Inflammation-induced loss of CFTR-expressing airway ionocytes in non-eosinophilic asthma.

BACKGROUND AND OBJECTIVE: Severe asthma is a heterogeneous disease with subtype classification according to dominant airway infiltrates, including eosinophilic (Type 2 high), or non-eosinophilic asthma. Non-eosinophilic asthma is further divided into paucigranulocytic or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in the airways. Severe non-eosinophilic asthma has few effective treatments and many patients do not qualify for biologic therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease and has proven a valuable therapeutic target. We hypothesized that the CFTR may also play a role in non-eosinophilic asthma. METHODS: Patient-derived human bronchial epithelial cells (hBECs) were isolated and differentiated at the air-liquid interface. Single cell RNA-sequencing (scRNAseq) was used to identify epithelial cell subtypes and transcriptional activity. Ion transport was investigated with Ussing chambers and immunofluorescent quantification of ionocyte abundance in human airway epithelial cells and murine models of asthma. RESULTS: We identified that hBECs from patients with non-eosinophilic asthma had reduced CFTR function, and did not differentiate into CFTR-expressing ionocytes compared to those from eosinophilic asthma or healthy donors. Similarly, ionocytes were also diminished in the airways of a murine model of neutrophilic-dominant but not eosinophilic asthma. Treatment of hBECs from healthy donors with a neutrophilic asthma-like inflammatory cytokine mixture led to a reduction in ionocytes. CONCLUSION: Inflammation-induced loss of CFTR-expressing ionocytes in airway cells from non-eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target.

Access to healthcare services during the COVID-19 pandemic: a cross-sectional analysis of income and user-access across 16 economically diverse countries.

BACKGROUND: National health systems have different strengths and resilience levels. During the COVID-19 pandemic, resources often had to be reallocated and this impacted the availability of healthcare services in many countries. To date there have been few quantitative contemporary studies of inequalities in access to healthcare within and between countries. In this study, we aim to compare inequality within and between 16 economically diverse countries. METHODS: Online surveys were conducted on 22 150 adults in 16 countries across six continents in 2022. Quota sampling and post-stratification weighting was used to obtain an age, gender, geographically, and educationally representative sample. The study assesses the differences in challenges in access to healthcare during the pandemic (for GP, surgical/clinical and digital GP services) using country-specific expanded health-needs-adjusted Erreygers' concentration indices and compares these values between countries using a Spearman's rank correlation coefficient. RESULTS: Results show wide variation in income-related challenges in access within countries for different types of care. For example, Erreygers' concentration index for digital services in Colombia exhibited highly regressive inequality at 0·17, compared to Japan with an index of -0·15. Inequalities between countries were also evident, with Spearman rank coefficients of -0·69 and -0·65 (p-values of 0·003 and 0·006) for digital and surgical access, indicating that lower income countries had greater inequality in healthcare access challenges. CONCLUSION: During the pandemic, inequalities in challenges to accessing healthcare were greatest in low and middle-income countries. Digital technologies offer a reasonable means to address some of this inequality if adequate support is provided and accessible digital infrastructure exists.

A full-factorial test of motivational and volitional intervention strategies for promoting exercise habit formation and exercise maintenance among new users of an online exercise class platform.

Interventions often fail to achieve long-term behavioral maintenance. Utilizing motivational and volitional strategies to promote behavioral maintenance factors may improve this. Using a full-factorial experiment, we tested the effects of three intervention components (focused on intrinsic motivation and identity, exercise preparation habit, and exercise instigation habit) on exercise participation over a year, among new users (N = 751; 91% identifying as female, 54% identifying as White race) of a global, online exercise class platform, run by Les Mills International Ltd, called LM+. We also tested the intervention components' theoretical mechanisms of action-habit formation, intrinsic motivation, identity, and self-efficacy. Multi-level models found some support for a main effect of the exercise preparation habit intervention component in promoting self-reported and objective exercise participation (behavioral outcomes measured via monthly surveys and the LM+ platform; mechanisms measured via monthly surveys)-in particular online exercise class frequency (fixed effect estimate = 0.84, p < 0.05, and = 0.12, p < 0.05, respectively). The preparation habit component also significantly increased preparation habit strength (0.30, p < 0.05) and instigation habit strength (0.33, p < 0.05). Other expected effects were nonsignificant. Helping individuals form an exercise preparation habit may facilitate initiating and maintaining exercise over time, in particular for attending online exercise classes, potentially through promoting greater preparation and exercise instigation habit strength.

