bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparision of the Clinical and Prognostic Characteristic in Adult and Pediatric AML1/ETO-Positive Acute Myeloid Leukemia
Authors: Yu Guopan , Zhou Jiaheng , Zhou Jinchan , Qiu Jiale , Yin Zhao , Yin Changxin , Xu Dan , Jiang Xuejie , Liu Qifa , Meng Fanyi 
Published: October 2019

Abstract
AML1/ETO-positive acute myeloid leukemia (AML) is a heterogeneous malignancy. Up until now, the difference between adult (>14-year old) and pediatric (≤14-year old) AML1/ETO+ AML remains unclear. In this retrospective multi-center study we analyzed 173 AML1/ETO+ AML patients including 98 adults and 75 kids, and found that AML-M2 phenotype was the most common morphology, especially higher in adult patients with an incidence of 92.9%, as compared with 82.7% (P=0.005) in pediatric patients. Furthermore, higher incidence of extramedulary leukemia (29.6% vs. 13.3%, P=0.001) and C-KIT mutation (21/67, 31.3% vs. 12/66, 18.2%, P=0.079) were observed in adult patients than pediatric patients. No significant difference in gender ratio, peripheral white blood cells count, immunology and cytogenetic abnormality including affiliated cytogenetic abnormalities and lose of sex chromosmoe between the two age groups. Among adult patients, idarubicin combined with cytarabine (IA) or daunorubicin combined with cytarabine (DA) was the major induction regimens, while FLAG (fludalabin,cytarabine and G-CSF) combined with idarubicin or DA combined with etoposid (DAE) was the main regimens in pediatric patients for one to two cycles. Not only the first-cycle complete remission (CR) rate (69/74, 93.2% vs. 56/95, 58.9%, P <0.001), but also the second-course cumulative CR rate (73/74, 98.6% vs. 82/95, 86.3%, P=0.004) in pediatric patients was much better than that in adult patients. After obtaining CR, standard dose cytarabine (SDAC)-based or medium dose cytarabine (MDAC)-based regimens were given to the adult patients as the major consolidation regimens, while pediatric patients received MDAC or homoharringtonine combined with cytarabine and etoposid (HAE). With a median of 23.5(2-126) months follow-up, cumulatively 35/87(40.2%) patients relapsed and 39/98(39.8%) cases died in adult group, which were much higher than that in pediatric patients, with the cumulative incidence of recurrence of 18/74(24.3%) (P=0.032) and cumulative death rate of 13/75(17.3%) (P=0.001). Survival analysis showed that EML [RFS: HR 3.20(1.63-6.28), P=0.001; OS: HR 2.92(1.55-5.51), P=0.001] and C-KIT mutation [RFS: HR 3.17(1.47-6.93), P=0.003; OS: HR 2.24(1.03-4.86), P=0.041] were the adverse factors for relapse free survival (RFS) and overall survival (OS). Nevertheless, neither these two factor were negative for the survival of pediatric patients. Taking together, significant difference in bone marrow morphology, incidence of EML and C-KIT mutation, also prognostic factors were observed between the adult and pediatric AML1/ETO+ AML patients. Intensive induction might be a main reason for higher CR rate and better survival in pediatric patients.

Disclosures
No relevant conflicts of interest to declare.
In Vitro Approach for the Identification of Exceptional Responders in Acute Myeloid Leukemia
Authors: O'Brien Eric , VanCauwenbergh Brett , Byerly Luke , Merk Alexander , Sarangdhar Mayur , Wunderlich Mark , Basu Mitali , Mizukawa Benjamin , Breese Erin H. , Seibel William , Perentesis John Peter 
Published: October 2019

