Unselected Patient Population Research Articles

P3855Incidence, risk factors and impact of readmission for heart failure after successful transcatheter aortic valve replacement

Abstract Background Incidence and correlates of readmission for heart failure in all-comers, after successful transcatheter aortic valve replacement (TAVR) remain unclear. Objective We sought to evaluate the incidence, risk factors and clinical impact of readmission for HF after successful TAVR in an unselected patient population. Methods All patients who underwent successful TAVR in two high-volume French tertiary centers from February 2010 to December 2016 were prospectively included and followed-up for one year. Cox multivariate model was used to assess risk factors of readmission for heart failure, evaluated a time-updated covariate and mortality. Results A total of 1139 patients (mean age 82.4±7.7 years, 52.2% male) were included. Readmission for heart failure occurred in 99 (8.7%) patients. Risk factors of readmission for HF were chronic pulmonary disease (adjHR 1.8; 95% CI [1.2–2.8], p=0.008), chronic kidney disease (adjHR 1.7; 95% CI [1.1–2.6], p=0.01), diabetes mellitus (adjHR 1.7; 95% CI [1.1–2.5], p=0.01), prior atrial fibrillation (adjHR 1.6; 95% CI [1.1–2.4], p=0.02) and post-TAVR left ventricular ejection fraction (LVEF) ≤35% (adjHR 2.1 95% CI 1.2–3.7, p=0.009). Readmission for HF was strongly associated with mortality (Figure) along with increased STS score (adjHR 1.07 95% CI 1.03–1.12, p=0.002), prior atrial fibrillation (adjHR 2.13 95% CI 1.53–2.96, p<0.001) and shock during the index hospitalization (adjHR 2.68 95% CI 1.48–4.87, p=0.001). Figure 1 Conclusion Readmission for heart failure occurs in one out of ten patients after successful TAVR and is strong risk factor of mortality. Comorbidities and post-TAVR LVEF≤35% are the main correlates of readmission for heart failure. Acknowledgement/Funding ACTION study group

P2875Comparison between ejection fraction, global longitudinal strain, mechanical dispersion and delta contraction duration in predicting first and subsequent arrhythmic events in ICD patients

Abstract Background According to current guidelines, left ventricular ejection fraction (LVEF) is currently the most important parameter for primary prevention of sudden cardiac death in patients with structural heart disease. Unfortunately, LVEF has low sensitivity in detecting arrhythmic events and presents a significant intra- and inter-operator variability. For these reasons, alternative predictors in patients with structural heart disease are being sought. Among those, speckle-tracking derived parameters such as global longitudinal strain (GLS), mechanical dispersion (MD), and delta contraction duration (DCD) have been proposed as better alternatives. Purpose To assess speckle-tracking derived parameters as predictors of first and subsequent arrhythmic events in implantable cardioverter-defibrillator (ICD) patients with structural heart disease, and to compare their performance with LVEF. Methods Prospective, observational study enrolling all consecutive patients with structural heart disease admitted for an ICD implant. Patients not followed by a home-monitoring system were excluded. 2D speckle-tracking analysis was used to derive GLS, MD, and DCD of all patients at enrolment. Home monitoring was checked weekly in order to detect all ventricular arrhythmias (VA) and ICD therapies. A recurrent-event statistical approach (Prentice, Williams, and Peterson model) was applied in order to evaluate subsequent events after the first ones. Results Two-hundred-and-three patients were consecutively enrolled and followed-up for a median follow-up of 2.2 years. Kaplan-Meier curves showed an increased risk of ATP or shock (Log-rank p=0.003) and VAs (Log-rank p=0.001) associated with lower quartiles of GLS (Figure 1). An impaired GLS was independently associated with an increased risk for the first ICD therapy (HR 1.94; 95% CI 1.30–2.91; p=0.001), and for the first VA (HR 1.42; 95% CI 1.01–1.98; p=0.04). GLS impairment was not significantly associated with an increased risk of recurrent ICD therapies or VAs. LVEF, MD and DCD were not associated with an increased risk of first, second and third ICD therapy or VA. Conclusions Impaired GLS is associated with an increased risk of VAs and appropriate ICD therapies in a consecutive, “real-world”, unselected population of remote-monitored patients with structural heart disease, although it does not seem reliable in predicting further arrhythmic event after the first one. LVEF, MD, and DCD do not predict first or subsequent arrhythmic events in ICD patients with structural heart disease. Acknowledgement/Funding Marche Polytechnic University

5196Coronary artery calcification predicts MACE and all-cause mortality in individuals undergoing non-cardiac computed tomography for non-cardiovascular indications

