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Background Recent studies have indicated that being overweight or obese could reduce the effect of anti-TNF treatment in patients (pts) with RA. 1,2 Other data show that certain biologic (b)DMARDs, such as abatacept, work independently of BMI. 3,4 Additional data on the role of BMI on treatment outcomes in clinical practice settings is required to inform clinical practice. Objectives To evaluate the impact of BMI on outcomes of disease activity in pts with RA treated with TNF and non-TNF agents (conventional or other bDMARDs). Methods Pts enrolled in a tertiary care centre RA registry, established in 2003, were analysed. The registry mostly comprises pts with established RA who were evaluated semi-annually for multiple clinical patient-reported outcomes and resource utilization parameters, and annually for composite disease activity measures such as DAS28 (CRP), CDAI and SDAI. The current analysis is based on pts enrolled in the RA registry with BMI values at time of enrolment. Pts were classified into groups based on BMI: normal (BMI 2 ), overweight (BMI ≥25 to 2 ) and obese (BMI ≥30 kg/m 2 ). Outcomes evaluated included change from baseline in DAS28 (CRP), CDAI, SDAI and joint counts at 12 months from treatment exposure. Treatments were categorized into TNF and non-TNF, which included conventional DMARDs and other non-TNF biologics. Multivariate linear regression analyses were used to evaluate impact of BMI on treatment outcomes controlling for baseline covariates of age, sex, disease duration, co-morbidities, baseline disease activity and serostatus. Separate models were run for the TNF and non-TNF groups. Results A total of 997 (78%) pts in the registry had baseline BMI values and were included in the analysis. Around 37% (n=371) had TNF exposure and were included in the TNF cohort; the remainder (63%; n=626) were included in the non-TNF cohort. Proportions of pts in the normal, overweight and obese groups for the TNF cohort were 45.5% (n=169), 27.5% (n=102) and 27.0% (n=100), respectively. For the non-TNF cohort, these were 41.7% (n=261), 33.1% (n=207) and 25.2% (n=158), respectively. In both cohorts, pts with normal BMIs were younger vs the overweight and obese BMI groups. However, obese BMI pts had higher disease activity measures at baseline (mean [SD] CDAI: 22.8 [17.8] for TNF and 24.9 [17.3] for non-TNF) vs the normal BMI pts (17.5 [15.9] for TNF and 19.9 [16.7] for non-TNF) and overweight BMI pts (20.9 [16.5] for TNF and 20.5 [15.0] for non-TNF). Adjusted mean change from baseline in disease activity in the TNF cohort was significantly reduced across all disease activity measures for the normal BMI group (p Conclusions Independent of BMI, non-anti-TNF therapy demonstrated similar outcomes in pts with RA. However, obese and overweight pts with RA (vs normal weight) had less improvement in disease activity (as measured by DAS28 [CRP]) with anti-TNF therapy. References Gremese E, et al. Arthritis Care Res 2013;65:94–100. Klaasen R, et al. Arthritis Rheum 2011;63:359–64. Gardette A, et al. Ann Rheum Dis 2015;74:1041. Disclosure of Interest E. Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Z. Guo Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, C. Iannaccone: None declared, M. Frits: None declared, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Biosciences, UCB, DxTerity, Consultant for: Amgen, Bristol-Myers Squibb, Crescendo Biosciences, UCB, AbbVie, Lilly, Pfizer, Roche, N. Shadick Grant/research support from: Bristol-Myers Squibb, UCB, Mallinckrodt, Amgen, Brescendo Biosciences, Consultant for: Bristol-Myers Squibb

Background Characterization of the blood labyrinth barrier (BLB) is extremely important to determine whether the BLB can be manipulated pharmacologically. However, experiments to investigate the BLB are technically difficult to perform. In this report, we demonstrated a unique method of controlling the BLB, and established the pharmacokinetics of gentamicin in perilymph, cerebrospinal fluid (CSF) and blood with and without mannitol. Study design Controlled animal research project. Methods Permeability of the BLB and the blood brain barrier (BBB) to gentamicin with and without mannitol was studied by collecting 175 samples from 44 guinea pigs using concentrations relevant to human clinical situations. Samples were taken from two groups of 22 animals, with each animal undergoing sampling at a different time after administration of either 10 mg/ml gentamicin (4 mg/kg) (Gardena, CA) alone or gentamicin with 20% mannitol (250 mg/kg) (Mallinckrodt Inc., KY). The sample times varied from 0.5 to 17.5 h post-infusion. Samples were also taken from 4 animals as negative controls after administration of normal saline. Our goal was to simultaneously assess the pharmacokinetics of gentamicin in each of three different fluid samples in the same animal. Thus at the pre-determined post-infusion sampling time, each animal was sampled once for perilymph, CSF, and blood before being euthanized. Each animal contributed to a single time point on the subsequent pharmacokinetic curves with more than one animal per time point. Results Mannitol increased the rate of entry and egress of gentamicin through BLB significantly (p = 0.0044) but the effects on the BBB did not reach statistical significance (p = 0.581). Mannitol did not alter renal clearance of gentamicin from the blood (p = 0.433). The concentration of gentamicin in perilymph and CSF was always significantly lower than in blood. Conclusions Mannitol administration transiently increases the permeability of the BLB. Potential clinical benefits may accrue from selected timing of administration of osmotic agents such as mannitol augmenting the rate of entry and egress of compounds such as gentamicin into and out of perilymph.

The present article reports a systematic review of the studies related to psychological well-being among East Asian international students. A total of 18 quantitative studies published in peer-reviewed journals from 2000 to 2011 were reviewed. Our review revealed three major results: (1) a majority of researchers (n=13, 72.2%) tend to choose Chinese international students as a representative of East Asian and Asian international students in their studies; (2) studies on psychological well-being of East Asian international students are closely associated with the following variables: length of stay in host country, English proficiency, attitudes toward seeking help, depression, and acculturation; (3) depression was the most frequently reported variable (n=6, 33.3%), followed by acculturation (n=5, 27.8%). Recommendations for further research in psychological well-being were provided.Keywords: psychological well-being, East Asian international students.Over the past six years, the growth in numbers of international students enrolled in U.S universities has been remarkable. Between 2006 and 2012, enrollment of international students has increased from 157,178 to 228,467, with an average rate of 8.2% per year (Institute of International Education, 2012a). Recent data show that in the 2011-2012 academic year, there were 764,495 international students studying on campuses in the United States (Institute of International Education, 2012a). Nearly 65% of international students are drawn from Asian countries such as China (25.4% of the total international student population), India (13.1%), South Korea (9.5%), Saudi Arabia (4.5%), Taiwan (3.0%), Japan (2.6%), and Vietnam (2.0%) (Institute of International Education, 2012a). Of Asian international students, 63% are from countries in East Asia (China, Japan, South Korea, Mongolia, and Taiwan).As the number of East Asian international students grows, the need for more ethnically sensitive and thorough study of this population becomes increasingly important. However, little scholarly literature provides a systematic review of the population, especially on their psychological well-being. Factors associated with a relative lack of research are multiple and complex. In terms of diversity and mobility, East Asian international students can be described as a group of people that consist of many different racial and ethnic groups (Chinese, Japanese, Taiwanese, and Korean). They usually stay in the host country for a short period of time to finish their degrees and then return to their country of origin (Bochner, 2006). Other factors, such as their perception of health and well-being, attitudes toward seeking professional psychological help, English proficiency, levels of acculturation, and racial and ethnic identity, have also been associated with psychological well-being in the literature but are less well studied. Accordingly, these factors have a negative impact on investigating psychological well-being among East Asian international students.Numerous published studies have described factors related to psychological well-being among East Asian international students, but many have been small, with a monolithic sample, or purely qualitative in nature. Moreover, a majority of these studies focused on a small number of variables, such as acculturative stress (Nilsson, Butler, Shouse, & Joshi, 2008), depression (Wei, Heppner, Mallen, Ku, Liao, & Wu, 2007), cultural adjustments (Camalcilar & Falbo, 2008; Nilsson et al., 2008; Wang & Mallinckrodt, 2006), health and well-being (Rosenthal, Russell, & Thomson, 2008), racial/ethnic identity and Asian value (Iwamoto & Liu, 2010). Our research of relevant databases (e.g., Academic Search Complete and Psychological & Behavioral Sciences Collection) revealed that no systematic reviews have been published on how these factors, alone or in combination, can differentially affect psychological well-being among East Asian international students, nor have systematic reviews been conducted seeking to summarize what is known about psychological well-being associated with the group. …

// Amy Barone 1,* , Rajarshi Sengupta 1,* , Nicole M. Warrington 1 , Erin Smith 2,3 , Patrick Y. Wen 4,5 , Rolf A. Brekken 6 , Barbara Romagnoli 7 , Garry Douglas 7 , Eric Chevalier 7 , Michael P. Bauer 7 , Klaus Dembowsky 7 , David Piwnica-Worms 2,3,8,9 and Joshua B. Rubin 1,10 1 Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 2 BRIGHT Institute , Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 3 Molecular Imaging Center, Mallinckrodt Institute of Radiology , Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 4 Center for Neuro-Oncology, Dana Farber/Brigham and Women’s Cancer Center, Brookline Ave, Boston, MA 5 Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital, Brookline Ave, Boston, MA 6 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Harry Hines Blvd. Dallas, TX 7 PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland 8 Department of Cell Biology & Physiology , Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 9 Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Holcombe Dr., Houston, TX 10 Department of Anatomy and Neurobiology , Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO * These authors contributed equally to this work Correspondence: Joshua B. Rubin, email: // Keywords : CXCR4, VEGF, perivascular, glioblastoma, stem cells Received : August 22, 2014 Accepted : September 08, 2014 Published : September 09, 2014 Abstract Glioblastoma recurrence involves the persistence of a subpopulation of cells with enhanced tumor-initiating capacity (TIC) that reside within the perivascular space, or niche (PVN). Anti-angiogenic therapies may prevent the formation of new PVN but have not prevented recurrence in clinical trials, suggesting they cannot abrogate TIC activity. We hypothesized that combining anti-angiogenic therapy with blockade of PVN function would have superior anti-tumor activity. We tested this hypothesis in an established intracranial xenograft model of GBM using a monoclonal antibody specific for murine and human VEGF (mcr84) and a Protein Epitope Mimetic (PEM) CXCR4 antagonist, POL5551. When doses of POL5551 were increased to overcome an mcr84-induced improvement in vascular barrier function, combinatorial therapy significantly inhibited intracranial tumor growth and improved survival. Anti-tumor activity was associated with significant changes in tumor cell proliferation and apoptosis, and a reduction in the numbers of perivascular cells expressing the TIC marker nestin. A direct effect on TICs was demonstrated for POL5551, but not mcr84, in three primary patient-derived GBM isolates. These findings indicate that targeting the structure and function of the PVN has superior anti-tumor effect and provide a strong rationale for clinical evaluation of POL5551 and Avastin in patients with GBM.

The developmental trajectory of body image dissatisfaction is unclear. Researchers have investigated sociocultural and developmental risk factors; however, the literature needs an integrative etiological model. In 2009, Cheng and Mallinckrodt proposed a dual mediation model, positing that poor-quality parental bonds, via the mechanisms of heightening romantic attachment anxiety and thin-ideal media internalization, increases body dissatisfaction. We tested 2 versions of this model, including an alternate model featuring attachment anxiety in close friendships. We recruited females ages 12-24, primarily from a mid-sized private religious university, to complete self-report measures. The participant sample was ethnically diverse, with approximately 40% endorsing minority status. Results showed that mother care and father care were negatively linked to friendship attachment anxiety and romantic attachment anxiety. Friendship and romantic attachment anxiety were positively linked to media susceptibility. Media susceptibility was positively linked to body image dissatisfaction. Mother care and father care were negatively, indirectly linked to body image dissatisfaction through the mediators of friendship attachment anxiety and media susceptibility. Mother care made a significant, albeit small, contribution to body image dissatisfaction after controlling for other variables. Overall, findings suggest that adverse parent-child relational factors may indirectly elevate body dissatisfaction, operating through attachment anxiety and susceptibility to sociocultural pressures.

We sought to determine whether the design of 3 different double-lumen endobronchial tubes (DLT) (Rusch, Mallinckrodt, Fuji) has an effect on the ease of placement over an airway exchange catheter (AEC) using a video laryngoscope. A convenience sample of 17 anesthesia residents and fellows with at least 3 years of anesthesia training was recruited from teaching hospitals in Toronto for a randomized crossover trial. Each participant passed each DLT over an AEC in an airway simulator, visualized and video recorded via a video laryngoscope (GlideScope). The order of exchange was randomized by blindly pulling the name of the manufacturer of a DLT from a box. The primary outcome was time to intubate, defined as time from the bronchial lumen entering the GlideScope view to the bronchial lumen passing the vocal cords. Also recorded were participants’ subjective rating of the ease of use and failure rate, defined as an attempt >150-second duration. Time to intubate was faster with the Fuji-Phycon DLT (median 2 seconds) compared with both the Rusch (median 27 seconds, P = 0.0144) and Mallinckrodt (median 21 seconds, P = 0.0117). On a scale of 1 to 10, with 10 being very easy to use and 1 being very difficult, the Fuji-Phycon was judged to be easier to use (median 10 seconds) compared with the Rusch (median 3, P = 0.0186) and the Mallinckrodt (median 4 seconds, P = 0.0123). The Rusch was associated with significantly more failures than the other DLTs, P = 0.002. The Fuji-Phycon DLT was easier to pass over an AEC in this simulator trial and warrants consideration in patients with difficult airways who require 1-lung ventilation.

