bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quality of Life Among Adolescents with Beta-Thalassemia Major (TM) in Qatar
Authors: Nashwan Abdulqadir Jeprel , Yassin Mohamed A , Babu Ganga , Nair Sindhumole LK , Libo-on Izette , Hijazi Hothaifah , De Sanctis Vincenzo , Soliman Ashraf Tawfiq 
Published: October 2019

Abstract
BACKGROUND: Thalassemia is a heterogeneous group of inherited disorders of hemoglobin synthesis. It is a common disease in Mediterranean, Southeast Asia, Indian subcontinent, and Middle East countries, including Qatar.
PURPOSE: The aim of this study was to assess the quality of life (QOL) among patients aged 14 to 18 years with thalassemia major (TM) in Qatar and correlates their QOL with bio-demographic data of the patients compared to healthy controls.
MATERIALS AND METHODS: This cross-sectional study measured the QOL in adolescents with thalassemia major who were attending ambulatory units in a tertiary hospital in Qatar. Forty children and adolescents with TM and 40 healthy participants were enrolled in the study. Forty-two (52.5%) participants were males and 38 (47.5%) females. Data were collected utilizing PedsQLTM 4.0 generic core scale and were analyzed using the appropriate statistical method.
RESULTS: Children with TM had significantly lower and more variable overall quality of life score (69.1 ± 16.8) compared to healthy matched children (77 ± 12.8), (p <0.001). Both groups were not different from the physical, emotional, and social domains. Thalassemic adolescents had also a significantly lower school performance.
CONCLUSIONS: TM adversely affects the QOL of children and adolescents and this necessitates applying more efforts to help them improve and achieve a desirable quality of life. Patients with TM need more attention in schools that can be accomplished by implementing a special program for their management that needs a mutual collaboration between Ministry of Public Health (MoPH) and Ministry of Education (MoE) in Qatar.

Disclosures
No relevant conflicts of interest to declare.
Low and Very Low Bone Mineral Density Among Adult Survivors of Childhood Cancer Can be Predicted
Authors: Van Atteveld Jenneke E. , Pluijm Saskia M.F. , Ness Kirsten K. , Hudson Melissa M. , Chemaitilly Wassim , Kaste Sue C. , Robison Leslie L. , Neggers Sebastian J.C.M.M. , Van den Heuvel-Eibrink Marry M , Wilson Carmen L. 
Published: October 2019

Abstract
Background: Although low bone mineral density (BMD) is prevalent among adult survivors of childhood cancer, evidence-based guidance for surveillance of low BMD among survivors by dual X-ray absorptiometry (DXA) is limited. Therefore, we aimed to develop and validate prediction models for low and very low BMD based on patient and treatment characteristics that identify adult survivors who require screening by DXA.
Methods: Caucasian survivors (N=2412, median attained age, 30.9 [range: 18.1-65.9] years, 60% survivors of hematologic malignancies) enrolled in the St. Jude Lifetime Cohort (SJLIFE, development) and survivors previously treated at the Erasmus Medical Center (validation), the Netherlands (N=410, median age, 24.5 [range: 18.0-49.3] years, 73% survivors of hematologic malignancies) were evaluated with DXA to determine lumbar spine (BMDLS) and total body (BMDTB) BMD, with low and very low BMD defined as BMDLS and/or BMDTB Z-score ≤-1 or ≤-2, respectively. Backward multivariable logistic regression was used to build prediction models; performance was assessed using receiver operating characteristic curves. Diagnostic values were calculated at different probabilities. Diagnostic values were calculated at different probabilities. The formula PlowBMD=e^(β0+β1*x1+...+βn*xn)/(1+e^(β0+β1*x1+...+βn*xn)) was used to predict individual probability of low BMD (β0=intercept; βn=regression coefficient (β) of each predictor xn).
Results: Low BMD was prevalent among 52% and 44% of SJLIFE and Dutch participants, and very low BMD among 20% and 10%, respectively. The model for low BMD included male sex (β=0.50), height (β=-0.05), weight (β=-0.03), age at cancer diagnosis (β=-0.02), current smoking (β=0.19) and cranial irradiation (β=0.31) as significant predictors. Areas under the curves (AUC's) were 0.72 (95%-CI 0.70-0.74) in SJLIFE and 0.70 (95%-CI 0.65-0.75) in the Dutch cohort. Sensitivity (69.6%), specificity (63.9%) and accuracy (66.9%) were optimized at a probability of 0.50. The model for very low BMD included male sex (β=0.55), height (β=-0.05), weight (β=-0.04), cranial (β=0.31) and abdominal (β=0.22) irradiation, yielding AUC's of 0.75 (SJLIFE cohort) and 0.72 (Dutch cohort).
Conclusion: Validated models for low BMD including sex, age at cancer diagnosis, height, weight, smoking status, cranial irradiation and abdominal irradiation correctly identified BMD status in most Caucasian survivors through age 50 years. Clinical applicability can be warranted using our online calculator.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Value of IPSS-R Score, Cytogenetic Aberrations, and Cytopenias on Outcome of Allogeneic Hematopoietic Stem Cell Transplant in Myelodysplastic Syndrome in GATA2 Deficiency
Authors: Scheiermann Julia , West Robert , Embree Lisa J. , Calvo Katherine R. , Shah Nirali N. , Tuschong Laura , Parta Mark , Hickstein Dennis D. 
Published: October 2019

