bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of the Timing of Venous Thromboembolic Events on Survival of Patients with Uterine Cancer
Authors: Remasankar Heera , Zhou Xiao , Vadhan-Raj Saroj 
Published: October 2019

Abstract
Background: Cancer patients are at high risk for venous thromboembolic event (VTE), and the occurrence of VTE can affect the prognosis. However, it is unclear if the timing of VTE can influence the prognosis. The purpose of this study was to evaluate the incidence and impact of the timing of VTE (early vs late) on the survival of patients with uterine cancers.
Methods: A retrospective cohort study was conducted. The study population included all uterine cancer patients who had newly diagnosed episode of VTE from January 1st 2006 to December 31st2007 at MD Anderson Cancer Center. Medical records of these patients were reviewed for cancer diagnosis, patient demographics, metastasis, date of diagnosis of VTE, type of VTE, the site of VTE, and any recurrences during the follow up period of 2 years since the first VTE. Clinical and laboratory parameters predictive for survival were also reviewed. All VTE episodes, including symptomatic as well as incidental VTEs were confirmed by the radiological studies using CT ANGIO, CT scan, Doppler compression ultrasound or V/Q perfusion scans. The survival time was defined as the time from the date of cancer diagnosis to the date of death, or to the date of last follow up. Survival analysis was conducted using Kaplan-Meier method and Cox proportional hazard models.
Results: Of the 2151 patients with newly diagnosed VTEs within the 2 years study period, 33 patients were found to have uterine cancers. The median age was 60 years (range 41-84 years). Among all the primary VTEs, 42% were pulmonary embolus (PE); 45% were deep vein thrombosis (DVT), and 12% were concurrent PE/DVT (diagnosed on the same day). The median time of VTE from the date of cancer diagnosis was 8 months (range 0 - 88 months). The majority of these VTE events (55%) were found to occur within 1 year from the date of cancer diagnosis. A total of 8 patients had 10 recurrent episodes of VTE (2 patients had 2 recurrent VTE episodes) during the follow up period. The median survival time was 33 months (range 2.6-121.6 months); 82% of these patients had a metastatic disease. Multivariate proportional hazards model showed that the diagnosis of VTE within 6 months from the cancer diagnosis [Hazard ratio: 3.8, 95% CI (1.1-12.9), p=0.03] and the presence of baseline white blood cell (WBC) count of greater than 11,000/uL [Hazard ratio: 3.5, 95% CI (1.0-12.2), p=0.045] were statistically significant independent predictors for 2 year survival adjusting for age, presence of central venous catheter (CVC), and the baseline platelet count of greater than 350,000/uL.
Conclusion: These findings suggest that the timing of VTE is an important indicator of prognosis in patients with uterine cancer; patients who had VTE within 6 months from cancer diagnosis had a shorter 2 year survival. Future larger studies may better define the impact of timing of VTE on survival of patients with Uterine Cancers.

Disclosures
No relevant conflicts of interest to declare.
Critical Role of T Cells in PF4/Heparin Antibody Production
Authors: Zheng Yongwei , Yu Mei , Padmanabhan Anand , Aster Richard H. , Wen Renren , Wang Demin 
Published: October 2019

