| 1. |
- Anderson, D., et al.
(författare)
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Comparison of two methods for measuring gamma-H2AX nuclear fluorescence as a marker of DNA damage in cultured human cells : applications for microbeam radiation therapy
- 2013
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 8, s. C06008-
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Tidskriftsartikel (refereegranskat)abstract
- Microbeam radiation therapy (MRT) delivers single fractions of very high doses of synchrotron x-rays using arrays of microbeams. In animal experiments, MRT has achieved higher tumour control and less normal tissue toxicity compared to single-fraction broad beam irradiations of much lower dose. The mechanism behind the normal tissue sparing of MRT has yet to be fully explained. An accurate method for evaluating DNA damage, such as the gamma-H2AX immunofluorescence assay, will be important for understanding the role of cellular communication in the radiobiological response of normal and cancerous cell types to MRT. We compare two methods of quantifying gamma-H2AX nuclear fluorescence for uniformly irradiated cell cultures: manual counting of gamma-H2AX foci by eye, and an automated, MATLAB-based fluorescence intensity measurement. We also demonstrate the automated analysis of cell cultures irradiated with an array of microbeams. In addition to offering a relatively high dynamic range of gamma-H2AX signal versus irradiation dose (>10 Gy), our automated method provides speed, robustness, and objectivity when examining a series of images. Our in-house analysis facilitates the automated extraction of the spatial distribution of the gamma-H2AX intensity with respect to the microbeam array - for example, the intensities in the peak (high dose area) and valley (area between two microbeams) regions. The automated analysis is particularly beneficial when processing a large number of samples, as is needed to systematically study the relationship between the numerous dosimetric and geometric parameters involved with MRT (e.g., microbeam width, microbeam spacing, microbeam array dimensions, peak dose, valley dose, and geometric arrangement of multiple arrays) and the resulting DNA damage.
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| 2. |
- Anderson, Danielle L., et al.
(författare)
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Spatial and temporal distribution of gamma H2AX fluorescence in human cell cultures following synchrotron-generated X-ray microbeams : lack of correlation between persistent gamma H2AX foci and apoptosis
- 2014
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Ingår i: Journal of Synchrotron Radiation. - 0909-0495 .- 1600-5775. ; 21, s. 801-810
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Tidskriftsartikel (refereegranskat)abstract
- Formation of gamma H2AX foci (a marker of DNA double-strand breaks), rates of foci clearance and apoptosis were investigated in cultured normal human fibroblasts and p53 wild-type malignant glioma cells after exposure to high-dose synchrotron-generated microbeams. Doses up to 283 Gy were delivered using beam geometries that included a microbeam array (50 mu m wide, 400 mu m spacing), single microbeams (60-570 mu m wide) and a broad beam (32 mm wide). The two cell types exhibited similar trends with respect to the initial formation and time-dependent clearance of gamma H2AX foci after irradiation. High levels of gamma H2AX foci persisted as late as 72 h post-irradiation in the majority of cells within cultures of both cell types. Levels of persistent foci after irradiation via the 570 mu m microbeam or broad beam were higher when compared with those observed after exposure to the 60 mu m microbeam or microbeam array. Despite persistence of gamma H2AX foci, these irradiation conditions triggered apoptosis in only a small proportion (<5%) of cells within cultures of both cell types. These results contribute to the understanding of the fundamental biological consequences of high-dose microbeam irradiations, and implicate the importance of non-apoptotic responses such as p53-mediated growth arrest (premature senescence).
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| 3. |
- Bouchet, Audrey, et al.
