bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intratumoral Inhibition of C5a Using Anti-C5a Monoclonal Antibody Inhibits Lymphoma Progression
Authors: Veeramani Suresh , Weiner George J. 
Published: October 2019

Abstract
Background : The complement system can have both pro-inflammatory and immunosuppressive effects. Our preliminary studies demonstrated that C5a can limit antigen-specific responses, in part, by enhancing the induction of immunosuppressive T regulatory (Treg) cells by primary human antigen-presenting cells and malignant B cells. The current study explored the effect of intratumoral C5a on B lymphoma progression and intratumoral T cells using the A20 murine lymphoma mouse model.
Methods :
(A) Co-injection approach: Female Balb/C mice were subcutaneously injected with A20 B lymphoma cells mixed with either 20 μg of rat anti-mouse C5a neutralizing monoclonal antibody (mAb) or matching isotype control mAb. Tumor growth was followed and the phenotype of tumor-infiltrating lymphocytes analyzed by flow cytometry.
(B) Therapeutic approach: Established subcutaneous A20 tumors (7-9 mm diameter) were treated intratumorally with 20 µg of anti-mouse C5a neutralizing mAb (considered as day 1). A second dose (20 µg) of mAb was given intratumorally on day 5. Control mice were treated similarly with matching isotype control mAb. Tumor growth was followed.
Data was analyzed using standard t-test (for tumor growth and immune responses) and Log-rank (Mantel-Cox) test (for comparing survival).
Results:
(A) Co-injection approach: Co-injection of anti-C5a mAb at the time of tumor cell inoculation significantly delayed A20 tumor growth (Fig. 1; p<0.05) and led to prolonged survival of anti-C5a-treated tumor-bearing mice when compared to the control mice (p=0.001).Tumors from mice that were co-injected with anti-C5a mAb showed significantly higher infiltration of activated CD8+ T cells producing IFNg than the control mice (Fig. 2; p=0.034). Anti-C5a-treated mice also had a lower percentage of circulating Tregs (p=0.023) and splenic Tregs (p=0.0001) compared to control mice.
(B) Therapeutic approach: Treatment of pre-established subcutaneous A20 tumors with anti-mouse C5a mAb slowed tumor growth significantly when compared to the control mice (Fig. 3; **p<0.01; *p<0.05). Tumor-bearing mice treated intratumorally with anti-C5a also showed significant improvement in the survival when compared to tumor-bearing mice treated with isotype control Ab (p=0.008).
Conclusions:
Intratumoral anti-C5a mAb therapy inhibits progression of B lymphoma and improves survival, likely by reducing immunosuppression. We are currently exploring the mechanisms behind C5a-promoted tumor immunosuppression.

Disclosures
No relevant conflicts of interest to declare.
Hydroxyurea for β-Thalassemia Major: A Meta-Analysis
Authors: Algiraigri Ali H. , Wright Nicola A. , Kassam Aliya 
Published: October 2019

Abstract
Background
β-thalassemia major (β-TM) is one of the most common inherited diseases worldwide, characterized by a reduced ability to produce hemoglobin resulting in life-long transfusion-dependent anemia. Chronic transfusions carry significant risks such as infection, and result in iron overload that can cause significant multisystem organ damage. Hydroxyurea, an oral chemotherapeutic drug, is anticipated to decrease the need for transfusions, either completely or partially by raising hemoglobin levels and thus decreasing the short and long term complications of chronic transfusions.
Objectives
To evaluate the clinical efficacy and safety of hydroxyurea in β-thalassemia major (β-TM) patients of any age.
Search strategy
We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ongoing trials registers, and major preceding conferences. Hand searches were also conducted using reference lists from primary studies. All searches were updated to June 5, 2014.
Selection criteria
Randomized controlled trials (RCTs) and observational studies (sample size ≥ 5) assessing the clinical efficacy of hydroxyurea alone for three months or longer, for the treatment of patients with β-TM were included.
Data collection and analysis
Two authors acted as reviewers and independently assessed study quality and extracted data from the included studies. Authors of included studies were contacted if further information was required. β-TM includes the classical β-TM as well as severe hemoglobin E/β thalassemia, both of which are characterized by lifelong transfusion needs. The effect size was estimated as a proportion (those showing response to treatment over the total number treated) and reported as overall response rate (ORR) or complete response rate (CRR). ORR was defined as ≥ 50% reduction in transfusion need and CRR was defined as complete cessation of regular transfusion. All data was analyzed using Stata, Version 13.0.
Results
A total of 10 observational studies involving 620 patients were included. Hydroxyurea was associated with a statistically significant decrease in transfusion need with CRR of 36% (95% CI, 23-50%) and ORR of 66% (95% CI, 52-79%).
All of the studies had several limitations, such as small sample size, lack of comparison group, under-reporting of data and methods, and being observational studies.
Adverse events (AEs) were transient and improved with temporary cessation of the drug and/or adjustment of the dose. No long-term AEs, including cancer or end organ damage were reported.
Authors’ conclusion
Hydroxyurea appears to be effective in the management of β-TM by decreasing the need for chronic blood transfusions completely or partially in a significant number of patients. It appears to be well tolerated and associated with mild and transient AEs. Patients with β-TM may benefit from a trial of hydroxyurea, though large RCTs assessing efficacy should be done to confirm the findings of this meta-analysis.