Abstract
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated disorder that can cause arterial or venous thrombosis/thromboembolism, and platelet factor 4 (PF4)/ heparin-reactive antibodies are essential to the pathogenesis of HIT. Our recent studies have demonstrated that marginal zone (MZ) B cells play a major role in production of PF4/heparin-specific antibodies. However, the role of T cells in production of these pathogenic antibodies is not clear. Here we showed that PF4/heparin complex-induced production of PF4/heparin-specific antibodies was markedly impaired in mice, in which CD4 T cells were depleted by administration of GK1.5 anti-CD4 monoclonal antibody. As expected, the CD4 T cell-depleted mice responded normally to T cell-independent antigen TNP-Ficoll but not T cell-dependent antigen NP-CGG, in agreement with the lack of CD4 T cells in these GK1.5-treated mice. Further, following adoptive transfer of a mixture of wild-type splenic B cells and splenocytes from B cell-deficient μMT mice, T and B cell-deficient Rag1 knockout mice responded to PF4/heparin complex challenge to produce PF4/heparin-specific antibodies. In contrast, Rag1-deficient mice that received a mixture of wild-type splenic B cells and splenocytes from Rag1-deficient mice barely produced PF4/heparin-specific antibodies upon PF4/heparin complex challenge. These data suggest that T cells are required for production of PF4/heparin-specific antibodies. Consistent with this concept, mice with B cells lacking CD40 molecule, a B cell costimulatory molecule that helps T cell-dependent B cell responses, displayed a marked reduction of PF4/heparin-specific antibody production following PF4/heparin complex challenge. Also as expected, mice with CD40-deficient B cells were able to respond to T cell-independent antigen TNP-Ficoll but not T cell-dependent antigen NP-CGG, consistent with the lack of T-cell help in these mice. Taken together, these findings demonstrate that T cells play an essential role in production of PF4/heparin-specific antibodies by MZ B cells.

Disclosures
No relevant conflicts of interest to declare.
Histone Acetylation Mediated by Brd1 Is Crucial for Cd8 Gene Activation during Early Thymocyte Development
Authors: Mishima Yuta , Wang Changshan , Miyagi Satoru , Saraya Atsunori , Hosokawa Hiroyuki , Yamaguchi Naoto , Nakayama Toshinori , Koseki Haruhiko , Taniuchi Ichiro , Iwama Atsushi 
Published: October 2019

Abstract
During T cell development, Cd8 expression is controlled via dynamic regulation of its cis-regulatory enhancer elements. Insufficient enhancer activity during initial Cd8 activation is known to cause a variegated CD8 expression, thereby generating a CD4+CD8-TCRb-/low population that should appear as CD4+CD8+ double-positive (DP) thymocytes. However, epigenetic and molecular mechanisms involved in initial Cd8 gene activation remain elusive. We previously reported that Brd1, also known as Brpf2, is responsible for the global acetylation of H3K14 as a subunit of the Hbo1 histone acetyltransferase (HAT) complex.
In this study, we generated conditional Brd1 knockout mice (Tie2-Cre;Brd1fl/fl mice), in which Brd1 is inactivated in all hematopoietic cells. Although Tie2-Cre;Brd1fl/fl mice were born and grew normally, detailed analysis revealed an abnormal thymocyte differentiation. Deletion of Brd1 resulted in the appearance of CD4+CD8-TCRβ-/low thymocytes that was indistinguishable from DP thymocytes in their properties. Hierarchical clustering of gene expression profile showed that Brd1Δ/Δ CD4+CD8-TCRβ-/low thymocytes retain an expression profile nearly identical to one observed in DP thymocytes. These results indicate that Brd1Δ/Δ CD4+CD8-TCRβ-/low thymocytes correspond to immature thymocytes that would normally appear as CD4+CD8+ DP thymocytes, and was generated because of a variegated activation of Cd8 gene. Importantly, in the gut intraepithelial lymphocyte (IEL) compartment, the population of CD4+CD8aa+ aβT cells, whose generation requires Cd8 gene reactivation in CD4+CD8− helper T cells, were significantly decreased in Tie2-Cre;Brd1fl/fl mice compared to the Tie2-Cre control mice. In addition, the percentage of CD8aa expressing gdT cells was significantly reduced. These findings suggest that Brd1 is also required to initiate Cd8a activation in gdT cells as well as Cd8 reactivation in CD4+T cells.
We further conducted retroviral transduction of Brd1 into Brd1Δ/Δ DN3 cells that were flowed by culture on TSt-4/DLL stromal cells. Upon exogenous Brd1 expression, CD8 expression was completely restored and thereby Brd1Δ/Δ DN3 cells differentiated into DP cells.
ChIP analysis demonstrated that Brd1 and Hbo1 co-localize at the known enhancers in the Cd8 locus and that their bindings are responsible for acetylation at H3K14. Biochemical results confirmed a presence of Brd1 in Hbo1 HAT complexes. These findings indicate that the Brd1-mediated HAT activity is crucial for efficient activation of Cd8 expression via acetylation at H3K14, which would serve as an epigenetic mark that promotes the recruitment of transcription machineries to the Cd8 enhancers.

