non-Hodgkin Lymphoma Etiology Research Articles

Епідеміологічні дані, етіологія, патогенез, фактори ризику, клінічні прояви, сучасні методи діагностики і лікування, прогнозування перебігу Неходжкінських лімфом (огляд літератури)

Non-Hodgkin lymphoma (NHL) is a group of malignant diseases characterized by clonal proliferation of lymphoid cells corresponding to different stages of differentiation of normal B- and T- lymphocytes or natural killer (NK) cells. NHL is histopathologically and clinically diverse and divided into two groups: B-cell lymphomas and T-cell lymphomas, and subtypes: indolent (slow) and aggressive, classic and extranodal. The etiology of NHL is environmental, infectious, immunological, iatrogenic and genetic factors. The pathogenesis of NHL consists in: 1) translocations of oncogenes; 2) cytogenetic aberrations and mutations of tumor suppressor genes. Clinical manifestations of NHL: 1) lymphadenopathy; 2) symptoms of the presence of an extranodal tumor (abdominal pain; jaundice; shortness of breath and/or pleural effusion; bleeding, symptoms of gastrointestinal obstruction; symptoms associated with infiltration by lymphoma cells of the skin, thyroid gland, salivary glands, etc.; neurological symptoms of central and/or peripheral origin); 3) symptoms of bone marrow infiltration; 4) general symptoms (fever, night sweats, weight loss, fatigue, loss of appetite). Diagnosis of NHL involves: 1) auxiliary research (histological, immunohistochemical, cytogenetic and molecular, use of more specific monoclonal antibodies, immunophenotypic diagnosis, gene sequencing); 2) diagnostic tactics (estimation of stage and determination of prognostic factors according to IPI); 3) differential diagnosis (covers other causes of symptoms). The choice of treatment program for NHL depends on the type of lymphoma and the patient's condition. The main methods of treatment: wait and watch; monotherapy with alkylating drugs; RT; combined РCT; combined РCT with the use of purine analogs; therapy with monoclonal antibodies; PCT+monoclonal antibodies; HDCT+THSC. Survival prognosis for NHL depends on the origin of the tumor and its stage.

Global burden, risk factors, and trends of non-Hodgkin lymphoma: A worldwide analysis of cancer registries.

Non-Hodgkin lymphoma (NHL) accounts for 90% of all malignant lymphomas. This study aimed to evaluate the global incidence, mortality, associated risk factors, and temporal trends of NHL by sex, age, and country. Data from 185 countries globally were used for analysis. NHL incidence and mortality were collected via the GLOBOCAN (2020), CI5 series I-X, WHO mortality database, the Nordic Cancer Registries, and the SEER Program. The WHO Global Health Observatory provided country-level, age-standardized prevalence of lifestyle and metabolic risk factors. Trends were examined and reported based on average annual percentage change (AAPC) calculated using Joinpoint regression analysis. Incidence and AAPC are based on data for the last 10 years across countries. Globally, age-standardized incidence and mortality rates for NHL were recorded at 5.8 and 2.6 per 100,000 individuals, respectively. At country-level, NHL incidence was significantly associated with various factors, including HDI (Human Development Index), GDP per capita, prevalence of tobacco and alcohol consumption, sedentary lifestyle, obesity, hypertension, diabetes and hypercholesterolaemia. Rising trend in NHL incidence was observed, with the highest increase recorded in Estonia (AAPCmale = 4.15, AAPCfemale = 5.14), Belarus (AAPCfemale = 5.13), and Lithuania (AAPCfemale = 4.68). While overall NHL mortality has been decreasing, certain populations experienced increased mortality over the decade. In Thailand, AAPC for mortality was 31.28% for males and 30.26% for females. Estonia saw an AAPC of 6.46% for males, while Slovakia experienced an AAPC of 4.24% for females. Colombia's AAPC was 1.29% for males and 1.51% for females. This study indicates a rising trend of NHL incidence over the past decade- particularly in developed countries, older males, and younger populations. Further research should investigate deeper insights into specific etiology and prognosis of NHL across subtypes, and potential contributors towards these epidemiologic trends.

The Effects of Adiponectin on the Behavior of B-Cell Leukemia Cells: Insights from an In Vitro Study.

Background: Non-Hodgkin's lymphoma (NHL), the most frequent hematological neoplasm worldwide, represents a heterogeneous group of malignancies. The etiology of NHL remains to be fully elucidated, but the role of adipose tissue (AT) in immune function via the secretion of adipokines was recently recognized. Among adipokines, adiponectin has garnered attention for its beneficial properties. This study aimed to explore the in vitro effects of AdipoRon, an adiponectin agonist, on JVM-2, a lymphoblast cell line used as a representative disease model. Methods: JVM-2 cells were treated with different concentrations of AdipoRon to evaluate its effects on viability (via an MTT test), cell cycle distribution (via an FACS analysis), invasiveness (via a Matrigel assay) and colony-forming ability; protein expression was assessed via a real-time PCR (qPCR) and/or Western blotting (WB). Results: We found that the prolonged exposure of JVM-2 cells to AdipoRon led to a reduction in their viability due to a cytostatic effect. Additionally, AdipoRon stimulated both the formation of cell colonies and the expression of E-cadherin. Interestingly, the administration of AdipoRon increased the invasive potential of JVM-2 cells. Conclusions: Our findings indicate that adiponectin is involved in the regulation of different cellular processes of JVM-2 cells, supporting its potential association with a pro-tumorigenic phenotype and indicating that it might contribute to the increased aggressiveness and metastatic potential of B lymphoma cells. However, additional studies are required to fully understand the molecular mechanisms of adiponectin's actions on lymphoblasts and whether it may represent a marker of disease.

