bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline Characteristics of Patients with Sickle Cell Disease in An Ongoing 5-Year, Prospective, Noninterventional Registry Trial
Authors: Heeney Matthew M. , Mueller Brigitta U. , Baltz Brad , Paley Carole , Esposito Jason , Sharma Surabhi , Vichinsky Elliott 
Published: October 2019

Abstract
Abstract 1060

Introduction:
The baseline characteristics and therapeutic management of sickle cell disease (SCD) can be quite variable depending on disease severity. This report describes baseline assessments and therapies of 420 patients in an ongoing registry designed to study current treatment patterns, natural history, and outcomes in patients with SCD.

Methods:
This registry trial involving 57 US hematology centers had a sequential recruitment target of 600 patients with SCD subdivided into 3 age groups (2-<12 yr, 12-<18 yr, ≥18 yr). Patients '2 years of age with HbSS, HbS/β-thalassemia, or HbSC were eligible. Follow-up visits were every 6 months for a maximum of 5 years. Assessments included demographics, SCD history, Karnofsky Performance Status, medical history, types of crises, frequency of crises and hospitalization, treatment history, transfusion practices and use of iron chelation. Differences between pediatric (<18 yrs) and adult (≥18 yrs) patients were examined. (ClinicalTrials.gov identifier, NCT01220115).

Results:
Enrollment: 420 patients (254 <18 yrs, 166 ≥18 yrs) completed the initial baseline visit. Baseline characteristics and medical history are shown in the Table and Figure.

Conclusions:
These data indicate differences in baseline characteristics and treatment patterns between adult and pediatric patients with SCD in this registry. Karnofsky performance status was worse, and serum ferritin levels were higher in adult versus pediatric patients. The percentage of patients having regular transfusions was higher in pediatric patients, while adult patients had higher rates of intermittent transfusions. As expected, the lifetime chelation exposure was more frequent in adult patients. Hospitalizations and use of hydroxyurea were also greater in pediatric patients. In terms of medical history related to SCDs, pediatric patients had higher frequencies of asthma, abnormal TCDs, dactylitis and splenic sequestration, while adults had more frequent evidence of avascular necrosis, gall bladder disease, leg ulcers and pulmonary hypertension. Pain was the most common crisis type in both cohorts, although this accounted for a greater relative proportion of crises in the adult cohort. The relative proportion of ACS events was lower in the adult versus pediatric patients; all other crisis types occurred in similar relative proportions in both cohorts. This ongoing registry will provide information about disease patterns, current treatment practices, and outcomes, thus contributing to a better understanding of the appropriate therapeutic management of patients with SCD.

Disclosures:
Heeney: Novartis: Consultancy, Research Funding. Baltz:Novartis: Research Funding. Paley:Novartis: Employment. Esposito:Novartis: Employment. Sharma:Novartis: Employment. Vichinsky:Novartis, Apotex, Ferrokin: Research Funding.
Cancer Patients Requiring Interruption of Long-Term Anticoagulant Therapy: The Use of Fixed Sub-Therapeutic Doses of Low-Molecular Weight Heparin
Authors: Saccullo Giorgia , Malato Alessandra , Coco Lucio Lo , Barbello Ilenia , Caracciolo Clementina , Raso Simona , Santoro Marco , Di Bartolo Orazio Graziano , Piazza Ambra Di , Abbadessa Vincenzo , Siragusa Sergio 
Published: October 2019

