| 1. |
- Jersin, R. A., et al.
(författare)
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Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 70:3, s. 680-695
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Tidskriftsartikel (refereegranskat)abstract
- Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.
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- Heggebo, L. C., et al.
(författare)
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Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden
- 2023
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Ingår i: Bmj Open. - : BMJ. - 2044-6055. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThe use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life.Methods and analysisPRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints.Ethics and disseminationTo implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums.Trial registration numberClinicalTrials.gov Registry (NCT05190172).
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| 9. |
- Majid, S., et al.
(författare)
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Validation of the Skåne University Hospital nomogram for the preoperative prediction of a disease-free axilla in patients with breast cancer
- 2021
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Ingår i: BJS Open. - : Oxford University Press (OUP). - 2474-9842. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Axillary staging via sentinel lymph node biopsy (SLNB) is performed for clinically node-negative (N0) breast cancer patients. The Skåne University Hospital (SUS) nomogram was developed to assess the possibility of omitting SLNB for patients with a low risk of nodal metastasis. Area under the receiver operating characteristic curve (AUC) was 0.74. The aim was to validate the SUS nomogram using only routinely collected data from the Swedish National Quality Registry for Breast Cancer at two breast cancer centres during different time periods. METHOD: This retrospective study included patients with primary breast cancer who were treated at centres in Lund and Malmö during 2008-2013. Clinicopathological predictors in the SUS nomogram were age, mode of detection, tumour size, multifocality, lymphovascular invasion and surrogate molecular subtype. Multiple imputation was used for missing data. Validation performance was assessed using AUC and calibration. RESULTS: The study included 2939 patients (1318 patients treated in Lund and 1621 treated in Malmö). Node-positive disease was detected in 1008 patients. The overall validation AUC was 0.74 (Lund cohort AUC: 0.75, Malmö cohort AUC: 0.73), and the calibration was satisfactory. Accepting a false-negative rate of 5 per cent for predicting N0, a possible SLNB reduction rate of 15 per cent was obtained in the overall cohort. CONCLUSION: The SUS nomogram provided acceptable power for predicting a disease-free axilla in the validation cohort. This tool may assist surgeons in identifying and counselling patients with a low risk of nodal metastasis on the omission of SLNB staging.
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- Battelino, T, et al.
(författare)
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Guideline Development for Medical Device Technology: Issues for Consideration
- 2023
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Ingår i: Journal of diabetes science and technology. - : SAGE Publications. - 1932-2968. ; 17:6, s. 1698-1710
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Tidskriftsartikel (refereegranskat)abstract
- Advances in the development of innovative medical devices and telehealth technologies create the potential to improve the quality and efficiency of diabetes care through collecting, aggregating, and interpreting relevant health data in ways that facilitate more informed decisions among all stakeholder groups. Although many medical societies publish guidelines for utilizing these technologies in clinical practice, we believe that the methodologies used for the selection and grading of the evidence should be revised. In this article, we discuss the strengths and limitations of the various types of research commonly used for evidence selection and grading and present recommendations for modifying the process to more effectively address the rapid pace of device and technology innovation and new product development.
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| 15. |
- De Bacquer, D, et al.
