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- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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- 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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- Arnetz, L, et al.
(författare)
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Copeptin, insulin-like growth factor binding protein-1 and sitagliptin: A report from the BEta-cell function in Glucose abnormalities and Acute Myocardial Infarction study
- 2016
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Ingår i: Diabetes & vascular disease research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 13:4, s. 307-311
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Tidskriftsartikel (refereegranskat)abstract
- To investigate whether sitagliptin affects copeptin and osmolality, suggesting arginine vasopressin activation and a potential for fluid retention, compared with placebo, in patients with a recent acute coronary syndrome and newly discovered type 2 diabetes or impaired glucose tolerance. A second aim was to confirm whether copeptin correlated with insulin-like growth factor binding protein-1. Methods: Fasting blood samples were used from the BEta-cell function in Glucose abnormalities and Acute Myocardial Infarction trial, in which patients recently hospitalized due to acute coronary syndrome and with newly detected abnormal glucose tolerance were randomized to sitagliptin 100 mg once daily ( n = 34) or placebo ( n = 37). Copeptin, osmolality and insulin-like growth factor binding protein-1 were analysed at baseline and after 12 weeks. Results: Copeptin and osmolality were unaffected by sitagliptin. There was no correlation between copeptin and insulin-like growth factor binding protein-1. Conclusion: Sitagliptin therapy does not appear to be related to activation of the arginine vasopressin system.
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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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| 24. |
- Kotseva, K, et al.
(författare)
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Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: Results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry
- 2019
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Ingår i: European journal of preventive cardiology. - : Oxford University Press (OUP). - 2047-4881 .- 2047-4873. ; 26:8, s. 824-835
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to determine whether the Joint European Societies guidelines on secondary cardiovascular prevention are followed in everyday practice. Design A cross-sectional ESC-EORP survey (EUROASPIRE V) at 131 centres in 81 regions in 27 countries. Methods Patients (<80 years old) with verified coronary artery events or interventions were interviewed and examined ≥6 months later. Results A total of 8261 patients (females 26%) were interviewed. Nineteen per cent smoked and 55% of them were persistent smokers, 38% were obese (body mass index ≥30 kg/m2), 59% were centrally obese (waist circumference: men ≥102 cm; women ≥88 cm) while 66% were physically active <30 min 5 times/week. Forty-two per cent had a blood pressure ≥140/90 mmHg (≥140/85 if diabetic), 71% had low-density lipoprotein cholesterol ≥1.8 mmol/L (≥70 mg/dL) and 29% reported having diabetes. Cardioprotective medication was: anti-platelets 93%, beta-blockers 81%, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers 75% and statins 80%. Conclusion A large majority of coronary patients have unhealthy lifestyles in terms of smoking, diet and sedentary behaviour, which adversely impacts major cardiovascular risk factors. A majority did not achieve their blood pressure, low-density lipoprotein cholesterol and glucose targets. Cardiovascular prevention requires modern preventive cardiology programmes delivered by interdisciplinary teams of healthcare professionals addressing all aspects of lifestyle and risk factor management, in order to reduce the risk of recurrent cardiovascular events.
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- 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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- Venskutonyte, L, et al.
(författare)
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Satisfaction with glucose-lowering treatment and well-being in patients with type 2 diabetes and myocardial infarction: a DIGAMI2 QoL sub-study
- 2013
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Ingår i: Diabetes & vascular disease research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 10:3, s. 263-269
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Tidskriftsartikel (refereegranskat)abstract
- The second Diabetes Glucose and Myocardial Infarction (DIGAMI 2) study randomised patients with diabetes and myocardial infarction to insulin or oral-based treatment. To determine the effects of insulin-based treatment, the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Psychological General Well-Being (PGWB) Index were administered at baseline and 12 months. Insulin-treated patients ( n = 197) had a worse risk profile and more co-morbidity at baseline than patients on oral glucose-lowering agents ( n = 127). The treatment satisfaction and psychological well-being was similar between insulin and oral groups at baseline [DTSQ: median (first–third quartile) 30 (24–34) vs 31 (27–34), NS; PGWB: 77 (73–82) vs 79 (76–82), NS] and at 12 months [DTSQ: 32 (28–35) vs 34 (30–36), NS; PGWB: 81 (78–84) vs 82 (78–84), NS]. Improvement was significant in both groups. Insulin-based therapy was well accepted and did not decrease treatment satisfaction or psychological well-being compared to oral glucose-lowering treatment in patients with type 2 diabetes and myocardial infarction.
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- Anselmino, M, et al.
(författare)
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Implications of abnormal glucose metabolism in patients with coronary artery disease
- 2008
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Ingår i: Diabetes & vascular disease research. - : SAGE Publications. - 1479-1641 .- 1752-8984. ; 5:4, s. 285-290
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal glucose metabolism and type 2 diabetes mellitus (T2DM) are becoming increasingly common. It has been recently confirmed that the period of time prior to the development of diabetes, when patients have impaired glucose tolerance, may also predispose them to increased cardiovascular risk. Therefore prevention and management of T2DM and its antecedents must have high priority when allocating healthcare resources. The present review summarises some information on detection, management and treatment of abnormal glucose metabolism in patients with established coronary artery disease, highlighting the importance of early detection of abnormal glucose metabolism in order to prevent the progression of prediabetes to T2DM and to delay the occurrence of those macrovascular and microvascular complications that impair quality of life and diminish survival.
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| 37. |
- Arner, P., et al.
(författare)
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Adipose lipid turnover and long-term changes in body weight
- 2019
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25:9, s. 1385-1389
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Tidskriftsartikel (refereegranskat)abstract
- The worldwide obesity epidemic(1) makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates(2,3). Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived C-14 in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.
