Indication for spinal sensitization in chronic low back pain: mechanical hyperalgesia adjacent to but not within the most painful body area.

Introduction: In 85% of patients with chronic low back pain (CLBP), no specific pathoanatomical cause can be identified. Besides primary peripheral drivers within the lower back, spinal or supraspinal sensitization processes might contribute to the patients' pain. Objectives: The present study conceptualized the most painful area (MP) of patients with nonspecific CLBP as primarily affected area and assessed signs of peripheral, spinal, and supraspinal sensitization using quantitative sensory testing (QST) in MP, a pain-free area adjacent to MP (AD), and a remote, pain-free control area (CON). Methods: Fifty-nine patients with CLBP (51 years, SD = 16.6, 22 female patients) and 35 pain-free control participants individually matched for age, sex, and testing areas (49 years, SD = 17.5, 19 female participants) underwent a full QST protocol in MP and a reduced QST protocol assessing sensory gain in AD and CON. Quantitative sensory testing measures, except paradoxical heat sensations and dynamic mechanical allodynia (DMA), were Z-transformed to the matched control participants and tested for significance using Z-tests (α = 0.001). Paradoxical heat sensations and DMA occurrence were compared between cohorts using Fisher's exact tests (α = 0.05). The same analyses were performed with a high-pain and a low-pain CLBP subsample (50% quantile). Results: Patients showed cold and vibration hypoesthesia in MP (all Ps < 0.001) and mechanical hyperalgesia (P < 0.001) and more frequent DMA (P = 0.044) in AD. The results were mainly driven by the high-pain CLBP subsample. In CON, no sensory alterations were observed. Conclusion: Mechanical hyperalgesia and DMA adjacent to but not within MP, the supposedly primarily affected area, might reflect secondary hyperalgesia originating from spinal sensitization in patients with CLBP.

Gujarati translation, validity and reliability of Walking Impairment Questionnaire in people with intermittent claudication due to peripheral artery disease.

INTRODUCTION: The Walking Impairment Questionnaire (WIQ) is a common and easy-to-use assessment of walking incapacity in people with claudication due to peripheral artery disease (PAD). It has four subscales: pain severity, walking distance, walking speed, and ability to climb stairs. It has not been translated into Gujarati, which limits its use in Indian subjects. AIM: This study aims to translate and assess the validity and reliability of a Gujarati version of WIQ. MATERIALS AND METHODS: This study had three phases: 1. Forward and backward translation and Cultural adaptation of WIQ into the Gujarati language by two independent translators, 2. Face and content validation by six clinical reviewers and 10 participants with PAD and Type II diabetes, 3. Concurrent and construct validity, test-retest reliability, and internal consistency of Gujarati, the WIQ was assessed on 160 participants with PAD and Type II diabetes who had a mean Ankle Brachial Index (standard deviation) <0.40 (0.1). The concurrent and construct validity of the WIQ was analyzed by correlating the WIQ distance and speed score with 6-minute walk distance (6MWD) and speed and WIQ total score with the Medical Outcome Study Questionnaire Short Form 36 (SF-36) score using Pearson's correlation coefficient. Test-retest reliability was analyzed using an intraclass correlation coefficient (ICC) with a seven-day interval between two questionnaire applications. Internal consistency of the total WIQ score was determined using Cronbach's alpha. RESULTS: Following translation, the Gujarati WIQ was considered acceptable and understandable by people with PAD. There was excellent correlation between the WIQ distance score and 6-minute walk test distance (r = 0.95, P < .05)) , the WIQ speed score and 6-minute walk test speed score (r = 0.89, P < .05)) and the Gujarati WIQ total score and total score of physical functioning domain of SF- 36 (r = 0.99, P < .05). There was excellent test-retest reliability over 7 days for total WIQ score (ICC = 0.94). The Cronbach's alpha for internal consistency of 0.97 for total WIQ score were excellent. This demonstrates the sufficient homogeneity of the total questionnaire. CONCLUSION: The Gujarati version of the WIQ is reliable and valid and can be used to assess self-reported walking impairment in Gujarati-speaking people with PAD and Type II Diabetes.

The High Price of Equity in Pulse Oximetry: A cost evaluation and need for interim solutions.

