bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition Of Wnt Signaling In Chronic Lymphocytic Leukemia Has Synergistic Cytotoxicity With Ibrutinib
Authors: Wu Christina C.N. , Choi Michael Y. , Lao Fitzgerald , Kipps Thomas J. , Carson Dennis A. 
Published: October 2019

Abstract
The Wnt pathway plays a major role in early embryonic development and in various cancers. We found that CLL cells have activated Wnt-signaling (Proc Natl Acad SciUSA 2004, PMID: 14973184) and express genes commonly associated with B-cell progenitors or stem cells, especially the Wnt factor-related genes such as LEF1, Wnt16, and Frizzled3 (FZD3). Also, compared to normal B lymphocytes, CLL cells express high levels of the putative cancer stem cell marker Aldehyde Dehydrogenase (ALDH), especially those CLL cells with high-risk prognostic features (Leuk and Lymph, 2013, PMID 22784365) and are highly sensitive to inhibitors of Wnt signaling (Proc Natl Acad SciUSA 2004, PMID: 3156152). Finally, next generation DNA sequencing studies have identified mutations in 12 different Wnt pathway genes in 15-20% of CLL patients. Collectively, the results of these studies imply that Wnt-signaling may be an excellent target for developing effective novel therapies for patients with CLL (Oncotarget 2011, PMID: 21860066).
We compared different classes of Wnt inhibitors identified by screening of natural compound and small molecule libraries for cytotoxicity in primary leukemic cells from patients with CLL. Among all the Wnt inhibitors tested, Salinomycin and Agelastatin (naturally occurring compounds targeting LRP5/6 degradation or LEF1 down-regulation as previously reported by our groups) consistently showed dose dependent cytotoxicity at concentrations lower than 1 µM. In contrast, small molecule Wnt inhibitors targeting more proximal elements of the Wnt pathway, porcupine (Wnt-C59) and tankyrase, (XAV-939) had little direct effect on in vitro CLL cell viability even at 10 µM.
The Wnt inhibitors were also utilized as tool compounds to evaluate the effect of combined inhibition of the Wnt pathway and other pathways. Interestingly, we identified synergistic activity between Wnt inhibitors and other inhibitors, including Ibrutinib and Idelalisib. By colorimetric and flow cytometry assays, we demonstrated that significant cell death was induced with combinations of the agents at concentrations at which little or no cytotoxicity was seen with either agent alone. The studies further demonstrate that the Wnt pathway is a viable target for the treatment of CLL and may potentiate other emerging CLL therapies.

Disclosures:
Kipps: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Janssen Pharmaceuticals: Speakers Bureau; Abbvie: Membership on an entity’s Board of Directors or advisory committees, Research Funding.
Visibility Of Bone Lesions In Relapsed Multiple Myeloma Can Be Improved By FDG-PET Scanning
Authors: De Waal Esther G.M. , Slart Riemer H.J.A. , Leene Marnix J. , Kluin Philip M. , Vellenga Edo 
Published: October 2019

