| 1. |
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| 2. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 3. |
- Tabassum, R, et al.
(författare)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 4. |
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| 5. |
- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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| 6. |
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| 7. |
- Bychkov, D, et al.
(författare)
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Deep learning identifies morphological features in breast cancer predictive of cancer ERBB2 status and trastuzumab treatment efficacy
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 4037-
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Tidskriftsartikel (refereegranskat)abstract
- The treatment of patients with ERBB2 (HER2)-positive breast cancer with anti-ERBB2 therapy is based on the detection of ERBB2 gene amplification or protein overexpression. Machine learning (ML) algorithms can predict the amplification of ERBB2 based on tumor morphological features, but it is not known whether ML-derived features can predict survival and efficacy of anti-ERBB2 treatment. In this study, we trained a deep learning model with digital images of hematoxylin–eosin (H&E)-stained formalin-fixed primary breast tumor tissue sections, weakly supervised by ERBB2 gene amplification status. The gene amplification was determined by chromogenic in situ hybridization (CISH). The training data comprised digitized tissue microarray (TMA) samples from 1,047 patients. The correlation between the deep learning–predicted ERBB2 status, which we call H&E-ERBB2 score, and distant disease-free survival (DDFS) was investigated on a fully independent test set, which included whole-slide tumor images from 712 patients with trastuzumab treatment status available. The area under the receiver operating characteristic curve (AUC) in predicting gene amplification in the test sets was 0.70 (95% CI, 0.63–0.77) on 354 TMA samples and 0.67 (95% CI, 0.62–0.71) on 712 whole-slide images. Among patients with ERBB2-positive cancer treated with trastuzumab, those with a higher than the median morphology–based H&E-ERBB2 score derived from machine learning had more favorable DDFS than those with a lower score (hazard ratio [HR] 0.37; 95% CI, 0.15–0.93; P = 0.034). A high H&E-ERBB2 score was associated with unfavorable survival in patients with ERBB2-negative cancer as determined by CISH. ERBB2-associated morphology correlated with the efficacy of adjuvant anti-ERBB2 treatment and can contribute to treatment-predictive information in breast cancer.
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| 9. |
- Glintborg, B., et al.
(författare)
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Biological treatment in ankylosing spondylitis in the Nordic countries during 2010-2016: a collaboration between five biological registries
- 2018
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 47:6, s. 465-474
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Large-scale observational cohorts may be used to study the effectiveness and rare side effects of biological disease-modifying anti-rheumatic drugs (bDMARDs) in ankylosing spondylitis (AS), but may be hampered by differences in baseline characteristics and disease activity across countries. We aimed to explore the research infrastructure in the five Nordic countries regarding bDMARD treatment in AS. Method: This observational cohort study was based on data from biological registries in Denmark (DANBIO), Sweden (SRQ/ARTIS), Finland (ROB-FIN), Norway (NOR-DMARD), and Iceland (ICEBIO). Data were collected for the years 2010-2016. Registry coverage, registry inventory (patient characteristics, disease activity measures), and national guidelines for bDMARD prescription in AS were described per country. Incident (first line) and prevalent bDMARD use per capita, country, and year were calculated. In AS patients who started first line bDMARDs during 2010-2016 (n = 4392), baseline characteristics and disease activity measures were retrieved. Results: Registry coverage of bDMARD-treated patients ranged from 60% to 95%. All registries included extensive prospectively collected data at patient level. Guidelines regarding choice of first line drug and prescription patterns varied across countries. During the period 2010-2016 prevalent bDMARD use increased (p < 0.001), whereas incident use tended to decrease (p for trend < 0.004), with large national variations (e.g. 2016 incidence: Iceland 10.7/100 000, Finland 1.7/100 000). Baseline characteristics were similar regarding C-reactive protein, but differed for other variables, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (range 3.5-6.3) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (2.7-3.8) (both p < 0.0001). Conclusion: Collaboration across the five Nordic biological registries regarding bDMARD use in AS is feasible but national differences in coverage, prescription patterns, and patient characteristics must be taken into account depending on the scientific question.
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| 10. |
- Stacchiotti, S., et al.
(författare)
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Epithelioid hemangioendothelioma, an ultra-rare cancer : a consensus paper from the community of experts
- 2021
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Ingår i: ESMO Open. - : Elsevier BV. - 2059-7029. ; 6:3
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Forskningsöversikt (refereegranskat)abstract
- Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.
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| 11. |
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| 12. |
- Andersson, Johanna, 1974, et al.
(författare)
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Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis
- 2006
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 130:6, s. 1573-81
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up. METHODS: Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing. RESULTS: KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST
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| 18. |
- Eriksson, Mikael, et al.
