tbuckley/cabot-search huggingface dataset:
PF537 THE STAT SIGNALING BIOSIGNATURE OF CD4+ T CELL SUBSETS REFLECT THE IMMUNOGENICITY OF HIGH‐RISK MDS AND PREDICT AZACYTIDINE TREATMENT OUTCOME
Authors: E. Lamprianidou, C. Kordella, E. Zoulia, M. Papoutselis, Z. Bezirgiannidou, G. Vrachiolias, E. Spanoudakis, T. Vassilakopoulos, A. Galanopoulos, S. Papageorgiou, V. Pappa, S. Vakalopoulou, V. Garipidou, M. Papaioannou, E. Hatjiharissi, P. Diamantopoulos, N.‐A. Viniou, I. Kotsianidis
Journal: HemaSphere (2019)

Background: Azacytidine (AZA) is the mainstream treatment in high‐risk Myelodysplastic Syndromes (MDS), but the exact mechanism of action and resistance is largely unknown. AZA potentially acts, at least partially, by upregulating the antitumor immune response, but literature reports are still contradictory. Similarly, CD4+ T cells appear to play a critical role in the antitumor immune response in MDS, even though the exact mechanism remains unclear. Aims: As STAT proteins are key regulators of both physiological and pathological polarization and differentiation of CD4+cells, we investigated the STAT signaling profile of high‐risk MDS patients during AZA treatment and its correlations with clinical and biological parameters. Methods: Peripheral blood mononuclear cells were isolated before the initiation of AZA from 67 high‐risk MDS patients and 13 age‐matched healthy donors. We applied phosphospecific flow cytometry to measure both basal and potentiated levels of pSTAT1, pSTAT3 and pSTAT5. A signaling profile (SP) was constracted for T conventional (Tconv) and T regulatory cells (Tregs) and their functional subsets: PD1 + cells, central memory (T CM ), naïve (T N ), effector memory (T EM ) and terminal effector memory (T EMRA ) cells. We further characterized the functional and polarization state of T cells by staining with Perforin, IFNg, IL4, IL17 and Helios. Results: pSTAT signaling profile of Tconv cells revealed three signaling clusters (SC). SC#2 was characterized by higher potentiated responses of pSTAT3 after IL‐6 stimulation (IL‐6/pSTAT3) and was enriched in patients with longer median‐overall survival (mOS, p = 0.047, figure 1A). The SP of both PD1 + Tconv and T EM revealed three SCs. In both cases patients with shorter median event free survival (mEFS) segregated in SCs with downregulated potentiated responses (p = 0.055 and p = 0.04 respectively). The pretreatment SP of Tregs was also associated with mEFS though without reaching significance (p = 0.068), whereas the SP of PD1 + Tregs separated patients with intermediate potentiated responses which showed longer OS (p = 0.023). Summary/Conclusion: Collectively, are results reveal for the first time the clinically significant heterogeneity of CD4+ T cell subsets and their diverse role in the antitumor immunity in MDS. Moreover, the beneficial effect of the activation of IL‐6/pSTAT3 pathway in CD4conv cells comes in line with current data in CAR‐T cells and further suggests that the STAT signaling biosignature on CD4 + cells may represent a response biomarker to AZA and a therapeutic target for high‐risk MDS. image
PB1818 CLINICAL FEATURES AND PROGNOSTIC FACTORS OF PRIMARY TESTICULAR DIFFUSE LARGE B‐CELL LYMPHOMA (PT‐DLBCL): EXPERIENCE OF 35 PATIENTS FROM FUSCC
Authors: Y.‐Z. Liu, P. Luo, Q.‐L. Zhang, K. Xue, J.‐N. Cao, X.‐N. Hong, F.‐F. Lv
Journal: HemaSphere (2019)

Background: Primary testicular lymphoma (PTL) is a rare extranodal lymphoma, with diffuse large B cell lymphoma (DLBCL) as the predominant histological subtype. Factors that contribute to precise stratification and guide the treatment of this disease are still not well understood. Aims: This study aims to identify clinical features and prognostic factors of PT‐DLBCL patients. Methods: A total of 35 patients were included in this retrospective study who were diagnosed as PT‐DLBCL and treated in Shanghai Cancer Center, China from March 2007 to May 2018. The demographic details, clinico‐pathologic characteristics of the patients were summarized. Kaplan‐Meier survival curves were constructed for survival analyses. Results: The median age of the patients was 59 (range 36‐76) years old. All patients presented with testicular swelling, two had the presence of B symptoms. 