bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isolated Brain Parenchyma Relapse of Non-Hodgkin’s Lymphoma (NHL): A Descriptive Analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG).
Authors: Doolittle Nancy D. , Abrey Lauren , Shenkier Tamara , Siegal Tali , Bromberg Jacoline , Neuwelt Edward , Soussain Carole , Johnston Patrick , Illerhaus Gerald , Schiff David , Batchelor Tracy , Montoto Silvia , Zucca Emanuele , Kraemer Dale 
Published: October 2019

Abstract
Background: Isolated brain parenchyma relapse as initial site of relapse is a rare complication of NHL and carries a poor prognosis. Few large series focus on treatment characteristics and outcomes of isolated brain parenchyma relapse of NHL.
Methods: The IPCG conducted a retrospective review of patient and treatment characteristics and outcomes of this complication. Following initial diagnosis and treatment of NHL (1980–2004), cases with brain parenchyma relapse as initial relapse site, with no evidence of lymphoma elsewhere in the body at the time of brain relapse, were eligible. Cases with brain, spine or leptomeningeal involvement at NHL diagnosis were not eligible.
Results: 113 cases were assembled from 13 investigators in 8 countries. Preliminary data summaries are: 94 (83%) cases had diffuse large B-cell NHL, 5 (4%) follicular lymphoma, 3 (3%) Burkitt’s lymphoma, other NHL subtypes (11) . Median age at NHL diagnosis was 61yrs (16–85 yrs). 55% were male. Median ECOG at NHL diagnosis was 1. Median time from NHL diagnosis to isolated brain relapse was 1.8 yrs (3 months–15.9 yrs). 76 (67%) relapsed in brain less than 3 yrs after NHL diagnosis. Symptoms at brain relapse included mental status changes in 37%, gait/balance disturbance (27%), motor/sensory symptoms (23%). Median ECOG at brain relapse was 2. Parenchyma relapse was documented by brain imaging plus biopsy in 54 (48%), or imaging without biopsy in 58 (52%); not reported (1). 53 (48%) cases had one brain lesion; 56 (50%) had two or more lesions; not reported (4). Site of relapse was cerebral hemispheres in 53 (48%) cases, deep brain structures (brain stem/cerebellum) in 30 (27%), cerebral hemispheres and deep brain structures in 23 (21%); not reported (7). At brain relapse, CSF was positive in 11 (10%) cases, negative in 56 (50%); not reported (46[40%]). Treatment for brain relapse was chemotherapy alone in 52 (46%) cases, WBRT alone in 34 (30%), chemotherapy followed by RT in 26 (23%), and brain surgery alone (1). 78 (69%) cases are deceased. Median survival from brain parenchyma relapse to death was 1.6 yrs (95% CI: 11 months–2.6 yrs). Effect of treatment type at brain relapse on survival, will be reported. Brain lymphoma was the cause of death in 49 (63%) cases; CNS toxicity was the cause in 6 (8%) cases.
Conclusion: Though a rare relapse site, prospective studies are needed to improve understanding and outcomes of isolated brain parenchyma relapse of NHL.
Activation of the Endoplasmic Reticulum (ER) Unfolded Protein Response (UPR) in Aggressive B-Cell Lymphomas.
Authors: Balague Olga , Colomo Luis , Lopez-Guillermo Armando , Campo Elias , Martinez Antonio 
Published: October 2019

Abstract
BACKGROUND The UPR is a prosurvival pathway activated in cells under ER stress induced by the accumulation of unfolded proteins. UPR activation in B cells normally occurs during the differentiation to antibody secreting plasma cells and requires XBP1activation. XBP-1 is a member of the TREB family of transcription factors that exists in the endoplasmic reticulum (ER) as a 33kDa protein, and in the nucleus as an active 50kDa transcription factor. The UPR stimulates two different ER proteins, ATF-6 and Ire-1, to increase XBP-1 transcription and XBP-1 mRNA splicing resulting in the accumulation of the active 50kDa nuclear protein. Moreover XBP1 is a target of proteosome inhibitors and is related to the aggressive behaviour of some carcinomas. The role of the activation of XBP-1 in lymphomas is still unknown.
