bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rare Presentation of Relapsed Extranasal Natural Killer/T Cell Leukemia Lymphoma Involving the Hypothalamus
Authors: Kim Byung Moon , Malik Mohsin , Roberts Todd F. 
Published: October 2019

Abstract
42 year old male was diagnosed with stage IV extranasal natural killer T cell leukemia/lymphoma in the liver in 2013. He was treated with 5 cycles of SMILE regimen and one cycle of gemcitabine based chemotherapy after which he achieved complete remission. He had 10/10 matched unrelated donor myeloablative allogeneic transplant on 2/26/2014. His Day 100 and 1 year work up showed complete remission and 100% donor chimerism. He had no chronic graft-versus-host-disease (cGVHD). In March 2015 he presented with change in mental status and electrolyte abnormalities. Patient was oriented to self only without focal neurologic deficits and initially presented with hypovolemic hypernatremia. His work up showed Central Diabetes Insipidous. CT head was unremarkable. MRI of brain showed bilateral hypothalamic, cerebellar and frontal hyperdensity concerning for tumor infiltration. Brain Biopsy of frontal lesion showed tumor cells diffusely infiltrating the neutrophil with perivascular predilection, tumor cells were positive for CD 3, CD 7, CD 56, bcl-2, and cytoplasmic positivity for granzyme B consistent with NK T cell leukemia/lymphoma. Cells were negative for EBV, CMV HSV, HHV-8, Polyoma virus and CD 20. This was similar to his pathologic finding at initial diagnosis. Further work up including bone marrow biopsy and aspirate, CSF analysis, and peripheral blood flow cytometry were unremarkable. He was treated with 6 cycles of high dose methotrexate. MRI brain at the end of treatment showed improvement in his brain lesion.
Mature T or NK/T-cell lymphoma makes up only 5-18% of all cases of non-Hodgkin lymphoma. In a case study among 1153 adult cases of peripheral T cell lymphoma, 11.8% were classified as extranodal NK/T cell lymphoma and only 26% of these were extranasal type. In published studies, NK/T-cell lymphoma extranasal type typically involve the skin, testis, cervix, intestine, liver, spleen, soft tissue, and orbit but CNS involvement is rare and has only been reported in only a select number of clinical cases. Primary CNS involvement of extranasal NK T cell lymphoma and direct intracranial extension and progression of nasal NK/T cell lymphoma have been reported as rare presentations however, to our knowledge, recurrence or relapse of extranasal NK/T cell lymphoma within the brain parenchyma and more importantly involving the hypothalamus after a year of disease remission has not yet been reported.

Disclosures
Roberts: Millenium: Speakers Bureau.
Prevalence and Clinico-Pathological Attributes of c-MYC Rearranged High-Grade B-Cell Non Hodgkin Lymphomas (NHL): Single Centre Experience
Authors: Sengar Manju , Epari Sridhar , Jain Hasmukh , Shet Tanuja , Gujral Sumeet , Menon Hari , Dangi Uma 
Published: October 2019

