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Background: In the SCHOLAR-1 study, the largest published retrospective analysis of outcomes in patients with refractory large B-cell lymphoma (LBCL), the objective response rate (ORR) was 26% and complete response (CR) rate was 7% with available salvage therapies in the pre-chimeric antigen receptor (CAR) T cell therapy era (Crump et al. Blood. 2017). These results served as a benchmark for assessing novel therapies. ZUMA-1 (NCT02348216) is the pivotal, multicenter, single-arm Phase 1/2 study evaluating axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR T cell therapy, in patients with refractory LBCL that supported the approval of axi-cel in the United States and Europe. At a median follow-up of 27.1 months, the ORR in ZUMA-1 was 83% and the CR rate was 58% (Locke et al. Lancet Oncol. 2019). Here, we describe comparative analyses of outcomes in ZUMA-1 and SCHOLAR-1 after adjusting for potential imbalances in refractory status between the 2 studies. Methods: Patients in both studies had refractory LBCL defined as stable disease of ≤ 6 months with ≥ 4 cycles of frontline or ≥ 2 cycles of later-line therapy, progressive disease as best response, or relapse ≤ 12 months post autologous stem cell transplant (SCT). To address potential imbalances between studies in refractory status which could affect response and survival outcomes, standardized analyses were performed which equally weighted the proportions of patients by refractory categorization (primary refractory, refractory to ≥ second-line therapy, or relapse after SCT) and presence of post-refractory SCT in each study. Stratified Cochran-Mantel-Haenszel (CMH) tests and Cox models were used to compare the odds ratio for response and hazard ratio (HR) for survival between ZUMA-1 and SCHOLAR-1. P values were descriptive and were not adjusted for multiplicity. Results: Axi-cel was administered to 101 patients in the pivotal Phase 2 portion of ZUMA-1. In the SCHOLAR-1 analysis, 508 patients were evaluable for response and 497 were evaluable for survival. The median follow-up in ZUMA-1 was 2.3 years, and the median follow-up from the overall SCHOLAR-1 study ranged from 7.6 to 14.8 years across different cohorts. In general, ZUMA-1 patients were more heavily pretreated with more patients receiving ≥ 3 lines of therapy as compared with SCHOLAR-1 (69% vs 23%). ZUMA-1 also had more patients who were refractory to second- or later-line therapy compared with SCHOLAR-1 (76% vs 62%). Fewer patients in ZUMA-1, however, were classified as primary refractory vs those in SCHOLAR-1 (26% vs 45%), and a similar proportion of patients between studies relapsed within 1 year of SCT (21% vs 18%). After standardization, the ORR and CR rate in ZUMA-1 vs SCHOLAR-1 were 72% and 54% vs 22% and 7%, respectively. The odds ratios for ORR and CR rate were 7.2-fold and 11.5-fold higher, respectively in ZUMA-1 vs SCHOLAR-1 (CMH test; P < .0001 for both ORR and CR rate). The 2-year survival rate after standardization was 50% (95% CI, 40% - 59%) in ZUMA-1 and 12% (95% CI, 9% - 15%) in SCHOLAR-1, which translated to a 73% reduction in the risk of death in ZUMA-1 relative to SCHOLAR-1 (HR, 0.27; P < .0001). Conclusions: This standardized analysis of the ZUMA-1 and SCHOLAR-1 studies indicates that treatment with axi-cel in this selected population results in 11.5-fold higher odds of CR and a 73% reduction in the risk of death compared with standard salvage regimens in an unselected population. Although limited by retrospective evaluation and cross-study comparisons, these results support the previous literature indicating that axi-cel is a highly effective treatment option for patients with refractory LBCL. Disclosures Neelapu: Pfizer: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Allogene: Consultancy; Acerta: Research Funding; Cell Medica: Consultancy; Celgene: Consultancy, Research Funding; Karus: Research Funding; Novartis: Consultancy; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding. Locke:Novartis: Other: Scientific Advisor; Kite: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Bartlett:Genentech, Inc.: Research Funding; Gilead: Research Funding; Autolus: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Affimed: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Miklos:Celgene-Juno: Consultancy; Novartis: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen: