Background: When tracheal intubation is difficult or unachievable before surgery or during an emergent resuscitation, this is a critical safety event. Consensus algorithms and airway devices have been introduced in hopes of reducing such occurrences. However, evidence of improved safety in clinical practice related to their introduction is lacking. Therefore, we selected a large perioperative database spanning 2002 to 2015 to look for changes in annual rates of difficult and failed tracheal intubation. Methods: Difficult (more than three attempts) and failed (unsuccessful, requiring awakening or surgical tracheostomy) intubation rates in patients 18 yr and older were compared between the early and late periods (pre- vs. post-January 2009) and by annual rate join-point analysis. Primary findings from a large, urban hospital were compared with combined observations from 15 smaller facilities. Results: Analysis of 421,581 procedures identified fourfold reductions in both event rates between the early and late periods (difficult: 6.6 of 1,000 vs. 1.6 of 1,000, P < 0.0001; failed: 0.2 of 1,000 vs. 0.06 of 1,000, P < 0.0001), with join-point analysis identifying two significant change points (2006, P = 0.02; 2010, P = 0.03) including a pre-2006 stable period, a steep drop between 2006 and 2010, and gradual decline after 2010. Data from 15 affiliated practices (442,428 procedures) demonstrated similar reductions. Conclusions: In this retrospective assessment spanning 14 yr (2002 to 2015), difficult and failed intubation rates by skilled providers declined significantly at both an urban hospital and a network of smaller affiliated practices. Further investigations are required to validate these findings in other data sets and more clearly identify factors associated with their occurrence as clues to future airway management advancements. Visual Abstract: An online visual overview is available for this article at http://links.lww.com/ALN/B635.

Background Little evidence exists for superiority of neurosurgical outcomes from care subspecialization. Outcomes of a single neurosurgeon after complex vascular neurosurgery in an academic medical center were compared against those in a community hospital. Methods In this retrospective analysis of extracranial-intracranial vascular bypass operations performed between July 1, 2013 and February 1, 2015, cases were identified by cross-referencing the electronic medical record with the surgeon's own records. Pre-, intra-, and postoperative variables were abstracted from cases performed at a tertiary center and a community hospital. Dichotomous postoperative data recorded included extubation in the operating room (OR), readmission, and survival to discharge, and length of stay was also analyzed. Due to small sample size and low readmission rate, Firth's penalized likelihood tests were incorporated in the logistic regression model for parameter estimation and testing. Results A total of 28 hemispheres in 26 patients were included: 18 hemispheres in 16 patients at the tertiary center and 10 hemispheres in 9 patients at the community hospital. Differences were found in operative time (tertiary mean: 7.21 + 2.5 hours, community mean: 5.19 + 0.9 hours, p = 0.0074) and readmission to the tertiary center (p = 0.078). However, significant difference was observed only for anesthetic type (more likely to include remifentanil and propofol at the tertiary center, p = 0.0104). Conclusion Subspecialty care alone may be insufficient to enhance outcome after complex neurosurgical procedures.

Doxorubicin (DOX) is a commonly used antineoplastic agent for the treatment of various malignancies, and its use is associated with unpredictable cardiotoxicity. Susceptibility to DOX cardiotoxicity is largely patient dependent, suggesting genetic predisposition. We have previously found that individual sensitivity to DOX cardiotoxicity was associated with differential expression of genes implicated in inflammatory response and immune trafficking, which was consistent with the increasing number of reports highlighting the important role of human leukocyte antigen (HLA) complex polymorphism in hypersensitivity to drug toxicity. This pilot study aimed to investigate DNA from patients treated with DOX-based chemotherapy for breast cancer and to correlate the results with the risk for DOX-associated cardiotoxicity. We have identified 18 SNPs in nine genes in the HLA region (NFKBIL1, TNF-α, ATP6V1G2-DDX39B, MSH5, MICA, LTA, BAT1, and NOTCH4) and in the psoriasis susceptibility region of HLA-C as potential candidates for association with DOX cardiotoxicity. These results, albeit preliminary and involving a small number of patients, are consistent with reports showing the presence of susceptibility loci within the HLA gene region for several inflammatory and autoimmune diseases, and with our previous findings indicating that the increased sensitivity to DOX cardiotoxicity was associated with dysregulation of genes implicated both in inflammation and autoimmune disorders.