Germline genetic mutations in a multi-center cohort of 248 phyllodes tumors.

PURPOSE: Germline genetic mutations in women with phyllodes tumors (PT) are understudied, although some describe associations of PT with various mutations. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in women with PT. METHODS: A 6-site multi-center study of women with a PT was initiated, then expanded nationally through an online "Phyllodes Support Group." All women underwent 84-gene panel testing. We defined eligibility for testing based on select NCCN (National Comprehensive Cancer Network) criteria (v1.2022). Logistic regression was used to estimate the association of covariates with the likelihood of a P/LP variant. RESULTS: 274 women were enrolled: 164 (59.9%) through multi-center recruitment and 110 (40.1%) via online recruitment. 248 women completed testing; overall 14.1% (N = 35) had a P/LP variant, and over half (N = 19) of these individuals had a mutation in genes associated with autosomal dominant (AD) cancer conditions. The most common AD genes with a P/LP variant included CHEK2, ATM, and RAD51D. A quarter of participants (23.8%) met NCCN criteria for testing, but we found no difference in prevalence of a P/LP variant based on eligibility (p = 0.54). After adjustment, the presence of P/LP variants was not associated with age, NCCN testing eligibility, or PT type (all p > 0.05). CONCLUSION: Our study demonstrates that 7.7% of women with PT harbor germline P/LP variants in genes associated with AD cancer conditions. Early identification of these variants has implications for screening, risk reduction, and/or treatment. National guidelines for women with PT do not currently address germline genetic testing, which could be considered.

Duration of Benefit and Risk of Dual Antiplatelet Therapy up to 72 Hours After Mild Ischemic Stroke and Transient Ischemic Attack.

BACKGROUND AND OBJECTIVES: Clopidogrel-aspirin initiated within 72 hours of symptom onset is effective in patients with mild ischemic stroke or transient ischemic attack (TIA) in the Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial. Uncertainties remain about the duration of the treatment effect. This study aimed to assess duration of benefit and risk of clopidogrel-aspirin in these patients. METHODS: The INSPIRES trial was a 2*2 factorial placebo-controlled randomized trial conducted in 222 hospitals in China. The 2 treatments did not interact and were evaluated separately. In this study, we performed secondary analyses based on antiplatelet treatment. All patients with mild stroke or TIA of presumed atherosclerotic cause within 72 hours of symptom onset enrolled in the trial were included. Patients were randomly assigned to receive clopidogrel-aspirin on days 1-21 followed by clopidogrel on days 22-90 or aspirin alone for 90 days. The primary efficacy outcome was major ischemic event which included the composite of ischemic stroke and nonhemorrhagic death. The primary safety outcome was moderate-to-severe bleeding. We estimated the risk difference between the 2 treatments for each stratified week. RESULTS: All 6,100 patients in the trial were included (3,050 in each group). The mean age was 65 years, and 3,915 patients (64.2%) were men. Compared with aspirin alone, the reduction of major ischemic events by clopidogrel-aspirin mainly occurred in the first week (absolute risk reduction [ARR] 1.42%, 95% CI 0.53%-2.32%) and remained in the second week (ARR 0.49%, 95% CI 0.09%-0.90%) and the third week (ARR 0.29%, 95% CI -0.05% to 0.62%). Numerical higher risk of moderate-to-severe bleedings in the clopidogrel-aspirin group was observed in the first 3 weeks (absolute risk increase 0.05% [95% CI -0.10% to 0.20%], 0.10% [95% CI -0.09% to 0.29%], and 0.18% [95% CI -0.03% to 0.40%] in the first, second, and third weeks, respectively). CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, the net benefit of clopidogrel-aspirin initiated within 72 hours of symptom onset was pronounced in the first week and continued to a lesser degree in the following 2 weeks, outweighing the low, but ongoing hemorrhagic risk. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03635749. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, the net benefit of clopidogrel-aspirin initiated within 72 hours of symptom onset was pronounced in the first week and continued to a lesser degree in the following 2 weeks, outweighing the low but ongoing hemorrhagic risk.