(författare)
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Chalcone JAI-51 improves efficacy of synchrotron microbeam radiation therapy of brain tumors
- 2012
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Ingår i: Journal of Synchrotron Radiation. - 0909-0495 .- 1600-5775. ; 19, s. 478-482
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Tidskriftsartikel (refereegranskat)abstract
- Microbeam radiation therapy (MRT), a preclinical form of radiosurgery, uses spatially fractionated micrometre-wide synchrotron-generated X-ray beams. As MRT alone is predominantly palliative for animal tumors, the effects of the combination of MRT and a newly synthesized chemotherapeutic agent JAI-51 on 9L gliosarcomas have been evaluated. Fourteen days (D14) after implantation (D0), intracerebral 9LGS-bearing rats received either MRT, JAI-51 or both treatments. JAI-51, alone or immediately after MRT, was administered three times per week. Animals were kept up to similar to 20 weeks after irradiation or sacrificed at D16 or D28 after treatment for cell cycle analysis. MRT plus JAI-51 increased significantly the lifespan compared with MRT alone (p = 0.0367). JAI-51 treatment alone had no effect on rat survival. MRT alone or associated with JAI-51 induced a cell cycle blockade in G2/M (p < 0.01) while the combined treatment also reduced the proportion of G0/G1 cells. At D28 after irradiation, MRT and MRT/JAI-51 had a smaller cell blockade effect in the G2/M phase owing to a significant increase in tumor cell death rate (<2c) and a proportional increase of endoreplicative cells (>8c). The combination of MRT and JAI-51 increases the survival of 9LGS-bearing rats by inducing endoreduplication of DNA and tumor cell death; further, it slowed the onset of tumor growth resumption two weeks after treatment.
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| 4. |
- Brændengen, Morten, et al.
(författare)
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Delineation of gross tumor volume (GTV) for radiation treatment planning of locally advanced rectal cancer using information from MRI or FDG-PET/CT : a prospective study
- 2011
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 81:4, s. e439-e445
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:Accurate delineation of target volumes is important to maximize radiation dose to the tumor and minimize it to nontumor tissue. Computed tomography (CT) and magnetic resonance imaging (MRI) are standard imaging modalities in rectal cancer. The aim was to explore whether functional imaging with F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), combined with CT (FDG-PET/CT) gives additional information to standard pretreatment evaluation and changes the shape and size of the gross tumor volume (GTV).METHODS AND MATERIALS:From 2007 to 2009, 77 consecutive patients with locally advanced rectal cancer were prospectively screened for inclusion in the study at two university hospitals in Sweden, and 68 patients were eligible. Standard GTV was delineated using information from clinical examination, CT, and MRI (GTV-MRI). Thereafter, a GTV-PET was defined in the fused PET-CT, and the target volume delineations were compared for total volume, overlap, and mismatch. Pathologic uptake suspect of metastases was also registered.RESULTS:The median volume of GTV-MRI was larger than that of GTV-PET: 111 cm3 vs. 87 cm3 (p < 0.001). In many cases, the GTV-MRI contained the GTV defined on the PET/CT images as subvolumes, but when a GTV total was calculated after the addition of GTV-PET to GTV-MRI, the volume increased, with median 11% (range, 0.5–72%). New lesions were seen in 15% of the patients for whom PET/CT was used.CONCLUSIONS:FDG-PET/CT facilitates and adds important information to the standard delineation procedure of locally advanced rectal cancer, mostly resulting in a smaller GTV, but a larger total GTV using the union of GTV-MRI and GTV-PET. New lesions were sometimes seen, potentially changing the treatment strategy.
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| 5. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 6. |
- Henry, Thomas, et al.
(författare)
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Proton Grid Therapy : A Proof-of-Concept Study
- 2017
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Ingår i: Technology in Cancer Research & Treatment. - : SAGE Publications. - 1533-0346 .- 1533-0338. ; 16:6, s. 749-757
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Tidskriftsartikel (refereegranskat)abstract
- In this work, we studied the possibility of merging proton therapy with grid therapy. We hypothesized that patients with larger targets containing solid tumor growth could benefit from being treated with this method, proton grid therapy. We performed treatment planning for 2 patients with abdominal cancer with the suggested proton grid therapy technique. The proton beam arrays were cross-fired over the target volume. Circular or rectangular beam element shapes (building up the beam grids) were evaluated in the planning. An optimization was performed to calculate the fluence from each beam grid element. The optimization objectives were set to create a homogeneous dose inside the target volume with the constraint of maintaining the grid structure of the dose distribution in the surrounding tissue. The proton beam elements constituting the grid remained narrow and parallel down to large depths in the tissue. The calculation results showed that it is possible to produce target doses ranging between 100% and 130% of the prescribed dose by cross-firing beam grids, incident from 4 directions. A sensitivity test showed that a small rotation or translation of one of the used grids, due to setup errors, had only a limited influence on the dose distribution produced in the target, if 4 beam arrays were used for the irradiation. Proton grid therapy is technically feasible at proton therapy centers equipped with spot scanning systems using existing tools. By cross-firing the proton beam grids, a low tissue dose in between the paths of the elemental beams can be maintained down to the vicinity of a deep-seated target. With proton grid therapy, it is possible to produce a dose distribution inside the target volume of similar uniformity as can be created with current clinical methods.