HSA Adductomics Reveals Sex Differences in NHL Incidence and Possible Involvement of Microbial Translocation.

The higher incidence of non-Hodgkin lymphoma (NHL) in males is not well understood. Although reactive oxygen species (ROS) have been implicated as causes of NHL, they cannot be measured directly in archived blood. We performed untargeted adductomics of stable ROS adducts in human serum albumin (HSA) from 67 incident NHL cases and 82 matched controls from the European Prospective Investigation into Cancer and Nutrition-Italy cohort. Regression and classification methods were employed to select features associated with NHL in all subjects and in males and females separately. Sixty seven HSA-adduct features were quantified by liquid chromatography-high-resolution mass spectrometry at Cys34 (n = 55) and Lys525 (n = 12). Three features were selected for association with NHL in all subjects, while seven were selected for males and five for females with minimal overlap. Two selected features were more abundant in cases and seven in controls, suggesting that altered homeostasis of ROS may affect NHL incidence. Heat maps revealed differential clustering of features between sexes, suggesting differences in operative pathways. Adduct clusters dominated by Cys34 oxidation products and disulfides further implicate ROS and redox biology in the etiology of NHL. Sex differences in dietary and alcohol consumption also help to explain the limited overlap of feature selection between sexes. Intriguingly, a disulfide of methanethiol from enteric microbial metabolism was more abundant in male cases, thereby implicating microbial translocation as a potential contributor to NHL in males. Only two of the ROS adducts associated with NHL overlapped between sexes and one adduct implicates microbial translocation as a risk factor.

A prospective analysis of red blood cell membrane polyunsaturated fatty acid levels and risk of non-Hodgkin lymphoma

Published studies report inconsistent associations of polyunsaturated fatty acid (PUFA) intake with non-Hodgkin lymphoma (NHL) risk. We conducted a nested case-control study in Nurses’ Health Study and Health Professionals Follow-Up Study participants to evaluate a hypothesis of inverse association of pre-diagnosis red blood cell (RBC) membrane PUFA levels with risk of NHL endpoints. We confirmed 583 NHL cases and matched 583 controls by cohort/sex, age, race and blood draw date/time. We estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL endpoints using logistic regression. RBC PUFA levels were not associated with all NHL risk; cis 20:2n-6 was associated with follicular lymphoma risk (OR [95% CI] per one standard deviation increase: 1.35 [1.03–1.77]), and the omega-6/omega-3 PUFA ratio was associated with diffuse large B-cell lymphoma risk (2.33 [1.23–4.43]). Overall, PUFA did not demonstrate a role in NHL etiology; the two unexpected positive associations lack clear biologic explanations.

Mode of Delivery, Birth Characteristics, and Early-Onset Non-Hodgkin Lymphoma in a Population-Based Case-Control Study.

The etiology of non-Hodgkin lymphoma (NHL) in children and in adolescents and young adults (AYA) is not well understood. We evaluated potential associations between mode of delivery, birth characteristics, and NHL risk in a population-based case-control study, which included 3,064 cases of NHL [490 with Burkitt lymphoma, 981 with diffuse large B-cell lymphoma (DLBCL), and 978 with T-cell NHL) diagnosed at the age of 0 to 37 years in California during 1988 to 2015 and 153,200 controls frequency matched on year of birth. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from an unconditional multivariable logistic regression model that included year of birth and birth characteristics. Individuals born via cesarean section had a decreased risk of pediatric Burkitt lymphoma (age 0-14 years; OR = 0.71, 95% CI: 0.51-0.99) and pediatric T-cell NHL (OR = 0.73, 95% CI: 0.55-0.97) compared with those born vaginally. Having a birth order of second (OR = 0.73, 95% CI: 0.57-0.93) or third or higher (OR = 0.76, 95% CI: 0.58-0.99) was associated with a lower risk of pediatric T-cell NHL compared with first-borns. AYA (age 15-37 years) with a heavier birthweight had an elevated risk of DLBCL (OR for each kg = 1.16, 95% CI: 1.00-1.35). Associations between other birth characteristics, including plurality, maternal age, maternal education, and NHL risk, also exhibited variations across subgroups based on age of diagnosis and histologic subtype. These findings support a role of mode of delivery and birth characteristics in the etiology of early-onset NHL. This study underscores the etiologic heterogeneity of early-onset NHL.

