bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain Magnetic Resonance Imaging and Angiography Findings in Ugandan Children with Sickle Cell Anemia; A Cross Sectional Study
Authors: Idro Richard , Green Nancy S. , Munube Deogratias , Buluma Linda Rosset , Kebirungi Bridget , Opoka Robert , Bangirana Paul , Mupere Ezekiel , Kayongo Edward , Sekibira Rogers , Kasirye Philip , Lubowa Samson K. , Kawooya Michael , LaRussa Phillip , Minja Frank 
Published: October 2019

Abstract
Sickle Cell Anemia (SCA) is a leading cause of childhood stroke in sub-Saharan Africa and sickle cell brain vasculopathy manifests either as overt stroke or clinically "silent infarcts". This study aimed to describe brain abnormalities seen on magnetic resonance imaging in Ugandan SCA children. Our hypothesis was that multi-model abnormalities would be associated with cerebrovasculopathy found on MRI/MRA.
Methods
As part of a larger study to determine the burden and spectrum of neurological and cognitive impairments in SCA children in Uganda, we selected 81 children ages 1-12 years with HbSS, a sample enriched for possible brain pathology from Mulago hospital SCA clinic out of a random sample of 265 stable children. None was receiving hydroxyurea. All had detailed clinical history, and physical, neurological and cognitive testing, trans-cranial Doppler (TCD) cerebral blood flow velocity determination and non-contrasted brain MRI/MRA using a 1.5 Tesla scanner. Cognitive testing was performed using age-specific tools validated for Ugandan children.
Results
Of the 81 participants imaged, 61 had one or more of history of stroke, an abnormal neurological exam, cognitive impairment or abnormal TCD, while 20 had normal test results. MR abnormalities were seen in 35/61 (63.9%) participants with probable brain pathology and in 4/20 (20.0%) without any probable brain pathology. They included different structural abnormalities seen in all brain regions ranging from only T2 weighted hyper-intensities, white matter lacuna infarction to bilateral ischemic and multi-focal cerebral infarcts with associated compensatory hydrocephalus. MRA abnormalities ranged from cerebral microangiopathy to multiple stenosis and occlusions of major arteries, including moya-moya in 4 subjects. Severe vessel obstructions were also seen in multiple young children <36 months.
Conclusions
Brain injury in Uganda children with SCA begins early in childhood and becomes a common finding during later childhood. Early screening for stroke and intervention therapy is warranted to prevent sickle brain vasculopathy initiated early after diagnosis. The risk factors for such early brain injury should be investigated.

Disclosures
No relevant conflicts of interest to declare.
MLL-USP2: An Underestimated New Entity of MLL-Rearranged Leukemia Identified By NGS Analysis
Authors: Meyer Claus , Lopes Bruno , Caye-Eude Aurélie , Cavé Hélène , Arfeuille Chloé , Sutton Rosemary , Venn Nicola , Larghero Patrizia , Oh Seung Hwan , Tsaur Grigory , Zaliova Marketa , Zuna Jan , Juvonen Vesa , Panzer-Grümayer Renate , Fazio Grazia , Cazzaniga Giovanni , Emerenciano Mariana , Marschalek Rolf 
Published: October 2019

