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Abstract Introduction: The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression and leukemic transformation in patients with myelofibrosis (MF) is well established. Further, emerging data suggests that the number and type of mutations may impact response to therapies such as ruxolitinib or imetelstat. Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment for MF patients. However, the impact of somatic mutations on overall survival (OS) and relapse-free survival (RFS) is poorly understood. Using next-generation sequencing of pre-transplant blood and bone marrow samples from a well clinically-annotated cohort of MF patients who underwent allo-HSCT, we sought to determine the impact of mutational burden on outcomes. Methods: A multicenter retrospective analysis of a cohort of 84 patients was carried out. This included 52 patients treated on the MPD-RC 101 prospective study (NCT00572897), 18 patients treated at Prince Margaret Hospital, and 14 patients treated at Memorial Sloan Kettering Cancer Center. Patient and transplant characteristics are displayed in Table 1. DNA was extracted from pre-transplant bone marrow aspirate samples or peripheral blood samples. High-throughput sequencing of a panel of genes was performed. Average coverage of 829x (standard deviation of ±130) was obtained. Mutect was utilized to call single point variants (comparing our samples to a pool of normal samples) and PINDEL was used to call short insertions and deletions. We excluded all mutations present in at least one database of known non-somatic variants (DBSNP and 1000 genomes) and absent from COSMIC. Univariate Cox regression and Kaplan-Meier graphics were used to investigate the association of patient, transplant, and disease characteristics with OS and RFS. Results: JAK2V617F was the most frequent mutation detected in 41(48.8%) patients (Table 2). Eighteen patients (21.4%) had triple negative disease (negative for JAK2, MPL, and CALR mutations). Univariate analysis included the following: patient characteristics (age, gender), transplant characteristics (related vs. unrelated donor, matched vs. mismatched donor and myeloablative vs. reduced intensity conditioning) and disease characteristics (DIPSS and presence of mutations). Decreased OS was associated with unrelated donor status (HR 2.09, 95% CI: 1.03-4.23, p=0.04), reduced intensity conditioning (HR 4.21, 95% CI: 1.01-17.59, p=0.049), triple negative disease (HR 2.09, 95% CI: 1.02-4.30, p=0.04), and presence of U2AF1 (HR 2.53, 95% CI: 1.10-5.81, p=0.03) or SUZ12 mutations (HR 3.92, 95% CI: 1.19-12.21, p=0.02). Decreased RFS was associated with unrelated donor status (HR 2.27, 95% CI: 1.16-4.45, p=0.02), and the presence of SUZ12 mutation (HR 6.97, 95% CI: 2.37-20.49, p<0.001). A descriptive decrease in RFS in patients with U2AF1 (HR 2.15, 95% CI: 0.94-4.88, p=0.07) was observed but did not reach statistical significance. Importantly, mutations previously reported to be associated with reduced OS and RFS in the non-transplant setting, such as ASXL1, EZH2, IDH1/2, and SRSF2, were not associated with poorer outcomes in this analysis in transplanted patients. In an exploratory multivariate analysis including donor type (related vs. unrelated) and presence of U2AF1 and SUZ12 mutations, there was a significantly reduced OS and RFS in patients who harbor these mutations regardless of donor type (OS: HR 5.30, 95% CI: 2.08-13.47, p<0.001; RFS: HR 5.49, 95% CI: 2.27-13.30, p<0.001). In patients without the above mutations, having an unrelated donor was associated with worse OS (HR 2.55, 95% CI: 1.09-5.96, p=0.03) and RFS (HR 2.61, 95% CI: 1.17-5.83, p=0.02, Figure 1). Conclusions: Our analysis demonstrates that mutations previously associated with poor prognosis in MF, such as ASXL1, do not appear to confer a worsened prognosis in patients undergoing allo-HSCT, suggesting transplant may be able to overcome the impact of these mutations. However, mutations in SUZ12 and U2AF1 are associated with reduced OS in univariate and multivariate analysis (together with donor type). Further studies with larger cohorts of patients are indicated to validate these findings, and to elucidate the impact of these mutations on disease biology. Disclosures Rampal: Incye and CTI: Consultancy. Mascarenhas:Janssen: Research Funding; CTi Biopharma: Research Funding; Promedior: Research Funding; Merk: Research Funding; Incyte: Research Funding. Mesa:Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Novartis: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