DESIGN: Reactive lymphoid tissues and 25 neoplastic human B-cell lines representing different stages of B-cell development were studied for XBP-1 expression by western blot and XBP-1, PAX-5, Blimp-1/prdm1, MUM-1/IRF-4 and ICSBP1/IRF-8 by immunohistochemistry. XBP-1 activation was assessed in 225 B-cell lymphomas from the archives of the laboratory of pathology by western blot, RT-PCR and immunohistochemistry . To further evaluate whether XBP-1 activation was related to the plasmacytic program or to ER stress signals we analyzed the cell lines by Western blot for XBP-1 and ATF-6 expression.
RESULTS We characterize XBP-1 expression in reactive lymphoid tissues, 25 human cell lines and 225 B-cell tumors. In nearly all tonsillar lymphoid cells XBP-1 was detected as a cytoplasmic protein with a paranuclear dot pattern. Nuclear positivity was observed only in scattered centrocytes in the light zone of the germinal centers and in plasma cells, always coexpressed with plasma cell related transcription factors as MUM-1/IRF-4 and Blimp1/prdm1. Active p50XBP-1 was found in 24/25 cell lines by western blot regardless ATF-6 expression and confirmed by immunohistochemistry . Moreover p50XBP1 was found in 27/31(87%) plasmacytomas, 36/64(56%) DLBCL-ABC and in 3/10(30%) DLBCL-GCB and 22/43(51%) plasmablastic lymphomas. Intriguingly, p50XBP1 was detected also in 2/11(18%)BL and 4/25(16%)MCL with blastic features.
CONCLUSIONS.XBP-1 is activated in a subset of follicular centre cells committed to plasma cell differentiation and in plasma cells.UPR prosurvival pathways in the neoplastic cell lines are activated independently of the extent of the ATF-6 activation.p50XBP1 is mostly activated in aggressive B-cell lymphomas regardless to the plasmacytic differentiation of the tumours.
Thus, p50XBP-1 may be a new molecular target in the treatment of aggressive B-cell malignancies.
Cell Adhesion Induces p27Kip1-Associated Cell-Cycle Arrest through Down-Regulating SCFSkp2 Ubiquitin Ligase Pathway in Mantle Cell and Other Non-Hodgkin’s B-Cell Lymphomas.
Authors: Lwin Tint , Hazlehurst Lori A. , Moscinski Lynn C. , Dalton William S. , Tao Jianguo 
Published: October 2019

Abstract
Mounting evidence now suggests that dynamic interactions between the tumor cell and its local and systemic microenvironment play a critical role in tumor development and that all of the clinical properties of a tumor, including cell cycle progression and response to therapy, depend heavily on the tumor stroma. However, the molecular mechanisms of the interaction between stroma and tumor cells are not well defined. In this study we used mantle cell lymphoma (MCL) as a model to characterize the mechanisms by which stroma regulate cell-cycle progression. We demonstrated that adhesion of MCL and other non-Hodgkin lymphoma (NHL) cells to bone marrow stroma cell (HS-5) resulted in a reversible G1 arrest associated with elevated p27Kip1 protein level. The adhesion mediated p27Kip1 increase was posttranslational and regulated through down-regulating Skp2, a substrate-recognition subunit of SCFSkp2 ubiquitin ligase. Overexpression of wild-type Skp2 in MCL decreases p27Kip1, whereas inhibition of Skp2 expression by siRNA increases p27Kip1 level. Furthermore, we found that cell adhesion up-regulated Cdh1, an activating subunit of anaphase-promoting complex (APC) ubiquitin ligase, and reducing Cdh1 by siRNA induced Skp2 accumulation and hence p27Kip1 degradation, implicating Cdh1 as an upstream effector of Skp2/p27Kip1 signaling pathway. Overall, this is a first report demonstrating that the bone marrow stroma controls tumor cell cycle via ubiquitin-proteasome proteolytic pathways in MCL and other NHL. The understanding of this novel molecular pathway may prove valuable in designing new therapeutic approaches modifying tumor cell growth and response to therapy.
Clinicopathologic Subtypes of Mantle Cell Lymphoma (MCL) Show Distinct Patterns of Genetic Copy Number Alteration.
