Unselected Patients Research Articles

International Map of Axial Spondyloarthritis (IMAS): results from the perspective of 5557 patients from 27 countries around the globe

BackgroundThe International Map of Axial Spondyloarthritis (IMAS) is a global initiative aimed to assess the impact and burden of axial spondyloarthritis (axSpA) and identify the unmet needs from the patient’s...

Exploring 6years of colorectal cancer surgery in rural Italy: insights from 648 consecutive patients unveiling successes and challenges.

The multidisciplinary management of patients suffering from colorectal cancer (CRC) has significantly increased survival over the decades and surgery remains the only potentially curative option for it. However, despite the implementation of minimally invasive surgery and ERAS pathway, the overall morbidity and mortality remain quite high, especially in rural populations because of urban - rural disparities. The aim of the study is to analyze the characteristics and the surgical outcomes of a series of unselected CRC patients residing in two similar rural areas in Italy. A total of 648 consecutive patients of a median age of 73years (IQR 64-81) was enrolled between 2017 and 2022 in a prospective database. Emergency admission (EA) was recorded in 221 patients (34.1%), and emergency surgery (ES) was required in 11.4% of the patients. Tumor resection and laparoscopic resection rates were 95.0% and 63.2%, respectively. The median length of stay was 8days. The overall morbidity and mortality rates were 23.5% and 3.2%, respectively. EA was associated with increased median age (77.5 vs. 71 ys, p < 0.001), increased mean ASA Score (2.84 vs. 2.59; p = 0.002) and increased IV stage disease rate (25.3% vs. 11.5%, p < 0.001). EA was also associated with lower tumor resection rate (87.3% vs. 99.1%, p < 0.001), restorative resection rate (71.5 vs. 89.7%, p < 0.001), and laparoscopic resection rate (36.2 vs. 72.6%, p < 0.001). Increased mortality rates were associated with EA (7.2% vs. 1.2%, p < 0.001), ES (11.1% vs. 2.0%, p < 0.001) and age more than 80years (5.8% vs. 1.9%, p < 0.001). In rural areas, high quality oncologic care can be delivered in CRC patients. However, the surgical outcomes are adversely affected by a still too high proportion of emergency presentation of elderly and frail patients that need additional intensive care supports beyond the surgical skill and alternative strategies for earlier detection of the disease.

A phase I study of highly potent oral ATR inhibitor (ATRi) tuvusertib plus oral PARP inhibitor (PARPi) niraparib in patients with solid tumors.

3018 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase and poly-ADP ribose polymerases (PARPs) are crucial components in the DNA damage response (DDR). Combining tuvusertib and niraparib may synergistically enhance synthetic lethality and increase apoptosis. Part B1 of the DDRiver Solid Tumors 301 study (NCT04170153) assessed this combination. Methods: Part B1 of this open-label multicenter dose-escalation phase Ib trial enrolled unselected patients with metastatic or locally advanced unresectable solid tumors refractory to standard treatment. The primary objective was to determine safety (including maximum tolerable dose and recommended dose(s) for expansion [RDE]). Secondary and tertiary objectives included determination of the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of different dosing regimens of tuvusertib plus niraparib. Multiple continuous and intermittent schedules were explored with tuvusertib doses ranging from 90–180 mg once-daily (QD) and niraparib doses from 100–200 mg QD. A partial ordering continual reassessment method was used to identify the RDEs. Results: As of 02 January 2024, 43 patients had been enrolled (all with baseline body weight &lt;77kg or platelet count &lt;150,000/mm3); 13 patients remained on treatment. Ten (26.3%) patients had dose-limiting toxicities (DLTs). The most common DLT was grade 3 anemia requiring blood transfusion (n=4; 10.5%); the most frequent grade ≥3 treatment-emergent adverse events were anemia (n=18; 41.9%), platelet count decrease (n=6; 14.0%) and fatigue (n=4; 9.3%). The PK of tuvusertib when combined with niraparib was consistent with that of tuvusertib monotherapy, suggesting a lack of any clinically meaningful mutual drug–drug interactions. Dose-dependent ɣ-H2AX inhibition (proximal PD marker) was observed at tuvusertib doses ≥130 mg QD. Preliminary efficacy data show 5 (15.6%) responses (3 confirmed) by RECIST v1.1 in 32 evaluable patients: 2 in patients with epithelial ovarian cancer (EOC; 1 with BRCA1-mutant [ BRCA1m] PARPi-resistant EOC, 1 with BRCA-wild type homologous recombination deficiency-positive EOC) and 1 each in patients with non-small cell lung cancer, estrogen receptor-positive HER2-negative BRCA1m breast cancer, and BRCA1m PARPi-resistant pancreatic cancer. Tuvusertib 180 mg QD and niraparib 100 mg QD or tuvusertib 90 mg QD and niraparib 200 mg QD, both given in a 1 week on/1 week off schedule, were identified as RDEs. Conclusions: The combination of tuvusertib plus niraparib, each administered on a 1 week on/1 week off schedule, has a manageable safety profile and is suitable for further investigation. A combination study in patients with PARPi-resistant EOC is planned. Clinical trial information: NCT04170153 .

