| 1. |
- Jansson, John-Olov, 1954, et al.
(författare)
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Body weight homeostat that regulates fat mass independently of leptin in rats and mice.
- 2018
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:2, s. 427-432
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Tidskriftsartikel (refereegranskat)abstract
- Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat ("gravitostat") that regulates fat mass.
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| 2. |
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| 3. |
- Schoultz, Elin, et al.
(författare)
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Tissue architecture delineates field cancerization in brafv600e-induced tumor development
- 2022
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Ingår i: DMM Disease Models and Mechanisms. - 1754-8403 .- 1754-8411. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAFmutant lineage becomes a cancerized lineage. The TgCreERT2; BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution.
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| 4. |
- Andersson, M., et al.
(författare)
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Evaluation of response in patients with hepatocellular carcinoma treated with intratumoral dendritic cell vaccination using intravoxel incoherent motion (IVIM) MRI and histogram analysis
- 2023
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Ingår i: Acta Radiologica. - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 64:1, s. 32-41
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Tidskriftsartikel (refereegranskat)abstract
- Background Immunotherapy of hepatocellular carcinoma (HCC) is an emerging method with promising results. Immunotherapy can have an antitumor effect without affecting tumor size, calling for functional imaging methods for response evaluation. Purpose To evaluate the response to intratumoral injections with the immune primer ilixadencel in HCCs with diffusion-weighted magnetic resonance imaging (DW-MRI) using intravoxel incoherent motion (IVIM) and histogram analysis. Material and Methods A total of 17 patients with advanced HCC were treated with intratumoral injections with ilixadencel on three occasions 2-5 weeks apart. The patients were examined with IVIM before each injection as well as approximately three months after the first injection. Results The 10th percentile of perfusion-related parameter D* decreased significantly after the first and second intratumoral injections of ilixadencel compared to baseline (P < 0.05). There was a non-significant trend of lower median region of interest f (perfusion fraction) before injection 2 compared to baseline (P = 0.07). There were significant correlations between the 10th percentile and median of D at baseline and change in tumor size after three months (r = 0.79, P < 0.01 and r = 0.72, P < 0.05, respectively). Conclusion DW-MRI with IVIM and histogram analysis revealed significant reductions of D* early after treatment as well as an association between D at baseline and smaller tumor growth at three months. The lower percentiles (10th and 50th) were found more important. Further research is needed to confirm our preliminary findings of reduced perfusion after ilixadencel vaccinations, suggesting a treatment effect on HCC.
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| 5. |
- Apelgren, Peter, et al.
(författare)
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Vascularization of tissue engineered cartilage-Sequential in vivo MRI display functional blood circulation
- 2021
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 276
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Tidskriftsartikel (refereegranskat)abstract
- Establishing functional circulation in bioengineered tissue after implantation is vital for the delivery of oxygen and nutrients to the cells. Native cartilage is avascular and thrives on diffusion, which in turn depends on proximity to circulation. Here, we investigate whether a gridded three-dimensional (3D) bioprinted construct would allow ingrowth of blood vessels and thus prove a functional concept for vascularization of bioengineered tissue. Twenty 10 x 10 x 3-mm 3Dbioprinted nanocellulose constructs containing human nasal chondrocytes or cell-free controls were subcutaneously implanted in 20 nude mice. Over the next 3 months, the mice were sequentially imaged with a 7 T small-animal MRI system, and the diffusion and perfusion parameters were analyzed. The chondrocytes survived and proliferated, and the shape of the constructs was well preserved. The diffusion coefficient was high and well preserved over time. The perfusion and diffusion patterns shown by MRI suggested that blood vessels develop over time in the 3D bioprinted constructs; the vessels were confirmed by histology and immunohistochemistry. We conclude that 3D bioprinted tissue with a gridded structure allows ingrowth of blood vessels and has the potential to be vascularized from the host. This is an essential step to take bioengineered tissue from the bench to clinical practice.
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| 6. |
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| 7. |
- Dalmo, Johanna, et al.
(författare)
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Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1.
- 2017
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: 177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu-octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice. RESULTS: Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A. CONCLUSIONS: Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.
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| 8. |
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| 9. |
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| 10. |
- Gustafsson, Oscar, 1989, et al.