Background We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS). Methods DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization. Results After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90–37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. Conclusion Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population. Trial Registration ClinicalTrials.gov NCT00203502

Chronic myelomonocytic leukemia (CMML) is an aggressive neoplasm with sparse data on outcomes at a population level. Using Surveillance Epidemiology and End Results (SEER) database, we identified 2238 patients with CMML diagnosed in the period 2003-2013. We found that the disease incidence was significantly higher with advancing age and lower in females, Blacks, and Asian/pacific islanders. Median OS declined significantly with increasing age (age 20-39 - 25 months, age 40-59 -20 months, age 60-79 -18 months, and age >= 80 - 11 months, p <. 01), but did not vary by gender or race. Median OS has improved in the period 2007-2013 as compared with 2003-2006 (17 months vs. 14 months, p <. 01). In spite of advances in CMML biology and therapeutics, in general, the survival of CMML

We used the Surveillance, Epidemiology, and End Results database to study the incidence and survival of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. We found that the disease incidence varied significantly by age, gender, and race, whereas survival was influenced by age, race, stage, period of diagnosis, and radiotherapy.Introduction: Systemic ALK-positive anaplastic large cell lymphoma (ALK-positive ALCL) is a T-cell lymphoma. Owing to its rarity, variations in incidence and survival at the population level are not clearly known. Materials and Methods: Using the Surveillance Epidemiology and End Results database (SEER 18), we selected patients aged >= 20 years with ALK-positive ALCL, diagnosed between 2001 and 2013. Incidence rate, overall survival (OS), and its determinants were analyzed with a significance level of P < .05. Results: We identified 1604 patients with a median age of 54 years. The disease incidence increased significantly with advancing age, with higher incidence in Blacks and lower incidence in American Indians and Asian/Pacific Islanders as compared with Whites. The 5-year OS significantly declined as the age advanced (age 20-40 years, 68.7%; age 41-60 years, 53.8%; age 61-80 years, 28.9%; age > 80 years, 15.2%; P < .01) and varied with race (Whites, 49.7% vs. Blacks, 37.7% vs. Asian/Pacific Islander, 42.8% vs. American Indian, 35.8%; P = .03). On multivariate analysis, treatment with radiation (hazard ratio [HR], 0.72; 95% confidence interval [95% CI], 0.59-0.87; P < .01) and year of diagnosis from 2009 through 2013 (HR, 0.77; 95% CI, 0.65-0.93; P < .01) were associated with lower mortality. Advanced age, Black race (HR, 1.37; 95% CI, 1.14-1.65; P < .01), and advanced disease stage (HR, 1.74; 95% CI, 1.51-2.02; P < .01) were associated with higher mortality. Conclusion: Incidence and survival of ALK-positive ALCL varies significantly with patients' demographic characteristics as identified in our study. Treatment strategies need to be tailored accordingly to address these variations and ensure uniform access to care.

INTRODUCTION:Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in breast cancer. Research in antiangiogenic cancer treatment has been marked by the development of the monoclonal antibody bevacizumab, which targets VEGF in many solid tumors. As patients do not equally benefit from bevacizumab, it has become necessary to define the profile of patients who will benefit from the drug.MATERIALS AND METHODS:We have conducted a prospective phase II study in 39 patients using bevacizumab in breast cancer in the neoadjuvant setting, and found improved pathologic complete response (pCR) when bevacizumab was added to chemotherapy in patients with hormone receptor negative and invasive ductal carcinoma. Blood samples were collected at baseline and serially while patients were on treatment. Circulating angiogenesis-related proteins angiopoietin (ANG)1, ANG2, basic fibroblast growth factor, IL-1a, matrix metalloproteinase 9, platelet derived growth factor - BB, platelet endothelial cell adhesion molecule -1, Tie2, VEGF, and vascular endothelial growth factor receptor 2 were measured at baseline and during treatment. This correlative study was conducted to identify specific serum angiogenic factor profiles that might be associated with pCR in the neoadjuvant setting in breast cancer patients receiving bevacizumab and chemotherapy.RESULTS:Elevated baseline serum Tie2 and basic fibroblast growth factor were associated with pCR in response to this combination. Changes in serum levels of these proteins were seen during treatment but were not significantly different between the pCR and non-pCR groups.CONCLUSIONS:Baseline-circulating Tie2 levels may help distinguish patients who will have pCR from those who will not and may form the basis for future development of antiangiogenic therapy in breast cancer. Larger studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT00203502.