Specific locations of myocardial inflammation and fibrosis are associated with higher risk of events in cardiac sarcoidosis.

BACKGROUND: 18F-FDG-PET/MR can identify inflammation and fibrosis, high-risk features in cardiac sarcoidosis. OBJECTIVE: To evaluate whether the involvement of certain myocardial segments is associated with higher risk compared to others. METHODS: 124 patients with suspected clinical sarcoidosis underwent 18F-FDG-PET/MR. Late gadolinium enhancement (LGE) and focal 18F-FDG uptake were evaluated globally and in the 16 myocardial segments. Presence of LGE was defined when the percentage of LGE exceeded 5.7% globally (relative to myocardial volume) and in each myocardial segment. Patients were followed up for 5.5 years. Events were defined as ventricular arrhythmia (VA, including sustained ventricular tachycardia, ventricular fibrillation, and appropriate ICD discharge), heart failure hospitalization, or all-cause death. RESULTS: Mean age was 57.1±8.9 years, and 39.5% were female; 22 patients (17.6%) had an event at follow-up, and 9 (7.2%) presented VA. LGE and 18F-FDG uptake were more frequent in patients with than without events (36.4% vs 7.8%, p=0.001). Presence of LGE or 18F-FDG in the basal anterior segment were independent predictors for events after adjustment by left ventricular ejection fraction and relative enhanced volume (LGE: OR 10.5[1.2-92.4]; p=0.034;18F-FDG: OR 5.5[1.1-27.5], p=0.038). LGE presence in basal to mid anterior, mid anteroseptal, and basal to mid inferoseptal segments was an independent predictor for VA. Presence of 18F-FDG in basal to mid anterior, mid inferoseptal and mid inferior segments was an independent predictor for VA. CONCLUSION: Involvement of specific myocardial segments, particularly basal to mid anterior and mid septal segments, is associated with higher rates of events in patients with suspected cardiac sarcoidosis.

Study protocol: process and outcome evaluation of the Walk with Ease program for fall prevention.

BACKGROUND: Falls are the leading cause of injury related morbidity and mortality in older adults. Primary and secondary prevention strategies that address modifiable risk factors are critically important to reduce the number of falls and fall related injuries. A number of evidence-based fall prevention programs are available, but few offer potential for broad dissemination and public health impact due to implementation barriers, such as a need for trained program leaders and clinicians. METHODS: The study will use a randomized controlled trial design to evaluate incorporating physical therapy exercises (primary prevention strategy) within an existing intervention called Walk with Ease. While Walk with Ease has an established evidence-base related to the management of arthritis pain and symptoms, the present study will determine the potential to also reduce falls and fall risk in community-dwelling older adults. The integrated process and outcome evaluation will determine the relative effectiveness of individually-prescribed exercises (compared to standardized exercises) as well as the potential of 'habit training' resources (relative to generic behavior prompts) to improve compliance with exercises in this population. DISCUSSION: The study, conducted through a local clinical-community partnership will advance both the science and practice of community-based fall prevention programming, while also informing implementation strategies needed to promote broader dissemination. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05693025, Registered January 20, 2023, Updated March 1, 2023.

The EORTC 22922/10925 trial investigating regional nodal irradiation in stage I-III breast cancer: Outcomes according to locoregional and systemic therapies.