Authors: deLeeuw Ronald J. , Malloff Chad A. , Kimm Lindsey R. , Connors Joseph M. , Dyer Martin J.S. , Gascoyne Randy D. , Lam Wan L. 
Published: October 2019

Abstract
Introduction: MCL is an aggressive NHL characterized by a t(11;14)(q13;q32). However this translocation alone cannot initiate lymphomagenesis and multiple secondary genomic alterations are necessary to induce the neoplastic phenotype. In addition, three distinct clinicopathologic subtypes of MCL (classic, blastoid, and leukemic) have been identified with differing prognosis. Secondary genomic alterations associated with each subtype have been poorly defined. Experimental
Design: Genomic profiles from a panel of MCL samples comprised of 20 classic, 5 leukemic (no nodal involvement), and 12 blastoid cases, were created using a tiling-resolution BAC array CGH platform. Alignment of profiles to identify regions of recurrent alteration was accomplished using a custom developed software package (SeeGH). In addition, specific genes were analyzed for copy number status. Statistically significant distributions were determined using Chi square and Fisher’s exact analyses.
Results: Twenty two regions of recurrent alteration were identified that were statistically different between subtypes (partial data in Table 1). As expected chromosome 9 losses were more prevalent in blastoid MCL. 13q34 losses were prevalent within classic and blastoid MCL, as opposed to leukemic MCL, which showed gains of this region. Analysis of biological pathways revealed that apoptotic signaling is not disrupted via copy number in a large portion of MCL cases (21%), while chromosomal instability genes show copy number disruption in 67% of MCL cases. Surprisingly, the glioblastoma pathway was preferentially disrupted in blastoid MCL (p=1.09x10−5), affecting all cases; whereas the p53 pathway was disrupted via copy number more often in leukemic MCL (p=0.0207).
Conclusions: Multiple genomic regions and cancer related genes show a differential pattern of altered copy number distribution between MCL subtypes. These regions and genes likely contribute to the different clinicopathologic subtypes of MCL cases.
Differential regions in MCL subtypes +/− chr. band size (Mb) clas% leuk% blast% enriched in deficient in − 1q25.2-q31.2 15.50 0 20 33 blast (p=0.03) class (p=0.01) − 2q26.3 2.91 5 0 33 blast (p=0.03) + 3cent-p12.1 4.18 0 60 25 leuk (p=0.02) class (p=0.005) + 7q11.23 3.24 0 0 33 blast (p=0.008) class (p=0.04) − 9p21.3 1.02 10 20 83 blast (p=0.00001) class (p=0.002) − 9q21.13 1.10 5 40 75 blast (p=0.0003) class (p=0.0002) − 9q21.2-q31.1 22.87 5 40 67 blast (p=0.001) class (p=0.0007) − 9q31.1 0.83 0 40 67 blast (p=0.0004) class (p=0.00006) − 9q34.12-qter 7.27 0 20 42 blast (p=0.009) class (p=0.005) + 10p12.2-p12.31 0.63 5 0 42 blast (p=0.009) − 13q34 1.69 40 0 75 blast (p=0.03) leuk (p=0.05) − 17p13.3-pter 2.28 5 60 25 leuk (p=0.04) − 17p13.1 1.21 5 60 25 leuk (p=0.04)
Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma (ALCL): Results of the European Intergroup Study.
Authors: Le Deley Marie Cécile , Brugières Laurence , Williams Denise , Reiter Alfred 
Published: October 2019

Abstract
Purpose and methods
In order to study prognostic factors of disease progression and relapse, the data of 235 children enrolled for an ALCL between 1987 and 1997 in the BFM (93 patients, pts), SFOP (82 pts) and UKCCSG (60 pts) studies have been merged in 1998. All these children have been treated according to protocols designed to treat childhood ALCL with a short and intensive chemotherapy treatment, similar to those used for B-cell. Slides had been reviewed by the national pathologist panel for 226 patients (96%). Hodgkin-like ALCL were excluded from this series. Follow-up has been updated in April 2006.
