bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allelic Forms Of PRDM9 Associated With High Hyperdiploid Childhood Acute Lymphoblastic Leukaemia
Authors: Woodward Eleanor L , Olsson Martin L. , Johansson Bertil , Paulsson Kajsa 
Published: October 2019

Abstract
Whilst a great deal is known about acquired somatic aberrations associated with the diagnosis and prognosis of acute leukaemias, relatively little is known about the effects of germline variation. A recent study reported a link between germline variations in the zinc finger (ZnF) binding domain array of the PR domain-containing 9 (PRDM9) gene, regulator of meiotic recombination, with the development of acute lymphoblastic leukaemia (ALL) in children. An excess of rare PRDM9 alleles that affect meiotic recombination events were seen in parents of children affected with B-cell precursor ALL (pre-B-ALL), and in an independent cohort of children with pre-B-ALL; in particular in aneuploid and infant ALL. In the present study, we carried out Sanger sequencing to investigate variation of PRDM9 alleles in a cohort of parents (n=59) with children diagnosed with high hyperdiploid ALL (HeH; 51-67 chromosomes) (n=31) and a control cohort of individuals (n=66) from the south of Sweden. Whereas similar numbers of rare PRDM9 alleles were observed in both groups, a larger number of rare alleles that affect recombination events were observed in the parents from the family cohort with children diagnosed with HeH ALL compared to individuals of the population control cohort (15.3% vs. 4.5%, P=0.0414). Two-thirds of the parents transmitted the rare allele to their affected children. A previously unreported ZnF repeat was also detected in two individuals of the control cohort but it was not detected in the family cohort. A statistically significant difference in frequency of rare alleles affecting recombination events between the two groups indicates a true association between PRDM9 allelic forms and HeH ALL in an independent cohort. Thus, our results confirm the previous findings that PRDM9 may play a role in the development of childhood ALL.

Disclosures:
No relevant conflicts of interest to declare.
The Polymorphisms Of Base Excision Repair Genes Influence The Cytogenetic Risk Factors In Acute Myeloid Leukemia
Authors: Iwasaki Atsushi , Saitoh Takayuki , Nitta Yasuhiro , Norjimaa Batchimeg , Omiya Chiharu , Kamiya Akira , Hatsumi Nahoko , Shimizu Hiroaki , Ishizaki Takuma , Hoshino Takumi , Takada Satoru , Handa Hiroshi , Sakura Toru , Yokohama Akihiko , Tsukamoto Norifumi , Murakami Hirokazu 
Published: October 2019

Abstract

Background
Base excision repair (BER) systems have important role for repairing oxidative DNA damage, and known to influence the carcinogenesis and the response to anti-cancer treatments. Although few studies have shown that several DNA repair genes are associated with an increased risk of leukemia, the clinical significance of BER polymorphisms in acute myeloid leukemia (AML) patients remains unclassified. The aim of this study was to evaluate the impact of polymorphisms in genes encoding four main proteins of BER system: OGG1 Ser326Cys, MUTYH Gln324His, APE1 Asp148Glu, and XRCC1 Arg399Gln, and on the risk of AML.

Methods
Between December 1991 and May 2013, 99 patients (male/female 55/44, median age 58 years, range 15-86 years) diagnosed as AML and 192 healthy controls were included in this study. Cytogenetic subgroups were classified as good, intermediate, and adverse risk according to NCCN guidelines. Genomic DNA was isolated from peripheral blood using the DNA extraction kit. Genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genotype and allele frequencies were compared between patients group and control group by using χ2-test. Probability values <0.05 were considered statistically significant. All patients and healthy controls received written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital.

Results
The APE1 Asp/Asp genotype increases the risk of AML (OR 2.30, 95% CI 1.41-3.77, p<0.001), whereas APE1 Glu/Glu genotype reduces the risk of AML (OR 0.34, 95% CI 0.14-0.80, p<0.05). In contrast, there were no significant differences in the genotype frequencies OGG1 Ser326Cys, MUTYH Gln324His, and XRCC1 Arg399Gln between AML patients and control group. Next we compared the frequency of cytogenetic abnormalities according to BER polymorphism. The AML patients with OGG1 Ser/Ser genotype increased the frequencies of (15;17) type (p<0.05) and good risk group. Moreover, the AML patients with MUTYH His/His genotype increased the frequencies of complex type (p<0.02) and reduced the frequencies of t(8;21) type.

