bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinico-Pathological Characteristics of RAS Associated Autoimmune Lymphoproliferative Syndrome Like Disease (RALD), and RAS Mutated Juvenile Myelomonocytic Leukemia (JMML)
Authors: Takagi Masatoshi , Morio Tomohiro , Koike Kenichi , Mizutani Shuki 
Published: October 2019

Abstract
Abstract 5169
Autoimmune lympho proliferative syndrome (ALPS) is a disease characterized by dysfunction of the FAS-mediated apoptotic pathway, currently categorized as Type Ia, germline TNFRSF6/FAS mutation; Type Ib, germline FAS ligand mutation; Type Is, somatic TNFRSF6/FAS mutation; and Type II, germline Caspase 10 mutation. Patients exhibit lymphadenopathy, hepatosplenomegaly, and autoimmune diseases such as immune cytopenia and hyper-γ-globulinemia. An additional subclassification has been proposed that includes Types III, which has been defined as that with no known mutation but with a defect in FAS-mediated apoptosis. Juvenile myelomonocytic leukemia (JMML) is a chronic leukemia in children. Patients show lymphadenopathy, hepatosplenomegaly, leukocytosis associated with monocytosis, anemia, thrombocytopenia. About 80% of patients with JMML have been shown to have a genetic abnormality in their leukemia cells including mutations of NF1, RAS family, CBL, or PTPN11. HSCT is currently considered the only curative treatment. However, some patients have been shown to achieve remission without HSCT. Interestingly, there are several cases of JMML reported simultaneously having clinical and laboratory findings compatible with autoimmune disease. Germline RAS pathway mutations cause Costello (HRAS), Noonan (PTPN11, KRAS, and SOS1), and cardio-facio-cutaneous (CFC) syndromes (KRAS, BRAF, MEK1, and MEK2). Patients with Costello and Noonan syndromes have an increased propensity to develop solid and hematopoietic tumors, respectively.
We have recently reported a unique disease which lies between ALPS and JMML. The patients were characterized by prominent autoimmune cytopenia, lymphoadenopathy/splenomegaly and moderate monocytosis resembling to ALPS and JMML, but they did not satisfy the diagnostic criteria for ALPS or JMML. KRAS mutation in hemopoietic precursors including T and myeloid linage is the common molecular feature, and we have recently proposed these cases to be defined under a new disease entity of RAS associated ALPS like disease (RALD). These patients were characterized by activated T cells resistant to IL-2 depletion but not to FAS-dependent apoptosis associated with the decreased expression of pro-apoptotic protein BIM.
Since somatic RAS mutation has been identified in classical JMML and RALD, it is tempting to speculate that the developmental stage dependent RAS mutation of hemopoietic stem/precursors may determine the clinical features of JMML and RALD. Clinico-pathological characteristics of three RALD cases and three JMML cases cured without SCT will be presented and discussed.

Disclosures:
No relevant conflicts of interest to declare.
Inflammation and Thrombosis In Essential Thrombocythemia
Authors: Cacciola Rossella , Di Francesco Ernesto , Ferlito Carmen , Pezzella Francesca , Seria Elisa , Cipolla Antonino , Cacciola Emma 
Published: October 2019

Abstract
Abstract 5175
The essential thrombocythemia (ET) is a myeloid neoplasm characterized by an inflammatory component responsible for coagulant activation and angiogenesis. Therefore, we evaluated platelets, interleukin-8 (IL-8) and interleukin-15 (IL-15), as inflammatory indicators, tissue factor (TF), as marker of coagulative activation, and vascular endothelial growth factor (VEGF), as indicator of angiogenesis, in patients with ET and thrombosis. We recruited 25 thrombocythemic patients (10 males and 15 females, mean age 58 years) who fulfilled WHO.criteria. Their mean duration of disease was 8 years (range, 5–21 years). All patients were on aspirin. None of the patients had thrombotic risk factors. Of 25 patients, 10 developed thrombosis including 5 episodes of microvascular thrombosis of extremities (erythromelalgia), 2 of transient ischemic attack (TIA), 2 of myocardial infarction (IMA) and 1 of deep vein thrombosis (DVT)) whereas 15 did not. Platelets were measured by automated analyser. IL-8, IL-15, and VEGF and DD were measured by ELISA and immunoturbidimetric assay, respectively. All patients had thrombocytosis (961±235×109/L). IL-8, IL-15, TF and VEGFPLT were higher in patients with thrombosis than patients without thrombosis (27±14 pg/ml and 14±4 pg/ml and 214±266 pg/ml and 2±1 pg/106l vs 14±7 pg/ml and 26±6 pg/ml and 108±64 μg/l and 1±0.9 pg/ml, respectively) (p=0.009 and p<.0001 and p=0.005 and p=0.059, respectively). A positive correlation there was between IL-8 and IL-15 (p<.0001) and between IL-15 and TF (p=0.046). A tendency towards correlation was found between IL-15 and VEGF (p=0.082). These findings suggest a inflammatory IL-8-IL-15 interplay responsible for coagulation and angiogenesis activation that might mean increased thrombophilia in ET.