Abstract
Each case of Acute Myeloid Leukemia (AML) represents a unique ecosystem. Despite recent advances in our understanding of the genetic landscape of AML, this information remains insufficient to accurately match patients with targeted therapies. While pediatric and adult AML share phenotypic similarities, pediatric AML represents a genetically distinct disease from adult AML, and will benefit from independent genomic studies and novel therapeutic strategies. Real-time ex-vivo functional screening can identify mechanisms underpinning drug response and diversity between tumors, aiding in patient stratification. We established an in vitro drug screening system that incorporates cytokine signaling to better model inflammation, stem cell function, and niche derived support of leukemic blasts. This approach provided insight into variability between patients who currently would be placed on the same therapeutic regimen.
Samples were acquired from 12 pediatric AML patients, after informed consent was obtained. Samples were enriched for blasts, and cultured in the presence of SCF, TPO, FLT3-L, IL-3, and IL-6 (KTF36). A panel of 38 drugs was selected from a larger screen of 1839 compounds done on commercially available hematological malignancy cell lines. Drugs included standard chemotherapy agents used in AML and drugs currently under clinical development. Cells were exposed to drugs for 72hrs. An MTS assay was performed and results reported as % of viable cells remaining, after normalization to vehicle control wells. Targeted DNA NGS sequencing of 406 genes, 31 introns, and RNA sequencing of 265 genes was performed for genetic characterization.
In vitro drug screening revealed variations in drug sensitivity between samples and revealed time ex-vivo and cytokine milieu to be important factors affecting response of the same cells to the same drugs. Engraftment of long term cultures into immunodeficient mice produced aggressive disease in all cases, indicating robust support of stem cell function via addition of KTF36 cytokines. When possible, clinical response to therapy was compared with in vitro response to the same drugs. This screening approach highlighted well established agents that showed significant activity in highly refractory disease providing rationale for further clinical trial development. An unsupervised clustering showed drug sensitivity primarily correlated with the presence of MLL-X fusion, NRAS/KRAS and PTPN11 alterations. Linear Regression with interaction effects showed drug sensitivity/resistance to be highly selective for single/signature of specific molecular alterations.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Does Race Impact Survival in Multiple Myeloma?
Authors: Kennedy-LeJeune Elizabeth , O'Neal Hollis , Miles Lauren , Hamer Diana , Cataldo Vince D. 
Published: October 2019

Abstract
Purpose:
Multiple myeloma (MM), a cancer involving abnormal antibody production from plasma cells, accounts for approximately 1.8% of all new cancer cases in the US. The International Staging System (ISS) for MM classifies patients with serum beta2 microglobulin < 3.5mg/l and serum albumin ≥3.5g/dl as having stage I disease, patients with serum beta2 microglobulin ≥ 5.5 mg/l as having stage III disease, and all others as having stage II disease. The median survival by stage at time of diagnosis is 62 months, 45 months, and 29 months, respectively, for stages I, II, and III.
The median age at time of diagnosis of MM is 69 years, with approximately 62% of all patients being at least 65 years old at time of diagnosis. There is a 2-fold increase in MM incidence amongst blacks as compared to whites in both the male and female population. This study was conducted to further characterize our MM patient population and to potentially identify racial and gender impact on mortality.
Methods:
A retrospective chart review of all patients in our geographic region diagnosed with MM between 2012 and 2017 was conducted using the Louisiana Tumor Registry Board database. Clinical data abstraction included epidemiology, laboratory, and pathologic data at time of diagnosis, and time to autologous stem cell transplant and death, if applicable. We performed chi-square analysis, linear regression, and survival analysis to compare survival outcomes between groups.
Results:
Chart review data was available for 184 of the 243 patients diagnosed with MM between 2012-2017, including 89 (47.6%) males and 98 females (52.4%), and 90 (48.1%) whites and 88 (47.1%) blacks. Females were significantly older than males (66.1 vs 62.6 years, p=0.037) at time of diagnosis yet whites were not significantly older compared to blacks (65.1 vs. 63.9 years, p=0.498). Among the 108 patients with documented stage of disease, 17 (15.7%) patients were diagnosed with stage I MM compared to 40 patients (37.0%) diagnosed at stage II and 51 (47.2%) diagnosed at stage III. With regards to stage, there was no significant difference between race or sex in our population. When adjusted for gender and age at diagnosis, race was a significant predictor of survival time with survival being 6.45 months shorter for black patients with MM compared to whites with the disease. (95% CI, 1.1 to 11.8; p = 0.019)
Conclusion:
Our data suggest that race exists as an independent predictor of shorter survival in our black patient population with MM. Additional studies investigating the biologic diversity of this disease are warranted to explain this racial disparity.