Abstract
Chromosomal rearrangements of the MLL gene are responsible for 5-10% of all acute leukemias, biphenotypic leukemias and myelodysplastic syndromes. The large number of known MLL fusions (>80) renders a precise diagnosis a demanding task. Even though all MLL rearrangements are associated with high-risk acute leukemia, the outcome (poor or very poor) is influenced by the partner gene. The applied diagnostic methods (LDI-PCR and multiplex PCR) allows the identification of MLL fusion genes at the nucleotide level, providing important information on the genetics of leukemia patients, and patient-specific biomarkers. These biomarkers are used for monitoring of minimal residual disease in acute leukemia patients during and after therapy. Thus, the identification of MLL gene fusions is necessary for rapid clinical decisions to determine the best therapy regimen.
We have developed a customized NGS panel for MLL diagnostics to utilize state of the art technology at DCAL. With this new tool, the whole MLL gene is analyzed in contrast to the LDI-PCR where only the main MLL breakpoint cluster region (BCR-1) is covered. The first results of the NGS analysis of 84 patients identified MLL breakpoints located outside the main BCR-1 of MLL. Furthermore, a novel MLL partner gene USP2 was identified in 16 patients. All MLL-USP2 positive patients had a breakpoint located outside BCR-1 and within a newly defined breakpoint cluster region BCR-2. The BCR-2 site was also used in 2 other patients with MLL-AFF1 and one patient with MLL-MLLT3.
These findings reveal USP2 as a new entity for MLL rearrangements affecting indifferently children aged 3 months to 10 years old (mean 30 months) with no gender bias (M/F=1.3). Interestingly, only 5/16 affected children were below 1 year of age at diagnosis and thus treated according to the Interfant trial. Clinical presentation as well as outcome associated with this new entity deserves further investigation to define whether those patients should be allocated, as other MLL-rearranged ones, in high-risk treatment groups. More MLL patients should also be analyzed to get a better idea of the frequency of breakpoints within BCR-2, especially the frequency of MLL-USP2 fusions. Indeed, standard FISH analysis and CGH array do not permit reliable detection of this fusion, explaining why they remained undetected so far. The biology of this novel MLL rearrangement also deserves further investigation, considering that USP2 is the only MLL partner fused exclusively to BCR-2.

Disclosures
No relevant conflicts of interest to declare.
Health-Related Quality of Life (HRQL) Trajectories during Treatment for Advanced Stage Pediatric Hodgkin Lymphoma (HL)
Authors: Parsons Susan K , Rodday Angie Mae , Bush Rizvan , Pei Qinglin , Waheed Anem , Keller Frank G , Kelly Kara M. , Henderson Tara O. , Castellino Sharon M. 
Published: October 2019

Abstract
Introduction: The treatment of advanced stage HL typically includes dose-dense chemotherapy with or without involved field radiation. However, little is known about the HRQL of pediatric patients during initial treatment. We describe the HRQL trajectory over time by child and parent-proxy rater and examine baseline patient characteristics associated with the trajectory.
Methods: Children and adolescents, ages 5-17.9 years newly diagnosed with advanced stage HL and enrolled in Children's Oncology Group AHOD 1331, and their parents were co-enrolled in an embedded study to assess HRQL (n=310). Children (age ≥11 years) and parent proxies (of children 5-17.9 years) reported on the child's global HRQL using the Child Health Rating Inventories (CHRIs) at four times: (1) baseline, (2) cycle 2, (3) cycle 5, and (4) end of therapy, approximately 6-7 months following initial diagnosis. The 7-item CHRIs-Global yields scores that range from 0-100, with higher scores indicating better HRQL. A repeated measures linear regression model was fit with categorical time (reference, baseline), rater, child race, ethnicity, and continuous age. An interaction of rater and time was tested and predicted means were plotted.
Results: 97% of age-eligible patients and parents completed baseline HRQL assessments with 93% completing planned follow-ups. Median child age was 15.5 years (q1=5.4, q3=18.9) and 50.3% were female. Most children were white (76.1%) and non-Hispanic (82.6%). There was no significant interaction between rater and time (Figure), so this was subsequently excluded from the model. Scores improved slightly at time 2 (β=2.5, 95%CI=0.3, 4.6) and 3 (β=2.8, 95%CI=0.3, 5.3) compared to baseline; larger improvements were seen by time 4 (β=10.6, 95%CI=7.9, 13.3) after completion of therapy. Children reported higher HRQL than their parent proxies (β=5.6, 95%CI=3.9, 7.2), males had higher HRQL than females (β=4.6, 95%CI=1.0, 8.3), and older age was associated with lower HRQL (β=-0.8, 95%CI=-1.5, -0.1). There was no significant effect of race or ethnicity.
Conclusions: Completion rates of HRQL were high across all time periods and for both raters. HRQL, impaired at baseline, likely from the disease process, improved slightly during treatment, with larger improvements by the end of initial therapy. Future research will examine how clinical and treatment factors impact the HRQL trajectory.
Figure. Figure.

