Citations

Malakoplakia is an inflammatory process related to defective macrophage response to bacterial infection. To further characterize the clinicopathologic manifestations of gastrointestinal malakoplakia, 26 cases were identified from 6 institutions. Hematoxylin and eosin-stained slides and available stains were reviewed, and pertinent clinicopathologic features analyzed. Sixteen patients were women (62%). Mean patient age was 64 (range: 24 to 83). Sites included the colorectum (n=23), appendix (n=1), and stomach (n=2). Clinical indications for tissue procurement included screening (n=14), tumor resection (n=5), diarrhea (n=1), adenoma surveillance (n=1), ulcerative colitis flare (n=1), abdominal pain (n=1), and appendicitis (1). All cases featured histiocytes with abundant, pale, eosinophilic cytoplasm focally containing Michaelis-Gutmann bodies. The process frequently involved the mucosa (n=19), with architectural distortion in 13 cases. Lymphoid aggregates were present in 18 cases, which were prominent or obscuring in 11 (all colon biopsies) and provoked concern for lymphoma in 2. Associated findings included adenocarcinoma (n=5), adenoma (n=2), gastric hyperplastic polyps (n=1), chemical gastritis (n=1), collagenous colitis (n=1), and active chronic colitis (n=2). In cases with available stains, Michaelis-Gutman bodies were highlighted by Periodic Acid-Schiff with diastase, Von Kossa, and iron stains. Although 2 cases were positive for Tropheryma whipplei antibody, no T. whipplei transcripts were detected on real-time polymerase chain reaction. All patients with available follow-up are alive and well with no additional instances of malakoplakia. Malakoplakia of the gastrointestinal tract is a benign, incidental finding. Although histologic features in the stomach and colon resections are similar to those at other sites, exuberant lymphocytic response in colon biopsies and immunoreactivity with T. whippleii antibody may provoke initial confusion and lead to unnecessary time and resource investment.

The mechanisms underlying regenerative function of endothelial progenitor cells (EPCs) are not completely understood. Since previous studies from several groups including ours suggest that biosynthesis of NO in EPCs is low, the present study was designed to determine ability of EPCs to produce and release prostacyclin (PGI 2 ). Outgrowth (“late”) EPCs were obtained from peripheral blood of healthy subjects. Enzymatic activity of eNOS was significantly lower in EPCs as compared to eNOS activity in human coronary endothelial cells (CAECs) (n=4‐6 subjects, P<0.05). In contrast, production and release of PGI 2 was four fold higher in EPCs as compared to CAECs (n=3, P<0.05). This was associated with significantly higher expression of cyclooxygenase‐1 (COX‐1) protein in EPCs whereas levels of COX‐2 protein were not different between progenitor and mature endothelial cells. Production of thromboxane A 2 and prostaglandin E 2 were low and identical in EPCs and CAECs. Most importantly, inhibition of COX isoforms with indomethacin impaired pro‐angiogenic effect of EPCs as assessed by in vitro tube formation assay (n=4‐6, P<0.05). Cell proliferation was also significantly reduced after inhibition of COX isoforms with indomethacin or inactivation of PGI 2 ‐synthase by siRNA (n=4‐6, P<0.05). Our findings suggest that production and release PGI 2 is an important mechanism contributing to regenerative capability of EPCs.

AbstractSystemic inflammation can lead to coagulopathy and disseminated intravascular coagulation (DIC). In prior studies, the recombinant A2 domain of human von Willebrand factor (VWF; A2 protein) attenuated DIC and decreased mortality in lipopolysaccharide (LPS)-treated mice. Here, we performed studies to dissect the mechanism by which the A2 protein moderates DIC. We used confocal microscopy to analyze the fibrin clot structure in plasma from healthy humans and endotoxemic mice, turbidity assays to examine fibrin polymerization, and a murine model for LPS-induced DIC and introduced a loss-of-function mutation into the A2 protein for fibrin. The mutation of the residue E1567 located in the α2 helix of the folded A2 domain of VWF inhibited binding activity for fibrin, possibly mapping a novel region containing a putative binding site for fibrin. The A2 protein increased the initial rate of change of fibrin polymerization, intercalated into the fibrin network, and modified the resultant clot structure in vitro. Furthermore, ex vivo experiments using plasma from mice with endotoxemia treated with the A2 protein revealed an increased rate of fibrin formation and an altered clot structure as compared with plasma from nontreated sick animals. Moreover, and in contrast to the A2 mutant, the A2 protein improved survival and reduced fibrin deposition and microvascular thrombosis in mice with endotoxemia-induced DIC. Importantly, in vivo and in vitro studies indicated that the A2 protein did not affect experimental thrombosis. Thus, we provide evidence for a novel treatment to attenuate systemic inflammation-induced coagulopathy/DIC via targeting fibrin formation, without an increased risk for bleeding.