Cardiomyopathy in First-Degree Relatives of Patients Presenting With Acute Myocarditis: Prevalence and Prognostic Significance.

Acute myocarditis has been genetically linked to dilated cardiomyopathy (DCM), but the clinical significance remains uncertain. We investigated the prevalence and long-term prognosis of DCM and heart failure (HF) among unselected patients hospitalized with acute myocarditis and their first-degree relatives compared with an age- and sex-matched cohort. This was an observational study utilizing the Danish nationwide registries, where all patients with a first-time myocarditis diagnosis from 1995 to 2018 were identified and matched (on birth year and sex) with 10 controls from the general population. Totally 3176 patients with acute myocarditis and 31 760 controls were included (median age, 49.8 [Q1-Q3, 32.5-70.2] years; 35.6% female). At baseline, patients with myocarditis had a higher prevalence of DCM (7 [0.2%] versus 8 [0.0%]) and HF (336 [10.6%] versus 695 [2.2%]) than controls; P<0.0001 for both. Patients with myocarditis more often had siblings with DCM (12 [0.4%] versus 17 [0.05%]) or HF (36 [1.1%] versus 89 [0.3%]); P<0.0001, odds ratios 7.09 (3.38-14.85) and 2.92 (1.25-6.80), respectively, whereas parental DCM and HF did not differ among patients with myocarditis and controls. Patients with myocarditis had greater 20-year incidence of DCM, HF, and all-cause mortality (0.5% [0.3%-0.9%], 15% [13%-17%], and 47% [44%-50%]) compared with controls (0.06% [0.03%-0.11%], 6.8% [6.4%-7.3%], and 34% [33%-35%]; P<0.0001). Having a first-degree relative with DCM or HF was associated with increased long-term mortality among the patients with myocarditis (hazard ratio, 1.40 [1.11-1.77]) but not among the controls (hazard ratio, 0.90 [0.81-1.01]; Pdifference=0.0008). Acute myocarditis aggregates with DCM within families, where it carries a worsened prognosis. A differential association between parents and siblings (with sibling preponderance) could suggest that additional environmental factors are important for myocarditis development even in predisposed individuals.

Factors Associated with Poor Mental Health in Patients with Axial Spondyloarthritis: Results from the International Map of Axial Spondyloarthritis (IMAS)

BackgroundThis study aims to assess the prevalence of poor mental health in axial spondyloarthritis (axSpA) and its associated factors in a large sample of patients from the International Map of...

Durvalumab and stereotactic ablative body radiotherapy (SABR) in locally advanced (LA) and borderline resectable (BR) pancreatic cancer (PDAC): Long-term outcomes and correlative insights.

4174 Background: Immune checkpoint blockade (ICB) has limited activity in genomically unselected patients (pts) with PDAC. While anti-tumor activity with combination SABR/ICB has been shown, biomarkers of response are poorly defined. We conducted a phase 1/2 study of PD-L1 inhibitor Durvalumab (D) and SABR after induction chemotherapy in LA and BR PDAC (NCT03245541). We report long-term outcomes and correlative biospecimen analyses. Methods: A multi-institutional, single arm phase 1/2 trial was conducted at Cedars-Sinai and Memorial Sloan Kettering. Initial clinical data reported by Tuli et al, ASCO 2023. Pre-treatment tissue assessed for p40 and GATA3 to determine classical vs basal subtype by immunohistochemistry. Tissue interrogated by immunofluorescence for PD-L1 expression and infiltration of immune cell subsets. Multiparametric immunophenotyping of peripheral blood mononuclear cells (PBMCs) by flow cytometry conducted on baseline and on treatment samples. Wilcoxon rank sum test used to determine difference in biomarkers from each timepoint; p-value &lt;0.05 significant. Results: N= 36 enrolled from 08/2017-05/2022; N=31(86%) LA, N=5 (14%) BR. N= 9 (25%) underwent resection; all R0. At median follow up 36.5 months, 6- and 12-month PFS 69%, 36%. Median PFS 8.7m (95% CI 6.1-14), median OS 16m (95% CI 13-26). N=2 (6%) alive without disease progression. Correlative analyses summarized (table). Key findings; Classical/basal subtyping feasible on N=9 (8 classical, 1 basal). Median PD-L1 score not associated with survival. Peri-tumoral, but not intratumoral CD8+ cells associated with PFS &gt;6 months. Flow cytometry feasible for 70 samples from N=35. Frequency of pre-treatment non-naïve CD4+ FoxP3+ Treg associated with PFS &gt;12. CD103+ CD8+ T Cells significantly expanded on treatment only in patients with PFS&gt;12m (p=0.038) and were significantly enriched relative to PFS&lt;12m on treatment. Conclusions: A proportion of pts with LA PDAC achieve durable control with D and SABR after induction chemotherapy. Baseline peri-tumoral CD8+ cells and peripheral CD103+ CD8 T cells and CD4+ Treg in PBMCs at baseline and on treatment may predict for benefit. Further analyses ongoing and validation in larger cohorts is warranted. Clinical trial information: NCT03245541 . [Table: see text]

Efficacy of nivolumab/ipilimumab as first-line treatment of pleural mesothelioma in the German real-world setting.

