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PURPOSENRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375 ) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.METHODSIDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.RESULTSOf the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup.CONCLUSIONThis study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

Background: There are limited data on the epidemiology and timing of in-hospital death (IHD) in patients with acute myocardial infarction-cardiogenic shock (AMI-CS). Methods: Adult admissions with AMI-CS with IHDs were identified using the National Inpatient Sample (2000–2016) and were classified as early (≤2 days), mid-term (3–7 days), and late (>7 days). Inter-hospital transfers and those with do-not-resuscitate statuses were excluded. The outcomes of interest included the epidemiology, temporal trends and predictors for IHD timing. Results: IHD was noted in 113,349 AMI-CS admissions (median time to IHD 3 (interquartile range 1–7) days), with early, mid-term and late IHD in 44%, 32% and 24%, respectively. Compared to the mid-term and late groups, the early IHD group had higher rates of ST-segment-elevation AMI-CS (74%, 63%, 60%) and cardiac arrest (37%, 33%, 29%), but lower rates of acute organ failure (68%, 79%, 89%), use of coronary angiography (45%, 56%, 67%), percutaneous coronary intervention (33%, 36%, 42%), and mechanical circulatory support (31%, 39%, 50%) (all p < 0.001). There was a temporal increase in the early (adjusted odds ratio (aOR) for 2016 vs. 2000 2.50 (95% confidence interval (CI) 2.22–2.78)) and a decrease in mid-term (aOR 0.75 (95% CI 0.71–0.79)) and late (aOR 0.34 (95% CI 0.31–0.37)) IHD. ST-segment-elevation AMI-CS and cardiac arrest were associated with the increased risk of early IHD, whereas advanced comorbidity and acute organ failure were associated with late IHD. Conclusions: Early IHD after AMI-CS has increased between 2000 and 2016. The populations with early vs. late IHD were systematically different.

6500 Background: ECOG-ACRIN 3311 examines reduced postoperative therapy in patients with “intermediate risk” p16+ oropharynx cancer (OPC) undergoing primary transoral surgical management. We report the primary endpoint of 2-year progression free survival (PFS) for patients randomized to 50Gy vs 60Gy without chemotherapy. Methods: Between December 2013 and July 2017, 82 credentialed surgeons performed transoral resection (TOS) for 519 OPC patients (cT1-2 stage III/IV AJCC7 without matted neck nodes); post-operative management was determined by pathologically assessed risk. Among 353 eligible and treated patients, Arm A enrolled 10% (N=37) for clear margins, 0-1 nodes, no extranodal extension (ENE)), Arms B (50Gy, N=102) or C (60Gy, N=104) randomized 58%, for clear/close margins, 2-4 + nodes, or ENE ≤1mm, while Arm D (N=110, 60-66Gy plus weekly cisplatin, 40 mg/m2, positive margin with any T stage, >4 + nodes, or >1mm ENE) enrolled 31%. Arm D assignment was based on >1mm ENE (76%), > 4 nodes (27%), and/or positive margins (11%). Intermediate-risk patients were stratified by smoking history (>10 pk-yr). Of the 80 pts (15%) deemed ineligible, 28 had scans/labs not done per protocol, however treatment arm distribution for all patients mirrored that for the 353 pts eligible and treated. Results: Median follow-up was 31.8 months. 2 yr PFS for Arms A, B and C were 93.9% (90% CI=87.3%, 100%), 95.0% (90% CI=91.4%, 98.6%) and 95.9% (90% CI=92.6%, 99.3%) respectively, while Arm D was 90.5% (90% CI=85.9%, 95.3%). The regimen of TOS + low-dose radiation is considered worthy of further study, since the primary endpoint of the upper bound of the 90% CI (in the intermediate risk group) exceeding 85% was met. Of 17 progression events, 7 were locoregional. There were 10 distant recurrences: Arm A=1, Arm B=2, Arm C=4, Arm D=3. Grade III/IV treatment-related AE rates were 15%/2% during surgery, 13%/2% for Arm B and 25%/0% for Arm C. There were 2 treatment-related deaths (one surgical and one Arm D). Conclusions: Transoral resection of p16+ OPC is safe and results in good oncologic outcome, presenting a promising deintensification approach. For patients with low-risk disease, 2-yr PFS is favorable without post-operative therapy. For those with uninvolved surgical margins, <5 involved nodes, and minimal (<1mm) ENE, reduced dose postoperative RT without chemotherapy appears sufficient. Transoral surgery plus 50Gy should be compared to optimal non-surgical therapy in a phase III trial. Clinical trial information: NCT01898494 .

