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505 Background: We investigated the clinical utility of SET2,3, a novel biomarker designed to measure to endocrine sensitivity. SET2,3 measures nonproliferative hormone receptor-related transcription (SETER/PR) adjusted for a baseline prognosis index derived from tumor size, nodes involved and a 4-gene molecular subtype (RNA4). CALGB 9471 is a seminal phase III study that showed improved DFS and OS from 2-weekly dose-dense (DD) vs 3-weekly chemotherapy in ER-negative cancers. Risk of recurrence (ROR-PT) score (intrinsic subtype, proliferation score and tumor size) measured by Nanostring assay was reported to be prognostic in CALGB 9741, but did not predict benefit from DD chemotherapy. Methods: SET2,3 was performed using an aliquot of 200-300 ng RNA (residual from prior ROR-PT testing) from 682 ER+ tumor samples and tested using the QuantiGene Plex bead-based hybridization assay (ThermoFisher, Luminex). We report results for the primary and two secondary objectives of the NCI/CTEP-approved correlative science proposal CSC0154) to evaluate SET2,3 in CALGB 9741 for prognosis (primary endpoint: 95%CI for 5-year (yr) DFS > 75% for High SET2,3 using the predefined prognostic cutpoint 2.10), SET2,3 prognostic independence from ROR-PT, and prediction of outcome according to chemotherapy regimen. We used Cox models to estimate hazard ratios (HR) for prognosis and comparison with ROR-PT results (using c-indices) and for prediction according to chemotherapy schedule using an interaction term (prespecified significance level for interaction: p < 0.10). Results: The study met its primary endpoint with a 5-yr DFS of 85.6% (95%CI 81.3-90.2) in the High-SET subset (244/613, 40%). High-SET vs Low-SET was significantly associated with favorable outcomes at 5 yr (DFS 85.6% vs 69%, p <.0001; OS 95.3% vs 84.6%, p <.0001) and 10 yr (DFS 77.7% vs 58.2%, p <.0001; OS 86.9% vs 65.9%, p <.0001). PAM50 ROR-PT and SET classification were available for 596 tumors. In multivariate models for DFS and OS, SET2,3 remained an independent prognostic variable for DFS (SET high vs low HR = 0.46, 95% CI, 0.34 – 0.63, p < 0.0001; PAM50 ROR-PT high vs low HR = 1.22, 95% CI, 0.91 – 1.64, p = 0.18) and for OS (SET high vs low HR = 0.36, 95% CI, 0.25 – 0.53, p < 0.0001; PAM50 ROR-PT high vs low HR = 1.26, 95% CI, 0.91 – 1.75, p = 0.16). Similar observations were seen in models including SET and PAM50 ROR-PT as continuous variables. Lower SET2,3 values predicted improved outcomes from DD vs 3-weekly chemotherapy (interaction p=0.0998 for DFS, 0.042 for RFS and 0.027 for OS). This was unrelated to menopausal status and lower SET2,3 values favored DD concurrent treatments. Conclusions: SET2,3 index was strongly prognostic, independent of ROR-PT, and predicted survival benefit from DD chemotherapy in pre- and postmenopausal women with ER+ cancer. Clinical trial information: NCT00003088.

Abstract Background Radium (Ra)‐223 is an established treatment option for patients with metastatic castrate‐resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP‐ribose polymerase inhibitors and platinum‐based therapies. This study aims to evaluate mCRPC response to Ra‐223 stratified by tumor genomics. Methods This is a retrospective study of mCRPC patients who received Ra‐223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate‐specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression‐free survival (PFS) and overall survival (OS) from time of first radium treatment. Results One hundred and twenty‐seven mCRPC patients treated with Ra‐223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra‐223 treatment was 61.0 and 68.6 years, respectively. Seventy‐nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2‐ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2‐ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0−NR) versus 26.8 months (95% CI 20.9−35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28−NR) versus 9.0 months (95% CI 7.3−11.1) and a lower OS 13.9 months (95% CI 5.2−NR) versus 26.5 months (95% CI 19.8−33.8). Conclusions Among mCRPC patients treated with Ra‐223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2‐ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra‐223.

