bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stratification of Vascular Profile in Multiple Myeloma Patients Using Thrombin Generation Test
Authors: Papageorgiou Loula , Van Dreden Patrick , Garderet Laurent , Grusse Matthieu , Elalamy Ismail , Gerotziafas Grigoris 
Published: November 2020

Introduction: Multiple myeloma (MM) is an hematological disease linked to a high thrombotic risk, estimated at around 10%/year, irrespective to disease onset. An important proportion of MM patients presents at least one of the well-defined vascular risk factors, such as diabetes, cardiac disease, hypertension or hyperlipidemia, which contribute to thrombotic risk. Thrombin Generation Test (TGT) could be an useful biomarker reflecting the prothrombotic profile of MM patients.
Aim: To evaluate the potential correlation between vascular risk factors and TGT in MM patients.
Materials and methods: This is a monocentric, prospective, non-interventional study on a cohort of 82 MM patients referred to the Hemostasis Center at Tenon University Hospital. Patients receiving already anticoagulant treatment of any kind were excluded. Thrombin generation was performed at their first visit using the Calibrated Thrombogram Assay (CAT®,Stago, Genevilliers, France), according to manufacturer's instructions. We collected all TGT parameters: lag time (LT), Endogenous Thrombin Potential (ETP) and Mean Rate Index (MRI).We also measured factor VIII activity (FVIII). Results were statistically analyzed using a two-sample t-test.
Results: Among 82 patients with a male/female ratio of 44/35 and a median age at 65.2 years, 39 patients (48%) presented at least one cardiovascular risk factor (group A) and 42 had no vascular risk factors (group B) The LT value was reduced but not reaching a statistical difference between groups A and B (3 vs 3.95 sec, p= 0.8). MRI representing velocity was statistically shorter in group A (100 vs 118 nmol/min , p&lt; 0.001). Surprisingly, ETP was significantly reduced in group A (1392 vs 1717 nmol/l x min, p &lt; 0.001). FVIII levels were increased in group A (216% vs 192 %, p&lt;0.05).
Conclusion: MM hypercoagulability can be easily identified with MRI, a chronometric TGT parameter. Increased FVIII levels observed in vascular patients are also facilitating an accelerated thrombin generation and are correlated with an endothelial activation. ETP decrease, reflecting the link between both content and container, must be seen as an adaptative response. Thus, endothelial activation could lead to TFPI release and this particular TGT profile in high vascular risk MM patients with a hypercoagulable state.

Disclosures
No relevant conflicts of interest to declare.
Primary Mediastinal B-Cell Lymphoma: The Dilemma of Radiotherapy
Authors: Saraiva Filipa , Saunders Christopher J. , Fevereiro Margarida , Monteiro Alexandra , Sousa Aida B 
Published: November 2020

Introduction: According to the WHO classification, primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a distinct entity, which has a close relationship with nodular sclerosing classical Hodgkin's lymphoma (cHL) in terms of clinical and molecular characteristics and sharing an excellent prognosis. When PMBCL is treated with R-CHOP, the addition of radiotherapy (RT) turns more than 90% of positron emission tomography (PET) positive cases into complete remissions (CR) and increases 5-year overall survival (OS) to 93%. However, the fear of potential late toxicities due to RT, has led an increasing number of centers to favor more intensive regimens like DA-EPOCH-R without RT. This controversy is deepened by the recent comparison between the latter regime with R-CHOP, unfavorable to the DA-EPOCH-R for toxicity reasons.
Objective: Evaluate the effectiveness and late toxicities of R-CHOP plus RT in our center and secondarily compare these results with the ones obtained in our cHL patients with bulky and early stage disease.
Methods: Retrospective analysis of patients with PMBCL treated between Jan/2007 and Dec/2017 according to clinical characteristics, late toxicities, rate of CR, OS and disease-free survival (DFS) estimated by Kaplan-Meier method.
Results: In 32 patients with a median age of 34 years (23-70), 56% were male, 91% had limited stage and 6% had an unfavorable IPI. The rate of CR was 91% (2 patients needed second line therapy to achieve CR) with 2 relapses (at 6 and 11 months, respectively) rescued with autologous transplantation. Three deaths were recorded due to disease progression. With a median follow-up of 86 months, OS and DFS at 10 years were 91% and 93%, respectively. As for late toxicities, besides 2 cases of severe pulmonary fibrosis, there were no other relevant late toxicities registered. These results overlap those obtained in our cHL patients with bulky and early stage disease treated with Stanford V plus RT with an OS and an event free survival of 93% and 84%, respectively.
Conclusion: These results support PMBCL's excellent prognosis, parallel to that of cHL. Given the low probability of late toxicities with this regimen our data uphold against the therapeutic strategy of more intensive regimens, that have an increased management complexity and are clinically more toxic.