Disclosures
No relevant conflicts of interest to declare.
Ripk-Mediated Necroptosis Induces Inflammation and Bone Marrow Failure in Mice
Authors: Roderick Justine E. , Hermance Nicole , Zelic Matija , Simmons Matthew , Polykratis Apostolos , Pasparakis Manolis , Kelliher Michelle 
Published: October 2019

Abstract
TNF-α and IFN-γ overproduction are features associated with human bone marrow failure syndromes such as Fanconi Anemia (FA) and Aplastic Anemia (AA). Cells from these patients are known to be hypersensitive to TNF-α and IFN-γ-induced cell death. The serine threonine kinases RIPK1 and RIPK3 interact to mediate necroptosis induced by TNF-α, type I or II interferons. We demonstrate that a hematopoietic RIPK1 deficiency results in hematopoietic stem and progenitor cell loss and induction of bone marrow failure. The cell death reflects cell-intrinsic survival roles for RIPK1 in hematopoietic stem and progenitor cells, as Vav-iCre Ripk1fl/fl fetal liver cells failed to reconstitute hematopoiesis in lethally irradiated recipients. Hematopoietic failure in these mice is accompanied by increases in serum pro-inflammatory cytokines/chemokines and reduced hematopoietic colony formation in the presence of TNF-α, type I or II interferon. We provide genetic evidence that a RIPK3 deficiency rescues the bone marrow failure and significantly reduces serum cytokine and chemokine levels in Vav-iCre Ripk1fl/fl mice. These data reveal that in the hematopoietic lineage RIPK1 prevents inflammation by suppressing RIPK3 activity and raise the possibility that human bone marrow failure patients may benefit from selective RIPK inhibitors.

Disclosures
No relevant conflicts of interest to declare.
Temozolomide Induced Bone Marrow Suppression- a Single Institution Outcome Analysis and Review of Literature
Authors: Kourelis Taxiarchis , Buckner Jan C , Gangat Naseema , Patnaik Mrinal M. 
Published: October 2019

Abstract
Background: Severe myelosuppression (MS) and bone marrow failure (BMF) are rare but well characterized adverse effect of temozolomide (TMZ). The existing literature is limited to case reports and data reported to regulatory agencies, which usually describe very severe cases and lack long term and detailed follow-up.
Methods: We identified cases of myelosuppression attributed to TMZ seen at the Mayo clinic, from 1998-2014. We also performed a literature (PubMed) search to identify published cases of TMZ induced MS and BMF. TMZ induced MS was defined as a decrease in at least 2 cell lines below normal that was clinically attributable to TMZ and persisted for > 28 days after the last TMZ dose. Severe MS was defined as bone marrow cellularity of <25% or at least 2 of: a) reticulocyte count <40,000/µL b) absolute neutrophil count (ANC)<500/ µL c) platelets <20,000/µL. Very severe MS was defined by an ANC <200/ µL.
Results: A total of 15 Mayo patients and 10 published cases were identified. The baseline characteristics of patients are shown in table 1. The median interval between initiation of TMZ and diagnosis of MS was 48 days (range 26-121). The hematologic outcomes of the group are shown in table 2. Seventeen patients developed neutropenic fever, 4 had severe sepsis, and 6 experienced bleeding complications. Kaplan-Meier recovery curves for each cell line are shown in the figure. Myelosuppression was fatal in 3 cases. Most patients recovered their ANC (median-62 days, range 28-180). Persistent thrombocytopenia was seen in 19 patients, without evidence for clonal evolution or myelodysplasia. Four patients remain dependent on growth factor support (G-CSF and thrombopoietin agonists).
Conclusion: MS is usually a non-fatal complication of TMZ. Most cell lines recover spontaneously and adequately with the exception of platelets, which can remain significantly suppressed for prolonged periods. Infectious complications are very common. Most patients respond to supportive care, including the use of growth factors.

