Substudy Of Trial Research Articles

Relevance of timing intake of everolimus (EVE) combined with adjuvant endocrine therapy (ET) in patients (pts) with high-risk early breast cancer: Results of a sub-study of the UCBG-UNIRAD trial.

542 Background: We reported the benefit of taking evening tamoxifen compared to morning/afternoon as adjuvant treatment for high-risk breast cancers in the UNIRAD phase III trial (NCT01805271) (1). Here, we examine the relevance of EVE timing intake in this trial. Methods: 1,277 pts with high-risk HR+/ HER2- primary BC were randomly assigned to adjuvant ET with placebo or EVE (1). Patients prospectively reported in a diary the daily timing for ET and EVE intake among four 6-h slots (06:00 to 11:59 (morning), 12:00 to 17:59 (afternoon), 18:00 to 23:59 (evening), or 24:00 to 05:59 (night). The association between EVE, ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial. Results: EVE timing was recorded by 513 of 632 patients (81.2%). Patients declaring EVE intake in the morning (n= 248, 48 %) or in the afternoon (n=52, 10%) were older than those declaring evening (n=207, 40 %) or night (n=6,1%) intakes ( p<0.001). They were more likely to be postmenopausal (p=0.001) and to take AI rather than tamoxifen (p = 0.03). Only 17 patients (3%) changed EVE intake timing throughout the study. EVE intake dialy times were binned into 2 categories for analyses: morning/afternoon group (n=300) and evening/night group (n = 213). The patients who took morning/afternoon EVE chose another timing for ET in 38% of the cases compared to 17.1% in evening/Night EVE group (p<0.01). The timing of EVE intake was not significantly associated with definitive EVE withdrawal ( p=0.62) in the whole population. Time to EVE withdrawal was significantly longer in the patients taking tamoxifen rather than AI (17.2 vs 10.9 months, p = 0.0047). Prolonged duration of EVE treatment was associated with evening/night intakes of both EVE and tamoxifen, compared to other drug timing modalities (p = 0.04). With a median follow-up of 85months, 15 patients relapsed locally (3%), 55 developed metastases (11%), 36 patients died (7%). Overall, EVE intake timing was not associated with DFS (HR=0.84 [95% CI, 0.53 - 1.35], p=0.4). There was a significant interaction between EVE timing intake and ET type ( P interaction= 0.001). Patients on evening/night EVE combined with tamoxifen had a reduced likelihood of relapse compared to those taking morning/afternoon EVE (HR = 0.17 [0.05- 0.59], p = 0.005). In contrast, no significant EVE effect was found in the AI group (HR = 1.56 [0.92 2.64], p = 0.1). Evening/Night intake of EVE plus tamoxifen was independently associated with DFS (HR 0.13 [0.03-0.6], p = 0.002) after adjustment for age, nodal status, tumor size, ET timing intake, and EVE dose (2.5, 5 or 10 mg). Conclusions: These exploratory results are consistent with a role of circadian rhythm in the efficacy of EVE when given with tamoxifen in pts with high risk early breast cancer. 1. S. Giacchetti et al, Abst 546, ASCO 2023. Clinical trial information: NCT01805271 .

Sonographic evaluation of intracranial hemodynamics and pressure after out-of-hospital cardiac arrest: An exploratory sub-study of the TAME trial

ObjectiveTargeted mild hypercapnia is a potential neuroprotective therapy after cardiac arrest. In this exploratory observational study, we aimed to explore the effects of targeted mild hypercapnia on cerebral microvascular resistance assessed by middle cerebral artery pulsatility index (MCA PI) and intracranial pressure estimated by optic nerve sheath diameter (ONSD) in resuscitated out-of-hospital cardiac arrest (OHCA) patients. Design, setting, participants and interventionsComatose adults resuscitated from OHCA were randomly allocated to targeted mild hypercapnia (PaCO2 50–55 mmHg) or targeted normocapnia (PaCO2 35–45 mmHg) for 24 h in the TAME trial. Main outcome measuresUsing transcranial Doppler and transorbital ultrasound, we obtained MCA PI and ONSD at 4, 24, and 48 h after randomization. Ultrasound parameters were compared between groups using a linear mixed effects model. ResultsTwelve consecutive patients were included, with seven patients in the mild hypercapnia group. MCA PI decreased from 4 to 24 h (p = 0.019) and was lower over the first 24 h in patients allocated to targeted mild hypercapnia compared with targeted normocapnia (p = 0.047). ONSD did not differ between groups or over time. ConclusionCerebral microvascular resistance assessed by MCA PI decreased over 24 h and was lower in OHCA patients treated with targeted mild hypercapnia compared with targeted normocapnia. Targeted mild hypercapnia did not exert substantial effect on intracranial pressure as estimated by ONSD.

