bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing a Specialized Nursing Care Guidelines Improves Acute Lymphoblastic Leukemia Patients' Outcome during Induction Phase; A Developing Country Experience
Authors: Hanafy Nesreen Fathy , Khedr Reham , Abd-Elwahab Eglal Ahmed , Abouelnaga Sherif 
Published: October 2019

Abstract
Introduction: Pediatric Cancer patients are treated with therapeutic research protocols that detail medical treatment in low- and middle-income countries (LMICs). Unfortunately, there is no precise definition of a structured nursing care plan that is mandatory to enhance the quality of care needed for these patients. Our study aimed to examine the impact of implementing a designed nursing care guidelines (NCG) on acute lymphoblastic leukemia (ALL) patient outcomes during the induction phase concerning; incidence, duration, and intensity of the patient's gastrointestinal tract GIT adverse events.
Methods: A Quasi-experimental research design was utilized in this study with posttest only control group conducted at the Hematology Units of Children Cancer Hospital Egypt 57357. Seventy-four oncology nurses received adequate education for the designed nursing care plan. A total of (132) ALL children in induction phase were enrolled in the study and were divided into two groups: group 1 (intervention group) was implemented the nursing care guidelines and group II (control group) who was left to the routine hospital care.
Tools: data collection instruments included; "patient outcomes audit chart" to assess the GIT adverse - events data: the incidence, duration, and intensity. The intensity grading of the adverse events Adopted from the NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events v4.0 (CTCAE) Published on May 28, 2009.
Results: A significant positive correlation between implementing the NCG and GIT adverse events incidence, duration and severity were observed (Figure 1). Incidence was reported higher in the control group than the study group with a mean score of ±SD (2.48± .949) versus (0.67± 0.751) respectively, and a p-value (P<0.0001). The duration of incidence was (15.32± 5.920) versus (3.70± 5.108) in the intervention group (t =12.074) df (130) and a p-value (P<0.0001). The intensity grading of the adverse events was less in the study group than the control. (figure 2)
Mean scores for nurses' post-NCG knowledge in the study group were significantly higher than the nurse's knowledge scores in the control group. The intensity of incidence revealed that a significantly higher on the intervention group.
Conclusion: Designing and implementing NCG for all treatment protocols is essential for the enhancement of patients' outcomes. Developing a pediatric oncology nurse residency program for education and teaching of the required practical skills in LMIC is mandatory.
Figure 1 Figure 2

Disclosures
No relevant conflicts of interest to declare.
Utilizing Y Chromosome FISH to Determine the Origin of Post-Transplant Lymphoproliferative Disease in Solid Organ Transplant Recipients
Authors: Ford James B. , Jennifer Sanmann N , Erickson Kelly , Grant Wendy J , Althof Pamela A , Langnas Alan , Shostrom Valerie , Bast Martin , Greiner Timothy C. , Coccia Peter F. 
Published: October 2019

Abstract
Background: Post-Transplant Lymphoproliferative Disease (PTLD) is a heterogeneous disease that arises as a complication after solid organ transplants (SOT) and unusually after bone marrow transplants (BMT). PTLD is generally of recipient origin in SOT patients and donor origin in BMT patients. Knowing the cellular origin of PTLD may provide insight into tumorigenesis and potentially guide treatment options.
Design/Methods: We identified gender mismatched SOT patients from our institutional databases who had PTLD tumor tissue for FISH analysis to determine the tumor origin (donor vs. recipient). From these samples, lesional and normal (when present) tissue was delineated by a hematopathologist (TG), and subsequent XY FISH studies were performed according to standard protocols for detection of the Y chromosome.
Results: Thirty-one gender mismatched PTLD patients were examined (20 were pediatric patients <18 yrs old). Transplants were: 8 isolated liver (L), 7 kidney (K), 3 small bowel (SB), 6 L/SB, 4 L/SB/pancreas (P), 2 K/L and one L/K/P. Of the 31 patients: 25 were 100% recipient origin; 5/31 demonstrated mixed chimerism; and 1 was 100 % donor origin. Of the 6 patients with chimerism (3 children), the percentage of donor cells ranged between 23% and 100%. Three of 31 had PTLD in the allograft, with 2 of 3 demonstrating mixed chimerism. One was a 2 y.o. F 3 months after a SB transplant and the other a 10 m.o. M 12 months after a L/SB/P transplant. Of the 28 with tumor tissue at other sites, 3 had mixed chimerism: a 60 y.o. M 9 months after a K/L transplant; a 7 m.o. M 8 months after a L/SB transplant; and a 64 y.o. F 3 months after a L transplant. The single patient with 100 % donor chimerism was a 27 year old female 5 months after a L/SB transplant. The 6 chimeric patients developed PTLD on average earlier than the 25 patients of recipient origin (6.9 months vs. 18.1 months). Of the 20 pediatric patient, 12 had transplants including small bowel and 3/12 demonstrated mixed chimerism. Mortality rate was similar between pediatric and adult populations (40% and 45% respectively).
Conclusion: As expected, the majority of patients in our series had tumors of recipient origin. However, 3/20 pediatric patients (15%) and 3/11 (27%) adult patients were chimeric in 23% to 100% of their tumor cells. Chimerism was more common in patients who received transplants that included L (4/5) and SB (3/5).