Disclosures
No relevant conflicts of interest to declare.
Osteoclast Stimulatory Transmembrane Protein (OCSTAMP) mRNA Levels and Clinical Variables in Persons with Plasma Cell Myeloma
Authors: Zhou Ya-Lan , Lu Jin , Gale Robert Peter , Yang Shen-Miao , Wu Li-Xin , Li Jin-Lan , Qin Ya-Zhen , Liu Yan-Rong , Jiang Hao , Jiang Qian , Zhang Xiaohui , Xu Lan-Ping , Liu Kai-Yan , Huang Xiao-Jun , Ruan Guorui 
Published: October 2019

Abstract
Background Bone disease is an important determinant of quality-of-life and survival of persons with plasma cell myeloma (PCM). Biomarkers of bone disease could be useful to predict risk and monitor therapy. In our prior analyses OCSTAMP (osteoclast stimulatory trans-membrane protein) mRNA levels were identified as increased above normals in persons with PCM. OCSTAMP encodes a membrane-anchored cell surface receptor promoting nucleation of osteoclasts involved in bone resorption and osteoclast differentiation.
Aims Measure levels of OCSTAMP mRNA in subjects with PCM and interrogate clinical associations.
Methods OCSTAMP mRNA levels were quantified by quantitative real-time polymerase chain reaction (RT-qPCR) in 224 bone marrow samples from 160 subjects with PCM including 160 newly-diagnosed; 55 in remission and 9 with recurrent PCM. Results were compared with 42 normals and data expressed as ratio of OSSTAMP mRNA/ABL mRNA. Associations with clinical variables were interrogated and comparisons analyzed using the Chi-square test.
Results OCSTAMP mRNA levels were significantly greater than normals in 111 subjects (69%, [95% confidence interval l[CI], 62-77%], P<0.001) with newly-diagnosed PCM, in 5 (56% [23,88%]; P=0.39) relapsing after initial therapy and in 12 in remission (22% [11-33%; P<0.001). mRNA levels in samples from newly-diagnosed subjects (median, 0.52%; range, 0-121%) were significantly higher than in samples from subjects in remission (0.01%; range, 0-4.7%) or normals (0.02%; range, 0-0.10%; both p<0.001). Levels in subjects in remission and normals were similar (p=0.85). Median OCSTAMP mRNA level was used to dichotomize subjects into low (median 0.06%; range, 0-0.51%) and high (3.8%; range, 0.54-121%) cohorts (P<0.001). Subjects in the high cohort were more likely to be in Durie/Salmon stage-3 (p=0.035), to have serum albumin concentrations <35g/L (p=0.036), have serum C-reactive protein (CRP) concentrations ≥8mg/L (p=0.03) and have ≥1 pathological bone fractures (p=0.002).
Conclusions OCSTAMP is highly transcribed in persons with newly-diagnosed and recurrent PCM compared with normals whereas persons in remission have similar levels to normals. OCSTAMP mRNA levels correlate with several clinical variables including Durie/Salmon stage, serum albumin C-reactive protein levels and likelihood of pathological bone fractures. OCSTAMP mRNA levels are potentially useful as a biomarker if our data are validated.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Rrx-001 Is a Phase 3 Small Molecule Dual Inhibitor of CD47 and Sirpα with Activity in Multiple Myeloma
Authors: Cabrales Pedro , Carter Corey , Oronsky Bryan , Reid Tony 
Published: October 2019

