bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Myeloma with IGH-Involving del(14q): Report of 34 Cases.
Authors: Wlodarska Iwona , Ross Fiona M. , Russell Lisa J. , Pospisilova Helena , Chiecchio Laura , Van Caillie Marie-Astrid , Dagrada GianPaolo , De Wolf-Peeters Christiane , Harrison Christine J. , De Paepe Pascale , Vandenberghe Peter , Michaux Lucienne 
Published: October 2019

Abstract
Chromosomal translocations involving the IGH locus on 14q32 are a hallmark of B-cell malignancies. These translocations are particularly frequent in non-hyperdiploid (NHD) multiple myeloma (MM), representing approximately 50% of myeloma cases. MM-associated primary t(14q32) target at least 7 partner genes including cyclins D (CCND1, −D3), MAF transcription factors (CMAF, MAF B and A) and MMSET/FGFR3. Some of the translocations are predictive of clinical outcome. Recently, we identified a novel interstitial del(14q) involving IGH and recurrent in chronic lymphocytic leukaemia and MM (Pospisilova et al, Leukemia, 2007). In spite of extensive studies, the mechanism(s) and molecular consequences of del(14q) remain unknown. We report here 34 cases of plasma cell (PC) malignancies with del(14q) involving IGH, as proven by FISH. Cases were collected in UK and Belgium. The estimated incidence of these aberrations in PC malignancies was 1.4%. There were 13 female and 21 male patients ranging in age from 49 to 86 years (average 68). Twenty seven patients had MM, one had SMM and 6 had MGUS. In almost all cases, the del(14q) was detected at diagnosis. Clinical data of the reported cases have been collected. The del(14q) were roughly mapped by FISH and grouped into 3 categories according to the proximal breakpoint:
del(14)(q24.1q32.33) involving the ZFP36L1 region (11 cases); deletions proximal to ZFP36L1 (14 cases) and deletions distal to ZFP36L1 (7 cases).
The size of del(14q) was not determined in 2 cases. Biallelic deletion of TRAF3/14q32.33 recurrently occurring in MM, was detected by FISH in 1 out of 9 analyzed cases. Additional FISH analysis showed that the del(14q) was predominantly associated with NHD tumors (62% vs 38% with hyperdiploid karyotypes) and frequently (60%) accompanied by del(13q), regarded as a poor prognostic factor. All reported cases were negative for t(4;14) and t(11;14); they also showed a normal status of CCND3, CMAF, MAFB and CMYC, when examined. A gain of 1q/CKS1B was found in 57% (8/14) of analyzed cases. The expression pattern of cyclin D1−D3 has been examined.
Oxidative-Stress Specific Interaction Between FANCD2 and FOXO3a.
Authors: Li Jie , Maynard Suzette , Andreassen Paul R. , Pang Qishen 
Published: October 2019

Abstract
Abstract 1089
Poster Board I-111
Fanconi anemia (FA) is a human genomic instability syndrome that is uniquely sensitive to oxidative stress. Members of the FA protein family are involved in repair of genetic damage caused by DNA cross-linkers. The molecular pathway in which the FA proteins function in oxidative stress response has not been defined. Here we report functional interaction between the FA protein FANCD2 and the forkhead transcription factor FOXO3a in response to oxidative stress. FOXO3a was colocalized to FANCD2 foci in cells subjected to oxidative stress. The FANCD2-FOXO3a complex was not detected in cells deficient for the FA core complex component FANCA, but could be restored after complementation with a functional FANCA. Consistent with this, a non-monoubiquitinated FANCD2 mutant failed to bind FOXO3a. While both DNA cross-linker mitomycin C and ionizing radiation induced monoubiquitination of FANCD2, neither was able to induce the association of FANCD2 and FOXO3a. This indicates that the FOXO3a-FANCD2 interaction is oxidative stress specific. Overexpression of FOXO3a reduced abnormal accumulation of reactive oxygen species, enhanced cellular resistance to oxidative stress, and increased antioxidant gene expression in corrected but not mutant FA-D2 cells. The novel oxidative stress response pathway converging FANCD2 and FOXO3a identified in this study is likely to contribute to cellular anti-oxidant defense.