Abstract Introduction Coronary artery calcification (CAC) measured on ECG-gated cardiac CT is a strong predictor of cardiovascular (CV) risk in asymptomatic individuals in a primary prevention setting. However, the prognostic value of CAC in an unselected population referred for non-gated non-cardiac chest CT (NCCT) is unknown. Purpose To determine whether CAC predicts major adverse cardiovascular events (MACE) and all-cause mortality in patients referred for NCCT for non-CV indications. Methods A random sample of 741 individuals, without prior known history of coronary artery disease (CAD) who underwent NCCT for non-CV indications at a tertiary care hospital in 2008 were included in this study. NCCT was assessed qualitatively for the presence and extent of CAC by two experienced physicians. Data abstraction was performed by electronic medical record (EMR) review. Our primary endpoint of MACE, defined as CV mortality, MI, PCI, CABG, heart failure and stroke as well as secondary endpoint of all-cause mortality, over a median follow up of 8 (IQR 4–10) years, was adjudicated per independent review. Results Among 741 individuals (mean age 61.1±15.5 years, 60% female, 91% Caucasian), 57% were hypertensive, 30% had hyperlipidemia, 14% were diabetic and the mean ASCVD score was 12.2±11.6. CAC was present in 425/741 (57.4%) individuals. Among those with CAC, it was mild in 172/425 (40%), moderate in 143/425 (34%) and severe in 110/425 (26%) individuals. Overall, MACE occurred in 115/741 (15.5%) patients. Compared to those without MACE, CAC was more prevalent (83% vs. 53%, p<0.001) and extensive (at least moderate: 67% vs. 28%, p<0.001) in those with MACE. Over a median follow up of 8 (IQR 3–10) years, the presence of any CAC was associated with a 4-fold higher risk of MACE (HR 4.22, 95% CI (1.4–8.9), p<0.001), after adjustment for age and gender. On stratification, severe CAC had a near 9-fold increased risk of MACE (HR 8.8, 95% CI (5.1–15.2), p<0.001), followed by moderate CAC with a near 6-fold increased risk of MACE (HR 5.7, 95% CI (2.8–9.8), p<0.001), and a near doubling of MACE risk with mild CAC (HR 1.99, 95% CI (1.1–4.3), p=0.034). Similar results were observed with all-cause mortality (Figure 1). Conclusions CAC is an independent predictor of MACE and all-cause mortality in an unselected patient population referred for NCCT for non-CV indications, which may provide an opportunity to improve population health without the need for additional imaging. Acknowledgement/Funding Dr. Banerji and Dr. Alvi were supported by NIH/NHLBI 5T32HL076136.

Measuring Tumor Mutational Burden Using Whole-Exome Sequencing.

Cancer immunotherapy, particularly a class of antibodies targeting the CTLA4 and PD-1/PD-L1 negative regulators of immune response (collectively called the immune checkpoint), is one of the most promising approaches for cancer treatment and the use of immune checkpoint inhibitors (ICI) has demonstrated remarkable success in several types of cancer. In studies of unselected patient populations, it was shown that melanoma, non small cell lung cancer (NSCLC), renal cell carcinoma and urothelial carcinoma patients treated with CTLA-4, PD-1 or PD-L1 inhibitors had an improved objective response and overall survival relative to chemotherapy or historical trends, and several ICIs have been approved for the treatment of these and other indications.More recently, several groups found that response to ICI therapy strongly correlates with a high burden of single nucleotide variant (SNV) mutations in the tumor genome, termed tumor mutational burden (TMB), usually expressed as the number of nonsynonymous single nucleotide variants per megabase of sequenced genome. These studies showed that TMB is a promising predictive biomarker for ICI response in melanoma, urothelial carcinoma and a subset of NSCLC patients. High TMB relates to ICI response via the production of increased numbers of novel, mutant peptide antigens (neoantigens), resulting in enhanced recognition and killing of neoantigen-presenting tumor cells by cytotoxic CD8+ T cells.In this chapter I describe the current best-practice methods for measuring TMB in tumor specimens using whole-exome sequencing (WES).

Men and women with chronic insomnia disorder and OSAS: Different responses to CPAP.

ObjectiveTo evaluate the response to CPAP in patients with chronic insomnia disorder (CID) with OSAS in an unselected patient population including all OSAS severity groups. As a secondary objective, we also wanted to evaluate the differences between patients that improve insomnia symptoms with CPAP and patients that do not improve, specifically evaluating possible gender differences. MethodsRetrospective study of patients with a diagnosis of OSAS treated with CPAP and CID at the first clinical visit, selected from a database of an outpatient sleep clinic of University Hospital. ResultsFrom a database of total of 827 patient, 90 patients were identified with OSAS and CID (53.3% women). Middle / moderate OSAS was diagnosed in 68.9% and severe OSA in 31.1%. Most patients (61.1%) improved insomnia symptoms after CPAP therapy. In the responders group, 58.2% had initial insomnia, 63.6% middle insomnia and 12.7% late insomnia. Responders to CPAP were more frequently women (women 61.8%, men 38.2%, p = 0.035) and there was no other difference between responders and non-responders. On subgroup analysis, this difference was significant only in severe OSAS (women 88.9%, men 31.6%, p = 0.013). ConclusionIn most patients with CID and OSA, there is a consistent reduction of insomnia symptoms with the CPAP use. This factor emphasizes the importance of performing PSG in CID. Insomnia in men with severe OSAS responds less frequently to CPAP suggesting that in these cases the insomnia phenotype is less dependent on the respiratory symptoms.

Pembrolizumab for the treatment of cervical cancer

ABSTRACTIntroduction: The prognosis of patients with recurrent and/or metastatic cervical cancer remains poor, with a 5-year survival rate of 17%. Most of cervical cancers are associated with the human papillomavirus (HPV) infection that leads to viral antigens production, supporting the development of immunotherapy in cervical cancer.Areas covered: Here we report the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of cervical cancer.Expert opinion: Single agent pembrolizumab has limited efficacy in the recurrent and/or metastatic setting in an unselected patient population. However, durable responses in PD-L1-expressing cervical cancer patients led the U.S. Food and Drug Administration to grant accelerated approval of pembrolizumab in this patient population. Outside this patient population, further development involves combinations with other treatment options including chemotherapy, radiotherapy and other immunotherapeutic agents. The identification of biomarkers of efficacy beyond PD-L1 expression will be essential in order to identify patients who will most likely benefit from pembrolizumab.

