Clinical Outcomes In High-risk Patients Research Articles

Acute post-procedural inducibility is a poor predictor of clinical outcomes in high-risk patients (PAINESD > 17) undergoing scar-related ventricular tachycardia ablation.

Ventricular tachycardia (VT) non-inducibility in response to programmed ventricular stimulation (PVS) is a widely used procedural endpoint for VT ablation despite inconclusive evidence with respect to clinical outcomes in high-risk patients. The aim is to determine the utility of acute post-ablation VT inducibility as a predictor of VT recurrence, mortality, or mortality equivalent in high-risk patients. We conducted a retrospective analysis of high-risk patients (defined as PAINESD > 17) who underwent scar-related VT ablation at our institution between July 2010 and July 2022. Patients' response to PVS (post-procedure) was categorized into three groups: Group A, no clinical VT or VT with cycle length > 240 ms inducible; Group B, only non-clinical VT with cycle length > 240 ms induced; and Group C, all other outcomes (including cases where no PVS was performed). The combined primary endpoint included death, durable left ventricular assist device placement, and cardiac transplant (Cox analysis). Ventricular tachycardia recurrence was considered a secondary endpoint (competing risk analysis). Of the 1677 VT ablation cases, 123 cases met the inclusion criteria for analysis. During a 19-month median follow-up time (interquartile range 4-43 months), 82 (66.7%) patients experienced the composite primary endpoint. There was no difference between Groups A and C with respect to the primary [hazard ratio (HR) = 1.21 (0.94-1.57), P = 0.145] or secondary [HR = 1.18 (0.91-1.54), P = 0.210] outcomes. These findings persisted after multivariate adjustments. The size of Group B (n = 13) did not permit meaningful statistical analysis. The results of post-ablation PVS do not significantly correlate with long-term outcomes in high-risk (PAINESD > 17) VT ablation patients.

Coronary Artery Plaque Phenotype and 5-Year Clinical Outcomes in Older Patients with Non-ST Elevation Acute Coronary Syndrome.

Lesions with thin-cap fibroatheroma (TCFA), small luminal area and large plaque burden (PB) have been considered at high risk of cardiovascular events. Older patients were not represented in studies which demonstrated correlation between clinical outcome and plaque characteristics. This study aims to investigate the prognostic role of high-risk plaque characteristics and long-term outcome in older patients presenting with non-ST elevation acute coronary syndrome (NSTEACS). This study recruited older patients aged 75 years with NSTEACS undergoing virtual-histology intravascular ultrasound (VH-IVUS) imaging from the Improve Clinical Outcomes in high-risk patieNts with acute coronary syndrome (ICON-1). Primary endpoint was the composite of major adverse cardiovascular events (MACE) consisting of all-cause mortality, myocardial infarction (MI), and any revascularisation. Every component of MACE and target vessel failure (TVF) including MI and any revascularisation were considered as secondary endpoints. Eighty-six patients with 225 vessels undergoing VH-IVUS at baseline completed 5-year clinical follow-up. Patients with minimal lumen area (MLA) 4 demonstrated increased risk of MACE (hazard ratio [HR] 2.37, 95% confidence interval [CI] 1.00-5.59, p = 0.048) with a worse event-free survival (Log Rank 4.17, p = 0.041) than patients with MLA 4 . Patients with combination of TCFA, MLA 4 and PB 70% showed high risk of MI (HR 5.23, 95% CI 1.05-25.9, p = 0.043). Lesions with MLA 4 had 6-fold risk of TVF (HR 6.16, 95% CI 1.24-30.5, p = 0.026). Small luminal area appears as the major prognostic factor in older patients with NSTEACS at long-term follow-up. Combination of TCFA, MLA 4 and PB 70% was associated with high risk of MI. NCT01933581.

Интракоронарное применение левокарнитина при стентировании коронарных артерий у пациентов высокого риска

The main causes of postoperative mortality associated with percutaneous coronary interventions involving the coronary artery stent insertion are perioperative myocardial infarction and acute heart failure due to inadequate protection of the myocardium against ischemia/reperfusion. The standard therapy includes beta blockers, anticoagulants, antiplatelet drugs. Two clinical cases of successful use of intravenous levocarnitine for cardioprotection in senile patients with acute forms of coronary heart disease with multivessel lesions are reported. The postoperative period went well, smooth dynamics of biomarker levels (troponin I, creatine phosphokinase, MB fraction of creatine phosphokinase) was observed, and ischemic ECG changes were relatively small. The expected results of the technique application include reduction of intraoperative and postoperative complications of ischemia/reperfusion and the increase in effectiveness of the stent insertion clinical outcomes in high-risk patients.

