bluuebunny/crossref_metadata_2025_split huggingface dataset:
Febrile Neutropenia in Children with Acute Lymphoblastic Leukemia Treated with BFM Protocols
Authors: Ozdemir Gul Nihal , Tuysuz Gulen , Apak Hilmi , Ozkan Alp , Yildiz Inci , Celkan Tiraje 
Published: October 2019

Abstract
Aim: Overall survival from leukemia is less in low and middle-income countries than in high-income countries. The aim of this study is to review febrile neutropenia (FN) episodes in children with acute lymphoblastic leukemia (ALL) treated with BFM (Berlin-Franfurt-Münich) protocols at a single center in Turkey.
Methods: Retrospective data were extracted from medical records of children (1-18 years old) with newly diagnosed and relapsed ALL and who were treated between 1995-2010 at Istanbul University, Cerrahpasa Medical Faculty, Pediatric Hematology Oncology Dept.
Results: Two hundred -forty-five FN episodes were detected in 96 evaluable children (mean age: 5.9±3.7 years; M/F: 50/46). According to BFM risk groups; 32 were SRG (standard risk group), 56 were MRG (medium risk group) and 8 were HRG (high risk group) patients. Fifteen patients had relapsed on follow-up and 2 of them had a second relapse. The mean number of FN episodes was 2.5 (±1.58; 0-8) per newly diagnosed patient and 3.6 (±1.88; 1-8) per relapsed patient. Febrile neutropenia episodes were more frequent at high risk patients compared to standart risk patients (p≤0.05). Patients diagnosed before year 2000 had less FN episodes compared to patients diagnosed after 2000 (p≤0.05). Fifty-seven of the FN episodes were fever of unknown origin, 16% were clinically documented infection and 27% were microbiologically documented infection. Of the microbiologically documented infections, 44% of them were caused by gram positive bacteria and 43% were by gram negative bacteria. Eight of 96 patients developed invasive fungal infection during initial treatment and 4 out of 15 patients who relapsed. Of 9 patients who expired on follow-up, the cause of death was fungal infections in 4 and FN in 1.
Conclusion: The high rate of infectious deaths in leukemia compared to that reported in high-income countries, suggests that improvements in infection care and prevention are necessary to improve survival in patients with leukemia. We showed that over the years FN episodes increased at our center in contrast to better quality of patient care. This increase in infections may be atrributed to more intensive treatment regimens. We also showed that high risk and relapsed patients who are treated more aggresively have increased infection rate. The most common cause of death was fungal infections.

Disclosures
No relevant conflicts of interest to declare.
A Dual Bcl-2/xL Inhibitor Induces Tumor Cell Apoptosis in a Hematopoietic Xenograft Model
Authors: Adam Ammar , Byth Kate , Secrist Paul , Schuller Alwin , Reimer Corinne , Lawson Deborah , MacIntyre Terry , Powell Francoise 
Published: October 2019

Abstract
Over-expression of the antiapoptotic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional standard of care therapies. Because Bcl-2 family members play key, but partially overlapping, roles as regulators of apoptosis, simultaneous inhibition of both Bcl-2 and Bcl-xL could serve as a promising anticancer strategy. Clinical validation of this concept has been demonstrated with multiple agents targeting different Bcl2 family members. For example, recent Phase I/II trials of the dual Bcl-2 / Bcl-xL inhibitor Navitoclax demonstrated a 20% response rate in relapsed, refractory CLL patients. However, in this study dosing was often limited by chronic thrombocytopenia, a well established side effect of inhibiting Bcl-xL.
Here we disclose for the first time a novel and potent BH3 mimetic (Bcl2-32), with nanomolar binding affinity for Bcl-2 and Bcl-xL, (Ki = 3.3 and 8.5nM respectively). In contrast to Navitoclax which requires daily oral administration for activity, Bcl2-32 has shown promising efficacy on an intermittent dosing schedule that allows full platelet recovery between doses. In this poster, we describe the in vitro and in vivo activity profile of Bcl2-32 in a variety of cell types that highlights its potential as a dual inhibitor of Bcl2 and BclXL. In addition to exhibiting potent single agent anti-cancer activity in a sensitive Acute Lymphocytic Leukemia (RS4; 11) model with (TGI >100%, P < 0.001), Bcl2-32 also potentiates the effectiveness of standard chemotherapeutic agents in less sensitive DLBCL xenograft models. Taken together, these data suggest that Bcl2-32 represents an exciting development opportunity as single agent or in combination in a broad range of hematopoietic malignancies.

