Publications by authors named "Eirik Malinen"

96 Publications

Spatially fractionated radiotherapy: tumor response modelling including immunomodulation.

Phys Med Biol 2021 08 24;66(17). Epub 2021 Aug 24.

Department of Physics, University of Oslo, PO Box 1048 Blindern, N-0316 Oslo, Norway.

A mathematical tumor response model has been developed, encompassing the interplay between immune cells and cancer cells initiated by either partial or full tumor irradiation. The iterative four-compartment model employs the linear-quadratic radiation response theory for four cell types: active and inactive cytotoxic T lymphocytes (immune cells, CD8T cells in particular), viable cancer cells (undamaged and reparable cells) and doomed cells (irreparably damaged cells). The cell compartment interactions are calculated per day, with total tumor volume (TV) as the main quantity of interest. The model was fitted to previously published data on syngeneic xenografts (67NR breast carcinoma and Lewis lung carcinoma; (Markovsky2019697-708)) subjected to single doses of 10 or 15 Gy by 50% (partial) or 100% (full) TV irradiation. The experimental data included effects from anti-CD8antibodies and immunosuppressive drugs. Using a new optimization method, promising fits were obtained where the lowest and highest root-mean-squared error values were observed for anti-CD8treatment and unirradiated control data, respectively, for both cell types. Additionally, predictive capabilities of the model were tested by using the estimated model parameters to predict scenarios for higher doses and different TV irradiation fractions. Here, mean relative deviations in the range of 19%-34% from experimental data were found. However, more validation data is needed to conclude on the model's predictive capabilities. In conclusion, the model was found useful in evaluating the impact from partial and full TV irradiation on the immune response and subsequent tumor growth. The model shows potential to support and guide spatially fractionated radiotherapy in future pre-clinical and clinical studies.
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http://dx.doi.org/10.1088/1361-6560/ac176bDOI Listing
August 2021

Repeatability of hypoxia dose painting by numbers based on EF5-PET in head and neck cancer.

Acta Oncol 2021 Jun 29:1-6. Epub 2021 Jun 29.

Department of Medical Physics, Oslo University Hospital, Oslo, Norway.

Background: Hypoxia dose painting is a radiotherapy technique to increase the dose to hypoxic regions of the tumour. Still, the clinical effect relies on the reproducibility of the hypoxic region shown in the medical image. F-EF5 is a hypoxia tracer for positron emission tomography (PET), and this study investigated the repeatability of F-EF5-based dose painting by numbers (DPBN) in head and neck cancer (HNC).

Materials And Methods: Eight HNC patients undergoing two F-EF5-PET/CT sessions (A and B) before radiotherapy were included. A linear conversion of PET signal intensity to radiotherapy dose prescription was employed and DPBN treatment plans were created using the image basis acquired at each PET/CT session. Also, plan A was recalculated on the image basis for session B. Voxel-by-voxel Pearson's correlation and quality factor were calculated to assess the DPBN plan quality and repeatability.

Results: The mean (SD) correlation coefficient between DPBN prescription and plan was 0.92 (0.02) and 0.93 (0.02) for sessions A and B, respectively, with corresponding quality factors of 0.02 (0.002) and 0.02 (0.003), respectively. The mean correlation between dose prescriptions at day A and B was 0.72 (0.13), and 0.77 (0.12) for the corresponding plans. A mean correlation of 0.80 (0.08) was found between plan A, recalculated on image basis B, and plan B.

Conclusion: Hypoxia DPBN planning based on F-EF5-PET/CT showed high repeatability. This illustrates that F-EF5-PET provides a robust target for dose painting.
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http://dx.doi.org/10.1080/0284186X.2021.1944663DOI Listing
June 2021

Treatment outcomes and prognostic factors after chemoradiotherapy for anal cancer.

Acta Oncol 2021 Jul 8;60(7):921-930. Epub 2021 May 8.

Department of Oncology, Oslo University Hospital, Oslo, Norway.

Background: Squamous cell carcinoma of the anus (SCCA) is a rare malignancy with rising incidence, associated with human papilloma virus (HPV). Chemoradiotherapy (CRT) is the preferred treatment. The purpose was to investigate treatment failure, survival and prognostic factors after CRT.

Material And Methods: In this prospective observational study from a large regional centre, 141 patients were included from 2013 to 2017, and 132 were eligible for analysis. The main inclusion criteria were SCCA, planned radiotherapy, and performance status (ECOG) ≤2. Patient characteristics, disease stage, treatment, and treatment response were prospectively registered. Disease-free survival (DFS), overall survival (OS), and locoregional treatment failure after CRT were analysed. Hazard ratios (HRs) were estimated with Cox`s proportional hazards model.

Results: Median follow-up was 54 (range 6-71) months. Eighteen patients (14%) had treatment failures after CRT; of these 10 (8%) had residual tumour, and 8 (6%) relapse as first failure. The first treatment failure was locoregional (11 patients), distant (5 patients), and both (2 patients). Salvage abdomino-perineal resection was performed in 10 patients, 2 had resections of metastases, and 3 both. DFS was 85% at 3 years and 78% at 5 years. OS was 93% at 3 years and 86% at 5 years. In analyses adjusted for age and gender, HPV negative tumours (HR 2.5,  = 0.024), N3 disease (HR 2.6,  = 0.024), and tumour size ≥4 cm (HR 2.4,  = 0.038) were negative prognostic factors for DFS.

Conclusion: State-of-the-art chemoradiotherapy for SCCA resulted in excellent outcomes, and improved survival compared with previous national data, with <15% treatment failures and a 3-year DFS of >80%.
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http://dx.doi.org/10.1080/0284186X.2021.1918763DOI Listing
July 2021

Predicting outcomes in anal cancer patients using multi-centre data and distributed learning - A proof-of-concept study.

Radiother Oncol 2021 06 20;159:183-189. Epub 2021 Mar 20.

Leeds Institute of Medical Research at St James's, University of Leeds, United Kingdom. Electronic address:

Background And Purpose: Predicting outcomes is challenging in rare cancers. Single-institutional datasets are often small and multi-institutional data sharing is complex. Distributed learning allows machine learning models to use data from multiple institutions without exchanging individual patient-level data. We demonstrate this technique in a proof-of-concept study of anal cancer patients treated with chemoradiotherapy across multiple European countries.

Materials And Methods: atomCAT is a three-centre collaboration between Leeds Cancer Centre (UK), MAASTRO Clinic (The Netherlands) and Oslo University Hospital (Norway). We trained and validated a Cox proportional hazards regression model in a distributed fashion using data from 281 patients treated with radical, conformal chemoradiotherapy for anal cancer in three institutions. Our primary endpoint was overall survival. We selected disease stage, sex, age, primary tumour size, and planned radiotherapy dose (in EQD2) a priori as predictor variables.

Results: The Cox regression model trained across all three centres found worse overall survival for high risk disease stage (HR = 2.02), male sex (HR = 3.06), older age (HR = 1.33 per 10 years), larger primary tumour volume (HR = 1.05 per 10 cm) and lower radiotherapy dose (HR = 1.20 per 5 Gy). A mean concordance index of 0.72 was achieved during validation, with limited variation between centres (Leeds = 0.72, MAASTRO = 0.74, Oslo = 0.70). The global model performed well for risk stratification for two out of three centres.

