bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Race, Age, and Sex in Follicular Lymphoma (FL): A Comprehensive SEER Analysis in the Pre- and Post-Rituximab Eras
Authors: Nabhan Chadi , Aschebrook-Kilfoy Briseis , Chiu Brian C-H , Kruczek Kimberly , Patel Anand , Smith Sonali M. , Evens Andrew M. 
Published: October 2019

Abstract
Abstract 1576

Background:
While racial disparity has been documented in a number of cancers, the impact of race, sex, and socioeconomic status (SES) on FL outcomes is not well defined. Furthermore, the impact of modern therapeutics on these disparities has not been fully explored.

Methods:
We examined population-based FL overall survival (OS) data from SEER 13 (1993–2008) for race, sex, age, and socioeconomic status (SES) over two consecutive 8-year periods: Era 1 (1993–2000, n=7,409) and Era 2 (2001–2008, n=9,083).

Results:
We identified a total 16,492 FL patients (pts) (white (W): n=13,441 (81.5%); Hispanic (H): n=1,417 (8.5%); Asian/Pacific Islander (A/PI): n=887 (5.3%); and Black (B): n=747 (4.5%)). Median age at diagnosis differed significantly according to race: (in years, yrs) W: 62.1, H: 57.3, A/PI: 60.5, B: 56.6; P<0.01 for each race vs. W. For all pts, OS was superior in Era 2 vs. Era 1 (5-yr OS: 77% vs. 68%, respectively, P<0.0001). Further, OS was significantly improved for all age groups (<50, 50–59, 60–69, and 70–79 yrs) as well as for males (P=0.0019) and females (P<0.0001) across eras. Interestingly, females had superior OS compared with males in Era 1 (P=0.004), but not in Era 2 (P=0.83). We subsequently compared OS within and across races (see Table). All races, except A/PI, had improved 5-yr OS rates (age adjusted) from Era 1 to Era 2 (W: <0.001, H: 0.049, A/PI: 0.15, B: 0.003). Notably, A/PIs had the highest OS in Era 1, while H had the poorest OS in Era 2. These differences were more evident in males compared with females within each race. Finally, pts with higher SES had improved OS compared with low SES in both eras (P=0.02 in era 1 and <0.0001 in era 2), although OS was improved across eras within low and high SES populations (P<0.0001).

Conclusions:
Collectively, we identified improved OS in FL across eras, which was apparent for all ages, both sexes, and all races. However, racial disparities persist, including inferior OS for H and superior OS for A/PIs in the contemporary era. The disproportionate improvement in OS over eras and persistent inequality in outcomes based on race warrants continued examination.

Disclosures:
No relevant conflicts of interest to declare.
Effects of Tyrosine Kinase Inhibitors On Spermatogenesis and Pituitary Gonadal Axis in Males with Chronic Myeloid Leukemia
Authors: Yassin Mohamed A. , Soliman Ashraf T , Elawa Ahmed S , El-Ayoubi Hanadi Rafii , Desanctis Vincenzo 
Published: October 2019

Abstract
Abstract 1688

Objective:
The introduction of several classes of targeted therapeutics for the treatment of chronic myelogenous leukemia (CML) raises the question of whether male fertility is affected and the degree of this affection, if any, among the different generations of tyrosine kinase inhibitors. When two drugs are equally effective, the drug with less toxic effect on fertility is favorable. Our aims were to evaluate semen parameters and pituitary gonadal function before and 4 months after starting tyrosine kinase inhibitors (TKI) namely, Dasatinib, Nilotinib, and Imatinib in patients with CML.

Design:
Prospective study.

Setting, Patients, Interventions:
We studied the effect of TKIs' first generation (Imatinib) and second generation ( Dasatinib and nilotinib) on semen parameters, endocrine functions in 20 euogonadal male patients with CML, and capacity to ejaculate, aged from 35 to 51 years. They were receiving either Imatinib, Dasatinib or Nilotinib as upfront therapy. We studied gonadotrophins (LH and FSH) and testosterone (T) secretion and evaluated sperm parameters before and after four months of using these TKIs.

