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Abstract Background : Thrombosis is a characteristic feature in essential thrombocythemia (ET) and polycythemia vera (PV). Previous studies had focused on thrombotic events occurring after diagnosis and did not always distinguish between arterial and venous thrombosis. Arterial thrombosis in ET has been associated with age >60 years, JAK2 mutations, leukocyte count >11 x 109/l, history of thrombosis and cardiovascular risk factors, and venous thrombosis with male sex (Blood 2011;117:5857). In the current two-enter study, we looked for associations between both driver and other mutations, with first incidences of arterial and venous thrombosis in ET and PV, analyzed together and separately. Methods : Study patients were recruited from the Mayo Clinic, Rochester, MN, USA and the University of Florence, Florence, Italy, based on availability of next-generation sequencing-derived mutation information. Diagnoses were according to the 2016 World Health Organization criteria (Blood. 2016;127:2391). Conventional statistics was employed to examine significance of associations, with separate analysis of arterial vs venous thrombosis, occurring at any time before or after formal diagnosis of ET or PV. For the purposes of the current study, only first events were considered. Results: 906 molecularly-annotated patients (416 from Mayo and 490 from Florence), including 502 ET and 404 PV cases, were included in the current study. The Mayo/Florence cohorts included 270/232 ET (median age 57/54 years, 60%/59% females) and 146/258 PV (median age 63/58 years, 52%/44% females) patients; median follow-up was 9.9/12.9 years for ET and 10.7/12.4 years for PV. Driver mutation distribution in ET was 55% JAK2, 27% CALR, 5% MPL and 13% triple-negative. Most frequent mutations, other than JAK2/CALR/MPL, were TET2 (14%; 11% in ET and 18% in PV) and ASXL1 (13%; 13% in ET and 13% in PV). 301 (33%) patients experienced first time thrombosis, before or after diagnosis, including 152 (30%) in ET and 149 (37%) in PV (p=0.03); arterial events occurred in 174 (19%) patients, including 96 (19%) in ET and 78 (19%) in PV (p=0.9); venous events occurred in 177 (20%) patients, including 82 (16%) in ET and 95 (24%) in PV (p=0.007). The number of vascular events after diagnosis was 174 (19%) for arterial and 154 (17%) for venous thrombosis, with no significant difference between ET and PV. Associations with arterial thrombosis: In multivariable logistic regression analysis that included both ET and PV (n=906), age >60 years (23% vs 16%; OR, 1.6, 95% CI 1.1-2.2) and absence of ASXL1 and RUNX1 mutations (21% vs 9%; OR 2.6, 95% CI 1.4-4.8) were associated with arterial thrombosis; these associations remained significant (or near significant) when ET and PV were analyzed separately; in addition, JAK2 mutations in ET displayed borderline significance (p=0.05). Overall incidence of arterial events in ET was estimated at 27% in the presence of all three risk factors (i.e. older age, presence of JAK2 mutations and absence of ASXL1/RUNX1 mutations), 21% with two risk factors, 13% with one risk factor and 9% in the absence of all three risk factors (p=0.01). Associations with venous thrombosis: In multivariable analysis, including both ET and PV (n=906), JAK2 mutations (p<0.001), higher leukocyte count (p=0.03) and younger age (p=0.04) were identified as being significant. Analysis of ET patients only (n=502) identified JAK2 mutations (p<0.001; OR 2.4, 95% CI 1.4-4.1), absence of SRSF2 mutations (p=0.03) and younger age (p=0.04) as independent risk factors and in PV patients (n=404), higher leukocyte count (p=0.06). Prognostic interaction between JAK2 mutations and age: In ET, the overall frequency of venous events was 27% for young patients with JAK2 mutations vs 13% for older JAK2 mutated cases vs 10% for JAK2 unmutated young patients vs 13% for JAK2 unmutated older patients (p<0.001). The corresponding percentages for arterial events were 20%, 24%, 14% and 19%, respectively (p=0.1). Conclusions: JAK2 mutations contribute to the risk of both venous (younger patients) and arterial (young and older patients) thrombosis, in an age-dependent manner; the association with venous thrombosis might explain the higher incidence of venous thrombosis in PV, compared to ET. Additional studies are required to confirm the observed lower risk of thrombosis in patients with ASXL1, RUNX1 and SRSF2 mutations and provide insight into the underlying biological explanation. Disclosures No relevant conflicts of interest to declare.