Disclosures
Ford: Novartis: Consultancy, Honoraria.
4-1BB-Costimulated CAR-Mediated Non-Canonical NF-Kb Signaling Enhances CAR T Cell Survival and Suppresses Bim Expression
Authors: Milone Michael C. , OConnor Roddy , May Michael , Albelda Steven , Philipson Benjamin 
Published: October 2019

Abstract
Chimeric Antigen Receptor (CAR) T cell therapy induces deep and durable responses in a large percentage of patients with B-cell malignancies. These responses often correlate with CAR T cell persistence in patients. The first two FDA-approved CAR-T cell therapies employ 2nd generation CARs that use different costimulatory domains derived from either CD28 or 4-1BB. Data from pre-clinical studies as well as clinical trials suggest that 4-1BB CAR (BBz) T cells persist longer than CD28 CAR (28z) T cells.
One signal associated with cellular survival and activated by endogenous 4-1BB, but not CD28, is the non-canonical NF-kB (ncNF-kB) pathway. NcNF-kB is required for memory T cell persistence and enhances tumor cell survival by suppressing pro-apoptotic gene transcription. Therefore, we hypothesize that the BBz, but not the 28z CAR, activates ncNF-kB signaling, which promotes CAR T cell persistence by suppressing pro-apoptotic gene expression.
Using primary human T cells isolated from the apheresis products of anonymous healthy donors, we generated 28z or BBz T cells by lentiviral transduction following activation by CD3 and CD28. Induction of ncNF-kB signaling following CAR activation was assessed by western blot. NcNF-kB function was evaluated by concomitant expression of a dominant-negative mutant of NF-kB-inducing Kinase (dnNIK) to block the ncNF-kB pathway. In addition to pathway analysis by western blotting, T cell proliferation, immunophenotype and survival were assessed by bead-based counting via flow cytometry. To explore mechanisms affecting survival, pro- and anti-apoptotic gene expression was analyzed by qPCR and western blot over three weeks following restimulation through the CAR.
Following CAR activation, ncNF-kB signaling was detected in BBz but not 28z T cell lysates. Control mRFP BBz T cells expanded approximately 10 fold more than BBz T cells coexpressing dnNIK. DnNIK-expressing BBz T cells exhibited higher rates of cell death contributing to the observed differences apparent in ex vivo expansion. This cell death was associated with a 2 fold increase in the message and nearly 3 fold increase in the expression of the pro-apoptotic protein, Bim, in the dnNIK BBz T cells relative to control. In contrast, dnNIK 28z T cells had no appreciable difference in proliferation or survival compared with control.
Therefore, BBz, but not 28z signaling activates the ncNF-kB pathway, which protects BBz T cells from cell death likely by restricting the expression of the pro-apoptotic protein, Bim.

Disclosures
Milone: Novartis: Patents & Royalties.
Experience and Outcome of Patients with Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) over 8 Years
Authors: Ali Syed S , George Reju 
Published: October 2019