Disclosures
Off Label Use: Hydroxyurea for β-Thalassemia.
Liver Enzymes Changes and Safety Profile of Deferasirox Iron Chelator in Omani Children with Thalassemia Major
Authors: Mevada Surekha Tony , AlDhuli Abdaluziz Sulieman , Al-Rawas A.Hakim , Al-Khabori Murtadha K. , Nazir Hanan , Zachariah Mathew , Wali Prof. Yasser 
Published: October 2019

Abstract
Background: Iron overload is a leading cause of morbidity and mortality in beta thalassemia and chelation therapy remains the mainstay in reducing iron burden. For effective chelation, optimal drug dosage with close monitoring of side effects is crucial. The safety and efficacy of deferasirox has been extensively studied in adult population. We aimed at evaluating the liver enzyme changes and safety profile of deferasirox in pediatric patients with thalassemia major.
Materials and Methods: A retrospective study of 30 patients (range 2-15 years) with thalassemia major on regular follow up at the Pediatric Day care Center, Sultan Qaboos University Hospital was performed to evaluate the side effects of deferasirox over a mean of 15 month follow-up period. Data from electronic patients' records was collected for age, gender, serum ferritin, alanine transaminase, (ALT), aspartate transaminase (AST), dose and side effects of deferasirox. Data were analyzed using SPSS software version 19.
Results: Thirteen (44.8 %) patients had either ALT or AST elevation above 2 times upper limit of normal (ULN). Except for two (6.8%) patients with enzyme elevations more than 5 times ULN, the majority of patients had mild transaminitis. None of the patients had liver enzyme elevation above 10 times ULN. The other side effects included fever (17.24%), nausea and vomiting (10.34% each), diarrhoea (13.79%), skin rash (21.4%), elevated serum creatinine with either 2 consecutive readings more than 33% of baseline level and/or single reading above 60% baseline (17.24%). The mean serum ferritin dropped from initial baseline level of 1236.21 ± 354 ng/ml (Range 534 -2821 ng/ml) to a level of 950 ± 320 ng/ml (Range 550-1900 ng/ml) at the end of the study period; with a mean deferasirox dose of 32.72 ± 4.79 mg/kg/day.
Conclusion: Majority of our patients had mild transaminitis not requiring dose modification or interruption of chelation. Patients with significant elevations of liver enzymes more than 5 times ULN showed prompt recovery of transaminitis within 4-5 weeks of dose reduction of deferasirox by 5 mg/kg/day and future dose increments were well tolerated. Except for significant elevations in serum creatinine requiring dose reduction or short interruption, the other adverse events were well tolerated and did not warrant dose modification. Deferasirox was effective in reducing serum ferritin levels and was well tolerated in our young patients with thalassemia major.
Table 1 PatientCharacteristics Numberof patients, n 30 Meanage of patients, years Range,years 7.24± 3.4 2-15 Meanserum ferritin, ng/ml Range,ng/ml 1236.21± 354 534-2821 Meandose of deferasirox (mg/kg/day) 32.72± 4.79
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
No Association Between Platelet Function and Hemophilia B Phenotype
Authors: Schutgens Roger E.G. , Bladel Esther R. van , Fischer Kathelijn , Roest Mark , Urbanus Rolf 
Published: October 2019