Objectives To integrate morphological, haemodynamic and mechanical analysis of carotid atheroma driving plaque disruption. Materials and methods First, we analysed the phenotypes of carotid endarterectomy specimens in a photographic dataset A, and matched them with the likelihood of preoperative stroke. Second, laser angioscopy was used to further define the phenotypes in intact specimens (dataset B) and benchmark with histology. Third, representative vascular geometries for each structural phenotype were analysed with Computational Fluid Dynamics (CFD), and the mechanical strength of the complicated atheroma to resist penetrating forces was quantified (n=14). Results In dataset A (n=345), ulceration (fibrous cap disruption) was observed in 82% of all plaques, intraplaque haemorrhage in 68% (93% subjacent to an ulcer) and false luminal formation in 48%. At least one of these ‘rupture’ phenotypes was found in 97% of symptomatic patients (n=69) compared with 61% in asymptomatic patients. In dataset B (n=30), laser angioscopy redemonstrated the structural phenotypes with near-perfect agreement with histology. In CFD, haemodynamic stress showed a large pulse magnitude, highest upstream to the point of maximal stenosis and on ulceration the inflow stream excavates the necrotic core cranially and then recirculates into the true lumen. Based on mechanical testing (n=14), the necrotic core is mechanically weak and penetrated by the blood on fibrous cap disruption. Conclusions Fibrous cap ulceration, plaque haemorrhage and excavation are sequential phenotypes of plaque disruption resulting from the chiselling effect of haemodynamic forces over unmatched mechanical tissue strength. This chain of events may result in thromboembolic events independently of the degree of stenosis.

Abstract Background A patent foramen ovale (PFO) is a persistent embryonic defect in the interatrial septum. Platypnoea-orthodeoxia syndrome is characterized by positional hypoxaemia that is most commonly due to right-to-left shunting through a PFO. Dynamic right-to-left shunting through a PFO can also exacerbate positional hypoxaemia without platypnea-orthodeoxia syndrome. Case summary A 78-year-old woman with hyperthyroidism and paroxysmal atrial fibrillation (AF) presented with positional hypoxaemia exacerbated by supine positioning. Diagnostic testing revealed intermittent right-to-left shunting through a PFO triggered by worsening atrial functional tricuspid regurgitation and elevated right atrial pressures. Diuresis, rate control, and thyroidectomy initially led to resolution of positional hypoxaemia, but recurrent AF episodes triggered right-to-left shunting with recurrent desaturation. Left atrial and cavo-tricuspid isthmus ablation led to restoration of normal sinus rhythm and resolution of positional hypoxaemia without PFO closure. Discussion The clinical presentation of intermittent intracardiac right-to-left shunting can mimic decompensated heart failure with pulmonary oedema. Persistent hypoxaemia out of proportion to the degree of pulmonary oedema and minimally responsive to supplemental O2 should raise suspicion for right-to-left shunt aetiology. Positional arterial blood gases can facilitate the diagnostic evaluation of refractory hypoxaemia in cases of suspected shunting. Diagnostic imaging for PFO detection includes both transthoracic and transesophageal echocardiography with Valsalva manoeuver and agitated saline injection. Closure of a PFO for management of arterial deoxygenation syndromes should not be performed before treating other causes of arterial deoxygenation and optimizing factors that may exacerbate shunting across the PFO.

AbstractGraft‐versus‐hostdisease (GVHD) following liver transplantation (LT) is rare but can lead tosignificant mortality. The leading cause of death following GVHD diagnosis isinfectious complications. However, there is a lack of clear descriptions concerning infection and antimicrobial management patterns. Our study aims toprovide the focused details of all infectious complications of acute GVHDfollowing LT. We retrospectively reviewed all adult LT recipients with acute GVHD at Mayo Clinic's Transplant Centers from January 1, 2010, to December 31, 2021. Detailed characteristics of infection in each case were described. Among 4,585 LTs performed during this period, 12 (0.3%) patients developed acuteGVHD. The median time from transplantation to GVHD diagnosis was 49.0 days [IQR 31.5–99.0]. Ten (83.3%) patients developed severe infections leading tomortality. The most common cause of infection was nosocomial bacteremia fromenteric bacteria such as vancomycin‐resistant enterococci and gram‐negative bacilli. Other infections included breakthrough invasive fungal infections,cytomegalovirus (CMV) reactivation, and Clostridioides difficile colitis. Antimicrobial prophylaxis strategies in most cases were based on the degree of neutropenia—these include levofloxacin for bacterial prophylaxis, nebulized pentamidine for Pneumocystis jiroveci pneumonia prophylaxis, posaconazole for invasive fungal prophylaxis, and valganciclovir based on CMVstatus. All GVHD patients with severe infections succumbed to thesecomplications. Ourstudy reiterates that despite prophylaxis, infectious complications in GVHDfollowing LT are common and lead to exceptionally high mortality. Individualizedantimicrobial treatment, prophylaxis and monitoring strategies remain a criticalcomponent of GVHD management. Further study to optimize these practices isrequired. image

