bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Level Survival for Patients with Multiple Myeloma: Variation and Growing Disparity for Patients of Minority Race or Ethnicity
Authors: Pulte Dianne , Redaniel Maria Theresa , Brenner Hermann , Jansen Lina , Jeffreys Mona 
Published: October 2019

Abstract
Abstract 3126

Background
Survival for patients with multiple myeloma has increased during the first decade of the 21st century, especially in people diagnosed at a younger age. It is currently unknown whether the improvements in survival have extended equally to people of minority ethnic and racial groups. A recent publication found higher incidence and lower survival for AA versus whites. However, the above publication did not include detailed data on changes in survival in different time periods and little data is currently available for the Hispanic or Asian population. Here, we examine changes in survival in patients with myeloma by racial and ethnic group.

Methods
Using cancer registry data from the Surveillance, Epidemiology and End Results Program (SEER9), we assessed trends in 5-year relative survival for patients with multiple myeloma by racial and ethnic group, including non-Hispanic whites (nHw), African-Americans (AA), Hispanics, and Asian-Americans (Asian) for the periods 1993–97 and 2003–07. Model-based period analysis was used to obtain the most up-to-date measurements of survival. Age adjusted analysis was performed using age-standardized survival with age adjustment according to the International Cancer Survival Standard.

Results
Overall, five-year relative survival improved for the time periods studied. Ethnic/racial analyses showed that this was the case for nHw and AA patients. Hispanic and Asian patients had the highest relative survival in the earlier time period, but smaller improvement in survival was seen in these compared to other groups (see table). Age at diagnosis varied significantly between racial and ethnic groups. Age adjusted 5-year relative survival rates showed an increase of 11.7 percentage units for nHw and smaller improvements for AA, Hispanic and Asian patients (see table.)

Conclusions
Although survival improved greatly for nHw with myeloma between 1993–97 and 2003–07, smaller improvements were observed for people of other racial or ethnic groups. Possible reasons for this disparity include lower rates of transplant among patients of minority ethnic or racial background, less frequent use of newer treatment options, later diagnosis, and differences in response rates to newer medications. Further explanatory studies are required to investigate these possibilities.

Disclosures:
No relevant conflicts of interest to declare.
Intravenous Gammaglobulin (IVIg) Therapy Prevents Antibody-Mediated Transfusion Related Acute Lung Injury (TRALI) by Directly Inhibiting Recipient Neutrophil Activation in a Murine Model
Authors: Semple John W. , Kim Michael , Hou Jing , Lee Young Jin , Tabuchi Arata , Kuebler Wolfgang M. , Lazarus Alan H 
Published: October 2019

Abstract
Abstract 42
Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion-related fatalities and most TRALI reactions are thought to be caused by donor antibodies. Because intravenous gammaglobulin (IVIg) therapy has been shown to be beneficial in many antibody-mediated disorders, we hypothesized that IVIg would be effective in treating antibody-mediated TRALI. TRALI was induced in CB.17 SCID mice by injection of an anti-murine major histocompatibility complex (MHC) class I antibody (34-1-2s). The mice were treated with doses of IVIg either prophylactically 18 hours before TRALI induction or after the first symptoms of TRALI were observed (within 3 minutes after 34-1-2s injection). Body temperatures, lung edema, mortality and neutrophil activation were assessed. In IVIg non-treated mice, injection of 34-1-2s caused significantly reduced body temperatures indicating systemic shock within 2 minutes post injection. Pulmonary neutrophil accumulation and mortality occurred within 1 hour post 34-1-2s injection and mortality reach 25% by 2 hours post administration. When bone marrow neutrophils were purified after 34-1-2s administration, they produced significantly more reactive oxygen species compared with 34-1-2s non-treated mice. In contrast, if the mice were pre-treated with either 1 or 2 g/kg IVIg 18 hours before 34-1-2s-TRALI induction, they were completely protected from systemic shock, lung edema and mortality. The prophylactic in vivo IVIg treatment also significantly reduced 34-1-2s-induced neutrophil ROS production. IVIg's effect on ROS production appeared to be due to a direct contact mechanism as titrations of IVIg significantly inhibited the ability of neutrophils to produce ROS in vitro. In mice treated with IVIg 2–3 minutes after 34-1-2s-TRALI induction (when symptoms were first observed), there was also significant protection against the lung damage and mortality. In contrast, IVIg treatment was not as effective against acute lung injury induced by acid inhalation. The results suggest that the treatment of antibody-mediated TRALI reactions with IVIg can effectively prevent pulmonary reactions and mortality and it does so by directly interfering with 34-1-2s-induced neutrophil activation.