Heat and Moisture Exchanger (HME) is a simple solution to the problems of warming and humidification of inspired gases during ventilator treatment. The device acts as an “artificial” nose or passive humidifier, added to the breathing circuit to retain and exchange heat and moisture between inspiration and expiration. The HME traps expiratory heat and moisture from patient’s exhaled breath in a porous medium and returns a portion of them through the subsequent inspiratory cycle. The aim of our paper is to develop a computational fluid dynamics (CFD) model of an HME device commonly used in anaesthesia and intensive care. The CFD results allow a better understanding of flow behaviour leading to the design of more efficient devices. The CFD model solves the gas flow, heat and mass transfer equations in a DAR Hygrobac S (Mallinckrodt DAR, Mirandola, Italy). The temperature, absolute humidity and pressure fields are obtained during expiratory phase to evaluate heat and moisture conserving efficiencies and air flow resistance. The effect of flow rate as one of the major parameters in ventilator setting on temperature, humidity and pressure drop is determined. Inside the HME device, areas of recirculation are observed. As the flow rate increases the output temperature and absolute humidity go up causing a reduction in heat and moisture conserving capacities. Comparison of the CFD results with previously obtained experimental data shows a satisfactory agreement.

MD reports a grant from AstraZeneca funding a non-drug PI-led study in Nottingham (Sons of Gout study) and honoraria for Advisory boards on osteoarthritis and gout for AstraZeneca, Grunenthal, Mallinckrodt, and Roche, outside the submitted work. WZ reports honoraria for Grunenthal and speaker fees for Bioiberica and Hisun, outside the submitted work. All other authors have declared no conflicts of interest.

Background: Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant in pediatric patients. Second-line therapies cause further immunosuppression, leaving patients vulnerable to life-threatening infections. Extracorporeal photopheresis (ECP) with methoxsalen (Uvadex®) sterile solution, in which apheresed leukocytes are photosensitized, exposed to ultraviolet A radiation ex vivo, and reinfused, is used to treat aGvHD because it has a low risk of infection, unlike systemic immunosuppressants. Safe use of ECP in children is not yet established. Aims: To report interim 4-week data from a 12-week phase 3 study evaluating the efficacy and safety of ECP using the photosensitizing agent methoxsalen with the Therakos® Cellex® Photopheresis System (Cellex; Mallinckrodt Pharmaceuticals, Bedminster, NJ) in pediatric/young adult patients with SR-aGvHD (NCT02524847). Methods: In this single-arm, open-label study, patients (aged 1-21 years; SR-aGvHD International Bone Marrow Transplant Registry [IBMTR] grade B-D) received ECP 3 times/wk for 4 weeks, followed by 2 times/wk for 8 weeks. Steroids were tapered according to physician discretion if SR-aGvHD responded to ECP. The primary endpoint was proportion of patients with an overall response (OR), defined using the Modified IBMTR Severity Index as complete response (CR; complete resolution of aGvHD in all evaluable organs, without next-line systemic treatment) or partial response (PR; improvement of 1 stage in ≥1 aGvHD target organ without progression in others or addition of next-line systemic treatment), after 4 weeks. The primary endpoint was considered significant if P48%. Secondary outcome measures included safety, duration of response, steroid-sparing effect, and organ-specific response. Results: Of 25 patients enrolled, 25 were evaluable for safety (patients who received ≥1 ECP treatment) and 23 were evaluable for efficacy. Patients' mean age was 9.2 years, 44% were female, mean body mass index was 18.3 kg/m2, and the majority (n=18) had Grade 3 aGvHD. Twelve patients (48%) completed all study visits; 5 withdrew early (2 deaths, 1 CR; 3 withdrew due to inadequate efficacy, 2 of whom started second-line therapy, and 3 no longer required treatment) A median of 27 ECP treatments were administered (range 3-28). OR was 61% (14/23 evaluable patients); there were 3 CRs (13%) and 11 PRs (48%; P Disclosures Kitko: Mallinckrodt: Honoraria; Novartis: Consultancy, Honoraria. Boodée:Mallinckrodt Pharmaceuticals: Employment. OffLabel Disclosure: UVADEXÃ'® (methoxsalen) Sterile Solution is indicated for extracorporeal administration with the THERAKOSÃ'® UVAR XTSÃ'® or THERAKOSÃ'® CELLEXÃ'® Photopheresis System in the palliative treatment of the skin manifestations of Cutaneous T-Cell Lymphoma (CTCL) that is unresponsive to other forms of treatment. Extracorporeal photopheresis (ECP) with methoxsalen (UvadexÃ'®) sterile solution is used to treat acute graft-versus-host disease (aGvHD), but there are few clinical trials in pediatric patients. This abstract reports on the interim results of a phase 3 clinical trial of ECP with methoxsalen used with the TherakosÃ'® CellexÃ'® Photopheresis System in pediatric/young adult patients with steroid refractory aGvHD.

Introduction: TP53 mutations have been associated with adverse outcomes in AML and MDS. While these mutations occur in less than 15-20% of pts, they are often associated with complex karyotypes and therapy-related (t)-myeloid neoplasms (MN). Previous studies showed poor outcomes with intensive chemotherapy (IC) and lower-intensity therapies [LIT] (e.g. hypomethylating agents [HMA]), and higher relapse rates after allogeneic hematopoietic stem cell transplant (alloSCT), leaving the question of optimal treatment unanswered. Methods: We conducted a retrospective review of all adult pts with MN and pathogenic TP53 mutations who were treated at Yale University from 9/1/2015 to 5/31/2019. We collected data on age, sex, ethnicity, prior malignancies and their treatments, white blood cell (WBC), hemoglobin, platelet count, disease risk, initial and subsequent lines of therapies, and use of alloSCT. Responses were recorded using modified International Working Group (IWG) criteria 2003 for AML and 2006 for MDS. Overall survival (OS) was measured using Kaplan Meier methods. Results: We identified 83 pts with TP53-mutated MN (45 AML, 31 MDS, 4 chronic myelomonocytic leukemia, and 3 JAK2-positive myeloproliferative neoplasms). Median age was 69 years (range [R], 27-88 years), 52% were male, and 88% were Caucasian [Table 1]. Prior malignancy was noted in 35 pts (42%) and 29 (17 AML, 12 MDS) pts were classified as t-MN. Median WBC on presentation was 3 x 109 /L (R, 0.2 - 74x109) with a median of 0% peripheral blasts (R, 0-43%). Complex (n=75; 90%) and monosomal karyotypes (n=54; 65%) were highly prevalent. We identified 101 unique, pathogenic or likely pathogenic mutations in the TP53 gene with 17 pts harboring more than 1 abnormal variant (16 pts with 2 mutations, 1 pt with 4 mutations). Missense variants were most commonly encountered (n=82 variants, 81%) followed by splicesite (n=9, 9%), frameshift (n=6, 6%), and nonsense variants (n=4, 4.0%). 52 pts had isolated somatic TP53 variants (63%). Among the other 31 pts DNMT3A (n=8 pts), JAK2 (n=6), and TET2 (n=5) variants were the most common somatic mutations. Of note, targetable driver mutations such as FLT3 (n=0), IDH1 (n=3), and IDH2 (n=1) were very rare. Notably, pts with complex karyotype were more likely to have isolated TP53 mutations compared to non-complex karyotype pts (complex karyotype + isolated TP53 mutations: 51 pts [68.0%] vs non-complex karyotype + isolated TP53 mutations: 2 pts [25.0%]; Fisher's exact test: p=0.024) [Table 2]. Median follow up of the cohort was 6.4 months (mos) [R: 0.2-55.3 mos]. Median OS in the entire study cohort was 7.6 mos (95% CI: 5.7-10.0 mos) with a 1-year OS rate of 30.5% (95% CI: 20.0-41.6%). Response rates and outcome for AML and MDS patients by treatment regimen are shown in Table 3. Among AML pts, IC did not appear to improve OS compared to pts receiving LIT (median OS 10.1 mos [95% CI: 6.4-15.5] vs 8.1 mos [95% CI: 1.9-13.6]; p=0.39). AML pts (median OS 6.7 mos [95% CI: 1.9-9.4]; 1-year OS: 23.2% [95% CI: 11%-38%]) had a statistically non-significant trend to poorer outcomes compared to MDS pts (median OS 10 mos [95% CI 5.7-12.9]; 1-year OS: 29.5% [95% CI 13.5-47.4%]; p=0.13). Notably, among the 10 pts who proceeded to alloSCT, only 3 pts relapsed after a median of 2.8 mos post-alloSCT. Relapse-free survival and median OS for pts who underwent alloSCT was not reached at a median follow up of 10.4 mos. Conclusions: In this case series we confirm the poor prognosis for pts with TP53-mutated MN. Median OS was only 7.6 mos, and IC did not appear to improve OS compared to LIT for AML pts. With limited follow-up, pts who underwent alloSCT appeared to benefit. Novel therapies are urgently needed to improve outcomes of this pt population. Disclosures Podoltsev: Kartos Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Prebet:Boehringer Ingelheim: Research Funding; Boehringer Ingelheim: Research Funding; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria; Tetraphase: Consultancy; novartis: Honoraria; novartis: Honoraria; Agios: Consultancy, Research Funding; novartis: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; Genentech: Consultancy; pfizer: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria; novartis: Honoraria. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Foss:Spectrum: Other: fees for non-CME/CE services ; Eisai: Consultancy; Acrotech: Consultancy; miRagen: Consultancy; Mallinckrodt: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services . Huntington:AbbVie: Consultancy; Celgene: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Pharmacyclics: Honoraria; Genentech: Consultancy; Bayer: Consultancy, Honoraria. Neparidze:Janssen Scientific Affairs, LLC: Research Funding; Eidos Therapeutics: Other: Member of Independent Diagnostic Committee; MMRF/Synteract: Membership on an entity's Board of Directors or advisory committees. Zeidan:Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a viable treatment option for many cancers but its clinical utility is limited due to the occurrence of graft-versus-host disease (GVHD). Understanding the impact of obesity on immune function has become increasingly important in the setting of the current obesity pandemic. We report here that obesity has a negative and selective impact on acute gut GVHD. Diet-induced obese (DIO) mice exhibited increased gut permeability, endotoxin translocation and radiation-induced gastrointestinal damage. After allo-HSCT, DIO recipients across strains and sex had markedly increased pro-inflammatory cytokines (IL-6, TNF), GVHD biomarker ST2, MHC class II expression and exhibited rapid mortality associated with severe acute gut pathology. This obesity-associated lethal acute gut GVHD was dependent on donor CD4 T cells and occurred even in minor MHC mismatch strain combination in which only a delayed skin chronic GVHD resulted in lean recipients. Pro-inflammatory cytokine blockade targeting both IL-6 and TNF ameliorated obesity-associated acute gut GVHD while maintaining graft-versus-tumor (GVT) effects. Microbiome assessment of DIO mice revealed markedly reduced microbiome diversity and decreased Clostridiaceae abundance. Additionally, DIO mice had a significant increase of GVHD-associated Akkermansia muciniphila before and after allo-HSCT compared to the controls. Extended antibiotic treatment of DIO mice protected from the endotoxin translocation, cytokine storm as well as gut GVHD pathology but did not protect later development of chronic skin GVHD. These results demonstrate that obesity alters the microbiome and imparts differential effects on GVHD following allo-HSCT with decreased survival and this inferior outcome can be pre-empted by combined pro-inflammatory cytokine blockade or antibiotic pretreatment. Disclosures Pai: Roche-Genentech: Employment. Holtan:CSL Behring: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy. Ferrara:ViraCor: Consultancy; Incyte: Consultancy; Kamada: Consultancy; Mallinckrodt: Consultancy; Enlivex: Consultancy; Xenikos: Consultancy; CSL Behring: Consultancy; National Institutes of Health: Research Funding. Levine:Novartis: Honoraria; Kamada: Research Funding; bluebird bio: Consultancy; National Cancer Institute: Research Funding; Incyte: Consultancy, Research Funding; Ironwood: Honoraria; Biogen: Other: non-financial support; Viracor: Patents & Royalties: biomarker patent. Abedi:Abbie: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau; Takeda: Speakers Bureau. Blazar:Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Alpine Immune Sciences, Inc.: Research Funding; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-Founder; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Introduction T cells transduced with a chimeric antigen receptor (CAR) have demonstrated significant clinical efficacy in patients with lymphoid malignancies including relapsed or refractory (r/r) B-lineage acute lymphoblastic leukemia (ALL) or r/r B-cell non-Hodgkin's lymphoma (NHL). Second-generation CAR T cells comprising 4-1BB or CD28 as costimulatory domains have become commercially available for the treatment of patients with CD19+ lymphoid malignancies. However, achievement of durable clinical responses remains a challenge in CAR T cell therapy. Consequently, third-generation CARs incorporating both elements might display short-term efficacy with potent and rapid tumor elimination (CD28) as well as long-term persistence (4-1BB). So far, only two clinical trials employing third-generation CAR T cells have been reported. Both enrolled 31 patients in summary and demonstrated favorable results for third-generation CAR T cells. Here, we report on first results of our investigator-initiated trial (IIT) on third-generation CD19-directed CAR T cells: The Heidelberg CAR trial 1 (HD-CAR-1; NCT03676504; EudraCT 2016-004808-60) is a phase I/II trial initiated in September 2018 with in-house leukapheresis and CAR T cell manufacturing in full compliance with European Good Manufacturing Practice (GMP) guidelines at the University Hospital Heidelberg. Methods Adult and pediatric patients with r/r ALL and patients with r/r chronic lymphocytic leukemia (CLL) or NHL including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL) are treated with autologous T lymphocytes transduced with a CD19 targeting third-generation CAR retroviral vector (RV-SFG.CD19.CD28.4-1BBzeta). The main purpose of HD-CAR-1 is to evaluate safety and feasibility of escalating third-generation CAR T cell doses (1-20×106 transduced cells/m2) after lymphodepletion with fludarabine (30 mg/m2/d on days -4 to -2) cyclophosphamide (500 mg/m2/d on days -4 to -2). Patients are monitored for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and/or other toxicities. In vivo function, survival and anti-tumor efficacy of CAR T cells are assessed. Results To date, 10 patients (3 adult ALL, 2 CLL, 2 MCL, 2 DLBCL, 1 transformed FL) have been enrolled and subjected to leukapheresis. Transduction efficiency of T lymphocytes ranged between 33%-66% and high numbers of transduced CAR T cells were harvested (70-123x106 CAR T cells). No production failure occurred. CAR T cell products were sterile and free from mycoplasma and endotoxins. The copy number per CAR T cell did not exceed 7. Eight patients (2 adult ALL, 2 CLL, 1 MCL, 2 DLBCL, 1 transformed FL) have received the CAR T cell product (6 patients: 106 transduced cells/m2; 2 patients 5×106 transduced cells/m2). No signs of CRS or ICANS > grade 2 have been observed. Only one patient required tocilizumab. No neurological side-effects occurred, even not in patients with involvement of the central nervous system (CNS). In quantitative real-time PCR, CAR T cells were detectable in the peripheral blood (PB) in 3 of 4 analyzed patients or the cerebrospinal fluid (CSF) of an ALL patient with CNS involvement. The CAR T cell frequency reached up to 200,000 copies/µg DNA, in some patients beyond end-of-study at day 90 after CAR T cell administration. Clinical responses to treatment were observed in 6/8 (75%) treated patients so far (2/8 patients have received CAR T cells recently and are not yet evaluable for response). Conclusion Leukapheresis and CAR T cell manufacturing were effective for all patients enrolled in the HD-CAR trial to date. Patients responded clinically to treatment despite low numbers of administered CAR T cells. CAR T cells displayed an excellent safety profile and were detectable for more than 3 months following administration. Furthermore, CAR T cells migrated into different compartments including the CSF in case of CNS involvement. For HD-CAR-1 leukapheresis, CAR T cell manufacturing, CAR T cell administration, patient monitoring and follow-up are performed in-house, providing autarky from transport or production sites outside the University Hospital Heidelberg. Altogether, HD-CAR-1 accounts to clinical evaluation of third-generation CAR T cells that might contribute to long-term CAR T cell persistence, hence improving efficient and durable responses in treated patients. Disclosures Schmitt: Therakos Mallinckrodt: Other: Financial Support . Sellner:Takeda: Employment. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Schmitt:Therakos Mallinckrodt: Other: Financial Support; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia.

