bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-Transplant Evaluation with Both CT and PET Following Second-Line Therapy Is Essential for Predicting Outcome in Patients with Transplant- Eligible Relapsed and Primary Refractory Hodgkin Lymphoma
Authors: Moskowitz Alison J. , Nimer Stephen D. , Zelenetz Andrew D. , Kewalramani Tarun , Vanak Jill M , Maragulia Jocelyn c , Yahalom Joachim , Moskowitz Craig 
Published: October 2019

Abstract
The standard treatment for relapsed and primary refractory (rel/ref) Hodgkin lymphoma (HL) for patients (pts) who demonstrate chemosensitivity to second-line chemotherapy (ST) is high dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT). Since 1994, four studies at our institution evaluated ICE (ifosfamide, carboplatin, and etoposide) based salvage therapy followed by HDT-ASCT in rel/ref HL. Chemosensitivity is a requirement for pts to proceed to HDT-ASCT, however the definition of chemosensitivity is broad. We use both functional imaging (gallium or PET) and CT to assess response to ICE; pts with chemosensitive disease fall into three groups: normalization of CT and FI (NRM), residual mass on CT but with negative FI (RM, FI-), and FI positivity regardless of CT finding (FI+). Here we report the outcome for pts who responded to ICE ST and proceeded to HDT-ASCT.
Between October 1994 and February 2008, 198 pts received ICE on 1 of 4 consecutive protocols (169 pts) or as per protocol (29 pts) and were deemed transplant-eligible. The median follow-up for surviving patients is 7.4 years. There were 99 male pts and 99 female pts; the median age was 31. With respect to the 3 pre-salvage chemotherapy risk factors (RF) (relapse within 1 year of primary treatment, presence of extranodal disease, and B symptoms): 44 pts had 0 RF, 64 had 1 RF, 75 had 2 RF, and 8 had 3 RF. Bulky disease defined as greater than 5cm or 10cm was present in 60 (30%) and 15 (7.5%) pts respectively.
The five year event free survival (EFS) and overall survival (OS) were 69% and 78% respectively. Seventy six (38%) had a NRM response to ST, 73 (37%) had a RM, FI- response, and 49 (25%) were FI+. The 5 year EFS and OS for the three groups were 86% and 93%, 71% and 79%, and 41% and 51% respectively. There was a statistically significant improvement in OS and EFS for the NRM and RM, FI- groups compared to the FI+ group (p<0.0001). Surprisingly, a comparison between the NRM and RM, FI- groups also revealed a statistically significant improvement in EFS and OS for the NRM group (p=0.05 and 0.04 respectively).
Response to ICE ST followed by HDT-ASCT is associated with a prolonged EFS and OS. The quality of response to ICE ST had a significant impact on outcome. Both a residual mass with normalized FI and abnormal FI after ST predicts for an inferior outcome following HDT-ASCT. However, residual radiotracer on FI was associated with the poorest outcome in both EFS and OS.
CONCLUSION: Outcome cannot be predicted by FI alone since both RM, FI- and FI+ groups had an inferior outcome compared to NRM. The most accurate post treatment evaluation includes both CT and PET.