Consultancy; Miltenyi: Consultancy, Research Funding; AlloGene: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Becton Dickinson: Consultancy; Precision Bioscience: Consultancy. Jacobson:Pfizer: Research Funding; Celgene: Consultancy, Other: travel support; Humanigen: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Bayer: Consultancy, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Siddiqi:BeiGene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Kite, A Gilead Company: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; Juno Therapeutics: Consultancy, Other: travel support, Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Crump:Kite/Gilead: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Servier: Consultancy. Kuruvilla:Seattle Genetics: Honoraria; Roche: Honoraria; Novartis: Honoraria; Merck: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; BMS: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Janssen: Research Funding; Roche: Research Funding. Van Den Neste:Gilead: Other: travel support. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Navale:Kite, A Gilead Company: Employment, Equity Ownership; Gilead: Equity Ownership; Allogene: Equity Ownership; Cellectis: Equity Ownership; Bluebird Bio: Equity Ownership; Amgen: Equity Ownership; Organesis: Equity Ownership; Jounce: Equity Ownership; Editas: Equity Ownership; Intellia: Equity Ownership. DePuy:Kite, A Gilead Company: Consultancy, Other: travel support. Kim:Kite, A Gilead Company: Employment.

Introduction Despite more robust attempts to deliver chemotherapy in the outpatient setting, certain regimens for hematologic malignancies require inpatient hospitalization for treatment and monitoring clinical status. Increased length of stay (LOS) for planned chemotherapy admissions leads to increased healthcare utilization and decreased patient satisfaction. We sought to identify potentially modifiable risk factors for increased LOS. Methods Planned chemotherapy admissions to the inpatient hematology services at Mayo Clinic (Rochester, MN) from October 2018 through March 2019 were reviewed. We included patients who had treatment plans based on four pre-specified common regimens for acute myeloid leukemia, relapsed non-Hodgkins lymphoma and multiple myeloma. Patients who remained in the hospital for lack of caregiver support were excluded. Patient characteristics, including age, malignancy type, and chemotherapy regimen were recorded. Encounter characteristics included day of week of admission, time of admission, time chemotherapy plan initiated, and whether or not all necessary procedures (labs, vascular access, chemo orders) were completed prior to admission. Primary outcome was LOS. Secondary outcome was time to treatment initiation (TTI) after admission. Results There were 100 planned admissions for patients receiving four regimens: cytarabine consolidation, EPOCH, ICE, VDT-PACE, during the six month review period. Thirty-six admissions did not occur as planned (regimen changed, rescheduled, or disease progression). Of the remaining 66 admissions, 11 outliers were excluded from primary analysis. Baseline characteristics are summarized in Table 1. Univariate analysis with independent t-test found no difference in LOS for patients who had physician chemotherapy orders in place prior to admission. To the contrary, we detected a non-significant trend toward longer mean length of stay for patients that were not seen in clinic on day of admission (Table 2). On ANOVA, there was a statistically significant difference in LOS when comparing Monday admissions 3.93 days (95% CI 3.07 to 4.79) vs Friday 5.25 days (95% CI, 4.86 to 5.64), but not between any other days. There were no statistically significant differences in TTI when comparing by day of week, physician order status, or chemotherapy regimen. Again, a non-significant trend toward increased TTI was observed for patients not seen in clinic on the same day as admission. Conclusions This study serves as a starting point towards identifying modifiable factors that are essential to delivery of safe, satisfying inpatient care to our hematological malignancy patients.Our noteworthy finding regarding patients who were admitted on Friday having a longer LOS than those admitted on Monday requires further exploration. This study is ongoing with mature data to be presented at the meeting. Disclosures No relevant conflicts of interest to declare.

