Median Day Of Onset Research Articles

PS1285 INVASIVE FUNGAL DISEASES IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION RECIPIENTS WITH HODGKIN'S LYMPHOMA

Background:Data on invasive fungal disease (IFD) in allogeneic hematopoietic stem cell transplantation (allo‐HSCT) recipients with relapsed/refractory Hodgkin's lymphoma (r/r HL) are limited. Outcome of allo‐HSCT in patients with prior IFD is still a subject of controversy.Aims:The aim is to study the epidemiology of IFD in allo‐HSCT recipients with r/r HL.Methods:Single center prospective observational study included 86 patients with classical r/r HL who underwent allo‐HSCT from 2002 to 2018. The median age was 27 (13–49) y.o., children (<18 yo) – 13% (n = 11). Allo‐HSCT from MUD was performed in 45,4% (n = 39), MRD – 24,4% (n = 21), MMUD – 15,1% (n = 13), haplo – 15,1% (n = 13), with RIC (100%) and predominantly PTCY‐based GvHD prophylaxis (71%). Primary antifungal prophylaxis was fluconazole in 85%, secondary – voriconazole (100%). EORTC/MSG 2008 criteria for diagnosis and response to therapy were used. In pts with CT‐scan lung lesions before allo‐HSCT bronchoscopy with BAL was used. “Active IFD” means IFD diagnosed just before HSCT. Median follow‐up time was 12 months [1–71].Results:Incidence of pre‐existing IFD in allo‐HSCT recipients with r/r HL was 12,8% (n = 11). All cases of IFD prior to HSCT were invasive aspergillosis (IA) with lungs involvement. Antifungal therapy before allo‐HSCT was used in 81,8% pts with median duration – 2 months. Complete response to antifungal therapy was in 45,4% pts, partial response or stabilization – 36,4%, and 18,2% pts had an “active IFD”. After allo‐HSCT all pts received voriconazole as an antifungal therapy or secondary prophylaxis. Cumulative incidence of relapse or progression of IA after allo‐HSCT was 18,2% with the median 49 day [19–79] of onset after HSCT, which were successfully treated with voriconazole. Incidence of IFD after allo‐HSCT for naïve patients was 17,6% (n = 13/74). Etiology of IFD after allo‐HSCT was IA – 69%, invasive candidiasis (IC) – 15%, mucormycosis – 8%, and combined IFD caused by Aspergillus fumigatus + Rhizopus stolonifer ‐ 8%. The median day of onset of IFD after allo‐HSCT was day+ 114 [1–489]. The main site of infection were lungs (88%), the main clinical symptom – febrile fever (100%). Antifungal therapy was following: voriconazole – 59%, micafungin – 17%, posaconazole – 8%, lipid amphotericin B – 8% and combination lipid amphotericin B with caspofungin – 8%. Overall survival (OS) at 12 weeks from the IFD diagnosis after allo‐HSCT was 80%. The 2‐year OS in children and adult with r/r HL after allo‐HSCT was 73,3%. Development of IFD after allo‐HSCT do not decrease the 2‐year OS rate (69,2% vs 74%, p = 0,77). The impact of prior IFD on 2‐year OS in allo‐HSCT recipients was not statistically significant in all group (63,6% vs 74,7%, p = 0,47), and separately in children and adults.Summary/Conclusion:Incidence of pre‐existing IFD in children and adults with r/r Hodgkin's lymphoma allo‐HSCT recipients was 12,8%. Incidence of IFD after allo‐HSCT in naïve patients with Hodgkin's lymphoma was 17,6%. The major etiology agent as before as after allo‐HSCT were Aspergillus spp. IFD was a late complication after allo‐HSCT. Despite the high incidence of IFD before or after allo‐HSCT didn’t influence the outcome in children and adults with r/r Hodgkin lymphoma.

PS1287 INVASIVE ASPERGILLOSIS IN PATIENTS WITH B-CELL LYMPHOMA

Background: Invasive yeast infection is rare invasive fungal disease but associated with high mortality rate in hematological patients. Data on Invasive yeast infection in hematopoietic stem cell transplantation (HSCT) recipients are limited. Aims: The aim of our study was to estimate epidemiology of invasive yeast infections in large HSCT recipients’ cohort for the 10-year period transplant activity in CIC725. Methods: Between 2008 and 2017 2430 stem cell transplantation have been performed in CIC 725: 1647 allogeneic HSCT and 783 autologous HSCT. A retrospective study included 30 cases of invasive yeast infections in patients with hematological malignances and non-malignant hematological diseases after HSCT. EORTC/MSG 2008 criteria were used for the diagnosis of proven yeast infections as well as to evaluate response to therapy. Results: Incidence of invasive yeast infections for the 10-year period of high transplant activity was 1,2%: 1,4% in allo-HSCT recipients (n = 23), 0,9% – auto-HSCT (n = 7) predominantly in patients with acute leukemia – 67% (n = 20). The median age was 10 y.o. (range, 1 month-59 years). In study population allo-HSCT from unrelated donor was performed in 50% (n = 15), haplo-HSCT in 27% (n = 8) and auto-HSCT in 23% (n = 7). In study cohort 30% of patients had no complete remission at the moment of HSCT. As a primary antifungal prophylaxis was used: fluconazole – 37% (n = 11), echinocandins – 13% (n = 4), without prophylaxis – 23% (n = 7); as a secondary prophylaxis – voriconazole in 27% (n = 8). The median day of onset of invasive yeast infections after allo-HSCT was 109 days (3–1337), auto-HSCT – 20 days (8–33). The etiology of invasive yeast infections was: Candida spp. – 87% (n = 26), Malassezia furfur – 7% (n = 2), Trichosporon asahii – 3% (n = 1), Cryptococcus spp. – 3% (n = 1). Febrile fever was the main clinical symptom and septic syndrome developed in 60% of cases. OS at 30 days from diagnosis of invasive yeast infection was 63%. The central venous catheter removal was the only factor significantly improved OS at 30 days after invasive yeast infection diagnosis (91% vs 17%, p = 0,001). Summary/Conclusion: Incidence of invasive yeast infections for the 10 years of observation was 1,2%: 1,4% in allo-HSCT recipients, 0,9% – auto-HSCT. The main etiology was Candida spp. (87%). Overall survival at 30 days from the diagnosis of invasive yeast infections was 60%. Removing of central venous catheter improved overall survival in hematological patients after HSCT with invasive yeast infections.