Acute lymphoblastic leukemia (ALL) is characterised by recurrent chromosomal abnormalities and genomic microdeletions. Although the incidence of adult ALL increases with age, very few studies have specifically examined the genetic aberrations in adults aged ≥60 years. The objectives of the study were to define the frequency of recurrent chromosomal abnormalities and characterise the copy number profile of ALL in older adults. All patients from UKALL14 and UKALL60+ clinical trials aged ≥60 years at diagnosis of ALL were considered in the study. Cytogenetic and fluorescence in situ hybridisation (FISH) results at diagnosis were used to classify patients in 1 of 5 genetic subgroups - BCR-ABL1, TCF3-PBX1, MLL/KMT2A rearranged (KMT2Ar), low hypodiploidy/near triploidy (HoTr) and high hyperdiploidy (HeH). T-ALL patients were considered separately. B-cell precursor (BCP) ALL patients lacking a primary chromosomal abnormality (B-other ALL - including normal, failed and complex karyotypes, and other non-recurrent chromosomal abnormalities), were selected for extended FISH screening to identify ABL-class fusions, JAK-STAT activating rearrangements and other primary translocations using dual colour break apart probes for ABL1, ABL2, PDGFRB/CSF1R, CRLF2, JAK2, IGH@, ZNF384 and MEF2D. Separately, single nucleotide polymorphism (SNP) arrays were performed to identify copy number abnormalities (CNAs). Multiplex ligation-dependent probe amplification (MLPA) was used to confirm CNAs in 9 specific genes/regions (EBF1, IKZF1, CDKN2A/B, JAK2, PAX5, ETV6, BTG1, RB1, and PAR1). 207 patients aged ≥60 years at diagnosis were identified from UKALL14 (n=91) and UKALL60+ (n=116). Median age was 64 years (range 60-83) and 50% were male. Cytogenetic data at diagnosis were available for 86% (n=178) of patients. Frequencies of individual genetic subgroups are shown in figure (A). Extended FISH screening of B-other ALL cases identified rearrangements in CRLF2 in 5% (8/146), ZNF384 in 2% (3/137) and MEF2D in SNP arrays were performed on 83 patient samples using Illumina CytoSNP 850k (n=52) or Affymetrix Cytoscan HD (n=31) arrays. Recurrent whole chromosome and whole arm abnormalities seen in >3 cases are shown in figure (B) (HeH and HoTr cases (n=10) excluded). Recurrent deletions were identified affecting IKZF1 in 52% (n=43), CDKN2A/B in 45% (n=37), PAX5 in 39% (n=32), RB1 in 22% (n=18), ETV6 in 21% (n=17), EBF1 in 19% (n=16), BTG1 in 12% (n=10), CD200/BTLA in 16% (n=13) and ATP10A in 13% (n=11). The frequency of individual deletions varied by genetic subtypes (Figure (C)). Recurrent novel and less-well described intragenic microdeletions were also seen in COL11A1 (n=11, 13%), MEF2C (n=8, 10%), MBNL1 (n=7, 8%), PTEN (n=6, 7%), NF1 (n=4, 5%), LEMD3 (n=5, 6%), and KDM6A (n=4, 5%). These deletions will need to be validated by a second technique. In this large cohort of older adults with ALL, we confirm that over a quarter of patients harbour BCR-ABL1. HoTr ALL is rare in younger patients but was the second most common specific chromosomal abnormality and good risk genetic subgroups were very uncommon. Additionally, we confirm the rarity of T-cell ALL in older adults ( Disclosures Menne: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. McMillan:Sandoz: Honoraria; Gilead: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; BMS: Honoraria; Pfizer: Honoraria, Research Funding; MSD: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Snowden:Kiadis: Membership on an entity's Board of Directors or advisory committees; Mallinckrodt: Honoraria; Janssen: Honoraria; IDMC: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Papaemmanuil:Celgene: Research Funding. Rowntree:Novartis: Consultancy. Fielding:Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

Introduction: Rituximab-based high-dose therapy (HDT) is frequently prescribed to DLBCL patients (pts) undergoing auto-HCT. However data supporting the benefit of adding R to auto-HCT conditioning are not available. Herein, we report the impact of R-based conditioning on auto-HCT outcomes of DLBCL pts. Methods: Using the Center for International Blood and Marrow Transplant Research registry, 862 adult (≥18 years) DLBCL pts undergoing auto-HCT, between 2003-2017 were included. Analysis was limited to pts receiving BEAM (BCNU, etoposide, cytarabine, melphalan)-based HDT, as R was infrequently used with non-BEAM conditioning regimens. All pts received R-containing chemoimmunotherapy in the frontline setting and had chemosensitive disease prior to HCT. Early chemoimmunotherapy failure (ECitF) was defined as not achieving a complete remission (CR) after frontline chemoimmunotherapy or relapsing within 1 year of initial diagnosis. Primary outcome was overall survival (OS). Secondary outcomes included non-relapse mortality (NRM), relapse, progression-free survival (PFS) and infectious complications within 100 days post-HCT. Results: The study cohort was divided into 2 groups; BEAM (n=667) and R-BEAM (n=195). The baseline characteristics of the 2 cohorts were comparable including age at auto-HCT, disease stage, Karnofsky performance score, extranodal involvement, time from diagnosis to auto-HCT, number of prior therapies, remission status, and ECitF. However, significantly more R-BEAM cohort patients received R as part of last therapy line before auto-HCT (75% vs. 86%; P=0.001). Median follow-up of survivors was 48 (range 1-171) and 64 (range 3-142) months in the BEAM and R-BEAM cohorts, respectively. On univariate analysis, the 4 year cumulative incidence of relapse (41% vs 44%), NRM (11% vs 9%), PFS (48% vs 47%; Figure 1) and OS (58% vs 61%; Figure 2) were similar in the R-BEAM and BEAM groups, respectively (Table 1). On multivariate analysis, no significant difference was seen in OS (HR 0.81; 95% CI 0.81-1.31; P=0.83) or PFS (HR 0.94; 95% CI 0.76-1.18; P=0.61) (Table 1) between the two cohorts. Addition of R had no impact on risk of relapse (HR 0.83; 95% CI 0.65-1.07; P=0.15) or NRM (HR 1.43; 95% CI 0.909-2.26; P=0.12). Variables independently associated with lower OS included older age (HR 3.05; 95% CI 1.81-5.13; P Conclusion: In this large registry analysis of DLBCL pts undergoing auto-HCT, adding R to BEAM conditioning had no impact on transplantation outcomes. Older age, absence of CR and ECitF were associated with inferior survival. Disclosures Majhail: Mallinckrodt: Honoraria; Incyte: Consultancy; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Atara Bio: Consultancy. Sureda:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Gilead: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria; BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Hamadani:ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Otsuka: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau.

Introduction Although a large variety of conditioning regimens are used in autologous hematopoietic stem cell transplantation (autoSCT), including the widely used BEAM (carmustine, etoposide, cytarabine, melphalan), there is no consensus regarding a standard approach. In the context of a carmustine shortage, we replaced it with thiotepa. However, clinical data on the TEAM (thiotepa, etoposide, cytarabine, melphalan) conditioning regimen are sparse and only retrospective. Thus, we designed a multicenter prospective study (NCT02504190) to assess the efficacy and toxicity of a TEAM conditioning regimen. Patients and methods The TEAM regimen consisted of a total dose of thiotepa of 8 mg/kg on day -6; etoposide 100 mg/m2/12h and cytarabine 200 mg/m2/12h (day -5 to -2); melphalan 200 mg/m2 on day-1. Inclusion criteria were the following: age between 18 and 65 years, biopsy-proven Hodgkin or non-Hodgkin lymphoma, HIV seronegative, and first autoSCT. Results Seventy-four male and eighteen female patients with a median age of 53 years (range, 19-65) were included. Karnofsky score was Median time to neutrophil recovery was 12 days (range, 9-48) and to platelet recovery >20 G/L was 13 days (range, 7-197). The most significant regimen-related toxicities were mucositis in 100% of patients (median grade=3, range, 1-4) and diarrhea in 98% of patients (median grade=1, range, 0-3). Other non-hematologic grade 3 adverse events occurred in 17 patients (18%). Blood cultures were positive for Staphyloccocus sp. in 27% patents, other Gram- positive bacteria in 5% and Gram negative in 6%. Central line-associated bloodstream infection occurred in 22 patients (24%). Invasive fungal infection occurred in 3 patients. Four patients required transfer to the intensive care unit. The median length of stay in hospital was 27 days (range, 16-62). At day+100, 89 patients were evaluable for response and all were in CR. Deaths directly attributed to disease progression or relapse occurred in 5 patients. After a median follow-up of 31 months (range, 15-48), the non-relapse mortality (NRM) was 3.3%. Two patients died of infection during aplasia and one patient died 67 days after autoSCT of necrotizing fasciitis. At last follow-up, 17 patients (19%) relapsed, 9 died and 83 were alive. The estimated 3-year overall survival (OS) and progression-free survival (PFS) were 90.2% and 77.2%, respectively. In patients with double expressor diffuse large B-cell lymphoma (n=15), the estimated 3-year OS and PFS were 93% and 73%, respectively. None of the 31 patients with intermediate or high-risk CNS international prognostic index experienced CNS relapse. Conclusion The TEAM conditioning regimen is a safe and valid platform in autoSCT for patients with high-risk or relapsed/refractory lymphoma. Although mucositis and diarrhea were frequent, the NRM was similar to that reported for BEAM conditioning. Most notably, no CNS relapse occurred in patients at intermediate or high-risk of CNS relapse. Disclosures Duléry: Keocyt: Honoraria. Choquet:Keocyt: Honoraria. Di Blasi:Novartis: Honoraria. Malard:Therakos/Mallinckrodt: Honoraria; Janssen: Honoraria; Keocyte: Honoraria; Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria. Coppo:Ablynx/Sanofi: Consultancy; Shire: Consultancy; Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Systemic glucocorticoids are the principal treatment for acute graft-versus-host disease (GVHD), which remains the major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). However, there are no validated biomarkers that measure a patient's response to glucocorticoid therapy, and thus response is evaluated by the change in clinical symptom severity. A major weakness in the predictive power of clinical responses is that changes to all organs are weighted equally even though the major driver of NRM is irreversible damage to the crypts of the GI tract. Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP has been considered a "liquid biopsy" that estimates the damage caused by GVHD to crypts throughout the lower GI tract (Hartwell et al., JCI Insight, 2017; Major-Monfried et al., Blood, 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker for GVHD and might compare favorably to the change in clinical symptoms that measures response to GVHD treatment, which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT, 2009; MacMillan et al., Blood, 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We measured the serum concentrations of REG3α and ST2 before and after systemic therapy for acute GVHD and computed MAPs, the changes in MAPs, and clinical responses for each patient. MAPs of patients who experienced 6 month NRM showed significantly greater increases than MAPs of patients who survived (p=0.0004). In patients whose MAPs at the start of treatment were low (Ann Arbor 1, MAP < 0.141) or intermediate (Ann Arbor 2, 0.141 ≤ MAP ≤ 0.290), 6 month NRM clustered among those who had the greatest increases in MAP after 28 days (Fig 1A,B). In patients with high MAPs at the start of treatment (Ann Arbor 3, MAP > 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). These changes in MAP suggested crossing a single threshold could predict risk of mortality. We found that patients whose MAPs rose above a threshold MAP of 0.290 (5% of Ann Arbor 1, 27% of Ann Arbor 2) had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold (66% of Ann Arbor 3) had a large increases in mortality (Fig 2). When measured at day 28, the MAP was significantly more accurate in predicting NRM than the gold standard of the clinical response, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p We conclude that the MAP is, to our knowledge, the first validated laboratory test to serve as response biomarker for the treatment for acute GVHD and a more accurate predictor of survival than clinical response after four weeks of treatment. The MAP may serve as a novel endpoint and an important complement to changes in clinical symptom severity in future trials of GVHD treatment. Disclosures Srinagesh: National Institutes of Health: Research Funding. Ozbek:Viracor: Patents & Royalties: Biomarker Patent. Ayuk:Novartis: Honoraria, Other: Advisory Board, Research Funding. Aziz:Doris Duke Charitable Foundation: Research Funding. Defilipp:Incyte: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards; Cure Genetics: Consultancy; Humanigen: Consultancy. Hexner:novartis: Research Funding. Kitko:Mallinckrodt: Honoraria; Novartis: Consultancy, Honoraria. Mielke:EBMT/EHA: Other: Travel support; ISCT: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; IACH: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; DGHO: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau. Merli:Sobi: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Bellicum: Consultancy. Pulsipher:Amgen: Other: Lecture; Miltenyi: Research Funding; Bellicum: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Honoraria. Qayed:Bristol-Myers Squibb: Honoraria. Reshef:Pfizer: Consultancy; Magenta: Consultancy; Kite: Consultancy, Research Funding; Atara: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Shire: Research Funding. Levine:Incyte: Consultancy, Research Funding; Biogen: Other: non-financial support; Viracor: Patents & Royalties: biomarker patent; Ironwood: Honoraria; bluebird bio: Consultancy; National Cancer Institute: Research Funding; Novartis: Honoraria; Kamada: Research Funding. Ferrara:National Institutes of Health: Research Funding; ViraCor: Consultancy; Incyte: Consultancy; Kamada: Consultancy; Mallinckrodt: Consultancy; Enlivex: Consultancy; Xenikos: Consultancy; CSL Behring: Consultancy.

