High-risk breast lesions, which comprise benign lesions and in situ carcinomas (lobular carcinoma in situ and ductal carcinoma in situ), are clinically, morphologically, and biologically ...heterogeneous and are associated with an increased risk of invasive breast cancer development, albeit to varying degrees. Recognition and proactive management of such lesions can help to prevent progression to invasive disease, and might, therefore, reduce breast cancer incidence, morbidity, and mortality. However, this opportunity comes with the possibility of overdiagnosis and overtreatment, necessitating risk-based intervention. Notably, despite the progress in defining the molecular changes associated with carcinogenesis, alterations identifying the individuals with high-risk lesions that will progress to invasive carcinoma remain to be identified. Thus, until reproducible clinicopathological or molecular features predicting an individual's risk of breast cancer are found, management strategies must be defined by population-level risks as determined by models such as the Gail or IBIS models, as well as patient attitudes toward the risks and benefits of interventions. Herein, we review the contemporary approaches to diagnosis and management of high-risk breast lesions. Progress in this area will ultimately be dependent on the ability to individualize risk prediction through better definition of the key drivers in the carcinogenic process.
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NUK, OILJ, SBMB, UL, UM, UPUK
To convene a multidisciplinary panel of breast experts to examine the relationship between margin width and ipsilateral breast tumor recurrence (IBTR) and develop a guideline for defining adequate ...margins in the setting of breast conserving surgery and adjuvant radiation therapy.
A multidisciplinary consensus panel used a meta-analysis of margin width and IBTR from a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus.
Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a 2-fold increase in the risk of IBTR compared with negative margins. This increased risk is not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins than no ink on tumor do not significantly decrease the rate of IBTR compared with no ink on tumor. There is no evidence that more widely clear margins reduce IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.
The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
The authors reexamine data on the size of tumor margins in breast cancer and conclude that negative margins are sufficient. Local recurrence is influenced more by tumor biology and therapy than ...surgical margin.
Survival after breast-conserving surgery, which consists of removal of the primary tumor and a margin of surrounding normal tissue (“lumpectomy”) and whole-breast irradiation, has been shown in six prospective, randomized trials to be equivalent to that after mastectomy.
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Minimizing tumor recurrence in the breast (local recurrence) is of major clinical importance, since local recurrence is associated with reduced survival and emotional distress.
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Remarkably, more than 20 years after these randomized trials, the most appropriate amount of normal breast tissue that should be removed (the surgical margin width) to minimize local recurrence remains controversial. The status of the surgical margin . . .
Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level ...data.
We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (RE-LY Randomized Evaluation of Long-Term Anticoagulation Therapy, ROCKET AF Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation, ARISTOTLE Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation, and ENGAGE AF-TIMI 48 Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (HRs 95% CIs) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex.
A total of 71 683 patients were included (29 362 on standard-dose DOAC, 13 049 on lower-dose DOAC, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 3.01% versus 1080/29 229 3.69%; HR, 0.81 95% CI, 0.74-0.89), death (2276/29 312 7.76% versus 2460/29 229 8.42%; HR, 0.92 95% CI, 0.87-0.97), and intracranial bleeding (184/29 270 0.63% versus 409/29 187 1.40%; HR, 0.45 95% CI, 0.37-0.56), but no statistically different hazard of major bleeding (1479/29 270 5.05% versus 1733/29 187 5.94%; HR, 0.86 95% CI, 0.74-1.01), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 3.96% versus 1080/29 229 3.69%; HR, 1.06 95% CI, 0.95-1.19) but a lower hazard of intracranial bleeding (55/12 985 0.42% versus 409/29 187 1.40%; HR, 0.28 95% CI, 0.21-0.37), death (1082/13 049 8.29% versus 2460/29 229 8.42%; HR, 0.90 95% CI, 0.83-0.97), and major bleeding (564/12 985 4.34% versus 1733/29 187 5.94%; HR, 0.63 95% CI, 0.45-0.88). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke or systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (
=0.01) and lower creatinine clearance (
=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (
=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction
=0.02) and lower-dose DOACs (interaction
=0.01) versus warfarin.
Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.
Background Controversy exists regarding the optimal negative margin width for ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and whole-breast irradiation (WBRT). Methods A ...multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 20 studies including 7883 patients and other published literature as the evidence base for consensus. Results Negative margins halve the risk of IBTR compared with positive margins defined as ink on DCIS. A 2 mm margin minimizes the risk of IBTR compared with smaller negative margins. More widely clear margins do not significantly decrease IBTR compared with 2 mm margins. Negative margins less than 2 mm alone are not an indication for mastectomy, and factors known to impact rates of IBTR should be considered in determining the need for re-excision. Conclusion The use of a 2 mm margin as the standard for an adequate margin in DCIS treated with WBRT is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcome, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins < 2 mm.