(författare)
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An assessment of Bayesian IVIM model fitting
- 2016
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Ingår i: ISMRM 2016 Annual Meeting. 7-13 May, Singapore. - : International Society for Magnetic Resonance in Medicine.
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Konferensbidrag (refereegranskat)abstract
- Bayesian model fitting has been proposed as an alternative to the commonly used least squares fitting of the IVIM model. In this work we used Monte Carlo simulations to study the convergence of a Markov Chain Monte Carlo implementation of Bayesian model fitting and compared the resulting model parameters to two least squares model fitting methods. We saw that the convergence of the Bayesian model fitting procedure was affected by noise and compartment sizes. Bayesian model fitting was beneficial for the diffusion coefficient and the perfusion fraction, especially at low SNR
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| 11. |
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| 12. |
- Gustafsson, Oscar, 1989, et al.
(författare)
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Impact of prior distributions and central tendency measures on Bayesian intravoxel incoherent motion model fitting
- 2018
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Ingår i: Magnetic Resonance in Medicine. - : Wiley. - 0740-3194 .- 1522-2594. ; 79:3, s. 1674-1683
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 International Society for Magnetic Resonance in Medicine.Purpose: Bayesian model fitting has been proposed as a robust alternative for intravoxel incoherent motion (IVIM) model-fitting parameter estimation. However, consensus regarding choice of prior distribution and posterior distribution central tendency measure is needed. The aim of this study was to compare the quality of IVIM parameter estimates produced by different prior distributions and central tendency measures, and to gain knowledge about the effect of these choices. Methods: Three prior distributions (uniform, reciprocal, and lognormal) and two measures of central tendency (mean and mode) found in the literature were studied using simulations and in vivo data from a tumor mouse model. Results: Simulations showed that the uniform and lognormal priors were superior to the reciprocal prior, especially for the parameters D and f and clinically relevant SNR levels. The choice of central tendency measure had less effect on the results, but had some effects on estimation bias. Results based on simulations and in vivo data agreed well, indicating high validity of the simulations. Conclusions: Choice of prior distribution and central tendency measure affects the results of Bayesian IVIM parameter estimates. This must be considered when comparing results from different studies. The best overall quality of IVIM parameter estimates was obtained using the lognormal prior.
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| 13. |
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| 14. |
- Huang, Junchi, et al.
(författare)
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Magnetic Resonance Imaging as a Tool for Monitoring Intratibial Growth of Experimental Prostate Cancer Metastases in Mice
- 2023
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Ingår i: Methods and Protocols (MP). - 2409-9279. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Bone metastases cause morbidity and mortality in several human cancer forms. Experimental models are used to unravel the mechanisms and identify possible treatment targets. The location inside the skeleton complicates accurate assessment. This study evaluates the performance of magnetic resonance imaging (MRI) of prostate cancer tumors growing intratibially in mice. MRI detected intratibial tumor lesions with a sensitivity and specificity of 100% and 89%, respectively, compared to histological evaluation. Location and some phenotypical features could also be readily detected with MRI. Regarding volume estimation, the correlation between MRI and histological assessment was high (p < 0.001, r = 0.936). In conclusion, this study finds MRI to be a reliable tool for in vivo, non-invasive, non-ionizing, real-time monitoring of intratibial tumor growth.
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| 15. |
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IVIM reveals increased blood perfusion of liver metastases after oral intake of Salovum®
- 2015
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Ingår i: Magnetic Resonance Materials in Physics, Biology and Medicine. - : Springer Science and Business Media LLC. - 0968-5243 .- 1352-8661.
