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AbstractBackgroundTo identify the clinical characteristics and prognostic factors of malignancies involving the pterygopalatine fossa (PPF).MethodsFifty‐seven patients who underwent curative surgery for malignant tumor involving PPF were reviewed.ResultsThe rates for three‐year local control (LC), five‐year disease‐free survival (DFS) and five‐year overall survival (OS) were 55.4%, 34.5%, and 52.7%, respectively. Perineural invasion (PNI) of the maxillary nerve with facial numbness (symptomatic V2 PNI) (P = .04) and cranial involvement (P = .03) were predictors for poor OS. Symptomatic V2 PNI was also a significant predictor for poor LC (P = .05) and DFS (P = .03). Within the subgroup analysis of patients with pathologically confirmed V2 PNI, asymptomatic V2 PNI patients had significantly better LC (71.2% vs 31.8%, P = .05) and DFS (43.8% vs 17.3%, P = .05) compared to symptomatic patients.ConclusionMalignant tumors involving the PPF have diverse pathologies and a poor prognosis. Symptomatic V2 PNI may be an independent poor prognostic factor.

Abstract Abstract 5247 Background: Vena cava filters (VCF) has been used as a method to prevent pulmonary embolism (PE). The indication for VCF in patients with venous thromboembolism (VTE) according to the American College of Chest Physicians (ACCP) guidelines has been changed to recommend that VCF is only indicated in case of contraindication to anticoagulation. Also, there is very limited data describing the long-term effectiveness and safety of these devices if they are not removed. There is no data for VCF in Korea. The aim of this study is to evaluate and compare the change of practice patterns of VCF according to the change of the ACCP guidelines and the outcomes of VCF. Patients and Method: The data from patients who had the placement of VCF from Jan 2001 to Mar 2010 was collected from 6 academic institutes in Korea, retrospectively. We analyzed the patients grouped into 3 groups according to ACCP guidelines published year. These are -2004 group, 2005–2008 group, and 2009- group. Results: All 460 cases were collected and analyzed. Permanent and retrievable filter was 109 (24%) and 351 (76%), respectively. 49% of retrievable filters was attempted to remove and 88% removal success rate was showed. The patient's number is 79 in -2004 group (17%), 254 in 2005–2008 group (55%), and 127 in 2009- group (28%), respectively. The number of patients in indications of VCF was contraindication to anticoagulation 177 (38%), extensive thrombosis for preventing PE 207 (45%), recurrent VTE during anticoagulation 39 (8%), and others 37 (9%), respectively. The practice pattern in indication for VCF was changed in recurrent VTE during anticoagulation (P=0.012). Any complications after VCF insertion were developed in 107/460 (23%) dung follow-up. Inferior vena cava thrombosis, new DVT after placement of VCF, and new DVT with PE after placement of VCF were developed in 45/460 (10%), 91/460 (20%), and 14/460 (3%), respectively. Median follow-up durations were 49.6 months (range, 0–124.4), 12.3 months (0–67.5) and 6.0 months (0–26.9) for -2004, 2005–2008, and 2009- group, respectively. Vena cava thrombosis was significantly decreased in 2009- group (P=0.022). 75% thrombosis-free time was 3.7 months, 13.0 months, and not estimable in -2004, 2005–2008, and 2009- group, respectively (P=0.10). Conclusion: This is first report on VCF in Korea. The practice for indication of VCF insertion in patients with VTE was still out of boundaries from the ACCP guidelines in Korea. Complications after VCF insertion was decreased as time went by. The more follow-up durations was needed to evaluate the development of complication or thrombosis after VCF insertion in 2005–2008 group and 2009- group. Prospective randomized study is needed in Korea to confirm that VCF insertion plus anticoagulation will truly decrease the development of PE than standard anticoagulation. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1280 Poster Board I-302 Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF) are defined as clonal hematopoietic stem cell disorders. These disorders show an inherent tendency for transformation into leukemia (MPN-blast phase) which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, obtained a comprehensive profile of genomic alterations associated with leukemic transformation by using single-nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. A relatively high number of genomic alterations was found in MPN after leukemic transformation with 4.6 ± 0.6 abnormalities per sample compared to only 1.4 ± 0.2 changes per patient in chronic phase (p<0.001). Compared to the cytogenetic data, SNP-chip analysis detected about 47% additional chromosomal changes in the MPN samples, and 31% more in the MPN-blast phase cases, whereas SNP-array allelokaryotyping practically captured all cytogenetic abnormalities in our study population. Several additionally altered regions were detected in patients with MPN-blast phase compared to chronic phase, including both deletion and copy-number neutral-loss of heterozygosity (CNN-LOH) on chromosome 12p (9%) and 21q (9%), involving ETV6 and RUNX1. Notably, deletion and CNN-LOH on 17p involving TP53 were diagnosed in 18% of MPN-blast phase samples, which was highly associated with preceding