Disclosures
Adam: Astrazenenca: Employment. Secrist:AstraZeneca: Employment.
EVI1 Expression Predicts Poor Survival in Acute Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation with Myeloblastic Conditioning
Authors: He Xuefeng , Chen Suning , Depei Wu , Sun Aining 
Published: October 2019

Abstract
The ecotropic viral integreation site 1 (EVI1 or MECOM) gene mapping to chromosome 3q26 exerts significant oncogene biological effects of anti-apoptosis, proliferation and differentiation on hematopoietic cells. It is considered as a poor prognostic factor in acute myeloid leukemia (AML). EVI1 positive AML accounts for about 10% of de novo AML pts. The remission rate and long time survive are poor. Whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) could salvage such kind of malignancy is still unknown. We conducted a survey of 161 AML pts (median age, 35 years[y]; range 8-60y) after first complete remission undergoing myeloblastic allo-HSCT at the first affiliated hospital of Soochow University. Source of hematopoietic stem cells came from match or partial matched related, unrelated or umbilical cord blood (UCB) donors (Table 1). Pretreated specimens were obtained and real-time polymerase chain reaction was performed to detect expression of EVI1-1d (one major splice of EVI1) and common EVI1 (cEVI) (normalized to PBGD gene). Standard plasmids of EVI1 and PBGD were prepared as calibrators. 13 nonmalignant single lineage cytopenia pts were tested as baseline. Quantities of EVI1-1d and cEVI ranges from negative to 154.2%PBGD and negative to 1214.3%PBGD in each group. Above five and ten folds to baseline in EVI1-1d and cEVI respectively were considered as positive. Accordingly 27 pts were EVI1 positive while 134 pts were negative (16.8% vs 83.2% separately). Unfavorable cytogenetic abnormalities showed a high proportion in EVI1 pos (11/27) than neg group (12/134). 5 and 40 mutations were detected in each group. Three cytogenetic abnormality concerning 11p15 pts expressed high level of EVI1.
Positive expression of EVI1 indicated significant shorter progress-free survival and overall survival (P= 0.0352 and 0.0436 respectively) comparing with negative group (Figure 1).
Table 1. Sources of donors Matched (n) Partial mathed (n) siblings 82 5 Parents or sons/daughters / 30 Unrelated PBSC 26 10 Unrelated UCB 3 5
Figure 1 Figure 1.
Figure 2 Figure 2.
Progress-free Survival (upper) and Overall Survival (below) in myeloblastic allo-HSCT pts according to EVI1 expression
In conclusion, high level of evi1 expression predicts worse prognosis even after myeloblastic allo-HSCT. New treatment strategies post allo-HSCT are needed to improve long time survival in such kinds of pts.

Disclosures
No relevant conflicts of interest to declare.
Identification of Leukemic Stem Cells in Acute Myeloid Leukemia Patients
Authors: Elmasry Manal M W , Elhaddad Alaa 
Published: October 2019

Abstract
Background: Acute myeloblastic leukemia (AML) can be viewed as newly formed, abnormal hemopoeitic tissue initiated by few leukemic stem cells (LSCs). Recognizing the LSC and identifying their behavior, plays a pivotal role in the approach of a targeted therapy.Colony-stimulating factor 1 (CSF-1), also known as M-CSF, is a protein ligand that acts on the CSF1R promotes mononuclear phagocytes survival, proliferation and differentiation.
Aim of the work: Defining the self-renewing [Thy1-, CD34+, CD38-] LICs in AML cases before and after induction chemotherapy as a predictor for relapse and to determine how CSF1R (Fms) and CD34 markers affect the growth and survival of human leukemic cells in the CD38- Thy1- population.
Patients and methods: This study was carried out on 30 samples from the peripheral blood of adult patients with de-novo acute myeloid leukemia. The majority of the patients were monocytic AML
Samples were sorted into four populations (Fms+CD34-, Fms+CD34+, Fms-CD34+ and Fms-CD34-) according to the surface markers of the cells. Cells were cultured on mouse stromal cells transfected with a plasmid containing human CSF-1. Samples were cultured using Iscove's modified Dulbecc's medium (IMDM).The cultures were assessed for survival of leukemic cells in days.
Results: The mean survival in days of the cells was 13.9 before chemotherapy and 14.1 after chemotherapy. The difference in growth was insignificant (p>0.05). The Fms-CD34+ population in all but two samples tested had the longest survival time in culture.
Conclusion: Our results suggest that leukemic stem cells may survive chemotherapy mainly due to their quiescence.
Human CSF-1 was shown to increase the number of leukemic cells in co-culture with mouse stroma after 5 weeks. A novel leukemic stem cell (Fms-CD34+) has been identified and is the cell responsible for the growth and maintenance of the leukemic bulk.