Disclosures:
No relevant conflicts of interest to declare.
Pseudotumor Cerebri Associated with All-Trans Retinoic Acid Treatment During Induction Therapy for Acute Promyelocytic Leukemia: A Case Report and Literature Review
Authors: Holmes Dylan , Aboulafia David M. 
Published: October 2019

Abstract
Abstract 4264
Pseudotumor cerebri (PC) is a rare disorder characterized by elevated intracranial pressure with normal cerebrospinal fluid composition, normal cranial imaging findings, and symptoms and signs of increased intracranial pressure. A number of medications have been linked to PC including vitamin A and its derivative all-trans-retinoic acid (ATRA). Herein, we describe the case of a 38-year-old woman who was diagnosed with PC during standard induction treatment for acute promyelocytic leukemia (APL). Her neurologic complaints of severe headache and diplopia improved slightly after ATRA was discontinued and she was treated with acetazolamide, but symptoms did not abate until fluconazole was held five days later. Through a literature review, we identified 41 case reports of APL patients with ATRA-associated PC, 23 of which provided details of clinical presentation and follow-up. The median age at diagnosis of PC was 27 for females and 16 for males; the female-to-male ratio was 1.3:1. All 23 patients complained of headache; papilledema was present in all 21 instances (100%) where a retinal exam was described. ATRA was held due to PC in 20 cases (87%), and neurologic symptoms resolved without further intervention in 7 of 20 (35%). The remaining 13 patients were treated with diuretics (11 of 13 cases, 85%), high-volume lumbar punctures (5, 38%), corticosteroids (4, 31%), and/or analgesics (3, 23%). Including our index patient, eight patients were rechallenged with ATRA after neurologic improvement, and 5 (63%) required further interventions to resolve recrudescent symptoms. We identified one other patient whose neurologic complaints persisted despite dose reductions in ATRA. This patient improved only after fluconazole was discontinued. Because both ATRA and fluconazole are metabolized by the cytochrome P-450 system, we suggest that if taken concurrently, they may exacerbate the risk of PC. Physicians should be aware of this interaction between ATRA and fluconazole and consider discontinuing both fluconazole and ATRA in APL patients who develop PC.

Disclosures:
No relevant conflicts of interest to declare.
Anti-Vascular and Anti-Tumor Effects of the Vascular Disrupting Agent ASA404 (DMXAA) in Human Acute Leukemia Xenograft Models
Authors: Schaefer Christopher W , Lal Deepika , Vethanayagam R Robert , Spernyak Joseph A , Seshadri Mukund , Wang Eunice S. 
Published: October 2019

