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Chronic mesenteric ischaemia is a severe and incapacitating disease, causing complaints of post‐prandial pain, fear of eating and weight loss. Even though chronic mesenteric ischaemia may progress to acute mesenteric ischaemia, chronic mesenteric ischaemia remains an underappreciated and undertreated disease entity. Probable explanations are the lack of knowledge and awareness among physicians and the lack of a gold standard diagnostic test. The underappreciation of this disease results in diagnostic delays, underdiagnosis and undertreating of patients with chronic mesenteric ischaemia, potentially resulting in fatal acute mesenteric ischaemia. This guideline provides a comprehensive overview and repository of the current evidence and multidisciplinary expert agreement on pertinent issues regarding diagnosis and treatment, and provides guidance in the multidisciplinary field of chronic mesenteric ischaemia.

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P < 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P < 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

Targeted agents have greatly improved outcomes for patients (pts) with chronic lymphocytic leukemia (CLL) and other B cell lymphomas; however, single agents have been limited by intolerance, resistance and depth/durability of responses. Current novel targeted agent combinations may improve depth of response, but such "full dose" strategies have been associated with significant AEs, dose reductions/interruptions and discontinuations. Our in vitro & in vivo screening/optimization studies identified that concurrent inhibition of BTK & mTOR targets plus IMiD at low doses of each inhibitor can synergistically kill B-cell malignancies and may address drug-resistance. DTRM-555 is an optimized oral triplet combination of a novel BTK inhibitor DTRMWXHS-12 (DTRM-12) with everolimus (EV) & pomalidomide (POM). This once daily therapy was tested in a stepwise, phase I, US multicenter study in patients with highest unmet medical needs including r/r CLL, Richter's transformation (RT) of CLL, DLBCL, transformed B-cell lymphomas. We conducted a 3+3 design phase I, first human trial exploring DTRM-555 in pts ≥18 years, ECOG PS ≤1 with CLL, B-cell NHL, or Hodgkin lymphoma (HL) with no available standard therapy (NCT02900716). Our goal was to determine optimal doses for triplet combination therapy through 3 escalating phases of study: DTRM-12 in escalating doses (50, 100, 200, & 300 mg/day) in Part Ia, DTRM-12 at 200 mg or 300 mg & EV at 5 mg (doublet or DTRM-505) in Part Ib Arm A while DTRM-12 at 200 mg or 300 mg, EV at 5 mg & POM at 2 mg in Part Ib Arm B. For all arms, treatment was administered for 21 consecutive days of a 28-day cycle, until disease progression or unacceptable toxicity. Safety was the primary endpoint, and the dose-limiting toxicity (DLT) period was cycle 1. Secondary endpoints included response (iwCLL 2018 or Cheson 2014), progression free survival, duration of response and pharmacokinetics. Intra-patient migration between arms (Mono to doublet to triplet) was permitted if subsequent doses were tolerated. The trial commenced 9/27/2016 and completed enrollment 7/25/2019. Thirty-three pts were enrolled, including 2 screen failures and 4 intra-cohort migrations, with r/r DLBCL (n=8), CLL/SLL (n=5), RT (n=6), FL (n=5), MCL (n=4), MZL/LPL (n=3), HL (n=2). 30 of 31 treated pts were evaluated: 8 pts participated in phase Ia (DTRM-12) while 23 pts were treated on phase Ib combinations (DTRM-505 & DTRM-555). Baseline characteristics: 70% male (n=23), median age 70 years (range 46-94) and 94% white. Median prior therapies were 3 (range 1-10), 53% had been treated with ≥1 prior targeted agent (i.e., CD19/CD3 bispecific antibody, obtinutuzumab, pembrolizumab, nivolumab, ibrutinib, venetoclax, PI3k-i), CAR-T or HSCT. 35% pts were previously treated with ibrutinib. Table 1 describes Grade (Gr) 3 and 4 AEs (all causality, stratified by treatment arm). Regarding safety, AEs were manageable, with a total of 5 DLTs were observed: 2 (Gr 3 febrile neutropenia, URI) in part Ib arm A, 3 (Gr 4 thrombocytopenia, Gr 3 diarrhea, G3 febrile neutropenia) in Part Ib arm B. No MTD was reached for the mono & doublet arms, with the MTD of the triplet determined to be DTRM-12 200 mg, EV 5 mg, & POM 2 mg. Spider plot (Figure 1a) shows the clinical response for individual CLL and lymphoma pts treated with mono, doublet and triplet therapies. Depth and durability of response improved with combination therapies (vs. mono). Of note, 48% of all patients had a ≥50% reduction in sum of the products of lymph node diameters. Representative PET-CT scans are in Figure 1b-c. Responses in multi-refractory pts are ongoing (including 15+ mos in a pt with r/r DLBCL and 5+ mos PR in a pt aged &gt; 90 yrs with r/r DLBCL; 4+ & 13+ mos PRs in two pts with RT). DTRM-12 plasma concentrations were unaffected by EV & POM (Once Daily Oral Therapies) in Figure 1d. The clinical trial met its primary endpoint as the triple combination DTRM-555 had an acceptable safety profile. Dose dependent drug levels with minimal inter-pt variations were observed in all arms, supporting once daily oral administration of this low-dose combination therapy. Encouraging clinical activity was observed in several high-risk, multi-refractory CLL and lymphoma pts, including those previously treated with ibrutinib. Thus synthetic lethality is a viable treatment approach. A phase II US expansion study is underway targeting pts with transformed lymphomas (follicular or prior CLL) and r/r DLBCL cohorts. Table 1. Disclosures Mato: AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding. Schuster:DTRM Biopharma: Research Funding. Foss:Mallinckrodt: Consultancy; Acrotech: Consultancy; miRagen: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; Eisai: Consultancy; Spectrum: Other: fees for non-CME/CE services . Isufi:Novartis: Consultancy; Astra Zeneca: Consultancy; Celgene: Consultancy. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Brander:Novartis: Consultancy; MEI: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Research Funding; AstraZeneca: Consultancy, Research Funding; Acerta: Research Funding; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; DTRM Biopharma: Research Funding. Tun:Mundi-pharma: Research Funding; TG Therapeutics: Research Funding; Curis: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; BMS: Research Funding. He:DTRM Biopharma: Employment, Equity Ownership. Kearney:DTRM Biopharma: Employment, Equity Ownership. Gui:DTRM Biopharma: Employment, Equity Ownership. Anderson:Theradex: Employment. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Huntington:Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Honoraria; DTRM Biopharm: Research Funding. OffLabel Disclosure: Everolimus in B cell lymphomas and CLL Pomalidomide in B cell lymphomas and CLL

