| 1. |
- Almqvist, Helena, et al.
(författare)
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CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.
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| 2. |
- Andre, Kadri, et al.
(författare)
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SERT and NET polymorphisms, temperament and antidepressant response
- 2015
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Ingår i: Nordic Journal of Psychiatry. - : Informa UK Limited. - 0803-9488 .- 1502-4725. ; 69:7, s. 531-538
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Tidskriftsartikel (refereegranskat)abstract
- Background: The genetic variations in norepinephrine transporter (NET) and serotonin transporter (SERT) genes have been associated with personality traits, several psychiatric disorders and the efficacy of antidepressant treatment. Aims: We investigated the separate effects and possible interactions between NET T-182C (rs2242446) and SERT 5-HTTLPR (rs4795541) polymorphisms on selective serotonin reuptake inhibitors (SSRI) treatment response and temperamental traits assessed by the Temperament and Character Inventory (TCI) in a clinical sample of subjects with major depressive disorder (MDD). Methods: Our sample of 97 patients with major depression completed the 107-item TCI temperament questionnaire (version IX) at the initial assessment of the study and after 6 weeks of follow-up. All subjects received selective SSRI medications. Temperament dimension scores at baseline (1) and endpoint (2) during antidepressant treatment were analyzed between NET and SERT genotypes. Results: SS-genotype of 5-HTTLPR was associated with higher baseline Persistence scores than SL- or LL-genotype. A corresponding but weaker association was found at endpoint. No differences were found between 5-HTTLPR genotypes and other temperament dimensions and 5-HTTLPR genotypes had no effect on treatment response. Conclusions: Our results suggest that the SS-genotype of 5-HTTLPR is associated with Persistence scores in patients with MDD. Higher Persistence could be viewed as a negative trait when recovering from stress and its association with short and "weaker" S-allele may be related to less efficient serotonin neurotransmission, possibly resulting in less effective coping strategies on a behavioral level.
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| 3. |
- Gram, D., et al.
(författare)
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Residual positioning errors and uncertainties for pediatric craniospinal irradiation and the impact of image guidance
- 2020
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Ingår i: Radiation Oncology. - : Springer Science and Business Media LLC. - 1748-717X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Optimal alignment is of utmost importance when treating pediatric patients with craniospinal irradiation (CSI), especially with regards to field junctions and multiple isocenters and techniques applying high dose gradients. Here, we investigated the setup errors and uncertainties for pediatric CSI using different setup verification protocols. Methods A total of 38 pediatric patients treated with CSI were identified for whom treatment records and setup images were available. The setup images were registered retrospectively to the reference image using an automated tool and matching on bony anatomy, subsequently, the impact of different correction protocols was simulated. Results For an action-level (AL)-protocol and a non-action level (NAL)-protocol, the translational residual setup error can be as large as 24 mm for an individual patient during a single fraction, and the rotational error as large as 6.1 degrees. With daily IGRT, the maximum setup errors were reduced to 1 mm translational and 5.4 degrees rotational versus 1 mm translational and 2.4 degrees rotational for 3- and 6- degrees of freedom (DoF) couch shifts, respectively. With a daily 6-DoF IGRT protocol for a wide field junction irradiation technique, the residual positioning uncertainty was below 1 mm and 1 degrees for translational and rotational directions, respectively. The largest rotational uncertainty was found for the patients' roll even though this was the least common type of rotational error, while the largest translational uncertainty was found in the patients' anterior-posterior-axis. Conclusions These results allow for informed margin calculation and robust optimization of treatments. Daily IGRT is the superior choice for setup of pediatric patients treated with CSI, although centers that do not have this option could use the results presented here to improve their margins and uncertainty estimates for a more accurate treatment alignment.
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| 4. |
- Haraldsson, André, et al.
(författare)
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A Helical tomotherapy as a robust low-dose treatment alternative for total skin irradiation
- 2019
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Ingår i: Journal of Applied Clinical Medical Physics. - : Wiley. - 1526-9914. ; 20:5, s. 44-54
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Tidskriftsartikel (refereegranskat)abstract
- Mycosis fungoides is a disease with manifestation of the skin that has traditionally been treated with electron therapy. In this paper, we present a method of treating the entire skin with megavoltage photons using helical tomotherapy (HT), verified through a phantom study and clinical dosimetric data from our first two treated patients. A whole body phantom was fitted with a wetsuit as bolus, and scanned with computer tomography. We accounted for variations in daily setup using virtual bolus in the treatment plan optimization. Positioning robustness was tested by moving the phantom, and recalculating the dose at different positions. Patient treatments were verified with in vivo film dosimetry and dose reconstruction from daily imaging. Reconstruction of the actual delivered dose to the patients showed similar target dose as the robustness test of the phantom shifted 10 mm in all directions, indicating an appropriate approximation of the anticipated setup variation. In vivo film measurements agreed well with the calculated dose confirming the choice of both virtual and physical bolus parameters. Despite the complexity of the treatment, HT was shown to be a robust and feasible technique for total skin irradiation. We believe that this technique can provide a viable option for Tomotherapy centers without electron beam capability.