Abstract
Introduction: NLPHL is an uncommon variant of Hodgkin lymphoma (HL) accounting for 5% incidence of all HL diagnoses. NLPHL represents a more indolent disease than classical HL, and is therefore managed uniquely. Unlike classical Hodgkin lymphoma (cHL), NLPHL shows CD20 immunoreactivity. Given the rarity of the disease, optimal management is unclear.
Here we present our retrospective clinical experience of nine cases of NLPHL diagnosed over the last 8 years at our institution.
Results: The median age at diagnosis was 45 years. Eight of the nine patients were males. The youngest patient was 21 years old and the oldest patient at diagnosis was 58 years old. One patient had Stage I, six had stage II and two patients had Stage-III disease. No patient had bone marrow involvement and only two patients had B symptoms. Interestingly, two sets of brothers diagnosed at different intervals were identified among this group of patients.
Three out of seven patients with Stage I/II disease received radiation as the primary modality of treatment. Four patients received chemotherapy only and two patients received combined modality treatment( chemotherapy followed by radiation). Only the youngest patient received R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) to avoid anthracycline related long term toxicity. A total of four patient received R-CHOP, two of these also received involved site radiation therapy (ISRT).One patient received six cycles of AVD (doxorubicin, vincristine and dacarbazine).
All the patients achieved complete response (CR) and durable remission except one patient. That particular patient had stage III NLPHL at diagnosis and was treated with R-CHOP initially. Three years later on relapse, he had T-cell rich large B cell lymphoma (TCRBCL) and is currently on a clinical trial with pembrolizumab and remains in complete remission.
Conclusions: As has been the experience with other institutions, the majority of the cases of NLPHL at our institution have presented with early stage disease. Treatments have included R-CHOP regimens in most of the cases with durable remission in the majority. Although R-CVP is not the standard regimen for NLPHL, the one young patient who had stage III disease at diagnosis and received R-CVP, achieved CR and remains disease free five years later. This highlights the importance of non-anthracycline chemotherapy regimens as an option for particularly young or older frail patients.
NLPHL occurs with higher than expected frequency among first-degree family members of patients with NLPHL as demonstrated in the Finnish Cancer Registry study reported in JCO 2013. Interestingly, in our small cohort, there were two sets of brothers identified with NLPHL, diagnosed metachronously. Unlike cHL, late relapse can occur as well as a propensity to transform to an aggressive B-cell Non-Hodgkin lymphoma.

Disclosures
No relevant conflicts of interest to declare.
Investigating the Role of C/Ebpδ-Deficiency in Radiation-Induced Bone Marrow Failure
Authors: Majumdar Debajyoti , Pietras Eric , Stumhofer Jason , Pawar Snehalata A 
Published: October 2019

Abstract
Background: Bone marrow (BM) failure is a common side-effect of toxicity to the hematopoietic tissue both in the clinical setting as well as in case of total body irradiation (TBI) exposure in the event of nuclear terrorism or disasters. Particularly IR-induced myelosuppression is considered a significant risk factor for infections and increased risk for long-term hematopoietic dysfunction and myelodysplasia.
Although a lot is known about the key regulatory proteins of steady-state hematopoiesis, not much is known about the regulatory factors involved in stress-induced hematopoiesis. Therefore delineating the mechanisms underlying the effects of IR stress-induced hematopoiesis is critical for the development of novel interventions with the potential to prevent or alleviate IR-induced BM injury/failure.
The transcription factor CCAAT/enhancer-binding protein delta (Cebpd; C/EBPδ) plays an important role in the regulation of inflammatory and stress responses, and in the innate and adaptive immune responses. We have previously reported that Cebpd-knockout (KO) mice display increased neutropenia, thrombocytopenia and myelotoxicity in response to IR exposure, which correlated with increased apoptosis of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). In the present study, we further investigated the underlying mechanisms of IR-induced bone marrow failure in the absence of C/EBPδ.
Methods: Cebpd+/+and Cebpd-/- mice (C57BL/6J background) aged 3 months were exposed to 6 Gy TBI. Bone marrow mononuclear cells (BM-MNCs) were isolated from femurs and tibiae harvested at early time-points (1h, 4h and 24h) as well as 2 weeks post-irradiation. The presence of reactive oxygen species (ROS) was measured using MitoSOX and the extent of DNA damage was measured using an antibody specific to g-H2AX at the above time points. BM-MNCs were labelled with fluorophore-tagged antibodies and analyzed by flow cytometry to measure the absolute numbers of long term-HSCs, multipotent progenitors, common lymphoid progenitors and myeloid progenitors at 2 weeks post-6 Gy. The changes in cell cycle distribution in response to IR exposure will also be analyzed by flow cytometry using a DNA-binding dye in conjunction with Ki67.
Results: Preliminary results reveal: (a) reduced numbers of HSCs, HPCs, common myeloid progenitors, myeloid-erythroid progenitors and granulocyte-monocyte progenitors and (b) increased accumulation of ROS and the DNA damage marker, γ-H2AX in HSCs and HPCs in Cebpd-/- mice compared to Cebpd+/+ mice at 2 weeks post-irradiation.
These results suggest that C/EBPδ may play a protective role in radiation-induced bone marrow injury. Studies are underway to further examine changes in cell cycle, ROS and DNA damage in the various BM cell lineages post-TBI.
(Funding support by NIGMS P20GM109005 & Department of Defense W81XWH-15-1-0489 is gratefully acknowledged)