treatment with alkylating agents (p=0.016). Moreover, trisomy 8, as well as amplification of 8q24.21 involving the MYC gene, were detected in 13% of patients with MPN-blast phase who were almost exclusively negative for the JAK2V617F mutation. Genome-wide inspection of further critical regions with promising new candidate genes involved in the evolution to the MPN-leukemic phase included deletion and CNN-LOH on 7q22.1 (SH2B2) in 18%, duplication/amplification on 19p13.2 (PIN1, ICAM1, CDC37) in 13% and 21q22.2 (ERG) in 9% of MPN patients with blast crisis. In contrast, we detected a decreased frequency of JAK2V617F in MPN-blast phase samples (52%) compared to chronic phase (71%). Also, the percentage of patients with homozygous mutant JAK2 as a result of CNN-LOH was lower in the MPN-blast phase (43%) compared to the chronic phase (53%). Taken together, the data suggest that gain-of-function mutation of JAK2 is not a perquisite for leukemic transformation. Remarkably, CNN-LOH on either 7q or 9p was related to decreased survival after leukemic transformation (p=0.02 and p=0.012, respectively). Given the variety of allelic imbalances, our data suggest that MPN-blast phase appears to be a heterogeneous disease prone to have evolved multiple mechanisms to provide a proliferative advantage to the abnormal leukemic clone. Our analysis of MPN genomes in the chronic compared to the leukemic stage provided new prognostic insights, as well as novel causative genes which might be involved in the transformation to MPN-blast phase. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: CMML is a heterogeneous malignancy characterized by peripheral monocytosis and a propensity for AML transformation. Given the low incidence of CMML and its broad range complexity, a large disease-specific data set is necessary to discern independent co-variates predictive of disease behavior. Several prognostic models derived from smaller data sets have been developed to stratify CMML patients into distinct groups that are predictive for OS. However, the validity of these models in a large international data set has never been investigated. Here, we present the largest International CMML data base established to date and report key baseline characteristics predictive for disease outcome. We externally validate and perform a detailed statistical comparison between the International Prognostic Scoring System (IPSS), Revised (R)-IPSS, Global MD Anderson Scoring System (MDASC), MD Anderson Prognostic Score (MDAPS), Dusseldorf Score (DS), Mayo, and Spanish Scoring Systems (CPSS). Methods: Data were abstracted by each contributing institution and deposited for central data review at the Moffitt Cancer Center. Manual review of cases was performed to ensure data quality prior to analysis. Only WHO defined CMML was included. The primary objective of this study was to establish an international CMML data set and validate the above models calculated at the time of presentation to each center. All prognostic models were calculated as previously described. The Kaplan–Meier (KM) method was used to estimate median OS and the log rank test was used to compare KM survival estimates with SPSS version 21.0. Random Forest Survival (RSF) and ROC analysis was done with R. Results: Between July 1981 and June 2014, 1832 CMML patients were captured in the International CMML database. Median age at diagnosis was 70 (16-93) years with a male (67%) predominance. By the WHO classification, the majority of patients had CMML-1 (79.9% vs. 20.1%) and most patients were evenly subcategorized as MPN-CMML (49.8%) versus MDS-CMML (50.2%) by FAB criteria. Splenomegaly was demonstrable in 25%. Most patients had favorable cytogenetics by both IPSS (70%) and CPSS (67.6%) classification schemas. Mean BM blast % was 5.6 and mean monocyte count was 4.85x103/dL. Median OS of the entire data set was 31.6 months. All tested prognostic models were valid and able to predict OS (p<0.0001). To compare relative model performance, 1013 complete cases with sufficient data to calculate all risk models were compared using time dependent receiver operator characteristic (ROC) curves and their area under the curves (AUC). ROC curves were calculated for OS at 36 months. The R-IPSS model had the highest AUC (0.694) while the DS model had the lowest (0.635). The difference in AUC between the R-IPSS and DS models was statistically significant (p = 0.003) whereas there was no significant difference from other models tested. To determine which models were most vulnerable to reclassification from low-risk to higher risk, we calculated a vulnerability score defined by the number of models able to up-stage low-risk disease in more than 15% of cases. Using this metric, the Mayo and MDASC scores were least vulnerable to up-staging by other models. Lastly, we used an orthogonal method for determination of variable importance (RSF for OS at 36 months). RSF is an ensemble method of classification and regression tree methodology. Ranking of variables by their weighted importance determined by this procedure identified the top five variables were hemoglobin, circulating blasts, platelet count, number of cytopenias, and karyotype. A new risk model was developed using the results of the RSF with an AUC of 0.720, which was comparable but not significantly different than other modern scoring systems. Conclusions: This represents the largest international CMML-specific data set derived from eight unique centers of excellence. All modern prognostic models were valid and performed comparably. Despite novel strategies for variable importance discovery, an improved model could not be constructed. This data suggest that the power of clinical variables has reached an asymptote and highlights the need for incorporation of molecular and other novel biological features. This data set is currently being populated with molecular data and is being leveraged to test published CMML molecular prognostic models which will be disclosed at the time of presentation. Disclosures Garcia-Manero: Epizyme, Inc: Research Funding. Fenaux:Celgene, Janssenm, Novartis: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION: Necrotizing pancreatitis is a serious complication of acute pancreatitis with high morbidity and mortality. We present a case of a 58 year old male diagnosed with necrotizing pancreatitis after cardiopulmonary bypass surgery and exposure to sulfamethoxazole-trimethoprim (TMP/SMX). CASE DESCRIPTION/METHODS: A 58 year old man presented with one week of jaundice and dyspnea. His history is significant for a recent cardiac surgery with coronary artery bypass grafts (CABG) and aortic valve repair (AVR) with a prolonged cardiopulmonary bypass time (CPBT) aortic cross-clamp time (ACCT). After the surgery, he was prescribed a course of TMP/SMX for an unknown indication. On assessment, he denied any other symptoms and had no history of alcohol use. He was hemodynamically stable with physical examination notable only for generalized jaundice. Lab findings were significant for hemoglobin 6.2 g/dL, WBC 19 × 10(9)/L, K 5.8 mmol/L, BUN 82 mg/dL, Cr 2.82 mg/dL, total calcium 6.7 mg/dL, serum glucose 110 mg/dL, total/direct bilirubin 8.7/6.8 mg/dL, alkaline phosphate 503 U/L, ALT 343 U/L, AST 640 U/L, lipase 540 U/L, and triglycerides 212 mg/dL. CT of the abdomen showed acute necrotizing pancreatitis. He was treated with fluid resuscitation and antibiotics. ERCP was deferred as his cholestasis was thought to be due to extrinsic compression. His course was complicated by hemorrhagic conversion, acute renal failure, shock liver and gastric ischemia. Ultimately, he expired on hospital day 20. DISCUSSION: Drug-induced pancreatitis accounts for 0.1-2% of cases of acute pancreatitis. Although TMP/SMX is classified as a potential cause of pancreatitis, the data is sparse with limited reported cases and a broad latency period ranging from 3 days to 20 years. Acute pancreatitis has also been described as a complication of cardiac surgery with an incidence of 0.4% per prior report. Notably, many of these patients are often asymptomatic, which makes early diagnosis of utmost priority. Factors that increase the risk of developing pancreatitis include prolonged CPBT/ACCT and combined CABG and valve repair, possibly related to splanchnic ischemia. Given that our patient with a recent cardiac surgery received a culprit antibiotic within several weeks of presentation, it is unclear whether TMP/SMX, cardiac surgery, or a combination caused our patient's episode of acute pancreatitis. Although rare, each of these factors should be considered when determining the cause of pancreatitis.

Background and Purpose— Hypertrophic cardiomyopathy patients with atrial fibrillation are at increased risk of stroke, and anticoagulation is strongly recommended. However, limited data are available regarding the safety and effectiveness of non–vitamin K antagonist oral anticoagulants (NOACs) for primary prevention of stroke. Methods— Using the Korean Health Insurance Review and Assessment Service database, we identified 2397 patients with hypertrophic cardiomyopathy and nonvalvular atrial fibrillation on oral anticoagulation from 2013 to 2016 without history of ischemic stroke, intracranial hemorrhage (ICH), or gastrointestinal bleeding (992 on warfarin and 1405 on NOACs). Inverse probability of treatment weighting with propensity scores was used to balance covariates between treatment groups. Risk for ischemic stroke, ICH, gastrointestinal bleeding, death, and their composite outcome associated with NOAC use was assessed with warfarin use as the reference. Results— During a mean follow-up of 1.6 years, the incidence rates of ischemic stroke, ICH, gastrointestinal bleeding, death, and composite outcome were all significantly lower in the NOAC than in the warfarin group (stroke, 2.8 versus 5.0; ICH, 0.5 versus 1.3; gastrointestinal bleeding, 2.3 versus 3.0; death, 3.0 versus 5.1; composite, 7.5 versus 12.5 events per 100 person-years). NOACs were associated with significantly lower risks of ischemic stroke (hazard ratio [HR], 0.47; 95% CI, 0.32–0.68), ICH (HR, 0.31; 95% CI, 0.14–0.69), gastrointestinal bleeding (HR, 0.62; 95% CI, 0.40–0.96), death (HR, 0.45; 95% CI, 0.31–0.65), and the composite outcome (HR, 0.48; 95% CI, 0.38–0.61) than warfarin. The same trend was observed regardless of the NOAC dose and across various high-risk subgroups. In analysis of individual NOACs, all NOACs were associated with lower risks of ischemic stroke and composite outcome. Conclusions— NOACs showed superior effectiveness and safety versus warfarin in the primary prevention of stroke versus warfarin in real-world Asian hypertrophic cardiomyopathy with atrial fibrillation.