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Proceedings (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- Introduction Elevated interstitial fluid pressure (IFP) of tumours impairs perfusion, which hinders anti-cancer drugs and oxygen to reach tumour cells1-3. AF-16, a 16 amino acid long sequence from the amino terminal end of the endogenous protein Antisecretory Factor (AF), supresses IFP in animal models of solid tumours4, and could improve drug delivery to tumour cells. Salovum®, a spray-dried egg yolk powder with high content of antisecretory peptides, should be tested on humans, but requires non-invasive tumour IFP/perfusion assessment methods. The IntraVoxel Incoherent Motion (IVIM) model applied to multi-b DWI enables measurement of tissue diffusion (D), pseudo-diffusion (D*) and voxel volume fraction of actively perfused capillaries (f) 5. The aim of this study was to investigate if f could be used to monitor changes induced by Salovum® in colorectal liver metastases in vivo Subjects and Methods Previously untreated patients (n=6) with colorectal liver metastases were imaged before, and 24h after intake of Salovum®, using IVIM-MRI (3T Philips, 16‐channel receiver; Single-shot, SE‐EPI (breath-hold); FOV covering liver, 3x3x5mm3 voxels; TR/TE/NSA/SENSE=1900ms/50ms/2/2; 11 b‐values (0-600); acquisition~10 min. MATLAB-based images processing comprised 1) Inter-scan image registration (volume preserving free-form deformation6); 2) Voxelwise fitting of D and A [eq.2] to S(b200-600) (for b>200, [eq.1] reduces to [eq.2], assuming D<2cm) on DWI (b=600), transfer of ROIs to corresponding f-maps for calculation of median ROI f before and after Salovum® intake and 4) Mann-Whitney U-test for statistical significance (α-level=0.05). Results Liver and metastases were well visualised on DWIs and f-maps Median f in metastatic tissue increased after intake of Salovum® in 5/6 patients, but decreased in one patient (Fig.2) (p<0.0001). Discussion/Conclusion The increased perfusion fraction on day 2 may offer a “window of opportunity” for improved transport of drugs to tumour cells. The increase in f was small, and perhaps not clinically significant, suggesting that additional time points after Salovum® intake and dose escalation be investigated, as well as intra-tumour effect heterogeneity. The proposed IVIM approach is a promising, non-invasive method for studying Salovum® induced changes in liver metastases in vivo. Further optimisation and fractionation studies should be conducted, and IVIM derived parameters should be compared to other techniques for perfusion or IFP measurements. References 1Rofstad,E.K.,et al.,Neoplasia. 2009;11(11):1243-51. 2Milosevic,M.F.,et al.,1999;43(5):1111-23. 3Wiig, H.,et al.,1982;42(2):159-64. 4Al-Olama, M.et al., 2011;50(7):1098-104. 5Le Bihan, D., et al., 1988;168(2):497-505. 6Rueckert, D., et al., 1999;18(8):712-21.
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| 16. |
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| 17. |
- Jalnefjord, Oscar, 1989, et al.
(författare)
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Comparison of methods for estimation of the intravoxel incoherent motion (IVIM) diffusion coefficient (D) and perfusion fraction (f)
- 2018
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Ingår i: Magnetic Resonance Materials in Physics, Biology and Medicine. - : Springer Science and Business Media LLC. - 0968-5243 .- 1352-8661. ; 31:6, s. 715-723
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Intravoxel incoherent motion (IVIM) shows great potential in many applications, e.g., tumor tissue characterization. To reduce image-quality demands, various IVIM analysis approaches restricted to the diffusion coefficient (D) and the perfusion fraction (f) are increasingly being employed. In this work, the impact of estimation approach for D and f is studied. Materials and methods: Four approaches for estimating D and f were studied: segmented IVIM fitting, least-squares fitting of a simplified IVIM model (sIVIM), and Bayesian fitting of the sIVIM model using marginal posterior modes or posterior means. The estimation approaches were evaluated in terms of bias and variability as well as ability for differentiation between tumor and healthy liver tissue using simulated and in vivo data. Results: All estimation approaches had similar variability and ability for differentiation and negligible bias, except for the Bayesian posterior mean of f, which was substantially biased. Combined use of D and f improved tumor-to-liver tissue differentiation compared with using D or f separately. Discussion: The similar performance between estimation approaches renders the segmented one preferable due to lower numerical complexity and shorter computational time. Superior tissue differentiation when combining D and f suggests complementary biologically relevant information.
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| 18. |
- Jalnefjord, Oscar, 1989, et al.