Abstract Background: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Few studies have evaluated patient-reported outcomes during treatment with non-experimental pharmacological regimens. Aims: The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify MPN symptom severity, frequency and quality of life at baseline and throughout treatment with non-experimental therapies utilizing the Myeloproliferative Neoplasm Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS; JCO 2012). In this abstract, we provide updated results for the prospective international cohort trial currently in active enrollment: the MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: This study aims to recruit 180 international ET, PV, and MF (including primary MF and post-ET or post-PV MF) patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF for seven consecutive days at enrollment and repeat the survey for an additional seven consecutive days between 90 days and six months. Patients also complete the European Organisation for Research and Treatment of Cancer (EORTC) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. At visits, physicians acquired demographic, laboratory, physical examination, and radiographic data. Descriptive statistics were used to summarize data. Results: Clinical Data The MEASURE trial opened for enrollment in 2012 and remains in recruitment phase with 15 participating international sites. To date, 39 patients have been enrolled and 25 have completed both study visits. Participants include ET (28%), PV (24%), and MF (48%; 50% primary MF, 8% post-ET, 42% post-PV) patients. The majority of patients are male (64%) and of expected age (mean 69.3, range 39-89) for the disorders. Seventeen percent had prior thrombosis, 9% required red blood cell transfusion, and none reported prior splenectomy or hemorrhage. Mean hematologic measures included hemoglobin 13.2 g/dL, WBC count 11.4 x109/L, ANC 8.5 x109/L, and platelets 514 x109/L. Therapies received prior to enrollment included aspirin (n=16), hydroxyurea (n=11), phlebotomy (n=8), warfarin/clopidogrel/anticoagulation (n=8), erythropoietin (n=2), and interferon (n=1). The most common current MPN therapies were hydroxyurea (n=9), aspirin (n=9), interferon (n=4), and phlebotomy (n=2). Symptom Assessment In comparing MPN-SAF TSS mean symptom scores, all symptoms except bony pain improved between the first and second visits, including fatigue, early satiety, abdominal discomfort, inactivity, concentration, night sweats, itching, fever, weight loss, and overall quality of life (Figure1). Total MPN-SAF TSS scores improved from a mean of 32.3 to 25.9. On the EORTC, mean scores for physical, role, emotional, and social functioning improved from the first to the second visit (Figure 2). Cognitive functioning showed a slight decline. Global health status measure improved from 60.2 to 72.9. On the MDASI, symptom severity scores decreased from 3.6 to 2.8 from the first to second visit (Figure 3). Symptom distress measure decreased from 4.1 to 3.0. Discussion: Interim results from the MEASURE trial demonstrate that standard, non-experimental treatment regimens offer improvement in quality of life-related symptoms on multiple patient-reported survey instruments including the MPN-SAF TSS, EORTC QLQ-C30, and MDASI. Updated data including symptom correlations and mutational analysis to be presented at the 2016 ASH conference. Disclosures Ross: Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Radia:Novartis: Honoraria; Pfizer: Honoraria. McMullin:Novartis: Honoraria, Speakers Bureau. Cargo:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Sekhar:Novartis: Research Funding. Mesa:Gilead: Research Funding; CTI Biopharma: Research Funding; Galena: Consultancy; Ariad: Consultancy; Incyte: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Promedior: Research Funding.

