bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zoledronic Acid Inhibits Cell Growth of Multiple Myeloma Cells and Shows Synergistic Antimyeloma Effects with Bortezomib Via CD38 /cADPR /Ca2+ /Ras /Pakt /NF-Kb /Pim-2 Pathway
Authors: Fu Rong , Liu Zhaoyun , Liu Hui , Song Jia , Wang Guojin , Wang Yihao , Li Lijuan , Shao Zonghong 
Published: October 2019

Abstract
The Third-generation biphosphonate Zoledronic acid (ZOL) can exhibit direct antitumour activity which is widely used in multiple myeloma (MM) patients with bone events. However,it remains unknown whether Zol alone or combined with Bortezomib(B) has any inhibitory effect on myeloma cells. In this study, cell line RPMI-8226 were treated with ZOL alone at various concentrations and combined with Bortezomib to observe the effect and probable molecular mechanisms.Cell proliferation,cell apoptosis,cell phenotype(CD38+ and CD138+),RT-PCR, measurement of intracellular [Ca2+] concentration and Western blot analyses were performed.We found that ZOL alone strongly inhibited proliferation of multiple myeloma cells in vitro, and induced their apoptosis.The same results were obtained in the myeloma cell group treated with ZOL combined with Bortezomib after 24h instead of 48h.On the mechanism study, we found that Zol alone or combined with Bortezomib in 24h suppressed the mean fluorescence intensity(MFI) of CD38 and the mRNA of cADPR,NF-Kb,pim-2 ,and the signal pathway protein Ras/pAkt/NF-Kb/pim-2 and the intracellular [Ca2+]i concentration.However, it did not show the same results in 48h. In conclusion, Zol inhibited cell growth of multiple myeloma cells probably via suppressing CD38/cADPR/Ca2+/Ras/pAkt/NF-Kb/pim-2 pathway.Combination of Zol with Bortezomib within 24 hours maybe more benefitial to alleviate tumour load in MM patients.

Disclosures
No relevant conflicts of interest to declare.
In the Novel Agents Era, Is the International Staging System Still Has the Prognostic Value in Patients with Renal Impairment?
Authors: Jung Sung-Hoon , Kim Hee Kyung , Kim Seok Jin , Lee Seung-Shin , Ahn Jae-Sook , Kim Yeo-Kyeoung , Yang Deok-Hwan , Kim Hyeoung-Joon , Lee Je-Jung , Kim Kihyun 
Published: October 2019

Abstract
The International Staging System (ISS) is a robust prognostic tool for patients with symptomatic multiple myeloma (MM). In this study, we evaluated the prognostic value of ISS in patients with renal impairment who were treated with novel agents. We retrospectively analyzed 456 MM patients who were treated upfront with novel-agent containing regimen. The degree of renal failure was classified according to the National Foundation Kidney Disease Outcome Quality Initiative chronic kidney disease (CKD) classification. Renal impairment (RI) was defined as an eGFR< 60 mL/min/1.73m2 (CKD3-5). Of the all patients, 207 (45.4%) patients had stage 3-5 CKD at initial diagnosis. The β2-microglobulin level were significantly negatively correlated with GFR (r = - 0.536, P < 0.001), and median β2-microglobulin level of patients with CKD 3-5 was 7,600 mg/L (range, 668-80,000 mg/L). Sixty-seven percent of patients with CKD3-5 had ISS-3, and 89.8% of patients with CKD 4-5 had ISS-3. Patients with CKD 3-5 had poor overall survival outcomes compared to CKD 1-2 in univariate and not in multivariate analysis. ISS was powerful prognostic tool in all patients (P=0.003), but ISS had no prognostic impact in patients with CKD 3-5 (P = 0.897). Furthermore, patients with ISS 3 showed favorable overall survival compared to patients with ISS 1 or 2 in CKD 3. By multivariate analysis, cytogenetic high risk (HR 2.232, 95% CI 1.319-3.777, P =0.003) and hypercalcemia ≥11.5 g/dl (HR 2.036, 95% CI 1.170-3.544, P=0.012) were significantly associated with overall survival. In conclusion, β2-microglobulin level increase in patients with RI, and most of patients with RI had ISS-3. In addition, the ISS had no prognostic value in patients with RI in the novel agent era. New prognostic tool including cytogenetic risk will be needed for patients with RI.

