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Abstract PURPOSE We investigated the long term impact of SRS and WBRT in two large prospective phase III trials. METHODS Patients with 1–4 BMs +/- resection were randomized to SRS or WBRT. Cognitive deterioration was a drop of >1 standard deviation from baseline in >2/6 cognitive measures (CM). Quality of life (QOL) scores were scored 0–100 point scale. CM and QOL scores were modeled using baseline adjusted Linear Mixed Models (LMM) with uncorrelated random intercept for subject and random slopes for time. Differences over time between groups and the effect of >2 cognitive scores with >2 SD change from baseline were assessed. RESULTS 88 patients were included with median follow up of 24 months. We observed decreasing CM over time (SRS: 4/6; WBRT: 5/6). Mean CM was significantly higher in SRS for Total recall and Delayed Recall at 3, 6, 9, 12 months. More patients in WBRT arm declined 1 SD in >1 and >2 CM at the 3, 6, 9, and 12 months. A 1 SD decline in >3 CM at 1 year was 21% SRS vs 47% WBRT (p=0.02). SRS had fewer patients with a 2 SD decline in >1 CM at every time point. SRS had fewer patients with a 2 SD decline at >2 and >3 CM. WBRT had lower QOL at 3 months, but switched to SRS having lower QOL at 24 months for PWB, EWB, FWB, FactG, BR, and FactBR (p< 0.05). A 2 SD decline in cognition decreased mean FWB by 6.4 units (95% CI: -11, -1.75; p=0.007) and decreased QOL by 5.1 units (95% CI: -7.7, -2.5; p< 0.001). CONCLUSIONS We report the first pooled prospective study demonstrating the long term outcomes of patients with BMs after cranial radiation. WBRT was associated with worse cognitive outcomes. Impaired cognition is associated with worse QOL.

Background: Extended trochanteric osteotomies (ETOs) provide wide femoral and acetabular exposure, give direct access to the femoral medullary canal, and facilitate implant removal and new implant placement during selected revision total hip arthroplasties (THAs). Previous studies are limited by modest patient numbers and limited length of follow-up. The goals of the current study were to assess the union rate, complications, and outcomes of contemporary ETOs performed during revision THAs. Methods: From 2003 to 2013, 612 ETOs were performed during revision THAs at 1 institution using 2 techniques: Paprosky (laterally based osteotomy; n = 367) and Wagner (anteriorly based osteotomy; n = 245). The indications for the revision procedures were aseptic loosening (65%), periprosthetic joint infection (18%), periprosthetic fracture (6%), femoral implant fracture (5%), and other (6%). The mean patient age was 69 years, and 57% of the patients were male. The mean number of previous THAs was 1.6. The median duration of follow-up was 5 years (range, 2 to 13 years). Results: The mean Harris hip scores increased from 57 preoperatively to 77 at the latest follow-up (p < 0.001). Radiographic and clinical union was achieved in 98% of the patients at a mean of 6 months (range, 1 to 24 months). The mean migration of the proximal trochanteric osteotomy fragment prior to union was 3 mm (range, 0 to 29 mm). ETO fragment migration of >1 cm occurred in 7% (37) of the 501 hips that had radiographic analysis. Nine hips (2%) had nonunion of the ETO. Intraoperative fracture of the ETO diaphyseal fragment occurred in 22 hips (4%), postoperative fracture of the ETO diaphyseal fragment occurred in 3 hips (0.5%), and postoperative fracture of the greater trochanter occurred in 41 hips (7%). Survivorship at 10 years free of revision for aseptic femoral loosening, free of femoral or acetabular component removal or revision for any reason, and free of reoperation for any reason was 97%, 91%, and 82%, respectively. Conclusions: This large series of ETOs shows that the union rate is high and clinically important trochanteric migration is infrequent. The most common complications are fracture of the osteotomy fragment intraoperatively or postoperatively. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Purpose Tarsal coalitions are congenital fusions of two or more tarsal bones and can lead to foot pain and stiffness. Few studies examine the long-term reoperation rates following paediatric tarsal coalition surgery. Methods A population-based database, linking medical records at all medical centres to capture the entire medical history of the full population of a Midwest county, was used to identify tarsal coalitions in children between 1966 and 2018. Records were reviewed for clinical data, surgical records and followed up to identify any subsequent surgical interventions. Results A total of 58 patients (85 coalitions) were identified; 46 calcaneonavicular (CN) coalitions, 30 talocalcaneal (TC) coalitions and nine other coalitions (seven talonavicular, one naviculocuboid, one naviculocuneiform). In all, 46 coalitions were treated surgically (43 coalition resections, three arthrodeses) and 39 were treated nonoperatively. Patients treated surgically were less likely to report ongoing symptoms at final follow-up compared with patients managed nonoperatively (33% versus 67%; p = 0.0017). With a median 14.4 years (interquartile range 9.3 to 19.7) follow-up, there was an overall re-operation rate of 8.7% (4/46). Differences in reoperation rates by initial surgery (resection versus arthrodesis; p = 0.2936), coalition type (CN versus TC versus Other; p = 0.6487) or composition (osseous versus fibrocartilaginous; p = 0.29) did not reach statistical significance. Conclusion This is the first population-based study demonstrating the durability of surgical management of tarsal coalitions in a paediatric population. At final follow-up, patients treated surgically are less likely to report persistent symptoms compared with patients managed nonoperatively. Long-term reoperation rates appear to be low (8.7%). Level of evidence III