Abstract
Introduction: MYC rearrangement in high-grade B-cell NHL(non-burkitt), either as single hit or double hit, has significant prognostic and therapeutic implications. There is remarkable paucity of data on frequency and clinico-pathological features of MYC-rearranged large B-cell lymphomas from developing world.
Method: This study included de-novo high grade B-cell NHL cases (>15 years of age) registered at Tata Memorial Centre between January 2013- December 2014. Demography details, clinical features (stage at presentation, bone marrow involvement, presence and extent of extranodal involvement, B-symptoms, international prognostic index),original histopathological diagnosis, chemotherapy and radiotherapy details were recorded from electronic medical or paper case records. Response to therapy, relapses or death if any, status at last follow up, dates of relapse and/or death and last follow up were recorded. All cases were reviewed by expert hematopathologists to categorize the high grade B-cell NHL as per the WHO-2008 classification of hematopoietic malignancies. All cases with adequate formalin-fixed paraffin embedded (FFPE) blocks were evaluated by FISH for c-MYC , BCl-2 and BCl-6 using Vysis dual colour break apart probes. Cases which showed >10% cells with split signal were considered to harbor rearrangement.
Result: A total of 114 cases of de-novo high-grade B-cell NHL with adequate FFPE blocks were evaluated. Based on WHO 2008 classification, 112 cases were classified as diffuse large B-cell lymphoma (DLBL)) and 1 each as Burkitt's (BL) and B- cell lymphoma unclassifiable -intermediate between DLBL and BL(BCLU). A total of 9/112 (8%) cases of DLBL showed MYC rearrangement. One of these 9 cases had both MYC and BCl-2 rearrangement. BCLU did not demonstrate MYC or BCl-2 rearrangement. The Ki-67 index was variable (40-95%)in MYC rearranged cases. The median age of the c-MYC rearranged cases was 55 year (range-23-79 years). 88% were males. Advanced stage disease, bulky mass and extranodal disease was seen in 67%, 44% and 55% of cases respectively. All but one patient had high LDH, however none of the patients had elevation more than 2XULN. These patients received rituximab based chemoimmunotherapy (RCHOP-4,RCEOP-4, REPOCH-1) and 77% achieved complete response. At median follow up of 5 months, 1 year-overall survival and progression free survivals were 80% and 75% respectively.
There were no significant differences in clinical features (except higher proportion of males in the c-MYC rearranged subset), LDH levels, ki-67 index , response to therapy and survival between DLBL with or without c-MYC rearrangement
Conclusion: In our study 8% of all DLBL cases showed c-MYC rearrangement. The frequency of double hit lymphoma was less than 1% (0.8%).

Disclosures
No relevant conflicts of interest to declare.
Profound Hypereosinophilia Secondary to Sezary Syndrome
Authors: Davarifar Ardy , Julian Ricklie , Vipul Pareek , Yilmaz Emrullah , Verma Amit 
Published: October 2019

Abstract
Background: Sezary syndrome is a subtype of cutaneous non-Hodgkin's lymphoma that is characterized by erythroderma, the presence of atypical lymphocytes in the blood, and lymphadenopathy. The clonal cell in Sezary syndrome is thought to be derived from mature Th-2 cells that are able to express Il-4, Il-5, and Il-13 which can stimulate the replication of eosinophils. It is has been shown that higher levels of eosinophilia correlate with a worse prognosis. One explanation is that the degree of eosinophilia represents the level of imbalance between Th-1 and Th-2 cells. Here we report the first case of end organ damage caused by hypereosinophilia secondary to the Sezary syndrome. In rare cases Sezary syndrome can cause hypereosinophilia but has never been reported to cause hypereosionphilia that results in end-organ damage. To our knowledge this is the first case that reports end-organ damage resultant from secondary hypereosinophilia from the Sezary syndrome.
Case presentation: A 75-year-old man was admitted for severe rash and pruritis, massive lymphadenopathy, and extremely high eosinophil count. He had recurrent skin rash with pruritis for five years with previous skin biopsies without evidence of malignancy. He had never had hypereosinophilia until he presented to our institution. Peripheral smear showed marked eosinophilia as well as the presence of Sezary cells. A skin biopsy and lymph node biopsy revealed cutaneous T cell lymphoma. Bone marrow biopsy showed atypical large T-cells comprising 29% of the total population with loss of CD5 and CD7 and 22% eosinophils. The patient ultimately sustained multiorgan failure and expired from respiratory failure. Tissue eosinophilia was later demonstrated on autopsy.
Conclusion: Our report indicates that the Sezary syndrome can cause extreme hypereosinophilia that can result in end-organ damage.