AbstractBackgroundChildren with diffuse intrinsic pontine gliomas (DIPG) have a dismal prognosis. Adavosertib (AZD1775) is an orally available, blood-brain barrier penetrant, Wee1 kinase inhibitor. Preclinical efficacy against DIPG is heightened by radiation induced replication stress.MethodsUsing a rolling six design, 7 adavosertib dose levels (DLs) (50 mg/m2 alternating weeks, 50 mg/m2 alternating with weeks of every other day, 50 mg/m2, then 95, 130, 160, 200 mg/m2) were assessed. Adavosertib was only given on days of cranial radiation therapy (CRT).The duration of CRT (54 Gy over 30 fractions; 6 weeks) constituted the dose limiting toxicity (DLT) period. Endpoints included tolerability, pharmacokinetics, overall survival (OS) and peripheral blood γH2AX levels as a marker of DNA damage.ResultsA total of 46 eligible patients with newly diagnosed DIPG [median (range) age 6 (3–21) years; 52% female] were enrolled. The recommend phase 2 dose (RP2D) of adavosertib was 200 mg/m2/d during days of CRT. Dose limiting toxicity included ALT elevation (n = 1, DL4) and neutropenia (n = 1, DL7). The mean Tmax, T1/2 and Clp on Day 1 were 2 h, 4.4 h, and 45.2 L/hr/m2, respectively. Modest accumulation of adavosertib was observed comparing day 5 versus day 1 AUC0-8h (accumulation ratio = 1.6). OS was 11.1 months (95% CI: 9.4, 12.5) and did not differ from historical control.ConclusionAdavosertib in combination with CRT is well tolerated in children with newly diagnosed DIPG, however, compared to historical controls, did not improve OS. These results can inform future trial design in children with high-risk cancer.

Background Although successful recanalization (modified Thrombolysis in Cerebral Infarction score 2b–3) can be achieved in >80% of patients experiencing stroke attributable to large‐vessel occlusion, up to 50% of patients may develop poor clinical outcomes (modified Rankin scale score at 90 days of 3–6), termed as futile recanalization (FR). The meta‐analysis aims to determine various risk factors associated with FR. Methods In February 2021, a comprehensive literature search on risk factors associated with FR was performed with keywords, including “stroke,” “thrombectomy,” “treatment outcome,” and “risk factors.” Their correlations with FR were evaluated using the random effect size meta‐analysis model. Results Twenty studies with 3037 patients were included with an FR rate of 51.0%. Our meta‐analyses showed that age (mean difference [MD], 5.6; 95% CI, 4.7–6.6), National Institutes of Health Stroke Scale score (MD, 4.2; 95% CI, 3.2–5.1), Alberta Stroke Program Early Computed Tomography (CT) Score (MD, −0.5; 95% CI, 0.8–0.3), hypertension (odds ratio [OR], 1.5; 95% CI, 1.3–1.9), systolic blood pressure (MD, 6.9; 95% CI, 3.6–8.7), atrial fibrillation (OR, 1.5; 95% CI, 1.2–1.8), IV tPA (tissue‐type plasminogen activator) (OR, 0.7; 95% CI, 0.5–0.8), puncture to recanalization time (MD, 9.6; 95% CI, 5.3–13.8), and time of onset to recanalization (MD, 32.1; 95% CI, 6.5–47.7) were significantly associated with FR ( P <0.001). Conclusions Age, admission National Institutes of Health Stroke Scale score, Alberta Stroke Program Early CT Score, comorbidities, including hypertension, systolic blood pressure, atrial fibrillation, and use of IV tPA, as well as time frames, including onset to recanalization and onset to arrival, were significant influencing factors for FR after mechanical thrombectomy. Future research on the mechanism underlying FR is warranted.

This work highlights recent advancements in the integration of analytical tools into DMF devices, and discusses the current challenges and potential solutions as well as future outlooks for an automated, integrative platform for POC applications.