bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-Term (10 Years or More) Survivors Of Multiple Myeloma: A Population-Based Analysis Of The US National Cancer Data Base
Authors: Raghavendra Meghana , Al-Hamadani Mohammed , Go Ronald S. 
Published: October 2019

Abstract

Introduction
Long-term survivors in multiple myeloma (MM), described as those surviving >10 years since their diagnosis, are uncommon. There is paucity of data describing this subgroup of patients and how they differ clinically from the rest.

Methods
Patients with MM diagnosed from 1998 to 2000 were identified in the National Cancer Data Base (NCDB). We obtained data associated with socio-demographics, type and location of care facility, as well as the use high dose chemotherapy/autologous stem cell transplant (ASCT) as initial treatment option. Four cohorts were created based on overall survival (OS): subgroup 1 (OS: < median); subgroup 2 (OS: median to 2X-median), subgroup 3 (OS: 2X-median to <10 years) and subgroup 4 (OS: >10 years).

Results
There were 27,987 MM patients. The median OS for the whole group was 26.7 months. Among them, 2,196 (7.9%) were long-term survivors. Subgroups 1, 2, and 3 comprised 54.8%, 19.0%, and 18.3% of the remaining patients, respectively. Majority were males (54.3%) with a mean age at diagnosis of 67.2 years (range, 19-90). Compared to the other subgroups (1/2/3), the long-term survivor subgroup had a significantly higher proportion of patients with high educational level (37.8% vs 28.4%/31.6%/33.9%; P < 0.001), high annual household income (41.5% vs 31.0%/34.2%/36.4%; P < 0.001), residence in a metro area (79.2% vs. 77.8%/78.7%/78.3%).; P=0.003), initial treatment at an academic center (46.6% vs 28.1%/34.6%/39.0%; P < 0.001), and had ASCT as part of initial therapy (16.5% vs 2.5%/6.4%/10.9%; P < 0.001). Multivariable analyses showed that younger age, non-Black race, lower educational level, non-Medicare/Medicaid primary payor, treatment at academic centers, and receipt of ASCT as part of initial treatment were significant independent predictors of survival > 10 years. In contrast, sex, ethnicity, type or geographic location of residence, and median annual household income were not significant.

Conclusions
In the US, approximately 1 in 13 MM patients diagnosed in 1998-2000 are long-term survivors. There are disparities in long-term outcomes according to socio-demographic characteristics, type of treatment facility, and receipt of ASCT as part of initial therapy.

Disclosures:
No relevant conflicts of interest to declare.
Ras-Pathway Inhibition With Targeted Therapies Abrogates Self-Renewal In Acute Myelogenous Leukemia
Authors: LaRue Rebecca S. , Nguyen Hanh , Sachs Karen , Mohd Hassan Nurul Azyan , Diaz-Flores Ernesto , Rathe Susan K. , Sarver Aaron G. , Bendall Sean C. , Ha Ngoc A. , Diers Miechaleen D. , Nolan Garry P. , Shannon Kevin , Sachs Zohar , Largaespada David A. 
Published: October 2019