Pancreatic stenting to prevent post-ERCP pancreatitis: a randomized multicenter trial

Background and study aims Acute pancreatitis (AP) is one of the most common gastrointestinal disorders leading to hospitalization and the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP). Besides pharmaco-prophylaxis, pancreatic stenting has been demonstrated to protect from post-ERCP pancreatitis (PEP). However, it remains unclear which patients benefit from pancreatic stenting. We therefore hypothesized that in an unselected population, inadvertent cannulation of the pancreatic duct during first-time ERCP increases risk of PEP and that this risk can be significantly reduced by pancreatic stenting. Patients and methods This study was a multicenter, prospective, randomized controlled trial conducted at four European centers. A total of 167 patients undergoing first-time ERCP were enrolled in this trial. In the case of inadvertent cannulation of the pancreatic duct, patients were randomly assigned to receive either a 5 French plastic pancreatic stent of various length or no routine prophylactic intervention for PEP. Results A total of 167 patients were included in the final analysis. Prophylactic stent insertion significantly reduced the rate of PEP during first-time ERCP (odds ratio 0.43; 95% confidence interval 0.19 – 0.98; P = 0.04). The number needed to treat to prevent one case of PEP by prophylactic stent insertion after inadvertent cannulation of the pancreatic duct was 8.1 for the intention-to-treat population. Conclusion In an unselected patient population, inadvertent cannulation of the pancreatic duct during first-time ERCP is associated with a high risk for PEP. This risk can be significantly reduced by prophylactic pancreatic stenting, which is a safe and feasible procedure.

Abstract LB-305: Circulating miR-652-3p as a biomarker of resistance to regorafenib in metastatic colorectal cancer patients

Abstract MicroRNAs (miRs) are small non-coding RNAs involved in cell homeostasis and carcinogenesis and control multiple oncogenic pathways. Numerous miRs are aberrantly expressed in colorectal cancer (CRC) and their deregulation is associated with clinical outcome and cancer progression. Chemo-refractory metastatic CRC (mCRC) patients are often treated with regorafenib, a multi-tyrosine kinase inhibitor with anti-angiogenic effect. Given the limited clinical benefits of regorafenib in unselected patient populations, there is an unmet need for better patient selection and identification of mechanisms of resistance. miRs are highly stable and have shown encouraging value as potential biomarkers for CRC detection and prognosis. Here we aimed to identify circulatory miRs that might be exploited for the upfront selection of patients’ candidate to regorafenib treatment. We ran a translational phase II trial of regorafenib in chemo-refractory mCRC patients. Serum, plasma and tissue biopsies were obtained at baseline (BL), every four weeks and at disease progression (PD). Patient Derived Organoids (PDOs) and PDO-xenotransplants were generated to study primary and acquired resistance to regorafenib. MiR profiling was performed in baseline serum of all patients by NanoString nCounter platform of 800 genes and validated with digital droplet (dd)PCR in serum, plasma, PDOs and by In Situ Hybridization (ISH) in matching tissue biopsies. Progression Free Survival (PFS) was measured from date of registration to date of first progression/relapse or death from cancer progression. Overall Survival (OS) was measured from date of randomisation to death from cancer. Further validation was performed by ddPCR in 97 patients from an independent patient’s cohort. MiR expression was tested in 43 BL sera and dysregulation in 28 miRs was associated with PFS and OS. Up-regulation of miR-652-3p was associated with worse PFS and OS. These results were validated by ddPCR on the same serum samples, and matching plasmas. ISH confirmed upregulation of this miR in sequential tissues biopsies, PDOs and PDO-xenotransplants of patients with primary and acquired resistance to regorafenib. Validation in an independent patient’s cohort confirmed direct association of miR-652-3p dysregulation with PFS and OS. Functional experiments to define miR652-3p mediated resistance have shown that there is a decrease of tumour growth and migration in miR-652-3p inhibition in PDOs. We provide initial evidence suggesting that circulating miR-652-3p might work as a negative predictive biomarker for the upfront selection of patients’ candidate to regorafenib treatment. Citation Format: Somaieh Hedayat, Khurum Khan, David Cunningham, George Vlachogiannis, Andrea Lampis, Silvia Marchetti, Matteo Fassan, Ruwaida Begum, Marta Schirripa, Fotios Fotios Loupakis, Nicola Valeri. Circulating miR-652-3p as a biomarker of resistance to regorafenib in metastatic colorectal cancer patients [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 LB-305.