Disclosures
No relevant conflicts of interest to declare.
Echocardiographic Changes of Carfilzomib Therapy in Multiple Myeloma Patients
Authors: Bahaj Waled , Albawaliz Anas , Begemann Madeline E , Shrestha Anuj , Sperry Brett , Raza Shahzad 
Published: November 2020

Introduction: Carfilzomib is a proteasome inhibitor that is known to be associated with cardiotoxicity. Current clinical data on Carfilzomib associated with cardiotoxicity is generated in clinical trials from which patients with severe cardiovascular comorbidities were excluded. In this study, we have reported real-word experience on outcome of cardiotoxicity in patients managed by physicians in a community setting.
Methods: We performed a retrospective analysis evaluating for cardiac complications in MM patients who received Carfilzomib at our institution in the last 5 years. Pre- and post-therapy echocardiogram findings were compared. Chi-square tests were used to compare categorical variables with an α level set at 0.05 for statistical significance.
Results: Among the 28 identified patients who had pre- and post- Carfilzomib therapy echocardiogram imaging, (18 patients, 64%) had at least one echocardiographic abnormality. The main changes were in heart functions (10/28), whereas systolic dysfunction is seen in 9 patients while only one patient had diastolic dysfunction, pulmonary artery pressure (6/28), and wall motion abnormalities (5/28). (11/28) patients had disease progression. We did not notice any correlation to variables such as; age, duration of therapy, dose differences, and number of lines of therapies. Furthermore, two patients were rechallenged with Carfilzomib after echocardiographic worsening; one of them tolerated the treatment well, while the other had further worsening that led to holding the therapy.
Conclusion: Several echocardiographic changes could be related to Carfilzomib therapy. Our study was limited due to the sample size and the retrospective nature of the analysis. Larger studies are needed to detect and correlate more echocardiogram variables in this population. Rechallenging these patients with Carfilzomib, particularly during relapse stages, will remain a difficult decision especially if the therapy was effective.

Disclosures
Raza: Advisory board Incyte, Amgen, Celgene, Kite, Janseen, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Moderna: Current equity holder in publicly-traded company; Drrx: Divested equity in a private or publicly-traded company in the past 24 months; Gilead, Sierra, Abbot, Acasti, Amicus: Current equity holder in private company; Received Honorarium/speaker bureu from Janseen, Celgene, Takeda: Ended employment in the past 24 months, Honoraria, Speakers Bureau.
Red Blood Cell Transfusion and the Use of Intravenous Iron in Iron Deficient Patients Presenting to the Emergency Department
Authors: Barghi Arvand , Balshaw Robert , Rimmer Emily , Leeies Murdoch , Garland Allan , Houston Brett L. , Houston Donald S. , Zarychanski Ryan 
Published: November 2020

Background: Red blood cell (RBC) transfusions are often used to treat patients with iron deficiency who present to the emergency department (ED) with symptomatic anemia. Intravenous (IV) iron is the preferred treatment in this setting, as it has been shown to increase hemoglobin concentration rapidly and durably. We aim to determine the incidence of iron deficiency anemia (IDA) and the management of these patients in the ED setting.
Objectives: To evaluate the incidence of IDA, the frequency of RBC transfusion and iron supplementation, and factors associated with RBC transfusion.
Study Design: Retrospective cohort study of all adult patients presenting to the St Boniface Hospital (Winnipeg, CAN) ED from January 2014 to January 2019.
Methods: We used electronic data from the Emergency Department Information System (EDIS) and Laboratory Information Services (LIS) databases to identify patients presenting with IDA, defined as anemia (hemoglobin &lt;120 g/L) with either a transferrin saturation less than 20% or ferritin less than 30 umol/L, or mean corpuscular volume (MCV) of &lt; 75 fL. A ferritin greater than 100 umol was used to exclude IDA, regardless of MCV. We extracted patient demographics, diagnoses, markers of iron storage, RBC transfusion and use of IV iron. Multivariate logistic regression analysis was used to evaluate factors associated with RBC transfusion.
Results: Of 39222 patients, 17945 (45%) were anemic. Of the anemic patients, iron parameters were ordered in 1848 (10.3%) patients, and IDA was present in 910 (5.1 %). In the IDA population, 95 patients (10.4 %) received 1 RBC unit, and 197 patients (21.6 %) received 2 or more units. Oral iron and IV iron were prescribed for 64 (7 %) and 14 (1.5 %) patients, respectively. Our logistic regression model demonstrated that hemoglobin concentration was the main determinant of whether patients received RBC transfusion. Other variables including patient age, cardiac symptoms, heart rate, blood pressure, and CTAS score were not associated with increased likelihood of receiving RBC transfusion.
Conclusion: Iron parameters were infrequently ordered in the evaluation of anemia in the ED, with limited use of oral and IV iron. The decision to transfuse RBCs was primarily influenced by hemoglobin concentration, but not other surrogates of hemodynamic instability. An interventional study to improve education and access to oral and IV iron is planned to reduce unnecessary RBC transfusions and their associated risks in patients with IDA.