Abstract
Abstract 1244

Introduction.
We tested the efficacy and safety of fixed doses of Low-Molecular Weight Heparin (LMWH) in cancer patients requiring interruption of Vitamin-k Antagonist (VKA) because of invasive procedures (defined as major and non major surgery) or chemotherapy inducing platelets depletion. Methodology. Cancer patients were defined to be at high (atrial fibrillation [AF] with previous stroke, prosthetic mitralic valves and venous thromboembolism [VTE] lasting < 3months) or low risk of thrombosis (AF without previous stroke, VTE lasted > 3 months, and prosthetic aortic valves). They discontinued VKA 5 + 1days before surgery or chemotherapy; in those at low-risk for thrombosis, LMWH was given at a prophylactic dosage of 3.800 U.I. (nadroparin) or 4.000 U.I. (enoxaparin) anti-FXa once daily the night before the procedure or the beginning of chemotherapy. In patients at high-risk for thrombosis, LMWH was started early after VKA cessation (when an INR < 1.5) and given at fixed sub-therapeutic doses (3.800 or 4.000 UI anti-FXa twice daily) until procedure or beginning of chemotherapy. In patients undergoing procedures, LMWH was reinitiated 12 hours after procedure while VKA the day after; in patients receiving chemotherapy, LMWH was reinitiated 12 h after a stable platelet count > 30.000 mmc3 and VKA 12 h after a stable platelet count > 50.000 mmc3. Heparin was continued until a therapeutic INR value was reached. The primary efficacy endpoints were the incidence of thromboembolism and major bleeding from VKA suspension to 30 + 2 days post-procedure or next chemotherapy. Results. A total of 156 patients (68, 53.9% at low-risk and 58, 46.1% at high-risk for thrombosis) were enrolled (Table 1); 44 (28.2%) underwent major surgery, 53 (33.9%) non-major surgery and 29 (18.5%) chemotherapy. Overall, thromboembolic events occurred in 5 patients (3.2%, 95% confidence intervals 0.5–5.9), 4 belonging to high-risk and 1 to low-risk group. Overall, major bleeding occurred in 5 patients (3.2%, 95 CI 0.5–5.9), all belonging to high-risk group (3 during major surgery and 2 during chemotherapy). The mean time of anticoagulation with LMWH was 7.5 days in patients underwent procedures and 13.2 days in those who received chemotherapy. Conclusion. LMWH given at fixed sub-therapeutic doses appears to be a feasible and relatively safe approach for bridging therapy in chronic anticoagulated cancer patients requiring VKA interruption.

Disclosures:
No relevant conflicts of interest to declare.
Hemophagocytic Lymphohistiocytosis in Adults: Updates in Diagnosis and Treatment
Authors: Kleynberg Roman Leonid , Schiller Gary J. 
Published: October 2019

Abstract
Abstract 5037
Hemophagocytic lymphohistiocytosis (HLH) is rare potentially life-threatening disorder that must be recognized and treated early to improve clinical response rates and outcomes. We describe a 36 year-old male with a longstanding history of ulcerative colitis who presented with a one-week history of lymphadenopathy, splenomegaly, fevers, and chills. Workup at an outside institution had been intensive - he had a long complicated hospital course that included hypoxemic respiratory failure requiring intubation and mechanical ventilation, acute kidney injury, hyperbilirubinemia, pancytopenia, coagulopathy, hypofibrinogenemia, CMV viremia, and Clostridium difficile colitis for which he was treated. At our facility, the patient presented with a white blood count of 0.19 109/L (N: 5%, L: 95%, M: 0%, E: 0%, B: 0%), hemoglobin 9.0 mg/L, platelets 54 x109/L, ferritin 538 ng/dL, and triglycerides of 280 mg/dL. A bone marrow biopsy revealed CMV positivity by immunohistochemistry and marked hemophagocytic histiocytosis. The patient was treated with the HLH-2004 chemo-immunotherapy protocol with dexamethasone, etoposide (VP-16), and cyclosporine A. He responded well and is now eight months status-post initial treatment.
HLH in adults is a disorder that little is known about. Acquired forms of HLH can occur in otherwise healthy adults, whereas in children, HLH often presents in its inherited (familial) form. In adults it is often associated with infections (i.e. Epstein-Barr virus, herpes simplex, cytomegalovirus), rheumatologic diseases (i.e. rheumatoid arthritis, systemic lupus erythematosus, adult onset systemic Still's disease), malignancy (i.e. natural killer cell leukemia, peripheral T-cell lymphoma, EBV in T-cell lymphoma, B-cell lymphoma, and a variety of other lymphomas). HLH in adults is characterized by cytokine dysfunction and results in the systemic accumulation of activated T-lymphocytes and activated histiocytes (macrophages). Natural killer (NK)-cell and cytotoxic T cell activity in HLH patients is commonly depressed. The standard chemo-immunotherapy protocol as recommended by the Histiocyte Society (HLH-2004) includes therapy with dexamethasone, etoposide (VP-16), cyclosporine A upfront and, in selected patients, cortiocosteriods and intrathecal methotrexate. Thus, early recognition and treatment of this disorder is essential to decrease associated morbidity/mortality. Hemophagocytic lymphohistiocytosis in adults is a diagnosis that must be in the differential whenever a patient presents with fever, cytopenia, hepatosplenomegaly, hypertriglyceridemia and/or hypofibrinogenemia.