Disclosures:
No relevant conflicts of interest to declare.
Early Macrophage and Mast Cell Responses in Diffuse Large B-Cell Lymphoma After Immunochemotherapy
Authors: Taskinen Minna , Raunio Anna , Pöyhönen Maria , Karjalainen-Lindsberg Marja-Liisa , Leppä Sirpa 
Published: October 2019

Abstract
Abstract 5206

Background:
The prognostic impact of tumor microenvironment on the survival of lymphoma patients has recently been reported. However, early molecular and cellular responses to immunochemotherapy are unknown. Here, we have compared the tumor-associated macrophage (TAM) and mast cell (MC) contents in the lymphoma tissue in vivo before and after the first immunochemotherapy course in a small cohort of aggressive B-cell lymphoma patients.

Patients and methods:
The population of this pilot study consisted of seven diffuse large B-cell lymphoma (DLBCL) and three grade IIIB follicular lymphoma (FL) patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen (immunochemotherapy). Paired tumor samples were collected before and a day after the first course of therapy, and evaluated immunohistochemically for CD68+, CD163+ macrophages and tryptase+ MCs. Freshly frozen lymphoma tissue containing enough material for paired mRNA analyses was available from 8 patients.

Results:
Comparing pre- and post-treatment tissue samples, an increase in the number of CD68+ TAMs was observed (p=0.023), whereas no variation in MC contents was found. If the patients were grouped according to response, i.e. remission (n=7) vs relapse (n=3), the most significant increase after therapy was observed in M2-type CD163+ TAM content (p=0.001). In the exon array analyses, the mRNA levels of both CD68 (p=0.052) and CD163 (p=0.023) genes increased after therapy.

Conclusions:
Our preliminary data suggest significant changes in macrophage content and their relative subsets in the lymphoma microenvironment after the first course of immunochemotherapy.

Disclosures:
No relevant conflicts of interest to declare.
Clinical, Phenotypic, and Genetic Characteristics of Non-CLL Type Monoclonal B Lymphocytosis (MBL)
Authors: Piran Siavash , Amato Dominick , Mullaithilaga Nisa , Wang Chen 
Published: October 2019

Abstract
Abstract 5209
Monoclonal B-cell lymphocytosis (MBL) has been established as a diagnostic category to denote the finding of clonal B lymphocytes in otherwise healthy and asymptomatic individuals. MBL likely represents early lesions in lymphoid neoplasms. Immunophenotypically, MBL is divided into CD5+ CLL-type and CD5- non-CLL type MBL, respectively. While most studies have focused on CLL-type MBL and provided evidence of progression of MBL to clinical CLL, the biological nature and clinical relevance of non-CLL type MBL remain unclear. In this study, we have identified and evaluated a series of 18 patients with non-CLL type MBL. This group comprised 10 males and 8 females with a median age of 74 years (range 53–95). All the patients presented initially with a mild to moderate absolute lymphocytosis. Clinical and laboratory evaluations were performed with a follow-up period of 1–20 years (median 8.5). Clonal B lymphocyte populations were confirmed by flow cytometry analysis. All the MBL clones showed negative for CD5, CD10 and CD103, positive for CD19 and CD20, and heterogeneous for CD23, CD25, CD79b, FMC7 and CD38. The phenotypic findings excluded CLL, mantle cell lymphoma and hairy cell leukemia, but may overlap with marginal zone lymphoma or lymphoplasmacytic lymphoma. Cytogenetics were available for 9 patients. Of the cytogenetic abnormalities, 7q deletion was found in two clones, 17 q deletion in two other clones, 11q deletion in one clone and t(2;7) in another clone. An overall tendency was shown toward clonal expansion with an increase in absolute lymphocyte count (ALC) over time (initial mean ALC of 4.9 ± 0.46 × 109/L to a recent mean ALC of 8.3 ± 2.18 × 109/L, p = 0.151). Three patients had an initial ALC >8 × 109/L which remained stable in one patient and decreased to <6 × 109/L in 2 patients. The patient with the longest follow-up of 20 years underwent a completely benign course, while the CD5- clonal B cell population was persistent but non-progressing. Of the progressive clones, three patients had an increase in ALC >10 × 109/L; one patient's ALC progressed over a period of 9 years to 35 × 109/L that required treatment. Clinically, three patients developed splenomegaly and one patient progressed with lymphadenopathy. Unlike the findings from population screening, this study represents a series of clinical MBL of non-CLL phenotype, and our results indicate the heterogeneity in genetic changes and clonal progression.