Abstract
Background:
CD47 binds to SIRPα on the surface of macrophages delivering a "do not eat" signal to suppress phagocytosis. To evade macrophage-mediated destruction, CD47 is frequently overexpressed in cancers, including multiple myeloma (MM). CD47 inhibition is an area of intense therapeutic interest with three anti-CD47 monoclonal antibodies (mAbs) currently in clinical trials. However, these mAbs have been associated with severe hematologic toxicities. RRx-001 is a minimally toxic small molecule that dually downregulates CD47 on tumor cells and SIRPα on macrophages and triggers tumor associated macrophage phagocytosis of tumor cells in vitro and in vivo. RRx-001 is entering Phase 3 trials for the treatment of multiple cancer indications.
Methods:
The effect of RRx-001 on the expression of CD47 and SIRPα on macrophages was evaluated with Western blotting and flow cytometry. An in vitro phagocytotic assay was used to determine whether RRx-001 promoted engulfment of multiple myeloma cells by macrophages. Transcriptional mRNA profiling in murine tumor associated macrophages (TAMs) was performed to analyze the cytokine profile of TAMs in the presence or absence of RRx-001. Finally, myeloma bearing mice were treated with RRx-001 in the presence or absence or absence of clodronate to determine the effect of macrophage depletion on RRx-001 anticancer activity.
Results:
RRx-001 was shown to downregulate CD47 and SIRPα expression on tumor cells and macrophages, respectively, and to promote the phagocytosis of multiple myeloma tumor cells. RRx-001 also stimulated the production of pro-inflammatory cytokines in TAMs. In tumor bearing mice, depletion of macrophages by clodronate reduced the antitumor effects of RRx-001.
Conclusions:
RRx-001 is a Phase 3-ready small molecule innate immune checkpoint inhibitor, which triggers tumor associated macrophage phagocytosis of high-expressing CD47 tumor cells. Dual downregulation of CD47 and SIRPα by RRx-001 results in TAM repolarization and phagocytosis of tumor cells. Depletion of macrophages by clodronate in tumor-bearing mice reduced the antitumor effects of RRx-001 and further suggests that the target of RRx-001 is the macrophage.

Disclosures
Cabrales: EpicentRx Inc: Research Funding. Carter:EpicentRx Inc: Employment. Oronsky:EpicentRx Inc: Employment. Reid:EpicentRx Inc: Employment.
Amino Bisphosphonates Are Associated with Decreased Mortality Compared to Non-Amino Bisphosphonates in the Treatment of Multiple Myeloma
Authors: Razavi Marianne , Mhaskar Rahul , Djulbegovic Benjamin 
Published: October 2019

Abstract
Introduction
Osteolytic bone lesion is a hallmark of multiple myeloma (MM). Bisphosphonates have been shown to be effective inhibitors of osteoclastic activity, leading to improvement of skeletal related morbidity in MM. Based on their chemical structure, bisphosphonates can be classified into two categories: amino bisphosphonates (ibandronate, pamidronate and zoledronate) and non-amino bisphosphonates (clodronate, etidronate). Although both categories are efficient for the management of myeloma related bone disease, their effect on mortality has been controversial. Some studies demonstrated beneficial effect associated with the administration of amino bisphosphonates, while others showed no such effect. We evaluated if amino bisphosphonates improve survival compared with non-amino bisphosphonates, when added to standard therapy for myeloma.
Methods
To address our objectives, we conducted a systematic review and network meta-analysis of all randomized controlled trials (RCT) estimating the effect of bisphosphonates in MM. We identified trials by searching electronic databases such as MEDLINE, CENTRAL and EMBASE. We compared the effect of amino bisphosphonates group to non-amino bisphosphonates group, versus the reference placebo group or no treatment. The primary outcome was overall mortality. We conducted a network meta-analysis under a random effects model. Pooled hazard ratios (HR) with 95% confidence intervals were estimated. To further evaluate the effect between the groups, a test for subgroup differences was applied. All analysis were conducted using Revman and R.
Results
Overall 14 studies were identified from 1982 to 2015, enrolling a total of 2706 patients: 5 studies tested bisphosphonates with non-amino group and 9 with amino group. The results from the network meta-analysis (Figure 1) showed a decrease in overall mortality for the amino bisphosphonates (HR 0.76, 95% CI 0.62 to 0.94) compared to the non-amino bisphosphonates (HR 1.06, 95% 0.87 to 1.3) and placebo. The statistical test for subgroup differences was significant (Q=4.69, p=0.03).
Conclusion
Based on the totality of randomized evidence, we showed for the first time that amino bisphosphonates compared to non-amino bisphosphonates versus placebo or no treatment reduce mortality in MM. The use of amino bisphosphonate should be further encouraged as anti-myeloma treatment and not solely as supportive treatment.