Abstract
Introduction
In hemophilia, unravelling the mechanisms behind interindividual variability in phenotype remains a big challenge.
Objectives
To study platelet activation and platelet responsiveness in relation to hemostatic phenotypes in hemophilia B by 1) comparing hemophilia B patients to healthy controls and 2) relating these to the clinical phenotype of the individual patients with severe hemophilia B.
Methods
Platelet reactivity was determined in whole blood measuring expression of P-selectin and binding of fibrinogen with FACS analysis after stimulating or inhibiting platelets with concentration series of several (ant-)agonists, including adenosine diphosphate (ADP), convulxin (CVX) and thrombin receptor associated protein (TRAP)and iloprost. Concentration of soluble platelet activation markers (soluble P-selectin, β-Thromboglobulin and RANTES) were measured in platelet poor plasma by ELISA.
Markers of platelet activation and responsiveness were compared between healthy controls (n=12), patients with mild/moderate (n=12) or severe hemophilia B (n=19).
In severe hemophilia patients, annual FIX consumption/kg was calculated over the last 6 years. Data were analysed with linear regression using SPSS 20.
Results
Levels of basal platelet activation (both P-selectin and fibrinogen) were equal between controls, mild/moderate and severe hemophilia B (Figure 1). For basal P-selectin expression, the mean area under the curves for were 28.5 (95% CI 23.3-33.6), 33.0(95% CI 24.4-41.6) and 28.4(95% CI 23.9-32.9) respectively (p=0.4). After stimulation with ADP, CVX and TRAP (with and without iloprost), platelet responsiveness was similar in all groups.
There was no relation between annual FIX consumption and any marker of platelet activity. For basal P-selectin expression, the beta coefficient was -0.212 (p=0.38)(Figure 2).
Conclusion
In hemophilia B, platelet activity and responsiveness was similar to healthy controls. In severe hemophilia patients, there was no relation between FIX consumption and platelet activity.
Figure 1. Basal P-selectin activity between healthy controls and hemophilia patients Figure 1. Basal P-selectin activity between healthy controls and hemophilia patients
Figure 2. Basal P-selectin activity according to FIX consumption in severe hemophilia B Figure 2. Basal P-selectin activity according to FIX consumption in severe hemophilia B

Disclosures
Schutgens: Pfizer: Research Funding.
Low dose Rituximab for Preemptive Management of Thrombotic Thrombocytopenic Purpura ( TTP )
Authors: Nelson John C. 
Published: October 2019

Abstract
Low dose rituximab has been successful in treating some patients with autoimmune cytopenias. Recently reported data indicate preemptive rituximab may postpone hematologic relapses of TTP in patients with chronic severe ADAMTS13 deficiency.
A now 22-year-old woman had multi-relapsing TTP with five episodes over the previous 10 years, three of which were successfully treated with four doses of rituximab 375 mg/m2. The most recent course in 2009 was given preemptively because intense ADAMTS13 monitoring had shown that previous hematologic relapses followed shortly after developing severe ADAMTS13 deficiency. Asymptomatic chronic IgG deficiency less than 300 mg% had followed this most recent rituximab course given in 2009.
In 2014, continued intense ADAMTS13 monitering disclosed a new progressive decrease in ADAMTS13 levels from normal to severely deficient levels with a weak inhibitor, but no hematologic or clinical changes. Just two 100 mg rituximab doses have been followed by a progressive rise of ADAMTS13 levels to solidly normal values with significant improvement by day 13 post initiation and normalization by day 34.
Low dose rituximab could be a viable alternative for preemptively managing TTP patients with persistently severly low ADAMTS13 levels.

Disclosures
Off Label Use: Off label use of rituximab to treat TTP.
Characteristics of Intracranial Haemorrhage in Haemophilic Children-Report in Single Center in China
Authors: Ding Wenjiao , Feng Xiaoqin , Sun Jing 
Published: October 2019

Abstract
Objectives: Intracranial haemorrhage (ICH) is the most severe complication for patients with haemophilia. Our study objectives were to analyze the characteristics of Intracranial haemorrhage in haemophilia children.
Methods: Intracranial haemorrhage cases in haemophilic children were retrospective analyzed from Jan. 2008 to Dec. 2013. Patients with sever trauma inhospitalized in the surgical department were excluded.
Results: Of 439 severe or intermediate haemophilic children 29(6.6%) experienced 32 events of ICH. The 29 children included 20 haemophilia A boys and 9 heamophilia B boys. The age of onset of ICH from 1 month to 17 years old (mediate age 3 years old). Head trauma histories was found in 79.3% (23/29) children 1 day to 1 week before ICH. Of 29 patients 15 (51.7%) had the presentation of convulsion or coma. The haemorrhage site included 2 events in extradural, 2 events in subdural, 6 events in brain parenchyma, 1 event in subarachnoid space, 21 events had multiple sites ICH. The ICH mortality was 6.9% (2/29). Only two children had done prophylaxis treatment with low dose (10-15u/kg, 2/w) before ICH. Inhibitor were only tested in 8 children who were all positive when ICH occurred.
Conclusion: The most significant risk factors for ICH included the presence of an inhibitor and reported head trauma. Our patients with ICH had low mortality maybe because most patients had no inhibitor who could have good response to factor treatment, and these patients had excluded patients with sever trauma in the surgical department.

