bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Serum Free Light Chains In Chinese Multiple Myeloma Patients
Authors: Fu Chengcheng , Qu Shiqiang , Depei Wu 
Published: October 2019

Abstract
Abstract 5011

Purpose:
Serum Free-Light Chain (sFLC) Assay is a sensitive tool recently used for diagnosis and response assessment of plasma cell disorders, especially in light chain multiple myeloma, nonsecretory multiple myeloma and primary amyloidosis. According to assemble analysis of multiple large-scale clinical research results, guideline of sFLC analysis was introduced by IMWG in 2008. But sFLC assay has not been routinely used in China and the clinical significance of the item has been explored in this study.

Patients and Methods:
Serum specimens from 36 cases of MM patients identified by IFE were analyzed. The median age was 56.2(36-74). 24(66.7%) patients were male. The M protein type was IgG in 50%, IgA in 22%, IgD in 3%, light chain in 25%. According to D-S staging, 11% pts was inIIA, 58% in IIIA, 31% in IIIB. 8% patients was in±of ISS staging, 17% inII and 75% in III. Normal range for FLC measurements is as follows: κ3.3–13.1 mg/L, λ5.7–26.3 mg/L, and κ/λ ratio of 0.26–1.65.

Results:
Abnormal rFLCs were detected 100% in 14 newly-diagnosed patients. 86% patients had measurable disease. In κ-MM patients, levels of sFLC-κ were (553.1±471) mg/L; sFLC-λ were (14.2±4) mg/L; the median of rFLC was 32.62. In λ-MM patients, levels of sFLC-κ were (5.3±2.67) mg/L; sFLC-λ were (2503±1043) mg/L; the median of rFLC was 0.002.
22 MM patients were detected during the follow up after treatment. Abnormal clonal rFLC could be found 100% in 3 PD patients, 66.7% in 12 PR/SD patients and 0 in 7 ≥VGPR patients. There was no statistical significance between sFLC and sTLC (p≥0.05). The value of iFLC in ≥VGPR group was statistical different from other response assessment groups (p<0.05). In 24 patients with measurable disease (9 with κ-MM,15 with λ-MM), an elevated level of iFLC was associated with increased myeloma cells in bone marrow and β2-microglobulin, but not with ALB, LDH.

Conclusions:
sFLC assay is a highly sensitive diagnostic and response monitoring tool for multiple myeloma. An elevated level of iFLC was associated with increased myeloma cells in bone marrow and β2-microglobulin, but not with ALB, LDH in measurable disease. More patients and longer follow-up are needed to further evaluate the diagnostic and prognostic significance of this judgment parameter.

Disclosures:
No relevant conflicts of interest to declare.
PTH- PTHR1 Axis Control on Anti-Myeloma Effect of Proteasome Inhibitors
Authors: Zangari Maurizio , Xiao Fang , Yang Ye , Xu Hongwei , Tricot Guido J. , Zhan Fenghuang 
Published: October 2019

Abstract
Abstract 5017
Multiple myeloma (MM) is a plasma cell malignancy with high osteolytic capacity and impaired bone formation. Our recent studies have demonstrated that PTH serum increases are associated with Bortezomib responses in multiple myeloma patients, indicating a possible role of PTH in anti myeloma effect of Bortezomib. We first tested the 5TGM1 cell line for sensitivity to bortezomib, PTH, and [TYR34]bPTH-(7-34) bovine (a specific PTHR1 inhibitor) in various combinations. In an in vitro study, 5TGM1 cells were sensitive to cytotoxicity of bortezomib and PTH in a dose dependent fashion. TYR compound was found to have no effect as single agent on 5TGM1 cell survival, but was able to partially block the inhibitory effect of bortezomib on cell growth (Figure 1). In an in vivo study using the 5TGM1 C 57BL/KaLwRijmice, we tested PTH-PTHR1 axis on bortezomib anti-myeloma activity. As shown in Figure 1, mice survival was positively affected by bortezomib administration (P = 0.04), and the combination of PTH + bortezomib showed a trend to further improve survival (P = 0.09). Interestingly, the concomitant use of [TYR] compound with bortezomib completely abrogated the efficacy of the proteasome inhibitor on survival. Tumor burden assessed by M-protein levels decreased consistently in mice treated with bortezomib alone, PTH alone, or a combination of PTH + bortezomib compared with the control group treated with PBS (P = 0.003, P = 0.05, P = 0.01 respectively). Importantly the tumor burden in the mice treated with bortezomib was significantly lower than in mice treated with bortezomib plus the PTH inhibitor (TYR), again indicating that the PTHR inhibitor abrogates the effect of Bortezomib on tumor growth. Similar results were obtained using the same systems for other commercially available proteasome inhibitors. Thus, we conclude that the PTH- PTHR1 pathway appears essential for proteasome inhibition activity in myeloma. Our observations may lead to novel treatment approaches in myeloma.