Figure Figure
Genome-Wide Analysis of B Cell Non-Hodgkin’s Lymphoma Disclosed Frequent Involvement of Genes in NFkB Pathway
Authors: Kato Motohiro , Nakazaki Kumi , Sato Yasuharu , Takeuchi Kengo , Sanada Masashi , Asakura Yoshitaka , Muto Satsuki , Chen Yuyan , Takita Junko , Hayashi Yasuhide , Igarashi Takashi , Watanabe Toshiki , Tobinai Kensei , Ishikawa Yuichi , Mori Shigeo , Kurokawa Mineo , Yoshino Tadashi , Kobayashi Yukio , Ogawa Seishi 
Published: October 2019

Abstract
B cell non-Hodgkin’s lymphoma (B-NHL) consists of different pathological entities that are frequently characterized by distinct genetic alterations. However, the knowledge on these genetic lesions in B-NHL is still limited. In order to obtain a more comprehensive view of genetic lesions in B-NHL, we performed genome-wide analysis of copy number (CN) alterations as well as allelic imbalances using Affymetrix SNP arrays in 190 B-NHL cases, including 64 samples of diffuse large B-cell lymphoma (DLBCL), 62 of follicular lymphoma (FL), 64 of mucosa-associated lymphoid tissue lymphoma (MALT-L). SNP array data were analyzed with CNAG/AsCNAR software, which enabled sensitive detection of CN alterations in allele-specific manner, and thus allelic imbalances, without depending on availability of paired normal controls. Most frequent numerical abnormalities in B-NHL were gains of chromosomes 3 and 18, although gains of chromosome 3 were less prominent in FL. Chromosomal deletions that lead to loss of heterozygosity (LOH) were commonly found in 1p, 6q and 10q. However, the more chracteristic feature of B-NHL genomes was high frequency of CN netural LOH or uniparental disomy (UPD), which was found in 35 cases of DLBCL (55%), 32 cases of FL (52%) and 18 cases of MALT-L (28%). It is widely distributed in the genome, but more frequently found in 1p, 1q, 6p, 6q and 12q. High-grade amplifications and homozygous deletions frequently provide a clue to identify relevant gene targets. In our series, 12 loci of high-grade amplifications and 14 loci of homozygous deletions were identified, and helped to specify the candidate genes. These regions included, FCGR2B amplified in 5 cases of DLBCL, RERE amplified in 2 cases of FL and CDKN2A/CDKN2B deleted in 9 cases of DLBCL. The most notable finding in the current study was, however, the identification of common genomic alterations in genes that regulate activation of NFkB pathway in more than 50% of B-NHL cases. Eight lymphoma cases harbored high-grade amplification of cREL gene, and gain including cREL was detected in 28 samples (14.7%). Fourteen cases had gains or amplification of TRAF6, and another 16 cases had deletion at 10q including PTEN. These abnormalities were supposed to cause dysregulation of NFkB. Aberrant NFkB activity has long been implicated in the pathogenesis of B-NHL, and our study confirmed that dysregulation of NFkB pathway was main mechanism of lymphomagenesis, providing further rationale that he treatment against malignant lymphoma with inhibitor of NF kappa B pathway.
Bortezomib Induces Osteoblast Differentiation Via Wnt-Independent Activation of Beta-catenin/TCF Signaling
Authors: Qiang Ya-wei , Hu Bo , Chen Yu , Zhong Ying , Barlogie Bart , Shaughnessy John D 
Published: October 2019

Abstract
Bone loss in multiple myeloma (MM) and other conditions represents a serious clinical problem, and extensive research is being conducted to develop new drugs that target signaling cascades whose disruption is known to cause bone loss. Inhibition of Wnt/beta-catenin/TCF signaling induces proliferation of mesenchymal stem cells and/or suppresses their differentiation into osteoblasts. Osteolysis in MM and several other diseases has recently been linked to the suppression of Wnt/beta-catenin/TCF signaling. The antitumor activity of the proteasome inhibitor bortezomib in MM has been linked to its bone anabolic effects. However, the molecular basis of bortezomib’s action on bone is not well characterized. Here we show that bortezomib activates the beta-catenin/TCF pathway in murine and human osteoblast progenitors and human mesenchymal stem cells derived from bone marrow of healthy donors and patients with MM, leading to their subsequent differentiation in-vitro as assessed by matrix mineralization and calcium deposition. Pull-down assays followed by immunoblotting and immunofluorescence microscopy revealed that bortezomib induced stabilization of beta-catenin in both the cytoplasm and nucleus. Nuclear translocation of stabilized beta-catenin was associated with the activation of beta-catenin/TCF transcriptional activity as detected by luciferase activity from TOPFLASH reporter constructs. This activation was not dependent on the drug inducing Wnt ligand or receptor expression, the suppression of Wnt signaling inhibitors or change in disheveled protein levels. Synergy experiments showed that recombinant Wnt3a or LiCl-induced inactivation of GSK3beta did not enhance bortezomib-induced changes in TCF activity. Matrix mineralization was not accompanied by the induction of alkaline phosphatase or osteoprotegerin, which can be activated by Wnt3a in these cell types. Blocking the activation of beta-catenin/TCF signaling by dominant negative TCF attenuated bortezomib-induced matrix mineralization. These results add to the growing body of evidence demonstrating a critical role of the Wnt/beta-catenin pathway in bone biology and provide mechanistic insights into the recently recognized bone anabolic effects of bortezomib. As the effects of bortezomib completely bypass all known regulatory mechanisms governing Wnt signaling, these data also provide a strong rationale for the use of bortezomib in the treatment of diseases linked to suppression of Wnt/beta-catenin signaling.