Disclosures
No relevant conflicts of interest to declare.
Clinical Significance of Absolute Monocyte Count in Venous Thromboembolism Patients with Lung Cancer
Authors: Go Se-Il , Song Haa-Na , Lee Gyeong-Won 
Published: October 2019

Abstract
Purpose: To investigate the role of the absolute monocyte count (AMC) as a predictor of response to anticoagulation and survival in lung cancer patients with venous thromboembolism (VTE).
Methods: We retrospectively collected the clinical data of 134 patients with lung cancer who were diagnosed with VTE and treated with anticoagulation between July 2008 and May 2014 in a single institution. Baseline characteristics, laboratory findings, response to anticoagulation, and survival since the diagnosis of VTE were analyzed in low (n = 67) and high (n = 67) AMC groups according to median AMC (640/μL) at the time of VTE diagnosis.
Results: The majority of patients had non-small cell lung cancer (n = 110, 82.1%), stage IV (n = 86, 64.2%), and pulmonary thromboembolism (n = 102, 76.1%) and were incidentally diagnosed with VTE without any sign of thrombosis (n = 103, 76.9%). Patients’ characteristics and laboratory values were not significantly different between low and high AMC groups. Among 90 patients available for evaluation of response to anticoagulation, high AMC group (n = 10/46, 21.7%) was more refractory to anticoagulation than low AMC group (n = 3/44, 6.8%) (p = 0.044). In addition, high AMC group showed worse overall survival than low AMC group (median 9.6 vs. 5.9 months, p = 0.038). In multivariate analysis, high AMC and low albumin were independent poor prognostic factors.
Conclusion: High AMC is associated with refractoriness to anticoagulation and poor prognosis in lung cancer patients with VTE. Further evaluation is warranted to confirm these findings.

Disclosures
No relevant conflicts of interest to declare.
Mesenteric Vein Thrombosis Associated to Elevated Factor VIII in a Patient Treated with Adjuvant Tamoxifen
Authors: Herrada Juan , Reiter Ethan A , Gupta Anuradha , Arango Carmen , Landeros Mark M , Mercedes Lorenzo-Medina , Gomez Jesus A , Vargas-Sanz Sacramento , Campos-Gines Angel F , Madrid Melissa , Briceno Jeannette 
Published: October 2019

Abstract
Introduction: Venous thrombosis is a well documented adverse effect in about one percent of patients treated with tamoxifen. Although the precise role of elevated factor VIII in defining venous thrombotic risk is not well understood, current data suggest that factor VIII is an independent risk factor for venous thrombosis.
Methods: Case report.
Results: In May 2011, a 76-year-old male underwent right modified radical mastectomy in May 2011. Tumor was a 2.5 cm well-differentiated, invasive ductal carcinoma, with lymphatic invasion present and widely negative surgical margins. The patient (pt) had one ipsilateral axillary lymph node (out of 26 sampled) with two microscopic foci (<1 mm) of metastatic ductal carcinoma. Additional evaluation on the mastectomy specimen showed that estrogen and progesterone receptors were strongly positive, Ki-67 was 25% and HER-2/neu showed negative (0 expression) by immunochemistry. The patient had no family history of venous thromboembolic events, and he had never smoked. His past medical history was significant for hypothyroidism and hypertension, both under good control. In June 2011 pt was started on adjuvant Tamoxifen 20 mg daily. In July of 2013 pt started with diffuse, ill-localized abdominal pain. No associated abdominal cramping, fever or nausea. No evidence of melena or rectorrahgia. An abdominal magnetic resonance imaging showed the presence of a superior mesenteric vein thrombosis. Tamoxifen was at that time discontinued and pt was started on enoxaparin 1 mg/Kg twice a day, with complete resolution of his symptoms within 7 days. Pt remained anticoagulated with enoxaparin for six months. After discontinuation of anticoagulation, radiologic and laboratory evaluation showed no evidence of underlying hypercoagulable state except for an elevation of serum factor VIII (> 150 IU/dl) that has persisted during his follow-up.
Conclusions: Our case supports the notion that high levels of factor VIII are a risk factor for venous thrombosis.