Abstract
Osseous involvement is one the predominant features of patients with multiple myeloma (MM). Whole body X-ray (WBX) is the standard method for detecting skeleton abnormalities but has limited value in relapsing disease since it cannot make a distinction between old and new active skeleton lesions. Therefore changes in metabolic activity might be a more useful method to detect new skeleton lesions in MM. This can be assessed by [F-18] fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. Consequently WBX and FDG-PET was studied in relapsing MM prior to treatment. In addition immunohistochemical staining on bone marrow biopsies was performed for glucose transport protein (GLUT) 3 expression, micro vessel density (MVD), and vascular endothelial growth factor (VEGF) to demonstrate whether these parameters might be predictive for the in vivo scanning results. This study included 44 patients (median age 62 yr (range 48-78)) with a median of 3.5 (range 2-12) relapses. Thus far 86% of the patients were treated with autologous stem cell transplantation in combination with bortezomib (78%) or lenalidomide (65%). New lesions on FDG-PET were more frequently demonstrated than new lesions on WBX (p=0.00001). In 78% of the patients FDG-PET demonstrated a median of 4 lesions (range 0-22) per patient with a median standard uptake value (SUV) max of 5.7 (range 0-24). In 42% of the patients new X-ray lesions (median 0 (range 0-7)) were demonstrated and these were concordant with the results of FDG-PET. In 5 % of the patients new X-ray lesions were observed without FDG-PET lesions. For the relapsing patients treatment consisted of dexamethasone in combination with bortezomib (65%) or lenalidomide (50%). CR was obtained in 27% of the patients, PR in 39% and progressive disease in 22%. Average time to next treatment (TTNT) was 11.7 months (2-43). However FDG-PET positivity was not predictive for PFS (p =0.55) and OS (p=0.40) neither if PET positivity was defined as more than 3 lesions nor if the cut off value of SUV max > 4.2 was applied. Immunohistochemical staining on bone marrow biopsies (n=20) with CD34 demonstrated a significant increased MVD of 39 ± 54 (mean ± SD, normal bone marrow MVD 3.5 ± 2.9), in particular when clusters of plasma cells were present. These enhanced MVD was associated with a significant increased expression of VEGF and GLUT-3. However MVD (p = 0.16), VEGF (p = 0.70) or GLUT-3 (p =0.70) expression were not predictive for having a positive or negative FDG-PET. In summary, our results demonstrate that FDG-PET is more informative than WBX for detecting skeleton lesions in relapsing MM patients. However, and in contrast to what was previously shown in patients with newly diagnosed MM, FDG-PET it is not predictive for treatment outcome. This might be due to heterogeneity in studied patients and treatments.

Disclosures:
No relevant conflicts of interest to declare.
Huachansu Injection Combined With Cemt Regimen On Patients With Relapsed Or Refractory Multiple Myeloma
Authors: Liu Qingchi , Zhang Huimin , Feng Xinwang , Wang Shujie 
Published: October 2019

Abstract

Objective
To observe the short-term treatment effect of Huachansu Injection combined with CEMT regimen on patients with relapsed or refractory multiple myeloma and evaluate the quality of life of the patients.

Methods
The 40 patients of relapsed or refractory multiple myeloma were divided into two groups, 20 patients were in the Chinese and western medicine treatment group, the rest in the control group. The patients in the control group received the CEMT regimen (Carboplatin, Etoposide, Methotrexate, and Thalidomide);and those in the Huachansu group received Huachansu injection on the basis of the CEMT treatment. The Huachansu injection in the 500ml 5% Glucose injection was given by intravenous drop once daily, 10'20ml for each time. The general treatment lasted 3 months and one treatment period was 4 weeks,during each period the patients received the medicine treatment for 7 days and had a rest for 2 days. The patients in each group were given the syndrome differentiation type of traditional chinese medicinal broth,decoction, once a day. The QLQ-C30 Quality of Life Questionaire(Chinese Version V3.0for clinical use) worked out by EORTC(European Organization For Research And Treatment Of Cancer) was adopted to evaluate and research the patients’ quality of life before and after the treatment.

Results
5 cases had complete remission,6 had part remission, 2 had stable and 7 cases had progresss and the total effectiveness reaches 65.0% in the Huachansu group group. In the control group, 3 cases had complete remission,4 had part remission, 1 had stable and 12 had progress and the total effectiveness reaches 40.0%. The effective rate of Huachansu group is higher than the control group,and the differences was statistically significant(P<0.05). The quality of life questionaire result also shows that the overall health status and the overall life quality of the patients in both groups have been improved as well as the patients’ physical and mental status. The difference in the patients’ life quality is less obvious in both groups. The 3-month treatment on their role functions and social functions have no outstanding effects after comparation.

Conclusion
The Huachansu Injection combined with CEMT regimen not only has excellent effect on on patients with relapsed or refractory multiple myeloma,but also improves the quality of life of patient.