Background: Core binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22) and is associated with a favorable outcome, particularly if treated with repetitive cycles of high-dose cytarabine as post-remission therapy. Long-time 10-year overall survival (OS) rate was reported of 58% in FLT3-ITD negative patients (pts; Allen et al. Leukemia 2013). Nevertheless, 30-40% CBF-AML pts experience relapse. FLT3-ITD mutations occur in roughly 5-10% of adult CBF-AML. However, their prognostic relevance is still controversial. Aims: To characterize CBF-AML with FLT3-ITD and compare outcomes according to their genetic background. Methods: We retrospectively studied 65 AML pts with CBF-AML and FLT3-ITD (median age at diagnosis, 54 years; range, 22-81 years) diagnosed between 1996 and 2018 within seven study groups/institutions of the US and Europe. Results: Thirty-two (49%) of the 65 pts harbored t(8;21). Median white blood cell and platelet counts at diagnosis of patients with t(8;21) and inv(16) were 18.3/nl (range, 1.8-202/nl) and 31/nl (range, 7-372/nl), respectively. AML diagnoses were de novo in 61 (94%) and therapy-related in 4 (6%) of the pts. Thirty (46%) pts were female. Cytogenetic analysis revealed additional abnormalities (abn) in 38 (58%) pts, most frequently loss of X or Y (n=13; n=12 associated with t(8;21)), complex karyotype (≥3 abn; n=12; n=7 occurring in t(8;21)), trisomy 22 (n=7, all associated with inv(16)) or trisomy 8 (overall n=6, n=5 occurring in inv(16)). Four pts were positive for both mutations, FLT3-ITD as well as FLT3-TKD. Median ITD allelic ratio were 0.44 (range, 0.003-50) and median ITD size 60 bp (range, 3-120 bp). Three older pts (median age, 75.5 years) were treated with either azacitidine + sorafenib, azacitidine + venetoclax or with etoposide + tipifarnib. All three patients receiving non-intensive therapy died within one year and were excluded from further analysis. Complete remission (CR) after anthracycline-based induction therapy was achieved in 98% (n=61/62) of patients fit for intensive treatment including two pts treated with 7+3 ± midostaurin within the RATIFY trial. One patient died during induction. Fifteen (24%) pts underwent allogeneic hematopoietic cell transplantation. Of those, 10 pts were transplanted in 1st and 5 pts in 2nd CR. Median follow-up for the entire cohort was 4.43 years (95%-CI, 3.35-8.97 years). Median and 4-year relapse-free survival (RFS) rates were 3.41 years (95%-CI, 1.26 years - not reached) and 44.9% (95%-CI, 32.9-61.4%). Median and 4-year overall survival rates (OS) were 4.48 years (95%-CI, 2.26 years - not reached) and 51.8% (95%-CI, 39.6.2-67.9%). Neither type of CBF-AML (p=0.60), nor additional chromosomal abn (p=0.80), nor presence of a complex karyotype (p=0.50) had a prognostic impact on OS. Higher age (≥60 years) was an in trend negative prognostic factor on RFS and OS (p=0.07, each). High allelic ratio (≥0.5) had no impact on RFS (p=0.3), but in trend on OS (p=0.10). Conclusions: Despite a high remission rate pts with FLT3-ITD had an inferior outcome as compared to previously published data on CBF-AML without FLT3-ITD. Thus, CBF-AML with FLT3-ITD should not be classified within the low-risk category. CBF pts with FLT3-ITD warrants further study and should be included in FLT3-inhibitor trials. Disclosures Brunner: Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Novak:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel,Accommodations; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stoelzel:Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding; JAZZ Pharmaceuticals: Consultancy. Thiede:Daiichi Sankyo: Honoraria; AgenDix GmbH: Employment, Equity Ownership; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Diaceutics: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Levis:Agios: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Erythropoiesis is orchestrated by the coordinated action of multiple transcription factors. The master erythropoietic regulator GATA1 is itself modulated via interactions with multiple co-regulatory factors, such as FOG1, KLF1, and LMO2. Though the PAX-SIX-EYA-DACH network (PSEDN) of conserved transcription factors has been well characterized in the formation of eyes, kidney, branchial structures, and skeletal muscles, a role for PSEDN members in hematopoietic systems has only recently been recognized (Liu et al., Nature 2019 PMID:30894749). Here, we studied the PSEDN member SIX1 and discovered its ability to drive erythroid differentiation of human hematopoietic cells. Enforced overexpression (OE) of SIX1 in human TF1 erythroleukemia cells or primary CD34+ hematopoietic stem-progenitor cells (HSPCs) stimulated the generation of erythroid cells, as determined by increased numbers of cells expressing erythroid-selective surface markers (CD235ahiCD71hiCD34-) and hemoglobin (HBB). Conversely, SIX1 knockout in TF1 cells or primary HSPCs reduced erythroid cell generation in response to erythropoietin (EPO). SIX1 OE could also stimulate TF1 cell erythroid differentiation in the absence of EPO. Further analysis of SIX1 OE in TF1 cells revealed that SIX1 stimulated the expression of multiple functionally important erythroid molecules including ALAS2, SLC4a1, EPOR, SPTA1, KLF1 and ANK1. By gene set enrichment analysis (GSEA) of global RNA-seq data, SIX1 OE stimulated heme metabolism genes as well as many genes known to be regulated by GATA1, including FOG1-dependent and -independent genes. SIX1 OE reduced GATA2 and increased GATA1 protein and RNA expression, resembling GATA switching downstream of EPO signaling. To determine whether GATA1 was necessary for SIX1 to stimulate erythropoiesis, we generated GATA1 knockout cells using CRISPR/Cas9 technology. In contrast to control cells, SIX1 OE in GATA1 knockout cells failed to stimulate erythropoiesis, indicating that SIX1 stimulation of erythropoiesis requires GATA1. To gain further insight into the mechanism by which SIX1 stimulates erythropoiesis, the promiscuous biotin ligase, BirA (Choi-Rhee et al., Protein Sci. 2004 PMID:15459338), was fused in-frame to SIX1 to determine the SIX1 proximal interactome. Streptavidin-enrichment of biotinylated proteins in SIX1-BirA OE lysates revealed GATA1 and FOG1 as proximal interactors of SIX1-BirA, but not of BirA alone. When co-expressed in HEK293T cells GATA1 and SIX1 were found to co-immunoprecipitate, suggesting the two proteins can physically interact in a complex. We demonstrated the functional consequence of the SIX1 interaction with GATA1 using a GATA1-dependent luciferase reporter gene harboring three copies of GATA binding sites. Cells in which SIX1 and GATA1 were co-expressed exhibited significantly higher levels of luciferase expression compared to cells expressing only GATA1, suggesting SIX1 could stimulate GATA1-dependent transcription. Introduction of mutations in SIX known to cause Branchio-Oto-Renal (BOR) (Ruf et al., PNAS 2004 PMID:15141091) syndrome did not inhibit the ability of SIX to bind GATA1 nor its ability to drive erythropoiesis. Taken together our results suggest that SIX1 can stimulate erythropoiesis via multiple mechanisms, including increased GATA1 expression and function. Our findings provide the first demonstration of a role for the PSEDN in erythropoiesis and reveal unknown physical and functional interactions between two central developmental transcriptional networks (GATA:FOG network and PSEDN). Disclosures No relevant conflicts of interest to declare.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract INTRODUCTION Opsoclonus–myoclonus syndrome (OMS) is a rare neurological disorder characterized by spontaneous multidirectional saccadic eye movements, myoclonus, and ataxia. It is suspected to be an autoimmune mediated process precipitated by a paraneoplastic or infectious trigger. Among the pediatric population, OMS is often associated with neuroblastoma and anti-Hu antibody. Paraneoplastic syndromes in adults manifesting as OMS are most commonly described in breast, gynecological and small cell lung cancer with associated anti-neuronal antibodies (ANNA-2; anti-Ri). We describe the first case of OMS associated with lung adenocarcinoma and Contactin-associated protein-like 2 (Caspr2) antibody. CASE REPORT: A 46-year-old-woman with history of limited small cell lung cancer (SCLC) status-post chemotherapy with cisplatin and etoposide and prophylactic whole brain radiation, presented with new onset gait instability, nausea, vomiting, vertigo, and opsoclonus. Two months prior to her presentation, a chest computed topography (CT) revealed no evidence of recurrent disease. Brain MRI revealed T2 hyperintensities in the white matter and central pons presumably related to chronic small vessel ischemic changes, unchanged from prior imaging. CSF studies revealed normal cell count, glucose, and protein. Gram stain, culture and meningoencephalitis panel were negative. Her paraneoplastic panel revealed a positive Caspr2 antibody. A repeat CT chest for cancer surveillance revealed a new lung mass. Immunotherapy treatment included plasmapheresis, corticosteroids, and intravenous immunoglobulin therapy. She underwent a biopsy of the new pulmonary lesion and the pathology was consistent with non-small cell lung carcinoma. Her symptoms slowly improved after treatment. Unfortunately, her disease progressed on repeat PET scan despite surgical resection of the lung mass. She ultimately elected for hospice. CONCLUSION We report a novel antibody, Caspr2, occurring in association with paraneoplastic OMS. While SCLC is the most common neoplasm associated with OMS among adults, non-small cell lung carcinoma should be considered. Prompt immunotherapy and neoplasm treatment may result in improvement.