Abstract Background: While several population-based studies have reported on adverse outcomes and life expectancy in myeloproliferative neoplasms (MPN) (JCO. 2015;33:2288; AJH. 1999;61:10; Leukemia. 2013;27:1874; JCO. 2012;30:2995), large-scale studies reporting mature data have been rare and important questions remain unanswered. The current study documents the Mayo Clinic (MC) decades-long experience with over 3,000 consecutive MPN patients including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) with the majority of patients followed until death. Herein, we provide mature, and importantly, risk-stratified survival data and disease complication estimates. Methods: Study patients were recruited from MC, Rochester, MN, USA between 10/27/1967 and 12/29/2017. All MPN diagnoses and documentation of fibrotic/leukemic transformations were in accordance with the 2016 World Health Organization criteria (Blood. 2016;127:2391). Clinical and laboratory data were abstracted from medical records. Risk-stratification used conventional risk models considering age, leukocytes, and venous thrombosis for PV (Leukemia. 2013;27:1874), international prognostic score for ET (Blood. 2012;120:1197), and dynamic international prognostic scoring system for PMF (Blood. 2010;115:1703). Statistical analyses were based on parameters obtained at the time of referral to MC which, in the majority of cases, coincided with or was within 1 year of diagnosis. All patients were followed from diagnosis until death or date of last follow-up/contact. Recipients of allogeneic stem cell transplants were censored at the time of transplant. Standard statistical methods and time-to-event curves prepared using the Kaplan-Meier method were used to compare MPN subgroups. Survival data for low-risk ET/PV were compared with age- and sex-matched controls from Olmstead County, MN, USA. JMP® Pro 13.0.0 software (SAS Institute, Cary, NC, USA) was used for all analyses. Results: 3,023 consecutive patients (median age 62 years, range 18-96; 51% males) were considered, including 89% diagnosed within the year: 665 PV, 1076 ET and 1282 PMF. Conventional risk stratification in 2925 evaluable patients revealed low, intermediate, and high-risk status in 26%, 29%, and 45% of PV and 30%, 42%, and 28% of ET patients, respectively, while PMF cases were attributed low (14%), intermediate-1 (38%) -2 (40%) and high (8%) risk (Table 1). After a median follow-up of 8.2 years for PV (range 0-39), 9.9 for ET (range 0-47), and 3.2 for PMF (range 0-31), 1631 (54%) deaths, 183 (6%) leukemic transformations, 244 (14%) fibrotic progressions, and 516 (17%) thrombotic events were recorded (Table 1). Median overall survival (OS) was 18 years for ET, 15 for PV and 4.4 for PMF (p<0.05 for all inter-group comparisons) (Figure 1A). Leukemia-free survival was similar for ET and PV (p=0.22) and significantly worse for PMF (p<0.001) (Figure 1B). PV, compared to ET, was associated with higher risk of fibrotic progression (p<0.001) (Figure 1C). Thrombosis risk after diagnosis was highest in PV and lowest in PMF (p=0.002 for PV vs ET; 0.56 for ET vs PMF; and 0.001 for PV vs PMF) (Figure 1D). Following risk stratification, median OS in low-risk ET (28 years) and low-risk PV (27 years) were superimposed (p=0.89) (Figure 2). Similarly, intermediate or high-risk PV and ET patients had comparable OS within each risk strata (p=0.23 and 0.11, respectively). Low-risk PMF survival was analogous to that of intermediate-risk PV (p=0.06). All other risk-stratified categories disclosed significantly different inter- and intra-group survival patterns (p<0.001) (Figure 2). Despite their categorization as favorable-risk disease, both low-risk ET and low-risk PV displayed excess mortality relative to age- and sex-matched controls with median survival of 26.7 and 28.1 years respectively, compared to the expected 37.5 and 39.2 years (p<0.001) (Figure 3). Conclusions: The current study provides large-scale and uniquely mature survival and outcomes data in MPN and highlights MPN subgroup risk categorization as cardinal in appraising disease natural history. Interestingly, OS was only marginally better in ET, compared to PV, while the latter clearly displayed a higher risk of thrombosis and fibrotic progression. Moreover, data disclosed shortened life expectancy relative to matched controls even in MPN with favorable risk attribution. Disclosures Busque: BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy.