Disclosures:
No relevant conflicts of interest to declare.
Comparison Between Bone Marrow Mesenchymal Stromal Cells (BM-MSC) and Lung Mesenchymal Stromal Cells (Lung-MSC) For Epithelial Regeneration
Authors: Ricciardi Mario , Midolo Martina , Bassi Giulio , Malpeli Giorgio , Bifari Francesco , Chilosi Marco , Zanotto Marco , Carusone Roberta , Zanoncello Jasmina , Pizzolo Giovanni , Krampera Mauro 
Published: October 2019

Abstract
Developing a therapeutic strategy for lung regeneration still remains complex. Stem cell-based therapeutical approaches have been suggested as a potential tool; among them, human mesenchymal stromal cells (MSC) possess some promising features to this aim. MSC are stem cells residing in many tissue, i.e. bone marrow (BM), adipose tissue, cord blood, lung, etc., and they are capable of differentiating into different cell types of mesodermal origin, such as fat, bone and cartilage.
To assess MSC epithelial differentiation potential, through a partially known process called Mesenchymal to Epithelial Transition (MET), MSC were collected from bone (BM) aspirates and lung biopsies after informed consent. MSC were characterized by immunophenotyping and clonogenicity assay. MSC mesodermal differentiation potential was assessed by testing their ability to differentiate into adipocytes, osteoblasts and chondrocytes. MSCs at different culture passages were induced to acquire the epithelial phenotype by culturing in presence of retinoic acid. The epithelial differentiation was checked by quantitative RT-PCR, immunofluorescence and a functional assay based on the Trans Epithelial Electrical Resistance Measurement (TEER).
In presence of retinoic acid, MSC from BM and, mostly, lung upregulated a panel of general epithelial genes (cytokeratin 18, occludin, tight junction protein and claudin) and downregulated some specific mesenchymal markers (smooth muscle actin, snail2, vimentin, THY1), as detected by quantitative RT-PCR. Immunofluorescence confirmed the presence of E-cadherin4, occludin and cytokeratin 18 in a small number of cells (about 0,2 %). Trans Epithelial Electrical Resistance (TEER) measurement confirmed that MSC can acquire in vitro partial epithelial polarization after retinoic acid treatment.
These data show that MSC can be induced to differentate into cells resembling some morphological, phenotypical and functional properties of epithelial cells. BM-MSC are less prone to acquire an epithelial phenotype as compared to hLung-MSC. Additional in vivo studies on mouse model with lung damage are in progress.

Disclosures:
No relevant conflicts of interest to declare.
Improved Vaccine Design For Adoptive Immunotherapy In Hematological Malignancies Through Chemically Modified Minor Histocompatibility Antigen Epitopes
Authors: Oostvogels Rimke , Hoppes Rieuwert , Lokhorst Henk , Spaapen Robbert M , Ovaa Huib , Mutis Tuna 
Published: October 2019

Abstract
Allogeneic stem cell transplantation (allo-SCT), alone or followed by donor lymphocyte infusion (DLI), is a potentially curative treatment for various hematological malignancies. In an HLA-matched transplantation setting, the therapeutic graft-versus-tumor (GvT) effect is mediated by donor T-cells directed at minor histocompatibility antigens (mHags), which are HLA-bound polymorphic peptides. Unfortunately, most patients don’t achieve complete response or relapse after allogeneic stem cell transplantation and thus still require additional therapies. Immunotherapy aimed at hematopoietically restricted mHags could theoretically provide an ideal method to augment the GvT effect, without causing GvHD. The most relevant mHags for immunotherapy are those antigens that are only expressed on hematopoietic tissue, are presented by frequent HLA molecules and display an equally balanced population frequency. UTA2-1 and HA-1 are two of these most broadly applicable mHags identified up until now and are therefore included in on-going clinical trials of mHag-peptide loaded dendritic cell vaccination in patients with various hematological malignancies. Another method for mHag-based immunotherapy could be adoptive transfer of ex vivo cultured mHag-specific cytotoxic T lymphocytes (CTL). However, initial results of both methods, also from preclinical models and trials in patients with solid tumors, postulate the necessity for improved strategies for efficient ex vivo and in vivo induction of tumour specific CTLs.
We here show for the HLA-A*02 restricted epitopes UTA2-1 and HA-1 that their MHC binding and consequent T cell reactivity can be improved through the incorporation of certain newly designed non-proteogenic amino acids at crucial MHC anchoring positions. With this novel approach we designed superior altered peptide ligands (APLs) for both epitopes, of which the best modifications not only increased MHC binding and stability, but also improved recognition by antigen specific T cells. Most importantly, these optimised peptides gave rise to superior antitumor T cell responses in vitro and in vivo in comparison to the native epitope, as they induced significantly enhanced proliferation of peptide-specific T cells with retained cytotoxic potential against malignant targets expressing the natural UTA2-1 antigen. Hence, these APLs designed with non-proteogenic amino acids with enhanced MHC-affinity and immunogenicity may improve the therapeutic outcome of mHag-based vaccination strategies, or can be utilized for ex vivo antigen-specific T cell enrichment and expansion for transfer into patients with haematological malignancies.