PS1286 INVASIVE YEAST INFECTIONS IN HEMATOLOGICAL PATIENTS AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION

Background:Invasive yeast infection is rare invasive fungal disease but associated with high mortality rate in hematological patients. Data on Invasive yeast infection in hematopoietic stem cell transplantation (HSCT) recipients are limited.Aims:The aim of our study was to estimate epidemiology of invasive yeast infections in large HSCT recipients’ cohort for the 10‐year period transplant activity in CIC725.Methods:Between 2008 and 2017 2430 stem cell transplantation have been performed in CIC 725: 1647 allogeneic HSCT and 783 autologous HSCT. A retrospective study included 30 cases of invasive yeast infections in patients with hematological malignances and non‐malignant hematological diseases after HSCT. EORTC/MSG 2008 criteria were used for the diagnosis of proven yeast infections as well as to evaluate response to therapy.Results:Incidence of invasive yeast infections for the 10‐year period of high transplant activity was 1,2%: 1,4% in allo‐HSCT recipients (n = 23), 0,9% – auto‐HSCT (n = 7) predominantly in patients with acute leukemia – 67% (n = 20). The median age was 10 y.o. (range, 1 month‐59 years). In study population allo‐HSCT from unrelated donor was performed in 50% (n = 15), haplo‐HSCT in 27% (n = 8) and auto‐HSCT in 23% (n = 7). In study cohort 30% of patients had no complete remission at the moment of HSCT. As a primary antifungal prophylaxis was used: fluconazole – 37% (n = 11), echinocandins – 13% (n = 4), without prophylaxis – 23% (n = 7); as a secondary prophylaxis – voriconazole in 27% (n = 8). The median day of onset of invasive yeast infections after allo‐HSCT was 109 days (3–1337), auto‐HSCT – 20 days (8–33). The etiology of invasive yeast infections was: Candida spp. – 87% (n = 26), Malassezia furfur – 7% (n = 2), Trichosporon asahii – 3% (n = 1), Cryptococcus spp. – 3% (n = 1). Febrile fever was the main clinical symptom and septic syndrome developed in 60% of cases. OS at 30 days from diagnosis of invasive yeast infection was 63%. The central venous catheter removal was the only factor significantly improved OS at 30 days after invasive yeast infection diagnosis (91% vs 17%, p = 0,001).Summary/Conclusion:Incidence of invasive yeast infections for the 10 years of observation was 1,2%: 1,4% in allo‐HSCT recipients, 0,9% – auto‐HSCT. The main etiology was Candida spp. (87%). Overall survival at 30 days from the diagnosis of invasive yeast infections was 60%. Removing of central venous catheter improved overall survival in hematological patients after HSCT with invasive yeast infections.

PB2339 GASTROINTESTINAL BLEEDING WAS ASSOCIATED WITH WORSE SURVIVAL IN PATIENTS WITH GASTROINTESTINAL ACUTE GRAFT‐VERSUS‐HOST DISEASE: SINGLE CENTER RETROSPECTIVE STUDY

Background:Acute graft‐versus‐host disease (aGVHD) is an important complication after allogeneic stem‐cell transplantation (allo‐SCT). GVHD is caused by alloreactive donor‐derived T lymphocytes and involves various organs such as the skin, liver, and gastrointestinal tract. Especially, gastrointestinal aGVHD (GI‐aGVHD) is associated with severe morbidity and high rate of mortality. Standard initial treatment for GVHD is corticosteroid, and response rate has been reported approximately 40% to 50%. However, patients who did not respond to initial treatment have shown poor survival rate of 5% to 30%, even if those patients received additional treatments.Aims:The aim of this study was to identify risk factors for mortality in patients with GI‐aGVHD after allo‐SCT.Methods:We retrospectively reviewed clinical records of the patients who underwent allo‐SCT for hematological disorders at our center between September 2006 and April 2018.Results:Seventy‐one patients who developed GI‐aGVHD were included in this study. The median age of the patient was 46 years (range; 19‐65 years). Twenty‐four patients had lymphoid malignancy, 42 patients had myeloid malignancy and 5 patients had other hematological disorders. Forty‐two patients were complete remission at allo‐SCT, and the other 29 patients were not in complete remission. Twenty‐five patients received reduced‐intensity conditioning, and 46 patients received myeloablative conditioning. Graft sources were bone marrow in 26 patients, peripheral blood stem cells (PBSC) in 22 patients and umbilical cord blood in 23 patients. Six out of 22 PBSC were obtained from HLA‐haploidentical related donors. Prophylaxes for aGVHD were tacrolimus‐based regimens in 57 patients and cyclosporine‐based regimens in 14 patients. Median onset day of GI‐aGVHD was 33 after allo‐SCT (range; 3‐134). Staging of GI‐aGVHD was as follows: stage 1,n = 44; stage 2, n = 12; stage 3, n = 6; stage 4, n = 9. Forty patients developed grade II aGVHD, 24 patients developed grade III aGVHD and 7 patients developed grade IV aGVHD. Forty‐five patients received systemic corticosteroid treatment for GI‐aGVHD, and 15 of the patients needed additional treatment.At the median follow‐up of 928 days (range; 259‐3434), estimated overall survival (OS) rate at 2 years was 46%. In a multivariate analysis using Cox regression model, patients with GI bleeding [hazards ratio (HR) = 1.26 (95%CI; 0.20‐0.81), p = 0.040] and concomitant with liver aGVHD [HR = 11.3 (95%CI; 1.1‐114), p = 0.040] were independently associated with worse OS.OS was not different between patients who received corticosteroid and patients who did not received corticosteroid by log‐rank test. However, patients who received additional treatment showed significantly worse OS (5‐year OS 43.4% vs. 0.0%, P < 0.001, Figure). Patients with GI bleeding or concomitant with liver aGVHD need to receive additional treatment (odds ratio (OR) = 28.9 (95%CI; 4.62‐340), p<0.001 for GI bleeding; OR = 11.4 (95%CI; 1.74‐134), p = 0.003 for concomitant with liver aGVHD, respectively).Summary/Conclusion:Among patients with GI‐aGVHD, GI bleeding or concomitant with liver aGVHD was associated with refractory to corticosteroid treatment, resulting in worse OS.image

Caspofungin for primary antifungal prophylaxis after T-cell-replete haploidentical stem cell transplantation with post-transplant cyclophosphamide.