Background: Graft-versus-leukemia (GVL) responses after allogeneic hematopoietic cell transplantation (alloHCT) for AML are mediated by alloreactive donor-derived immune effector cells including T lymphocytes and natural killer (NK) cells. The function of NK cells is regulated by inhibitory and activating signals mediated through cell-surface receptors, including KIRs. Various models of NK cell alloreactivity have been associated with post-transplant outcomes, including leukemia relapse. However, these results have varied widely between different investigators employing similar models of NK cell alloreactivity. Assessment of somatic mutations in AML on post-transplant outcomes has not been investigated in the context of KIR profiles. Methods: In this single-institution retrospective cohort study, we investigated KIR haplotypes (haplotype AA vs. Bx [associated with multiple activating KIRs]; Cooley S., et al. Blood. 113:726-732. 2009) in the context of somatic mutations. We included 34 adult patients with AML who underwent alloHCT from a matched related donor from 2006 to 2013. A targeted multi-amplicon deep NGS panel of 79 commonly mutated genes in myeloid neoplasia was performed. Post-HCT outcomes were assessed based on mutational status and KIR haplotype with Kaplan-Meier method and log-rank test. Results: Median age at transplant was 54 (range 31-73). Cytogenetic risk groups were 9% favorable, 56% intermediate, and 35% poor based on 2017 ELN classification. HCT-CI scores included 26% low, 32% intermediate, and 41% high. Disease risk group defined by ASTCT included 71% low, 26% intermediate, and 3% high. Disease status at HCT included 74% CR1 and 26% CR2. Frequencies of somatic mutations prior to HCT were: 21% DNMT3A, 18% IDH2, 9% each for STAG2 and NRAS, 6% each for ASXL1, JAK2, PHF6, RUNX1, TET2, and 3% each for CBL, FLT3, NPM1, and U2AF1. Overall, 53% of patients had at least 1 mutation: 24%, 18%, 9%, and 3% of patients had 1, 2, 3, and 4 mutations, respectively. 41% were carriers of KIR haplotype AA, and 59% were haplotype Bx. Relapse (p=0.40), relapse-free (p=0.33), and overall survival (p=0.30) between haplotypes AA and Bx were not statistically different. However, when considering somatic mutations in the context of KIR haplotypes, those with any somatic mutation (n= 18) present had inferior relapse-free (p=0.002) and overall survival (p=0.002; figures A-B) as compared to those with none. Further assessment of outcomes was then considered for those who had the following poor prognostic mutations (n=12): ASXL1, DNMT3A, FLT3, NRAS, RUNX1, and TET2. KIR haplotype AA with one or more of these mutations was associated with inferior relapse-free (p=0.05) and overall survival (p=0.008). At median follow-up of 83 (range 66-137) months, 38% were alive. Non-relapse mortality rates were 21% (9-36) at 1 year and 29% (15-39) at 3 years. The most common causes of death for all patients were relapse (48%) followed by infection (33%). Conclusion: In presence of somatic mutations, carrying KIR haplotypes Bx was associated with better survival in AML post-alloHCT. The presence of multiple activating KIRs may also help mitigate the worse prognosis associated with some of the more deleterious somatic mutations in AML. These observations may have implications for improving patient risk stratification prior to transplant and optimizing donor selection. Future investigation with larger cohorts interrogating KIR haplotypes in the context of pre-transplant AML somatic mutations on post-transplant outcomes may further elucidate which patients may benefit most from transplant. Disclosures Nazha: Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; MEI: Other: Data monitoring Committee. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Advani:Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Abbvie: Research Funding. Gerds:Sierra Oncology: Research Funding; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Pfizer: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Majhail:Mallinckrodt: Honoraria; Atara Bio: Consultancy; Anthem, Inc.: Consultancy; Nkarta: Consultancy; Incyte: Consultancy. Maciejewski:Novartis: Consultancy; Alexion: Consultancy.

Introduction Intestinal Graft-versus-Host Disease (GvHD), following allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), comes with a high mortality rate and a reduced life-expectancy. In this context, failure to respond to steroid therapy is associated with an absence of further therapeutic options, thereby representing an unmet medical need. A marked reduction in gut microbiota diversity leading to loss of functions was strongly associated with reduced overall survival in GvHD, while a high gut microbiota diversity appears to be protective. Aiming at restoring microbiome functions, Fecal Microbiota Transfer proved to be a promising treatment modality in this challenging clinical situation, with recent studies reporting favorable results in steroid refractory-acute GVHD (SR-aGvHD) patients. Here we report on the use of "MaaT013", a standardized, pooled-donor, high-richness microbiota biotherapeutic, used to treat 8 patients with intestinal-predominant aGvHD. Patients and methods Eight allo-HSCT recipients with steroid-dependent or steroid-refractory gastrointestinal GvHD (classical aGVHD n=3, late-onset aGVHD n=2; aGvHD with overlap syndrome n=3) were treated with the MaaT013 biotherapeutic as part of a compassionate use program. These patients had previously received and failed 1 to 5 lines (median 2.5) of GvHD systemic treatments. MaaT013 microbiota biotherapeutics were provided as a pharmaceutical preparation to hospitals by the developer, "MaaT Pharma". Each patient received 1 to 3 doses (median: 3; total doses administered: 21) of MaaT013, a 150 mL bag, by enema (n=7) or nasogastric tube (n=1). GvHD response was evaluated 7 days after each administration and 28 days after the first dose. Prepared under Good Manufacturing Practices, MaaT013 biotherapeutics are characterized by a highly consistent richness of 455 +/- 3% Operational Taxonomic Units (OTUs) and an Inverse Simpson index greater than 20. Batch release specifications are based on potency (viability), identity (diversity), and purity (microbiological safety testing following regulatory guidelines and proportion of proinflammatory species), ensuring the desired consistency between batches. Results We observed 6/8 positive responses at D28 after first dosing, including 3 Complete Responses (CR), one Very Good Partial Response (VGPR), and 2 Partial Responses (PR). Considering the best GI response achieved, all (8/8) patients experienced at least a PR, with 3 CRs, 2 VGPRs and 3 PRs. The 3 patients with CR were still alive at last follow-up (60 to 192 days after last dosing; median: 115 days) and were able to taper and stop steroids and immunosuppressants without relapse of GI symptoms. Of note, among these 3 patients, mild mouth chronic GvHD symptoms persisted in one patient, and relapse of hematologic malignancy was observed in another patient. Among the 8 treated patients, 5 were still alive at last follow-up (60 to 232 days after last dosing; median: 125 days). The safety of the MaaT013 microbiota biotherapeutic was satisfactory in all patients. One patient developed a possibly related sepsis one day after the third MaaT013 administration. In the latter case, no pathogen was identified in blood cultures, and the patient recovered after a course of antibiotics. Conclusions We herein report for the first time the treatment of 8 patients with steroid-dependent or steroid-refractory intestinal aGvHD using a full ecosystem, standardized, pooled-donor, high-richness biotherapeutic. Overall, 3/8 patients attained a complete response following treatment with the off-the-shelf MaaT013 product, shown to be safe and effective in these immunocompromised patients with severe conditions, warranting further exploration of the full ecosystem microbiota restoration approach. Disclosures Malard: Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria; Therakos/Mallinckrodt: Honoraria; Keocyte: Honoraria; Janssen: Honoraria. Plantamura:MaaT Pharma: Employment. Carter:MaaT Pharma: Employment. Chevallier:Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

It has been proposed that bacteria play a direct role in progression of cutaneous T cell lymphoma (CTCL), although definitive evidence is missing, and the underlying mechanism of how microbes contribute to disease progression remains unknown. The skin of CTCL patients is frequently colonized with Staphylococcus aureus (S. aureus) strains and infections with hospital and community associated strains of S. aureus are a frequent cause of morbidity and mortality among patients with advanced CTCL. Here we provide a comprehensive analysis of the association between CTCL and S. aureus colonization, and use our unique pre-clinical animal model of CTCL to determine the cause-effect relationship between skin-associated S. aureus and CTCL progression. To understand the relationship between bacterial colonization and CTCL we collected skin swabs from active lesions, unaffected skin and nares of CTCL patients to perform S. aureus cultures and 16S rRNA gene sequencing. Skin swabs of psoriasis patients and healthy donors served as controls. The frequency of S. aureus colonization determined by culture based techniques revealed that >65% of advanced stage patients had S. aureus present at lesional/tumor sites, while corresponding sites in patients with psoriasis and in healthy controls rarely had detectable S. aureus. Colonization rates correlated positively with the disease stage. Unbiased, 16s sequencing based analysis of the skin microbiome from advanced CTCL patients revealed that the overall skin microbiome of these patients is distinct from that of healthy individuals and patients with psoriasis. A lower phylogenetic diversity and significantly higher relative abundance of Staphylococcus species was found in CTCL patients. To determine the causal relationship between skin flora and progression of CTCL we used our mouse model of CTCL and assessed disease progression in both conventionally housed specific-pathogen-free (SPF) conditions and in germ free (GF) isolators using a standardized clinical score. The CD4CreSTAT3stopfl/+ mice express a hyper-active STAT3C mutant protein selectively in T lymphocytes and virtually all mutant mice develop T cell infiltration in the epidermis causing skin lesions resembling CTCL, by eight months of age. In contrast to the SPF housed animals, GF mice remained disease free or developed only a mild phenotype (clinical score 1 out of 5) after 11 months of follow-up. Notably, when GF CD4CreSTAT3stopfl/+ mice were transitioned to SPF conditions they all developed advanced disease. Finally, we examined the role of T cell antigen receptor (TCR) signaling in mediating the transformation of T lymphocytes. R26STAT3Cstopfl/+CD4Cre Rag2KO OTII mice express only OVA-specific TCRs. T cells from R26STAT3Cstopfl/+ CD4Cre Stim1fl/fl mice express a normal TCR repertoire, but exhibit defective T cell receptor signaling due to compromised calcium influx. Both strains failed to develop typical skin lesions, suggesting an essential role for TCR interaction with tumor microenvironment and microbial antigens in the pathogenesis of CTCL. In conclusion, we demonstrate a strong correlation between CTCL staging and rates of S. aureus colonization. Our study supports a cause-effect relationship between skin flora and CTCL oncogenesis. We propose that CTCL represents an antigen driven malignancy. Further studies using mono-colonization with single bacterial strains are needed to further interrogate the role of specific bacteria. Disclosures Hymes: Celgene: Consultancy. Odum:Micreos human Health B.V: Consultancy. Geskin:Merck: Other: Supported/Contracted Research; UpToDate: Patents & Royalties: Royalty, Receipt of Intellectual Property Rights / Patent Holder; Mallinckrodt: Consultancy, Honoraria, Other: Supported/Contracted Research; Helsinn: Consultancy, Honoraria, Other: Supported/Contracted Research; Stratpharma: Other: Supported/Contracted Research; Medivir: Consultancy, Honoraria; Medscape: Speakers Bureau; Actelion: Other: Supported/Contracted Research.