Disclosures
No relevant conflicts of interest to declare.
Assessment of Iron Overload in the Pediatric Allogeneic HSCT Recipient
Authors: DePriest Brittany Paige , Huang Mikey 
Published: October 2019

Abstract
Background: Owing to improved strategies in pediatric bone marrow transplantation, a larger number of transplanted children are now becoming long term survivors. These post-transplant patients remain at risk for late complications including iron overload, which has the potential to impair quality of life and adversely affect later outcomes. While literature has previously focused on iron overload in the adult sickle cell patient, there has been minimal research into its effect on the pediatric bone marrow transplant recipient. Thus, no current guidelines exist for screening, management or treatment of iron overload in this patient population. Our study focuses specifically on this population and reports the relationship between number of PRBC transfusions and current diagnostic tools.
Objectives: To identify the presence or absence of correlation between the number of red blood cell transfusions and indicators of iron overload via two different modalities: ferritin values and the T2* MRI liver iron concentration (Ferriscan).
Methods: A retrospective chart review of the allogeneic pediatric bone marrow transplant patients over the past 5 years at a single center (n = 32). Quantitative data obtained which included number of PRBC transfusions, ferritin, and T2* MRI LIC. Correlation analysis subsequently performed between pre-and post-transplant values.
Results: There was significant (p < 0.001) moderate correlation (r = 0.62) between the number of pre-transplant PRBC transfusions and the pre-transplant ferritin value. No significant (p >0.1) correlation between the number of pre-transplant PRBC transfusions and the pre-transplant T2* LIC. Also, no significant (p > 0.1) correlation between pre-transplant ferritin and T2* LIC. The total number of PRBC transfusions up to 100 days post-transplant did have significant (p = 0.008) moderate correlation (r= 0.62) with post-transplant ferritin values. There was significant (p = 0.01) strong correlation (r= 0.87) between the total number of PRBC transfusions up to 100 days post-transplant with post-transplant T2*LIC values. No significant correlation (p > 0.1) between post-transplant ferritin and T2* MRI LIC values.
Conclusions: In terms of modalities utilized for evaluation of iron overload in the pediatric allogeneic BMT population, no significant correlation exists between ferritin values and T2* MRI liver iron concentration values. While ferritin is an acceptable screening tool the post-transplant T2*MRI LIC is a more accurate diagnostic indicator of transfusion burden. Future studies will be used to explore associated adverse outcomes of patients diagnosed with iron overload.

Disclosures
No relevant conflicts of interest to declare.
Wnt5a Induces Association of ROR1 with Ca2+/Calmodulin-Dependent Protein Kinase II and ROR1-Dependent Calcium Influx in Chronic Lymphocytic Leukemia
Authors: Chen Liguang , Chen Yun , Yu Jian , Zhang Ling , Rassenti Laura Z. , Kipps Thomas J. 
Published: October 2019

