| 1. |
- Witjes, J. Alfred, et al.
(författare)
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EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer – An International Collaborative Multistakeholder Effort : Under the Auspices of the EAU-ESMO Guidelines Committees
- 2020
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 77:2, s. 223-250
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.SETTING: Online Delphi survey and consensus conference.PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.PATIENT SUMMARY: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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| 2. |
- Bergh, Jonas, et al.
(författare)
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Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer : A randomised trial
- 2000
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 356:9239, s. 1384-1391
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. Methods: 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. Findings: At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. Interpretation: Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.
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| 4. |
- Björkblom, Carina, et al.
(författare)
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Estrogenic and androgenic effects of municipal wastewater effluent on reproductive endpoint biomarkers in three-spined stickleback (Gasterosteus aculeatus)
- 2009
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Ingår i: Environmental Toxicology and Chemistry. - : Wiley-Blackwell. - 0730-7268 .- 1552-8618. ; 28:5, s. 1063-1071
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Tidskriftsartikel (refereegranskat)abstract
- Municipal wastewater treatment plants have been associated with the release of endocrine-disrupting chemicals, which consequently lead to alterations of reproductive function in aquatic organisms. The three-spined stickleback (Gasterosteus aculeatus) has quantifiable biomarkers for assessment of both estrogen (vitellogenin) and androgen (spiggin) activity, which makes this species very valuable in the research of endocrine disruption. The estrogenic and androgenic biomarkers were used for evaluating exposure effects of municipal wastewater effluent. We evaluated the effects of 17alpha-ethinylestradiol (EE2), 17alpha-methyltestosterone (MT), and wastewater effluents on induction of vitellogenin and spiggin production, gonadosomatic index, hepatosomatic index, nephrosomatic index, plasma steroid levels, and histopathology. Adult female and male sticklebacks were exposed to 20 ng/L of EE2, 10 microg/L of MT, and wastewater effluent (10, 50, and 80% of original concentration) in a flow-through system for an exposure of one week and an extended exposure of four weeks. Chemical analyses of the steroids were done for verification of exposure concentrations and presence in the used wastewater. Our results show that municipal wastewater effluent exerts estrogenic action on three-spined stickleback as observed by elevated vitellogenin levels in exposed fish, corresponding to the effect seen in fish exposed to EE2. Furthermore, wastewater and EE2 exerted similar histopathological effects on testis of exposed fish. Although domestic effluent is suspected to have a high content of natural androgens, no obvious androgenic effect of wastewater was observed in the present study.
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| 5. |
- Björkbom, Carina, et al.
(författare)
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Assessment of reproductive biomarkers in three-spined stickleback (Gasterosteus aculeatus) from sewage effluent recipients
- 2013
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Ingår i: Environmental Toxicology. - : Wiley-Blackwell. - 1520-4081 .- 1522-7278. ; 28:4, s. 229-237
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine the occurrence of endocrine disruption close to sewage treatment plant effluent discharges along the Finnish Baltic Sea coast using a set of reproductive biomarkers present in adult three-spined stickleback (Gasterosteus aculeatus). Possible variation and sensitivity of the biomarkers during an entire reproductive period were also examined. The analysis of vitellogenin (VTG) for estrogenic activity and spiggin for androgenic activity, together with histopathological analysis indicated that sticklebacks were exposed to estrogenic loads sufficient to cause inappropriate production of VTG and to disrupt normal testicular structure in adult male sticklebacks. No androgenic disruption was observed. The results emphasize the need of a combination of several reproductive biomarkers in fish and repeated sampling for the detection of potential endocrine modulating substances under field condition
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| 6. |
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| 7. |
- Graham, Ian, et al.
(författare)
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New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk.