Conclusions: Using distributed learning, we accessed and analysed one of the largest available multi-institutional cohorts of anal cancer patients treated with modern radiotherapy techniques. This demonstrates the value of distributed learning in outcome modelling for rare cancers.
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http://dx.doi.org/10.1016/j.radonc.2021.03.013DOI Listing
June 2021

A comparison of methods for fully automatic segmentation of tumors and involved nodes in PET/CT of head and neck cancers.

Phys Med Biol 2021 03 4;66(6):065012. Epub 2021 Mar 4.

Faculty of Science and Technology, Norwegian University of Life Sciences, Ås, Norway.

Target volume delineation is a vital but time-consuming and challenging part of radiotherapy, where the goal is to deliver sufficient dose to the target while reducing risks of side effects. For head and neck cancer (HNC) this is complicated by the complex anatomy of the head and neck region and the proximity of target volumes to organs at risk. The purpose of this study was to compare and evaluate conventional PET thresholding methods, six classical machine learning algorithms and a 2D U-Net convolutional neural network (CNN) for automatic gross tumor volume (GTV) segmentation of HNC in PET/CT images. For the latter two approaches the impact of single versus multimodality input on segmentation quality was also assessed. 197 patients were included in the study. The cohort was split into training and test sets (157 and 40 patients, respectively). Five-fold cross-validation was used on the training set for model comparison and selection. Manual GTV delineations represented the ground truth. Tresholding, classical machine learning and CNN segmentation models were ranked separately according to the cross-validation Sørensen-Dice similarity coefficient (Dice). PET thresholding gave a maximum mean Dice of 0.62, whereas classical machine learning resulted in maximum mean Dice scores of 0.24 (CT) and 0.66 (PET; PET/CT). CNN models obtained maximum mean Dice scores of 0.66 (CT), 0.68 (PET) and 0.74 (PET/CT). The difference in cross-validation Dice between multimodality PET/CT and single modality CNN models was significant (p ≤ 0.0001). The top-ranked PET/CT-based CNN model outperformed the best-performing thresholding and classical machine learning models, giving significantly better segmentations in terms of cross-validation and test set Dice, true positive rate, positive predictive value and surface distance-based metrics (p ≤ 0.0001). Thus, deep learning based on multimodality PET/CT input resulted in superior target coverage and less inclusion of surrounding normal tissue.
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http://dx.doi.org/10.1088/1361-6560/abe553DOI Listing
March 2021

A comparison of fully automatic segmentation of tumors and involved nodes in PET/CT of head and neck cancers.

Phys Med Biol 2021 Feb 11. Epub 2021 Feb 11.

Faculty of Science and Technology, Norwegian University of Life Sciences, As, Akershus, NORWAY.

Target volume delineation is a vital but time-consuming and challenging part of radiotherapy, where the goal is to deliver sufficient dose to the target while reducing risks of side effects. For head and neck cancer (HNC) this is complicated by the complex anatomy of the head and neck region and the proximity of target volumes to organs at risk. The purpose of this study was to compare and evaluate conventional PET thresholding methods, six classical machine learning algorithms and a 2D U-Net convolutional neural network (CNN) for automatic gross tumor volume (GTV) segmentation of HNC in PET/CT images. For the latter two approaches the impact of single vs. multimodality input on segmentation quality was also assesed. 197 patients were included in the study. The cohort was split into training and test sets (157 and 40 patients, respectively). Five-fold cross-validation was used on the training set for model comparison and selection. Manual GTV delineations represented the ground truth. Tresholding, classical machine learning and CNN segmentation models were ranked separately according to the cross-validation Sørensen-Dice similarity coefficient (Dice). PET thresholding gave a maximum mean Dice of 0.62, whereas classical machine learning resulted in maximum mean Dice scores of 0.24 (CT) and 0.66 (PET; PET/CT). CNN models obtained maximum mean Dice scores of 0.66 (CT), 0.68 (PET) and 0.74 (PET/CT). The difference in cross-validation Dice between multimodality PET/CT and single-modality CNN models was significant (p ≤ 0.0001). The top-ranked PET/CT-based CNN model outperformed the best-performing thresholding and classical machine learning models, giving significantly better segmentations in terms of cross-valdiation and test set Dice, true positive rate, positive predictive value and surface distance-based metrics (p ≤ 0.0001). Thus, deep learning based on multimodality PET/CT input resulted in superior target coverage and less inclusion of surrounding normal tissue.
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http://dx.doi.org/10.1088/1361-6560/abe553DOI Listing
February 2021

Deep learning-based auto-delineation of gross tumour volumes and involved nodes in PET/CT images of head and neck cancer patients.

Eur J Nucl Med Mol Imaging 2021 08 9;48(9):2782-2792. Epub 2021 Feb 9.

Faculty of Science and Technology, Norwegian University of Life Sciences, Ås, Norway.

Purpose: Identification and delineation of the gross tumour and malignant nodal volume (GTV) in medical images are vital in radiotherapy. We assessed the applicability of convolutional neural networks (CNNs) for fully automatic delineation of the GTV from FDG-PET/CT images of patients with head and neck cancer (HNC). CNN models were compared to manual GTV delineations made by experienced specialists. New structure-based performance metrics were introduced to enable in-depth assessment of auto-delineation of multiple malignant structures in individual patients.

Methods: U-Net CNN models were trained and evaluated on images and manual GTV delineations from 197 HNC patients. The dataset was split into training, validation and test cohorts (n= 142, n = 15 and n = 40, respectively). The Dice score, surface distance metrics and the new structure-based metrics were used for model evaluation. Additionally, auto-delineations were manually assessed by an oncologist for 15 randomly selected patients in the test cohort.

Results: The mean Dice scores of the auto-delineations were 55%, 69% and 71% for the CT-based, PET-based and PET/CT-based CNN models, respectively. The PET signal was essential for delineating all structures. Models based on PET/CT images identified 86% of the true GTV structures, whereas models built solely on CT images identified only 55% of the true structures. The oncologist reported very high-quality auto-delineations for 14 out of the 15 randomly selected patients.

Conclusions: CNNs provided high-quality auto-delineations for HNC using multimodality PET/CT. The introduced structure-wise evaluation metrics provided valuable information on CNN model strengths and weaknesses for multi-structure auto-delineation.
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http://dx.doi.org/10.1007/s00259-020-05125-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263429PMC
August 2021

Phantom-based quality assurance for multicenter quantitative MRI in locally advanced cervical cancer.

Radiother Oncol 2020 12 12;153:114-121. Epub 2020 Sep 12.

Department of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.

Background And Purpose: A wide variation of MRI systems is a challenge in multicenter imaging biomarker studies as it adds variation in quantitative MRI values. The aim of this study was to design and test a quality assurance (QA) framework based on phantom measurements, for the quantitative MRI protocols of a multicenter imaging biomarker trial of locally advanced cervical cancer.

Materials And Methods: Fifteen institutes participated (five 1.5 T and ten 3 T scanners). Each institute optimized protocols for T2, diffusion-weighted imaging, T1, and dynamic contrast-enhanced (DCE-)MRI according to system possibilities, institutional preferences and study-specific constraints. Calibration phantoms with known values were used for validation. Benchmark protocols, similar on all systems, were used to investigate whether differences resulted from variations in institutional protocols or from system variations. Bias, repeatability (%RC), and reproducibility (%RDC) were determined. Ratios were used for T2 and T1 values.