Disclosures
No relevant conflicts of interest to declare.
Association between Cancer and Anatomical Site of Venous Thromboembolic Disease
Authors: Froehling David A , Houghton Damon E. , Wysokinski Waldemar E. , McBane Robert D. , Vlazny Danielle , Hodge David , Peterson Lisa , Casanegra Ana I 
Published: November 2020

Background:There is limited published data on the association between malignancy and the location of venous thromboembolism (VTE) in the body.
Aims:Assess the location of VTE in the body in patients with active cancer and compare these results in patients without malignancy.
Methods:Consecutive patients enrolled in the Mayo Clinic VTE Registry between March 1, 2013 and November 30, 2019 for acute VTE were followed prospectively. Anatomical site of thrombosis and malignancy status were recorded. Patient outcomes were assessed in person, by mailed questionnaire, or by a scripted phone interview. Active cancer was defined as treatment for malignancy within the last six months or not yet in remission.
Results:During the study period there were 2,798 patients with acute VTE (1256 with and 1542 without active cancer). Pulmonary emboli were more common in patients with active cancer compared to patients without cancer (49.5% vs. 39.7%, p&lt;0.001). Upper extremity deep vein thrombosis (11.4 % vs. 7.7%, p&lt;0.001), renal vein thrombi (1.4% vs. 0.2%, p&lt;0.001) and splanchnic vein thrombi (9.3% vs. 6.0%, p=0.001) were all more common in patients with active cancer compared to patients without cancer.
Conclusion:Compared to those without malignancy, patients with active cancer were more likely to have pulmonary emboli, upper extremity deep vein thrombosis, renal vein thrombi, and splanchnic vein thrombi.

Disclosures
No relevant conflicts of interest to declare.
Clinical Efficacy and Safety of TPO in Combination with Eltrombopag in Patients with Solid Tumor Chemotherapy-Induced Thrombocytopenia
Authors: Zhou Fuling , Liu Shuai , Liu Yin 
Published: November 2020

Aim: To evaluate the efficacy and safty of TPO in combination with eltrombopag in the treatment of solid tumor chemotherapy-induced thrombocytopenia (CIT).
Methods: 7 patients with thrombocytopenia after standard solid tumor chemotherapy were enrolled in this study, including gastric cancer(n=1), breast cancer(n=1), lung cancer(n=3) and liver cancer(n=2). They were treated with TPO (15000IU q.i.d.) in combination with eltrombopag (25mg t.i.d.) until the platelet count was recovered to 100 × 109 / L or the medication time was up to 14 days. The time required for platelets to recover to &gt; 50 × 109 / L and ≥ 100 × 109 / L, platelet transfusion times and adverse reactions were observed.
Results: After the treatment, the platelet counts of all patients were recovered to &gt; 50 × 109 / L, and 3 of them ≥ 100 × 109 / L. The adverse reactions include muscle soreness(n=1), liver and kidney dysfunction(n=1), no case of them was above grade 3 according to WHO classification criteria for adverse reactions.
Conclusion: TPO in combination with eltrombopag is an effective and safe method for the treatment of solid tumor chemotherapy-induced thrombocytopenia (CIT).

Disclosures
No relevant conflicts of interest to declare.
A Rare Glanzmann Thrombasthenia Pedigree of C.1067T&gt;C Heterozygous Mutation in ITGA2B Gene
Authors: Liu Jiaying , Shen Lijing , Zhuansun Shiya 
Published: November 2020