(författare)
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Percentage low-density lipoprotein-cholesterol response to a given statin dose is not fixed across the pre-treatment range: Real world evidence from clinical practice: Data from the ESC-EORP EUROASPIRE V Study
- 2020
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Ingår i: European journal of preventive cardiology. - : Oxford University Press (OUP). - 2047-4881 .- 2047-4873. ; 27:15, s. 1630-1636
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Tidskriftsartikel (refereegranskat)abstract
- Recent European guidelines recommend in patients with atherosclerotic cardiovascular disease to achieve a reduction of low-density lipoprotein-cholesterol of at least 50% if the baseline low-density lipoprotein-cholesterol level is between 1.8 and 3.5 mmol/L. Systematic reviews have associated a given statin/dose combination with a fixed percentage low-density lipoprotein-cholesterol response. Algorithms for detecting cases and estimating the prevalence of familial hypercholesterolaemia often rely on such fixed percentage reductions. Methods and results We used data from 915 coronary patients participating in the EUROASPIRE V study in whom atorvastatin or rosuvastatin therapy was initiated at hospital discharge and who were still using these drugs at the same dose at a follow-up visit 6 or more months later. Pre and on-treatment low-density lipoprotein-cholesterol levels were compared across the full low-density lipoprotein-cholesterol range. The prevalence of FH was estimated using the Dutch Lipid Clinic Network criteria, once using observed pre-treatment low-density lipoprotein-cholesterol and once using imputed pre-treatment low-density lipoprotein-cholesterol by following the common strategy of applying fixed correction factors to on-treatment low-density lipoprotein-cholesterol. Inter-individual variation in the low-density lipoprotein-cholesterol response to a fixed statin and dose was considerable, with a strong inverse relation of percentage reductions to pre-treatment low-density lipoprotein-cholesterol. The percentage low-density lipoprotein-cholesterol response was markedly lower at the left end of the pre-treatment low-density lipoprotein-cholesterol range especially for levels less than 3 mmol/L. The estimated prevalence of familial hypercholesterolaemia was 2% if using observed pre-treatment low-density lipoprotein-cholesterol and 10% when using imputed low-density lipoprotein-cholesterol. Conclusion The inter-individual variation in the percentage low-density lipoprotein-cholesterol response to a given dose of a statin is largely dependent on the pre-treatment level: the lower the pre-treatment low-density lipoprotein-cholesterol level the smaller the percentage low-density lipoprotein-cholesterol reduction. The use of uniform correction factors to estimate pre-treatment low-density lipoprotein-cholesterol is not justified.
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| 16. |
- de Boniface, J., et al.
(författare)
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Omitting axillary dissection in breast cancer with sentinel-node metastases
- 2024
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 390:13, s. 1163-1175
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups.METHODS We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44.RESULTS Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy–only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy–only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin.CONCLUSIONS The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.).
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| 18. |
- Dollet, L, et al.
(författare)
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Glutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 71:4, s. 624-636
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of skeletal muscle metabolism influences whole-body insulin sensitivity and glucose homeostasis. We hypothesized that type 2 diabetes–associated alterations in the plasma metabolome directly contribute to skeletal muscle immunometabolism and the subsequent development of insulin resistance. To this end, we analyzed the plasma and skeletal muscle metabolite profile and identified glutamine as a key amino acid that correlates inversely with BMI and insulin resistance index (HOMA-IR) in men with normal glucose tolerance or type 2 diabetes. Using an in vitro model of human myotubes and an in vivo model of diet-induced obesity and insulin resistance in male mice, we provide evidence that glutamine levels directly influence the inflammatory response of skeletal muscle and regulate the expression of the adaptor protein GRB10, an inhibitor of insulin signaling. Moreover, we demonstrate that a systemic increase in glutamine levels in a mouse model of obesity improves insulin sensitivity and restores glucose homeostasis. We conclude that glutamine supplementation may represent a potential therapeutic strategy to prevent or delay the onset of insulin resistance in obesity by reducing inflammatory markers and promoting skeletal muscle insulin sensitivity.
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| 34. |
- Kurtz, Sherry L., et al.