BACKGROUND:Acute leukemia of ambiguous lineage (ALAL) is a rare leukemia with sparse data availability about the survival and management strategies in elderly patients. METHODS:We used the Surveillance Epidemiology and End Results (SEER)-Medicare database to describe the overall survival (OS) and treatment pattern of elderly patients (age > 65 years) with ALAL. OS analysis was done using the Kaplan-Meier method, and its determinants were analyzed using the Cox proportional hazard regression method with a significant P < .05. RESULTS:We included 705 patients with ALAL and a median age of 80 years. The 2-year OS was 16.4% for patients aged 66 to 70 years, 8.1% for patients aged 71 to 75 years, 5.5% for patients aged 76 to 80 years, and 3.7% for patients aged > 80 years (P < .01). Two-year OS did not significantly vary by race or gender. Among the study cohort, 151 patients received chemotherapy. Two-year OS was 17% in the chemotherapy group and 3% in the no-chemotherapy group (P < .001). On multivariate analysis, age less than 80 years (Age 66-70 years: hazard ratio [HR]; 0.66, 95% confidence interval [CI], 0.52-0.85; age 71-75 years: HR, 0.80; 95% CI, 0.65-0.99; age 76-80 years: HR, 0.80; 95% CI, 0.66-0.98; P = .004) and chemotherapy (HR, 0.51; 95% CI, 0.42-0.62; P = .001) significantly reduced the hazard for mortality. CONCLUSION:Our study suggests that the OS of elderly patients with ALAL remains poor. Although treatment improved the OS, only 21.5% of patients received therapy. The optimal choice of therapy needs to be determined by prospective studies.

The objective of this study was to explore the cancer incidence rates among HIV-infected persons with commercial insurance who were on antiretroviral therapy and compare them with those rates in the general population. Paid health insurance claims for 63,221 individuals 18 years or older, with at least one claim with a diagnostic code for HIV and at least one filled prescription for an antiretroviral medication between January 1, 2006, and September 30, 2012, were obtained from the LifeLink® Health Plan Claims Database. The expected number of cancer cases in the general population for each gender-age group (<30, 30–39, 40–49, 50–59, and >60 years) was estimated using incidence rates from the Surveillance Epidemiology and End Results (SEER) program. Standardized incidence ratios (SIRs) were estimated using their 95% confidence intervals (CIs). Compared to the general population, incidence rates for HIV-infected adults were elevated (SIR, 95% CI) for Kaposi sarcoma (46.08; 38.74–48.94), non-Hodgkin lymphoma (4.22; 3.63–4.45), Hodgkin lymphoma (9.83; 7.45–10.84), and anal cancer (30.54; 25.62–32.46) and lower for colorectal cancer (0.69; 0.52–0.76), lung cancer (0.70; 0.54, 0.77), and prostate cancer (0.54; 0.45–0.58). Commercially insured, treated HIV-infected adults had elevated rates for infection-related cancers, but not for common non-AIDS defining cancers.

e18072 Background: CMML is a rare hematological malignancy with characteristics of both myelodysplastic and myeloproliferative disorders. Population level data about its overall survival (OS) in the recent years is sparse. In this study, we aimed to delineate the characteristics and trends in OS of CMML in the US. Methods: The Surveillance, Epidemiology and End Results (SEER-18) database was used to identify patients with age > 20 years diagnosed with CMML (ICD-O-3 code –9945) between 2000 to 2011. Baseline characteristics were described in frequencies. OS was calculated using Kaplan-Meier method and compared by log rank test. Multivariate analysis was performed using Cox proportional hazard regression method. Results: 3520 patients with CMML had a median age of 76 years (range 22-94). Patient characteristics included age > 60 (89.3%), 62.4% males, 88.4% Whites, 6.2% African Americans and 5.2% other racial groups. About 74.7% patients had primary CMML and 25.3% had secondary CMML. Incidence of CMML has increased from 0.5/100,000 to 0.6/100,000 population from 2000 to 2011. Median OS was worse in patients with age > 60 vs. age < 60 (13 months vs.18 months, p < 0.001), males vs. females (13 months vs. 14 months, p = 0.04) and secondary CMML vs. primary CMML (10 months vs. 14 months, p < 0.001). Median OS did not differ significantly with race (Whites -14 months, African Americans- 8 months and other races -15 months; p = 0.07). We found that OS has improved in patients diagnosed from 2007-2011 as compared to diagnosis from 2000-2006 (Median OS – 15 months vs. 12 months, 2-year OS – 35.7% vs. 32.5%, p < 0.01). On multivariate analysis age > 60 years (HR-1.47, 95% CI 1.29-1.68, p < 0.01) and secondary CMML (as compared to primary CMML, HR-1.20, 95% CI 1.10-1.31, p < 0.01) were significantly associated with higher mortality. Diagnosis from 2007-2011 was associated with lower mortality (HR 0.89, 95% CI 0.82-0.96, P < 0.01). Conclusions: Our data suggests that age > 60 and secondary CMML portend worse prognosis. Although the OS of CMML in US seems to be improving in the era of hypomethylating agents, stem cell transplant and supportive care, its dismal prognosis indicates the need for novel therapies.

