bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low Psoas Muscle/BMI Ratio Is a Bad Prognostic Index Of Non-Relapse Survival After Allogeneic Stem Cell Transplantation
Authors: Kim Soo Jeong , Kim Yundeok , Hwang Doh Yu , Hyun Shin Young , Jang Ji Eun , Lee Jung Yeon , Cheong June-Won , Kim Jin Seok , Min Yoo Hong 
Published: October 2019

Abstract

Background
Physical and functional status affect the survival after allogeneic stem cell transplantation. There are several indices to measure risk of complication and non-relapse mortality after stem cell transplantation. Karnofsky score and ECOG score are the mostly used indices for measuring functional status. However they are measured subjectively by observer and can be changed in brief time. Recently a few reports documented relationship between the mortality and sarcopenia in various malignant or non-malignant diseases. Therefore we tried to measure the patient’s functional status by measuring psoas area in abdominal CT scan which was taken before allogeneic stem cell transplantation.

Patients and Methods
The medical records of total 83 patients from August 2010 to April 2012 were retrospectively reviewed. Every patients took abdominal CT scan 2 weeks to 1 month before transplantation according to the protocol for pre-transplant workup of Severance Hospital (Seoul, Korea). The area of bilateral psoas muscle at the level of upper margin of L4 vertebral body was manually measured by one trained observer using polygon tool of CENTRICITY Radiology RA1000 program (GE Healthcare Integrated IT Solutions, IL, USA).

Results
Male patients were 49 and female patients were 34. Median age was 37.0 years (range 15-60). Underlying diagnosis was AML (n=31), ALL (n=24), SAA (n=7), MDS (n=5), lymphoma (n=7), CML (n=6) and others (n=3). Myeloablative conditioning was applied in 54 patients. Stem cell source was mostly peripheral blood (n=68). 8 patients received HLA-mismatched transplantation. The total non-relapse mortality was 20.4%. 32.5% of patients had higher BMI than 25 kg/m2. In whole patients, psoas muscle area didn’t affect non-relapse survival. However, when low psoas area/BMI ratio show significant correlation with non-relapse survival (median 733 days vs. 966 days, P=0.009). In univariate analysis for non-relapse survival, age, pre-transplant disease status, and psoas/BMI ratio showed statistical correlation. And in multivariate analysis psoas/BMI ratio was the sole prognostic index.

Summary
Low psoas/BMI ratio is related to increased treatment related mortality in obese patients. This index can be used in part to estimate risk of transplant in obese patients.

Disclosures:
No relevant conflicts of interest to declare.
Loss Of Canonic Notch Signaling In The Microenvironment Causes a Myeloproliferative Syndrome Via Derepression Of The miR155 Promoter
Authors: Wang Lin , Zhang Huajia , Rodriguez-Rodriguez Sonia , Cao Liyun , Parish Jonathan , Zollman Amy , Kamocka Malgorzata , Boswell H. Scott , Srour Edward F. , Chitteti Brahmananda Reddy , Manshouri Taghi , Verstovsek Srdan , Kapur Reuben , Cardoso Angelo A. , Carlesso Nadia 
Published: October 2019

Abstract
The Notch signaling pathway is an important regulator of normal hematopoiesis, and is involved in leukemogenesis. Although the cell-autonomous roles of Notch signaling on hematopoietic cells have been extensively studied, its contribution to the regulation of the bone marrow (BM) niche has not been investigated yet. In our study, we used a Notch loss-of-function model in which deletion of the DNA-binding domain of RBPJ by Mx1-Cre results in the loss of signaling from all Notch receptors, in both hematopoietic cells and stromal cells of the BM microenvironment. In this model, we observed that loss of RBPJ-dependent Notch signaling in the hematopoietic microenvironment leads to a lethal myeloproliferative-like disease. Transplantation studies revealed that the microenvironment (ME) of RBPJ KO mice is necessary for the development and maintenance of the disease. Kinetics of engraftment of BM cells by intravital microscopy of the BM niche showed that WT donor cells engrafted more rapidly and had a greater expansion when transplanted into the RBPJ KO ME than in WT ME. Analysis of the serum and of supernatants from BM stroma showed increased cytokine levels in the RBPJ KO mice compared to controls, in particular G-CSF and TNF-alpha. Histological analysis of BM and spleen of RBPJ recipients showed increased microvascular density and increased CD31+ endothelial cells (EC) by IHC, preceding the onset of disease, suggesting an activated state of the endothelium. Specific deletion of RBPJ in the endothelium by using Tie2CreER model confirmed a critical contribution of EC to the myeloproliferative disease. We observed also that RBPJ KO BM-derived stroma exhibit increased expression of inflammatory microRNAs, in particular of miR155, a microRNA involved in inflammation and cancer. miR155 promoter analysis indicated the existence of two RBPJ binding sites, and direct interaction of RBPJ and the miR155 promoter was confirmed by ChIP assay. Loss of transcriptional repression by RBPJ in BM stromal cells induced miR155 upregulation and increased cytokine levels supporting greater expansion of myeloid progenitors. Double knock-out of RBPJ-/- and miR155-/- mice validated the requirement of miR155 for the hematopoietic changes due to RBPJ deletion. Finally, Analysis of patient’s samples affected by myeloproliferative neoplasia showed elevated levels of miR155 in the BM, suggesting miR-155 as a potential therapeutic target in myeloproliferative disorders.