Abstract
Hyperactivated Ras-pathways serve as oncogenic drivers in multiple human tumors including acute myelogenous leukemia (AML) (Ahearn et al. Nat Rev Mol Cell Biol 2011). The specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. Recently, we have shown that NRASG12V–activated signaling pathways are critical to leukemia stem cell maintenance (Sachs et al. submitted). To elucidate which Ras-activated signaling molecules mediate self-renewal in AML, we employed a murine model that harbors Mll-AF9 and a tetracycline repressible, activated NRAS (NRASG12V) and develops AML (Kim et al. Blood 2009). Primary leukemia cells were treated with therapeutic agents targeting Ras-activated signaling pathways. We used PD325901 to inhibit the Mek-Erk pathway, GDC0941 to inhibit the Pi3k pathway, and RAD001 to inhibit the mTor pathway. Using MTS assays, we identified the IC50 dose for each of these agents. Inhibitor-treated leukemia cells were submitted for RNA sequencing in order to investigate the effects of these agents on leukemia gene expression. Previously, we identified a list of NRASG12V responsive genes in our model. In these studies, we identified that PD325901-treatment most closely recapitulates the effect of NRASG12V inhibition on this comprehensive list of RAS-responsive genes. However, when we study the effects of these inhibitors on the subset of RAS-responsive genes that mediate leukemia self-renewal, we find that both PD325901 and RAD001 independently recapitulate the effects of NRASG12V withdrawal on this subset of genes implicating the Mek and mTor pathways in leukemia self renewal. Next, we treated primary leukemia cells with the IC50 dose of each drug and plated them in colony forming assays. We found that Mek or mTor inhibition, but not Pi3k inhibition, abrogated secondary colony formation corroborating our gene expression analyses and showing that, at doses that have equivalent effects on cell growth, only the Mek and mTor pathways are important for leukemia cell stem cell maintenance. These studies provide potential targets for leukemia stem cell-specific therapies.

Disclosures:
Sachs: Silicon Valley Biosystems: Consultancy. Bendall:DVS Sciences: Consultancy. Nolan:SAB for DVS Sciences and Nodality: Chairman Other; Cell Signalling Technologies and Becton Dickenson, Inc: Consultancy. Largaespada:Discovery Genomics, Inc: Consultancy, Share Holder Other; NeoClone Biotechnology, Inc: Consultancy, Share Holder, Share Holder Other.
Transferrin Deficiency Leads To Specific and Partially Reversible Iron Overload
Authors: Bartnikas Thomas Benedict , Herrera Carolina , Pettiglio Michael A. 
Published: October 2019

Abstract
Studies in hpx mice, a model of inherited transferrin deficiency, have demonstrated that transferrin is essential for iron delivery to the erythron and regulation of expression of hepcidin, a hormone that inhibits dietary iron absorption. Here we address two other putative roles for s transferrin. First, we determined if transferrin is essential for metabolism of metals other than iron. Metal content analysis of fractionated mouse sera indicated that iron was the most abundant metal in transferrin-rich fractions. Organ metal content analysis demonstrated severe imbalances for iron and minimal to moderate imbalances for copper, zinc and manganese in hpx tissues. Analysis of metal-dependent gene expression and organ metal content in a mouse model of inherited hepcidin excess suggested that hpx tissue imbalances in copper, zinc and manganese levels were not all physiologic or specific to primary transferrin deficiency. Second, we tested if transferrin modulates the mobilization of tissue iron stores. Transferrin treatment of hpx mice decreased iron levels in most tissues analyzed. Iron mobilization was independent of hepcidin, as iron levels decreased in hpx mice deficient in hemojuvelin, a membrane protein essential for hepcidin expression. Iron mobilization led to decreased ferritin iron and heavy chain levels. The decrease in liver ferritin iron stores did not match the decrease in total liver iron stores, suggesting that iron was mobilized from multiple storage sites. Overall, our analysis suggests that the primary consequences of transferrin deficiency are largely specific to iron and that transferrin can modulate the mobilization of tissue iron stores.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Outcomes For Patients With Sickle Cell Disease: 24-Month Follow-Up In An Ongoing 3-Year, Prospective, Non-Interventional Registry Trial
Authors: Heeney Matthew M , Mueller Brigitta U. , Baltz Brad , Adams-Graves Patricia , Yang Elizabeth , Paley Carole , MSHS Jason Esposito , MSHS CCRA McNamara Katie , Vichinsky Elliott 
Published: October 2019

Abstract

Introduction
Patients (pts) with sickle cell disease (SCD) experience a heterogeneous clinical course, with a range of symptoms and sequelae. We describe clinical outcomes and treatment patterns from a prospective registry of pediatric and adult pts with SCD.