Replication of negative-strand RNA viruses relies on two components: a helical ribonucleocapsid and an RNA-dependent RNA polymerase composed of a catalytic subunit, the L protein, and a cofactor, the P protein. We show that the measles virus (MeV) C protein is an additional component of the replication complex. We provide evidence that the C protein is recruited to the ribonucleocapsid by the P protein and map the interacting segments of both C and P proteins. We conclude that the primary function of MeV C is to improve polymerase processivity and accuracy, rather than uniquely to antagonize the type I interferon response. Since most viruses of the Paramyxoviridae family express C proteins, their primary function may be conserved.

Introduction and Purpose IRAK4 kinase activity is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in a variety of myeloid and lymphoid cell types. Dysregulated signaling in these pathways is frequently observed in NHL, particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM). A phase 1 trial in patients with NHL is being conducted to determine safety, pharmacokinetics, and preliminary efficacy of CA-4948 as monotherapy. Patients and Methods At the 18-Jul-2019 data cut-off date, 22 patients have been treated with single-agent CA-4948. Five dose-escalation cohorts from 50 mg QD to 200 mg BID have been tested and cleared; a cohort of patients treated at 400 mg BID dose is currently being evaluated. Patients were diagnosed with relapsed or refractory NHL, including DLBCL (n=13), FL (n=5), HGBL with MYC and BCL2 and/or BCL6 rearrangement (n=1), WM (n=1), LPL (n=1) and MCL (n=1), had a performance status of 0 or 1 (ECOG) at baseline, and were treated in 21-day cycles until progression of disease or unacceptable toxicity, lost to follow-up or death. 5 patients had prior autologous bone marrow transplants. Results CA-4948 has been generally well tolerated. Grade 3/4 treatment-related adverse events included amylase/lipase increased, diarrhea, neutrophil count decreased, rash, rhabdomyolysis. Pharmacokinetics has shown favorable characteristics with dose-proportional increases in exposure. Five patients have been on treatment through the end of Cycle 4, including one patient in Cycle 10 on study for over 7 months. Five patients experienced overall tumor burden decreases of ≥20% from baseline, including at least 2 of 4 patients treated at 200 mg BID. Downstream pharmacodynamic markers of IRAK4 activity are being evaluated. Molecular characteristics including cell-of-origin will be presented. Conclusion CA-4948 demonstrates preliminary clinical activity. Enrollment is on-going and the MTD has not been reached. These encouraging results warrant further clinical testing in patients with advanced hematological malignancies. Clinical trial: NCT03328078. Disclosures Younes: Roche: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding; Abbvie: Honoraria; Epizyme: Consultancy, Honoraria. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Tun:Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Lunning:Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Martell:Curis, Inc.: Employment. Patel:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Sunesis: Consultancy.