His bundle pacing implantation in octogenarian patients: a substudy of the PACE-CONDUCT trial

Abstract Background His bundle pacing (HBP) is gaining recognition as a valuable alternative for the management of various cardiac conduction disorders. This substudy, conducted within the framework of the PACE-CONDUCT trial, investigates the outcomes of HBP implantation in patients aged 80 years and older, comparing them with a younger cohort. Methods We examined a total of 61 consecutive patients who underwent HBP implantation, utilizing DDD pacemakers, CRT-P, or CRT-D devices, during the years 2021 to 2023. Patients were categorized into two subgroups: those aged younger than 80 years and those aged 80 years or older. The mean age of the entire cohort was 73 years, spanning from 51 to 86 years, with 15 patients (comprising 24.6% of the total) falling into the octogenarian category. His bundle threshold was assessed on the day of implantation, one day post-implantation, and four weeks post-implantation. All HBP implantations were deemed successful, incorporating both selective and non-selective His bundle pacing. Complications were classified as major (necessitating lead or pocket revision) or minor (requiring no revision). Threshold values were converted to volts per milliseconds (volts x milliseconds) for statistical analysis, conducted with IBM SPSS Statistics 29.0. Results Initial analysis revealed a consistent success rate of HBP implantation across all patients, with no discernible differences between the two age groups. Threshold measurements at the day of implantation and after one day indicated no differences between the younger and the older group. However, at the four-week mark, a statistically significant lower threshold of His bundle pacing was observed in the octogenarian group (one-sided p-value 0.028), suggesting a faster stabilization to the chronic threshold of the active fixation His Bundle lead. The comparison of major and minor complications between the age groups, conducted using chi-square tests, revealed no age-related discrepancies. Conclusions This substudy of the PACE-CONDUCT trial underscores the feasibility and safety of His bundle pacing implantation in octogenarian patients, comparable to their younger counterparts. While no initial threshold variations are observed, the octogenarian group demonstrated improved His bundle pacing thresholds approximately four weeks post-implantation. Importantly, the study revealed no heightened complication risk associated with advanced age, affirming that very old patients aged 80 or older can derive the benefits of His bundle pacing without increased complication rates. Given the relatively modest patient cohort in this study, further investigations are warranted to validate and extend these findings.T-tests and Chi square tests

The pursuit of gender equality: a substudy of the PACE-CONDUCT trial on gender differences in His bundle pacing implantation

Abstract Background His bundle pacing (HBP) is an effective alternative to traditional right ventricular pacing, providing physiological pacing. The impact of gender on the success of HBP implantation has not been extensively explored. We conducted a substudy of the PACE-CONDUCT registry to investigate gender differences in HBP implantation success. Methods We analyzed successful HBP implantations performed from 2021 to 2023. A total of 61 patients were included, comprising 22 females (36%) and 39 males (64%) . The mean age of the entire cohort was 73 years, with ages ranging from 51 to 86 years. His bundle thresholds were assessed at implantation, the day following implantation, and four weeks post-implantation. All data were analyzed using IBM SPSS Statistics 29.0, and thresholds were converted into volts × milliseconds for statistical analysis. Results The minimal HBP threshold across all measurements was 0.10 volts × milliseconds, equivalent to a standard threshold of 0.25 volts by 0.4 milliseconds, while the maximal threshold was 7.13 volts × milliseconds, corresponding to a standard threshold of 4.75 volts by 1.5 milliseconds. Gender differences were examined, dividing the patient cohort into male and female groups, and an independent-samples t-test was conducted. The results did not reveal any statistically significant differences in HBP threshold between the two groups at the time of implantation, one day post-implantation, or one month post-implantation. Chi square tests were conducted to determine if there could be any gender differences analyzing the complication rates, also finding negative results. Conclusion This substudy of the PACE-CONDUCT trial found no significant gender-based differences in the success of His bundle pacing implantations, taking the threshold at implantation, one day after and four weeks after implantation as a surrogate of goodness of the HBP implantation itself. Although the cohort size was limited, our findings provide initial insights, suggesting that gender is not a decisive factor in HBP threshold outcomes or in complication rates. Further investigations with larger sample sizes are warranted to explore this topic in greater depth.statistics output

Temporal evolution of His bundle pacing thresholds: a sub-study of the PACE-CONDUCT trial