Methods
Pts ≥2 years old with HbSS, HbSC, or HbS/β-thalassemia were enrolled from 57 US centers and assessed every 6 months (mos) for up to 3 years. Differences between pediatric and adult pts at 24 mos follow-up are reported. (ClinicalTrials.gov NCT01220115).

Results
A total of 498 pts completed the baseline visit (74.1% HbSS disease, 15.3% HbSC, and 10.4% HbS/β-thalassemia) (Table 1
). At baseline, the following conditions were more frequent in adults: avascular necrosis, gallbladder disease, leg ulcers, and pulmonary hypertension. Pediatric pts had more frequent asthma/reactive airway disease, dactylitis, and splenic sequestration. The nature of sickle-related events varied between adult and pediatric pts (Table 2
). Prior to study, adults had higher frequencies of pain crises, strokes, and priapism, while pediatric pts had more frequent infections and acute chest syndrome (ACS)/pneumonia. On study, a similar proportion of pediatric and adult pts (56.4% overall) were hospitalized, most frequently due to pain, fever, and ACS/pneumonia; a greater proportion of pediatric pts were hospitalized due to fever (P<0.05). The percentage of pts who received a transfusion and/or chelation while on study was similar between adult and pediatric pts. Almost half of the pediatric and adult groups received hydroxyurea prior to and during the study. High rates of absenteeism were observed, with 51% of pediatric pts and 44.4% of adults missing 1 to 10 days of school or work in the year before study.

Conclusions
Despite advances in care, SCD is associated with significant morbidity that contributes to high rates of hospitalization and absenteeism in both pediatric and adult pts. Continued follow-up in this registry will provide additional information about disease patterns and pt management.

Disclosures:
Heeney: Novartis: Consultancy, Research Funding; Eli Lilly: Research Funding. Off Label Use: Hydroxurea is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult patients with sickle cell anemia. It is not approved for use in children. Mueller:Novartis: Research Funding. Adams-Graves:Novartis: Consultancy, Speakers Bureau. Paley:Novartis: Employment. Esposito:Novartis: Employment. Katie:Novartis: Employment. Vichinsky:Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Research Funding; ARUP: Research Funding, Research Laboratory, Research Laboratory Other.
Hemoglobinuria Is a Risk Factor For Kidney Disease Progression In Sickle Cell Anemia
Authors: Saraf Santosh L. , Zhang Xu , Kanias Tamir , Lash James P. , Molokie Robert E. , Gowhari Michel , Hassan Johara , Gladwin Mark T. , Gordeuk Victor R. 
Published: October 2019