8085 Background: The approval of nivolumab/ipilimumab (IO) has extended the first-line treatment options in unresectable pleural mesothelioma (PM). In the Checkmate 743 trial, first-line IO treatment resulted in similar survival benefit for both non-epithelioid (NE) and epithelioid (E) subtype with median survival of 18 months. However, data about efficacy in unselected populations from the real-world setting are scarce. Methods: We retrospectively collected clinical data of patients (pts) with PM diagnosed between 2010-2023 from twelve centers in Germany and analyzed cases that received at least one cycle of IO in the first-line setting. Median progression-free (mPFS) and overall survival (mOS) were estimated using Kaplan-Meier method and compared using the log-rank method. All statistical analyses were conducted using R software (4.3.2). Results: Overall 1574 patients were collected, of which 931 received any first-line systemic treatment and 135 were treated with IO in the first-line. The latter were mostly male (85%), older than 65 years (78%), current or former smokers (54%), and had E histology (67%). Mean age was 72 (standard deviation [SD] 8.4) years. The ECOG PS score (PS) was ≥2 in 5 cases only, but not available in 23. Only 64/135 (47%) pts went on to receive any second-line treatment, i.e. platinum/pemetrexed in 47, monochemotherapy (pemetrexed, gemcitabine or vinorelbine) in 15, IO re-challenge in 1 and nivolumab in 1. With median follow-up of 9 months (IQR 4.8-14.5), the mOS for the entire cohort was 13.6 mo (95% confidence interval [CI] 10.64-17.35). By histology, the mOS in NE was 16.6 mo vs. 13.6 mo in E histology [HR 0.89 (95%CI 0.54-1.48), p=0.65]. The mOS difference in pts with PS 0 vs 1 vs. &gt;=2 was 16.6 mo vs. 12.8 mo vs. 3.5 mo [HR 1.45 (95% CI 0.90-2.36); p=0.13]. 2/5 pts with PS ≥ 2 died within first 4 months. When age at diagnosis was considered, mOS in age group “&lt; 65”, “≥ 65 to &lt;75” and “≥75”-years were 18.8 mo, 16.6 mo, and 9.6 mo [HR 1.37 (95%CI 1-1.88), p=0.047], respectively. The mOS in never (N=42) vs. current or past smokers (N=52) was 10 mo vs. 14 mo [HR 0.67 (95%CI 0.39-1.14), p=0.14], respectively. The mPFS for the entire cohort was 4.76 mo (95% CI 3.7-6.7), 5.6 mo for the NE and 4.2 mo for E histology [HR 0.77 (95% CI 0.51 -1.16); p=0.21]. Subsequent treatment with Platin/Pemetrexed yielded a numerically longer mOS of 10 mo compared to 6.3 mo with monochemotherapy [HR 1.96 (95%CI 0.88-4.3), p=0.09]. Conclusions: In this real-world analysis of unselected patients, survival benefit with nivolumab/ipilimumab was somewhat less pronounced in both non-epithelioid and epithelioid subtypes compared to the Checkmate 743 trial. Older patients had worse prognosis, while there was also a tendency for shorter survival of never smokers and patients with worse ECOG performance status. Further analysis of larger real-world datasets with longer follow-up will be essential to validate these results.

A Clinical Picture of Unselected Patients with Systemic Lupus Erythematosus in a Tertiary Hungarian Center-A Spectrum Ranging from Pure Lupus to Overlap Syndromes.

Introduction: Systemic lupus erythematosus (SLE) is a multidimensional disease; however, the association of another systemic autoimmune disease further complicates its clinical presentation. Aim: We decided to investigate whether the association of overlap syndromes is linked with a different clinical picture compared to pure lupus and whether this association changes the sensitivity of the following commonly used criteria: the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR), the ACR-1997 and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Method: We performed a retrospective observational study among 382 patients afflicted with lupus: we measured as much of the full clinical and laboratory picture as possible in an unselected cohort. The diagnosis of SLE and other systemic autoimmune diseases was established by the rheumatologist in routine care and then the authors compared the characteristics of patients with pure lupus and those with overlapping pathologies. The diagnosis rates were compared to those that were determined based on the three classification criteria in order to identify various sensitivities and whether the existence of an overlap affects their rates. The fulfillment of each set of criteria was calculated using an Excel-based automatic calculation. Results: Among the patients, the ACR 1997's sensitivity was 81.2% (310 patients), and the SLICC 2012 criteria achieved 94.5% sensitivity (361 patients). The 2019 EULAR/ACR classification criteria resulted in a slightly lower sensitivity (90.3%-345 patients) when compared to the original publication (96%) due to the lower sensitivity of our anti-nuclear antibody (ANA) test (measured via enzyme-linked immunosorbent assay (ELISA)). Nearly all ANA-negative (21/22-95%) patients showed a positive lupus-associated antibody test. The proportion of ANA-negative cases showed no significant difference among pure and overlap patients. No significant difference was found between patients with overlap (138 patients-36%) and pure SLE (244 patients-64%) through the use of these criteria, with the exception of the SLICC criteria (ACR: 80.4% vs. 81.6%; SLICC: 97.4% vs. 92.6%, p = 0.035; EULAR/ACR 2019: 91.4% vs. 89.6%). Patients with an overlap syndrome were significantly older (55 vs. 50 years, p = 0.001), more likely to suffer from interstitial lung disease (ILD: 20% vs. 11%, p = 0.0343) and less frequently showed class III/IV lupus nephritis (7% vs. 14%, p = 0.029) when compared with their pure lupus counterparts. Conclusion: All investigated criteria regarding sensitivity were similar to the original publication's findings. The sensitivity of the EULAR/ACR 2019 classification criterion in cases with overlap syndrome proved excellent, with results very similar to patients afflicted with pure SLE. In the presence of an overlap syndrome, we found significantly fewer patients with lupus nephritis III/IV but no differences in other typical lupus organ manifestation beyond the kidney, whereas we found a higher proportion of ILD in patients with an overlap, indicating that the presence of an overlap syndrome significantly influences the observed clinical picture in real-world conditions.