Abstract Background His bundle pacing (HBP) has become a valuable alternative for cardiac resynchronization therapy, offering physiological pacing. This substudy of the PACE-CONDUCT trial aimed to explore the influence selective and non-selective HBP on threshold height. We assessed these parameters in patients with both normal conduction and bundle branch block conduction. Methods Our study included 61 consecutive patients with a median age of 73 years, who underwent a successful HBP implantation for indications such as sick sinus syndrome, AV Block 2 type 2, binodal disease, and ablate and pace therapy prior to AV-node ablation. Among these patients, 18 exhibited QRS durations exceeding 150 ms, indicating a complete and broad bundle branch block which made them candidates for cardiac resynchronization therapy (CRT). All patients received HBP implantation with the assistance of a 3D electroanatomical system. This system allowed for low-fluoroscopic, atraumatic evaluation of the His bundle (HB) area, presenting the His voltage as a color-coded map for precise electrode placement. Results The feasibility of bundle branch correction is generally accepted in selective HBP distal to the site of block, albeit associated with higher threshold values and potentially lower battery duration. Our analysis encompassed 61 patients who underwent HBP implantation, with 23 patients (37,7%) exhibiting selective HBP and 38 (62,3%) non-selective HBP. Remarkably, 10 out of the 23 patients with selective HBP demonstrated a complete bundle branch block correction after HBP implantation even with a basal QRS durations exceeding 150 ms. We evaluated HBP thresholds at implantation, one day post-implantation, and one month post-implantation, correlating these data with selective and non-selective HBP. Threshold values were converted to volts per millisecond (volts × milliseconds) for analysis. Statistical analysis conducted with IBM SPSS 29.0 revealed a significant difference at the day of implantation, indicating higher threshold capture in selective HBP compared to non-selective HBP (one-sided p-value: < 0.01, two sided p value 0.01). However, this difference could not be sustained at the one-day and one-month threshold follow-ups, suggesting normalization of the selective HBP threshold. Conclusion In our study, the initially higher threshold in selective HBP normalized within 24 hours compared to non-selective HBP. Additionally, our study demonstrated the feasibility of selective His pacing in patients with complete bundle branch block and broad QRS durations. These findings provide insights into HBP optimization and encourage further investigations with larger patient cohorts to validate our observations and enhance patient care in the realm of cardiac pacing.Threshold trend

Effect of Low-Dose Aspirin on the Course of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. The Aspirin in Reducing Events in the Elderly-AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. Aspirin (100 mg daily, enteric coated) or placebo. Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. anzctr.org Identifier: ACTRN12613000755730.

Validation of a simple clinical tool for screening of acute lacunar stroke-A substudy of the WAKE-UP trial.

Lacunar stroke represents around a quarter of all ischemic strokes; however, their identification with computed tomography in the hyperacute setting is challenging. We aimed to validate a clinical score to identify lacunar stroke in the acute setting, independently, with data from the WAKE-UP trial using magnetic resonance imaging. We analyzed data from the WAKE-UP trial and extracted Oxfordshire Community Stroke Project (OCSP) classification. Lacunar score was defined by National Institutes of Health Stroke Scale (NIHSS) < 7 and OCSP lacunar syndrome. Assessment of lacunar infarct by two independent investigators was blinded to clinical data. We calculated sensitivity, specificity, negative and positive predictive value (NPV and PPV, respectively) of lacunar score. We included 503 patients in the analysis, mean (±SD) age 65.2 (±11.6) years, 325 (65%) males, median (IQR) NIHSS = 6 (4-9); 108 (22%) lacunar infarcts were identified on magnetic resonance (MR), patients fulfilling lacunar score criteria were 120 (24%), of which 47 (44%) had a lacunar infarct. Lacunar score was negative in 322 (82%) of patients without lacunar infarct. Patients with lacunar score had lower NIHSS (4 vs 7, p < 0.001), higher systolic (157 vs 151 mmHg, p = 0.001) and diastolic (86 vs 83 mmHg, p = 0.013) blood pressure and smaller infarct volume (2.4 vs 9.5 mL, p < 0.001). Performance of lacunar score was as follows: sensitivity 0.44; specificity 0.82; PPV 0.39; NPV 0.84; and accuracy 0.73. Assuming a prevalence of lacunar stroke of 13%, PPV lowered to 0.30 but NPV was 0.90. Lacunar score performed better for supratentorial lacunar infarcts. Lacunar score had a very good specificity and NPV for screening of lacunar stroke. Implementation of this simple tool into clinical practice may help hyperacute management and guide patient selection in clinical trials. Data supporting the results of this paper are available upon reasonable request to the corresponding author.