Abstract 19044: Upfront Right Ventricular Assist Device at the Time of Lvad Implantation Reduces Mortality, Stroke, and Major Bleeding Risk

Introduction: Right ventricular failure (RVF) is a major cause for increased morbidity and mortality after continuous-flow left ventricular assist device (cf-LVAD) implantation. Patients who are high-risk for developing RVF would benefit from early support via right ventricular assist devices (RVADs) to improve hemodynamics and reduce RVF associated complications. However, current RVF prediction models have limited predictive value. To reduce RVF complications, select institutions have implemented upfront RVAD use in those deemed high-risk with mixed results. In this study, we examined our institutional cohort of high-risk RVF patients who received either emergent or upfront RVADs during LVAD implantation and associated one-year outcomes. Hypothesis: Does providing temporary RVAD support upfront to high-risk patients during LVAD implantation impact associated complications and outcomes. Goals/Aims: To assess one-year clinical outcomes for high-risk patients receiving RVADs during LVAD implantation. Methods: We retrospectively reviewed patients who underwent placement of both LVAD and upfront RVAD at our institution between January 2015 and August 2022. Patients were stratified by the type of RVAD placed (percutaneous vs central) and timing of support (upfront vs emergent). Outcomes were assessed up to one-year post-LVAD implantation. Results/Data: Of the 50 patients reviewed, 36 (72%) underwent upfront RVAD implantations and 14 (28%) underwent emergent RVAD implantations. The upfront cohort consisted of 16 of the total 19 INTERMACS 1 patients, 15 of total 21 INTERMACS 2 patients, 4 of total 9 INTERMACS 3 patients, and 1 of 1 INTERMACS 4 patients. Compared to emergent RVADs, patients who received upfront RVAD had significantly decreased one-year mortality (17.1% vs 50.0%, p=0.031), decreased cerebrovascular accidents (2.8% vs 28.6%, p=0.018), and decreased major bleeding (0% vs 40%, p=0.005). There was no significant difference in the length of stay, arrhythmias, gastrointestinal bleed, hemodialysis requirement, driveline infections or vasoplegia. Conclusion: Patients receiving upfront RVAD at the time of cf-LVAD implantation have improved survival and decreased incidence of cerebrovascular accidents.

Transcatheter Mitral Edge-to-Edge Repair for Treatment of Acute Mitral Regurgitation.

Acute mitral regurgitation (AMR) is a medical emergency which may lead to rapid clinical deterioration and is associated with high morbidity and mortality. The severity of the clinical presentation varies according to several factors, ranging from cardiogenic shock to a milder presentation. The medical management of AMR includes intravenous diuretics, vasodilators, inotropic support, and potentially mechanical support to stabilise patients. Patients persisting with refractory symptoms despite optimal medical therapy are considered for surgical intervention, but high-risk patients deemed to be inoperable frequently experience poor outcomes. This review highlights the variety of clinical presentations of AMR and the pitfalls in diagnosis and management. The emerging role of transcatheter edge-to-edge repair (TEER), particularly in high-risk patients early after myocardial infarction requiring urgent intervention, has demonstrated feasibility and promising efficacy. TEER is well tolerated and improves hemodynamic parameters in AMR. In a recent analysis, the in-hospital and 1-year mortality rates were significantly higher with surgical mitral interventions compared with TEER. The global TEER experience for treating AMR is encouraging, with reports indicating improved clinical outcomes in high-risk patients and its potential as a bridge to recovery. Early recognition of AMR, validated criteria for patient selection, optimal timing of the intervention as well as long-term outcomes and additional prospective data should be addressed in future studies.

Utility of residual SYNTAX score to predict clinical outcome after acute myocardial infarction

Abstract Aims Acute myocardial infarction (AMI) represents a huge health burden and a growing economical challenge, particularly with recurrent major adverse cardiovascular events (MACE). Large attention is critically mandated to identify population at higher risk for recurrent MACE to maximize secondary preventive measures. This study aimed to evaluate the utility of residual SYNTAX Score (RSS) after percutaneous coronary intervention (PCI) to the culprit vessel(s) in patients with AMI (STEMI or NSTEMI) to predict 6-months clinical outcomes. Methods and results A total of 492 eligible AMI patients were recruited through a period of 12 months. The RSS was systematically calculated after the PCI procedures. Median RSS was 4 (minimum 0–maximum 47.5). RSS showed excellent association to mid-term clinical outcomes. At cut-off value of RSS 3 had robust prediction for subsequent heart failure (HF), recurrent AMI, unplanned revascularization and the composite of MACE (P < 0.001). A significantly higher RSS was found in those who developed heart failure through the 6-months follow up period compared to those who did not (10 vs. 3, P < 0.001). Similar significant difference was found for recurrent ACS (11.5 vs. 3, P < 0.001), unplanned revascularization (15 vs. 3, P < 0.001) and occurrence of MACE (12 vs. 3, P < 0.001). Conclusions RSS is a sensitive predictor for 6-months adverse clinical outcomes after AMI. Calculating RSS at the end of PCI can guide intensification of secondary preventive measures. Ability of RSS- tailored management to impact clinical outcomes in high-risk patients is to be evaluated.Improvement, with subsequent amelioration of LV diastolic function. The Dapa group had a significantly greater improvement in LVEF at four months and six months compared to the Empa group. While the Empa group showed a significant improvement in HbA1C at six months compared to the Dapa group. Additional Content An author video to accompany this abstract is available on https://academic.oup.com/eurheartjsupp. Please click on the arrow next to ‘More Content’ and then click on ‘Author videos’.