(författare)
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Data-driven identification of tumor subregions based on intravoxel incoherent motion reveals association with proliferative activity
- 2019
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Ingår i: Magnetic Resonance in Medicine. - : Wiley. - 0740-3194 .- 1522-2594. ; 82:4, s. 1480-1490
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Intravoxel incoherent motion (IVIM) analysis gives information on tissue diffusion and perfusion and may thus have a potential for e.g. tumor tissue characterization. This work aims to study if clustering based on IVIM parameter maps can identify tumor subregions, and to assess the relevance of obtained subregions by histological analysis. Methods: Fourteen mice with human neuroendocrine tumors were examined with diffusion-weighted imaging to obtain IVIM parameter maps. Gaussian mixture models with IVIM maps from all tumors as input were used to partition voxels into k clusters, where k = 2 was chosen for further analysis based on goodness of fit. Clustering was performed with and without the perfusion-related IVIM parameter D*, and with and without including spatial information. The validity of the clustering was assessed by comparison with corresponding histologically stained tumor sections. A Ki-67-based index quantifying the degree of tumor proliferation was considered appropriate for the comparison based on the obtained cluster characteristics. Results: The clustering resulted in one class with low diffusion and high perfusion and another with slightly higher diffusion and low perfusion. Strong agreement was found between tumor subregions identified by clustering and subregions identified by histological analysis, both regarding size and spatial agreement. Neither D* nor spatial information had substantial effects on the clustering results. Conclusions: The results of this study show that IVIM parameter maps can be used to identify tumor subregions using a data-driven framework based on Gaussian mixture models. In the studied tumor model, the obtained subregions showed agreement with proliferative activity.
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| 19. |
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| 20. |
- Jalnefjord, Oscar, 1989, et al.
(författare)
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Optimization of b-value schemes for estimation of the diffusion coefficient and the perfusion fraction with segmented intravoxel incoherent motion model fitting
- 2019
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Ingår i: Magnetic Resonance in Medicine. - : Wiley. - 0740-3194 .- 1522-2594. ; 82:4, s. 1541-1552
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Intravoxel incoherent motion (IVIM) modeling for estimation of the diffusion coefficient (D) and perfusion fraction (f) is increasingly popular, but no consensus on standard protocols exists. This study provides a framework for optimization of b-value schemes for reduced estimation uncertainty of D and f from segmented model fitting. Theory: Analytical expressions for uncertainties of D and f from segmented model fitting were derived as Cramer-Rao lower bounds (CRLBs). Methods: Optimized b-value schemes were obtained for 3 to 12 acquisitions and in the limit of infinitely many acquisitions through constrained minimization of the CRLBs, with b-values constrained to be 0 or 200 to 800 s/mm2. The optimized b-value scheme with eight acquisitions was compared with b-values linearly distributed in the allowed range using simulations and in vivo liver data from seven healthy volunteers. Results: All optimized b-value schemes contained exactly three unique b-values regardless of the total number of acquisitions (0, 200, and 800 s/mm2) with repeated acquisitions distributed approximately as 1:2:2. Compared with linearly distributed b-values, the variability of estimates of D and f was reduced by approximately 30% as seen both in simulations and in repeated in vivo measurements. Conclusion: The uncertainty of IVIM D and f estimates can be reduced by the use of optimized b-value schemes. © 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine
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| 23. |
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| 26. |
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| 27. |
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| 28. |
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| 29. |
- Lundholm, Lukas, et al.
(författare)
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VERDICT MRI for radiation treatment response assessment in neuroendocrine tumors.
- 2022
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Ingår i: NMR in biomedicine. - : Wiley. - 1099-1492 .- 0952-3480. ; 35:6
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Tidskriftsartikel (refereegranskat)abstract
- Non-invasive methods to study changes in the tumor microstructure would enable early assessment of treatment response and thus facilitate personalized treatment. The aim of this study was to evaluate the diffusion MRI model Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors (VERDICT) for early response assessment to external radiation treatment and to compare the results to those of more studied sets of parameters derived from diffusion-weighted MRI data. Mice xenografted with human small intestine tumors were treated with external radiation treatment, and diffusion MRI experiments were performed on the day before and up to two weeks after treatment. The diffusion models VERDICT, ADC, IVIM, and DKI were fitted to MRI data, and the treatment response of each tumor was calculated based on pre-treatment tumor growth and post-treatment tumor volume regression. Linear regression and correlation analysis were used to evaluate each model and their respective parameters for explaining the treatment response. VERDICT analysis showed significant changes from day -1 to day 3 for the intracellular and extracellular volume fraction, as well as the cell radius index (P < 0.05; Wilcoxon signed-rank test). The strongest correlation between the diffusion model parameters and the tumor treatment response was seen for the ADC, kurtosis-corrected diffusion coefficient, and intracellular volume fraction on day 3 (τ = 0.47, 0.52, and -0.49 respectively, P < 0.05; Kendall rank correlation coefficient). Of all tested models, VERDICT held the strongest explanatory value for the tumor treatment response on day 3 (R2 = 0.75, P < 0.01; linear regression). In conclusion, VERDICT holds potential for early assessment of external radiation treatment and may provide further insight into the underlying biological effects of radiation on tumor tissue. In addition, the results suggested that the time window for assessment of treatment response using dMRI may be narrow.