Quantitative systems pharmacology modeling of macrophage-targeted therapy combined with PD-L1 inhibition in advanced NSCLC.

Immune checkpoint inhibitors remained the standard-of-care treatment for advanced non-small cell lung cancer (NSCLC) for the past decade. In unselected patients, anti-PD-(L)1 monotherapy achieved an overall response rate of about 20%. In this analysis, we developed a pharmacokinetic and pharmacodynamic module for our previously calibrated quantitative systems pharmacology model (QSP) to simulate the effectiveness of macrophage-targeted therapies in combination with PD-L1 inhibition in advanced NSCLC. By conducting in silico clinical trials, the model confirmed that anti-CD47 treatment is not an optimal option of second- and later-line treatment for advanced NSCLC resistant to PD-(L)1 blockade. Furthermore, the model predicted that inhibition of macrophage recruitment, such as using CCR2 inhibitors, can potentially improve tumor size reduction when combined with anti-PD-(L)1 therapy, especially in patients who are likely to respond to anti-PD-(L)1 monotherapy and those with a high level of tumor-associated macrophages. Here, we demonstrate the application of the QSP platform on predicting the effectiveness of novel drug combinations involving immune checkpoint inhibitors based on preclinical or early-stage clinical trial data.

Left bundle fascicular versus left bundle trunk pacing: a comparison of their electrical synchrony parameters

Abstract Background Variation in human left bundle branch (LBB) anatomy has a significant effect on the sequence of left ventricular depolarization. However, little is known regarding the electrophysiological characteristics of pacing different LBB fascicles. Objective We aimed to analyse the different electrocardiographic characteristics of LBB pacing (LBBP) attending to the site of pacing at the LBB system. Methods In consecutive patients with confirmed LBBP, we distinguished left bundle trunk capture (LBTP) from any LB fascicular pacing (LBFP) based on the presence of LB potentials and paced QRS morphologies in the frontal axis. We compared them regarding procedure, LBBP criteria and electrical synchrony parameters. Results 309 patients with LBBAP attempt were analysed, with 290 successful cases. Among them, 223 were considered LBBP. 25 cases without a proper ECG tracing in the frontal leads were excluded from the final analysis. 173 patients with LBFP were compared to 25 patients with LBTP. There were not significant differences in the baseline characteristics, but the native QRS width was higher in the LBFP group (119.2±31.4 ms vs 103.2±20.5 ms; p=0.014). Regarding the procedural duration, there was not any significant difference. QRS transition criteria (80.0% vs 61.8%; p=0.077), selective LBBP (40.0 vs 21.5%; p=0.101), paced QRS width (110.3±16.8 ms vs 115.4±14.9 ms; p=0.117), V6-RWPT (79.2±10.7 ms vs 75.3±9.7 ms; p=0.068) and interpeak interval (42.5±19.1 ms vs 45.7±12.9 ms; p=0.282) were not significantly different between LBTP and LBFP. All short-term complications occurred in LBFP, mainly driven by septal perforations (n=23), without any difference in the pacing parameters. Among the LBFP subgroups, left septal (LSFP) and posterior (LPFP) fascicles were significantly more prevalent than left anterior (LAFP) in LBFP (46.8%, 41.0% and 12.2% respectively). Regarding the baseline characteristics, the procedural performance and the electrical synchrony parameters, there were not significant differences among the LBFP subgroups. Only aVL-RWPT was longer when the posterior fascicle was paced, and shorter in LAFP (84.7±13.3 ms vs 64.9±15.1 ms; p&amp;lt;0.001). The consecution of LSFP was more frequent with lumenless leads (97.5% vs 83.1% vs 81.0%, p=0.006). Attending to the LBBP criteria, transition criteria were more frequent in LSFP (71.6% vs 53.2%; p=0.039), along with selective capture (29.6% vs 16.3%%; p=0.042), and transition during pacing manoeuvres (82.8% vs 69.2% vs 40.0%; p=0.013). Conclusions LBFP is much more prevalent than LBTP in unselected consecutive patients with LBBP. LBFP seems more feasible, and as good as LBTP in terms of electrical synchrony and pacing safety, without significant differences among the LBFP subgroups. The recognition of the different paced QRS morphologies in the frontal axis, along with the analysis of the Purkinje potentials, arise as important tools to fully understand the whole map of LBBAP.Left bundle branch area sites of pacingProcedural and LBBP characteristics

