Gain of chromosome 1q (+1q) is commonly identified in multiple myeloma and has been associated with inferior outcomes. However, the prognostic implication of +1q has not been evaluated in the setting of standard triplet regimens. We retrospectively analyzed 201 consecutive patients with newly diagnosed myeloma who received induction with lenalidomide, bortezomib, and dexamethasone (RVD) and were tested for +1q at diagnosis by fluorescent in-situ hybridization. Patients with +1q (n = 94), compared to those without +1q (n = 107), had shorter median progression-free survival (PFS) (41.9 months vs 65.1 months, p = 0.002, HR = 1.90) and overall survival (median not reached (NR) for either arm, p = 0.003, HR 2.69). In subgroup analyses, patients with co-occurring +1q and t(4;14), t(14;16) or del(17p) or with 4 or more copies of 1q had significantly worse PFS (25.1 months and 34.6 months, p < 0.001 and p = 0.0063, respectively), whereas patients with three copies and no other high-risk cytogenetic abnormalities had no significant difference in PFS. These data suggest that when treated with RVD induction, patients with +1q should be considered at very high risk for early progression in multiple myeloma when ≥4 copies are detected or in the context of other high-risk cytogenetic abnormalities.
• Blockade of NAE and bortezomib induces phosphatidylinositol 3-kinase/ mTOR inhibition.• NAE inhibition and bortezomib combined induce synergistic plasma cell apoptosis.The function and survival of normal and malignant plasma cells depends on the elaborately regulated ubiquitin proteasome system. Proteasome inhibitors such as bortezomib have proved to be highly effective in the treatment of multiple myeloma (MM), and their effects are related to normal protein homeostasis which is critical for plasma cell survival. Many ubiquitin ligases are regulated by conjugation with NEDD8. Therefore, neddylation may also impact survival and proliferation of malignant plasma cells. Here, we show that MLN4924, a potent NEDD8 activating enzyme (NAE) inhibitor, induced cytotoxicity in MM cell lines, and its antitumor effect is associated with suppression of the AKT and mammalian target of rapamycin (mTOR) signaling pathways through increased expression of REDD1. Combining MLN4924 with the proteasome inhibitor bortezomib induces synergistic apoptosis in MM cell lines which can overcome the prosurvival effects of growth factors such as interleukin-6 and insulin-like growth factor-1. Altogether, our findings demonstrate an important function for REDD1 in MLN4924-induced cytotoxicity in MM and also provide a promising therapeutic combination strategy for myeloma. (Blood. 2014;123(21):3269-3276)
2576 Cerebrospinal fluid (CSF) involvement by leukemic blasts occurs in fewer than 10 % of adult patients with newly diagnosed acute lymphoblastic leukemia/lymphoma (ALL). Leukemic meningitis is diagnosed by microscopic detection of blasts in the CSF. Flow cytometry is a highly sensitive tool for detection of aberrant cells. We sought to analyze the additional benefit flow cytometry might provide for the diagnosis of leukemic meningitis. Between 11/2007 and 8/2011, 80 patients were diagnosed with ALL and treated at Emory University. 800 CSF samples were available for analysis 80 of which were collected from a diagnostic lumbar puncture (LP), 689 from follow-up LPs and 31 from LPs obtained at the time of relapse. As shown in the table, flow cytometry confirmed the presence of leukemic blasts in one, four and five samples diagnosed with leukemic meningitis by cytology at diagnosis, different stages of treatment and relapse, respectively. One and three samples were positive for leukemic blasts by cytology but negative by flow cytometry during different treatment stages and relapse respectively. We conclude that flow cytometry provided no additional benefit to cytology in the diagnosis of leukemic meningitis. Table: CSF Cytology and Flow Cytometry in 80 Adult ALL patients: CSF samples New Diagnosis N=80 Induction/Consolidation/Intensification/Maintenance/Remission/Post-transplant N = 689 Systemic relapse N = 31 N Cytology N = 80 Flow cytometry N = 66 Cytology N = 689 Flow cytometry N = 188 Cytology N = 31 Flow cytometry N = 13 Negative 79/80 65/66 684/689 184/188 23/31 8/13 Positive 1/80 1/66∼ 5/689 4/188∼* 8/31 5/13∼** ∼ CSF samples positive by flow cytometry were also positive by cytology * One CSF sample was positive by cytology but negative by flow cytometry ** CSF flow cytometry was not done in 3/8 positive CSF samples by cytology Disclosures: No relevant conflicts of interest to declare.