Disclosures:
No relevant conflicts of interest to declare.
Prevalence and Prognostic Molecular Profiles in Hepatitis B Virus Infected Patients with Diffuse Large B Cell Lymphoma: A Retrospective Study From Chinese Population
Authors: Wang Huijie , Cao Junning , Hong Xiaonan 
Published: October 2019

Abstract
Abstract 5211

Introduction:
Meta-analysis demonstrated that B cell lymphoma appears to be at high risk of infection by Hepatitis B Virus (HBV). Recently, cohort study showed HBV infection is associated with the increasing risk of B cell type lymphoma. Retrospective studies demonstrated high prevalence of HBV infection in Chinese lymphoma patients, with HBsAg-positive rates ranging from 23.5% to 30.5%. HBsAg-positive Diffuse Large B Cell Lymphoma (DLBCL) patients are associated with younger age and more advanced stage. However, the relation between HBV infection and poor prognosis in DLBCL remains uncertain. Molecular markers based on Immunohistochemical (IHC) expression were widely used as prognostic markers in DLBCL. Our study aimed to investigate the prevalence of HBVinfection in the different subtypes of lymphoma, and the molecular prognostic profiles in HBsAg-positive DLBCL.

Patient and Methods:
From Jan 2008 to Dec 2010, a total of 672 patients diagnosed as lymphoma were tested for HBsAg. Of these, 399 were male and 273 were female; 426 were B-NHL, 216 were T-NHL and 30 were HL. The expressions of BCL-2, BCL-6, CD10, MUM-1 were tested in patients diagnosed with DLBCL.

Results:
We found the overall HBsAg-positive rate was 15.9% (107/672) in total lymphoma patients. The positive rate of HBsAg was higher in B-NHL patients (20%,85/426) than T-NHL(9.7%,21/216) and HL (3.3%,1/30) (P<0.001).The lower prevalence were observed several subtypes of lymphoma including mantle cell lymphoma (0/20, 0%), Burkett's lymphoma (0/13, 0%), HL (1/29, 3.3%) and PTCL (4/53, 7.5%).The rate of HBV infection was higher in DLBCL patients (20.9%, 68/326). Among prognostic molecular profiles in DLBCL, the positive expression rates of BCL-2, BCL-6, CD10 and MUM-1 were 65.4% (134/205), 51.3% (116/226), 17% (39/230) and 61.5% (139/226), respectively. The non-GCB subtype accounted of 68.7% of DLBCL. Between HBsAg negative and positive group of DLBCL, the positive expression rates of BCL-2 were 64.1% vs 69.2% (P=0.498), CD 10 were 16.6% v 18.2%(P=0.781), MUM-1 were 60.5% vs 64.8%(P=0.567). However, the BCL-6 positive rate was slight higher in HBsAg negative group compared with positive group (55% vs40%, P=0.053). Finally, non-GCB subtype rates were 67.7% vs 68.7% in HBsAg negative and positive group DLBCL.

Conclusion:
Our date demonstrated that the infection rate of HBV was higher in DLBCL, whereas lower in the subtypes of mantle cell lymphoma, burkitt's lymphoma and HL. Based on IHC analysis, non-GCB subtype accounted of two-third of DLBCL in our series. Patients with HBsAg-positive DLBCL had lower positive rate of BCL-6. However, the expression of Bcl-2, CD10, MUM-1 seems no significant difference between patients with HBsAg-positive and negative DLBCL.

Disclosures:
No relevant conflicts of interest to declare.
Thromboelastography - Viscoelastic Haemostatic Assay (VHA) Versus Routine Plasma Based Coagulation Parameters in Trauma Patients to Detect Coagulopathy within 24 Hrs After Injury
Authors: Shah Bhaumik Arvindkumar , Subramanium Arulselvi , Sharma Subhadra , Agrawal Deepak , Chhabra Gaurav , Mukhopadhyay Asok Kumar 
Published: October 2019

Abstract
Abstract 5248
In India trauma related deaths occur every 1.9 minutes. Mortality in severe traumatic injury (ISS>16) is six times higher in developing country like India. Coagulopathy is observed in almost 25– 30% of trauma patients which itself is an independent risk factor for haemorrhage. Coagulopathy detected early after injury is indicative of injury severity and itself is a prognostic factor for mortality.