Disclosures
No relevant conflicts of interest to declare.
Comprehensive Protein Expression Analysis of Chronic Lymphocytic Leukemia Uncovers a Correlation of CDK4, P27 and P53 with Hierarchical Risk and Suggests a Dichotomy of Apoptosis and Proliferation.
Authors: Winkler Dirk , Schneider Christof , Nitsch Daniela , Schulze Kerstin , Zenz Thorsten , Mohr Julia , Buehler Andreas , Habermann Annett , Zucknick Manuela , Benner Axel , Döhner Hartmut , Stilgenbauer Stephan , Mertens Daniel 
Published: October 2019

Abstract
Abstract 1255
Poster Board I-277
Chronic lymphocytic leukemia (CLL) has a variable clinical course. Genomic aberrations identify prognostic subgroups, pointing towards distinct underlying biological mechanisms. However, for a subset of aberrations, the affected cellular pathways are unknown. Even though the importance of posttranscriptional regulation, e.g. by micro RNAs, has become evident, the proteome of CLL remains little characterized. Therefore, the expression of 23 proteins involved in cell cycle, DNA damage, apoptosis and signaling was investigated in a total of 206 cytogenetically well characterized CLL cases by Western blotting. CLL cases were categorized according to the hierarchical model by Döhner et al. (NEJM 2000) into del(17p) (N=41), del(11q) (N=39), del(13q) (N=39) as sole abnormality, trisomy 12 (N=58) or normal karyotype (N=28). VH mutation status was available in 198 of 206 cases. For statistical analyses, protein expression was quantified by densitometry in 185 patients. Interestingly, in CLL subgroups with a good prognosis, differentially expressed proteins were rather involved in apoptosis. In contrast, in cytogenetic subgroups with a worse prognosis, deregulated proteins were associated with DNA damage and cell cycle control (see figure). In addition, higher levels of CDK4, P27 and P53 significantly correlated with increasing hierarchical risk as defined by genetic subgroups. Inter-protein correlations pointed to either STAT6-signaling or AKT1-signaling to be affected in CLL, but the low number of significant partial correlations between proteins underlines the major influence of genetic aberrations on the cellular CLL phenotype. In summary, differences in protein levels define distinct molecular phenotypes with a dichotomy of apoptosis and proliferation in CLL associated with prognostic subgroups. These findings open new therapeutic options for patient-tailored treatment of CLL.
Figure:
Overview of protein regulations in hierarchical subgroups of CLL suggesting a dichotomy of apoptosis and proliferation in CLL associated with benign and aggressive subgroups, respectively. The figure illustrates an increasing number of deregulated proteins associated with proliferation/DNA damage and a decreasing number of deregulated proteins that control apoptosis with higher genetic risk category (arrows indicate upregulation or downregulation when compared to other risk categories; two arrows: proteins with significant differential expression; single arrows: significant before adjustment for multiple testing (trend)).

Disclosures
No relevant conflicts of interest to declare.
Evaluation of Potential role for Valproic Acid in IL-3-Mediated Megakaryopoiesis and Erythropoiesis in Serum-Free and Serum-Containing Cultures.
Authors: Ohishi Kohshi , Liu Bing , Masuya Masahiro , Heike Yuji , Takaue Yoichi , Katayama Naoyuki 
Published: October 2019