Abstract Abstract 664 Background: Survivors of childhood acute lymphoblastic leukemia (ALL) who received prophylactic cranial radiation therapy (CRT) are at increased risk for deficits in neurocognitive skills, including attention, working memory and processing speed. As survivors age, global brain injury from CRT may reduce cognitive reserve, placing them at risk for early onset dementia or long-term memory deficits. The prevalence of dementia and memory abnormalities in adult survivors of childhood ALL has not previously been established. Methods: Analyses were conducted on 265 of 445 (60%) eligible survivors of childhood ALL (median age 36 years, range 26–54 years; 52% female) treated with 18Gy (n=127) or 24Gy (n=138) CRT with a median time from CRT of 30 years (range 15–46 years). Participants completed the Wechsler Memory Scale IV, including the Brief Cognitive Status Exam (BSCE), and the Wechsler Abbreviated Scale of Intelligence (WASI). Age-adjusted standard scores were calculated and the BSCE was also adjusted for education level. Prevalence of memory impairment (<1 SD below age-expected mean), stratified by RT dose exposure, is reported and logistic regression used to identify risk factors for impairment. A subset of survivors (n=85) completed brain magnetic resonance imaging (MRI), including assessment of hippocampal volume, cortical thickness, white matter volume, diffusion tensor imaging, and functional MRI (fMRI) during a cued-recall memory task. Results: Survivors who received 24 Gy CRT had increased impairment on global measures of both short-term recall (33%; p<0.001) and long-term recall (30%; p<0.001), while no increase in impairment was seen after 18Gy. Impaired short-term recall was associated with smaller right (p=0.02) and left (p<0.01) temporal lobe volumes, while impaired long-term recall was associated with thinner parietal and frontal cortices. On subtests evaluating narrative memory (i.e. story recall) and design memory, increasing RT dose (24 vs. 18Gy) was associated with an increased prevalence of long-term memory impairment (narrative: 28% vs. 12%, p=0.001; designs: 13% vs. 3.2%, p=0.003). However, no CRT dose response was identified for short term narrative and design memory. Survivors with impaired long-term memory for designs demonstrated a compensatory increase in left hippocampal fMRI activation (p=0.005), and the effect was greater in the higher dose group (p = 0.04). The mean score for long-term narrative memory among survivors who received 24Gy was equivalent to the mean score of a 70–74 year old adult population. Neither young age (0–4 years) at CRT (Odds Ratio [OR] 1.4, 95% confidence interval [CI] 0.8–2.7), time from CRT (OR 1.0, 95% CI 0.9–1.1) nor intrathecal methotrexate exposure (OR 3.9, 95% CI 0.4–36.1) were significantly associated with long-term memory deficits. Reduced cognitive status (by BSCE) was identified after 18Gy (9%, p=0.11) and 24Gy (18%, p<0.001), suggesting a CRT dose-response effect. On diffusion tensor imaging, increased radial diffusivity in the frontal, parietal and temporal regions, an inverse measure of white matter integrity, was associated with reduced BSCE. Current employment rates were equivalent (63%) in both CRT dose groups, suggesting no difference in functional status. Conclusions: Aging adult survivors of ALL who received 24Gy CRT have reduced cognitive status and significant impairment in short-term and long-term memory. There appears to be a dose response effect selective for long-term narrative and design memory, but not for short term narrative and design memory. These patterns are consistent with early onset of age-related (long-term) memory loss, and early stage dementia, yet at a median age of only 36 years. After 24Gy, survivors have the narrative memory equivalent to a 70 year-old in the general population. Survivors with memory impairment demonstrated reduced integrity on structural and functional neuroimaging in anatomical regions established as essential for memory formation and long-term recall. However, these memory impairments do not seem to affect functional status (employment rates) suggesting that, rather than frank dementia, deficits in middle adulthood are consistent with mild cognitive impairment (MCI). Longitudinal evaluation of this population is needed as MCI often progresses into early onset dementia with age. Disclosures: No relevant conflicts of interest to declare.

INTRODUCTION: Prometheus IBD sgi Diagnostic (SGI) is an Inflammatory Bowel Disease (IBD) advanced diagnostic test developed by Prometheus Laboratories. It employs a diagnostic algorithm combining serologic, genetic, and inflammatory markers to help with clinical decision making in determining the accuracy of a diagnosis of IBD in patients suspected to have the disease. Moreover, among those it identifies as having IBD, it also seeks to assist in distinguishing those with Crohn's vs. those with ulcerative colitis (UC). In this observational clinical decision making study, we sought to examine the real world application of the SGI at a single tertiary care IBD practice especially in correctly identifying those with Crohn's vs. those with UC. METHODS: We included all adult IBD patients seen at a single tertiary IBD center practice from 2014 to 2017 that had baseline SGI done and during care at the practice, had a diagnosis of IBD (Crohn's or UC) established. We calculated sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and area under the curve based on results of SGI at baseline visit and the eventual established diagnosis of UC or CD. RESULTS: Of a total of 275 patients, there were 96 (34.9%) male patients and 179 (65.1%) female patients. The median age of these patients was 45.8. There were a total of 201 patients with biopsy proven CD. Of these, 104 were identified as having CD based on the baseline SGI and 97 who were identified as not having CD. Based on these data, the sensitivity of the SGI for CD at the practice was 52%, specificity was 88%, PPV was 92%, NPV was 40.1%, diagnostic accuracy was 61.5%, and Area under ROC was 70%. There were 66 patients with biopsy proven UC. Of these, 44 were identified as having UC based on the baseline SGI and 22 were identified as not having UC. Based on these data, the sensitivity of the SGI for UC at the practice was 67%, specificity was 85%, PPV was 58%, NPV was 89%, accuracy was 80%, and Area under ROC was 76%. CONCLUSION: Based on the results of this study, we conclude that the SGI is not a robust initial test in identifying those with Crohn's or those with UC. However, in a cohort of IBD patients seen at a tertiary care IBD practice, it is reasonably specific and accurate when it comes to correctly confirming Crohn's and even more so UC in patients with a caveat that the results should be interpreted in the proper clinical context and with the backing of other clinical indicators.

