bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Prevalence of May Thurner Syndrome in Children with Ileo-Femoral Deep Vein Thrombosis- Does It Take 2 to Tango?
Authors: Subburaj Divya , Cox Pamala , Price Victoria E. , Kulkarni Ketan 
Published: November 2021

Abstract
Introduction:
May-Thurner syndrome (MTS) is characterised by compression of the left external iliac vein by overriding right common iliac artery resulting in venous stasis. It carries a higher risk of left iliofemoral deep vein thrombosis (DVT), however the prevalence and management guidelines are unclear in pediatrics. We reviewed the prevalence of MTS in children diagnosed with left iliofemoral DVT at our center, associated prothrombotic risk factors and their clinical outcomes.
Methods:
This is a retrospective audit of pediatric patients (&lt;18 years) with left iliofemoral DVT treated at the IWK Health Center from January 1 2008 to December 31 2020.
Results:
Twelve pediatric patients with left iliofemoral DVT were identified at our center and all patients except one had MRV/CTV during their course of anticoagulation to evaluate for MTS. MTS was diagnosed on imaging in 8 of the eleven evaluable patients with DVT and one patient had an incidental diagnosis of MTS with no DVT. The median age at diagnosis of MTS was 15 years (13-16), male:female ratio of 1:8. The overall prevalence rate was of MTS was 72.72% (8/11) in patients with left iliofemoral DVT. All patients with iliofemoral DVT and MTS had at least one other prothrombotic risk factor- initiation of estrogen containing contraceptive pills in the preceding 3 months of the DVT (n=5), inherited thrombophilia (n=2) and obesity (n=2).
All patients with MTS were referred to vascular surgery. Only one patient required catheter directed thrombolysis and stenting at presentation of DVT, the remaining 7 patients were managed with anticoagulation alone. Complete (n=1) or partial (n=7) resolution of the thrombus was seen in all 8 patients. Median duration of follow up was 3 years. Recurrent DVT was seen in 1 patient and two patients came off anticoagulation at 6 months post therapy. Post thrombotic syndrome was seen in 4 patients, mild in 3 and moderate in 1; as per modified Villalta score.
Conclusion:
We observed a high prevalence of MTS in patients with left iliofemoral DVT which may be due our screening approachwith upfront radiographic evaluation for MTS in all patients with left iliofemoral DVT. A second pro-thrombotic risk factor was identified in all patients, which raises the possibility of a "two hit theory" for the occurrence of DVT in MTS. Compared to published adult studies, majority of our pediatric patients were managed conservatively with anticoagulation therapy alone.

Disclosures
No relevant conflicts of interest to declare.
Analysis of the Tumor Microenvironment By Quantitative Immunohistochemistry Reveals Novel Predictors in Classic Hodgkin Lymphoma Treated with Anti-PD1 Therapy
Authors: Yu Hui , Ni Jiali , Sun Zhenchang , Zhang Mingzhi 
Published: November 2021

Abstract
Classical Hodgkin Lymphoma (cHL) is characterized histologically by the presence of neoplastic Hodgkin and Reed-Sternberg cells surrounded by mixed immune cells. Anti-PD-1 therapy is the principal treatment option for relapsed or refractory cHL. To reveal biomarkers for predicting the cHL patients' responses to immunotherapy, pathological tissues of twenty patients with cHL who have been treated with anti-PD1 therapy were collected. Tumor immune microenvironment was investigated by immunostaining and quantitative measurement of CD68 (for macrophages), CD8 (for cytotoxic T-cells), FoxP3 (for Treg), PD-1, PD-L1 and PD-L2 expression levels. The in situ hybridization for Epstein-Barr virus (EBER-ISH) were also performed. The results showed that the main immune indicators of the tumor microenvironment we had tested were independent of the histological subtypes. Patients who were positive for EBER-ISH had higher mean density of PD-L1 than those were negative for EBER-ISH. Single-factor analysis revealed the high expression of PD-L1 and positive EBER-ISH were associated with significantly increased 2-year PFS in cHL treated with anti-PD1, while CD68, CD8, FoxP3, PD-1 and PD-L2 were not. Therefore, we propose that PD-L1 and EBER-ISH may serve as novel predictors for the treatment outcomes of cHL patients with anti-PD1 therapy.