8597 Background: Studies on multiple myeloma demonstrate an improvement in overall survival (OS) and increased risk of second primary malignancy (SPM); Population level data on OS and the risk of SPM in primary plasmacytoma (PP) is sparse. Hence, we aimed to determine the trends in OS and SPM in patients with PP in US. Methods: The Surveillance, Epidemiology and End Results (SEER-13) database was used to identify patients with age > 20, diagnosed with solitary plasmacytoma of bone (SPB) or extramedullary plasmacytoma (EMP) (ICD-O-3 codes –9731, 9734) as the first primary malignancy between 1992 to 2011. OS analysis was performed using Kaplan-Meier method and compared by log rank test. SPM was identified using SEERstat software (version 8.1.5) with a latency period of 6 months from radiotherapy (RT). Multivariate analysis of OS was performed using Cox proportional hazard regression method. Results: 2064 patients with SPB/EMP had a median age of 62 years (range 20-96). Baseline characteristics included 63.6% males, 54.2% with age > 60, 79.2% Whites, 14% African americans and 6.8% other races. About 48.4% of patients received RT alone, 23.5% had surgery and RT, 10.5% had surgery and 17.6% did not receive surgery or RT. OS at 10 years was higher in patients with age < 60 vs. age > 60 (62.5% vs. 22.2%, p < 0.01) and for other races vs. Whites vs. African americans (51.1% vs. 40.1% vs. 34.5% respectively, p = 0.01). Use of RT and surgery resulted in better 10-year OS (51.2%) than surgery alone (44.1%), RT alone (39.8%) or no RT/surgery (21.2%) (p < 0.01).On multivariate analysis, age > 60 (HR 3.01, 95% CI 2.61-3.46; p < 0.01), Whites vs. other races (HR 1.35, 95% CI 1.02-1.77; p = 0.03) and African americans vs. other races (HR 1.52, 95% CI 1.11-2.08; p < 0.01) predicted worse OS, whereas the use of RT along with surgery Vs. RT alone (HR 0.82, 95% CI 0.70-0.97; p = 0.02) predicted better OS. Patients treated with RT had more SPM as compared to general population- all sites standardized incidence ratio (SIR) 1.49, with more leukemia/lymphoma (SIR 6.37) and bone tumors (SIR 19.93) (p < 0.05). Conclusions: Our study demonstrates that the use of RT and surgery for PP significantly improves the OS, despite an increased risk of SPM with RT. Our study also shows a significant racial disparity in the long-term OS of PP.

Anastrozole is an aromatase inhibitor (AI) used as adjuvant therapy for breast cancer. Anastrozole is subject to direct glucuronidation catalyzed by UDP-glucuronosyltransferase1A4 (UGT1A4). Interindividual variability in anastrozole glucuronidation may be affected by UGT1A4 SNPs. Interplay between drug metabolizing genes such as UGT1A4 and transporter genes may also be affected by genetic variability. Thus, we hypothesize that genetic variability in MRPs could influence anastrozole glucuronidation. The correlation between UGT1A4 and MRP2 or MRP3 transporter gene expressions and the correlation between MRP2 or MRP3 mRNA and anastrozole glucuronidation were analyzed in normal human liver samples. MRP2 and MRP3 mRNA levels were significantly correlated with UGT1A4 mRNA, with anastrozole glucuronidation and with each other (p<0.05). The data also demonstrated that MRP2 SNPs are positively correlated with MRP2 mRNA expression, while there was no association between MRP3 SNPs from this study and MRP3 expression. Significant correlations (p<0.05) between certain MRP2 SNPs (3972C>T, 2366C>T and -24C>T) and anastrozole glucuronidation were observed. There were no observed correlations between MRP3 SNPs and anastrozole glucuronidation. MRP2 polymorphisms have been identified as playing a role in the disposition of other drugs, and the data presented here indicate for the first time that MRP2 SNPs could influence anastrozole metabolism and contribute to interindividual variation in treatment responses.