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| 7. |
- Larsson, Emanuel
(författare)
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Evaluation of the Dual-Modal usage of contrast agents by means of Synchrotron X-ray Computed Microtomography and Magnetic Resonance Imaging using Macrophages loaded with Barium Sulfate and Gadolinium Nanoparticles for Detection and Monitoring in Animal Disease Models
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ¨This thesis focuses on evaluating the dual-modal Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) capabilities of contrast agents. For such purposes a gadolinium based contrast agent is of high interest, due to its paramagnetic properties, which while present inside a magnetic field will hence interact with the protons spins of water (in tissue and fat) and shorten their the T1 relaxation time, thereby creating a positive image contrast in MRI. Furthermore, the X-ray Mass Attenuation Coefficient (MAC) of gadolinium is relatively high, thus suggesting its potential use, also as a CT contrast agent.Gadolinium nanoparticles (GdNPs) can be loaded into cells, such as macrophages, which offers the possibility to track cells inside entire organisms. In the first step the uptake of GdNPs inside cells was investigated, together with a test for toxicity. To show the potential of using GdNP loaded macrophages for functional imaging of inflammation, an acute allergic airway inflammation mouse model (mimicking asthma in humans) was used and analyzed by in-situ synchrotron phase contrast CT. In the first step this approach was evaluated using macrophages loaded with a clinical contrast agent containing barium sulphate (BaSO4), since this agent is known to provide high contrast in CT. In the ultimate step a combination of both BaSO4 and GdNP loaded macrophages was used in the same asthmatic mouse model and analyzed by dual modal Synchrotron phase contrast CT and Micro Magnetic Resonance Imaging (μ-MRI).Complementary results in terms of the biodistribution of injected macrophages could only be obtained by the combination of both synchrotron phase contrast CT and μ-MRI, where the first modality allows a detailed localization of clustered BaSO4 loaded macrophages, but fails to detect single macrophages, which could instead be indirectly observed by μ-MRI as an increase of the T1-contrast, coming from the soft tissue of mice injected with GdNP loaded macrophages.
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| 8. |
- Mondlane, Gracinda, 1987-
(författare)
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Comparative study of Radiation Therapy of Targets in the Upper Abdomen with Photon- or Scanned Proton-beams
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Recently, there has been an increase in the number of proton beam therapy (PBT) centers operating worldwide. For certain cases, proton beams have been shown to provide dosimetric and radiobiological advantages when used for cancer treatment, compared to the regular photon-beam based treatments. Under ideal circumstances, the dose given to the tissues surrounding a target can be reduced with PBT. The risk for side effects following treatment is then expected to decrease. Until present, mainly stationary targets, e.g. targets in the brain, have been treated with PBT. There is currently a growing interest to treat also target volumes in other parts of the body with PBT. However, there are sources of uncertainties, which must be more carefully considered when PBT is used, especially for PBT carried out with scanned proton beams. PBT is more sensitive to anatomical changes, e.g. organ motion or a variable gas content in the intestines, which requires that special precautions are taken prior to treating new tumour sites. In photon beam radiotherapy (RT) of moving targets, the main consequence of organ motion is the loss of sharpness of the dose gradients (dose smearing). When scanned proton beams are used, dose deformation caused by the fluctuations in the proton beam range, due to varying tissue heterogeneities (e.g., the ribs moving in and out of the beam path) and the so-called interplay effect, can be expected to impact the dose distributions in addition to the dose smearing. The dosimetric uncertainties, if not accounted for, may cause the planned and accurately calculated dose distribution to be distorted, compromising the main goal of RT of achieving the maximal local disease control while accepting certain risks for normal tissue complications.Currently there is a lack of clinical follow-up data regarding the outcome of PBT for different tumour sites, in particular for extra-cranial tumour sites in moving organs. On the other