Disclosures:
Lokhorst: Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.
Prophylactic
Levofloxacin In Pediatric Neutropenic Patients During Autologous Hematopoietic Stem Cell Transplantation (HSCT)
Authors: Hafez Hanafy Ahmed , Yousef Dalia , Abbassi Maggie , Elborai Yasser , Elhaddad Alaa 
Published: October 2019

Abstract

Background
Bacterial sepsis continues to be a leading cause of morbidity and toxic death in children receiving myelosuppressive chemotherapy and for those undergoing hematopoietic stem cell transplants.
Using fluoroquinolones in prophylaxis against gram negative bacterial infection is not the standard of care in neutropenic pediatric patients, and till now it is a controversial issue. This study was conducted to assess the effect of levofloxacin prophylaxis on prevention of bacterial infection and on the duration of antibiotic use during profound neutropenia in pediatric patient with hematopoietic stem cell transplantation.

Methods
Non-randomized comparative study between 2 groups of pediatric neutropenic patients underwent autologous stem cell transplantation; one group didn’t receive prophylactic levofloxacin (control group), the other group received prophylactic levofloxacin (10mg/kg/day) starting from the first day of the conditioning till engraftment or 1stspike of fever.

Results
A total of 96 patients who underwent autologous stem cell transplantation were analyzed (46 patients in the control group and 50 patients taking levofloxacin). The median duration till onset of 1stfever was 11 days from the beginning of conditioning regimen in the control group as compared to 15 days in patients who were receiving levofloxacin, (p ≤ 0.001). Both groups had the same rate of bacteremia (30%) but the percentage of gram negative infections was higher in the control group (50%) as compared to (20%) in levofloxacin group, also the incidence of bacterial sepsis was higher in patients without levofloxacin (4/46) than those with levofloxacin (1/50). The median duration of antibiotic use was significantly lower in the levofloxacin group (10 days) as compared with (14 days) in patients on control group, (p <0.001).

Conclusion
Levofloxacin use can decrease the incidence of the gram negative bacteremia and their septic complications and will shorten the duration of antibiotic use, but its impact on emergence of resistant organisms should be closely monitored.

Disclosures:
No relevant conflicts of interest to declare.
Femoral Head Necrosis In Three Patients After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Zhao Gang , Li Zhi , Ding Jiahua , Wang Jun , Yu Zhengping , Chen Baoan , Zhu Han , Yu Xinnian 
Published: October 2019

Abstract
Femoral head necrosis (FHN) is one of common complications after hematopoietic stem cell transplantation (HSCT). It impacts on patients' normal life with severe pain. To investigate FHN after allogeneic HSCT, We performed retrospective analyses. Since 2003, our department has conducted 98 cases of allogeneic hematopoietic stem cell transplantation for patients with hematologic diseases. Chemotherapy regimens and transplant conditioning regimen before transplantation were steroid-free. FHN occurred in 3 out of 98 cases. The 3 patients were treated with steroid for preventing graft versus host disease (GVHD) after transplantation. However, all the three patients suffered from GVHD, which was cured with steroidal medication subsequently. Then, symptoms of FHN come out and were significantly improved after conservative treatment in all the three patients. The occurrence of FHN might be associated with GVHD and corticosteroids prescription. Early prevention might be helpful in reducing the incidence and improving outcomes.