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| 5. |
- Haraldsson, André, et al.
(författare)
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Implementing safe and robust Total Marrow Irradiation using Helical Tomotherapy – A practical guide
- 2019
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Ingår i: Physica Medica. - : Elsevier BV. - 1120-1797. ; 60, s. 162-167
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Tidskriftsartikel (refereegranskat)abstract
- Total Marrow Irradiation (TMI) with Helical Tomotherapy is a radiotherapy treatment technique that targets bone marrow and sanctuary sites prior to stem cell or bone marrow transplantation (SCT/BMT). TMI is a complex procedure that involves several critical steps that all need to be carefully addressed for a successful implementation, such as dose homogeneity in field junctions, choice of target margins, integrity of treatment and back-up planning. In this work we present our solution for a robust and reproducible workflow throughout the treatment chain and data for twenty-three patients treated to date. Material & Methods: Patients were immobilized in a whole body vacuum cushion and thermoplastic mask. CT-scanning and treatment were performed in two parts with field matching at the upper thigh. Target consisted of marrow containing bone and sanctuary sites. Lungs, kidneys, bowel, heart and liver were defined as organs at risk (OAR). A fast surface scanning system was used to position parts of the body not covered by the imaging system (MVCT) as well as to reduce treatment time. Results: All patients completed their treatment and could proceed with SCT/BMT. Doses to OARs were significantly reduced and target dose homogeneity was improved compared to TBI. Robustness tests performed on field matching and patient positioning support that the field junction technique is adequate. Replacing MVCT with optical surface scanning reduced the treatment time by 25 min per fraction. Conclusion: The methodology presented here has shown to provide a safe, robust and reproducible treatment for Total Marrow Irradiation using Tomotherapy.
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| 6. |
- Haraldsson, André, et al.
(författare)
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Organ sparing total marrow irradiation compared to total body irradiation prior to allogeneic stem cell transplantation
- 2021
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 107:4, s. 393-407
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Total body irradiation (TBI) is commonly used prior to hematopoietic stem cell transplantation (HSCT) in myeloablative conditioning regimens. However, TBI may be replaced by total marrow irradiation (TMI) at centres with access to Helical TomoTherapy, a modality that has the advantage of delivering intensity-modulated radiotherapy to long targets such as the entire bone marrow compartment. Toxicity after organ sparing TMI prior to HSCT has not previously been reported compared to TBI or with regard to engraftment data. Methods: We conducted a prospective observational study on 37 patients that received organ sparing TMI prior to HSCT and compared this cohort to retrospective data on 33 patients that received TBI prior to HSCT. Results: The 1-year graft-versus-host disease-free, relapse-free survival (GRFS) was 67.5% for all patients treated with TMI and 80.5% for patients with matched unrelated donor and treated with TMI, which was a significant difference from historical data on TBI patients with a hazard ratio of 0.45 (P =.03) and 0.24 (P <.01). Engraftment with a platelet count over 20 [K/µL] and 50 [K/µL] was significantly shorter for the TMI group, and neutrophil recovery was satisfactory in both treatment cohorts. There was generally a low occurrence of other treatment-related toxicities. Conclusions: Despite small cohorts, some significant differences were found; TMI as part of the myeloablative conditioning yields a high 1-year GRFS, fast and robust engraftment, and low occurrence of acute toxicity.
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| 7. |
- Haraldsson, André, et al.
