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Abstract Both genome wide association studies (GWAS) of common variation and exome wide association studies (EXWAS) of rare variation have successfully identified disease susceptibility variants for a variety of diseases. One GWAS of inherited susceptibility to Acute Myeloid Leukemia (AML) has been conducted, but no EXWAS have been performed to measure risk of AML attributable to low-frequency constitutional genetic variation. We performed the first EXWAS of risk of AML as a nested case-control study in the DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to one-Year mortality after BMT) cohorts. The DISCOVeRY-BMT parent study examined transplant-related mortality in leukemia patients undergoing unrelated donor allogeneic BMT. To identify low frequency variants and genes contributing to increased susceptibility to AML we used genotype data from the Illumina HumanExome BeadChip typed in the DISCOVeRY-BMT cohorts; the HumanExome BeadChip contains 242,901 variants, which are mainly protein-coding variants. The optimal sequence kernel association test (SKAT-O) was used to analyze gene-level associations with risk of AML. These gene-based tests evaluate the cumulative effects of multiple single gene variants on risk of AML. Analyses were performed in all European American AML cases and two subtypes: 1) de novo AML, 2) de novo AML with normal cytogenetics. Models were adjusted for age at transplant and principal components to control for population stratification. For gene-based tests at least 2 variants with minor allele frequency (MAF) ≤ 5%, were required to be present in the gene. This yielded a total of 13,687 genes tested, and a Bonferroni corrected significance level of P<3.65 x 10-6. Association tests were performed in 1,189 AML cases reported to CIBMTR 2000-08 (Cohort 1) and 327 AML cases reported to CIBMTR from 2009-11 (Cohort 2). Controls in Cohorts 1 (n=1,986) and 2 (n= 515) were 10/10 HLA-matched unrelated donors who passed a comprehensive medical exam and deemed healthy. We used metaSKAT to combine Cohorts 1 and 2 and obtain p-values of association with AML. We present the results of gene-level tests significant in both cohorts. The likely pathogenicity of these variants was determined in silico using SIFT, PolyPhen and MutationTaster. Patient characteristics are in Table 1. DNMT3A, on chromosome 2, was associated in the gene-based test with risk of AML (Pmeta=1.70x10-9, Table 2). Three missense variants at MAF <1% comprise both overall AML and de novo AML gene-based association: exm177559 (Asn->Ser), exm177507 (Arg->His), and exm177543 (Arg->Trp). Normal cytogenetics de novo AML gene-based assocations consisted of only 2 of these variants: exm177559 and exm177507 (Table 2). While prevalence of exm177507 is <1% for all AML cases, in de novo AML with normal cytogenetics the MAF was higher at 3%. The other 2 variants had a MAF<1% irrespective of subtype. Somatically, DNMT3A is most frequently mutated in hematologic malignancies, with >30% of de novo AML cases with a normal karyotype and >10% of MDS patients having DNMT3A mutations. Although these are germline gene associations all three of the variants found have been reported somatically in hematologic malignancies. In 200 AML cases from The Cancer Genome Atlas (TCGA) p.R882H (represented as exm177507 on the exome chip) was a frequent somatic mutation (25%). Exm177543 (p.R635W) and exm177559 (p.N501S) are reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) as somatic mutations involved in hematopoietic and lymphoid tissue in both cell lines and humans. Exm177507 and exm177543 show evidence of pathogenicity in all three in silico tools, while exm177559 was reported as deleterious and disease causing by Sift and MutationTaster, respectively. Our results show that multiple potentially pathogenic missense germline variants in DNMT3A comprise the gene-based association with AML, specifically de novo AML with normal cytogenetics. Given the functional nature of these variants it is possible germline risk stratification could be informative in determining AML risk, and subsequently development of AML harboring DNMT3A mutations. Confirmation of these findings in additional cohorts could have implications for individualized risk screening, prediction and prognosis. Additional cytogenetic subgroup analyses, including treatment-related AML, are underway. Disclosures Hahn: Novartis: Equity Ownership; NIH: Research Funding. McCarthy:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sucheston-Campbell:NIH/NCI: Research Funding.