Aim
To find out the usefulness of thromboelastography (TEG) in detecting coagulopathy in contrast to conventional methods of plasma based standard coagulation parameters (PT, aPTT, TT, fibrinogen, D-dimer)

Objective
To detect coagulopathy early by TEG in trauma patients within 24 hrs after injury which can be useful to guide haemostatic therapies to reduce mortality.

Materials and methods
Patients admitted to trauma casualty were studied within 24 hrs after injury. Native whole blood was withdrawn through venepuncture appropriately in syringe using 21G needle and TEG was performed within 2 mins. Blood was also collected in citrated tube to assess standard coagulation parameters (prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer) and also by means of thromboelastography.

Results
Patients (n=87,New ISS-24.78(mean)) admitted to J.P.N Apex trauma centre casualty from 1st April,2011 to 31st July,2011 were studied. The cases included in the study were isolated head injury (n=40, NISS-25.87(mean)), multiple trauma with head injury (n=13,NISS – 30.69 (mean)) and trauma other than head injury (n=34, NISS-21.24 (mean)).Thromboelastography was performed using whole blood (n=69) and citrated blood (n=18). Coagulation tests were performed on all 87 patients using both TEG and conventional coagulation parameters. Total 52 patients showed coagulopathy by TEG and only 14 patients showed coagulopathy by standard coagulation parameters (prothrombin time, activated partial thromboplastin time). Only in 10 cases coagulopathy was detected by both methods. 4 patients showed coagulopathy only by conventional methods while 42 patients showed coagulopathy by only Thromboelastography (TEG). To find out whether there is any stastistical significance in the observed apparently better result by TEG, McNemar Test was carried out and P value was <0.0001.

Conclusion
Thromboelastography could be a better technique as compared to conventional measurements of PT, aPTT, TT, Fibrinogen, D-dimer in early detection of coagulopathy in trauma patients.

Disclosures:
No relevant conflicts of interest to declare.
Venous Thromboembolism (VTE) In Hospitalized Patients: What Proportion Is Attributable to Malignancy?
Authors: Akwaa Frank , Khorana Alok 
Published: October 2019

Abstract
Abstract 5250

Background:
VTE is a public health burden in hospitalized patients, affecting the length of hospital stay and overall cost of care. Recent studies suggest increasing incidence of VTE among cancer patients, but contemporary data regarding proportion of VTE attributable to cancer and non-cancer populations are lacking.

Methods:
Hospital-acquired VTE is a reportable event to New York State and we studied all reported VTE events among patients hospitalized at the University of Rochester Medical Center from January 2003 through April 2009. We utilized electronic medical records to identify additional information including demographics and diagnosis of malignancy.

Results:
We identified 2031 patients with 2185 documented VTE events during the study period. Of these, 1102 (54.3%) were men and 929 (45.7%) were women. VTE events included deep vein thrombosis (DVT) (N=1428, 65 %), pulmonary embolism (PE) (N=757, 34.6%), and concurrent DVT and PE (N=153, 7 %). Of the 2031 hospitalized patients with VTE, 492 (24.2%) had a concurrent diagnosis of cancer and 1539 (75.8%) did not. Of 492 cancer-related VTE, 167 (34%) were associated with hematologic malignancies, and 324 (66%) with solid tumors. The proportion of cancer-associated VTE varied by year, ranging from 21% to 31%.

Conclusions:
Approximately one-fourth of all VTE in hospitalized patients occurred in patients with cancer, including a substantial proportion with hematologic malignancy. Public health efforts to reduce hospital-associated VTE should focus on improving compliance with thromboprophylaxis for this population.

Disclosures:
No relevant conflicts of interest to declare.
Advanced Age As a Risk Factor for Folate-Induced Cobalamin (Cbl) Deficiency
Authors: Solomon Lawrence R. 
Published: October 2019