Importance: Disparities in pulse oximetry accuracy, disproportionately affecting patients of color, have been associated with serious clinical outcomes. Although many have called for pulse oximetry hardware replacement, the cost associated with this replacement is not known. Objective: To estimate the cost of replacing all pulse oximetry hardware throughout a hospital system. Design: Single-center survey, 2023. Setting: Single center. Participants: One academic medical center with three hospitals. Main Outcomes and Measures: Cost of fleet replacement as identified by current day prices for hardware. Results: New and used prices for 5,079/5,678 (89.5%) across three hospitals for pulse oximetry devices were found. The average equipment cost to replace pulse oximetry hardware is $15,704.12 per bed. Replacement and integration costs are estimated at $28.5-31.8 million for the entire medical system. Extrapolating these costs to 5,564 hospitals in the United States results in an estimated cost of $14.1 billion. Conclusions and Relevance: "Simply replacing" pulse oximetry hardware to address disparities may be neither simple, cheap, or timely. Solutions for addressing pulse oximetry accuracy disparities leveraging current technology may be necessary. Trial Registration: Pro00113724, exempt.

Inequity in exercise-based interventions for adults with rheumatoid arthritis: a systematic review.

Objectives: This systematic review describes the extent to which PROGRESS-Plus equity factors were considered in the eligibility criteria of trials of exercise interventions for adults with RA. Methods: Electronic databases were searched for published (Cinahl, Embase, Medline, Physiotherapy Evidence Database), unpublished (Opengrey) and registered ongoing (International Standard Randomized Controlled Trial Number registry) randomized controlled trials (RCTs) of exercise interventions for adults with RA. Two authors independently performed study selection and quality assessment (Cochrane risk of bias tool). Results: A total of 9696 records were identified. After screening, 50 trials were included. All trials had either some concerns or high risk of bias and reported at least one PROGRESS-Plus equity factor within the eligibility criteria; this included place of residence, personal characteristics (age and disability), language, sex, social capital, time-dependent factors or features of relationship factors. Where reported, this equated to exclusion of 457 of 1337 potential participants (34%) based on equity factors. Conclusion: This review identified the exclusion of potential participants within exercise-based interventions for people with RA based on equity factors that might affect health-care opportunities and outcomes. This limits the generalizability of results, and yet this evidence is used to inform management and service design. Trials need to optimize participation, particularly for people with cardiovascular conditions, older adults and those with cognitive impairments. Reasons for exclusions need to be justified. Further research needs to address health inequalities to improve treatment accessibility and the generalizability of research findings. PROSPERO registration: CRD42021260941.

Inequity in exercise-based interventions for adults with intermittent claudication due to peripheral arterial disease: a systematic review.

PURPOSE: To determine the equity in access to trials of exercise interventions for adults with intermittent claudication due to peripheral arterial disease. METHODS: Systematic electronic database searches of MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Clinical Trials, PEDRO, Opengrey, ISRCTN and ClinincalTrials.gov for randomised controlled trials of exercise interventions for adults with intermittent claudication were conducted. Data extraction was informed by Cochrane's PROGRESS-Plus framework. RESULTS: Searches identified 6412 records. Following the screening of 262 full texts, 49 trials including 3695 participants were included. All trials excluded potential participants on at least one equity factor. This comprised place of residence, language, sex, personal characteristics (e.g., age and disability), features of relationships (e.g., familial risk factors) and time-dependent factors, (e.g., time since revascularisation). Overall, 1839 of 7567 potential participants (24.3%) were excluded based on equity factors. Disability was the most frequently reported factor for exclusions. CONCLUSION: Trialists endeavour to enrol a representative sample in exercise trials whilst preserving the safety profile of the intervention. This review highlights that these efforts can inadvertently lead to inequities in access as all trials excluded potential participants on at least one equity factor. Future exercise trials should optimise participation to maximise generalisability of findings. PROSPERO registration no. CRD42020189965.Implications for rehabilitationEquity factors influence health opportunities and outcomes.All trials of exercise for people with intermittent claudication excluded adults on at least one equity factor.Disability was the predominant factor for exclusions from trials.Trials should optimise participation to maximise generalisability of results as these findings are used to inform treatment and service design.

Health System Redesign of Cardiac Monitoring Oversight to Optimize Alarm Management, Safety, and Staff Engagement.

OBJECTIVE: The purpose of this quality improvement project was to improve health system patient safety by creating a cardiac monitoring structure aligned with national standards. BACKGROUND: Excessive alarms pose patient safety threats and are often false or clinically insignificant. The Joint Commission identified reduction of nonactionable alarms as a National Patient Safety Goal. METHODS: The conversion to structured monitoring occurred in 4 phases: 1) defining health system monitoring structure and processes; 2) co-create sessions; 3) implementation and impact analysis; and 4) ongoing evaluation and optimization. RESULTS: Twenty-two clinical units participated. At the conclusion of phase 4, total 30-day alarm rates decreased by 74% at the academic hospital and by 92% and 95% at the community hospitals and were sustained for 12 months. CONCLUSIONS: Decreasing alarm frequency can be safely achieved in academic and community hospitals by creating a system-wide monitoring infrastructure and standardized processes that engage interdisciplinary teams.