Impact of photoplethysmography-based smartphone rhythm monitoring on atrial fibrillation detection and management after cardiac surgery: a pragmatic randomized trial

Abstract Introduction Postoperative atrial fibrillation (POAF) occurring after cardiac surgery is common and associated with adverse outcomes. Systematic monitoring of POAF beyond discharge is cumbersome. The emergence of photoplethysmography (PPG)-based rhythm monitoring with digital consumer devices could potentially mitigate these hurdles. Selected smartphone applications leveraging this technology have demonstrated excellent usability and accuracy for the detection of atrial fibrillation (AF). However, the impact of PPG-detected POAF on real-life clinical practice remains uncertain. Purpose To determine whether intermittent PPG-based smartphone rhythm monitoring, after being discharged home following cardiac surgery, impacts AF management. Methods The SURGICAL-AF 2 study is a pragmatic, investigator-initiated, open-label, multicenter, randomized clinical trial, conducted in three Belgian centers. The intervention group performed one-minute rhythm checks three times daily with a smartphone-based PPG application after hospitalization for cardiac surgery until the first follow-up visit with a cardiologist, scheduled at 21 – 91 days. Rhythm monitoring was not mandated in the usual care group. The primary endpoint was a composite of initiation of oral anticoagulation (OAC), cardioversion, up-titration or initiation of antiarrhythmic drugs (Vaughan-Williams class I or III) or implantation of a cardiac implantable electronic device (CIED). Secondary endpoints were incidence of POAF and actionable POAF, defined as a detection in patients with CHA2DS2-VASc score ≥2 for women or ≥1 for men who are not treated with OAC. Results Of the 450 patients randomized (238 patients in the intervention group and 212 patients in the usual care group; mean [SD] age, 64.1 [9.2] years; 96 women [21.3%]; 130 patients with AF before inclusion [28.9%]; 103 patients on OAC [22.9%], median [interquartile range] CHA2DS2-VASc score, 2 [1-3]), 98.7% completed the trial. In the intent-to-treat analysis, the primary end point occurred in 24 patients (10.3%) in the intervention group versus 5 patients (2.4%) in the usual care group (odds ratio (OR) 4.7, 95% CI, 1.8 - 12.6; P =.002). POAF was detected in 44 patients (18.8%) in the intervention group and was actionable in 25 patients (10.7%) versus 4 patients (1.9%) in the usual care group and actionable in 2 patients (0.9%). (POAF detection, OR 12.0, 95% CI, 4.2 - 34.5; P &amp;lt; .001; actionable POAF, OR 12.5, 95% CI, 2.9 - 52.6; P &amp;lt; .001) Conclusions In unselected patients discharged home following cardiac surgery, PPG-based smartphone monitoring revealed significantly more POAF which led to changes in AF management (OAC initiation, rhythm control therapy or CIED insertion). Longer follow-up is needed to determine whether these changes will lead to improved outcomes.

Predictors of low-voltage areas in the left atrium in patients with atrial fibrillation

Abstract Background Low-voltage areas (LVA) in the left atrium (LA) electroanatomical map are potent predictors of the efficacy of atrial fibrillation (AF) ablation. Clinical factors predicting the presence of LVA have moderate accuracy. The aim of the study was to find clinical and echocardiographic factors predicting the presence of LVA in patients undergoing AF ablation. Methods Consecutive unselected patients undergoing AF ablation were included in the retrospective analysis. All patients underwent transthoracic (including LA strains) and transesophageal echocardiography, pulmonary vein isolation and LA electroanatomical mapping using multipolar catheter. LVA were defined as an area greater than 2cm2 with a voltage below 0.5mV (or 0.3mV when measured during AF). Results A total of 432 patients were included in the analysis, 107 (24.8%) had LVA. The mean age of the study population was 62.8 years, 185 patients had nonparoxysmal AF (42.8%). In the univariate logistic regression analysis numerous clinical parameters (age, female sex, presence of heart failure, diabetes, coronary artery disease, AF during examination), echocardiographic parameters (LA reservoir strain - LASr, LA emptying fraction, LA volume index, E/e’, LA appendage velocity - LAAV) and mean LA pressure (measured invasively) were significant predictors of the presence of LVA. In the multivariate logistic regression analysis age (HR 1.11 per 1 year increase, p&amp;lt;0.001), LASr (HR 0.89 per 1% increase, p=0.014) and LAAV (HR 0.93 per 1cm/s increase, p&amp;lt;0.001) were significant predictors of the presence of LVA. In receiver-operator curve (ROC) analysis LASr and LAAV were potent predictors of LVA in patients tested on sinus rhythm (AUC 0.86 and 0.87 respectively), while they had moderate predictive value in patients tested on AF (LASr AUC 0.67, LAAV AUC 0.77). Conclusions Age, LASr, and LAAV were significant predictors of LVA in patients undergoing AF ablation. The predictive value of LASr and LAAV was better in patients examined during sinus rhythm than in patients examined during AF.

Cardiac Damage After SARS-CoV2 Infection.