Main Outcome Measures and Results:
Four months after starting TKIs there were significant decreases in serum testosterone, LH, FSH concentrations. The total sperm count, total and rapid progressive sperm motility, and % sperms with normal morphology decreased significantly versus before treatment. (table 1). After 4 months of therapy, Dasatinib effects on sperm count (SC), volume(SV), all sperm motilities and % of sperms with normal morphology(%NM) were significantly less harmful compared to Imatinib and Nilotinib. (Table 2).
Significant correlations were found between serum T concentrations and semen parameters before and after TKIs therapy including SC ( r = 0.658 and r = 0.73 respectively, p < 0.001), rapid progressive motility (r = 0.675 and r = 0.758 respectively p < 0.001), and the % NM(r = 0.752 and r = 0.834 respectively, p < 0.001). After TKIs therapy, LH were correlated significantly with T concentrations ( r = 0.434, p < 0.001) and SV and SC (r = 0.439 and r = 0.376 respectively, p: 0.01).

Conclusion:
Our study suggests that in patients with CML TKIs are associated with significant decrease of sperm parameters and decreased concentrations of serum T, LH, FSH. These potentially toxic effects on spermatogenesis are less prominent in patients treated with Dasatinib compared to Imatinib and Nilotinib. The mechanisms and pathways for these effects need further human and/or experimental studies.

Disclosures:
Yassin: Hamad medical corporation MRC: Employment, Research Funding. Soliman:Hamad medical corporation MRC: Employment, Research Funding. Elawa:Hamad medical corporation MRC: Employment, Research Funding.
Risk of Thromboembolic Events in ET and Early/Prefibrotic PMF: The Relevance of an Accurate Histological Diagnosis
Authors: Rupoli Serena , Goteri Gaia , Picardi Picardi , Canafoglia Lucia , Micucci Giorgia , Scortechini Anna Rita , Federici Irene , Giantomassi Federica , Lio Lidia Da , Zizzi Antonio , Leoni Pietro 
Published: October 2019

Abstract
Abstract 1735

Background:
Essential Thrombocytemia (ET) is a myeloproliferative neoplasm characterized by increased risk of vascular events. Established thrombosis risk factors are age and previous vascular events. The clinical and prognostic relevance of WHO histologic criteria for ET and prefibrotic/early Primary Myelofibrosis (PMF) has been well recognized. Our aim was to evaluate the correlation between histologic interpretation and vascular events in our series of thrombocytemias.

Material and methods:
From our files, we retrieved all patients consecutively diagnosed as having ET with complete clinical data (N = 283) who had undergone to a bone marrow trephine biopsy before any treatment at or within 1 year of diagnosis (N= 133). The histologic slides were reviewed in order to separate true ET cases from early/prefibrotic PMF; vaso-occlusive events at diagnosis and in the follow-up were than compared in the two groups.

Results:
Histologic review reclassified 61 cases as ET and 72 cases as prefibrotic/early PMF. Prefibrotic/early PMF showed a significant higher prevalence of thrombosis history and thrombotic events at diagnosis, and an increased leukocyte count than ET (22% vs 8%, 15.2% vs 1.6%, 8389/mmc vs 7500/mmc, respectively); furthermore, venous thromboses (mainly atypical) were relatively common in PMF, as opposed to WHO-defined ET. During follow-up, patients with prefibrotic PMF, although younger, showed a significant higher risk of developing thrombosis: the 15-year risk of thrombosis was 48% in prefibrotic PMF (grade 0), 16% in early PMF (grade 1, 2) and 17% in ET. Multivariate analysis confirmed that age and histopathology are independent risk factors for thrombosis during follow-up. Patients older than 60 or with prefibrotic PMF are high risk patients whereas those younger and with non prefibrotic PMF or ET should be considered at low risk (20-year risk of thrombosis 47% vs 4%, p=0.005).