Disclosures:
No relevant conflicts of interest to declare.
Zinc Deficiency In Patients Adults Undergoing To Hematopoietic Stem Cell Post-Transplantation
Authors: Pereira Andrea Z , Juliana Silva Bernardo , MF Pivocari Silvia , Tanaka Marcia , Ana Paula Barrere N , Lucio Fabiana , Castro Claudio Galvão , Feitosa Ribeiro Andreza Alice , Hamerschlak Nelson 
Published: October 2019

Abstract

Introduction
Zinc is an important trace mineral for the body, being a cofactor of enzymes responsible for the synthesis of nucleic acids, and maintaining the immune system. Symptoms of zinc deficiency, such as alopecia, diarrhea, skin rash and growth failure, can be confused with those of hematopoietic stem cell post-transplant (HSCT). Some studies show that zinc supplementation, with the purpose of increase of its serum level, reducing the incidence of mucositis, xerostomia, pain and loss of taste. Zinc deficiency is reported in children with leukemia, but there are very few studies in adults.

Material and methods
45 adult patients were evaluated, 22 women and 23 men, mean age 49 ± 16 years-old, undergoing HSCT in Hospital Israelita Albert Einstein during the period of 1 year (2012-2013). The serum zinc level, whose average was 69 ± 16 mg/dl, was evaluated in the first day of hospitalization for HSCT and no patient took zinc supplements before it.

Results
48% of patients had zinc deficiency, being most prevalent in patients > 60 years, which had 60%. There was no difference between the sexes.

Conclusion
Some studies believe that zinc, will be a very important agent in transplant medicine, due to its action on the improvement of the severity of mucositis induced by chemotherapy in patients with leukemia. In our study we found a high prevalence of zinc deficiency in adults and the elderly. Therefore, the assessment of zinc serum levels should be considered in patients submitted to HSTC, as a purpose of treatment and improvement of complications related to it.

Disclosures:
No relevant conflicts of interest to declare.
Surviving Stem Cell Transplantation Program In War Time In Syria
Authors: Rajeh Nabeel , Manchi Maha , Suliman Seham , Fahed Zahera , Barali Muhamad , Kalta Muhamad 
Published: October 2019

Abstract
Substantial medical care deterioration occurred during Syrian civil war, including complete destruction of over 50 hospitals and 400 medical centers. We report result of 17 cases of stem cell transplantation in private sector in Damascus in Syria in the period between 2012 and 2013 during major hardship and shortage of all medical care.
Stem cell transplantation is standard of care for certain hematologic malignancies. This sophisticated treatment has not been developed in Syria for economic and logistic reasons. Our group of six doctors adamantly worked hard over four years to establish local stem cell transplantation unit in private sector. We were able to start everything from scratch engineering the unit and training of all human resources. By the time we are ready to operate our first case of stem cell transplantation we had major obstacle, civil war eruption all over Syria. Some of our trained human resources has to leave the country other unable to reach the center. There was major medical supplies and medications shortage due to embargo and flight restrictions to Syria. With great difficulties and neighboring medical community assistance we were able to keep up the work and perform in the first year of operation seventeen cases of autologous stem cell transplantation.
From May2012 –June 2013 we admitted 17 cases for autologous stem cell transplantation. Median age 36 years half of them from Damascus and the rest from all other municipals. Relapse Hodgkin’s and none Hodgkin’s lymphoma, and consolidation multiple myeloma, are the majority of stem cell indication. CD 34 counts collected for patients ranged from 3-166 million cell/ KG (Median 66) with viability 90-99% (Median 95%) one week after freezing. Most conditioning regimens were standard BEAM and Melphelan 200. Median white blood cells engraftment to ANC 500 was D +13. Median platelets engraftment to platelets transfusion free was D +22. Infections are the major morbidity presented as febrile neutropenia. Grade III and IV Mucositis occurred in 35% of patient. All patient required transfusion support with PRBC’s and Random Donor Platelets while 25% of the required total parental nutrition. Two of the patients died during the first 100 days of transplant, one from massive pulmonary hemorrhage d+16, who was heavily pretreated with radiation and previous stem cell transplantation, the other case, none Hodgkin’s lymphoma who is heavily pretreated had engraftment failure and died from multi-organ failure on D+41.

Conclusion
Our group survived stem cell transplant program in extremely difficult time for Syria. During war economic deterioration of people is another obstacle were patients pay out of pocket for health care and medical insurances are underdeveloped. We were able to continue deliver high quality and technology edge treatment during civil war hardship for Syrian people.

Disclosures:
No relevant conflicts of interest to declare.