ObjectivesT‐cell–replete haploidentical stem cell transplantation (Haplo‐SCT) with post‐transplant cyclophosphamide (PT‐Cy) is at high risk of invasive fungal infections (IFI), and anti‐mold–active drug is required for primary antifungal prophylaxis (PAP) according to international guidelines. No data are available on the efficacy of caspofungin as PAP in this setting.MethodsHere, we report our retrospective experience with 103 consecutive patients treated with caspofungin as PAP after Haplo‐SCT. Caspofungin was administered only during the pre‐engraftment phase.ResultsHundred‐day cumulative incidence of proven‐probable IFI (PP‐IFI) was 8.7% and median day of onset was 19 post‐SCT. No patient died of PP‐IFI, and overall survival (OS) and non‐relapse mortality (NRM) hazard ratio (HR) for patients experiencing IFI were 1.02 (P = 0.9) and 0.7 (P = 0.7), respectively. Three‐year overall survival (OS) and 1‐year non‐relapse mortality (NRM) were 55% and 19%, respectively. By univariate analysis, duration of neutropenic phase and partial remission pre‐transplant disease status were associated with increased incidence of IFI, but were not confirmed by multivariate analysis.ConclusionIn summary, PAP with caspofungin is an effective strategy for preventing IFI in the context of Haplo‐SCT with PT‐Cy. Further efforts are required in order to identify more potent strategies able to avoid the occurrence of breakthrough infections.

Cytokine Release Syndrome after Peripheral Blood T-Cell Replete Haploidentical Transplantation Is Not Prevented By Dexamethasone and Limits Its Full-Outpatient Conduction

Introduction: Our center has implemented an outpatient-based peripheral blood haploidentical HSCT (haplo-HSCT) program since 2012. Cytokine release syndrome (CRS) associated with T-cell replete haplo-HSCT is characterized by fever and high levels of inflammatory cytokines with symptom onset typically occurring early after cell infusion, coinciding with maximal in vivo T-cell expansion. In this study, we report our analysis of CRS development after T cell-replete haplo-HSCT after using prophylactic dexamethasone and focusing on the impact of CRS on hospitalization and transplant outcomes in our outpatient program.Methods: In this retrospective study, adult patients undergoing a T-cell replete haplo-HSCT at our transplant center between January 2016-2018 were included. CRS was defined and graded using the criteria described by Lee et. al. Conditioning was based on fludarabine 25 mg/m2/day (day -5 to -3), cyclophosphamide 350 mg/m2/day (day -5 to -3), and oral melphalan 50-100 mg/m2 (day -2 to -1). For graft-versus-host disease (GVHD) prophylaxis we used post-transplant cyclophosphamide (PTCy) 50 mg/kg on days +3 and +4 as well as mycophenolate mofetil and either cyclosporine or tacrolimus starting on day +5. All patients received dexamethasone 8 mg IV on day 0 to +2 as prophylaxis against CRS. Disease-risk index (DRI) and HCT-Comorbidity Index (HCT-CI) were calculated based on established definitions. The primary objective was to evaluate the incidence of CRS with dexamethasone prophylaxis during an outpatient-based peripheral blood haplo-HSCT. Secondary objectives were to describe factors associated with CRS and to determine the impact of CRS on transplant outcomes and hospitalizations.Results: There were 42 patients included; the median age was 32.5 years (range, 16-66). The median DRI score was 3 (range, 1-4). The most common underlying diagnosis was acute lymphoblastic leukemia (n=14, 33%), followed by acute myeloid leukemia (n=8, 19%), and lymphoma (n=7, 16.6%). Conditioning was myeloablative (n=33, 79%) or reduced-intensity (n=9, 21%). Thirty patients (71.4%) developed CRS. CRS severity was grade 1-2 in 28 patients (66.7%) and grade 3 in 2 patients (4.8%). Median day of onset occurred on day +2 (range 0-4) and usually resolved after PTCy on day +5 (range, 1-11). The incidence of CRS was not associated with recipient age, number of CD34+ cells infused, DRI score, baseline HCT-CI score, and conditioning intensity. Time to neutrophil and platelet engraftment was not different in patients with CRS compared with patients without. Hospitalization was required in 36 cases (87%) while 6 patients (13%) were followed in a fully-outpatient basis, including 2 patients with grade 1 CRS. The median length of hospitalization was 13 days (range, 0-50) for patients with CRS and 8 days for patients without CRS (range, 0-44). The most common signs and symptoms besides fever were gastrointestinal manifestations (36.6%), hypoxemia (30%), fluid-responsive hypotension (16%) while 2 patients required vasopressors.Conclusion: The completely ambulatory conduct of haplo-HSCT was limited by the development of CRS. However, even in patients who developed CRS median length of hospitalization was short. CRS was common despite dexamethasone prophylaxis although most CRS were of grade 1 or 2. None of the factors evaluated were associated with CRS development in this context, and CRS did not influence time to engraftment, cumulative incidence of acute or chronic GVHD. New strategies are required to prevent CRS and prevent hospitalizations associated with haplo-HSCT. [Display omitted] DisclosuresGomez-Almaguer:AbbVie: Consultancy; Novartis: Consultancy.

High-Dose Intravenous Immunoglobulin and Immunosuppressive Therapy Have Therapeutic Potential for Non-Infectious Myelopathy and Peripheral Neuropathy Following Cord Blood Transplantation

BACKGROUND: We previously reported higher incidence of central nervous system complications (CNSCs) after cord blood (CB) than after bone marrow or peripheral blood transplantation (Kageyama K, et al. ASH 2016). Infectious complications such as human herpes virus type 6 (HHV-6) associated limbic encephalitis and/or myelitis have been the major cause of CNSCs. In this study, we now focused on non-infectious myelopathy and peripheral neuropathy (NIMPN) for which the main diseased focus located outside of cerebrum or cerebellum, since there has been little information available about them. The aim of the study is to clarify the incidence and the outcome of NIMPN after CBT.METHODS: We retrospectively studied medical records of 459 patients who underwent CBT as the first transplantation at Toranomon Hospital between July 2012 and March 2018. NIMPNs were diagnosed when the patients developed myelopathy or peripheral neuropathy without detection of pathogens tested in cerebrospinal fluid (CSF) or without radiological findings indicating hemorrhage, ischemia, or focal lesions suggestive of infections. We excluded the patients whose ECOG performance status scale was 3 or 4, and who had neurological symptoms before transplantation. Institutional review board of Toranomon Hospital approved the study (research number #1205-H)RESULTS: NIMPNs developed in 8 patients within 2 years after transplantation (2 myelopathies and 6 peripheral neuropathies [PN]). Their characteristics are as follows: the median age, 53 years (range, 37 - 62); 5 males and 3 females; AML-NOS (n = 5), AML with MRC (n = 1), therapy-related MDS or AML (n = 2). All except one were not in remission before transplantation. The combination of fludarabine, busulfan, and melphalan with or without high-dose cytarabine was used as conditioning regimen. Tacrolimus (Tac) alone (n = 2), Tac and mycophenolate mofetil (n = 5), and Tac and methotrexate (n = 1) were used as GVHD prophylaxis. The cumulative incidence of NIMPNs was 1.74% at 2 years after transplantation (95% confidence interval, 0.54 - 3.93). The median onset day of NIMPNs was 90 days after transplantation for all patients (range, 25 - 255); 40 days for myelopathy, and 100 days for PN. All had varying degree of hypesthesia or paresis and were unable to walk by themselves at diagnosis. All developed neurological symptoms after engraftment. Grade 2 - 3 of acute GVHD preceded NIMPNs in all patients. At diagnosis, the following pathogens were confirmed to be negative by PCR in CSF; HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, BKV, toxoplasma. CSF cell count and protein level did not increase in all of them. Myelin basic protein level in CSF was elevated in 3 out of 6 patients (519 ng/L and 1358 ng/L for myelopathies, 1321 ng/L for PN), which suggested demyelinating changes. Oligoclonal bands were not detected. Spinal MRI study performed in 4 patients showed no abnormality. In line with previous reports, axonal degeneration was confirmed by nerve biopsy in 2 patients with PN. After the diagnosis of NIMPNs, all patients were treated with high dose intravenous immunoglobulin (IVIG) (400 mg/kg for 5 days). The median interval from diagnosis to treatment was 28 days (range, 5 - 71). IVIG was administered monthly for the median of 2 courses (range, 2 - 5). In 2 patients, rituximab or steroid pulse therapy was added on IVIG, respectively. After these treatments, symptoms improved in 6 out of 8 patients and they finally were able to walk by themselves (1/2 of myelopathy and 5/6 of PN). The remaining one died of severe liver acute GVHD and another one is hospitalized until now without recovery. The median follow-up days of survivors was 498 days (range, 74 - 2190). Seven out of 8 patients are currently alive.CONCLUSION: NIMPNs were observed after CBT with low incidence. Although all patients presented severe neurological symptoms at diagnosis, IVIG and immunosuppressive therapy had a therapeutic benefit, and their prognosis with respect to neurological symptoms and survival was not dismal. DisclosuresYamamoto:Bristol-Myers Squibb: Honoraria.