Abstract High-grade gliomas (HGGs) nearly always recur after standard initial treatment, and the resulting mixture of recurrent tumor and treatment-induced reactive changes presents major diagnostic challenges. Anatomical imaging, such as MRI, cannot adequately distinguish progressive disease from treatment effect (pseudo-progression). Furthermore, there is marked intra-tumoral heterogeneity, such that some areas of a tumor may demonstrate necrotic treatment effect and others frank recurrence. Due to this difficulty reliably differentiating between these two clinical findings, analytic methods using multiple modalities are necessary to further our understanding of this disease process. To this end, we sought to correlate radiographic, histopathologic and molecular features of surgically sampled post-treatment suspected recurrence to identify markers distinguishing tumor growth from treatment effect. We performed Stimulated Raman Histology (SRH) imaging and highly multiplexed RNA-sequencing (PLATE-seq) on 84 MRI-localized biopsies from 39 patients with clinically suspected recurrent HGG. The SRH images were classified as recurrent tumor or gliotic/reactive tissue using a convolutional neural network trained on an independent cohort including a large set of recurrent HGG, and an automated cell-counting algorithm was used to quantify cellularity from the SRH image of each sample. Differential gene expression analysis of the PLATE-seq data was used to identify gene sets that distinguish recurrent tumor from treatment effect, and single sample gene set variation analysis (GSVA) was used to further assess the molecular and cellular composition of each MRI-localized sample. The histopathologic and molecular features of each sample were also correlated with the MRI features of the corresponding biopsy sites, and this data is currently being used to train machine learning models that predict the distribution of recurrent tumor and treatment-induced reactive changes within a patient’s radiographic lesion. These predictive radiomic models will help to guide neurosurgical sampling, and improve our ability to monitor glioma progression and response to therapy.

Abstract Systemic immunosuppression following neurological insults including stroke, traumatic brain injury, and glioblastoma (GBM) causes mortality and leads to failure of immune-modulating therapies. Exact immunological nature and the underlying mechanisms of this immunosuppression are unknown. Our goal was to define effects of neurological insults given exclusively to the brain on the thymus. The thymus is the primary immune organ responsible for T-cell development and maintenance both in children and in adults. We evaluated the brain-thymus communication using the following neurological insults: physical injury, CNS viral infection, sterile injury, tumor implantation, and seizures. All insults resulted in significant thymic involution that was reversible upon clearance of the insult. Thymic involution did not occur following similar peripheral insults. We next demonstrated that the GL261 model of GBM recapitulates hallmark features of peripheral immunosuppression observed in GBM patients including low CD4 T-cell counts. Thus, we aimed to further study the immunosuppression affecting the thymus in this clinically relevant model. Principle component analysis following RNA-sequencing of thymi from naïve and glioma-bearing mice revealed unbiased separation of the groups suggesting that the thymus is directly affected by a brain tumor. To determine the extent to which thymic involution was caused by a soluble factor we employed parabiosis. We demonstrated that thymic involution was transferable from glioma-bearing to non-tumor-bearing parabionts. Similarly, serum taken from GL261 glioma-bearing mice potently inhibited proliferation of T-cells in vitro. Together our data demonstrate that CNS-specific insults, regardless of nature, cause immunosuppression by prompting thymic involution through circulating factors. This accounts at least partially for immune deficiencies observed following neurological injuries. Identification of this suppressive factor is crucial in designing future therapeutics for GBM patients, and patients with other acute and chronic neurological trauma.

