Common Subtype Of non-Hodgkin Lymphoma Research Articles

Germinal Center Kinase Regulates The Proliferation and Survival Of Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). The pathogenesis of DLBCL represents a multi-step process that involves the accumulation of multiple genetic and molecular lesions. Marked advances in the understanding of DLBCL pathobiology have been made by the application of gene expression arrays, comparative genomic hybridization arrays and “next” generation sequencing. This led to the identification of previously unrecognized DLBCL subtypes (germinal center-like (GCB) and activated B cell-like (ABC)) as well as type specific-deregulation of particular signaling pathways. These approaches focused on genetic aberrations and mRNA expression profiles, whereas the crucial events transforming normal cells are executed by proteins. Kinases play an important role in neoplastic transformation. Herein, we have undertaken the task of profiling kinase activity in DLBCL to further delineate potential mechanisms of DLBCL pathogenesis and develop novel therapeutic agents.A comprehensive analysis of global kinase activity/protein expression was performed using KiNativ technology. Kinomic analysis of 8 DLBCL cell lines, as compared to non-cancerous primary B-cells, led to the discovery of 13 members of the MAPK cascade which were activated and/or overexpressed in DLBCL. Only three of the detected MAPK members were inactive or had reduced expression compared to their non-cancerous counterparts. To determine whether these findings could be extended to de novo primary human DLBCL tumors, we performed immunohistochemistry (IHC) of the proximally activated kinase, MAP4K2 or “Germinal Center Kinase” (GCK) and the phosphorylated forms of its downstream targets: MAP3K1, MAP2K4, MAP2K7, and C-jun N-terminal Kinase 1 (JNK1). Analyzed kinases were expressed and activated in more than 80% of primary DLBCL tumors, confirming the KiNativ cell line data. The kinase array data was further corroborated with classical immunoprecipitation-based JNK and p38 assays. Hierarchical clustering analysis of 36 DLBCL specimens stained for GCB and ABC markers demonstrated that GCK expression/activation is not DLBCL subtype specific. Notably, in a cohort of 151 primary DLBCL cases, we found that patients whose tumors did not express GCK had an estimated progression free survival (PFS) of 85% at 10 years of follow up, whereas those tumors expressing GCK were associated with significantly reduced PFS of 53% (p=0.04). While there was a similar trend in overall survival, it did not reach statistical significance, which may be due to the relatively small number of DLBCL cases not expressing GCK and the potential rescue of these patients with second line treatments.RNA interference studies in DLBCL cell lines confirmed the importance of GCK for the survival of these tumors, resulting in reduced viability and G0/G1 arrest. We next developed a small molecule inhibitor, HG6-64-1. KiNativ, Ambit and Invitrogen profiling of HG6-64-1 targets revealed that it potently inhibited GCK. In vitro treatment with the novel GCK inhibitor, HG6-64-1, led to cell cycle arrest and the induction of apoptosis in DLBCL cell lines and primary DLBCL tumors. G452, a DLBCL cell line minimally expressing GCK, was not affected by HG6-64-1. In vivo treatment with HG6-64-1, via intratumoral and intraperitoneal injections, significantly decreased the tumor growth rate resulting in a significantly extended lifespan of DLBCL xenograft mouse models. Overall our results identified a previously unrecognized activation of the GCK pathway which contributes to the proliferation and survival of DLBCLs and can be used as a therapeutic target using novel GCK inhibitors. Disclosures:Patricelli:ActivX Biosciences: Employment. Nomanbhoy:ActivX Biosciences: Employment.

Primary Bone Marrow DLBCL, Unraveling The Unique Biology Of This Very Rare Presentation

IntroductionDiffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) accounting for approximately 25 percent of NHL cases. It is increasingly appreciated that the diagnostic category of DLBCL is quite heterogeneous in terms of morphology, genetics, and biologic behavior. Patients with DLBCL typically present with a rapidly enlarging lymph node. Extra nodal disease can also occur anywhere in the body and usually denotes an advanced stage.Approximately 60 percent of patients will present with advanced stage DLBCL (stage III or IV disease). The bone marrow (BM) involvement, as a part of systemic multifocal disease, at presentation is 8-10%, but can be up to 30% during the course of the disease, especially if discordant histologic subtypes, such as follicular lymphoma, are included. BM involvement is a negative prognostic factor of DLBCL despite modern therapy. Primary bone marrow lymphoma (PBML) is a very rare entity in which clinicobiological significance is not well defined, but perceived to represent a particularly poor-risk subclass. Herein, we present a case of primary bone marrow DLBCL and try to explore the unique presentation based on DLBCL-bone marrow microenvironment interactions. Cadherins, for example, are transmembrane proteins that play important roles in cell adhesion and are recently recognized as a component of myeloma and leukemia-bone marrow microenvironment interactions. We hypothesized that DLBCL cells would express N-cadherin. In this study, we evaluated E -cadherin and N-cadherin expression in BM samples from this patient. Case descriptionA 77-year-old presented with progressive fatigue, and rapidly developed pancytopenia with transfusion dependence over 3 months. He had no bone pain or B symptoms at presentation. Clinical examination revealed pallor, but no lymph node enlargement or abdominal organomegaly. His hemoglobin was 5.7 g/dL, Platelets 29 X103/µL, and absolute neutrophil count 800/ µL. LDH was elevated at 444 UL. A BM aspirate was a dry tap, BM biopsy showed hyper cellular marrow (90-100%), and greater than 90% involvement by malignant lymphocytes that were positive for CD20, CD79a, Pax5, CD45, NSE, Mum1, and vimentin. Only 5% Mib1 proliferation index was appreciated on the biopsy specimen, probably due to decalcification effect. There was moderately increased reticulin fibrosis. The morphologic and immunophenotypic features were consistent with DLBCL. Cytogenetic studies showed a complex near-triploid abnormal clone. FISH analysis showed no evidence of MYC rearrangement, t(14;18), or t(11;14).PET-CT scan showed marked increase in metabolic activity diffusely involving the axial skeleton but no metabolically active lymphadenopathy or extramedullary disease, no destructive or lytic lesions were found [Fig.1]. [Display omitted] Immunohistochemistry stains showed strong N-cadherin staining the malignant cells [Fig.2]. E-cadherin staining was negative. [Display omitted] The patient was treated with 6 cycles of R-CHOP. Doxorubicin dose was reduced due to advanced age. His post-treatment BM biopsy and PET scan were consistent with complete response. BM fibrosis significantly decreased [Fig. 3]. His cytopenias completely corrected early during therapy. [Display omitted] DiscussionCriteria to diagnose PBML encompass isolated bone marrow infiltration, with no evidence of nodal or extranodal involvement, including the bone, and the exclusion of leukemia/lymphomas that are considered to primarily involve the bone marrow. In a retrospectively reviewed by the International Extranodal Lymphoma Study Group from 12 institutions in 7 different countries over a 25-year period, there were only 15 cases of DLBCL that met these criteria. The biology behind the exclusive confinement to the BM compartment remains elusive.On further analysis of this case, E-cadherin was negative. Expression of the adhesion molecule marker N-cadherin on lymphoma cells might help explain the confinement to the BM microenvironment in our case. Future studies should focus on exploring the role of N-cadherin in this rare entity of DLBCL. Disclosures:No relevant conflicts of interest to declare.

Expression Of Histological markers and PET-CT Maximal Standardized Uptake for Follicular Lymphoma

BackgroundFollicular lymphoma is the second most common non-Hodgkin lymphoma subtype. PET-CT is a useful tool to evaluate staging and monitoring of follicular lymphoma. Calculation of maximal standardized uptake value (SUV max) is variable and related to the aggressiveness of lymphoma. In tumor cells, there is an increase in uptake and consumption of glucose. Therefore GLUT-1, a membranous glucose transporter, may have an impact on the SUV max. To our knowledge, data regarding eventual correlation between GLUT-1 and SUV in different subtypes of lymphoma is sparse (Hye Kyung Shim et al, Nuclear Medicine and Biology 2009; S. Hartmann et al, BMC Cancer 2012), especially in follicular lymphoma.In addition, Ki67, a marker of cell proliferation is also linked to the metabolism of tumors cells. Only few studies have shown a correlation between SUV max and Ki-67 in follicular lymphoma (Tomas Papjik et al, European Journal of Haematology 2010; Yi shou et al, Journal of Cancer Research and Therapeutics 2012). Elsewhere, it was demonstrated that microenvironment composed of dendritic cells, macrophages, T cells and vascular endothelium play a key role in the prognosis of follicular lymphoma (Pedro Farinha et al, Blood 2005), it could have also an impact on SUV max.The aim of our study was to identify histological markers involved in glucose metabolism, cell proliferation and microenvironment, influencing SUV max in follicular lymphoma. Materials and MethodsLymph node biopsies of 21 patients treated in our hematologic department at diagnosis and/ or relapse were retrospectively included. Patients underwent PET-CT and node biopsy simultaneously. Five histological markers (Ki67, GLUT 1, CD20 for B lymphocytes, CD3 for T lymphocytes, and CD68 for macrophages) were analyzed. Pathologists perform visually the immunostaining analysis without knowledge of the PET-CT results. Percentage of expression of immunological markers was compared with SUV max from the biopsy site. The correlation was analyzed using Spearman's method to calculate the coefficient of correlation r. ResultsKi-67 (median 40, range [3; 80]) and GLUT1 (median 53, range [0; 100]) were not related to the level of expression of the SUV max (respectively r = 0.3603 and p = 0.1086, r = 0.0215 and p = 0.9283). Concerning the microenvironment, CD68 (median 6, range [0; 18]) and CD3 (median 22, range [7; 60]) did not show any correlation (respectively r = 0.1370 and p = 0.5536, r = -0.2115 and p = 0.3708). Interestingly, percentage of CD20 expression (median 79, range [51; 99]) appears to be correlated significantly with the SUV max (r = 0.4924, p = 0.0274). Discussion and ConclusionIn this study, it was not possible to identify a specific histological marker influencing the SUV max. Otherwise, interest in glucose metabolism and particularly other isoforms of GLUT receptor or enzymes involved in the metabolism, like hexokinase, appears to be a promising track. Considering that CD20 stains B tumor cell and normal B lymphocyte in the tumor, it could be interesting to analyze the ratio of CD20/CD10, assuming that all tumor cells express CD10. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Racial disparity in diffuse large B-cell lymphoma survival.