Results
Among the 235 pts included in the study, 206 pts (88%) achieved a CR. With a median follow-up of 7.4 years, 77 events were observed (13 early progressions, 55 relapses, 3 secondary leukaemias, 6 toxic deaths) and 46 patients died. The 5-year overall survival and event-free survival of the whole population is 81% [95%CI, 76–86%] and 69% [63–75%] respectively. Event-free survival differs significantly according to the treatment (p=.01) : the risks of failure of children treated in the SFOP studies and in the UKCCSG studies are multiplied by 1.8 [1.05–3.2] and 2.3 [1.3–4.1] respectively, as compared to pts treated in the BFM studies.
Several factors seem to be prognostic of the risk of early progression or relapse in univariate analysis: B-symptoms, mediastinal involvement, skin lesions, visceral involvement, St Jude stage 3–4 or Ann Arbor stage 3–4 or elevated LDH. Patients with bone lesions seem to have a better prognosis than others. Soft tissue masses do not worsen the prognosis.
In multivariate analysis, three factors are found to be associated to the risk of progression/relapse :
* mediastinal involvement (hazard ratio of progression/relapse, HR=2.2 [1.3–3.6], p=.003), * visceral involvement defined as lung, liver or spleen involvement (HR=2.1 [1.3–3.5], p=.005), * skin lesions (HR = 1.9 [1.2–3.2], p=.01).
Based on the results of this Cox model, it is possible to define:
* a good prognosis group (85 patients without skin, mediastinal or visceral involvement) with 89% pts [82–96%] free of progression/relapse at 5 year * a poor prognosis group (150 patients with skin and/or mediastinal and/or visceral involvement) with 61% pts [53–69%] free of progression/relapse at 5 year
This risk group classification appears significant in each of the three treatment groups.
Conclusion :
Results obtained with BFM-studies are significantly better than those obtained with the French and British pediatric studies. Pts with mediastinal involvement, visceral involvement and/or skin lesions are at a higher risk of disease failure. These results was the basis of ALCL99 aiming to improve EFS of high risk pts by adding vinblastine to BFM protocol.
Array CGH Analysis for PTCL-U Revealed Two Genetically Distinct Subgroups.
Authors: Nakagawa Masao , Oshiro Aya , Tagawa Hiroyuki , Karnan Sivasundaram , Tsuzuki Shinobu , Ohshima Koichi , Nakamura Shigeo , Seto Masao 
Published: October 2019

Abstract
Peripheral T-cell lymphoma, unspecified (PTCL-U) is the most common group among Peripheral T-cell lymphomas (PTCLs). This category consists of the cases which do not belong to any of the recognizable subtypes of PTCLs in WHO classification. PTCL-U comprises heterogeneous groups in morphology and phenotype. Molecular basis of clinical heterogeneity is needed to identify distinct subgroups with clnical relevance. Several reports of conventional cytogenetic studies including comparative genomic hybridization (CGH) showed some recurrent aberrations, but failed to identify the genetic hallmarks to categorize distinct subgroups. So far, no array-based comparative genomic hybridization (array CGH) study for PTCL-U has been reported. Here we analyzed 29 cases of PTCL-U by means of array CGH consisting of 2265 artificial chromosome clones that cover the whole genome at a 1.3 mega base resolution. The analysis clearly divided these cases into two distinct subgroups on the basis of frequency of genomic alterations. One group consists of 17 cases which showed significant lower copy number changes (average copy number gains: 0.5 regions, average copy number losses: 0.1 regions). The other group had average copy number gains of 15.7 regions and losses of 15.0 regions in 12 cases. We designate the former as “simple type” and the latter as “complex type”. In the complex type, regions of recurrent (>20%) gain are detected on chromosome 1q23.3-24.2, 3q25.31-tel, 4p15.1-16.1, 4q28.3-31.23, 5q34, 6p24.1-25.1, 7p21.3-tel, 7p21.1, 7q, 8q24.23, 11q13.4-tel, 12p11.21-11.22, 16p12.3-13.3, 17q11.2-22. Regions of recurrent (>20%) losses are detected on chromosome 1p13.1-13.3, 2q37.3, 4q21.21-21.23, 4q34.3-35.1, 5q21.2-23.1, 6p12.1-q14.3, 6q23.2-24.1, 6q25.1-26, 7p14.3-22.1, 9p21.3, 10p14-qtel, 12p13.1-13.2, 13, 14q12, 16q, 17p, 18p, 20q13-2, 22q11.21-12.2. Median age is 62 years in the simple type and 73 years in the complex type, respectively. Median survival is 27 months in the simple type and 11 months in the complex type. Log-rank test for overall survival between the simple type and the complex type showed inferior survival for the complex type but significance was marginal (p=0.21). Our findings showed that PTCL-U comprised two genetically distinct subgroups, implying that distinct mechanisms underlay in molecular pathogenesis of PTCL-U. Furthermore cilinicopathological features of each group are also being studied.