Serum butyrylcholinesterase as a marker of COVID-19 mortality: Results of the monocentric prospective observational study

The COVID-19 pandemic represents an excessive burden on health care systems worldwide and the number of patients who require special care in the clinical setting is often hard to predict. Consequently, there is an unmet need for a reliable biomarker that could predict clinical outcomes of high-risk patients. Lower serum butyrylcholinesterase (BChE) activity was recently linked with poor outcomes of COVID-19 patients. In line with this, our monocentric observational study on hospitalized COVID-19 patients focused on changes in serum BChE activity in relation to disease progression. Blood samples from 148 adult patients of both sexes were collected during their hospital stay at the Clinics of Infectiology and Clinics of Anesthesiology and Intensive Care, Trnava University Hospital in alignment with routine blood tests. Sera were analyzed using modified Ellman's method. Patient data with information about the health status, comorbidities and other blood parameters were collected in pseudonymized form. Our results show a lower serum BChE activity together with progressive decline of BChE activity in non-survivors, while higher stable values were present in discharged or transferred patients requiring further care. Lower BChE activity was associated with higher age and lower BMI. Moreover, we observed a negative correlation of serum BChE activity with the routinely used inflammatory markers, C-reactive protein and interleukin-6. Serum BChE activity mirrored clinical outcomes of COVID-19 patients and thus serves as a novel prognostic marker in high-risk patients.

Femoral-Physeal-Sparing ACL Reconstruction With Lateral Extra-articular Tenodesis and Inside-Out Repair of Lateral Meniscus in a Skeletally Immature Patient

Background: Anterior cruciate ligament (ACL) reconstructions in skeletally immature patients have an increased risk of graft failure and a decreased rate of successful return to sports. Anterior cruciate ligament reconstructions (ACLRs) combined with lateral extra-articular tenodesis (LET) procedures are reported to limit anterolateral rotary instability of the knee, decreasing tension on the ACL graft. However, the open physes found in pediatric patients present unique challenges for ACLR. This video demonstrates a technique to avoid the femoral physis and necessary precautions for performing an ACLR with LET in a skeletally immature patient. Indications: The indications for combined ACLR and LET, as opposed to ACLR alone, mainly center on the risk factors for graft failure. These include the following: posterior tibial slope >12°, revision ACLR, high-grade pivot shift on physical examination, meniscal deficiency, generalized ligamentous hyperlaxity, and—especially pertinent to this procedure—skeletally immature patients. Technique Description: Standard plain radiographs and long-leg alignment films, along with a magnetic resonance imaging (MRI) study, are necessary to assess for malalignment, bone age, and concomitant meniscal and chondral pathology. This technique describes the senior author’s preferred technique for pediatric ACLR with LET. The senior author’s preferred order of operations includes performing the autologous hamstring graft harvest and LET before performing the diagnostic arthroscopy. This is followed by the intra-articular work including the ACLR. It is also the senior author’s preference to perform physeal-sparing femoral tunnels, using fluoroscopy for tunnel placement. Results: Getgood et al reported that an ACLR with an LET in young patients with a high risk of graft failure had a significant reduction in graft rupture compared to an ACLR alone. Furthermore, Noyes et al reported a significantly lower rate of graft failure and a higher rate of return to sports in those who received LET in addition to ACLR compared with those who received ACLR alone. Discussion: An ACLR combined with an LET has been reported to reduce graft failure rates and improve clinical outcomes in high-risk patients. An ACLR with LET may also be considered in skeletally immature patients with appropriate indications and extra precautions to avoid growth arrest or deformity. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Real-world experience of postoperative adjuvant chemoimmunotherapy in patients with perihilar cholangiocarcinoma at high risk of recurrence.