Disclosures
Parsons: Seattle Genetics: Research Funding. Rodday:Seattle Genetics: Research Funding. Henderson:Seattle Genetics: Research Funding.
Hypercalcemia- Leukocytosis Syndrome: A Rare Ominous Indicator in Lung Cancer
Authors: Hanson Taylor , Patel Ravi , Sahu Nitasa , Ayaz Zain , Caler Julie , Jones Kirk , Jain Rohit 
Published: October 2019

Abstract
Introduction:
Paraneoplastic syndromes are signs and symptoms that occur in association with malignancy at sites distant from the primary tumor or metastases. They occur in approximately 10% of patients with lung cancer (1).
Case:
A 59-year-old male with a history of tobacco abuse, COPD, and Stage IV Lung Adenosquamous cancer with brain metastases status post chemotherapy presented with weakness and lethargy. Patient was normotensive and on room air. Clinical exam was significant for confusion with noted chronic cachexia. Labs most prominent were a WBC count of 46.8 (16.3 1mo prior, 44.6 3wks prior) , Cr of 1.9, Ca of 11.9 , and Lactic acid of 3.7. Imaging was consistent with an increase in his RUL cavitary lesion with pleural based lesions and 11 metastatic deposits throughout the brain. He was admitted and started on aggressive intravenous fluids. Furthermore, infectious workup was initiated and empiric antibiotics administered for possible pneumonia. By day 3 of admission his creatinine, calcium, and lactic acid normalized but his wbc continued to trend up to 98.6 despite negative infectious workup. His severe metastatic disease burden along with his failure to thrive carried a poor prognosis. Subsequently, a family meeting was held and he was transitioned to comfort measures. Patient passed away shortly thereafter.
Discussion:
The case clearly demonstrates poor prognostic indicators with hypercalcemia and severe leukocytosis in the setting of end stage lung adenosquamous carcinoma. Classically, paraneoplastic hypercalcemia is associated with PTHrP production in Squamous Cell carcinoma. Overall incidence of hypercalcemia in lung cancer ranges from to 8%-12% with median survival time (MST) of 3.8 months (1,2).Paraneoplastic Leukocytosis meanwhile is most often associated with adenocarcinoma (42%) and squamous cell carcinoma (36%) with incidence ranging between 16 and 30% and MST of 1.9 months (1,2). Nonetheless, the combination of these two known as Hypercalcemia-Leukocytosis syndrome has been identified an independent clinical entity with an even shorter median survival time in comparison with leukocytosis or hypercalcemia alone of 1.5 months (2). The incidence of this was studied to be 0.5% over a 10 year interval (2). Given this rare occurrence, it is prudent for clinicians to recognize this clinical syndrome and the very poor prognosis it bears .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127595/
G.R. Mundy, K.J. Ibbotson, S.M. D'Souza, E.L.Simpson, J.W. Jacobs, T.J. MartinThe hypercalcemia of cancer. Clinical implications and pathogenic mechanismsN Engl J Med, 310 (1984), pp. 1718-1727
.https://www.sciencedirect.com/science/article/pii/S0169500203004549?via%3Dihub Hypercalcemia-leukocytosis syndrome associated with lung cancer

Disclosures
No relevant conflicts of interest to declare.
Regulatory T Cells Control PF4/Heparin Antibody Production in Mice
Authors: Zheng Yongwei , Zhu Wen , Haribhai Dipica , Williams Calvin B. , Aster Richard H. , Wen Renren , Wang Demin 
Published: October 2019

Abstract
Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that can cause fatal arterial or venous thrombosis/thromboembolism. Immune complexes consisting of heparin, platelet factor 4 (PF4) and PF4/heparin-reactive antibodies are central to the pathogenesis of HIT. Regulatory T (Treg) cells are a subpopulation of CD4 T cells that modulate immune system by suppressing or down-regulating immune response and play an important role in immune homeostasis. However, the role of Treg cells in controlling PF4/heparin-specific antibody production is not known. Here we found that FoxP3-deficient mice, which have no functional Treg cells, spontaneously generated PF4/heparin-specific antibodies as early as three weeks after birth. Similarly, following transplantation with bone marrow cells from FoxP3-deficient mice, Rag1-deficient mice that have no endogenous B cells and T cells spontaneously produced PF4/heparin-specific antibodies. In contrast, Rag1-deficient mice that received wild-type bone marrow cells failed to produce PF4/heparin-specific antibodies. In addition, adoptively transferred Treg cells prevented spontaneous production of PF4/heparin-specific antibodies in FoxP3-deficient mice. Adoptively transferred Treg cells, not conventional CD4 T cells, also suppressed PF4/heparin complex-induced production of PF4/heparin-specific IgGs in wild-type mice. Treg cells suppress immune response mainly through releasing anti-inflammatory cytokines, such as interleukin-10 (IL-10). Deficiency of IL-10 led to spontaneous production of PF4/heparin-specific antibodies in mice. Moreover, BM chimeric mice with CD4 T cell-specific deletion of IL-10 increased PF4/heparin-specific IgG production following PF4/heparin complex challenge. Taken together, these findings demonstrate that Treg cells play an important role in suppressing PF4/heparin-specific antibody production in mice.