hand, the use of photon beams for this kind of cancer treatment is well-stablished. A treatment planning comparison between RT carried out with photons and with protons may provide guidelines for when PBT could be more suitable. New clinical applications of particle beams in cancer therapy can also be transferred from photon-beam treatments, for which there is a vast clinical experience. The evaluation of the different uncertainties influencing RT of different tumour sites carried out with photon- and with proton-beams, will hopefully create an understanding for the feasibility of treating cancers with scanned proton beams instead of photon beams. The comparison of two distinct RT modalities is normally performed by studying the dosimetric values obtained from the dose volume histograms (DVH). However, in dosimetric evaluations, the outcome of the treatments in terms of local disease control and healthy tissue toxicity are not estimated. In this regard, radiobiological models can be an indispensable tool for the prediction of the outcome of cancer treatments performed with different types of ionising radiation. In this thesis, different factors that should be taken into consideration in PBT, for treatments influenced by organ motion and density heterogeneities, were studied and their importance quantified.This thesis consists of three published articles (Articles I, II and III). In these reports, the dosimetric and biological evaluations of photon-beam and scanned proton-beam RT were performed and the results obtained were compared. The studies were made for two tumour sites influenced by organ motion and density changes, gastric cancer (GC) and liver metastases. For the GC cases, the impact of changes in tissue density, resulting from variable gas content (which can be observed inter-fractionally), was also studied. In this thesis, both conventional fractionations (implemented in the planning for GC treatments) and hypofractionated regimens (implemented in the planning for the liver metastases cases) were considered. In this work, it was found that proton therapy provided the possibility to reduce the irradiations of the normal tissue located near the target volumes, compared to photon beam RT. However, the effects of density changes were found to be more pronounced in the plans for PBT. Furthermore, with proton beams, the reduction of the integral dose given to the OARs resulted in reduced risks of treatment-induced secondary malignancies.
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| 9. |
- Mondlane, Gracinda, 1987-, et al.
(author)
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Comparative study of the calculated risk of radiation-induced cancer after photon- and proton-beam based radiosurgery of liver metastases
- 2017
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In: Physica medica (Testo stampato). - : Elsevier BV. - 1120-1797 .- 1724-191X. ; 42, s. 263-270
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Journal article (peer-reviewed)abstract
- IntroductionThe potential of proton therapy to improve the sparing of the healthy tissue has been demonstrated in several studies. However, even small doses delivered to the organs at risk (OAR) may induce long-term detriments after radiotherapy. In this study, we investigated the possibility to reduce the risk of radiation-induced secondary cancers with intensity modulated proton therapy (IMPT), when used for radiosurgery of liver metastases.Material and methodsTen patients, previously treated for liver metastases with photon-beam based stereotactic body radiation therapy (SBRT) were retrospectively planned for radiosurgery with IMPT. A treatment plan comparison was then performed in terms of calculated risk of radiation-induced secondary cancer. The risks were estimated using two distinct models (Dasu et al., 2005; Schneider et al., 2005, 2009). The plans were compared pairwise with a two-sided Wilcoxon signed-rank test with a significance level of 0.05.ResultsReduced risks for induction of fatal and other types of cancers were estimated for the IMPT plans (p < 0.05) with the Dasu et al. model. Using the Schneider et al. model, lower risks for carcinomainduction with IMPT were estimated for the skin, lungs, healthy part of the liver, esophagus and the remaining part of the body (p < 0.05). The risk of observing sarcomas in the bone was also reduced with IMPT (p < 0.05).ConclusionThe findings of this study indicate that the risks of radiation-induced secondary cancers after radiosurgery of liver metastases may be reduced, if IMPT is used instead of photon-beam based SBRT.
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| 10. |
- Mondlane, Gracinda, 1987-, et al.