Disclosures
No relevant conflicts of interest to declare.
Late Nephrotoxicity of Intensive Modified Program NHL-BFM-90 in Adult Poor Prognosis Patients with Diffuse Large B-Cell Lymphoma
Authors: Dorokhina Elena , Magomedova Aminat Umaraskhabovna , Kulikov Sergei M , Biryukova Ludmila , Vorobiev Andrey , Kravchenko Sergey , Savchenko Valeri 
Published: October 2019

Abstract
Aim. To evaluate late nephrotoxicity of intensive modified program NHL-BFM-90 (mNHL-BFM-90) in adult poor-prognosis patients with diffuse large B-cell lymphoma (DLBCL).
Materials and methods. The data of laboratory tests of blood and urine of 40 patients with DLBCL which received mNHL-BFM-90 protocol in the Hematology Research Center in the period from 2002 to 2009 years was analyzed. Group consisted of 20 men, 20 women, aged from 31 to 76 years, median age - 56.5 years at the time of the survey, the median period after therapy- 6 years. Individual cumulative dose of ifosfamide - 8-12 g / m2, cyclophosphamide - 2-3 g / m2, methotrexate - 6-9 g / m2. Comparison group included 19 patients (8 men and 11 women), aged from 39 to 78 years, median age - 70 years at the time of the survey, who received therapy to CHOP or R-CHOP. The median period after therapy - 5,5 years. Individual cumulative dose of cyclophosphamide - 3-6 g / m2. Laboratory tests of blood and urine were performed before chemotherapy and after 5 years after treatment.
Results. From all 40 patients with DLBCL received mNHL-BFM-90, signs of chronic kidney disease were found in 32 (80%) patients, only 2 (5%) of them showed a decrease in creatinine clearance daily. In comparison group signs of chronic kidney disease were found in 12 (63%) patients, 2 patients (10.5%) showed a reduction in the daily creatinine clearance. No significant differences in the manifestations of nephrotoxicity in the long term between comparison groups were found. No significant differences in the manifestations of nephrotoxicity in the long term period were found between two groups of patients (who underwent and not underwent acute renal failure during high-dose chemotherapy). Amount of nephrotoxicity signs was significantly dependent on the presence of hypertensive disease in history (p = 0.02).
Conclusion. Nephrotoxicity of high-dose mNHL-BFM 90 exceeds significantly nephrotoxicity program CHOP / R-CHOP. Conducting high-dose chemotherapy in 10 (25%) patients complicated by acute renal failure, 2 (20%) patients required hemodialysis in contrast to the group of standard chemotherapy without such complications (p=0,01). However, in the long term observations there weren't significant differences in the nephrotoxic manifestations between two groups. Impaired renal function in the long term period observed in 100% of patients undergoing acute renal failure during treatment and only in 71% of patients without acute renal failure (p=0,04). It was comparable repairing of renal function in the long term in patients undergoing high-dose therapy between patients with and without acute renal failure among those who showed signs of chronic kidney disease.

Disclosures
No relevant conflicts of interest to declare.
Disruption of the Peripheral Lymphoid Niche Contributes to Lymphopenia in CML Patients Undergoing Imatinib Treatments
Authors: Thiant Stephanie , M.Moutuou Moutuaata , Laflamme Philippe , Sidi Boumedine Radia , Larochelle Fanny , Leboeuf Dominique , Roy Denis-Claude , Guimond Martin 
Published: October 2019