Abstract

Chronic kidney disease (CKD) is a frequent complication of sickle cell anemia (SCA) and is a predictor of early mortality. To determine the predictors of deteriorating kidney function in SCA, we followed 164 patients treated at the University of Illinois at Chicago for a median of 32 months (range 3-88 months). Steady-state estimated glomerular filtration (eGFR), albuminuria, and hemoglobinuria assessments were obtained at baseline and during the follow-up period. Steady-state was defined as greater than four weeks from a vaso-occlusive pain episode or a red blood cell transfusion. Hemoglobinuria was defined as positive for blood on dipstick and < 2 red blood cells on microscopy. Fifty-six (34%) of the patients had hemoglobinuria at baseline. We confirmed in a subset of 43 patients that dipstick positive hemoglobinuria (n=17) was associated with higher urine cell-free hemoglobin concentrations determined by ELISA than dipstick negative urine (n=26) (23.1 vs. 11.5 ng/mL, p<0.0001) (Figure 1). Age and mean arterial blood pressures were similar in patients with hemoglobinuria at baseline compared to those without but markers of hemolysis were higher (LDH, indirect bilirubin, AST, and reticulocyte percentage; p<0.0001). Sixty-one percent (95%CI: 48-73%) of patients with hemoglobinuria at baseline had hemoglobinuria at most recent follow up compared to 9% (95%CI: 5-18%) of patients without hemoglobinuria at baseline (p<0.0001). The proportion of patients with CKD progression defined by a 50% reduction in eGFR calculated by the CKD-EPI formula or requirement for hemodialysis or kidney transplant was higher in patients with baseline hemoglobinuria (13%, 7/56) versus without hemoglobinuria (1%, 1/108) (HR 14, 95%CI: 2-113; logrank p=0.001) (Figure 2). Progression of albuminuria category from normoalbuminuria (albuminuria < 30mg/g creatinine) to either microalbuminuria (albuminuria = 30-300 mg/g creatinine) or macroalbuminuria (albuminuria > 300mg/g creatinine) or microalbuminuria to macroalbuminuria was also higher in patients with baseline hemoglobinuria (42%, 11/26) versus without hemoglobinuria (13%, 9/67) (HR 3.1, 95%CI: 1.3-7.7; logrank p=0.004) (Figure 3).
In conclusion, hemoglobinuria determined by urinalysis at steady-state is a valid assessment of increased urine cell-free hemoglobin concentration and is fairly consistent on repeat testing at steady-state visits. The presence of hemoglobinuria is significantly associated with a greater risk for progression of CKD and albuminuria. Our findings are consistent with the possibility that cell-free hemoglobin contributes to the progression of kidney disease in SCA. Further research including measures to decrease cell-free hemoglobin exposure to preserve kidney function are warranted.Figure 1Figure 1. Figure 2Figure 2. Figure 3Figure 3.

Disclosures:
No relevant conflicts of interest to declare.
Role of Epigenetic Readers in Pathogenesis and Therapy of Acute Leukemias
Authors: Huntly Brian J. P. 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a dismal survival rate of less than 30 percent and is thus a disease where novel therapeutics are urgently required. AML is highly heterogeneous at both the molecular and clinical level. However, recurrent themes of altered transcriptional and epigenetic control are evident from sequencing and mechanistic studies. Recently, critical epigenetic regulators have surfaced as mediators of leukemogenesis and potential therapeutic targets in AML and other hematological malignancies. We and others have recently demonstrated that the Bromodomain and Extra Terminal (BET) protein family of transcriptional adapter proteins are required for transformation by MLL-fusion proteins, where they facilitate the localization of aberrant transcriptional complexes to chromatin at genes critical for leukemogenesis. Furthermore, we and others have demonstrated that small molecule inhibitors, such as I-BET151 and JQ1, of the protein-protein interactions between these proteins and acetylated lysine residues in histone tails are effective in pre-clinical models of MLL leukemias. We have recently extended studies of BET inhibition to other forms of AML using I-BET151 and found a range of sensitivities across a panel of AML cell lines and patient samples with common recurrent mutations. These cell lines also demonstrate a common cellular response to MLL-fusion leukemias, with induction of apoptosis and G1/0 arrest, suggesting that similar transcriptional programs may be targeted. In further investigating this, we identified a common transcriptional program downregulated in sensitive leukemia subtypes. In addition, using diagnostic gene expression profiles, we also demonstrate that this program can classify AML patients, suggesting that the program may provide predictive biomarkers and potentially identify those patients most likely to respond to BET inhibitions. Focusing on the most common mutation in AML, mutations of the nucleophosmin gene (NPM1c mutations), we present evidence to suggest that wild-type NPM1 has an inhibitory influence on BRD4, which is relieved upon NPM1c mutation and cytosplasmic dislocation. NPM1c mutation allows upregulation of the core transcriptional program facilitating leukemia development, and this program is abrogated by I-BET therapy. Finally, we demonstrate the efficacy of I-BET151 in human cell lines, a unique murine model, and in primary patient samples of NPM1c AML. Taken together, we have used BET inhibitors as a laboratory tool to dissect out mechanisms of aberrant transcriptional control in AML. Furthermore our pre-clinical evaluation supports clinical trials of BET inhibitors across multiple AML subtypes and identifies potential predictive biomarkers of sensitivity and response to inform these studies.