PB2131 CTDA VERSUS MPT FOR MULTIPLE MYELOMA: REAL WORLD DATA FROM THE WEST OF SCOTLAND CANCER NETWORK

Background:Multiple myeloma has a median age at presentation of approximately 70 years and many patients are unsuitable for intensive induction chemotherapy and autologous stem cell transplant due to advanced age or co‐morbidity. Current West of Scotland Cancer Network, BCSH and NICE Clinical Management Guidelines supports the use of either CTDa (attenuated Cyclophosphamide, Thalidomide and Dexamethasone) or MPT (Melphalan, Prednisolone, Thalidomide) as options for first line treatment in patients ineligible for high dose therapy. Despite these recommendations there are little reported data directly comparing the efficacy of these two commonly used chemotherapy regimens.Aims:In order to determine whether the choice of either CTDa or MPT as first line therapy had any influence on survival among our patient population, we retrospectively analysed real‐world data from patients treated initially with either CTDa or MPT in the West of Scotland Cancer Network between 1/1/2013 and 1/1/2016.MethodsPatient data including demographics, details of treatment regimens, ECOG performance status, ISS and renal function at diagnosis were extracted, where available, from electronic prescribing records and electronic notes. Individual patient mortality data was collected for 6 years from initiation of their treatment. All data were analysed using “R” software (v3.5.2).Results:In total 171 patients were treated with either CTDa (n = 126) or MPT (n = 45) first line for multiple myeloma between 1/1/13 and 1/1/2016. Patients received a similar number of cycles (median 6 CTDa vs 5 MPT). Mean age for patients treated with CTDa was 74 (72.8‐75.2) and MPT 76.9 (75.4‐78.4), male to female ratio was 1:1.06 for CTDa and 1:1.8 for MPT. Kaplan Meier curves were constructed and compared using the logrank test. Median survival was 1258 days for CTDa and 785 days in the MPT group. Although the Kaplan Meier curves appeared to show some benefit to probability of survival in favour of CTDa, there was no statistically significant difference between the Kaplan Meier curves (p = 0.15). Due to the retrospective nature of our data collection we were unable to provide details of response rate or progression free survival.Summary/Conclusion:Our data show comparable survival between patients treated with CTDa or MPT in an unselected patient population. Our results are similar to those reported in the prospective UK Myeloma IX trial1. It should be noted that patients treated with both CTDa and MPT in our dataset had extensive modifications to their treatment regimen diverging from the established protocol. Most frequently patients treated with CTDa received once weekly Dexamethasone instead of four‐day steroid pulses, as reflects common clinical practice in frail or elderly patients. However, it was reassuring to note that regimen modification did not appear to adversely affect OS when compared to published data.imageAcknowledgement:The authors are grateful to Christine Crearie and colleagues in the West of Scotland Cancer Network and West of Scotland Haematology Audit Group for support and access to patient data.

DOZ047.107: Increased quality of life burden related to obstructive sleep apnea in children with aerodigestive disease

Abstract Objective The aim of this study was to determine the impact of sleep-disordered breathing on quality of life (QOL) in children with aerodigestive disease compared to children without aerodigestive disease. Methods Retrospective, IRB-approved, single-institution review of OSA-18 survey results administered to an unselected population of pediatric otolaryngology patients, some of whom had also been seen in the multidisciplinary aerodigestive clinic, was carried out. Results 476 non-aerodigestive patients and 43 aerodigestive patients were compared using total OSA-18 score and the summed scores from the 5 domains that comprise the OSA-18: (1) sleep disturbance, (2) physical suffering, (3) emotional distress, (4) daytime problems, and (5) caregiver concern. Sleep-related QOL was significantly worse for children with aerodigestive disease compared to those without aerodigestive disease across domains of sleep disturbance (P = 0.011), physical suffering (P = 0.028), and caregiver concern (P = 0.016). Total OSA-18 scores were in the mild impact range, and they did not differ significantly between the two populations. Conclusion While the focus of many aerodigestive programs is on the pathophysiological relationship between the upper digestive tract, the laryngotracheal airway, and the lungs, the present study elucidates a significant impact of upper airway obstruction during sleep on the QOL of children with aerodigestive disease. In recognition of this impact, certain airway centers have added a multidisciplinary approach to upper airway obstruction to their aerodigestive treatment armamentarium. At the minimum, airway treatment centers should consider systematic screening of all children with aerodigestive disease for QOL burden related to OSA.

Real-world data on PD-1 inhibitor therapy in metastatic melanoma

Introduction: Phase III studies of PD-1 inhibitors have demonstrated remarkable improvements in the survival of patients with metastatic melanoma (MM). If these results are generalizable to an unselected patient population treated in clinical routine is unknown. This study aimed to investigate and describe clinical efficacy and safety of PD-1 inhibitors in patients with MM treated in routine clinical practice.Material and methods: A retrospective descriptive study of patients with metastatic or inoperable cutaneous melanoma treated with PD-1 inhibitors at a single institution (Department of Oncology, Sahlgrenska University Hospital) from 1 September 2015 to 31 August 2017. Data were obtained from medical records.Results: A total of 116 patients were included in the analyses. The overall survival (OS) at 12-month follow-up was 70.2% and the median OS was 27.9 months. Patients with BRAF mutated tumors had increased OS, whereas ECOG PS ≥2, LDH > ULN and presence or history of brain metastases (stage M1d) were associated with impaired survival. Immune-related AEs of any grade occurred in 64 (55.2%) patients and 15 (12.9%) patients experienced immune-related AEs of grades 3 and 4. Notably, rheumatic adverse events occurred at a higher rate (15.5%) than previously reported. The occurrence of immune-related AEs was associated with a benefit in OS, while the severity of immune-related AEs did not affect survival, nor did the use of systemic corticosteroids.Conclusions: The efficacy and safety of PD1 inhibitors in routine clinical practice appear comparable to that described in clinical trials.

Characteristics of Patients with Type-1 or Type-2 Diabetes Receiving Insulin Glargine U300: An Analysis of 7268 Patients Based on the DPV and DIVE Registries.