All lactate are not equal substudy of the BOX trial

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The BOX trial was supported by a grant (NNF17OC0028706) from the Novo Nordisk Foundation. Dr. Hassager's work is funded by a grant (R186-2015-2132) from the Lundbeck Foundation. Background Lactate levels following out-of-hospital cardiac arrest (OHCA) are associated with arrest duration (time to ROSC) and mortality. However, given the complexity of lactate generation and clearance, lactate levels assessed at hospital arrival represent not only time to ROSC but also the quality of resuscitation, circulatory stability following ROSC, dose of epinephrine administered, kidney, liver, and mitochondrial function in the early post-cardiac arrest phase. Accordingly, we describe the lactate levels at hospital arrival according to time to ROSC and one-year mortality. Method In this sub-study of the randomized clinical BOX trial, blood lactate levels were measured immediately at hospital arrival. Time to ROSC was registered in the medical records. Patients were divided into two groups according to median time to ROSC (≤ 18 min or &amp;gt; 18 min). The primary outcome was one-year mortality. Results The study included 768 (97% of the randomized population) patients of which 386 (50%) patients had ≤ 18 min and 382 (50%) patients had &amp;gt; 18 min to ROSC. The median age (64 (54-73) years) and sex distribution (81% men) was similar in both groups. One-year mortality was 76 (20%) and 199 (52%) in the ≤ 18 min and &amp;gt; 18 min to ROSC groups respectively. Mean lactate levels were 3.8 mmol/L (95%CI: 3.5-4.1) and 5.9 mmol/L (95%CI: 5.4-6.2), respectively. Lactate levels differed significantly between one-year survivors and non-survivors in the patients with ≤ 18 min to ROSC (mean difference: 1.9 mmol/L, 95%CI: 1.0 - 2.8) but not for patients with &amp;gt; 18 min to ROSC (mean difference: 0.6 mmol/L, 95%CI: -0.1-1.3), Figure 1. Further, lactate’s ability to predict one-year mortality was fair in the ≤ 18 min group with an Area Under Receiver Operating Characteristic Curve (AUC) of 0.68 (95%CI: 0.62-0.75) but poor for the &amp;gt; 18 min groups with an AUC of 0.55 (95%CI: 0.50-0.61) (DeLong's test for two ROC curves, p = 0.004), Figure 2. Conclusion Lactate's predictive value for one-year mortality decreases with increasing time to ROSC in OHCA. This highlights the importance of individualized clinical approaches based on lactate dynamics in OHCA patients.Figure 1Figure 2

Oxygen targets following immediate percutaneous coronary intervention in comatose survivors of out-of-hospital cardiac arrest - a BOX sub-study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Novo Nordisk Foundation The Lundbeck Foundation. Background Treatment with supplemental oxygen in patients with acute myocardial infarction (AMI) has previously been associated with poorer outcomes. However, in patients with AMI resuscitated from out-of-hospital cardiac arrest (OHCA) and undergoing immediate revascularization, evidence regarding specific oxygen targets is sparse. Purpose To assess the impact of a restrictive versus a liberal oxygen target on infarct size in OHCA patients undergoing immediate percutaneous coronary intervention (PCI). Methods The current study is a sub-study of the BOX trial, a randomized trial with a 2-by-2 factorial design, in which comatose OHCA patients with a presumed cardiac cause of arrest were randomly assigned to either a restrictive oxygen target (partial pressure of arterial oxygen (Pao2) of 9 to 10 kPa) or a liberal oxygen target (Pao2 of 13 to 14 kPa). In this sub-study we included patients who underwent immediate revascularization with PCI. The primary outcome was myocardial infarct size as assessed by the cardiac enzyme troponin-T (TnT). TnT was measured repeatedly during the first 72 hours and analyzed with a repeated measures variance component model with baseline adjustment. Secondary outcome was one-year all-cause mortality assessed by Kaplan-Meier and Cox proportional hazards analyses. Results A total of 329 patients underwent immediate PCI, whereof 172 patients were randomized to the restrictive oxygen target and 157 to the liberal oxygen target. The oxygen intervention was successful with a significantly higher PaO2 in the liberal oxygen target group during the first 72 hours (p&amp;lt;0.0001). Baseline characteristics and findings on coronary angiography (CAG) were similar in the two oxygen target groups. Thus, median age was 63 (interquartile range (IQR) 55–71), 81% were male, and estimated left ventricular ejection fraction on arrival to hospital was 35% (IQR 25–45%). Further, 74% of the patients had an initial postresuscitation electrocardiogram with ST-segment elevations, and the left anterior descending artery was deemed as culprit lesion in 49% of the patients. There was no difference in peak TnT between the restrictive and liberal oxygen target group (median 2540 (IQR 925–6420) versus 3410 (792–8630), ng/l, p=0.23), nor did TnT differ between the groups during the first 72 hours after admission (Figure 1, p=1.00). Within one year from admission, 120 patients (36.5%) had died. There was no difference in mortality between the restrictive (34%) and liberal (39%) oxygen target group (hazard ratio, 0.80; 95% CI, 0.56-1.14; p=0.21) (Figure 2). Conclusion Targeting a restrictive versus a liberal oxygen level in comatose survivors of OHCA who underwent immediate revascularization did not affect infarct size nor did it result in a significant difference in one-year mortality rate.Figure 1:Troponin-T levelsFigure 2:Kaplan-Meier curves

Prolonged mass azithromycin distributions and macrolide resistance determinants among preschool children in Niger: A sub-study of a cluster-randomized trial (MORDOR).