Disclosures
No relevant conflicts of interest to declare.
Higher Than Reported Response Rates to Decitabine Observed in Indian AML Patients - Is There a Genomic Basis
Authors: Damodar Sharat , Nataraj KS , Niveditha SR , Purnaiya Rajeev , Kumar Madan , Nagaraj Ashwin , Ram Prahlad 
Published: October 2019

Abstract
Between May 2012 and May 2014, 15 elderly patients (median 64yrs, range 54-80yrs) who presented with acute myeloid leukemia (AML) with comorbidities preventing them from receiving standard induction, were treated with decitabine at a dose of 20 mg/m2 for 5 days at monthly intervals. All patients received a minimum of 3 cycles of decitabine with a range of 3-9 cycles. Bone marrow examination was conducted at the end of 3 cycles to assess response. As opposed to the 40% CR rate reported by Ritchie et al (2013) in an elderly western population, we observed a response rate of 60% in our cohort. 9 out of 15 patients achieved remission, with 7 of the 9 patients regaining normal blood counts. The median clinical follow-up was 375 days with a range of 74-800 days. All 9 patients who responded positively to decitabine are alive and well.
This 50% higher response rate to decitabine in Indian patients led us to examine the genetic basis for this observed difference. We conducted an observational prospective study of 14 Indian AML patients either at diagnosis or at relapse. Whole genome expression data from bone marrow aspirate samples was analyzed using PeCaSo™ (APT Life Sciences, Bangalore, India). PeCaSo is a genetic interaction network analysis platform that provides a ranked list of chemotherapeutic agents, as well as other approved pharmaceutical agents which can potentially be used as adjuvant therapy. For the 14 patients enrolled in the study, we looked at their response to decitabine as predicted by PeCaSo (see figure). As a comparison, PeCaSo was also used to retrospectively analyze whole genome expression data of Caucasian AML patients (n=16) available at The Cancer Genome Atlas (TCGA).
Figure 1 Figure 1.
PeCaSo’s genomic network analysis indicates a higher response rate to decitabine for the Indian AML cohort when compared with a Caucasian cohort, strongly suggesting a potential genetic basis for the clinically observed difference.
This study provides supportive evidence for considering decitabine for induction therapy of AML in Indian patients. Our study’s genomic approach confirms that the heterogeneity and genetic basis of cancer has to be factored in prescribing personalized protocols for the treatment of cancer.

Disclosures
Damodar: APT Life Sciences, Bangalore, India: Research Funding. KS:APT Life Sciences, Bangalore, India: Research Funding. Purnaiya:APT Life Sciences, Bangalore, India: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kumar:APT Life Sciences, Bangalore, India: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Nagaraj:APT Life Sciences, Bangalore, India: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Ram:APT Life Sciences, Bangalore, India: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
High IDH1 Expression Is Associated with a Poor Prognosis in Cytogenetically Normal Acute Myeloid Leukemia
Authors: Ma Qiu-Ling , Wang Jing-Han , Wang Yun-gui , Hu Chao , Mu Qi-Tian , Yu Meng-Xia , Wang Lei , Wang Dong-Mei , Yang Min , Yin Xiu-Feng , Chen Fei-Fei , Lu Sha-Sha , Chen Jian , Zhu Zhi-Juan , Chen Sai-Juan , Jin Jie 
Published: October 2019

Abstract
ABSTRACT
The prognostic value of IDH1 mutations has been systematically evaluated in acute myeloid leukemia (AML) patients recently. However, the role of IDH1 expression in AML is still under exploration. To investigate the clinical significance, we analyzed the IDH1 expression in 320 patients with cytogenetically normal AML (CN-AML) by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR). High expression of IDH1 was predominant in patients with FLT3-ITD and DNMT3A mutations, and less prevalent in cases with CEBPA double allele mutations. Strong association was observed between high IDH1 expression and low expression of micro-RNA 181 family. Prognosis was adversely affected by high IDH1 expression with shorter overall survival (OS) and event free survival (EFS) in the context of clinical characteristics including age, WBC, and gene mutations of NPM1, FLT3-ITD, CEBPA, IDH1, IDH2, and DNMT3A in CN-AML. Moreover, the clinical outcome of IDH1 expression in terms of OS, EFS and complete remission rate still remained in multivariate models in CN-AML. Importantly, the prognostic value was validated using the published microarray data from 79 adult patients treated according to the German AMLCG-1999 protocol. Our results demonstrated that high IDH1expression is associated with a poor prognosis of CN-AML.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Factors and Outcomes in Primary Effusion Lymphoma in HIV-Infected Patients: A Single Center Experience
Authors: Sen Shiraj , Marley Eileen , Naina Harris V. 
Published: October 2019