(författare)
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Benefit of pazopanib in advanced gastrointestinal stromal tumours: results from a phase II trial (SSG XXI, PAGIST)
- 2021
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Ingår i: ESMO Open. - : Elsevier BV. - 2059-7029. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. PATIENTS AND METHODS: Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. RESULTS: Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. CONCLUSION: Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.
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| 19. |
- Filippou, A, et al.
(författare)
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ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients’ stratification are caveats in the disease treatment. Anoctamin 1 (ANO1) gene is amplified in 30% of HNSCC cases. Evidence suggests involvement of ANO1 in proliferation, migration, and evasion of apoptosis; however, the exact mechanisms remain elusive. Aim of this study was to unravel the ANO1-dependent transcriptional programs and expand the existing knowledge of ANO1 contribution to oncogenesis and drug response in HNSCC. We cultured two HNSCC cell lines established from primary tumors harboring amplification and high expression of ANO1 in three-dimensional collagen. Differential expression analysis of ANO1-depleted HNSCC cells demonstrated downregulation of MCL1 and simultaneous upregulation of p27Kip1 expression. Suppressing ANO1 expression led to redistribution of p27Kip1 from the cytoplasm to the nucleus and associated with a cell cycle arrested phenotype. ANO1 silencing or pharmacological inhibition resulted in reduction of cell viability and ANO1 protein levels, as well as suppression of pro-survival BCL2 family proteins. Collectively, these data provide insights of ANO1 involvement in HNSCC carcinogenesis and support the rationale that ANO1 is an actionable drug target.
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| 28. |
- Joensuu, J, et al.
(författare)
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Maternal childbirth experience and pain relief methods: a retrospective 7-year cohort study of 85 488 parturients in Finland
- 2022
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 12:5, s. e061186-
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to analyse the relation between the used labour pain relief and childbirth experience measured by Visual Analogue Scale (VAS).DesignA retrospective cohort study.SettingChildbirth in five Helsinki University Hospital delivery units from 2012 to 2018.Primary outcome measureChildbirth experience measured by VAS and classified in three groups (negative VAS=1–5, positive VAS=6–8 and highly positive=9–10).ResultsThe use of epidural or non-epidural compared with non-medical pain relief methods decreased the likelihood to experience highly positive childbirth for primiparous (adjusted OR (aOR)EPIDURAL=0.64, 95% CI 0.57 to 0.73; and aORNON-EPIDURAL=0.76, 95% CI 0.66 to 0.87) and multiparous (aOREPIDURAL=0.90, 95% CI 0.84 to 0.97 and aORNON-EPIDURAL=0.80, 95% CI 0.74 to 0.86) parturients. The effects of epidural differed between primiparas and multiparas. In multiparas epidural was associated with decreased odds for experiencing negative childbirth compared with the non-medical group (aOR=0.70, 95% CI 0.57 to 0.87), while the effect of epidural was considered insignificant in primiparas (aOR=1.28, 95% CI 0.93 to 1.77).ConclusionWhile the use of medical—epidural and non-epidural—pain relief methods were not associated with odds for experiencing negative childbirth in primiparas, using epidural helps to avoid negative experience in multiparas. However, the odds for experiencing highly positive childbirth were decreased if the parturients used any medical pain relief for both primiparas and multiparas. Consequently, the effect of pain relief on the childbirth experience is strongly confounded by indication. Thus, the use of pain relief per se plays a limited role in the complex formation of the overall childbirth experience.
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| 29. |
- Joensuu, J, et al.
(författare)
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Maternal childbirth experience and time of delivery: a retrospective 7-year cohort study of 105 847 parturients in Finland
- 2021
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:6, s. e046433-
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Tidskriftsartikel (refereegranskat)abstract
- To explore how the time of delivery influences childbirth experience.DesignA retrospective cohort study.SettingChildbirth in the four Helsinki and Uusimaa Hospital District hospitals, Finland, from 2012 to 2018.Participants105 847 childbirths with a singleton live fetus.Main outcome measuresChildbirth experience measured by Visual Analogue Scale (VAS).ResultsThe major difference in average childbirth experience measured by VAS was between primiparas (8.03; 95% CI 8.01 to 8.04) and multiparas (8.47; 95% CI 8.45 to 8.48). Risk ratio (RR) of the low VAS (≤5) was 2.3 when primiparas were compared with multiparas. Differences in VAS between distinct periods were found in two stages: annual and time of day. The decrease in VAS from 2012–2016 to 2017–2018 in primiparas was from 7.97 (95% CI 7.95 to 7.99) to 7.80 (95% CI 7.77 to 7.83) and from 2014–2016 to 2017–2018 in multiparas from 8.60 (95% CI 8.58 to 8.61) to 8.49 (95% CI 8.47 to 8.52). Corresponding RRs of low VAS were 1.3 for primiparas and 1.2 for multiparas. Hourly differences in VAS were detected in primiparas between office hours 08:00–15:59 (7.97; 95% CI 7.94 to 7.99) and other times (night 00:00–07:59; 7.91; 95% CI 7.88 to 7.94; and evening 16:00–23:59; 7.90; 95% CI 7.87 to 7.92). In multiparas differences in VAS were detected between evening (8.52; 95% CI 8.50 to 8.54) and other periods (night; 8.56; 95% CI 8.54 to 9.58; and office hours; 8.57; 95% CI 8.55 to 8.59).ConclusionThe maternal childbirth experience depended on the time of delivery. Giving birth during the evening led to impaired childbirth experience in both primiparas and multiparas, compared with delivery at other times. The impact of labour induction on childbirth experience should be further examined. The reorganisation of delivery services and the reduction of birth preparations might affect annual VAS. VAS is a simple method of measuring the complex entity of childbirth experience, and our results indicate its ability to capture temporal variation.