This study aimed to assess whether postoperative adjuvant chemoimmunotherapy could lead to better clinical outcomes for high-risk patients with perihilar cholangiocarcinoma (pCCA). In the cohort study, we retrospectively reviewed patients who received surgical resection for pCCA with curativeintent from January 2018 to December 2021 at the Sun Yat-sen Memorial Hospital. The patients athighriskforrelapse were further analyzed. Among them, 20 patients received adjuvant chemoimmunotherapy, 28 patients received adjuvant chemotherapy, and 33 patients received surgery alone. The oncological outcomes and drug-associated adverse events were evaluated. The 2-year overall survival (OS) rates in patients treated with adjuvant chemoimmunotherapy, adjuvant chemotherapy, and surgery alone were 80.0%, 49.4% and 22.6%, respectively. Univariable and multivariable Cox analyses showed that the treatment regimen and TNM stage were associated with adverse OS. Adjuvant chemoimmunotherapy led to an increase in OS compared with adjuvant chemotherapy [hazard ratio (HR) = 3.253; 95% confidence interval (CI) 1.072-9.870; P = 0.037] or surgery alone (HR = 7.560; 95% CI 2.508-22.785; P < 0.001). The median recurrence-free survival was 22.0months for the adjuvant chemoimmunotherapy group, 17.0months for the adjuvant chemotherapy group, and 13.2months for the surgery alone group (P = 0.177); these differences were not significant. The chemoimmunotherapy group was associated with more frequent hematological side effects than the chemotherapy group, but the difference was not statistically significant. Postoperative adjuvant chemoimmunotherapy for resectedpCCA patients showed improved OScompared with adjuvant chemotherapy or surgery alone, and further prospectively randomizedcontrolledtrials are necessary to validate these results.

Five-year clinical outcomes in patients with frailty aged ≥75 years with non-ST elevation acute coronary syndrome undergoing invasive management.

AimFrailty is associated with adverse outcomes in older patients with acute coronary syndrome (ACS). The impact of frailty on long-term clinical outcomes following invasive management of non-ST elevation ACS (NSTEACS) is unknown.Methods and resultsThe multi-centre Improve Clinical Outcomes in high-risk patieNts with ACS 1 (ICON-1) prospective cohort study consisted of patients aged >75 years undergoing coronary angiography following NSTEACS. Patients were categorized by frailty assessed by Canadian Study of Health and Ageing Clinical Frailty Scale (CFS) and Fried criteria. The primary composite endpoint was all-cause mortality, unplanned revascularization, myocardial infarction, stroke, and bleeding. Of 263 patients, 33 (12.5%) were frail, 152 (57.8%) were pre-frail, and 78 (29.7%) were robust according to CFS. By Fried criteria, 70 patients (26.6%, mean age 82.1 years) were frail, 147 (55.9%, mean age 81.3 years) were pre-frail, and 46 (17.5%, mean age 79.9 years) were robust. The composite endpoint was more common at 5 years among patients with frailty according to CFS (frail: 22, 66.7%; pre-frail: 81, 53.3%; robust: 27, 34.6%, P = 0.003), with a similar trend when using Fried criteria (frail: 39, 55.7%; pre-frail: 72, 49.0%; robust: 16, 34.8%, P = 0.085). Frailty measured with both CFS and Fried criteria was associated with the primary endpoint [age and sex-adjusted hazard ratio (HR) compared with robust groups. CFS: 2.22, 95% confidence interval (CI) 1.23–4.02, P = 0.008; Fried: HR 1.81, 95% CI 1.00–3.27, P = 0.048].ConclusionIn older patients who underwent angiography following NSTEACS, frailty is associated with an increased risk of the primary composite endpoint at 5 years.Registration:Clinicaltrials.gov NCT01933581

SMYD3 Promotes Cell Cycle Progression by Inducing Cyclin D3 Transcription and Stabilizing the Cyclin D1 Protein in Medulloblastoma.

Simple SummaryMedulloblastoma is the most common malignant pediatric brain tumor and is classified into four molecular subgroups: Wnt, Shh, Group 3, and Group 4. Of these subgroups, patients with Myc+ Group 3 MB have the worst prognosis. Using an RNAi functional genomic screen, we identified the lysine methyltransferase SMYD3 as a crucial epigenetic regulator responsible for promoting Group 3 MB cell growth. We demonstrated that SMYD3 drives MB cell cycle progression by inducing cyclin D3 transcription and preventing cyclin D1 ubiquitination. Using in vitro and ex vivo studies, we showed that SMYD3 suppression by shRNA and BCI-121 significantly impaired proliferation, resulting in the downregulation of cyclin D3, cyclin D1, and pRBSer795. Moreover, we are the first to show that SMYD3 methylates the cyclin D1 protein, indicating that the SMYD3 stabilizes cyclin D1 through post-translational modification. Collectively, our studies position SMYD3 as a promising treatment option for Group 3 Myc+ MB patients.Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Maximum safe resection, postoperative craniospinal irradiation, and chemotherapy are the standard of care for MB patients. MB is classified into four subgroups: Shh, Wnt, Group 3, and Group 4. Of these subgroups, patients with Myc+ Group 3 MB have the worst prognosis, necessitating alternative therapies. There is increasing interest in targeting epigenetic modifiers for treating pediatric cancers, including MB. Using an RNAi functional genomic screen, we identified the lysine methyltransferase SMYD3, as a crucial epigenetic regulator that drives the growth of Group 3 Myc+ MB cells. We demonstrated that SMYD3 directly binds to the cyclin D3 promoter to activate its transcription. Further, SMYD3 depletion significantly reduced MB cell proliferation and led to the downregulation of cyclin D3, cyclin D1, pRBSer795, with concomitant upregulations in RB in vitro. Similar results were obtained following pharmacological inhibition of SMYD3 using BCI-121 ex vivo. SMYD3 knockdown also promoted cyclin D1 ubiquitination, indicating that SMYD3 plays a vital role in stabilizing the cyclin D1 protein. Collectively, our studies demonstrate that SMYD3 drives cell cycle progression in Group 3 Myc+ MB cells and that targeting SMYD3 has the potential to improve clinical outcomes for high-risk patients.