Clinical efficacy, onset time and safety of bright light therapy in acute bipolar depression as an adjunctive therapy: A randomized controlled trial

BackgroundBright light therapy (BLT) is an effective treatment for seasonal affective disorder and non- seasonal depression. The efficacy of BLT in treating patients with bipolar disorder is still unknown. AimsThe aim of this study is to examine the efficacy, onset time and clinical safety of BLT in treating patients with acute bipolar depression as an adjunctive therapy (trial registration at ClinicalTrials.gov: NCT02009371). MethodsThis was a multi-center, single blind, randomized clinical trial. Seventy-four participants were randomized in one of two treatment conditions: BLT and control (dim red light therapy, dRLT). Sixty-three participants completed the study (33 BLT, 30 dRLT). Light therapy lasted for two weeks, one hour every morning. All participants were required to complete several scales assessments at baseline, and at the end of weeks 1 and 2. The primary outcome measures were the clinical efficacy of BLT which was assessed by the reduction rate of HAMD-17 scores, and the onset time of BLT which was assessed by the reduction rate of QIDS-SR16 scores. The secondary outcome measures were rates of switch into hypomania or mania and adverse events. Results1) Clinical efficacy: BLT showed a greater ameliorative effect on bipolar depression than the control, with response rates of 78.19% vs. 43.33% respectively (p < 0.01). 2) Onset day: Median onset day was 4.33 days in BLT group. 3) BLT-emergent hypomania: No participants experienced symptoms of hypomania. 4) Side effects: No serious adverse events were reported. ConclusionBLT can be considered as an effective and safe adjunctive treatment for patients with acute bipolar depression.

Differential Expression of Immunity Related Genes and Early Prediction of Severe Graft Versus Host Disease after Allogeneic Hematopoietic Cell Transplantation

Background:Allogeneic hematopoietic cell transplantation (HCT) is curative for hematological malignancies. However, Graft versus host disease (GVHD) is the most common and debilitating complication of HCT as 10-15% HCT recipients die and 25% suffer long-term due to GVHD. Effective but toxic prophylaxes for GVHD (e.g., anti-thymocyte globulin) exist that can be given preemptively to patients with high risk of GVHD. However, an early and accurate identification of patients who are at a high risk of developing severe GVHD is the prerequisite for any preemptive therapy. The 'onset' of symptoms associated with GVHD is the final manifestation of a series of cellular and molecular perturbations that take place when host epithelial cells are attacked by the donor immune cells. With the aim of identifying potential functional biomarkers for early prediction of severe GVHD, a comprehensive panel of 594 genes shared among 24 immunology-related gene networks were retrospectively analyzed at different posttransplant time points prior to the onset of GVHD .Methods:Two hundred and two RNA specimens from 117 first allogeneic HCT recipients with (n=49) or without (n=68) clinically significant GVHD were analyzed. RNA was extracted from cryopreserved peripheral blood mononuclear cells (PBMNCs) collected at three early post-transplant time points: one week (n=32), one month (n=85) and two months (n=80) after transplantation. Messenger RNA counts for 594 human genes with immunity related functions and 15 internal reference genes were obtained using Nanostring based gene expression CodeSet profiling. Empirical Bayes statistics for differential gene expression, receiver operating characteristic (ROC) and principle component analyses were performed using R statistical packages to identify the gene sets with highest sensitivity and specificity for early prediction of clinically significant GVHD.Results:A 'GVHD transcript panel' comprising of highly upregulated 6 genes with T cell related pro-inflammatory functions was identified at one month post transplantation in patients with clinically significant GVHD (grade II-IV acute GVHD (median day of onset = 34 days) and/or chronic GVHD requiring systemic therapy, median day of onset = 108 days). The panel consists of CD27 (AUC=0.93; p=3.4X10-8); B- and T-lymphocyte attenuator, BTLA ((AUC=0.92; p=3.4X10-8),Inducible T-cell Co-stimulator, ICOS (AUC=0.90; p=3.5X10-7), CD5 (AUC=0.87; p=8.5X10-7), CD3D (AUC=0.88; p=8.8X10-7) and CD28 (AUC=0.91; p=9.9X10-7). The GVHD transcript panel predicted clinically significant GVHD with sensitivity of 85% and specificity of 95%.Conclusions:The findings strongly favor the early prediction of clinically significant GVHD made possible by differential expression profile of genes associated with T cell related pro-inflammatory functions The identified 'GVHD transcript panel' is highly sensitive and specific in identifying patients at a high risk of developing GVHD and can pave the way to precision HCT medicine. DisclosuresNo relevant conflicts of interest to declare.