Disclosures:
No relevant conflicts of interest to declare.
A New Induction Combination Therapy (ThalDoDex) for Multiple Myeloma. Preliminary Results of a Phase II Study
Authors: Sammassimo Simona , Agazzi Alberto , Bassi Simona , Calabrese Liliana , Bertazzoni Paola , Vanazzi Anna , Gardellini Angelo , Gigli Federica , Andreola Giovanna , Martinelli Giovanni 
Published: October 2019

Abstract
Abstract 5030
Treatment for multiple myeloma is dramatically changed over the past 5 years. Thalidomide containing regimen is now widely accepted as standard treatment for multiple myeloma in first line. The mechanism of action and the toxicity profile of Thalidomide, make this drug suitable for combination with chemotherapeutic agents.
We report clinical results in terms of efficacy and safety of an antracycline containing regimen [liposomal doxorubicin (Myocet), Dexamethasone and Thalidomide (ThalDoDex)] In multiple myeloma before autologous transplantation.
From June 2007 to June 2010, ThalDoDex was delivered to 28 previously untreated multiple myeloma patients. Median age was 59 years (range 42–71); 5 patients were staged IIA and 21 patients staged IIIA and 2 IIIB; 15, 8 and 5 patients were ISS I, II, III respectively. Fifteen patients presented IgG monoclonal immunoglobuline, 6 IgA, 5 patients light chains myeloma, 1 patient plasma cell leukaemia and one other secretory multiple myeloma. Treatment schedule was as follows: Thalidomide 100 mg/day for 14 days then 200mg/day until the end of induction; Dexamethasone 40 mg days 1à4; Liposomal Antracycline (MYOCET) 50 mg/sqm day 1 for 4 cycles at 4 weekly intervals. LMWH 100UI/kg/day was added to all patients for DTV prophylaxis. All patients were considered for a peripheral blood stem cell transplantation program according to age and clinical outcome.
Twenty-five patients are evaluable for response. Fifteen patients (60%) achieved a CR (1 pt) or a nCR (5 pts), or a VGPR (9 pts) with an overall response rate of 80% (CR, nCR, VGPR, PR).
Six patients developed transient febrile neutropenia which solved with antibiotics. During neutropenia two patients developed pneumonia treated with appropriate antimicrobial therapy. No major haematological toxicity was observed. No neurological toxicity or thrombotic event was reported.
Our experience suggests that ThalDoDex is effective and safe as induction phase in newly diagnosed multiple myeloma patients. The clinical results are similar to those reported with other Thalidomide containing regimens. Liposomal doxorubicin in combination with Thalidomide and steroid may induce an important rate of CR and nCR as requested for the best clinical result of subsequent autologous transplant procedure. Our combination regimen avoiding alkylating agents and proteosome inhibitors may deserve the use at eventually subsequent relapse.

Disclosures:
No relevant conflicts of interest to declare.
Acute Myeloid Leukemia Cells Fuse with Vascular Endothelium
Authors: Masri Azzah Al , Goldman Devorah C , Asbaghi Steven A. , Clark Hilary A. , Leon Ronald P. , Liu Qiuying , Hickey Raymond D. , Grompe Markus , Kurre Peter , Fleming William H 
Published: October 2019