Abstract
Abstract 2746
Poster Board II-722
Although attention has been paid to the antitumor activity of histone deacetylase (HDAC) inhibitors in hematologic disease, a role for HDAC in normal hematopoiesis has not been clearly defined. Previous study have shown that the potent HDAC inhibitor FK228 (romidepsin, depsipeptide) stimulates IL-3-mediated erythropoiesis in serum-free cultures. Here, we precisely examined the effects of well-tolerated antiepileptic drug valproic acid (VPA) on IL-3-mediated megakaryopoiesis and erythropoiesis in serum-free and serum-containing cultures. After incubation of CD34+ cells in serum-free medium containing IL-3+SCF, CD61+GPA− megakaryocytic, a CD61+GPA+ mixture of megakaryocytic and erythroid, and CD61−GPA+ erythroid precursors were generated. Pharmacological concentration of VPA (100 μg/ml) and FK228 (0.45 ng/ml) remarkably increased the number of CD61+GPA+ cells by 7-fold and 9-fold, respectively. Other populations were also increased by FK228 and VPA. VPA and FK228 enhanced the generation of megakaryocytic and erythroid precursors from more mature CD34+ cell-derived CD36+ erythroid and megakaryocytic precursors. Thus, VPA was found to be as potent as FK228 in stimulating the IL-3-mediated megakaryopoiesis and erythropoiesis. In the presence of GM-CSF+SCF, CD61−GPA+ erythroid precursors were mostly developed. Addition of VPA to the cultures mainly promoted the generation of CD61−GPA+ erythroid precursors, while the generation of megakaryocytic precursors was also moderately enhanced. In serum-containing cultures, there were only low numbers of CD61+ or GPA+ cells detected even in the presence of IL-3+SCF. Nevertheless, addition of VPA to the cultures containing IL-3+SCF increased the numbers of CD61+GPA−, CD61+GPA+, and CD61−GPA+ cells by 3-fold, 18-fold, and 4-fold, respectively from three independent experiments. In megakaryopoiesis and erythropoiesis, GATA-1 and GATA-2 are shown to play important roles in the proliferation and differentiation process, respectively. By quantitative RT-PCR analysis, after incubation of CD34+ cells with IL-3+SCF, GATA-2 m-RNA expression was increased at day1 but returned to initial levels at day3. VPA increased the expression level of GATA-2 gene by 1.6-fold and 1.7-fold at day1 and day3, respectively. While GATA-1 gene expression was remarkably elevated at day1 and day3, its expression was not affected by VPA. Our data reveal a potential for VPA to promote the ability of IL-3 to stimulate megakaryopoiesis and erythropoiesis in serum-free and serum-containing cultures and thus implicate a novel therapeutic approach of epigenetic therapy for treatment of hematologic disease such as myelodysplastic syndrome.

Disclosures:
No relevant conflicts of interest to declare.
Prediction of Response to Treatment with Lenalidomide in Patients with Non-Del 5q Myelodysplastic Syndrome by Gene Expression Profiling Remains Difficult.
Authors: Hofmann Wolf-Karsten , Nolte Florian , Benlasfer Ouidad , Thiel Eckhard , Ehninger Gerhard , Platzbecker Uwe 
Published: October 2019

Abstract
Abstract 2781
Poster Board II-757
Lenalidomide belongs to a proprietary class of immunmodulatory drugs showing therapeutic activity in patients with myelodysplastic syndrome (MDS), in particular in those having the 5q-abnormality, but also in patients not showing this cytogenetical aberration. In 2008, Ebert et al. (PLos Med. 2, e35) could demonstrate that there is a specific gene expression profile in bone marrow cells collected from MDS-patients either with 5q- syndrome as well as MDS-patients having no 5q-abnormality which is strongly correlated with the clinical response to treatment with lenalidomide. Whereas this finding is not of clinical importance in patients with MDS del 5q (overall response 75 %) it may play a pivotal role for prediction of clinical response to lenalidomide in non-del 5q MDS-patients. Therefore, we have studied gene expression profile (HG-U133plus2.0, Affymetrix, Santa Clara, CA) of routinely isolated low-density mononuclear bone marrow cells from 8 patients with IPSS low/int-1 risk MDS having no deletion on chromosome 5 but were subsequently treated with lenalidomide 5 mg/day. All of the patients were transfusion dependent for red blood cells. The median duration of treatment with lenalidomide was 22 weeks. RNA was extracted by Trizol and quality controlled by using a Bioanalyzer 2100 system (Agilent, Waldborn, Germany) to exclude RNA degradation. Microarray hybridization was performed according to the standard Affymetrix protocol. Data were analyzed by Microarray Analysis Suites 5.0 (MAS 5.0; Affymetrix) and GeneSpring (Agilent Technologies, Santa Clara, CA). For clustering analysis we utilized the gene list of 68 discriminating genes as published by Ebert et al. the molecular analysis did clearly separate two groups of patients having specific gene expression profiles according to the responder/non-responder group as published previously. Furthermore, single sample prediction could discriminate three out of 8 patients to be possible responders to lenalidomide but this was not correlated to the clinical course of those patients while on treatment with lenalidomide. However, none of the MDS-patients receiving lenalidomide did show significant clinical response as defined by reduction of transfusion requirement by 50 % or transfusion independence. In conclusion, prediction of response to lenalidomide in non-del 5q patients by gene expression profiling so far remains critical. Prospective analysis of molecular changes including DNA analysis in larger clinical trials using lenalidomide in non-del 5q MDS-patients are required to establish reliable predictive markers in MDS.

