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Despite the rapidly emerging evidence on the contributions of physical activity to improving cancer-related health outcomes, adherence to physical activity among young adults with lymphoma remains suboptimal. Guided by self-determination theory (SDT), the Lymfit intervention (a 12-week individualized exercise program with bi-weekly kinesiologist support and an activity tracker) aimed to foster autonomous motivation toward physical activity. This pilot randomized controlled trial aimed to evaluate the feasibility, acceptability, and preliminary effects of Lymfit. Young adults (N = 26; mean age of 32.1 years) with lymphoma who were newly diagnosed and those up to six months after completing treatment were recruited and randomly assigned one-to-one to either the intervention group (n = 13) or a wait-list control group (n = 13). All a priori feasibility benchmarks were met, confirming the feasibility of the study in terms of recruitment uptake, retention, questionnaire completion, intervention fidelity, missing data, Fitbit wear adherence, and control group design. The intervention acceptability assessment showed high ratings, with eight out of ten items receiving >80% high ratings. At post-intervention, an analysis of covariance models showed a clinically significant increase in self-reported physical activity levels, psychological need satisfaction, and exercise motivation in the intervention group compared to controls. Lymfit also led to meaningful changes in six quality-of-life domains in the intervention group, including anxiety, depression, fatigue, sleep disturbance, social roles and activities, and pain interference. The findings support Lymfit as a promising means to meet psychological needs and increase the autonomous motivation for physical activity in this group. A fully powered efficacy trial is warranted to assess the validity of these findings. [ABSTRACT FROM AUTHOR]

In this retrospective cohort study of 174 consecutive, newly diagnosed cases of diffuse large B-cell lymphoma (DLBCL), clinical and pathological variables, treatment, response and survival were compared for patients aged 80 and over ( n = 40) to those under 80. Eastern Cooperative Oncology Group (ECOG) status and International Prognostic Index (IPI) were significantly worse among older patients. Standard treatment was given to only 32.5% of older versus 86.6% of younger patients, and 65% of the elderly did not receive standard therapy. At 12 months, overall and event-free survival were 51.3% (95% confidence interval [CI]: 35-66%) vs. 93% (CI: 88-97%) and 41.9% (CI: 25-58%) vs. 84.8% (CI: 77-90%), for older versus younger patients, respectively. Choice of therapy was significantly associated with survival in the elderly, and low albumin but not comorbidity score was associated with not receiving standard therapy. Patients with DLBCL aged 80 and over are distinct from all other age groups with regard to treatment tolerance. A minority can receive standard therapy, but for the majority, novel therapeutic options are needed. [ABSTRACT FROM AUTHOR]

Abnormalities of the MYC oncogene on chromosome 8 are characteristic of Burkitt lymphoma and other aggressive B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We recently described a colorimetric in situ hybridization (CISH) method for detecting extra copies of the MYC gene in DLBCL and the frequent occurrence of excess copies of discrete MYC signals in the context of diploidy or polyploidy of chromosome 8, which correlated with increased mRNA signals. We further observed enlarged MYC signals, which were counted as a single gene copy but, by their dimension and unusual shape, likely consisted of "clusters" of MYC genes. In this study, we sought to further characterize these clusters of MYC signals by determining whether the presence of these correlated with other genetic features, mRNA levels, protein, and overall survival. We found that MYC clusters correlated with an abnormal MYC locus and with increased mRNA. MYC mRNA correlated with protein levels, and both increased mRNA and protein correlated with poorer overall survival. MYC clusters were seen in both the germinal center and activated B-cell subtypes of DLBCL. Clusters of MYC signals may be an underappreciated, but clinically important, feature of aggressive B-cell lymphomas with potential prognostic and therapeutic relevance. [ABSTRACT FROM AUTHOR]

Despite advances in the understanding of diffuse large B-cell lymphoma (DLBCL) biology, only the clinically based International Prognostic Index (IPI) is used routinely for risk stratification at diagnosis. To find novel prognostic markers, we analyzed flow cytometric data from 229 diagnostic DLBCL samples using an automated multiparameter data analysis approach developed in our laboratory. By using the developed automated data analysis pipeline, we identified 71 of 229 cases as having more than 35% B cells with a high side scatter (SSC) profile, a parameter reflecting internal cellular complexity. This high SSC B-cell feature was associated with inferior overall and progression-free survival (P = .001 and P = .01, respectively) and remained a significant predictor of overall survival in multivariate Cox regression analysis (IPI, P = .001; high SSC, P = .004; rituximab, P = .53). This study suggests that high SSC among B cells may serve as a useful biomarker to identify patients with DLBCL at high risk for relapse. This is of particular interest because this biomarker is readily available in most clinical laboratories without significant alteration to existing routine diagnostic strategies or incurring additional costs. [ABSTRACT FROM AUTHOR]

Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features. In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq). Here we show a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator CIITA (MHC2TA) in KM-H2 cells. In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%). Furthermore, we find that CIITA is a promiscuous partner of various in-frame gene fusions, and we report that CIITA gene alterations impact survival in primary mediastinal B-cell lymphoma (PMBCL). As functional consequences of CIITA gene fusions, we identify downregulation of surface HLA class II expression and overexpression of ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and CD273/PDL2). These receptor-ligand interactions have been shown to impact anti-tumour immune responses in several cancers, whereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity. Thus, our findings suggest that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying tumour-microenvironment interactions across a spectrum of lymphoid cancers. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-κB pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified. Here we report recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro. [ABSTRACT FROM AUTHOR]

Effective treatment of diffuse large B-cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in a DLBCL cohort treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA sequencing data revealed novel deletions in RCOR1 to be associated with unfavorable progression-free survival (P = .001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (P = .023). The prognostic significance of the 233-gene signature for overall survival was reproduced in an independent cohort comprising 195 R-CHOP-treated patients (P = .039). Additionally, we discovered that within the International Prognostic Index low-risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. We present a novel and reproducible molecular subgroup of DLBCL that impacts risk-stratification of R-CHOP-treated DLBCL patients and reveals a possible new avenue for therapeutic intervention strategies. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive form of non-Hodgkin lymphoma with variable biology and clinical behavior. The current classification does not fully explain the biological and clinical heterogeneity of DLBCLs. In this study, we carried out genomewide DNA methylation profiling of 140 DLBCL samples and 10 normal germinal center B cells using the Hpall tiny fragment enrichment by ligation-mediated polymerase chain reaction assay and hybridization to a custom Roche NimbleGen promoter array. We defined methylation disruption as a main epigenetic event in DLBCLs and designed a method for measuring the methylation variability of individual cases. We then used a novel approach for unsupervised hierarchical clustering based on the extent of DNA methylation variability. This approach identified 6 clusters (A-F). The extent of methylation variability was associated with survival outcomes, with significant differences in overall and progression-free survival. The novel clusters are characterized by disruption of specific biological pathways such as cytokine-mediated signaling, ephrin signaling, and pathways associated with apoptosis and cell-cycle regulation. In a subset of patients, we profiled gene expression and genomic variation to investigate their interplay with methylation changes. This study is the first to identify novel epigenetic clusters of DLBCLs and their aberrantly methylated genes, molecular associations, and survival. [ABSTRACT FROM AUTHOR]