Abstract
Abstract 504
The hematopoietic niche supports both normal and malignant hematopoiesis. We have evaluated the functional interactions between leukemic cells and the endothelial cell component of the hematopoietic niche. Highly enriched populations of circulating human acute myeloid leukemia (AML) cells were obtained by therapeutic leukapheresis. These primary AML cells rapidly homed to and associated with pre-existing vascular tubes in vitro. Co-culture of human lung microvascular endothelial cells (HLMVEC) with AML cells both inhibited AML apoptosis by ∼50% (p <0.005) and significantly increased AML cell number (p<0.01), indicating an important supportive effect of the endothelium on AML growth. A direct pro-angiogenic effect of the AML cells was revealed by the induction of vascular tube formation by HLMVECs in co-culture. Screening of known angiogenic factors showed an induction of GCSF expression and an increase in IL-6 levels in AML and HLMVEC co-cultures. Together, these findings indicate a mutually supportive, functional interaction between AML cells and endothelium in vitro. To evaluate the interactions of AML and vascular endothelium in vivo, primary human AML cells were transplanted into NOD/SCID IL2Rγ null mice. In highly engrafted mice (>50% human AML cells in the bone marrow) we observed leukemic infiltration into the perivascular region of both large and small vessels of the mouse liver, and AML cells were frequently integrated into the vascular endothelium. Confocal microscopy surprisingly revealed the co-expression of human CD45 and the mouse endothelial cell marker CD31. To evaluate these apparently fused leukemia/endothelial cells further, single cell suspensions from the livers of mice engrafted with AML cells were FACS sorted based on the co-expression of human CD33 and mouse CD31. Multiplex PCR analysis of single hCD33+/mCD31+ cells verified the presence of both mouse genes (fah and tspy or D2Mit206) and human genes (flt3 and tty-15). The presence of the patient specific, leukemia-associated Flt3-ITD mutation confirmed that fusion occurs between malignant cells and vascular endothelium. AML and endothelial cell fusion was also confirmed by interphase fluorescent in situ hybridization (FISH) with species specific centromeric probes. In conclusion, the results from this study indicate that the functionally important cross-talk between normal hematopoietic stem/progenitor cells and vascular endothelium extends to malignant hematopoiesis. The fusion of primary AML cells with normal endothelial cells raises the possibility that vascular endothelium may serve as a reservoir for occult leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Small Compound 6-O-Angeloylplenolin Induces Mitotic Arrest and Exhibits Therapeutic Potential In Multiple Myeloma
Authors: Liu Ying , Chen Xiaoqin , Cheng Yongxian , Zhou Guangbiao 
Published: October 2019

Abstract
Abstract 5043
Multiple myeloma (MM), the second most frequent hematological malignancy that remains incurable, is a disease of cell cycle dysregulation and loss of apoptotic control. Here we report that 6-O-angeloylplenolin (6-OAP), a sesquiterpene lactone extracted from Centipeda minima L. (Compositae), suppresses the proliferation of drug-sensitive and drug-resistant cell lines and primary CD138+ MM cells, but does not affect normal peripheral blood mononuclear cells. 6-OAP caused mitotic arrest, accompanied by upregulation of cyclin B1 and downregulation of phospharylated Cdc2, indicating activation of cyclin B1/Cdc2 complex which is critical to the control of G2-M transition. We show that 6-OAP activates spindle assembly checkpoint, enhances Mad2/Cdc20 binding activity, leading to inhibition of ubiquitiniation and subsequent proteasomal degradation of cyclin B1. 6-OAP potentiates cytotoxicity of dexamethasone, doxorubicin and bortezomib, and overcomes the protective effects of interleukin-6 and insulin-like growth factor-2 on MM cells. Moreover, 6-OAP inhibits tumor growth but does not affect animal body weight in an in vivo xenograft model for human MM. Taken together, these results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potential for treating MM.

Disclosures:
No relevant conflicts of interest to declare.
Hereditary Haemorrhagic Telangiectasia Spectrum of ALK1/ENG Mutation
Authors: Corinaldesi Giorgio 
Published: October 2019

Abstract
Abstract 5066
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by two common criteria: angiodysplastic mucocutaneous telangiectasies, and epistaxis; hematemesis, melena, hemoptysis, stroke and visceral artero-venous malformation (AVMv) have also been associated with a significant risk of morbidity and mortality; HHT is divided into two forms: HHT-1 which is caused by a mutation in ENG (endoglin) gene mapping on chromosome 9q33–34, and HHT-2 which is caused by a mutation in ALK1 (activin receptor-like kinase 1) gene mapping on the pericentromeric region of chromosome 12q12–13.
Endoglin is an homodimeric disulphide-linked integral membrane glycoprotein (CD105) expressed on endothelial cells of all vessels; it binds TGF-beta 1 and 3, and it is very important to mediate vascular remodelling, the increase of blood flow, cellular migration and adhesion, extracellular matrix synthesis, through the modulation on endothelial cells, smooth muscle cells, fibroblasts and pericytes.
ALK1 increases in response to vessel wall stress or injury, and has a specific role in the differentiation of new vessels.
The majority of mutations in both genes are null, nonsense or splite-site and are non coding; the spectrum of mutations that have been reported of the two genes are short insertions, deletions, or missense and are present with a high level of consanguinity; homozygous patients with these mutations have severe haemorrhages.
We have identified on chromosome 12 a large deletion in exon 7, (8.4 kbp long fragment) of ALK1 encoding for the extracellular ligand-bindig domain involved in the TGF-beta/kinase activity signalling pathway, and in exon 8 (6.4 kbp long fragment) of ALK1 encoding serine-threonine kinase activity. The latter was a 28-year-old woman showing skin telangiectasies, recurrent and significant nosebleeds; the typical puntiform telangiectasies were evident since the age of 16, she also demonstrated with gastrointestinal endoscopy numerous gastric telangiectasies; abdominal and thoracic CT were performed and pulmonary involvement was present with a single artero-venous malformation and minimal respiratory symptoms (dyspnea, cyanosis); on the other hand, MRN did not revealed any cerebrovascular damage.
Mutations that disrupt ALK1 affect endothelial cells development and the process of angiogenesis; they are associated with mild clinical manifestation, and it has been observed that pulmonary arteriovenous malformations occur less frequently.