Randomized controlled trials found that twice-yearly mass azithromycin administration (MDA) reduces childhood mortality, presumably by reducing infection burden. World Health Organization (WHO) issued conditional guidelines for mass azithromycin administration in high-mortality settings in sub-Saharan Africa given concerns for antibiotic resistance. While prolonged twice-yearly MDA has been shown to increase antibiotic resistance in small randomized controlled trials, the objective of this study was to determine if macrolide and non-macrolide resistance in the gut increases with the duration of azithromycin MDA in a larger setting. The Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95% CI 1.5 to 3.51, Punadj < 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability. In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored. NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.

Aortic remodelling based on false lumen communications in patients undergoing acute type I dissection repair with AMDS hybrid prosthesis: a substudy of the DARTS trial.

The Dissected Aorta Repair Through Stent (DARTS) Implantation trial demonstrated positive proximal aortic remodelling following aortic dissection repair with the AMDS hybrid prosthesis. In this study, we look to identify predictors of aortic remodelling following aortic dissection repair with AMDS including whether communications between branch vessels and the false lumen (FL) predict aortic growth. The DARTS implantation trial included patients who underwent acute DeBakey type I aortic dissection (ATAD I) repair with the AMDS from March 2017 to January 2019. Anatomic measurements were collected from original computerized tomography scans. Measurements were taken at zones 2, 3, 6 and 9. Patients were grouped based on the number of FL communications with the supra-aortic branch vessels or visceral branch vessels. Forty-seven patients were included in the original DARTS implantation trial. Patients with FL communications with the supra-aortic branch vessels tended to have significant growth at zone 3 (P = 0.02-0.0018), while greater numbers of visceral FL communications tended to predict aortic growth at zones 3 (P = 0.003), 6 (P = 0.017-0.0087) and 9 (P = 0.0016-0.0003). Aortic remodelling following ATAD I repair using the AMDS may be predicted by local FL communications with branch vessels. Patients undergoing ATAD I repair were more likely to experience significant aortic growth in zone 3 with more head vessel communications and in zones 3, 6 and 9 with more visceral FL communications. Predictors of aortic remodelling may help to guide initial surgical management for aortic dissection patients.

Abstract PO1-12-10: Zoledronic acid to prevent rebound fractures after stopping adjuvant denosumab: a randomized controlled sub-study of the ABCSG-18 trial

Abstract Introduction ABCSG-18 trial showed that 60mg denosumab subcutaneously every 6 months halves fracture risk in postmenopausal patients with early breast cancer, who are treated with adjuvant aromatase inhibitors. However, it has been reported that stopping denosumab may lead to overactivation of osteoclasts resulting in so called rebound vertebral fractures. As shown previously, zoledronic acid (ZA), when given to patients of the ABCSG-18 trial after stopping denosumab prevents a high bone turnover state that can occur in some patients. Here we report the impact of a single ZA dose on bone mineral density (BMD) and fractures after stopping denosumab. Methods ABCSG-18 trial patients, who had received adjuvant denosumab were re-randomized to receive a single dose of ZA 5mg i.v. or not, 8 months +- 4 weeks after their last denosumab dose. DXA scans, lateral spine X-rays and bone turnover markers (CTX and osteocalcin) were assessed at baseline and at 6, 12 and 18 months thereafter. New clinical fractures were assessed until 18 months after randomization. Results 50 patients were randomized to either ZA (24pts) or control (26pts). All patients of the ZA arm and 25 out of 26 patients of the control arm had received 7 doses of denosumab within the ABCSG 18 trial before re-randomization. Baseline bone health factors were well balanced between the 2 arms: Baseline BMD did not differ between the two arms with regard to femoral neck (ZA: 0.817 g/cm2; SOC: 0.816g/cm2), total hip (ZA: 0.918g/cm2; SOC: 0.921g/cm2) and lumbar spine (ZA: 1.128 g/cm2; SOC 1.142 g/cm2), respectively. Relative changes in BMD differed significantly between both arms for femoral neck after 12 months (ZA: 0.5%; control: -4.98%, p 0.004) and for total hip after 6 months (ZA: -0.73%; control: -4.61%, p&amp;lt; 0.001) and after 12 months (ZA: -0.13%; control: -5.62%; p&amp;lt; 0.001). There was a trend towards a greater decline in BMD at lumbar spine after 6 months in the control arm versus the ZA arm (-3.35% vs 0.67%, p=0.052). After randomization, 3 asymptomatic fractures (lumbar vertebral and thoracic vertebral in one patient and thoracic vertebral in a second patient) occurred in the ZA arm, whereas 2 clinical fractures (one radius fracture and one lumbar vertebral fracture) occurred in the SOC arm. Conclusion A single dose of Zoledronic acid prevents high bone turnover state resulting in loss of BMD in some patients after stopping denosumab. ZA may therefore be offered to breast cancer patients with aromatase inhibitor after stopping denosumab. Citation Format: Georg Pfeiler, Christian F. Singer, Dominik Hlauschek, Manfreda Diether, Ferdinand Haslbauer, Paul Sevelda, Kristin Köck, Karl Tamussino, Arno C. Reichenauer, Florian Fitzal, Dietmar Heck, Richard Greil, Claudia Pasterk, Sonja Heibl, Walter Herz, Marija Balic, Daniel Egle, Lidija Sölkner, Michael Gnant. Zoledronic acid to prevent rebound fractures after stopping adjuvant denosumab: a randomized controlled sub-study of the ABCSG-18 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-10.