Purpose
A 50-year-old female with excessive menstruation and severe epistaxis since childhood was studied by using phenotype and genetic diagnosis. She was diagnosed as Glanzmann thrombasthenia (GT), meanwhile, her family members with severe epistaxis were also studied. Mutation sites were detected in them. Bioinformatics software was used to explore the molecular pathogenesis which provide evidence for in vitro and in vivo experiments.
Methods
Platelet count and morphology, coagulation function and platelet aggregation were detected for phenotype diagnosis. Platelet membrane glycoproteins (GP) αIIb and β3 were measured by flow cytometry (FCM). Exons and their end 15bp introns of 89 genes associated with hemorrhage and thrombosis from proband were amplified by PCR and analyzed by direct DNA sequencing. Mutation site was measured by sanger sequencing in other family members. ClustalX-2.1-win software was used to analyze homology of nucleotide. PROVEAN and SIFT was used to analyze the risk of mutation site.
Results
The proband, along with her brother and nephew, had normal platelet account and morphology. Coagulation function showed normal while platelet aggregation in response to ADP and AA were reduced. However, they had normal platelet aggregation in response to ristocetin. FCM demonstrated that expression level of CD41 and CD61 were significantly reduced. ITGA2B c.1067T&gt;C heterozygous missense mutation, which led to a Val356→Ala substitution in αIIb protein, existed in the three people. This mutation site was highly conserved among human, mouse, rat and zebrafish. PROVEAN prediction scored -3.48 and SIFT prediction scored 0.001. These results demonstrated ITGA2B p.Val356Ala was pathogenic.
Conclusion
Glanzmann thrombasthenia is a rare autosomal recessive bleeding disorder results from quantitative or qualitative defect of αIIbβ3 integrin which encoded by ITGA2B and ITGB3. The nature of GT mutations is highly variable and most cases are sporadic. In our study, ITGA2B c.1067T&gt;C (Val356Ala) heterozygous missense mutation caused Glanzmann thrombasthenia and aroused obvious symptoms. And in general, homozygous mutation in ITGA2B were recognized to led to Glanzmann thrombasthenia while ITGA2B heterozygous mutation carriers showed mild symptoms. However, there are also some patients with gain-of-function in ITGA2B showed abnormal platelet function or amount. More experiments should be conducted to identify the function of this heterozygous mutation.

Disclosures
No relevant conflicts of interest to declare.
Cfi-400945 Induces Cytokinesis Failure By Activating Hippo Signaling Pathway in Diffuse Large B-Cell Lymphoma
Authors: Zhao Yi , Yang Juan , Liu Jiarui , Ren Shuai , Cai Yiqing , Hu Shunfeng , Zhou Xiangxiang , Wang Xin 
Published: November 2020

Targeting mitosis has been found to be a therapeutic strategy for cancer since microtubule poisons have proved efficacy in a broad range of malignancies. Cytokinesis failure can increase chromosomal instability beyond a critical threshold that triggers tumor suppression. Thus, agents developed to block cytokinesis can stop proliferation of cancer cells. We previously demonstrated that the polo-like kinase 4 (PLK4) inhibitor, CFI-400945, triggers growth inhibition and apoptotic death in diffuse large B-cell lymphoma (DLBCL). Since PLK4 is involved in centrosome duplication for cell division, we aimed to explore the effects of CFI-400945 on cytokinesis in DLBCL cells.
Here, we demonstrated that CFI-400945 induces cytokinesis failure in DLBCL. CFI-400945-treated cells led to binucleated/multinucleated cells (Fig. 1a). Previous study showed that the Hippo signaling pathway played a critical role in cytokinesis. Consistent with this finding, we found that CFI-400945 led to phosphorylation of LATS1 and YAP (Fig. 1b). Confocal microscopy confirmed the reduced nuclear YAP upon treatment of CFI-400945 (Fig. 1c). These results show that reduced nuclear YAP levels and activities contribute to growth inhibition by CFI-400945 in DLBCL cells.
In addition, we further explored the synergy of CFI-400945 and doxorubicin (DOX) both in vitro and in vivo. A combined treatment of CFI-400945 and DOX significantly inhibited DLBCL cell survival and induced more apoptosis compared with CFI-400945 or DOX alone (Fig. 1d, Fig. 1e).In the mice xenograft model, the combination of CFI-400945 and DOX significantly delayed tumor progression compared to those treated with vehicle or DOX alone (Fig. 1f). Tumors from combination-treated mice displayed an increase in γ-H2AX staining and a reduction in Ki67 staining (Fig. 1g). Strikingly, tumor cells were generally larger, heterogeneous in size and frequently binucleated (Fig. 1h).
Combined, our results indicate for the first time that CFI-400945 treatment induces cytokinesis failure and activation of Hippo signaling pathway, leading to vulnerability to mitotic catastrophe. Moreover, this study proves an attractive combination treatment that simultaneous targeting PLK4 with CFI-400945 could exacerbate mitotic defects to improve response of anthracycline-based chemotherapy in DLBCL.
Figure 1

Disclosures
No relevant conflicts of interest to declare.
GADD45a Controls Self-Renewal in Acute Myeloid Leukemia Stem Cells
Authors: Hassan Nunki , Yi Hangyu , Gaspard-Boulinc Lucie , Chen Franklin , Datuin Jayvee , Yang Jonason , Wang Jenny Yingzi 
Published: November 2020