Disclosures:
Hofmann: Celgene: Research Funding. Platzbecker:Celgene: Research Funding.
Incidence of Centrosome Amplification in Multiple Myeloma.
Authors: Smejkalova Jana , Dementyeva Elena , Nμmec Pavel , Fedor Kryukov , Raja Karthick Raja Muthu , Grešlíková Henrieta , Smetana Jan , Zaoralova Romana , Kupska Renata , Kuglik Petr , Hajek Roman 
Published: October 2019

Abstract
Abstract 2827
Poster Board II-803
Centrosome amplification (CA) has been previously detected in hematological malignancies including multiple myeloma (MM) and is usually associated with disease progression. CA leads to the formation of multipolar mitotic spindles that may lead to chromosome segregation errors and genomic instability. In this pilot study, we have evaluated the occurrence of CA in two populations of B-lineage cells including B-lymphocytes and plasma cells (PCs) of MM patients. We have analyzed possible associations of CA with established prognostic factors including the most common chromosomal abnormalities in malignant PCs.
Immunofluorescence labeling was used for the evaluation of centrosome amplification (CA) in B-cells (CD19+) and PCs (CD138+) of MM patients. The centrin (centrosome protein) copy numbers were used to define three cellular subpopulations: (1) no centrin signal (Non-CS), (2) 1-4 centrin signals (1-4CS) or (3) more than 4 signals of centrin (CA). Samples with ≥11% of B-cells or ≥10% of PCs with >4 fluorescence signals of centrin were considered CA positive. A total of 70 patients were evaluated for CA in PCs and/or B-cells, including 18 patients who had analysis of both cell types. The patient population characteristics were as follows: males/females 34/36, median age of 65 years (range, 40-84 years). Most patients had advanced stage of MM (DS II/III n = 48; ISS II/III; n = 21). Peripheral blood samples from 20 healthy donors were used as controls and for the estimation of CA positivity threshold for B-cells (Mean + 3SD).
There was a statistically significant difference between the percentage of B-cells subpopulations with centrosome amplification in MM patients and that in healthy donors ([Mean ± SD] 9.9 ± 7.9% versus 3.2 ± 2.5%; P<0.0001). The frequency of MM cases positive for CA was 34% (17/50) and 37% (14/38) based the analysis of PC samples and B-cell samples, respectively. Overall, 22% (4/18) MM patients were double-positive. No significant correlation was detected between B-cells and PCs (r=0.387; P=0.113) obtained from patients with both available samples. No significant associations were identified between CA status and the following common cytogenetic abnormalities in PCs: del(13)(q14) (p= 1.000); del(17)(p13) (p=0.132); gain(1)(q21) (p= 1.000), hyperdiploidy (p= 1.000).
In summary, we have confirmed the presence of centrosome amplification in B-cells of MM patients. Immunofluorescence staining is a sensitive method for the detection of abnormal subpopulations of B-cells that probably represent a reservoir of clonogenic cells in MM.
This study was supported by grants NR 8945-4/2006, MSM 0021622434, MZ LC 06027 and IGA NR 9317 from the Departments of Education and Health of the Czech Republic.