2518 Background: This study sought to evaluate the prognostic significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/non-codel, and IDHmt/codel) in NRG Oncology/RTOG 0424, a phase II trial of high-risk low-grade gliomas treated with radiation (RT) and concurrent and adjuvant temozolomide (TMZ) after biopsy/surgical resection. Notably, this is the first clinical study to evaluate the prognostic value of the WHO subgroups in RT + TMZ-treated high-risk grade II (G2) gliomas using prospectively-collected long-term survival data. Methods: IDH1/2 mutation status was determined by next-generation sequencing. 1p/19q co-deletion status was determined by Oncoscan and/or 450K methylation data. Overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a post-hoc analysis. Patient pre-treatment characteristics were included as covariates in multivariate analyses. Results: Of all the eligible patients (N=129), 80 (62%) had sufficient quality DNA for both IDH and 1p/19q analyses. Of these 80, 54 (67.5%) were IDHmt, and 26 (32.5%) were IDHwt. Of the 54 IDHmt patients, 26 (32.5% of total, 48% of IDHmt) were IDHmt/codel, and 28 (35% of total, 52% of IDHmt) were IDHmt/non-codel. Both IDHmt subgroups were significantly correlated with longer PFS ( IDHmt/co-del = 8.1yrs (5.2-not reached (NR)); IDHmt/non-codel = 7.5yrs (3.9-11.8); IDHwt = 1.0yr (0.6-1.7), p<0.001) and OS ( IDHmt/co-del = 9.4yrs (8.2-NR); IDHmt/non-codel = 8.8yrs (5.9-NR); IDHwt = 2.3yrs (1.4-3.4), p<0.001) relative to the IDHwt subgroup. Upon univariate and multivariate analyses, both molecular IDHmt subgroup comparisons relative to IDHwt remained significant (p<0.001) even after incorporation of known clinical variables. Conclusions: These analyses suggest that G2 glioma patients harboring IDH1/2 mutations, regardless of co-deletion status, demonstrated longer survival with RT + TMZ relative to IDHwt tumors, although sample size is limited and analyses were post-hoc. These results also support the notion that outcomes for IDHwt high-risk G2 gliomas remain dismal (median = 2.3yrs, similar to G3 anaplastic astrocytoma); these patients should be separated from IDHmt patients in future G2 glioma trials, and warrant novel treatment strategies. Funding: U10CA180868, U10CA180822, U24CA196067, CURE, PA Dept. of Health, and Merck. Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850, BTFC, OSUCCC (all to AC). Clinical trial information: NCT00114140 .

Background: With the rising cost of critical care and limited availability of critical care resources, improvements are need in the current cardiac intensive care unit (CICU) triage process. We sought to determine whether the Mayo Clinic Intensive Care Unit Admission Risk Score (M-CARS) could be used to predict which CICU patients will require critical care resources. Methods: Adult patients admitted to our CICU from 2007 to 2018 were retrospectively reviewed. The M-CARS was calculated using data from the time of admission. Groups were compared using Wilcoxon test for continuous variables and chi-squared test for categorical variables. Results: We included 12,428 patients with a mean age of 67 ± 15 years (37% females). The mean M-CARS was 2.1 ± 2.1, including 5,890 (47.4%) patients with M-CARS <2 and 644 (5.2%) patients with M-CARS >6. Critical care therapies were frequently used, including mechanical ventilation in 28.0%, vasoactive medications in 25.5%, dialysis in 4.8% and invasive lines in 44.3%. The low-risk cohort with M-CARS <2 was less likely to require invasive or noninvasive mechanical ventilation (8.0% vs. 46.1%), vasoactive medications (10.1% vs. 38.8%), dialysis (1.0% vs. 8.2%) or invasive lines (34.6% vs. 53.0%), as compared to patients with M-CARS ≥2 (all p<0.001). A higher M-CARS was associated with greater use of critical care therapies and longer CICU and hospital length of stay. Conclusions: In addition to predicting hospital mortality, the M-CARS predicts resource utilization during CICU admission and could be used in the triage of critically ill cardiac patients. Patients with M-CARS <2 infrequently require critical care resources and have extremely low mortality, yet account for nearly half of all CICU admissions, suggesting a potential to avoid CICU admission in many patients.