Acute myeloid leukemia (AML) is a heterogenous malignancy, where the persistence of chemo-resistant leukemia stem cells (LSCs) contributes to disease relapse. We have previously demonstrated the clinical significance of WNT/β-catenin signaling in driving AML LSCs (Science, 327:1650-1653, 2010; Cancer Cell, 38:1-16, 2020). In this study, we uncover that GADD45a (growth arrest and DNA-damage inducible protein) is an essential regulator of β-catenin signaling pathway and its loss promotes LSC function and leukemia progression.
Transgenic knockout of Gadd45a led to a progressive increase in aberrant self-renewal and leukemogenesis in vivo. Gadd45a-/- leukemic cells developed a more aggressive leukemia with a shorter latency than Gadd45a+/+ cells in mice, indicating the involvement of Gadd45a loss in AML initiation and progression. Subsequent serial transplantation experiments showed that Gadd45a deletion enhanced LSC self-renewal in vivo. In agreement with our findings in murine LSCs, deletion of GADD45a by CRISPR/Cas9 in AML patient-derived xenograft (PDX) cells revealed increased engraftment and tumor burden in NSG mice. Consistent with our phenotypic observations, knockout of GADD45a increased βcatenin activity and key WNT/self-renewal target genes in human AML cells. In addition, our cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) data showed that GADD45a deletion in patient-derived LSCs was associated with cell metabolism, reactive oxygen species and tumor progression, as well as poor patient outcomes in AML. Further studies are being conducted to evaluate transcriptional mechanisms discovered by our single-cell sequencing.
Taken together, this study is the first to demonstrate that GADD45a loss promotes LSC potential and consequently enhances tumor growth in murine and PDX models of AML, thus showcasing GADD45a as a promising therapeutic target in AML.
References:
Wang Y, Krivtsov AV, Sinha AU, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327:1650-1653.
Salik B, Yi H, Hassan N, et al. Targeting RSPO-LGR4 signaling for leukemia stem cell eradication in acute myeloid leukemia. Cancer Cell. 2020; 38:1-16.

Disclosures
No relevant conflicts of interest to declare.
Venetoclax and Posaconazole Plus Standard Dose Cytarabine or Azacytidine for Newly Diagnosed Acute Myeloid Leukemia
Authors: Tan Tran-Der , Chiou Lun-Wei 
Published: November 2020

Background: The present standard induction treatment for newly diagnosed acute myeloid leukemia (ND AML) is three days' daunorubicin or idarubicin plus seven days' cytarabine chemotherapy (3+7). Venetoclax plus azacytidine or low dose cytarabine is effective and better than azacitidine or low dose cytarabine alone for ND AML in VIALE A and VIALE C trials, respectively and the outcome by Venetoclax dose levels was not different between 400 mg, 800 mg, or 1200 mg a day. As a strong CYP3A inhibitor, posaconazole can increase serum level of Venetoclax and the dosage could be reduced to 75~100mg a day.
Method: We treat ND AML patients with uninterrupted Venetoclax 100 mg plus posaconazole 300 mg daily and 7 days' standard dose of cytarabine (100 mg/m2/day) or 7 days' azacitidine (75 mg/m2/d), followed by 5 days' consolidation cytarabine (100 mg/m2/d) or another 7 days' azacitidine, and then followed by allogeneic hematopoietic stem cell transplantation.
Results: Eight patients have enrolled the treatment including 7 underwent venetoclax/posaconazole/cytarabine and one venetoclax/posaconazole/azacitidine patients and four patients are secondary AML (one myeloma, one MDS, and 2 breast cancer patients). All patients were hematologic complete remission achieved in one month and 6 patients underwent allogeneic hematopoietic stem cell transplantation including one from matched sibling, two from matched unrelated, and three from haplo-identical donors (sons). Febrile neutropenia rates were similar to 3+7 treatment patients on historical comparison but shorter period of febrile illness. There was no grade II or higher adverse effect of oral mucosa and gastrointestinal tract as compared with conventional 3+7 therapy. Two out of six allo-transplant patients got leukemia relapse then salvage treatment ensued and the other 2 non-transplant and 4 allo-transplant patients are persisted in complete remission.
Conclusion: Venetoclax plus posaconazole and standard dose cytarabine is a feasible choice of induction therapy in ND AML and high CR rate and transplant rate achieved and there was no detrimental effect upon the hematopoietic recovery during induction and transplant therapy.
Figure

Disclosures
No relevant conflicts of interest to declare.