Disclosures:
Schiller: BMS: Research Funding; Celgene: Research Funding; Ambit: Research Funding; Novartis: Research Funding; Sunesis: Research Funding.
Platelet Activation in Cardiovascular Disease
Authors: Corinaldesi Giorgio 
Published: October 2019

Abstract 5242
Platelets play a pivotal role in the pathogenesis of coronary artery disease (CAD). Among a number of platelet integrin receptors ITGA2B and ITGB3 appear to be fundamental mediators of platelet aggregation as they interact with fibrinogen, VWF, fibronectin, vitronectin, and thrombospondin; for these major properties these two receptors are risk-determining factors for increased platelet thrombogenicity, enhancement of leukocytes trafficking and activation by CD11a/CD18 (LFA-1) and CD11b/CD18 (MAC-1), thus leading to CAD.
Receptor clustering promote cell adhesion by increasing the number of ligand receptor bonds GPIb-IX-VWF, fibrinogen /alfaIIb-beta 3 which promote platelet aggregation; this is showed by various parameters including increased platelet-monocyte aggregates, P-selectin (CD62P), CD42b, CD63, and EMMPRIN (CD147). The link between platelet activation, leukocyte recruitment, endothelial dysfunction, progression of atherosclerosis plaque and CAD has been demonstrated through the involvement of inflammatory cytokines that play a central role in the development of atherosclerotic plaques with MCP-1, CCL-2, Rantes, IL-8, and CD40L.
In this study, we investigated a total of 38 subjects (mean age of 62 +/− 6 years) with confirmed CAD (unstable angina: 18 patients; ST elevation myocardial infarction: 20 patients) on coronary angiography and 32 controls. They were examined for CD62P, CD63, CD42b, and CD147 expression, troponin level, creatine-kinase-MB level (indicator of myocardial injury), C-reactive protein, and IL-6 (being both indicators of systemic inflammation).
Patients with CAD had significantly higher markers of platelet activation (p<0.001) which were constituted by the expression of GP receptors (CD62P/PSGL-1, CD162, CD61/63, CD147). This activity closely correlates with a significant increase of acute phase reactant in cases than in controls (p<0.0001), and mostly, it confirmed that these associations may be largely responsible of cardiovascular events.

Disclosures:
No relevant conflicts of interest to declare.
Podia in Multiple Myeloma (MM) Cells Promote Adhesion with Bone Marrow (BM) Fibroblastic Stromal Cells
Authors: Ramasamy Karthik , Anwar Amna , Kazmi Majid A. , Schey Steve , Calle Yolanda 
Published: October 2019

Abstract
Abstract 626
The physical contact between MM cells and the BM microenvironment can lead to cell adhesion mediated drug resistance. Although some components of adhesive structures in MM cells have been identified very little is known about their exact organisation and dynamics. We have observed formation of proteoglycan CD138 and F-actin containing membrane extensions in MM cells in in vitro cultures of BM aspirates as well as in sections of BM trephines of MM patients. MM membrane extensions elongated on the surface of BM stromal cells or interconnected MM cells forming seemingly cellular networks. Morphologically, MM membrane extensions appear similar to other structures in haematopoietic cells such as nanotubes formed by T-cells involved in cell communication and podia in CD34+ cells and leukemia cell lines whose function remains unknown. Dexamethasone (a drug commonly used clinically against MM) increased the percentage of MM cells displaying membrane extensions and the length of these structures. This correlated with enhanced expression of surface CXCR4, increased adhesion of MM cells on fibroblastic stromal cells and protection of MM cells against Dexamethasone-mediated apoptosis. Treatment with Bortezomib at clinically achievable doses decreased CXCR4 levels in MM cells and did not induce podia formation/extension and correlated with inhibition of MM cell adhesion and induction of MM cell apoptosis in a dose dependent manner. Blocking CXCR4 signalling with Plerixafor (AMD3100) inhibited the rate of formation and length of MM membrane extensions and correlated with sensitisation of MM cells to Dexamethasone. Similar inhibitory results were obtained using Dexamethasone in combination with the c-Abl/Src kinase inhibitor Dasatinib. Neither Dasatinib nor Plerixafor at doses achievable in patients directly induced apoptosis in MM or BM stromal cells. We conclude that membrane extensions/podia formed by MM cells are involved in the interaction with BM stromal cells, require CXCR4 and Src and/or c-Abl activity and could be involved in resistance to treatment with Dexamethasone.