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| 30. |
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| 31. |
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| 32. |
- Montelius, Mikael, 1979, et al.
(författare)
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Identification of Potential MR-Derived Biomarkers for Tumor Tissue Response to 177Lu-Octreotate Therapy in an Animal Model of Small Intestine Neuroendocrine Tumor.
- 2018
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Ingår i: Translational oncology. - : Elsevier BV. - 1936-5233. ; 11:2, s. 193-204
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Tidskriftsartikel (refereegranskat)abstract
- Magnetic resonance (MR) methods enable noninvasive, regional tumor therapy response assessment, but associations between MR parameters, underlying biology, and therapeutic effects must be investigated.The aim of this study was to investigate response assessment efficacy and biological associations of MR parameters in a neuroendocrine tumor (NET) model subjected to radionuclide treatment.Twenty-one mice with NETs received 177Lu-octreotate at day 0. MR experiments (day -1, 1, 3, 8, and 13) included T2-weighted, dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI) and relaxation measurements (T1/T2*). Tumor tissue was analyzed using proteomics. MR-derived parameters were evaluated for each examination day and for different radial distances from the tumor center. Response assessment efficacy and biological associations were evaluated using feature selection and protein expression correlations, respectively.Reduced tumor growth rate or shrinkage was observed until day 8, followed by reestablished growth in most tumors. The most important MR parameter for response prediction was DCE-MRI-derived pretreatment signal enhancement ratio (SER) at 40% to 60% radial distance, where it correlated significantly also with centrally sampled protein CCD89 (association: DNA damage and repair, proliferation, cell cycle arrest). The second most important was changed diffusion (D) between day -1 and day 3, at 60% to 80% radial distance, where it correlated significantly also with peripherally sampled protein CATA (association: oxidative stress, proliferation, cell cycle arrest, apoptotic cell death).Important information regarding tumor biology in response to radionuclide therapy is reflected in several MR parameters, SER and D in particular. The spatial and temporal information provided by MR methods increases the sensitivity for tumor therapy response.
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| 33. |
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| 34. |
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| 35. |
- Montelius, Mikael, 1979, et al.
(författare)
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Multiparametric MR for non-invasive evaluation of tumour tissue histological characteristics after radionuclide therapy.
- 2019
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Ingår i: NMR in biomedicine. - : Wiley. - 1099-1492 .- 0952-3480. ; 31:3
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Tidskriftsartikel (refereegranskat)abstract
- Early non-invasive tumour therapy response assessment requires methods sensitive to biological and physiological tumour characteristics. The aim of this study was to find and evaluate magnetic resonance imaging (MRI) derived tumour tissue parameters that correlate with histological parameters and that reflect effects of radionuclide therapy. Mice bearing a subcutaneous human small-intestine neuroendocrine tumour were i.v. injected with 177 Lu-octreotate. MRI was performed (7T Bruker Biospec) on different post-therapy intervals (1 and 13days) using T2-weighted imaging, mapping of T2* and T1 relaxation time constants, as well as diffusion and dynamic contrast enhancement (DCE-MRI) techniques. After MRI, animals were killed and tumours excised. Four differently stained histological sections of the most central imaged tumour plane were digitized, and segmentation techniques were used to produce maps reflecting fibrotic and vascular density, apoptosis, and proliferation. Histological maps were aligned with MRI-derived parametric maps using landmark-based registration. Correlations and predictive power were evaluated using linear mixed-effects models and cross-validation, respectively. Several MR parameters showed statistically significant correlations with histological parameters. In particular, three DCE-MRI-derived parameters reflecting capillary function additionally showed high predictive power regarding apoptosis (2/3) and proliferation (1/3). T1 could be used to predict vascular density, and perfusion fraction derived from diffusion MRI could predict fibrotic density, although with lower predictive power. This work demonstrates the potential to use multiparametric MRI to retrieve important information on the tumour microenvironment after radiotherapy. The non-invasiveness of the method also allows longitudinal tumour tissue characterization. Further investigation is warranted to evaluate the parameters highlighted in this study longitudinally, in larger studies, and with additional histological methods.