OR41 Transcriptome analysis of immunity related genes as early predictor of graft versus host disease

Background Graft versus host disease (GVHD) is the most common and debilitating complication of allogeneic hematopoietic cell transplantation (HCT) as 10–15% HCT recipients die and 25% suffer long-term due to GVHD. Effective but toxic prophylaxes for GVHD (e.g., anti-thymocyte globulin) exist that can be given preemptively to patients with high risk of GVHD. The major barrier to this ’preemptive therapy’ is the lack of sensitive and specific assays that can identify patients at high risk of GVHD. Since allo-immune responses generated through recognition of host antigens by donor T cells culminate into GVHD, we performed the transcriptome analysis of 594 genes with immunity related functions at different posttransplant time points to predict ensuing GVHD. Methods A total of 147 RNA specimens from 65 first allo-HCT recipients were analyzed. RNA was extracted from cryopreserved PBMNCs collected at one week (n = 22), one month (n = 65) and two months (n = 60) post transplantation. Transcriptome analysis for 594 human genes with immunity related functions and 15 internal reference genes was performed using Nanostring based gene expression CodeSet profiling. Empirical Bayes statistics, receiver operating characteristic ( ROC ) and principle component analyses were performed to identify gene expression pattern predictive of GVHD. Results A ’GVHD transcript signature’ comprising of highly upregulated 6 genes with T cell related pro-inflammatory functions were identified at one month after HCT in patients with clinically significant GVHD (median day of onset = 100 days). The genes identified were CD27 (AUC = 0.93; p = 3.4X10 −8 ); B- and T-lymphocyte attenuator, BTLA (AUC = 0.92; p = 3.4X10 −8 ), Inducible T-cell Co-stimulator, ICOS (AUC = 0.90; p = 3.5X10 −7 ), CD5 (AUC = 0.87; p = 8.5X10 −7 ), CD3D (AUC = 0.88; p = 8.8X10 −7 ) and CD28 (AUC = 0.91; p = 9.9X10 −7 ). The GVHD transcript panel predicted clinically significant GVHD with sensitivity of 85% and specificity of 95%. Conclusions Early posttransplant transcript profile of genes with T cell related pro-inflammatory functions has a prominent impact on the occurrence of GVHD. The identified ‘6-genes GVHD transcript signature’ is highly sensitive and specific in early identification of patients at high risk of developing GVHD and could pave the way to precision HCT medicine.

Biomarkers for Idiopathic Pneumonia Syndrome after Hematopoietic Cell Transplantation: Comparison with Viral Infectious Pneumonia

Background: Idiopathic pneumonia syndrome (IPS) is a non-infectious pulmonary complication with diffuse lung injury that develops in 5-10% of patients who undergo hematopoietic cell transplantation (HCT) and the mortality rate remains high at 50-90%. IPS is difficult to distinguish from occult pneumonia after HCT, because it is hard to exclude all infectious etiologies. There are currently no laboratory tests to aid physicians in the early detection of IPS and other pulmonary infections. The aim of this study was to identify prognostic biomarkers of future occurrence of IPS and compare their profiles to that for subjects with infectious pneumonia.Patients and methods: Among patients transplanted between 1988 and 2014 at FHCRC, we identified 42 patients with IPS based on radiographic findings and exclusion of possible pathogens using frozen bronchoalveolar lavage (BAL) samples of occult viral infections as recently reported (Blood 2015: 24: 3789-97). HCT recipients who did not require bronchoscopic examination and who did not grow any bacterial or fungal blood cultures within 100 days after HCT were considered as controls (n=163) and samples were collected at similar timepoints as IPS cases. We examined cases of viral pneumonia confirmed by positive BAL: human rhinovirus (HRV, n=18) and parainfluenza (PIV, n=21). A set of 1129 plasma samples from pre-HCT, day 7, day 14, day 21 post-HCT and at onset of each event was analyzed. The "onset sample" for controls was the sample closest to day 24 (median day of onset for patients with pulmonary symptoms). We measured six proteins by ELISA: Suppressor of tumorigenicity 2 (ST2), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), lymphocyte vessel endothelial receptor (LYVE)-1, endothelial protein C receptor (EPCR), and herpes virus entry mediator (HVEM). TNFR1, LYVE-1, EPCR and HVEM were discovered through a proteomics approach, and ST2 and IL-6 were also measured due to their associations with endothelial processes and IPS (Blood 2015: 15: 2435-44), respectively.Multivariable logistic regression was used to evaluate the association of each protein with IPS vs. controls and IPS vs. HRV+PIV. Protein concentrations were log10 transformed and values below the lower limit of detection were replaced with that value (this occurred in 28% of the IL-6 measurements only). All analyses were adjusted for age, sex, transplant year, and acute GVHD status (grade 0-1 vs 2-4). Odds ratios indicate an increase in the odds of IPS for a tenfold increase in the protein concentration (Table 1). Receiver Operating Characteristic (ROC) curves were generated for each marker and if the area under the ROC (AUC) was greater than 0.7, then the analyte was considered an informative predictor of IPS.Results: Patients' characteristics are detailed in Table 1. Of the six proteins, TNFR1, ST2, LYVE-1, HVEM, and IL-6 were significantly elevated at the onset of IPS compared to controls at similar time point (adjusted, Table 2). ST2 and IL-6 were also elevated in infectious cases, although to a lesser degree. However, the biomarkers were able to distinguish IPS cases from viral infections (HRV and PIV) occurring approximately at the same time post HCT (Figure 1A). We also evaluated the prognostic value of the proteins by analyzing samples measured at day 7 post-HCT. All six proteins were elevated in IPS cases versus controls as early as day 7 with AUC from 0.85 to 0.75 (data not shown), and distinguished IPS from HRV and PIV infections (Figure 1B).Conclusion: Five proteins, TNFR1, ST2, LYVE-, HVEM, and IL-6 were significantly elevated at the onset of respiratory failure in IPS patients as compared to patients without pulmonary injury. Although the markers were also elevated in viral pulmonary infections, they were able to distinguish IPS from HRV and PIV. Importantly, these markers were elevated as early as day 7 after HCT, prior to the clinical signs of IPS. Additional analyses combining proteins together to form a composite panel are currently ongoing. [Display omitted] [Display omitted] [Display omitted] DisclosuresPaczesny:Viracor laboratories: Patents & Royalties: "Methods of detection of graft-versus-host disease" (US- 13/573,766).