Abstract
Abstract 4293
Acute leukemia growth and expansion within the marrow microenvironment is linked to increased vascularization. Vascular delivery of chemotherapy drugs within the marrow space may also be an important mediator of anti-leukemic activity. We examined the effects of a tumor -vascular disrupting agent (tumor-VDA), ASA404 (DMXAA; Vadimezan), against human acute leukemia alone and in combination with anthracycline therapy. Exposure of human acute leukemia cells (HEL, Raji) to ASA404 (200–1000 mM) in vitro for up to 72 hours resulted in no evidence of direct cytotoxicity. However, contrast-enhanced magnetic resonance imaging (CE-MRI) performed in mice bearing subcutaneous HEL xenografts revealed an early increase in vascular permeability 4 hours after treatment with a single dose of ASA404 (25 mg/kg). This was followed by significant vascular disruption at 24 hours after therapy as determined by tumor immunohistochemistry. In systemic leukemia xenograft models established with luciferase-transfected HEL and Raji cells, continuous ASA404 treatment (20 mg/kg twice weekly) slowed overall systemic leukemia disease progression (as determined by whole animal bioluminescent imaging) in association with marked marrow vessel dilation, loss of vascular patency, and marked erythrocyte extravasation within the marrow microenvironment. These effects were accompanied by 20–30-fold elevations of circulating systemic TNF-alpha levels in ASA404 versus vehicle treated animals. Combining in vivo ASA404 treatment with anti-human VEGF antibody (bevacizumab) therapy further inhibited leukemia growth as compared with vehicle- or single-agent treated controls. However, concomitant administration of ASA404 with doxorubicin chemotherapy did not improve anti-leukemia effects and was in fact less effective than single agent therapy. In summary, our results demonstrate that ASA404 therapy is capable of mediating in vivo anti-tumor, anti-vascular and immunomodulatory effects in human acute leukemia models. Further strategies to modulate the marrow environment by combining a vascular disrupting agent with other biological agents for acute leukemia therapy may be warranted. However, given the time-dependent effects of VDAs such as ASA404 on tumor vascular function, combining VDAs with chemotherapy is likely to require further optimization of sequence and schedule of administration to ensure adequate marrow drug delivery and maximal therapeutic efficacy in hematological malignancy.

Disclosures:
No relevant conflicts of interest to declare.
Detection of CD55- and CD59-Negative Immature Reticulocytes May Improves Sensitivity/Specificity to Identify a Minor Population of PNH-Type Cells in Patients with Myelodysplastic Syndrome/Aplastic Anemia
Authors: Obara Naoshi , Satoh Shoko , Okoshi Yasushi , Chiba Shigeru , Ninomiya Haruhiko 
Published: October 2019

Abstract
Abstract 4373

[Background]
Paroxysmal nocturnal hemogloblinuria (PNH) is a hemolytic disease characterized by complement-sensitive red blood cells (RBC). Sometimes, a tiny amount of PNH-type, i.e., CD55- or CD59-negative, red blood cells as well as neutrophils can be detected in peripheral blood from patients with myelodysplastic syndrome (MDS)/ aplastic anemia (AA). It has been reported that the presence of PNH-type cells is correlated with a good response to immunosuppressive therapy foe these disease. However, the ratio of PNH-type RBCs to normal RBCs is always underestimated because PNH-type red blood cells have a shortened life span in the circulation, and there are some patients who have very low number of circulating granulocytes.

[Metods]
Peripheral blood was obtained from 37 patients with MDS or AA and 30 normal subjects. Mononuclear cells were then stained with antibodies against CD55, CD59, and CD71, and analyzed by a flowcytometer. Subsequently, CD55 and CD59-negative and CD71-positive reticulocytes, representing an immature fraction of reticulocytes, were identified. Sensitivity and specificity were compared for the detection of PNH-type immature reticulocytes with those evaluated by a PNH-type RBC- and granulocyte-detecting method.

[Results and discussion]
All 30 normal subjects were negative when the cut-off value for CD55 and CD59-negative and CD71-positive reticulocytes was set at 0.008%. With this cut-off value, PNH-type immature reticulocytes were detected in 18 out of 37 MSA/AA patients. When the cut-off values for PNH-type RBCs and granulocytes were set at 0.005% and 0.01%, respectively, in accordance with the original report by Sugimori, et al, 16 and 18 cases among 37 MDS/AA patients were positive for PNH-type RBCs and granulocytes, respectively. All the 16 cases positive for PNH-type RBCs were also positive for PNH-type granulocytes and immature reticulocytes, while 2 cases negative for PNH-type RBCs were evaluated to be positive for both PNH-type granulocytes and immature reticulocytes. All the cases positive for granulocytes were also positive for immature reticulocytes, and vice versa. These observations indicate that the method to detect minor population of PNH-type immature reticulocytes is feasible and comparable with that to detect PNH-type granulocytes, and could be superior to the PNH-type RBC-detection method in terms of sensitivity, without reducing specificity. If the evaluation of PNH-type granulocytes is difficult, PNH-type immature reticulocytes may be a good alternative to be evaluated.