Background: Allogeneic transplant (alloHCT) is a curative therapy for patients with acute lymphocytic leukemia (ALL). However, the curative potential of alloHCT is hampered by relapse, which is the major cause of treatment failure. Risk factors for relapse include minimal residual disease (MRD) before or after allogeneic transplantation, patients transplanted in second complete remission or beyond, and reduced intensity conditioning (RIC) regimens. Overall, relapse rates for these patients are in the range of 30% to 50% with the majority of these relapses occurring within the first year after alloHCT. After relapse, the options for disease control are limited and overall survival rates are poor. Currently, there are no standard post-transplant therapy for patients with ALL to reduce the likelihood of relapse. Post alloHCT maintenance approaches may provide time for the graft-versus-leukemia effect to develop, while possibly treating minimal-residual disease, prolonging leukemia-free-survival and decreasing relapse rates. Inotuzumab ozogamicin (INO) is a CD22 monoclonal antibody bound to calicheamicin which has been shown to have significant activity against relapsed ALL. INO has also been used in patients with relapsed / refractory ALL in a phase 3 randomized clinical trial with an overall CR rate of 81% in the INO arm compared to 29% in the standard arm. We hypothesize that low dose post-alloHCT maintenance therapy of INO will be safe and will reduce relapse rates after alloHCT for ALL. Once the appropriate dose has been found, the study will expand to a phase II. Methods: Eligibility included patients aged 16-75 who have undergone all-HCT for CD22+ALL in complete remission, have a high risk for relapse after alloHCT, have adequate graft and organ function, are between day 40 and 100 post-transplant, do not have active grade III/IV GVHD or any active GVHD of the liver, and have no history of VOD. The primary objective of this phase I clinical trial is to define a post-alloHCT maximum tolerated dose (MTD) of INO. Secondary objectives include describing the safety profile of INO post-alloHCT, determining the rate of veno-occlusive disease in this setting, evaluating non-relapse mortality (NRM), disease free survival (DFS) and overall survival (OS) at 1 year post-alloHCT, determining the incidence of myeloid toxicity and secondary graft failure, and determining if INO at these doses are effective at eradicating MRD in this cohort of patients. Pre-treatment tests include a bone marrow biopsy and aspirate to assess disease state and MRD. The trial design is a 3+3 model. The study treatment consists of a total of four 28 day cycles of INO starting at dose level 0 (0.3mg/m2) given on day 1. The first cycle must be initiated between day 40 and 100 after alloHCT. Dose limiting toxicities (DLT) include VOD, prolonged cytopenia (more than 28 days), and death. If there are no DLTs experienced in a cohort, patients may be enrolled in the next highest dose level (Table 1). Patients will be monitored with routine blood work during each cycle. At 1 year after alloHCT, patients will be assessed by restaging bone marrow biopsy and aspirate. Results: As of July 29th, 2019, 8 patients have been treated. One patient went off treatment after 1 cycle of INO (patient choice) and two went off treatment after 3 cycles of INO (patient choice and physician choice). All continued to be followed for safety. We have completed 1 year post-transplant follow up on 4 patients. All patients are alive and in CR. No patients experienced VOD or other DLTs. Significant side effects include thrombocytopenia and neutropenia. The percentage of any aGVHD is 62.5% and the rate of grade III/IV aGVHD is 0%. The percentage of any cGVHD is 42.8%. Patient characteristics are described below (Table 2). Conclusions: In this phase 1 study, INO at doses of 0.3 and 0.4mg/m2 was well tolerated. Thrombocytopenia may be the dose limiting toxicity. The absence of disease recurrence in this small cohort of high risk ALL patients is very promising. Disclosures Metheny: Takeda: Speakers Bureau; Incyte: Speakers Bureau. Majhail:Anthem, Inc.: Consultancy; Mallinckrodt: Honoraria; Nkarta: Consultancy; Incyte: Consultancy; Atara Bio: Consultancy. Malek:Adaptive: Consultancy; Amgen: Speakers Bureau; Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau. Gerds:Roche: Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Imago Biosciences: Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. OffLabel Disclosure: Low dose inotuzuamb ozogamicin in the post-allogeneic transplant setting for patients with ALL.

Background: Axicabtagene Ciloleucel (Axi-cel), the first chimeric antigen receptor T-cell therapy (CAR-T), is approved for refractory/relapsed (R/R) aggressive B-cell lymphoma with the ZUMA-1 trial reporting an objective response in 83% and complete response in 58% patients at a median duration of 27 months (Locke et al. 2019). The availability to successfully deliver CAR-T therapy may be restricted by socio-economic, technical/manufacturing challenges and comorbidities related to aggressive B-cell lymphoma and its treatment. In this intent-to treat (ITT) analysis, we compared the outcomes of patients at our center with R/R B-cell lymphoma who received Axi-cel with those for whom Axi-cel therapy was intended but not administered, in order to identify factors that may limit its use in this population. Methods: We reviewed medical records of consecutive adult patients with R/R diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL) and primary mediastinal B-cell lymphoma (PMBCL) for whom letters of medical necessity (LMN) were sent to request approval for Axi-cel, from March 2018 to May 2019 at our center. Patients were grouped according to whether or not they ultimately received Axi-cel. Baseline characteristics between Axi-cel and Non-Axi-cel group were compared using Fischer's exact test for categorical and Wilcoxon rank sum test for continuous variables. Comorbidities were assessed using the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (Sorror 2013). Time-dependent outcomes were calculated from the date of LMN. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: LMNs were sent for a total of 38 patients, 27 male (71%) with a median age of 63 (range, 25-77) years. 24 patients (63%) had an ECOG PS of 0 or 1 at study entry, while median IPI at diagnosis was 2 (range, 0-5). The most common histology was DLBCL in 25 patients (66%) and 18 (47%) had a germinal center B-cell (GCB) subtype. Four patients had double/triple hit lymphoma. The median number of prior therapies was 4 (range, 2-6) and 21 patients (55%) underwent prior autologous transplant. Forty-seven percent had relapsed and 53% had refractory disease. Patient characteristics are shown in Table 1. Twenty seven (71%) patients received Axi-cel, while 11 patients (29%) were considered candidates for but could not receive Axi-cel. The median time from LMN to cell infusion was 62 (range, 33-248) days. A higher HCT-CI score was observed in the Non-Axi-cel group as compared to the Axi-cel group (median score of 4 vs 2, P=0.04). The two groups did not differ with respect to age, ECOG PS, IPI, number of prior therapies or transplant status. Median follow- up was 5 (range, 2-16) months. At the time of last follow-up, 8 out of 27 patients (30%) in the Axi-cel and 10 out of 11 (91%) in the Non-Axi-cel group had died. The median OS for the entire cohort was 10 months (95% CI, 3.7 to 13), Axi-cel group was 13 months (95% CI, 7.7 to N.R.) and Non-Axi-cel group was 1 month (95% CI, 0.4 to 3.7) (Figure 1). In the Non-Axi-cel group, 3 patients underwent leukapheresis but died prior to infusion (including 1 manufacturing failure and 2 patients with rapid systemic progression). The other 7 deaths in this group were prior to leukapheresis (3 due to sepsis, 3 due to rapid progression including 1 case of active CNS disease and 1 patient could not receive therapy due to caregiver and financial barriers). The one surviving patient in the Non-Axi-cel group had refractory CNS relapse at the time of last follow-up. Conclusions: In this retrospective ITT analysis, approximately one third of patients with R/R aggressive B-cell lymphoma for whom CAR-T therapy was intended were unable to receive it and had extremely short median OS. Patients who could not receive Axi-cel had a higher comorbidity index at the time of decision to proceed with CAR-T therapy; the majority of them died before leukapheresis from disease progression or complications of prior treatment. Improved strategies are needed to safely bridge patients with aggressive B-cell lymphoma intended to receive Axi-cel. New targeted agents such as polatuzumab vedotin and tafasitamab (formerly MOR208) may increase the proportion of patients with aggressive B-cell lymphoma who ultimately receive and benefit from CAR-T therapy. Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau. Gerds:Incyte: Consultancy, Research Funding; Imago Biosciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pfizer: Consultancy; Roche: Research Funding. Majhail:Anthem, Inc.: Consultancy; Incyte: Consultancy; Atara Bio: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding.

Introduction: Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). While transplant-related mortality has decreased substantially over the last few decades, little progress has been made in outcomes and no standard of care exists for patients (pts) with post-alloHCT relapse. In the recent era, several new therapies, including targeted agents, have been approved for ALL, AML, and MDS. We conducted a study to evaluate outcomes of pts with these diseases who relapse after alloHCT in the contemporary period with routine availability of these newer therapeutic agents. Methods: We performed a single-institution retrospective cohort study to review treatment strategies and outcomes of relapse post-alloHCT. We identified 420 adult pts who received their first alloHCT in 2010-2018 using any conditioning regimen or donor source. Overall, 115 (27%) pts experienced relapse (ALL=17/64 [27%], AML=67/242 [28%], MDS=31/114 [27%]) and were included in the analysis. Results: Myeloablative (54%) matched-unrelated donor grafts (50%) were the most common types of HCTs. Peripheral blood stem cell graft (49%) and bone marrow graft (48%) were used the most. Median time from alloHCT to relapse was 5 (range 1-65) months, and 83% of relapses occurred within the first year. Only 24% and 11% of pts experienced grade II-IV acute and any chronic GVHD prior to relapse, respectively. Seven of 17 pts had Philadelphia chromosome positive ALL. Mutation panel was tested in 56% of AML and MDS. Median follow-up period after relapse was 19 (range 6-80) months. The estimated survival after relapse for all diseases was 32% (95% CI 24-41%) at 6 months, 21% (14-28%) at 12 months, and 14% (8-21%) at 24 months (Fig 1). Excluding pts treated with supportive care only, the majority received a combination of different treatments; pts with ALL received median 3 (range 1-5), pts with AML received median 2 (1-4), and pts with MDS received median 1 (1-3) agent. Targeted therapies used for ALL pts included blinatumomab (n=5) and BCR-ABL targeting tyrosine kinase inhibitors with (n=2) or without (n=4) chemotherapy. Among AML pts, targeted agents were used in 15 pts (sorafenib [n=7], 2 each with enasidenib, gemtuzumab ozagamicin, and ivosidenib, and 1 each with venetoclax and SEL24 [a dual pan-PIM/FLT3 inhibitor]). One pt each was treated with enasidenib, gemtuzumab ozagamicin, and PTC299 (an inhibitor of VEGFA mRNA translation) followed by SEL24 for MDS. Second alloHCTs (n=5) were performed median 5 (range 1-16) months after first HCT and median 1 month (range 0-5 months) after relapse. Two pts received no bridging therapy, while 3 pts received chemotherapy (n=2) or donor lymphocyte infusions (DLI [n=1]) prior to the second transplant. DLI without second transplant was used in 25 pts at a median of 20 (range 3-18) months after ALL relapse, median 2 (range 0-13) months after AML relapse, and median 3 (range 1-5) months after MDS relapse. Following DLI, 53% pts developed GVHD. Targeted therapy was associated with a trend towards better survival compared to other therapies (Fig 2, HR 0.65, 95% CI 0.41-1.03, p=0.06). Based on multivariable analysis, matched unrelated (vs. matched sibling, HR 1.70, p=0.027) or haploidentical donor grafts (HR 2.69, p=0.003), presence of grade II-IV acute GVHD before relapse (HR 2.46, p12 months, HR 6.34, p12 months, HR 3.16, p=0.005) were adverse prognostic features with survival after relapse post-alloHCT (Table 1). Conclusion: Outcomes of pts with ALL, AML, and MDS who relapse following alloHCT remain poor in the contemporary era when several newer therapies, including targeted agents, are available for their treatment. Targeted agents were used only in a minority of post-alloHCT relapses likely due to the combination of pt status, absence of the target mutation, the agents' availability, and other factors. Pts who developed grade II-IV acute GVHD and had shorter "disease-free" duration from unrelated or haploidentical donor grafts had the significantly shorter survival following relapse. More innovative treatment strategies to prevent and treat relapse post-alloHCT are needed. Disclosures Hill: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celegene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding. Anwer:In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Majhail:Atara Bio: Consultancy; Anthem, Inc.: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria; Incyte: Consultancy.

Introduction: Systemic steroids with their strong immunosuppressive and anti-inflammatory effects are the current gold standard for initial treatment of the graft-versus-host disease (GvHD). But, the effectiveness of high-dose steroids comes along with an increased susceptibility to infections and other secondary malignancies. Extracorporeal photophoresis (ECP), an immunotherapeutic therapy, is currently being used as a clinically well-established second-line treatment for GvHD. Contrary to steroid treatment, there is no clinical data showing that ECP is associated with an increased risk of infection. However, the exact mechanism of action how ECP preserves the anti-viral and anti-leukemic effects on the cellular level has not been discovered yet. Materials and methods: Thirty-four patients with steroid-refractory/resistant aGvHD ≥ II and moderate to severe cGvHD were treated with ECP at the University Hospitals in Heidelberg, Greifswald in Germany and Chaim Sheba Medical Center in Israel. A comprehensive analysis of cell subsets was performed using multi-parametric flow cytometry. Additionally, the quantity and quality of CMV-specific T cells was determined by tetramer staining and interferon-γ enzyme-linked immunospot assay. The NK activity in terms of killing functionality and cytokine release was analyzed by intracellular cytokine staining and chromium-51 release assay, respectively. The proliferative capacity of effector cells was determined by carboxyfluorescein succinimidyl ester (CFSE) staining. Results: ECP therapy was effective with an overall response rate of 75% for patients with aGvHD (x/y) and 78% (x/y) for patients with cGvHD. Of note, all patients showed neither the increased susceptibility to infections nor the reactivation of CMV nor the tumor relapse. Overall, the frequency of well-established protective cell subsets in terms of cytotoxic CD8+ T cells, CD4+CD8+ T cells, γδ T cells, NK cells and NKT cells remained constant under the ECP therapy. Specifically, no significant influence of ECP therapy on the CD56dimCD57+NKG2C+ NK cells, a specialized anti-viral/tumor population, and the CMV+CD8+ T cells could be observed. The further phenotyping of CMV+CD8+ T cells showed that CD45RA+CCR7-CMV+CD8+ TE cells and CD45RA-CCR7-CMV+CD8+ TEM cells could keep stable under the ECP therapy. Besides these, priming, differentiation and maturation of NK cells through upregulation of CD57 by ECP therapy bridged the T-cell-deficient period after HSCT in order to control the viral infections and eliminate the residual malignant cells. Moreover, ECP could reduce the CD62L expression on TE population which not only facilitates the hematopoietic engraftment and contributes to the phenotypic and functional T cell reconstitution after transplantation without causing GvHD, but also enhances the functional immune reconstitution against tumor and viral antigens. Functionally, neither IFN-g released by virus specific T cells nor production of TNF-a and IFN-g by NK cells in response to K562 cells was hampered by ECP. Of note, the functions of NK cells in terms of the MFI of cytokines and the polyfunctionality of NK cells were stable under ECP treatment. Additionally, the proliferation of NK cells, CD4+ T cells and CD8+ T cells providing an expanded pool of effector cells against the pathogens was not hampered by ECP therapy as well. Conclusions: ECP therapy constitutes an effective strategy to treat GvHD. In addition, ECP appears to be a safe therapy compared to continued steroid use. Our current results suggest that ECP allows to maintain immunity against infections and tumors. Disclosures Schönland: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Dreger:Neovii, Riemser: Research Funding; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Schmitt:Therakos Mallinckrodt: Other: Financial Support .