Purpose
Controversy exists regarding the optimal negative margin width for ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and whole-breast irradiation.
Methods
A ...multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 20 studies including 7,883 patients and other published literature as the evidence base for consensus.
Results
Negative margins halve the risk of IBTR compared with positive margins defined as ink on DCIS. A 2-mm margin minimizes the risk of IBTR compared with smaller negative margins. More widely clear margins do not significantly decrease IBTR compared with 2-mm margins. Negative margins narrower than 2 mm alone are not an indication for mastectomy, and factors known to affect rates of IBTR should be considered in determining the need for re-excision.
Conclusion
Use of a 2-mm margin as the standard for an adequate margin in DCIS treated with whole-breast irradiation is associated with lower rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins narrower than 2 mm.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Controversy exists regarding the optimal margin width in breast-conserving surgery for invasive breast cancer.
A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral ...breast tumor recurrence (IBTR) from a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus.
Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a two-fold increase in the risk of IBTR compared with negative margins. This increased risk is not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins do not significantly decrease the rate of IBTR compared with no ink on tumor. There is no evidence that more widely clear margins reduce IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.
The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. J Clin Oncol 32. 2014 American Society of Clinical Oncology®, American Society for Radiation Oncology®, and Society of Surgical Oncology®. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology.
Abstract
Aims
The prognosis of patients with atrial fibrillation (AF) and ischemic stroke while taking oral anticoagulation is poorly understood. This study aimed to characterize the outcomes of ...patients following a stroke event while on oral anticoagulation.
Methods and results
Individual participant data from five pivotal randomized trials of antithrombotic therapy in AF were used to assess the outcomes of patients with a post-randomization ischemic stroke while on study medication (warfarin, standard-, or lower-dose direct oral anticoagulant regimen) during trial follow-up. The primary outcome was recurrent ischemic stroke after the first post-randomization ischemic stroke. The primary analysis included 1163 patients with a first post-randomization ischemic stroke while on study medication (median age 73 years, 39.3% female, 35.4% history of stroke before trial enrollment). During a median continued follow-up of 337 days, 74 patients had a recurrent ischemic stroke cumulative incidence at 1 year: 7.0%, 95% confidence interval (CI) 5.2%–8.7%. The cumulative incidence of mortality at 3 months after stroke was 12.4% (95% CI 10.5%–14.4%). Consistent results for the incidence of recurrent ischemic stroke at 1 year were obtained in an analysis accounting for the competing risk of death (6.2%, 95% CI 4.8%–7.9%) and in a landmark analysis excluding the first 2 weeks after the index stroke and only including patients without permanent study drug discontinuation since then (6.8%, 95% CI 4.6%–8.9%).
Conclusion
Patients with AF and ischemic stroke while on oral anticoagulation are at increased risk of recurrent ischemic stroke and death. These patients currently have an unmet medical need.
Structured Graphical Abstract
Structured Graphical Abstract
Outcomes of patients with atrial fibrillation and ischemic stroke while on oral anticoagulation. Abbreviations: ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation, AVERROES, Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment, CI, confidence interval, COMBINE AF, A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation, DOAC, direct oral anticoagulant, ENGAGE AF-TIMI 48, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48, RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy, ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.
Purpose
Controversy exists regarding the optimal margin width in breast-conserving surgery for invasive breast cancer.
Methods
A multidisciplinary consensus panel used a meta-analysis of margin width ...and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus.
Results
Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a two-fold increase in the risk of IBTR compared with negative margins. This increased risk is not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins than no ink on tumor do not significantly decrease the rate of IBTR compared with no ink on tumor. There is no evidence that more widely clear margins reduce IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.
Conclusion
The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Adaptation of a coaxial sheath-flow interface for CE–ICP-MS hyphenation.•Comparison of the analytical performance to a commercially available interface.•Optimization of key parameters for CE–ICP-MS ...hyphenation.•Proof-of-principle experiments demonstrated very good analytical performance.
Capillary electrophoretic analyses benefit significantly from hyphenation to mass spectrometric techniques. While the coupling to ESI–MS is routinely performed, for example by using a coaxial sheath-flow interface, hyphenating it to inductively coupled plasma mass spectrometry is more technically challenging. We use a commercially available coaxial sheath-flow interface (CSFI) and a simple PTFE-based end-cap for easy, inexpensive CE–ICP-MS hyphenation with improved sensitivity and analytical performance compared to commercially available interfaces. We have optimized key nebulizer parameters such as capillary position, sheath liquid flow rate, and carrier gas flow rate, and compared the CSFI with a commercially available interface. In a set of proof-of-principle experiments employing the anticancer agent cisplatin it was demonstrated that the signal to noise response and sensitivity were considerably improved leading to detection limits for 195Pt of 0.08 μM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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