bluuebunny/crossref_metadata_2025_split huggingface dataset:
Central Nervous System Involvement By Chronic Lymphocytic Leukemia
Authors: Strati Paolo , Uhm Joon , Kaufmann Timothy , Parikh Sameer A. , Hanson Curtis A. , Chaffee Kari , Achenbach Sara , Call Timothy G. , Shanafelt Tait D. 
Published: October 2019

Abstract
INTRODUCTION. Although uncommon, involvement of the central nervous system (CNS) is the most common extramedullary manifestation of Chronic Lymphocytic Leukemia (CLL). Nonetheless, a broad array of conditions can lead to neurologic symptoms in CLL patients and distinguishing between clinically significant CLL involvement of the CNS and other etiologies can be challenging. The actual prevalence of CNS involvement by CLL is unknown, the only available data being case reports and small case series.
METHODS. Between 01/1995 and 11/2014, 186 of the 4317 (4%) patients with CLL followed at our center underwent an MRI of the CNS (e.g. brain, spine) and/or a lumbar puncture (LP) with cerebral spinal fluid (CSF) analysis to evaluate neurologic symptoms. As the mere presence of CLL cells in the CSF is not diagnostic of clinically significant CNS disease, a final diagnosis of clinically significant CNS involvement by CLL was established by the collaborative review of the pathologist, neurologist and treating hematologist based on comprehensive work-up and multi-disciplinary evaluation.
RESULTS. After evaluation, the etiology of neurologic symptoms was clinically significant involvement of the CNS by CLL in 19 (10%) patients, CNS Richter Syndrome (RS) in 15 (8%), infection in 42 (23%), autoimmune conditions in 31 (17%), other cancer in 9 (5%), and another etiology in 70 (37%). The sensitivity of LP to detect clinically significant CNS involvement by CLL was 89%, however its specificity was only 42% where CLL cells were also frequently observed in the CSF in concomitance with inflammatory processes, such as infections and autoimmune disease. Factors associated with clinically significant CNS involvement by CLL/RS were mutated IGHV (p=0.04), low CSF glucose (p=0.02), elevated CSF total nucleated cells (TNC)(p=0.004), lymphocytes (p=0.02) and CLL cells, both as absolute count (p=0.05) and percentage of TNC (p=0.02). Median OS among patients with clinically significant CNS involvement by CLL or RS were 21 and 11 months, respectively. Median OS for patients with neurological symptoms secondary to infection was 6 months, to autoimmune process was 63 months, to other cancers was 19 months, and to other non-CLL related etiologies was 37 months.
CONCLUSIONS. Clinically significant CNS involvement by CLL and RS are rare conditions. Neurologic symptoms in patients with CLL are attributable to non-CLL-related etiologies in the majority of cases, even when CLL B-cells are present in the CSF. Analysis of the CSF has high sensitivity but limited specificity to distinguish clinically significant CNS involvement by CLL from other etiologies. Comprehensive evaluation is required before attributing neurologic symptoms to CLL.

Disclosures
No relevant conflicts of interest to declare.
Management of T-Cell Large Granular Lymphocyte Leukemia with Methotrexate or Cyclophosphamide
Authors: Kovacs Matthew R. , Hsia Cyrus C. , Lazo-Langner Alejandro , Kovacs Michael J. 
Published: October 2019

Abstract
Background. T-Cell Large Granular Lymphocyte Leukemia (T-LGL Leukemia) is an extremely rare lymphoproliferative disorder which can originate from either mature T cells (CD3+) or natural killer cells (CD3-). T-LGL leukemia is a slowly progressing disease, rarely presenting with an aggressive course and in general patients have prolonged survival. Treatment is commonly monotherapy with methotrexate (with or without prednisone), cyclosporine, or cyclophosphamide. Herein we review our experience with the management of T-LGL in the last 15 years.
Patients and Methods. We conducted a retrospective cohort study of all patients diagnosed with T-LGL at our center between 2000 and 2015. Patients were included if they had a positive study for T-Cell Receptor gene rearrangement. Response was evaluated using the criteria of Loughran et al (Leukemia 2015). Data was analyzed using descriptive statistics.
Results. We included 23 patients, (16 male). All of the patients were caucasian with the exception of two. The average age at diagnosis is 65.1 years. Patients were treated for symptomatic cytopenias or splenomegaly with transfusions and/or chemotherapy. Six patients did not need any treatment. Fourteen of the 23 patients were treated with oral methotrexate monotherapy. The methotrexate dose ranged from 5mg/week to 15mg/week orally. Seven patients had a complete response, 2 had a partial response, 3 patients failed treatment, 1 patient was not evaluable, and 1 was stable. Four patients were treated with methotrexate and prednisone. Two patients obtained a complete response, with 1 partial response, and 1 patient was not evaluable due to the short duration of the prescription. Nine patients were treated with oral cyclophosphamide at doses of 50mg or 100mg po daily. Four patients achieved a complete response, 2 patients achieved a partial response, while the other 3 patients did not respond. Only 2 patients were treated with oral cyclosporine, at 400mg/day and at 500mg/day. One patient failed treatment while the other is still on therapy. Two patients died while on the study at 22 and 42 months, both deaths were due to other illnesses not associated with T-LGL Leukemia. The median time since diagnosis for the remaining patients is 41 months.
Conclusion. T-LGL is a rare lymphoproliferative disorder. Most patients responded to simple oral therapy with methotrexate or cyclophosphamide and patients generally have prolonged survivals.