Disclosures
No relevant conflicts of interest to declare.
High Level of Soluble Interleukin-2 Receptor in Serum Predicts Treatment Resistance and Poor Progression Free Survival in Multiple Myeloma
Authors: Wang Liang , Xia Zhongjun 
Published: October 2019

Abstract
Background: The IL-2/IL-2 receptor (IL-2R) system plays a central role in maintaining normal T cell immunity, and its disturbance is associated with several hematologic disorders. Studies have found in several types of lymphoma that abnormal amounts of soluble IL-2R (sIL-2R) may result in imbalance of the IL-2/IL-2R system and hence of the T cell immunoregulation. Whether the level of sIL-2R in blood could predict treatment response and survival outcomes or not needs to be investigated in multiple myeloma (MM) patients.
Methods: The level of sIL-2R in serum was measured using enzyme-linked immunosorbent assay (ELISA) in 81 patients with newly diagnosed MM. 26 patients (32.1%) were treated with bortezomib-based regimens and 55 patients (67.9%) received old drugs-based regimens.
Results: The mean concentration of sIL-2R for myeloma patients was 8.51ng/ml, significantly higher than that of healthy controls (0.56ng/ml, p<0.0001). The best cutoff value for sIL-2R in predicting high risk for disease progression is 6.049ng/ml with an area under curve (AUC) of 0.665 (p = 0.013). 36 patients (44.4%) were classified as higher sIL-2R level group (>6.049ng/ml), and 45 patients (55.6%) as lower group (=<6.049ng/ml). The overall response rate (ORR) was 60.0% in lower sIL-2R level group, higher than that in higher level group (41.7%, p=0.156). The 3-year progression free survival (PFS) and overall survival (OS) rate was 16% and 64%, respectively. In a multivariate survival analysis including ECOG performance status score, treatment response, and sIL-2R level, it was found that all these three parameters were significantly independent prognostic factors for PFS (p=0.032, 0.016, and 0.043, respectively), but none factors maintained their value in predicting OS. Subgroup analysis revealed that high level of sIL-2R correlated with significantly inferior PFS in patients treated with bortezomib-based regimens (p=0.004).
Conclusions: Serum sIL-2R level is a valuable biomarker for predicting treatment response and an independent prognostic factor for PFS, indicating novel drugs targeting the imbalance of IL-2/IL-2R system may be a promising strategy in MM.

Disclosures
No relevant conflicts of interest to declare.
Notch Is a Novel Critical Signaling Pathway Regulating Responses of T Cell and Antigen Presenting Cells in Multiple Murine aGVHD Models
Authors: Luo Xiaodan , Qin Pengfei , Wang Chunyan , Huang Zhenqian , Tan Huo 
Published: October 2019

Abstract
Introduction: Acute graft-versus-host disease (aGVHD) is a potentially life-threatening complication mediated by both host-derived antigen presenting cells (APCs) and donor T cells after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite prophylaxis and treatments, aGVHD stell occurs in many allo-HSCT patients. The role of Notch1 signal inhibition becomes more and more important in aGVHD study. This study is to investigate the role of Notch1 inhibition by γ-secretase inhibitor DAPT in murine aGVHD model.
Methods: We established a C57BL/6 BALB/c murine aGVHD model. γ-secretase inhibitor-DAPT is used to inhibit Notch1 signal in vivo and in vitro before transplantation. The degree of clinical and histopathologic GVHD is assessed by aGVHD scores and body weight. The functions of host-derived APCs and donor T cells are analyzed by flow cytometry, ELISA and PCR.
Results: All mice survived at least 14 days after transplantation and all of them developed aGVHD (n=20). The expression of Hes-1, as one of the target genes of Notch1 signal pathway, decreased significantly after DAPT inhibition. Body weight of mice in control groups decreased significantly compared to mice with Notch1 inhibition by DAPT after transplantation. Notch1 inhibited recipients produced markedly decreased amounts of the pro-inflammatory cytokines IFN-γ. The expressions of CD4 and Foxp3 increased while CD11c, CD80 and CD86 decreased after Notch1 inhibition.
Conclusions: These results indicate that Notch is a novel critical signaling pathway regulating responses of T cell and antigen presenting cells in multiple murine aGVHD models. Notch signaling inhibition appears to limit the harmful effects of aGVHD.