Abstract
Primary effusion lymphoma (PEL) is a human herpesvirus 8-associated non-Hodgkin lymphoma (NHL) that predominantly develops in serous body cavities leading to recurrent lymphomatous effusions. It is poorly understood and very uncommon, accounting for only 3% of all HIV-related NHL. While outcomes have improved in patients with HIV-associated NHL since the widespread use of HAART, the prognosis of PEL remains very poor and median survival is less than 6 months. This study reports our institution’s experience with PEL over the past decade.
Between 2004 and 2014, we treated 8 patients with HIV-associated PEL. All patients were male. The median age was 46.5 years old (range 35-63), three were Caucasian, four were Hispanic, and one was African-American. The primary site of involvement was pericardial in 3 patients, pleural in 3 patients, and extra-cavitary in 2 patients. All patients were Ann Arbor stage IV at the time of diagnosis. The mean LDH and CD4 count at time of diagnosis was 625 U/L and 161 cells/mm3, respectively.
Of the eight patients identified with PEL, four have achieved complete remission (CR). Prognostic factors associated with achieving CR include compliance with HAART therapy prior to PEL diagnosis as well as lower serum lactate dehydrogenase (LDH) levels (202±30 versus 1049±290, p=.03). Patients achieving CR also had a higher average CD4 count (228±93 versus 95±35, p=.22) at time of diagnosis. Median survival is nearly 6 years for those in CR whereas it was 32 days in patients that died (one from an acute stroke, one from septic shock, and two from progressive disease). All patients who achieved CR had previously diagnosed HIV whereas two of the four who died were previously undiagnosed with HIV. Interestingly, pericardial sites of involvement were associated with significantly better outcomes as compared to pleural sites in our case series, as well. There was no association between outcome and HIV viral load, duration of HIV infection prior to PEL diagnosis, or presence of AIDS-defining illnesses. The patients achieving CR were treated with HAART in addition to Hyper-CVAD (1a-3b) or 6 cycles of CHOP or EPOCH. In addition, two patients received bortezomib as initial therapy. Given its rarity, our knowledge of PEL relies heavily on case reports and small case series. Here we report our institution’s experience with PEL, identify LDH and CD4 as possible prognostic factors in PEL, and suggest bortezomib-based chemotherapy as an effective treatment option in HIV-associated PEL.

Disclosures
No relevant conflicts of interest to declare.
Serum Levels of CCL22 and CCL25 Might Predict Skin Rash Induction、the Common Adverse Event By Bendamustine Therapy in Malignant Lymphoma
Authors: Terui Yasuhito , Ueda Kyoko , Kusano Yoshiharu , Gunji Tadahiro , Nishimura Noriko , Hatake Kiyohiko 
Published: October 2019

Abstract
Introduction: Bendamustine has been recently approved for the treatment of low-grade malignant lymphoma. In spite of the better efficacy, skin rash is the commonest adverse event by bendamustine in the treatment of malignant lymphoma. To understand the mechanism of the skin rash, we prospectively examine the relationship between skin rash and chemokines. Methods: After informed consent to the patients, who would received bendamustine (B) or bendmustine+rituximab (BR), the sera were collected before and after the treatment of B or BR. Cytokine/Chemokine array was performed by Bio-Plex system. Results: 20 patients with FL (n=18), MCL (n=1), and low-grade B-cell lymphoma (n=1) were enrolled in this study. All patients wee treated with B or BR regimen. 9 patients showed skin rash after the treatment of bendamustine. In Cytokine/Chemokine array, serum levels of CCL22 and CCL25 before the treatment were significantly higher in skin rash group (p=0.010738476 and p=0.030366028, respectively) (Figure 1 and 2), and serum levels of CXCL10 and CXCL11 after skin rash were higher significantly (p=0.000923527 and p=0.014890795, respectively). Conclusion: Serum levels of CCL22 and CCL25 might predict skin rash inductionAthe commonest adverse event by bendamustine and CXCL10 and CXCL11might contribute to induction of skin rash by bendamustine.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Pediatric Hodgkin’s Lymphoma: 5-Year Experience at Single Center in Pakistan
Authors: Riaz Shazia , Khan Safia , Badar Farhana 
Published: October 2019