- 2018
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Ingår i: European heart journal. Cardiovascular pharmacotherapy. - : Oxford University Press (OUP). - 2055-6845 .- 2055-6837. ; 4:2, s. 119-127
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Tidskriftsartikel (refereegranskat)abstract
- The very high occurrence of cardiovascular events presents a major public health issue, because treatment remains suboptimal. Lowering LDL cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels. Opportunities for innovation in dyslipidaemia treatment should address the substantial risk of lipid-associated cardiovascular events among patients optimally treated per guidelines but who cannot achieve LDL-C goals and who could benefit from additional LDL-C-lowering therapy or experience side effects of statins. Fresh approaches are needed to identify promising drug targets early and develop them efficiently. The Cardiovascular Round Table of the European Society of Cardiology (ESC) convened a workshop to discuss new lipid-lowering strategies for cardiovascular risk reduction. Opportunities to improve treatment approaches and the efficient study of new therapies were explored. Circulating biomarkers may not be fully reliable proxy indicators of the relationship between treatment effect and clinical outcome. Mendelian randomization studies may better inform development strategies and refine treatment targets before Phase 3. Trials should match the drug to appropriate lipid and patient profile, and guidelines may move towards a precision-based approach to individual patient management. Stakeholder collaboration is needed to ensure continued innovation and better international coordination of both regulatory aspects and guidelines. It should be noted that risk may also be addressed through increased attention to other risk factors such as smoking, hypertension, overweight, and inactivity.
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| 8. |
- Hill, Deirdre A., et al.
(författare)
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Breast cancer risk following radiotherapy for Hodgkin lymphoma : modification by other risk factors
- 2005
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 106:10, s. 3358-65
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Tidskriftsartikel (refereegranskat)abstract
- The importance of genetic and other risk factors in the development of breast cancer after radiotherapy (RT) for Hodgkin lymphoma (HL) has not been determined. We analyzed data from a breast cancer case-control study (105 patients, 266 control subjects) conducted among 3 817 survivors of HL diagnosed at age 30 years or younger in 6 population-based cancer registries. Odds ratios (ORs) and excess relative risks (ERRs) were calculated using conditional regression. Women who received RT exposure (> or = 5 Gy radiation dose to the breast) had a 2.7-fold increased breast cancer risk (95% confidence interval (CI) 1.4-5.2), compared with those given less than 5 Gy. RT exposure (> or = 5 Gy) was associated with an OR of 0.8 (95% CI, 0.2-3.4) among women with a first- or second-degree family history of breast or ovarian cancer, and 5.8 (95% CI, 2.1-16.3) among all other women (interaction P = .03). History of a live birth appeared to increase the breast cancer risk associated with RT among women not treated with ovarian-damaging therapies. Breast cancer risk following RT varied little according to other factors. The additional increased relative risk of breast cancer after RT for HL is unlikely to be larger among women with a family history of breast or ovarian cancer than among other women.
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| 9. |
- Laakso, Mervi, et al.
(författare)
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Basoluminal carcinoma: A new biologically and prognostically distinct entity between basal and luminal breast cancer
- 2006
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:14, s. 4185-4191
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Breast carcinomas expressing basal epithelium cytokeratins constitute a tumor subgroup that is typically hormone receptor negative and shows a distinct gene expression profile. Based on variable basal cytokeratin immunostaining patterns, we hypothesized that the "basal phenotype" tumor group may comprise more than one biological entity. Experimental Design: Basal cytokeratins 5 and 14 (CK5/14) were stained by immunohistochemistry and the percentage of positive cells was defined by image analysis. The results thus obtained were compared with clinicopathologic characteristics and relapse-free survival. Results: Of the 506 breast tumors, 53 (10.5%) showed immunoreactivity for CK5/14. Basal cytokeratin expression showed up as two microscopically distinguishable subtypes, i.e., a uniformly positive type ("basal") and a partially positive type ("basoluminal") often displaying a checkerboard-type intratumoral heterogeneity. These subgroups could also be separated with a third basal cytokeratin (CK17, P < 0,0001). Both basal and basoluminal subtypes were hormone receptor negative and of high grade, but differed with respect to the Ki-67 labeling index (P = 0.0014), vimentin (P = 0.005), and c-kit (P = 0.02), which were more frequently expressed in basal than in basoluminal tumors. In contrast, the amplification of HER-2 was found almost exclusively in the basoluminal subgroup (P = 0.009). Compared with the basal tumors, basoluminal tumors associated with significantly shorter relapse-free survival (P = 0.01), which was not explained by their more frequent HER-2 amplification. Conclusions: We conclude that the intratumoral heterogeneity in basal cytokeratin expression can be used to define two distinct breast cancer subtypes, basal and basoluminal, with distinctive features related to proliferation activity, oncogene and biomarker status, and patient survival.
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| 10. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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