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| 40. |
- 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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| 41. |
- Beulens, JWJ, et al.
(författare)
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Risk and management of pre-diabetes
- 2019
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Ingår i: European journal of preventive cardiology. - : Oxford University Press (OUP). - 2047-4881 .- 2047-4873. ; 26:2_SUPPL2_suppl, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes mellitus (T2DM) is associated with a two- to four-fold increased risk of developing cardiovascular disease (CVD) and microvascular complications, which may already be present before diagnosis. It is, therefore, important to detect people with an increased risk of T2DM at an early stage. In order to identify individuals with so-called ‘pre-diabetes’, comprising impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), current guidelines have developed definitions based on fasting plasma glucose, two-hour glucose concentrations and haemoglobin A1c. Subjects with pre-diabetes are at an increased risk of developing T2DM and CVD. This elevated risk seems similar according to the different criteria used to define pre-diabetes. The risk of progression to T2DM or CVD does, however, depend on other risk factors such as sex, body mass index and ethnicity. Based on the risk factors to develop T2DM, many risk assessment models have been developed to identify those at highest risk. These models perform well to identify those at risk and could be used to initiate preventive interventions. Many studies have shown that lifestyle modification and metformin are effective in preventing the development of T2DM, although lifestyle modification seems to have a more sustainable effect. In addition, lifestyle modification seems more effective in those with IGT than those with IFG. In this review, we will describe the different definitions used to define pre-diabetes, progression from pre-diabetes to T2DM or other vascular complications, risk factors associated with progressions and the management of progression to T2DM, ending with clinical recommendations.
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| 43. |
- Chew, Michelle, et al.
(författare)
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Extravascular lung water index: Diagnostic accuracy and relation to lung injury and mortality in patients with shock
- 2011
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Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 37:1 Suppl, s. 98-98
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Konferensbidrag (refereegranskat)abstract
- INTRODUCTION. The diagnosis of acute lung injury may be more robust if more accurate physiological markers can be identified. Extravascular lung water index (EVLWI) may be useful and has been shown to correlate with respiratory function and mortality in patients with sepsis and ARDS. Whether this applies to a wider population, and which index performs best, are unclear. OBJECTIVES. We hypothesized that EVLWI correlates with respiratory function and mortality in patients with documented systemic inflammation and shock. We investigated EVLW indexed to actual and predicted body weight, and pulmonary blood volume. We investigated the diagnostic accuracy of EVLWI for lung injury. METHODS. In 51 patients with shock and SIRS, EVLWI was measured within 6 h of ICU admission and indexed to actual weight (EVLWI/ABW), predicted body weight (EVLWI/ PBW) and pulmonary blood volume (EVLWI/PBV). Relationships to lung injury and ICUmortality were investigated. Positive and negative likelihood ratios, pre- and post-test odds and ROC curves were calculated. RESULTS. EVLWI was higher among patients with lung injury and was significantly correlated with respiratory parameters. EVLWI/ABW was higher among non-survivors and gave the best positive likelihood ratios for diagnosing ALI/ARDS. In contrast, EVLWI/PBV gave better diagnostic value for severe lung injury according to Murray's LIS criteria. The post-test odds for ALI and ARDS increased threefold when using EVLWI/ABW as a bedside test. The post-test odds of severe lung injury increased eightfold using EVLWI/PBV. EVLWI/ABW and EVLWI/PBV generated the best ROC curves for mortality prediction with a sensitivity of 68% and specificity of 63-72%. CONCLUSIONS. EVLWI was associated with degree of lung injury, regardless of the index used, supporting its usefulness as a bedside indicator for disease severity. EVLWI/PBV and EVLW/ABW gave the best diagnostic accuracies for the diagnosis of lung injury, and generated the bestROCcurves for mortality prediction.EVLWI/ABWwas significantly increased in non-survivors. Further studies are needed to confirm the additional value of EVLWI for the early identification of lung injury.
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| 45. |
- 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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| 46. |
- 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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| 49. |
- Dolled-Filhart, Marisa, et al.
(författare)
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Classification of breast cancer using genetic algorithms and tissue microarrays
- 2006
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:21, s. 6459-6468
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: A multitude of breast cancer mRNA profiling studies has stratified breast cancer and defined gene sets that correlate with outcome. However, the number of genes used to predict patient outcome or define tumor subtypes by RNA expression studies is variable, nonoverlapping, and generally requires specialized technologies that are beyond those used in the routine pathology laboratory. It would be ideal if the familiarity and streamlined nature of immunohistochemistry could be combined with the rigorously quantitative and highly specific properties of nucleic acid-based analysis to predict patient outcome. EXPERIMENTAL DESIGN: We have used AQUA-based objective quantitative analysis of tissue microarrays toward the goal of discovery of a minimal number of markers with maximal prognostic or predictive value that can be applied to the conventional formalin-fixed, paraffin-embedded tissue section. RESULTS: The minimal discovered multiplexed set of tissue biomarkers was GATA3, NAT1, and estrogen receptor. Genetic algorithms were then applied after division of our cohort into a training set of 223 breast cancer patients to discover a prospectively applicable solution that can define a subset of patients with 5-year survival of 96%. This algorithm was then validated on an internal validation set (n=223, 5-year survival=95.8%) and further validated on an independent cohort from Sweden, which showed 5-year survival of 92.7% (n=149). CONCLUSIONS: With further validation, this test has both the familiarity and specificity for widespread use in management of breast cancer. More generally, this work illustrates the potential for multiplexed biomarker discovery on the tissue microarray platform.
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| 50. |
- 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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