Abstract PO1-15-07: Subtyping-directed precision treatment refines traditional one-size-fits-all therapy in HR+/HER2- breast cancer: a sub-study of the MULAN umbrella trial

Abstract Background: The standard approach of using one-size-fits-all endocrine therapy for hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancers has faced significant challenges due to variations in treatment response among individuals. Consequently, there is still an urgent need to understand the molecular biology of HR+/HER2- breast cancer and explore precision treatment strategy. Methods: We established a multiomics cohort (n = 351), multicenter real-world clinical cohorts (n = 643), a prospective clinical cohort (MULAN trial), and a drug-testing platform containing patient-derived organoids (n = 126) and patient-derived tumor fragments (n = 49) of HR+/HER2- breast cancers. Integrating "bench" and “bedside” data, we conducted comprehensive preclinical and clinical translational research on precision strategies in HR+/HER2- breast cancer. Results: We implemented a comprehensive classification system for HR+/HER2- breast cancer, comprising four distinct subtypes. We further demonstrated the efficacy and mechanisms of subtyping-directed precision treatment strategies through clinical cohort studies, omics analysis and functional assays: endocrine therapy alone for the canonical luminal subtype; the addition of CDK4/6 inhibitor and PARP inhibitor for the proliferative subtype; the immunotherapy for the immunogenic subtype; and tyrosine kinase inhibitors for the receptor tyrosine kinase-driven subtype. Using clinically applicable subtyping methods, we validated that matched precision treatment strategies outperformed unmatched approaches in a real-world cohort, almost doubling the median progression-free survival time for patients with refractory advanced HR+/HER2- breast cancer (9.83 months [95% CI, 5.74-13.93] vs 4.77 months [95% CI, 3.35-6.18]; hazard ratio 0.64 [95% CI, 0.41-0.99]). Importantly, the first-stage analysis of the MULAN phase II umbrella clinical trial (NCT04355858) verified the higher objective response rate (88.9%, 95%CI: 51.7%-99.7%) of the subtyping-directed precision treatment. Conclusion: Our study emphasizes the superiority of subtyping-directed precision treatment strategies for HR+/HER2- breast cancer, refines traditional “one-size-fits-all” therapy, and facilitates the translation of precision treatment strategies from bench to bedside. Overall study design Part 1 Subtype Molecular Characteristics: Molecular features of the four subtypes of HR+/HER2- breast cancer. Part 2 Multidimensional Efficacy Validation: Integrating data from a multiomics cohort, real-world study, drug testing platform and prospective clinical research to validate the subtyping-directed precision treatment strategy in HR+/HER2- breast cancer. Part 3 Subtyping-directed Precision Treatment Strategy: Integrating clinical cohort studies, omics analysis and functional assays revealed the heterogeneity of treatment response in HR+/HER2- breast cancer, and proposed a subtyping-directed precision treatment strategy. CIN, chromosomal instability; RTK, receptor tyrosine kinase; CNA, copy-number alteration; ER, estrogen receptor; HR, hormone receptor; HER2, human epidermal growth factor receptor 2. Citation Format: Xiu-Zhi Zhu, Xi Jin, Hu-Yun-Long Zhang, Xiyu Liu, Yi-Fan Zhou, Yi-Yu Chen, Tong Fu, Ming-Liang Jin, Ya-Xin Zhao, Yi-Fan Xie, Ruo-Xi Wang, Zhong-Hua Wang, Lei Fan, Yi-Zhou Jiang, Zhi-Ming Shao. Subtyping-directed precision treatment refines traditional one-size-fits-all therapy in HR+/HER2- breast cancer: a sub-study of the MULAN umbrella trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-15-07.

Endoscopic transoral outlet reduction induces enterohormonal changes in patients with weight regain after Roux-en-Y gastric bypass