Disclosures
Haribhai: AbbVie Inc.: Employment. Aster:BloodCenter of Wisconsin: Patents & Royalties.
Diverse Bloodstream Pathogens Are Identified in the Gut Microbiome Prior to Infection in Hematopoietic Stem Cell Transplantation Recipients
Authors: Andermann Tessa M , Tamburini Fiona , Tkachenko Ekaterina , Senchyna Fiona , Banaei Niaz , Bhatt Ami S. 
Published: October 2019

Abstract
Recipients of hematopoietic stem cell transplantion (HCT) are at high risk for bloodstream infections (BSI); culture-based and marker gene sequencing approaches have been previously applied to interrogate the intestine as a reservoir of these pathogens. Identifying the source of bloodstream infections can impact infection control and prevention practices such as removing central venous catheters and placing patients in isolation. To evaluate the genomic concordance of bloodstream pathogens and bacterial strains within the intestinal microbiome, we developed StrainSifter (Figure 1), a streamlined bioinformatic pipeline using whole genome shotgun sequencing to compare nucleotide variation between bacterial isolate strains and metagenomes. We applied StrainSifter to bloodstream isolates and stool metagenome samples from a cohort of 30 HCT recipients with bloodstream infections at a single academic center. StrainSifter is designed to 1) identify single nucleotide variants (SNVs) between isolate and metagenomic short reads aligned to assembled draft genomes using stringent alignment, coverage, and variant frequency criteria, and 2) output both phylogenetic trees and SNV counts for clinical and epidemiologic strain typing and comparison. Using StrainSifter, we identified enteric BSI isolates - including Enterococcus faecium, Klebsiella pneumoniae, Escherichia coli, and Streptococcus mitis - that were identical or nearly identical with those in the gut microbiota. We also identified highly concordant strains of Staphylococcus epidermidis and Pseudomonas aeruginosa between the bloodstream and gut microbiome, an unexpected finding for typically non-enteric organisms. Although intestinal domination by pathogenic bacteria preceded BSI with E. faecium and E. coli as previous studies have demonstrated, we found significant heterogeneity in the relative abundance of pathogens prior to infection for other bacteria. These findings demonstrate the utility of StrainSifter in strain matching between isolate and metagenomic sequencing data, and provide a more precise and comprehensive investigation of the intestine as a potential reservoir of diverse pathogens capable of causing bloodstream infections in HCT recipients. These findings may have implications for the tracking and prevention of BSI previously classified as central-line associated bloodstream infections.

Disclosures
No relevant conflicts of interest to declare.
Development of Potency Assays for Quality Assessment of an Advanced Therapy Medicinal Product: Mitomycin C-Induced Peripheral Blood Mononuclear Cell (MIC) Product
Authors: NI Ming , Wang Lei , Kleist Christian , Terness Peter , Opelz Gerhard , Morath Christian , Schaier Matthias , Müller-Tidow Carsten , Zeier Martin , Schmitt Michael , Schmitt Anita 
Published: October 2019