Disclosures:
No relevant conflicts of interest to declare.
Efficacy of the Combination of Bortezomib and Dexamethasone in Systemic AL Amyloidosis.
Authors: Lamm Wolfgang , Willenbacher Wolfgang , Zojer Niklas , Müldür Ercan , Ludwig Heinz , Lang Alois , Zielinski Christoph C , Drach Johannes 
Published: October 2019

Abstract
Abstract 2871
Poster Board II-847

Introduction:
AL amyloidosis is characterized by misfolding of structurally unstable light chains that form deposits in various organs thereby causing impaired organ function. Treatment of AL amyloidosis remains challenging and is primarily directed towards the underlying abnormal plasma cell clone. Novel agents with proven efficacy in multiple myeloma like the proteasome inhibitor bortezomib have also shown initial promising results in patients with AL amyloidosis, but its value needs to be further established. In this retrospective analysis, we have collected data regarding efficacy and tolerability of treatment with bortezomib plus dexamethasone in patients with AL amyloidosis.

Patients and Methods:
25 patients with histologically proven systemic AL amyloidosis were included in this analysis. All patients received bortezomib at a standard dose of 1.3mg/m2 (days 1, 4, 8, 11 of a 3-week cycle) in combination with dexamethasone (8mg to 20mg administered on the day of bortezomib and the day after). Routine clinical and laboratory parameters including evaluation were obtained on a monthly basis.

Results:
Patients (male n=13, female n=12) were at a median age of 57 years (range 42-83), and 17 patients (68%) received bortezomib/dexamethasone as their first line treatment. The majority of patients had an ECOG performance status of < 2. Twelve patients (48%) had only one organ involved, whereas > 2 organs were involved in 6 patients (24%). Organs most frequently involved were kidneys (100%), heart (28%), liver (12%) and the gastrointestinal tract (12%). At the time of analysis, a median of 3 cycles of bortezomib/dexamethasone (range, 1 to 8) have been administered. A hematologic response was observed in 14 patients (56%) including 5 patients (20%) qualifying for a complete response (CR). All CR patients received bortezomib/dexamethasone as their first line treatment, and parameters of organ function also improved in these patients. Median overall survival has not yet been reached after a median follow-up of 12 months. Grade 3 and 4 toxicities were rare and consisted predominantly of transient thrombocytopenia. Grade 2 neurotoxicity was observed in 24% of patients. Other grade 1/2 toxicities observed at higher frequencies included hypotension (16%), edema (16%), and fatigue (12%).

Conclusion:
Our results confirm the activity of bortezomib/dexamethasone in patients with AL amyloidosis (hematologic response rate 56% including a 20% CR rate).

Disclosures:
Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria.
Integrative Analysis of MicroRNA and Gene Expression Profiling Contributes to Understand Mantle Cell Lymphoma Pathogenesis.
Authors: Di Lisio Lorena , Gómez-López Gonzalo , Sáanchez-Beato Margarita , Rodríguez Maria Elena , Abad Cristina Gómez , Villuendas Raquel , Mollejo Manuela , Martínez Miguel A. , Menarguez Javier , Diaz-Alderete Andrea , Gil Juana , Cigudosa Juan , Pisano David G. , Piris Miguel A. , Martínez Nerea 
Published: October 2019