6569 Background: Although blacks have a lower risk of non-Hodgkin lymphoma (NHL) compared to whites, black non-Hodgkin lymphoma (NHL) patients experience worse survival than white patients. This study aims to examine in patients with diffuse large B-cell lymphoma (DLBCL), the most common subtype of NHL, how much of the racial disparity in survival can be explained by differences in certain demographic (age, sex and area-level education) and access-to-care-related (stage, treatment, health insurance status) factors. Methods: Our cohort included 3716 non-Hispanic white or black DLBCL patients aged 18-64, diagnosed in 2004-2005 from the National Cancer Database (NCDB), a nationwide, hospital-based cancer registry. The analysis included only HIV/AIDS-negative patients. Kaplan-Meier survival curves were drawn for blacks and whites. Cox proportional hazards model was fitted to estimate hazard ratios (HR) and the 95% confidence intervals (CI) for race with and without controlling for demographic factors (age, sex and area-level education), stage, treatment and health insurance status. Results: Black patients had a worse survival than white patients (5-year survival rate 66.6% in blacks vs. 73.3% in whites, log-rank test p-value = 0.0006). Without adjusting for other factors, blacks had a 34% higher risk of death compared to whites (crude HR=1.34, 95% CI =1.13-1.58). After adjusting for demographic factors including age, sex and area-level education, the HR reduced to 1.27 (95% CI=1.06-1.51). After further adjustment for stage, treatment and insurance status, the association disappeared (HR=1.03, 95% CI= 0.86-1.23). Conclusions: Demographic factors and access-to-care-related factors including stage, treatment and health insurance status fully explained the black-white racial disparity in DLBCL survival in this cohort. Our findings suggest that improvements towards timely diagnosis, appropriate treatment and other adequate access to health care measures could potentially eliminate the survival disparity between black and white DLBCL patients.

Risk of non-Hodgkin lymphoma in relation to tricyclic antidepressant use

PurposeWe investigated the relationship between use of tricyclic antidepressants (TCAs) and risk of non-Hodgkin lymphoma (NHL). Previous studies provided some evidence of an association, but did not assess risk of NHL subtypes. MethodsCases and controls were members of Group Health, an integrated healthcare delivery system. Cases were persons diagnosed with NHL between 1980 and 2011 at age 25 years or older; eight control subjects were matched to each case on age, sex, and length of enrollment. Information on previous TCA use was ascertained from automated pharmacy data. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for NHL, overall and for common subtypes, for various patterns of TCA use. ResultsWe identified 2768 cases and 22,127 matched control subjects. We did not observe an appreciably increased risk of NHL among TCA ever-users compared to non-users (OR, 1.1; 95% CI, 1.0–1.2). Overall risk of NHL was associated to at most a small degree with longer-term use (OR, 1.2; 95% CI, 1.0–1.4; ≥10 prescriptions), high-dose use (OR, 1.1; 95% CI, 0.8–1.5; ≥50 mg), or non-recent use (OR, 1.0; 95% CI, 0.9 = 1.2; >5 years previously). TCA use was not associated with NHL subtypes, except chronic lymphocytic leukemia/small lymphocytic lymphoma (OR, 1.5; 95% CI, 1.1–2.0; longer-term use). ConclusionsWe found little evidence that the use of TCAs increases the risk of NHL overall or for specific common subtypes of NHL.