Figure 3 Figure 3.

Disclosures
No relevant conflicts of interest to declare.
Serum IL- 10 As a Predictive Marker of Response to Chemotherapy in Advanced Stage Hodgkin Lymphoma
Authors: Allahloubi Nasr Mohamed A. , Abdelhamid Thoraya Mohamed , Shamaa Sameh S. , Abd El Ghaffar Hassan , Saied Wageeh El-Sebaey , Awad Mohamed 
Published: October 2019

Abstract
Background: Cytokines and chemokines produced by HRS cells and the surrounding microenvironment are believed to be involved in the pathogenesis of HL by modulating immune functions and inflammatory responses.Among those cytokines; IL-10 seems to be most relevant for the shaping of a microenvironment favoring survival of HRS cells. Elevated IL-10 serum levels were even associated with a worse clinical outcome in patients with HL.
The aim of this study is to show the prognostic and predictive relevance of serum IL10 in advanced stage HL.
Patients and method: the study included 60 patients with advanced stage HL, treatment regimen was ABVD regimen (n=30) or BEACOPP baseline regimen (n=30). Serum IL10 assay employs the quantitative sandwich enzyme immunoassay technique. Evaluation of IL10 level was done at diagnosis then after 4 and 8 cycles of chemotherapy.
Results: The median agewas 41 years (range 20-65), 37 males (61.7%) and 23 females (38.3 %) were included. For patients treated with ABVD regimen, complete response (CR) was achieved in 18 cases (60%) compared to a CR rate of 66.7% for the BEACOPP regimen (CR= 20 cases) P=0.6. There was no significant difference between both treatment regimens regarding PFS and DFS (p=0.6 and 0.9 respectively). High pretreatment serum IL10 (>10pg/ml) showed significant relation to high LDH (p=0.001), male sex (p=0.018), more advanced stage IV versus IIB and III (p=0.0001) and the IPI score of 4 or more for advanced HL. This study showed that 83.3% of the patients with pretreatment serum IL 10 ≤ 10 pg/ml achieved CR compared to 45.2% of patients with IL-10>10 pg/ml did not achieved CR after 8th cycle of chemotherapy with (P= 0.035), Also the patients who achieved CR after 8 cycles had low level of IL-10 after treatment with a median of 9.35pg/ml (range 5.49-73.16) compared to a median of 30.66 (range 5.36-145.6) for patients who did not show CR (P<0.001). This significant relation between the CR rate and serum IL10 before and after treatment was also documented after the 4th cycles of chemotherapy (p=.006 and 0.003respectively). Our study found no significant relation between the IL-10 level prior to therapy and occurrence of relapse, disease progression or mortality.
Conclusion: There is a significant relations between high pretreatment serum level of IL-10 with poor response to chemotherapy after the 4th cycle and the 8th cycle of chemotherapy denoting that pretreatment serum level of IL- 10 is a good predictive marker of response.

Disclosures
No relevant conflicts of interest to declare.
Identification of a Subset of Peripheral T-Cell Lymphoma, Not Otherwise Specified, Characterized By FOXP3-Positive Regulatory T-Cell Phenotype, HTLV-1 Negativity and Poor Outcome
Authors: Pedersen Martin Bjerregaard , Hamilton-Dutoit Stephen Jacques , Bendix Knud , Nørgaard Peter H. , Michael Møller Boe , Raffeld Mark , Pittaluga Stefania , Steiniche Torben , Bergmann Anke , Vater Inga , Siebert Reiner , Chan Wing-Chung , d'Amore Francesco 
Published: October 2019