COVID-19 is a viral disease that can manifest acutely in the respiratory tract and other organs. In this study, we aimed to investigate potential long-term damage to the heart from COVID-19. For this study, we divided 97 consecutive unselected COVID-19 patients aged 18-80 years at a cardiology practice in Cologne, Germany, into two groups based on the severity of their infection. We performed a resting ECG and a resting transthoracic echocardiography three and six months after SARS-CoV2 infection. The key discriminator determining disease severity was bed confinement or hospital admission. Group 1 included patients with less severe COVID-19, whereas group 2 contained more severe cases. Heart rate as the primary ECG endpoint was lower by a statistically significant amount for the entire study population (p=0.024), subdivided by gender (pwomen <0.001, pmen <0.001) and in group 1 p =0.003compared to three months. QTc time and repolarization disturbances as primary ECG endpoints and the echocardiographic primary endpoints, left ventricular ejection fraction, and left ventricular end-diastolic diameter (LVEDD), showed no relevant difference between the subgroups at three and six months or between the measurements taken at each point. In contrast, LVEDD normalized to body surface area was statistically significantly lower at six months in women in group 1 compared to group 2 (p=0.048) and in the overall study population at six months compared with the data after three months (p=0.034). E/E' was statistically lower at six months than at three months in the whole population (p=0.004) and in women (p=0.031). All measured echocardiographic and electrocardiographic mean values were within the normal range in all groups and follow-up controls. Overall, the prospective study conducted showed no significant evidence of long-term cardiac damage from COVID-19 disease, as evidenced by electrocardiographic and echocardiographic examinations at three and six months after infection.

Hypoperfusion index ratio and pretreatment with intravenous thrombolysis are independent predictors of good functional outcome in acute ischemic stroke patients with large vessel occlusion treated with acute reperfusion therapies.

We aimed to investigate the performance of several neuroimaging markers provided by perfusion imaging of Acute Ischemic Stroke (AIS) patients with large vessel occlusion (LVO) in order to predict clinical outcomes following reperfusion treatments. We prospectively evaluated consecutive AIS patients with LVO who were treated with reperfusion therapies, during a six-year period. In order to compare patients with good (mRS scores 0-2) and poor (mRS scores 3-6) functional outcomes, data regarding clinical characteristics, the Alberta Stroke Programme Early Computed Tomography Score (ASPECTS) based on unenhanced computed tomography (CT), CT angiography collateral status and perfusion parameters including ischemic core, hypoperfusion volume, mismatch volume between core and penumbra, Tmax > 10s volume, CBV index and the Hypoperfusion Index Ratio (HIR) were assessed. A total of 84 acute stroke patients with LVO who met all the inclusion criteria were enrolled. In multivariable logistic regression models increasing age (odds ratio [OR]: 0.93; 95%CI: 0.88-0.96, p = 0.001), lower admission National Institute of Health Stroke Scale (NIHSS)-score (OR: 0.88; 95%CI: 0.80-0.95, p = 0.004), pretreatment with intravenous thrombolysis (OR: 3.83; 95%CI: 1.29-12.49, p = 0.019) and HIR (OR:0.36; 95%CI: 0.10-0.95, p = 0.042) were independent predictors of good functional outcome at 3months. The initial univariable associations between HIR and higher likelihood for symptomatic intracranial hemorrhage (sICH) and parenchymal hematoma type 2 (PH2) were attenuated in multivariable analyses failing to reach statistical significance. Our pilot observational study of unselected AIS patients with LVO treated with reperfusion therapies demonstrated that pre-treatment low HIR in perfusion imaging and IVT were associated with better functional outcomes.

Very elevated hCGβ (≥10 multiple of the median) in maternal marker screening for Down syndrome: Frequency, etiologies, outcomes, and guidelines.

This aim of this study was to detail maternal and fetal anomalies observed on a national scale in a large French cohort of patients presenting high hCG values (≥10 multiple of the median [MoM]) at Down syndrome screening in order to define clear and optimal guidelines. This is a retrospective multicenter study based on a French annual database of all trisomy 21 screenings. Our study targeted and studied cases with hCG or hCGβ values ≥10 MoM. Complementary exams and outcomes were analyzed. The calculated frequency was 0.05% for hCGβ ≥10 MoM in unselected patients. For this series of 289 cases, a complication of the pregnancy or a poor outcome was observed in 145 cases (51%) as follows: 96 (66%) cases of fetal disease, 23 (16%) of maternal disease, 5 (3.5%) of placental anomalies and 21 (14.5%) of systemic disease concerning mother, fetus and placenta. This study establishes the frequency of hCG or hCGβ values ≥10 MoM, presents a flow chart that optimizes follow-up, and gives clear information for patients presenting with such abnormal values at trisomy 21 screening.

Selenium and Arsenic Levels, Prevalence of Common Variants of Genes Involved in Their Metabolism, and Psoriasis Disease.