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| 36. |
- Montelius, Mikael, 1979
(författare)
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Multiparametric MRI for evaluation of tumour treatment response : Studies of 177Lu-octreotate therapy of neuroendocrine tumour
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Clinical assessment of tumour response to treatment largely relies on estimates of tumour size by, e.g., measuring the largest tumour diameters on magnetic resonance (MR) or computed tomography (CT) images, weeks or months after treatment. However, most tumours are heterogeneous, and treatment may result in different effects in different parts of the tumour. Therefore, non-invasive methods sensitive to biological effects that precede changes in tumour size would improve our understanding of tumour biology and therapeutic effects, facilitate personalized treatments and speed up development of anti-cancer therapeutics. MR methods have the potential to provide non-invasive imaging biomarkers of the relevant tumour biology, but the understanding of the information provided by MR methods is still limited. The aim of this project to was to improve the understanding and evaluate the feasibility of multiparametric MR methods for therapy response assessment of tumours after radionuclide therapy. Mice xenografted with human neuroendocrine tumours received 15 MBq 177Lu-octreotate i.v. on day 0, and MR imaging experiments were performed on days -1, 1, 3, 8 and 13, using dynamic contrast enhanced-, quantitative T1 and T2*- and diffusion weighted MR on a 7T small animal MR system. Optimization studies were performed to improve tissue model parameter estimates, and to ensure accurate MR based tumour volume estimation for response verification. MR parameter maps were spatially registered to corresponding histologically stained tumour section for correlation analysis, and tumour tissue samples were analysed using quantitative proteomics. Several statistically significant correlations were found between MR parameters and histological tumour characteristics, as well as with proteins associated with radiobiological effects on tumours, and collectively evaluated they provided information on apoptotic and proliferative activity, microvascular density and fibrosis in tumours, which are all important prognostic tumour characteristics. Spatial and temporal MR parameter variations before and after therapy seem to be predictive of tumour shrinkage or stabilization. Most effects on MR parameters were seen already one day after treatment initiation. This work demonstrates the feasibility of multiparametric MR for therapy response assessment in an animal tumour model, and highlights the importance of spatial and temporal evaluation of the MR parameters. Future efforts should include improvement of methods for spatial registration of in vivo MR images and ex vivo histological sections. For clinical applications, MR acquisition times need to be reduced.
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| 37. |
- Montelius, Mikael, 1979, et al.
(författare)
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Multiparametric MRI (mpMRI) for spatiotemporal characterization of tumor tissue response to radionuclide treatment
- 2016
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Ingår i: 62nd Annual International Meeting Radiation Research Society, Waikoloa, HI, USA, October 16-19, 2016.
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Konferensbidrag (refereegranskat)abstract
- Background: Development and optimization of efficient tumor treatment methods are needed. Increased understanding of the complex and heterogeneous tumor microenvironment in response to treatment is thus required, necessitating multiple, non-invasive biomarker acquisition with spatiotemporal resolution. mpMRI potentially offers methods with the required capabilities. Aim: To assess the possibility to non-invasively retrieve multiple, complementary information on radionuclide treatment effects on tumor microenvironment, using spatiotemporally resolved mpMRI. Methods: 19 mice with neuroendocrine tumors (~1 cm) received 15 MBq 177Lu-octreotate i.v. on day 0 (tumor dose ~4 Gy) and were imaged on day -1, 1, 3, 8 and 13. Imaging included IVIM (reflecting apoptosis/necrosis (AN) and capillary activity (CA)) [1], T1/T2* mapping (microstructural alterations (MA) and hypoxia/hemorrhage (HH)), DCE (microvessel integrity/perfusion tracer kinetics (IK)) and T2w MRI (morphology/size). Matlab based post-processing included voxelwise model fitting and tumor delineation to define a binary mask for volumetry and parameter extraction. An automatic separation of the mask into annular disks of preserved tumor shape but stepwise decreased size was performed, allowing separate regional analyses of central to peripheral parts of the tumor. Results: Groups with high/low response (HRG n = 8/LRG n = 4), based on post-treatment tumor volume (monotonically decreasing/increasing days 1-13) were identified. Post-treatment changes with significant separation of HRG from LRG (p < 0.05) were found in parameters related to AN: 1‡ parameter, CA: 1‡, HH: 1, IK: 10 (3†, 7‡) and MA: 1. Pre-treatment HRG/LRG prediction was possible in all 15 (8†) parameters; AN: 1, CA: 1, HH: 1, IK: 11 (8†) and MA: 1. (†Only after spatial separation. ‡Only transiently). Conclusions: Multiple, complementary biomarker information related to radionuclide tumor treatment could be extracted using spatiotemporally resolved mpMRI. Several parameters required separate analysis of sub-tumoural regions in order to separate high from low responding tumors, and some were only transiently affected, highlighting the importance of repeated measurements with spatially resolved techniques. References: 1.Le Bihan et al. Radiology, 1988
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| 38. |
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| 39. |
- Montelius, Mikael, 1979, et al.
