bluuebunny/crossref_metadata_2025_split huggingface dataset:
PPARγ Agonists Inhibit Adhesion Signal to Endothelial Cells in the Differentiation Induction of HL-60 Acute Promyelocytic Leukemia Cells
Authors: Park Jinny , Yoon JiWon , Yu Hong-Nu , Noh Eun-Mi , Hong On-Yoo , Kim Jong-Suk 
Published: October 2019

Abstract
All-trans retinoic acid (ATRA) has successfully been used in the treatment of acute promyelocytic leukemia (APL) patients, with a remission rate of greater than 90% . Despite the high cure rates, induction mortality is a still a problem in APL. One of the most common causes of death was the differentiation syndrome (DS) . The early administration of high-dose dexamethasone at the onset of the first signs or symptoms of DS is crucial, however specific biological therapies to counteract the syndrome are still not available. Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-dependent transcription factor and a member of the nuclear receptor superfamily, which is expressed in normal monocytes, various leukemias, and epithelial malignancies. PPARγ is highly induced in differentiating myeloid cells and subsequently contributes to their differentiation. Differentiation induction of APL cells is associated with increased expression of specific adhesion molecules and inflammatory cytokines, which may promote activation, migration, and adhesion of these cells. Here, we studied the effect of PPARγ agonists on the adhesion of a human leukemia cell line (HL-60) to endothelial cells. HL-60 cells were differentiated into macrophage-like cells by a PKC activator, 12-O-Tetradecanoylphorbol-13-acetate (TPA). Differentiation was determined by an increase in reactivity with the CD11b antibody. For the adhesion assay, the Matrigel transwell system was used. During the differentiation of HL-60 cells, PPARγ agonists acitvate TPA-induced CD11b expression. However, PPARγ agonists completely blocked TPA-induced ICAM-1 expression of endothelial cells, which resulted in the inhibition of adhesion of HL-60 cells to endothelial cells. These responses also were reversed by PPARγ antagonist (GW9662), indicating that PPARγ agonists inhibits the adhesion of the HL-60 cells to endothelial cells through a PPARγ dependent mechanism. These results suggest that PPARγ agonists inhibit TPA-induced adhesion signal in the between HL-60 cells and endothelial cells, and may control differentiation syndrome in APL patients.

Disclosures
No relevant conflicts of interest to declare.
Bridging to Second Allogeneic Peripheral Blood Stem Cell Transplantation with Nelarabine in a Patient with Multiply Relapsed/Refractory T-Cell ALL
Authors: Baptista Jacqueline , Tollkuci Eris , Nathan Sunita , Maciejewski John J. , Larson Melissa L. , Akpek Gorgun 
Published: October 2019