Abstract 5268
Folate therapy can induce or exacerbate neuro-cognitive changes in patients with clinically significant Cbl deficiency. High serum folate (sFol) values in subjects with low Cbl levels have also been associated with increases in the Cbl-dependent metabolite, methylmalonic acid (MMA) as well as with hematologic, neuro-cognitive and fetal abnormalities, raising concerns about the use of both folate supplements and folate-fortified grains. However, in a more recent study of young adults, MMA values were unaffected by high sFol values. Significantly, advanced age is also linked to increased MMA values even when Cbl values are normal. Thus, a retrospective study was performed of 91 non-diabetic subjects with normal renal function and low-normal Cbl values (201–300 pg/ml) who were evaluated for Cbl deficiency in an ambulatory care setting over a 10 year period to determine if age is a significant determinant of the metabolic interaction of sFol and Cbl when Cbl levels are within the normal reference range. In older individuals (≥60 yrs) with low-normal serum Cbl values, the geometric mean MMA value was significantly higher (401 nmol/l; n=11) when sFol values were elevated (>20 ng/ml) than when sFol values were normal (298 nmol/l; n=35)(p<0.025). In contrast, in younger subjects, mean MMA values were similar in both high and normal sFol groups (302 nmol/l; n=15 vs 270 nmol/l; n=30)(p=0.52). There was no correlation between MMA and sFol when sFol values were within the normal range in either age group (r≤0.07). Finally, when sFol levels were elevated, Cbl therapy significantly decreased MMA values in 8 of 9 younger subjects (89%) and in all 7 older individuals (100%) studied. It is concluded that: 1) MMA values are increased when sFol levels are elevated and Cbl values are low-normal but this effect is age-dependent; 2) the effect of sFol on MMA is not progressive but occurs only at sFol values above the normal range; and 3) Cbl therapy decreases MMA values in almost all subjects regardless of pretreatment sFol values. Since these findings may have clinical significance, caution in the use of folate supplements is advised.

Disclosures:
No relevant conflicts of interest to declare.
Molecular Epidemiology of β-Thalassemia in Pakistan: Far Reaching Implications
Authors: Ansari Saqib Hussain , Shamsi Tahir S , Bohray Muneera , Khan Mohammed Tahir , Farzana Tasneem , Perveen Kousar , Erum Sajida 
Published: October 2019

Abstract
Abstract 5309

Introduction:
β -Thalassaemia, an autosomal recessive hemoglobinopathy, is one of the commonest genetically transmitted disorders throughout the world. Collective measures including carrier identification, genetic counseling and prenatal diagnosis are required for preventing β -thalassemia. To achieve this objective, Identification of the spectrum of genetic mutations, especially for various ethnic backgrounds in Pakistan, since the country is a High Burdon Country. Therefore, we designed a cross sectional study to identify the frequency of various gene mutations in different ethnic groups of Pakistan.

Methodology:
Over a period of five years, venous blood samples were collected from 466 individuals belonging to different ethnic groups residing in Karachi, having at least one affected family member known to have β-thalassemia major/ HbE- β-thalassemia/ HbE homozygotes/ β-thalassemia trait. Chorionic villus sampling at 11 to 15 weeks gestational age for 143 couples referred by thalassemia clinics as also used to obtain allele information. In all, 648 mutated alleles were identified. The diagnosis of β-thalassemia trait, β-thalassemia major and Hb E thalassemia were established from clinical data, hematological indices and hemoglobin electrophoresis by cellulose acetate method. DNA was extracted from whole blood for detection of mutations. Primers were designed for simultaneous detection of the following previously described mutations in a single reaction: IVS 1–5 (G-C), Fr 8–9, IVS 1-1 (G-T), Cd-30 (G-C), Cd-5 (−CT), Del 619bp, Cd-15 (G-A), Fr 41–42, Fr 16 (−C) and Cap +1 (A-C) along with two Hb variants: HbS and HbE.

Results:
The genetic heterogeneity in Karachi is reflected by the identification of all the common β-thalassemia alleles and two Hb variants but following eight mutations were more common: IVS 1–5 (G-C), Fr 8–9, Del 619 bp, IVS 1-1 (G-T), Fr 41–42, Cd-30 (G-C), Cd-5 (−CT) and Cd-15 (G-A), accounting for 93.9% of the β-thalassemia alleles. However, the distribution was uneven.
Although IVS 1–5 (G-C) was the most common mutation (40.89% of the sample), its frequency varied from 20% in the immigrant (from India) population to 76.9% in the Balochis. The second most frequent mutation was Fr 8–9, constituting 15.7% of the allele pool. Fr 8–9 was the most common mutation in the Pathans (31.3%) as it was in people of Saraikee origin (47%).

Discussion:
IVSI-5 (G-C),(40.89%), Fr8-9(15.7%), & IVSI-I(G-T),(8.17%), were the most common genetic mutations identified in Pakistan. Knowledge of the predominant mutation in a given ethnic group will not only help in developing a short panel of (population-specific) primers of mutations thereby providing a cost-effective method for prenatal diagnosis and also help the clinicians for genetic counseling and pregnancy termination.

Disclosures:
No relevant conflicts of interest to declare.