Abstract
Abstract 2936
Poster Board II-912
Mantle cell lymphoma (MCL) pathogenesis is still partially unexplained. Although the overexpression of CyclinD1 dependent of t(11;14) is a distinctive molecular hallmark of this neoplasm, this event alone cannot account for the increased survival signaling that characterizes this lymphoma type. Here we investigate whether microRNA (miRNA) expression profile may help to explain the changes in the expression of gene pathways that are characteristic of MCL.
Twenty-three frozen MCL samples, 11 frozen control tissues (7 lymph nodes and 4 tonsils), 8 MCL cell lines and 3 samples of CD19+IgD+CD27- cells obtained from tonsils, were studied for miRNAs and gene expression. MiRNA one color microarray data for 470 human miRNA were analyzed using SAM (Significance Analysis of Microarrays) algorithm. MiRNA targets were predicted by miRanda and TargetScan methods. Pathways identification and analysis was carried out by GSEA (Gene Set Enrichment Analysis) online resource.
The analysis of 23 MCL cases compared to 11 control tissues showed a miRNA signature that included 117 miRNAs with FDR<0.05, 85 of which downregulated and 32 upregulated. Combined analysis of these miRNAs and changes in the gene expression profile, paired with bioinformatic target prediction, revealed a group of genes and pathways potentially targeted by the miRNAs, including essential pathways for lymphoma survival. An interesting correspondence was found between the simultaneous increase in CD40, MAPK, NFKB and others pathway signaling with the downregulation of 15 miRNA predicted to target genes belonging to these pathways. Functional validation in MCL cell lines demonstrated NF-kB nuclear translocation to be regulated by the expression of one of these miRNAs. Most of the MCL cell lines exhibit a strong expression of the mir-17-92 polycistron (Oncomir-1).
MiRNAs were used also for the identification of survival prognostic markers; using different analysis (22 frozen specimens) and validation (54 paraffin embedded cases) series. A single miRNA distinguished a group of MCL cases with a 72.2% survival at 60 m.
This study identifies a set of miRNAS involved in MCL pathogenesis, which could be used in MCL recognition and clinical prognostication.

Disclosures:
No relevant conflicts of interest to declare.
Incidence and Clinical Outcomes of Occult Malignancies Detected by Computed Tomographic Pulmonary Angiography in Patients with Acute Pulmonary Embolism.
Authors: Shen Yi-Hao , Wells Phil , Dennie Carole , Carrier Marc 
Published: October 2019

Abstract
Abstract 2983
Poster Board II-959

Introduction:
Venous thromboembolism (VTE) can be the earliest sign of malignancy. Approximately 10% of patients with unprovoked VTE will be diagnosed with cancer within the next 12 months. Diagnosis of pulmonary embolism (PE) using computed tomographic pulmonary angiograhy (CTPA) allows the visualization of anatomy in addition to thoracic vasculature. Hence, CTPA might be useful for detecting occult cancers in patients with PE.

Objective:
To evaluate the incidence and clinical outcomes of occult cancers detected by CTPA in patients with acute PE.

Methods:
This is a retrospective cohort study of consecutive patients with suspected PE undergoing CTPA at the Ottawa Hospital from Jan 1, 2007 to Dec 31, 2008. PE was defined as a subsegmental or larger pulmonary artery filling defect on CTPA. Occult malignancy was defined as any new cancer first detected by CTPA with index PE diagnosis in patients with no known history of malignancy. All patients were followed for a minimum of 6 months after the index PE.

Results:
A total of 4410 CTPA were reviewed and 748 (17%) were positive for acute PE. Of these, 57 (7.6%; 95% CI: 5.7 to 9.5) revealed abnormalities suggestive of possible occult cancers. Twenty-two (2.9%; 95% CI: 1.7 to 4.2) patients were diagnosed with occult cancers. Among these 22 patients with occult cancers, 20 (91%) had unprovoked PE. Thirteen (59%) patients had occult lung cancer and 16 (73%) had advanced stage (stage 3 or 4) cancers. Sixteen (73%) patients have died following the diagnosis of occult cancer, and their median survival following the diagnosis of PE was 51 days.

Conclusion:
CTPA detected occult cancers in approximately 3% of patients with acute PE. Most of these cancers were detected at an advanced stage and were associated with high mortality and short survival.

Disclosures:
No relevant conflicts of interest to declare.