Downregulation of Ribosomal Proteins Is Seen in Non 5q- MDS
Authors: Sohal Davendra P. , Pellagati Andrea , Zhou Li , Mo Yongkai , Opalinska Joanna B. , Alencar Christina , Heuck Christoph , Wickrema Amittha , Friedman Ellen , Greally John , Ebert Benjamin L. , Warner Jonathan , Boultwood Jacqueline , Verma Amit 
Published: October 2019

Abstract
Recent work (Ebert et al, Nature 2008, Jan 17:335-9) has shown that ribosomal protein S14 (RPS14) is underexpressed in myelodysplasia (MDS) with deletion of chromosome 5q and plays a role in its pathogenesis. The role of ribosomal proteins in other more common subtypes of MDS is unknown. We conducted a meta-analytical comparison of gene expression profiles of 60 cases of non 5q- MDS CD34+ cells with 52 normal CD34+ profiles. These datasets were obtained from seven independent studies from NCBI’s GEO database. The data was integrated based on UniGene IDs and were quantile normalized to ensure cross-study comparability. (Based on our previous approach; Sohal et al PLOS One, 2008, Zhou et al, Blood, 2008). Using significance analysis of microarrays (SAM) and a false discovery rate (FDR) of just 0.04%, we found that ribosomal protein were the class of genes that were most significantly altered in MDS. We observed that RPL35a, RPS9, RPL10, RPL22, RPS14, RPS10, RPS15a, RPS24, RPL24, RPL36, RPL21, RPL23 were strikingly downregulated in non-5q- MDS CD34+ cells. To determine if these alterations were a result of changes in DNA copy numbers of these genes, we examined 20 MDS samples by high resolution array comparative genome hybridization (aCGH) performed on Nimblegen whole genome tiling arrays. aCGH at 6kb resolution revealed deletions in RPL14, RPL22, RPL36, RPS10, RPS5 and even RPS14 in distinct selected cases of non 5q- MDS. These small deletions, which were not identifiable by traditional karyotyping methods, may be putative mechanisms of ribosomal protein downregulation and ultimately, in MDS development and/or progression. Since MDS is also characterized by aberrant epigenetic silencing of genes, we next examined the methylation status of ribosomal gene promoters by high resolution global DNA methylation profiling by using the HELP assay (HpaII tiny fragment Enrichment by Ligation-mediated PCR; Khulan et al, Genome Res. 2006 Aug;16(8)). This assay uses differential methylation-specific digestion by HpaII and MspI followed by amplification, two color labeling and hybridization to quantitatively determine individual promoter CpG island methylation. While there were sporadic changes in some patients, we did not observe any consistently significant changes in methylation of these ribosomal gene promoters on comparison with normal anemic controls.
In summary, we show novel widespread alterations in ribosomal protein expression in MDS, at least some of which are associated with genomic deletions. These findings illustrate the applicability of meta-analytical genomic approaches in a heterogeneous disease such as MDS. Most importantly, our data points to the dramatic role of alteration in the protein translational machinery in pathogenesis of MDS.
Cyclin D1 as a Universally-Expressed Mantle Cell Lymphoma-Associated aTumor Antigen for Immunotherapy
Authors: Wang Michael , Sun Luhong , Qian Jianfei , Han Xiaohong , Zhang Liang , Lin Pei , Yi Qing 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) accounts for 5% to 10% of all non-Hodgkin lymphomas and has the worst prognosis among all lymphomas. The hallmark of MCL is a t(11;14) translocation resulting in overexpression of cyclin D1 by tumor cells of virtually all patients. In this study we examined whether cyclin D1 could be an effective tumor-associated antigen for immunotherapy. We identified a cyclin D1 peptide (P101) for HLA-A*0201, created heteroclitic peptide (Py101) for better binding, and generated peptide-specific T-cell lines from HLA-A*0201+ blood donors and MCL patients. After 5 to 7 rounds of in vitro stimulation with peptide-pulsed autologous dendritic cells (DCs), T-cell lines were obtained, which contained about 45% CD4+ and 55% CD8+ T cells. As exemplified by the results of peptide-tetramer staining, the frequencies of peptide-specific CD8+ T cells increased during in vitro stimulation, from 5.7% of specific T cells at fourth stimulation to 19.7% at sixth stimulation. These cell lines proliferated in response to autologous DCs pulsed with cyclin D1 peptide Py101 (but not unpulsed), as measured by 3[H]-thymidine incorporation and CFSE-dilution assays. These results indicate that the T cells are indeed specific for cyclin D1 