Insulin glargine 300 U/ml (U300) was registered based on the EDITION clinical trial program. The aim of this database analysis was to describe the profile of adult U300 recipients with type-1 (T1DM) or type-2 diabetes (T2DM). The analysis was based on data from the German DIVE/DPV registries. Patients were sampled in May (DIVE) and in March 2018 (DPV) and divided into those who commenced U300 within the 1st year (early adopters) or 2nd year (late adopters). Patients were further compared to patients receiving U100 during the same time period. Among 581,519 adult patients contained in the databases, 7268 with either T1 or T2DM received U300 and 22,050 U100. Baseline characteristics of U300 and U100 recipients did not differ substantially in both types of diabetes. Patients with T2DM had many risk factors and comorbidities. The median HbA1c (both T1DM and T2DM, 8.1% for U300 and 7.9 and 8.3% for U100) and fasting blood glucose values were similar at baseline. Severe hypoglycemia was less prevalent in T2DM and among recipients of U300 (3.1 vs. 3.9%), whereas in T1DM the rate was higher (10.6 vs. 10.1%). There were minor, but clinically probably irrelevant, differences in age and BMI for T1DM and T2DM between the first and second years. Patients with T2DM being initiated in the second year had a higher HbA1c value (8.6 vs. 8.3%) than those initiated during the first year. Patients in clinical practice showed substantially higher HbA1c values in both T1DM and T2DM, and doses used were lower than those reported from the EDITION trial program. U300 patients had a longer diabetes duration (T1 and T2DM), a higher BMI and received higher basal insulin doses (T1 and T2DM) compared to U100. While HbA1c was comparable, the rate of severe hypoglycemia under U300 was reduced in T2DM but not T1DM with or without adjustment for differences in baseline characteristics in T2DM. The data confirm the clinical profile documented for U300 in the EDITION studies during the first years of its registration. In an unselected patient population, there was a lesser rate of severe hypoglycemia but at a comparable HbA1c. German Centre for Diabetes Research (DZD) (01GI1106), the European Foundation for the Study of Diabetes (EFSD) and the German Diabetes Society (DDG). The DIVE registry (organized as Diabetes Agenda 2010 GmbH, Berlin, Germany) received funding from Sanofi, AstraZeneca, Bayer, and Abbott and was conducted under the auspices of diabetesDE.

A phase I study of the APE1 protein inhibitor APX3330 in patients with advanced solid tumors.

3097 Background: APX3330 is an orally administered anti-cancer, anti-CIPN agent targeting the APE1 protein. APE1 maintains NFkB, STAT3, AP-1 and HIF-1a in a reduced form, acting as a regulator of transcription factors. A dual function protein, APE1 also plays a role in protecting against oxidative DNA damage in neurons. APX3330 is a highly selective inhibitor of APE1 redox function in tumors that enhances the neuronal protection function of APE1. Methods: We report on study NCT03375086 evaluating APX3330 in patients with incurable malignancies. Eligibility required adequate organ function, PS 0-2 and tumors not amenable to curative therapy. 1° and 2° objectives included determining the recommended phase 2 dose (RP2D), the safety and PK/PD profiles of APX3330 and reporting any RECIST anti-tumor activity. Patients received APX3330 b.i.d, in 21-day cycles. AE evaluation included 1 pt/cohort until the occurrence of ≥ G2 toxicity at which time the study proceeded in a 3+3 design. Additional patient were also recruited in cohorts in order to attain PK/PD and biopsy samples. Results: Between 2/18 and 8/18, 19 subjects (13M, 6F) with median age of 69 y started therapy. Dose (mg/d) escalation and number of patients treated (n) per each cohort proceeded as follows: 240 mg (1), 360 (4), 480 (2), 600 (6) and 720 (6). APX3330 was well tolerated at dose levels from 240-600 mg/d. The most frequent treatment-related adverse event (all grades) was G1 fatigue. A G3 rash occurred in two subjects at the 720 mg level defining 600 mg/d as the RP2D for further development. Six subjects had disease stabilization for ≥ 4 cycles, and of these, four subjects with the following diagnosis, RECIST response and days on study included: (CRC, PR, 356), (Endometrial, SD, 316), (Melanoma, SD, 245), (Prostate, SD, 246). Final PK and PD data, including proteomic, transcriptome, APE1 serum levels and CTC analyses are pending and will be reported at the conference. Conclusions: APX3330 is an orally administered inhibitor of APE1. This phase I study identified 600 mg PO daily as the RP2D for further development. RECIST evaluation identified signs of clinical activity in this un-selected population of patients with advanced cancer. PD analyses indicate APX3330 mediated targeting of the APE1 protein. Clinical trial information: NCT03375086.

GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.