INTRODUCTION: Crohn's Disease (CD) is a chronic inflammatory condition, primarily of the gastrointestinal tract with an increasing incidence and prevalence worldwide. In clinical practice, gastroenterologists are often faced with challenges in evaluating disease activity, severity, and prognosis to guide appropriate management of CD. We studied the association between serum albumin level and the rate of active clinical disease in CD patients seen at a tertiary care Inflammatory Bowel Disease (IBD) referral center. METHODS: We designed a retrospective cohort study using adult patients (>18 years) with CD followed for at least one year at University of Alabama at Birmingham (UAB) IBD center by a single trained IBD specialist between 2014-2018. Serum albumin levels were divided into: low mean serum albumin (≤3.2 mg/dL) vs. appropriate mean serum albumin (>3.2 mg/dL). Clinical disease activity was measured using the Harvey-Bradshaw index (HBI). Active disease was defined as HBI score of 8 or higher. Poisson Regression Models (GPR) for Rate Data were used to estimate partially adjusted and fully adjusted incidence rate ratios (IRR) of active clinical disease among CD patients. We also examined IRRs for serum albumin level as a continuous variable. RESULTS: In this single IBD practice at UAB, 269 patients with CD had albumin drawn at initial visit and serially at each subsequent visit. Poisson regression model adjusted for age, gender, race, duration of disease, steroid use, smoking and Crohns location demonstrated that CD patients with a low mean serum albumin during clinical observation were approximately 1.5 times more likely to have active clinical disease during observation (IRR 1.49, 95% CI 1.04-2.15, P = 0.032) compared to those with a serum albumin level of >3.2 mg/dL. The adjusted model with serum albumin as a continuous variable demonstrated that with every unit (0.1 mg/dL) reduction in mean serum albumin, there was 30% higher likelihood of active Crohns in clinic (IRR 1.30, 95% CI 1.02-1.66, P = 0.037). CONCLUSION: Lower mean serum albumin during clinical observation is associated with a higher likelihood of active clinical disease among CD patients. Whether interventions designed to correct or increase serum albumin stores/levels in these patients would be beneficial remains to be examined.

Abstract This study was designed to correlate clinical findings with the extent of pathologic a-synuclein (aSyn) in the brain using the Unified Staging System for Lewy Body disorders (USSLB). Data from 280 cases from the Arizona Study of Aging and Neurodegenerative Disorders are presented. Each case had a complete USSLB staging and at least 1 full research clinical assessment, including subspecialty neurologist-administered movement and cognitive evaluation. Of the 280, 25.7% were cognitively normal, 8.6% had mild cognitive impairment, and 65.7% had dementia. All cases could be categorized into 1 of 5 USSLB stages (8.6% stage I—olfactory bulb only; 15.4% IIa—brainstem predominant; 13.6% IIb—limbic predominant; 31.8% III—brainstem and limbic; and 30.7% IV—neocortical) yet using the Braak staging system 70 cases (25.3%) could not be classified. Those with USSLB stages III and IV died at a younger age. Multiple measures of motor parkinsonism, cognitive impairment, hyposmia, and probable RBD were significantly correlated with increasing USSLB stage. We conclude that the USSLB is the most comprehensive staging system for all Lewy body disorders and allows for categorization and ranking of all brains with significant correlations to many motor and nonmotor clinical signs and symptoms.

ABSTRACTBackgroundAbnormal color vision and contrast acuity may have significant impact on daily activities.ObjectiveEvaluate color visual acuity, at high and low contrast, in Parkinson's disease (PD) and controls using an iPad application.MethodsColor visual acuity was tested with the Variable Contrast Acuity Chart (King‐Devick Test LLC, Oakbrook Terrace, IL) on an iPad 2 at 40 cms using five colors (red, green, blue, yellow, and black) at low (2.5%) and high (100%) contrast. A numerical score (0–95) was assigned based on the number of correctly identified letters.ResultsThirty‐six PD (mean ± standard deviation age 68 ± 10 years) and 36 controls (72 ± 11.2 years) were studied. PD disease duration was 6.4 ± 4.6 years; MDS‐UPDRS part II was 11.7 ± 7.0, and part III was 24.5 ± 9.9. After adjusting for age and sex, PD patients had significantly (P < 0.05) lower scores at high (100%) as well as low (2.5%) contrast for all five colors tested (red, green, blue, yellow, and black), except yellow low contrast (2.5%; P = 0.10). The largest effect size (0.88) was with yellow high contrast, and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy using a cut‐off score of 82 was 31%, 97%, 92%, 58%, and 64%, respectively. No correlation to disease duration was found.ConclusionsThis iPad application may be a simple‐to‐use biomarker for assessing color vision in PD. Further research is needed to determine disease specificity and whether there is a role in monitoring disease progression, treatment response, and identifying prodromal PD.