Nonalcoholic fatty liver disease, a major cause of abnormal liver function, is often associated with obesity. Arginine (ARG) plays a role in modulating body weight/fat, but limited data exist as to the role of ARG in soy protein's ability to protect from liver steatosis. We investigated the role of native ARG in the soy protein isolate (SPI) in reducing liver steatosis in male obese Zucker rats. Rats (N=48; 6 weeks old) were randomly assigned to one of three diets for 8 or 16 weeks: the casein (CAS) diet as control (0.6% ARG), CAS diet supplemented to contain 1.3% ARG, or an SPI diet containing isoflavones (1.3% ARG). SPI and ARG rats gained significantly more weight (P<.05) than CAS rats after 16 weeks only. The SPI rats had lower liver steatosis scores after 8 and 16 weeks (P<.05 and P<.001, respectively) compared to CAS and ARG rats. SPI rats had lower serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (P<.05) compared to CAS after 16 weeks, and AST was lower (P<.05) compared to ARG rats. After 16 weeks, the SPI rats had lower (P<.05) serum ALT and AST levels than at 8 weeks. Our results suggest that a longer period of SPI feeding results in lower liver steatosis and serum ALT and AST levels, while the ARG diet had no effect on steatosis or ALT and AST levels. We found that the SPI diet reduced (P<.001) serum tumor necrosis factor-α (TNF-α) compared to CAS and ARG diets after 8 and 16 weeks. The SPI diet significantly reduced (P<.001) interleukin-6 (IL-6) when compared to the CAS diet at 8 weeks, but there was no significant difference at 16 weeks. Based on the findings of our study, the protective effect of SPI in reducing liver steatosis is not modulated by its native arginine content.

CYP19A1 facilitates the bioconversion of estrogens from androgens. CYP19A1 intron single nucleotide polymorphisms (SNPs) may alter mRNA splicing, resulting in altered CYP19A1 activity, and potentially influencing disease susceptibility. Genetic studies of CYP19A1 SNPs have been well documented in populations of European ancestry; however, studies in populations of African ancestry are limited. In the present study, ten ‘candidate’ intronic SNPs in CYP19A1 from 125 African Americans (AA) and 277 European Americans (EA) were genotyped and their frequencies compared. Allele frequencies were also compared with HapMap and ASW 1000 Genomes populations. We observed significant differences in the minor allele frequencies between AA and EA in six of the ten SNPs including rs10459592 (p<0.0001), rs12908960 (p<0.0001), rs1902584 (p = 0.016), rs2470144 (p<0.0001), rs1961177 (p<0.0001), and rs6493497 (p = 0.003). While there were no significant differences in allele frequencies between EA and CEU in the HapMap population, a 1.2- to 19-fold difference in allele frequency for rs10459592 (p = 0.004), rs12908960 (p = 0.0006), rs1902584 (p<0.0001), rs2470144 (p = 0.0006), rs1961177 (p<0.0001), and rs6493497 (p = 0.0092) was observed between AA and the Yoruba (YRI) population. Linkage disequilibrium (LD) blocks and haplotype clusters that is unique to the EA population but not AA was also observed. In summary, we demonstrate that differences in the allele frequencies of CYP19A1 intron SNPs are not consistent between populations of African and European ancestry. Thus, investigations into whether CYP19A1 intron SNPs contribute to variations in cancer incidence, outcomes and pharmacological response seen in populations of different ancestry may prove beneficial.

7112 Background: Hypomethylating agents were approved for use in treatment of MDS after 2004. This study aims to delineate the discrepancies in survival of MDS at population level before and after approval of these agents. Methods: Using Surveillance, Epidemiology and End Results (SEER-17) database, adult patients with primary MDS, diagnosed between 2001 to 2010 were identified. Overall survival analysis was performed using Kaplan-Meier method and compared by log rank. Period of diagnosis for survival was analyzed between 2001-2005 and 2006-2010. Multivariate analysis was performed using Cox Proportional Hazards regression method. Results: 22,051 patients with MDS with a median age of 76 years were included. Median overall survival (OS) for different age groups was as follows: age < 60 – 59 months, age 60 to70 – 36 months, age > 70 – 23 months, p < 0.001). We found that 5 year OS has improved across all age groups diagnosed from 2006-2010 compared to 2001-2005 (age < 60 – 50.3% vs. 16%, age 60-70 – 37.8% vs. 14 %, age > 70 – 23% vs. 3% p<0.01). Females had a better overall survival than males (32 month vs 24 months respectively, p < 0.001). Blacks had a higher overall survival than whites or other races (34 months vs 27 months) (p-not significant). On multivariate analysis age > 60 years ( HR-1.38 95% CI 1.30-1.46, p<0.01) and male sex ( HR-1.17, 95% CI 1.13-1.21, p<0.01) were significantly associated with higher mortality. Diagnosis after the year 2005 was associated with decreased mortality (HR 0.78, 95% CI 0.74-0.82, P<0.001). Conclusions: Overall survival has continued to improve across all age groups with introduction of hypomethylating agents and better supportive care.