Results: The institutional protocols showed a range in bias of 0.88-0.98 for T2 (median %RC = 1%; %RDC = 12%), -0.007 to 0.029 × 10 mm/s for the apparent diffusion coefficient (median %RC = 3%; %RDC = 18%), and 0.39-1.29 for T1 (median %RC = 1%; %RDC = 33%). For DCE a nonlinear vendor-specific relation was observed between measured and true concentrations with magnitude data, whereas the relation was linear when phase data was used.

Conclusion: We designed a QA framework for quantitative MRI protocols and demonstrated for a multicenter trial for cervical cancer that measurement of consistent T2 and apparent diffusion coefficient values is feasible despite protocol differences. For DCE-MRI and T1 mapping with the variable flip angle method, this was more challenging.
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http://dx.doi.org/10.1016/j.radonc.2020.09.013DOI Listing
December 2020

The FLUKA Monte Carlo code coupled with an OER model for biologically weighted dose calculations in proton therapy of hypoxic tumors.

Phys Med 2020 Aug 16;76:166-172. Epub 2020 Jul 16.

Department of Physics and Technology, University of Bergen, Allégaten 55, 5007 Bergen, Norway.

Introduction: The increased radioresistance of hypoxic cells compared to well-oxygenated cells is quantified by the oxygen enhancement ratio (OER). In this study we created a FLUKA Monte Carlo based tool for inclusion of both OER and relative biological effectiveness (RBE) in biologically weighted dose (ROWD) calculations in proton therapy and applied this to explore the impact of hypoxia.

Methods: The RBE-weighted dose was adapted for hypoxia by making RBE model parameters dependent on the OER, in addition to the linear energy transfer (LET). The OER depends on the partial oxygen pressure (pO) and LET. To demonstrate model performance, calculations were done with spread-out Bragg peaks (SOBP) in water phantoms with pO ranging from strongly hypoxic to normoxic (0.01-30 mmHg) and with a head and neck cancer proton plan optimized with an RBE of 1.1 and pO estimated voxel-by-voxel using [F]-EF5 PET. An RBE of 1.1 and the Rørvik RBE model were used for the ROWD calculations.

Results: The SOBP in water had decreasing ROWD with decreasing pO. In the plans accounting for oxygenation, the median target doses were approximately a factor 1.1 lower than the corresponding plans which did not consider the OER. Hypoxia adapted target ROWDs were considerably more heterogeneous than the RBE-weighted doses.

Conclusion: We realized a Monte Carlo based tool for calculating the ROWD. Read-in of patient pO and estimation of ROWD with flexibility in choice of RBE model was achieved, giving a tool that may be useful in future clinical applications of hypoxia-guided particle therapy.
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http://dx.doi.org/10.1016/j.ejmp.2020.07.003DOI Listing
August 2020

Combining imaging- and gene-based hypoxia biomarkers in cervical cancer improves prediction of chemoradiotherapy failure independent of intratumour heterogeneity.

EBioMedicine 2020 Jul 21;57:102841. Epub 2020 Jun 21.

Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Ullernchausseen 70, 0379 Oslo, Norway; Department of Physics, University of Oslo, Sem Sælands vei 24, 0371 Oslo, Norway. Electronic address:

Background: Emerging biomarkers from medical imaging or molecular characterization of tumour biopsies open up for combining the two and exploiting their synergy in treatment planning of cancer patients. We generated a paired data set of imaging- and gene-based hypoxia biomarkers in cervical cancer, appraised the influence of intratumour heterogeneity in patient classification, and investigated the benefit of combining the methodologies in prediction of chemoradiotherapy failure.

Methods: Hypoxic fraction from dynamic contrast enhanced (DCE)-MR images and an expression signature of six hypoxia-responsive genes were assessed as imaging- and gene-based biomarker, respectively in 118 patients.

Findings: Dichotomous biomarker cutoff to yield similar hypoxia status by imaging and genes was defined in 41 patients, and the association was validated in the remaining 77 patients. The two biomarkers classified 75% of 118 patients with the same hypoxia status, and inconsistent classification was not related to imaging-defined intratumour heterogeneity in hypoxia. Gene-based hypoxia was independent on tumour cell fraction in the biopsies and showed minor heterogeneity across multiple samples in 9 tumours. Combining imaging- and gene-based classification gave a significantly better prediction of PFS than one biomarker alone. A combined dichotomous biomarker optimized in 77 patients showed a large separation in PFS between more and less hypoxic tumours, and separated the remaining 41 patients with different PFS. The combined biomarker showed prognostic value together with tumour stage in multivariate analysis.

Interpretation: Combining imaging- and gene-based biomarkers may enable more precise and informative assessment of hypoxia-related chemoradiotherapy resistance in cervical cancer.

Funding: Norwegian Cancer Society, South-Eastern Norway Regional Health Authority, and Norwegian Research Council.
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http://dx.doi.org/10.1016/j.ebiom.2020.102841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317686PMC
July 2020

Radiotherapy-related lymphopenia in patients with advanced non-small cell lung cancer receiving palliative radiotherapy.

Clin Transl Radiat Oncol 2020 May 19;22:15-21. Epub 2020 Feb 19.

Department of Medical Physics, Oslo University Hospital, Oslo, Norway.

Background: Lymphopenia during radiotherapy (RT) may have an adverse effect on treatment outcome. The aim of this study is to investigate associations between lymphopenia and RT parameters in patients with advanced lung cancer. Moreover, to investigate the prognostic role of lymphopenia, blood protein levels, and treatment and patient-related factors.

Material And Methods: Sixty-two advanced stage non-small cell lung cancer (NSCLC) patients were retrospectively analyzed. Blood counts were available prior to, during, and after RT (3Gyx10). For each patient, a thoracic volume of interest (VOI) -including thoracic soft tissue and trabecular bone- was obtained by applying a CT window of -500 to 1200 HU in the planning CT. Dose parameters from thoracic VOI and other regions including lungs and vertebrae were calculated. Association between risk of lymphopenia ≥ G3 (lymphocytes at nadir according to CTCAE v4.0) and therapeutic parameters was investigated using Logistic regression. Relationships between overall survival (OS) and RT dose parameters, baseline blood counts and protein levels, and clinical factors were evaluated using Log-rank and Cox models.

Result: Mean thoracic RT dose (odds ratio [OR] 1.67; p = 0.04), baseline lymphocytes (OR 0.65; p = 0.01), and corticosteroids use (OR 6.07; p = 0.02) were significantly associated with increased risk of lymphopenia ≥ G3 in multivariable analysis. Worse OS was associated with high mean thoracic RT dose, high CRP/Albumin, large tumor volume and corticosteroids use (p < 0.05, univariate analysis), but not with lymphopenia ≥ G3. CRP/Albumin ratio > 0.12 (hazard ratio [HR] 2.28, p = 0.03) and corticosteroid use (HR 2.52, p = 0.01) were independently associated with worse OS.

Conclusion: High thoracic RT dose gave a higher risk of lymphopenia ≥ G3; hence limiting dose volume to the thorax may be valuable in preventing severe lymphopenia for patients receiving palliative fractionated RT. Still, lymphopenia ≥ G3 was not associated with worse OS. however, high baseline CRP/Albumin was associated with poorer OS and may carry important information as a prognostic factor of OS in advanced NSCLC receiving palliative RT.
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http://dx.doi.org/10.1016/j.ctro.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063172PMC
May 2020

Re-irradiation for recurrent rectal cancer - a single-center experience.

