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Abstract BACKGROUND Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine. METHODS Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (< or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression. RESULTS Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p< 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis. CONCLUSION For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.

Abstract Glioblastoma, the most common and lethal of brain tumors, is both highly invasive and proliferative. This allows tumor cells to infiltrate into regions of the brain with an intact blood brain barrier and be protected from effective therapeutics. Thus, an ideal glioblastoma therapy needs to target cellular components that drive both invasion and proliferation, with inhibitors that penetrate the blood brain barrier. The mitotic kinesin KIF11 meets these criteria and it can be targeted with ispinesib, a highly specific small molecule inhibitor. However, to be effective, ispinesib needs to cross the blood brain barrier and be retained within brain long enough to target glioblastoma cells when they are vulnerable, during mitosis.. We have examined the factors that affect distribution of ispinesib to both brain and glioblastoma. We find that delivery of ispinesib is limited by P-gp and Bcrp-mediated drug efflux at the blood brain barrier. Consequently, ispinesib levels are significantly lower in the infiltrative tumor margin relative to the tumor core, where the blood brain barrier is defective. We also show that elacridar—an inhibitor of the P-gp and Brcp efflux transporters—enhances delivery of ispinesib, and that co-administration of ispinesib with elacridar markedly slows tumor proliferation and prolongs survival in a mouse model of this disease. These results demonstrate the feasibility and efficacy of combining a potentially ideal therapeutic with a compound that enhances brain retention of this therapeutic, and provides support for utilizing this approach in clinical investigations of KIF11 inhibitors in GBM.

Objective To evaluate onset of effect of galcanezumab in patients with episodic migraine. Background Galcanezumab is a monoclonal antibody that binds to calcitonin gene‐related peptide and is indicated for preventive treatment of migraine. Design/Methods Data on the primary outcome measure were analyzed from 2 previously published double‐blind, Phase 3 studies (EVOLVE‐1 [N = 858] and EVOLVE‐2 [N = 915]) wherein adult patients with episodic migraine were randomized to receive monthly subcutaneous injections of galcanezumab 120 mg (with 240‐mg loading dose) or 240 mg or placebo for up to 6 months. Monthly onset of effect was defined as the earliest month at which galcanezumab achieved and subsequently maintained statistical superiority to placebo on the mean change from baseline in the number of monthly migraine headache days (MHDs). If onset occurred in Month 1, weekly onset was evaluated and defined as the earliest week at which galcanezumab statistically separated from placebo and maintained statistical separation for remaining weeks in that month. Day of onset of effect was also analyzed, as were monthly and weekly onset, for occurrence of ≥50% reduction from baseline in number of MHDs. Results For both studies, change from baseline in monthly MHDs showed a statistically significant separation of galcanezumab from placebo at Month 1 and each subsequent month (each P < .001). Analysis of the first month for both studies indicated onset of effect in the first week, with galcanezumab‐treated patients having significantly higher odds of having fewer MHDs in the first week (odds ratio [95% confidence interval] for EVOLVE‐1, 2.71 [2.00, 3.66], and for EVOLVE‐2, 2.88 [2.16, 3.86]; both P < .001) and each subsequent week compared with placebo‐treated patients ( P ≤ .004). Daily analysis showed onset of effect at Day 1 (first day after injection day). Galcanezumab also demonstrated superiority to placebo on occurrence of ≥50% reduction in MHDs starting at Week 1 (percentage of patients with 50% response in galcanezumab group vs placebo group for EVOLVE‐1, 54.3% vs 32.4% [ P < .001], and for EVOLVE‐2, 59.4% vs 38.0% [ P < .001]). Conclusion Rapid onset of preventive effect on the first day after injection of galcanezumab was confirmed in both studies of episodic migraine.

Abstract The presence of family caregivers in clinical encounters is becoming more common with the aging of the US population and the continued shift of care responsibilities from health professionals in clinical settings to family caregivers at home. Patients accompanied to clinical encounters by caregivers are more likely to be older, sicker, and have lower health literacy. Research shows, however, that providers often do not initiate any caregiver participation and when they do, conversations center on relaying technical medical information rather than preferences and capacity to provide caregiving assistance. Little is known about provider perceptions of engaging caregivers in clinical encounters. Using data from 20 semi-structured interviews with physicians from primary and specialty care, we identified 3 inter-related themes about engaging caregivers in clinical encounters: 1) ambivalence about caregivers’ role in clinical encounters; 2) trepidation about posing questions directly to caregivers; and, 3) beliefs that systemic barriers exist that inhibit integration of caregivers. Providers, especially in primary care encounters, chiefly view caregivers as sources of supplemental information or for absorbing or reinforcing clinical instructions for care at home. Providers also voiced concerns about the ethics of assessing caregiver capacity to provide assistance to the patient without having clinical authority to treat or adequate resources to provide to caregivers. Finally, providers identified structural barriers, including time constraints, for integrating caregivers into the clinical care team. Findings provide insight into provider attitudes on the caregivers’ role, a perspective that is essential for understanding opportunities and challenges for implementing caregiver interventions in clinical settings.