Abstract Abstract 3009FN2 Objective: To determine toxicity and efficacy of adding fludarabine (FLU) to a regimen of total body irradiation (TBI), anti-thymocyte globulin (ATG) and cyclophosphamide (CY), with de-escalation of the CY dose. The goal is to minimize CY-related toxicities while preserving (or improving) engraftment and survival in patients with SAA receiving an unrelated donor marrow transplant. Patients and Methods: Since May 2006, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), sponsored by the NHLBI and NCI, has conducted a prospective Phase I/II clinical trial of unrelated donor marrow transplantation in SAA (BMT CTN 0301). Patients with SAA are eligible if they are < 65 years, have adequate organ function, and have an available unrelated marrow donor matched 7 of 8 HLA-A, B, C, DRB1 loci. Patients with Fanconi anemia and other marrow failure syndromes are excluded. All patients receive TBI 200 cGy, ATG (either thymoglobulin: 3 mg/kg IV or ATGAM 30 mg/kg IV daily × 3, days –4 to –2), FLU (30 mg/m2 IV daily × 4, days –5 to –2). The Phase I portion of the trial sequentially tested four CY dose levels: 150 mg/kg (administered days –4 to –2); 100 mg/kg (days –3 to –2); 50 mg/kg (day –2); and, 0 mg/kg, and allowed enrollment of up to six patients at each CY dose level unless toxicity or graft failure boundaries were crossed. In the Phase II portion of the trial, patients enroll onto the optimal CY dose level, which is chosen using adaptive Bayesian criteria to rank desirability of the CY doses. All patients are followed for two years after transplantation. Early stopping guidelines are used to monitor for graft failure and early transplant-related mortality through day 100. Results: Twenty-one patients accrued to the Phase I portion of the trial. CY dose level 0 mg/kg was closed after all three enrolled patients developed secondary graft failure. All received a second allograft. One patient remains alive at 23 months after the first transplantation. The other two died from adult respiratory distress syndrome (ARDS) at 114 days after the first transplant and idiopathic pneumonia at 200 days after the first transplant. Review of Phase I results for the other three dose levels suggested CY dose 150 mg/kg as the optimal dose level for Phase II testing. However, after an additional eight patients were treated at this dose, the level was closed to further accrual because of excess toxicity. Seven of the 14 patients receiving 150 mg/kg of CY (and 7 of the last 8 enrolled) died. Causes of death were cardiac/pulmonary/multi-organ failure (n=4), ARDS (n=2), and parainfluenza virus type 3 pneumonia (n=1). Bayesian evaluation of the two remaining dose levels indicates very similar desirability scores and accrual continues at both the CY 100 mg/kg and 50 mg/kg levels. As of July 15, 2011, a total of 61 patients have been enrolled, 17 on the two closed levels, 33 on the 100 mg/kg level and 11 on the 50 mg/kg level. Conclusions: Early analysis of this trial, made necessary by these unexpected severe adverse events, revealed two important findings among patients receiving low-dose TBI, ATG, and FLU at the doses outlined: 1) CY dose 0 mg/kg is associated with higher than expected graft failure; and, 2) CY dose 150 mg/kg is associated with excess transplant-related toxicity. Neither CY dose level should be tested further in the context of the regimen used in this trial. To date, the two intermediate CY dose levels (100 mg/kg and 50 mg/kg) have not crossed the graft failure or fatality stopping boundaries and accrual is in progress. Disclosures: Pulsipher: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background and Purpose— Evidence suggests that atrial fibrillation (AF) is associated with increased risk of cognitive decline and dementia, even in the absence of stroke. White matter disease (WMD) is a potential mechanism linking AF to cognitive impairment. In this study, we explored the association between prevalent AF and WMD. Methods— We performed a cross-sectional analysis of participants attending the ARIC-NCS (Atherosclerosis Risk in Communities–Neurocognitive Study) in 2011 to 2013 who underwent brain magnetic resonance imaging. AF was ascertained from study visit electrocardiograms or prior hospitalization codes. Extent of WMD was defined by measures of white matter (WM) microstructural integrity and WM hyperintensity volume. Multivariable linear regression models were used to assess the association between AF and WMD. Results— Among 1899 participants (mean age, 76 years; 28% black; 60% women), 133 (7%) had prevalent AF. After multivariable adjustment, differences between participants with and without AF were −0.001 (95% CI, −0.006 to 0.004) for global WM fractional anisotropy, 0.031×10 −4 mm 2 /s (95% CI, −0.075 to 0.137) for global WM mean diffusivity, and 0.08 mm 3 (95% CI, −0.14 to 0.30) for WM hyperintensity volume. Conclusions— The results suggest that there is no association between prevalent AF and WMD.

SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss‐of‐function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation‐positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow‐growing hypothalamo‐pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.