Conclusions
According to our data, BER gene polymorphisms may affect the carcinogenesis and the cytogenetic risk of AML.

Disclosures:
No relevant conflicts of interest to declare.
Development Of a Preclinical Human Xenograft Model For Myelodysplastic Syndrome In Immunodeficient Mice Expressing Human Growth Factors
Authors: Scaria George , Bendzick Laura , Shultz Leonard , Kaufman Dan S. 
Published: October 2019

Abstract
Myelodysplastic syndromes (MDS) are a diverse class of hematopoietic disorders, defined by progressive bone marrow failure, myeloid dysplasia, and an increased risk of acute myeloid leukemia (AML). The development of treatments for MDS has been hampered by the lack of an adequate in vivo model of disease. Mouse xenograft models for MDS have been challenging, as samples from patients with MDS have exhibited poor engraftment when transplanted into immunodeficient mice, with little evidence of persistent disease in recipient mice. Here, we tested a novel xenograft mouse model of MDS using an immunodeficient mouse strain that constitutively expresses human hematopoietic growth factors, SCF, GM-SCF and IL-3 (SGM3). These mice demonstrate improved engraftment of human hematopoietic cells from MDS patient samples. We have used bone marrow from patients diagnosed with MDS with blast counts ranging from 2-15% and differing cytogenetic profiles. Unfractionated bone marrow cells we injected into both NOD/LtSz-scid IL2RG-/- (NSG) and NOD/LtSz-scid IL2RG-/- SGM3 (NSGS) mice. These studies demonstrate significantly improved engraftment in the NSGS mice compared to NSG mice. Specifically, 1 out of 4 MDS patient samples demonstrated engraftment in NSG mice, but 3 out of 4 MDS samples demonstrated engraftment in NSGS mice. In NSG mice, we noted approximately 5-6% of human CD45+ cells in peripheral blood at 6 weeks after injection in one MDS sample, but subsequent to that, there was a drop to less than 1 percent of human CD45+ cells detected at 9 and 12 weeks post injection. The NSGS mice demonstrated more robust engraftment up to 15% human CD45+ cells in the peripheral blood at the 6 week time point in some samples, but subsequently fall to 1-2 % at 12 weeks post injection. This demonstrates that the NSGS strain of mice demonstrates improved xenograft efficiency of MDS bone marrow samples. Surprisingly, higher levels of blasts in the patient samples did not necessarily correspond to increased human CD45+ cell engraftment in the NSGS mice. This suggests the NSGS mice do model the MDS patient characteristics rather than overt leukemia. These results support our hypothesis that constitutive expression of human growth factors can promote engraftment of hematopoietic cells from patients with MDS. These studies will allow us to now use of this NSGS mouse model to test novel drug and/or immunotherapy approaches against human MDS in an in vivo mouse model system.

Disclosures:
No relevant conflicts of interest to declare.
GLI Transcription Factors Modulate IgM Secretion In Waldenström Macroglobulinemia
Authors: Amarsaikhan Nansalmaa , Dennison Joel R. , Boi Shannon K. , Neil Matthew S. , Elsawa Sherine F. 
Published: October 2019