Disclosures
Lazo-Langner: Bayer: Honoraria; Pfizer: Honoraria. Kovacs:Daiichi Sankyo Pharma: Research Funding; LEO Pharma: Honoraria; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.
Clinicopathological Analysis of CNS Involvement in Multiple Myeloma
Authors: Togano Tomiteru , MINE Sohtaro , Miwa Akiyoshi , Hagiwara Shotaro 
Published: October 2019

Abstract
Background
Extramedullary disease (EMD) is often observed in end stage of multiple myeloma (MM).However, central nervous system (CNS) involvement is very rare. Thus, little is known about CNS involvement of MM. We conducted clinicopathological analysis.
Methods
We reviewed medical records and pathological specimens of multiple myeloma cases between 1979 and 2015 at the National Center for Global Health and Medicine in Tokyo, Japan. Patient information and duration of illness, clinical finding including type of monoclonal protein, Durie & Salmon's (DS) staging, treatment and pathological findings were collected. CNS involvement was diagnosed pathologically.
Results
We found 15 cases of CNS involvement multiple myeloma. In 15 cases, 66.6 % was male. Mean age and the duration of illness were 56 years old and 35.7 months, respectively. DS stage was 3A (46 %), 2A (20 %), 2A (20 %), 1A (13 %). Monoclonal protein was IgG (46 %), IgA (33 %), BJP (0.6 %) and non-secretary (13 %). Lambda chain was 62 %. Manifestation at diagnosis CNS involvement was disturbance of consciousness (40 %), visual disturbance (20 %), dysphagia (13%), paresthesia of extremities (20 %), vomiting or nausea (13 %). Other organ involvement was spleen (60 %), pancreas (53 %), liver (53 %), adrenal gland (46 %), testis (31 %) and plasma cell leukemia (40 %). In two cases, peripheral nerve involvement was found. Seven of 15 patients were previously treated with novel agents such as bortezomib, thalidomide, and lenalidomide. Recent 5 years, the frequency of CNS involvement increased more than threefold (1.0 case/year), compared to 1979-2010 (0.3 case/year). In all cases, myeloma cells infiltrated dura mater or subarachnoid cavity. Infiltration in parenchyma of brain was seen in only 2cases. Myeloma cells were seen at loose section of connective tissue around vascular in most cases. Interestingly, myeloma cells were often infiltrated at peripheral nerve, spinal cord cavity and central canal without spinal cord.
Conclusions
In the era of novel agents, the incidence of CNS involvement in patients with multiple myeloma has increased. We found myeloma cells were often infiltrated at peripheral nerve, spinal cord cavity and central canal without spinal cord. Our study revealed that exposure to novel agents, lambda type MM, multi-organ involvement and plasma cell leukemia were associated with CNS involvement.

Disclosures
Hagiwara: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.
IgM Multiple Myeloma Presenting As Hyperviscosity Syndrome with Isolated Skin Manifestation
Authors: Ghelani Ghanshyam , Thomas Lisa , Shi Qi , Jecmenica Midaen 
Published: October 2019