Abstract Background: Therapeutic plasma exchange (TPE) is used in the treatment of thrombotic microangiopathy (TMA). For several reasons, the timing of initiation of TPE in patients with TMA admitted to the hospital varies greatly. In this study, we have aimed to retrospectively compare the short term outcomes, costs and in-hospital mortality of early versus late TPE in patients with TMA admitted to US hospitals. Methods: Using Nationwide Inpatient Sample database, we identified all hospital discharges related to TMA as the primary diagnosis and TPE as the primary procedure from 2007 through 2011. ICD 9 codes were used to identify the diagnosis and procedure related information. Data on patient demographics, day of initiation of TPE, length of stay (LOS), cost of hospitalization and deaths were obtained. Patients were divided into early TPE (day 0 or day 1 of hospital admission) and late TPE groups (beyond day 1 of admission). Comparison of outcomes was also made for patients who were initiated on TPE at day 0 versus day 1 of admission. Outcomes were described using descriptive statistics and analyzed using Mann Whitney U test and Chi -square test. Multivariate logistic regression method was used to determine the factors associated with mortality. Results: Based on sample weights, an estimated 3823 patient discharges were identified nationwide between 2007-2011 with TMA as the primary diagnosis and TPE as the primary procedure. Patients had a median age of 46 years in early TPE and 47 years in late TPE group. Baseline characteristics of the study group are summarized in Table 1. Mean LOS was 11.69±0.17 days in the early TPE group versus 15.97±0.37 days in the late TPE group (p=0.01). Mean cost of hospitalization was $ 128226.51±2482.66 in the early TPE group versus $ 170909.05±6638.03 in late TPE group (p < 0.01). In-hospital mortality was 4.2% (n=124) in the early TPE group versus 7.2% (n=60) in the late TPE group (p =0.01). On comparing the outcomes between initiation of TPE on day 0 versus day 1 of hospitalization, no significant differences were noted in mean LOS (11.76±0.25 days in TPE day 0 group vs 11.62±0.23 days in TPE day 1 group, p=0.44), cost ($129865.23±3799.70 in TPE day 0 group vs $126442.55±3127.68 in TPE day 1, p=0.36), and mortality (TPE day 0 = 4% vs TPE day 1 = 4.3%, p=0.82). On multivariate analysis, initiation of TPE on day 0 or day 1 was associated with reduced mortality (OR 0.55, CI 0.40-0.76, p <0.01) as compared to TPE initiated after day 1, whereas age > 50 years (OR 4.37, CI 3.13-6.08, p<0.01) was associated with higher mortality. Conclusions: Early TPE for TMA significantly reduces the in-hospital mortality, hospitalization cost and LOS as compared to those who received late TPE. However, these outcomes did not differ significantly when comparing TPE initiation on day 0 versus day 1 of hospital admission. Hence, undue delays in initiation of TPE should be avoided in patients with TMA in order to improve their outcome. Table 1: Baseline study characteristics Variable Early TPE (n=2995) Late TPE (n=828) P value Median Age in years (range) 46 (10-90) 47 (9-85) 0.03* Sex Males Females Missing 989 1995 11 254 574 0 0.20 Race Whites Blacks Others Missing 1248 1058 400 289 325 367 76 60 0.01* Insurance status Medicare Medicaid Private Others Missing 584 616 1335 441 19 216 155 325 127 5 0.01* Admission day Weekend Weekday 616 2379 169 659 0.96 *p <0.05-significant Disclosures No relevant conflicts of interest to declare.