33(94%) patients underwent orchiectomy. All patients received combination chemotherapy for 4‐6 cycles and central nervous system prophylaxis consisting of MTX for 4‐6 doses. 87% (28/32) patients achieved complete response, and ORR was 96.9% (31/32). 21 patients continued contralateral testis irradiation in our hospital. The median follow‐up time was 980 days (range 156‐2976 days). Median overall survival (OS) was not reached at the time of reporting. The estimated 5‐year PFS and OS rate were 67% and 84%. None of the 21 patients who received radiotherapy to the contralateral testis experienced relapse in that location in our study. All three patients who suffered from central nervous system relapse had the germinal center B‐cell subtype of DLBCL. Kaplan‐Meier analysis showed that PT‐DLBCL patients characterized by late stage (Stage III/IV) ( P = 0.003), higher IPI score (IPI≥ 2) ( P = 0.001) had a shorter progression free survival (PFS). More importantly, we found that patients with the ratio of the LDH level in CSF to the serum LDH level more than 6.5 suffered from a worse PFS ( P = 0.032). Summary/Conclusion: Our work revealed that staging III/IV, IPI score ≥ 2 were adverse factors of PT‐DLBCL patients’ PFS. Significantly, the PT‐DLBCL patients with ratio of LDH level in CSF to the serum LDH level &gt; 6.5 were indicated to have a worse PFS.
S906 PRECLINICAL EVALUATION OF THE PRESERVATION OF RED BLOOD CELL CONCENTRATES IN HYPOXIA BY HYPOXIC STORAGE TECHNOLOGY FOR TRANSFUSION IN SICKLE CELL DISEASE.
Authors: L. Bencheikh, K.‐A. Nguyen, P. Chadebech, L. Kiger, G. Bodivit, A. Jouard, S. Pakdaman, S. Adypagavane, E. Audureau, K. Tebbakha, N. Hebert, F. Pirenne, S. Sowemimo‐Coker, A. Dunham, P. Bartolucci
Journal: HemaSphere (2019)

Background: Sickle cell disease (SCD) is the most common genetic disease, due to a mutation of the sixth amino acid of gene coding for the Hemoglobin (Hb) beta chain. The mutated Hb, called HbS, is able to polymerize which entails red blood cell (RBC) sickling, leading to chronic hemolysis and painful vaso‐occlusive crisis. Transfusion exchange is one of the therapeutic strategies used for this pathology since it allows the replacement of sickle RBCs. The quality of the transfused RBCs is essential, both to improve the transfusion yield but also to limit the pathological interactions between RBCs and endothelial cells, damaged by hemolysis. RBC concentrates can be stored up to 42 days at 4°c, however, during their hypothermic storage, the quality of RBCs decreases, mainly because of oxidative damage. Hypoxic storage technology helps to keep RBC in hypoxia, improving the concentration of ATP, 2‐3DPG, hemolysis and deformability of RBCs. Aims: The purpose of our study was to compare the quality of conventionally conserved RBCs with those conserved with hypoxic storage technology. Methods: We assessed several parameters including sickle RBC flow adhesion to HUVEC (human umbilical vein endothelial cells), previously exposed to hemolysate, to mimic endothelial damage present in patients. We also evaluated hypoxic RBC senescence parameters by flow cytometry. In that purpose, we measured intracellular calcium and reactive oxygen species (ROS) concentration as well as phosphatidylserine exposure by annexin V staining in hypoxic RBCs and control RBCs, after incubation 24 h in plasma from healthy donors and SCD patients. RBC adherence on thrombospondin (TSP) under flow was also quantified, since RBC adhesion to TSP was shown to increase during storage and since TSP concentration is elevated in sickle cell disease patients during acute chest syndrome (ACS) or at risk of ACS. In addition, we assessed hemolysis in the bags by measuring free hemoglobin concentration in the supernatant by spectroscopy. Results: We found a reduction in the concentration of free Hb (produced by RBC lysis) in hypoxic storage bag, a decrease in RBC senescence (ROS and calcium intracellular concentrations) in hypoxic RBCs and a reduced adherence to thrombospondin when hypoxic RBCs are incubated during 24 h in plasma from healthy donors or SCD patients. There was no difference of RBC adhesion to endothelial cells. Summary/Conclusion: These results suggest that hypoxic storage technology meets the safety criteria for transfusion in SCD patients and may provide significant clinical benefits.