(författare)
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Transcriptional signatures measured in whole blood correlate with protection against tuberculosis in inbred and outbred mice
- 2023
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:8
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Tidskriftsartikel (refereegranskat)abstract
- Although BCG has been used for almost 100 years to immunize against Mycobacterium tuberculosis, TB remains a global public health threat. Numerous clinical trials are underway studying novel vaccine candidates and strategies to improve or replace BCG, but vaccine development still lacks a well-defined set of immune correlates to predict vaccine-induced protection against tuberculosis. This study aimed to address this gap by examining transcriptional responses to BCG vaccination in C57BL/6 inbred mice, coupled with protection studies using Diversity Outbred mice. We evaluated relative gene expression in blood obtained from vaccinated mice, because blood is easily accessible, and data can be translated to human studies. We first determined that the average peak time after vaccination is 14 days for gene expression of a small subset of immune-related genes in inbred mice. We then performed global transcriptomic analyses using whole blood samples obtained two weeks after mice were vaccinated with BCG. Using comparative bioinformatic analyses and qRT-PCR validation, we developed a working correlate panel of 18 genes that were highly correlated with administration of BCG but not heat-killed BCG. We then tested this gene panel using BCG-vaccinated Diversity Outbred mice and revealed associations between the expression of a subset of genes and disease outcomes after aerosol challenge with M. tuberculosis. These data therefore demonstrate that blood-based transcriptional immune correlates measured within a few weeks after vaccination can be derived to predict protection against M. tuberculosis, even in outbred populations.
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| 35. |
- Kurtz, Sherry L., et al.
(författare)
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Whole genome profiling refines a panel of correlates to predict vaccine efficacy against Mycobacterium tuberculosis
- 2020
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Ingår i: Tuberculosis. - : Elsevier. - 1472-9792 .- 1873-281X. ; 120
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Tidskriftsartikel (refereegranskat)abstract
- New vaccines are needed to combat the public health threat posed by M. tuberculosis (M. tb), but no correlates have been defined to aid vaccine development. Using mouse models, we previously developed an in vitro system that measures the ability of M. tb-immune lymphocytes to control bacterial replication during co-culture with M. tb-infected macrophages. We demonstrated that the degree of in vitro growth control by lymphocytes from mice given vaccines of varying efficacy reflected the relative degree of in vivo protection against lethal challenge. Further, using targeted analyses of gene expression in lymphocytes recovered from co-cultures, we found mediators whose relative expression also correlated with in vitro and in vivo outcomes. Here we advanced those findings by employing genome-wide expression analyses. We first screened splenocytes recovered from co-cultures by microarray, revealing additional genes whose expression correlated with protection. After applying pathway analyses to down-select gene candidates, we used both splenocytes and peripheral blood lymphocytes to validate microarray findings by qRT-PCR. We then subjected data from top candidates to rigorous statistical analyses. Resulting correlate candidates, including CXCL9, IFN-γ, and CCL5, significantly predicted protection with high specificity. These findings therefore refine and extend a panel of relevant immune correlates to advance vaccine development.
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| 36. |
- Larsson, L. E., et al.
(författare)
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Association of Sarcopenia and Its Defining Components with the Degree of Cognitive Impairment in a Memory Clinic Population
- 2023
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press BV. - 1387-2877 .- 1875-8908. ; 96:2, s. 777-788
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sarcopenia and cognitive impairment are two leading causes of disabilities. Objective: The objective was to examine the prevalence of sarcopenia and investigate the association between sarcopenia diagnostic components (muscle strength, muscle mass, and physical performance) and cognitive impairment in memory clinic patients. Methods: 368 patients were included (age 59.0±7.25 years, women: 58.7%), displaying three clinical phenotypes of cognitive impairments, i.e., subjective cognitive impairment (SCI, 57%), mild cognitive impairment (MCI, 26%), and Alzheimer's disease (AD, 17%). Sarcopenia was defined according to diagnostic algorithm recommended by the European Working Group on Sarcopenia in Older People. Components of sarcopenia were grip strength, bioelectrical impedance analysis, and gait speed. They were further aggregated into a score (0-3 points) by counting the numbers of limited components. Multi-nominal logistic regression was applied. Results: Probable sarcopenia (i.e., reduced grip strength) was observed in 9.6% of the patients, and 3.5% were diagnosed with sarcopenia. Patients with faster gait speed showed less likelihood of MCI (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.06-0.90) and AD (OR: 0.12, 95% CI: 0.03-0.60). One or more limited sarcopenia components was associated with worse cognitive function. After adjusting for potential confounders, the association remained significant only for AD (OR 4.29, 95% CI 1.45-11.92). Conclusion: The results indicate a connection between the sarcopenia components and cognitive impairments. Limitations in the sarcopenia measures, especially slow walking speed, were related to poorer cognitive outcomes. More investigationsare required to further verify the causal relationship between sarcopenia and cognitive outcomes.