Activation of the PI3K/AKT/mTOR pathway in diffuse large B cell lymphoma: clinical significance and inhibitory effect of rituximab

Diffuse large B cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma and accounts for approximately 30% of newly diagnosed lymphoid neoplasms in Western countries, and 40-50% in China. A better understanding of the biology of DLBCL is needed for the development of potential therapeutic agents that target specific intracellular pathways. In this study, expression of the important components of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway and their clinical significance were investigated in 73 DLBCL cases. The effect of rituximab alone or combined with the PI3K/AKT/mTOR pathway inhibitor rapamycin was further evaluated in the DLBCL cell lines. A total of 73 patients were identified, including 45 men and 28 women aged 18 to 78 years (median age 50 years). Of these patients, p-AKT was positive in 40 cases (54.8%), p-p70S6K in 34 cases (46.6%), and p-4E-BP1 in 33 cases (45.2%). Activation of the PI3K/AKT/mTOR pathway was related to poor disease outcome in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) but not in those treated with rituximab-CHOP. Rituximab combined with rapamycin synergically downregulated the PI3K/AKT/mTOR signaling pathway. Western blot analysis revealed a baseline activation status of the PI3K/AKT/mTOR pathway in DLBCL cell lines, with high levels of p-AKT, p-mTOR, in addition to downstream molecules p-p70S6K and p-4E-BP1. The results indicate that the PI3K/AKT/mTOR pathway is a potentially important signaling route and an unfavorable prognostic factor for DLBCL. Patients with PI3K/AKT/mTOR activation experience a more rapidly deteriorating clinical course with poor treatment response and decreased survival time. Addition of rituximab could downregulate PI3K/AKT/mTOR activation, reversing its negative effect on chemotherapy-treated patients. In addition, our results indicate that the combination of rituximab and inhibition of the activated PI3K/AKT/mTOR pathway could be a promising target for DLBCL therapeutic intervention in the future.

Lymphoblastic Lymphoma in Childhood and Adolescence

Lymphoblastic lymphoma (LBL) are thought to derive from immature precursor T-cells or B-cells. LBL are the second most common subtype of Non-Hodgkin Lymphoma (NHL) in children and adolescents. LBL are closely related to acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Using ALL-type treatment regimen to treat children with LBL was an important development in the treatment of LBL. During the last decades, several systematic clinical trials contributed to the controlled optimization of treatment. Today event-free survival (EFS) can be achieved for 75–90% of patients. However, acute and long-term toxicity, the lack of prognostic parameters and the poor outcome for patients who suffer from refractory or relapsed LBL remain highly relevant subjects for improvement. To date, the pathogenesis of LBL is poorly understood. Learning more about the biology and pathogenesis of LBL might pave the way for targeted treatment to improve survival especially in relapsed and refractory patients.

Mapping of the IRF8 Gene Identifies a 3′UTR Variant Associated with Risk of Chronic Lymphocytic Leukemia but not Other Common Non-Hodgkin Lymphoma Subtypes

Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk. To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes. The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 3' untranslated region (UTR) of IRF8 (rs1044873, log additive OR = 0.7, P = 1.81 × 10(-6)). This SNP was not associated with the other NHL subtypes (all P > 0.05). We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology. These data provide support that a functional variant within the 3'UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.

CXCR5 Polymorphisms in Non-Hodgkin Lymphoma (NHL) Risk and Prognosis.