Association of early molecular response to nilotinib with probability of cytogenetic response in chronic myeloid leukemia patients (pts) who fail imatinib.
Authors: S. Branford, G. Martinelli, G. Saglio, D. Kim, Y. Shou, J. Reynolds, R. C. Woodman, H. Kantarjian, A. Hochhaus, J. P. Radich
Journal: Journal of Clinical Oncology (2010)

6513 Background: Response dynamics in pts treated with nilotinib for imatinib failure may be different than imatinib in front line. Many pts treated with nilotinib in the second line achieved cytogenetic responses early (median time to MCyR and CCyR of 2.8 mo and 3.3 mo). A previous landmark analysis demonstrated BCR-ABL% (IS) at 3 months (mo) on nilotinib predicted achievement of subsequent cytogenetic response. Here, we investigated whether early molecular response before 3 mo was associated with subsequent cytogenetic response. Methods: CML-CP pts (N = 321) with imatinib resistance or intolerance were grouped by 1 mo BCR-ABL% (IS) and landmark analyses were performed to evaluate probability of cytogenetic response with a minimum follow-up of 24 mo. Results: Early molecular response of BCR-ABL% (IS) ≤ 10 occurred in 19% of pts who received nilotinib. Pts with BCR-ABL% (IS) >1 – ≤10 (n = 37) had higher probability of MCyR by 12 mo (84%) compared with pts with BCR-ABL% (IS) >10 (55%) (n = 202). Pts with BCR-ABL% (IS) >1 – ≤10 also had higher probability of achieving CCyR by 12 mo (72%) compared with pts with BCR-ABL% (IS) >10 (38%). Similar trends in the probability of achieving MCyR and CCyR on nilotinib by 12 mo were observed for pts when analyzed by the presence or absence of baseline (BL) mutations (Table). Similar results were seen when analyzing the probability of cytogenetic response by 24 mo. Estimated MCyR and CCyR by 12 mo by BCR-ABL% (IS) at 1 mo on nilotinib therap. Conclusions: Molecular response to nilotinib at 1 mo was associated with cytogenetic responses by 12 and 24 mo, even in the presence of BL mutations. While treatment decisions based on 1 mo BCR-ABL% (IS) are not recommended, these data indicate that reductions in BCR-ABL transcripts may occur before 3 mo on nilotinib and are associated with subsequent cytogenetic responses in these pts. BCR-ABL% (IS) at 1 Mo > 1 – ≤ 10 > 10 p value (log-rank test) MCyR by 12 Mo All pts, n = 239 84% 55% <0.0001 Pts with BL mutations, n = 95 76% 42% <0.0001 Pts without BL mutations, n = 121 89% 64% <0.0001 CCyR by 12 Mo All pts, n = 241 72% 38% <0.0001 Pts with BL mutations, n = 96 58% 25% 0.0022 Pts without BL mutations, n = 122 89% 45% <0.0001 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, MSD, Novartis, Wyeth Novartis Bristol-Myers Squibb, Celgene, MSD, Novartis Bristol-Myers Squibb, Genzyme, Novartis, Wyeth
THU0270 THE BURDEN OF CHRONIC KIDNEY DISEASE IN SYSTEMIC LUPUS ERYTHEMATOSUS: A NATIONWIDE EPIDEMIOLOGIC STUDY
Authors: Arthur Mageau, Jean-Francois Timsit, Anne Perozziello, Benedicte Giroux Leprieur, Stephane Ruckly, Claire Dupuis, Lila Bouadma, Thomas Papo, Karim Sacre
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Clinical-epidemiological research has advanced our knowledge on the negative impact of lupus nephritis (LN) on systemic lupus erythematosus (SLE) outcomes. Impaired renal function at LN diagnosis and failure to normalize renal function upon aggressive immunosuppressive therapy are associated with a very poor long-term renal outcome. Most reports on that field are however based on tertiary care data of limited sample size that impede the ability to generalize the findings. In order to measure the impact of renal function impairment on clinical outcome such as death or cardiovascular events effectively, updated comprehensive information at national level is needed. <h3>Objectives</h3> We conducted an analysis of a French nationwide database to assess the characteristics associated with the presence of CKD (i.e. eGFR &lt;60mL/min/1.73m<sup>2</sup>) and the prognosis associated with CKD in SLE patients <h3>Methods</h3> Characteristics of all admitted SLE patients experiencing