Objective To evaluate patient‐reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression‐free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death‐ligand 1 (PD‐L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC). Patients and methods Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks ( n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks ( n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6‐week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2‐point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib. Results Completion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue‐related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22–0.71); RCC symptoms, 0.22 (0.12–0.41); and symptom interference, 0.36 (0.22–0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. Conclusion PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).

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

Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 studies. Persistence of CAR T cells post infusion may be one determinant of duration of response. bb21217 is a next-generation anti-BCMA CAR T cell therapy based on investigational therapy idecabtagene vicleucel (bb2121) (Friedman 2018, Hum Gene Ther 29:585) that uses the same lentiviral CAR T design as bb2121, but adds the phosphoinositide 3-kinase inhibitor bb007 during ex vivo culture to enrich the drug product for memory-like T cells. Evidence suggests that CAR T cells with this phenotype may be more persistent and more potent than unselected CAR T cells. CRB-402 is a first-in-human study of bb21217 in patients with RRMM designed to assess safety, pharmacokinetics, efficacy and duration of effect. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 planning to enroll 74 patients with RRMM who received ≥ 3 prior regimens, including a proteasome inhibitor and an immuno-modulatory agent, or are double-refractory to both classes. During dose escalation, enrollment is restricted to patients with ≥ 50% BCMA expression by IHC on malignant plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for transduction, expansion and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive bb21217 as a single infusion. Planned dose levels are 150, 450, 800, and 1,200 x 106 CAR+ T cells and intermediate dose levels are allowed. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ T cells in blood. Results: Asof April 20, 2019, 22 patients (median age 63 [min;max 42 to 74]) have received bb21217 (12 at 150, 6 at 300 and 4 at 450). Eleven had high tumor burden, defined as ≥ 50% bone marrow plasma cells pre-infusion. Patients had a median of 7 (min;max 4 to 17) prior lines of therapy and 18/22 had prior autologous stem cell transplant; 7/22 had high-risk cytogenetics. Of the 22 patients, 19 received prior daratumumab, 13 received prior Bort/Len/Car/Pom/Dara. Median follow-up after bb21217 infusion was 23 weeks (&lt;1 to 77 weeks). As of data cut-off, 13/22 patients developed cytokine release syndrome (CRS; 5 G1, 7 G2, 1 G3) and responded to supportive care, tocilizumab and/or corticosteroids. Five patients developed neurotoxicity [1 G1, 2 G2, 1 G3 (vertigo/dizziness), 1 G4 (encephalopathy, previously reported)]. For the 1 patient with G4 neurotoxicity, G3 CRS was also reported; both have resolved. A total of 18 patients were evaluable for response with ≥ 2 months of follow up or PD within 2 months. Fifteen (83%) patients demonstrated clinical response per IMWG criteria. Six of these subjects subsequently progressed. Nine patients remained in response, including 2 patients with ongoing response at months 15 and 18. MRD negative results at 10-5 nucleated cells or better were obtained by NGS in 10/10 evaluable responders at month 1. Overall, 6/8 patients evaluable at 6 months and 2/2 patients evaluable at 12 months had detectable CAR T cells in blood. Updated data from this study will be presented, including extended follow-up on the initial patients treated and early clinical and CAR T cell persistence data from at least 15 additional patients treated with up to 450 x 106 CAR+ T cells. Conclusions: The adverse events observed to date were manageable and consistent with known toxicities of CAR T therapies. Initial efficacy results with bb21217 CAR T therapy in heavily pretreated RRMM are encouraging, with 83% of patients demonstrating clinical response. Emerging data demonstrate long-term persistence of CAR T cells in long-term responders. Updated data to be presented will help determine whether treatment with bb21217 results in sustained CAR T cell persistence and durable clinical responses, and whether bb21217 is tolerated at higher doses. Disclosures Berdeja: AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. Shah:Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jagannath:Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Merck: Consultancy. Madduri:Abbvie: Consultancy; Celgene: Consultancy; Takeda: Consultancy; undation Medicine: Consultancy. Kaufman:Janssen: Honoraria; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Celgene: Consultancy. Munshi:Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Abbvie: Consultancy. Rosenblatt:BMS: Other: Advisory Board ; Parexel: Consultancy; Imaging Endpoint: Consultancy; Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; BMS: Research Funding; Amgen: Other: Advisory Board; Celgene: Research Funding; Merck: Other: Advisory Board. Turka:bluebird bio: Employment. Lam:bluebird bio: Employment. Massaro:bluebird bio: Employment. Campbell:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees. Petrocca:bluebird bio: Employment. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.