Acta Oncol 2020 May 14;59(5):534-540. Epub 2020 Feb 14.

Department of Oncology, Oslo University Hospital, Oslo, Norway.

There is no clear consensus on the use of re-irradiation (reRT) in the management of locally recurrent rectal cancer (LRRC). The aim of the present study was to investigate all reRT administered for rectal cancer at a large referral institution and to evaluate patient outcomes and toxicity. All patients with rectal cancer were identified who had received previous pelvic radiotherapy (RT) and underwent reRT during 2006-2016. Medical records and RT details of the primary tumor treatments and rectal cancer recurrence treatments were registered, including details on reRT, chemotherapy, surgery, adverse events, and long-term outcomes. Of 77 patients who received ReRT, 67 had previously received pelvic RT for rectal cancer and were administered reRT for LRRC. Re-irradiation doses were 30.0-45.0 Gy, most often given as hyperfractionated RT in 1.2-1.5 Gy fractions twice daily with concomitant capecitabine. The median time since initial RT was 29 months (range, 13-174 months). Of 36 patients considered as potentially resectable, 20 underwent surgery for LRRC within 3 months after reRT. Operated patients had better 3-year overall survival (OS) (62%) compared to those who were not operated (16%; HR 0.32,  = .001). The median gross tumor volume (GTV) was 107 cm, and 3-year OS was significantly better in patients with GTV <107 cm (44%) compared to patients with GTV ≥107 cm (21%; HR 0.52,  = .03). Three-year survival was significantly better for patients who underwent surgery after reRT or who had small tumor volume. Prospective clinical trials are recommended for further improvements in patient selection, outcomes, and toxicity assessment.
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http://dx.doi.org/10.1080/0284186X.2020.1725111DOI Listing
May 2020

Ultra-early changes in vascular parameters from dynamic contrast enhanced MRI of breast cancer xenografts following systemic therapy with doxorubicin and liver X receptor agonist.

Cancer Imaging 2019 Dec 19;19(1):88. Epub 2019 Dec 19.

Department of Physics, University of Oslo, P.O. Box 1048 Blindern, 0316, Oslo, Norway.

Background: Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) may be used to depict tumour vascular structure and for therapy response assessment in various tumour sites. The purpose of the current work is to examine whether ultra-early changes in tumour physiology following cytotoxic treatment with doxorubicin and liver X receptor (LXR) agonist GW3965 are detectable by DCE-MRI.

Methods: 36 female, athymic nude foxn1nu mice with bilaterally implanted breast cancer xenografts (17 with ER-positive HBCx34, 19 with triple-negative HBCx39) were randomised in the following treatment groups; control, GW3965 (40 mg/kg p.o.), doxorubicin (8 mg/kg i.v.) and a combination therapy of GW3965 and doxorubicin. DCE-MRI (3D FLASH on a 7 T preclinical scanner) was performed at baseline and one and six days after onset of treatment. Wash-in (30 s p.i.) and wash-out (300 s p.i.) enhancement were quantified from dynamic uptake curves, before voxel-by-voxel fitting to the pharmacokinetic Tofts model and generation of maps for the resulting parameters K, ν and ν. Treatment effect was evaluated by univariate repeated measures mixed-effects maximum likelihood regression models applied to median tumour data.

Results: We found no effects of any treatment 24 h post treatment. After 6 days, doxorubicin given as both mono- and combination therapy gave significant increases of ~ 30% in wash-in enhancement (p < 0.011) and K (p < 0.017), and 40-50% in ν (p < 0.024) for HBCx34, but not for HBCx39. No effects of GW3965 were observed at any time (p > 0.1).

Conclusions: Twenty-four h after onset of treatment was too early to evaluate treatment effects by DCE-MRI. Early enhancement and K were approximately equally sensitive metrics to capture treatment effects six days pt. Pharmacokinetic modelling however allowed us to attribute the observed effect to changes in tumour perfusion rather than increased retention.
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http://dx.doi.org/10.1186/s40644-019-0280-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924064PMC
December 2019

Synthesis, radiosynthesis, and positron emission tomography neuroimaging using 5-[ F]fluoro-L-amino suberate.

J Labelled Comp Radiopharm 2020 01 8;63(1):6-14. Epub 2019 Dec 8.

Realomics Strategic Research Initiative (SRI), Department of Chemistry, University of Oslo, Oslo, Norway.

System xc- (Sx -) has emerged as a new biological target for PET studies to detect oxidative and excitotoxic stress. Notably, applications have, thus far, been limited to tumour imaging although Sx ) may play a major role in neurodegeneration. The synthesis procedures of tosylate precursor and its translation to Sx - PET tracer 5[18F]fluoro-L-amino suberate by manual and automated radiosyntheses are described. A brain-PET study has been conducted to evaluate the tracer uptake into brain in healthy mice.
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http://dx.doi.org/10.1002/jlcr.3814DOI Listing
January 2020

Influx rate of F-fluoroaminosuberic acid reflects cystine/glutamate antiporter expression in tumour xenografts.

Eur J Nucl Med Mol Imaging 2019 Sep 1;46(10):2190-2198. Epub 2019 Jul 1.

Department of Physics, University of Oslo, P.O. Box 1048 Blindern, 0316, Oslo, Norway.

Purpose: F-fluoroaminosuberic acid (F-FASu) is a recently developed amino acid tracer for positron emission tomography (PET) of oxidative stress that may offer improved tumour assessment over the conventional tracer F-fluorodeoxyglucose (F-FDG). Our aim was to evaluate and relate dynamic F-FASu and F-FDG uptake with pharmacokinetic modelling to transporter protein expression levels in a panel of diverse tumour xenograft lines.

Methods: Four different tumour xenograft lines were implanted in female athymic nude mice: MAS98.12 and HBCx3 (breast), TPMX (osteosarcoma) and A549 (lung). Dynamic PET over 60 min was performed on a small animal unit. The time-activity curves (TACs) for F-FASu and F-FDG in individual tumours were used to extract early (SUV; 2 min p.i.) and late (SUV; 55 min p.i.) standardised uptake values. Pharmacokinetic two-tissue compartment models were applied to the TACs to estimate rate constants K-k and blood volume fraction v. Relative levels of cystine/glutamate antiporter subunit xCT were assessed by western blotting, and expression of GLUT1 and CD31 by immunohistochemistry.

Results: F-FASu showed higher SUV, whilst F-FDG exhibited higher SUV. Influx rate K for F-FASu was significantly correlated with xCT levels (p = 0.001) and was significantly higher than K for F-FDG (p < 0.001). K for F-FDG was significantly correlated with GLUT1 levels (p = 0.002). v estimated from F-FASu and F-FDG TACs was highly consistent and significantly correlated (r = 0.85, p < 0.001). Two qualitatively different F-FASu uptake profiles were identified: type α with low xCT expression and low K (A549 and HBCx3), and type β with high xCT expression and high K (MAS98.12 and TPMX).

Conclusion: The influx rate of F-FASu reflects xCT activity in tumour xenografts. Dynamic PET with pharmacokinetic modelling is needed to fully appraise F-FASu distribution routes.
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http://dx.doi.org/10.1007/s00259-019-04375-8DOI Listing
September 2019

The prognostic role of 18F-fluorodeoxyglucose PET in head and neck cancer depends on HPV status.