Abstract
Elevated immunoglobulin (Ig) secretion by malignant cells is a characteristic feature of several malignancies including Waldenström macroglobulinemia (WM), where elevated IgM is associated with significant morbidity and poor prognosis. Thus, the identification and characterization of the mechanisms controlling Ig secretion are of great importance for the development of future therapeutic approaches for these diseases. Here, we defined a novel pathway involving the oncogenic GLI transcription factors modulating IgM secretion by WM malignant cells. Initial screening of molecules involved in Ig secretion identified components of the Hedgehog-GLI pathway as modulators of this cellular process. Inhibition of smoothened (SMO), the signaling component of the Hedgehog receptor, with the pharmacological inhibitor cyclopamine had no effect on cell proliferation by XTT assay. Cyclopamine inhibition had no effect on cell viability by Annexin V/Propidium Iodide staining, but had a modest in IgM secretion by ELISA in BCWM.1 but not in MWCL-1 and RPCI-WM1 cells. Interestingly, pharmacological inhibition of GLI proteins (GLI1, 2 and 3), downstream effectors of the pathway, using GANT61 reduced the expression of GLI1 and GLI2 and had no effect on cell proliferation or viability. However, it resulted in a significant reduction in IgM secretion (40-60%) in BCWM.1 (p=0.0030), MWCL (p=0.0206) and RPCI-WM1 (p=0.0303) cells. Validation of these results using RNAi showed that out of the three GLI transcription factors, only GLI2 knockdown impaired IgM secretion by BCWM.1 (p=0.0415) and MWCL-1 (p=0.0075) cells. To further characterize the mechanism of regulation of IgM secretion by GLI2, we screened for pathways that are known to modulate Ig secretion. We identified the IL-6 receptor (IL-6R) alpha subunit as a potential mechanism mediating GLI2-IgM axis. Treatment of B-cells with GANT61 resulted in reduced IL-6R expression. Furthermore, overexpression of GLI2 in B-cells increased IL-6R expression. Conversely, GLI2 knockdown reduced IL-6R expression suggesting the involvement of IL-6R in GLI2 mediated regulation of IgM secretion. Taken together, these results identify a novel role for GLI proteins, particularly GLI2, as modulators of IgM secretion by malignant B-cells. Therefore therapies targeting this signaling axis may provide efficacy in patients with Ig-mediated diseases.

Disclosures:
No relevant conflicts of interest to declare.
NF10 Project: An International, Prospective, Observational Study Of Patients With Indolent Non-Follicular Lymphoma. Analysis Of First 215 Patients
Authors: Arcaini Luca , Luminari Stefano , Cesaretti Marina , Gaidano Gianluca , Rattotti Sara , Merli Michele , Cabras Maria Giuseppina , Spina Michele , Baldini Luca , Tedeschi Alessandra , Orsucci Lorella , Gomes da Silva Maria , Marcheselli Luigi , Marcia Torresan Delamein , Federico Massimo 
Published: October 2019

Abstract

Background
Indolent non follicular B-Cell Lymphomas (INFL) are a heterogeneous group of lymphomas and include small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphomas (LPL), and marginal zone lymphomas (MZL). In 2010 the NF10 study was proposed by the Fondazione Italiana Linfomi as a prospective registry specifically devised for investigating the prognosis of this group of lymphomas with particular emphasis on splenic MZL.

Methods
The purpose of the study is to verify whether a prospective collection would provide more accurate data to better define prognosis of INFL. The registration of consecutive patients with newly diagnosed INFL satisfying entry criteria is ongoing at a dedicated website via secure HTTP protocols. Each patient should be followed for up to 5 years. So far the study has been activated in several centers in Europe, South America and Asia. Patients who have a locally established diagnosis of SLL, LPL, or MZL and have never received anti-lymphoma therapy are eligible for inclusion in the study. All ages and disease stages were allowed.

Results
Between September 1st 2011 and August 1st 2013, 215 cases from 28 European and South American Institutions have been registered. At time of current analysis, data on 186 cases were available. Based on local pathology report 12% of cases were registered as SLL, 19% as LPL and 57% as MZL, including splenic (20%), nodal (15%), and extranodal (22%) subtypes; 12% of cases were classified has CD5-negative B-cell chronic lymphoproliferative disorders. Median age was 66 years (rage 28-90), 54% of patients were males; Ann Arbor stage was I-II in 23% and III-IV in 77%; 13% had B symptoms, 10% had ECOG performance status > 1, LDH and Beta2-microglobulin were elevated in 19%, and 49% of cases, respectively. Six percent of cases were HCV positive. Regarding HBV infection, 20% of patients were HBcAb-positive and only 3% of patients were HbsAg-positive. Among baseline characteristics, also details on initial treatment plan were collected; an immediate systemic therapy was planned in 48% of cases and included the use of anti-CD20 monoclonal antibody in 94% of cases, the use of alkylating agents-based regimens in 57%, CHOP/like in 15% and bendamustine in 15%. Patient enrollment and data collection on actual therapy, response and follow-up and histological revision are currently ongoing.

Conclusions
The NF10 confirms that a web based world-wide cooperation allows the collection of a relevant and quite complete set of data in a limited period of time, providing a platform for future prognostic and therapeutic studies.