The EORTC 22922/10925 trial aimed to investigate the impact on overall survival (OS) of elective internal mammary and medial supraclavicular (IM-MS) radiation therapy (RT) in breast cancer stage I-III. Surgery for the primary tumour and axillary lymph nodes, chest wall RT, boost RT after whole breast RT in breast conserving therapy (BCT), RT to operated axilla, and systemic therapy were per physician's preference. The aim of the current analysis is to assess breast cancer outcomes according to different locoregional and systemic therapy used in the trial. MATERIAL/METHODS: Data with a median follow-up of 15.7 years were extracted from the trial's case report forms. Kaplan-Meier curves of disease-free and OS and cumulative incidence curves of breast cancer events were produced. An exploratory analysis of the effect of the type of locoregional and systemic therapy on breast cancer outcomes was conducted using the Cox model or the Fine & Gray model accounting for competing risks, both models being adjusted for baseline patient and disease characteristics and treatment. The significance level was set at 5 %, 2-sided. RESULTS: Of the 4,004 patients included, 625 (16%) did not receive any postoperative systemic therapy, 1,185 (30%) received endocrine therapy only, 994 (25%) chemotherapy only, and 1,200 (30%) both chemotherapy and endocrine therapy, without differences between the randomisation arms. Administration and type of therapy was associated with age, menopausal status, clinical T- and N-stage and ER status (p < 0.0001). Local control was better with mastectomy (with/without postmastectomy RT) as compared to BCT, but mastectomy was associated with more distant metastasis (DM) as first event. Similarly, DM as first event occurred more in the BCT group that received a boost as compared to no boost and in those who received RT to the lower axillary level. IM-MS RT reduced significantly regional recurrences and improved disease-free survival in a sensitivity stratified analysis. OS was worse with mastectomy as compared to BCT and with irradiation of the axilla but better with sentinel node dissection and adjuvant combined chemo and hormonal therapy. CONCLUSION: Different components of therapy influenced the site of first event. IM-MS RT improved outcomes in different breast cancer outcomes were most probably related that the group were balanced due to the trial arms and stratification methods.

The Impact of Unrelated Future Medical Costs on Economic Evaluation Outcomes for Different Models of Diabetes.

OBJECTIVE: This study leveraged data from 11 independent international diabetes models to evaluate the impact of unrelated future medical costs on the outcomes of health economic evaluations in diabetes mellitus. METHODS: Eleven models simulated the progression of diabetes and occurrence of its complications in hypothetical cohorts of individuals with type 1 (T1D) or type 2 (T2D) diabetes over the remaining lifetime of the patients to evaluate the cost effectiveness of three hypothetical glucose improvement interventions versus a hypothetical control intervention. All models used the same set of costs associated with diabetes complications and interventions, using a United Kingdom healthcare system perspective. Standard utility/disutility values associated with diabetes-related complications were used. Unrelated future medical costs were assumed equal for all interventions and control arms. The statistical significance of changes on the total lifetime costs, incremental costs and incremental cost-effectiveness ratios (ICERs) before and after adding the unrelated future medical costs were analysed using t-test and summarized in incremental cost-effectiveness diagrams by type of diabetes. RESULTS: The inclusion of unrelated costs increased mean total lifetime costs substantially. However, there were no significant differences between the mean incremental costs and ICERs before and after adding unrelated future medical costs. Unrelated future medical cost inclusion did not alter the original conclusions of the diabetes modelling evaluations. CONCLUSIONS: For diabetes, with many costly noncommunicable diseases already explicitly modelled as complications, and with many interventions having predominantly an effect on the improvement of quality of life, unrelated future medical costs have a small impact on the outcomes of health economic evaluations.

Increased Risk of 10-Year Revision Following Total Hip Arthroplasty for Femoral Neck Fracture.

INTRODUCTION: As the incidence of femoral neck fracture (FNF) increases with the aging population, understanding its impact on surgical outcomes is important to improving implant survival and patient satisfaction. Despite increasing use of total hip arthroplasty (THA) as management for FNF, few studies have examined long-term implant survivability. Thus, this study sought to determine the 10-year cumulative incidence of revision and indications for revision in patients undergoing THA for FNF in comparison to osteoarthritis. METHODS: Patients who underwent primary THA for FNF or osteoarthritis were identified using a national administrative claims database and propensity-score matched in a 1:2 ratio based on age, gender, the Charlson Comorbidity Index (CCI), smoking, obesity, and diabetes mellitus. Kaplan-Meier and Cox proportional hazards analyses were used to observe the cumulative incidence and risk of all-cause revision, periprosthetic joint infection (PJI), dislocation, mechanical loosening, and periprosthetic fracture (PPF) within 10 years of primary THA. In total, 19,735 patients who underwent THA for FNF and 39,383 patients who underwent THA for osteoarthritis were included. RESULTS: The 10-year cumulative incidences of all-cause revision (7.1 versus 4.9%), PJI (5.0 versus 3.3%), dislocation (6.8 versus 3.8%), mechanical loosening (3.1 versus 1.9%), and PPF (7.8 versus 4.0%) were significantly higher for those who underwent THA for FNF versus osteoarthritis. Femoral neck fractures were associated with higher risks of revision (hazard ratio [HR]: 1.6), PJI (HR: 1.7), dislocation (HR: 2.0), mechanical loosening (HR: 1.6), and PPF (HR: 2.2) (P < 0.001 for all). DISCUSSION: Despite the advantages of THA, femoral neck fractures remain a major risk factor for long-term complications. Tailored preoperative planning, surgical techniques, and postoperative bone health optimization in these patients may help minimize poor outcomes.