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| 30. |
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| 31. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 32. |
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| 33. |
- Kellokumpu-Lehtinen, PLI, et al.
(författare)
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Triweekly docetaxel versus biweekly docetaxel as a treatment for advanced castration resistant prostate cancer: Quality of life analysis
- 2014
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Ingår i: JOURNAL OF CLINICAL ONCOLOGY. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 32:4
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- 23 Background: Bi-weekly docetaxel (T) with prednisone improved progression free survival and overall survival when compared with the standard tri-weekly T as first-line treatment for advanced castration resistant prostate cancer (CRPC) (Lancet Oncol. 2013;14:117-124). We report here the quality of life (QoL) results of this prospective randomized trial. Methods: Three hundred and forty-six patients were randomly allocated centrally to receive intravenous therapy T of either 75 mg/m² d1 q3 wks (the triweekly arm) or 50 mg/m² d1 and d 14, q4 wks (the biweekly arm) (identifier NCT00255606). Prednisone (10 mg/d) was administered orally in both groups. The baseline patients characteristics were well balanced between the groups with respect to the performance status, mean age (69, range 45 to 87 vs. 68, range 46 to 85), and median serum prostate-specific antigen (PSA) content (109 µg/L, range 11 to 1,230 vs. 116 µg/L, range 12 to 1,870). Quality of life (QoL), the frequency and severity of symptoms including pain were assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) version 4.0 questionnaire. Results: The baseline (QoL) of both treatment groups was compared to QoL after six months of the treatment within each treatment group and between groups. Changes in fatigue, symptoms of pain and nausea, and the overall performance status did not differ between the groups. There were statistically significant differences in overall quality of life values (p=0.010) and discomforting pain values (p=0.028) favoring the bi-weekly treatment arm. Conclusions: Bi-weekly T is better tolerated than the tri-weekly standard T. Following the results from the clinical outcome and the QoL outcome in the PROSTY trial we would recommend the use of bi-weekly docetaxel as first line treatment of CRPC Clinical trial information: NCT00255606.
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| 34. |
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| 35. |
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| 36. |
- Lehtomaki, K, et al.
(författare)
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Lead Time and Prognostic Role of Serum CEA, CA19-9, IL-6, CRP, and YKL-40 after Adjuvant Chemotherapy in Colorectal Cancer
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:15
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Tidskriftsartikel (refereegranskat)abstract
- In colorectal cancer (CRC), 20–50% of patients relapse after curative-intent surgery with or without adjuvant therapy. We investigated the lead times and prognostic value of post-adjuvant (8 months from randomisation to adjuvant treatment) serum CEA, CA19-9, IL-6, CRP, and YKL-40. We included 147 radically resected stage II–IV CRC treated with 24 weeks of adjuvant 5-fluorouracil-based chemotherapy in the phase III LIPSYT-study (ISRCTN98405441). All 147 were included in lead time analysis, but 12 relapsing during adjuvant therapy were excluded from post-adjuvant analysis. Elevated post-adjuvant CEA, IL-6, and CRP were associated with impaired disease-free survival (DFS) with hazard ratio (HR) 5.21 (95% confidence interval 2.32–11.69); 3.72 (1.99–6.95); 2.58 (1.18–5.61), respectively, and elevated IL-6 and CRP with impaired overall survival (OS) HR 3.06 (1.64–5.73); 3.41 (1.55–7.49), respectively. Elevated post-adjuvant IL-6 in CEA-normal patients identified a subgroup with impaired DFS. HR 3.12 (1.38–7.04) and OS, HR 3.20 (1.39–7.37). The lead times between the elevated biomarker and radiological relapse were 7.8 months for CEA and 10.0–53.1 months for CA19-9, IL-6, CRP, and YKL-40, and the lead time for the five combined was 27.3 months. Elevated post-adjuvant CEA, IL-6, and CRP were associated with impaired DFS. The lead time was shortest for CEA.
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| 37. |
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| 39. |
- Martinez-Majander, N., et al.