A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study

Graft-versus-host disease (GVHD) is the major cause of non-relapse mortality after allogeneic haemopoietic stem-cell transplantation (SCT). The severity of symptoms at the onset of GVHD does not accurately define risk, and thus most patients are treated alike with high dose systemic corticosteroids. We aimed to define clinically meaningful risk strata for patients with newly diagnosed acute GVHD using plasma biomarkers. Between April 13, 2000, and May 7, 2013, we prospectively collected plasma from 492 SCT patients with newly diagnosed acute GVHD and randomly assigned (2:1) using a random number generator, conditional on the final two datasets having the same median day of onset, into training (n=328) and test (n=164) sets. We used the concentrations of three recently validated biomarkers (TNFR1, ST2, and Reg3α) to create an algorithm that computed the probability of non-relapse mortality 6 months after GVHD onset for individual patients in the training set alone. We rank ordered the probabilities and identified thresholds that created three distinct non-relapse mortality scores. We evaluated the algorithm in the test set, and again in an independent validation set of an additional 300 patients who underwent stem cell transplant and were enrolled on multicentre clinical trials of primary therapy for acute GVHD. In all three datasets (training, test, and validation), the cumulative incidence of 6-month non-relapse mortality significantly increased as the Ann Arbor GVHD score increased. In the multicentre validation set, scores were 8% (95% CI 3-16) for score 1, 27% (20-34) for score 2, and 46% (33-58) for score 3 (p<0·0001). Conversely, the response to primary GVHD treatment within 28 days decreased as the GVHD score increased 86% for score 1, 67% for score 2, and 46% for score 3 in the multicentre validation set, p<0·0001). Biomarker-based scores can be used to guide risk-adapted therapy at the onset of acute GVHD. High risk patients with a score of 3 are candidates for intensive primary therapy, while low risk patients with a score of 1 are candidates for rapid tapers of systemic steroid therapy. The National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Doris Duke Charitable Fund, the American Cancer Society, and the Judith Devries Fund.

Safety and Efficacy of Thiotepa-Based Conditioning Therapy for Allogeneic Transplantation in Acute Myeloid Leukemia - a Survey from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

▪BackgroundThiotepa (TTP) is an alkylating compound with an antineoplastic activity that has been used since the early nineties. However, few studies focused on the analysis of the benefit of TTP in the pre-allogeneic hematopoietic stem cell transplantation (HSCT) conditioning in a specific disease category. Beside its antineoplastic activity, TTP has immunosuppressive properties and the ability to penetrate the blood-brain barrier in conjunction with a good toxicity profile that makes it an attractive compound to use in the transplant setting. Therefore, the aim of the current analysis was to investigate the potential impact of TTP as part of the conditioning therapy for acute myeloid leukemia (AML) patients in first complete remission (CR1) and beyond.MethodsThis retrospective multicentre study was performed by the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Inclusion criteria were adults with AML who received TTP as part of the conditioning regimen for first allogeneic HSCT between 1992 and 2012 (median 2008).ResultsA total of 310 patients with AML (13% secondary) were identified. Median age was 46.5 years; 54% were males and 46% females. 14% of the patients received a previous autologous HSCT. Disease status at HSCT was CR1 in 50%, CR2+ in 23.5%, while 26.5% of the patients had an advanced disease at time of transplant. Cytogenetics was good, intermediate and poor in 8%, 69% and 14%, respectively. Transplantation was performed from an haploidentical donor (35%), matched sibling donor (27%), an unrelated donor (20%) or cord blood (18%). Seventy percent of patients received a myeloablative and 30% a reduced-intensity conditioning regimen. TTP was mostly combined with fludarabine (43%), fludarabine + busulfan (32%) and cyclophosphamide (25%). Median dose of TTP was 10 mg/kg (IQR: 10 – 16).Neutrophil engraftment was 92±3% at a median day of 16 (range, 8 – 38). Mucositis (all grades) occurred in 46.8% of patients with a median day of onset at day 3 after HSCT. Incidence of sinusoidal obstruction syndrome (SOS) was low: 4.3% of patients developed SOS with a median day of onset at day 8 post-transplant.Non-relapse mortality after 100 days was 19±2%. Incidence of acute GvHD (Grade> II) was 26% at day 100, while chronic GvHD occurred in 28±3% at 3 years (56% with limited and 44% with extensive disease).204 patients died. Main cause of death was infection (35%), original disease (31%), GvHD (10%), interstitial pneumonia (6%), SOS (2%) and other transplant related causes (15%). Two patients died due to a secondary malignancy (1%).With a median follow-up of 37 months, non-relapse mortality at 3 years was 38±4%, 50±6% and 45±6% for patients in CR1, CR2+ and advanced disease, respectively (p=0.10). Relapse incidence at 3 years was 20±3% (CR1), 31±5% (CR2+) and 41±5% (advanced disease; p=0.002). Three-year leukemia-free survival and overall survival were 41±1% and 46±4% (CR1), 20±10% and 28±5% (CR2+) and 14±4% and 14±4% (advanced disease), respectively (p<10-4 for both, leukemia-free and overall survival).ConclusionThis large survey suggests that TTP-based conditioning therapy in AML is feasible and effective, with main outcomes being comparable to results achieved with other regimens. Of note, side effects incidence (e.g. SOS and mucositis) is relatively low. The latter might explain the increased use of this agent in conditioning regimens prior to allogeneic HSCT. DisclosuresMohty:Riemser : Research Funding.

The DOT1L Inhibitor EPZ-5676: Safety and Activity in Relapsed/Refractory Patients with MLL-Rearranged Leukemia

The DOT1L Inhibitor EPZ-5676: Safety and Activity in Relapsed/Refractory Patients with MLL-Rearranged Leukemia

Can a national dataset generate a nomogram for necrotizing enterocolitis onset?

Mother's own milk and donor human milk use is increasing as a means of necrotizing enterocolitis (NEC) prevention. Early onset of enteral feeding has been associated with improvement of many outcomes but has not been shown to reduce the incidence of NEC. Better definition of the window of risk for NEC by gestational strata should improve resource management with respect to donor human milk and enhance our understanding of NEC timing and pathogenesis. Our objective was to establish a NEC dataset of sufficient size and quality, then build a generalizable model of NEC onset from the dataset across gestational strata. We used de-identified data from the Pediatrix national dataset and filtered out all diagnostic confounders that could be identified by either specific diagnoses or logical exclusions (example dual diagnoses), with a specific focus on NEC and spontaneous intestinal perforation (SIP) as the outcomes of interest. The median day of onset was plotted against the gestational age for each of these diagnoses and analyzed for similarities and differences in the day of diagnosis. Onset time of medical NEC was inversely proportional to gestation in a linear relationship across all gestational ages. We found the medical NEC dataset displayed characteristics most consistent with a homogeneous disease entity, whereas there was a skew towards early presentation in the youngest gestation groups of surgical NEC (suggesting probable SIP contamination). Our national dataset demonstrates that NEC onset occurs in an inverse stereotypic, linear relationship with gestational age at birth. Medical NEC is the most reliable sub-cohort for the purpose of determining the temporal window of NEC risk.