291 Background: Cholangiocarcinoma (CCA) has limited treatment options. Genomic analyses have led to development of targeted therapies now in clinical trials, and may enable discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Comparative data regarding circulating tumor DNA (ctDNA) analysis and tissue based profiling in CCA are limited. Methods: We performed ctDNA NGS analysis along with tissue based profiling in pts with advanced CCA (January 2015- February 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA) which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes and the majority of tissue based profiling using Foundation One. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance was defined as alterations within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic IRB requirements. Results: Among 124 pts and 139 total samples, ctDNA NGS revealed at least one genomic alteration (excluding variants of uncertain significance and synonymous mutations) in 89% of pts. Median number of alterations per pt was 3 [range, 1-15], with a median MAF of 0.42% (range, 0.1% - 94.2%). The total number of unique alterations was 321. The most commonly altered genes: TP53 (31%), KRAS (11%), FGFR2 (7%), APC and PIK3CA (each 5%) and ARID1A (3%). Amplifications were noted in 14 genes: BRAF, CCND1, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, MET, MYC, PDGFRA, and PIK3CA. Tissue-based profiling was available in 57 (46%) pts, with a median of 63 days between liquid and tissue biopsy. IDH1, FGFR2, TP53 and KRAS were most common gene mutations found in pts who had both liquid and tissue biopsy done. (Comparative results to be shown). Conclusions: ctDNA plasma profiling of pts with advanced CCA is a feasible alternative method to gather comprehensive genomic data. Further larger cohort studies comparing landscape of alterations seen on ctDNA versus tissue-based assays are needed.

289 Background: PDAC has limited treatment options. Genomic analyses have led to development of targeted therapies now in several clinical trials, and may enable the discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Data regarding circulating tumor DNA (ctDNA) profiling in PDAC during real time clinical practice is limited. Methods: We performed ctDNA NGS analysis in pts with advanced PDAC (December 2014–August 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA), which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance (TR) was defined as possible treatments within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic Institutional Review Board requirements. Results: Among 171 pts and 206 total samples, ctDNA NGS revealed at least one genomic alteration in 150 pts (88%). Median number of alterations per patient was 3 [range, 1-15]. The total number of unique alterations was 450 with the most commonly altered genes being: TP53 (181 alterations, 40%), followed by KRAS (118 alterations, 26%), CDKN2A (23 alterations, 5%), SMAD4 (15 alterations, 3%), EGFR (11 alterations, 2.4%), PIK3CA (9 alterations, 2%), GNAS (8 alterations, 1.5%). Amplifications were noted in 16 genes, including BRAF, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, KIT, KRAS, MET, MYC, PDGFRA, PIK3CA and RAF1. Therapeutically relevant alterations were seen in 95 pts of the 150 pts (63%). Tissue based profiling (Results to be shown) was done in 56 (33%) pts of total 171 pts with a median of 130 days between ctDNA and tissue biopsy. KRAS and TP53 were the most common gene mutations found in patients with both liquid and tissue biopsy results. Conclusions: ctDNA plasma profiling of pts with advanced PDAC is a feasible alternative method to gather comprehensive genomic data.

288 Background: Obesity is a risk factor for developing cholangiocarcinoma (CCA). However, the effect of obesity on survival of CCA is unclear. The primary aim of this study was to analyze the impact of obesity upon overall survival of CCA patients. Secondary aims were to analyze impact of obesity upon other disease characteristics such as tumor site, stage, age, sex, BMI and Ca 19-9. Methods: A total of 411 unique pts diagnosed with CCA at Mayo Clinic Florida between 2000 and 2018 were retrieved from our collective SDMS database. Variables evaluated included:demographics, Body Mass Index (BMI), AJCC stage, tumor location and Ca 19-9.A total of 185 pts had all data available pertaining to these variables. We further restricted the analysis to pts with intrahepatic CCA classified BMI as per CDC criteria normal (18.5-25kg/m2), overweight (25-29.9kg/m2) and obese (≥30 kg/m2), thus leaving a total of 152 pts. Continuous and categorical variables were compared across BMI groups using Chi-squared or Fisher’s exact test. Overall survival rates after diagnosis at 1, 2 and 3 years were estimated using Kaplan-Meier method. Results: Among 152 pts included in the study, 28% were normal weight, 40% were overweight and 32% were obese. The overall survival rate at 1, 2 and 3 years for normal weight pts with all stages combined was 54.1%, 35%, and 30.7%, respectively. The overall survival rate at 1, 2 and 3 years for overweight pts with all stages combined was 59.7 %, 32.6%, and 25.4%, respectively. The overall survival rate at 1, 2 and 3 years for obese pts with all stages combined was 63.9%, 37.6%, and 26.7%, respectively(p = 0.8766). Multivariate analysis demonstrated is no significant difference in overall survival for obese pts compared to normal or overweight pts.(Table to be shown) However it showed, gender and Ca19-9 were statistically significant predictors of overall survival, with males and pts with Ca19-9≥100 doing worse (HR1.65 (CI = 1.05, 2.61, p = 0.031) and HR 2.31 (CI = 1.49, 3.59, p = < 0.01), respectively). Conclusions: BMI did not make a significant impact on the overall survival, though there may be a trend toward worse OS for ptswith higher BMI. A larger, stage focused evaluation is warranted for further exploration of this trend.