Abstract There is a high background risk of venous thrombotic events (VTE) in patients with Multiple Myeloma (MM) and this is significantly increased following treatment with Thalidomide. The risk may be mediated by the production of a prothrombotic state, via an angiopathic mechanism, or alternatively it may arise from the release of prothrombotic factors from dying myeloma cells targeted by the treatment. No unifying evidence of a prothrombotic state has been demonstrated to date and it remains important to understand the mechanism underlying VTEs in order to prevent them effectively. Inherited genetic variants in the form of SNPs can affect the behaviour of clotting factors. These SNPs are functional and well characterised in the coagulation system and we have used them to analyse the mechanism underlying thalidomide induced VTE. As part of the Bank On A Cure TM project we have carried out an analysis of SNPs in 11 genes: GPIIA, ITGA, MTHFR, MTR, PPARG2, TFP1, VCAM, factor V, HABP2, prothrombin and THDB in a case series of 90 patients treated with thalidomide, with and without DVTs. This study showed a significant association with MTHFR and factor V polymorphisms. In order to validate and extend these initial observations we carried out an analysis of a second nested case control study using 131 Myeloma patients from within the MRC Myeloma IX trial, comprising 47 cases with a VTE and 94 age and sex matched controls exposed to the same treatment. We used a SNPlex panel containing 16 functional venous thrombosis associated SNPs, all of these functional polymorphisms have reported mechanisms and biology. We looked at polymorphisms in the genes: fibrinogen A (Ala331Thr), B (-455G&gt;A, Lys478Arg) and G polypeptides (His140Tyr); Coagulation factors V(Arg534Gln), VIII (Glu1260Asp), IX(Ala194Thr), XI (Phe339Cys) and XII(-4G&gt;T); PROCR(Gly219Ser); prothrombin(19911A&gt;G ,20210G&gt;A); MTHFR(Glu429Ala, Ala222Val); Serpine1(-844G&gt;A) and TFPI(Met292Val). We have typed our selected SNPs using the SNPlex™ Genotyping System, which is based on the oligonucleotide ligation/PCR assay with a universal fluorescently labeled ZipChute™ probe detection. The probes are hybridized to complementary ZipCode™ sequences that are part of genotype-specific amplicons. Probes are eluted and detected on a Applied Biosystems 3130x DNA Analyser. This approach is an attractive alternative to existing genotyping methodologies, as it requires only three unlabeled probes per SNP, and consumes very little gDNA. The data analysis on the polymorphisms frequencies is ongoing to examine associations of thalidomide treatment with VTE events and will be presented. These datasets will allow a better definition of the pathogenesis of thalidomide related VTE, so that we can intervene therapeutically in a rational fashion.