Disclosures:
No relevant conflicts of interest to declare.
Mechanisms of Neutrophil Release from the Bone Marrow
Authors: Link Daniel 
Published: October 2019

Abstract
Neutrophils are an essential component of the innate immune response and a major contributor to inflammation. Consequently, neutrophil homeostasis in the blood is tightly regulated. This is achieved by balancing neutrophil production and release from the bone marrow with clearance of senescent neutrophils from the circulation. Here, we highlight recent studies elucidating the signals that regulate neutrophil homeostasis. Constitutive chemokine expression by bone marrow stromal cells plays a key role in regulating neutrophil egress. Specifically, CXCL12 from CXCL12-abundant reticular (CAR) cells and possibly endothelial cells serves to retain neutrophils in the bone marrow. Conversely, CXCL1/2 expression from endothelial cells may promote neutrophil egress. Consistent with these observations, gain-of-function mutations of CXCR4 (the major receptor for CXCL12) or loss-of-function mutations of CXCR2 (the major receptor for CXCL1/2) are associated with myelokathexis in humans. G-CSF promotes neutrophil release from the bone marrow, in large part, by decreasing CXCL12 expression in bone marrow stromal cells, while increasing CXCL2 expression in bone marrow endothelial cells. CXCL12 production from bone marrow stromal cells may be a target of a feedback loop involving the clearance of senescent neutrophils. Specifically, macrophage engulfment of senescent neutrophils in the bone marrow attenuates CXCL12 expression, thereby facilitating neutrophil egress. Recent data suggest that signals from gut microbiota may play a significant role in regulating neutrophil homeostasis. In particular, mice raised under germ-free conditions display marked neutropenia. Gut microbiota appear to regulate neutrophil homeostasis, at least in part through toll-like receptor signaling. These data suggest new pathways that might be targeted therapeutically to modulate neutrophil number in the blood.

Disclosures:
No relevant conflicts of interest to declare.
Characteristics and Prognostic Significance of CRLF2 High Expression and the Co-Existence with JAK1 Mutations and Ikaros Deletion in Adult Acute Lymphoblastic Leukemia
Authors: Ge Zheng , Liu Juan , Zhang Run , Guo Xing , Xu Jing-Yan , Li Min , Qiao Chun , Li Jian-Yong 
Published: October 2019

Abstract
Objective Cytokine receptor-like factor 2 (CRLF2) play an important role in differentiation and proliferation of lymphoid precursor cells through activation of JAK signaling pathway. Increased CRLF2 expression associates with mutations in JAK2, a combination that transforms hematopoietic cells, suggesting that mutants in JAK family members and CRLF2 may cooperate to contribute to acute lymphoblastic leukemia (ALL) pathogenesis. Moreover, the Ikaros deletion is also associated with the development of T-/B-cell ALL with poor outcome and relapse of high-risk leukemia. The aim of this study was to determine the clinical characterization and prognostic values of CRLF2 high expression and its concomitant expression with JAK1 mutations and Ikaros deletion in adult ALL patients.
Methods Quantitative PCR (qPCR) was performed to detect the expression of CRLF2 in 133 newly diagnosed adult patients with ALL. Genomic DNA was amplified to detect the mutations of the exon 13, 14, 16, 18 and 19 of JAK1, and IKZF1 exons 4 through 7 deletions (△4–7) by direct sequencing or sequencing after cloning. The CD34, CD13, CD33 and other markers were detected on the leukemia cells from bone marrow of the patients by flow cytometry, and the correlations of the CRLF2 high expression with the clinical features, survival, and with co-expression of JAK1 mutations and Ikaros deletion were statistically analyzed with Pearson's chi-square test or Fisher's exact test and Kaplan–Meier curves analysis.
Results CRLF2 high expression was detected in 22.8% of newly diagnosed adult ALL. The patients with CRLF2 high expression has significantly higher percentage of CD34, CD13 or CD33 positive than those with low expression（91.3% vs 62%, P=0.008; 76.2% vs 46.3%, P=0.016; 80.0% vs 37.9%, P=0.001), higher frequency of splenomegaly（60.0% vs 32.0%, P=0.040) in the adult ALL and shorter overall survival and event-free survival（9.5 months vs 16 months, P=0.029; 3 months vs 9 months, P=0.030）in the Philadelphia chromosome negative ALL. Moreover, the 4 JAK1 point mutations with amino acid changes were detected in the patients, which had significant CRLF2 high expression compared to that without mutation（75% vs 21.3%, P=0.037). The co-existence of CRLF2 high expression and IKZF1 exons 4-7 deletion (isoform Ik6) was found in 4 of 10 patients.
Conclusion CRLF2 high expression predicts poor survival, and significantly co-exists with JAK1 mutation and Ikaros deletion in adult ALL patients. Our result also suggested that CRLF2, JAK1 and IKZF1 could be integrated in future prognostic model of adult ALL as possible markers for high-risk leukemia.