Outcome-Related Genome Loci in T-Cell Non-Hodgkin’s Lymphoma Identified by High-Resolution SNP-Typing Arrays.
Authors: Fujiwara Shin-ichiro , Yamashita Yoshihiro , Nakamura Naoya , Abe Masafumi , Ozawa Keiya , Mano Hiroyuki 
Published: October 2019

Abstract
Peripheral T-cell lymphoma, unspecified (PTCL) and angioimmunoblastic T-cell lymphoma (AITL) are non-Hodgkin’s lymphoma of T-cell origin. Despite their relatively poor outcome, little is yet understood for the molecular pathogenesis of these disorders. To screen for transforming/tumor-suppressor genes among PTCL/AITL, we here tried to examine copy number alterations (CNAs) among HTLV-I-negative lymph node specimens of PTCL (n = 32) and AITL (n = 42). Utilization of high-density SNP-typing arrays (GeneChip Mapping 100K Hind III, Affymetrix) has allowed us to measure CNA at a mean resolution of 47 kbp among the samples. Interestingly, both of PTCL and AITL cells have frequent CNAs throughout the genome. Among the 55,700 SNP sites examined for PTCL, for instance, chromosome copy number at 20,860 sites was shown to be ≥ 3 in at least 2 specimens, while loss of copy number (≤ 1) was found at 2,287 sites in ≥ 2 samples. Similarly, among the AITL specimens, copy number gain (≥ 3) in ≥ 2 samples was observed at 9,897 SNP sites, and copy number loss in ≥ 2 samples was identified at 43 sites. We further searched for frequent CNAs among the whole dataset, revealing that copy number gain of ≥ 4 was observed in ≥ 10 cases at 1q, 2p, 2q, 8q, 9p, 13q, 15q, and 19q. On the other hand, copy number of ≤ 1 was found among ≥ 10 cases at 14q. Further, the copy number of a genomic region was shown to be linked to a differential diagnosis of PTCL/AITL. From the same dataset, we could also reveal a vast number of loss-of-heterozygosity (LOH) regions with a divergent length. Frequent LOH (≥ 5 cases) was mapped to 2q, 5q, 8p and 9p. By using a Cox proportional hazard analysis, we then investigated whether chromosome copy number or LOH likelihood is statistically linked to prognosis of the patients enrolled in this study. Interestingly, the copy number of narrow regions at 2q, 5p, 5q and 17q was shown to be statistically associated with the clinical outcome (P <0.01) while the LOH-likelihood at 8q was linked to it (P <0.05). The chromosomal regions identified in our screening are the good candidates where transforming- or/and clinical character-related genes are mapped. Especially, the narrow regions thus identified contain a few genes per region, and provide us with a provocative list of PTCL/AITL-related genes.
Genomic Profiling of Chronic Lymphocytic Leukemia Identifies Novel Genetic Subtypes.
Authors: Malek Sami N. , Kujawski Lisa A. , Erba Harry P. , Kaminski Mark S. , Jakubowiak Andrzej , Dressel Amanda , Saddler Chris M. , Shedden Kerby A. , Ouillette Peter D. 