Disclosures
No relevant conflicts of interest to declare.
Clinical Characteristic and Prognosis of Post-Transplant Lymphoproliferative Disorder in Pediatric Heart Transplant Recipients in Japan
Authors: Miyamura Takako , Hashii Yoshiko , Fukushima Norihide , Kogaki Shigetoyo , Yoshida Hisao , Takahashi Kunihiko , Narita Jun , Ozono Keiichi 
Published: October 2019

Abstract
Purpose: Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein-Barr virus (EBV) has recently has been recognized as a serious complication of various organ transplantations. In our institute, we have followed-up 34 pediatric patients after heart transplantation. We retrospectively investigated clinical features of PTLD in heart transplant recipients.
Methods: The evaluation period was from July 2004 to June 2015. Six patients with PTLD (4 boys, 2 girls) were diagnosed by blood examination, lymph node histology and EBV viral load in peripheral blood and invasive organ.
Results: Median age at onset of PTLD was 4.5 years old (range, 3.2-16.2 years). Median time from transplantation to onset was 18 months (range, 7-45 months). Bone marrow and central nervous system invasion were not detected in all cases. Four patients were EBV-seronegative recipients for EBV-seropositive donors. We performed the lymphoma-based chemotherapy combined with the anti-CD20 monoclonal antibody rituximab and achieved remission. As a result, five patients remained alive in remission, and one patient died of therapy-related toxicity. Although one patient relapsed after chemotherapy, she achieved second remission after multimodal chemotherapy combined with rituximab. Abdominal lymph node involvement was detected in four cases, and one patient experienced severe abdominal symptoms including intestinal perforation.
Conclusion: EBV serostatus and the period from transplantation to onset of PTLD appear to represent important prognostic factors. Early detection followed by pre-emptive reduction of immunosuppressive agents is essential to the management of PTLD, but may increase the risk of fatal rejection. We administered chemotherapy combined with rituximab, and this treatment strategy might be effective. However, severe fatal toxicity developed in one patient, and severe abdominal symptoms due to tumor lysis were noted in many cases. These findings suggested the importance of carefully selecting the induction treatment and perform various supportive therapies. We should establish appropriate treatment strategies according to prognostic factors because of the distinctive characteristics of PTLD by accumulating more cases.

Disclosures
No relevant conflicts of interest to declare.
Frequency of Invasive Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation Conditioned with Reduced BUCY2 and Antifungal Prophylaxis with Low Dose Amphotericin B
Authors: Armillas Canseco Flor Maria , Rivera Franco Monica M , Leon Rodriguez Eucario , Terrazas Marin Ricardo Antonio 
Published: October 2019

Abstract
Introduction: Invasive fungal infection (IFI) is a major cause of morbidity and mortality in patients with allogeneic stem cell transplantation (allo-SCT). One well-known risk factor for fungal infection includes bowel mucosal damage due to conditioning chemotherapy regimens. The use of reduced-intensity conditioning may favorably impact the epidemiology of IFI after allo-SCT. Data for IFI in this population are scarce. On the other hand, despite the low incidence of IFI with the use of the new antifungal drugs, the costs remain to be high and sometimes unaffordable for the patients.
Objective: To analyze the frequency of invasive fungal infections in patients who underwent stem cell transplantation conditioned with reduced BUCY2, at INCMNSZ, from November 1998 to December 2014.
Material and methods: A retrospective analysis was performed in 58 patients receiving reduced BUCY2 as part of their SCT conditioning regimen. Most of the patients received antifungal prophylaxis with low dose of amphotericin B (˂20 mg/day) during the neutropenia following transplant.
Results: Fifty eight patients undergoing allo-SCT with conditioning regimen reduced BUCY2, from November 1998 to December 2014, were included. Patients (male, 57%) had a median age of 39 years (range 17-67). The median follow-up was 90 months. The patients had a following range of underlying diseases: myelodysplastic syndrome (n=14, 24.1%), chronic myeloid leukemia (CML, n=14, 24.1%), acute myeloid leukemia (AML, n=12, 21%), acute lymphoblastic leukemia (LLA, n=10, 17%), lymphomas (n=3, 5.2%), myelofibrosis (n=2, 3.4%), or others (n=3, 5.2%). All patients were conditioned with 12mg/kg of busulfan and 80mg/kg of cyclophosphamide. 22% of patients presented mucositis grade III-IV. 85% (50/59) of patients received fungal prophylaxis with low dose amphotericin B. Four patients (6.8%) presented IFI during the first 100 days post-transplant, and one (1.7%) presented late IFI. The mortality secondary to IFI was 5%. Transplant related mortality (TRM) was 17%.
Conclusion: From the beginnings of our transplant program we have had a low incidence of IFI and low TRM, with the prophylactic use of low dose amphotericin B and the modified conditioning regimen reduced BUCY2, compared to the reported literature. The use of reduced BUCY2 and low dose amphotericin B can be cost-effective in medical centers in developing countries.