Abstract
T-cell acute lymphoblastic leukemia (ALL) is a very challenging disease to attain durable remission once relapses. We treated a 40 year-old female with T-cell ALL, normal cytogenetic who relapsed twice after her matched related donor allogeneic stem cell transplantation (allo-SCT) with Nelarabine achieving third complete remission prior to second allo-SCT. She was initially treated with HyperCVAD x 5 cycles with IT chemo (negative cytopathology). After achieving complete remission (CR), she received PK-directed IV Busulfan and Fludarabine myeloablative conditioning followed by 12/12 HLA-MRD allo-SCT with 11.06 x 106 CD34+cells/kg. GVHD prophylaxis was Tacrolimus and mini-Methotrexate (5 mg/m2/dose). She engrafted on time. She never had GVHD. On day+ 100, bone marrow biopsy revealed relapsed disease involving 60% of marrow space. Patient was treated with one cycle augmented HyperCVAD resulted in second CR. She developed elevated transaminases, liver biopsy was consistent with NASH and drug-induced liver injury, negative for GVHD. She was given alpha interferon 3 million units MWF in attempt to induce GVHD/GVL while pending insurance approval for donor lymphocyte infusion. She developed full donor chimerism as well as extensive chronic GVHD involving skin, liver, skin, lung, eyes, vagina, and mouth after interferon. She was treated only with topical steroid therapies and remained in CR until day+266. On Day+266, she was again found to have relapse of her disease with significant leukocytosis and circulating blasts. CT scan showed recurrent large anterior mediastinal mass. She was treated with Cytoxan (500 mg/m2) and Etoposide (100 mg/m2 x 5 days), complicated with neutropenic fevers before receiving outpatient Nelarabine. She recovered with progressive leukemia, which was treated with a single dose of Cytoxan 600mg/m2. She developed diffuse alveolar hemorrhage, treated in the MICU with high dose steroids and antimicrobials. She was discharged to outpatient clinic and given Nelarabine at 1500 mg/m2 on days +1, +3, +5, every 3 weeks for 2 cycles. Her clinical condition and peripheral counts improved with disappearing peripheral blasts after the initial cycle of Nelarabine. She received second cycle and subsequent restaging studies showed remission marrow (CR-3) with complete resolution of mediastinal mass on CT scan. She developed mild neuropathy after Nelarabine. She is currently inpatient receiving her for second MRD allo-SCT. This case is noteworthy and clearly illustrates lack of GVL effect in T-cell ALL and an efficacy of two cycles of Nelarabine even in the setting of refractory T-cell ALL relapsing twice after allogeneic SCT.

Disclosures
No relevant conflicts of interest to declare.
TP53 Mutations Determine Outcome of Patients (pts) with High-Risk Myelodysplastic Syndrome (HRMDS) and Acute Myelogenous Leukemia (AML) Regardless of Karyotype and ELN Risk Stratification
Authors: McCloskey James K. , McKenna Marshall , Koprivnikar Jamie L. , Depadova Samantha , Stanislaus Genique , Goldberg Stuart L. , Faderl Stefan 
Published: October 2019

Abstract
Background: Cytogenetic and molecular abnormalities are the backbone of risk stratification for pts with AML/MDS. Yet, the current stratification systems still fail to identify some pts at high risk for treatment failure. TP53 mutations have been linked to poor outcome and treatment resistance in many malignancies. We conducted a retrospective case-control study of pts with HRMDS and AML with TP53 mutations (TP53 m) to define disease characteristics, response, and outcome after transplant (HSCT).
Methods: Twenty-one consecutive pts with HRMDS or AML were treated between January 2014 and March 2016 who wereTP53 m. The pts were compared to a control cohort of 46 pts with wild type TP53 (TP53 wt). Mutation analysis was performed using next generation sequencing. All AML pts were treated with a standard 3+7 induction protocol. Pts were excluded for incomplete cytogenetic and molecular data.
Results: A total of 21 patients were identified with TP53 m (14 HRMDS, 11 AML). The median age of the 21 pts was 64 years (range 32-84). Pts with TP53 m were older (median age 64 vs 55 years, p=.0256) and exhibited a higher rate of adverse cytogenetics (71% vs 30.4%, p=.043) when compared to TP53 wt. Secondary AML was also more common with TP 53 m (57% vs 31%, p=.05). Pts with TP53 m were less likely to achieve CR (33% vs 74%, p=.009). Three pts with TP53 m proceeded to transplant (2 with HRMDS and 1 with AML).
With a median follow up of 3.4 months (range 0.3-73) the estimated PFS and OS at 18 months was superior in TP 53 wt compared to TP 53 m (17% vs 69%, p=.037 and 17% vs 50%, p=.0095 respectively). HSCST was associated with a 70% reduction in mortality, but this was not statistically significant (p=.067).
Conclusion: TP 53 mutations in pts with HRMDS and AML are associated with advanced age, high risk cytogenetic abnormalities, and secondary AML. Our findings demonstrate that TP53 m in HR MDS and AML is associated with poor clinical outcome including lower CR rates, and lower PFS and OS. Different treatment strategies need to be devised for these pts.