Abstract
Background: T-cell malignancies originating from regulatory T (Treg) cells are almost exclusively confined to human T-cell leukemia virus 1 (HTLV-1) associated adult T-cell leukemia/lymphoma (ATLL), although sporadic cases of other peripheral T-cell lymphomas (PTCLs) with hypothesized Treg derivation have been reported.
Patients and methods: We investigated a series of 169 well characterized PTCLs for the expression of Treg-cell phenotypic markers FOXP3, CD25 and CD4 by immunohistochemistry (IHC) using tissue microarray on formalin-fixed paraffin embedded tissue. Clinico-pathological data for patients enrolled were retrieved from the Danish Lymphoma Registry and medical records. Treg tumors were further invetsigated by Affymetrix OncoScan analysis and Illumina Infinium HumanMethylation450 BeadChips.
Results: Variable amounts of FOXP3-positive Treg cells were often (99% of the cases) found as part of the non-neoplastic cellular infiltrate. However, in five cases (3%) classified as PTCL, not otherwise specified (PTCL-NOS) the vast majority of what morphologically appeared to be the neoplastic cell population displayed a strong positivity for FOXP3, CD4, CD25 and CD3 suggesting a probable Treg origin of these cells. Cases were HTLV-1 negative and showed monoclonal rearrangements of the T-cell receptor genes. All cases were male older than 60 years and showed an aggressive clinical course with overall survival less than two years, despite all patients had low IPI-risk profile at the time of diagnosis. The PTCL with Treg phenotype showed a complex pattern of chromosomal imbalances. Moreover, as compared to normal T-cell subsets their DNA methylation profiles were mostly related to that of normal Treg cells but significantly differed from that.
Conclusions: We suggest that FOXP3-positve PTCL, in the absence of HTLV-1 infection, constitute a distinct entity separated from PTCL-NOS, occurring predominantly in elderly male patients and characterized by a highly aggressive clinical behavior. Further genomic analyses are ongoing. The identification and characterization of these cases may be useful to guide upfront therapeutic strategies.

Disclosures
No relevant conflicts of interest to declare.
CD180 Expression in B-Cell Lymphomas: A Multicenter Geil Study
Authors: Mayeur-Rousse Caroline , Guy Julien , Miguet Laurent , Bouyer Sabrina , Genevieve Franck , Robillard Nelly , Solly Francoise , Maar Aida , Bene Marie-C , Mauvieux Laurent 
Published: October 2019

Abstract
CD180 is a Toll-Like Receptor homolog strongly expressed on normal human B-cells and involved in innate immune responses. Previous proteomic analyses on microparticles derived from mature B-cell neoplasms allowed us to identify CD180 as a marker of marginal zone lymphomas (MZL)(Miguet, Leukemia, 2013). Using flow cytometry on blood samples we showed that this protein is lost or underexpressed at the plasma membrane for almost all B-cell lymphomas except MZL. In order to confirm its clinical relevance, we conducted a prospective multicenter flow cytometry study in 5 French University Hospital laboratories, on behalf of the GEIL. Blood or bone marrow samples from 236 patients were studied (20 normal controls ; 74 chronic lymphocytic leukemia (CLL); 21 mantle cell lymphoma (MCL); 42 lymphoplasmacytic lymphoma (LPL); 13 follicular lymphoma (FL) ; 58 MZL, 14 of which with numerous villous lymphocytes; 8 hairy cell leukemia (HCL)). Analyses were performed either on FACSCanto II (BD Biosciences, 3 centers) or on Navios (Beckman Coulter, 2 centers) instruments. Harmonization process was performed using Rainbow beads (Spherotech).
For the CLL group, CD180 Median fluorescence (MdFI) in each center was not significantly different (Anova test, p>0.05). Instruments’ harmonization was therefore effective enough to obtain similar data from all centres. In the whole cohort, CD180 was significantly less expressed in the group of lymphomas -including CLL, MCL, LPL and FL- than in controls (Mann-Whitney test, p<0.05). Conversely, in the group of MZL and HCL, CD180 MdFI was not different from those of controls (Mann-Whitney test, p>0.05) but significantly higher than in CLL, MCL, LPL and FL (Mann-Whitney test, p<0.0001). Distinction between MZL and lymphomas with numerous villous lymphocytes was possible (Mann-Whitney test, p=0.0012) but not between MZL and HCL. ROC curve analysis determined a CD180 MdFI threshold of 1800 which allow the positive diagnosis of MZL with a sensitivity of 77% and specificity of 92%.
These results underline the efficiency of CD180 as a single positive and robust marker for MZL diagnosis, and confirm that between centers and between instruments harmonization is largely feasible in routine practice as published recently (Solly F et al. Cytomery part A, 2013). It should be emphasized that among the group of lymphomas with intense expression of CD180, all interestingly originating from the spleen, those with numerous villous lymphocytes display the highest expression. We described for the first time in this study the strong positivity of CD180 in HCL. Anti-CD180 antibody may be included in diagnosis combination markers in order to improve the diagnosis of chronic B-cell malignancies