Radiother Oncol 2019 11 6;140:54-61. Epub 2019 Jun 6.

Department of Oncology, Oslo University Hospital, Norway. Electronic address:

Background And Purpose: Standardized uptake value (SUV) and related parameters derived from 2-deoxy-2-[18F]-fluoro-d-glucose (FDG) PET/CT prior to radiochemotherapy of head and neck cancer (HNC) were significantly associated with survival in a number of studies. The aim of this study was to validate these findings and to evaluate the prognostic role of PET parameters also including clinical factors and HPV status.

Materials And Methods: We reviewed 166 HNC cases with a radiotherapy planning FDG PET/CT scan. All patients received radiotherapy, 68-70 Gy with or without concomitant cisplatin. Primary endpoint was disease-free survival (DFS). Twelve clinical factors, including HPV, performance status, stage and treatment parameters and ten PET/CT image parameters including gross tumor volume (GTV), metastatic lymph node volume, SUVmax, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were collected. Univariate and multivariate Cox regression analyses were employed.

Results: Of the 166 patients included, 48 had locoregional and 23 had metastatic recurrence. None of the FDG PET parameters were significant in the univariate analysis using DFS as endpoint. HPV status, ECOG status and GTV-U (primary tumor and lymph node volume from CT) were statistically significant (p < 0.01). Only in the subgroup of HPV-unrelated HNC (HPV negative oropharyngeal cancer [OPC] and non-OPC; n = 73), the multivariate model could be improved by including MTV (p < 0.001). DFS events were 29 (31%) in HPV-related and 53 (73%) in HPV-unrelated HNC.

Conclusion: FDG PET parameters appear less important for overall prognostication of radiochemotherapy outcome for HNC. Still, the association between the FDG PET parameters and survival is strong for HNC not related to HPV. Tumor volume from CT is generally more closely related to outcome than parameters derived from FDG PET/CT.
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http://dx.doi.org/10.1016/j.radonc.2019.05.019DOI Listing
November 2019

Anal cancer chemoradiotherapy outcome prediction using F-fluorodeoxyglucose positron emission tomography and clinicopathological factors.

Br J Radiol 2019 May 11;92(1097):20181006. Epub 2019 Mar 11.

1 Department of Medical Physics, University of Oslo , Oslo , Norway.

Objective: To assess the role of [F]fluorodeoxyglucose (FDG) positron emission tomography (PET), obtained before and during chemoradiotherapy, in predicting locoregional failure relative to clinicopathological factors for patients with anal cancer.

Methods: 93 patients with anal squamous cell carcinoma treated with chemoradiotherapy were included in a prospective observational study (NCT01937780). FDG-PET/CT was performed for all patients before treatment, and for a subgroup ( = 39) also 2 weeks into treatment. FDG-PET was evaluated with standardized uptake values (SUV), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and a proposed Z-normalized combination of MTV and SUV (ZMP). The objective was to predict locoregional failure using FDG-PET, tumor and lymph node stage, gross tumor volume (GTV) and human papilloma virus (HPV) status in univariate and bivariate Cox regression analysis.

Results: N3 lymph node stage, HPV negative tumor, GTV, MTV, TLG and ZMP were in univariate analysis significant predictors of locoregional failure ( < 0.01), while SUV were not ( > 0.2). In bivariate analysis HPV status was the most independent predictor in combinations with N3 stage, ZMP, TLG, and MTV ( < 0.02). The FDG-PET parameters at 2 weeks into radiotherapy decreased by 30-40 % of the initial values, but neither absolute nor relative decrease improved the prediction models.

Conclusion: Pre-treatment PET parameters are predictive of chemoradiotherapy outcome in anal cancer, although HPV negativity and N3 stage are the strongest single predictors. Predictions can be improved by combining HPV with PET parameters such as MTV, TLG or ZMP. PET 2 weeks into treatment does not provide added predictive value.

Advances In Knowledge: Pre-treatment PET parameters of anal cancer showed a predictive role independent of clinicopathological factors. Although the PET parameters show substantial reduction from pre- to mid-treatment, the changes were not predictive of chemoradiotherapy outcome.
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http://dx.doi.org/10.1259/bjr.20181006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580918PMC
May 2019

Dose painting for re-irradiation of head and neck cancer.

Acta Oncol 2018 Dec 3;57(12):1693-1699. Epub 2018 Oct 3.

a Department of Oncology , Oslo University Hospital , Oslo , Norway.

Background: For patients with recurrent or second primary disease, re-irradiation can be challenging due to overlap with previously irradiated volumes. Dose painting may be attractive for these patients, as the focus is on delivering maximal dose to areas of high tumor activity. Here, we compare dose painting by contours (DPBC) treatment plans based on F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with conventional plans.

Material And Methods: We included 10 patients with recurrent or second primary head and neck cancer (HNC) eligible for re-irradiation. Our conventional re-irradiation regimen is hyperfractionated radiotherapy 1.5 Gy twice daily over 4 weeks, giving a total dose of 60 Gy. For DPBC, we defined two prescription volumes, PV33 and PV66, corresponding to 33 and 66% of the highest FDG uptake in the tumor. The clinical target volume (CTV) prescription dose was 60 Gy, PV33; 65-67 Gy and PV66; 70-73 Gy. The DPBC plan is to be given the first 20 fractions and the conventional plan the last 20 fractions. Dose to organs at risk (OARs) were compared for DPBC and conventional treatment. By summation of the initial curative plan and the re-irradiation plan, we also evaluated differences in dose to the 2 ccm hot spot (D).

Results: We achieved DPBC plans with adequate target coverage for all 10 patients. There were no significant differences in OAR doses between the standard plans and the DPBC plans (p=.7). Summation of the initial curative plan and the re-irradiation plan showed that the median D increased from 130 Gy (range 113-132 Gy; conventional) to 140 Gy (range 115-145 Gy; DPBC).

Conclusions: Our proposed DPBC could be straightforwardly implemented and all plans met the objectives. Re-irradiation of HNC with DPBC may increase tumor control without more side effects compared to conventional radiotherapy.
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http://dx.doi.org/10.1080/0284186X.2018.1512753DOI Listing
December 2018

Comparison of time curves from dynamic F-fluciclovine positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging for primary prostate carcinomas.

Phys Imaging Radiat Oncol 2018 Jul 2;7:51-57. Epub 2018 Oct 2.

Department for Research and Development, Division for Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.

Background And Purpose: Multimodal imaging is increasingly included in the assessment of prostate cancer patients, and there is a need to study whether different techniques provide similar or complementary information. In the initial perfusion phase contrast agents and radioactive labelled tracers act as blood-pool agents and may show similar characteristics. The purpose of the current work was to compare time-activity- and time-concentration-curves (TCs) of dynamic F-fluciclovine (F-anti-1-amino-2-[F]-fluorocyclobutane-1-carboxylic acid, FACBC) positron emission tomography (PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI).

Materials And Methods: Dynamic FACBC PET and DCE MRI were performed on 22 patients with intermediate or high-risk prostate cancer within 23 days prior to robot-assisted laparoscopic prostatectomy. Index tumour was delineated in the images using whole mount tissue sections as reference standard. Tumour TCs from PET and MRI were compared visually and quantitatively by calculating correlation coefficients between the curves at different time points after injection.