Although alloHCT is an accepted salvage treatment in defined settings of poor-risk NHL, its potential benefit in these indications remains controversial because virtually all published studies are uncontrolled and restricted to patients who were actually able to undergo transplantation. Here, we aimed at assessing the impact of alloHCT by measuring its outcome from the time of donor search indication rather than from the time of transplant, thereby taking into account those patients who fail to proceed to allografting for any reason. Study design and patients : In a single centre retrospective analysis, course and outcome of all patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PTCL) who were considered as having an alloHCT indication according to accepted guidelines between 2004 and 2018 were recorded. Primary endpoint was overall survival (OS) from start of donor search. A key secondary endpoint was comparison of OS from the 3-month landmark by donor availability. Accepted donors were matched related donors (MRD), 10/10 matched unrelated donors (MUD), 9/10 compatible unrelated donors (MMUD), and mismatched related donors (MMRD), with haplo donors being used at our institution only since 2014. Results : Altogether a donor search was initiated in 187 patients (DLBCL 32%, FL 17%, MCL 23%, PTCL 28%). Median age was 54 (19-69) years with 74% being male. Within a median time from diagnosis to search initiation of 1.1 (0.1-19) years, a median of 4 (1-9) treatment lines had been administered, including an autoHCT in 50%. 69% of the patients had active disease at the time of search initiation. Only 2 patients underwent donor search in 1st remission (for Richter transformation and hepatosplenic T cell lymphoma, respectively). With a median follow-up of 6.2 (0.6-15.9) years, OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 25%, 44%, 52%, and 50%, respectively (Fig 1). 171 patients (91%) were alive at the 3-month landmark. For these, an MRD (20%), MUD (44%), MMUD (25%), or MMRD (7%) could be identified in 96% of the cases. AlloHCT was performed in 72% of all 187 patients, and in 79% of the patients alive at the 3-month landmark, with a significantly lower rate in DLBCL (69%) compared to the other entities. In patients who were actually transplanted, 5-year OS from landmark for DLBCL, FL, MCL and PTCL was 32%, 63%, 62%, and 62%, respectively, whereas only 5 of the 36 patients (14%) alive at the 3-month landmark not undergoing alloHCT for any reason survived long term. Due to the low rate of unsuccessful searches, donor vs no-donor landmark survival analyses were not possible. Conclusions: Despite donor search now being successful in virtually all cases, 20-30% of those patients intended for alloHCT for NHL will never proceed to transplant. However, long-term OS by ITT does not seem substantially worse than alloHCT outcome observed in registry studies restricted to patients actually transplanted, with DLBCL appearing inferior to the other 3 entities. Patients surviving the 3-month landmark but not undergoing alloHCT for any reason have a poor outlook. These results may serve as benchmark for novel therapeutic options entering the NHL treatment landscape. Disclosures Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.

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 > 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

Background: There is a large unmet need for relapsed/refractory T cell lymphoma. For patients (pts) with recurrent disease, the efficacy of salvage and autologous stem cell transplant (if feasible) is moderate and the 3-year overall survival is less than 30%. Romidepsin is a histone deacetylase inhibitor (HDACi) that is FDA approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma. Immune checkpoint blockade (CPB) of PD1/PDL-1 has been successful in many malignancies. In a recent report, PDL1 expression was observed 5-17% of tumor cells and 43%-57% in stromal histiocytes in PTCL-NOS or AITL. A phase II single agent study of the PD1 monoclonal antibody (mAB) pembrolizumab in PTCL demonstrated modest responses (Barta et.al). In addition, PTCL often carries multiple gene mutations in epigenetic modifier genes (TET2, IDH2, DNMT3A) and others (RHOA, FYN) that may impair immunogenicity and promote immune escape. This was the rationale for combining HDACi and CPB. We report this single center, single arm, nonrandomized trial of pembrolizumab in combination with romidepsin in subjects with relapsed or refractory PTCL that have failed to achieve a complete response or progressed after at least one systemic treatment regimen (NCT03278782). METHODS: This is a phase I/II study to examine the safety and efficacy of pembrolizumab 200 mg fixed dose administered every 3 weeks (Q3W) in combination with romidepsin. The safety of the combination was tested in the lead-in phase I study with a strategy of dose de-escalation, keeping the starting dose of romidepsin 14 mg/m2 on days 1 and 8. This eventually became the dosing for the phase II study. Adverse events were monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary objectives of the trial are to determine safety, tolerability, and overall response rate (ORR) of the combination. Secondary objectives include further analysis of various efficacy parameters [complete remission rate (CRR), progression free survival (PFS), overall survival(OS) and duration of response (DOR)]. Response assessment was performed utilizing Lugano Revised Response Criteria, and PD-L1 expression assessed by immunohistochemistry and exploratory analysis of targeted Next Generation Sequencing in the primary lymphoma tissue. Changes in peripheral blood T-cell repertoire were assessed primarily by flow cytometry. RESULTS: 15 pts were evaluable for the primary endpoint (demographics in figure 1). The phase I part was expanded from 3 to 6 pts, because of a dose limiting toxicity (DLT) of hypotension and renal insufficiency which resolved. The phase II is ongoing with 9 pts enrolled. The overall response rate was 44%; 3 pts. achieved a complete response and 2 achieved PR. The median follow-up was 6 months (3 weeks- 12 months). The 3 complete responders remain in remission > 10 months. One patient with refractory ALCL who achieved CR after 3 cycles is now 6 months post Haplo-identical transplant. Nausea and vomiting was the most common adverse event (Grade 1/2-). The most common ≥ grade 3 treatment-emergent adverse events were Nausea/vomiting and fatigue ( n =1 and n= 2). Two patients experienced hyperprogression within the first 10 days after the treatment. Correlative studies including NGS, expression of PD-L1, CD4+ T lymphocytes counts are in progress. CONCLUSIONS: The combination of Romidepsin and Pembrolizumab has demonstrated acceptable safety and early encouraging results. Table. Disclosures Iyer: Spectrum: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Trillium Therapeutics: Research Funding; Rhizen: Research Funding. Neelapu:BMS: Research Funding; Allogene: Consultancy; Acerta: Research Funding; Incyte: Consultancy; Cell Medica: Consultancy; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Karus: Research Funding; Cellectis: Research Funding; Poseida: Research Funding. Nieto:Affimed: Research Funding; Novartis: Research Funding; Astra-Zeneca: Research Funding; Affimed: Consultancy. Westin:Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; 47 Inc: Research Funding; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:Bayer: Honoraria; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding. Duvic:Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau; PleXus Communications: Speakers Bureau; Therakos: Speakers Bureau; Eisai: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Jonathan Wood & Assoc.: Speakers Bureau; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Soligenetics: Research Funding; Evidera, Inc.: Consultancy; Guidepoint Global: Consultancy; Cell Medica Inc.: Consultancy; UT MD Anderson Cancer Center: Employment; Shape: Research Funding; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spatz Foundation: Research Funding; Oncoceuticals: Research Funding; Millennium (formerly Takeda): Research Funding; Allos: Research Funding; Rhizen Pharma: Research Funding; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; Cell Medica Ltd.: Honoraria; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Tetralogic: Research Funding. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding. OffLabel Disclosure: Pembrolizumab in T cell lymphoma

Five years after getting BioVectra in its acquisition of the drugmaker Questcor, Mallinckrodt is selling the Canadian drug services company to the investment firm H.I.G. Capital for $250 million. The deal was announced a day after Mallinckrodt settled an Ohio opioid addiction case, while others are scheduled to go to trial next month. BioVectra, headquartered in Charlottetown, Prince Edward Island, began in 1970 as a manufacturer of clinical reagents. Questcor bought it in 2013 for $50 million, and Mallinckrodt acquired Questcor the following year. BioVectra supplies the active pharmaceutical ingredient in Questcor’s H.P. Acthar Gel, a topical hormone treatment for autoimmune diseases. In recent years, BioVectra has expanded a fledgling microbial fermentation business with the purchase of a factory in Windsor, Nova Scotia. It has invested over $60 million in the site and aims to grow biologics to at least 25% of its business. The firm reported sales of $56

Mallinckrodt Chemical Works (MCW) was the earliest uranium processing facility in the United States, beginning in 1942. The 2,514 workers included in the epidemiologic study were exposed to external gamma radiation, medical x-rays, internal radiation from intakes of pitchblende ore and its extracted radionuclides (mainly uranium isotopes and radium-226), and ambient levels of radon and its progeny [1].

BACKGROUND Studies have compared sealing effects of the newly developed tapered endotracheal tube cuff with the conventional cylindrical cuff. In this study, we compared the difference between cuffs with regard to the increase in intracuff pressure during nitrous oxide (N(2)O) exposure. METHODS Two types of cuffs were studied using a model trachea connected to a mechanical test lung: high-volume, low-pressure cuff (Mallinckrodt Hi-Lo(TM), Covidien, Dublin, Ireland) and tapered cuff (Mallinckrodt TaperGuardTM, Covidien). The intracuff pressure was set at 20 cm H(2)O, and the increase in pressure was measured during mechanical ventilation using 66% N(2)O. Intracuff pressures were recorded after 5, 10, 15, 30, 45, and 60 minutes of exposure to N(2)O. RESULTS The intracuff pressure recorded during the first 15 minutes of N(2)O exposure in high-volume, low-pressure cuffs was significantly higher than tapered cuffs (2-way repeated-measures analysis of variance, P < 0.0001 for internal diameters [IDs] 7.0 and 7.5 mm, P = 0.0004 for ID 8.0 mm, P = 0.0013 for ID 8.5 mm), and there were also statistically significant differences regarding interaction of time and cuff type (P < 0.0001 for IDs 7.0, 7.5, 8.0, and 8.5 mm). The difference in mean cuff pressures among groups after 10 minutes of N(2)O exposure was -18.5 (SE, 1.4; 99% confidence interval, -22.8 to -14.2; P < 0.0001) for ID 7.5 mm. Tapered endotracheal tube cuffs sealed the trachea with fewer dimples on the carina side of the cuff. Dimples on the cuff surface probably increase the surface for N(2)O diffusion. Therefore, fewer dimples result in a smaller surface area through which N(2)O can diffuse. CONCLUSION During general anesthesia with N(2)O, the intracuff pressure of tapered endotracheal tube cuffs did not increase as rapidly as it did in conventional high-volume, low-pressure cuffs. The pressure in both types of cuffs increased rapidly when exposed to 66% N(2)O, and hence continuous or frequent monitoring is recommended.

Kay H. Vydareny, MD, is Associate Executive Director for Diagnostic Radiology at the American Board of Radiology; E. Stephen Amis Jr, MD, is Professor and University Chair in the Department of Radiology, Albert Einstein College of Medicine/Montefiore; Gary J. Becker, MD, is Executive Director of the American Board of Radiology; James P. Borgstede, MD, is a Vice Chairman and Professor at the University of Colorado Hospital; Dorothy I. Bulas, MD, is in the Division of Diagnostic Imaging and Radiology, Children’s National Medical Center, and Professor of Radiology and Pediatrics at the George Washington University Medical Center; Jannette Collins, MD, is Ben Felson Professor and Chair of Radiology in the Department of Radiology, University of Cincinnati Medical Center; Lawrence P. Davis, MD, is Vice Chair and Program Director in the Department of Radiology, Long Island Jewish Medical Center; Jennifer E. Gould, MD, is Program Director and Assistant Professor of Radiology at the Mallinckrodt Institute of Radiology, Washington University; Jason Itri, MD, PhD, is Assistant Professor and Director of Quality and Safety in the Department of Radiology, University of Pittsburgh; Jeanne M. LaBerge, MD, is Professor of Radiology and Director of the VIR Fellowship Program at the University of California, San Francisco, School of Medicine; Lynne Meyer, PhD, MPH, is Executive Director for the Resident Committee of Diagnostic Radiology at the Accreditation Council for Graduate Medical Education; Duane G. Mezwa, MD, is Chair of Diagnostic Radiology and Molecular Imaging at the Oakland University-William Beaumont School of Medicine; Richard L. Morin, PhD, is Brooks-Hollern Professor in the Department of Radiology at the Mayo School of Graduate Medical Education; Steven P. Nestler, PhD, is Senior Consultant in the Education Department at the Accreditation Council for Graduate Medical Education; and Robert Zimmerman, MD, is Vice Chair for Education and Professor of Radiology at Weill Cornell Medical College.