Disclosures
McCloskey: Incyte: Consultancy; Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Koprivnikar:Alexion: Consultancy, Speakers Bureau. Depadova:Amgen: Speakers Bureau. Stanislaus:Novartis: Consultancy, Speakers Bureau. Goldberg:COTA Inc: Employment; Bristol Myers Squibb, Novartis: Speakers Bureau; Neostem: Equity Ownership; Novartis: Consultancy; Pfizer: Honoraria. Faderl:Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Amgen: Speakers Bureau.
Adverse Hematological Effects of Benzene Exposure Among Elderly Subjects after a Flaring Disaster at the BP Refinery Plant in Texas City
Authors: D'Andrea Mark A , Reddy G. Kesava , Mitter Ajay 
Published: October 2019

Abstract
Objective: To evaluate the health risks associated with benzene exposure in elderly subjects following a flaring disaster at the BP refinery in Texas City, Texas.
Methods: Elderly subjects aged 60 years and older who had been exposed and unexposed to benzene were included. We reviewed medical charts and compared measures of white blood cells (WBC), platelets, hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), aspartate amino transferase (AST), and alanine amino transferase (ALT) in exposed and unexposed elderly subjects.
Results: Records from 294 elderly subjects (benzene exposed, n=216 and unexposed, n=78) were reviewed. Benzene exposed subjects had significantly higher levels of WBC (X 103 per µL) (7.7±1.9 versus 6.3±1.5, P=0.0000) and platelet (X 103 per µL) counts (256.8 ± 51.6 versus 237.9 ± 41.9, P=0.0104) compared with the unexposed subjects. Serum creatinine levels (mg/dL) were also significantly increased in the exposed group compared with the unexposed group (1.1 ± 0.4 versus 0.9±0.2, P=0.000). Serum levels of ALP (IU/L) were significantly elevated in the exposed subjects compared with the unexposed subjects (87.5 ± 23.6 versus 72.5 ± 17.8, P=0.000). Similarly, benzene exposed subjects had significantly higher levels of AST (24.8 ± 6.2 versus 19.2 ± 5.1, IU/L, P=0.000) and ALT (24.2 ± 8.6 versus 19.1 ± 4.8, IU/L, P=0.000) compared with those unexposed to benzene.
Conclusion: Benzene exposure resulted in significant alterations in hematological and hepatic profiles among elderly subjects.

Disclosures
No relevant conflicts of interest to declare.
Impact of Previous Invasive Fungal Infections on the Outcome of Patients Undergoing Allogeneic Hematopoietic Stem Cells
Authors: Maffongelli Gaetano , Maffongelli Gaetano , Maffongelli Gaetano , Cudillo Laura , Di Piazza Fabio , Malagnino Vincenzo , de Santis Giovanna , Mariotti Benedetta , Ceresoli Eleonora , Cerretti Raffaella , Picardi Alessandra , Andreoni Massimo , Arcese William , Sarmati Loredana 
Published: October 2019