Abstract #the authors contributed equally to this work While survival outcomes after HLA-matched unrelated donor (URD) blood and marrow transplant (BMT) have significantly improved over the last two decades, about 40% of patients die before 1-year post URD BMT. Previously we performed a genome-wide association study (GWAS) named DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT) to investigate the contributions of common genetic variants on survival outcomes. To address the specific contributions of low frequency (≤ 1%) exonic variants on survival outcomes, we used the DISCOVeRY-BMT cohorts typed with the Illumina HumanExome BeadChip containing 242,901 variants, which are mainly protein-coding variants. We used a gene-based test (the optimal sequence kernel association test (SKAT-O)) to evaluate the cumulative effects of multiple genetic variants within a gene on overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) 1 year after URD BMT. SKAT-O measures the overall significance of the gene and allows the variants to have different directions and magnitude of effects. We used a 2-stage study design: SKAT-O analysis was carried out in Cohort 1 consisting of 1,972 AML, ALL or MDS patients reported to the Center for International Blood and Marrow Transplant Research from 2000 to 2008 and their 2,006 10/10 HLA-matched URD. Genes with a suggestive association with each outcome (P < 1×10-3) entered the final meta-analysis including Cohort 1 and an independent cohort (Cohort 2), consisting of 503 recipients and 520 10/10 HLA-matched URD from 2009 to 2011. The analysis included recipients and URD of European descent due to the low frequency of other populations. All association models included age at BMT, diagnosis (AML, ALL, MDS), disease status at BMT, cell source (peripheral blood, marrow), year of BMT, and principal components from EIGENSTRAT to control for population stratification. Only coding variants (missense and nonsense) with minor allele frequency ≤ 1% were included in our analysis, which resulted in > 12,000 genes tested in our gene-based analysis in recipients and donors. Exome-wide significance was set at Pmeta< 4.10×10-6 after Bonferroni correction for the total number of genes tested. The likely pathogenicity of these variants was determined in silico using SIFT and PolyPhen. In recipients, we identified OR51D1, a member of the olfactory receptor gene family, as significantly associated with both OS and TRM. The OS association with ORD51D1 is driven by TRM as the same six missense variants contribute to both TRM and OS, but not to DRM. In donors, four (ALPP, EMID1, SLC44A5, LRP1), one (HHAT), and two (LYZL4, NT5E) genes were significantly associated with OS, TRM, and DRM, respectively (Table). ALPP encodes an alkaline phosphatase. SLC44A5 is a member of the solute carrier gene family. LRP1 (low density lipoprotein receptor-related protein 1) encodes an endocytic receptor involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. HHAT encodes an enzyme that acts within the hedgehog secretory pathway, which is involved in hematologic malignancy. LYZL4 is a member of a family of lysozyme-like genes, which have a protective role in host defense. The encoded protein of NT5E, CD270, is used as a determinant of lymphocyte differentiation. The likely pathogenicity of several of the functional variants in all significant genes identified was predicted to be both (possibly or probably) damaging and deleterious (Table), thus indicating that the amino acid substitution of the variant may not be well tolerated. One damaging variant in LRP1 has been identified as a somatic mutation in hematopoietic and lymphoid tissue. Our study is the first analysis of the low-frequency coding variant contribution to URD BMT survival outcomes. We found that the missense variants contributing to many of these significant gene associations shows evidence of pathogenicity and thus it is biologically plausible these variants are contributing to survival outcomes. Further confirmation of these findings, and studies of the functional consequences of protein-coding changes in these genes, may provide more individualized risk prediction and prognosis as well as alternative donor selection strategies. Table. Table. Disclosures McCarthy: Gamida Cell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hahn:Novartis: Equity Ownership; NIH: Research Funding. Sucheston-Campbell:NIH/NCI: Research Funding.