Disclosures:
No relevant conflicts of interest to declare.
Local Treg Immunomodulation Cures Metastatic Lymphoma Including CNS Sites
Authors: Marabelle Aurelien , Kohrt Holbrook E , Brody Joshua , Torchia James Anthony , Zhou Gang , Luong Richard , Rajapaksa Ranjani , Tse Victor , Levy Ronald 
Published: October 2019

Abstract LBA-2

Background:
CD4+CD25+FOXP3+ regulatory T-cells (Tregs) protect cancers from the immune system. They express important functional molecules such as CTLA-4 and Ox40 on their surface. Anti-CTLA4 monoclonal antibody (mAb) is the first drug to improve survival of refractory metastatic melanoma. Its recent approval by the FDA/EMEA inaugurates a paradigm shift in cancer therapy where the immune system is targeted rather than the tumor itself.

Scientific question:
Does local immunomodulation of tumor specific Tregs trigger a systemic anti-tumor immune response and cure disseminated lymphoma?

Results:
The Tregs that infiltrate the tumor site preferentially express CTLA4 and OX40 compared to their counterparts in the blood and other lymphoid organs, both in mice and in humans. Upon injection of low doses of anti-CTLA4 and anti-OX40 together with CpG, a TLR-9 agonist, directly into the tumor, tumor-specific Tregs are depleted from the tumor-infiltrate. This immunomodulatory combination therapy triggers an anti-tumor immune response able to cure mice with established disseminated disease. The triple combination is uniquely required as neither CpG alone nor mAbs without CpG are effective. The local Treg immunomodulation with anti-CTLA4+anti-OX40+CpG in a single sub-cutaneous tumor eradicates disease in mice with established CNS lymphoma, even with leptomeningeal and spinal cord metastases, whereas chemotherapies or mAb therapy directed against the tumor cells have little effect in the CNS site. Moreover, these cured mice have a long term intra-cranial anti-tumor immunity since they are protected against late intra-cranial re-challenge.

Significance:
Immunomodulatory antibodies are currently under clinical development for cancer treatment, and their major side effect is the triggering of auto-immune diseases. We show here that injecting very little doses of these antibodies in combination with CpG at one tumor site is sufficient to trigger a systemic anti-tumor response able to eradicate distant sites, including in the CNS which is usually considered a sanctuary site for conventional systemic therapies.

Impact:
We recently have published positive results of intra-tumoral CpG in patients with follicular Lymphoma (Brody,Levy, et al. JCO, 2010). Anti-CTLA4 has just been FDA approved in patients with metastatic melanoma, and anti-Ox40 antibodies are currently being tested in phase I/II clinical trials. Therefore, the combination described here can be tested in patients with injectable sites of lymphoma, even if they have CNS disease.

Disclosures:
No relevant conflicts of interest to declare.
Distress Screening Scores of Malignant and Benign Hematology Patients: Results of a Pilot Project.
Authors: McLellan Linda , Pohlman Brad , Rybicki Lisa , Foster Larry , Tench Shawnda , Cooper Michele , McKenzie Millie , Kilbane Megan , Wright Cheryl , Dimitrov Julie , Bauer Julianne , Dabney Jane , Savage Barbara , Poole Christa , Barrat-Gordon Rene' , Fireman Karen , Bolwell Brian J. 
Published: October 2019