Background Left ventricular ( LV ) recovery in takotsubo syndrome ( TTS ) occurs over a wide‐ranging interval, varying from hours to weeks. We sought to investigate the clinical predictors and prognostic impact of recovery time for TTS patients. Methods and Results TTS patients from the International Takotsubo Registry were included in this study. Cut‐off for early LV recovery was determined to be 10 days after the acute event. Multivariable logistic regression was used to assess factors associated with the absence of early recovery. In‐hospital outcomes and 1‐year mortality were compared for patients with versus without early recovery. We analyzed 406 patients with comprehensive and serial imaging data regarding time to recovery. Of these, 191 (47.0%) had early LV recovery and 215 (53.0%) demonstrated late LV improvement. Patients without early recovery were more often male (12.6% versus 5.2%; P =0.011) and presented more frequently with typical TTS (76.3% versus 67.0%, P =0.040). Cardiac and inflammatory markers were higher in patients without early recovery than in those with early recovery. Patients without early recovery showed unfavorable 1‐year outcome compared with patients with early recovery ( P =0.003). On multiple logistic regression, male sex, LV ejection fraction <45%, and acute neurologic disorders were associated with the absence of early recovery. Conclusions TTS patients without early LV recovery have different clinical characteristics and less favorable 1‐year outcome compared with patients with early recovery. The factors associated with the absence of early recovery included male sex, reduced LV ejection fraction, and acute neurologic events. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01947621.

Abstract Background Sports activities may promote arrhythmias in the setting of acute myocarditis. International cardiovascular society recommendations to return to sports activities following acute myocarditis are based on expert consensus in the absence of prospective studies. Purpose We sought to identify patients who may safely resume sports activities 3 months after acute myocarditis. Methods We prospectively enrolled 27 patients with newly diagnosed myocarditis based on clinical parameters, elevated high sensitive troponin (TnT-hs) and cardiac magnetic resonance imaging (CMR) with mildly reduced or preserved LVEF. Follow-up examination included laboratory findings, electrocardiogram (ECG), 48-hour-Holter ECG, echocardiography, exercise stress testing and CMR. Cessation of physical activity was recommended for 3 months. All patients were followed for cardiac events for 12 months. Results Average age was 35 (19–80) years with 73% male patients. All patients performed 3- and 6-month follow-up with above mentioned diagnostic tests. Eight patients did not present for 12-month follow-up, but were contacted by phone. No cardiac events occurred within the interval of 12 months. After 3 months, participants achieved an average of 92% of predicted maximum power on stress test. One case of non-sustained ventricular tachycardia was recorded during 48-hour-Holter ECG. Except for this case, all patients were allowed to resume physical exercise after 3 months. At 6- (n=26) and 12-month (n=19) follow-up no arrhythmias, recurrent myocarditis, worsening left ventricular ejection fraction (LVEF) or physical performance were recorded. TnT-hs, creatine kinase (CK), myoglobin (Mb), and C-reactive protein (CRP) normalized. Conclusion The risk of cardiac events and decreasing LVEF appears to be low after early resumption of exercise in asymptomatic patients who recover from acute myocarditis. Acknowledgement/Funding Forschungskredit of the University of Zurich,the Holcim Foundation, the Hartmann Müller Foundation, and the Walter and Gertrud Siegenthaler Foundation