Disclosures
No relevant conflicts of interest to declare.
Exome Sequencing Identifies Somatic Mutations of DDX3X in Natural Killer/T-Cell Lymphoma
Authors: Jiang Lu , Gu Zhao-Hui , Yan Zi-Xun , Zhao Xia , Xie Yin-Yin , Zhang Zi-Guan , Pan Chun-Ming , Hu Yuan , Cai Chang-Ping , Dong Ying , Wang Li , Shen Yang , Meng Guoyu , Zhou Jian-Feng , Hu Jian-Da , Wang Jin-Fen , Yang Lin-Hua , Zhang Feng , Wang Jian-Min , Wang Zhao , Peng Zhi-Gang , Chen Fang-Yuan , Sun Zi-Min , Ding Hao , Huang Jin-Yan , Liu Yuan-Hua , Shi Jumei , Hou Jian , Yan Jin-Song , Shi Jing-Yi , Xu Lan , Li Yang , Lu Jing , Zheng Zhong , Xue Wen , Zhao Wei-Li , Chen Zhu , Chen Sai-Juan 
Published: October 2019

Abstract
Natural-killer/T cell lymphoma (NKTCL) is a malignant proliferation of CD56+/cytoCD3+ lymphocytes and constitutes a heterogeneous group of aggressive lymphoma prevalent in Asian and South American populations. NKTCL represents a distinct clinicopathologic entity of non-Hodgkin’s lymphoma, characterized by male predominance, strong association with Epstein-Barr virus (EBV) infection, prominent tissue necrosis and aggressive clinical course. However, molecular pathogenesis of NKTCL remains largely elusive.
Here we identified somatic mutations by whole-exome sequencing in 25 NKTCL patients and extended validation through targeted sequencing in an additional 80 cases. Functional experiments including RNA unwinding test, colony forming assay, cell proliferation assay and gene expression profiling were also performed.
Overall, 50.5% of NKTCL patients displayed somatic mutations of RNA helicase family, tumor suppressors (TP53 and MGA), and/or epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). Recurrent mutations were most frequently discovered in RNA helicase gene DDX3X (21/105 cases, 20.0%). Mutations of DDX3X were seldom overlapped with those of TP53. Functionally, DDX3X mutants exhibited reduced RNA unwinding activity and enhanced cell proliferation. Similar stimulatory effect on cell proliferation was observed in cells transfected with specific siRNA targeting DDX3X. Gene expression profiling revealed an association of DDX3X mutations with activation of NF-kB and MAPK pathways. The clinical follow-up data showed that DDX3X-mutated patients presented a poor prognosis.
Our work suggests the heterogeneity of gene mutational spectrum of NKTCL and provides a potential therapeutic target for relevant cases.

Disclosures
No relevant conflicts of interest to declare.