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- Kersting, J., et al.
(författare)
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Effect of Radiotherapy Dose on Outcome in Nonmetastatic Sarcoma
- 2023
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Ingår i: Advances in Radiation Oncology. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS.Methods and Materials: The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S & RT group) and/or RT (RT group). EFS and OS were analyzed with uni-and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response.Results: S & RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose =53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose > 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S & RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 (P = .42) and in the RT group 52.9%, 62.5%, and 70.3% (P = .63), respectively. Multivariable Cox regression revealed age > 15 years (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S & RT group (sex, P = .96; histologic response, P = .07; tumor volume, P = .50; dose, P = .10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P = .15; age, P = .08; sex, P = .40).Conclusions: In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias.
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| 2. |
- Tulstrup, M., et al.
(författare)
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Effects of germ line DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia
- 2020
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 136:10, s. 1161-1168
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Tidskriftsartikel (refereegranskat)abstract
- Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 x 10(-8)) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 x 10(-9)) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.
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| 7. |
- Nielsen, S. N., et al.
(författare)
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No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study
- 2021
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 88, s. 271-279
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Tidskriftsartikel (refereegranskat)abstract
- Purpose 6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. Methods TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m(2) for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 - 3.0 x 10(9)/L. Results Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 - 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 - 890.3] versus 492.7 [IQR 382.1 - 634.6] fmol/mu g, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 - 1.06, p = 0.67). Conclusion TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008.
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| 9. |
- Kymn, Christopher J., et al.
(författare)
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Computing with Residue Numbers in High-Dimensional Representation
- 2023
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Annan publikation (populärvet., debatt m.m.)abstract
- We introduce Residue Hyperdimensional Computing, a computing framework that unifies residue number systems with an algebra defined over random, high-dimensional vectors. We show how residue numbers can be represented as high-dimensional vectors in a manner that allows algebraic operations to be performed with component-wise, parallelizable operations on the vector elements. The resulting framework, when combined with an efficient method for factorizing high-dimensional vectors, can represent and operate on numerical values over a large dynamic range using vastly fewer resources than previous methods, and it exhibits impressive robustness to noise. We demonstrate the potential for this framework to solve computationally difficult problems in visual perception and combinatorial optimization, showing improvement over baseline methods. More broadly, the framework provides a possible account for the computational operations of grid cells in the brain, and it suggests new machine learning architectures for representing and manipulating numerical data.
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| 10. |
- Layek, R K, et al.
(författare)
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Tailoring of the physical and mechanical properties of biocompatible graphene oxide/gelatin composite nanolaminates via altering the crystal structure and morphology
- 2021
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Ingår i: Materials Advances. - : Royal Society of Chemistry (RSC). - 2633-5409.
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Tidskriftsartikel (refereegranskat)abstract
- Despite substantial progress being made relating to 2D-nanofiller-based composite nanolaminates, the fabrication of composite nanolaminates with enhanced ductility and toughness is still challenging. In this study, layered structure graphene oxide (GO)/gelatin powder (GP) composites nanolaminates with enhanced ductility and toughness have been achieved by a simple vacuum filtration of aqueous dispersion of GO/GP composite solution containing 5 wt% of GO. The composite film containing 5 wt% GO shows outstanding improvement of 200% in the stress at break value, with simultaneous enhancement of 52% of the strain at break value compared to GP film. A significant improvement in toughness from 2.2 MJ m(-3) to 9.5 MJ m(-3) is observed in the composite film containing 5 wt% GO. These significant enhancements of the mechanical properties of the composite film are obtained via the formation of an intercalated nanolaminate structure, H-bonding interactions, and the tailoring of the crystal structure of GP in the composite film, as proved via field-emission scanning electron microscopy, Fourier-transform infrared spectroscopy, and wide-angle X-ray diffraction studies. The growing of fibroblast cells on the composite films signifies that they are not cytotoxic. These GO/GP composites with significant mechanical properties and biocompatibility are very promising for various biomedical applications.
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| 11. |
- Murumagi, A, et al.
(författare)
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Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma
- 2023
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 128:4, s. 678-690
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Tidskriftsartikel (refereegranskat)abstract
- Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.
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| 12. |
- Varpula, Reetta, et al.
(författare)
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Early suppression policies protected pregnant women from COVID-19 in 2020 : A population-based surveillance from the Nordic countries
- 2024
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - 0001-6349. ; 103:6, s. 1063-1072
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The Coronavirus 2019 Disease (COVID-19) pandemic reached the Nordic countries in March 2020. Public health interventions to limit viral transmission varied across different countries both in timing and in magnitude. Interventions indicated by an Oxford Stringency Index ≥50 were implemented early (March 13–17, 2020) in Denmark, Finland, Norway and Iceland, and on March 26, 2020 in Sweden. The aim of the current study was to assess the incidence of COVID-19-related admissions of pregnant women in the Nordic countries in relation to the different national public health strategies during the first year of the pandemic. Material and methods: This is a meta-analysis of population-based cohort studies in the five Nordic countries with national or regional surveillance in the Nordic Obstetric Surveillance System (NOSS) collaboration: national data from Denmark, Finland, Iceland and Norway, and regional data covering 31% of births in Sweden. The source population consisted of women giving birth in the included areas March 1–December 31, 2020. Pregnant women with a positive SARS-CoV-2 PCR test ≤14 days before hospital admission were included, and admissions were stratified as either COVID-19-related or non-COVID (other obstetric healthcare). Information about public health policies was retrieved retrospectively. Results: In total, 392 382 maternities were considered. Of these, 600 women were diagnosed with SARS-CoV-2 infection and 137 (22.8%) were admitted for COVID-19 symptoms. The pooled incidence of COVID-19 admissions per 1000 maternities was 0.5 (95% confidence interval [CI] 0.2 to 1.2, I2 = 77.6, tau2 = 0.68, P = 0.0), ranging from no admissions in Iceland to 1.9 admissions in the Swedish regions. Interventions to restrict viral transmission were less stringent in Sweden than in the other Nordic countries. Conclusions: There was a clear variation in pregnant women's risk of COVID-19 admission across countries with similar healthcare systems but different public health interventions to limit viral transmission. The meta-analysis indicates that early suppression policies protected pregnant women from severe COVID-19 disease prior to the availability of individual protection with vaccines.
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