Citations

153 Background: The prognostic significance of DDR alterations in mCRPC remains unclear, with conflicting data from prior reports. Whether DDR alterations are predictive of outcomes with therapeutic agents other than PARP inhibitors in mCRPC is also poorly understood. With increasing use of molecular profiling in mCRPC, understanding the full prognostic and predictive utility of plasma DDR alterations is paramount. Methods: A next-generation sequencing Predicine liquid biopsy assay was used to profile cfDNA and germline DNA in 407 mCRPC patients (pts) from two independent international cohorts (n=162 Australia, n=245 US). DDR genes profiled were BRCA2, ATM, BRCA1, MLH1 and MSH2. Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between DDR alterations and clinical outcomes including PSA response rate (PSA RR), progression-free survival and overall survival (OS). Results: Median age was 74 (IQR 67-79), with median follow up 74 months and median OS 23 months. 65/407 (16%) harboured pathogenic DDR alterations, including 21 patients with ³1 alteration. Frequency of genomic aberrations are shown in the table. BRCA2 alterations were further classified as heterozygous loss (66%), homozygous loss (14%), monoallelic mutation (11%) and biallelic mutation/loss of heterozygosity (9%). Aberrations in any DDR gene, ATM, MLH1 + MSH2 or BRCA2 were associated with shorter OS on univariable analysis, but only any DDR or BRCA2 aberration remained significant upon adjusting for clinical prognosticators and ctDNA fraction (Table). Pre-treatment BRCA2 aberration was associated with significantly shorter OS and lower PSA RR compared to BRCA2 wt for pts receiving an AR pathway inhibitor (ARPI) (18 vs 32 months, p=0.006; 36 vs 60%, p=0.04 respectively) but not for taxane chemotherapy (17 vs 20 months, p=0.3; 45 vs 66, p=0.1 respectively). Conclusions: Detection of an aberration in any DDR gene or BRCA2 was an independent poor prognostic factor across 2 large independent cohorts of mCRPC patients. Intriguingly, patients with a BRCA2 alteration appeared to have worse outcomes with ARPI but not chemotherapy, suggesting predictive utility of DDR profiling. Our data collectively speak to the potential role of DDR alterations, in particular BRCA2, as prognostic and/ or predictive biomarkers in mCRPC.[Table: see text]

150 Background: With the evolving use of targeted therapies exploiting genomic vulnerabilities in mCRPC, screening patients for sensitizing alterations is of increasing relevance. However, the influence of age on the detection of relevant genomic alterations is incompletely understood. In this study, we compared the cell-free DNA (cfDNA) profiles of younger (age <70) versus older (age ≥70) men with mCRPC and assessed the relative prognostic impact of common genomic alterations. Methods: A next-generation sequencing-based Predicine cfDNA assay was used to profile 276 mCRPC patients from two independent international cohorts. The frequency of genomic alterations across age categories was compared using the chi-squared test, while circulating tumour DNA fraction (ctDNA%) was compared using the Mann–Whitney U test. Cox proportional hazards analysis with interaction testing was used to assess the association between age, genomic alteration and overall survival. Results: The median age of the combined cohort was 72 years (IQR 66-78), with 170 (62%) patients ≥70 years old. Despite differences in baseline characteristics (poorer performance status in older patients, higher Gleason score and de novo metastatic disease in younger patients), there was no significant difference in ctDNA% (median 22% vs 30%, p=0.6). We observed similar frequencies of genomic alterations across the 10 most commonly aberrant genes, including AR (<70 vs ≥70: 46% vs 49%, p=0.6), TP53 (40% vs 36%, p=0.6), BRCA2 (29% vs 21%, p=0.13) and PTEN (39% vs 35%, p=0.5). This similarity persisted when analysing mutations and copy number alterations in isolation. While driver alterations in both age categories were strongly associated with unfavourable outcomes (Table), an exploratory analysis revealed that copy number gain in PIK3CA may have a worse prognostic impact in younger men ( p for interaction = 0.03), with a lesser effect observed in AR gain ( p = 0.1) and MYC gain ( p = 0.1). Conclusions: The genomic profiles of pertinent alterations between younger and older men are comparable. Certain genomic alterations may carry a worse prognosis in younger men. Patients should be considered for precision medicine assessment and directed therapies, regardless of age. [Table: see text]

Introduction: Mechanical thrombectomy (MT) has become the standard of care for acute ischemic stroke (AIS) patients due to large vessel occlusion (LVO). Clinical outcome of successful recanalization (mTICI 2b or higher) varies greatly and is associated with some baseline characteristics. Many studies have reported the relation of thrombus composition with MT outcomes however the association of thrombus composition with the prognosis of successful recanalization remains to be elucidated. Hypothesis: thrombi retrieved from patients with good clinical outcome may have different compositions compared to that of patients with poor clinical outcome. Methods: Thrombi retrieved from AIS-LVO patients with successful recanalization were included. Patients were divided according to modified Rankin Scale at 90 days (mRS-90days) into good clinical outcome (mRS-90days 0-2) and poor clinical outcome (mRS-90 days 3-6). Representative slide for each thrombus was stained with Martius Scarlet Blue (MSB) for red blood cells (RBCs), white blood cells (WBCs), fibrin (FIB), and platelet (PLT). Immunohistochemistry (IHC) was also performed for NETs (anti-citrullinated H3; CitH3) and vWF in thrombi. The overall mean value of each thrombus composition was calculated. Thrombus was considered rich in given composition if that composition was higher than its overall mean. We compared the thrombus composition and type between patients with good and poor clinical outcomes. Results: A total of 94 patients were included. Fifty-six patients had good clinical outcome. The overall average percentage of RBCs, WBCs, fibrin, platelet, NETs (CitH3), and vWF components in thrombi were 44.3%, 3.6%, 29.3%, 22.8%, 20.3% and 12.5% respectively. There was no association between thrombus type (including RBC-rich, FIB-rich, PLT-rich, vWF-rich, and NETs-rich) and clinical outcomes (P values>0.05). Multivariate logistic regression analysis showed no association between thrombus composition and clinical outcome (good vs poor) while adjusting for age, initial NIHSS score, ASPECT score, pre-MT IV-tPA, and MT technique and number of the device passes. Conclusion: we found no association between thrombus composition and clinical outcome after successful recanalization.