Disclosures:
No relevant conflicts of interest to declare.
The clinical significance of STAT3 mutation, LDH and β2-MG in T-cell large granular lymphocytic Leukemia
Authors: Qiu Zhi-Yuan , Fan Lei , Wang Li , Qiao Chun , Wu Yu-Jie , Zhou Jian-Feng , Xu Wei , Li Jian-Yong 
Published: October 2019

Abstract

Background
T-cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder of cytotoxic T cells (CTLs) and often associated with autoimmune disorders. The signal transducer and activator of transcription 3 (STAT3) is an oncogene, and its activation plays a key role in cell signaling transduction pathways in many types of cancer. The aim of the current study was to analyze the characteristics of T-LGLL.

Methods
We did this by determining the mutation status of STAT3 in 28 patients presenting with T-LGLL and evaluating STAT3 status in association with serum level of lacticdehydrogenase (LDH) and β2-microglobulin (β2-MG). Flow cytometric analysis for immunophenotype and TCR variable β-chain (Vβ) was performed in the patients.

Results
FC-Vβ analysis was performed in 26 patients, and 22 (84.6%) patients had a restricted Vβ reactivity pattern, with predominance of a single Vβ mAb reactivity. There was no significant difference between serum LDH levels, gender, age or symptoms at diagnosis (P=0.062), lymphocytosis, anemia (P=0.057), thrombocytopenia, splenomegaly, LGL count or STAT3 mutation status. However, high β2-MG levels (P=0.005), neutropenia (P=0.018) and pure red blood cell aplasia (PRCA) (P=0.001) all displayed a significant association with STAT3 mutations. In univariate analysis, treatment-free survival (TFS) was affected by STAT3 mutation status (P=0.008) and β2-MG (P=0.006). In multivariate analysis, only anemia (P<0.001) was found to be an independent risk factor of shorter TFS.

Conclusions
We found an incidence of STAT3 mutations of 21.4% in patients presenting with T-LGLL and two mutations, E616V and V671F, had not been previously reported. Our results further demonstrate the remarkable correlation of STAT3 mutation with anemia, neutropenia and β2-MG. β2-MG and LDH is commonly used laboratory indicators, and detecting of them is helpful in estimating clinical characteristics and guiding treatment. We conclude from our data that FC-Vβ analysis is a fast and relatively economical alternative approach that can be used as a powerful tool in screening patients with suspected T-LGLL. Our study not only confirmed some of the previously reported observations, but it also provided new information on clinical associations, laboratory findings, prognostic factors, therapy and outcome in these patients.

Disclosures:
No relevant conflicts of interest to declare.
Costimulation Through GITR Increases Follicular Helper T Cell Formation and Leads To Control Of A Chronic Viral Infection
Authors: Pascutti Fernanda M , Poplonski Tomasz , Van Lier René A.W. , Brandao Claudia , Nolte Martijn A. 
Published: October 2019

Abstract
The glucocorticoid-induced TNF receptor family-related protein (GITR) is an important costimulatory receptor on T cells. We have previously shown that enhanced costimulation through GITR increases the formation of both effector and regulatory CD4+ T cells. Here we explored whether it could also affect humoral immunity and T cell help to B cells. Although development of mature B cells was not affected in GITRL transgenic (tg) mice, we found that the number of follicular helper T cells (CXCR5+ PD1+ CD4+ T cells, Tfh) was significantly increased, including the absolute number of Tfh-B cell conjugates, as revealed by ImageStream analysis. Tfh from GITRL tg mice had normal expression levels of ICOS, SLAM and CD44 and slightly lower levels of CD62L and CCR7 compared to wild-type (WT) littermates. Interestingly, Tfh from GITRL tg mice produced more IFN-g and IL-10, which was accompanied by a biased antibody repertoire (decreased IgG3 and increased IgA, IgG2a and IgG2b). Since Tfh have been implicated in the late control of viral replication, we infected WT and GITRL tg mice with LCMV Clone 13. Surprisingly, at day 30 after infection, we could not detect viral genome in spleen and liver from GITRL tg mice, while WT mice were still infected. Also, PD-1 expression was strongly decreased on virus-specific CD8+ T cells, which correlated with faster viral clearance. All in all, these results indicate that GITR-mediated costimulation enhances the control of chronic viral infections, by boosting and modulating Tfh cell responses.