Abstract
PURPOSE: Chronic myelogenous leukemia (CML) is a disorder affecting early hematopoietic stem cells (HSC) and is characterized by excessive proliferation and accumulation of myeloid progenitors and progeny in the periphery. During the chronic phase of the disease, CML patients are normally at low risk of developing infections but such complications tend to rise during the progression of the disease. Gleevec (imatinib mesylate) is currently administered as first line therapy for patients with Philadelphia chromosome-positive CML. Despite the relative high specificity of tyrosine kinase inhibitor (TKI) treatment towards the BCR-ABL fusion protein, off-target multikinase inhibitory effects occur and can interfere with normal hematopoiesis. This study was conducted to evaluate how myeloid and lymphoid immune homeostasis are affected by Imatinib mesylate.
METHODS: Healthy volunteer donors (n=25) and CML patients were recruited during their first visit at our CML clinic. Seven CML patients were treated with Imatinib (400mg). The median time of Gleevec treatment was 2.9 years (range: 0.5-10.9). The median time of remission post TKI was 1.1 years (range: 0.3-3). Phenotypic analysis of dendritic cell (DCs) subsets: plasmacytoid (pDCs) and myeloid type 1, 2 and 3 (mDC1, mDC2, mDC3) were evaluated by flow cytometry. Percentage and absolute numbers of naive and memory CD4+ and CD8+ T cells, NK cells and B cells were also evaluated. DCs were differentiated from purified CD34+ cells culturedwith GM-CSF (800 U/ml) or Flt3-L (50ng/ml), IL-4 (10 U/ml) and TNFa (50 U/ml), in the presence of varying concentrations of Imatinib mesylate (0 to 5µM/mL). TCR and IL-7 signaling were evaluated based on ERK-phosphorylation (-p) and STAT5-p after incubation with 3µM of Imatinib.
RESULTS AND CONCLUSION: At diagnosis, several CML patients have a deficit in DCs resulting from a severe skewing affecting BM progenitor cells. After initiating Gleevec therapy, normalization of stem cell progenitors occurs but DC counts remain well below normal levels in all CML patients. We demonstrated a direct and dose dependent interference of Imatinib on GM-CSF and Flt3-L pathways for DC differentiation from CD34+ stem cells. For T lymphocytes, Imatinib interfered with TCR and IL-7 signaling through the inhibition of ERK and STAT5 phosphorylation respectively. The failure to maintain adequate numbers of DCs combined to diminished homeostatic response to cytokines and TCR stimuli explains T cell lymphopenia in these patients. Such immune dysfunction is at least in part responsible for infectious complications that are often increased in patients treated with Imatinib.

Disclosures
No relevant conflicts of interest to declare.
PDGF/PDGFR May be Involved in the Physiopathologic Mechanism of Essential Thrombocythemia
Authors: Zhou Li Xia , Ye Jieyu , Liang En Yu , Li Chunfu , Chong Beng H , Yang Mo 
Published: October 2019

Abstract
Our previous studies have demonstrated that PDGF (Platelet-derived growth factor) has a potential effect in the regulation of hematopoiesis and megakaryopoiesis (Yang et al, Thromb Haemastasis, 1997; Ye et al, Haematologica, 2010). Essential Thrombocythemia (ET) is characterized by persistently elevated platelet counts in the context of a normal red cell mass. However, the physiopathologic mechanism of ET is still under investigation. Here, we tested the bone marrow plasma levels of PDGF-BB in essential thrombocythemia patients (n=16) and normal control (n=8), and found an increased PDGF-BB levels in ET patients (2070.92±123.98 pg/ml), compared with normal control (1381.85±128.37pg/ml) (P=0.002). Furthermore, we have demonstrated the presence of functional PDGF receptors (PDGFR) in human megakaryocytes, and their ability to mediate a mitogenic response by bone marrow colony-forming unit-megakaryocyte (CFU-MK) formation assay (n=6). PDGF-BB stimulated in vitro megakaryopoiesis via PDGFR. It also showed a direct stimulatory effect of PDGF-BB on c-Fos expressions in megakaryocytic cells, CHRF. We speculate that these transcription factors might be involved in the signal transduction of PDGF on the regulation of megakaryopoiesis. PDGF also enhanced platelet recovery in mice model with radiation-induced thrombocytopenia. Studies showed that PDGF, like thrombopoietin (TPO), significantly promoted platelet recovery and the formation of bone marrow CFU-MK in this irradiated-mouse. An increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis were found in the bone marrow histology sections. We also demonstrated that PDGF activated the p- Akt, p-Jak2 and p-Stat3 expression, while addition of imatinib mesylate reduced p-Akt, p-Jak2 and p-Stat3 expression in CHRF cells. Our findings suggested that the PDGF-initiated megakaryopoiesis is likely to be mediated via PDGF receptors with subsequent activation of the Akt and Jak2/ Stat3 pathways. These studies provide a possible explanation that PDGF/PDGFR may be involved in the physiopathologic mechanism of essential thrombocythemia.