Abstract
Sporadic or familial germline mutations in GATA2 frequently result in a bone marrow failure syndrome characterized by recurrent life-threatening infections, cytopenias, and progression to myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), or chronic myelomonocytic leukemia (CMML). Hematopoietic stem cell transplantation (HSCT) represents the only definitive therapy for GATA2 deficiency. However, the highly variable disease penetrance in different families, and in mutation positive individuals within a single family, make the timing of HSCT challenging. We assessed the utility of scoring patient characteristics according to the Revised International Prognostic Scoring System (IPSS-R) to predict survival after HSCT in a cohort of 51 patients with GATA2 deficiency who had progressed to MDS. Higher IPSS-R scores significantly correlated with reduced overall survival after transplant. In evaluating the components of the IPSS-R score for patients with GATA2 deficiency, cytopenias, including anemia, neutropenia, and thrombocytopenia, were important variables in placing these patients in higher risk IPSS-R categories. Since GATA2 deficiency patients have very low peripheral blood monocyte, B cell, and NK cell counts, we evaluated these cytopenias in conjunction with IPSS-R scoring. These cytopenias also had prognostic value for outcome after HSCT in patients with GATA2 deficiency. Cytogenetics, another component of the IPSS-R score, also placed patients with GATA2 deficiency into higher risk categories. In particular, patients harboring monosomy 7 had poorer survival outcomes than patients with normal cytogenetics or trisomy 8. Of note, all five patients with GATA2 deficiency and trisomy 1q successfully underwent HSCT. Clonal cytogenetic progression with the development of additional cytogenetic aberrations was a harbinger of myeloid progression and led to HSCT. In a cohort of four patients who underwent HSCT following progression to AML/CMML, there was only one survivor. Thus, HSCT is recommended in patients with GATA2 deficiency and intermediate or high-risk IPSS-R scores before the development of AML or CMML.

Disclosures
No relevant conflicts of interest to declare.
Thrombotic Thrombocytopenic Purpura in Oman; Manifestations and Outcome. Retrospective Study
Authors: Al Hashmi Khalid Nasser , Al Dowaiki Samata 
Published: October 2019