Results: For the first minute post injection, the mean correlation coefficient between the TCs from PET and MRI was 0.92 (range; 0.75-0.99). After the first minute, MRI showed washout while PET showed plateau kinetics.

Conclusion: Dynamic FACBC and DCE MRI showed similar wash-in time curve characteristics. At later time points, FACBC plateaued whereas MR contrast medium washed out. In DCE MRI, the usefulness of wash-in information is well documented. Whether wash-in information from dynamic FACBC can provide added value remains to be documented.
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http://dx.doi.org/10.1016/j.phro.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807538PMC
July 2018

Dynamic TSPO-PET for assessing early effects of cerebral hypoxia and resuscitation in new born pigs.

Nucl Med Biol 2018 11 24;66:49-57. Epub 2018 Aug 24.

Div. of Radiology and Nuclear Medicine, Oslo University Hospital, PO box 4950, Nydalen, N-0424 Oslo, Norway; Faculty of Medicine, University of Oslo, PO Box1078, Blindern, N-0316 Oslo, Norway.

Introduction: Inflammation associated with microglial activation may be an early prognostic indicator of perinatal hypoxic ischemic injury, where translocator protein (TSPO) is a known inflammatory biomarker. This piglet study used dynamic TSPO-PET with [F]GE180 to evaluate if microglial activation after global perinatal hypoxic injury could be detected.

Methods: New born anesthetized pigs (n = 14) underwent hypoxia with fraction of inspired oxygen (FiO)0.08 until base excess -20 mmol/L and/or a mean arterial blood pressure decrease to 20 mm Hg, followed by resuscitation with FiO 0.21 or 1.0. Three piglets served as controls and one had intracranial injection of lipopolysaccharide (LPS). Whole body [F]GE180 Positron emission tomography-computed tomography (PET-CT) was performed repeatedly up to 32 h after hypoxia and resuscitation. Volumes of interest were traced in the basal ganglia, cerebellum and liver using MRI as anatomic correlation. Standardized uptake values (SUVs) were measured at baseline and four time-points, quantifying microglial activity over time. Statistical analysis used Mann Whitney- and Wilcoxon rank test with significance value set to p < 0.05.

Results: At baseline (n = 5), mean SUVs ±1 standard deviation were 0.43 ± 0.10 and 1.71 ± 0.62 in brain and liver respectively without significant increase after hypoxia at the four time-points (n = 5-13/time point). Succeeding LPS injection, SUV increased 80% from baseline values.

Conclusions: Cerebral inflammatory response caused by severe asphyxia was not possible to detect with [F]GE180 PET CT the first 32 h after hypoxia and only sparse hepatic uptake was revealed.

Advances In Knowledge: Early microglial activation as indicator of perinatal hypoxic ischemic injury was not detectable by TSPO-PET with [F]GE180.

Implications For Patient Care: TSPO-PET with [F]GE180 might not be suitable for early detection of perinatal hypoxic ischemic brain injury.
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http://dx.doi.org/10.1016/j.nucmedbio.2018.08.004DOI Listing
November 2018

Mapping Bone Marrow Response in the Vertebral Column by Positron Emission Tomography Following Radiotherapy and Erlotinib Therapy of Lung Cancer.

Mol Imaging Biol 2019 04;21(2):391-398

Department of Medical Physics, Oslo University Hospital, PO Box 4953, Nydalen, N-0424, Oslo, Norway.

Purpose: To map functional bone marrow (BM) by 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) positron emission tomography (PET) in the vertebral column of lung cancer patients prior to, during, and after treatment. Moreover, to identify radiation- and erlotinib-induced changes in the BM.

Procedures: Twenty-six patients with advanced non-small cell lung cancer, receiving radiotherapy (RT) alone or concomitantly with erlotinib, were examined by [F]FDG PET before, during, and after treatment. A total of 61 [F]FDG PET scans were analyzed. Vertebral column BM [F]FDG standardized uptake value normalized to the liver (SUV) was used as uptake measure. Wilcoxon signed-rank test was used to assess changes in BM uptake of [F]FDG between sessions. Effects of erlotinib on the BM activity during and after treatment were assessed using Mann-Whitney U test.

Results: A homogeneous uptake of [F]FDG was observed within the vertebral column prior to treatment. Mean SUV (± S.E.M) in the body of thoracic vertebrae receiving a total RT dose of 10 Gy or higher was 0.64 ± 0.01, 0.56 ± 0.01, and 0.59 ± 0.01 at pre-, mid-, and post-therapy, respectively. A significant reduction in the mean SUV was observed from pre- to both mid- and post-therapy (p < 0.05). Mean SUV was significantly higher at post-therapy compared to mid-therapy for patients receiving erlotinib in addition to RT (p < 0.05).

Conclusions: RT reduces BM [F]FDG uptake in the vertebral column, especially in the high-dose region. Concomitant erlotinib may stimulate a recovery in BM [F]FDG uptake from mid- to post-therapy.

Trial Registration: NCT02714530. Registered 10 September 2015.
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http://dx.doi.org/10.1007/s11307-018-1226-7DOI Listing
April 2019

Serum cytokine profiles and metabolic tumor burden in patients with non-small cell lung cancer undergoing palliative thoracic radiation therapy.

Adv Radiat Oncol 2018 Apr-Jun;3(2):130-138. Epub 2018 Feb 13.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.

Purpose: Radiation therapy effectively kills cancer cells and elicits local effects in the irradiated tissue. The aim of this study was to investigate the kinetics of cytokines in the serum of patients with lung cancer undergoing radiation therapy and to identify associations with metabolic tumor burden as determined by 2-deoxy-2-fluoro-D-glucose (F-FDG) positron emission tomography (PET).

Methods And Materials: Forty-five patients with advanced non-small cell lung cancer were included in a phase 2 clinical trial and randomized between fractionated thoracic radiation therapy alone or concurrent with an epidermal growth factor receptor inhibitor. Blood was sampled at 4 different time points: prior to treatment, midtherapy, at the end of therapy, and 6 to 8 weeks after the start of treatment. The serum concentrations of 48 cytokines and 9 matrix metalloproteinases were measured with multiplex immunoassays. A subset of patients was examined by F-FDG PET/computed tomography before, during, and after radiation therapy. The maximum standardized uptake values (SUV) of the primary lung tumor, whole-body metabolic tumor volume, and total lesion glycolysis were calculated, and correlations between the PET parameters and cytokines were investigated.

Results: The SUV decreased from baseline through midtherapy to posttherapy F-FDG PET/computed tomography ( = .018). The serum levels of C-C motif chemokine ligand (CCL) 23, CCL24, C-X3-C motif chemokine ligand 1, and interleukin-8 (C-X-C motif ligand [CXCL]8) were significantly correlated to SUV, metabolic tumor volume, and total lesion glycolysis before, during, and after radiation therapy. CXCL2 ( = .030) and CXCL6 ( = .010) decreased after the start of therapy and changed significantly across the sample time points. Serum concentrations of CCL15 ( = .031), CXCL2 ( = .028), and interleukin-6 ( = .007) were positively correlated to the irradiated volume during the second week of treatment.