Clinical outcomes of high-risk patients treated with percutaneous cholecystostomy tube drainage: application of comorbidity scores in a retrospective cohort study

Clinical outcomes of high-risk patients treated with percutaneous cholecystostomy tube drainage: application of comorbidity scores in a retrospective cohort study

Impact of Lipoprotein(a) Levels on Perioperative Outcomes in Cardiac Surgery.

Altered lipid metabolism has been shown to be of major importance in a range of metabolic diseases, with particular importance in cardiovascular disease (CVD). As a key metabolic product, altered lipoprotein(a) (Lp(a)) levels may be associated with adverse clinical outcomes in high-risk cardiovascular patients undergoing cardiac surgery. We aimed to investigate the impact of the important metabolite Lp(a) on complications and clinical outcomes in high-risk patients. A prospective observational cohort study was performed. Data were derived from the Bern Perioperative Biobank (ClinicalTrials.gov NCT04767685), and included 192 adult patients undergoing elective cardiac surgery. Blood samples were collected at 24 h preoperatively, before induction of general anaesthesia, upon weaning from cardiopulmonary bypass (CPB), and the first morning after surgery. Clinical endpoints included stroke, myocardial infarction, and mortality within 30 days after surgery or within 1 year. Patients were grouped according to their preoperative Lp(a) levels: <30 mg/dL (n = 121; 63%) or >30 mg/dL (n = 71, 37%). The groups with increased vs. normal Lp(a) levels were comparable with regard to preoperative demographics and comorbidities. Median age was 67 years (interquartile range (IQR) 60.0, 73.0), with median body mass index (BMI) of 23.1 kg/m2 (23.7, 30.4), and the majority of patients being males (75.5%). Over the observational interval, Lp(a) levels decreased in all types of cardiac surgery after CPB (mean decline of approximately −5 mg/dL). While Lp(a) levels decreased in all patients following CPB, this observation was considerably pronounced in patients undergoing deep hypothermic circulatory arrest (DHCA) (decrease to preoperative Lp(a) levels by −35% (95% CI −68, −1.7), p = 0.039). Increased Lp(a) levels were neither associated with increased rates of perioperative stroke or major adverse events in patients undergoing cardiac surgery, nor with overall mortality in the perioperative period, or at one year after surgery. Other than for cohorts in neurology and cardiology, elevated Lp(a) might not be a risk factor for perioperative events in cardiac surgery.

Predictive value of overt and non-overt volume overload in patients with high- or low-gradient aortic stenosis undergoing transcatheter aortic valve implantation.

The plasma volume status (PVS) is considered a marker of non-overt cardiac congestion and is of prognostic value. Patients with low-flow, low-gradient (LFLG) aortic stenosis (AS) suffer from impaired left ventricular function and show signs of heart failure (HF). We hypothesized that PVS might predict post-interventional rehospitalization and cardiovascular mortality in high-risk patients undergoing transcatheter aortic valve implantation (TAVI). In this retrospective, observational analysis, PVS before transfemoral TAVI was calculated by a formula taking into account hematocrit and weight. The predictive performance of PVS was compared with that of prior cardiac decompensation (PCD). In the entire cohort of n=2,458 patients, PVS >-4% (high plasma volume) identified patients (n=1,013) with a higher post-interventional 1-year mortality rate than patients (n=1,445) with a PVS ≤-4% (low plasma volume). However, PVS lost prognostic independence when adjusted for anemia, whereas PCD did not. A high PVS and PCD were not correlated, and both parameters similarly revealed a low sensitivity and specificity but a high negative predictive value (NPV) for future HF events. PVS was not different between control patients (n=1,512) and those with intermediate (paradoxical LFLG-AS, n=327) or high risk scores (LFLG-AS, n=239). The accuracy of high PVS in predicting adverse events in these subpopulations was the same as in the study population overall. Kaplan-Maier analyses demonstrated similar prognostic impacts for PVS and PCD. PVS and PCD represent two independent parameters of volume overload with unfavorable prognostic significance. Pre-interventional PVS does not appear to be suitable for predicting clinical outcomes in high-risk patients undergoing TAVI.