(author)
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Comparison of gastric-cancer radiotherapy performed with volumetric modulated arc therapy or single-field uniform-dose proton therapy
- 2017
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In: Acta Oncologica. - 0284-186X .- 1651-226X. ; 56:6, s. 832-838
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Journal article (peer-reviewed)abstract
- Background: Proton-beam therapy of large abdominal cancers has been questioned due to the large variations in tissue density in the abdomen. The aim of this study was to evaluate the importance of these variations for the dose distributions produced in adjuvant radiotherapy of gastric cancer (GC), implemented with photon-based volumetric modulated arc therapy (VMAT) or with proton-beam single-field uniform-dose (SFUD) method. Material and methods: Eight GC patients were included in this study. For each patient, a VMAT- and an SFUD-plan were created. The prescription dose was 45 Gy (IsoE) given in 25 fractions. The plans were prepared on the original CT studies and the doses were thereafter recalculated on two modified CT studies (one with extra water filling and the other with expanded abdominal air-cavity volumes). Results: Compared to the original VMAT plans, the SFUD plans resulted in reduced median values for the V18 of the left kidney (26%), the liver mean dose (14.8 Gy (IsoE)) and the maximum dose given to the spinal cord (26.6 Gy (IsoE)). However, the PTV coverage decreased when the SFUD plans were recalculated on CT sets with extra air- (86%) and water-filling (87%). The added water filling only led to minor dosimetric changes for the OARs, but the extra air caused significant increases of the median values of V18 for the right and left kidneys (10% and 12%, respectively) and of V10 for the liver (12%). The density changes influenced the dose distributions in the VMAT plans to a minor extent. Conclusions: SFUD was found to be superior to VMAT for the plans prepared on the original CT sets. However, SFUD was inferior to VMAT for the modified CT sets.
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| 11. |
- Mondlane, Gracinda, 1987-, et al.
(author)
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Dosimetric Comparison of Plans for Photon- or Proton-Beam Based Radiosurgery of Liver Metastases
- 2016
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In: International Journal of Particle Therapy. - 2331-5180. ; 3:2, s. 277-284
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Journal article (peer-reviewed)abstract
- Purpose: Radiosurgery treatment of liver metastases with photon beams has been an established method for more than a decade. One method commonly used is the stereotactic body radiation therapy (SBRT) technique. The aim of this study was to investigate the potential sparing of the organs at risk (OARs) that the use of intensity-modulated proton therapy (IMPT), instead of SBRT, could enable.Patients and Methods: A comparative treatment-planning study of photon-beam and proton-beam based liver-cancer radiosurgery was performed. Ten patients diagnosed with liver metastasis and previously treated with SBRT at the Karolinska University Hospital were included in the study. New IMPT plans were prepared for all patients, while the original plans were set as reference plans. The IMPT planning was performed with the objective of achieving the same target dose coverage as with the SBRT plans. Pairwise dosimetric comparisons of the treatment plans were then performed for the OARs. A 2-sided Wilcoxon signed-rank test with significance level of 5% was carried out.Results: Improved sparing of the OARs was made possible with the IMPT plans. There was a significant decrease of the mean doses delivered to the following risk organs: the nontargeted part of the liver (P = .002), the esophagus (P = .002), the right kidney (P = .008), the spinal cord (P = .004), and the lungs (P = .002). The volume of the liver receiving less than 15 Gy was significantly increased with the IMPT plans (P = .004).Conclusion: The IMPT-based radiosurgery plans provided similar target coverage and significant dose reductions for the OARs compared with the photon-beam based SBRT plans. Further studies including detailed information about varying tissue heterogeneities in the beam path, due to organ motion, are required to evaluate more accurately whether IMPT is preferable for the radiosurgical treatment of liver metastases.
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| 12. |
- Mondlane, Gracinda, 1987-, et al.
(author)
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Estimation of Risk of Normal-tissue Toxicity Following Gastric Cancer Radiotherapy with Photon- or Scanned Proton-beams
- 2018
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In: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 38:5, s. 2619-2625
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Journal article (peer-reviewed)abstract
- Background/Aim: Gastric cancer (GC) radiotherapy involves irradiation of large tumour volumes located in the proximities of critical structures. The advantageous dose distributions produced by scanned-proton beams could reduce the irradiated volumes of the organs at risk (OARs). However, treatment-induced side-effects may still appear. The aim of this study was to estimate the normal tissue complication probability (NTCP) following proton therapy of GC, compared to photon radiotherapy. Patients and Methods: Eight GC patients, previously treated with volumetric-modulated arc therapy (VMAT), were retrospectively planned with scanned proton beams carried out with the single-field uniform-dose (SFUD) method. A beam-specific planning target volume was used for spot positioning and a clinical target volume (CTV) based robust optimisation was performed considering setup- and range-uncertainties. The dosimetric and NTCP values obtained with the VMAT and SFUD plans were compared. Results: With SFUD, lower or similar dose-volume values were obtained for OARs, compared to VMAT. NTCP values of 0% were determined with the VMAT and SFUD plans for all OARs (p>0.05), except for the left kidney (p<0.05), for which lower toxicity was estimated with SFUD. Conclusion: The NTCP reduction, determined for the left kidney with SFUD, can be of clinical relevance for preserving renal function after radiotherapy of GC.