Disclosures
No relevant conflicts of interest to declare.
Loss of HDAC11 Promotes Myeloid-Derived Suppressor Cells Inhibition of T Cell Function in a Murine Lymphoma Microenvironment
Authors: Chen Jie , Cheng Fengdong , Wang Michael , Sahakian Eva , Powers John J. , Pinilla Ibarz Javier , Smith Mitchell R. , Sotomayor Eduardo 
Published: October 2019

Abstract
Myeloid-derived suppressor cells constitute a heterogeneous population of immature myeloid cells derived from bone marrow that negatively regulate both innate and adaptive immunity in the tumor microenvironment. Previous work in our lab had demonstrated that MDSCs lacking histone deacetylase 11 (HDAC11) displayed an increase in suppressive activity against IFN-γ producing CD8+ T cells. The upregulated suppressive activity of HDAC11KO MDSCs was associated with a more aggressive tumor growth pattern when compared with wild type control mice.
Mechanistically we have found that tumor infiltrated HDAC11KO MDSCs isolated from lymphoma-bearing mice displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function, when compare with wild type MDSCs. However, both arginase activity and NO production were at a similar level in the wild type and HDAC11KO MDSCs isolated from spleens of the same lymphoma-bearing mice. This finding suggests that HDAC11KO MDSCs are more suppressive within the tumor microenvironment. Moreover, the aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been previously shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription.
Unlike MDSC's in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of both MDSC and/or T-cells from either wild type or HDAC11 KO mice into C57BL/6 lymphoma-bearing animals. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the HDAC11KO T cells in the lymphoma microenvironment
Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs phenotype and function in a murine lymphoma model. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells in vivo.

Disclosures
No relevant conflicts of interest to declare.
Description of Molecular Prognostic Markers in AML Uruguayan Patients
Authors: Zubillaga Maria Noel , Dell Oca Nicolas , Cappetta Mónica , Manrique Gonzalo , Elizondo Maria , Verónica Perez , Tort José 
Published: October 2019

Abstract
Acute myeloblastic leukemias (AML) are the most frequent acute leukemias in adults. Recent genomic and candidate gene studies identified novel recurrent somatic mutations in patients with AML with biological, clinical and therapeutic significance. In Uruguay, the characterization of AML is dependent on the integration of cytomorphology, immunophenotype, cytogenetics and molecular biology (mutations in FLT3, NPM1, CEBPA and cKIT). This allows stratification in prognostic risk groups and rationalization of therapeutic resources. However, with this molecular markers, complete stratification is not always succesful in patients with normal karyotype ( NK) .
In order to expand the AML genetic markers analysis in Uruguayan patients ( 3.000.0000 persons country ) ; DNA samples from 49 adult patients at the onset of the disease and 3 healthy controls were analyzed by next generation sequencing (NGS, Illumina) using a customized panel of 30 cancer associated genes. After excluding synonymous variants and those with a population frequency >1%, we ended with 493 variants in promoters and intron ends, and 173 in the 28 genes coding regions. Notably, all patients had at least one variant.
While none of the non-coding region variants were reported as pathogenic in COSMIC and/or ClinVar databases, 45 of those falling in coding regions were reported as pathogenic. The pathogenic variants were detected in 36/49 patients and 1 healthy control distributed in 16 genes. The most affected genes were TET2, NRAS, DNMT3, FLT3 and cKIT with 7, 6, 5, 4, 4 variants respectively.
This preliminar findings in this study, highlight the relevance of detecting gene variability underlying prognostic risk subgroups to deliver patient tailored clinical decision support. The correlation between the genetic abnormalities, associated with the clinicopahtological features and the epigenetic studies have prognostic significance, and are continued to be analyzed.

Disclosures
No relevant conflicts of interest to declare.