Abstract
Abstract:
Background: Thrombotic Thrombocytopenic Purpura( TTP) is a rare life threatening disease. It is caused by congenital deficiency of metalloprotease ADAMTS -13 or acquired autoantibodies to this enzyme which normally cleaves vWF macromolecules. This results in Microangiopathic hemolytic anemia (haemolytic anemia, low platelets, and schiztocytes), systemic microvascular thrombi formation and subsequent end organ ischemia (renal and neurological manifestations). Nowadays the early recognition and treatment modalities resulted in survival rate reaching up to >=90%. So far, in Oman there have been no studies evaluating this rare disease.
Aim: This is a retrospective study conducted in a tertiary center in Oman aims to describe the clinical and the demographic characteristics of Omani patients diagnosed of TTP, their remission rate, and survival.
Methods:. We included all patients who were diagnosed between 2006 and 2018 who meet the diagnostic criteria of TTP and aged ≥ 12 years old. Data on patients' age, gender, region, ADAMTS-13 level, clinical presentation, lab results, treatment modalities and condition on discharge are described.
Results: Total of 38 patients met diagnostic criteria of TTP during the study period. 25 Females (66%) and 13 Males (34%),with Female: Male ratio was 1.9:1. Age ranges between12-83 years (mean: 42 years). Mean age at onset: 36 years (range 1- 79 years). Majority of patients were from Governates Al-Batinah 39% and Muscat 21%. Clinical features in descending order of frequency: fever (63%), petechiae/ ecchymosis (31%), seizures (21%), high BP reading(21%), headache(15%) , confusion(15%), postpartum presentation(15%) and stroke (7.9%). The mean values at presentation are consistent with microangiopathic hemolytic anemia. Deranged RFT was found in 19 patients (50%), ADAMTS 13% was tested in 18 cases, congenital deficiency was found in 4 patients, deficiency due to autoantibodies was found in 7 patients. Treatment modality received were steroids and Plasma exchange (number of sessions ranges between 3-30 sessions, average 9 sessions). 19 cases required rituximab and 10 patients required cyclosporin. 5 patients (13%) had renal derangement requiring dialysis as inpatients, only 1 patient continued to dialyze after discharge. None of the 3 patients with documented stroke had neurological deficits on discharge. Patients who had seizures (3 patients) were free of seizures and on maintenance antiepileptic medications. Relapses after first presentation was noted in 7 patients (17%) with mean relapse ranges 1 to 7 years (mean of 3 years) after first presentation. There was 1 death with TTP in a relapsed Non- Hodgkin's lymphoma pateint. Overall survival rate was 97% at 10 years study period.
Conclusion:This is the first study that demonstrates the demographic, clinical and survival rate of TTP patients in Oman, and provides a general picture of the TTP patients in our country

Disclosures
No relevant conflicts of interest to declare.
MM-derived exosomes can promote apoptosis and inhibit proliferation of HD-CD4+T, inhibit apoptosis and promote proliferation but inhibit perforin secretion of HD-CD8+T, inhibit apoptosis and promote proliferation HD-Treg, and promotes IL-10 secretion
Authors: Fu Rong , Shao Qing , Zhaoyun Liu , Liu Hui , Chen Jin , Shao Zonghong 
Published: October 2019

Abstract
OBJECTIVE: To study the effects of multiple myeloma (MM)-derived exosomes on the number and function of CD4+T, CD8+T and regulatory T cells in healthy donors (HD) and MM patients.
METHODS: MM cell-derived (OPM2, U266) exosomes were extracted by ultracentrifugation and kit method and co-cultured with CD4+T, CD8+T and CD4+CD25+CD127dimT cells (Treg) from HD and MM patients sorted by magnetic beads. Flow cytometry was used to detect the apoptosis rate of T cells, level of perforin and granzyme B in CD8+T. Cell viability was detected by CCK8 kit, and IL-10 and TGF-β levels were detected by ELISA.
RESULTS: HD-CD4+T apoptotic rate was higher in the OPM2 group (6.24±1.24%) and U266 group (5.42±1.07%) than in the control group (4.37±0.96%). The HD-CD4+T viability in U266 group (85.45±6.09%) decreased compared with the control group. The apoptotic rate of HD-CD8+T was decreased in the OPM2 group (9.97±1.28%) and the U266 group (11.00±1.75%) compared with the control group (16.12±2.95%). HD-CD8+T cell viability was increased in the OPM2 group (112.63±3.88%) and the U266 group (111.70±3.62%) compared with the control group. Perforin of HD-CD8+T in U266 group (9.34±2.36%) was lower than the control group (12.76±3.31%); Perforin of MM-CD8+T in OPM2 group (6.48±1.06%) and U266 group (5.63±1.15%) decreased compared with the control group (10.55 ± 2.50%). The apoptosis rate of HD-Treg was lower in OPM2 group (15.33±3.87%) and U266 group (11.71±2.71%) than in control group (19.61±3.50%). The apoptosis rate of MM-Treg was higher in U266 group (37.29±6.54%) than the control group (29.95 ± 6.68%). The viability of HD-Treg in U266 group (173.48±34.99%) was higher than the control group. The viability of MM-Treg in OPM2 group (82.29±12.16%) was lower than the control group. The supernatant IL-10 from HD-Treg in OPM2 group (18.53±8.08 pg/ml) was higher than the control group (8.49±4.02 pg/ml). The supernatant TGF-βfrom MM-Treg was decreased in the OPM2 group (290.29±23.21pg/ml) and the U266 group (230.03±15.96pg/ml) compared with the control group (387.49±21.60pg/ml) (P<0.05).
Conclusion: MM-derived exosomes can promote apoptosis and inhibit proliferation of HD-CD4+T, inhibit apoptosis and promote proliferation but inhibit perforin secretion of HD-CD8+T, inhibit apoptosis and promote proliferation HD-Treg, and promotes IL-10 secretion.