Abstract Background and study aims Transoral outlet reduction (TORe) has long been employed in treating weight regain after Roux-en-Y gastric bypass. However, its impact on gut hormones and their relationship with weight loss remains unknown. Patients and methods This was a substudy of a previous randomized clinical trial. Adults with significant weight regain and dilated gastrojejunostomy underwent TORe with argon plasma coagulation (APC) alone or APC plus endoscopic suturing (APC-suture). Serum levels of ghrelin, GLP-1, and PYY were assessed at fasting, 30, 60, 90, and 120 minutes after a standardized liquid meal. Results were compared according to allocation group, clinical success, and history of cholecystectomy. Results Thirty-six patients (19 APC vs. 17 APC-suture) were enrolled. There were no significant baseline differences between groups. In all analyses, the typical postprandial decrease in ghrelin levels was delayed by 30 minutes, but no other changes were noted. GLP-1 levels significantly decreased at 12 months in both allocation groups. Similar findings were noted after dividing groups according to the history of cholecystectomy and clinical success. The APC cohort presented an increase in PYY levels at 90 minutes, while the APC-suture group did not. Naïve patients had significantly lower PYY levels at baseline (P = 0.01) compared with cholecystectomized individuals. This latter group experienced a significant increase in area under the curve (AUC) for PYY levels, while naïve patients did not, leading to a higher AUC at 12 months (P = 0.0001). Conclusions TORe interferes with the dynamics of gut hormones. APC triggers a more pronounced enteroendocrine response than APC-suture, especially in cholecystectomized patients.

Oxidative stress, redox status and surfactant metabolism in mechanically ventilated patients receiving different approaches to oxygen therapy (MecROX): An observational study protocol for mechanistic evaluation

Background MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury. Additionally, hyperoxaemia (excess blood oxygen levels) may exacerbate whole-body oxidative stress leading to cell death, autophagy, mitochondrial dysfunction, bioenergetic failure and multi-organ failure resulting in poor clinical outcomes. However, there is a lack of in-vivo human models evaluating the mechanisms that underpin oxygen-induced organ damage in mechanically ventilated patients. Aim The aim of the MecROX mechanistic sub-study is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale to the UK-ROX trial findings. The objectives are to quantify in-vivo surfactant composition, synthesis, and metabolism with markers of oxidative stress and systemic redox disequilibrium (as evidenced by alterations in the ‘reactive species interactome’) to differentiate between groups of conservative and usual oxygen targets. Methods and design After randomisation into the UK-ROX trial, 100 adult participants (50 in the conservative and 50 in usual care group) will be recruited at two trial sites. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3 mg/kg methyl-D9-choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been extensively used to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the in-vivo surfactant synthesis and breakdown (by hydrolysis and oxidation), oxidative stress and redox disequilibrium from sequential plasma and bronchial samples using an array of analytical platforms. We will compare conservative and usual oxygenation groups according to the amount of oxygen administered. Trial registration: ISRCTN ISRCTN61929838, 27/03/2023 https://doi.org/10.1186/ISRCTN61929838.

Blood pressure and cerebral oxygenation with physiologically-based cord clamping: sub-study of the BabyDUCC trial

BackgroundCord-clamping strategies may modify blood pressure (BP) and cerebral tissue oxygen saturation (rStO2) immediately after birth.MethodsWe conducted a sub-study nested within the Baby-Directed Umbilical Cord-Clamping trial. Infants ≥32+0 weeks’ gestation assessed as requiring resuscitation were randomly allocated to either physiologically-based cord clamping (PBCC), where resuscitation commenced prior to umbilical cord clamping, or standard care where cord clamping occurred early (ECC). In this single-site sub-study, we obtained additional measurements of pre-ductal BP and rStO2. In a separate observational arm, non-randomised vigorous infants received 2 min of deferred cord clamping (DCC) and contributed data for reference percentiles.ResultsAmong 161 included infants, n = 55 were randomly allocated to PBCC (n = 30) or ECC (n = 25). The mean (SD) BP at 3–4 min after birth (primary outcome) in the PBCC group was 64 (10) mmHg compared to 62 (10) mmHg in the ECC group, mean difference 2 mmHg (95% confidence interval −3–8 mmHg, p = 0.42). BP and rStO2 were similar across both randomised arms and the observational arm (n = 106).ConclusionWe found no difference in BP or rStO2 with the different cord clamping strategies. We report reference ranges for BP and rStO2 for late-preterm and full-term infants receiving DCC.ImpactAmong late-preterm and full-term infants receiving varying levels of resuscitation, blood pressure (BP, at 3–4 minutes and 6 min) and cerebral tissue oxygen saturation (rStO2) are not influenced by timing of cord clamping in relation to establishment of ventilation.Infants in this study did not require advanced resuscitation, where cord clamping strategies may yet influence BP and rStO2.The reference ranges for BP and rStO2 represent the first, to our knowledge, for vigorous late-preterm and full-term infants receiving deferred cord clamping.rStO2 > 90% (~90th percentile) may be used to define cerebral hyperoxia, for instance when studying oxygen supplementation after birth.

Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines—an exploratory sub-study of the BRACE trial

The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E.coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children's. BRACE trial funding is detailed in acknowledgements.

Alzheimer's disease genetic risk score and neuroimaging in the FINGER lifestyle trial.