Disclosures:
Federico: MedImmune: Research Funding.
Acquired Factor VIII Inhibitor: A Single Institution Experience With 62 Patients
Authors: Wysokinska Ewa M. , Mehta Ramila , Grill Diane , Pruthi Rajiv K. 
Published: October 2019

Abstract

Background
Acquired Factor VIII inhibitor or autoimmune hemophilia A (AHA), has an estimated incidence of up to 1.5 cases per million/year and may result in severe hemorrhagic complications and death. Approximately 50% of cases have an underlying condition such as malignancies, autoimmune disorders and post-partum state. AHA should be suspected in any patient presenting with unexplained bleeding and an inhibited aPTT. Management consists of maintaining hemostasis and elimination of the inhibitor, however management is not standardized. We present 62 cases of AHA managed at Mayo Clinic Rochester, over the course of 36 years. We also analyzed whether aPTT at presentation correlated with the strength of inhibition measured by Bethesda Titer.

Methods
After IRB approval, medical records of patients with AHA were reviewed and all clinical data collected. Cumulative incidence of death was estimated by Kaplan-Meier analysis. Spearman correlation was used to calculate relation of APTT to Bethesda titer.

Results
Between 1976 and 2012, we identified 62 patients (male: 35), with a median age at diagnosis of AHA 69 years (mean 64, range 20-86). Clinical presentation consisted of extensive ecchymoses (n=40, 64%) in majority of cases. 29/62 (47%) patients had at least 1 identifiable predisposing condition with 12/62 (19%) patients with an underlying malignancy and 16/62 (26%) with underlying autoimmune conditions. Median Bethesda titer was 29 (range 1 to 1178). Bethesda titer was not related to the number or duration of hospitalizations. Most (69%) patients had at least one hospitalization and 12 (19%) had more than one hospitalization for bleeding complication. Inpatient therapy for bleeding consisted most commonly of FEIBA in 21 pts (34%) and rFVIIa in 6 pts (10%). Prednisone was the most common immunosuppressant used in 54 (87%) patients while Rituximab was used in 11 (18%) patients. Of 32 patients with available follow up labs most (69%) achieved remission. There was no difference in remission rates between patients treated or not treated with Rituximab (p=0.1735).

Conclusion
Acquired Hemophilia A is a rare condition with very heterogenous presentation. It affects mostly older male patients who present with ecchymoses and elevated APTT. The degree of APTT prolongation at the time of diagnosis does not correlate with the strength of the Bethesda titer and should not guide choice of therapy in a patient presenting with an acute bleed. Rituximab use in the 11 patients treated at Mayo did not seem to influence remission rates or survival.

Disclosures:
No relevant conflicts of interest to declare.
Predictors Of Cancer Associated Thrombosis
Authors: Tafur Alfonso , Dale George L. , Rathbun Suman , Mansfield Aaron S. , Cherry Mohamad , Comp Philip C. , Wren Jonathan , Stoner Julie 
Published: October 2019

Abstract

Introduction
Cancer associated thrombosis is the second most common cause of mortality among patients with malignancy. While preventive low molecular weight heparin is effective in preventing venous thromboembolism (VTE), lack of agreement on risk stratification methods have precluded its widespread use. The most studied VTE prediction tool is the Khorana score, but it does not capitalize on the use of novel biomarkers. We aimed to evaluate the value of biomarkers in prediction of VTE among patients with active cancer receiving outpatient chemotherapy.

Methods
We prospectively collected pre-chemotherapy blood samples on adult patients with solid organ tumors. We excluded patients on anticoagulation and those unable or unwilling to consent. Along with demographics and cancer specific variables, potential novel predictors of VTE were selected a priori and included: coated platelets (CP), D dimer (DD), protein C (PC), fibrin monomers (FM), mean platelet volume (MPV), platelet microparticles (PMP). Type of cancer was grouped according to the Khorana score (Very high risk: Stomach, Pancreas; High risk: Lung, Gynecologic, Bladder, Testicular; Low/Moderate risk: all other sites). VTE events were adjudicated at 6 months of follow up. For all statistical analyses we used SAS 9.2 (SAS Institute Inc., Cary, NC, USA). A p value of <0.05 was considered as statistically significant. We only performed univariate analysis at this point of our study due to the stage of recruitment and period of follow-up.