CKD in France from 2009 to 2015 were analyzed through the French medico-administrative database. Factors associated with CKD and major clinical outcomes such as end-stage renal disease (ESRD), cardiovascular event (CVE), septic shock and death were assessed. We used a multivariate Cox proportional hazard model and subdistribution hazard models to analyze survival without major clinical events according to the presence of CKD. <h3>Results</h3> From 2009 to 2015, 26 320 SLE patients were hospitalized in France. Among them, 6 439 (86.5% women; mean age 45.7 [16.5] years old) had a baseline stay in 2009 during which CKD was reported in 428 (6.7%) cases. Multivariate analysis showed that lupus nephritis (OR 6.6 [5.2-8.4]), high blood pressure (OR 3.5 [2.8-4.5]), septic shock (OR 3.2 [1.7-6.0]) and past cardiovascular history (OR 1.4 [1.0-2.0]) were associated with CKD status. From 2009 to 2015, ESRD, CVE, septic shock, and death occurred in 4.0%, 14.4%, 6.3% and 9.6% of the 6 439 SLE patients. CKD at baseline was independently and strongly associated with the occurrence of ESRD (sdHR 15.9 [11.6-21.9]), CVE (sdHR 1.7 [1.4-2.2]), septic shock (sdHR 2.1 [1.5-2.8]) and death (HR 1.7 [1.3-2.2]) during the follow up <h3>Conclusion</h3> CKD is a major risk factor for overall morbidity and mortality in SLE patients, highlighting the need for early pre-CKD lupus nephritis diagnosis and treatment <h3>Disclosure of Interests:&nbsp;</h3> Arthur Mageau: None declared, Jean-Francois Timsit: None declared, Anne Perozziello: None declared, Benedicte Giroux Leprieur: None declared, Stephane Ruckly : None declared, Claire Dupuis: None declared, Lila Bouadma: None declared, Thomas Papo: None declared, karim sacre Grant/research support from: GSK&nbsp;
Long-Term Prophylaxis with Activated Recombinant FVII in Children with Hemophilia a and Inhibitor, Receiving Treatment with ITI Protocol
Authors: Ekaterina Shiller, Victor Petrov, Pavel Svirin, Vladimir Vdovin, Igor Koltunov, Artem Bullikh, Eugene Nikitin, Dmitry Kudlay, Ekaterina Klykova
Journal: Blood (2016)
PF584 C‐MYC‐DRIVEN AND PRMT5‐DEPENDENT REGULATION OF MULTIPLE MYELOMA CELL PROLIFERATION THROUGH SMCHD1 GENE
Authors: X. Peipei, D. guo
Journal: HemaSphere (2019)

Background: The protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetrical bimethylation of arginine residues, which plays an important regulatory role in the life process. Transcription factor c‐Myc is widely proved involved in the alteration and development of tumors, while the regulatory mechanism of c‐Myc ‐mediated gene expression has not been fully understood. Aims: In this article we try to investigate the functional role of PRMT5 and c‐Myc in regulating multiple myeloma cell proliferation Methods: The protein and mRNA expression levels of PRMT5 in myeloma cells and normal cells were detected by Western Blot and qPCR. Lentivirally transduced shRNAs targeting PRMT5 (sh‐PRMT5) was constructed using lentivirus mediated RNAi technology, and was packaged to infect MM cells to select positive colonies. The effect of PRMT5 on the proliferation of MM cells was detected by cck‐8 assay. Annexin V/7‐AAD double staining flow cytometry was used to detect cell survival and apoptosis rate. The expression of apoptotic suppressor gene c‐Myc in sh‐PRMT5 cell lines was detected by Western Blot and qPCR. Finally, double‐knockdown of PRMT5 and c‐myc was performed and gene expression differentiation were identified by RNA sequencing (RNA‐seq). Results: PRMT5 expression in MM cell lines (RPMI8226 and U266) was relatively high compared with peripheral blood mononuclear cells (PBMCs), which was correlated with progression‐free survival (PFS) and overall survival (OS) in MM patients. After sh‐PRMT5 infection to MM cell lines, puromycin selection was performed and efficient gene knockdown was evaluated by Western Blot and qPCR. After targeted silencing of PRMT5 expression, the proliferation of MM cells was decreased and apoptosis was significantly increased (P &lt; 0.05). C‐Myc protein and mRNA levels were