Py101 peptide. Moreover, the T cells efficiently lysed peptide-pulsed but not unpulsed T2 cell and autologous DCs, and cyclin D1+ and HLA-A*0201+ human MCL lines MINO, SP53, Jeko-1, and Granta 519, and more importantly, HLA-A*0201+ primary lymphoma cells from MCL patients. No killing was observed on HLA-A*0201− primary lymphoma cells or HLA-A*0201+ normal blood cells including B cells. These results indicate that these T cells are potent cytotoxic T cells and recognize cyclin D1 peptides naturally presented by patient lymphoma cells in the context of surface HLA-A*0201 molecules. Flow cytometry analysis was used to examine the expression of granzymes, perforin, and Fas ligand (FasL) by the T cells. Based on these results, T cells may kill their target cells via the perforin/granzyme pathways, because they express perforin and high levels of granzymes but not FasL. Two independent methods were used to examine the cytokine expression profiles of the T cells. Upon restimulation with DCs pulsed with Py101 peptide, but not with unpulsed DCs, 11.2% of the T cells expressed IFN-γ by intracellular cytokine staining. IL-4-expressing T cells were very few (0.3%). To detect cytokine secretion, an ELISPOT assay was used to enumerate IFN-γ-secreting cells. After restimulation with DCs pulsed with cyclin D1 peptides, or with cyclin D1+/HLA-A*0201+ SP53 and cyclin D1+/HLA-A*0201+ primary lymphoma cells from patients, large numbers of IFN-γ-secreting cells were detected. Taken together, our work identifies cyclin D1 as a potentially important antigen for immunotherapy in MCL.
Cancer Stem Cell Activity in Mantle Cell Lymphoma Is Inhibited by TLR9 Activation
Authors: Brennan Sarah , Meade Brooke , Wang Qiuju , Weiner George , Matsui William 
Published: October 2019

Abstract
Patients with Mantle Cell Lymphoma (MCL) often respond to initial cytotoxic therapy, but invariably relapse. This clinical pattern suggests that standard therapies fail to eliminate a population of chemoresistant cells responsible for tumor regrowth and disease relapse. Studies in myeloid leukemias and multiple myeloma have suggested that cancer stem cells (CSC) are relatively quiescent and that this property promotes drug resistance. Therefore, the induction of CSC proliferation may increase their susceptibility to anti-cancer treatment. Unmethylated CpG DNA sequences induce the activation and differentiation of normal B cells through toll like receptor 9 (TLR9), and synthetic CpG oligonucleotides (ODN) are currently undergoing clinical trials in MCL and other B cell non-Hodgkin’s lymphomas. We initially examined the effects of TLR9 agonists on the clonogenic growth of the human MCL cell lines Granta 519, Jeko-1, and Rec-1 and found that the unmethylated CpG ODN 2006 (5ug/mL, 48 hours) significantly inhibited the ability of each of these cell lines to form colonies in methylcellulose (p<0.01). We previously demonstrated that clonogenic CSC in multiple myeloma and Hodgkin’s lymphoma may be identified based on the relative activity of the intracellular detoxification enzyme aldehydedehydrogenase (ALDH). Similarly, each of the MCL cell lines contained small populations (0.5−2.3%) of ALDH+ cells that were enriched for in vitro clonogenic growth upon primary and secondary plating in methylcellulose. Following treatment with CpG ODN 2006, the population of ALDH+ cells was significantly reduced in each cell line (p<0.05). The self-renewal potential of normal and cancer stem cells is lost through the process of differentiation, and treatment of the MCL cell lines with CpG ODN 2006 resulted in the loss of CD19 and CD20 expression and induction of the plasma cell antigen CD138 by FACS. Similarly, RT-PCR for regulators of B cell differentiation revealed decreased PAX-5 and BCL-6 expression coupled with increased transcription of BLIMP-1 and XBP-1. We hypothesized that the plasma cell differentiation induced by TLR9 agonists may improve the efficacy of anti-tumor agents with known activity against plasma cells, specifically the proteosome inhibitor bortezomib. Treatment with CpG ODN 2006 or bortezomib (10–100nM, 48 hours) alone induced apoptosis in a small percentage of cells within each MCL line, but the combination of these agents synergistically increased the proportion of Annexin V+ cells. In summary, cellular activation by CpG ODN 2006 reduces MCL clonogenicity and stem cell function through the induction of differentiation. In turn, plasma cell maturation appears to increases the sensitivity of MCL to bortezomib and suggests a novel mechanism for the anti-tumor activity of CpG ODN.