Conclusions: Cytokine serum levels vary and correlate with metabolic tumor burden in patients with advanced non-small cell lung cancer undergoing palliative thoracic radiation therapy.
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http://dx.doi.org/10.1016/j.adro.2017.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000081PMC
February 2018

Assessment of pulmonary F-FDG-PET uptake and cytokine profiles in non-small cell lung cancer patients treated with radiotherapy and erlotinib.

Clin Transl Radiat Oncol 2017 Jun 15;4:57-63. Epub 2017 Jun 15.

Department of Medical Physics, Oslo University Hospital, Oslo, Norway.

Purpose: To investigate effects of radiotherapy (RT) and erlotinib on pulmonary glucose uptake using 2-deoxy-2-(18F)fluoro-D-glucose (F-FDG) positron emission tomography (PET) during and after treatment of non-small cell lung cancer (NSCLC) and to identify associations between serum cytokine levels and lung glucose uptake.

Material And Methods: Twenty-seven patients with advanced NSCLC, receiving RT alone or concomitant RT and erlotinib therapy, were examined by F-FDG PET before, during, and after treatment. A total of 57 F-FDG PET scans were analyzed. Pulmonary F-FDG uptake and radiotherapy dose mapping were used to acquire dose-response curves for each patient, where subsequent linear regression gave a glucose uptake level in the un-irradiated parts of the lungs (SUV) and a response slope (ΔSUV). Serum cytokine levels at corresponding time points were assessed using a multiplex bioassay. Correlations between the most robust cytokines and lung F-FDG dose response parameters were further investigated.

Results: From the dose response analysis, SUV at post-therapy was significantly higher (P < 0.001) than at mid- and pre-therapy (45% and 58%, respectively) for the group receiving RT + erlotinib. Also, SUV at post-therapy was higher for patients receiving RT + erlotinib compared to RT alone (42%; P < 0.001). No differences in ΔSUV were seen with treatments or time. SUV was positively associated (r = 0.47, P = 0.01) with serum levels of the chemokine C-C motif ligand 21 (CCL21) for patients receiving RT + erlotinib.

Conclusions: Concomitant RT and erlotinib causes an elevation in pulmonary F-FDG uptake post treatment compared to RT alone. Pulmonary glucose uptake is associated with an upregulation of a chemokine (CCL21) involved in inflammatory reactions.
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http://dx.doi.org/10.1016/j.ctro.2017.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833916PMC
June 2017

Target volume delineation of anal cancer based on magnetic resonance imaging or positron emission tomography.

Radiat Oncol 2017 Sep 6;12(1):147. Epub 2017 Sep 6.

Department of Oncology, Oslo University Hospital, Oslo, Norway.

Purpose: To compare target volume delineation of anal cancer using positron emission tomography (PET) and magnetic resonance imaging (MRI) with respect to inter-observer and inter-modality variability.

Methods: Nineteen patients with anal cancer undergoing chemoradiotherapy were prospectively included. Planning computed tomography (CT) images were co-registered with 18F-fluorodexocyglucose (FDG) PET/CT images and T2 and diffusion weighted (DW) MR images. Three oncologists delineated the Gross Tumor Volume (GTV) according to national guidelines and the visible tumor tissue (GTV). MRI and PET based delineations were evaluated by absolute volumes and Dice similarity coefficients.

Results: The median volume of the GTVs was 27 and 31 cm for PET and MRI, respectively, while it was 6 and 11 cm for GTV. Both GTV and GTV volumes were highly correlated between delineators (r = 0.90 and r = 0.96, respectively). The median Dice similarity coefficient was 0.75 when comparing the GTVs based on PET/CT (GTV) with the GTVs based on MRI and CT (GTV). The median Dice coefficient was 0.56 when comparing the visible tumor volume evaluated by PET (GTV) with the same volume evaluated by MRI (GTV). Margins of 1-2 mm in the axial plane and 7-8 mm in superoinferior direction were required for coverage of the individual observer's GTVs.

Conclusions: The rather good agreement between PET- and MRI-based GTVs indicates that either modality may be used for standard target delineation of anal cancer. However, larger deviations were found for GTV, which may impact future tumor boost strategies.
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http://dx.doi.org/10.1186/s13014-017-0883-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585969PMC
September 2017

A new method to assess pulmonary changes using F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy.

Acta Oncol 2017 Nov 29;56(11):1597-1603. Epub 2017 Aug 29.

a Department of Physics , University of Oslo , Oslo , Norway.

Background: F-fluoro-2-deoxyglucose positron emission tomography (F-FDG-PET) may be used for assessing radiation induced alterations in the lung. However, there is a need to further develop methodologies to improve quantification. Using computed tomography (CT), a local structure method has been shown to be superior to conventional CT-based analysis. Here, we investigate whether the local structure method based on F-FDG-PET improves radiotherapy (RT) dose-response quantification for lung cancer patients.

Material And Methods: Sixteen patients with lung cancer undergoing fractionated RT were examined by F-FDG-PET/CT at three sessions (pre, mid, post) and the lung was delineated in the planning CT images. The RT dose matrix was co-registered with the PET images. For each PET image series, mean (μ) and standard deviation (σ) maps were calculated based on cubes in the lung (3 × 3 × 3 voxels), where the spread in pre-therapy μ and σ was characterized by a covariance ellipse in a sub-volume of 3 × 3 × 3 cubes. Mahalanobis distance was used to measure the distance of individual cube values to the origin of the ellipse and to further form local structure 'S' maps. The structural difference maps (ΔS) and mean difference maps (Δμ) were calculated by subtracting pre-therapy maps from maps at mid- and post-therapy. Corresponding maps based on CT images were also generated.

Results: ΔS identified new areas of interest in the lung compared to conventional Δμ maps. ΔS for PET and CT gave a significantly elevated lung signal compared to a control group during and post-RT (p < .05). Dose-response analyses by linear regression showed that ΔS between pre- and post-therapy for F-FDG-PET was the only parameter significantly associated with local lung dose (p = .04).

Conclusions: The new method using local structures on F-FDG-PET provides a clearer uptake dose-response compared to conventional analysis and CT-based approaches and may be valuable in future studies addressing lung toxicity.
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http://dx.doi.org/10.1080/0284186X.2017.1349336DOI Listing
November 2017

In Quest of the Alanine R3 Radical: Multivariate EPR Spectral Analyses of X-Irradiated Alanine in the Solid State.

J Phys Chem A 2017 Sep 19;121(38):7139-7147. Epub 2017 Sep 19.

Faculty of Science and Technology, Norwegian University of Life Sciences , P.O. Box 5003, 1432 Ås, Norway.

The amino acid l-α-alanine is the most commonly used material for solid-state electron paramagnetic resonance (EPR) dosimetry, due to the formation of highly stable radicals upon irradiation, with yields proportional to the radiation dose. Two major alanine radical components designated R1 and R2 have previously been uniquely characterized from EPR and electron-nuclear double resonance (ENDOR) studies as well as from quantum chemical calculations. There is also convincing experimental evidence of a third minor radical component R3, and a tentative radical structure has been suggested, even though no well-defined spectral signature has been observed experimentally. In the present study, temperature dependent EPR spectra of X-ray irradiated polycrystalline alanine were analyzed using five multivariate methods in further attempts to understand the composite nature of the alanine dosimeter EPR spectrum. Principal component analysis (PCA), maximum likelihood common factor analysis (MLCFA), independent component analysis (ICA), self-modeling mixture analysis (SMA), and multivariate curve resolution (MCR) were used to extract pure radical spectra and their fractional contributions from the experimental EPR spectra. All methods yielded spectral estimates resembling the established R1 spectrum. Furthermore, SMA and MCR consistently predicted both the established R2 spectrum and the shape of the R3 spectrum. The predicted shape of the R3 spectrum corresponded well with the proposed tentative spectrum derived from spectrum simulations. Thus, results from two independent multivariate data analysis techniques strongly support the previous evidence that three radicals are indeed present in irradiated alanine samples.
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http://dx.doi.org/10.1021/acs.jpca.7b06447DOI Listing
September 2017

Hypoxia in cervical cancer: from biology to imaging.