Registered Dietitian Nutritionists Are Associated with Improved Long-Term Clinical Outcomes in High-Risk Patients

Abstract Objectives Treatment from registered dietitian nutritionists (RDNs) has been shown to improve weight and hemoglobin A1c in high-risk patients, yet little is known about these outcomes long term. The current study investigated the association between RDN care and changes in weight and HbA1c compared to primary care in high-risk patients (BMI ≥35 kg/m2 or HbA1c ≥7%) long term up to 24 months. Methods This was a retrospective cohort study of high-risk adults. Electronic medical records were reviewed for participants who were 18 years or older with BMI ≥35 kg/m2 or HbA1c ≥7.0% at first visit to a patient centered medical home in Boston, MA. Mean change in weight (kg) and HbA1c (%) at six, 12, and 24 months were compared between patients who saw an RDN and patients who received primary care only. Paired sample t-tests and repeated measures ANOVA adjusting for age, sex, gender, days from baseline at follow-up visit, and number of clinic visits at follow-up were used to analyze outcomes. Results 1902 patients with BMI &amp;gt;35 and 1240 patients with a HbA1c &amp;gt;7.0% were included. There was no significant difference in 24-month weight loss between RDN care and standard primary care. HbA1c decreased significantly with RDN care at all time points (P &amp;lt; 0.001). Patients with at least one RDN visit had a significantly greater mean change in HbA1c of −0.8 ± 0.2 (95% CI −1.0 to −0.5) and −0.6 ± 0.1 (95% CI −0.8 to −0.3) after 12 and 24 months from baseline, respectively (P &amp;lt; 0.001). Conclusions RDN care resulted in statistically and clinically significant improvements in HbA1c at 12 and 24 months compared to standard primary care alone. Funding Sources The authors received no specific funding for this work.

P195 Cost-effectiveness of a 17-gene classifier to guide initial treatment choice in Crohn’s disease in the UK

Abstract Background PredictSURE IBD™ is a CE-marked whole blood-based biomarker test that predicts long-term clinical outcomes in inflammatory bowel disease (Crohn’s disease, CD and ulcerative colitis, UC). PredictSURE IBD™ uses a 17-gene qPCR-based classifier to stratify patients into two prognostic subgroups, high and low risk. High-risk patients experience significantly more aggressive disease than low-risk patients, with the need for earlier and more frequent treatment escalation over time. Early stratification could enable personalised treatment strategies, such as ‘top-down’ use of biologics in high-risk patients. Our objective was to examine the cost-effectiveness of PredictSURE IBD™ in guiding the use of early biologic therapy in newly diagnosed CD patients in the UK. Methods A decision tree leading into a Markov state-transition model was constructed in MS Excel to compare two treatment approaches: (1) standard of care therapy following established UK clinical guidelines, consisting of sequences of immunomodulator followed by biologic upon relapse (‘step-up’ treatment), (2) targeted therapy guided by PredictSURE IBD™, whereby patients identified as high-risk receive sequences of anti-TNF biologic treatment followed by other biologic classes upon relapse (‘top-down’ treatment), Figure 1. Parameters were informed by patient data from PredictSURE IBD™ clinical studies and the literature. Results Top-down treatment guided by PredictSURE IBD™ resulted in an incremental cost-effectiveness ratio (ICER) of £7,179 per quality-adjusted life-year (QALY), with £1,852 incremental costs and 0.258 incremental QALYs vs. standard of care generated over a 15-year time horizon. Additional costs relating to earlier biologic use were offset by reductions in the costs of flares, hospitalisations and surgery. Incremental QALYs were driven by increased time spent in remission and improved quality of life from reduced flares and surgery. The model was most sensitive to the time horizon, rates of mucosal healing on top-down vs. step-up therapy, the costs of hospitalisation and the costs and quality of life in the severe disease health state. Conclusion Modelling shows that upfront use of biologic guided by PredictSURE IBD™ could substantially improve clinical outcomes for high-risk patients by increasing remission rates and reducing flares, surgery and treatment escalations. The ICER for PredictSURE IBD™ was well below the £20–£30k/QALY threshold used by the UK National Institute for Health and Care Excellence (NICE). Top-down treatment guided by PredictSURE IBD™ would not only represent a treatment paradigm shift for CD patients but would also be a highly cost-effective use of resources in the UK National Health Service.