(författare)
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Surface-guided tomotherapy improves positioning and reduces treatment time : A retrospective analysis of 16 835 treatment fractions
- 2020
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Ingår i: Journal of Applied Clinical Medical Physics. - : Wiley. - 1526-9914. ; 21:8, s. 139-148
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In this study, we have quantified the setup deviation and time gain when using fast surface scanning for daily setup/positioning with weekly megavoltage computed tomography (MVCT) and compared it to daily MVCT. Methods: A total of 16 835 treatment fractions were analyzed, treated, and positioned using our TomoTherapy HD (Accuray Inc., Madison, USA) installed with a Sentinel optical surface scanning system (C-RAD Positioning AB, Uppsala, Sweden). Patients were positioned using in-room lasers, surface scanning and MVCT for the first three fractions. For the remaining fractions, in-room laser was used for setup followed by daily surface scanning with MVCT once weekly. The three-dimensional (3D) setup correction for surface scanning was evaluated from the registration between MVCT and the planning CT. The setup correction vector for the in-room lasers was assessed from the surface scanning and the MVCT to planning CT registration. The imaging time was evaluated as the time from imaging start to beam-on. Results: We analyzed 894 TomoTherapy treatment plans from 2012 to 2018. Of all the treatment fractions performed with surface scanning, 90 % of the residual errors were within 2.3 mm for CNS (N = 284), 2.9 mm for H&N (N = 254), 8.7 mm for thorax (N = 144) and 10.9 for abdomen (N = 134) patients. The difference in residual error between surface scanning and positioning with in-room lasers was significant (P < 0.005) for all sites. The imaging time was assessed as total imaging time per treatment plan, modality, and treatment site and found that surface scanning significantly reduced patient on-couch time compared to MVCT for all treatment sites (P < 0.005). Conclusions: The results indicate that daily surface scanning with weekly MVCT can be used with the current target margins for H&N, CNS, and thorax, with reduced imaging time.
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| 8. |
- Lindberg, Sara, et al.
(författare)
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Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors
- 2023
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Ingår i: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS. - 0360-3016 .- 1879-355X. ; 117:5, s. 1222-1231
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. Methods and Materials: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses.Results: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopul-monary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively.Conclusions: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Simi-lar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.
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| 9. |
- Movahed, Allen, et al.
(författare)
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International multi-institutional bench mark study on dosimetric and volumetric modulation using helical tomotherapy treatment planning for malignant pleural mesothelioma tumors
- 2015
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Ingår i: World Congress on Medical Physics and Biomedical Engineering, 2015. - Cham : Springer International Publishing. - 9783319193861 - 9783319193878 ; 51, s. 381-383
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Konferensbidrag (refereegranskat)abstract
- Determining the most desirable and achievable target dose and organ at risk (OAR) sparing using helical TomoTherapy planning system for mesothelioma treatment plans. A range of planning parameters was used. The reviewers’ ranking assessment (Ranking in Groups: 1 = Good, 2 = Above Average, 3 = Average, 4 = Poor).The overall rankings revealed that a plan with a balanced tradeoff among all planning objectives was preferred by most participants and reviewers. Other studies found low doses to the contralateral lung to be limiting. This was not the case in our study, with TomoTherapy we found the dose to contra lateral lung to be as low as V5Gy=0.87%. A pitch value of 0.287 or 0.43 would provide better result. A delivered modulation factor of above 1.7 and a treatment time around 500 sec will be beneficial consideration in planning.
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| 10. |
- Änghede Haraldsson, André
(författare)
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Helical tomotherapy for total marrow and total skin irradiation : Optimisation, verification, and clinical results
- 2021. - 1
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In modern cancer therapy, radiotherapy (RT) is a vital part of most treatments. Most RT treatments in Sweden are performed using intensity-modulated radiotherapy (IMRT) with fixed or dynamic arc delivery. The dose gradients outside the target are steep, the margins are small, and the treatment delivery is complicated. Complicated treatments increase the requirement for control of the uncertainties in planning and delivery. This requires robust treatments and mitigation of the various uncertainties. In addition, robust planning and rigorous quality assurance (QA) of the patient treatments that takes account of all types of uncertainties are essential. A TomoTherapy device (Accuray Inc., Madison, WI, USA) is an RT device with a linear accelerator mounted on a slip-ring construction, giving it the ability to irradiate while continuously rotating around the patient, very similar to a CT scanner but with megavoltage instead of X-ray energy generation. Since helical tomotherapy can entail long and complicated irradiations, new treatment types targeting RT to large parts of the body have emerged. These new techniques are challenging regarding the optimization and verification of the planning and treatment process. Recurring blood cancers (leukaemias) can be treated with RT and chemotherapy before stem cell transplantation. Traditionally, the patient is irradiated with whole-body irradiation using a conventional linac at a large distance. The treatment can be performed with helical tomotherapy to avoid organs at risks to a greater extent. Another emerging treatment with helical tomotherapy is irradiation of whole-body neoplastic skin lesions, such as mycosis fungoides. These patients were traditionally treated with electron irradiation in different positions, subsequently complemented with x-ray fields in ‘hard-to-reach’ sites. Delivering this treatment with photons is complex but opens the possibility for integrated boost treatments of lesions and simultaneously avoiding OAR and previously treated areas.The clinical follow-up illustrated the potential and usefulness of helical tomotherapy targeting the bone marrow, with more patients surviving without severe complications after one year, than with the previous technique. Further, we showed the possibility to implement irradiation of the entire skin with helical tomotherapy. Overall, we demonstrated the usefulness of helical tomotherapy, and solutions to overcome challenges in implementing large-target techniques.
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