Background Sulfotransferase 1A1 ( SULT1A1 ) gene expression is tissue specific, with little to no expression in normal breast epithelia. Expression in breast tumors has been documented, but the transcriptional regulation of SULT1A1 in human breast tissue is poorly understood. We identified Nuclear Factor I (NFI) as a transcription factor family involved in the regulation of SULT1A1 expression. Methods Transcription Factor Activation Profiling Plate Array assay was used to identify the possible transcription factors that regulate the gene expression of SULT1A1 in normal breast MCF-10A cells and breast cancer ZR-75-1 cells. Expression levels of NFI-C and SULT1A1 were determined by real-time RT-PCR using total RNA isolated from 84 human liver samples. Expression levels of SULT1A1, NFI-A, NFI-B, NFI-C, and NFI-X were also determined in different human breast cancer cell lines (MCF-7, T-47D, ZR-75-1, and MDA-MB-231), in the transformed human epithelial cell line MCF-10A, and in ZR-75-1 cells that were transfected with siRNAs directed against NFI-A, NFI-B, NFI-C, or NFI-X for 48 h. The copy numbers of SULT1A1 in cell lines ZR-75-1, MCF-7, T-47D, MDA-MB-231, and MCF-10A were determined using a pre-designed Custom Plus TaqMan ® Copy Number kit from Life Technologies. Results In normal human liver samples, SULT1A1 mRNA level was positively associated with NFI-C. In different human breast cancer and normal epithelial cell lines, SULT1A1 expression was positively correlated with NFI-B and NFI-C. SULT1A1 expression was decreased 41% and 61% in ZR-75-1 cells treated with siRNAs against NFI-A and NFI-C respectively. SULT1A1 gene expression was higher in cells containing more than one SULT1A1 copy numbers. Conclusions Our data suggests that SULT1A1 expression is regulated by NFI, as well as SULT1A1 copy number variation in human breast cancer cell lines. These data provide a mechanistic basis for the differential expression of SULT1A1 in different tissues and different physiological states of disease.

Background: Estrogen is known to decrease the risk of colon cancer in postmenopausal women, and may exert its actions by decreasing interleukin-6 (IL6) production via stabilization of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappa B). Estrogens are biosynthesized by CYP19A1 (aromatase), so it is possible that genetic variations in CYP19A1 influences the risk of colon cancer by altering expression of CYP19A1. Further, studies on gene-gene interactions suggest that single nucleotide polymorphisms in one gene may affect expression of other genes. The current study aims to explore the role of CYP19A1 single nucleotide polymorphisms on CYP19A1, NF kappa B1 and IL6 gene expression.Methods: Phenotype-genotype associations, cross-associations between genes, and haplotype analyses were performed in both normal human colon (n=82) and liver (n=238) samples.Results: CYP19A1 rs10459592, rs1961177, and rs6493497 were associated with CYP19A1 expression in colon samples (P=0.042,P=0.041, and P=0.013, respectively). CYP19A1 single nucleotide polymorphisms (rs12908960, rs730154, rs8025191, and rs17523880) were correlated with NF kappa B1 expression (P=0.047, P=0.04, P=0.05, and P=0.03, respectively), and CYP19A1 rs11856927, rs2470152, and rs2470144 (P=0.049, P=0.025, P=0.047, respectively) were associated with IL6 expression in the colon. While rs730154 and rs17523880 could not be analyzed in the liver samples, none of the other associations with the colon were replicated in the liver samples. Haplotype analysis revealed three separate haplotypes of the CYP19A1 single nucleotide polymorphism that were significantly associated with CYP19A1, NF kappa B1, and IL6 gene expression.Conclusion: CYP19A1 single nucleotide polymorphisms are associated not only with CYP19A1 expression but also with NF kappa B1 and IL6 expression. These data demonstrate the possible functional consequences of genetic variation within the CYP19A1 gene on other genes in a biologically plausible pathway.