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| 13. |
- Mondlane, Gracinda, 1987-, et al.
(author)
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Estimation of the risk for radiation-induced liver disease following photon- or proton-beam radiosurgery of liver metastases
- 2018
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In: Radiation Oncology. - : Springer Science and Business Media LLC. - 1748-717X. ; 13
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Journal article (peer-reviewed)abstract
- Background: Radiotherapy of liver metastases is commonly being performed with photon-beam based stereotactic body radiation therapy (SBRT). The high risk for radiation-induced liver disease (RILD) is a limiting factor in these treatments. The use of proton-beam based SBRT could potentially improve the sparing of the healthy part of the liver. The aim of this study was to use estimations of normal tissue complication probability (NTCP) to identify liver-metastases patients that could benefit from being treated with intensity-modulated proton therapy (IMPT), based on the reduction of the risk for RILD.Methods: Ten liver metastases patients, previously treated with photon-beam based SBRT, were retrospectively planned with IMPT. A CTV-based robust optimisation (accounting for setup and range uncertainties), combined with a PTV-based conventional optimisation, was performed. A robustness criterion was defined for the CTV (V95% > 98% for at least 10 of the 12 simulated scenarios). The NTCP was estimated for different endpoints using the Lyman-Kutcher-Burman model. The ΔNTCP (NTCPIMPT − NTCPSBRT) for RILD was registered for each patient. The patients for which the NTCP (RILD) < 5% were also identified. A generic relative biological effectiveness of 1.1 was assumed for the proton beams.Results: For all patients, the objectives set for the PTV and the robustness criterion set for the CTV were fulfilled with the IMPT plans. An improved sparing of the healthy part of the liver, right kidney, lungs, spinal cord and the skin was achieved with the IMPT plans, compared to the SBRT plans. Mean liver doses larger than the threshold value of 32 Gy led to NTCP values for RILD exceeding 5% (7 patients with SBRT and 3 patients with the IMPT plans). ΔNTCP values (RILD) ranging between − 98% and − 17% (7 patients) and between 0 and 2% (3 patients), were calculated.Conclusions: In this study, liver metastases patients that could benefit from being treated with IMPT, based on the NTCP reductions, were identified. The clinical implementation of such a model-based approach to select liver metastases patients to proton therapy needs to be made with caution while considering the uncertainties involved in the NTCP estimations.
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| 14. |
- Mondlane, Gracinda, et al.
(author)
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Evaluation of the risk for radiation-induced liver disease following photon- or proton-beam radiosurgery of liver metastases
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Other publication (other academic/artistic)abstract
- Background: Radiotherapy of liver metastases is being performed with photon-beam stereotactic body radiation therapy (SBRT). However, the high risk for radiation-induced liver disease (RILD) is the treatment limiting factor. The use of proton beams in these treatments could improve the sparing of the healthy part of the liver. The aim of this study was to evaluate the use of estimations of normal tissue complication probability (NTCP) to identify liver-metastases patients that could benefit from being treated with intensity-modulated proton therapy (IMPT), based on the reduction of the risk for RILD. Methods: Ten liver metastases patients, previously treated with photon-beam radiosurgery, were retrospectively planned with IMPT. A CTV-based robust optimisation (accounting for setup and range uncertainties) combined with PTV-based conventional optimisation, was performed. A robustness criterion was defined for the CTV (V95%>98% for at least 10 of the 12 simulated scenarios). The NTCP was estimated for different endpoints using the Lyman-Kutcher-Burman model. The ΔNTCP (NTCPIMPT - NTCPSBRT) for RILD was registered for each patient. The patients for which the NTCP (RILD) < 5 % were also identified. A generic relative biological effectiveness of 1.1 was assumed for the proton beams. Results: For all patients, the objectives set for the PTV and the robustness criterion set for the CTV were fulfilled with the IMPT plans. An improved sparing of the healthy part of the liver, right kidney, lungs, spinal cord and the skin, was achieved with the IMPT plans. Mean liver doses larger than the threshold value of 32 Gy led to values of NTCP for RILD exceeding 5 % (7 patients for SBRT and 3 patients for IMPT). ΔNTCP values (RILD) ranging between -98% and -17 % (7 patients) and between 0 % and 2 % (3 patients) were estimated. Conclusions: In this study, liver metastases patients that could benefit from being treated with IMPT, based on the NTCP reductions, could be identified. The clinical implementation of such model-based approach to select liver metastases patients to proton therapy needs to be made with caution and considering the uncertainties involved in the NTCP estimations.