Abstract
Background:
Immunoglobulin M-producing multiple myeloma (IgM MM) accounts for less than 1% of all myeloma cases. Because the disorder is rare,its clinical characteristics and long-term prognosis remain unknown. Hyperviscosity occurs from pathologic changes of either cellular or protein fractions of the blood such as are found in MM (particularly IgA and IgG3) and other diseases.
Case Presentation
A 65-year-old male smoker presented to emergency room (ER) with headache, dizziness, shortness of breath, symmetrical finger pain, nose bleeds, and blood in stool. On lab work hemoglobin was 7.9 gm/dl. Review of the peripheral blood smear showed atypical lymphocytes. CT chest showed left axillary and supraclavicular lymphdenopathy. Serum protein was 13 gm/dl, Serum protein electrophoresis showed a monoclonal IgM kappa gammopathy with UIEP confirming the bence jones proteinuria. A bone marrow biopsy showed about 80% cellularity with diffuse and solid neoplastic plasma cell infiltrates that were CD138+, CD20- and CD3-. Flow cytometric analysis of the bone marrow aspirate demonstrated a small fraction of clonal plasma cell population that were CD38+, CD138+, CD45-, and CD56-, Fluorescent in Situ Hybridization confirmed neoplastic plasma cells with kappa light chain restriction, and cyclinD1-. On examination, the patient had a erythematous skin changes and edematous bilateral symmetrical finger findings.
Discussion:
MM with IgM gammaglobulin is a rather distinct subtype of MM displaying clinical and pathologic features of both MM and WM. The clinical presentation of WM is similar to that of MM except that organomegaly is common in WM but is uncommon in MM and lytic bone disease and renal disease are uncommon in WM but are common in MM.
The criteria for diagnosis of IgM myeloma (and its differentiation from WM) requires the presence of either lytic bone lesions and/or evidence of the t(11;14) translocation. It is also characterized by negative CD20, D56 and CD117 phenotype. All the reported cases of IgM myeloma had been treated with melphalan and prednisolone with suboptimal results. Some patients were treated with VAD (vincristine, adriamycin and dexamethasone) regimen, others with CTD protocol. The results were similar to the MP regimen. Radiotherapy was mainly used as palliative measure.
Conclusion:
Our case suggests that IgM multiple myeloma can presents as hyperviscosity syndrome with isolated skin manifestation and may have unique clinical characteristics.

Disclosures
No relevant conflicts of interest to declare.
Homozygous Mutation of the ETS DNA-Binding Domain of FLI1 Causes a Bleeding Disorder with Giant Alpha Granules Similar to Paris-Trousseau Thrombocytopenia
Authors: Stevenson William S , Rabbolini David John , Brighton Timothy , Mackay Joel , Ward Christopher M , Morel-Kopp Marie-Christine 
Published: October 2019

Abstract
Deletion of a variable region on chromosome 11q containing FLI1 causes a platelet-related bleeding disorder in Paris-Trousseau thrombocytopenia and Jacobsen syndrome. We report a kindred with the autosomal recessive inheritance of an ETS domain mutation of FLI1, c.970C>T, that causes macrothrombocytopenia with large alpha granule fusion similar to that observed in Paris-Trousseau thrombocytopenia but with no other syndromal features of Paris-Trousseau or Jacobsen syndromes. Affected individuals are moderately thrombocytopenic (mean = 71 x109/L), have absent collagen-induced platelet aggregation and a lifelong mucosal bleeding history. Platelet MYH10 levels were increased in affected members of the kindred consistent with previous reports of elevated MYH10 in Paris-Trousseau thrombocytopenia. Luciferase reporter assays in HEK293 cells demonstrate that the mutant FLI1 transcript is associated with decreased transcription at the FLI target genes GP6, GP9 and ITGA2B compared to the wild-type transcript (23 vs 31, n=9, P<0.01; 3.8 vs 6.5, P<0.01, n=12; 11 vs 14, n=9, P=0.01, respectively). This transcriptional change was consistent with reduced expression of GPVI (P<0.01), GPIbIX (P<0.01) and GPIIbIIIa (P=0.04) observed on western blotting of platelet lysates from affected family members. This mutation replaces the conserved Arg324 with a tryptophan in the DNA-binding loop between the alpha-2 and alpha-3 helices of the FLI1 ETS domain. Protein modelling suggests that Arg324 does not directly bind DNA but may instead make direct contact with an N-terminal autoinhibitory domain of FLI1 that is considered to regulate DNA-binding affinity through a transition between a folded and unfolded state. This mutation may disrupt this important conformational change. These data suggest abnormalities of FLI1 function may be responsible for the complex platelet defect observed in Paris-Trousseau thrombocytopenia and Jacobsen Syndrome and confirm the role of FLI1 as an important transcriptional regulator of normal platelet development.