Disclosures
No relevant conflicts of interest to declare.
P-Selectin Deficiency in Sickle Cell Disease Mice Leads to Senescence Induced Organ Injury
Authors: Vats Ravi , Kaminski Tomasz W. , Gudapati Shweta , Brzoska Tomasz , Sundd Prithu , Pradhan-Sundd Tirthadipa 
Published: November 2021

Abstract
Sickle cell disease (SCD) is caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, vaso-occlusion, and premature hemolysis . Vaso-occlusion and hemolysis are the two predominant pathophysiologic events in SCD that contribute to chronic organ damage and acute systemic painful vaso-occlusive episode (VOE). Previous studies both in vivo and in vitro have confirmed the role of endothelial and platelet adhesion marker P-selectin in sickle cell vasoocclusive crisis. Moreover, a phase 2 study showed a significant reduction in painful vaso-occlusive episodes among SCD patients receiving the P-selectin-blocking antibody crizanlizumab . However, the long-term effect of crizanlizumab in SCD and associated organ injuries is not known. To understand the roles and regulation of P-selectin dependent vasoocclusion in SCD associated organ injuries, we have introduced the first SCD mice genetically lacking P-selectin in hematopoietic and nonhematopoietic compartments. Using this model (SS-Selp −/−) we have shown that P-selectin deficiency protects SCD mice from lung vaso-occlusion. Here we have used this model to study the liver injury in SCD. Using quantitative liver intravital imaging (qLIM) technique, we show that P-selectin deficiency protects SCD mice from liver vaso-occlusion. However, we found persistent hepatobiliary injury in SS-Selp −/−  mice. Mechanistically, we show that blocking P-selectin causes significant enrichment of circulating inflammatory cells however the organ specific recruitment of inflammatory cells was drastically impaired. Remarkably, impairment of organ specific recruitment of inflammatory cells exacerbated cellular senescence and injury in sickle mouse. We found significant enrichment of senescent markers including P21, P16 and phosphor P53 using both western blot and immunohistochemistry. Colocalization analysis confirmed that hepatocytes, cholangiocytes and macrophages were susceptible to senescence. Moreover, we also found impaired iron trafficking in in SS-Selp −/−  mice. Work is currently underway to understand how p-selectin loss promotes liver senescence and impaired iron trafficking in the liver. In summary, our results reveal a significant defect in iron homeostasis and exacerbated senescence in the liver of SS-Selp −/−  mice suggesting that increased liver senescence might impair iron homeostasis which then contribute to hepatobiliary injury in SCD. Thus, the efficacy of P-selectin inhibition in preventing SCD warrants further studies to determine whether long term inhibition of P-selectin would lead to end stage complications.

Disclosures
Sundd: Bayer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Research Funding.
Development and Validation of a Specific and Sensitive Anti-Drug Antibody Assay for Abelacimab That Avoids False Positive Results Due to Factor XI Interference
Authors: Cullen Connie , Cai Xiao-Yan , Dernek Cansu , Freedholm Debra 
Published: November 2021

Abstract
Abelacimab is a fully human IgG1 monoclonal antibody that has dual activity against the inactive zymogen Factor XI (FXI) and the activated Factor XI (FXIa). Clinical trials for this investigational product are ongoing.
As part of the initial assessment of abelacimab safety and efficacy, an anti-drug antibody (ADA) assay was validated and implemented in two single ascending dose studies conducted in the United States and Japan in healthy subjects. In those studies, ADA positive results were detected in up to 31.1% of subjects. There was no apparent impact on PK, PD, or development of immunogenicity-adverse events in study subjects who were ADA positive relative to those who were ADA negative in either study. Further, the rates of ADA positive subjects seemed inconsistent with a single administration of a fully human IgG1 monoclonal antibody therapeutic. Given the homodimeric structure of FXI, it appeared that the ADA assay was returning false positive results due to cross-linking through FXI. To address this issue, a novel ADA assay, following the 3-tiered approach of screening, confirmation, and titer determination was developed and validated. The assay was shown to be sensitive, specific, and did not show false positive interference by FXI. Two subsequent clinical trials (ANT-003 A randomized, subject- and investigator-blinded, placebo-controlled study conducted in healthy subjects and in obese, but otherwise healthy, subjects aged 18 to 60 years of age and ANT-004 A randomized, subject- and investigator-blinded, placebo-controlled, multiple ascending dose study in patients with atrial fibrillation (AF) or atrial flutter aged 18 to 85 years old with a CHA 2DS 2-VASc risk score of 0-1 for men and 1-2 for women and in whom the use of an anticoagulant for stroke prevention was not planned for the duration of the trial) showed no treatment-emergent ADA responses from either trial. The screen positive rate from the two studies was approximately 5% with no screen positive samples confirmed as positive indicating that the new assay format successfully addressed the false positive issue, and that the sensitivity was appropriately set to achieve the FDA-recommended 5% false positive rate for ADA assays.