AbstractAbstract 2702 Background:CXCR5 [chemokine (C-X-C motif) receptor 5; also known as Burkitt lymphoma receptor 1 (BCR1)] is expressed on mature B-cells, subsets of CD4+ and CD8+ T-cells, and skin-derived migratory dendritic cells. CXCL13 is the ligand for CXCR5, and together they are involved in guiding B-cells into the B-cell zones of secondary lymphoid organs as well as T-cell migration. CXCR5 is also expressed in malignant cells in NHL patients. Single nucleotide polymorphisms (SNPs) in CXCR5 have not been extensively studied, although two studies reported that SNPs from this chromosome 11 gene were associated with risk of primary biliary cirrhosis in a European population and with risk of NHL in an Asian population. This study evaluated the role of common germline genetic variation in the risk and prognosis of the common NHL subtypes of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and peripheral T-cell lymphoma (PTCL). Methods:Ten SNPs in CXCR5 were genotyped using a clinic-based study of 2694 NHL cases (including 586 DLBCL, 588 FL, 137 MCL, 230 MZL, and 158 PTCL) and 1521 controls enrolled from 2002–2009 in the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma SPORE. Clinical data were abstracted for all NHL patients and all were prospectively followed for disease progression, retreatment, transformation and death. SNPs were selected from HapMap using a standard tagging approach (r2≥0.80 and minor allele frequency (MAF) ≥0.05) and included SNPs 5kb upstream and downstream from the gene. Genotyping was conducted using a custom Illumina iSelect panel. All SNPs were in Hardy-Weinberg equilibrium in the control group. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled as having a log-additive effect in the regression model. For risk of NHL, odds ratios (ORs) and 95% confidence intervals were calculated using unconditional logistic regression, adjusted for age and gender. For prognosis, hazard ratios (HR) were calculated for both event-free (EFS) and overall (OS) survival using Cox proportional hazards regression, adjusting for age, treatment type, and IPI (DLBCL, PTCL), FLIPI (FL), or MIPI (MCL). To determine risk of FL transformation to DLBCL, a competing risk Cox model was used. A p<0.05 was declared as statistically significant. Results:Of the 10 CXCR5 tag SNPs in our study, 5 were associated with risk of NHL, with rs1790192 (MAF=0.39 among controls) having the strongest association (OR=1.19, 95%CI 1.08–1.30; p=0.0003). This SNP was strongly associated with FL (OR=1.44, 95%CI 1.25–1.66; p=3.1×10−7), and was also associated with DLBCL (OR=1.16, 95%CI 1.01–1.33; p=0.038) and PTCL (OR=1.29, 95%CI 1.02–1.64; p=0.037) but not MCL or MZL. For FL, none of the SNPs were associated with EFS or OS, although rs1790192 was associated with better outcome among FL patients that were observed (HR=0.64; 95%CI 0.47–0.87; p=0.0039). For DLBCL, none of the SNPs were associated with EFS, while three SNPs were associated with OS: rs523604 (HR=0.79; 95%CI 0.64–0.97; p=0.028), rs12363277 (HR=0.57; 95%CI 0.33–0.99; p=0.046), and rs3922 (HR=0.79; 95%CI 0.65–0.97; p=0.027). The latter SNP was also associated with risk of transformation from FL to DLBCL (HR=0.61; 95%CI 0.40–0.91; p=0.016). For MCL, MZL and PTCL, none of the SNPs were associated with either EFS or OS. Conclusions:Several germline CXCR5 polymorphisms were associated with NHL risk, particularly rs1790192 with risk of FL as well as DLBCL and PTCL. CXCR5 SNPs did not appear to be important in prognosis for most NHL subtypes, although rs1790192 was associated with a better outcome in untreated FL and rs3922 was associated with OS in DLBCL patients and with risk of FL transformation. These results provide additional evidence for a role of host genetic variation in CXCR5 in lymphomagenesis, mainly in risk of disease development, although there may also be a role for CXCR5 in FL and DLBCL prognosis. Replications of these findings in additional studies are needed. Disclosures:Ansell:Seattle Genetics, Inc.: Research Funding.

The association between early life and adult body mass index and physical activity with risk of non-Hodgkin lymphoma: impact of gender

PurposeTo evaluate the association of body mass index (BMI) and physical activity (PA) during adulthood and at the age of 18 years with risk of non-Hodgkin lymphoma (NHL). MethodsWe enrolled 950 newly diagnosed NHL patients and 1146 frequency-matched clinic-based controls. Height, weight, and PA (recent adult and at the age of 18 years) were self-reported. Odds ratios (ORs), 95% confidence intervals, and tests for trend were estimated using unconditional logistic regression adjusted for age, gender, and residence. ResultsBMI at the age of 18 years was associated with an increased NHL risk (OR, 1.38 for highest vs. lowest quartile; p-trend = .0012), which on stratified analysis was specific to females (OR, 1.90; p-trend = .00025). There was no association of adult BMI with NHL risk. Higher PA in adulthood (OR, 1.03; p-trend = .85) or at the age of 18 years (OR, 0.88; 95% confidence interval, 0.72–1.07) was not associated with risk, but there was an inverse association for adult PA that was specific to females (OR, 0.71; p-trend = .039). Only BMI at the age of 18 years remained significantly associated with NHL risk when modeled together with PA in adulthood or at the age of 18 years. There was little evidence for heterogeneity in these results for the common NHL subtypes. ConclusionsEarly adult BMI may be of greatest relevance to NHL risk, particularly in females.

Polymorphisms in pattern‐recognition genes in the innate immunity system and risk of non‐Hodgkin lymphoma

