bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Case Series: Chiari Malformation and Sickle Cell Disease
Authors: Gowhari Michel , Molokie Robert , Testai Fernando , Gordeuk Victor R. , Ajayi Olaide I. 
Published: October 2019

Abstract
Abstract 4772

Introduction:
Chiari type I malformation is defined as tonsillar herniation of at least 3 to 5 mm below the foramen magnum. The prevalence of Chiari type I malformation in the general population is estimated to be 0.1 to 0.5%. In the SIT (Silent Infarct Transfusion) Trial in children with sickle cell disease, Chiari type I malformation was found as an incidental finding in 22 of 953 (2.3%) of the individuals imaged. Thus, the incidence of Chiari type I malformation in the SIT Trial appeared to be about five times greater than in the general population (Jordan et al Pediatrics 2010). Recently, four hemoglobin SS patients aged 6–17 years with and Chiari type I malformation were reported from one institution (Chonat el al J Pediatr Hematol Oncol 2011). Here we describe six sickle cell disease patients aged 17–24 years with Chiari type I malformation from two institutions.

Discussion:
All of the cases had severe sickling phenotype, either hemoglobin SS or sickle/B°thalassemia. The majority of the patients were experiencing neurologic symptoms that were subsequently attributed to Chiari type I malformation. Five of the six cases were eventually evaluated by neurosurgery. Neurosurgical intervention with posterior fossa decompression was recommended in four of these individuals. To date one patient has undergone surgery with relief of symptoms. Although Chiari type I malformation is thought to be primarily a congenital disorder, it has also been associated with disorders that are non-congenital. Individuals with sickle cell disease may have a thick calvarium as a result of erythroid hyperplasia and expansion of the diploe of the skull bones. Other conditions with severe anemia and thalassemia have been associated with increased thickness of the calvarium caused by diploic erythroid hyperplasia. One can question whether the increased thickness of the calvarium in some sickle cell patients results in craniocephalic disproportion with a subsequent acquired cerebellar ectopia, hence the increased Chiari type I malformation in patients with sickle cell disease. Central nervous system involvement in sickle cell disease is common. Any patient with sickle cell disease presenting with symptoms indicative of an ongoing or impending neurological event requires an in depth investigation and entails a broad differential. Chiari malformations may need to be part of this differential diagnosis.

Disclosures:
No relevant conflicts of interest to declare.
Outcome of Acute Myeloid Leukemia AML &High Risk MDS Treated According to the Standard of Care in Community Hospital, Data From Single Center ( 2001–2010)
Authors: Al-Ameri Ali , Abdelfatah Mohamed , Kanaan Zeyad , Haller Nairmeen 
Published: October 2019

Abstract
Abstract 4796

Background:
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults causing the highest number of annual deaths secondary to leukemias in the United States. Age, cytogenetics, molecular features are the most important factors in the prognosis, whereby increased age and monosomal karyotypes carry the worst prognosis. The most favorable cytogenetics are patients with normal karyotypes, who can receive standard therapy.

Aim:
Study the overall survival (OS) of AML/High risk MDS treated according to standard of care at a community teaching hospital.

Methods:
A retrospective study of AML & High risk MDS patients treated at AGMC, Akron, Ohio USA, during 2002–2010. After IRB approval, we reviewed patient demographics, diagnosis types/subtypes, treatment, and cytogenetics. Patients were classified as low-intermediate risk or high risk according to cytogenetics background using WHO criteria. We also classified patients according to presence of bone marrow fibrosis and health insurance coverage at the time of diagnosis. Overall survival (OS) rates were determined by Kaplan-Meier Survival Analysis. Prognostic factors were evaluated by Log Rank analysis.

Results:
We were able to classify 98 (75%) pts, with 52 (53%) pts as high risk and 46 (47%) pts as low-intermediate risk. Median age was 55 years (range: 19–90), 43 (45%) pts were older than 75 years. AML pts made up 71%, 45 patients (35%) had complex cytogenetics, and 15% had AML arise from MDS. Median survival overall was 22.4 weeks; 14.4 weeks for high risk and 53.8 weeks for low risk (p<0.01). Median survival for pts greater than 75 years was 11.5 weeks compared to 35.8 weeks for those younger than 75 years (p<0.05). We classified 103 pts according to insurance; 29 pts had private insurance and 74 pts had medicare/Medicaid. Cox regression analysis was performed to examine for the net effect of each of age, insurance, and fibrosis status after controlling for the effect of other variables in the model. Data showed that survival is inversely related to age at diagnosis (p value=.01) while the variables fibrosis status, medicaid/uninsured, and private insurance did not contribute significantly to the model (p value=.97 and.14.34, respectively).