Disclosures
Cullen: Anthos Therapeutics, Inc: Consultancy. Freedholm: Anthos Therapeutics, Inc: Current Employment, Current holder of stock options in a privately-held company.
Genotype-Phenotype Relationship Among 1200 Unrelated White Patients with Inherited FVII Deficiency: A Three-Center Database Study
Authors: Halimeh Susan , Kenet Gili , Kuta Piotr , Shneyder Maria , Bajorat Tido , Nowak-Göttl Ulrike 
Published: November 2021

Abstract

Background: Congenital factor VII (FVII) deficiency is a rare bleeding disorder caused by mutations in F7 gene with autosomal recessive inheritance. A clinical heterogeneity with poor correlation with FVII:C levels has been described. Aim of this study was to identify genetic defects and to evaluate their relationships with clinical phenotype in a large cohort of 1228 white patients with FVII:C below the age-dependent cut-off %.
Methods: Probands with confirmed inherited factor VII deficiency were i) genotyped (Sanger method & multiplex ligation-dependent probe amplification [MLPA]) for F7 mutations including common polymorphic variants and were ii) classified according to clinical bleeding scores (BC). In addition, common thrombophilic variants and blood groups were determined. Results: Probands included asymptomatic subjects (referred for laboratory work up of recurrent prolonged prothrombin time; n=415; mean age 30 + 19 yrs.; female 52%) and patients who presented with mild, moderate or severe bleeding episodes (n=805; mean age 34 + 18 yrs.; female 70%). Bleeding symptoms included epistaxis, gum bleeding, GI bleeding, hematuria, postoperative and gynecologic hemorrhage. Median FVII activity (entire cohort) measured with clotting-based assays (ACL TOP 750 and/or BCS-XP) was 49% (range 5-78%) and the median ISTH BS recorded within a period of two years prior to work-up was 1(0-17). The latter was significantly higher in women compared with males (2 versus 1; p &lt; 0.001). The corresponding PBAC-Score prior to hormonal treatment was 163 (25-1200). Blood group 0 was present in 40.6% of cases. Known and novel mutations in the F7 gene, including coding regions, exon/intron boundaries and the promoter region, are found in 534 patients (44%) and common polymorphisms were detected in 666 subjects (95%). Logistic regression analysis adjusted for clinical and laboratory data (blood group, FVII activity, presence of F7 gene mutations and /or polymorphisms, thrombophilia status and further factor deficiencies) revealed that older age (increase per year) at referral (odds/95% CI: 1.01/1.007-1.025) and female gender (odds/95% CI: 3.25/2.35-4.50) in part explain differences in clinical bleeding phenotype associated with FVII deficiency.
Conclusion: Overall there is poor correlation between the FVII level and the bleeding phenotype. Older patients and females are more likely to have symptomatic disease as a result of gynecological or muco-cutaneous bleeding.