Introduction: Outcomes of mechanical thrombectomy (MT) are influenced by the composition of thrombi. Amongst the risk factors affecting clot composition, diabetes mellitus (DM) may be associated with more thrombus structural and mechanical alterations resulting in fibrinolysis-resistant thrombi. However, extensive analysis of the composition of thrombi obtained from patients is needed to elucidate this relationship. Hypothesis: Thrombi retrieved from patients with DM may have different compositions compared to that of patients with no history of DM. Methods: MT retrieved-thrombi from patients suffering from large vessel occlusion (LVO) stroke were included. Thrombi sections were stained with Martius Scarlet Blue (MSB) for main thrombus components including red blood cells (RBCs), white blood cells (WBCs), fibrin and platelet. Additionally, immunohistochemistry (IHC) was performed to identify neutrophil extracellular traps (NETs) (anti-citrulinated H3; CitH3; NETs-specific marker) and von Willebrand Factor (vWF) in thrombi. Slides were then scanned and analyzed and the thrombus composition was compared between patients with or without a DM diagnosis at the time of stroke presentation. Results: A total of 140 patients were included of which 35 had a diagnosis of DM at stroke presentation. Baseline characteristics (excluding age), IV-tPA use prior to MT, and MT outcomes (number of device passes and final mTICI score) were similar between DM and non DM patients. The overall average percentage of RBCs, WBCs, fibrin, platelet, NETs (CitH3), and vWF components in thrombi were 47.4%, 3.2%, 27.4%, 21.8%, 25.9% and 17.6%, respectively. Thrombi from patients with DM were not statistically significant different from those of patients with no DM in terms of RBCs (44.3 vs 48.4 p=0.37), WBCs (2.7 vs 3.3 p=0.05), fibrin (29.5 vs 26.7 p=0.37), platelet (23.3 vs 21.3 p=0.57), NETs (25.6 vs 22.3 p=0.54), and vWF (17.5 vs 17.7 p=0.96). Conclusion: DM has no effect on the composition of thrombi as no significant difference was found in thrombi obtained from patients with and without DM.

Introduction: Ample evidence exists in support of the anti-inflammatory properties of statins which in turn could affect arterial thrombosis. Compositional analysis of thrombi retrieved by MT may provide us with knowledge useful for evaluating the effect of current Statin therapy on thrombus composition. Methods: Consecutive AIS-LVO patients were included. Histopathological evaluation of thrombi retrieved during MT was performed using Martius Scarlet Blue staining (MSB) and immunohistochemistry for von Willebrand Factor (vWF) and anti-citrulinated H3 (CitH3; NETs marker) and the composition of thrombi was determined using image analysis software. Thrombus was considered rich in a given composition if that composition was higher than its overall mean. We reviewed patient’s medication records and cataloged any statin therapy prior to MT. Results: 117 patients were included in this study. The mean density of red blood cells (RBCs), white blood cells (WBCs), platelets (PLT), fibrin (FIB), vWF and NETs (CitH3) in thrombi was 43.4%, 3.7%, 23.6%, 29.3%, 14.3% and 21.1% respectively. Twenty-seven patients were taking Statins at the time of MT. Statins were not associated with pre-thrombectomy IV-tPA, and stroke etiology (p values: >0.05). There was no association between Statins and thrombi composition and type (p values: >0.05 for all thrombus components and type). Additionally, Statins were not associated with MT outcomes including number of device passes and final mTICI score. Conclusion: Pre-stroke Statin therapy was not associated with differences in thrombus composition.

INTRODUCTION: Although an additional coronavirus disease 2019 vaccine dose for immunocompromised persons has been recommended in some countries, further data to guide vaccination strategies for patients with inflammatory bowel disease (IBD) are urgently needed. We sought to identify factors affecting initial humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among patients with IBD. METHODS: In this prospective cohort of SARS-CoV-2 immunized patients with IBD, we evaluated associations between participant age, sex, vaccine type, medication use, and the presence of a detectable antireceptor binding domain antibody and quantitative antibody level. RESULTS: In total, 1,909 participants were included (1,123, 692, and 94 received BNT162b2, mRNA-1273, and Ad26.COV2.S, respectively) of whom 96% achieved a positive antibody response. On multivariable analysis, factors associated with lack of antibody response were older age ( P = 0.043), BNT162b2 vs mRNA-1273 (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.0–3.9), and combination therapy with anti-TNF and 6MP, azathioprine, or methotrexate (OR 4.2, 95% CI 2.4–7.3). The use of 5-aminosalicylate or sulfasalazine (OR 0.3, 95% CI 0.1–0.8) and ustekinumab (OR 0.2, 95% CI 0.05–0.8) was associated with decreased odds of lacking antibody response. DISCUSSION: Most patients with IBD mount an initial response to SARS-CoV-2 vaccination; however, older patients and those treated with anti-TNF and immunomodulator have blunted responses and may benefit the most from an additional vaccine dose. Patients treated with other classes of immunosuppressive medications have more robust initial immune responses to vaccination. These data should inform key decisions about patient selection for additional coronavirus disease 2019 vaccine doses in patients with IBD.