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| 39. |
- Narbe, U., et al.
(författare)
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St Gallen 2019 guidelines understage the axilla in lobular breast cancer : a population-based study
- 2021
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 108:12, s. 1465-1473
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The St Gallen 2019 guidelines for primary therapy of early breast cancer recommend omission of completion axillary lymph node dissection (cALND), regardless of histological type, in patients with one or two sentinel lymph node (SLN) metastases. Concurrently, adjuvant chemotherapy is endorsed for luminal A-like disease with four or more axillary lymph node (ALN) metastases. The aim of this study was to estimate the proportion of patients with invasive lobular cancer (ILC) versus invasive ductal cancer of no special type (NST) with one or two SLN metastases for whom cALND would have led to a recommendation for adjuvant chemotherapy. METHODS: Patients with ILC and NST who had surgery between 2014 and 2017 were identified in the National Breast Cancer Register of Sweden. After exclusion of patients with incongruent or missing data, those who fulfilled the St Gallen 2019 criteria for cALND omission were included in the population-based study cohort. RESULTS: Some 1886 patients in total were included in the study, 329 with ILC and 1507 with NST. Patients with ILC had a higher metastatic nodal burden and were more likely to have a luminal A-like subtype than those with NST. The prevalence of at least four ALN metastases was higher in ILC (31.0 per cent) than NST (14.9 per cent), corresponding to an adjusted odds ratio of 2.26 (95 per cent c.i. 1.59 to 3.21). Luminal A-like breast cancers with four or more ALN metastases were over-represented in ILC compared with NST, 52 of 281 (18.5 per cent) versus 43 of 1299 (3.3 per cent) (P < 0.001). CONCLUSION: Patients with ILC more often have luminal A-like breast cancer with at least four nodal metastases. Omission of cALND in patients with luminal A-like invasive lobular cancer and one or two SLN metastases warrants future attention as there is a risk of nodal understaging and undertreatment in one-fifth of patients.
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| 41. |
- Rautio, E., et al.
(författare)
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Patients With Type 2 Diabetes Have an Increased Demand for Pacemaker Treatment: A Comparison With Age- and Sex-Matched Control Subjects From the General Population
- 2020
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Ingår i: Diabetes care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 43:11, s. 2853-2858
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Patients with type 2 diabetes have an increased risk for cardiovascular disease, including arrhythmias. The prevalence of bradyarrhythmia and the subsequent need for treatment with pacemakers (PMs) is less well explored in a contemporary patient population. The current study explores1) whether patients with type 2 diabetes have an increased demand for PM implantation compared with an age- and sex-matched control population without diabetes and2) patient characteristics associated with an increased demand for receiving a PM. RESEARCH DESIGN AND METHODS In this population-matched registry study, a total of 416,247 patients with type 2 diabetes from the Swedish National Diabetes Registry and 2,081,235 age- and sex-matched control subjects selected from the general population were included between 1 January 1998 and 31 December 2012 and followed until 31 December 2013. Mean follow-up time was 7 years. Cox proportional hazards regression analyses were performed to estimate the demand of PM treatment and the factors identifying patients with such demand. RESULTS Type 2 diabetes was associated with an increased need of PM treatment (hazard ratio 1.65 [95% CI 1.60-1.69];P< 0.0001), which remained (1.56 [1.51-1.60];P< 0.0001) after adjustments for age, sex, educational level, marital status, country of birth, and coronary heart disease. Risk factors for receiving a PM included increasing age, HbA(1c), BMI, diabetes duration, and lipid- and blood pressure-lowering medication. CONCLUSIONS The need for PM treatment is higher in patients with type 2 diabetes than in matched population-based control subjects. Age, diabetes duration, and HbA(1c)seem to be risk factors for PM treatment.
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| 48. |
- Smaradottir, M. I., et al.