Abstract Purpose: Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in cancer and may be targeted by the monoclonal antibody bevacizumab (B). We have conducted a prospective phase II study using neoadjuvant B and chemotherapy (CT) in breast cancer patients and showed improved pathologic complete response (pCR) with the combination compared to the expected pCR with CT alone (41% vs. 25%, p=0.029 one sided). We evaluated baseline serum levels of ten angiogenesis-related proteins (ANG1, ANG2, bFGF, IL-1a, MMP-9, PDGF-BB, PECAM-1, Tie-2, VEGF and VEGFR2) and found that baseline Tie-2 and bFGF serum levels were associated with pCR. The goal of the current study is to explore the association of germline single-nucleotide polymorphisms (SNPs) to pCR obtained with bevacizumab therapy. Methods: Our original patient population consisted of 27 whites (EA) and 12 African Americans (AA) who received docetaxel/cyclophosphamide/bevacizumab and doxorubicin. Only 22 EA and 11 AA had buffy coat samples available for genotyping with the Illumina® HumanOmni2.5-8v1-1 BeadChip. We tested 555 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes. Results: Univariate analysis revealed that 73% AA patients achieved pCR compared to 27% EA (p=0.012) and that 54% of the patients with ductal carcinomas achieved pCR compared to 11% with lobular or poorly differentiated tumors (p=0.021). We therefore included race and cancer type as covariates in a logistic regression model testing for association between pCR and each of the 555 SNPs. There were five SNPs in ANGPT1, five in ANGPT2, and four in FGF2 that were associated with pCR (p<0.05). Because of the modest sample size, none of these SNPs reached levels of significance after adjusting for multiple comparisons. Conclusion: ANGPT1, ANGPT2 and FGF2 are promising targets for future research. SNP analysis results support our hypothesis that the interaction of the host's angiogenic profile and the type of cancer explains differences in clinical response to VEGF inhibition. Specifically, our work showed that variants of the ANGPT1, ANGPT2, and FGF2 genes or their respective proteins might render certain tumors more susceptible to targeting of VEGF.. Citation Format: Issam Makhoul, Robert Griffin, Stephen Erickson, Ishwori Dhakal, Venay R. Raj, Dorothy A. Graves, Jeannette Y. Lee, Mohammed S. Orloff, Eric R. Siegel, Susan A. Kadlubar. Germline genetic variants in ANGPT1 & 2 and FGF2 are associated with pathologic complete response to bevacizumab in breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2825. doi:10.1158/1538-7445.AM2014-2825

Abstract Introduction: Systemic ALK positive Anaplastic large cell lymphoma (ALK+ALCL) is a rare T-cell lymphoma (TCL). It is generally considered to have a good prognosis as compared to other TCL cases. However, due to its rarity, the discrepancies in its survival at population level are unclear. In this study, we have described the trends and determinants of survival of systemic ALK+ALCL using the Surveillance Epidemiology and End Results (SEER) database. Methods: Patients were selected from the SEER 13registry (Nov 2013 submission data) using the ICD-0-3 code for ALK+ALCL (9714). Patients included had age 20 years and above, with microscopy confirmed ALK+ALCL as the first primary malignancy diagnosed between 1992-2011. We excluded patients diagnosed only at autopsy/death certificate and those with cutaneous or subcutaneous ALCL. Patients were evaluated by their demographic characteristics, radiotherapy status, disease stage and site of involvement. Five year overall survival (OS) was calculated by Kaplan-Meier method and compared by log rank test. Determinants of OS were analyzed with Cox-regression method. Statistical analyses were done with significance level of p < 0.05. Results: A total of1160 patients with systemic ALK+ALCL were identified. Median age of the cohort was 54 years (20-85 years) with majority of patients being > 60 years (20-40 years – 26.9%, 41-60 years-34.2% and > 60-38.9%). There were more males than females (59.9% vs 40.1%), more whites than blacks and other races (78.7% vs 21.3%). Patients commonly presented with nodal disease (81.3%) and advanced stage (stage III and IV-52.8%). The 5-year OS significantly declined as the age advanced (66.2% in age < 40, 46.6% in age 41-60 and 28.1% in age > 60, p<0.01). Females had a better OS than males (5 year OS 47.2% in females vs. 42.8% in males, p=0.02). 5 year OS did not significantly differ by patient’s race (Blacks 42.6% vs whites 44.4% vs others 42.5%, p=0.32).Although the 5-year OS was comparable for nodal and extranodal presentations overall (44.6% vs. 43.4% respectively, p=NS), certain extranodal presentations had a significantly poor outcome (5 year OS for disease in GI - 32.9%) while Head and neck involvement had a better outcome (5 year OS- 59.2%) (p=0.01). Treatment with radiotherapy improved the 5-year OS across the cohort (5 year OS for RT received- 57.8% vs RT not received -40.5%, p< 0.01). On Multivariate analysis, female sex (HR 0.83, CI 0.70-0.96, p=0.02), early disease stage (0.62, 0.52-0.73, p< 0.01), and treatment with radiation (HR 0.71, CI 0.57-0.87, p< 0.01) were associated with lower mortality and age > 60 was associated with higher mortality (HR 3.31, CI 2.64-4.14, P=0.001). Conclusion: Even though ALK+ALCL is considered to have a better prognosis, significant discrepancies in the survival have been identified in our large population based study. Treatment with radiotherapy significantly improves the outcome. Prospective studies with large patient population are needed to address these discrepancies and formulate better treatment strategies for these high risk groups. Disclosures No relevant conflicts of interest to declare.