Disclosures
Kenet: Alnylam: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Opko Biologics: Research Funding; Pfizer: Consultancy, Research Funding; Shire: Research Funding; Novo Nordisk: Consultancy; Roche: Consultancy; Takeda: Consultancy.
A Novel Pathogenic Variant of G6PC3 Gene Presenting As Cyclic Neutropenia in a Pediatric Patient
Authors: Bruni Christian M , de la Rua Wendy , Sadre Sara Y , Nestor Jennifer M , Ahmed Rafat 
Published: November 2021

Abstract
Background: Cyclic neutropenia is a rare hematologic disorder affecting neutrophils. It is classified by recurrent neutropenia (typically every three weeks) with associated symptoms including fever, malaise, and recurrent mucosal and skin infections. Pathogenic variants of ELANE, the gene that encodes neutrophil elastase, are thought to cause these findings, however, other pathogenic variants of different genes have also been noted. The estimated frequency of cyclic neutropenia is 1/10 6 in the general population. It is most commonly diagnosed in children but may rarely be diagnosed in adulthood. There is no known increased prevalence in women as compared to men. Whole Exome Sequencing can be used for diagnosis when genetic concerns are present.
Objective: This case report aims to describe a novel pathogenic variant in a pediatric patient with cyclic neutropenia.
Design/Method: Single subject case report
Results: This is a single case report of a 7-year-old female with past medical history of cyclic neutropenia, anemia, recurrent skin and buccal infections, speech delay, and behavioral problems. The patient initially presented at age 1 with high fevers and skin infections and was found to have decreased neutrophil counts. Work up at that time was consistent with cyclic neutropenia. Bone marrow aspirate and biopsy performed at 1 and 7 years of age showed decreased neutrophil count with normal maturation without any evidence of MDS. Her peripheral blood for bone marrow failure evaluation was non-contributory. Due to persistent neutropenia, normal bone marrow findings, and being on weekly chronic G-CSF administration Whole Exome Sequencing was evaluated. Results of which showed a novel compound heterozygous pattern for two variant copies of the G6PC3 gene, with our patient inheriting a copy from each parent.
Discussion: The G6PC3 gene encodes the expressed glucose-6-phosphate enzyme which catalyzes the final step in glycogenolysis. It is hypothesized that this deficiency causes unregulated levels of glucose, resulting in increased stress of the endoplasmic reticulum leading to apoptosis of neutrophils. Pathogenic variants of G6PC3 cause autosomal recessive G6PC3 deficiency and this can be clinically characterized as severe congenital neutropenia. Classic G6PC3 deficiency includes severe congenital neutropenia as well as cardiovascular abnormalities, urogenital abnormalities, and pulmonary hypertension. This novel pathogenic variant is likely responsible for the cyclic neutropenia observed in our patient. G6PC3 variants are an important differential diagnosis in the work-up of other causes of neutropenia. Whole Exome Sequencing is a cost-effective method for diagnosis and a valuable tool in evaluation and management of complex hematologic disorders.

Disclosures
No relevant conflicts of interest to declare.
Erythropoiesis Stimulating Agents (ESAS) in Supportive Care of Low-Risk Myelodysplastic Syndromes: Recamds Registry FINAL Results
Authors: Cerchione Claudio , Alfinito Fiorella , Vitagliano Orsola , Soriente Ilaria , Danise Paolo , Cerciello Giuseppe , Pane Fabrizio , Martinelli Giovanni 
Published: November 2021

Abstract
Erythropoiesis stimulating agents (ESAs) are the frontline treatment in low-risk anemic MDS patients and an employment of this therapy in the earlier stage of the disease can delay the need for RBC transfusion, hypothetically by slowing the disease course. It's matter of debate whether the clinical response is a result of proliferation and maturation of the dysplastic clone or stimulation of residual normal erythropoiesis by ESAs.
Macrocytosis is one of the cytological hallmarks of dyserithropoiesis in MDS: an analysis of the erythropoietic response to ESAs therapy in a cohort of anemic non trasfusion-dependent MDS patients, enrolled in a retrospective register, RECAMDS, subgroup of Italian register, was performed.
183 patients, treated with standard-dose ESAs, have been retrospectively analyzed. Data analysis was performed, according to IWG 2006 criteria, at the baseline, after 3 and 6 months of continuous treatment, with a subanalysis of the patients according to WHO and R-IPSS risk stratification. ESAs were started at mean Hb concentration of 9.31 g/dl, mean serum EPO concentration: 51 mU/L, after a mean time from diagnosis of 6 months (r.1-118).
ORR was 83.6% (153/183), no difference among WHO and IPSS subgroups was found: 132/183 (72.1%) achieved response after 3 months of treatment, while other 21/183 (11.2%) after 6 months. 19 patients with stable disease
(non-responders, according to IWG criteria), in which treatment was continued, achieved response after 9 months. In the macrocytic-responders group 83.2% exhibits again macrocytosis after 3 months, while 16.8% become normocytic. In the normocytic-responders group 89.8% exhibits again normocytosis, while 10.2% become macrocytic: in these patients, after 3 months, there was a contemporary worsening in neutropenia and thrombocytopenia, with transfusion-dependence, regarded as first signs of progression of disease. Non-responders were 30/183 (16.3%): in the macrocytic non-responders group 89% exhibit again macrocytosis after 3 months, while 11% become normocytic; in the normocytic group 76% exhibits again macrocytosis, while 24% become normocytic.
These preliminary data can suggest that, in the majority of MDS patients responsive to ESAs, the increase of Hb concentration occurs mainly stimulating erythroid production in MDS clones; in the minority of patients probably it happens recruiting residual polyclonal erythropoiesis.
It is interesting to note that stimulating effects of ESAs last even when the expression of dysplasia progresses.
Figure 1 Figure 1.