Moving nursing innovation to prime time through the use of creative partnerships.

Nurses are well-positioned to solve many problems in healthcare through engagement in innovation. Support from healthcare organizations to facilitate creative partnerships may accelerate nurses' ability to innovate and improve job satisfaction. The value of creative partnerships is rooted in the diversity of experiences and skillsets of each project team member. While nurses may be content experts and key stakeholders, they often lack experience with project management, information technology, product development, and other important skills. We describe the use of co-creation approaches in creative partnerships with diverse stakeholders to enhance the ability of nurse-led project teams to build valuable and sustainable products or services.

Implementing Best Practices to Redesign Workflow and Optimize Nursing Documentation in the Electronic Health Record.

BACKGROUND: Documentation burden associated with electronic health records (EHR) is well documented in the literature. Usability and functionality of the EHR are considered fragmented and disorganized making it difficult to synthesize clinical information. Few best practices are reported in the literature to support streamlining the configuration of documentation fields to align clinical workflow with EHR data entry elements. OBJECTIVE: The primary objective was to improve performance, reduce duplication, and remove nonvalue-added tasks by redesigning the patient assessment template in the EHR using best practice approaches. METHODS: A quality improvement approach and pre-/postdesign was used to implement and evaluate best approaches to redesign standardized flowsheet documentation workflow. We implemented standards for usability modifications targeting efficiency, reducing redundancy, and improving workflow navigation. The assessment type row was removed; a reassessment section was added to the first three flowsheet rows and documentation practices were revised to document changes from the initial assessment by selecting the corresponding body system from the dropdown menu. Vendor-supplied timestamp data were used to evaluate documentation times. Video motion-time recording was used to capture click and scroll burden, defined as steps in documentation, and was analyzed using the Keystrok Level Model. RESULTS: This study's results included an 18.5% decreased time in the EHR; decrease of 7 to 12% of total time in flowsheets; time savings of 1.5 to 6.5 minutes per reassessment per patient; and a decrease of 88 to 97% in number of steps to perform reassessment documentation. CONCLUSION: Workflow redesign to improve the usability and functionality decreased documentation time, redundancy, and click burden resulting in improved productivity. The time savings correlate to several hours per 12-hour shift which could be reallocated to value-added patient care activities. Revising documentation practices in alignment with redesign benefits staff by decreasing workload, improving quality, and satisfaction.

Development and evaluation of a prospective staffing model to improve retention.

AIMS: To improve predictability and accuracy of hiring using historical staffing data, quality improvement and workforce engagement. BACKGROUND: Twenty-three per cent of newly licensed nurses leave their first job within one year, costing employers $52,100 per nurse replacement. Tools for anticipatory hiring strategies are not available in the literature. METHODS: We used retrospective, secondary data analysis to develop a Prospective Staffing Model and conduct a five-year longitudinal evaluation of the implementation of the model in a convenience sample at a quaternary academic Cardiothoracic Intensive Care Unit. We used a team-based, quality improvement approach to restructure recruitment and hiring strategies, standardize new graduate nurse orientation and implement AACN Healthy Work Environment standards. RESULTS: Over the five-year prospective evaluation period (2014-2018), 388 nurses were hired and included in the evaluation cohort. Retention increased (n = 286 days) and turnover decreased (17.6%) between 2014 and 2018. Improvements in workforce stability were sustained at five years. CONCLUSIONS: Use of a Prospective Staffing Model is associated with improved nurse retention and decreased turnover, and may improve workforce stability. IMPLICATIONS FOR NURSING MANAGEMENT: Results suggest that an innovative tool can mitigate the deleterious effects of turnover, adding to current knowledge and providing a method for anticipatory assessment of local turnover.

Outcomes in Hospitalized Ischemic Stroke Patients with Dementia on Admission: A Population-Based Cohort Study.