Abstract Background Optimization of mechanical ventilation (MV) in patients with cardiac arrest (CA) may help improve outcomes in these patients. We sought to investigate the association between hyperoxia, PCO2, and positive end-expiratory pressure (PEEP) with mortality in patients with CA. Methods Patients admitted to our medical center CICU from 2001 through 2012 (MIMIC-III database) who received MV with available information on MV parameters and had arterial blood gases sampling were included. Hyperoxia was defined as time-weighted mean of PaO2 &gt;120 mmHg and non-hyperoxia as PaO2 ≤120 mmHg, while Hypercarbia was defined as PCO2 &gt;35 mmHg during CICU admission. The primary outcome was in-hospital mortality. Multivariable logistic regression was used to assess the association between hyperoxia and in-hospital mortality adjusted for age, female sex, Oxford Acute Severity of Illness Score, creatinine, lactate, pH, PaO2/FiO2 ratio, PCO2, PEEP, and time spent on PEEP. Results Among 136 patients, PaO2 = 139±55 mmHg, PCO2 = 39±10 mmHg, and PEEP = 6.4±2.2cmH2O. Unadjusted mortality was higher in the hyperoxic group (51.4%) compared to the non-hyperoxic group (29.0%) (long rank test p=0.0034, figure). In multivariable analysis, hyperoxia was independently associated with higher in-hospital mortality (OR 4.046, 95% CI: 1.501–10.907, p=0.0057). Additionally, there was no association between the presence of hypercarbia and in-hospital mortality (OR 0.896, 95% CI: 0.319 to 2.521, p=0.836) nor when PCO2 was analyzed as a continuous variable (OR 1.063 per 1 mmHg increase in CO2, 95% CI: 0.111–10.145, p=0.957). Similarly, there was no assocation between PEEP and in-hospital mortality (OR 1.012 per 1cmH2O increase, 95% CI: 0.807 to 1.270, p=0.917). Post-hoc analysis with PaO2 as a continuous variable was consistent with the primary analysis (OR 1.214 per 10 mmHg increase in PaO2, 95% CI: 1.059–1.391, p=0.005). Conclusions In patients with CA, hyperoxia was associated with increased mortality, while PCO2 and PEEP levels were not. Optimal MV parameters are important in the management of patients with CA. Further research is warranted to confirm this association and explore the mechanisms behind these observations. These studies can help establish the best MV strategies for patients with CA. Funding Acknowledgement Type of funding source: None

Background and Purpose: Few community-based studies investigating young adult strokes exist. The aim of this study was to determine the diagnostic yield of head and neck CTA in evaluation of anterior circulation ischemic stroke in young adults. Materials and Methods: This retrospective review is limited to patients between the ages of 18-50 presenting to the Mayo Clinic Rochester emergency department or referred from smaller institutions in adjacent counties. Patients with posterior circulation infarcts, amaurosis fugax, central retinal artery occlusion or transient ischemic attacks were excluded. The presence of carotid dissection, webs, plaque, or other high-risk lesions were recorded. Results: A total of 136 patients met inclusion criteria. Mean degree of carotid stenosis ipsilateral to infarct was 14.1%, compared to 6.5% on the contralateral side (p = .006). Ipsilateral mean carotid wall thickness measured .79 mm, compared to contralateral thickness of .80 mm (p = .51). Ipsilateral low-density plaque was observed in 22 patients (16.2%), and 21 patients (15.4%) on the contralateral side (p = .87). Ipsilateral calcified plaque was observed in 37 patients (27.2%), and 29 patients (21.3%) on the contralateral side (p = .31). 20 (14.7%) ipsilateral dissections were noted, compared to 4 (2.9%) contralateral dissections (p = .001). 3 (2.2%) ipsilateral carotid webs were identified, compared to 0 contralateral webs (p = .25). Conclusion: Carotid dissection was the most common cause of anterior circulation infarct identified on cervical CTA in this population. Carotid webs and atherosclerosis were not common findings.

AbstractClinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

Abstract Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that BRCA1 silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to codepletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1. Silencing of MAD2L1 phenocopied BRCA1 and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex vivo vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in BRCA1/MAD2L1-positive explants compared with 0% in BRCA1/MAD2L1-negative explants. In 48 patients, BRCA1 and/or MAD2L1 loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double-positive patients (5.9 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.