PI3Kδ Inhibition Enhances Sensitivity of Primary High-Risk Childhood B-Cell Acute Lymphoblastic Leukemia Cells to Glucocorticoid Chemotherapy

Introduction: Despite excellent 5-year survival for most patients with B-cell acute lymphoblastic leukemia (B-ALL), those with high-risk (HR) B-ALL continue to have inferior outcomes. The prognosis is even worse for patients who respond poorly to chemotherapy, and improvements to current therapy approaches are needed. Glucocorticoids (GCs) are a key component of chemotherapy regimens. Rapid response to GC monotherapy is a well-documented predictor of favorable outcomes, while slow response to GCs correlates with poor outcomes. We hypothesized that enhancing specific GC toxicity to B-ALL cells can improve clinical outcomes for high-risk patients without increasing systemic toxicity. PI3Kδ is a promising target for this purpose. PI3Kδ is a critical component of the B-cell receptor cell-survival pathway; it restrains GC signaling, while GCs repress its expression. PI3Kδ expression is restricted to lymphoid cells, making it an appealing precision target to enhance GC toxicity in lymphoid cells while minimizing risk of increased systemic GC-associated toxicity. We previously demonstrated synergy between dexamethasone (dex) and the FDA-approved isoform-selective PI3Kδ inhibitor idelalisib (idela) in B-ALL cell lines, patient specimens, and patient-derived xenograft models (Kruth et al Blood 2017). In clinical practice, both dex and prednisone (pred) are essential components of childhood ALL chemotherapy. In this study, we sought to elucidate the extent to which idela in combination with dex or pred could induce synergistic killing of HR B-ALL specimens with various genetic backgrounds. Methods: Peripheral blood or bone marrow from patients ages 1-31 years with newly-diagnosed NCI HR or standard-risk (SR) B-ALL at the University of Iowa Stead Family Children's Hospital was obtained after informed consent on an Institutional Review Board-approved research study. Mononuclear cells were isolated from the specimens via Ficoll gradients and cultured in vitro in 384-well plates. Immediately after isolation, cells were treated with serial dilutions of the GCs dex or pred and idela in RPMI1640+10% FBS medium. Cell viability was measured with PrestoBlue (Invitrogen) after 72 hours of treatment. Survival curves were plotted to determine the LD50 of each drug using GraphPad. Dose effects around the LD50 for each drug were analyzed using Compusyn to determine if the drug combination was synergistic (combination index, CI &lt;1), additive (CI=1), or antagonistic (CI &gt;1). Results: As of August 1, 2019, 5 HR B-ALL patient specimens of various genetic alterations have been tested. Two patients were high-risk at diagnosis due to steroid pre-treatment (MAP011) or by NCI risk criteria (age &gt;10 years and/or WBC count &gt;50K/mm3; MAP014). Three patients with initially SR B-ALL were upstaged due to minimal residual disease (MRD) &gt;1% at day 8 in peripheral blood (MAP012) or marrow MRD ≥0.01% at end of induction (MAP009, MAP010). In our in vitro studies, only one sample (MAP014) showed reduced viability with GC alone, while 4 specimens (all except MAP012) responded to idela alone. Most specimens showed a synergistic response to dex or pred in combination with idela with greater reduction in cell viability compared to GC monotherapies. Surprisingly, one specimen (MAP010) had an antagonistic response with pred and idela combination. This near-haploid B-ALL specimen had reduced viability with idela monotherapy, but an antagonistic response with single-agent pred, raising the question of whether GC/idela synergy is influenced by genetic background. Conclusions: In pilot studies, idela sensitized HR B-ALL cells to GC chemotherapy and is a promising strategy for further evaluation in a larger cohort of specimens. Our results highlight the potential impact of genetic heterogeneity within childhood B-ALL upon differential therapeutic responses to standard steroid chemotherapy and demonstrate a potential precision medicine approach to augment GC sensitivity via combination with selective PI3Kδ inhibition. Disclosures Tasian: Gilead Sciences: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte Corportation: Research Funding.

Abstract 1687: Identification of bladder cancer subtypes with different sensitivities to immunotherapy

Abstract Bladder urothelial carcinoma (BLCA) is pathologically categorized as non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancers. But its clinical heterogeneity has been suggested that biologically relevant subtypes may exist within and between NMIBC and MIBC. Here we identified that BLCA could be subgrouped into four major classes with distinct molecular characteristics regardless of previously known clinicopathological factors, using a series of unsupervised learning approaches. The predictor to discriminate distinct molecular subgroups of BLCA was constructed in a training cohort and validated in six independent cohorts with a total of 1,992 samples. The predictor showed a prognostic significance of the four subtype of BLCA, especially aggressive clinical behavior of the class 3 subtype. Interestingly, class 3 subtype has distinct biological features associated with potential responsiveness to immunotherapy, such as high somatic mutation rates and alterations of genes involved in DNA damage response and repair (DDR). Analyses of anti-PD-L1-treated BLCA patient tumor samples suggested that class 3 subtype was correlated with response to immune checkpoint inhibitors. Our findings have the potential to lead to the improvement of the current molecular classification system of BLCA and the achievement of better clinical outcomes for high-risk patients with BLCA treated with immunotherapy. Note: This abstract was not presented at the meeting. Citation Format: In-Sun Chu, Bic-Na Song, Sun-Hee Leem. Identification of bladder cancer subtypes with different sensitivities to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1687.

