automatic scoring of DNA DSB with a reduced degree of bias.

An Automated Microscopic Scoring Method for the γ-H2AX Foci Assay in Human Peripheral Blood Lymphocytes

Journal of Visualized Experiments

Ionizing radiation is a potent inducer of DNA damage and a well-documented carcinogen. Biological... more Ionizing radiation is a potent inducer of DNA damage and a well-documented carcinogen. Biological dosimetry comprises the detection of biological effects induced by exposure to ionizing radiation to make an individual dose assessment. This is pertinent in the framework of radiation emergencies, where health assessments and planning of clinical treatment for exposed victims are critical. Since DNA double strand breaks (DSB) are considered to be the most lethal form of radiation-induced DNA damage, this protocol presents a method to detect DNA DSB in blood samples. The methodology is based on the detection of a fluorescent labelled phosphorylated DNA repair protein, namely, γ-H2AX. The use of an automated microscopy platform to score the number of γ-H2AX foci per cell allows a standardized analysis with a significant decrease in the turnaround time. Therefore, the γ-H2AX assay has the potential to be one of the fastest and sensitive assays for biological dosimetry. In this protocol, whole blood samples from healthy adult volunteers will be processed and irradiated in vitro in order to illustrate the usage of the automated and sensitive γ-H2AX foci assay for biodosimetry applications. An automated slide scanning system and analysis platform with an integrated fluorescence microscope is used, which allows the fast, automatic scoring of DNA DSB with a reduced degree of bias.

Molecular MRI in preclinical research

In vivo magnetic resonance imaging of acute radiation induced inflammation using ICAM1 targeted micron-sized particles of iron oxide (ICAM-MPIO)

The Path Toward PET-Guided Radiation Therapy for Glioblastoma in Laboratory Animals: A Mini Review

Frontiers in Medicine, 2019

Glioblastoma is the most aggressive and malignant primary brain tumor in adults. Despite the curr... more Glioblastoma is the most aggressive and malignant primary brain tumor in adults. Despite the current state-of-the-art treatment, which consists of maximal surgical resection followed by radiation therapy, concomitant, and adjuvant chemotherapy, progression remains rapid due to aggressive tumor characteristics. Several new therapeutic targets have been investigated using chemotherapeutics and targeted molecular drugs, however, the intrinsic resistance to induced cell death of brain cells impede the effectiveness of systemic therapies. Also, the unique immune environment of the central nervous system imposes challenges for immune-based therapeutics. Therefore, it is important to consider other approaches to treat these tumors. There is a well-known dose-response relationship for glioblastoma with increased survival with increasing doses, but this effect seems to cap around 60 Gy, due to increased toxicity to the normal brain. Currently, radiation treatment planning of glioblastoma patients relies on CT and MRI that does not visualize the heterogeneous nature of the tumor, and consequently, a homogenous dose is delivered to the entire tumor. Metabolic imaging, such as positron-emission tomography, allows to visualize the heterogeneous tumor environment. Using these metabolic imaging techniques, an approach called dose painting can be used to deliver a higher dose to the tumor regions with high malignancy and/or radiation resistance. Preclinical studies are required for evaluating the benefits of novel radiation treatment strategies, such as PET-based dose painting. The aim of this review is to give a brief overview of promising PET tracers that can be evaluated in laboratory animals to bridge the gap between PET-based dose painting in glioblastoma patients.

New fluoroethyl phenylalanine analogues as potential LAT1-targeting PET tracers for glioblastoma

Scientific Reports, 2019

The use of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) as a positron emission tomography (PET) t... more The use of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) as a positron emission tomography (PET) tracer for brain tumor imaging might have some limitations because of the relatively low affinity for the L-type amino acid transporter 1 (LAT1). To assess the stereospecificity and evaluate the influence of aromatic ring modification of phenylalanine LAT1 targeting tracers, six different fluoroalkylated phenylalanine analogues were synthesized. After in vitro Ki determination, the most promising compound, 2-[18F]-2-fluoroethyl-l-phenylalanine (2-[18F]FELP), was selected for further evaluation and in vitro comparison with [18F]FET. Subsequently, 2-[18F]FELP was assessed in vivo and compared with [18F]FET and [18F]FDG in a F98 glioblastoma rat model. 2-[18F]FELP showed improved in vitro characteristics over [18F]FET, especially when the affinity and specificity for system L is concerned. Based on our results, 2-[18F]FELP is a promising new PET tracer for brain tumor imaging.

Kinetic Modeling and Graphical Analysis of 18F-Fluoromethylcholine (FCho), 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET for the Fiscrimination between High-Grade Glioma and Radiation Necrosis in Rats

PloS one, 2016

Discrimination between glioblastoma (GB) and radiation necrosis (RN) post-irradiation remains cha... more Discrimination between glioblastoma (GB) and radiation necrosis (RN) post-irradiation remains challenging but has a large impact on further treatment and prognosis. In this study, the uptake mechanisms of 18F-fluorodeoxyglucose (18F-FDG), 18F-fluoroethyltyrosine (18F-FET) and 18F-fluoromethylcholine (18F-FCho) positron emission tomography (PET) tracers were investigated in a F98 GB and RN rat model applying kinetic modeling (KM) and graphical analysis (GA) to clarify our previous results. Dynamic 18F-FDG (GB n = 6 and RN n = 5), 18F-FET (GB n = 5 and RN n = 5) and 18F-FCho PET (GB n = 5 and RN n = 5) were acquired with continuous arterial blood sampling. Arterial input function (AIF) corrections, KM and GA were performed. The influx rate (Ki) of 18F-FDG uptake described by a 2-compartmental model (CM) or using Patlak GA, showed more trapping (k3) in GB (0.07 min-1) compared to RN (0.04 min-1) (p = 0.017). K1 of 18F-FET was significantly higher in GB (0.06 ml/ccm/min) compared to RN ...

P16.04 * Use of 18F-FLUOROMETHYLCHOLINE Pet in Early Treatment Response Assessment in Glioblastoma Patients

Neuro-Oncology, 2014