BACKGROUND: Aspiration of colonized oropharyngeal secretions is a major factor in the pathogenesis of ventilator-associated pneumonia (VAP). A tapered-cuff endotracheal tube (ETT) has been demonstrated to reduce aspiration around the cuff. Whether these properties are efficacious in reducing VAP is not known. METHODS: This 2-period, investigator-initiated observational study was designed to assess the efficacy of a tapered-cuff ETT to reduce the VAP rate. All intubated, mechanically ventilated patients over the age of 18 were included. During the baseline period a standard, barrel-shaped-cuff ETT (Mallinckrodt Hi-Lo) was used. All ETTs throughout the hospital were then replaced with a tapered-cuff ETT (TaperGuard). The primary outcome variable was the incidence of VAP per 1,000 ventilator days. RESULTS: We included 2,849 subjects, encompassing 15,250 ventilator days. The mean SD monthly VAP rate was 3.29 1.79/ 1,000 ventilator days in the standard-cuff group and 2.77 2.00/1,000 ventilator days in the tapered-cuff group (P .65). While adherence to the VAP prevention bundle was high throughout the study, bundle adherence was significantly higher during the standard-cuff period (96.5 2.7%) than in the tapered-cuff period (90.3 3.5%, P .01). CONCLUSIONS: In the setting of a VAP rate very near the average of ICUs in the United States, and where there was high adherence to a VAP prevention bundle, the use of a tapered-cuff ETT was not associated with a reduction in the

Sporadic adrenomedullary hyperplasia may mimic pheochromocytoma. Laparoscopic adrenalectomy is recommended for the management of this entity., Background and Objectives: Sporadic adrenomedullary hyperplasia (AMH) is characterized by a medical history of hypertension, excessive catecholamine excretion, and histomorphometric evidence of increased adrenomedullary tissue relative to the cortex in the absence of multiple endocrine neoplasia. The aim of this study was to perform a retrospective analysis of patients after laparoscopic adrenalectomy for AMH, an early form of sporadic adrenal medulla–related endocrine hypertension, as well as to update our understanding of the clinical features and management of this clinicomorphologic entity. Methods: We performed a retrospective review of the medical records of patients operated on between 2007 and 2011 at Reina Sofia University General Hospital, Murcia, Spain, with a diagnosis of AMH. Patient characteristics, diagnostic studies, surgical procedures, and histologic findings were analyzed. Results: Seven hypertensive patients with intermittent adrenergic crises were found to have AMH (3 men and 4 women; mean age, 44 years). Catecholamine levels were increased. Radiologic studies included 1 or more of the following: magnetic resonance imaging, computed tomography, positron emission tomography imaging with fluorodeoxyglucose, dihydroxyphenylalanine–positron emission tomography–computed tomography, Octreoscan (Mallinckrodt Pharmaceuticals, St. Louis, MO, USA) and 123I-metaiodobenzylguanidine scintigraphy. Laparoscopic adrenalectomy was performed in all cases. One patient underwent bilateral adrenalectomy because of persistent symptomatology after unilateral adrenalectomy. Surgery was associated with normalization of catecholamine hypersecretion and complete disappearance of symptoms, as well as the reduction or abstention of antihypertensive therapy. Conclusions: Sporadic AMH is a clinicomorphologic entity that may mimic pheochromocytoma clinically. Recent advances in diagnostic and surgical methods have changed the management and outcome of this unusual disease. Laparoscopic adrenalectomy may be recommended as the gold standard in the treatment of this entity. Definitive diagnosis is provided by histologic study.

Over the past decade, counselors have become keenly interested in how individuals develop different adult attachment styles and perfectionism dimensions over the life span (e.g., Brennan, Clark, & Shaver, 1998; Wei, Heppner, Russell, & Young, 2006). Stoeber and Otto (2006) and another author (e.g., Hamachek, 1978) have argued that two formations of perfectionism can be identified: maladaptive perfectionism and adaptive perfectionism. Maladaptive perfectionism is associated with extreme self-criticalness and a persistent sense of failure to live up to personal high standards of performance. Conversely, adaptive perfectionism is associated with a sense of individual striving toward personal high standards without a crippling self-critical voice when these elevated standards are not met. A considerable body of research has developed supporting the multidimensional nature of perfectionism. For instance, both the standards and self-criticism dimensions of perfectionism can be measured by the Standards and Discrepancy subscales of the Almost Perfection Scale-Revised (APS-R; Slaney, Rice, Mobley, Trippi, & Ashby, 2001). When partialling out the overlap between the two dimensions, as noted in recent studies (e.g., Ashby, Dickinson, Gnilka, & Noble, 2011; Ashby, Noble, & Gnilka, 2012; Rice, Leever, Christopher, & Porter, 2006; Rice, Tucker, & Desmond, 2008), the high standards dimension is positively associated with multiple positive outcomes, such as lower levels of depressive symptoms, a decreased sense of hopelessness, increased levels of hope, and a higher sense of life satisfaction. On the other hand, the discrepancy dimension is associated with multiple negative outcomes, such as increased levels of depressive symptoms, increased feelings of hopelessness, lower levels of self-esteem, and higher usage of unhelpful coping strategies (Dunkley, Sanislow, Grilo, & McGlashan, 2006; Dunkley, Zuroff, & Blankstein, 2003; Rice, Ashby, & Slaney, 1998; Rice et al., 2006). While researchers have investigated how various perfectionism dimensions are related to various psychological outcomes, investigators are starting to explore the precursors to the development of perfectionism. One promising construct that has gained increased attention is adult attachment. Similar to perfectionism, considerable research notes that adult attachment can be viewed in two dimensions: attachment anxiety and attachment avoidance (Brennan et al., 1998). Adults with high levels of adult attachment anxiety report feelings of rejection and abandonment and can easily feel overwhelmed by negative emotions; in addition, adults with high levels of adult attachment avoidance may feel uneasy with being close to others and have a high need for independence and self-reliance. Adults who report low levels of both anxiety and avoidance are considered to have the ability for more stable and secure attachments with others (Besser & Priel, 2003; Brenan et al., 1998; Lopez & Brennan, 2000). Both attachment anxiety and attachment avoidance can be measured by the Anxiety and Avoidance subscales of the Experiences in Close Relationship Questionnaire-Revised (ECR-R; Fraley, Waller, & Brennan, 2000). Higher levels of either or both attachment anxiety and attachment avoidance are associated with various psychological outcomes, including low self-confidence (Lopez & Gormley, 2002), ineffective coping strategies (Lopez & Gormley, 2002), low self-esteem (Rice & Lopez, 2004), and high levels of depression (Wei, Mallinckrodt, Russell, & Abraham, 2004; Wei et al., 2006). Over the past decade, only a few studies have used more complex models to explain the relationships between attachment, perfectionism, and psychological outcome. In one of the first studies investigating the relationship between attachment and perfectionism, Rice and Mirzadeh (2000) concluded that maladaptive perfectionism and insecure parental attachment were related, whereas adaptive perfectionism and secure parental attachment were related. …

Traumatic luxation or subluxation of the cervical vertebrae can cause unstable spinal injuries, such trauma has the potential to disrupt the subarachnoid blood vessel and produce hematoma that will compress the spinal cord. Being located in the soft tissue of the marrow that hematoma will be impossible to examine through conventional radiography. A 1 year, Rottweiler dog was brought for radiography examination presenting neck pain and tetra paresis. Radiographic exposures were done in lateral and dorso-ventral recumbency to examine the cervical vertebrae. Cervical myelography was done using contrast agent Optiray 350 (Ioversol, manufactured by Mallinckrodt Pharmaceuticals), 0,5 ml/kg. The contrast agent was injected in the cervical area in occipito-athloidian space. Conventional radiography shows a normal aspect of the cervical vertebrae without any sign of fractures. It was observed a narrowing of the space between occipital and atlas. Puncture of the cervical area of the spine show no cerebrospinal fluid. Injection of the contrast agent was done easily. Myelography was performed at intervals of 2 minutes. Myelography revealed a filling defect in the dorsal part of the marrow caudally of the atlas that corresponded to a hematoma. Myelography is useful in determining the filling defects due to blood clot formation on the marrow after a posttraumatic event. Â

On reading the article by Dr. Yeoh and colleagues entitled “Lung Injury from Use of a Suction Catheter Via the DoubleLumen Tube,” we would like to share our experiences of a similar case and emphasize the preventive measures that can be taken to reduce suction-catheter-related complications. A previously healthy 49-year-old man (weight 63 kg; height 170 cm) presented with patchy consolidation in the right lower lobe and was scheduled for video-assisted thoracoscopic surgery (VATS). After induction of anesthesia with IV propofol, fentanyl, and rocuronium, the trachea was intubated with a 35-Fr left-sided double-lumen tube (DLT) (Mallinckrodt, Covidien, Mansfield, MA). Subsequently, the patient was positioned in the left lateral position, and the right lung was isolated after the tube position was rechecked via fiberoptic bronchoscopy. An endobronchial suction catheter was applied ( 20 kPa suction), via the proximal end of the tracheal lumen of the DLT, to expedite the collapse of the operated lung. After the insertion of the thoracoscope by the surgeon and confirmation

Catalytic and photocatalytic 2-propanol dehydration was carried out by using a supported Keggin heteropolyacid H3PW12O40 (PW12). Binary materials were prepared by impregnation and/or solvothermal treatment by using commercial supports: SiO2 (Mallinckrodt), TiO2 (Evonik P25) and multiwall carbon nanotubes (Sunnano) or home solvothermically prepared SiO2 and TiO2. All the materials have been characterized by X-ray diffraction (XRD), scanning electron microscopy observations (SEM) coupled with EDX microanalysis, specific surface area measurements, diffuse reflectance spectroscopy (DRS), FTIR and Raman spectroscopy. (Photo)catalytic 2-propanol dehydration was studied in gas-solid regime by using a continuous (photo)reactor working at atmospheric pressure and 80 °C. FTIR spectra of the gas-phase over the PW12-support composites, where 2-propanol had been previously adsorbed, were recorded. Propene and diisopropyl ether were the main reaction products. For the continuous photo-assisted runs the reactor was also illuminated with UV light. The apparent activation energy of 2-propanol catalytic and photocatalytic dehydration was determined in the range 60–120 °C. The irradiance increased significantly the dehydration reaction rate. Important differences were observed between the different supported materials. The Keggin heteropolyacid species played a key role both for the catalytic and the photo-assisted catalytic reactions; in fact, the acidity of the cluster accounts for the catalytic role, whereas both the acidity of the cluster and the oxidant ability of PW12 were responsible for the increase of the reaction rate of the photo-assisted catalytic reaction. Moreover, the photo-generated electrons on the solid semiconductor conduction band can account for a further increase of the reaction rate, when the heteropolyacid was supported on TiO2. Formation of a pseudo-liquid phase played an important role to determine the (photo)activity.

From the Division of Vascular and Interventional Radiology, Jefferson Radiology, Hartford Hospital, 85 Seymour St, Ste 200, Hartford, CT 06106 (P.C.M.); Department of Radiology, Boston Healthcare System, VAMC Boston, Massachusetts (C.J.G.); Department of Medical Imaging, Scarborough General Hospital, Richmond Hill, Ontario, Canada (S.K.); Department of Radiology, GI/GU Division, Massachusetts General Hospital, Boston, Massachusetts (D.A.G.); Department of Radiology and Radiologic Sciences, Uniformed Services University of the Health Sciences and Department of Radiology, National Naval Medical Center, Bethesda, Maryland (D.L.M.); RADIA, Everett, Washington (R.B.O.); Department of Radiology, University of Florida, Gainesville, Florida (D.W.P.); Department of Medical Imaging, Division of Vascular and Interventional Radiology, University of Toronto, University Health Network, Toronto, Ontario, Canada (D.K.R.); Department of Interventional Radiology, The Reading Hospital and Medical Center, West Reading, Pennsylvania (D.S.); Radiology Associates of Central Florida, Mt Dora, Florida (M.S.S.); Mallinckrodt Institute of Radiology, St Louis, Missouri (D.A.Z.); and Geisinger System Radiology, Geisinger Health System, Danville, Pennsylvania (J.F.C.). Received November 18, 2008; accepted November 24, 2008. Address correspondence to P.C.M.; E-mail: pmalloy@ jeffersonradiology.com

Excipient selection is key to product development because it affects their processability and physical properties, which ultimately affect the quality attributes of the pharmaceutical product.To study how the flowability of lubricated formulations affects acetaminophen (APAP) homogeneity.The formulations studied here contain one of two types of cellulose (Avicel 102 or Ceollus KG-802), one of three grades of Mallinckrodt APAP (fine, semi-fine, or micronized), lactose (Fast-Flo) and magnesium stearate. These components are mixed in a 300-liter bin blender. Blend flowability is assessed with the Gravitational Displacement Rheometer. APAP homogeneity is assessed with off-line NIR.Excluding blends dominated by segregation, there is a trend between APAP homogeneity and blend flow index. Blend flowability is affected by the type of microcrystalline cellulose and by the APAP grade.The preliminary results suggest that the methodology used in this paper is adequate to study of the effect of blend flow index on APAP homogeneity.

Mallinckrodt Baker, Inc. (MBI) has developed an aqueous fluoride-based cleaner (AFC1) that shows improved ultra-low k (ULK) and cobalt tungsten phosphide (CoWP) compatibility over dilute hydrofluoric acid (dHF) and a simple solvent based cleaner (SFC1). Performance and compatibility testing was performed with beaker tests at MBI and on 45 nm wafers by GLOBALFOUNDRIES. Our results indicate that AFC1 may be a good alternative to dHF for future Cu technologies.

Purpose: During oral fiberoptic intubation, advancement of an endotracheal tube (ETT) into the trachea is occasionally impeded by laryngeal structures. The curved flex tip Parker ETT has been shown to improve the likelihood of successful advancement as opposed to a standard ETT that is advanced in neutral orientation. However, a Parker tube has not been compared to a standard ETT oriented 90° counterclockwise from the neutral position. We hypothesize that fiber-optically-guided advancement of an ETT into the trachea will be more successful when using a Parker tube than a 90° counterclockwise-oriented standard ETT. Methods: This unblinded, randomized controlled trial compares the rate of successful advancement of a fiberoptically-guided endotracheal tube into the trachea. Two groups of randomly assigned patients with non-difficult airways are compared: a Parker flex-tip tube (Parker Group; n = 57) versus a standard ETT oriented 90° counterclockwise (Standard Group; n = 58). Our primary outcome is the first pass success rate of advanceing the ETT into the trachea. Results: First pass success occurred in 48 of 57 (84%) patients in the Parker Group vs. 39 of 58 (67%) of patients in the Standard Group (p = 0.0497). Conclusion: When advancing an ETT over an oral fiberoptic scope and into the trachea, a Parker curved flex tip ETT is statistically more likely to be placed successfully on the first pass than is a standard ETT oriented 90° counterclockwise.

Three counseling psychology colleagues (Lichtenberg, 2011; Mallinckrodt, 2011; Murdock, 2011 [all this issue]) provide differing perspectives about the findings from our target article (Scheel et al., 2011) of the decline of published counseling-related research in our major journals. In this rejoinder we respond to each author’s viewpoints concerning the decline.We reiterate our explanations for the decline, which include (a) stringent and narrowly defined criteria for publication, (b) elimination of analogue research from publication, (c) fewer mentors of process and outcome research, (d) declining interest in counseling-related research, and (e) difficulties in gaining access to counseling-related data.We offer a metaphor for the current state of research in counseling psychology of creating a confusing pile of bricks, not building edifices, and suggest it is time to create specialized journal outlets in counseling psychology to focus and connect counseling-related research with other important contexts of our field.