Conclusions:
No significant differences in OS regarding insurance status or presence of bone marrow fibrosis. This was likely because the majority of pts received standard of care therapy and overall survival, in general, was low in the study population. OS was lowest in high risk patients and those greater than 75 years, and was better in low risk pts and those younger than 75 years respectively. Early referral to a specialized center, or possible clinical trial enrollment may be an alternative way to approach those pts.

Disclosures:
No relevant conflicts of interest to declare.
Gain-of-Phosphorylation Mutations in Coiled-Coil and DNA-Binding Domain of STAT1 Identified in Japanese Patients with Chronic Mucocutaneous Candidiasis
Authors: Mizoguchi Yoko , Okada Satoshi , Tsumura Miyuki , Hirata Osamu , Casanova Jean-Laurent , Morio Tomohiro , Kobayashi Masao 
Published: October 2019

Abstract
Abstract 4831
Chronic mucocutaneous candidiasis (CMCD) is a rare congenital disorder characterized by persistent or recurrent skin, nails and mucosal membranes infections caused by Candida albicans. Several studies suggest that impairment of development in Th17 lineage and/or IL-17 signaling could be responsible for development of CMCD and seven responsible genes, CARD9, STAT3, IL12B, IL12RB1, IL17RA, IL17F, and AIRE have been identified. Recently, heterozygous mutations in coiled-coil domain (CCD) and DNA-binding domain (DBD) of STAT1 are identified in approximately 40% of patients with CMCD. Signal transducer and activation of transcription 1 (STAT1) is a DNA-binding factor which regulates specific gene transcription. IFN-γ stimulation results in phosphorylation of STAT1 at Tyr701 (pSTAT1) to induce the homodimerization, a gamma-activated factor (GAF), through the conformational change and the nuclear import. The GAF binds to the gamma-activated sequence (GAS) to induce the transcriptional activities. STAT1 mutations identified in patients with CMCD are gain-of-phosphorylation, gain-of-GAF DNA binding and gain-of-GAS transcription activity in response to IFN-γ, IFN-α and IL-27. Based on the results of transient gene experiments, impairment in dephosphorylation of STAT1 has been considered to be a molecular pathogenesis underlying the increased pSTAT1.
Here we report six heterozygous missense mutations in CCD and DBD of STAT1, including two novel heterozygous STAT1 mutation, 1060C>A (L354M) and 986C>T (P329L), in two sporadic and four multiplex cases with CMCD in Japan. We investigated functional significance of these mutations by transient gene expression experiments using U3C STAT1 null fibrosarcoma cells. Similar to the previous studies, all mutant proteins showed increased pSTAT1 in response to IFN-α and IFN-γ. Increased GAF-DNA binding and GAS transcription activity were observed in mutant expressed cells. Thus, these mutations are gain-of-function mutations against GAF mediated transcription activity.
We then studied dephosphorylation of STAT1 using peripheral blood mononuclear cells (PBMCs) from the patients. The PBMCs were incubated with Staurosporine, tyrosine kinase inhibitor, followed by IFN-γ stimulation and analyzed by flowcytometry and immunoblot. In both experiments, PBMCs from the patients showed increased pSTAT1 after IFN-γ stimulation. Furthermore, we observed persistent pSTAT1 after Staurosporine treatment. These findings suggest that excess pSTAT1 is caused by an impairment of dephosphorylation. The flowcytometry analysis showed no overlap in mean flow intensity of pSTAT1 between 6 patients and 11 healthy controls after Staurosporine treatment. Therefore, this method can be useful for rapid test of STAT1 function in patients with CMCD.