Disclosures
Martinelli: Roche: Consultancy; Stemline Therapeutics: Consultancy; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy; Daichii Sankyo: Consultancy; Astellas: Consultancy, Speakers Bureau.
Identification of Pre-Gmps and Pre-Meps: Two Novel Types of Committed Progenitor Cells in Bone Marrow
Authors: Mack Ryan , Zhang Lei , Joshi Kanak , Liu Shanhui , Sellin Mark , Wei Wei , Breslin Peter , Zhang Jiwang 
Published: November 2021

Abstract
Elucidating the stepwise differentiation processes that leads from multipotent hematopoietic stem cells to mature effector cells is critical for understanding both normal and neoplastic hematopoiesis. Early studies suggested that common myeloid progenitors (CMPs) are oligo-lineage hematopoietic progenitors that produce all lineages of myeloid cells, including granulocytes, monocytes, erythrocytes and megakaryocytes. CMPs do so by first giving rise to megakaryocyte-erythroid progenitors (MEPs) and granulocyte-monocyte progenitors (GMPs), two types of bi-lineage progenitors. However, this concept was challenged by several recent studies where single cell techniques demonstrated that CMPs, GMPs and MEPs are highly heterogenic. The existence of lineage-restricted subsets within the CMP population leads to questions about whether erythroid and megakaryocytic lineage commitment is actually initiated at the multipotent progenitor or CMP stage. During the past 15 years, several lineage-restricted subsets of progenitors have been separated out from CMP population, including monocyte-dendritic progenitors, megakaryocyte progenitors, and erythroid progenitors based on expression of CD115/Flt3, CD41/CD150, and CD105/CD150, respectively. However, the remaining CMP population is still highly heterogenic. Thus, further separation of functional subsets within the CMP compartment is required.
By screening cell surface markers that can further separate CMPs, we have identified CD27 as a reliable marker to separate all megakaryocyte/erythrocyte-committed progenitors from granulocyte/monocyte-committed progenitors. In addition, we found that CD62L is only expressed on granulocyte/monocyte-committed progenitors. CD27 and CD62L co-staining can separate CMP into CD27 +CD62L +, CD27 +CD62L - and CD27 -CD62L - subsets. Biology and morphology study showed that CD27 +CD62L - cells are closely associated with GMPs, whereas CD27 -CD62L - cells are closely associated with MEPs. In vitro culture and in vivo transplantation functional studies demonstrated that 1) CD27 +CD62L + cells are pre-GMPs that give rise to FcGRII/III + GMPs and only produce granulocytes and monocytes; 2) CD27 -CD62L - cells are pre-MEPs that give rise to MEPs and primarily produce erythrocytes and megakaryocytes with minimal contribution to granulocytes and monocytes; 3) CD27 +CD62L - subset enriches cells with genuine CMP potential capable of producing GMPs, MEPs, and subsequent progeny. Taken together, we have identified two novel populations of committed progenitors that serve as intermediates between CMP-GMP and CMP-MEP commitment pathways. Identification of pre-GMPs and pre-MEPs fills in the gap between CMPs-GMPs and CMPs-MEPs, supporting the hierarchal relationship of myeloid lineage differentiation.

Disclosures
No relevant conflicts of interest to declare.