Abstract
Introduction: Outcome in allogeneic HSCT varies widely depending on disease type, stage, stem cell source, HLA-matched status and conditioning regimen. IFI is a possible complication of HSCT and a prior IFI increases the patient's risk for transplant related mortality due to the possibility of reactivation of the fungal infection. This study aimed to evaluate the impact of a previous IFI history on transplant outcome
Methods: We retrospectively collected the clinical data of patients considered eligible for allogeneic HSCT during 2014 at the Rome Transplant Network (RTN), a JACIE accredited metropolitan transplant program established in Rome since 2006. The observation of patients was continued until 31 December 2015. The diagnosis of IFI were defined as possible, probable and proven as established by European Organization for Research and treatment of Cancer.
Results: Twenty-one (37%) out of 57 eligible patients had an IFI episode before transplant: 6 of the episodes were proven, 4 probable and 11 possible. Overall, 10 (47%) pneumonia, 4 (19%) gastroenteritis, 3 sinusitis, 2 candida sepsis, 1 meningitis and 1 cutaneous abscess were registered. Five out of 21 patients (23%) died before HSCT versus 2 of 36 patients (5%) without previous documented IFI, [OR 5.31 95% CI 0.93- 30.40 , p value 0.06 Fisher Test], .
A larger percentage of patients with past IFI waited HSCT over 6 months from the date of eligibility in comparison with those without previous IFI [43% vs 30% ; OR 1.87 95% CI 0.54-6.40 , p value 0.5 Yates test]; Sixteen (57%) out of 28 dead patients in the pre-transplant period have had a previous IFI episode vs 5(17%) out of patients alive [OR 6.4, 95% CI 1.89-21.68, p value: 0.004 Yates Test].
In the post-transplant period, only 6% of patients with a past IFI, experienced an engraftment in a time of < 15 days, vs 30% of patients without past IFI [OR 4.86 CI 95% 0,5-43,2, p value 0,2 Yates test]. In the post-transplant period, a IFI was diagnosed in 13 (26%) patients; ten (76%) out of 13 patients had a past IFI versus 9 (24%) of the patients without IFI.. [OR 7.87, CI 95% 1,8-34,2, p value 0,005 Yates test].Among the dead HSCT patients, those who had a previous IFI had a lower median survival [160 days (range 22- 480)] compared to patients without a previous IFI who died [196.5 days period (range 20-820)].
Conclusions: A previous IFI episode in the pre transplant period slow the accessibility to the transplant, adversely affects the engraftment, and is significantly associated with increased post-transplant mortality

Disclosures
No relevant conflicts of interest to declare.
Durable Remission and Survival in Relapsed/Refractory Multiple Myeloma after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Cornelison A. Megan , Saliba Rima M , Ahmed Sairah , Nieto Yago , Bashir Qaiser , Shah Nina , Parmar Simrit , Patel Krina , Hosing Chitra , Popat Uday R. , Shpall Elizabeth J. , Champlin Richard E. , Qazilbash Muzaffar H. 
Published: October 2019

Abstract
Background: The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the setting of refractory multiple myeloma (MM) is still controversial. Although potentially curative in a subset of pts, concerns regarding treatment related mortality (TRM) and graft vs. host disease (GVHD) preclude its universal use. In this study, we evaluated the role of allo-HSCT for pts with relapsed MM.
Methods: 110 consecutive pts with relapsed MM underwent allo-HSCT at our institution between 2000 and 2014. The primary objective was to assess progression-free (PFS) and overall survival (OS).
Results: Median age at allo-HSCT was 54 (range, 32-71) years and median time from diagnosis to allo-HSCT was 35.7 (range, 8.6 to 228.8) months. Fifty-two (47%) and 49 (45%) pts had standard-risk (SR) and high-risk (HR) cytogenetics at the time of allo-HSCT, respectively. Pts received a median of 5 (range, 1-9) prior chemotherapy regimens and 99 (90%) pts had at least 1 (range, 0-3) prior auto-HSCTs. One hundred one (92%) pts received either a proteasome inhibitor (PI) or an immunomodulatory drug (IMiD) prior to allo-HSCT, with 65 (59%) receiving both. Sixty eight (62%) received allo-HSCT from matched related, 34 (31%) from matched unrelated, 5 (4%) from cord blood, and 3 (3%) from mismatched donors. Preparative regimen was fludarabine/melphalan-based in 88 (80%) and fludarabine/busulfan-based in 16 (15%) pts. Median time to neutrophil and platelet engraftment was 12 (range, 8-30) and 13 (range, 0-81) days, respectively. Ten pts died of non-relapse causes within 100 days (100-day TRM: 9%) and 21 (19%) within 1 year. Grade 1-4 acute GVHD was seen in 50 (45%) and cGVHD in 35 (32%) pts, respectively. Eighteen (16%) achieved a CR, 26 (23%) a VGPR and 38 (34%) achieved a PR, with an overall response rate of 73%. With a median follow up of 41.9 months (range, 6.4 to 172.9) in surviving pts, 1- and 2-year PFS were 23% and 15%, respectively (Fig 1). One and 2-year OS were 50% and 32%, respectively (Fig 2). HR cytogenetics at allo-HSCT were associated with a significantly shorter 2-year PFS (6% for HR vs. 23% for SR; p=0.007) and OS (p=0.01). A response <PR after allo-HSCT was also associated with significantly shorter 2-year PFS (p<0.001) and OS (p<0.001).
Conclusions: Allo-HSCT is associated with durable remission and survival in approximately 15% of heavily pretreated pts with relapsed/refractory MM. Novel, more effective approaches are needed for patients with HR cytogenetic abnormalities.
Figure 1 Progression-Free Survival Figure 1. Progression-Free Survival Figure 2 Overall Survival Figure 2. Overall Survival