Purpose The Mayo Clinic Biobank was established to provide a large group of patients from which comparison groups (ie, controls) could be selected for case–control studies, to create a prospective cohort with sufficient power for common outcomes and to support electronic health record (EHR) studies. Participants A total of 56 862 participants enrolled (21% response rate) into the Mayo Clinic Biobank from Rochester, Minnesota (77%, n=43 836), Jacksonville, Florida (18%, n=10 368) and La Crosse, Wisconsin (5%, n=2658). Participants were all Mayo Clinic patients, 18 years of age or older and US residents. Findings to date Overall, 43% of participants were 65 years of age or older and female participants were more frequent (59%) than males at all sites. Most participants resided in the Upper Midwest regions of the USA (Minnesota, Iowa, Illinois or Wisconsin), Florida or Georgia. Self-reported race among Biobank participants was 90% white. Here we provide examples of the types of studies that have successfully utilised the resource, including (1) investigations of the population itself, (2) provision of controls for case–control studies, (3) genotype-driven research, (4) EHR-based research and (5) prospective recruitment to other studies. Over 270 projects have been approved to date to access Biobank data and/or samples; over 200 000 sample aliquots have been approved for distribution. Future plans The data and samples in the Mayo Clinic Biobank can be used for various types of epidemiological and clinical studies, especially in the setting of case–control studies for which the Biobank samples serve as control samples. We are planning cohort studies with additional follow-up and acquisition of genetic information on a large scale.

Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) and spindle cell lipoma are lipomatous tumors with distinct clinical, molecular, and prognostic features. Although histological and immunophenotypic features can overlap between ALT/WDL and spindle cell lipoma, the oncogenesis and clinical behavior are markedly different. In borderline cases, molecular analysis for MDM2 or CDK4 amplification can aid in distinguishing ALT/WDL from spindle cell lipoma. Although dedifferentiated liposarcoma has been reported to harbor both MDM2 amplification and loss of the RB1 region, we are not aware of a reported RB1 loss in well-differentiated ALT/WDL. In this article, we present a 69-year-old woman with a lipomatous tumor in the gluteal region that histologically, immunohistochemically, and molecularly mimicked spindle cell lipoma (with positive immunohistochemical staining for CD34 and loss of the RB1 gene region), yet harbored amplification of MDM2 and CDK4 confirmed by fluorescence in situ hybridization, supporting classification as ALT/WDL. This case strengthens the argument that in atypical clinical contexts, molecular studies for MDM2/CDK4 should be considered in tumors resembling spindle cell lipoma.

Abstract The NAPRTCS has collected clinical information on children undergoing renal transplantation since 1987 and now includes information on 12 920 renal transplants in 11 870 patients. Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in patient and allograft outcomes after pediatric renal transplantation in addition to identifying factors associated with both favorable and poor outcomes. The registry has served to document and influence practice patterns, clinical outcomes, and changing trends in renal transplantation and also provides historical perspective. This report highlights current practices in an era of major changes in DD kidney allocation and continuing steroid minimization. This report presents outcomes of the patients in the NAPRTCS transplant registry up to end of 2017. In particular, an increase in the cumulative incidence of late first AR has occurred in the most recent cohort, while all prior cohorts had a lower cumulative incidence of late first AR.

Abstract Objectives Smoking is a major risk factor for the development of both cardiovascular disease (CVD) and RA and may cause attenuated responses to anti-rheumatic treatments. Our aim was to compare disease activity, CVD risk factors and CVD event rates across smoking status in RA patients. Methods Disease characteristics, CVD risk factors and relevant medications were recorded in RA patients without prior CVD from 10 countries (Norway, UK, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico). Information on CVD events was collected. Adjusted analysis of variance, logistic regression and Cox models were applied to compare RA disease activity (DAS28), CVD risk factors and event rates across categories of smoking status. Results Of the 3311 RA patients (1012 former, 887 current and 1412 never smokers), 235 experienced CVD events during a median follow-up of 3.5 years (interquartile range 2.5–6.1). At enrolment, current smokers were more likely to have moderate or high disease activity compared with former and never smokers (P &lt; 0.001 for both). There was a gradient of worsening CVD risk factor profiles (lipoproteins and blood pressure) from never to former to current smokers. Furthermore, former and never smokers had significantly lower CVD event rates compared with current smokers [hazard ratio 0.70 (95% CI 0.51, 0.95), P = 0.02 and 0.48 (0.34, 0.69), P &lt; 0.001, respectively]. The CVD event rates for former and never smokers were comparable. Conclusion Smoking cessation in patients with RA was associated with lower disease activity and improved lipid profiles and was a predictor of reduced rates of CVD events.