significantly downregulated after PRMT5 gene silencing. The results showed that PRMT5 promoted the proliferation of MM cells and inhibited the apoptosis of MM cells by regulating the expression of apoptotic suppressor gene c‐Myc . Subsequently, RNA‐seq confirmed SMCHD1 as the common candidate target gene of c‐myc and PRMT5. Therefore, we speculated that PRMT5 and c‐Myc may jointly regulate SMCHD1 gene to promote the proliferation of MM cells. Summary/Conclusion: Altogether, our study not only proposed the mechanism PRMT5 and c‐myc in regulating multiple myeloma related gene expression, but also provided a new strategy and theoretical basis for clinical treatment of multiple myeloma.
PB1958 SUDDEN ONSET HEARING AND VISUAL LOSS: AN UNUSUAL PRESENTATION OF CHRONIC PHASE CHRONIC MYELOID LEUKEMIA
Authors: None S., S. Tandon, R. Gupta, S. Nityanand
Journal: HemaSphere (2019)

Background: Hearing loss and blindness are seldom encountered as primary manifestations in patients with chronic myeloid leukemia. Chronic myeloid leukemia (CML) commonly presents with weakness, dysphagia, abdominal distension and pain and rarely constitutional symptoms. Chronic myeloid leukemia rarely presents with auditory or visual manifestations. Hyperleukocytosis at presentation can lead to obstruction of the small vessels of mainly brain, lungs and kidneys leading to organ dysfunctions. Headache, convulsions, stroke, papilledema, hearing loss, tinnitus and vertigo constitute the rare neurological spectrum of CML. Aims: We present a case series of four patients who presented with bilateral sudden onset of hearing and visual loss. This report highlights the unusual presentation of chronic phase CML with visual and sensorineural hearing loss. Methods: A detailed evauation of hisory, clinical examination, ENT &amp; Eye examination was done in each patients. Related radiological evaluation was done as needed. Results: Chronic myeloid leukemia rarely presents with visual or hearing loss and till date, only 29 cases of CML with deafness have been reported. Neurological involvement including deafness, blindness and tinnitus was reported as 15.5% in a series of 33 adults with CML. Otological findings, for instance, sudden hearing loss, vertigo, tinnitus, facial weakness, and infection, were found in 16–40% of patients. However, deafness as an initial sign of this disease is very rare. Bilateral sudden sensorineural hearing loss, vertigo, and nausea were the presenting manifestations of CML in our patients. CML associated deafness presents itself as sensorineural, unilateral, bilateral or starting unilaterally and developing into bilateral. The pathogenesis of this clinical symptom in leukemia is very complex, and may include multiple mechanisms such as leukemic infiltration, hyperviscosity syndrome, inner ear hemorrhage, and infection. A relationship between leukemic infiltration of the cochlea and impairment of hearing in CML has also been mentioned in literature. Cochlear and retinal blastic infiltration may also cause sensorioneural deficit other than leukostasis in CML. Inner ear hemorrhage has been shown as a cause of sudden hearing loss in leukemia by some authors. Hyperleukocytosis is considered to be the foremost pathogenesis of CML with hearing loss, as suggested by recovery of hearing upon leukapheresis in some cases. Summary/Conclusion: CML should be considered as one of the rare diagnostic possibilities in patients presenting with sudden onset of hearing and visual impairment and managed on an emergent basis as delay can result in permanent impairment. image
Abstract 15406: Gene-Dietary Fat Interactions on Obesity Among Postmenopausal Women Participated in the Women's Health Initiative Study
Authors: Qing Liu, Kei-hang K Chan, Xi Luo, Alexander P Reiner, Stephen T McGarvey, Simin Liu
Journal: Circulation (2017)

Introduction: Genome-wide association studies of obesity identified over 300 statistically significant loci associated with BMI and other adiposity-related traits, but accounted for less than 10% o...
