| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
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| 3. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 4. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 5. |
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| 6. |
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| 7. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 8. |
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| 10. |
- Ellingson, Benjamin M., et al.
(författare)
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Post-chemoradiation volumetric response predicts survival in newly diagnosed glioblastoma treated with radiation, temozolomide, and bevacizumab or placebo
- 2018
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 20:11, s. 1525-1535
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Tidskriftsartikel (refereegranskat)abstract
- Background. In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV). Methods. Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had > 4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses. Results. A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline. Conclusions. The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.
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| 11. |
- Ellingson, Benjamin M., et al.
(författare)
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Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma
- 2018
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Ingår i: Neuro-Oncology. - : OXFORD UNIV PRESS INC. - 1522-8517 .- 1523-5866. ; 20:9, s. 1240-1250
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Tidskriftsartikel (refereegranskat)abstract
- Background. In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS). Methods. Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O-6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS. Results. A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status. Conclusion. Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.
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| 12. |
- Hagiwara, Akifumi, et al.
(författare)
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Incidence, molecular characteristics, and imaging features of "clinically-defined pseudoprogression" in newly diagnosed glioblastoma treated with chemoradiation
- 2022
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Ingår i: Journal of Neuro-Oncology. - : Springer. - 0167-594X .- 1573-7373. ; 159, s. 509-518
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Pseudoprogression (PsP) remains an elusive and clinically important, yet ill-defined, phenomena that, generally, involves a period of early radiographic progression (enhancement) followed by a period of radiographic stability or regression. In the current study, we utilized data from the control arm of a phase III clinical trial in newly-diagnosed glioblastoma to explore imaging characteristics of “clinically-defined PsP”, or early radiographic progression (PFS < 6 months from chemoradiation) followed by a long post-progression residual overall survival (ROS > 12 months).Methods: One hundred sixty-nine patients with newly-diagnosed GBM from the control arm of the AVAglio trial (NCT00943826) who presented with early radiographic progressive disease (PD) (< 6 months) were included. Clinical characteristics, topographical patterns, and radiomic features were compared between newly-diagnosed GBM exhibiting early PD and early death (< 12-month ROS, “true PD”) with those exhibiting early PD and a long residual survival (> 12-month ROS, “clinically-defined PsP”).Results: “Clinically-defined PsP” occurred to 38.5% of patients with early PD, and was more associated with MGMT methylation (P = 0.02), younger age (P = 0.003), better neurological performance (P = 0.01), and lower contrast-enhancing tumor volume (P = 0.002) at baseline. GBM showing “true PD” occurred more frequently in the right internal capsule, thalamus, lentiform nucleus, and temporal lobe than those with “clinical PsP”. Radiomic analysis predicted “clinical PsP” with > 70% accuracy on the validation dataset.Conclusion: Patients with early PD that eventually exhibit “clinically-defined PsP” have distinct clinical, molecular, and MRI characteristics. This information may be useful for treating clinicians to better understand the potential risks and outcome in patients exhibiting early radiographic changes following chemoradiation.
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| 13. |
- Nowosielski, Martha, et al.
(författare)
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Radiologic progression of glioblastoma under therapy : an exploratory analysis of AVAglio
- 2018
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 20:4, s. 557-566
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Tidskriftsartikel (refereegranskat)abstract
- In this exploratory analysis of AVAglio, a randomized phase III clinical study that investigated the addition of bevacizumab (Bev) to radiotherapy/temozolomide in newly diagnosed glioblastoma, we aim to radiologically characterize glioblastoma on therapy until progression and investigate whether the type of radiologic progression differs between treatment arms and is related to survival and molecular data. Five progression types (PTs) were categorized using an adapted algorithm according to MRI contrast enhancement behavior in T1- and T2-weighted images in 621 patients (Bev, n = 299; placebo, n = 322). Frequencies of PTs (designated as classic T1, cT1 relapse, T2 diffuse, T2 circumscribed, and primary nonresponder), time to progression (PFS), and overall survival (OS) were assessed within each treatment arm and compared with molecular subtypes and O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. PT frequencies differed between the Bev and placebo arms, except for "T2 diffuse" (12.4% and 7.1%, respectively). PTs showed differences in PFS and OS; with "T2 diffuse" being associated with longest survival. Complete disappearance of contrast enhancement during treatment ("cT1 relapse") showed longer survival than only partial contrast enhancement decrease ("classic T1"). "T2 diffuse" was more commonly MGMT hypermethylated. Only weak correlations to molecular subtypes from primary tissue were detected. Progression of glioblastoma under therapy can be characterized radiologically. These radiologic phenotypes are influenced by treatment and develop differently over time with differential outcomes. Complete resolution of contrast enhancement during treatment is a favorable factor for outcome.