We assessed a genetic risk score for Alzheimer's disease (AD-GRS) and apolipoprotein E (APOE4) in an exploratory neuroimaging substudy of the FINGER trial. 1260 at-risk older individuals without dementia were randomized to multidomain lifestyle intervention or health advice. N=126 participants underwent magnetic resonance imaging (MRI), and N=47 positron emission tomography (PET) scans (Pittsburgh Compund B [PiB], Fluorodeoxyglucose) at baseline; N=107 and N=38 had repeated 2-year scans. The APOE4 allele, but not AD-GRS, was associated with baseline lower hippocampus volume (β=-0.27, p=0.001), greater amyloid deposition (β=0.48, p=0.001), 2-year decline in hippocampus (β=-0.27, p=0.01), total gray matter volume (β=-0.25, p=0.01), and cortical thickness (β=-0.28, p=0.003). In analyses stratified by AD-GRS (below vs above median), the PiB composite score increased less in intervention versus control in the higher AD-GRS group (β=-0.60, p=0.03). AD-GRS and APOE4 may have different impacts on potential intervention effects on amyloid, that is, less accumulation in the higher-risk group (AD-GRS) versus lower-risk group (APOE). First study of neuroimaging and AD genetics in a multidomain lifestyle intervention. Possible intervention effect on brain amyloid deposition may rely on genetic risk. AD-GRS and APOE4 allele may have different impacts on amyloid during intervention.

Atrioventricular optimization improves cardiac resynchronization response in patients with long interventricular electrical delays: A pooled analysis of the SMART-AV and SMART-CRT trials

BackgroundThe utility of atrioventricular (AV) optimization (AVO) algorithms remains in question. A substudy of the SMART-AV trial found that patients with prolonged interventricular delays ≥70 ms were more likely to benefit from cardiac resynchronization therapy (CRT) with AVO. The SMART-CRT trial evaluated AVO on the basis of these results, but the study was underpowered. ObjectiveTo increase statistical power, data from SMART-AV patients meeting the inclusion criterion of interventricular delay ≥70 ms were pooled with data from SMART-CRT to reassess AVO. MethodsSMART-CRT and SMART-AV were prospective, randomized, multicenter clinical trials. Patients in both studies were randomized to be programmed with an AVO algorithm (SmartDelay) or fixed AV delay (120 ms). Paired echocardiograms obtained at baseline and 6 months were compared, with CRT response defined as ≥15% reduction in left ventricular end-systolic volume. ResultsA total of 451 complete patient data sets were pooled and analyzed. The baseline demographics between studies did not differ statistically in terms of age, sex, left ventricular ejection fraction, or left ventricular end-systolic volume. The AVO group had a greater proportion of CRT responders (SmartDelay, 73.9%; fixed, 63.1%; P = .014) and greater changes in measures of reverse remodeling. SmartDelay patients with a recommended sensed AV delay outside the nominal range (100–120 ms) had 2.3 greater odds of CRT response than fixed AV delay patients. ConclusionGreater CRT response and measures of reverse remodeling were observed in patients with SmartDelay enabled vs a fixed AV delay. This study supports the use of SmartDelay in patients with a CRT indication and interventricular delay ≥70 ms.

The Association of CHADS-P2A2RC Risk Score With Clinical Outcomes in Patients Taking P2Y12 Inhibitor Monotherapy After 3 Months of Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention.

Concerns remain that early aspirin cessation may be associated with potential harm in subsets at high risk of ischemic events. This study aimed to assess the effects of P2Y12 inhibitor monotherapy after 3-month dual antiplatelet therapy (DAPT) vs. prolonged DAPT (12-month or longer) based on the ischemic risk stratification, the CHADS-P2A2RC, after percutaneous coronary intervention (PCI). This was a sub-study of the SMART-CHOICE trial. The effect of the randomized antiplatelet strategies was assessed across 3 CHADS-P2A2RC risk score categories. The primary outcome was a major adverse cardiac and cerebral event (MACCE), a composite of all-cause death, myocardial infarction, or stroke. Up to 3 years, the high CHADS-P2A2RC risk score group had the highest incidence of MACCE (105 [12.1%], adjusted hazard ratio [HR], 2.927; 95% confidence interval [CI], 1.358-6.309; p=0.006) followed by moderate-risk (40 [1.4%], adjusted HR, 1.786; 95% CI, 0.868-3.674; p=0.115) and low-risk (9 [0.5%], reference). In secondary analyses, P2Y12 inhibitor monotherapy reduced the Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding without increasing the risk of MACCE as compared with prolonged DAPT across the 3 CHADS-P2A2RC risk strata without significant interaction term (interaction p for MACCE=0.705 and interaction p for BARC types 2, 3, or 5 bleeding=0.055). The CHADS-P2A2RC risk score is valuable in discriminating high-ischemic-risk patients. Even in such patients with a high risk of ischemic events, P2Y12 inhibitor monotherapy was associated with a lower incidence of bleeding without increased risk of ischemic events compared with prolonged DAPT. ClinicalTrials.gov Identifier: NCT02079194.