Mother's milk microbiota is associated with the developing gut microbial consortia in very-low-birth-weight infants.

Mother's milk contains diverse bacterial communities, although their impact on microbial colonization in very-low-birth-weight (VLBW, <1,500 g) infants remains unknown. Here, we examine relationships between the microbiota in preterm mother's milk and the VLBW infant gut across initial hospitalization (n = 94 mother-infant dyads, 422 milk-stool pairs). Shared zero-radius operational taxonomic units (zOTUs) between milk-stool pairs account for ∼30%-40% of zOTUs in the VLBW infant's gut. We show dose-response relationships between intakes of several genera from milk and their concentrations in the infant's gut. These relationships and those related to microbial sharing change temporally and are modified by in-hospital feeding practices (especially direct breastfeeding) and maternal-infant antibiotic use. Correlations also exist between milk and stool microbial consortia, suggesting that multiple milk microbes may influence overall gut communities together. These results highlight that the mother's milk microbiota may shape the gut colonization of VLBW infants by delivering specific bacteria and through intricate microbial interactions.

Cord blood granulocyte levels are associated with severe bronchiolitis in the first year of life.

Objectives: Bronchiolitis is a leading cause of infant hospitalisation in the first year of life, and it preferentially affects infants born to mothers with asthma. Here, we evaluate cord blood granulocytes in infants born to mothers with asthma participating in the Breathing for Life Trial (BLT), to investigate early life determinants of bronchiolitis hospitalisation within the first year of life. Methods: Cord blood from 89 participants was collected into EDTA tubes and processed within 6 h of birth. Cells were stained in whole cord blood for eosinophils (CD45+, CD193+, CD16-), and neutrophils (CD45+, CD193-, CD16+). Medical records were reviewed for bronchiolitis hospitalisation in the first 12 months of life. Statistical analyses were conducted using Stata IC16.1. Results: Logistic regression adjusted for caesarean section, gestational age, maternal smoking during pregnancy, foetal heart deceleration during labour, and season of birth revealed an association between cord blood eosinophil levels and bronchiolitis hospitalisation in the first 12 months of life with an Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC) curve of 0.943 (aOR = 1.35, P = 0.011). Neutrophils were associated with the risk of bronchiolitis hospitalisation in a univariable logistic regression (OR = 0.93, P = 0.029); however, there was no statistical significance in the adjusted model. Conclusions: Higher eosinophil numbers in cord blood were associated with bronchiolitis hospitalisation in the first 12 months in a cohort of infants born to asthmatic mothers. This suggests that susceptibility to bronchiolitis in later life is influenced by the immune cell profile prior to viral infection.

A description of lineage 1 Mycobacterium tuberculosis from papua, Indonesia.

Indonesia has the third highest number of tuberculosis (TB) patients infected with Mycobacterium tuberculosis (MTB) Lineage 1 (L1). Most of these MTB L1 cases can be found in Indonesia's remote easternmost province of Papua, one of Indonesia's most underdeveloped provinces with a particularly high burden for TB. In this study, we sequenced and described 42 MTB L1 isolates from a well-characterized cohort of patients. We found a genetically diverse MTB L1 population with no association between pathogen genetic relatedness and place of residence or pathogen genetic relatedness and patient ethnicity, which could reflect mixing between different locales and ethnicities or our low sampling fraction. Only a small number showed genetic variants associated with drug resistance (5/42, 11.9 %), probably due to a lack of effective treatment programs. The Papuan isolates showed similarities to other Island Southeast Asian Countries due to the high proportion of L1.2.1.2.1 (30/42, 71.4 %), especially East Timor and the Philippines. This study fills a research gap of MTB L1 in Indonesian Papua and should serve as a stepping stone for further research in the region.