Clin Transl Imaging 2017 10;5(4):373-388. Epub 2017 Jul 10.

Department of Medical Physics, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Purpose: Hypoxia imaging may improve identification of cervical cancer patients at risk of treatment failure and be utilized in treatment planning and monitoring, but its clinical potential is far from fully realized. Here, we briefly describe the biology of hypoxia in cervix tumors of relevance for imaging, and evaluate positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques that have shown promise for assessing hypoxia in a clinical setting. We further discuss emerging imaging approaches, and how imaging can play a role in future treatment strategies to target hypoxia.

Methods: We performed a PubMed literature search, using keywords related to imaging and hypoxia in cervical cancer, with a particular emphasis on studies correlating imaging with other hypoxia measures and treatment outcome.

Results: Only a few and rather small studies have utilized PET with tracers specific for hypoxia, and no firm conclusions regarding preferred tracer or clinical potential can be drawn so far. Most studies address indirect hypoxia imaging with dynamic contrast-enhanced techniques. Strong evidences for a role of these techniques in hypoxia imaging have been presented. Pre-treatment images have shown significant association to outcome in several studies, and images acquired during fractionated radiotherapy may further improve risk stratification. Multiparametric MRI and multimodality PET/MRI enable combined imaging of factors of relevance for tumor hypoxia and warrant further investigation.

Conclusions: Several imaging approaches have shown promise for hypoxia imaging in cervical cancer. Evaluation in large clinical trials is required to decide upon the optimal modality and approach.
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http://dx.doi.org/10.1007/s40336-017-0238-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532411PMC
July 2017

Patterns of local-regional recurrence after conformal and intensity-modulated radiotherapy for head and neck cancer.

Radiat Oncol 2017 May 25;12(1):87. Epub 2017 May 25.

Department of oncology, Division of cancer Medicine, Surgery and Transplantation (KKT), Oslo University Hospital-Radium hospital, Montebello, 0310, Oslo, Norway.

Aim: To evaluate the patterns of loco-regional recurrences in head and neck cancer patients METHODS: Twenty-six out of 112 patients treated with primary or postoperative 3D CRT or IMRT for their primary and recurrent disease between 2007 and 2013 were included. The CT images of recurrent disease were rigidly registered with the primary CT images for each patient. To assess overlaps and overlap localization, the recurrence volume overlapping with the primary target volume was identified. For relapses occurring in the regional lymph nodes, the epicenter distance in recurrences and primary volumes and dose in recurrences were also identified. The recurrences were defined as in-field, marginal or out-of-field.

Results: The majority of the failures occurred within 1 year after completed primary treatment. The dose differences in recurrence volume were not statistically significant when patients were treated with IMRT or 3D CRT. Recurrence in 15/26 of the included patients occurred in the regional lymph nodes located fully or partly inside the primary target volume or the elective lymph node region. The majority of recurrences were recognized as in-field, independent of the primary treatment.

Conclusion: Recurrence in the majority of the patients occurred in the regional lymph nodes located in high dose area. The cause of recurrence may be due to inadequate total dose in the primary treatment and/or lack of optimal primary diagnosis leading to inadequate primary target delineation.
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http://dx.doi.org/10.1186/s13014-017-0829-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444101PMC
May 2017

Autodelineation of cervical cancers using multiparametric magnetic resonance imaging and machine learning.

Acta Oncol 2017 Jun 8;56(6):806-812. Epub 2017 Feb 8.

a Faculty of Science and Technology , Norwegian University of Life Sciences , Ås , Norway.

Background: Tumour delineation is a challenging, time-consuming and complex part of radiotherapy planning. In this study, an automatic method for delineating locally advanced cervical cancers was developed using a machine learning approach.

Materials And Methods: A method for tumour segmentation based on image voxel classification using Fisher?s Linear Discriminant Analysis (LDA) was developed. This was applied to magnetic resonance (MR) images of 78 patients with locally advanced cervical cancer. The segmentation was based on multiparametric MRI consisting of T2- weighted (T2w), T1-weighted (T1w) and dynamic contrast-enhanced (DCE) sequences, and included intensity and spatial information from the images. The model was trained and assessed using delineations made by two radiologists.

Results: Segmentation based on T2w or T1w images resulted in mean sensitivity and specificity of 94% and 52%, respectively. Including DCE-MR images improved the segmentation model?s performance significantly, giving mean sensitivity and specificity of 85?93%. Comparisons with radiologists? tumour delineations gave Dice similarity coefficients of up to 0.44.

Conclusion: Voxel classification using a machine learning approach is a flexible and fully automatic method for tumour delineation. Combining all relevant MR image series resulted in high sensitivity and specificity. Moreover, the presented method can be extended to include additional imaging modalities.
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http://dx.doi.org/10.1080/0284186X.2017.1285499DOI Listing
June 2017

Monte Carlo simulations of a low energy proton beamline for radiobiological experiments.

Acta Oncol 2017 Jun 22;56(6):779-786. Epub 2017 Feb 22.

a Department of Physics and Technology , University of Bergen , Bergen , Norway.

Background: In order to determine the relative biological effectiveness (RBE) of protons with high accuracy, radiobiological experiments with detailed knowledge of the linear energy transfer (LET) are needed. Cell survival data from high LET protons are sparse and experiments with low energy protons to achieve high LET values are therefore required. The aim of this study was to quantify LET distributions from a low energy proton beam by using Monte Carlo (MC) simulations, and to further compare to a proton beam representing a typical minimum energy available at clinical facilities.

Materials And Methods: A Markus ionization chamber and Gafchromic films were employed in dose measurements in the proton beam at Oslo Cyclotron Laboratory. Dose profiles were also calculated using the FLUKA MC code, with the MC beam parameters optimized based on comparisons with the measurements. LET spectra and dose-averaged LET (LET) were then estimated in FLUKA, and compared with LET calculated from an 80 MeV proton beam.

Results: The initial proton energy was determined to be 15.5 MeV, with a Gaussian energy distribution of 0.2% full width at half maximum (FWHM) and a Gaussian lateral spread of 2 mm FWHM. The LET increased with depth, from approximately 5 keV/μm in the entrance to approximately 40 keV/μm in the distal dose fall-off. The LET values were considerably higher and the LET spectra were much narrower than the corresponding spectra from the 80 MeV beam.

Conclusions: MC simulations accurately modeled the dose distribution from the proton beam and could be used to estimate the LET at any position in the setup. The setup can be used to study the RBE for protons at high LET, which is not achievable in clinical proton therapy facilities.
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http://dx.doi.org/10.1080/0284186X.2017.1289239DOI Listing
June 2017
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