Disclosures:
No relevant conflicts of interest to declare.
A Novel and Highly Selective Dual PI3K/mTOR Kinase Inhibitor VS-5584, Shows Promising Therapeutic Potential For The Treatment Of Multiple Myeloma
Authors: Mustafa Nurulhuda , Hart Stefan , Chng Wee-Joo 
Published: October 2019

Currently, most multiple myeloma (MM) patients experience relapse and develop resistance to standard treatments. A recent study showed that patients who relapsed had poor outcomes, with an overall survival of only 6 months and an event-free survival of 1 month. The PI3K/mTOR/AKT pathway represents a critical target in MM because it stimulates proliferation, survival, and drug resistance of MM cells. VS-5584 is a novel agent, with specific and equipotent activity against mTOR and all 4 Class I PI3K isoforms, without relevant activity on 400 other lipid and protein kinases. Here we report that VS-5584 is highly efficacious against a wide panel of MM cells including Velcade- and Doxorubucin- resistant cell lines. This efficacy is maintained even in the presence of additional MM growth factors, IL-6 and IGF-1, and seems independent of PTEN status in the cell lines. Importantly, VS-5584 shows similar efficacy in patient myeloma cells and preferential tumor cell targeting compared to healthy peripheral blood mononuclear cells. Further testing in a myeloma xenograft mouse model further confirmed the potency of this compound in vivo. We have also observed synergistic activity in combination with both MM clinical therapeutic Dexamethasone, and novel anti-MM candidate Panabinostat. Comparing the basal expression profile of hypersensitive (H929) vs less sensitive (OPM2, U266) cell lines have identified the interferon alpha/beta pathway as a marker for association with sensitivity. Just recently, VS-5584 has been reported to evidence very favourable pharmaceutical and pharmacological properties in a wide range of solid tumors resistant to standard care therapies. Taken together with our data, this offers a compelling rationale for its clinical development as a single or combination therapy in multiple myeloma.

Disclosures:
No relevant conflicts of interest to declare.
Modulated Cyclophosphamide-Based In Vivo T-Cell Depletion Promotes Engraftment With Minimal Gvhd and Low Toxicity In Fanconi Anemia Patients
Authors: Thakar Monica S , Walters Mark C. , Sandmaier Brenda M. , Storb Rainer , D. Flowers Mary E. , Deeg H. Joachim , O'Donnell Paul , Woolfrey Ann E. , Kiem Hans-Peter 
Published: October 2019

Building on a successful non-myeloablative conditioning regimen developed in Seattle (Blood 2003), Luznik and O´Donnell et al created a protocol that incorporates post-transplant cyclophosphamide (CY) after human leukocyte antigen (HLA)-haploidentical hematopoietic cell transplantation (HCT) (BBMT 2008). This method both promotes engraftment while selectively-depleting alloreactive donor T cells to prevent graft-versus-host disease (GVHD). We have previously shown that Fanconi Anemia (FA) patients can be treated with CY 60 mg/kg in a conditioning regimen with minimal toxicity (BBMT 2007), thus we adapted this post-HCT CY strategy for in vivo T-cell depletion in patients with FA. Between 2008 and 2012, four patients from three North American centers with FA and severe marrow failure in the absence of HLA-matched donors underwent HLA-haploidentical HCT. All four patients were referred for transplantation with minimal to no transfusion burden and all were in excellent clinical condition with HCT-CI scores of 0-2 and Lansky scores of 90-100%. Median age at transplant was 9.7 (6.9-11.9) years old. Patients were transplanted at a median of 1.6 (range, 0.6 -7.1) years after FA diagnosis. Conditioning consisted of fludarabine (150 mg/m2) and 2 Gy total body irradiation; one patient also received CY (10 mg/kg), which was deleted in subsequent patients to decrease the risk of mucositis. Marrow was infused on day 0, followed by post-grafting immunosuppression with CY (25 mg/kg/day, days +3, +4), mycophenolate mofetil, and cyclosporine, the latter two beginning at day +5 with plans to continue until days +35 and +180, respectively. Full donor engraftment was seen in all patients. Two patients developed acute grade I GVHD and none of the four patients has developed chronic extensive GVHD to date. With a follow-up of 5 years, 1 year, 11 months, and 9 months, all four patients are alive with stable, full donor chimerism, and are transfusion independent. While two patients required cyclosporine beyond day +180, only one patient currently remains on low-dose immunosuppression for treatment of limited chronic skin GVHD, which has now resolved. Our results confirm that modulated post-HCT CY can be used in patients with FA to promote engraftment across histocompatibility barriers. Despite concerns for both excessive toxicity related to CY and severe GVHD related to minimizing the dose of post-transplant CY, none of the FA patients in our small series experienced these problems. Our findings also suggest that transplant should not be delayed when there is lack of an HLA-matched donor. FA patients with few comorbidities and minimal transfusion burden can successfully undergo this HLA-haploidentical HCT approach.