Abstract Over the past decade, there have been numerous published candidate gene association studies of non-HLA variants, genes and/or pathways in relation to BMT survival outcomes. Most of these studies investigated a small number of candidate single nucleotide polymorphisms (SNPs), chosen based on known gene function, in a limited number of cases without replication. Here we test the association of previously reported SNPs with survival outcomes (overall survival (OS), progression-free survival (PFS), death due to disease (DD) or transplant-related mortality (TRM)) after URD BMT using data from the DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to one-Year mortality after BMT) study which included 2,052 European descent recipient-unrelated donor pairs (Cohort 1) and 763 recipient-unrelated donor pairs (Cohort 1) reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2000-2009 and 2009-2011, respectively. DISCOVeRY-BMT is a Genome Wide Association Study (GWAS) that includes over 9 million typed or imputed SNPs. This represents the largest study to date and is well powered to test both SNP and gene-based association hypotheses. We conducted an extensive literature review of PubMed using MESH terms related to transplant and hematologic disease which yielded 76 candidate gene association studies that investigated a total of 46 genes with any survival outcome. Of the 46 genes, 11 genes (CTLA4, CYP2B6, CYP2C19, GSTM1, GSTT1, IL23R, IL6, MTHFR, NOD2/CARD15, TNFSRF1B, and VDR) were studied in at least 2 publications. A total of 16 SNPs in 8 of these genes reported a significant (P< 0.05) association with at least one survival outcome (OS, PFS, DD or TRM). We tested these 16 SNPs for an association with the survival outcome originally reported in each article (Table 1). All association models included age at BMT, diagnosis (AML, ALL, MDS), disease status at BMT, cell source (blood, bone marrow) and year of BMT. P-values from Cohorts 1 and 2 were combined using a fixed-effects model in METAL software. Since the candidate gene studies have a gene-based hypothesis, we also performed gene-level testing using the VErsatile Gene-Based Association Study (VEGAS2) software to measure the aggregate effect of all available typed and imputed SNPs from our GWAS data in these 8 genes. The candidate gene association studies included heterogeneous patient populations of autologous and/or allogeneic (related or unrelated donors) BMT for a variety of hematologic diseases. Most candidate gene studies performed genotyping on both donors and recipients, and SNPs were tested either independently for donor or recipient genomes, or considering the total number of variant alleles the recipient-donor pair had at a given locus (0-4) (Table 1). The 16 SNPs from the previous candidate gene association studies were not significantly associated at a nominal P<0.05 to either the survival outcome reported in the original published paper, or to any survival outcome (Table 1). Likewise, the VEGAS2 gene-based analysis did not reveal any statistically significant associations for any of the 8 genes at P<0.05. Our study also corroborated prior reports of SNPs and genes that were not associated with survival outcomes. Candidate gene association studies use a priori biological knowledge to select genes that are likely associated with outcome and subsequently SNPs within the gene thought likely to affect function based on knowledge at the time of the investigation. Our findings suggest that neither the genetic variation tested in these candidate genes, nor other individual SNPs in the gene independently or collectively are not associated with survival outcomes in recipients of URD BMT. Our failure to replicate the prior candidate gene studies may be due to these SNPs being dependent on the underlying disease (ie. AML, ALL, etc), the donor relation (related, unrelated, autologous), or that there is no true association of these SNPs with the outcomes studied. #These authors contributed equally Table 1. Table 1. Disclosures McCarthy: Gamida Cell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hahn:Novartis: Equity Ownership; NIH: Research Funding. Sucheston-Campbell:NIH/NCI: Research Funding.