Disclosures
No relevant conflicts of interest to declare.
hnRNP K Overexpression Drives AML Progression By Altering Pathways Critical for Myeloid Proliferation and Differentiation
Authors: Hornbaker Marisa J , Gallardo Miguel , Zhang Xiaorui , Ma Huaxian , Hu Peter , Khoury Joseph D , Kornblau Steven M. , Bueso-Ramos Carlos E , Post Sean M. 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a disease largely defined by recurrent genetic and chromosomal abnormalities. As such, The Cancer Genome Atlas' recent detailed examination of the most common genetic abnormalities that drive AML uncovered relatively few novel alterations. However, within this list of recurrently mutated genes was heterogeneous nuclear ribonucleoprotein K (HNRNPK). While previously unknown to impact AML, we recently identified HNRNPK as a haploinsufficient tumor suppressor at the 9q21.32 locus. In contrast to its tumor suppressive roles, hnRNP K is most customarily overexpressed, rather than underexpressed, in several solid tumors.
In this study, we show through FISH analyses, RNA expression profiling, and reverse phase protein array analyses that the HNRNPK gene is amplified with corresponding mRNA and protein overexpression in a sizeable cohort of patients with AML that do not carry a 9q.21.32 deletion. Together, this indicates that hnRNP K may be an uncharacterized oncogene in this context. Increased hnRNP K correlated with decreased event-free and overall survival, increased WBC, and increased bone marrow and peripheral blood blast percentage. High hnRNP K levels also correlated with elevated expression of histone modifiers (e.g., ASH2L and TRIM24), regulators of ribogenesis (e.g., nucleolin and EBP1), and potent oncogenes, such as c-Myc. Together, these observations indicate that increased hnRNP K expression significantly alters the landscape of myeloid biology and may thus contribute to the etiology of AML.
To directly interrogate this possibility in vivo, we generated a Vav-Cre;HnrnpkTg mouse model. In addition to significant differences in hnRNP K expression compared to Vav-Cre mice, Vav-Cre;HnrnpkTg mice exhibited reduced survival, development of transplantable myeloid malignancies, and enhanced HSPC proliferation and differentiation potential. Reflecting data from our patients, Vav-Cre;HnrnpkTg mice also exhibited elevated expression of critical oncogenic pathways such as c-Myc.
Currently, we are examining pharmacologic methods to abrogate the effects of aberrant hnRNP K expression on various activated pathways. Transplant models using diseased bone marrow from Vav-Cre;HnrnpkTg mice are being utilized to evaluate the efficacy of specific pathway inhibitors (i.e., bromodomain inhibitors or bortezomib) in prolonging survival and decreasing leukemic burden. These studies will provide the rationale for potential clinical trails that employ these agents for patients with hnRNP K-overexpressing AML.