Disclosures:
No relevant conflicts of interest to declare.
Efficacy and SAFETY of Dasatinib 50 MG Once Daily DOSE In PATIENTS with CHRONIC PHASE CML WHO Failed IMATINIB
Authors: Yassin Mohamed A. , El-Ayoubi Hanadi R. , Kamzoul Rami T 
Published: October 2019

Abstract
Abstract 4440

Background:
Dasatinib is multi-targeted kinase inhibitor and it is approved therapy for patients with imatinib-resistant or imatinib-intolerant CML or newly diagnosed CML (chronic phase). The recommended dosing regimen is Dasatinib 100 mg once daily (QD), based on results from the CA180-034 dose-optimization study in patients with CML-CP and resistance or intolerance to prior therapy and it is active against the vast majority of BCR/ABL mutations apart from T315I and can overcome emerging resistance.

Aims:
to assess the efficacy and safety of 50 mg once daily dose of Dasatinib in achieving complete hematological remission (CHR),complete cytogenetic remission(CCYR) and major molecular response (MMR) in patients with CML-CP and resistance or intolerance to prior imatinib therapy.

Patients and Methods:
nine adult patients (aged ≥18 years) with prior imatinib failure were enrolled in this study after informed consent, between September and November 2009 and followed for 18 months. Received Dasatinib 50 mg once daily as second line therapy and were evaluated at baseline,3,6, 12, and 18 months as per European leukemia net(ELN) guidelines for response CHR, CCYR, MMR mutation analysis was not done because it is not available in our centre. Patients with baseline pleural effusion or ejection fraction less than 50% were excluded. Chest x-rays were performed at baseline and at 6 months, or more frequently if indicated clinically. Pleural effusions were graded according to CTCAE v3.0 criteria: grade 1, asymptomatic; grade 2, symptomatic, ≤ 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, > 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability.

Results:
All patients achieved complete hematological as well as complete cytogenic response within three months and remains so at 6 and 12 months assessment, 18 months assessment for molecular response showed that 8 out of 9 achieved major molecular response and one patient achieved complete molecular response, grade two or more toxicity were not seen in any patient. Anemia and neutropenia Grade ≥ 2 were not observed in any patient, thrombocytopenia grade one was observed in one patient. Non-hematologic adverse drug reactions like fluid retention; including pleural effusion, nausea vomiting, myalgia, muscle inflammation and rash were not observed in any patient.

Conclusion:
In patients with chronic phase chronic myeloid leukemia who failed first generation TKI (Imatinib). Dasatinib 50 mg once daily is safe, effective and capable of achieving complete hematological and cytogenetic remissions well as major molecular response‘ with better toxicity profile keeping in consideration the small number of patient’s further studies are needed to confirm this result.

Disclosures:
No relevant conflicts of interest to declare.
Induction Therapy with Novel Agents Improves Relapse-Free Survival After Autologous Stem-Cell Transplantation in Multiple Myeloma
Authors: Eder Sandra , Lamm Wolfgang , Gruber Michaela , Schauer Beatrice , Ackermann Jutta , Gisslinger Heinz , Drach Johannes 
Published: October 2019

Abstract
Abstract 4494

Introduction:
Multiple myeloma (MM) is still an incurable disease. Initial treatment depends on age, risk stratification and co-morbidities. High-dose therapy followed by autologous stem-cell transplantation (ASCT) is the standard of care in transplant eligible patients.
In recent years, novel agents became a promising role in newly diagnosed, relapsed myeloma as well as in maintenance treatment. Bortezomib, a proteasome inhibitor, and thalidomide or lenalidomide, immunomodulatory agents have been found to be superior to chemotherapy regimens.