Citrate is critical for acid-base homeostasis and to prevent calcium nephrolithiasis. Both metabolic acidosis and hypokalemia decrease citrate excretion and increase expression of Na+-dicarboxylate cotransporter 1 (NaDC1; SLC13A2), the primary protein involved in citrate reabsorption. However, the mechanisms transducing extracellular signals and mediating these responses are incompletely understood. The purpose of the present study was to determine the role of the Na+-coupled electrogenic bicarbonate cotransporter (NBCe1) A variant (NBCe1-A) in citrate metabolism under basal conditions and in response to acid loading and hypokalemia. NBCe1-A deletion increased citrate excretion and decreased NaDC1 expression in the proximal convoluted tubules (PCT) and proximal straight tubules (PST) in the medullary ray (PST-MR) but not in the PST in the outer medulla (PST-OM). Acid loading wild-type (WT) mice decreased citrate excretion. NaDC1 expression increased only in the PCT and PST-MR and not in the PST-MR. In NBCe1-A knockout (KO) mice, the acid loading change in citrate excretion was unaffected, changes in PCT NaDC1 expression were blocked, and there was an adaptive increase in PST-MR. Hypokalemia in WT mice decreased citrate excretion; NaDC1 expression increased only in the PCT and PST-MR. NBCe1-A KO blocked both the citrate and NaDC1 changes. We conclude that 1) adaptive changes in NaDC1 expression in response to metabolic acidosis and hypokalemia occur specifically in the PCT and PST-MR, i.e., in cortical proximal tubule segments; 2) NBCe1-A is necessary for normal basal, metabolic acidosis and hypokalemia-stimulated citrate metabolism and does so by regulating NaDC1 expression in cortical proximal tubule segments; and 3) adaptive increases in PST-OM NaDC1 expression occur in NBCe1-A KO mice in response to acid loading that do not occur in WT mice.

4009 Background: Interim analysis of a global, phase 2 KEYNOTE-059 study (NCT02335411) reported manageable safety and promising antitumor activity for pembro alone or pembro + chemo in pts with G/GEJ cancer. Here we report long-term efficacy and safety data of all cohorts. Methods: Pts with recurrent or metastatic G/GEJ adenocarcinoma were enrolled in 3 cohorts. Cohort 1 pts (PD-L1–positive or –negative) received pembro alone after ≥2 prior lines of therapy. Cohort 2 pts (PD-L1–positive or –negative) received pembro + cisplatin (80 mg/m2 day 1) + 5-fluorouracil (800 mg/m2 days 1-5 Q3W) or capecitabine (in Japan only, 1000 mg/m2 twice daily) as first-line. Cohort 3 pts (PD-L1–positive, combined positive score ≥1% using the PD-L1 IHC 22C3 pharmDx assay) received pembro alone as first-line. All pts received pembro 200 mg Q3W for up to 2 years. End points included safety, ORR, DOR, and OS. Results: At data cutoff (Aug 8, 2018), median (range) follow-up was 6 (1-38), 14 (2-40), and 21 (2-36) months for cohorts 1 (n = 259), 2 (n = 25), and 3 (n = 31), respectively. In cohort 1, confirmed ORR (95% CI) was 11.6% (8-16) overall, 15.5% (10-22) in PD-L1–positive, and 6.4% (3-13) in PD-L1–negative tumors. In cohort 2, confirmed ORR was 60.0% (39-79) overall, 73.3% (45-92) in PD-L1–positive, and 37.5% (9-76) in PD-L1–negative tumors. In cohort 3, confirmed ORR was 25.8% (12-45). Median (range) DOR in months was 16.1 (2-35+), 4.6 (3-37+), and not reached (2.1-32.5+) in cohorts 1, 2, and 3, respectively. OS at 1 year/2 years was 24.6%/12.5%, 52%/32%, and 63.6%/40.1% in cohorts 1, 2, and 3, respectively. In cohorts 1, 2, and 3, grade 3-5 treatment-related adverse event (TRAE) incidence was 46 (18%), 20 (80%), and 8 (26%) respectively. TRAEs led to discontinuation in 6 (2%) and 3 (12%) pts in cohorts 1 and 2, respectively, and to death in 2 (1%) pts in cohort 1. No TRAEs led to discontinuation or death in cohort 3. Conclusions: These updated results demonstrate manageable safety, durable clinically meaningful activity of pembro in heavily pretreated pts, and promising efficacy of first-line pembro (alone or + chemo) in pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.