Disclosures:
Off Label Use: MMF.
Association Of Chemokine Receptor CCR5, CCR6 and CCR7 Expressions On T Lymphocyte Subsets In Recipients After Allo-HSCT With Acute GvHD
Authors: Wang Meng , Ren Han-Yun , Dong Yu-Jun , Liang Ze-Yin , Qiu Zhi-Xiang , Liu Wei , Wang Li-Hong 
Published: October 2019

Introduction
To study the correlation of chemokine receptors expression on T lymphocyte subsets in recipients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with acute graft-versus-host disease (acute GVHD).

Methods
Forty-four recipients of family donor allogeneic hematopoietic stem cell transplantation were included in this study. According to the severity of acute GVHD, the recipients were divided into Grade II-IV acute GVHD group (n=16) and Grade 0-I acute GVHD group (n=28). Additionally,fifty healthy donors were also included in this study as the control group (n=50). The expression of chemokine receptors (CCR2,CCR5,CCR6,CCR7,CCR9 and CXCR3) on CD4+ and CD8+T cells in the peripheral blood after transplantation were detected using flow cytometry (FCM) respectively. The differences of the chemokine receptors expression between each group were compared.

Results
In both Grade 0-I acute GVHD group (on the 30th day after transplantation) and Grade II-IV acute GVHD group (at the peak of GVHD), CCR5 expression was significantly higher than that in the control group (p<0.01), and the expression of CCR7 was significantly lower than that in the control group (p<0.01). However, compared with the Grade 0-I acute GVHD group, the Grade II-IV acute GVHD group showed lower CD4+/CD8+ cell ratio (0.36 ± 0.30 vs 0.76 ± 0.61, p=0.003), higher CD4+CCR5+ ratio (65.20 ± 20.17% vs 50.82 ± 28.59%, p=0.048), decreased expression of CCR6 and CCR7 on CD4+ T cells (17.02 ± 12.43% vs 34.69 ± 18.58%, p=0.006; 20.28 ± 4.37% vs 25.45 ± 10.47%, p=0.025).

Conclusions
Chemokine receptors on T cell subsets are involved in the pathogenesis of acute GVHD. Expression of chemokine receptors can be used as a powerful marker for early diagnosis and differential diagnosis of acute GVHD. And targeting chemokine receptors might be the new direction of prevention and treatment of acute GVHD.

Disclosures:
No relevant conflicts of interest to declare.
Higher Counts Of Plasmacytoid Dendritic Cells In The Allograft Are Associated Increased Risk Of Acute Gvhd After Stem Cell Transplantation
Authors: Vescovi Gonçalves Matheus , Yamamoto Mihoko , Kimura Eliza Y. S. , Renzi Colturato Vergilio Antonio , Ikoma Maura Valerio , Mauad Marcos , Pedro de Souza Mair , Alvarenga Gomes de Oliveira Paulo Guilherme , Vaz Carvalho Ana Paula , Kerbauy Fabio R. , Hamerschlak Nelson , Novis Yana , Ginani Valeria Cortez , Seber Adriana , Rocha Vanderson , Orfao Alberto , Rodrigues Celso Arrais 
Published: October 2019

Background
Recent studies suggest that higher circulating dendritic cell counts after hematopoietic stem cell transplantation (HSCT) may be associated with lower risk of graft versus host disease (GVHD) and mortality. Plasmacytoid dendritic cells (pDC) have tolerogenic properties and may explain such results. However, only a few studies with conflicting results analyzed pDC counts in the allograft, mainly in the related HSCT setting.