Abstract Background: Many patients (pts) with anemia due to impaired erythropoiesis fail to respond to currently available erythropoiesis-stimulating agents or do not wish to receive these agents due to safety concerns. For these pts, novel approaches are needed. DYRK3, an evolutionarily conserved member of an emerging family of serine-threonine kinases, is expressed at high levels in erythropoietic progenitors; murine models suggest that DYRK3 selectively inhibits red cell production during stress erythropoiesis. We sought to determine DYRK3 expression in pts with anemia, and whether in vitro inhibition of DYRK3 augments erythropoiesis. Methods: We performed quantitative RT-PCR for DYRK3 and 4 control genes using whole peripheral blood (WPB) from 14 healthy persons, 5 pts with anemia due to multiple myeloma (MM), and 3 pts with anemia of chronic disease (ACD); in addition, peripheral blood mononuclear cells (PBMCs) were assayed in the 3 ACD and 5 MM pts and bone marrow mononuclear cells (BMMCs) in the MM pts. Erythrocyte subpopulations (CD36+, CD71+, and dual CD36+/CD71+) were quantified by flow cytometry. CFU-E growth was measured from PBMCs and BMMCs in the presence of varying concentrations of GSK626616, an orally bioavailable first-generation DYRK3 kinase inhibitor. Results: Normalized expression of DYRK3 in WPB was 7.2 fold higher in MM pts (p=0.0001) and 3.4 fold higher in pts with ACD (p=0.026) compared to healthy controls. DYRK3 expression was proportional to the degree of anemia, and WPB and PBMC expression of DYRK3 in MM pts correlated well with BMMC expression. The level of DYRK3 expression was proportional to the population of marrow CD36+/CD71+ erythroid progenitors, and inversely proportional to the size of the more mature CD36−/CD71+ population, suggesting that high DYRK3 expression is associated with maturation arrest in humans at a stage of erythroid differentiation roughly corresponding to pre-Ter119pos/CD71high inhibition observed in murine models. Although incubation of pt-derived BMMC or PBMC with GSK626616 at concentrations up to 30 μM, either in the presence or absence of physiological concentrations of erythropoietin, did not augment in vitro CFU-E formation, CFU-E growth overall was poor in the pt samples studied. Conclusion: DYRK3 is expressed at high levels in pts with anemia due to neoplasia or inflammation, and elevated DYRK3 expression is associated with decreased numbers of CD36−/CD71+ red cells. Further studies of the effects of DYRK3 antagonists on human erythropoiesis in vitro are necessary, and clinical trials in anemic patients will be required to determine if DYRK3 antagonists can reverse DYRK3-associated inhibition.

Abstract Aims The aim of this study is to evaluate the contemporary use of a pulmonary artery catheter (PAC) in acute myocardial infarction-cardiogenic shock (AMI-CS). Methods and results A retrospective cohort of AMI-CS admissions using the National Inpatient Sample (2000–2014) was identified. Admissions with concomitant cardiac surgery or non-AMI aetiology for cardiogenic shock were excluded. The outcomes of interest were in-hospital mortality, resource utilization, and temporal trends in cohorts with and without PAC use. In the non-PAC cohort, the use and outcomes of right heart catheterization was evaluated. Multivariable regression and propensity matching was used to adjust for confounding. During 2000–2014, 364 001 admissions with AMI-CS were included. PAC was used in 8.1% with a 75% decrease during over the study period (13.9% to 5.4%). Greater proportion of admissions to urban teaching hospitals received PACs (9.5%) compared with urban non-teaching (7.1%) and rural hospitals (5.4%); P &lt; 0.001. Younger age, male sex, white race, higher comorbidity, noncardiac organ failure, use of mechanical circulatory support, and noncardiac support were independent predictors of PAC use. The PAC cohort had higher in-hospital mortality (adjusted odds ratio 1.07 [95% confidence interval 1.04–1.10]), longer length of stay (10.9 ± 10.9 vs. 8.2 ± 9.3 days), higher hospitalization costs ($128 247 ± 138 181 vs. $96 509 ± 116 060), and lesser discharges to home (36.3% vs. 46.4%) (all P &lt; 0.001). In 6200 propensity-matched pairs, in-hospital mortality was comparable between the two cohorts (odds ratio 1.01 [95% confidence interval 0.94–1.08]). Right heart catheterization was used in 12.5% of non-PAC admissions and was a marker of greater severity but did not indicate worse outcomes. Conclusions In AMI-CS, there was a 75% decrease in PAC use between 2000 and 2014. Admissions receiving a PAC were a higher risk cohort with worse clinical outcomes.