2034 Background: Patients (pts) with recurrent glioblastoma (rGB) have a poor prognosis, and no treatment option demonstrated to improve survival in a randomized trial. Axitinib (AXI), an oral VEGFR 1-3 inhibitor has demonstrated single agent activity in rGB and reduces the need for corticosteroids (CS). Avelumab (AVE) is a fully human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types. Combination of AXI and AVE may improve the outcome of pts with rGB. Methods: This open-label, dual-strata, single-center phase 2 clinical trial investigated the activity of AXI plus AVE in adult pts with rGB following prior surgery, RT and temozolomide. Pts were stratified according to their baseline use of CS. Pts without baseline need for CS initiated treatment with AXI (5 mg oral BID) plus AVE (10 mg/kg IV Q2W) (cohort-1). Pts in need of CS initiated AXI as a monotherapy; AVE could be added to AXI after 6 wks if the CS dose could be tapered to a physiologic dose level or less (cohort-2). Six-month-PFS served as the primary endpoint (with a prespecified threshold of ≥ 50% for cohort-1) according to Fleming one-stage design. Results: Between Jun 2017 and Aug 2018, 54 pts (27 per cohort) were enrolled (med age 55 y [range 19-75]; 63% male; 91% WHO PS 0-1). All pts in cohort-1 and 16 pts (59%) in cohort-2 received at least 1 dose of AVE. The 6-month-PFS was 18% (95% CI 4-33) in both cohorts. At the time of analysis, 2 pts were progression-free and continuing study treatment. Median OS in cohort-1 and -2 was respectively 26 wks (95% CI 21-32) and 18 wks (95% CI 14-22). No clear relation was found between baseline cognitive functioning (Cogstate subtests) and PFS/OS. The best overall response rate (iRANO) was 41% and 26% respectively for pts in cohort-1 and -2. The most frequent all-grade treatment-related adverse events (TRAE) were dysphonia (67%), lymphopenia (50%), diarrhea (48%), hypertension (48%), and fatigue (46%). The incidence of grade 3-4 TRAE was 30%; there were no grade 5 AE. Conclusions: The combination of AVE plus AXI is sufficiently well tolerated but did not meet the threshold for activity justifying further investigation in an unselected population of patients with rGB. Clinical trial information: NCT03291314.

Association of noninvasive, radiographic measurement of prostate-specific membrane antigen (PSMA) expression with response to PSMA-targeted radionuclide therapy (TRT).

5013 Background: Prostate surface membrane antigen (PSMA) is usually overexpressed in PC and is enriched in castration-resistant tumors. PSMA-TRT is of increasing interest to the field. Many in the field of theranostics have assumed that PSMA uptake on imaging is a pre-requisite for response. We have conducted a number of trials which have incorporated PSMA imaging, but have not selected patients for treatment based upon imaging results and performed an analysis examining the relationship between imaging and response. Methods: Men with mCRPC had either planar radiolabeled J591 imaging (111In-J591 and/or 177Lu-J591) or 68Ga-PSMA11 PET/CT. Visual scores were assigned based upon PSMA uptake in tumors compared to liver uptake and scored on a 0-4 scale. Imaging scores were associated with PSA decline (≥30%, ≥50%) using Cox regression analysis. As several studies were dose-escalation in nature with prior demonstration of dose-response, we controlled for dose administered. Results: 216 men with metastatic CRPC, median PSA 72.45ng/dl, were treated with PSMA-TRT as follows: 177Lu-J591 (n=136), 177Lu-PSMA-617 (n=38), Lu-J591 + Lu-PSMA-617 combination (n=6), 225Ac-J591 (n=7), 90Y-J591 (n=29). 116 (53.7%) pts received low dose and 100 (46.3%) high dose as previously defined in the individual studies. 55 (25.5%) pts had low PSMA expression by imaging (VS 0-1) whereas 161 (74.5%) had high PSMA (VS 2-4). High PSMA expression was associated with more frequent PSA decline (≥30%: 39.2 vs 17.9% p=0.003; ≥50%: 27.5 vs 8.9% p=0.004). When controlling for dose level, this association remained significant for low (≥30%: 25 vs 8.6% p=0.04) and high doses of radionuclide therapy (≥50%: 34.9 vs 9.5% p=0.02). 13 (6%) pts with no PSMA uptake (VS=0) had PSA declines. Conclusions: This is the first study to formally analyze response to PSMA-TRT by PSMA imaging expression in an unselected patient population. The level of PSMA expression measured by imaging is associated with the chance of response. However, a subset of patients without any significant PSMA uptake on imaging did demonstrate response to PSMA-TRT, indicating that imaging cannot exclude all patients that might benefit. Clinical trial information: NCT03545165, NCT03276572, NCT03042468, NCT02552394.

Comparison of outcomes in a population-based cohort of women with metastatic breast cancer receiving anti-HER2 therapy with clinical trial outcomes.

1037 Background: Little data exist for comparing cardiac safety and survival outcomes of anti-HER2 therapy with concurrent trastuzumab (T) and pertuzumab (P) or ado-T emtansine (TDM1) in metastatic breast cancer (MBC) patients enrolled in randomized clinical trial (RCT) vs those in the real world. Furthermore, whether older patients have worse outcomes is unknown. Methods: This was a retrospective population-based cohort of all women with MBC treated with concurrent T with P or TDM1 in Ontario (between 2012 and 2017), identified from New Drug Funding Program and linked to Ontario Cancer Registry and other administrative datasets. Outcomes were incident heart failure (HF, defined as hospitalization or emergency room visit for HF) and overall survival (OS). RCT data were obtained from digitizing survival curves as per established methods and compared with cohort OS data using log-rank test. Age based comparison of outcomes was conducted for women ≥ 65 years old vs younger. Results: Our cohort composed of 833 (28% > 64 years old), and 397 (28% > 64 years old) women treated with P and TDM1, respectively, of which 46 and 30 had baseline HF, respectively. 49% and 99.5% of women received T prior to P and TDM1, respectively. Incident HF following P or TDM1 initiation was low (P 26 women, TDM1 8 women; Table). HF events was not more in women ≥ 65 years old compared to women < 65 treated with P (16 vs. 10, p = 0.23). Unadjusted OS was significantly worse than RCT OS (Table; P HR 1.67, 95% CI 1.37-2.03, p < 0.0001; TDM1 HR 2.80, 95% CI 2.27-3.44, p < 0.0001). Older women had worse OS than younger women for P (HR 1.54, 95% CI 1.22-1.96, p = 0.0003), but not for TDM1 (HR 1.08, 95% CI 0.81-1.43, p = 0.62). Conclusions: HF incidence during P or TDM1 therapy in this real world cohort was relatively low. Survival in this cohort was significantly worse compared to RCT, particularly for older women, suggesting importance of evaluating effectiveness in an unselected patient population to facilitate informed decision-making based on real-world risks and survival outcomes.[Table: see text]