Disclosures
No relevant conflicts of interest to declare.
Patient-Reported Outcome Labeling for Malignant Hematology Drugs Approved in the United States: 2011-2017
Authors: Zettler Marjorie E , Basch Ethan , Nabhan Chadi 
Published: October 2019

Abstract
Introduction: Patient-reported outcomes (PROs), defined as any report on the status of a patient's health condition that comes directly from the patient without interpretation by anyone else, play an increasingly important role in drug development. In 2009 the FDA issued final guidance on using PRO measures to support labeling claims, to incorporate the patient perspective into the drug approval process. The 21st Century Cures Act emphasizes PROs as a differentiating element in the FDA approval process of new drugs, beyond traditional clinical outcome measures. Further, recent data has shown that intervention based on PROs can improve survival in metastatic cancers (Basch et al; 2017). The incorporation of PROs into the labeling of new drugs for malignant hematology disorders has not been studied and is the subject of this investigation.
Methods: We reviewed the FDA's Novel New Drug Summaries (2011-2017) to identify drugs approved for malignant hematology indications. Drug approval packages and product labeling were accessed via the Drugs@FDA database and analyzed for PRO endpoints, measures, and labeling claims. Clinical trial designs and published study results were retrieved via the ClinicalTrials.gov website and PubMed.
Results: Of 250 novel drugs approved by the FDA between 2011 and 2017, 22 (8.8%) were approved for malignant hematology indications. Interestingly, only 1 had PRO-based claims in their labeling, even though 13 of the 22 drugs (59%) collected PRO data in pivotal trials that led to their approval. Notably, the proportion of malignant hematology trials assessing PROs has increased over time, with 4 of the 5 drugs approved in 2017 for malignant hematology indications evaluating PROs in their development programs, compared with 9 of the 17 drugs approved in the preceding 6 years (80% vs. 53%). PROs evaluated included generic instruments such as the EQ-5D, and disease-specific instruments such as the EORTC QLQ-C30 (see table). Reasons cited for rejection of PRO data inclusion in drug labeling were single arm trial design, excessive missing data, statistical issues, and use of an inappropriate PRO instrument.
Conclusions: While the FDA encourages PRO data submission as part of the new drug approval process, and although more than half of all malignant hematology drugs approved in the past 7 years assessed PROs during development, only 1 was able to successfully acquire labeling claims. Whether this is due to lack of PRO expertise on clinical development teams or absence of strong regulatory guidance on how best to implement PROs remains unknown and requires further research. Designing strategies to develop, validate and report PROs effectively is needed to meet regulatory requirements and enhance patients' voices in their own care.
Table. Table.

Disclosures
Nabhan: Cardinal Health: Employment, Equity Ownership.
Propensity Score Matched Analysis of Risk for Malignancies in Sickle Cell Anemia
Authors: Afzal Amber , Siddiqui Nauman , Godara Amandeep , Khan Zarmina , Tuncer Hande H. 
Published: October 2019

