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- Fransson, P., et al.
(författare)
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Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, 3 trial
- 2021
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Ingår i: Lancet Oncology. - : Elsevier BV. - 1470-2045. ; 22:2, s. 235-245
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Tidskriftsartikel (refereegranskat)abstract
- Background The HYPO-RT-PC trial compared conventionally fractionated radiotherapy with ultra-hypofractionated radiotherapy in patients with localised prostate cancer. Ultra-hypofractionation was non-inferior to conventional fractionation regarding 5-year failure-free survival and toxicity. We aimed to assess whether patient-reported quality of life (QOL) differs between conventional fractionation and ultra-hypofractionation up to 6 years after treatment in the HYPO-RT-PC trial. Methods HYPO-RT-PC is a multicentre, open-label, randomised, controlled, non-inferiority, phase 3 trial done in 12 centres (seven university hospitals and five county hospitals) in Sweden and Denmark. Inclusion criteria were histologically verified intermediate-to-high-risk prostate cancer (defined as T1c-T3a with one or two of the following risk factors: stage T3a; Gleason score >= 7; and prostate-specific antigen 10-20 ng/mL with no evidence of lymph node involvement or distant metastases), age up to 75 years, and WHO performance status 0-2. Participants were randomly assigned (1:1) to conventional fractionation (78.0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultra-hypofractionation (42.7 Gy in seven fractions, 3 days per week for 2.5 weeks) via a minimisation algorithm with stratification by trial centre, T-stage, Gleason score, and prostate-specific antigen. QOL was measured using the validated Prostate Cancer Symptom Scale (PCSS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline, the end of radiotherapy, months 3, 6, 12, and 24 after radiotherapy, every other year thereafter up to 10 years, and at 15 years. The primary endpoint (failure-free survival) has been reported elsewhere. Here we report QOL, a secondary endpoint analysed in the perprotocol population, up to 6 years after radiotherapy. The HYPO-RT-PC trial is registered with the ISRCTN registry, ISRCTN45905321. Findings Between July 1, 2005, and Nov 4, 2015, 1200 patients were enrolled and 1180 were randomly assigned (conventional fractionation n=591, ultra-hypofractionation n=589); 1165 patients (conventional fractionation n=582, ultra-hypofractionation n=583) were included in this QOL analysis. 158 (71%) of 223 patients in the conventional fractionation group and 146 (66%) of 220 in the ultra-hypofractionation group completed questionnaires at 6 years. The median follow-up was 48 months (IQR 25-72). In seven of ten bowel symptoms or problems the proportion of patients with clinically relevant deteriorations at the end of radiotherapy was significantly higher in the ultra-hypofractionation group than in the conventional fractionation group (stool frequency [p<0.0001], rush to toilet [p=0.0013], flatulence [p=0.0013], bowel cramp [p<0.0001], mucus [p=0.0014], blood in stool [p<0.0001], and limitation in daily activity [p=0.0014]). There were no statistically significant differences in the proportions of patients with clinically relevant acute urinary symptoms or problems (total 14 items) and sexual functioning between the two treatment groups at end of radiotherapy. Thereafter, there were no clinically relevant differences in urinary, bowel, or sexual functioning between the groups. At the 6-year followup there was no difference in the incidence of clinically relevant deterioration between the groups for overall urinary bother (43 [33%] of 132 for conventional fractionation vs 33 [28%] of 120 for ultra-hypofractionation; mean difference 5.1% [95% CI -4.4 to 14.6]; p=0.38), overall bowel bother (43 [33%] of 129 vs 34 [28%] of 123; 5.7% [-3.8 to 15.2]; p=0.33), overall sexual bother (75 [60%] of 126 vs 59 [50%] of 117; 9.1% [-1.4 to 19.6]; p=0.15), or global health/QOL (56 [42%] of 134 vs 46 [37%] of 125; 5.0% [-5.0 to 15.0]; p=0.41). Interpretation Although acute toxicity was higher for ultra-hypofractionation than conventional fractionation, this long-term patient-reported QOL analysis shows that ultra-hypofractionation was as well tolerated as conventional fractionation up to 6 years after completion of treatment. These findings support the use of ultra-hypofractionation radiotherapy for intermediate-to-high-risk prostate cancer.
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- Beckmann, K., et al.