Five-year outcomes in cardiac surgery patients with atrial fibrillation undergoing concomitant surgical ablation versus no ablation. The long-term follow-up of the PRAGUE-12 Study

The long-term effect of concomitant surgical ablation (SA) on clinical outcomes in an unselected population of patients has not been sufficiently reported in randomized studies. The aim of this study was to assess clinical outcomes of the SA after 5 years of follow-up. The PRAGUE-12 study was a prospective, randomized clinical trial assessing cardiac surgery with ablation for AF vs cardiac surgery alone. Patients with AF who were also indicated for cardiac surgery (coronary artery disease [CAD], valve surgery) were randomized to SA or control (no ablation) group. All patients were followed for 5 years. The primary endpoint was a composite of cardiovascular death, stroke, hospitalization for heart failure, or severe bleeding. Secondary endpoint was a recurrence of AF. A total of 207 patients were analyzed (SA group = 108 patients, control group = 99 patients). Both groups were similar relative to important clinical characteristics except for CAD, which was more common in the control group. Cumulative incidence curves showed a higher incidence of the primary endpoint in the control group (P = .024, Gray's test). However, after adjusting for all covariables, the difference between groups was not significant (subhazard ratio [SHR] 0.69 [0.47-1.02], P = .068). The incidence of stroke and AF recurrences were significantly reduced in the SA group, and remained significant even after adjustment for all covariables, including CAD (stroke: SHR 0.32 [0.12-0.84], P = .02, AF recurrences: SHR 0.44 [0.31-0.62], P < .001). Concomitant SA of AF is associated with a greater likelihood of maintaining sinus rhythm and a decreased risk of stroke.

The effects of zolpidem in obstructive sleep apnea - An open-label pilot study.

New knowledge on hypnotics and their effects on the phenotypic causes of obstructive sleep apnea indicate that zolpidem has therapeutic potential for certain patients. Specifically, zolpidem increases the threshold for arousal threshold and pharyngeal dilator muscle responsiveness. However, the effects of a standard dose of zolpidem (10 mg) on obstructive sleep apnea severity and symptoms have not been investigated. In an open-label pilot study, 12 unselected people with obstructive sleep apnea were recruited following a diagnostic in-laboratory sleep study. Participants then returned for a single-night sleep study in which 10 mg of zolpidem was given just prior to sleep. Tolerability, next-day sleepiness and the effects of zolpidem on polysomnography variables were assessed. Zolpidem was well tolerated and significantly improved the sleep efficiency compared with the no-drug night (77 ± 12% versus 84 ± 9%, p = 0.005). Individual responses on obstructive sleep apnea severity to zolpidem in this unselected obstructive sleep apnea patient population were variable with no overall systematic difference in apnea-hypopnea index (29 ± 18.2 events per hr versus 33 ± 28 events per hr, p = 0.45) or other key respiratory parameters (e.g. event duration or hypoxemia). Next-day sleepiness assessed via the Karolinska Sleepiness Scale was not different between visits (4 ± 1 versus 4 ± 2, p = 0.85). These findings provide the first insight into the effects of a standard dose of zolpidem in obstructive sleep apnea, and highlight its tolerability and potential to improve sleep quality. The variable effects on obstructive sleep apnea severity observed in this pilot also underscore the need for larger trials that incorporate phenotypic characterisation (e.g. arousal threshold, Pcrit and muscle responsiveness) to understand inter-individual heterogeneity and the therapeutic potential of zolpidem for certain people with obstructive sleep apnea.

Abstract 269: Patients &gt;65 Years of Age Have Higher Mortality After In-hospital Cardiac Arrest With Lower Utilization of Healthcare Resources