Abstract
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen that is expressed on CLL cells, but not on normal postpartum tissues. We found that ROR1 was a receptor for Wnt5a, which could enhance CLL-cell proliferation (Yu J, et al, JCI 126:585, 2016; Yu J, et al, Leukemia 31:2608, 2017; Hasan MK, et al, Blood 132:170, 2018). We performed mass spectrometry-based proteomics to interrogate immune-precipitates of Wnt5a-activated ROR1 and identified Ca2+/calmodulin-dependent protein kinase II (CaMKII), a serine/threonine-specific protein kinase. Recent studies demonstrated that high levels of different isoforms of CaMK, especially CaMKII, were expressed in several cancers. CaMKII phosphorylates nearly 40 different proteins, including enzymes, ion channels, kinases, and transcription factors and can play a critical role in the regulation of proliferation and survival of various cancer cells (Wang YY, et al, Oncotarget 20:11725, 2015; Chi M, et al, Sci Rep 6:33132, 2016; Hoffman A, et al, Cell Signal 26:748, 2014). We validated our mass spectrometry finings in co-immunoprecipitation studies and immunoblot analyses. These studies showed that Wnt5a could induce the specific phosphorylation and recruitment of CaMKII to ROR1. Moreover, these studies demonstrated that Wnt5a-induced recruitment of CaMKII to ROR1 could be blocked by cirmtuzumab, a first-in-class humanized anti-ROR1 mAb undergoing clinical testing in patients with CLL (Choi MY, et al, Cell Stem Cell 22:951, 2018). CaMKs serve as a ubiquitous intracellular receptor for Ca2+ and their activity are regulated through Ca2+ signaling. Therefore, we examined calcium influx in CLL cells by flow cytometry. Treatment of CLL cells cultured overnight in serum-free medium induced calcium influx within seconds. Moreover, the relative capacity of Wnt5a to induce calcium influx was associated with the relative expression level of ROR1 on CLL cells of different patients. Furthermore, Wnt5a could enhance calcium influx induced by treatment with anti-µ in CLL cells that expressed ROR1, but not in CLL cells that lacked expression of ROR1. Knockdown of ROR1 using ROR1 siRNA or treatment with cirmtuzumab inhibited the capacity of Wnt5a to enhance calcium influx induced by treatment with anti-µ. Collectively, these data demonstrate that Wnt5a-induced ROR1-signaling in CLL can influence BCR-signaling and activation of the Ca2+/calmodulin-dependent protein kinase II signaling pathway.

Disclosures
No relevant conflicts of interest to declare.
Low Relapse Rate after 2 Years in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP and Achieved Complete Response
Authors: Kang Junho , Lee Kyoungmin , Hong Jung Yong , Yoon Dok Hyun , Kim Shin , Park Jung Sun , Lee Sang Wook , Park Chan-Sik , Ryu Jin-Sook , Huh Jooryung , Suh Cheolwon 
Published: October 2019

Abstract
Introduction : Patients with DLBCL usually relapse early after the first treatment but some relapse after 2 years (defined as late relapses). In a previous study, patients with DLBCL who achieved event free survival at 24 months had a subsequent overall survival equivalent to the general population. We analyzed the time of relapse and clinical characteristics of late relapse in patients with DLBCL who achieved complete response (CR) after frontline R-CHOP.
Methods: We retrospectively reviewed prospectively collected lymphoma registry of the Asan Medical Center in Seoul, Korea, between 2002 and 2015. We found 1,047 DLBCL patients who have been treated with R-CHOP as the first line modality. Among 1,047 patients, 859 (82.0%) patients achieved CR. Chi-square or Fisher's exact test was used for comparison of categorical variables and Student's t-test or Mann-Whitney U-test for continuous variables, as appropriate. Two-sided p-value of <0.05 was considered significant.
Results : Among 859 patients, 182 (21.2%) patients relapsed and 51 (5.9%) patients had late relapse after 2 years from the end of treatment evaluation that confirmed CR. For patients who had a late relapse, median time from diagnosis to relapse was 4.0 years (range, 2.0 to 10.0 years), median age was 61 years old (range, 39-78), and 27 (52.9%) patients were male. Twenty-six (51%) patients had stage I-II, and 36 (70.6%) patients had low/low-intermediate International Prognostic Index (IPI) score at diagnosis. Compared with early relapses (n=131, 12.5%), late relapses were associated with low IPI score (median, 2 vs. 3; p = 0.001), low LDH (median, 244 vs. 337 IU/L; p < 0.001), low beta-2-microglobulin (median, 2.4 vs. 2.6 mg/L p = 0.002), higher germinal center phenotype rate (30.6% vs. 15%; p=0.05). Median overall survival from the end of treatment evaluation that confirmed CR was significantly higher in the late relapse group compared with early relapse group [112.6 months (95% CI 73.1-152.0) vs. 19.9 months (95% CI 15.3-24.4); p<0.001 by log rank].
Conclusion: Our study demonstrated that relapse rate after 2 years was low (5.9%) in patients with DLBCL who achieved CR after R-CHOP. Patient with late relapse showed favorable clinical characteristics and survival outcomes compared with patients with early relapse.

Disclosures
No relevant conflicts of interest to declare.