The pattern-recognition pathway plays an important role in infection recognition and immune responses, and previous studies have suggested an association between genetic variation in innate immunity genes and non-Hodgkin lymphoma (NHL). We evaluated NHL risk associated with genetic variation in pattern-recognition genes using data from a case-control study of NHL conducted in Connecticut women. Single nucleotide polymorphisms (SNPs) in 27 pattern-recognition genes were genotyped in 432 Caucasian incident NHL cases and 494 frequency-matched controls. Unconditional logistic regression was used to compute odds ratios (ORs) for NHL and common NHL subtypes in relation to individual SNPs and haplotypes. A gene-based analysis that adjusted for the number of tagSNPs genotyped in each gene showed a significant association with overall NHL for the MBP gene (P = 0.028), with the diffuse large B-cell lymphoma (DLBCL) subtype for the MASP2 gene (P = 0.011), and with the follicular lymphoma (FL) subtype for DEFB126 (P = 0.041). A SNP-based analysis showed that MBP rs8094402 was associated with decreased risks of overall NHL (allele risk OR = 0.72, P-trend = 0.0018), DLBCL (allele risk OR = 0.72, P-trend = 0.036), and FL (allele risk OR = 0.67, P-trend = 0.021), while MASP2 rs12711521 was associated with a decreased risk of DLBCL (allele risk OR = 0.57, P-trend = 0.0042). We also observed an increased risk of FL for DEFB126 rs6054706 (allele risk OR = 1.39, P-trend = 0.033). Our results suggest that genetic variation in pattern-recognition genes is associated with the risk of NHL or specific NHL subtypes, but these preliminary findings require replication in larger studies.

Management of indolent lymphoma: Where are we now and where are we going

Indolent lymphoma comprises a unique and challenging subset of non-Hodgkin lymphoma (NHL). While definitions of indolence will vary, the most common indolent NHL subtypes include follicular lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma. Patients with indolent NHL (iNHL) excluding those with rare localized presentations are often met with an incurable but highly treatable NHL. In the rituximab era, response rates are approaching 90% with rituximab plus chemotherapy and time to next treatment are beginning to be measured in years. As a result of a prolonged natural history, we are encountering a gridlock of novel regimens and agents that appropriately fill peer-reviewed journals. In this review, we tackle a spectrum of topics in the management of indolent lymphoma including the initial approach to the newly diagnosed patient, approaches to first cytotoxic chemotherapy, maintenance and consolidation techniques, as well as highlight promising treatments on the horizon in iNHL. Clinicians continue to face tough choices in the management of iNHL. Through well-thought out clinical trials and peer-reviewed vetting of data we will continue to determine how to best manage the clinical continuum that is iNHL.

Cigarette smoking is associated with a small increase in the incidence of non-Hodgkin lymphoma: a meta-analysis of 24 observational studies

Previous studies have evaluated the association between cigarette smoking and incidence of non-Hodgkin lymphoma (NHL) with inconclusive results. Our main objective was to evaluate this relationship using a meta-analysis of observational studies. A literature search was undertaken through October 2011 looking for pertinent studies. Seven prospective cohort and 17 case–control studies were included in this meta-analysis. Outcomes were calculated using the random-effects model and are reported as odds ratio (OR). Meta-regression was used to evaluate the dose–response of intensity and duration of smoking in NHL incidence. Our study found an OR of 1.40 (95% confidence interval [CI] 1.14–1.73; p = 0.001) in current female smokers seen only in case–control studies. No increased odds of NHL was seen in men. There was no association between smoking and the most common NHL subtypes, with the exception of a statistical trend toward a higher incidence of T-cell lymphoma. In conclusion, there appears to be an increase in the odds of NHL in current female smokers.

Abstract 1025: Risk of diffuse large B-cell lymphoma in solid organ transplant recipients

Abstract Introduction: Solid organ transplants, while potentially life-saving treatments, are associated with increased risk of non-Hodgkin lymphomas (NHL) due to chronic immunosuppression, viral infection, and other factors. Given the etiologic heterogeneity of NHL subtypes, we conducted the first comprehensive evaluation among solid organ transplant recipients of factors that may specifically impact risk for diffuse large B-cell lymphoma (DLBCL), a common and highly aggressive NHL subtype that has been closely associated with immune perturbation. Materials and Methods: Data from the Scientific Registry of Transplant Recipients (SRTR) were linked to 14 population-based U.S. cancer registries by probabilistic matching and manual review to identify a cohort of 178,522 transplant recipients for follow-up and ascertainment of incident DLBCL. We calculated standardized incidence ratios (SIR = observed/expected cases) to compare the relative risk of DLBCL in transplant recipients with that expected in the general population. Differences between SIRs among patient groups were evaluated in multivariable Poisson regression models. Results: We identified 948 cases of DLBCL in the cohort, accounting for more than half of the 1,617 NHLs diagnosed, compared with 70.0 cases expected in the general population (SIR = 13.5, 95% CI = 12.7-14.4). Kidney was the most commonly transplanted organ in the cohort (59%, SIR = 11.0, 95% CI =10.0-12.1), but the SIR for DLBCL was highest after lung (SIR = 39.5, 95% CI = 31.7-48.7) and pancreas or kidney-pancreas transplants (SIR = 32.6, 95% CI = 24.6-42.5; Phomogeneity &amp;lt;0.01). The very high SIR in recipients aged 0-19 at transplantation (SIR = 378.9, 95% CI 318.3-447.6) dropped rapidly with advancing age (Ptrend&amp;lt;0.01) but was still markedly elevated among recipients aged ≥65 at transplantation (SIR = 5.8, 95% CI 4.6-7.3). Females had higher SIRs for DLBCL than males (15.8 vs. 12.6; Phomogeneity = 0.02). DLBCL risks were particularly striking for recipients who were Epstein-Barr virus (EBV) seronegative at time of transplant (SIR = 43.7, 95% CI = 34.7-54.3) compared with EBV seropositive recipients (SIR = 9.3, 95% CI = 7.6-11.1; Phomogeneity &amp;lt;0.01). This difference was even more pronounced for DLBCLs occurring within 2 years of transplantation (SIR = 78.8 vs. 11.8 in EBV seronegative vs. seropositive recipients). Conclusion: The risk of DLBCL, a common and aggressive subtype of NHL, was found to be greatly increased in solid organ transplant recipients compared with the general population. Particularly high SIRs were observed for the youngest recipients, as well as recipients who were EBV seronegative at time of transplant, highlighting the importance of primary EBV infection following transplant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1025. doi:1538-7445.AM2012-1025