(författare)
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Radical radiotherapy for prostate cancer: patterns of care in Sweden 1998-2016
- 2020
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 59:5, s. 549-557
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Radiotherapy is an established treatment option for prostate cancer (PCa), both as primary treatment and secondary treatment after radical prostatectomy (RP). Since 1998, detailed data on radiotherapy delivered to Swedish men with PCa (e.g. treatment modalities, absorbed doses, fractionation) have been collated within PCa data Base Sweden (PCBaSe). This study reports patterns of radical radiotherapy for PCa in Sweden over the past two decades. Materials and methods: All men with non-metastatic PCa (1998-2016) who received external beam radiotherapy (EBRT) or high or low dose-rate brachytherapy (HDR-BT/LDR-BT) were identified in PCBaSe. Analyses included: trends in radiation techniques, fractionation patterns and total doses over time; PCa-specific survival comparing treatment in 2007-2017 with 1998-2006; and regional variation in type of primary radiotherapy. Results: About 20,876 men underwent primary radiotherapy. The main treatment modalities include conventionally fractionated (2.0 Gy/fraction) EBRT (51%), EBRT with HDR-BT boost (27%) and hypofractionated (>2.4 Gy/fraction) EBRT (11%). EBRT with photon or proton boost and HDR-BT and LDR-BT monotherapies were each used minimally. Use of dose-escalated EBRT (>74 Gy) and moderate hypofractionation increased over time, while use of HDR-BT declined. Considerable regional variation in treatment modalities was apparent. Risk of PCa death following primary radiotherapy had declined for intermediate-risk (HR: 0.60; 95%CI 0.47-0.87) and high-risk PCa (HR: 0.72; 95%CI 0.61-0.86). Discussion: Increased use of dose escalation and hypofractionated EBRT has occurred in Sweden over the past two decades, reflecting current evidence and practice guidelines. Disease-specific outcomes have also improved. Data collected in PCBaSe provide an excellent resource for further research into RT use in PCa management.
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- Fernández de Salas, Pablo, et al.
(författare)
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Dark matter local density determination : recent observations and future prospects
- 2021
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Ingår i: Reports on progress in physics (Print). - : IOP Publishing. - 0034-4885 .- 1361-6633. ; 84:10
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Forskningsöversikt (refereegranskat)abstract
- This report summarises progress made in estimating the local density of dark matter (ρDM,⊙), a quantity that is especially important for dark matter direct detection experiments. We outline and compare the most common methods to estimate ρDM,⊙ and the results from recent studies, including those that have benefited from the observations of the ESA/Gaia satellite. The result of most local analyses coincide within a range of , while a slightly lower range of is preferred by most global studies. In light of recent discoveries, we discuss the importance of going beyond the approximations of what we define as the ideal Galaxy (a steady-state Galaxy with axisymmetric shape and a mirror symmetry across the mid-plane) in order to improve the precision of ρDM,⊙ measurements. In particular, we review the growing evidence for local disequilibrium and broken symmetries in the present configuration of the Milky Way, as well as uncertainties associated with the galactic distribution of baryons. Finally, we comment on new ideas that have been proposed to further constrain the value of ρDM,⊙, most of which would benefit from Gaia's final data release.
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- Josefsson, Andreas, 1979, et al.
(författare)
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Effect of docetaxel added to bicalutamide in Hormone-Naive non-metastatic prostate cancer with rising PSA, a randomized clinical trial (SPCG-14)
- 2023
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Ingår i: Acta Oncologica. - 0284-186X. ; 62:4, s. 372-380
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundHistorically, endocrine therapy was used in a range of scenarios in patients with rising PSA, both as a treatment for locally advanced non-metastatic prostate cancer and PSA recurrence following curative intended therapy. In the present study the objective was to investigate if chemotherapy added to endocrine therapy could improve progression-free survival (PFS).Materials and MethodsPatients with hormone-naive, non-metastatic prostate cancer and rising prostate-specific antigen (PSA), enrolled from Sweden, Denmark, the Netherlands, and Finland, were randomized to long-term bicalutamide (150 mg daily) or plus docetaxel (75 mg/m(2), q3w, 8-10 cycles) without prednisone, after stratification for the site, prior local therapy or not, and PSA doubling time. The primary endpoint was 5-year PFS analyzed with a stratified Cox proportional hazards regression model on intention to treat basis.ResultsBetween 2009 and 2018, a total of 348 patients were randomized; 315 patients had PSA relapse after radical treatment, 33 patients had no prior local therapy. Median follow-up was 4.9 years (IQR 4.0-5.1). Adding docetaxel improved PFS (HR 0.68, 95% CI 0.50-0.93; p = 0.015). Docetaxel showed an advantage for patients with PSA relapse after prior local therapy (HR 0.67, 95% CI 0.49-0.94; p = 0.019). One event of neutropenic infection/fever occurred in 27% of the patients receiving docetaxel. Limitations were slow recruitment, lack of enrolling patients without radical local treatment, and too short follow-up for evaluation of overall survival in patients with PSA relapse.ConclusionDocetaxel improved PFS in patients starting bicalutamide due to PSA relapse after local therapy or localized disease without local therapy. Confirmatory studies of the efficacy of docetaxel in the setting of PSA-only relapse in addition to endocrine therapies may be justified if longer follow-up will show increased metastatic-free survival.
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| 8. |
- Thysell, Elin, et al.