Counselor educators are called to be effective researchers; however, limited study has investigated research constructs within counselor educators-in-training. This study investigated the levels of research self-efficacy (Greeley et al., 1989), perceptions of the research training environment (Gelso, Mallinckrodt, & Judge, 1996), and interest in research (Bishop & Bieschke, 1994) within a sample of counselor education doctoral students (N = 89). Doctoral students in their 3rd year of preparation had higher research self-efficacy scores than did 1st- and 2nd-year students. Additionally, higher research self-efficacy was associated with higher interest in research and scholarly publication experience. Implications for counselor education are discussed.

The purpose of this study was twofold: to examine the relationship between authenticity and psychological well-being, and to examine the effects of creating and interpreting mandalas on the levels of authenticity and psychological well-being of college students. The results and their implications for practice and future research are discussed. ********** Authenticity is a developmental process whereby individuals explore, discover, accept, and behave in accordance with their true selves (Goldman, 2006). This process becomes prominent during the college years and can eventually culminate as the hallmark of an achieved identity (Erikson, 1968; Harter, 2002). However, the concept of authenticity has received scant attention compared with the concept of identity formation, which has been the focal point of a voluminous amount of writing and research (Chickering & Reisser, 1993; Marcia, 2002; Marcia, Waterman, Matteson, Archer, & Orlofsky, 1993). Yet authenticity is a concept worthy of investigation because it holds significant implications regarding individuals' psychological development and well-being (Goldman & Kernis, 2002; Harter, 2002; Sheldon, Ryan, Rawsthorne, & Ilardi, 1997). The transition to college can be a stressful occurrence as students engage in a process of adjusting to new academic, social, and emotional challenges (Chickering & Reisser, 1993; Hutz, Martin, & Beitel, 2007). Difficulties in this adjustment process can result in depression (Dyson & Renk, 2006), feelings of loneliness (Pargetter, 2000), isolation (Lawrence, 2001), generalized psychological distress (Compas, Wagner, Slavin, & Vannatta, 1986), and greater rates of attrition (Gerdes & Mallinckrodt, 1994). Research results also suggest that the development of an authentic sense of self can reduce feelings of distress often experienced during transitional periods (Reich, Harber, & Siegel, 2008). Yet some scholars suggest that individuals are encountering increasing difficulty establishing an authentic sense of self because of the social dynamics inherent in a postmodern society (Gergen, 1991; Harter, 2002). Thus, it would be germane to examine the concept of authenticity, its relationship to the psychological well-being of college students, and methods that college counselors might use to facilitate greater authenticity and psychological well-being. The concept of authenticity dates back to ancient Greek philosophy, which proclaimed that well-being and happiness resulted from being true to oneself and acting congruently with one's values, desires, and beliefs (Harter, 2002; Waterman, 1993). Most modern theoretical references to authenticity are framed within a humanistic view of personality. This view generally espouses the existence of a "true serf" that emerges through serf-exploration and self-acceptance and has relevance to one's psychological well-being (Hansen, 2005). For example, Rogers (1961) posited that authenticity arises as individuals strive for serf-actualization, a process that leads to congruence between one's life experiences and one's serf-concept. As individuals become more authentic they become more "fully functioning," that is, more open to experience, more self-accepting, and more inclined toward continued personal growth and development. Denying or distorting one's perceived inner experiences (i.e., emotions and thoughts about one's self), however, results in inauthentic feelings and ultimately to maladjustment. Thus, the main goal of the humanistic approach to counseling is the realization of a congruent and unified serf (Hansen, 2005). Borrowing from a humanistic theoretical framework, Goldman and Kernis (2002) defined authenticity as one's true core self as displayed in everyday life. Specifically, authenticity is a multidimensional concept that includes the components of awareness and unbiased processing. Awareness refers to one's awareness of one's motives, feelings, desires, and self-relevant cognitions, whereas unbiased processing includes an objective and honest assessment of one's positive and negative self-aspects, qualities, and attributes (Goldman & Kernis, 2002). …

Counselors often engage in conflict mediation in professional practice. A model for understanding the complex and subtle nature of conflict resolution is presented. The ecosystemic complexity theory of conflict is offered to assist practitioners in navigating the fog of conflict. Theoretical assumptions are discussed with implications for clinical settings. ********** Conflict resolution is a rapidly growing area in professional counseling practice (Brinson, Kottler, & Fisher, 2004; Messing, 1993). Corcoran and Mallinckrodt (2000) emphasized that "counselors increasingly perform the role of professional mediator for their clients" (p. 481). McFarland (1992) proposed that professional counselors could educate and train their clients in peaceful resolution skills and are "poised to empower people" (p. 20) if they are equipped with a strong theoretical foundation and the proper tools. School counselors, marriage and family counselors, and group counselors all work with people in conflict on a regular basis. Often, commanders in battle discuss how difficult it is to understand exactly what is happening on a field of battle, and they call this the "fog of war" (Clausewitz, 1984). Counselors frequently report the same feelings of ambiguity and confusion about conflict situations, and we call this the "fog of conflict." Even coming to a basic understanding of the interplay in the dynamics of the conflicting parties is often daunting. Participants in a conflict often provide contradictory stories and may not understand what has happened or why they are in conflict. This is because conflict occurs as a dynamic process eluding simplistic linear views of its nature and origin. In the present article, we discuss the ecosystemic complexity theory of conflict (ECTC), which can provide a structure to navigate the fog that surrounds most conflicts. ECTC is based on the theoretical, clinical, and research foundations of C. Brack, G. Brack, and associates, who have mapped the usefulness of systems theory with a variant of complexity theory for helping professionals in a wide domain of human services (C. Brack, Brack, & Zucker, 1995; G. Brack, Brack, Hill, & Frielich, 1998; G. Brack, Jones, Smith, White, & Brack, 1993; Kurpius, Brack, Brack, & Dunn, 1993). The following five assumptions are largely drawn from the fields of systems and complexity theory and form the foundation for ECTC: 1. Human dynamics are nonlinear and often incapable of being understood from a Newtonian view of the human condition. 2. These human dynamics exist in a multilayered social field that contains various factors that affect how conflict originates, how conflict is addressed, and how conflict is resolved. 3. Human dynamics, especially in conflictual areas, are unpredictable and difficult to impossible to control. 4. Despite the unpredictability of human conflict, there are certain emergent patterns that appear and offer opportunities for positive change. 5. Rather than devising control-oriented interventions toward conflict, the counseling practitioner must rely on adaptation and change to bring about mutually satisfying resolutions. Using a case scenario to illustrate the ECTC model and how it may be useful to counselors, we explore the complex and subtle nature of conflict and its resolution in the following discussion. Each of the assumptions is delineated in the following sections and then related to the practice of counseling in the 21st century, specifically as applied to the fictional case of Bob and Renee. Bob, a 39-year-old man, is a full-time MBA student. He has been married to Renee for 8 years and dated her for 6 years prior to marriage. They have one child, a 4-yearold boy, Philip. Like many couples, Bob and Renee have had their ups and downs. Over the 14-year relationship, they seem to have maintained the same fights. …

The graduate advising relationship is generally considered to be a critical aspect of graduate student development. This is due, in part, to the highly involved and interactive nature of the relationship; graduate advisors assume responsibility for guiding their advisees in successful completion of several degree requirements, including theses/dissertations, coursework, and applied work. Despite the significance of this relationship, research on graduate advising across Canadian psychology programmes remains limited. The current study assessed Canadian psychology graduate students (n = 387) from clinical, experimental, counselling, and education programmes using an online questionnaire regarding students' perceptions of their advisory relationship and the advising they received in specific training areas. Overall, advising in self-care and work-life balance was the greatest predictor of perceived quality of the advisory relationship for clinical students, research design for experimental students, and clinical work for counselling students, respectively. Implications for training and future research are discussed. Keywords: psychology graduate students, advisory relationship, student funding, research productivity The graduate advising relationship is considered to be essential to the professional development of the graduate psychology student (Gelso & Lent, 2000; Royalty, Gelso, Mallinckrodt, & Garett, 1986). This relationship is uniquely significant, in part, because graduate advisors are charged with furthering the academic and professional development of their students. To illustrate, it is necessary for the advisor to cultivate the student's research skills, thereby facilitating conception, development, and ultimate completion of theses and dissertations as well as other research. The advisor must also ensure that the necessary degree requirements (e.g., coursework) are fulfilled and, in clinical and counselling domains, he or she may act also as a clinical advisor. Aside from providing guidance in academic and clinical spheres, the advisor also facilitates the student's navigation through more peripheral aspects of graduate life, such as negotiating professional politics (e.g., resolving conflict with a faculty member; Schlosser & Gelso, 2005) and financial and professional opportunities. For example, to apply for funding from a tri-council agency (i.e., Social Sciences and Humanities Research Council, Canadian Institutes of Health Research, National Sciences and Engineering Research Council), students must procure a letter of support from their academic advisor that details their research competence and the importance of a planned program for future research. Similarly, when applying for clinical placements, counselling and clinical students are often dependent on the academic advisor to furnish a reference letter commenting on their clinical skills. Indeed, the advisor assumes a diverse set of responsibilities for a student's progression through graduate training and, as such, represents a key determinant of a student's overall development. Despite the apparent significance of the advisory relationship (Gelso & Lent, 2000; Magoon & Holland, 1984; Schlosser & Gelso, 2001), there is a dearth of empirical research on such relationships. In one of the first published studies on advising, Schlosser and Gelso (2001) created and validated the Advisory Working Alliance Inventory-Student Version (AWAI-S). The AWAI-S is a self-report measure used to assess the working alliance (i.e., the cooperation, mutuality, and collaboration in regard to work being conducted that provides the basis for members of the dyad to work together toward mutual goals; Bordin, 1979; Meara & Patton, 1994) between the advisor and the student from the advisee's perspective. Results indicated students' perceptions of the advisory alliance were positively correlated with their perceptions of the advisor's expertness, attractiveness, and trustworthiness, as measured by the Counsellor Rating Form-Short (Corrigan & Schmidt, 1983). …

Multiple-gated blood pool angiography (MUGA) using 99mTc-UltraTag (Mallinckrodt Inc., Maryland Heights, MO) labeled RBCs was performed in a patient with B-cell lymphoma for evaluation of the left ventricular ejection fraction before starting chemotherapy. Quantitative measurements from MUGA demonstrated normal left ventricular ejection fraction. However, cine images revealed delayed contraction of the left ventricle compared with that of the right, and phase contrast images demonstrated offset of the ventricles' phases. Evaluation with ECG showed delayed depolarization of the left ventricle consistent with LBBB. Phase imaging abnormalities detected on MUGA may be overlooked. Specific patterns of phase abnormalities may direct the physicians' attention toward yet unrecognized diagnoses.

The prevalence of diabetes mellitus in the United States has increased dramatically over the past 30 years, to where it now affects *24 million of adults and with that number expected to double by 2050. This greater prevalence includes both type-1 diabetes mellitus (T1DM) and type-2 diabetes mellitus (T2DM), although the latter predominates primarily because of the increase in obesity. Cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients accounting for approximately two-thirds of all deaths. In addition to its tremendous health burden, there is a substantial economic burden with the cost of diagnosis and treatment of cardiovascular complications in diabetic patients estimated to be *$22 billion annually. Although coronary atherosclerosis is the major cause of cardiovascular disease, diabetes mellitus can impair cardiovascular function independent of atherosclerosis. For example, the presence of T2DM is an independent risk factor for developing left ventricular hypertrophy and congestive heart failure and worsens the prognosis for those who develop these conditions. Cardiovascular autonomic dysfunction (CAN) is another often overlooked complication of this disease. It reflects abnormalities in the sympathetic and/or parasympathetic neuronal systems with their relative contributions defining patient symptomatology. The prevalence of CAN ranges from *1% to 90% in T1DM and from *20%-75% in patients with T2DM. The wide ranges reflect both inconsistencies in criteria used to define CAN and variable study design. CAN may be present the time of diagnosis of diabetes and the prevalence increases with age, disease duration, and worsening glycemic control. There are multiple clinical manifestations of CAN including resting tachycardia, impaired heart rate variability, exercise intolerance, abnormal regulation of blood pressure, orthostatic hypotension, and silent myocardial ischemia. Moreover, CAN is associated with impaired diastolic function and has been posited to be a potential contributor to the cardiomyopathy of diabetes mellitus, although direct causality has been difficult to prove. These diverse manifestations of CAN are likely the reasons it is a key contributor to the increase in CV morbidity and mortality associated with diabetes mellitus. The pathogenesis of CAN is likely multifactorial and reflects the yet to be defined proportional contributions of numerous factors such as hyperglycemia-induced neuronal ischemia/injury, neurovascular insufficiency, autoimmune damage, and neurohormonal growth factor deficiency. The importance of hyperglycemia in the pathogenesis of CAN is supported by multi-center trials such as the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Trial demonstrating that intensive glycemic control had persistent beneficial effects on the incidence, severity, and progression of CAN in patients with T1DM. The results in patients with T2DM are less clear but appear to suggest that intensive glycemic control in combination with aggressive CV risk factor modification reduces the prevalence of CAN in patients with microalbuminuria. Despite these encouraging results, there is intense interest in developing therapeutic approaches to reduce the incidence and clinical severity of CAN. Reprint requests: Robert J. Gropler, MD, Division of Radiological Sciences, Cardiovascular Imaging Laboratory, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, St. Louis, MO 63110; Groplerr@mir.wustl.edu J Nucl Cardiol 2014;21:842–4. 1071-3581/$34.00 Copyright 2014 American Society of Nuclear Cardiology.