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| 14. |
- Reijneveld, Jaap C, et al.
(författare)
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Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033) : a randomised, open-label, phase 3 intergroup study.
- 2016
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 17:11, s. 1533-1542
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy.METHODS: We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0-1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m(2) daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819.FINDINGS: Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI -4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up.INTERPRETATION: The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma.FUNDING: Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.
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| 15. |
- Schweinsberg, Martin, et al.
(författare)
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Same data, different conclusions : Radical dispersion in empirical results when independent analysts operationalize and test the same hypothesis
- 2021
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Ingår i: Organizational Behavior and Human Decision Processes. - : Elsevier BV. - 0749-5978 .- 1095-9920. ; 165, s. 228-249
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Tidskriftsartikel (refereegranskat)abstract
- In this crowdsourced initiative, independent analysts used the same dataset to test two hypotheses regarding the effects of scientists' gender and professional status on verbosity during group meetings. Not only the analytic approach but also the operationalizations of key variables were left unconstrained and up to individual analysts. For instance, analysts could choose to operationalize status as job title, institutional ranking, citation counts, or some combination. To maximize transparency regarding the process by which analytic choices are made, the analysts used a platform we developed called DataExplained to justify both preferred and rejected analytic paths in real time. Analyses lacking sufficient detail, reproducible code, or with statistical errors were excluded, resulting in 29 analyses in the final sample. Researchers reported radically different analyses and dispersed empirical outcomes, in a number of cases obtaining significant effects in opposite directions for the same research question. A Boba multiverse analysis demonstrates that decisions about how to operationalize variables explain variability in outcomes above and beyond statistical choices (e.g., covariates). Subjective researcher decisions play a critical role in driving the reported empirical results, underscoring the need for open data, systematic robustness checks, and transparency regarding both analytic paths taken and not taken. Implications for orga-nizations and leaders, whose decision making relies in part on scientific findings, consulting reports, and internal analyses by data scientists, are discussed.
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| 16. |
- Stupp, Roger, et al.
(författare)
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Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma
- 2005
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Ingår i: The New England journal of medicine. - 1533-4406. ; 352:10, s. 987-996
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety.METHODS: Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival.RESULTS: A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.CONCLUSIONS: The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.
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| 17. |
- Taphoorn, Martin J. B., et al.
(författare)
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Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma
- 2015
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 33:19, s. 2166-U205
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Tidskriftsartikel (refereegranskat)abstract
- Purpose As glioblastoma progresses, patients experience a decline in health-related quality of life (HRQoL). Delaying this decline is an important treatment goal. In newly diagnosed glioblastoma, progression-free survival was prolonged when bevacizumab was added to radiotherapy plus temozolomide (RT/TMZ) versus placebo plus RT/TMZ (phase III AVAglio study; hazard ratio, 0.64; 95% CI, 0.55 to 0.74; P < .001). To ensure that addition of bevacizumab to standard-of-care therapy was not associated with HRQoL detriment, HRQoL assessment was a secondary objective. Patients and Methods Patients completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BN20 at each tumor assessment (Appendix Table A1, online only). Raw scores were converted to a 100-point scale and mean changes from baseline scores were evaluated (stable: < 10-point change; clinically relevant deterioration/improvement: 10-point change). Deterioration-free survival was the time to deterioration/progression/death; time to deterioration was the time to deterioration/death. Results Most evaluable patients who had not progressed (> 74%) completed all HRQoL assessments for at least 1 year of treatment, and almost all completed at least one HRQoL assessment at baseline (98.3% and 97.6%, bevacizumab and placebo arms, respectively). Mean changes from baseline did not reach a clinically relevant difference between arms for most items. HRQoL declined at progression in both arms. The addition of bevacizumab to RT/TMZ resulted in statistically longer (P < .001) deterioration-free survival across all items. Time to deterioration was not statistically longer in the placebo plus RT/TMZ arm (v bevacizumab) for any HRQoL item. Conclusion The addition of bevacizumab to standard-of-care treatment for newly diagnosed glioblastoma had no impact on HRQoL during the progression-free period.
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