Disclosures
No relevant conflicts of interest to declare.
Is Initial CD3+ T Cell Dose in Donor Lymphocyte Infusion for Relapsed Hematological Malignancies a Prognostic Determinant?
Authors: Atilla Erden , Ataca Pinar , Toprak Selami Kocak , Yuksel Meltem Kurt , Topcuoglu Pervin , Arslan Onder , Ozcan Muhit , Demirer Taner , Ilhan Osman , Beksac Meral , Akan Hamdi , Gurman Gunhan , Civriz Bozdag Sinem 
Published: October 2019

Abstract

Introduction: Patients after relapsing allogeneic hematopoietic stem cell transplantation (AHSCT) have a treatment option of donor lymphocyte infusion (DLI). DLI is a form of adoptive immunotherapy which induces graft versus leukemia effect. Severe forms of graft versus host disease (GVHD) and marrow aplasia are known complications. In this study, we aimed to detect the effect of the infused CD3+ T cell dose on response, GVHD and overall survival (OS) of hematological malignancies after AHSCT.
Methods: We retrospectively evaluated 78 DLI procedures in 57 patients with different hematological malignancies for relapse after AHSCT from June 2000 through June 2015. Initial DLI CD3+ cell dose/kg recipient body weight was ≤ 1x10^7 (n=20; Group 1), >1.0 to ≤ 5 x10^7 (n=29; Group 2), 5-10 x10^7 (n=29; Group 3). Chi-square test was used in comparison between groups. P<.05 was considered statistically significant.
Results: The median age during DLI was 33,8 ± 13,2 (range 16-67 years) in 57 patients (38M/19F). The median time interval from HCT to DLI was 8.08 (2-69) months. Ten patients (18%) had bone marrow while 47 patients (82%) had peripheral blood as stem cell source. All patients received transplants from HLA-matched related siblings. There was no difference found between the three groups according to age, diagnosis, stem cell source and conditioning regimen. Achieving complete remission after DLI was detected in thirty two (56%) patients. Disease status after DLI, acute and chronic GVHD rates were not statistically different between the groups. Overall survival which was not statistically significant according to initial DLI cell dose at 2 years were 25%, 38% and 24%, respectively.
Conclusion: An initial DLI CD3+ cell dose of 10 x10e7 or higher has been shown improve overall survival but increase GVHD rates with no effect on risk of relapse in previous reports. Response rate, GVHD and survival outcomes were found to be similar in comparison of three different DLI dose groups in our study.

Disclosures
No relevant conflicts of interest to declare.
Related or Unrelated Donor Results in Similar Outcomes after Hsct; Single Center Experience in Colombia
Authors: Abello Virginia , Rosales Carmen , Rosales Manuel , Figueroa Javier , Cordoba Iris , Borda Molina Andres Armando , Pedraza Enrique , Esguerra Herman , Villamizar Liceth 
Published: October 2019

Abstract
INTRODUCTION
ASTC is the standard treatment in multiple hematologic diseases; unfortunately most patients do not have a compatible family donor, URD ASCT is an alternative to those patients. There is evidence from developed countries that outcomes may be similar regardless the donor, but there is not enough information from Latin America regarding survival after URD ASCT. We compared survival at 1 and 3 years from patients transplanted using related or unrelated donors in a single center in Colombia.
MATERIALS AND METHODS
Paired analysis was performed comparing one URD ASCT with one or two RD ASCT with similar characteristic in terms of age, diagnosis (AML, ALL, aplasia, CML, MDS), EBMT risk, year of transplant and conditioning regimen. Chi-square or Fisher exact test was used to compare the groups (p<0.05). The survival curves of Kaplan-Meier and log-rank test (p<0.05) were used to estimate the probabilities of one (OS1) and three (OS3) overall survival in different groups according to EMBT score risk.
RESULTS
28 URD ASCT were performed between 2011 and 2014, 24 of those (18 matched and 6 missmatched URD ASCT) were paired with 41 RD ASCT. Of those 62% were males, mean age was 33.4 years, 70.8% patients were in early stages, almost 60% had more than 12 months interval between diagnosis and transplant. Most common diagnoses were acute lymphoid leukemia and acute myeloid leukemia. 80% of donors where found through NMDP. No significant differences in sex, age, disease status (early, intermediate, late), time interval from diagnosis to transplantation, and patient-donor sex combination, ranked according to EBMT risk score, were find between the tow groups.
Median follow-up was 322 days (range 165-693), for the whole group. There were no significant differences in the OS1 or OS3 between URD o RD ASCT, in different EBMT score groups. Low risk: OS1: URD 86.6% vs RD 75.8%, p = 0.46; OS3: 86.6% vs 68.9%, p = 0.28. High risk OS1 75% vs 63.6%, p=0.92; OS3 75% vs 63.6%, p=0.92.
CONCLUSIONS
In this cohort of patients, the type of donor had no influence in the outcome measured in terms of OS. This is the first experience with URD ASCT in Colombia; longer follow up of this cohort is needed to confirm this results, but our findings suggest this transplantation modality is a real alternative to patients in our country in need of a transplant without an HLA identical related donor.