Conclusion:
The results of present study indicate prefibrotic PMF as a myloproliferative neoplasm with the highest tendency to develop vascular events compared to early PMF and ET. Therefore we suggest to include histopathology interpretation in the risk stratification of so-called ET patients.

Disclosures:
No relevant conflicts of interest to declare.
Inhibition of Mitogen Activated Protein Kinase Kinase (MEK1) Is Effective Against CLL Cells Cultured in Media Alone or in a Supportive Microenvironment and Is Synergistic with Fludarabine in a Mechanism That Involves Decreased Levels of Reactive Oxygen Species and MCL-1 Protein
Authors: Best Giles , Crassini Kyle , Stevenson Williams , Mulligan Stephen P. 
Published: October 2019

Abstract
Abstract 1804

Background
Despite the high response rates of patients with Chronic Lymphocytic Leukemia (CLL) to the fludarabine (F), cyclophosphamide (C), rituximab (R) regimen, relapsed or refractory disease is common. Novel therapeutic approaches are required that are effective in this setting.
Targeting specific signaling molecules is proving an effective strategy for treating patients who are refractory to FCR. Given that the mitogen-activated protein kinase pathway (MAPK) pathway is constitutively active in CLL cells and that inhibitors of mitogen-activated protein kinase kinase (MEK1) in this pathway are in clinical trials for solid tumors, we sought to investigate the potential of MEK1 as a therapeutic target in CLL.

Results
Inhibition of MEK1/2 using MEK inhibitor I (MEKi; Calbiochem/Merck) induced apoptosis in the MEC1 cell line and in 18 patient samples. Importantly, sensitivity of the patient samples occurred irrespective of ATM/TP53 functional status, of poor prognostic features or of treatment history. MEKi was also effective against 4 CLL patient samples cultured in an in vitro model of the tumor microenvironment, albeit with a significantly higher IC50 than observed against CLL cells cultured in media alone.
As fludarabine-based therapies have become the mainstay of CLL treatment, we investigated the effect of combining the MEK inhibitor with this purine analogue. Synergy between MEKi and fludarabine was apparent against the MEC-1 cell line and 10 patient samples. Dose reduction indices (DRI) calculated from the drug combination indicate this synergy was predominantly due to an increase in fludarabine sensitivity. Investigation of the mechanisms of the synergy between MEKi and fludarabine suggests decreased levels of reactive oxygen species (ROS) and expression of the pro-survival protein, MCL-1, may be contributing factors (see figure).

Summary
These data suggest for the first time that inhibition of MEK1/2 may represent a potential therapeutic option for CLL patients. The efficacy of the MEK inhibitor against CLL cells cultured in the supportive in vitro environment suggest that this approach may also be effective at targeting the proliferative fraction of CLL cells in the tumor microenvironment. As clinical trials of MEK1/2 inhibitors are currently underway in solid tissue malignancies, our data suggest that trials of these agents may also be warranted for high risk CLL.

Disclosures:
No relevant conflicts of interest to declare.
The Chromosomal Abnormalities Del(17p), t(4;14), and +1q21 Predict Progression From Smoldering to Symptomatic Multiple Myeloma
Authors: Neben Kai , Jauch Anna , Hielscher Thomas , Hillengass Jens , Lehners Nicola , Raab Marc S , Ho Anthony D. , Goldschmidt Hartmut , Hose Dirk 
Published: October 2019

Abstract
Abstract 1806

Background:
Smoldering Multiple Myeloma (SMM) is a plasma cell disorder defined by the presence of ≥10% plasma cells in bone marrow and/or a monoclonal protein level of ≥3 g/dl in serum without organ damage. The aim of the study was to analyze the prognostic impact of chromosomal aberrations on time to progression (TTP) from SMM to symptomatic MM.