Disclosures:
No relevant conflicts of interest to declare.
Analysis of the Effect On the Expression of Global Gene Expression Profiles in Lymphocyte Subpopulations Treated by Extracorporeal Photopheresis
Authors: Knobler Robert M , Just Ulrike , Klosner Gabriele , Klinglmueller Florian , Bilban Martin , Kuzmina Zoya , Greinix Hildegard T. , Trautinger Franz 
Published: October 2019

Abstract
Abstract 4841

Introduction
After the initial introduction of extracorporeal photopheresis (ECP) for the therapy of Sezary syndrome (CTCL) it has been found to have significant clinical effect on other T-cell mediated diseases including graft-versus-host disease (GvHD), organ transplant rejection, systemic sclerosis and other autoimmune disorders.
To obtain information about modifications in gene expression patterns before and after ECP and to define gene sets with important changes in expression we analysed gene expression profiles in major lymphocyte subsets of patients before and after treatment with 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) irradiation.

Patients, Materials, and Methods
For this initial study 6 female patients suffering from chronic GvHD under treatment with ECP were included. Affymetrix® Human Genome U133 Plus 2.0 Arrays were used to compare global gene expression profiles in CD4+ and CD8+ lymphocytes before and after ECP. Lymphocyte subsets were isolated before and immediately after exposure to 8-MOP/UVA during a standard ECP treatment cycle. Total RNA was isolated from each cell sample and processed and analyzed according to standard procedures.

Results
Preliminary data suggest a significant effect in CD4+ and CD8+ lymphocytes in patients with chronic GvHD on gene transcription after 8-MOP/UVA exposure. In CD4+ cells 20 times more gene transcription can be detected when compared to CD8+ cells.
These findings underline the possible key role of CD4+ cells in the mechanisms of action of ECP. Recent research in animal models found evidence for a role of CD4+ regulatory T cells in the immunomodulatory activity of ECP.

Conclusion
The scientific approach of this study has the advantage of exploring global gene regulatory effects of ECP without any experimental bias based on earlier evidence or on a mechanistic hypothesis. Its results offer the advantage of finding new and so far unexplored effects of ECP on the treated cells; information which should be able to generate significant data to help define key targets for subsequent research into the mechanism of action of ECP.

Disclosures:
No relevant conflicts of interest to declare.
Analysis of Prognostic Factors for Survival in 75 Chinese Patients with Peripheral T-Cell Lymphoma (PTCL)
Authors: Han Yue , Ruan Jia , Zhu Qian , Chen Xiaochen , Zhao Shixiang , Zhang Wenjuan , WANG Qian , Jin Zhengming , Qiu Huiying , Sun Aining , Depei Wu 
Published: October 2019

Abstract
Abstract 4852

Background:
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with poor clinical outcomes. The aim of this retrospective study was to correlate the clinical characteristics, risk factors, and treatment methods with overall survial in 75 Chinese patients with PTCL.

Methods:
Retrospective chart review was conducted to identify patients with newly diagnosed PTCL who were treated at our center from April 2004 to November 2011. Clinical information including demographics, histology, treatment, and survival were collected. Probability of overall survival was estimated using the Kaplan-Meier method. Univariate analysis and log rank test were used to correlate survival with prognostic variables. SPSS1 program (version 7.0) was used for statistic analysis.

Results:
A total of 75 patients were identified. The median age was 48 years (range 18–73), and M:F ratio was 2:1. Histologic subtypes included PTCL-not-otherwise specified (PTCL-NOS) (n=37, 49.3%), natural killer/T-cell lymphoma (NK/TCL) (n=25, 33.3%), anaplastic large cell lymphoma (ALCL) (n=11, 14.7%), and angioimmunoblastic T-cell lymphomas (AITL) (n=2, 2.7%). The induction chemotherapy consisted primarily of CHOP (n=49, 65.3%), hyperCVAD (n=12, 75%) and SMILE (n=4, 5.3%). Fifty-nine patients (79%) received chemotherapy alone, while 16 patients (21%) received additional autologous hematopoietic stem cell transplantation (HSCT). Of all the patients, overall survial (OS) at 5-year and 3-year were 41.5% and 64.1%, respectively. The 5-year OS was significantly better (P<0.05) in patients who 1) were less than 60 years (46.8% vs 24.5%, comparing to those older than 60); 2) had normal LDH (74.6% vs 24.2%, comparing to high LDH; 3) had IPI score ≤2 (46.5% vs 22.4%, comparing to IPI score>2); 4) had HSCT (80% vs 30.8%, comparing to those receiving chemothrapy only). OS at 5-year for patients treated with chemotherapy alone was lower with CHOP compared to more intensive regimens (28.7 vs 71.3%, P<0.05). Meanwhile, OS at 5-year was higher in patients treated with etoposide containing chemotherapy (60% vs 27.4%, P<0.05). The 3-year OS was higher (P<0.05) in those with 1) normal β2-microglobulin (92.9% vs 49.3%, comparing to elevated β2-microglobulin), 2) Ki-67<10% (86.2% vs 47%, comparing to Ki-67≥10%), 3) PIT score ≤2 (70% vs 28.6%, comparing to PIT score>2). In addition, failure to achieve complete remission after chemotherapy and bone marrow involvement were correlated to poor survival.