Disclosures:
No relevant conflicts of interest to declare.
Evaluation of the Mantle Cell Lymphoma International Prognostic Index (MIPI) as An Indicator of Overall Survival, Progression Free Survival, Survival From Relapse
Authors: Shah Bijal D. , Cultrera Jennifer L. , Sokol Lubomir , Chervenick Paul A. , Bello Celeste M. , Sagatys Elizabeth M. , Moscinski Lynn C. , Zhang Ling , Tao Jianguo , Sotomayor Eduardo M. 
Published: October 2019

Abstract
Abstract 5082

Background:
Prognosis for survival in mantle cell lymphoma (MCL) has recently been characterized using the MIPI algorithm. Using a retrospectively generated dataset of 150 patients with MCL seen at the H Lee Moffitt Cancer Center we sought to validate this approach in a more heterogeneous population.

Methods:
Patients were identified by physician survey, and through the use of our pathology and Total Cancer Care databases. Retrospective analysis was conducted with approval of our Institutional Review Board. In total 150 patients with MCL were identified, among whom MIPI data was available for 85 patients with a median followup of 36.8 months. Survival (expressed in months) was verified using our institutional records and the Social Security Death Index. Exploratory analysis of progression (n=79) and survival from the time of relapse (n=43) as stratified by MIPI were also conducted among evaluable patients. Data were compared using Kaplan-Meier survival analyses.

Results:
Median age was 65y (range 31–87), 73% male, 3% ECOG >1, 88% stage III/IV disease, 36% with extranodal involvement, and 38% with splenomegaly. Evaluation of the entire cohort shows median OS 57 (95% CI: 48, 70.9), median PFS 21.8 (95% CI: 14.2, 25.6), and median survival after relapse 27.6 (95% CI 25.4, 30.8). No benefit in OS was observed among patients receiving Cytarabine (HR 1.04, p=0.91) and/or Rituximab (HR 1.31, p=0.61) with initial chemotherapy. Relationship between PFS and survival after relapse demonstrated rho=0.51 (p<.0001).
Among 85 evaluable patients 36% had elevated LDH, while 36% were MIPI-Low, 38% MIPI-Int, and 28% MIPI-High. Stratification by MIPI shows median OS of 30.4 (12.4, 42) for MIPI-High, 64.8 (53,-) for MIPI-Int, and has not been reached by MIPI-Low, with little separation between MIPI-Low and MIPI-Int groups before 60 months. PFS was 6.3 (3.7,15) for MIPI-High, 25.6 (16.5,31) for MIPI Int, and 26.5 (14,40.3) for MIPI-Low, with little separation between MIPI-Low and MIPI-Int groups before 30 months. Survival after relapse was 12.4 (9.1,25.4) for MIPI-High, 34.2 (27.6,-) for MIPI-Int, and was not reached for MIPI-Low, again with little separation between MIPI-Low and MIPI-Int groups before 30 months.

Conclusions:
In our experience, the MIPI remains an effective tool for stratification of OS in MCL, however, extended followup is needed to realize such differences among those with MIPI-Low and MIPI-Int disease. The MIPI was similarly effective in predicting a poor PFS and survival from relapse among those with high risk disease, though was of less utility among MIPI-Low and MIPI-Int patients.

Disclosures:
No relevant conflicts of interest to declare.
Thymidylate Synthase (TS) Expression In Diffuse Large B-Cell Lymphoma (DLBCL): Identification of a Potential Therapeutic Target
Authors: Racila Emilian , Syrbu Sergei I , Nasr Michel , Juweid Malik E. 
Published: October 2019

Abstract
Abstract 5107

Purpose:
TS is critical for the de novo synthesis of thymidine needed for tumor cell proliferation and DNA damage repair, whereas thymidine kinase 1 (TK1) is key to the salvage pathway providing thymidine recovered from plasma. While TK1 expression has been previously shown to correlate with proliferation in DLBCL, little is known about TS levels in these neoplasms. We hypothesized that, similarly to TK1, TS expression levels associate with increased proliferation and thus may represent a novel therapeutic target in large cell lymphoma.