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| 15. |
- Mondlane, Gracinda, 1987-
(author)
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Radiation therapy of upper gastrointestinal cancers with scanned proton beams : A treatment planning study
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Proton beam therapy (PBT), using scanned beams, is an emerging modality used for the treatment of cancer. The clinical advantages of PBT, compared to commonly used photon beam therapy, have been demonstrated in different studies. However, the techniques used for planning and delivering treatments with photon beams have gradually been improved over the years. With the introduction of PBT in the clinic, guidelines to select patients to photon- or proton-beam therapy are indispensable.A simple approach used for selecting patients for PBT is based on the patient age. The paediatric patient group is considered to be the most radiosensitive and, therefore, in larger need of RT techniques that provide improved sparing of the organs at risk (OARs). With the increasing number of cancer clinics with access to PBT, combined with the constant clinical need of reducing the frequency of acute and late toxicities, there has been an increased use of PBT also for adult patients. At present, there is only limited clinical follow-up data available regarding the outcome of PBT for different tumour sites, in particular for extra-cranial tumours. The use of photon beams for such cancer treatments is, on the other hand, well-established. Therefore, the expected benefit of using proton beams in cancer therapy can be translated from the results obtained in the clinical experience attained from photon-beam treatments. The evaluation of the different uncertainties influencing the radiotherapy (RT) of different tumour sites carried out with photon- or proton-beams, will also create an improved understanding of the feasibility of treating cancer with scanned proton beams instead of with photon beams. The comparison of two distinct RT modalities is normally performed by studying the calculated dose distributions superimposed on the patient CT images and by evaluating the dosimetric values obtained from the dose volume histograms (DVHs). The dosimetric evaluation can be complemented with treatment outcome predictions in terms of local disease control and normal tissue toxicity. In this regard, radiobiological models can be an indispensable tool for the prediction of the outcome of cancer treatments performed with different types of ionising radiation. These estimates can in turn be used in the decision process for selecting patients for treatments with a specific RT modality.This thesis consists of five articles. In these studies, treatment plans for RT with scanned proton-beams have been prepared and compared with clinical plans used for photon-beam based RT. For this purpose, dosimetric and biological-model based evaluations of these plans were performed. These studies were carried out for two distinct upper gastrointestinal (GI) cancers, namely, gastric cancer (GC) and liver metastases. RT treatments with both conventional fractionation schemes (implemented in the planning for the GC treatments) and hypofractionated regimens (implemented in the planning for the liver metastases cases) were considered. For the GC cases, the impact of changes in tissue density, resulting from a variable gas content (which can be observed inter-fractionally), was investigated. Proton therapy was found to provide the possibility to reduce the doses given to normal tissues surrounding the target volumes, compared to photon RT. This dose reduction with PBT resulted in reduced risks for both treatment-induced normal tissue toxicities and secondary malignancies. The impact of the introduced density changes on the dose distributions were found to be more pronounced for the PBT plans, if plan robustness approaches were disregarded. The findings presented in this thesis can be of clinical importance in the selection process between different RT modalities.
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| 16. |
- Thomas, Henry, et al.