Abstract Background: Limited data exist to describe the clinical features and outcomes for elderly pts with FL. The FLASH group performed a prospectively planned pooled analysis of IPD from first-line RCTs and examined associations between age (<= 70 vs. > 70 years), clinical characteristics and FL outcomes. Methods: We identified 18 randomized controlled multicenter clinical trials in the FLASH database which enrolled elderly pts (> 70 yrs). From these 18 studies, 5922 previously untreated FL pts were included for this analysis. Complete response (CR) at 24 and 30 months were defined as whether the pt achieved and remains in CR at 24 months and 30 months after initiation of induction treatment. PFS24 is defined as proportion of pts progression-free and alive at 24 months post-randomization. Time to progression (TTP) and overall survival (OS) were defined as time from randomization to the date of progression (censoring for death without progression) and date of death due to any cause, respectively. Progression-free survival (PFS) was defined as time from randomization to the date of progression or death, due to any cause, whichever comes first. Non-lymphoma death was defined as death without prior progression. Early disease outcomes, i.e. CR24, CR30, and PFS24 were primary outcomes; secondary outcomes were TTP, OS, and PFS. For time-to-event outcomes, Kaplan-Meier method and log-rank test were used for univariate estimation and comparison; stratified Cox proportional hazard modeling was used for multivariable analyses. Cumulative incidence methods were used to model PFS while treating disease progression as the primary event of interest and non-lymphoma death as a competing risk. For binary outcomes, multivariable logistic regression was used to estimate the association between age groups and outcomes. Variable adjusted in the regression models are FLIPI score without the age component, ECOG performance status (>= 2 vs < 2), and rituximab use. Results: Among 5922 previously untreated FL pts from 18 RCTs, 63% (n = 3728) were <= 60, 28% (n = 1652) 61-70, and 9% (n = 542) > 70 yrs. Pts age > 70 (vs. <= 70) more commonly had elevated LDH (42% vs 36%, p = 0.02), hemoglobin < 12 g/dL (27% vs 19%, p < 0.0001), ECOG PS >= 2 (8.8% vs 5.0%, p = 0.0004), and elevated β2-microglobulin (68% vs 49%, p < 0.001), less often had > 4 lymph nodes involved (54% vs 65%, p < 0.001), and had similar FLIPI scores without age component (p = 0.17). There were no significant differences between groups in: Ann Arbor stage (94% vs 95% stage III/IV) or rituximab use (62% vs 58%). Median survival follow-up was 5.6 yrs. Pts > 70 yrs did not differ from pts <= 70 in rates of CR24 (27% vs 30%, p=0.32), CR30 (29% vs 31%, p=0.55) or PFS24 (63% vs. 67%, p=0.10). Median TTP was 3.8 and 4.0 years for pts > 70 and <= 70, respectively (HR=1.08, 95% CI 0.96-1.23, p=0.20). With a median OS of 14.6 years for all pts, median OS was 7.4 and 15.7 years for pts > 70 and <= 70, respectively (HR=2.35, 95% CI=2.03-2.73, p<0.001). PFS was statistically significantly different but clinically similar at median 3.1 and 3.8 years for pts > 70 and <= 70, respectively (HR=1.26, 95% CI =1.12-1.41, p<0.001). Further investigation showed the difference in PFS was due to higher incidence of non-lymphoma death in pts > 70 with no difference in disease progression (Figure). In regression models, adjusting for rituximab use, ECOG PS >= 2, and FLIPI score without the age component, age > 70 was a significant predictor of OS and PFS (due to higher incidence of non-lymphoma death), but not PFS24, CR24 or CR30 (Table). Conclusions: FL pts > 70 yrs treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs. Disclosures Flowers: Genentech: Consultancy, Research Funding; NIH: Research Funding; Mayo Clinic: Research Funding; TG Therapeutics: Research Funding; Millenium/Takeda: Research Funding; ECOG: Research Funding; Acerta: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Roche: Consultancy, Research Funding; AbbVie: Research Funding; Infinity: Research Funding; Gilead: Consultancy, Research Funding. Ou:Mayo Clinic: Employment. Shi:Mayo Clinic: Employment. Hochster:Genentech: Consultancy, Other: Consultancy fees for advisory boards for GI cancer and bevacizumab with amounts within Yale University de minims guidelines. Brice:Roche: Honoraria; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Bristol Myers-Squibb: Honoraria; Gilead: Honoraria; Seattle Genetics: Research Funding. Hiddemann:Roche: Other: Grants; Roche: Membership on an entity's Board of Directors or advisory committees; Genentech: Other: Grants. Marcus:Takeda: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Kimby:Abbvie: Consultancy, Honoraria; Jansen: Consultancy, Honoraria; Celgene: Honoraria; Baxalta: Consultancy; Gilead: Honoraria. Herold:Gilead: Other: Personal fees from member advisory board; Celgene: Honoraria; Genentech: Other: Grants; Roche: Honoraria, Other: Grants. De Bedout:Celgene: Employment. Nielsen:Hoffmann-La Roche: Employment. Morschhauser:Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria. Rummel:Mundipharma GmbH: Other: Personal fees, Research Funding; Roche Pharma AG: Other: Personal fees, Research Funding. Vitolo:Gilead: Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures. Salles:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria. Sargent:Celgene: Research Funding.