Epoetin Alfa Reduces the Need for Red Blood Cell Transfusions and Does Not Affect Remission Rate or Survival When Given to Patients with Hematologic Malignancies Receiving Hyper-CVAD Therapy.
Authors: Mattiuzzi Gloria , Kantarjian Hagop , Cabanillas Maria , Foudray Maria , Garris Rebecca , O’Brien Susan , Thomas Deborah A. , Cortes Jorge 
Published: October 2019

Abstract
Background: Recent reports suggest that the use of erythropoietic stimulating agents (ESA) may adversely affect survival when used in the management of patients with certain solid tumors. Anemia is common in patients with acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), and Burkitt’s lymphoma (BL). The use of erythropoietin (EPO) in this group of patients may be beneficial; however, the impact of EPO on the survival of patients with hematologic malignancies is unknown.
Objective: To evaluate the effects of EPO on rate of transfusions, survival and remission rates in patients with ALL, LL and BL treated with Hyper-CVAD.
Methods: We evaluated 109 pts with newly diagnosed acute lymphocytic leukemia (ALL), lymphoblastic lymphoma (LL), and Burkitt’s lymphoma (BL) who participated in a randomized trail comparing EPO (40,000 units SQ weekly within 14 days of starting chemotherapy) vs. standard of care. Both arms received blood transfusions as per institutional guidelines.
Results: From September 2003 to July 2008, 109 pts were included in the study, 5 patients were excluded from the survival analysis because they did not receive study drug (1) or for violation of the study (4), randomized to no EPO but received EPO. The median age of patients was 41 years (range: 15–84), the majority had ALL (82 pts, 79%). Median baseline Hgb was 8.8 g/dl (range 6–12.6). There was no difference in the complete remission rate or survival between the 2 groups (Table 1). Seventy-six patients (38 in each arm) who remained in the study for at least 5 months were evaluable for number of transfusions during that period of time. Patients randomized to EPO received significantly less number of transfusions than patients that did not receive EPO [N=, 16 units (range 6–32) versus 19 units (range 11–40)], p = 0.026 (Mann-Whitney U test). Five patients (deep vein thrombosis = 3; pulmonary embolism =1; and CVA = 1) in the EPO group and 2 patients (deep vein thrombosis =2) in the NO EPO group developed possible related adverse events over 6 months of evaluation (p= 0.285)
EPO (N= 54) No EPO (N= 50) P value Complete remission, n (%) 51 (94) 48 (96) 0.873 Survival at 1 year (%) 80 81 NS Survival at 2 years (%) 75 70 Survival at 3 years (%) 72 70
Conclusions: The use of EPO appears not to have a negative impact on remission rate or survival in patients with ALL, LL or BL receiving HyperCVAD treatment, while EPO significantly decreased the number of transfusions required. There was no significant increase in the risk of thrombotic events associated with EPO.
Phosphoinositide 3-Kinase p110δ Is Dispensable for HoxA9/Meis1 and MLL-AF9 Mediated Leukemogenesis.
Authors: Gibbs Kenneth , Nolan Garry P. 
Published: October 2019

Abstract
The Phosphoinositide 3-kinase(PI3K)/PTEN pathway has been implicated in the pathogenesis of a number of hematopoietic malignancies and solid tumors. The only PI3K subunit invariably expressed in AML blasts is the catalytic p110δ. Recent reports have demonstrated that impairment of p110δ activity prevents growth of AML blasts in culture and increases their sensitivity to apoptosis inducing agents. However, a definitive requirement for p110δ in AML pathogenesis remains undefined. To identify the requirement of p110δ in AML initiation, the transforming potential of two retroviral models of AML (HoxA9/Meis1 and MLL-AF9) was compared in hematopoietic progenitors from wildtype (WT) and p110δD910A/D910A mice (homozygous knock-in for a catalytically inactive form of p110δ). Mice transplanted with p110δD910A/D910A progenitors expressing either HoxA9/Meis1 or MLL-AF9 oncogenes developed a phenotypically similar AML at rates comparable to those transplanted with transformed WT progenitors. Moreover, tumors derived from p110δD910A/D910A progenitors were transplantable to secondary recipients. These results indicate that the catalytic activity of p110δ is not required for HoxA9/Meis1 or MLL-AF9 driven leukemogenesis, suggesting that there are compensatory mechanisms that require further investigation.