Design and Methods:
For selection of the patients, we used the same criteria as previously described by Kyle (Kyle et al., NEJM, 2007). We analyzed the prognostic value of 5 chromosomal abnormalities and hyper-/non-hyperdiploidy (HD and NHD, respectively) in a series of 231 patients with SMM by fluorescent in situ hybridization (FISH). Gains of at least 2 of the 3 chromosomes 5, 9, and 15 defined HD status.

Results:
Interphase-FISH analysis on CD138-enriched plasma cells detected gains of chromosomes 1q21 (29.4%) as well as deletions of chromosomes 13q14 (19.3%) and 17p13 (6.1%). Furthermore, the IgH-translocations t(4;14) and t(11;14) were observed in a frequency of 9.2% and 22.3%, respectively. The presence of t(4;14) was correlated with the serum heavy chain IgA (p<0.001). For the entire group, the median TTP was 4.9 years (95% CI, 3.9 – NA). Of all analyzed chromosomal abnormalities, del(17p13), t(4;14), and +1q21 showed a significant impact on TTP, whereas the presence of t(11;14) and del(13q14) was of no statistical significance. The median TTP for patients with del(17p13) was 2.7 years (vs. 4.9 years without, p=0.019), with t(4;14) 2.9 years (vs. 5.2 years without, p=0.021), and with +1q21 3.7 years (vs. 5.3 years without, p=0.013), respectively. In addition, HD was associated with a statistically shorter median TTP of 3.9 vs. 5.7 years in patients with NHD, respectively (p=0.036). A multivariate analysis identified t(4;14), +1q21, HD, reduction of uninvolved immunoglobulins (no.), and the risk score defined by Kyle et al. as independent factors for adverse outcome.

Conclusions:
The study shows that the overall risk of progression in SMM is significantly influenced by markers for tumor burden (i.e. Kyle risk score) as well as the presence of the chromosomal aberrations del(17p13), t(4;14), and +1q21. Our findings provide evidence that specific chromosomal aberrations are not only associated with early tumor progression and drug resistance in patients with overt MM but also to drive transition from asymptomatic into symptomatic stage of disease.

Disclosures:
No relevant conflicts of interest to declare.
Microfluidic Platform Enabling Primary Multiple Myeloma Mono- and Cis-Co-Culture Analysis
Authors: Chorom Pak , Young Edmond WK , Callander Natalie , Beebe David J , Miyamoto Shigeki 
Published: October 2019

Abstract
Abstract 1830
Multiple myeloma (MM) is a universally fatal disease, comprising 15% of hematological malignancies and 1% of all cancers. It has a median survival of 5–7 years from diagnosis. While newer drugs, such as the proteasome inhibitor bortezomib, have increased response to therapy, resistance and relapse still remain a key concern. Therefore, there is a need to understand the mechanism(s) of drug resistance. Ideally, this needs to be accomplished in a patient-specific manner. One approach is to directly examine biological responses of patient myeloma cells in the presence of their own stromal components under different drug conditions. However, individually collected patient bone marrow samples yield a limited number of MM tumor and associated stromal cell types, which limit the number of conditions as well as replicates that can be performed for such functional analyses.
To address this technical barrier, we have developed a first generation functional microfluidics-based microchannel platform that enables the analysis of these limited samples in mono- and/or cis-coculture (Figure 1). CD138+ patient myeloma cells are seeded into the central channel, which has a well to retain the suspension MM cells. CD138- “stromal” or mononuclear cells are seeded into each side channel. Each side channel communicates with the central channel via diffusion ports, which are only large enough for media and soluble factors to flow through. In this manner, both without (monoculture) and with the patients own stromal components (cis-co-culture) can be analyzed for MM cell responses.
Here we employed this assay platform to analyze CD138+ MM tumor cells' drug responses to the proteasome inhibitor bortezomib/Velcade and whether CD138- mononuclear cells from the same patient provide a protective effect. We added 7500 CD138+ in the central channel with or without 8000 CD138- mononuclear cells in each side channel, which were obtained from the same bone marrow aspirates. We were able to measure dose-dependent reductions in cell viability in multiple patient MM cells. Such MM cell viability was protected by the presence of patients' own CD138- mononuclear cells to varying degrees.
More patient samples are currently being analyzed and will be similarly assessed to determine whether such in vitro bortezomib responses have any relevance to patient drug responses in the clinic. Additional improvements will be incorporated with the goal to make the assay platform more robust and quantitative in its predictive capacity.