Using an Inductively Coupled Plasma Mass Spectrometer we measured the concentration of selenium and arsenic in serum and blood samples from 336 unselected psoriatic patients and 336 matched healthy controls to evaluate any associations with the clinical course of the disease. We genotyped 336 patients and 903 matched controls to evaluate the prevalence of SOD2 (rs4880), CAT (rs1001179), GPX1 (rs1050450), and DMGDH (rs921943) polymorphisms using Taqman assays. The mean selenium (Se) level in serum was 74 µg/L in patients and 86 µg/L in controls (p < 0.001). The mean Se level in blood was 95 µg/L in patients and 111 µg/L in controls (p < 0.001). Psoriasis risk was greatest among participants with the lowest serum (<68.75 µg/L, OR: 8.30; p < 0.001) and lowest blood concentrations of Se (<88.04 µg/L, OR: 10.3; p < 0.001). Similar results were observed in subgroups of males and females. We found an inverse correlation of selenium levels with PASI, NAPSI, and BSA scores. There was no significant difference in the distribution of the CAT, GPX1, DMGDH, and SOD2 polymorphisms. Among carriers of rs4880, rs1001179, and rs921943 polymorphisms, blood selenium levels were significantly lower. The mean arsenic level in serum was 0.79 µg/L in patients and 0.7 µg/L in controls (p = 0.2). The mean concentration in blood was 1.1 µg/L in patients and 1.3 µg/L in controls (p < 0.001). In conclusion, we found that lower selenium levels, in blood and serum, are associated with psoriasis risk and its more severe course. Future prospective studies should focus on the optimalisation of the concentration of this trace element not only for prophylactic guidance but also to support the treatment of this disease.

Procedural Results and Long-term Outcome of Chronic Total Occlusion Percutaneous Coronary Intervention in a UK Non-surgical Centre.

Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has evolved a great deal over recent years, with increased procedural success and lower complication rates being reported. This study aims to evaluate the feasibility, safety and success of a dedicated CTO programme in a large UK PCI centre without on-site cardiothoracic surgery facilities. Clinical and procedural data were retrospectively collected for consecutive unselected patients undergoing CTO PCI between 2015 and 2019 from the local database and regional electronic patient records. In-hospital outcomes and long-term major adverse cardiovascular events (all-cause mortality, MI, stroke and target vessel revascularisation) were recorded. A total of 170 patients underwent 191 CTO procedures during the study period. The mean age was 63 ± 10 years and 80.6% of patients were male (n=137). The clinical indications were: stable chronic coronary syndromes in 88.5% (n=169) of patients; staged procedures in the context of acute coronary syndromes in 1.6% (n=3); and presentation with acute coronary syndrome in 9.9% (n=19). The procedural success rate was 50.0% (n=25) for general interventional cardiologists and 90.1% (n=127) for dedicated CTO operators. In-hospital major adverse cardiovascular events occurred once (0.5%) and interhospital transfer for emergency salvage cardiac surgery was not required. Long-term follow-up data at a median duration of 3.8 years revealed 4 (2.4%) cardiac deaths, 14 (8.3%) spontaneous MI events and 10 (5.9%) target vessel revascularisations. These data suggest CTO PCI using contemporary techniques is both safe and effective when undertaken in a high-volume non-surgical centre by experienced operators.

Anti-PD-1 alone or in combination with anti-CTLA-4 for advanced melanoma patients with liver metastases

BackgroundThe combination of anti-PD-1 and anti-CTLA-4 has been associated with improvement in response and survival over anti-PD-1 monotherapy in unselected patients with advanced melanoma. Whether patients with liver metastases also benefit from the combination of anti-PD-1 and anti-CTLA-4 over anti-PD-1, is unclear. In this study, we sought to assess whether the combination of anti-PD-1 and anti-CTLA-4 leads to better response, progression-free survival and overall survival, compared with anti-PD-1 monotherapy for patients with liver metastases. MethodsWe have conducted an international multicentre retrospective study. Patients with advanced melanoma with liver metastases treated with 1st line anti-PD1 monotherapy or with anti-CTLA-4 were included. The endpoints of this study were: objective response rate, progression-free survival and overall survival. ResultsWith a median follow-up from commencement of anti-PD-1 monotherapy or in combination with anti-CTLA-4 of 47 months (95% CI, 42–51), objective response rate was higher with combination therapy (47%) versus anti-PD-1 monotherapy (35%) (p = 0.0027), while progression-free survival and overall survival were not statistically different between both treatment groups. However, on multivariable analysis with multiple imputation for missing values and adjusting for predefined variables, combination of anti-PD1 and anti-CTLA-4 was associated with higher objective response (OR 2.21, 1.46 – 3.36; p < 0.001), progression-free survival (HR 0.73, 0.57 – 0.92; p = 0.009) and overall survival (HR 0.71, 0.54 – 0.94; p = 0.018) compared to anti-PD1 monotherapy. ConclusionsFindings from this study will help guide treatment selection for patients who present with liver metastases, suggesting that combination therapy should be considered for this group of patients.

Immunotherapy drives mesenchymal tumor cell state shift and TME immune response in glioblastoma patients.