SAT0203 THE CORRELATION BETWEEN THE SERUM 1,25(OH)2D3 LEVEL AND CLINICAL DATA OF PATIENTS WITH PRIMARY SJOGREN’S SYNDROME
Authors: Shi Qiao, Hong-Yan Wen, Wenjuan Niu, Yang Liu, Yanan Duan, Chong Gao, LI Xiaofeng
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The role of vitamin D in regulating immune function in autoimmune diseases has been extensively studied. While there is less research on vitamin D in Sjogren's syndrome. This study will explain the relationship between vitamin D and Sjogren's syndrome. <h3>Objectives:</h3> To explore the relationship between the serum 1,25(OH)<sub>2</sub>D<sub>3</sub> level and the changes of disease activity in patients with Primary Sjogren's Syndrome (PSS) <sup>[1]</sup>, and to explore whether supplementation of VD could be a potential therapy for the treatment of PSS. <h3>Methods:</h3> PSS patients (n=60, according to the 2002 International Classification (Diagnostic) Standard for Sjogren's Syndrome) were enrolled and health individuals were normal controls. Laboratory examinations were analyzed including that serum levels of 1,25-dihydroxycholecalciferol [1,25(OH)<sub>2</sub>D<sub>3</sub>], lymphocytes and CD4+T cell subsets by flow cytometry, urine pH value, ALT, AST, BUN, Cr, IgG, C3, C4, ESR, CRP, serum levels of 1,25(OH)<sub>2</sub>D<sub>3</sub>. Physical examination data include Salivary flow rate, secretion of tears, breakup time of tear film (BUT), and labial glands biopsy. Patient's disease activity was accord to ESSDAI (EULAR SS disease activity index, 2010) classification. <h3>Results:</h3> Compared with that in normal controls, the levels of serum VD in patients with PSS was decrease significantly, Z= -7.367, P &lt;0.001(Figure 1). Spearman correlation analysis and comparison with the collected indexes, showed that VD was significantly correlated with secretion of tears (r=-0.455, p&lt;0.002), IgG (R=-0.581, p&lt;0.000), B cell absolute count (R=-0.474, p=0.002), B cell percent (R=-0.391, p=0.005), Th1 absolute count (R=0.318, p=0.023), Th17 absolute count (r=0.297, p=0.034), Th17 percent (r=0.282, p=0.007), ration of Th1/Th2(r=0.385, p=0.004) and ration of Th17/Tregs(r=0.385, p=0.004) (Table 2). <h3>Conclusion:</h3> The level of serum VD in PSS patients was significantly lower than that in normal controls, which was negatively correlated to secretion of tears, IgG, the absolute number of B, Th1, and Th17, the percentage of B and Th17, and radios of Th1/Th2 and Th17/Tregs. Raising serum VD levels by supplementation of VD, may be a potential Therapy for Sjogren's syndrome. <h3>References</h3> [1] Garcia-Carrasco M, Jimenez-Herrera EA, Galvez-Romero JL, de Lara LV, Mendoza-Pinto C, Etchegaray-Morales I, et al. Vitamin D and Sjogren syndrome. Autoimmun Rev. 2017;16(6):587-93. Results are given as median (P<sub>25</sub>,P<sub>75</sub>), <b><i>patients with PSS</i></b> 10.2 0(9.00,15.11), <b><i>healthy people</i></b> 20.71(15.16,26.41) Z=-7.37 P&lt;0.001 <h3>Disclosure of Interests:</h3> None declared