Disclosures:
Beebe: Bellbrook Labs: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
GATA1 and the BET Family Protein Brd3 Form a Mitotic Bookmarking Complex
Authors: Kadauke Stephan , Campbell Amy E , Stonestrom Aaron J , Jain Deepti P , Hardison Ross C , Blobel Gerd A 
Published: October 2019

Abstract
Abstract 282
Erythroid-specific transcription patterns are maintained throughout cell division. During mitosis, transcription is silenced globally. This raises the question whether mechanisms are in place that ensure the spatially and temporally correct reassembly of transcriptional regulators and thus maintain lineage fidelity. We recently found that, in contrast to most nuclear regulators, the master hematopoietic regulator GATA1 remains associated at a subset of its targets within mitotic chromosomes in erythroid cells (Kadauke et al., Cell 2012). GATA1 appears to function by creating an epigenetic “bookmark” to facilitate timely post-mitotic transcription reactivation of its mitotic target genes.
GATA1 is acetylated at two lysine-rich domains near its zinc finger domains. We recently discovered that acetylated GATA1 recruits the double bromodomain protein Brd3 to erythroid target genes (Lamonica et al., PNAS 2011). Brd3 interacts with acetylated GATA1 via its first bromodomain, and Brd3 recruitment to GATA1 target sites is critically required for induction of terminal erythroid target genes such as α- and β-globin. Notably, Brd3 belongs to a family of proteins (called the BET family) of which two members (Brd2 and Brd4) are known to be retained on mitotic chromosomes.
We now find by immunofluorescence and live cell confocal imaging that Brd3 globally binds to mitotic chromosomes. ChIP-seq experiments demonstrate a high degree of co-localization of Brd3 and GATA1 genome-wide both in interphase and in mitosis. We further demonstrate that GATA1 directly recruits Brd3 to mitotic GATA1 target sites. Transient mitosis-specific disruption of the Brd3-GATA1 interaction using the small molecule BET bromodomain inhibitor JQ1 removed Brd3, but not GATA1, from mitotic binding sites and led to a profound delay in the reactivation of GATA1-bookmarked genes. This suggests that Brd3 is an integral component of GATA1's bookmarking function. In concert, these studies support a requirement of mitotic bookmarking by a GATA1/Brd3 complex for the propagation of lineage-specific transcription programs in dividing erythroid cells.

Disclosures:
No relevant conflicts of interest to declare.
Critical Role of the Gab2/PI3K/mTOR Pathway in the Pathogenesis of Ptpn11 (Shp2) Mutation-Induced Myeloproliferative Disease.
Authors: Liu Wei , Liu Xia , Qu Cheng-Kui 
Published: October 2019