Randomised controlled trials on radiation dose fractionation in breast cancer: systematic review and meta-analysis with emphasis on side effects and cosmesis.

OBJECTIVE: To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023). STUDY SELECTION: Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions). DATA EXTRACTION: Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration's tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively. DATA SYNTHESIS: Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran's Q test and I2 statistic. Network meta-analysis was used to integrate all available evidence. MAIN OUTCOME MEASURES: The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics. RESULTS: From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF. CONCLUSIONS: MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023460249.

Differential Prognostic Value of Residual Nodal Burden in Breast Cancer Subtypes.

Purpose: Residual cancer burden (RCB) index after neoadjuvant chemotherapy (NAC) is highly prognostic in patients with breast cancer (BC) but does not account for subtype or the precise impact of residual nodal burden (RNB). We aimed to precisely de ne the effect of RNB on survival by subtypes. Methods: Adult women with non-metastatic BC diagnosed from 2006-2021 in the National Cancer Database (NCDB) who received NAC followed by surgery within 8 months were included. RNB was also evaluated as a predictor of mortality with multivariable logistic regression. Kaplan-Meier analyses were performed to compare overall survival. Results: 51,917 patients were included. After adjustment, ypN stage was the strongest predictor of mortality, with an odds ratio (OR) of 2.24 (95% CI 2.08-2.41) for ypN1 vs ypN0 and increased with increasing nodal burden - ypN2 vs ypN0 OR 5.03, 95% CI 4.60-5.51 and ypN3 vs ypN0 OR 8.85, 95% CI 7.88-9.93. Stratification of survival curves with higher RNB is most pronounced for triple-negative breast cancer (TNBC) with an absolute difference of 64% in 5-year overall survival between ypN0 and ypN3 patients, and lowest for the ER+/HER2- subtype with a 25% absolute difference in 5-year OS between ypN0 and ypN3 patients. On interaction analysis, ypN status was a stronger predictor of mortality for the TNBC subtype compared to other subtypes. Conclusion: RNB has a significantly different impact on survival by BC subtypes. Future study of optimal therapeutic strategies for patients with residual nodal disease after NAC should account for subtype specific differences in prognosis.

Clopidogrel and Aspirin Initiated Between 24 to 72 Hours for Mild Ischemic Stroke: A Subgroup Analysis of the INSPIRES Randomized Clinical Trial.