Background: Telestroke can provide indispensable expert stroke care for rural hospitals. The Stroke Telemedicine for Arizona Rural Residents program was developed in 2006 by Mayo Clinic to provide stroke expertise across the region. However, little data currently exist to determine whether this telestroke program had an impact on accepted acute stroke care metrics, such as door-to-needle time. Hypothesis: Participation of spoke sites in a telestroke program improves stroke care over time, as defined by currently accepted metrics, such as door-to-needle time. Methods: A retrospective analysis was performed on the telestroke database from Mayo Clinic Arizona between the years of 2011 to 2018. All patients with a diagnosis of acute ischemic stroke, who underwent a telestroke consultation and received intravenous alteplase were included in the analysis. Univariate linear regression was performed to look for associations between variables and defined outcomes. Results: A total of 563 patients were identified who met inclusion criteria. Average last-known normal to needle times decreased across all telestroke participating spoke sites from 176 to 147 min, with univariate linear regression showing a trend of decreased time of 3.4 min per year, which was statistically significant (p = 0.0042). Average door-to-needle times decreased from 112 to 81 min, with univariate linear regression modeling showing a decreasing trend of 3.7 min per year (p < 0.0001). Conclusions: Telestroke network participation may be associated with improved acute stroke care metrics over time, with the analysis illustrating improved last-known normal to needle and door-to-needle times among participating spoke sites.

Background: Some epidemiology studies suggest that atherosclerotic cardiovascular disease (ASCVD) risk factors increase the risk of developing Parkinson’s disease (PD). However, conflicting data suggest lower rates of ASCVD in PD. Objective: The objective of this study is to determine, with data from a longitudinal clinicopathological study, whether ASCVD risk factors are associated with a PD diagnosis and/or increased brain or peripheral load of Lewy-type synucleinopathy (LTS). Methods: All subjects were followed to autopsy and neuropathological examination in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Multivariable regression models, including age, gender, and smoking history, were used to investigate the association of a PD diagnosis or brain or submandibular gland LTS load with ASCVD risk factors. Results: 150 subjects were included (PD n = 60, controls n = 90). Univariable comparisons and regression models showed a general trend to inverse associations. The multivariable odds ratio (OR) of brain LTS load for carotid artery disease was 0.93 (95% CI: 0.86 to 0.98; p = 0.02), for anticoagulant use 0.95 (95% CI: 0.90 to 0.99; p = 0.04) and for abnormal heart weight 0.96 (95% CI: 0.92 to 0.99; p = 0.01). Composite clinical and overall (clinical + pathology composite risk scores) composite risk scores were also significantly lower in the PD subjects ( p = 0.0164 and 0.0187, respectively). Submandibular gland LTS load was not significantly related to ASCVD conditions. Conclusions: This study shows associations of higher brain LTS with lower prevalence of both clinical and pathological indices of ASCVD in PD subjects versus age-similar controls. We suggest that this is due to α-synuclein pathology-induced sympathetic denervation in PD.

Abstract Background Guidelines to provide recommendations about driving restrictions for patients with brain metastases are lacking. We aim to determine whether clinical neurologic examination is sufficient to predict suitability to drive in these patients by comparison with an occupational therapy driving assessment (OTDA). Methods We prospectively evaluated the concordance between neurology assessment of suitability to drive (pass/fail) and OTDA in 41 individuals with brain metastases. Neuro-oncology evaluation included an interview and neurological examination. Participants subsequently underwent OTDA during which a battery of objective measures of visual, cognitive, and motor skills related to driving was administered. Results The mean age of patients who failed OTDA was age 68.9 years vs 59.3 years in the group members who passed (P = .0046). The sensitivity of the neurology assessment to predict driving fitness compared with OTDA was 16.1% and the specificity 90%. The 31 patients who failed OTDA were more likely to fail Vision Coach, Montreal Cognitive Assessment, and Trail Making B tests. Conclusions There was poor association between the assessment of suitability to drive by neurologists and the outcome of the OTDA in patients with brain metastases. Subtle deficits that may impair the ability to drive safely may not be evident on neurologic examination. The positive predictive value was high to predict OTDA failure. Age could be a factor affecting OTDA performance. The results raise questions about the choice of assessments in making recommendations about driving fitness in people with brain metastases. OTDA should be strongly considered in patients with brain metastases who wish to continue driving.