Published: October 2019

Abstract
CLL is the most common leukemia in the Western world and displays considerable clinical heterogeneity. Genetic approaches to elucidate defects in CLL genomes have resulted in the identification of recurrent chromosomal abnormalities with prognostic importance. A genome-wide high-density unbiased view of chromosomal copy number changes or loss of heterozygosity (LOH) may allow for further refinements of genomics-based risk prognostication. We have conducted a genomic profiling study using 50KSNP-oligonucleotide arrays (Affymetrix) on FACS-sorted CD19+ cells and paired buccal DNA from 120 patients with typical CLL (CD5+/CD23+) at various stages of presentation enrolled in a clinical translational protocol. We have found novel genetic subtypes, including novel regions of recurrent LOH and chromosomal copy loss on chromosomes 3p, 14q and 18p at frequencies of 3–6%. Fine mapping of the clinically important regions del(6q), del(11q), del(13q14) and del(17p) suggests molecular heterogeneity of these lesions. Anatomic criteria suggest existence of multiple distinct subtypes of del13q14. Furthermore, the clinically important del(17p) is associated with almost uniform deletion of most of 17p, occasionally displays copy-neutral LOH (undetectable by FISH) with p53 mutations and occurs without p53 mutations in a subset of patients as previously reported. Finally, using a genome-wide composite genomic instability score of copy gains and losses we found a subset of CLL cases (18%) with high genomic instability values (greater than 2 lesions per genome). These findings may have implications for CLL risk-adapted therapies.
Flavopiridol Decreases Mcl-1 and Initiates Early Mitochondrial Damage in Chronic Lymphocytic Leukemia (CLL) Cells.
Authors: Lucas David M. , Hussain Syed-Rehan A. , Johnson Amy J. , Smith Lisa L. , Wagner Amy J. , Allison Jamie M. , Guster Sara E. , Lin Thomas S. , Byrd John C. , Julian Mark W. , Crouser Elliott D. , Grever Michael R. 
Published: October 2019

Abstract
We have noted impressive activity of the cyclin-dependent kinase inhibitor flavopiridol in advanced-stage CLL patients, including those with a deletion of chromosome 17p13. Using a novel, effective schedule of flavopiridol, substantial and sometimes dramatic evidence of tumor cell death is observed as early as 4–6 hours. This is accompanied by hyperkalemia, hyperphosphatemia, hypocalcemia, and dramatic elevation in LDH consistent with acute tumor lysis syndrome. Studies by several groups including our own have demonstrated that Mcl-1 protein and mRNA is down-regulated with flavopiridol. Mcl-1 is an important protein that contributes to mitochondrial membrane stability. We have therefore sought to determine the role of mitochondria disruption in the mechanism of action of flavopiridol. By flow cytometry using the voltage-sensitive dye JC-1, loss of mitochondrial membrane potential was detected in flavopiridol-treated whole blood as early as five hours, prior to the onset of annexin-V or propidium iodide staining. This is in contrast to in vitro studies using human serum, in which mitochondrial depolarization and annexin-V staining occurred simultaneously. In isolated CLL cells treated with flavopiridol in vitro, loss of mitochondrial membrane potential was not affected by inhibitors of caspases 8 or 9 or by the broad caspase inhibitor Z-VAD-fmk, although apoptosis was effectively blocked by Z-VAD-fmk and caspase-8 inhibitor, and to a lesser extent, caspase-9 inhibitor. Flavopiridol was also able to effectively induce apoptosis and mitochondrial membrane depolarization in Jurkat cell lines deficient in caspase-8 or its adapter protein FADD. Additionally, lymphoid cells overexpressing Bcl-2 are resistant to flavopiridol-mediated apoptosis relative to the vector control. This suggests there is not direct binding of flavopiridol or its metabolites to APAF-1 (cytosolic adapter protein) and apoptosome assembly, as this process is insensitive to Bcl-2 family proteins. Further mechanistic studies were undertaken using isolated liver mitochondria. While the electron transport system was not uncoupled in this system, potential mechanisms of mitochondrial injury in leukemic cells from CLL patients are currently under exploration. Taken together, these observations suggest that mitochondrial perturbation contributes significantly to the death process induced by flavopiridol. Further studies to identify the mechanism of mitochondrial perturbation will be essential to understanding flavopiridol’s mechanism of action and for predicting patients at risk for acute tumor lysis syndrome. (Support for this work was provided by the Samuel Waxman Foundation and the Leukemia & Lymphoma Society.)