Disclosures
No relevant conflicts of interest to declare.
In vivo Stem Cell Clonal Dynamics
Authors: Camargo Fernando D. 
Published: October 2019

Abstract
Tremendous progress has been achieved in the characterization of the hematopoietic system over the past two decades. Historically, the main experimental approach used to elucidate and define these cellular relationships in the bone marrow (BM) has been the transplantation assay. For this reason, most of our knowledge about the in vivo properties of hematopoietic stem cells (HSCs) and progenitor cells has been derived from studies in the transplant context. Because of the lack of tractable systems, the mechanistic nature of non-transplant hematopoiesis has remained largely unexplored. Over the past several years, my laboratory has developed novel genetic tools for the clonal tracing and imaging of hematopoietic populations in the unperturbed niche that aim to bring insight into the biology of stem and progenitor cells in situ. Our work using a transposon-mediated cellular tagging approach indicated that progenitors, and not the classical long-term HSCs, are the cells mainly responsible for the day-to-day production of blood cells in the adult. Our data also suggested that lineage restricted progenitors are the main contributors to hematopoiesis at steady state. These data represent the first systematic analysis of clonal fate in an unperturbed hematopoietic niche and revealed a novel cellular mechanism for homeostatic blood regeneration. We have now utilized this clonal tracing model to bring insight into the dynamics of stem and progenitor biology during embryonic hematopoiesis and in the severely aged hematopoietic system. These data will be discussed at the meeting.

Disclosures
Camargo: Cell Signaling Technologies: Consultancy; Vital Therapies: Consultancy.
Hypoxia Drives AML Proliferation in the Bone Marrow Microenvironment Via Macrophage Inhibitory Factor
Authors: Abdul-Aziz Amina M , Shafat Manar S , Zaitseva Lyubov , Lawes Matthew J , Rushworth Stuart A , Bowles Kristian M 
Published: October 2019

Abstract
Introduction
Hypoxia is an important component of the bone marrow microenvironment and the hematopoietic stem cell niche. Studies have shown that hypoxia contributes to the development and maintenance of acute myeloid leukemia (AML) cells within the bone marrow microenvironment. Hypoxia is principally maintained by members of the hypoxia-inducible factor (HIF), in particular HIF1a and its target genes, including MIF. We have previously shown that AML cells express constitutively high macrophage migration inhibitory factor (MIF) which drives IL-8 expression by the BM-MSC which in turn supports AML cell survival and proliferation. The aim of the present study is to determine if there is a connection between the role of hypoxia in regulating AML survival and MIF survival signals. Furthermore we investigate the role BM-MSC in regulating the hypoxic response.
Methods
Primary AML and BM-MSC were isolated from AML patients following informed consent and under approval from the UK National Research Ethics Service (LRCEref07/H0310/146). AML cell lines and primary AML blasts were cultured under normoxic (20% oxygen) or hypoxic conditions (1% oxygen) for 4 - 24 hours, mRNA expression of MIF, HIF1a, VEGF and IL-8 were determined by RT-PCR. MIF and IL-8 protein was determined using target specific ELISA. HIF1a protein expression was determined by western blotting. Hypoxia-mimetic agents, cobalt chloride (CoCl2) and desferrioxamine (DFO) were used. Cell proliferation was determines using CellTiter Glo and trypan blue exclusion. CFU-assays were performed using complete methylcellulose media.
Results
To determine If MIF is regulated by HIF1a in AML cells, we mimicked hypoxic conditions using CoCl2 and DFO in AML cells. Both CoCl2 and DFO upregulate MIF transcription and protein expression in OCI-AML3 cell lines and in primary AML blasts. Moreover, hypoxia increases both MIF mRNA expression and MIF chemokine expression compared to normoxic conditions. Lentiviral mediated knockdown of MIF in AML cells show significantly reduced cell proliferation and colony formation in methylcellulose media. Recombinant MIF induced interleukin-8 in AML blasts and the MIF inhibitor blocked MIF induced IL-8 release. Lentiviral mediated KD of HIF1a decreased MIF expression in human AML cells and a significant reduced their proliferative capacity. Finally we found that hypoxia increased MIF in AML blasts which was further increased when in co-culture with BM-MSC.
Conclusions
The results reported here suggest that hypoxia significantly affects the expression of the survival cytokine MIF in AML blasts. Furthermore, we show that BM-MSC regulate HIF1a induced MIF expression in AML under hypoxic conditions. We propose this hypoxia regulated HIF1a/MIF axis is essential to blast survival in the bone marrow niche.