Disclosures
No relevant conflicts of interest to declare.
Influence of Pretransplantation Serum Ferritin on Children Beta-Thalassemia Major Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Ruan Yongsheng , Wu Xuedong , Feng Xiaoqin , He Yuelin , Li Chunfu 
Published: October 2019

Abstract
Objectives: To evaluate the influence of pretransplantation serum ferritin on children β-thalassemia major (β-TM) undergoing allogeneic hematopoietic stem cell transplantation.
Methods: A retrospective analysis of 266 HLA-matched children with β-TM from January 2009 and November 2014 was performed. Transplantation conditioning regimen of these children was the NF-08-TM protocol. Median follow-up time was 28 months (3~62months). We observed the relationship between pretransplantation serum ferritin level and transplantation complications which included infection, graft versus host disease(GVHD),veno-occlusive disease(VOD) and death.
Results: Transplantation-related death occurred in 18 of 266 patients (6.8%). Five-year overall survival (OS) was found to be 92.8%. Among various complications, only infection was significantly associated with the high serum ferritin level (t=-2.673, P=0.008), especially serum ferritin above 3449.5μg/L(P=0.000). Meanwhile infection was the most common complication and severe infection would be main cause of deaths.
Conclusions: NF-08-TM conditioning regimen was the optimization for HLA-matched β-TM patients. High pretransplantation serum ferritin level would bring high infection occurrence.

Disclosures
No relevant conflicts of interest to declare.
The Thrombotic Microangiopathy Registry of North America
Authors: Metjian Ara , Tanhehco Yvette , Pham Huy Phu , Aqui Nicole A. , Bhoj Vijay , Onwuemene Oluwatoyosi , Marques Marisa , Arepally Gowthami M 
Published: October 2019

Abstract
The thrombotic microangiopathies (TMAs) are rare, life-threatening thrombotic disorders of diverse etiologies. Systematic studies of TMA have been difficult to perform due to their rare occurrence, disease heterogeneity and, lack of an organized research network in the United States. Whereas a multi-institutional approach has been used in Europe and Canada, TMA research in the US has been largely single-center based. To overcome the limitations of single institutional registries and to expand the number of TMA patients available for study, four academic centers convened during the 2013 ASFA annual meeting to establish the TMA Registry of North America (TRNA) with the following goals: (1) design and develop a registry to define "best practices" for the diagnosis, treatment, and management of TMA; (2) develop a platform for conducting observational and interventional clinical trials; (3) and, establish a national bio-repository of samples from patients with TMA to facilitate future studies. This abstract reports the first multi-institutional network in the United States designed to study TMA. Members met through bimonthly tele-conferences to develop a clinical registry using REDCap (Research Electronic Data Capture), a HIPAA-compliant, internet-based software program for data entry. To facilitate a cohesive and streamlined review of IRB applications, the TRNA utilized IRBshare, a portal for rapid approval of multi-site investigations. IRB consent included participation in a bio-repository arm for collecting blood and apheresate. Following approval through the Duke IRB in June 2014, study documents were uploaded to the IRBshare website. Since August 2015, 16 study participants with TMA have been consented, 13 of which have had their clinical information entered into the database. Preliminary data shows our population is 73% African-American and female. Average laboratory values at presentation included hemoglobin of 9.7 g/dL, platelets 53 x10^9/L, and LDH 1,150 u/L. ADAMTS13 testing was performed in 77% (10/13), of which 60% (6/10) measured at <10%. Current efforts include expansion of network sites to expand the registry and to develop clinical protocols for future studies. With its clinical and IRB infrastructure in place, the TRNA, which is the first U.S. research network designed to study TMA, is poised to perform cooperative observational and interventional trials in the near future.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.