Results
We have recruited a total of 101 patients (mean + standard deviation age 59.7+11 years, 68% female), 20% of the 75 patients with complete follow up have developed a VTE. We found no significant association between the incidence of VTE and age, gender, or baseline Khorana score. The variables associated with incident VTE were: BMI (odds ratio [OR] 8.5 for BMI<25 kg/m2, p<0.001), type of cancer (OR 14.5 for very high risk compared to high risk, p<0.01) and protein C (OR 3.3 for protein C<110ug/mL the lowest tertile, p=0.05). The rest of the tested potential biomarkers did not have a strong association with incident VTE in the current analysis (Table). Twenty percent of the patients were on aspirin and none of them developed VTE compared to 23% of those not taking aspirin who developed VTE, (p=0.2).

Conclusion
Pre Chemotherapy level of Protein C is a potential biomarker for the incidence of VTE. We confirm that cancer type and BMI are predictors of cancer associated VTE. In addition, lower BMI is not usually recognized as a potential predictor of VTE in other prediction scores. We were underpowered to detect differences in the VTE incidence according to Khorana score. Finally, aspirin may have a role in outpatient cancer associated VTE prevention and deserves further investigation.

Disclosures:
Tafur: Stago Diagnostica: Research Funding. Rathbun:Stago Diagnostica: Research Funding.
Symptomatic and Incidental Venous Thromboembolic Disease Are Both Associated With Mortality In Patients With Prostate Cancer
Authors: Chaturvedi Shruti , Sidana Surbhi , Khorana Alok A. , McCrae Keith R. 
Published: October 2019

Abstract

Introduction
The association between malignancy and venous thromboembolism (VTE) is well established. Less is known about the independent impact of VTE, both symptomatic and incidental, on survival in patients with prostate cancer.

Methods
We conducted a retrospective cohort study of 457 consecutive patients with prostate cancer who received outpatient clinical care at the Cleveland Clinic from January 2006 to June 2006. Data were collected regarding clinical characteristics, treatment and outcomes. Fisher exact (for categorical variables) and t-test (continuous variables) were utilized to test associations with VTE and mortality. Survival functions were estimated using the Kaplan Meier method and a Cox regression model was used to model the mortality hazard ratio (HR) with date of diagnosis as time origin.

Results
The mean age of our cohort of patients was 65.86 ± 8.64 years. Three hundred and fifty eight (78.3%) had clinically localized disease, 76 (16.7%) had locally advanced disease and 41 (8.9%) had metastatic cancer at diagnosis. One hundred twenty four (27.1%) men underwent surgery, 315 (68.9%) received radiotherapy, 201 (44%) received hormonal therapy and 71 (15.5%) received chemotherapy. Complete follow up was available on 403 patients of which 109 (27%) died during the period of follow up. VTE occurred in 42 (9.2%) patients (33 deep vein thrombosis, 5 pulmonary embolism, and 4 patients with both DVT and PE), of which 27 (64.3%) were symptomatic and 15 (35.7%) were incidentally diagnosed. Twenty-three were outpatients and 17 were hospitalized when VTE was diagnosed. Metastatic disease (p<0.0021), and chemotherapy (p=0.002) were associated with VTE. There was no association of VTE with more traditional risk factors such as obesity, renal disease, rheumatologic disease, hip fracture, COPD, and smoking.
Metastatic disease (p=0.002), ECOG score of 3 or 4 (p<0.001), and VTE (p<0.001) were predictors of mortality. Adjustment for stage of disease was included in the multivariate analysis. Mean survival of patients with and without VTE was 91.8±11.3 months and 144.8±3.6 months respectively (p<0.01). Five-year survival rates were also significantly lower for patients with VTE compared to those without (45.2% vs. 87.8%, p<0.001). Patients with both symptomatic and incidental VTE had significantly poorer survival than those without however there was no significant difference in survival between patients with symptomatic or incidental VTE (70.78±44.82 years versus 77.87±63.07, p=0.674).

Conclusion
VTE, both symptomatic and incidental, is a predictor of poor survival in patients with prostate cancer, especially those with advanced disease. This finding has implications for the clinical care of patients with prostate cancer. Further studies are needed to evaluate the benefit of prophylactic and therapeutic anticoagulation in this population.

Disclosures:
No relevant conflicts of interest to declare.