Abstract
Abstract 2856
Germline and somatic mutations (heterozygous) in Ptpn11 (Shp2), a protein tyrosine phosphatase implicated in multiple cell signaling processes, have been identified in juvenile myelomonocytic leukemia (JMML), a childhood myeloproliferative disease (MPD), and pediatric acute leukemias. These mutations cause hyperactivation of Shp2 catalytic activity and enhance the binding of mutant Shp2 to signaling partners. Ptpn11 mutations are sufficient to drive the development of JMML-like MPD and acute leukemias in mice, suggesting that they play a causal role in the pathogenesis of hematological malignancies. However, the mechanisms by which Ptpn11 mutations induce these malignancies are not completely understood and the signaling partners that mediate the pathogenic effects of Ptpn11 mutations have not been explored. We previously generated a line of conditional knock-in mice with Ptpn11E76K mutation, the most common and most active Ptpn11 mutation found in JMML and acute leukemias. Induced knock-in of this mutation in hematopoietic cells resulted in MPD with full penetrance as a result of aberrant activation of hematopoietic stem cells (HSCs) and myeloid progenitors (J. Exp. Med., 2011). Recently, we discovered that the interaction between Shp2 E76K and Gab2, a prominent interacting protein of Shp2 and a scaffolding protein important for cytokine-induced PI3K/Akt/mTOR signaling, was greatly enhanced, and that mTOR was highly activated in Ptpn11E76K/+ MPD cells. To address the role of Gab2 and mTOR in the pathogenesis of Ptpn11E76K/+ mutation-induced MPD, Ptpn11E76K/+/Gab2-/- double mutant mice were generated and their phenotypes were compared with those of Ptpn11E76K/+ single mutant mice. MPD phenotypes were markedly attenuated in Ptpn11E76K/+/Gab2-/- double mutant mice. Overproduction of myeloid cells in the bone marrow was alleviated, and splenomegaly was diminished in the double mutants. Myeloid cell infiltration in the liver also decreased. Cytokine (IL-3 and GM-CSF) sensitivity of myeloid progenitors was significantly decreased in Ptpn11E76K/+/Gab2−/− mice as compared to that in Ptpn11E76K/+ mice. Hyperactivation of HSCs and excessive myeloid differentiation caused by Ptpn11E76K mutation were largely corrected by deletion of Gab2. Furthermore, we treated Ptpn11E76K/+ mice with Rapmycin, a specific and potent mTOR inhibitor, which substantially diminished MPD phenotypes. Collectively, this study reveals the essential role of the Gab2/PI3K/mTOR pathway in mediating the pathogenic effects of Ptpn11E76K/+ mutation and suggests that Gab2 and mTOR are potential therapeutic targets for the treatment of Ptpn11-associated hematological malignancies.

Disclosures:
No relevant conflicts of interest to declare.
Human Multiple Myeloma and Breast Cancer Cells Evade Immune Rejection Through Expression of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6.
Authors: Witzens-Harig Mathias , Hose Dirk , Jünger Simone , Pfirschke Christina , Khandelwal Nisit , Seckinger Anja , Conrad Heinke , Brackertz Bettina , Reme Thierry , Gückel Brigittte , Meissner Tobias , Hundemer Michael , Ho Anthony D , Rossi Jean-Francois , Neben Kai , Bernhard Helga , Goldschmidt Hartmut , Klein Bernard , Beckhove Philipp 
Published: October 2019

Abstract
Abstract 2942
Tumor-specific cytotoxic T cells are common in tumor patients, but ineffectively react against autologous tumor cells. Here, we demonstrate in multiple myeloma and breast cancer that human tumor cells escape recognition by tumor-specific CD8+ T cells through carcinoembryonic antigen-related cell adhesion molecule-6 (CEACAM-6) expression. We demonstrate for the first time CEACAM-6 expression in primary and established myeloma and examined the effects of altered CEACAM expression on cytotoxic T cell activity and cytokine secretion against myeloma and breast cancer cells in vitro —, and in vivo, using a xenotransplant mouse model. Cytotoxic T cells from multiple myeloma patients reacted against myeloma antigens presented by dendritic cells, but not against autologous myeloma cells, which expressed CEACAM6. Gene knockdown or blocking of CEACAM6 on myeloma cells restored CD8+ T-cell reactivity against malignant plasma cells. SiRNA-mediated CEACAM6 knockdown or inhibition by specific mAbs also restored cytokine secretion, cytotoxic activity, and antigen-specific lysis of CEACAM6-positive breast cancer cells. Moreover, CEACAM-6 inhibition was a prerequisite for efficient treatment of xenotransplanted breast tumors by adoptive T cell transfer. CEACAM6 thus plays an important role in inhibiting CD8+ T-cell responses against hematological and epithelial human tumors. Therapeutic targeting of CEACAM6 may be a promising strategy for improving cancer immunotherapy.

Disclosures:
No relevant conflicts of interest to declare.