Abstract
BACKGROUND:
The survival of sickle cell patients is limited as compared to the general population. The major morbidity and mortality comes from sickle cell complications including cardiovascular disease, renal failure, infections and thrombosis (Manci Br J Haematol 2013). However, literature is conflicting about risk for malignancies in this population and remains to be investigated by larger studies. Our retrospective study is aimed at studying the prevalence of different malignancies in a large cohort of hospitalized sickle cell patients in the year 2014 using the National Inpatient Sample (NIS).
METHODS:
Study Population:
We identified hospitalized sickle cell patients in NIS using ICD-9 codes (282.5,282.6X -282.6X) for year 2014. We also identified the various malignancies through ICD-9 codes and studied the prevalence of individual malignancies in hospitalized sickle cell patients (SCD/cases) compared to a matched cohort of hospitalized patients with no sickle cell disease (No SCD/controls).
Statistical Analysis:
The 1:N Case-Control Matching Macro (Parsons LS et al SUGI 29) was used to match cases with controls with respect to potential confounders including age, race, gender in the ratio of 1:4. Chi Square was used to determine the difference in the proportions of individual malignancies between the two groups. P value <0.05 was considered statistically significant. All analyses were performed using SAS 9.4.
RESULTS:
We identified 117,405 hospitalized sickle cell patients in the NIS database who were matched to 469,620 controls (Table 1). A total of 1890 malignancies were found in sickle cell cohort. The prevalence of malignancies in hospitalized sickle cell patients was 1.6% as compared to 4.6% in controls (OR 0.34; range:0.30-0.38). The prevalence of all studied malignancies including hematological malignancies was lower in hospitalized sickle cell patients as compared to a matched population of hospitalized patients with no sickle cell disease (Table 2).
CONCLUSION:
Our study showed a lower prevalence of both solid tumors and hematological malignancies in patients with sickle cell disease as compared to matched cohorts. Future prospective cohort studies are needed to evaluate the risk of malignancies in sickle cell anemia and identify if any protective mechanisms exist against the development of malignancy in this patient population.

Disclosures
No relevant conflicts of interest to declare.
Preclinical Development of CTX120, an Allogeneic CAR-T Cell Targeting Bcma
Authors: Dar Henia , Henderson Daniel , Padalia Zinkal , Porras Ashley , Mu Dakai , Kyungah Maeng , Police Seshidhar , Kalaitzidis Demetrios , Terrett Jonathan , Sagert Jason 
Published: October 2019

Abstract
Autologous CAR-T cells targeting BCMA have induced robust and durable responses in patients with relapsed/refractory multiple myeloma. However, autologous cell therapies face several challenges which will likely limit the number of patients that will have access to these therapies. These limitations include manufacturing failure rates, wait time and supply constraints in addition to other factors such as reimbursement. Allogeneic CAR-T cells can potentially overcome these access challenges, and may have several other advantages over autologous therapies. Allogeneic CAR-T cells are derived from robust healthy donor T cells through a batch manufacturing process, which may result in a highly consistent product with greater potency and enable better safety management. Here we show further development and preclinical data for CTX120, an allogeneic "off the shelf" CAR-T cell targeting BCMA. CTX120 is produced using the CRISPR/Cas9 system to eliminate TCR and MHC class I, coupled with specific insertion of the CAR at the TRAC locus. CTX120 shows consistent and high percent CAR expression from this controlled insertion and exhibits target-specific cytotoxicity and cytokine secretion in response to BCMA positive cell lines. CTX120 CAR-T cells retain their cytotoxic capacity over multiple in vitro re-challenges, demonstrating durable potency and lack of exhaustion. In mouse models of multiple myeloma, CTX120 showed typical CAR-T persistence and eliminated tumors completely, resulting in long-term survival as compared to untreated animals. These data support the ongoing development of CTX120 for treatment of patients with multiple myeloma and further demonstrate the potential for our CRISPR/Cas9 engineered allogeneic CAR-T platform to generate potent CAR-T cells targeting different tumor antigens.

Disclosures
Dar: CRISPR Therapeutics: Employment, Equity Ownership. Henderson:CRISPR Therapeutics: Employment, Equity Ownership. Padalia:CRISPR Therapeutics: Employment, Equity Ownership. Porras:CRISPR Therapeutics: Employment, Equity Ownership. Mu:CRISPR Therapeutics: Employment, Equity Ownership. Kyungah:CRISPR Therapeutics: Employment, Equity Ownership. Police:CRISPR Therapeutics: Employment, Equity Ownership. Kalaitzidis:CRISPR Therapeutics: Employment, Equity Ownership. Terrett:CRISPR Therapeutics: Employment, Equity Ownership. Sagert:CRISPR Therapeutics: Employment, Equity Ownership.