(författare)
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Multiparametric MRI with spatiotemporal evaluation reveals potential therapy response biomarkers for 177Lu-octreotate therapy of mice with human neuroendocrine tumor
- 2017
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Ingår i: ISMRM 25th Annual Meeting. 22-27 April 2017, Honolulu, Hawaii, USA.
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Konferensbidrag (refereegranskat)abstract
- Tissue parameters derived from multiparametric MRI were evaluated as potential imaging biomarkers for therapy response assessment in mice with human neuroendocrine tumor treated with 177Lu-octreotate. Animals were imaged before and repeatedly after 177Lu-octreotate treatment, using T2w, IVIM-DWI, DCE-MRI, T1- and T2*-mapping techniques. MR-parameters were evaluated regionally and longitudinally, and quantitative proteomics was used to evaluate underlying biological response in central and peripheral tumor separately. Several MR-parameters showed strong correlation with tumor response, as verified by MRI-based tumor volume measurements, but also with proteins associated with radiobiological effects on tumor tissue. Spatial and temporal evaluation increased sensitivity of the methods.
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| 40. |
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| 41. |
- Montelius, Mikael, 1979, et al.
(författare)
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Optimal ROI Size for IVIM Imaging parameter determination
- 2012
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Ingår i: European Society for Magnetic Resonance in Medicine and Biology (ESMRMB), Oct 4-6 2012, Lisbon/PT.
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Konferensbidrag (refereegranskat)abstract
- The use of multiple b-values in diffusion weighted (DW) imaging allows calculation of the tissue molecular diffusion parameter D, the perfusion-related diffusion parameter D* and the perfusion fraction f, by applying the intravoxel incoherent motion (IVIM) model (Le Bihan 1988). Region of interest (ROI) based signal analysis is a widely used approach, where the normalized average ROI signal is plotted vs. b-value, and the acquired signal decay curve is fitted to a bi-exponential model in order to extract D, D* and f. However, the use of this approach requires consideration regarding the ROI area used for signal averaging, since a too small area would lead to uncertainties in the parameter determination, e.g. due to noise and patient motion. Likewise, a too large area increases the likelihood of including unwanted large vessels in the ROI, which confounds the interpretation of the perfusion fraction parameter. Better knowledge on how to choose the ROI size could lead to better and more reproducible estimations of D, D* and f; important parameters in e.g. tumor therapy response assessment. In this work we investigated the variability of these parameters due to the use of different ROI areas in liver IVIM experiments, and thereby empirically determined an optimal area for signal averaging.
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| 42. |
- Montelius, Mikael, 1979, et al.
(författare)
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Optimal ROI Size for Parameter Determination in IVIM Imaging
- 2012
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Ingår i: European Association of Nuclear Medicine (EANM), October 27 - 31, 2012, Milan/ITALY.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Successful delivery of therapy agents to tumor cells depends on tumor tissue perfusion and diffusion. Assessment of these parameters prior to and during treatment would facilitate decision-making regarding e.g. treatment strategy. The intravoxel incoherent motion (IVIM) model (Le Bihan 1988) applied to multi b-value diffusion weighted MRI offers non-invasive quantification of tissue diffusion (D), perfusion-related pseudo diffusion (D*) and perfusion fraction (f). However, the quantification is highly affected by the size of the analyzed region of interest (ROI). In this work, the optimal ROI size for quantification of D, D* and f was determined.
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| 43. |
- Montelius, Mikael, 1979, et al.
(författare)
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Tumour size measurement in a mouse model using high resolution MRI.