Abstract
Abstract 3173
The Cleveland Clinic Taussig Cancer Institute completed a pilot project on distress screening as part of the plan to address the American College of Surgeons Commission on Cancer requirement (Standard 3.2: Psychosocial Distress Screening) to screen malignant and benign hematology patients for distress and psychosocial health needs. Over a two week period every hematology patient seeing a physician or mid-level provider completed the distress screening instrument Emotions Thermometer (ET), a five dimensional tool that includes four predictor domains: distress, anxiety, depression, anger and one outcome domain of need for help. Each domain is rated on a 0 to 10 Likert type scale, in a thermometer format. With respect to validity and reliability, the sensitivity and specificity of the ET tool has been found comparable to known validity and reliability of other accepted measures of distress, depression, and anxiety (Mitchell, et al, 2009). Per National Comprehensive Cancer Network (NCCN) guidelines, a score of 4 or higher on distress screening warrants a referral to a psychosocial professional. Distress scores 4 and over were compared among the diagnoses using the Chi-Square test. When the overall P-value was significant (P <0.05), at least two groups differed, and pairwise comparisons were conducted to determine which diagnostic groups differed.
Of the five thermometer domains, patients scored highest on anxiety. There were no differences among diagnoses on anger (P=0.51), but there were differences in the other four domains (P<0.001 distress, depression, and need for help; P=0.026 anxiety). For all four, pairwise comparisons indicated that multiple myeloma patients had higher (worse) scores on anxiety, distress, depression, and need for help than all other diagnoses; there were no differences among benign hematology, leukemia/MDS/CML, or lymphoma/CLL.
While this pilot project does not answer why multiple myeloma patients report levels of psychosocial distress significantly higher than other hematology patients, increased attention needs to be given to address these patients' experience of anxiety, depression, and distress. This project provides valuable information about the levels of distress experienced among all hematology patients and is useful for determining staffing levels of psychosocial professionals needed to address distress.
Percentage of Emotion Thermometer Scores Over 4 Diagnosis Distress Anxiety Depression Anger Help Benign Hem 18% 27% 18% 12% 7% Leuk/MDS/CML 19% 28% 17% 9% 14% Lymph/CLL 18% 31% 16% 14% 13% Myeloma 38% 44% 35% 15% 27% P-value <0.001 0.026 <0.001 0.51 <0.001

Disclosures:
No relevant conflicts of interest to declare.
Partial Reversal of Dabigatran Effect by a Prothrombin Complex Concentrate in a Model of Thrombin Generation
Authors: Hoffman Maureane R. , Volovyk Zoya , Monroe Dougald M. 
Published: October 2019

Abstract
Abstract 3420
Dabigatran etexilate (Pradaxa) is a prodrug that is metabolised to a small molecule direct thrombin inhibitor. It has some more desirable charactersitics than warfarin for long-term anticoagulation of patients with atrial fibrillation, particularly the fact that it does not routinely need laboratory monitoring. However, it has the drawback that it is not readily reversable. While the package insert suggests administration of fresh frozen plasma or recombinant FVIIa as “antidotes”, there is no good theoretical or experimental basis to support this recommendation. Several sutdies have suggested that prothrombin complex concentrates (PCCs) can partially reverse the effects of dabigatran on laboratory assays. However, there is still much controversy over the potential of PPCs to reverse dabigatran anti-coagulation. The goal of our studies was to assess the effects of a 4-component PCC (Beriplex, CSL-Behring) on parameters of thrombin generation in PRP and a cell-based model. This allow us to use varying levels of dabigatran and varying levels of PCC, a cell-associated source of tissue factor (TF), fresh platelets, and either plasma or plasma levels of coagulation factors. Thrombin generation was assessed continuously using a fluorogenic thrombin substrate in a fluorescent plate reader. Dabigatran (Selleck Chemicals) was dissolved in DMSO and added to the test plasma at concentrations from 189–944 ng/mL. Beriplex was added to test plasma at concentrations from 0.25 FIX units/mL to 2.0 FIX units/mL. As others have reported for conventional calibrated automated thrombogram (CAT) assays, we found that dabigatran prolonged the lag before onset of thrombin generation. It also progressively depressed the rate and peak level of thrombin production. We found that the addition of Beriplex increased the rate and peak level of thrombin generation in a dose-dependent manner, but had little effect on the lag. This effect was seen at all levels of dabigatran tested, with a level of 1 U/mL restoring the rate and peak levels of thrombin generation, as well as the area-under-the-curve, to normal levels. The addition of FIX alone at 1 U/mL had no significant effect on thrombin generation in the presence of dabigatran. The effects of Beriplex were similar, though not identical, to the pattern seen when prothrombin alone was added to this model. Thus, we hypothesize that Beriplex has its dominant effect on reversal of dabigatran effects by a prothrombin-mediated mechanism. This increases the burst of platelet surface thrombin generation. However, this unactivated PCC does not reverse the inhibitory effect of dabigatran on the amplification phase of hemostasis as reflected in the lag time before the onset of thrombin generation. Thus, Beriplex corrects some, but not all, parameters all of thrombin generation affected by dabigatran in this model.

Disclosures:
Hoffman: CSL Behring: Research Funding.