OBJECTIVE Assess the efficacy of inControl AP, a mobile closed-loop control (CLC) system. RESEARCH DESIGN AND METHODS This protocol, NCT02985866, is a 3-month parallel-group, multicenter, randomized unblinded trial designed to compare mobile CLC with sensor-augmented pump (SAP) therapy. Eligibility criteria were type 1 diabetes for at least 1 year, use of insulin pumps for at least 6 months, age ≥14 years, and baseline HbA1c &lt;10.5% (91 mmol/mol). The study was designed to assess two coprimary outcomes: superiority of CLC over SAP in continuous glucose monitor (CGM)–measured time below 3.9 mmol/L and noninferiority in CGM-measured time above 10 mmol/L. RESULTS Between November 2017 and May 2018, 127 participants were randomly assigned 1:1 to CLC (n = 65) versus SAP (n = 62); 125 participants completed the study. CGM time below 3.9 mmol/L was 5.0% at baseline and 2.4% during follow-up in the CLC group vs. 4.7% and 4.0%, respectively, in the SAP group (mean difference −1.7% [95% CI −2.4, −1.0]; P &lt; 0.0001 for superiority). CGM time above 10 mmol/L was 40% at baseline and 34% during follow-up in the CLC group vs. 43% and 39%, respectively, in the SAP group (mean difference −3.0% [95% CI −6.1, 0.1]; P &lt; 0.0001 for noninferiority). One severe hypoglycemic event occurred in the CLC group, which was unrelated to the study device. CONCLUSIONS In meeting its coprimary end points, superiority of CLC over SAP in CGM-measured time below 3.9 mmol/L and noninferiority in CGM-measured time above 10 mmol/L, the study has demonstrated that mobile CLC is feasible and could offer certain usability advantages over embedded systems, provided the connectivity between system components is stable.

ABSTRACT Aims Left atrial (LA) mechanical function may play a significant role in the development and progression of heart failure with preserved ejection fraction (HFpEF). We performed a systematic review and meta-analysis to evaluate association of impaired LA function with outcomes in HFpEF. Methods and results Multiple databases were searched for original studies measuring different phases of LA function in HFpEF patients. Comparative LA function between HFpEF patients and healthy controls was assessed by pooling weighted mean differences (WMD). Adjusted hazard ratios (HRs) with 95% confidence intervals were pooled to evaluate the prognostic utility of LA function. Twenty-two studies (2 trials, 20 observational) comprising 1974 HFpEF patients and 751 healthy controls were included. HFpEF patients had decreased LA reservoir [WMD = −12.21% (−15.47, −8.95); P &lt; 0.001], LA conduit [WMD = −5.68% (−8.56, −2.79); P &lt; 0.001], and pump [WMD = −11.07% (−14.81, −7.34); P &lt; 0.001] emptying fractions compared with controls. LA reservoir [WMD = −13.38% (−16.07, −10.68); P &lt; 0.001], conduit [WMD = −4.09% (−6.77, −1.42); P = 0.003], and pump [WMD = −3.53% (−4.47, −2.59); P &lt; 0.001] strains were also significantly lower in HFpEF patients. Decreased LA reservoir strain [HR 1.24 (1.02, 1.50); P = 0.03] was significantly associated with risk of composite all-cause mortality or heart failure hospitalization. Conclusions Impaired LA function appears to have diagnostic and prognostic value in HFpEF, but whether indices of LA function truly refine discrimination for diagnosis or prognosis remains to be fully determined. Larger studies are needed to better evaluate associations between LA function and clinical outcomes and the role of LA function as a target for novel HFpEF therapies.

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.