- 2012
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Ingår i: BMC medical imaging. - : Springer Science and Business Media LLC. - 1471-2342. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Animal models are frequently used to assess new treatment methods in cancer research. MRI offers a non-invasive in vivo monitoring of tumour tissue and thus allows longitudinal measurements of treatment effects, without the need for large cohorts of animals. Tumour size is an important biomarker of the disease development, but to our knowledge, MRI based size measurements have not yet been verified for small tumours (102-101g). The aim of this study was to assess the accuracy of MRI based tumour size measurements in small tumours on mice. METHODS: 2D and 3D T2-weighted RARE images of tumour bearing mice were acquired in vivo using a 7 T dedicated animal MR system. For the 3D images the acquired image resolution was varied. The images were exported to a PC workstation where the tumour mass was determined assuming a density of 1 g/cm3, using an in-house developed tool for segmentation and delineation. The resulting data were compared to the weight of the resected tumours after sacrifice of the animal using regression analysis. RESULTS: Strong correlations were demonstrated between MRI-and necropsy determined masses. In general, 3D acquisition was not a prerequisite for high accuracy. However, it was slightly more accurate than 2D when small (<0.2 g) tumours were assessed for inter-and intraobserver variation. In 3D images, the voxel sizes could be increased from 1603um3 to 2403um3 without affecting the results significantly, thus reducing acquisition time substantially. CONCLUSIONS: 2D MRI was sufficient for accurate tumour size measurement, except for small tumours (<0.2g) where 3D acquisition was necessary to reduce interobserver variation. Acquisition times between 15 and 50 minutes, depending on tumour size, were sufficient for accurate tumour volume measurement. Hence, it is possible to include further MR investigations of the tumour, such as tissue perfusion, diffusion or metabolic composition in the same MR session.
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| 44. |
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| 45. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer.
- 2019
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Ingår i: PloS One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.
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| 46. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Increased therapeutic effect on medullary thyroid cancer using a combination of radiation and tyrosine kinase inhibitors : Increased effect on medullary thyroid cancer by combining radiation with tyrosine kinase inhibitors
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.
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| 47. |
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| 48. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Tyrosinkinashämmare kan öka effekten från strålbehandling av medullär tyreoideacancer
- 2019
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Ingår i: Nationellt möte om sjukhusfysik.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- SYFTE Medullär tyreoideacancer (MTC) är en neuroendokrin cancertyp som har sitt ursprung i sköldkörtelns hormonproducerande C-celler. Många MTC överuttrycker receptorer för somatostatin vilket möjliggör radionuklidterapi med exempelvis 177Lu-oktreotat. Få patienter botas dock helt och optimering av behandlingen behövs. Ett sätt att optimera behandlingen är att kombinera 177Lu-oktreotat med ett annat läkemedel i syfte att öka effekten från strålningen. Nyligen godkändes två tyrosinkinashämmare (vandetanib och cabozantinib) för behandling av MTC. Syftet med denna studie var att undersöka ifall en ökad effekt kan fås då strålbehandling kombineras med tyrosinkinashämmare för behandling av MTC. METOD Nakna möss (BALB/c) transplanterades med humana MTC-celler (GOT2) och behandlades med extern strålbehandling och/eller tyrosinkinashämmare. Behandlings-effekten, som tumörvolym efter behandling, jämfördes med den hos obehandlade möss. För att möjliggöra detektion av en eventuellt ökad behandlingseffekt hos de möss som fick kombinationsbehandling (både strålbehandling och tyrosinkinas¬hämmare) valdes den absorberade dosen och mängden läkemedel så att en suboptimal effekt erhölls då respektive behandling gavs som singelbehandling. RESULTAT Kombinationsbehandling resulterade i störst minskning av tumörvolym och längst tid till progression. Exempelvis hade tumörvolymen hos de möss som fick kombinationsbehandling minskat med ca 70-75% efter två veckor jämfört med obehandlade möss. Även som singelbehandling resulterade båda behandlingar i en tydlig effekt på tumörvolymen, med en minskning på ca 50-65% efter två veckor. KONKLUSIONER Effekten från strålbehandling av möss med MTC-tumörer kan ökas genom kombinationsbehandling med tyrosinkinashämmare. Framtida studier bör utvärdera möjligheten att använda en kombination av 177Lu-oktreotat och tyrosinkinashämmare för behandling av patienter med MTC.
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