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract BACKGROUND: Most cancer patients with bone metastases report significant pain and substantial impairment in their ability to function. In particular, patients with MM are susceptible to bone pain because of bone damage. Patient-reported outcomes such as a general health outcome measure and a legacy pain instrument may provide valuable information in determining the impact of this condition. The goal of this study was to provide a descriptive profile of health status for cancer patients using the EQ-5D-3L (EQ-5D), a commonly used tool to measure health utility scores. Another goal is to evaluate the predictive information provided by the Brief Pain Inventory (BPI), a self-report pain assessment tool designed to capture pain severity and interference in patients. These information may be useful in estimating the health status of patients where the EQ-5D was not administered. METHODS: Data was pooled across three denosumab registrational trials '20050136', '20050103', and '20050244'. Patients completed the EQ-5D and the BPI at baseline. Eligible patients had histologically confirmed advanced cancers, radiographic evidence of at least one bone metastasis (or lytic bone lesion from multiple myeloma), ECOG of 2 or better and adequate organ function. Using data from patients with MM (N=168), descriptive statistics were used to present summary information on health-related quality of life states and utility scores. Linear regressions were used to examine how BPI severity and interference subscale scores relate with EQ-5D utility scores. Ordinal regressions were used to evaluate how well BPI items predict EQ-5D individual items. Bonferroni adjustments were made when evaluating the relationships of BPI items to individual EQ-5D items. These analyses were repeated using data across several groups of cancer patients to determine if similar results can be obtained (breast cancer, N=2,044, prostate cancer, N=1,819 and others, N=1,509). RESULTS: About 9% of MM patients reported perfect health compared with 11% of all cancer patients. Of the 5 dimensions measured by the EQ-5D, the MM cohort rated pain (80%) the highest with moderate to extreme problems. This was followed by usual activities (68%), mobility (63%), anxiety/depression (49%), and self-care (36%). Similar order was observed across all cancer groups, but with slightly lower percentages for most items: pain (78%), usual activities (58%), mobility (55%), anxiety/depression (57%), and self-care (26%). Although pain interference subscale score explained more of the variability in the EQ-5D utility scores compared with pain severity items in the MM cohort (39% vs 31%) and for all patients (41% vs 34%), model fit was less than ideal (mean squared error=0.23 - 0.25). Hence, BPI items were fitted into individual EQ-5D items. Ordinal regression models fitting BPI items into individual EQ-5D items for the MM cohort showed good predictive power as measured by the concordance index c for mobility (86%), self-care (80%), usual activities (83%), pain (90%) and anxiety/depression (78%). For all patients, similar model fit were obtained for mobility (83%), self-care (78%), usual activities (81%), pain (90%) and anxiety/depression (72%). Further examination of the ordinal regression models across all groups showed that three BPI pain severity items, 'pain at its worst', 'average pain' and 'pain now' in addition to interference with activity and interference with work significantly predicted the EQ-5D pain item. Five interference items, activity, walking ability, work, sleep and enjoyment of life significantly predicted the EQ-5D usual activities item. Finally, 'pain now' and four interference items, relationship with others, enjoyment of life, mood, and activity significantly predicted the EQ-5D anxiety/depression item. CONCLUSIONS: Patients with MM reported several functional limitations on the EQ-5D. Majority of the patients reported moderate to extreme problems in all EQ-5D dimensions except self-care. Model fit of ordinal regression models relating BPI items with EQ-5D items are reasonable underscoring the benefit of using the BPI for planning patient care and health status evaluation. This consistency was also found across cancer groups that primarily include breast and prostate. The resultant model demonstrates the significant contribution of pain severity and interference in determining health status in this patient population. Disclosures Mendoza: Amgen Inc.: Consultancy. Shi:Amgen Inc.: Consultancy. Ma:Amgen Inc.: Employment. Zhang:Amgen Inc.: Employment. Qian:Amgen Inc.: Employment. Cleeland:Amgen Inc.: Consultancy.