Disclosures
Rushworth: Infinity Pharmaceuticals: Research Funding.
TP53 Immunostaining in Double-Hit and Double-Expressing High-Grade B-Cell Lymphoma
Authors: Oduro Kwadwo Asare , Kovach Alexandra E. , Abramson Jeremy S. , Hasserjian Robert P. , Sohani Aliyah R 
Published: October 2019

Abstract
Background: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma, but comprises a heterogenous group. Recent studies have identified aggressive subsets of DLBCL including double-hit lymphomas (DHL, with rearrangements of both MYC and BCL2 oncogenes and often classified in a separate DLBCL/Burkitt overlap category) and double-expressing lymphomas (DEL, which overexpress both MYC and BCL2). These subsets respond poorly to standard R-CHOP chemotherapy and account for most of the mortality associated with DLBCL. While recent studies have associated TP53 protein overexpression with worse prognosis in DLBCL, the effect of TP53 aberrations on these more aggressive DLBCL subsets is still uncertain.
Design: We performed a retrospective single institution analysis of a cohort of 26 DHL and a cohort of 65 R-CHOP-treated DLBCL, including 10 DEL. We recorded clinical information, treatment, and patient outcome. The DHL cases were treated with either R-CHOP or a more intensive regimen. A tissue microarray or recuts from original blocks were used for immunostains for TP53, BCL2, MYC, and cell-of-origin determination by Hans algorithm, which were scored blindly.
Results: TP53 expression (>10% of tumor cells) was significantly associated with higher expression of BCL2 (p=0.02), MYC (p=0.0009), and DEL status (p=0.005) in the DLBCL group. With respect to the association of DEL with TP53 expression, 7/10 (70%) cases of DEL were TP53+ compared to 10/55 (18%) of non-DEL DLBCL. There was no association with TP53 expression and cell-of-origin. No statistically significant difference in overall or relapse free survival between TP53+ and TP53- cases was identified in either cohort.
Conclusion: The findings in this small sample suggest that the relationship between TP53 staining and DLBCL outcome is more complex than previously reported, and may reflect an association of TP53 expression with DEL. The use of intensified treatment regimens (such as R-EPOCH) in the DHL cohort may abrogate any negative effects of TP53 overexpression in the TP53+ subset.

Disclosures
Abramson: Seattle Genetics: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Kite Pharma: Consultancy.
Uncovering Clonal and Subclonal Druggable Targets in Multiple Myeloma Using Omic Data
Authors: Scott Adam David , Yellapantula Venkata D , Yoon Christopher J , Wendl Michael , Tomasson Michael H. , Fiala Mark A , DiPersio John F. , Vij Ravi , Ding Li 
Published: October 2019

Abstract
The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial is the keystone program working towards personalized medicine in multiple myeloma (MM). CoMMpass has characterized over 730 samples from 669 patients, a subset having time-course data, using multiple platforms and has made these data publicly available. Screening for druggable somatic mutations and gene expression outliers revealed great potential for repurposing existing pharmacotherapies.
We have developed and curated a Database of Evidence for Precision Oncology (DEPO) that includes 442 mutations and 49 genes with expression changes implicated as drug targets from 34 cancer types. We found 43.6% of CoMMpass samples have one of 26 somatic mutations that could be targeted by 9 different drugs, suggesting many drugs may be repurposed for use in MM. HotSpot3D, a protein-structure-guided analysis tool, showed 3.3% (24/730) of samples have mutations involving BRAF and KRAS, clustering with known drug targets, and another 2.1%(15/730) have mutations in clusters formed from a prior TCGA pan-cancer analysis involving 22 cancer types. This indicates additional potential drug targets and functional mutations in MM.
Interestingly, 11 samples (including relapse), have subclonal mutations in both KRAS and BRAF with variable allelic fractions, implicating different treatment requirements for tumor subpopulations and disease stages. Additionally, druggable gene expression outlier analysis of 591 samples reveals an average of nearly 5 outlier genes per sample from among 49 known target genes, with 18.1% (107/591) of samples with MYCN gene outliers as compared to MYC 1.4% (8/591), despite MYC being a known driver of MM. Other top outliers are DLL3 10.2%, EGFR 10.5%, FGFR1 10.2%, and FGFR2 12.5%. Our study highlights candidate drug targets previously omitted in MM. Taken together, it suggests that heterogeneity analysis and pharmaceutical repurposing could lead to substantially improved outcomes.

Disclosures
No relevant conflicts of interest to declare.