Association Between Sedating Medications and Delirium in Older Inpatients

To examine the association between Beers criteria sedative medications and delirium in a large cohort of hospitalized elderly adults with common medical conditions. Retrospective cohort and nested case-control studies. 374 U.S. hospitals. All individuals aged 65 and older admitted to the hospital between September 2003 and June 2005 with one of six principal diagnoses (acute myocardial infarction, chronic obstructive pulmonary disease, community-acquired pneumonia, congestive heart failure, ischemic stroke, urinary tract infection). Primary outcome was presumed hospital-acquired delirium, defined as initiation of an antipsychotic medication or restraints on hospital Day 3 or later. Logistic and proportional hazards regression were used to model the associations between sedative exposure and delirium. The dataset contained 225,028 participants (median age 82; 58% female). Four percent fit the definition of hospital-acquired delirium (median onset Day 5). In all, 38,883 (17%) participants received one or more sedative medications. In the cohort study, diphenhydramine (adjusted odds ratio (AOR) = 1.22, 95% confidence interval (CI) = 1.09-1.36) and short-acting benzodiazepines (AOR = 1.18, 95% CI = 1.03-1.34) were associated with greater risk of subsequent delirium. In the nested case-control study, diphenhydramine, short- and long-acting benzodiazepines and promethazine were associated with delirium. Amitriptyline and muscle relaxants were not associated with delirium in either study. Confounding by indication could not be excluded for drugs that are sometimes used improperly to treat delirium. An association was found between several Beers criteria sedative medications and delirium in hospitalized medical patients. Given the prevalence of these medications and the morbidity associated with delirium, further investigation into the appropriateness of such prescribing is warranted.

Role of Allogeneic Stem Cell Transplantation for Adult T-Cell Leukemia in an HTLV-1 Non-Endemic Area of Japan.

AbstractAbstract 3089Adult T-cell leukemia/lymphoma (ATL) mainly occurs in HTLV-1 endemic areas such as the southwest island in Japan (Kyushu) and Caribbean countries. A recent report showed that the incidence of ATL was increasing in HTLV-I non-endemic areas (1). Although allogeneic stem cell transplantation (allo-SCT) has been considered to be the only curative treatment for ATL (2, 3), there has been no report about the treatment strategy for ATL occurring in HTLV-1 non-endemic area. We therefore conducted a retrospective analysis for all of the patients who developed ATL and received allo-SCT in an HTLV-1 non-endemic area of Japan, Hokkaido (a northernmost island).Clinical data for 56 patients who received allo-SCT were collected from 12 SCT centers in Hokkaido, Japan. The median age of the patients was 57 years (range: 37 – 69 years). Twenty-eight of the patients had acute type and 22 had lymphoma type. Median count of white blood cells and median levels of serum LDH and serum soluble interleukin-2 receptor (sIL-2R) at diagnosis were 10900/mL, 352 IU/L and 11153 mg/dL, respectively. After chemotherapies mainly using CHOP or VCAP–AMP–VECP regimens, twenty-three of the patents received allo-SCT in complete remission (CR), and the other patients received allo-SCT in non-CR (partial remission, n=16; primary refractory, n=9; relapse, n=23). Median levels of serum LDH and sIL-2R before the conditioning regimen were 218 IU/L and 1153 mg/dL, respectively. HCT-CI scoring was available in 42 of the patients, and the scores were 0 in 15 patients, 1 in 10 patients, 2 in 5 patients and more than 3 in 9 patients. Thirty-nine of the patients received bone marrow, 11 of the patients received peripheral blood stem cells and 6 of the patients received cord blood. Thirty of the patients received SCT from HLA-matched siblings, 22 of the patients received SCT from HLA-matched unrelated donors and 14 of the patients received SCT from HLA-mismatched donors. Seventeen patients received myeloablative conditioning and the other 39 patients received reduced-intensity conditioning. Fifty-three (95%) of the patients achieved neutrophil engraftment at median day of 16. Acute graft-versus-host disease (AGVHD) and grade II-IV AGVHD occurred in 40 (75%) and 31 (58%) evaluable patients, respectively, at median onset day of 29. Chronic GVHD (CGVHD) occurred in 24 (38%) evaluable patients at the median onset day of 168. After a median follow-up period of 48 months, 1-year overall survival (OS) and 5-year OS rates were 56.3% and 46.5%, respectively The survival curve reached a plateau at 22 months after SCT. Univariate analysis showed that year in which SCT was performed, male sex, high level of sIL-2R both at diagnosis and at SCT, and disease status (non-CR at SCT) were significant risk factors for overall survival. SIL-2R at SCT (P=0.02) was determined to be a significant risk factor for disease progression and male sex was marginally significant (P=0.06) by univariate analysis. Non-CR at SCT was marginally significant for transplant-related mortality (P=0.07). Worse survival for male patients and patients in non-CR at SCT were confirmed by using multivariate analysis with Cox’s regression model [hazard ratio of 3.15 (95% confidence interval: 1.36–7.30) for male patients and hazard ratio of 2.70 (95% confidence interval: 1.01–7.24) for non-CR patients].This is the first report on ATL patients in a non-endemic area who received allo-SCT, and we think that this report shows very important information for management of ATL patients in non-endemic areas. Disclosures:No relevant conflicts of interest to declare.

An Algorithm Combining Clinical Characteristics and Day 7 Biomarker Concentrations Predicts Future Graft-Versus-Host Disease Following Related Donor Hematopoietic Cell Transplantation