Key PointsIKZF1 associations with high-risk B-ALL may differ by age and sex. A novel variant on chromosome 14, rs189434316, is associated with over a 3.5-fold risk of normal cytogenetic B-ALL.

Background: Electroacupuncture (EA) has been shown to improve complete spontaneous bowel movements (CSBMs), but the duration of its effects remains unknown. The objective of this study was to explore the duration of acupuncture effects after treatment and its associated factors for chronic severe functional constipation (CSFC). Methods: This was a secondary analysis of a multicenter, randomized, sham-acupuncture (SA) controlled trial that included 1075 participants with CSFC. The primary outcome, the duration of acupuncture effects after treatment, was the number of weeks during the 12-week follow-up period that participants were to meet the weekly CSBM responder criteria. A weekly CSBM responder was defined as a participant who had at least three CSBMs for a given week and an increase from baseline of at least one CSBM for that same week. We performed a retrospective multivariate analysis to explore potential factors associated with sustained acupuncture effects. Results: The duration of acupuncture effects in the EA group (5.5 weeks) was significantly higher than the duration of SA effects in the SA group (2.2 weeks) with a between-group difference of 3.2 weeks (95% CI, 2.77–3.78; p < 0.001). A younger age and higher baseline CSBMs per week [regression coefficient (RC) –0.06, 95% confidence interval (CI) (−0.06 to −0.04); RC 2.43, 95% CI 1.78–3.60; respectively] were associated with longer durations of acupuncture effects. Conclusions: EA had sustained post-treatment effects for CFSC. A significant association among a younger age, higher baseline CSBMs and sustained acupuncture effects was observed. Further research is needed to confirm the association. Trial registration: ClinicalTrials.gov (NCT01726504). Registered on 26 August 2012.

Hereditary renal cystic diseases are characterized by defects in primary cilia of renal tubular epithelial cells and abnormality of tubular epithelium, which ultimately result in the development of renal cysts. However, the mechanism leading from abnormality of the tubular epithelium to cystogenesis is not well understood. In this report, we demonstrate a critical role for Robo2 in regulating epithelial development, including ciliogenesis, polarization, and differentiation. We found that Robo2 deficiency results in cystic kidneys, and the cyst cells showed defective cilia and polarity defects in tubular epithelium. The cyst cells, less than terminally differentiated, continue to proliferate. We further established that Robo2 works with p53 as well as polarity and ciliary proteins (Par3, PKCς, ZO-2, and Claudin-2) to regulate these processes. Robo2 binds to Baiap2 (also known as IRSp53) through the IRSp53/MIM homology domain in renal epithelial cells. This binding allows Robo2 to phosphorylate MDM2 at Ser166 via Baiap2 and maintain p53 homeostasis. Disruption of the Robo2-Baiap2 complex causes MDM2 to be subjected to dephosphorylation, leading to a high level of active p53, and initiated p53-mediated cellular senescence via p21 and decreased the expression of ZO-1, ZO-2, PKCς, Par3, and Claudin-2 proteins, resulting in defects in epithelial development, including ciliogenesis, polarization, and differentiation. Importantly, double knockout of Robo2 and p53 rescued all the epithelial defects in kidneys compared with those in Robo2 -knockout kidneys. Taken together, the present results demonstrate that Robo2 deficiency causes renal cystic disease, which is largely dependent on defective Robo2-Baiap2 integrated signaling in kidneys.