(author)
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Development of an interlaced-crossfiring geometry for proton grid therapy
- 2017
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In: Acta Oncologica. - 0284-186X .- 1651-226X. ; 56:11, s. 1437-1443
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Journal article (peer-reviewed)abstract
- Background: Grid therapy has in the past normally been performed with single field photon-beamgrids. In this work, we evaluated a method to deliver grid therapy based on interlacing and crossfiringgrids of mm-wide proton beamlets over a target volume, by Monte Carlo simulations.Material and methods: Dose profiles for single mm-wide proton beamlets (1, 2 and 3 mm FWHM) inwater were simulated with the Monte Carlo code TOPAS. Thereafter, grids of proton beamlets weredirected toward a cubic target volume, located at the center of a water tank. The aim was to deliver anearly homogeneous dose to the target, while creating high dose heterogeneity in the normal tissue,i.e., high gradients between valley and peak doses in the grids, down to the close vicinity of thetarget.Results: The relative increase of the beam width with depth was largest for the smallest beams(þ6.9mm for 1 mm wide and 150MeV proton beamlets). Satisfying dose coverage of the cubic targetvolume (r< ±5%) was obtained with the interlaced-crossfiring setup, while keeping the grid pattern ofthe dose distribution down to the target (valley-to-peak dose ratio<0.5 less than 1 cm before the tar-get). Center-to-center distances around 7–8 mm between the beams were found to give the best com-promise between target dose homogeneity and low peak doses outside of the target.Conclusions: A nearly homogeneous dose distribution can be obtained in a target volume by crossfir-ing grids of mm-wide proton-beamlets, while maintaining the grid pattern of the dose distribution atlarge depths in the normal tissue, close to the target volume. We expect that the use of this methodwill increase the tumor control probability and improve the normal tissue sparing in grid therapy.
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| 17. |
- Tsubouchi, Toshiro, et al.
(author)
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Quantitative evaluation of potential irradiation geometries for carbon-ion beam grid therapy
- 2018
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In: Medical physics (Lancaster). - : Wiley. - 0094-2405 .- 2473-4209. ; 45:3, s. 1210-1221
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Journal article (peer-reviewed)abstract
- Purpose: Radiotherapy using grids containing cm-wide beam elements has been carried out sporadically for more than a century. During the past two decades, preclinical research on radiotherapy with grids containing small beam elements, 25 m-0.7 mm wide, has been performed. Grid therapy with larger beam elements is technically easier to implement, but the normal tissue tolerance to the treatment is decreasing. In this work, a new approach in grid therapy, based on irradiations with grids containing narrow carbon-ion beam elements was evaluated dosimetrically. The aim formulated for the suggested treatment was to obtain a uniform target dose combined with well-defined grids in the irradiated normal tissue. The gain, obtained by crossfiring the carbon-ion beam grids over a simulated target volume, was quantitatively evaluated.Methods: The dose distributions produced by narrow rectangular carbon-ion beams in a water phantom were simulated with the PHITS Monte Carlo code. The beam-element height was set to 2.0 cm in the simulations, while the widths varied from 0.5 to 10.0 mm. A spread-out Bragg peak (SOBP) was then created for each beam element in the grid, to cover the target volume with dose in the depth direction. The dose distributions produced by the beam-grid irradiations were thereafter constructed by adding the dose profiles simulated for single beam elements. The variation of the valley-to-peak dose ratio (VPDR) with depth in water was thereafter evaluated. The separation of the beam elements inside the grids were determined for different irradiation geometries with a selection criterion.Results: The simulated carbon-ion beams remained narrow down to the depths of the Bragg peaks. With the formulated selection criterion, a beam-element separation which was close to the beam-element width was found optimal for grids containing 3.0-mm-wide beam elements, while a separation which was considerably larger than the beam-element width was found advantageous for grids containing 0.5-mm-wide beam elements. With the single-grid irradiation setup, the VPDRs were close to 1.0 already at a distance of several cm from the target. The valley doses given to the normal tissue at 0.5 cm distance from the target volume could be limited to less than 10% of the mean target dose if a crossfiring setup with four interlaced grids was used.Conclusions: The dose distributions produced by grids containing 0.5- and 3.0-mm wide beam elements had characteristics which could be useful for grid therapy. Grids containing mm-wide carbon-ion beam elements could be advantageous due to the technical ease with which these beams can be produced and delivered, despite the reduced threshold doses observed for early and late responding normal tissue for beams of millimeter width, compared to submillimetric beams. The treatment simulations showed that nearly homogeneous dose distributions could be created inside the target volumes, combined with low valley doses in the normal tissue located close to the target volume, if the carbon-ion beam grids were crossfired in an interlaced manner with optimally selected beam-element separations. The formulated selection criterion was found useful for the quantitative evaluation of the dose distributions produced by the different irradiation setups.
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| 18. |
- Willer, Cristen J., et al.
(author)
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Discovery and refinement of loci associated with lipid levels
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
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Journal article (peer-reviewed)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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