(författare)
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Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C
- 2022
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 16:4, s. 846-859
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Tidskriftsartikel (refereegranskat)abstract
- To improve treatment of metastatic prostate cancer, the biology of metastases needs to be understood. We recently described three subtypes of prostate cancer bone metastases (MetA-C), based on differential gene expression. The aim of this study was to verify the clinical relevance of these subtypes and to explore their biology and relations to genetic drivers. Freshly-frozen metastasis samples were obtained as hormone-naive (n = 17), short-term castrated (n = 21), or castration-resistant (n = 65) from a total of 67 patients. Previously published sequencing data from 573 metastasis samples were also analyzed. Through transcriptome profiling and sample classification based on a set of predefined MetA-C-differentiating genes, we found that most metastases were heterogeneous for the MetA-C subtypes. Overall, MetA was the most common subtype, while MetB was significantly enriched in castration-resistant samples and in liver metastases, and consistently associated with poor prognosis. By gene set enrichment analysis, the phenotype of MetA was described by high androgen response, protein secretion and adipogenesis, MetB by high cell cycle activity and DNA repair, and MetC by epithelial-to-mesenchymal transition and inflammation. The MetB subtype demonstrated single nucleotide variants of RB transcriptional corepressor 1 (RB1) and loss of 21 genes at chromosome 13, including RB1, but provided independent prognostic value to those genetic aberrations. In conclusion, a distinct set of gene transcripts can be used to classify prostate cancer metastases into the subtypes MetA-C. The MetA-C subtypes show diverse biology, organ tropism, and prognosis. The MetA-C classification may be used independently, or in combination with genetic markers, primarily to identify MetB patients in need of complementary therapy to conventional androgen receptor-targeting treatments.
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| 9. |
- Widmark, Albin, 1991-, et al.
(författare)
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ADAR1-and ADAR2-mediated regulation of maturation and targeting of miR-376b to modulate GABA neurotransmitter catabolism
- 2022
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Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 298:3
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Tidskriftsartikel (refereegranskat)abstract
- miRNAs are short noncoding RNA molecules that regulate gene expression by inhibiting translation or inducing degradation of target mRNAs. miRNAs are often expressed as polycistronic transcripts, so-called miRNA clusters, containing several miRNA precursors. The largest mammalian miRNA cluster, the miR-379-410 cluster, is expressed primarily during embryonic development and in the adult brain; however, downstream regulation of this cluster is not well understood. Here, we investigated adenosine deamination to inosine (RNA editing) in the miR-379-410 cluster by adenosine deaminase acting on RNA (ADAR) enzymes as a possible mechanism modulating the expression and activity of these miRNAs in a brain-specific manner. We show that the levels of editing in the majority of mature miRNAs are lower than the editing levels of the corresponding site in primary miRNA precursors. However, for one miRNA, miR-376b-3p, editing was significantly higher in the mature form than in the primary precursor. We found miR-376b-3p maturation is negatively regulated by ADAR2 in an editing activity-independent manner, whereas ADAR1-mediated and ADAR2-mediated editing were observed to be competitive. In addition, the edited miR-376b-3p targets a different set of mRNAs than unedited miR-376b-3p, including 4-aminobutyrate aminotransferase, encoding the enzyme responsible for the catabolism of the neurotransmitter gamma aminobutyric acid (GABA). Expression of edited miR-376b-3p led to increased intracellular GABA levels as well as increased cell surface presentation of GABA type A receptors. Our results indicate that both editing and editing-independent effects modulate the expression of miR-376b-3p, with the potential to regulate GABAergic signaling in the brain.
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| 10. |
- Widmark, A., et al.
(författare)
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Weighing the Galactic disk in sub-regions of the solar neighbourhood using Gaia DR2
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 646
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We infer the gravitational potential of the Galactic disk by analysing the phase-space densities of 120 stellar samples in 40 spatially separate sub-regions of the solar neighbourhood, using Gaia's second data release (DR2), in order to quantify spatially dependent systematic effects that bias this type of measurement.Methods. The gravitational potential was inferred under the assumption of a steady state in the framework of a Bayesian hierarchical model. We performed a joint fit of our stellar tracers' three-dimensional velocity distribution, while fully accounting for the astrometric uncertainties of all stars as well as dust extinction, and we also masked angular areas of known open clusters. The inferred gravitational potential is compared, post-inference, to a model for the baryonic matter and halo dark matter components.Results. We see an unexpected but clear trend for all 40 spatially separate sub-regions: Compared to the potential derived from the baryonic model, the inferred gravitational potential is significantly steeper close to the Galactic mid-plane (less than or similar to 60 pc), but flattens such that the two agree well at greater distances (similar to 400 pc). The inferred potential implies a total matter density distribution that is highly concentrated to the Galactic mid-plane and decays quickly with height. We see a dependence on the Galactic radius that is consistent with a disk scale length of a few kiloparsecs. Apart from this, there are discrepancies between stellar samples, implying spatially dependent systematic effects which are, at least in part, explained by substructures in the phase-space distributions.Conclusions. In terms of the inferred matter density distribution, the very low matter density that is inferred at greater heights (greater than or similar to 300 pc) is inconsistent with the observed scale height and matter distribution of the stellar disk, which cannot be explained by a misunderstood density of cold gas or other hidden mass. Our interpretation is that these results must be biased by a time-varying phase-space structure, possibly a breathing mode, that is large enough to affect all stellar samples in the same manner.
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