Disclosures
No relevant conflicts of interest to declare.
Reversal of Radiation Damage to Marrow Stem Cells By Mesenchymal Stem Cell Derived Vesicles
Authors: Quesenberry Peter J , Wen Sicheng , Dooner Mark S , Carpanetto Andrea 
Published: October 2019

Abstract
Extracellular vesicles (exosomes and microvesicles) have been found to deliver both mRNA and transcriptional modulators to target cells and affect their phenotype. Marrow mesenchymal stem cell derived vesicles (MSC-DV) have also been shown to reverse renal and hepatic injury. We have studied the capacity of MSC-DV to reverse radiation injury to marrow stem cells.
B6.SJL mice were exposed to 100 centigrade whole body radiation (WBI), and 4, 24, and 168 hours later marrow is harvested and established in culture for 24-48 hours with either human or murine marrow-derived mesenchymal stem cells (MSV-DV) or vehicle. These cells were then transplanted into 950 cGy exposed C57/BL mice and engraftment evaluated at 3 weeks to 8 months. Alternatively cells were engrafted without competition into 200 centigrade exposed mice. Significant (p<0.05) restoration of engraftment was seen in each setting; restoration of secondary engraftment was also seen. Mice were also subjected to 500 cGy WBI and injected at 6, 24 and 72 hours with human MSC-DV and peripheral blood counts determined. Granulocyte levels were restored to 86% of control at 3 weeks post irradiation and significant restoration seen at multiple other time points. Restoration was seen was seen in both peripheral blood and marrow. Further studies on the murine hematopoietic cell line, FDC-P1 exposed to 500 centigrade showed dramatic recovery on exposure to murine or human MSC-DV. Additional work, employing differential ultracentrifugation as a separative technique for vesicles, showed that a preparation with both exosomes and microvesicles was superior to either microvesicles or exosomes alone. Studies with irradiated FDC-P1 cells indicated that exposure to vesicles decreased apoptosis. These studies indicate that vesicles from marrow-derived mesenchymal stem cells from different sources have the capacity to reverse radiation damage to bone marrow stem cells. Thus administration of MSC-DV to patients exposed to radiation could represent an important new strategy in radiation mitigation.

Disclosures
No relevant conflicts of interest to declare.
Human Mesenchymal Stem Cells Promote Resistance to Death Signals By Potentiating FGF Signaling in Mantle Cell Lymphoma
Authors: Sehgal Lalit , Mathur Rohit , Braun Frank K , Berkova Zuzana , Neelapu Sattva , Samaniego Felipe 
Published: October 2019

Abstract
Introduction
Mantle cell lymphoma (MCL) represents an aggressive, incurable form of non-Hodgkin’s lymphoma (NHL). The health complications associated with advanced age of MCL patients further restrict treatment with intense chemotherapy. Translocation t(11;14), responsible for overexpression of cyclin-D1 is the hallmark of MCL. An intense analysis of primary MCL had been delayed until development of a tissue culture system, using human mesenchymal stromal cells (hMSC), suitable for propagation of primary MCL cells. We hypothesized that tumor-initiating cells are responsible for MCL relapse and chemoresistance and thus, identification of survival signals responsible for survival and maintenance of MCL-initiating cells (MCL-ICs) is essential for design of successful treatment strategies.
Methods
Isolates of primary MCL cells (n=24) were co-cultured with hMSC and content of MCL-ICs was analyzed by flow-cytometry based on marker expression profile; CD34-CD3-CD45+CD19-. Cytokine array was used to identify the soluble factors enriched in the cocultures and the expression of these factors was confirmed by RT-PCR analysis. The signaling pathways employed by the newly-identified factors were blocked in 3 MCL cell lines (JVM2, Mino, Z138) and cell survival was monitored.
Results
Co-cultures of primary MCL isolates with hMSCs supported the growth of MCL cells for over 4 weeks with continued presence of MCL-ICs (CD34-CD3-CD45+CD19-) representing about 1% of MCL cells. We found IL-6 triggered a FGF/FGFR autocrine loop in primary MCL in cocultures. Patients with MCL showing high FGFR levels in MCL tissues compared to lymphocytes, and the highest FGFR expressing cohort of patients showed a lower overall survival rated compared to those with low FGFR levels. Blockage of FGF/FGFR rendered MCL cells dead and also sensitized the cells to the killing effects of death receptor ligands.
Conclusion
We establish that primary MCL use an FGFR autocrine loop for propagation in cocultures with hMSCs. We defined the factors supporting MCL and MCL-ICs survival; such knowledge is essential for targeting MCL and MCL-ICs.

Disclosures
No relevant conflicts of interest to declare.