Disclosures
No relevant conflicts of interest to declare.
Antibodies from Donor B Cells Are Not Required for Initiating but Required for Persisting Scleroderma in Chronic Gvhd
Authors: Jin Hua , Ni Xiong , Deng Ruishu , Young James , Johnston Heather F , Liu Qifa , Zeng Defu 
Published: October 2019

Abstract
We recently reported that in a chronic graft versus host disease (GVHD) model of DBA/2 donor to MHC-matched BALB/c recipient, donor CD4+ T and B cell interaction resulted in not only hyperglobulinemia and glomerulonephritis but also scleroderma (J. Immunol. 2012). It is well known that glomerulonephritis is caused by immune complex deposition. However, the role of antibodies from donor B cells in the pathogenesis of scleroderma remains unclear. To address this question, we generated DBA/2 mice whose B cells have APC function but cannot secrete antibodies by backcrossing IgHµg1 mice from Dr. Rajewsky’s lab (JEM 2007). We observed that, while transplanting T-cell-depleted bone marrow (TCD-BM) and spleen cells from littermate control mice induced proteinuria and scleroderma, transplanting BM and spleen cells from IgHµg1 DBA/2 mice induced no proteinuria, but the recipients developed scleroderma ~35 days after HCT. Interestingly, the scleroderma gradually recovered ~55 days after HCT. 40 days after HCT, scleroderma recipients transplanted with WT spleen cells (Rec-WT) or recipients transplanted with IgHµg1 spleen cells (Rec-IgHµg1) both had high percentage (~12%) of IFN-g+ or IL-17+ CD4+ T cells in the peripheral lymph node (PLN) and skin tissues, as compared to that (~3%) of GVHD-free recipients given TCD-BM alone (Rec-TCD). While Rec-WT had severe reduction of CD4+CD8+ thymocytes, the Rec-IgHµg1 had no reduction of the thymocytes, as compared to that of Rec-TCD. By day 60 after HCT, the Rec-WT with ongoing scleroderma still had ~10% IFN-g+ or IL-17+ CD4+ T cells in the PLN and skin tissues; in contrast, although the Rec-IgHµg1 with reversal of scleroderma still had >10% IFN-g+or IL-17+ CD4+ T cells in the PLN, those cells in the skin had reduced to <2%. This reduction was associated with DC upregulation of B7H1 and T cell upregulation of PD-1. These results suggest that antibodies from B cells are required for maintaining inflammatory status of tissue DCs and persistence of scleroderma in chronic GVHD. (This work was supported by NIH R01 AI066008).

Disclosures
No relevant conflicts of interest to declare.