Conclusion:
Chinese patients with PTCL have heterogeneous and generally poor outcomes. Bone marrow involvement, older age, elevated LDH, high β2-microglobulin, Ki-67≥10%, IPI >2 and PIT >2 were associated with inferior survival. Intensive chemotherapy and HSCT may improve the long-term survival of PTCL.

Disclosures:
No relevant conflicts of interest to declare.
CHOEP-21 Chemotherapy without Autologous Stem Cell Transplantation (ASCT) for Newly Diagnosed Nodal Peripheral T-Cell Lymphomas (PTCLs) in the Northern Part of Thailand
Authors: Rattarittamrong Ekarat , Norasetthada Lalita , Tantiworawit Adisak , Chai-adisaksopa Chatree , Nawarawong Weerasak 
Published: October 2019

Abstract
Abstract 4857

Background:
Several previous studies demonstrated the poor treatment outcomes for the patients with nodal peripheral T-cell lymphomas (PTCLs) including PTCL, not otherwise specified (PTCL-NOS), ALK-negative anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL) when compared with ALK-positive ALCL and aggressive B-cell lymphomas. For the treatment of T-cell lymphomas, promising results of chemotherapy regimens including etoposide in several studies were evidenced. We conducted the prospective study to determine the effectiveness and tolerability of the combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with addition of etoposide (CHOEP-21) for newly diagnosed nodal peripheral T-cell lymphomas (PTCLs) treated at Maharaj NakornChiang Mai Hospital in the Northern part of Thailand.

Method:
From October 2008 to November 2011, patients ages 18–60 years with newly diagnosed nodal PTCLs excluding ALK-positive ALCL were enrolled to receive CHOEP-21 (CHOP plus etoposide 100 mg/m2 days 1–3) every 3 weeks for 8 cycles with granulocyte colony-stimulating factor (G-CSF) starting from day 4–11. None of them proceeded to undergo autologous stem cell transplantation (ASCT) due to financial problems. Event-free survival (EFS) which is the primary endpoint, was calculated from the date of diagnosis until disease progression or relapsed, change to other treatment, or death from any cause. Secondary end point of the study was overall survival (OS), response rate and toxicities of regimen.

Results:
24 patients were enrolled. Twenty of them were male with a mean age of 49 years. Majority of the patients had PTCL, NOS (n = 16), 7 patients had AITL and only one ALK-negative ALCL patient. Almost all except one were in stage III-IV with 62% of the patients had international prognostic index (IPI) ≥ 2. From median follow up of 16 months, overall response (OR) was 58% (33% CR) but 28.5% of these patients eventually relapsed as shown in table 1. Estimated 2-year EFS and OS were 33.8% and 55%, respectively. When compared with the 11 historical control receiving CHOP regimen, the outcomes including EFS, OS and OR were not statistically different, even though patients receiving CHOEP had more advanced stage and bone marrow involvement than those receiving CHOP regimen (Table 2, Figure 1 and 2). Infection (grade 3–4 of 8.3%) and hematologic toxicities were the most common adverse effects with acceptable grade 3–4 neutropenia (7.6%) and thrombocytopenia (4.6%).

Conclusion:
The CHOEP-21 without following ASCT did not seem to improve outcomes in patients with nodal PTCLs. Other treatment strategies are warranted to study in these groups of patients.