Abstract Background The incidence and impact of acute infection among patients with type 1 (T1MI) and 2 myocardial infarction (T2MI) is not well known. Inflammation and increased procoagulant activity can lead to T1MI, whereas cytokine release can cause hemodynamic alterations affecting myocardial oxygen consumption and contribute to T2MI. Purpose Determine the incidence and prognostic impact of acute infection among patients with T1MI and T2MI. Methods Post-hoc analysis of UTROPIA (NCT02060760), a prospective, observational cohort study involving 1,640 consecutive emergency department patients with serial cardiac troponin (cTn) I measurements obtained on clinical indication. The incidence of acute infection, antibiotic use, and/or laboratory evidence of infection were examined among patients with T1MI and T2MI. 5-year cumulative survival curves were plotted using the Kaplan-Meier method, frequencies were compared via Chi-Square, and a multivariate cox-proportional hazards model was used to assess the impact of infection on mortality. Results Among 217 patients with acute MI (T1MI, n=77 and T2MI, n=140), acute infection occurred in 63 (29%) of patients. Acute infection was more common in patients with T2MI than T1MI (35% vs. 18%, p=0.009). The predominant source of infection was pneumonia (59%), followed by urinary tract infections (11%). Patients with T2MI were also more likely than T1MI to have sepsis (11% vs. 1%, p=0.012), bacteremia (30% vs. 18%, p=0.057), and antibiotic use (35% vs. 17%, p=0.005). At 5-years, patients with acute MI and acute infection had a higher mortality rate than patients without infection (49% vs. 25%, p=0.0006) (Figure). Among the 31 deaths in MI patients with acute infection, most deaths were non-cardiac (65%) and occurred in those with T2MI (77%). Following adjustment for age, sex, and comorbidities in a Cox proportional hazards model, acute infection was an independent predictor of death (hazard ratio: 2.2, 95% CI: 1.3–3.5, p=0.0016). Conclusion Acute infection occurs in almost a third of patients that are diagnosed with acute MI during the index hospitalization. Most infections are due to pneumonia and occur most often in patients classified as having T2MI. Acute infection is an independent risk factor for 5-year mortality, with nearly half of all patients with acute MI in whom concomitant acute infection is present during the index hospitalization dead at 5-years. Most deaths are non-cardiac and the vast majority occur in patients with T2MI. Acknowledgement/Funding Abbott Diagnostics and Hennepin Healthcare Research Institute (formerly MMRF)e

Abstract Background Few studies address long-term outcomes among patients with type 2 myocardial infarction (T2MI). It has been suggested that patients with T2MI with concomitant stable ischemic heart disease are at higher-risk. Purpose Our goals were two-fold. First, to examine 5-year mortality rates and mode of death among patients with type 1 (T1MI) and T2MI. Second, to evaluate the prognostic impact of coronary artery disease (CAD) on long-term outcomes among patients with T2MI. Methods Post-hoc analysis of UTROPIA (NCT02060760), a prospective, observational cohort study involving 1,640 consecutive emergency department patients with serial cardiac troponin (cTn) I measurements obtained on clinical indication. 5-year death rates, including mode of death, were examined among patients with T1MI and T2MI. CAD was defined as the presence of any of the following: history of CAD, prior MI, prior coronary artery bypass graft surgery, prior percutaneous coronary intervention, prior coronary stenting, or documented CAD (≥50%) on index admission angiography. Results Among 1640 patients, acute MI was diagnosed in 217 patients, including 77 (4.7%) classified as T1MI and 140 (8.5%) as T2MI. At 5-years, 23% (n=18) of patients with T1MI had died, with 61% (n=11) categorized as cardiac deaths. For T2MI, 37% (n=52) had died at 5-years, with 36% (n=19) categorized as cardiac deaths. Patients with T2MI had a higher 5-year mortality than T1MI (37% vs 23%, p=0.038) (Figure, Panel A), with T2MI more likely than T1MI to die from non-cardiac causes (64% vs. 39%, p=0.04). CAD was present in 22% (n=31) of patients with T2MI and associated with worse outcomes (p=0.0496) (Figure, Panel B). Conclusion T2MI has worse long term outcomes than T1MI. The predominant mode of death among patients with T2MI is non-cardiac. However, approximately 40% of deaths are cardiac. Further, we confirm the presence of CAD identifies a subset of patients with T2MI at high-risk. Acknowledgement/Funding Abbott Diagnostics and Hennepin Healthcare Research Institute (formerly MMRF)