Background Examining spatial patterns of DLBCL incidence has identified of areas of elevated and decreased risk (Bulka, Cancer 2013). Examining the relationships between DLBCL clusters and residential exposures to potential carcinogens can provide insight about potential environmental and socio-demographic risk factors. Methods In order to investigate the spatial patterns of DLBCL incidence among adults (≥ 20 years), we linked and geocoded cancer incidence data for the period 1999-2008 from the Georgia Comprehensive Cancer Registry (a CDC-supported a statewide population-based cancer registry) with population data from the 2000 U.S. Census, and the EPA toxic release inventory. DLBCL cases were aggregated to the census tract level. DLBCL incidence in Georgia was standardized indirectly by age, sex, and race to national rates obtained from SEER*Stat software. Choropleth maps were created to depict the ratio of observed to expected incidence (standardized incidence ratios [SIR]) by census tract using ArcGIS. Spatial Empirical Bayes smoothing was performed on the SIR values. To assess spatial correlation of SIRs, we conducted global and local cluster analyses by calculating global Moran’s I and Local Indicators of Spatial Autocorrelation [LISA] values. Cluster analyses were repeated, stratifying by age (20-59 years, ≥60 years), sex, and race (Caucasian and African American). The Lawson-Waller Score test was used to individually assess each of the release sites for focal clustering of DLBCL. We adjusted our alpha level using the Bonferroni correction. Poisson regression models were constructed under the assumption that the number of observed incident cases for each census tract had a Poisson distribution that was dependent on the number of expected cases for that census tract, based on its age, sex, and race demographics, and the explanatory variable of mean distance from the toxic release sites. Median year moved into residence was also assessed as a potential confounder and/or effect modifier. Results Between 1988 and 1998, facilities in Georgia reported release of: 1,3 butadiene (3 sites), 2,4-D (1 site), benzene (19 sites), ethylene oxide (7 sites), formaldehyde (60 sites), pentachlorophenol (5 sites), styrene (86 sites), tetrachloroethylene (33 sites), and trichloroethylene (40 sites). Total releases, calculated as the sum of fugitive air releases, stack air releases, and surface water discharges between 1988 and 1998 for each site ranged from 52 to 3,830,097 pounds of benzene, 171,437 to 216,659 pounds of 1,3 butadiene, 250 pounds of 2,4-D, 4,220 to 581,077 pounds of ethylene oxide, 5 to 872,835 pounds of formaldehyde, 164 to 3,845 pounds of pentachlorophenol, 2 to 4,472,334 pounds of styrene, 5 to 1,575,644 pounds of tetrachloroethylene, and 5 to 3,730,069 pounds of trichloroethylene. 3,851 incident DLBCL cases occurred among adults residing in Georgia between 1999 and 2008. Clustering of high SEB-smoothed SIRs appears to be located in the metro-Atlanta area for Caucasians and African Americans. All 9 toxic release exposures showed some evidence for focal clustering. The Lawson-Waller score test identified significant focal clustering of higher than expected DLBCL incidence around: 86% of ethylene oxide, 68% benzene, 48% of tetrachloroethylene, 29% of styrene, 23% of formaldehyde, 20% of trichloroethylene, and 20% of all release sites. No statistically significant Poisson coefficients emerged for the interaction term between mean distance to toxic release site and time in residence. Conclusions We identified spatial clustering of DLBCL and associations between excess DLBCL incidence and residential proximity to EPA-designated toxic release sites. Confirmatory studies using geospatial mapping in other locations and epidemiological studies can aid in identifying risk factors for the development of DLBCL. Disclosures: Flowers: Genentech BioOncology: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Abbott: Research Funding.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.