Introduction: With a median overall survival (OS) measured in months, successful treatment of Richter's transformation (RT) of chronic lymphocytic leukemia (CLL) to diffuse large B-cell lymphoma (DLBCL) remains a major unmet medical need. While targeted agents, such as Bruton tyrosine kinase inhibitor (BTKi) monotherapy, have greatly improved outcomes for patients (pts) with CLL and some B-cell lymphomas, available BTKi therapies have been ineffective for RT, as well as for large cell transformation of indolent B-cell lymphomas and relapsed/refractory (r/r) DLBCL, which rapidly develop mechanisms of resistance by activation of downstream targets of BTKi or upregulation of alternative/parallel pathways. Focusing on a synthetic lethality approach via in vitro and in vivo studies, we discovered that concurrent inhibition of BTK & mTOR targets plus an IMiD synergistically kill malignant B-cells. DTRM-555 is an optimized oral triple combination of a novel irreversible BTKi DTRMWXHS-12 (DTRM-12), everolimus (EV) and pomalidomide (POM). This once daily therapy was tested in a stepwise, phase I, multicenter study in pts with the greatest unmet medical needs. Here we present results for this novel combination therapy in pts with RT, and r/r DLBCL. Methods: We conducted a phase I (3+3 design), first in human trial exploring DTRM-555 in adult pts with B-cell lymphomas with no available standard therapies (NCT02900716) at 6 US cancer centers. Our goal was to determine the optimal dose for DTRM-555. In phase Ia, an MTD was not reached for DTRM-12 monotherapy; In phase Ib and expansion cohorts, we evaluated double (DTRM-12/EV at 200mg/5mg or 300mg/5mg) and triple combinations (DTRM-12/EV/POM at 200mg/5mg/2mg or 300mg/5mg/2mg) administered once daily for 21 days of a 28-day cycle, until disease progression or unacceptable toxicity. The primary endpoint was safety and the dose limiting toxicity (DLT) period was cycle 1 (28 days). Secondary endpoints included overall response rate (ORR; Cheson 2014), duration of response (DOR), and DTRM-12 pharmacokinetics. The trial began on 9/27/2016 and completed enrollment with evaluable follow-up data cut-off date on 08/06/2020. Results: 39 pts were enrolled and treated, including 24 with RT (n=12) or r/r DLBCL (n=12). The safety analyses included all 39 pts treated with combination therapies while efficacy analyses were focused on RT and r/r DLBCL. Baseline characteristics (n=39): 66% male, median age 71 years (range 43-94) and 94% white. For the entire study cohort, median number of prior therapies was 3 (range 1-10), 49% had been treated with prior BTKi monotherapy,13% prior CAR-T or stem cell transplant (SCT) and 59% ≥1 prior small molecule targeted agent. For pts with RT and r/r DLBCL (n=24), median prior therapies were 5 (range 1-10) and 2 (range 10), respectively. Table 1 summarizes prior therapies for the 24 RT and r/r DLBCL pts. Table 2 describes Grade 3 and 4 related AEs for 39 pts treated with the combination therapies. AEs were manageable and similar to known AEs for BTKi, EV or POM, with a total of 4 DLTs observed with combination therapies. The most common AEs were hematological events; specifically, thrombocytopenia, neutropenia, and anemia. The MTD of DTRM-555 was determined to be DTRM-12 200mg, EV 5mg, & POM 2mg. For 11 evaluable RT pts, ORR was 45% (1 CR, 4 PR); 1 RT pt has not undergone first response assessment. For 10 evaluable DLBCL pts, ORR was 60% (2 CR, 4 PR). Responders with RT or r/r DLBCL have durable responses (Figure 1). Kaplan Meier estimated median duration of response for RT and DLBCL pts was 15 months as of the cut-off. Dose dependent DTRM-12 drug plasma levels were observed in all arms with minimal inter-pt variability. Conclusions: This clinical trial met its primary endpoint. The once-daily oral triple combination therapy DTRM-555 has an acceptable safety profile. Encouraging clinical activity was observed in several high-risk, multi-refractory pts with RT (median 5 prior therapies, ORR 45%) or r/r DLBCL (median 2 prior therapies, ORR 60%), including pts previously treated with targeted therapies, cellular therapies, checkpoint inhibitors and other experimental agents. A phase II US expansion study is underway targeting pts with RT, r/r DLBCL, r/r transformed follicular lymphoma and BTKi/BCL2 inhibitor exposed r/r CLL pts. Disclosures Mato: Adaptive: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding. Ding:DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brander:Tolero: Research Funding; NCCN: Other; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; MEI Pharma: Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; DTRM: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding. He:DTRM Biopharma LLC: Current Employment. Kearney:DTRM Biopharma LLC: Current Employment. Gui:DTRM Biopharma LLC: Current Employment. McKinlay:DTRM Biopharma LLC: Current Employment. Roeker:American Society of Hematology: Research Funding; AbbVie: Other: spouse with minority ownership interest ; Abbott Laboratories: Other: spouse with minority ownership interest . Huntington:Pharmacyclics: Honoraria; Novartis: Consultancy; Genentech: Consultancy; DTRM: Research Funding; AbbVie: Consultancy; Astrazeneca: Honoraria; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding.

Abstract Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni &lt; 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P &lt; 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.