The link between genetic polymorphism of glutathione-S-transferases, GSTM1, and GSTT1 and diffuse large B-cell lymphoma in Egypt

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. A number of studies have examined the role of genetic polymorphisms in the risk of DLBCL, and several variants have been identified as potential susceptibility genes, of those glutathione-S-transferases T1 and M1 (GSTT1 and GSTM1). The aim of the current study was to investigate the influence of inherited genetic polymorphisms of GSTM1 and GSTT1 genes on the susceptibility to DLBCL in Egypt. Genotyping of the candidate genes was performed for 71 Egyptian DLBCL patients and 100 age- and gender-matched healthy controls by multiplex polymerase chain reaction technique. The frequencies of GSTT1 null, GSTM1 null, and dual null genotypes among DLBCL patients were 47.9, 52.1, and 23.9 % respectively. GSTT1 null genotype conferred almost fourfold increased risk of DLBCL (OR = 3.9, 95 % CI = 1.97-7.75), and the risk increased when confined to male patients (OR = 4.4, 95 % CI = 1.57-12.63), while GSTM1 null genotype was not associated with DLBCL risk. Further studies on the functional consequences of GSTT1 and GSTM1 genetic polymorphisms would pave the way to declare their role in the pathogenesis of DLBCL or as possible predictors for response to therapy.

Pathophysiology and molecular aspects of diffuse large B-cell lymphoma

Diffuse large B-Cell lymphoma is the most common subtype of non-Hodgkin lymphoma in the West. In Brazil, it is the fifth cause of cancer, with more than 55,000 cases and 26,000 deaths per year. At Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - HCFMUSP, diffuse large B-Cell lymphoma represents 49.7% of all non-Hodgkin lymphoma cases. Initially, the classification of non-Hodgkin lymphoma was based on morphology, but advances in immunology and molecular medicine allowed the introduction of a biological classification for these diseases. As for other cancers, non-Hodgkin lymphoma involves patterns of multifactorial pathogenesis with environmental factors, as well as genetic, occupational and dietary factors, contributing to its development. Multiple lesions involving molecular pathways of B-cell proliferation and differentiation may result in the activation of oncogenes such as the BCL2, BCL6, and MYC genes and the inactivation of tumor suppressor genes such as p53 and INK4, as well as other important transcription factors such as OCT-1 and OCT-2. A dramatic improvement in survival was seen after the recent introduction of the anti-CD20 monoclonal antibody. The association of this antibody to the cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (CHOP) regimen has increased overall survival of diffuse large B-Cell lymphoma and follicular lymphoma patients by 20%. However, 50% of all diffuse large B-Cell lymphoma patients remain incurable, creating a demand for more research with new advances in treatment. Thus, it is important to know and understand the key factors and molecular pathways involved in the pathogenesis of diffuse large B-Cell lymphoma.

Clinical course and prognostic factors of children with Burkitt's lymphoma in a developing country: the experience of a single centre in Brazil

Objective: Burkitt's lymphoma is the most common subtype of non-Hodgkin lymphoma in children. The aim of this study was to characterize the clinical course and prognostic factors of children and adolescents with Burkitt's lymphoma treated in the Hematology Unit of Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG). Methods: A retrospective cohort study was made of 50 consecutive cases of children and adolescents aged 16 years or less with Burkitt's lymphoma admitted between January 1981 and December 2007. Prognostic factors associated with death were evaluated using the Kaplan-Meier method and compared by the two-tailed log-rank test. Results: The median age at diagnosis was 4.7 years. Most patients had abdominal tumors (66.7%) and advanced disease (68.9%) at diagnosis. Thirty-eight patients (84.4%) achieved complete clinical remission and 33 (73.3%) were alive at the first remission. Twelve children (26.7%) died. The median follow-up was 35 months with the probability of overall survival being 73% (89.2% and 35.7% for patients with uric acid < 7 mg/dL and ≥ 7.0 mg/dL, respectively - p-value < 0.001). Uric acid was the only significant prognostic factor at diagnosis. Conclusion: Our findings confirm the favorable prognosis of children with Burkitt's lymphoma even when treated with intermediate doses of methotrexate (500 mg/m2). Survival was significantly lower for individuals with concentrations of uric acid > 7 mg/dL.