(författare)
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Copeptin is associated with mortality in elderly people
- 2021
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Ingår i: European Journal of Clinical Investigation. - : John Wiley and Sons Inc. - 0014-2972 .- 1365-2362. ; 51:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Elevated copeptin, a marker for vasopressin release, has been associated with impaired prognosis in acute myocardial infarction (MI). The aim was to investigate whether this association extends beyond the acute phase and whether it is related to markers of stress (cortisol) and heart failure (NTproBNP). Methods: Copeptin, cortisol and NTproBNP were measured in 926 participants (age: 76.0; male: 48.5%) in the ICELAND MI study whereof 246 had a previous MI (91 recognizable (RMI) and 155 previously unrecognizable (UMI) detected by cardiac magnetic resonance imaging). The primary endpoint was cardiovascular events (CVEs), and secondary endpoints were total mortality, heart failure and MI (median follow-up was 9.1 years). The relation between copeptin and prognosis was assessed with the Cox proportional hazard regression (unadjusted, adjusted for cortisol and NTproBNP, respectively, and a multiple model: copeptin, cortisol, NTproBNP, age, sex, serum creatinine, heart failure). Results: Copeptin was higher in participants with MI (8.9 vs. 6.4 pmol/L; P <.01), with no difference between RMI vs. UMI. Increased copeptin correlated with evening cortisol (r =.11; P <.01) and NTproBNP (r =.07; P =.04). Copeptin was associated with CVE and total mortality after adjusting for cortisol and NTproBNP separately, and remained significantly associated with total mortality in the multiple model. Conclusions: Copeptin was higher in subjects with previous MI regardless whether previously recognized or not. Copeptin correlated weakly with cortisol and NTproBNP, and was independently associated with total mortality. This indicates that the prognostic implications of copeptin are not only mediated by heart failure or stress, supporting the assumption that copeptin is a marker of general vulnerability.
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| 49. |
- Vallon-Christersson, J., et al.
(författare)
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RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer
- 2022
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 33:Suppl 3, s. 144-145
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Konferensbidrag (refereegranskat)abstract
- BackgroundMultigene expression assays for molecular subtypes and biomarkers can aid clinical management of early invasive breast cancer. Based on RNA-sequencing we aimed to develop single-sample predictor (SSP) models for conventional clinical markers, molecular intrinsic subtype and risk of recurrence (ROR).MethodsA uniformly accrued breast cancer cohort of 7743 patients with RNA-sequencing data from fresh tissue was divided into a training set and a reserved test set. We trained SSPs for PAM50 molecular subtypes and ROR assigned by nearest-centroid (NC) and SSPs for conventional clinical markers from histopathology data. Additionally, SSP classifications were compared with Prosigna® in two external cohorts. Prognostic value was assessed using distant recurrence-free interval.ResultsIn the test set, agreement between SSP and NC classifications for PAM50 (five subtypes) and Subtype (four subtypes) was high (85%, Kappa=0.78) and very high (90%, Kappa=0.84) respectively. Accuracy for ROR risk category was high (84%, Kappa=0.75, weighted Kappa=0.90). The prognostic value for SSP and NC was assessed as equivalent. Agreement for SSP and histopathology was very high or high for receptor status, while moderate and poor for Ki67 status and Nottingham histological grade, respectively. SSP concordance with Prosigna® was high for subtype and moderate and high for ROR risk category. In pooled analysis, concordance between SSP and Prosigna® for emulated treatment recommendation for chemotherapy (yes vs. no) was high (85%, Kappa=0.66). In postmenopausal ER+/HER2-/N0 patients SSP application suggested changed treatment recommendations for up to 17% of patients, with nearly balanced escalation and de-escalation of chemotherapy.ConclusionsSSP models for histopathological variables, PAM50, and ROR classifications can be derived from RNA-sequencing that closely matches clinical tests. Agreement and outcome analyses suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level. Retrospective evaluation in postmenopausal ER+/HER2-/N0 patients suggested that molecular testing could lead to a changed therapy recommendation for almost one-fifth of patients.
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