Abstract
OBJECTIVES:
To review patients’ characteristics and treatment outcome pattern of pediatric hodgkinlympoma in a well funded center in developing country
MATERIALS & METHOD: This was retrospective review of data of 301 pediatric hodgkin lymphoma patients up to 18 years of age treated in Shaukat Khanum Memeorial Cancer Hospital & Research Center, Lahore, Pakistan, during 2009 to 2013.
RESULTS:
Total No. of patients was 301, 81% were male. The median age of studied data was 9 years; ranging from 2 to 18 years. B symptoms in the form of fever, weight loss and night sweats were found in 51%, 29% and 34%, respectively. Median stage was 3 with neck bulky disease in 28% and Medistinal widening in 18% of patients. Trend of histopathology was mixed cellualrity at 56.5%. Most common treatment regime was ChlVPP/ABVD (59.5%); 30.6% of these 301 patient also got radiotherapy. At the end of treatment complete response was reported in 76.5%; 11.3% of these were relapsed afterward.
CONCLUSION:
Our data shows excellent outcome of pediatric hodgkin lympoma and results are comparable to that of developed countries.

Disclosures
No relevant conflicts of interest to declare.
ONC201/TIC10 Is Effective As a Monoagent and Synergizes with Chemotherapy to Induce Cell Death in Non-Hodgkin Lymphoma
Authors: Talekar Mala K. , Allen Josh , Dicker David T. , El-Deiry Wafik S. 
Published: October 2019

Abstract
Outcome for Non-Hodgkin lymphoma (NHL) patients using conventional treatment standards remains unsatisfactory, particularly in advanced stage/ relapsed disease creating an imminent need for investigating novel treatment strategies. ONC201/TIC10 is a small molecule (Allen et al, 2014) that induces p53-independent cell death in tumor cells (sparing normal cells) through inactivation of prosurvival kinases Akt and ERK. ONC201 is scheduled to enter Phase I/II clinical trials as a monoagent for advanced cancers in adults in 2014. We have previously shown that ONC201 induces significant cytotoxicity in preclinical models of human lymphomas (Talekar et al, ASPHO 2014). Here, we show that ONC201 is not only effective as a monoagent across several NHL cell lines, but that it also synergizes with several chemotherapeutic agents to cooperatively induce cell death in vitro.
We found that ONC201 induces significant apoptosis in a diverse panel of seven human NHL cell lines at low micromolar concentrations (1.3 to 5.06 uM). Increased surface TRAIL and surface DR5 expression was noted in a dose-dependent manner across representative cell lines. The increase in surface TRAIL correlated with increase in subG1 DNA content, which suggests TRAIL as a potential biomarker of ONC201 response. ONC201-induced apoptosis was inhibited using a pan-caspase inhibitor and was blocked by an anti-TRAIL antibody RIK-2. Western blot analysis of ONC201-treated representative cell lines suggests ERK inhibition and Foxo3a activation as a potential mechanism of cytotoxicity via TRAIL induction. In agreement with this notion, we observed upregulation of PARP & DR5 and caspase-3 activation in response to ONC201 treatment.
We further found that ONC201 synergizes to potentiate cytotoxicity with several chemotherapeutic agents approved for NHL treatment, particularly anthracyclines (doxorubicin), nitrogen mustard (bendamustine), antimetabolite (cytarabine) and proteasome inhibitor (bortezomib) via CellTiter-Glo cell viability experiments that were corroborated by apoptosis assays.
Together these results suggest that ONC201 is a potent antitumor agent in NHL as monoagent and in combination with approved therapies. The ultimate goal of this project is to provide a preclinical rationale for a phase Ib/II trial of ONC201 as a combination therapy in pediatric lymphoma.

Disclosures
Allen: Oncoceutics, Inc.: Employment, Equity Ownership, Ownership interests (including stock options) in a start-up company, the stock of which is not publicly traded Other, Patents & Royalties. El-Deiry:Oncoceutics, Inc.: Equity Ownership, Founder and Shareholder in Oncoceutics, Inc. The potential conflict of interest has been disclosed to and is being managed by his academic employer. Other.