Disclosures:
No relevant conflicts of interest to declare.
Obinutuzumab (GA101) Displays Higher Efficiency Than Rituximab in a Follicular Lymphoma 3D Model
Authors: Decaup Emilie , Jean Christine , Laurent Camille , Gravelle Pauline , Fruchon Séverine , Capilla Florence , Marrot Alain , AlSaati Talal , Frenois François-Xavier , Laurent Guy , Klein Christian , Fournié Jean-Jacques , Varoqueaux Nathalie , Bezombes Christine 
Published: October 2019

Abstract
Abstract 4868
Follicular lymphomas (FL) account for 35–40% of all adult lymphomas. Treatment typically involves chemotherapy combined with the anti-CD20 monoclonal antibody (MAb) rituximab (RTX). The development of type II anti-CD20 MAb obinutuzumab (GA101) aims to improve treatment further. Using FL cells, here we showed that RTX and GA101 displayed similar efficiency towards 2D culture. However, 2D culture does not mimic tumor spatial organization and conventional 2D models do not reflect the effects of MAbs seen from preclinical and in vivo studies. Thus, we created a NHL 3D culture system, the so-called multicellular aggregates of lymphoma cells (MALC), and compared RTX with GA101 activity. Our result showed that both MAbs displayed greater bioactivity towards FL cells in 3D culture compared to 2D culture. Moreover, we observed that GA101 was more effective than RTX in inhibiting tumor growth through induction of apoptosis, lysosomal cell death and senescence. GA101 was also more effective than RTX in inhibiting intracellular signaling pathways such as mTOR, Akt, PLCgamma and Syk. Altogether, our study demonstrates that spatial organization strongly influences response to MAbs treatment. Additionally, we provide evidences that GA101 is more effective than RTX in inhibiting FL development in MALC model, which suggests the possibility for better patient treatment with GA101.

Disclosures:
Decaup: roche: Employment, Research Funding. Klein:Roche Glycart AG: Employment. Varoqueaux:Roche S.A.S: Employment. Bezombes:Roche: Research Funding.
Immunoglobulin Expression Is a Major Determinant Of Patient Sensitivity To Proteasome Inhibitors
Authors: Tuch Brian B , Loehr Andrea , Degenhardt Jeremiah D , Kwei Kevin A , Keats Jonathan J , Kirk Christopher J. 
Published: October 2019

Abstract
Several therapies for multiple myeloma are now approved and many more are in development, promising improved outcomes for patients with this incurable cancer. With expanding treatment options, however, comes a pressing need to pair each patient with the most efficacious and safe treatment. Proteasome inhibitors, such as carfilzomib and bortezomib, have become a standard therapy across all lines of multiple myeloma treatment. Despite extensive study, the mechanism of selective tumor cell death following proteasome inhibition is poorly understood. However, the uniquely high sensitivity of myeloma cells to proteasome inhibition, the uniquely high burden of protein (immunoglobulin) secretion these cells experience, and the key role of the proteasome in maintaining protein homeostasis, together point toward a unifying model in which protein load drives proteasome inhibitor sensitivity. This simple model is supported by published studies of murine and human myeloma cell lines (e.g., Meister et al. & Bianchi et al.). As part of company-sponsored Phase II & III clinical trials of proteasome inhibitors, CD138+ tumor cells collected during patient screening were banked for comprehensive genomic analyses. Patient samples banked on bortezomib trials were utilized in now-published microarray-based RNA studies, while samples from carfilzomib trials are currently being used for NGS-based DNA and RNA studies. Here, examining our early carfilzomib data along with publically-available bortezomib data, we find a strong association between higher immunoglobulin expression and sensitivity to each compound (Wilcoxon P-value = 3x10-3 and P-value = 2x10-4, respectively). In fact, using IGH expression alone, we are able to classify response with 55% sensitivity and 91% specificity in our carfilzomib training data. As expected for a bona fide predictive biomarker of proteasome inhibition, an association between IG expression and response was not found in patients treated with single agent dexamethasone (Wilcoxon P-value = 0.82). Median time to progression for IGH-high carfilzomib patients was 6-fold longer than for IGH-low carfilzomib patients (7.6 months vs. 1.4 months; log-rank P-value = 0.003). This is the first report that high levels of IG expression correlate with response to proteasome inhibitors and therefore IG expression represents, to our knowledge, the first validated biomarker for this important class of anti-tumor agents.

Disclosures:
Tuch: Onyx Pharmaceuticals: Employment, Equity Ownership. Loehr:Onyx Pharmaceuticals: Employment, Equity Ownership. Degenhardt:Onyx Pharmaceuticals: Employment, Equity Ownership. Kwei:Onyx Pharmaceuticals: Employment, Equity Ownership. Kirk:Onyx Pharmaceuticals: Employment, Equity Ownership.