Glioblastoma is a highly aggressive type of brain tumor for which there is no curative treatment available. Immunotherapies have shown limited responses in unselected patients, and there is an urgent need to identify mechanisms of treatment resistance to design novel therapy strategies. Here we investigated the phenotypic and transcriptional dynamics at single-cell resolution during nivolumab immune checkpoint treatment of glioblastoma patients. We present the integrative paired single-cell RNA-seq analysis of 76 tumor samples from patients in a clinical trial of the PD-1 inhibitor nivolumab and untreated patients. We identify a distinct aggressive phenotypic signature in both tumor cells and the tumor microenvironment in response to nivolumab. Moreover, nivolumab-treatment was associated with an increased transition to mesenchymal stem-like tumor cells, and an increase in TAMs and exhausted and proliferative T cells. We verify and extend our findings in large external glioblastoma dataset (n = 298), develop a latent immune signature and find 18% of primary glioblastoma samples to be latent immune, associated with mesenchymal tumor cell state and TME immune response. Finally, we show that latent immune glioblastoma patients are associated with shorter overall survival following immune checkpoint treatment (P = .0041). We find a resistance mechanism signature in one fifth of glioblastoma patients associated with a tumor-cell transition to a more aggressive mesenchymal-like state, increase in TAMs and proliferative and exhausted T cells in response to immunotherapy. These patients may instead benefit from neuro-oncology therapies targeting mesenchymal tumor cells.

Abstract PS06-08: Longitudinal Neoadjuvant and Post-operative Evaluation of Circulating Tumor DNA in Early Breast Cancer using a Tumor-Informed Assay: Updated Analysis of the TRACER Cohort

Abstract Background: ctDNA is detectable in early breast cancer (EBC) using sensitive assays and treatment-related changes in ctDNA are associated with clinical response. RaDaR® (NeoGenomics), a tumor-informed assay, has been shown to detect circulating tumor DNA (ctDNA) prior to clinical recurrence. We retrospectively quantified ctDNA using RaDaR in serial samples from a large cohort of patients with EBC receiving standard neoadjuvant therapy (NAT). Methods: Unselected patients with EBC were enrolled prior to NAT in the TRACER cohort from 2015 onwards. Plasma samples were collected at baseline, during treatment, perioperatively, and in follow-up. For patients with available tissue for assay generation, RaDaR was performed on all available plasma timepoints. Clinical and pathologic characteristics (assessed on core biopsy), treatment, and outcomes were recorded. Results: Of 128 patients evaluated, 9 (7.0%) were excluded from this analysis due to panel quality control metrics, leaving 119 patients (41 ER+, 32 TNBC, 46 HER2+) with 681 individual timepoints (median=6, range: 1-12). 103/119 patients (86%) received neoadjuvant anthracycline- and taxane-based chemotherapy. Median followup from diagnosis was 3.8 years (range: 0.6-6.3 years) and 16 recurrences have occurred (9 ER+, 6 TN, 1 HER2+). 114 patients had a baseline plasma sample collected prior to NAT, in which the detection rate was 77% (70% ER+, 90% TNBC, 76% HER2+), with a median estimated variant allele frequency (eVAF) of 0.0823% (range: 2.90E-5 - 7.5%). All patients with clinical recurrence had ctDNA detected at baseline. Baseline detection was associated with tumor grade (p=0.050) but not size (p=0.65) or clinical nodal status (p=0.36). There were non-significant associations between eVAF and grade (p=0.097) and eVAF and tumor size (p=0.086). Persistent ctDNA detection midway through neoadjuvant therapy (pre-cycle 5) was associated with an increased risk of recurrence in patients with ER+ (HR: 10.27, 95%CI: 1.61-65.4; p=0.014) and TNBC (HR: 20.17, 95%CI: 1.97-206.4; p=0.011). Residual cancer burden (RCB) status further stratified the risk of recurrence; those with RCB-2/3 disease and ctDNA detected pre-cycle 5 were at the highest risk. Few patients had detectable ctDNA in pre- or initial post-operative specimens, all of which had residual disease (non-pCR). 9/16 patients with clinical recurrence had evaluable post-operative and follow-up samples for lead time calculation; ctDNA was detected prior to recurrence in 7/9 (78 %), with a median lead time of 152 days (range: 13-699 days). Of the 2 patients without a positive test, one had an ipsilateral local recurrence (grade 2, 1.8 mm), the other had a negative, but borderline, test 72 days prior to recurrence (solitary 8 mm lung nodule on PET). Follow up is ongoing for two patients with ctDNA detected but no recurrence at data cutoff (time since last positive test: 0.60 and 1.78 years). Any ctDNA detection postoperatively or in follow-up was strongly associated with disease recurrence (HR: 37.35, 95%CI: 2.7-520.7; p&amp;lt; 0.0001). Conclusion: RaDaR detects ctDNA in most patients prior to the initiation of NAT for EBC. Changes in ctDNA levels during treatment and its presence are associated with clinical outcomes. Prospective evaluation and integration of RaDaR testing into clinical trials are warranted. Further analysis of ctDNA detection, clinical outcomes, and genomic data will be presented at the meeting. Citation Format: Mitchell Elliott, Jesus Fuentes Antras, Philippe Echelard, Aaron Dou, Zachary Veitch, Philippe Bedard, Eitan Amir, Michelle Nadler, Nicholas Meti, Nancy Gregorio, Elizabeth Shah, Celeste Yu, Nathan Campbell, Christodoulos Pipinikas, Karen Howarth, Lillian Siu, Hal Berman, David Cescon. Longitudinal Neoadjuvant and Post-operative Evaluation of Circulating Tumor DNA in Early Breast Cancer using a Tumor-Informed Assay: Updated Analysis of the TRACER Cohort [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 PS06-08.