Disclosures
No relevant conflicts of interest to declare.
Validation of the Khorana Score in a Large Cohort of Cancer Patients with Venous Thromboembolism
Authors: Chaudhury Ateefa , Balakrishnan Asha , Thai Christy , Holmstrom Bjorn , Nanjappa Sowmya , Ma Zhenjun , Zhou Junmin , Patel Ankita , Visweshwar Nathan , Jaglal Michael V. 
Published: October 2019

Abstract

BACKGROUND:
Venous thromboembolism is a well-known complication of malignancy. The Khorana Risk Score (KRS) utilizes the type of cancer, blood counts, and body mass index to predict risk of thrombosis in cancer patients. Patients with a KRS of greater than 3 are considered high risk for developing blood clots and may benefit from prophylactic anticoagulation. We wanted to determine if the use of the KRS would have led to prophylactic anticoagulation (AC) in these cancer patients prior to their thrombotic events.
METHODS:
This study utilized a group of 286 patients treated at Moffitt Cancer Center between May 1, 2010 and June 30, 2015 with a wide variety of cancer diagnoses with known venous thromboembolic events (VTE) (pulmonary embolism or deep venous thrombosis). We aimed to validate the KRS by retrospective analysis to determine if the KRS would have predicted VTE in these patients on the day of their venous thromboembolic event. The demographics are summarized using descriptive statistics. Wilcoxon rank-sum test is used for testing the difference in continuous variables. Fisher exact test is used for testing the difference in categorical variables.
RESULTS:
We found that the majority of these cancer patients with known VTE (89%) would have been classified as low risk of having VTE. Only 11% would have been classified as high risk to where prophylactic anticoagulation might have been indicated.
CONCLUSIONS:
We found that in a diverse group of cancer patients who had thrombotic events, the KRS did not appropriately stratify patients at the highest risk of VTE. The majority of patients with VTE were actually found to be low risk which would not have led to improved awareness or medication prophylaxis. Improved risk stratification methods are needed for cancer patients to implement an effective prophylactic strategy.
Table Table.

Disclosures
No relevant conflicts of interest to declare.
Dissecting Antigen-Specific T-Cell Immunity in Human Cancer and Acquired Resistance to Immunotherapy
Authors: Restifo Nicholas 
Published: October 2019

Abstract
T lymphocytes are at the very center of the rapidly expanding universe of cancer immunotherapy. We now know that each T cell clonotype can in fact contain a stem cell-like system, which is capable of self-renewal and differentiation. We have described the identification of human T memory stem cells (TSCM). TSCM maintain robust replicative capacity and are multipotent in their ability to give rise to cytolytic effector and memory progeny. Stem-cell-like T cells are epigenetically distinct. From their poised epigenetic and metabolic states, TSCM efficiently can give rise to cells with a multiplicity of identities required for successful immune responses, and collectively provide protection against infections and cancer.
We have visualized the chromatin states of TSCM on a whole genome level. We have found that the transcription factor Bach2 is a repressor of T cell receptor-driven programs. These findings go a long way in identifying a molecular mechanism that enables T cells to maintain their stem cell-like state. We have direct evidence that sufficient T cell activation can overwhelm the repressive influence of Bach2 through the action of the Akt kinase. Akt mediates the core events of T cell differentiation and it is possible to selectively block the Akt pathway with an allosteric inhibitor enabling the creation of long-lived, less-differentiated T cells that are much more effective therapeutically in a mouse model of established tumor. These findings form the basis for a novel immunometabolomic approach to improve cell-intrinsic features of therapeutic T cells in the clinic.
Finally, we will describe how even the most effective T cells can be thwarted by mechanisms in place in the tumor microenvironment. Our recent and unpublished findings involve two elements from the periodic table - potassium and oxygen - that can be immunosuppressive under certain physiologic conditions. We have also described an internal T cell checkpoint mechanism called Cish. We furthermore seek to find ways of overcoming the powerful physiology that can enable tumors to grow and kill their hosts. These efforts can produce T cells that are capable of increased anti-tumor efficacy.

Disclosures
No relevant conflicts of interest to declare.