Disclosures
Yang: National Natural Science Foundation of China(81270580): Research Funding.
Significance of Fecal Occult Blood Test Followed By Colonoscopy for Asymptomatic Dasatinib-Induced Hemorrhagic Colitis (CML1501 Study)
Authors: Nishiwaki Satoshi , Maeda Matsuyoshi , Yamada Masahiro , Okuno Shingo , Harada Yasuhiko , Suzuki Kotaro , Kurahashi Shingo , Urano Fumihiro , Okamura Shozo , Sugiura Isamu 
Published: October 2019

Abstract

Introduction: Positive fecal occult blood test (FOBT) was occasionally observed in some chronic myeloid leukemia (CML) patients treated with a tyrosine kinase inhibitor (TKI). Although there are several case reports of hemorrhagic colitis in patients treated with dasatinib, the incidence of TKI-induced hemorrhagic colitis and the screening efficacy of FOBT followed by colonoscopy are unknown.
Methods: We prospectively enrolled CML patients treated with a TKI. The first FOBT (FOBT1) was performed for all patients. The first CF (CF1) was performed for patients with positive FOBT1. When there were any lesions, tissue biopsy was performed for pathological analyses. After confirmation of TKI-induced colitis by pathological analyses, the TKI was interrupted for 2-4 weeks. And then, FOBTs were re-evaluated (FOBT2).
Results: Between February 2015 and September 2015, 30 patients were enrolled in this study. All patients were in chronic phase. FOBT1 was positive in 10 of 30 patients. All patients with positive FOBT1 were treated with dasatinib and revealed no symptoms. CF1 was performed for 10 patients with positive FOBT1. All patients showed abnormal endoscopic findings: colitis in 6 patients, polyps in 3, and hemorrhoid in 1. Dasatinib-induced hemorrhagic colitis was confirmed in 6 of 18 patients treated with dasatinib (33%). Median duration of dasatinib before FOBT1 was 16 months (range 3-35 months). Median dose of dasatinib was 85mg (range 50-100mg). It had been reduced in 3 patients due to pleural effusion. Its endoscopic feature was read flare and/or erosion. Immunohistological analyses showed CD3+, CD8+, CD56+ and Granzyme B+ cytotoxic T lymphocyte infiltration. Dasatinib was discontinued at a median of 27 days after CF1 in patents with dasatinib-induced hemorrhagic colitis. Discontinuation period was 14 days in 4 patients, 27 days in 1, and 28 days in 1. FOBT2 was negative in all but one patient who had concurrent colorectal polyps. No CML progression due to dasatinib discontinuation was observed.
Conclusion: Dasatinib-induced hemorrhagic colitis was observed in a third of asymptomatic patients treated with dasatinib. FOBT can be a useful non-invasive screening for the disease, and it can be confirmed by the following CF and pathological analyses. It was caused by cytotoxic T lymphocytes, and hemorrhage was resolved after dasatinib discontinuation.

Disclosures
No relevant conflicts of interest to declare.
Thrombospondin-1-Derived Peptide Rfyvvmwk Improves the Adhesive Phenotype of CD34+ Cells from Atherosclerotic Patients with Type II Diabetes
Authors: Cointe Sylvie , Rhéaume Eric , Martel Catherine , Blanc-Brude Olivier P. , Dubé Evemie , Sabatier Florence , Dignat-George Francoise , Tardif Jean-Claude , Bonnefoy Arnaud 
Published: October 2019