Importance: Prior trials showed that dual antiplatelet therapy could reduce the risk of early new stroke in patients with acute mild ischemic stroke or transient ischemic attack (TIA) within 24 hours of symptom onset. However, it is currently uncertain whether dual antiplatelet therapy can reduce the risk of early new stroke in patients with a more delayed initiation time window. Objective: To evaluate the efficacy and safety of clopidogrel and aspirin among patients with mild ischemic stroke or TIA when initiated within 24 hours, from more than 24 hours to 48 hours, and from more than 48 hours to 72 hours. Design, Setting, and Participants: The Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis randomized clinical trial was a double-blind, placebo-controlled, multicenter, 2-by-2 factorial randomized clinical trial conducted at 222 hospitals in China from September 17, 2018, to October 15, 2022. All patients with acute mild ischemic stroke and TIA were included in this subgroup analysis and categorized into 3 groups according to time from symptom onset to randomization (group 1: ≤24 hours; group 2: >24 to ≤48 hours; and group 3: >48 to 72 hours). Patients were followed up for 90 days. Interventions: All patients received clopidogrel combined with aspirin (clopidogrel 300 mg loading dose on day 1, followed by 75 mg daily on days 2 to 90, and aspirin 100 to 300 mg on the first day and then 100 mg daily for days 2 to 90) or aspirin alone (100 to 300 mg on day 1 and then 100 mg daily for days 2 to 90) within 72 hours after symptom onset. Main Outcomes and Measures: The primary outcome was new stroke (ischemic or hemorrhagic) within 90 days. The primary safety outcome was moderate-to-severe bleeding, according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria. Results: This analysis included a total of 6100 patients (3050 in the clopidogrel-aspirin group and 3050 in the aspirin group). The median age was 65 years (IQR, 57-71 years), and 3915 patients (64.2%) were male. In the population with time to randomization of 24 hours or less, stroke occurred in the next 90 days in 97 of 783 patients (12.4%); among those randomized from more than 24 hours to 48 hours, in 211 of 2552 patients (8.3%) among those randomized from more than 24 hours to 48 hours, and in 193 of 2765 patients (7.0%). The clopidogrel-aspirin group had a lower risk of new stroke within 90 days compared with the aspirin alone group both in patients with time to randomization of from 48 to 72 hours (5.8% vs 8.2%; hazard ratio [HR], 0.70 [95% CI, 0.53-0.94]), of more than 24 to 48 hours (7.6% vs 8.9%; HR, 0.85 [95% CI, 0.65-1.12]), and of 24 hours or less (11.5% vs 13.4%; HR, 0.83 [95% CI, 0.55-1.25]) (P = .38 for interaction). Among those with time to randomization of more than 48 to 72 hours, moderate-to-severe bleeding occurred in 12 patients (0.9%) in the clopidogrel-aspirin group and in 6 patients (0.4%) in the aspirin-alone group (HR, 2.00 [95% CI, 0.73-5.43]), while moderate-to-severe bleeding in those with time to randomization of more than 24 hours to 48 hours occurred in 9 patients (0.7%) in the clopidogrel-aspirin group and in 4 patients (0.3%) in the aspirin-alone group (HR, 2.25 [95% CI, 0.68-7.39]) and in those with time to randomization of within 24 hours, occurred in 6 patients (1.5%) in the clopidogrel-aspirin group and in 3 patients (0.8%) in the aspirin-alone group (HR, 1.57 [95% CI, 0.36-6.83]) (P = .92 for interaction). Conclusions and Relevance: In this randomized clinical trial of antiplatelet therapy in China, patients with mild ischemic stroke or TIA had consistent benefit from dual antiplatelet therapy with clopidogrel and aspirin vs aspirin alone when initiated within 72 hours after symptom onset, with a similar increase in the risk of moderate-to-severe bleeding. Patients should receive dual antiplatelet therapy with clopidogrel and aspirin within 72 hours after symptom onset. Trial Registration: ClinicalTrials.gov Identifier: NCT03635749.

Differential prognostic value of residual nodal burden in breast cancer subtypes.

PURPOSE: Residual cancer burden (RCB) index after neoadjuvant chemotherapy (NAC) is highly prognostic in patients with breast cancer (BC) but does not account for subtype or the precise impact of residual nodal burden (RNB). We aimed to precisely define the effect of RNB on survival by subtypes. METHODS: Adult women with non-metastatic BC diagnosed from 2006 to 2021 in the National Cancer Database (NCDB) who received NAC followed by surgery within 8 months were included. RNB was also evaluated as a predictor of mortality with multivariable logistic regression. Kaplan-Meier analyses were performed to compare overall survival. RESULTS: 51,917 patients were included. After adjustment, ypN stage was the strongest predictor of mortality, with an odds ratio (OR) of 2.24 (95% CI 2.08-2.41) for ypN1 vs ypN0 and increased with increasing nodal burden-ypN2 vs ypN0 OR 5.03, 95% CI 4.60-5.51 and ypN3 vs ypN0 OR 8.85, 95% CI 7.88-9.93. Stratification of survival curves with higher RNB is most pronounced for triple-negative breast cancer (TNBC) with an absolute difference of 64% in 5-year overall survival between ypN0 and ypN3 patients, and lowest for the ER+/HER2- subtype with a 25% absolute difference in 5-year OS between ypN0 and ypN3 patients. On interaction analysis, ypN status was a stronger predictor of mortality for the TNBC subtype compared to other subtypes. CONCLUSION: RNB has a significantly different impact on survival by BC subtypes. Future study of optimal therapeutic strategies for patients with residual nodal disease after NAC should account for subtype-specific differences in prognosis.