Objectives
To compare pDC counts among different cell sources [umbilical cord blood (UCB), bone marrow (BM), and peripheral blood (PBSC)] and to correlate the pDC content on the graft with main HSCT outcomes.

Methods
Plasmacytoid dendritic cells (pDC: lineage negative, HLA-DR+ and CD123+) were quantified by multiparametric flow cytometry in the graft just before its infusion. Overall, 77 patients (49 male; median age 21y, range 1-74y) receiving UCB (n=26), BM (n=34) or PBSC (n=17) HSCT from unrelated (n=67) or related donors (n=10) were studied. The most common diagnosis was acute leukemia (ALL, 30 cases; AML, 22). Most patients received myeloablative conditioning regimens (n=47, 61%). Antithymocyte globulin was used in 30 patients (39%) and total body irradiation in 41 (53%). Median follow up time was 15 months (4-33).

Results
Median time to neutrophil engraftment was 19 days (range: 11-49) and 35 days to platelet engraftment (range 2-176). The median percentage of pDC on the graft was 0.20% of non erythroid nucleated cells (range: 0.02-0.67) and no differences were noticed among sources. Cumulative incidence (CI) of grade II-IV acute GVHD at 100 days was higher on patients receiving grafts with higher percentages of pDC (22% for patients with less than 0.15%pDC graft content vs. 52% for patients receiving grafts with higher counts, p=0.026). There was no impact of graft pDC content on mortality, relapse, chronic GVHD or overall survival. In a multivariate analysis, graft pDC content remains an independent risk factor for acute GVHD [HR: 3.0, CI (95%): 1.15-7.8].

Conclusion
Higher pDC graft percentages were associated with increased risk of acute GVHD, but had no impact on non-relapse mortality or survival. The precise role of pDC on immunity after HSCT deserves further investigation and might be related not only to pDC biology itself but to the chronology of the pDC interaction with host antigens.

Disclosures:
No relevant conflicts of interest to declare.
Erythrocytosis and Normal Erythropoietin Levels In a 3 Year Old Female With High-Risk Neuroblastoma
Authors: Barr Erin Kelly , Ross Mary Elizabeth , Al-Rahawan Mohamad M. 
Published: October 2019

Introduction
Erythrocytosis has been reported in a number of cancers as a result of tumor production of Erythropoietin (EPO). There has been one reported case that we are aware of in a pediatric patient with neuroblastoma (Wang LY, et al. J Pediatr Hematol Oncol. 2003 Aug;25(8):649-50). Erythrocytosis in a pediatric neuroblasotoma patient with normal EPO levels, which is the subject of this case report, has not been reported previously.

Case
A three year-old female presented with a right sided abdominal pain of one week duration as well as constipation and decreased appetite of one month duration. Radiology studies showed a large abdominal mass, which turned out to be a poorly differentiated high-risk neuroblastoma on an incisional biopsy. For the first three months of this patient’s therapy and despite intense chemotherapy she was noted to have abnormally high hemoglobin levels. The peak hemoglobin level was 18 g/dL but she maintained hemoglobin levels greater than 14g/dL, which was greater than the 97th percentile for her age group (Dallman PR, et al. J Pediatr. 1979 Jan;94(1):26-31). Testing for EPO when the hemoglobin level was elevated showed a level of 8.1 mIU/ml, which was within the normal range for the patient’s age group (Krafte-Jacobs B, et al. J Pediatr. 1995 Apr;126(4):601-3). After tumor resection but before the conclusion of the myleosuppressive chemotherapy, hemoglobin levels fell below 10 for the majority of time.

Discussion
Although there has been a case reported of a pediatric patient with neuroblastoma having erythrocytosis, this is the first case where the patient was actually found to have normal EPO levels. Case reports looking at EPO and erythrocytosis in children with Wilms tumors have reported a couple cases of children who had normal EPO levels (Lal A, et al. J Pediatr Hematol Oncol. 1997 May-Jun;19(3):263-5). This report showed no recurrence of polycythemia when the tumors were removed in these patients. The authors concluded that tumor or surrounding renal tissue was at some point producing EPO despite their inability to detect it.

Conclusion
We speculate that neuroblastoma tumors and possibly other pediatric tumors may be releasing a novel erythropoietic cytokine. Hormone-like cytokines have been reported with other cancers, such as hypercalcemia produced by PTH related peptide in breast and lung cancers. More research is needed to determine what, if any, novel EPO-like hormones are being released by neuroblastoma cells resulting in erythrocytosis despite normal EPO levels.

Disclosures:
No relevant conflicts of interest to declare.