OBJECTIVES: Prokinetics are recommended for the treatment of functional dyspepsia (FD) but systematic reviews give conflicting results on the efficacy of these agents. We have therefore conducted an updated systematic review to support the 2017 joint ACG/CAG dyspepsia guidelines. METHODS: Electronic databases, including MEDLINE, EMBASE, and CENTRAL, were searched until September 2017 for randomized controlled trials (RCTs) comparing either prokinetics and placebo or two types of prokinetics to improve FD symptoms. The primary outcome was absence or improvement of dyspeptic symptoms at the end of treatment. Double-blind eligibility assessment and data extraction was performed. Pooled risk ratios of symptoms persisting or adverse events occurring, and standardized mean difference of quality-of-life (QoL) scores with 95% CI, using a random effects model, were calculated. Quality of evidence was assessed using GRADE. RESULTS: The search identified 1388 citations; 38 studies in 35 papers were included. Of these, 29 trials comparing prokinetics with placebo were found. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR 0.81, 95% CI 0.74 to 0.89; I 2 91%; NNT 7), regardless of FD subtype or ethnicity. When comparing two types of prokinetic, the most commonly used comparator was domperidone. There was no difference in reducing global symptoms (RR 0.94, 95% CI 0.83 to 1.07). QoL was not improved with prokinetic treatment. The adverse events with individual prokinetics were not different from placebo, except for cisapride. The GRADE assessment rated the quality of the evidence in each outcome as very low. CONCLUSIONS: From the current evidence, prokinetics may be effective for the treatment in all subtypes of FD, with very low quality of evidence. There was no difference between prokinetics for dyspeptic symptom improvement. High-quality RCTs with large sample sizes of FD patients are needed to verify the efficacy of prokinetics.

Objectives/HypothesisThere are currently no established recommendations for the use of perioperative antibiotics (PAs) to prevent surgical site infections (SSIs) for direct microlaryngoscopy (DML). This study examined the incidence of SSI in patients undergoing DML with and without PAs.Study DesignRetrospective, multi‐institutional chart review.MethodsA retrospective, multi‐institutional chart review was performed at four tertiary referral academic medical centers. Patients undergoing DML from 2010 to 2017 were identified using Current Procedural Terminology codes. Medical records of patients undergoing DML with biopsy, microsurgery, laser ablation, or vocal fold injection who had adequate follow‐up were reviewed. Procedures with significant cartilage destruction, concurrent open surgery, or esophageal surgery were excluded. Data recorded included age, gender, pacemaker history, American Society of Anesthesiologists class, wound class, indication for surgery, use of laser, complications, emergency room visits, hospitalizations, pain, fever, and postoperative steroid and antibiotic prescriptions. Presence or absence of SSIs was evaluated by a fellowship‐trained laryngologist.ResultsThere were 834 patients who met inclusion criteria. Of those, 698 did not receive PAs and 136 received PAs. The median age of patients was 54 years of age in the PA group and 57.5 years of age in the non‐PA group, and all cases were recorded as wound class II. Overall, 58% of surgeries involved use of carbon dioxide or potassium‐titanyl‐phosphate laser. Only one SSI was reported on follow‐up in a patient who did receive PAs.ConclusionsSSIs are exceedingly rare following DML. PA use is not indicated for routine DML.Level of Evidence4 Laryngoscope, 128:2838–2843, 2018

AbstractFirst‐line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second‐line drugs of choice include pegylated interferon‐α, busulfan and anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928‐1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis‐free (MFFS) and thrombosis‐free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1‐1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7‐6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide. Whether or not anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.