Abstract
Background: CD34+ progenitor cells are growingly used for vascular repair. However, in diabetic individuals with cardiovascular diseases, these cells have dysfunctional engraftment capabilities, which compromise their use for autologous cell therapy. The thrombospondin-1-derived peptide RFYVVMWK has previously been reported to stimulate cell adhesiveness through CD47 and integrin activation pathways.
Objectives: Our aim was to test whether RFYVVMWK preconditioning could modulate CD34+ cells phenotype and enhance its pro-adhesive properties in diabetic patients.
Patients/methods: Peripheral blood mononuclear CD34+ cells isolated from 40 atherosclerotic patients with (TIID; n=20) or without (NonTIID; n=20) type II diabetes were pre-conditioned with 30µM of RFYVVMWK (or truncated peptide RFYVVM. CD34+ cell adhesion was assessed on a vitronectin-collagen matrix and on a TNFa or IL-1b-stimulated HUVEC monolayers. Adhesion receptors, platelet/CD34+ cell conjugates, and cell viability were analyzed by flow cytometry and confocal microscopy.
Results: RFYVVMWK increased by 8 folds the adhesion of TIID CD34+ cells to the vitronectin-collagen matrix (p <0.001) corresponding to a 3-fold increase compared to unstimulated NonTIID CD34+ cells. The peptide induced the formation of platelet/CD34+ conjugates and increased the expression of TSP-1, CD29, CD51, and CD62P in both TIID and NonTIID cells. However, RFYVVMWK treatment did not affect the viability/apoptosis of CD34+ progenitor cells.
Conclusions: Priming CD34+ cells with RFYVVMWK may be instrumental to enhance their vascular engraftment during autologous pro-angiogenic cell therapy.

Disclosures
No relevant conflicts of interest to declare.
Inactivation of Zika Virus By Solvent/Detergent Treatment or Pasteurization
Authors: Schmidt Torben , Kuehnel Denis , Mueller Sebastian , Pichotta Alexander , Radomski Kai Uwe , Volk Andreas , Knaub Sigurd 
Published: October 2019

Abstract

BACKGROUND: Since 2015 Zika virus (ZIKV) has spread within the Americas and even before in other regions. In 2016, the World Health Organisation (WHO) declared the ZIKV as a "Public Health Emergency of International Concern" (PHEIC). Therefore, it is very important to confirm the pathogen safety of blood plasma products. These products generally demand an effective donor selection as well as robust pathogen elimination/reduction steps within the manufacturing processes. Here, we provide experimental evidence that both solvent/detergent (S/D) treatment and pasteurization effectively inactivate ZIKV.
STUDY DESIGN AND METHODS: The ZIKV inactivation capacity of the pasteurization step and the S/D treatment for different products and process conditions were investigated. Therefore, in-process material from commercial batches was collected and spiked with ZIKV in a ratio of approximately 1:10. Viral loads were determined prior to the safety steps and at pre-defined intervals during the individual processes to investigate the inactivation kinetics. Each process was investigated in duplicate runs.
RESULTS: Sixty minutes after S/D treatment the viral titer was below detection limit during manufacturing of human plasma resulting in mean ZIKV reduction factor (LRF) of ≥ 6.78 log10. For immunoglobulin (IgG) after 240 min of S/D treatment the LRF was determined to be ≥ 7.00 log10. ZIKV was inactivated ≥ 6.18 log10 after 480 min by S/D treatment during the manufacture of factor VIII.
During pasteurization of human albumin ZIKV infectivity was already below the detection limit after the heat-up phase. This finding was confirmed by subsequent test samples up to 2 hours. A LRF of ≥ 7.48 log10 was demonstrated.
CONCLUSION: We showed that different S/D treatment procedures inactivate the ZIKV to below the detection limit. This effect was seen independently of various product matrices or the choice of S/D reagent at various concentrations and temperatures, while taking product-specific treatment times into consideration. We also showed that pasteurization is a very efficient inactivation step for the ZIKV. These results demonstrate the effectiveness of S/D treatment against even newly emerging lipid-enveloped viruses like ZIKV in the manufacturing of human plasma and derivatives thereof, such as IgG or factor VIII.

Disclosures
Schmidt: Octapharma: Employment. Kuehnel:Octapharma: Employment. Mueller:Octapharma: Employment. Pichotta:Octapharma: Employment. Radomski:Octapharma: Employment. Volk:Octapharma: Employment. Knaub:Octapharma: Employment.