Abstract

Introduction:
Quality assessment in terms of product specificity and product potency is obligatory and strictly required by EMA and FDA to provide a platform for analysis of product comparability, stability and compatibility, and for clinical development to help predict product clinical efficacy. Mitomycin-treated donor peripheral blood mononuclear cells (MICs) could induce donor-specific tolerance via generation of recipient-derived tolerogenic dendritic cells (tDCs). To evaluate the immunomodulating capacity of the MIC product, we assessed the phenotype of tDCs, the immunosuppressive capacity of tDCs on allo-reactive CD4+ and CD8+ T cells as well as on CMV-specific CD8+ T cells.
Methods:
For standardization of the potency assay, third-party PBMCs positive for HLA-A2 and anti-CMV IgG were used. Immature DCs (iDCs) were generated 3 days before MIC production. MICs were generated under Good Manufacturing Practice (GMP) conditions. Each batch of MICs was introduced to iDCs at different ratios (1:0, 1:1, 1:10, 1:20) for a two-hour interaction followed by adding a DC maturation cocktail for overnight co-culture. Thereafter tDCs were purified by magnetic negative separation. The morphology of tDCs was observed by microscopy. The expression of HLA-DR, CD80, CD83, CD86 and CD103 was analyzed by flow cytometry. The inhibitory capacity on allo-reactive T cells and virus specific T cells was determined by mixed lymphocyte reaction (MLR) assay, by ELISpot assay and by Tetramer staining assay after one week of expansion in mixed lymphocyte peptide culture (MLPC).
Results:
In light microscopy (magnification: x 40), tDCs showed a relative smooth membrane surface. While the conventional mDCs were significantly larger in size with rough surface, richer ruffles on the cell membrane, and bigger, longer protrusions or pseudopodia. MIC products could inhibit the expression of costimulatory molecules on tDCs with an inhibition of 41% of CD80, 27% of CD83 and 23% of CD86. In parallel, the inhibitory marker CD103 was up-regulated about 65% on tDCs. Functionally, both tDCs and MICs could inhibit the IFN-γ secretion by CMV-specific CD8+ T cells, respectively. Moreover, the proliferation of allo-reactive T cells and CMV-specific T cells could be inhibited by tDCs and MICs.
Conclusions:
In summary, the potency assays, including the measurement of physicochemical parameters, the morphology and marker expression of tDCs, as well as the biologic characterization, the functionally immunosuppressive capacity of tDCs, comprise valuable parameters for the evaluation of clinically used advanced therapeutic cellular products.

Disclosures
No relevant conflicts of interest to declare.
Poor Outcome of CRLF2 Rearranged Philadelphia Negative Acute Lymphoblastic Leukemia Adults Patients
Authors: Elnahass Yasser H , Fahmy Omar A , Samra Mohamed Abdel Mooti , Elrefaey Fatma A , Bokhary Mahmoud T , Elsherif Haitham , Afifi Hazem H , Elkomy Abdallah S , Hola Mona , Mahmoud Hossam K 
Published: October 2019

Abstract
BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph'-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1 positive ALL and a poor outcome. Rearrangements of cytokine receptor like factor 2 (CRLF2) are identified in approximately 50% of Ph'-like and 10% of B-other ALL patients.
AIM: To identify the incidence of CRLF2 rearrangements and the frequency of relapse in a cohort of B-other Precursor B-ALL adults Egyptian patients who were treated with conventional therapy at National Cancer Institute, Cairo University.
METHODS: The routine diagnostic work-up at diagnosis included Bone marrow aspiration, immunophenotyping, karyotyping, fluorescent in situ hybridization (FISH) for BCR-ABL1 and KMT2A (MLL) and CRLF2 rearrangements (IGH-CRLF2 or P2RY8-CRLF2), and molecular analyses of BCR-ABL1 translocations. Patients within the age group 18-25 years received Total XV protocol while patients >25 years received Hoelzer's protocol.
RESULTS: Forty patients were included (22 males, 18 females). Median age at diagnosis was 25 years (18 -65). Median TLC was 14.9 x109/L (1.1 - 201), median Hb was 9.9 gm/dl (5-12.9), median platelet count was 47 x 109/L (19-359) and median BM blasts count was 90% (30-100). CRLF2 rearrangement was detected in 4/40 (10%) patients. All CRLF2 positive patients (100%) relapsed at 6 months vs. 11/36 (30%) CRLF2 negative (p<0.001). At 6 months follow up, disease free survival (DFS) was 70% in CRLF2 negative patients vs. 0% in CRLF2 rearranged (p=0.04). At 1 year follow up, overall survival (OS) was 30 (75%) for CRLF2 negative vs. 0 (0%) for CRLF2 positive patients (p=0.01).
CONCLUSION: CRLF2 rearrangements constitute a high risk independent prognostic factor in adult precursor B-ALL patients denoting a poor outcome and should be studied in ALL Ph' negative patients. Additional TKI therapy should be included for this category of patients in our protocols to improve outcome.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.