Methods:
To address this hypothesis, we determined the expression of TS in lymph node biopsies from 43 DLBCL patients sequentially enrolled in the study with no pre-selection criteria other than the primary histological diagnosis of lymphoma, and then compared it to TK1 expression. In addition, Ki-67 (MIB1) was included as an established marker of cell proliferation. Pearson correlation along with the correlation coefficient and two-tailed P values were calculated to measure the extent of covariation.

Results:
TS expression and both MIB1 and TK1 were significantly correlated with correlation coefficients of 0.43 and 0.65, respectively (95% CI 0.13 to 0.65 and 0.44 to 0.8; P values = 0.006 and <0.0001, respectively). The correlation between TS and MIB1 expression was in fact stronger than between MIB1 and TK1 (P values 0.006 and 0.04, respectively). Mean percent positive cells and standard deviations for MIB1, TS and TK1 were 44.5% (SD=35), 51.8% (SD=33.4), and 44% (SD=28.5), respectively. Despite the general good correlation, however, six patients had relatively high TS levels (defined as % cell staining above the mean for TS) and relatively low TK1 levels (% cell staining below the mean for TK1), while the reverse was true in seven patients. Eight patients had high levels of TK1 and TS with ≥ 70% cells positive for both; seven patients had low levels of both proteins (≤30% of cells stained).

Conclusion and Significance:
This is the first report of TS expression in DLBCL. TS is frequently expressed in DLBCL and there is a significant correlation between TS and TK1 or MIB1 expression. Further studies are warranted to determine the correlation between TS or TK1 expression and patient prognosis in comparison to MIB1. Importantly, the common expression of TS in patients with DLBCL indicates that TS may be a suitable target for TS inhibitors (TSIs) in these neoplasms. Preclinical studies are underway to test this hypothesis.

Disclosures:
No relevant conflicts of interest to declare.
RNAi Identifies Survivin as a Potential Target for Therapy In Pediatric Acute Lymphoblastic Leukemia
Authors: Chang Bill H , Tyner Jeffrey W , Jemal Abdusebur , Thayer Mathew , Druker Brian J 
Published: October 2019

Abstract
Abstract 5108

Background:
Pediatric Acute Lymphoblastic Leukemia (ALL) remains the most common pediatric malignancy. Despite advances in treatment and outcomes, there continue to be subsets of patients that are refractory to standard intensive chemotherapy and hematopoietic stem cell transplant. Therefore, novel gene targets for therapy are needed to further advance treatment for this disease. Survivin, a member of the chromosome passenger complex and inhibitor of apoptosis has been shown to be over-expressed in malignant cells and in relapsed disease. Therefore, survivin may be a potential target for therapy in pediatric ALL. Further, RNAi technology can be used as a rapid functional screen to identify target genes crucial for viability in ALL cell lines and in primary patient samples.

Design/methods:
Pediatric lymphoblastic cell lines and fresh primary mononuclear cells from newly diagnosed patients with ALL were used for all studies. Survivin was silenced by transfecting cells (via electroporation or transductin (IDT)) with siRNA SMARTpools obtained from Dharmacon. Protein expression was identified 48 hours after treatment with siRNA. Viability was measured using a standard methane-thiosulfonate viability assay. Activation of apoptosis was identified using the Guava nexin Annexin V binding assay.

Result:
Survivin is highly expressed in multiple ALL cell lines and in many primary ALL samples. Silencing of survivin expression with siRNA decreases viability and increases apoptosis in ALL cell lines and in primary ALL samples. Decreased protein expression of approximately fifty percent was sufficient to cause an increase in cell death. Finally, inhibition of P53 expression abrogates this phenotype suggesting that the mechanism of cell death induced following survivin silencing involves activation of the P53 pathway.

Conclusion:
Gene silencing with siRNA can be used as a rapid functional screen to identify potential targets for therapy. Implementing this technique identified survivin as a potential target for therapy in pediatric ALL. The results of these experiments will be used as a foundation to develop a comprehensive understanding of the mechanisms of survivin dependence in pediatric ALL. Future studies will also be designed to develop a model system for targeting of survivin in a therapeutically-relevant manner such that these findings can be translated into improved treatments for patients with ALL.

Disclosures:
No relevant conflicts of interest to declare.