Methods:
121 adult patients (50 female, 71 male) with a median age of 53.5 years at diagnosis underwent autologous stem-cell transplantation at the Medical University of Vienna between June 1985 and September 2010. Median age at ASCT was 57.4 years.
46 patients received novel therapeutic agents, such as VDT (bortezomib, dexamethasone, thalidomide), Rd (lenalidomide, low dose dexamethasone) and VD (bortezomib, dexamethasone), whereas 75 patients were treated on the basis of chemotherapy schedules, e.g. VAD-based (vincristine, doxorubicin, dexamethasone).

Results:
Progression-free survival (PFS) after ASCT was 7.9 months (6,4 – 9,3, 95% CI) after treatment with chemotherapy, whereas it was increased to 21,6 months (5 – 38,1, 95% CI) after initial treatment with either bortezomib and/or thalidomide/lenalidomide (p= 0.001).
Post-induction VGPR or better was superior with new agents compared to chemotherapy, 34,1% versus 11,9%, respectively. Post-transplant VGPR or better was as high as 68% after initial therapy with novel agents prior to transplant, whereas VGPR or better was reached in 48.6% in patients receiving chemotherapy.

Conclusion:
Novel agents significantly prolong relapse-free survival in patients eligible for autologous stem-cell transplantation. Previous studies showed improved remission duration with thalidomide or lenalidomide maintenance after ASCT. The data of maintenance therapy after ASCT at our department will be presented at the meeting.

Disclosures:
No relevant conflicts of interest to declare.
Design, Synthesis and Biological Evaluation of A Boron Containing Retinoid As a Novel Therapeutic Agent for Acute Promyelocytic Leukemia
Authors: Schinke Carolina D. , Das Bhaskar C , Goel Swati , Bhagat Tushar , Nischal Sangeeta , Minucci Saverio , Kabalka George , Gallagher Robert E. , Evans Todd , Platanias Leonidas C , Verma Amit 
Published: October 2019

Abstract
Abstract 5008
Cure rates of acute leukemia remain poor emphasizing the need to for novel therapies. All trans retinoic acid (ATRA) is an effective therapeutic agent in a subtype of acute myeloid leukemia and relieves transcriptional repression induced by the PML-RAR oncoprotein by binding to the retinoic acid receptor. Even though ATRA is effective, the treatment course is characterized by a high rate of toxicity and ATRA resistance is seen in some cases of acute promyelocytic leukemia. In an attempt to improve outcomes, we devised a methodology for creation of boronic acid and other newer retinoic acid analogues. Our lead compound, MA-21 was generated by replacing the terminal carboxyl group of ATRA with a boronic ester using Wittig reactions. Computation modeling revealed that MA-21 can fit in the RARa pocket and can form increased covalent bonding with cysteine residues within the receptor. As opposed to other synthetic retinoids, the addition of a boron atom resulted in significantly enhanced cytotoxicity in leukemic cell lines, even those that were resistant to ATRA. MA-21 at 1uM dose led to significant reduction in proliferation of ATRA sensitive NB4 APL cell line (1.8 fold decrease after 96hrs, p= 0.028) as well as in ATRA resistant cell lines NB4.007/6 (3.3 fold decrease after 72hrs and 2.1 decrease after 96hrs, p values of 0.018 and 0.046) and NB4.306 (2.6 fold decrease after 96hrs, p= 0.032). MA-21 was able to induce these effects by inducing significant G2/M cell cycle arrest and not by increased apoptosis or cellular differentiation. Cell cycle was assessed by Flow Cytometry after 96hrs of incubation and showed a significant increase in G2/M percentage in the ATRA sensitive and resistant cell lines compared to DMSO (NB4 cell line- 1.35 fold increase, p= 0.035; NB4.007/6- 1.35 fold increase, p= 0.015 and NB4.306- 2 fold increase, p= 0.023). Thus, we demonstrate novel synthetic methodology to synthesize boron containing novel retinoids and demonstrate the potential of these compounds as therapeutic agents in resistant leukemias.Figure1:Structures of ATRA and MA-21Figure1:. Structures of ATRA and MA-21

Disclosures:
No relevant conflicts of interest to declare.