AbstractAbstract ▪463▪This icon denotes a clinically relevant abstractWe have recently described an algorithm combining biomarkers and clinical characteristics, such as severity, that, when assessed at the onset of GVHD symptoms, predicts outcomes such as response to treatment and non-relapse mortality [Levine, Blood, 2012]. This approach maximizes the information (both laboratory and clinical) utilized to develop the predictive algorithm. We have now evaluated whether a combination of pre-HCT clinical characteristics and GVHD biomarkers measured early post-HCT can predict the future occurrence of GVHD with sufficient accuracy and lead time to facilitate the preemptive treatment of a large majority of patients at high risk prior to the onset of GVHD symptoms.We studied 393 patients who received a first allogeneic HCT from related donors between 2001 and 2011 at the University of Michigan whose clinical data and plasma samples were collected prospectively on an IRB-approved protocol. The cumulative incidence of grade 2–4 GVHD by day 100 was 31% (n=121; biopsy proven in 91%); at onset of symptoms (median = day 40), GVHD affected skin alone in 40 pts (33%), GI tract alone in 48 (40%), liver alone in three (2%), and multiple organs in 30 (25%). We divided patients randomly into a training set (n=264) to develop an algorithm to predict acute GVHD using clinical and biomarker parameters by logistic regression, and a validation set (n=129) to test the algorithm. There were no statistically significant differences in pre-HCT clinical parameters between the two sets. We measured a panel of 4 informative GVHD biomarkers (IL-2Rα, TNFR1, elafin, and REG3α) on plasma samples taken at day 7 after HCT by ELISA.We postulated that day 7 biomarker concentrations would be most accurate in predicting early acute GVHD, and we therefore used grade 2–4 GVHD onset in the first two months post-HCT as the predictive endpoint. We developed three predictive models for GVHD in the training set: one model used 5 validated clinical characteristics alone (patient age, graft source [BM], HLA-match, GVHD prophylaxis, myeloablative conditioning [MA], use of TBI [Jagasia, Blood 2012]); the second used 4 biomarker concentrations alone; and the third used the combination of all 9 clinical and biomarker parameters. We postulated that an algorithm with a specificity of 50% or higher would be useful, so we compared all three models at a specificity of 50% for their respective sensitivities. The 5 pre-HCT characteristics alone provided 51% sensitivity; 4 biomarkers alone provided 66% sensitivity; and the combined 9 clinical and biomarker parameters provided 77% sensitivity (Table; combined vs clinical model, p<0.001; vs biomarker model, p=0.07). We then tested the sensitivity of the combined model in the validation set and found it to be 75%. The similar sensitivities in the two sets allowed us to combine them for further analyses.We used the algorithm to classify patients as “high risk” (n=211) or “low risk” (n=182) for the occurrence of acute GVHD. Patients with a high risk panel were much more likely to develop grade 2–4 GVHD (Figure 1A; cumulative 38% vs 20%, p<0.001) which developed almost one month earlier than in the low risk group (median day of onset = 39 vs 65). The greater incidence of acute GVHD in high risk patients resulted in significantly greater non-relapse mortality (NRM) by day 180 post-HCT (12% vs 3%; p=0.001; Figure 1B). The relapse rate was identical in both groups (24%) and thus overall survival was significantly better in the low risk group (84% vs 73%, p=0.004). At one year post-HCT, the differences between high and low risk patients remained significant for NRM (17% vs 6%, p<0.001) and overall survival (61% vs 72%, p=0.01).In conclusion, the best algorithm to predict acute GVHD in recipients of related donor HCT combined a panel of 4 biomarkers at day 7 after HCT and 5 pre-HCT clinical characteristics. The algorithm successfully stratified patients into high and low risk groups for acute GVHD, six month NRM and overall survival. We hypothesize the use of such an algorithm one week after HCT may permit preemptive treatment of patients who are at greatest risk early in their transplant course. We are currently analyzing whether biomarkers at a later time point will identify patients at greatest risk for late-onset GVHD.TableCombined predictive algorithmScore = -3.57 + 0.54xAge–16.83xBM + 1.35xMismatch - 0.08xGVHD prophy + 0.35xMA + 0.47xTBI + 0.37xlogIL2Rα – 0.06xlogTNFR1 – 0.12xlogElafin – 0.03xlogREG3α [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Prevalence of Acute Lung Injury Among Medical Patients in the Emergency Department

Acute lung injury (ALI) affects an estimated 190,000 persons per year in U.S. intensive care units (ICUs), but little is known about its prevalence in the emergency department (ED). The objective was to describe the prevalence of ALI among mechanically ventilated adult nontrauma patients in the ED. The hypothesis was that the prevalence of ALI in adult ED patients would be low. This was a retrospective cohort study of admitted nontrauma patients presenting to an academic ED. Two trained investigators abstracted data from patient records using a standardized form. The use of mechanical ventilation in the ED was identified in two phases. First, all ED patients were screened for the current procedural terminology (CPT) code for endotracheal intubation (CPT 31500) from January 1, 2003, to December 31, 2006. Second, each patient record was reviewed to verify the use of mechanical ventilation. ALI was defined in accordance with a modified version of the American-European Consensus Conference criteria as: 1) hypoxemia defined as PaO(2) /FiO(2) ratio ≤300 mm Hg on all arterial blood gases (ABGs) in the ED and the first 24 hours of admission, 2) the presence of bilateral infiltrates on chest radiograph, and 3) the absence of left atrial hypertension. Data are presented in absolute numbers and percentages. Interobserver agreement was evaluated using the kappa statistic. Of the 552 patients who received mechanical ventilation in the ED and were subsequently admitted, a total of 134 (24.3%, 95% confidence interval [CI] = 20.8% to 28.0%) met hypoxemia criteria. Of these, 34 had evidence of left atrial hypertension, 52 did not have chest radiograph findings consistent with ALI, and two did not have a chest radiograph performed; the remaining 46 met ALI criteria. An additional two patients who died in the ED had clinical evidence of ALI. Thus, 48 of 552, or 8.7% (95% CI = 6.6% to 11.3%), met criteria for ALI. The kappa value for determination of ALI was 0.84 (95% CI = 0.54 to 1.0). The prevalence of ALI was nearly 9% in adult nontrauma patients receiving mechanical ventilation in the ED. Further study is required to determine which types of patients present to the ED with ALI, the extent to which lung protective ventilation is used, and the need for ED ventilator management algorithms.

P.3.c.025 A randomised, double-blind, placebo-controlled 24-week trial of aripiprazole in recently remitted bipolar I patients

Bright light therapy (BLT) is an effective treatment for seasonal affective disorder and non- seasonal depression. The efficacy of BLT in treating patients with bipolar disorder is still unknown.The aim of this study is to examine the efficacy, onset time and clinical safety of BLT in treating patients with acute bipolar depression as an adjunctive therapy (trial registration at ClinicalTrials.gov: NCT02009371).This was a multi-center, single blind, randomized clinical trial. Seventy-four participants were randomized in one of two treatment conditions: BLT and control (dim red light therapy, dRLT). Sixty-three participants completed the study (33 BLT, 30 dRLT). Light therapy lasted for two weeks, one hour every morning. All participants were required to complete several scales assessments at baseline, and at the end of weeks 1 and 2. The primary outcome measures were the clinical efficacy of BLT which was assessed by the reduction rate of HAMD-17 scores, and the onset time of BLT which was assessed by the reduction rate of QIDS-SR16 scores. The secondary outcome measures were rates of switch into hypomania or mania and adverse events.1) Clinical efficacy: BLT showed a greater ameliorative effect on bipolar depression than the control, with response rates of 78.19% vs. 43.33% respectively (p < 0.01). 2) Onset day: Median onset day was 4.33 days in BLT group. 3) BLT-emergent hypomania: No participants experienced symptoms of hypomania. 4) Side effects: No serious adverse events were reported.BLT can be considered as an effective and safe adjunctive treatment for patients with acute bipolar depression.