BACKGROUND: Dementia prevalence is rising, and it will double in the next 20 years. This study sought to understand the prevalence of dementia in hospitalized patients with ischemic stroke, and its impact on outcomes. METHODS: Using the Canadian Institute of Health Information's (CIHI) Discharge Abstract Database (DAD), all acute ischemic stroke admissions from April 2003 to March 2015 in Canada (excluding Quebec) were analyzed. Concurrent dementia at the time of admission was assessed based on hospital diagnostic codes. Characteristics and in-hospital outcomes were compared in patients with and without dementia using χ 2 and negative binomial, as well as Poisson regression analysis. RESULTS: During the observed period, 313,138 people were admitted to a hospital in Canada for an ischemic stroke. Of those, 21,788 (7.0%) had a concurrent diagnosis of dementia. People with dementia had older median age (84 vs. 76 years; p<0.0001), were more often female (59.6% vs. 48.4%; p<0.0001) and more often had Charlson-Deyo Comorbidity Index ≥2 (64.5% vs. 43.5%; p<0.0001). Patients with dementia were less likely to be discharged to a rehabilitation facility (adjusted risk ratio [RR] 3.089, 95% confidence interval [CI] 2.992-3.188, p<0.0001) or home independently (adjusted RR 0.756, 95% CI 0.737-0.776, p<0.0001).InterpretationApproximately 1 in 13 hospitalized ischemic stroke patients has coded dementia. Patients with ischemic stroke and concurrent dementia have higher mortality, face significantly more dependence after stroke and utilize greater healthcare resources than stroke patients without dementia. Causative conclusions are limited by the administrative data source. Early care planning and coordination could potentially optimize outcomes.

Facilitation of child health research in hospital settings: The views of nurses.

AIMS AND OBJECTIVES: To explore the views of nurses towards child health research and to identify factors influencing their willingness to facilitate it in practice. BACKGROUND: Child health research in clinical practice is increasing throughout the UK. Nurses and midwives facilitate access to patients, enact research study protocols and have a critical role in parental decisions to enrol children into research studies. Little is known about their perception of this process. DESIGN: This study was a descriptive study design. METHODS: A newly designed questionnaire was completed in 2013 by 105 nurses in three neonatal and two children's units in two discrete acute hospital sites. RESULTS: Overwhelming support for clinical research was reported. Participants were motivated to facilitate research in order to improve patient care and contribute to the evidence base, but discouraged by external organisational factors and ethical concerns. Training, education and a dedicated team to support research were considered important. Misconceptions regarding consent and the allocation of treatment were reported. Participants raised particular concerns about trials of investigational medicinal product. CONCLUSION: Negative views of nurses towards research, combined with a lack of knowledge of research processes, governance and ethics, have the potential to threaten the success of clinical research studies. RELEVANCE TO CLINICAL PRACTICE: Focus on three main areas: staff education, improved communication and the demonstration of managerial commitment to clinical research.

HER2 Gene Amplification Testing by Fluorescent In Situ Hybridization (FISH): Comparison of the ASCO-College of American Pathologists Guidelines With FISH Scores Used for Enrollment in Breast Cancer International Research Group Clinical Trials.

Purpose ASCO and the College of American Pathologists (ASCO-CAP) recently recommended further changes to the evaluation of human epidermal growth factor receptor 2 gene (HER2) amplification by fluorescent in situ hybridization (FISH). We retrospectively assessed the impact of these new guidelines by using annotated Breast Cancer International Research Group (BCIRG) -005, BCIRG-006, and BCIRG-007 clinical trials data for which we have detailed outcomes. Patients and Methods The HER2 FISH status of BCIRG-005/006/007 patients with breast cancers was re-evaluated according to current ASCO-CAP guidelines, which designates five different groups according to HER2 FISH ratio and average HER2 gene copy number per tumor cell: group 1 (in situ hybridization [ISH]-positive): HER2-to-chromosome 17 centromere ratio ≥ 2.0, average HER2 copies ≥ 4.0; group 2 (ISH-positive): ratio ≥ 2.0, copies < 4.0; group 3 (ISH-positive): ratio < 2.0, copies ≥ 6.0; group 4 (ISH-equivocal): ratio < 2.0, copies ≥ 4.0 and < 6.0; and group 5 (ISH-negative): ratio < 2.0, copies < 4.0. We assessed correlations with HER2 protein, clinical outcomes by disease-free survival (DFS) and overall survival (OS) and benefit from trastuzumab therapy (hazard ratio [HR]). Results Among 10,468 patients with breast cancers who were successfully screened for trial entry, 40.8% were in ASCO-CAP ISH group 1, 0.7% in group 2; 0.5% in group 3, 4.1% in group 4, and 53.9% in group 5. Distributions were similar in screened compared with accrued subpopulations. Among accrued patients, FISH group 1 breast cancers were strongly correlated with immunohistochemistry 3+ status (P < .0001), whereas groups 2, 3, 4, and 5 were not; however, groups 2, 4 and, 5 were strongly correlated with immunohistochemistry 0/1+ status (all P < .0001), whereas group 3 was not. Among patients accrued to BCIRG-005, group 4 was not associated with significantly worse DFS or OS compared with group 5. Among patients accrued to BCIRG-006, only group 1 showed a significant benefit from trastuzumab therapy (DFS HR, 0.71; 95% CI, 0.60 to 0.83; P < .0001; OS HR, 0.69; 95% CI, 0.55 to 0.85; P = .0006), whereas group 2 did not. Conclusion Our findings support the original categorizations of HER2 by FISH status in BCIRG/Translational Research in Oncology trials.

Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial.

BACKGROUND: mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer. METHODS: In this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment for advanced disease except endocrine therapy. Patients were randomly assigned (2:1) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m(2) on days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added during the course of the study, before unmasking based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here. This trial is registered with ClinicalTrials.gov, number NCT00876395. FINDINGS: Between Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41·3 months (IQR 35·4-46·6). In the full population, median progression-free survival was 14·95 months (95% CI 14·55-17·91) with everolimus versus 14·49 months (12·29-17·08) with placebo (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·1166). In the HR-negative subpopulation (n=311), median progression-free survival with everolimus was 20·27 months (95% CI 14·95-24·08) versus 13·08 months (10·05-16·56) with placebo (hazard ratio 0·66, 95% CI 0·48-0·91; p=0·0049); however, the protocol-specified significance threshold (p=0·0044) was not crossed. The most common adverse events with everolimus were stomatitis (314 [67%] of 472 patients in the everolimus group vs 77 [32%] of 238 patients in the placebo group), diarrhoea (267 [57%] vs 111 [47%] patients), and alopecia (221 [47%] vs 125 [53%]). The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia (117 [25%] vs 35 [15%]), stomatitis (59 [13%] vs three [1%]), anaemia (46 [10%] vs six [3%]) and diarrhoea (43 [9%] vs 10 [4%]) On-treatment adverse event-related deaths were reported in 17 (4%) patients in the everolimus group and none in the placebo group. INTERPRETATION: Although progression-free survival was not significantly different between groups in the full analysis population, the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative, HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial. FUNDING: Novartis Pharmaceuticals.

Presumed primary and secondary hepatic copper accumulation in cats.

OBJECTIVE: To determine signalments, clinical features, clinicopathologic variables, imaging findings, treatments, and survival time of cats with presumed primary copper-associated hepatopathy (PCH) and to determine quantitative measures and histologic characteristics of the accumulation and distribution of copper in liver samples of cats with presumed PCH, extrahepatic bile duct obstruction, chronic nonsuppurative cholangitis-cholangiohepatitis, and miscellaneous other hepatobiliary disorders and liver samples of cats without hepatobiliary disease. DESIGN: Retrospective cross-sectional study. ANIMALS: 100 cats with hepatobiliary disease (PCH [n = 11], extrahepatic bile duct obstruction [14], cholangitis-cholangiohepatitis [37], and miscellaneous hepatobiliary disorders [38]) and 14 cats without hepatobiliary disease. PROCEDURES: From 1980 to 2013, cats with and without hepatobiliary disease confirmed by liver biopsy and measurement of hepatic copper concentrations were identified. Clinical, clinicopathologic, and imaging data were compared between cats with and without PCH. RESULTS: Cats with PCH were typically young (median age, 2.0 years); clinicopathologic and imaging characteristics were similar to those of cats with other liver disorders. Copper-specific staining patterns and quantification of copper in liver samples confirmed PCH (on the basis of detection of > 700 µg/g of liver sample dry weight). Six cats with PCH underwent successful treatment with chelation (penicillamine; n = 5), antioxidants (5), low doses of elemental zinc (2), and feeding of hepatic support or high-protein, low-carbohydrate diets, and other hepatic support treatments. One cat that received penicillamine developed hemolytic anemia, which resolved after discontinuation of administration. Three cats with high hepatic copper concentrations developed hepatocellular neoplasia. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that copper accumulates in livers of cats as primary and secondary processes. Long-term management of cats with PCH was possible.

Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial.

BACKGROUND: We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. METHODS: BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740. FINDINGS: Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72-79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. INTERPRETATION: Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. FUNDING: Sanofi.

Adjuvant trastuzumab in HER2-positive breast cancer.

BACKGROUND: Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. METHODS: We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. RESULTS: At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. CONCLUSIONS: The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).