Background: Studies have shown that age is not an independent predictor of short-term and long-term neurological outcomes after cardiopulmonary resuscitation. These findings were reported for both in-hospital and out-of-hospital cardiac arrest. Yet, elderly patients are less aggressively treated and have higher mortality. We investigated the current outcomes and therapeutic approach in a large unselected population of patients. Methods: In a retrospective cohort study, using the 2014 Nationwide Inpatient Sample, we analyzed patients &gt;65 years of age with in-hospital cardiac arrest. We performed univariate analysis of age, sex, race, hospital location, hospital teaching status, insurance type, hospital bed size, Charlson Comorbidity Index and other relevant comorbidities such as ventricular arrhythmias and we included variables with p&lt;0.2 in the multivariate logistic regression model. Results: A total of 39397 patients, who underwent in-hospital cardiopulmonary resuscitation (CPR) were identified. Patients &gt;65 years of age (55%) had mean age of 78+/_0.06, vs 50+/_0.22, p&lt;0.001 and a higher percentage of them were female (46% vs 40%, p&lt;0.001). They were less likely to have ESRD (9% vs 11%, p&lt;0.001), abuse drugs (0.7% vs 10%, p&lt;0.001) and alcohol (0.3% vs 11.5%, p&lt;0.001) and had lower incidence of ventricular tachycardia or ventricular fibrillation (20% vs 23%, p&lt;0.001). They were more likely to have chronic kidney disease (25% vs 11%, p&lt;0.001), diabetes mellites (29% vs 21%, p&lt;0.001), hypertension (69% vs 50%, p&lt;0.001) and heart failure (26% vs 17%, p&lt;0.001). Patients &gt;65 years of age had higher mortality (OR=1.51, 95%CI =1.43-1.61, p&lt;0.001) and were less likely to undergo therapeutic hypothermia (OR=0.66, 95%CI=0.56-0.79, p&lt;0.001), receive cardioverter-defibrillator (OR=0.77, 95%CI=0.64-0.92, p=0.005) and extracorporeal membrane oxygenation (OR=0.32, 95%CI =0.23-0.45, p&lt;0.001). There was no difference in utilization of short-term mechanical circulatory support, dialysis in the setting of acute kidney injury and blood product transfusion. There was also no difference in the incidence of ischemic stroke and placement of percutaneous endoscopic gastrostomy with lower utilization of tracheostomies (OR=0.64, 95% CI= 0.56-0.73, p&lt;0.001) and higher utilization of palliative care consult (OR=1.44, 95% CI=1.33-1.56, p&lt;0.001) in older patients. Patients &gt;65 years of age had lower length of stay (Coef. =-1.46, 95% CI=-1.85- -1.08), p&lt;0.001) and the total charges from hospital stay (Coef. =-49889$, 95% CI= -56803$- -42975, p&lt;0.001). Conclusion: Patients &gt;65 years of age, who underwent in-hospital CPR had higher mortality, which could be related to lower utilization of healthcare resources and contribute to a shorter hospital stay and lower total charges. Furthermore, our study unravels lower utilization of a palliative care consult in a younger population of patients.

Abstract 270: Patients With Acute Ischemic Stroke and Associated Diagnosis of Obstructive Sleep Apnea Have Lower In-hospital Mortality

Background: Obstructive sleep apnea (OSA) is present in almost 60% of patients with cerebrovascular disease and it is an independent predictor of ischemic stroke. Yet, the impact of OSA on outcomes of ischemic stroke is unclear. Some, small cohort studies indicate increased short-term mortality, whereas larger studies, with more complex logistic regression models, show decreased in-hospital mortality. Lower mortality could be attributed to chronic intermittent episodes of hypoxia affecting the remodeling of cerebral collateral circulation. We thought to investigate outcomes in a large unselected population of patients presenting with acute ischemic stroke. Methods: In a retrospective cohort study, using the 2014 Nationwide Inpatient Sample (NIS), we analyzed adult patients with acute ischemic stroke and OSA. We performed univariate analysis of age, sex, race, hospital location, hospital teaching status, insurance type, hospital bed size, Charlson Comorbidity Index and other relevant comorbidities and we included variables with p&lt;0.2 in the multivariate logistic regression model. Results: A total of 95282 patients with acute ischemic stroke were identified. Patients with the associated diagnosis of OSA (5%) had a mean age of 66+/_0.2, vs 71+/_0.1, p&lt;0.001 and a higher percentage of them were male (63% vs 48%, p&lt;0.001). Patients with OSA were more likely to have hypertension (88% vs 83%, p&lt;0.001), heart failure (24% vs 14%, p&lt;0.001), chronic kidney disease (20% vs 14%, p&lt;0.001) ESRD (3% vs 2%, p&lt;0.001) and diabetes mellites (40% vs 30%, p&lt;0.001). Patients with associated diagnosis of OSA had higher incidence of ventricular fibrillation and ventricular tachycardia (OR=1.27, 95%CI=1.02-1.58, p=0.27) with no difference in incidence of cardiac arrest (OR=1.14, 95%CI=0.78-1.66, p=0.50) and lower in-hospital mortality (OR=0.68, 95%CI =0.57-0.82, p&lt;0.001). They were less likely to have hemiplegia (OR= 0.83, 95% CI=0.74-0.95, p=0.004) and less likely to receive a blood product transfusion (OR =0.71, 95%CI =0.54-0.93, p&lt;0.014). There was no difference in utilization of percutaneous endoscopic gastrostomy (OR=0.90, 95%CI=75-1.07, p=0.23), incidence of shock (OR=1.13, 95% CI =0.66-1.90, p=0.66) and utilization of mechanical ventilation (OR=0.96, 95%CI =0.82-1.11, p=0.55) as well as in length of stay (Coef. =-0.039, 95% CI=-0.23—0.16, p=0.70) and total costs of hospitalization (Coef. =180.73, 95% CI= -1925-2287, p=0.87). Conclusion: Patients with OSA and ischemic stroke have a higher number of cardiovascular comorbidities. After adjustment with a complex multivariate regression model in a large population of patients, they have lower in-hospital mortality and lower incidence of hemiplegia. We also uncovered underdiagnosing of obstructive sleep apnea in National Inpatient Sample registry, which is a limitation of the study.