Predictors for euthyroid sick syndrome and its impact on in-hospital clinical outcomes in high-risk patients undergoing coronary artery bypass grafting.

The purpose of this cohort study was to investigate the independent relationship between euthyroid sick syndrome and in-hospital outcomes in high-risk patients undergoing isolated coronary artery bypass grafting, and we also examined the direct correlation between pre- or intra-operative variables and the incidence of coronary artery bypass grafting-associated euthyroid sick syndrome. The present study enrolled high-risk patients undergoing coronary artery bypass grafting from 1 January 2017 to 31 December 2017 in Beijing Anzhen hospital, including 387 (58.7%) patients with coronary artery bypass grafting-associated euthyroid sick syndrome and 272 (41.3%) patients without coronary artery bypass grafting-associated euthyroid sick syndrome. The mean age of euthyroid sick syndrome group was significantly older than that of no euthyroid sick syndrome group (65.9 ± 7.5 vs 60.9 ± 9.6, p < 0.0001). Compared with the control group, significantly higher proportions of patients with euthyroid sick syndrome had presented with the following clinical characteristics at hospital admission: moderate and poor left ventricular ejection fraction (42.9% vs 28.7%, p < 0.0001), higher euroscore II (9.2 ± 4.1 vs 8.0 ± 3.9, p < 0.0001). Multivariate logistic regression analysis on the total patients revealed that the independent risk factors for coronary artery bypass grafting-associated euthyroid sick syndrome were advanced age (odds ratio = 1.07, 95% confidence interval = 1.05-1.09, p < 0.0001), higher euroscore II (odds ratio = 1.06, 95% confidence interval = 1.01-1.11, p = 0.013), and moderate and poor left ventricular ejection fraction (odds ratio = 2.26, 95% confidence interval = 1.61-3.18, p < 0.0001). Furthermore, euthyroid sick syndrome was independently correlated with an increased risk of in-hospital major adverse cardiovascular and cerebral events (odds ratio = 3.40, 95% confidence interval = 1.64-7.02, p = 0.001) and post-infection (odds ratio = 8.11, 95% confidence interval = 3.97-16.57, p < 0.0001) Besides, we also confirmed coronary artery bypass grafting-associated euthyroid sick syndrome was associated with Sequential Organ Failure Assessment maximum greater than 11 (odds ratio = 2.98, 95% confidence interval = 1.90-4.65, p < 0.0001), which predicted an in-hospital death rate of 95%, independently. Coronary artery bypass grafting-associated euthyroid sick syndrome exerted detrimental effects on short-term clinical outcomes in high-risk patients undergoing isolated coronary artery bypass grafting. Advanced age, higher euroscore II, and moderate and poor left ventricular ejection fraction were independent risk factors for coronary artery bypass grafting-associated euthyroid sick syndrome.

Clinical outcomes in high-risk patients with a severe aortic stenosis: a seven-year follow-up analysis.

The aim of this study was to assess the clinical outcomes of high-risk patients with severe aortic stenosis (AS) allocated to medical treatment (MT), transcatheter aortic valve replacement (TAVR), and surgical aortic valve replacement (SAVR) through extended follow-up. Consecutive patients with severe symptomatic AS included in a prospective single centre registry underwent sweep follow-up between March and August 2016. Clinical outcomes were assessed using a competing risk model. A total of 442 patients (median age 83 years; 52% female) were allocated to MT (n = 78), SAVR (n = 107), or TAVR (n = 257) with a gradient of surgical risk as assessed by logistic EuroSCORE (MT: 27.9 &plusmn; 14.5%, TAVR: 24.7 &plusmn; 24.9%, SAVR: 12.5 &plusmn; 8.2%; p &lt;0.001). Survival after a median duration of follow-up of seven years was 6.4% (MT), 30.4% (TAVR), and 46.7% (SAVR), respectively (p &lt;0.001). One TAVR and one SAVR patient underwent repeat intervention for valvular degeneration between 4.5 and 8.4 years after intervention. Compromised left ventricular function (LVEF &lt;40%) was associated with increased mortality (HR 1.62, 95% CI 1.22&ndash;2.15; p &lt;0.0001), whereas female sex was protective (HR 0.68, 95% CI 0.53&ndash;0.88; p = 0.0006). Both TAVR and SAVR reduced mortality compared to MT throughout a median duration of follow-up of seven years. Repeat interventions for valvular degeneration were rare.