Treatment of diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in all countries and all age groups. DLBCL is potentially curable, and the outcome of patients with DLBCL has completely changed with the introduction of therapy involving the monoclonal antibody rituximab in combination with chemotherapy. Nonetheless, relapse is detected after treatment with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone in approximately 30% of patients. It has recently become clear that DLBCL represents a heterogeneous admixture of quite different entities. Gene expression profiling has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses; however, incorporation of this information into treatment algorithms awaits further investigation. Future approaches to DLBCL treatment will use this new genetic information to identify potential biomarkers for prognosis and targets for treatment.

Autologous bone marrow transplantation in patients relapsed one year after R-CHOP?

I have studied and worked with non-Hodgkin lymphoma (NHL) for at least 16 years in the Hospital das Clinicas and Instituto do Câncer do Estado de Sao Paulo of the Faculdade de Medicina da Universidade de Sao Paulo (FMUSP). Last year we attended 300 new patients with NHL and 49.5% (almost 150 patients) had diffuse large B-cell lymphoma (DLBCL)(1). This is in agreement with the literature that describes DLBCL as the most common subtype of NHL (30% to 35%). Over the last four decades there has been a significant increase in the 5-year survival of patients with DLBCL. This is due to the development of anthracycline-based polychemotherapy regimens such as is used in the CHOP protocol and more recently, with the incorporation of immunotherapy with the monoclonal antibody anti-CD20 (rituximab) in the CHOP-regimen. However, 10% to 15% of DLBCL patients remain unable to acquire complete remission (CR) even in the rituximab era and 30% to 50% of the patients that acquire a first CR will relapse(2). As we have almost 150 patients per year with DLBCL in our service, we can assume that about 60 patients per year will have refractory or relapsed disease. Hence, we have a huge challenge every year with the main question being what is the best approach to offer to relapsed DLBCL patients? The unquestionable answer to this question is that patients have to be salvaged with a second line regimen and it is always possible to consolidate the patient with autologous stem cell transplantation (ASCT). In this article I will try to examine the level of evidence of this approach and to introduce the experience I acquired over these 16 years of NHL.

Food‐frequency questionnaire‐based estimates of total antioxidant capacity and risk of non‐Hodgkin lymphoma

Antioxidants, primarily from fruits and vegetables, have been hypothesized to protect against non-Hodgkin lymphoma (NHL). The oxygen radical absorbance capacity (ORAC) assay, which measures total antioxidant capacity of individual foods and accounts for synergism, can be estimated using a food-frequency questionnaire (FFQ). We tested the hypothesis that higher intake of antioxidant nutrients from foods, supplements and FFQ-based ORAC values are associated with a lower risk of NHL in a clinic-based study of 603 incident cases and 1,007 frequency-matched controls. Diet was assessed with a 128-item FFQ. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals adjusted for age, sex, residence and total energy. Dietary intake of α-tocopherol (OR=0.50; p-trend=0.0002), β-carotene (OR=0.58; p-trend=0.0005), lutein/zeaxanthin (OR=0.62; p-trend=0.005), zinc (OR=0.54; p-trend=0.003) and chromium (OR=0.68; p-trend=0.032) was inversely associated with NHL risk. Inclusion of supplement use had little impact on these associations. Total vegetables (OR=0.52; p-trend<0.0001), particularly green leafy (OR=0.52; p-trend<0.0001) and cruciferous (OR=0.68; p-trend=0.045) vegetables, were inversely associated with NHL risk. NHL risk was inversely associated with both hydrophilic ORAC (OR=0.61, p-trend=0.003) and lipophilic ORAC (OR=0.48, p-trend=0.0002), although after simultaneous adjustment for other antioxidants or total vegetables, only the association for lipophilic ORAC remained significant. There was no striking heterogeneity in results across the common NHL subtypes. Higher antioxidant intake as estimated by the FFQ-ORAC, particularly the lipophilic component, was associated with a lower NHL risk after accounting for other antioxidant nutrients and vegetable intake, supporting this as potentially useful summary measure of total antioxidant intake.