(författare)
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Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial
- 2020
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 27:5, s. 841-848
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Cancer is a frequent finding in ischaemic stroke patients. The frequency of cancer amongst participants in the NAVIGATE ESUS randomized trial and the distribution of outcome events during treatment with aspirin and rivaroxaban were investigated. Methods Trial participation required a recent embolic stroke of undetermined source. Patients' history of cancer was recorded at the time of study entry. During a mean follow-up of 11 months, the effects of aspirin and rivaroxaban treatment on recurrent ischaemic stroke, major bleeding and all-cause mortality were compared between patients with cancer and patients without cancer. Results Amongst 7213 randomized patients, 543 (7.5%) had cancer. Of all patients, 3609 were randomized to rivaroxaban [254 (7.0%) with cancer] and 3604 patients to aspirin [289 (8.0%) with cancer]. The annual rate of recurrent ischaemic stroke was 4.5% in non-cancer patients in the rivaroxaban arm and 4.6% in the aspirin arm [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.78-1.24]. In cancer patients, the rate of recurrent ischaemic stroke was 7.7% in the rivaroxaban arm and 5.4% in the aspirin arm (HR 1.43, 95% CI 0.71-2.87). Amongst cancer patients, the annual rate of major bleeds was non-significantly higher for rivaroxaban than aspirin (2.9% vs. 1.1%; HR 2.57, 95% CI 0.67-9.96; P for interaction 0.95). All-cause mortality was similar in both groups. Conclusions Our exploratory analyses show that patients with embolic stroke of undetermined source and a history of cancer had similar rates of recurrent ischaemic strokes and all-cause mortality during aspirin and rivaroxaban treatments and that aspirin appeared safer than rivaroxaban in cancer patients regarding major bleeds. (NCT02313909).
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| 40. |
- Pulkka, OP, et al.
(författare)
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Anagrelide for Gastrointestinal Stromal Tumor
- 2019
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1557-3265. ; 25:5, s. 1676-1687
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Tidskriftsartikel (refereegranskat)
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| 41. |
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| 42. |
- Reichardt, P., et al.
(författare)
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Adjuvant therapy in primary GIST: state-of-the-art
- 2012
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 23:11, s. 2776-2781
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Forskningsöversikt (refereegranskat)abstract
- The management of primary gastrointestinal stromal tumours (GISTs) has evolved with the introduction of adjuvant therapy. Recently reported results of the SSG XVIII/AIO trial by the Scandinavian Sarcoma Group (SSG) and the German Working Group on Medical Oncology (AIO) represent a significant change in the evidence for adjuvant therapy duration. The objectives of this European Expert Panel meeting were to describe the optimal management and best practice for the systemic adjuvant treatment of patients with primary GISTs. A panel of medical oncology experts from European sarcoma research groups were invited to a 1-day workshop. Several questions and discussion points were selected by the organising committee prior to the conference. The experts reviewed the current literature of all clinical trials available on adjuvant therapy for primary GISTs, considered the quality evidence and formulated recommendations for each discussion point. Clinical issues were identified and provisional clinical opinions were formulated for adjuvant treatment patient selection, imatinib dose, duration and patient recall, mutational analysis and follow-up of primary GIST patients. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs. Patient selection for adjuvant therapy should be based on any of the three commonly used patient risk stratification schemes. R1 surgery (versus R0) alone is not an indication for adjuvant imatinib in low-risk GIST. Recall and imatinib restart could be proposed in patients who discontinued 1-year adjuvant imatinib within the previous 3 months and may be considered on a case-by-case basis in patients who discontinued within the previous year. Mutational analysis is recommended in all cases of GISTs using centralised laboratories with good quality control. Treatment is not recommended in an imatinib-insensitive D842V-mutated GIST. During adjuvant treatment, patients are recommended to be clinically assessed at 1- to 3-month intervals. Upon discontinuation, computed tomography scan (CT) scans are recommended every 3 to 4 months for 2 years when the risk of relapse is highest, followed by every 6 months until year 5 and annually until year 10 after treatment discontinuation. Key points in systemic adjuvant treatment and clinical management of primary GISTs as well as open questions were identified during this European Expert Panel meeting on GIST management.
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- Zardavas, Dimitrios, et al.
(författare)
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Tumor PIK3CA Genotype and Prognosis in Early-Stage Breast Cancer: A Pooled Analysis of Individual Patient Data
- 2018
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Ingår i: Journal of Clinical Oncology. - : AMER SOC CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 36:10, s. 981-
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Tidskriftsartikel (refereegranskat)abstract
- PurposePhosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data.Patients and MethodsAssociations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes.ResultsData from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P amp;lt; .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P amp;lt; .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P amp;lt; .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); amp;gt; 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS (P = .043), but not for the DDFS and OS end points.ConclusionIn this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors. (C) 2018 by American Society of Clinical Oncology
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