Expression of Simian Virus 40 Large T-Antigen: A Case Control Study of Non-Hodgkin Lymphoma

Background: Cancer such as neoplasma lymphoma is related to the immune system. Of all lymphoma cases, about 90% are Non-Hodgkin Lymphoma (NHL). In the United Kingdom, NHL is among the five most frequently diagnosed cancer cases. In Indonesia, based on statistical data from the Dharmais Cancer Center Hospital in 2006, NHL was in the ten most commonly diagnosed cancers. The global incidence of NHL continues to increase annually in western countries, especially in Caucasian populations, men and the elderly. The etiology of NHL is uncertain. Viral infection is thought to be associated with the pathogenesis of NHL. One of them is the Simian 40 virus (SV 40) infection. In some studies, positive SV40 sequencing was found in the majority of NHL cases, but other research found no significant relationship between SV40 infection and NHL. Objective: This study aimed to identify the frequency of SV40 infection in NHL cases in Yogyakarta and to determine the relationship between SV40 infection in NHL cases and clinical patients. Methods: This study examined 102 samples of paraffin blocks from subjects diagnosed with NHL in the Anatomical Pathology Laboratory of Dr. Sardjito Hospital from 2014 through 2016. DNA extraction was done and the results were used for PCR. SV40 genome primer sets were used for the PCR process to identify any positive cases. Results: In this study, all 102 subjects did not indicate genomic L-Tag positive cases of NHL. Conclusion: It cannot be proved that SV40 has a role in the pathogenesis of NHL in Indonesia.

Association between occupational exposure to trichloroethylene and serum levels of microRNAs: a cross-sectional molecular epidemiology study in China.

The objective of our study was to evaluate the association between occupational exposure to trichloroethylene (TCE), a suspected lymphomagen, and serum levels of miRNAs in a cross-sectional molecular epidemiology study of TCE-exposed workers and comparable unexposed controls in China. Serum levels of 40 miRNAs were compared in 74 workers exposed to TCE (median: 12ppm) and 90 unexposed control workers. Linear regression models were used to test for differences in serum miRNA levels between exposed and unexposed workers and to evaluate exposure-response relationships across TCE exposure categories using a three-level ordinal variable [i.e., unexposed, < 12ppm, the median value among workers exposed to TCE) and ≥ 12ppm)]. Models were adjusted for sex, age, current smoking, current alcohol use, and recent infection. Seven miRNAs showed significant differences between exposed and unexposed workers at FDR (false discovery rate) < 0.20. miR-150-5p and let-7b-5p also showed significant inverse exposure-response associations with TCE exposure (Ptrend= 0.002 and 0.03, respectively). The % differences in serum levels of miR-150-5p relative to unexposed controls were -13% and -20% among workers exposed to < 12ppm and ≥ 12ppm TCE, respectively. miR-150-5p is involved in B cell receptor pathways and let-7b-5p plays a role in the innate immune response processes that are potentially important in the etiology of non-Hodgkin lymphoma (NHL). Further studies are needed to replicate these findings and to directly test the association between serum levels of these miRNAs and risk of NHL in prospective studies.

Childhood infectious diseases and risk of non-Hodgkin's lymphoma according to the WHO classification: A reanalysis of the Italian multicenter case-control study.

Since 1960, incidence of non-Hodgkin's lymphoma (NHL) has been increasing in most industrialized countries, but causes of this trend remain unclear. A role of the decreased exposure to infectious agents during childhood has been proposed. Our study evaluates the association between common childhood infectious diseases and the risk of NHL and its major subtypes by a reanalysis of the Italian multicenter case-control study. After exclusion of next-of-kin interviews, 1,193 cases, diagnosed between 1990 and 1993, and 1,708 population-based controls were included in the analyses. OR estimates were obtained by logistic regression, adjusting for gender, age, residence area, education, smoking habit and exposure to radiations, pesticides and aromatic hydrocarbons. Among B-cell lymphomas (n = 1,102) an inverse association was observed for rubella (OR = 0.80, 95% CI: 0.65-0.99), pertussis (OR = 0.74, 95% CI: 0.62-0.88) and any infection (OR = 0.75, 95% CI: 0.61-0.93). A negative trend by number of infections was observed, which was more evident among mature B-cell lymphoma (OR = 0.66 for three infections or more, 95% CI: 0.48-0.90). Our results indicate a potential protective role of common childhood infections in the etiology of B-cell NHL.

Markers of Immune Activation and Inflammation, and Non-Hodgkin Lymphoma: A Meta-Analysis of Prospective Studies.

BackgroundChronic inflammation and immune activation are reported to play a key role in the etiology of non-Hodgkin lymphoma (NHL). We conducted a meta-analysis on the associations between prediagnosis circulating levels of immune stimulatory markers, interleukin 6 (IL-6), IL-10, tumor necrosis factor α (TNF-α), CXCL13, soluble CD23 (sCD23), sCD27, sCD30, and the risk of NHL.MethodsRelevant studies were identified from PubMed, EMBASE, and Web of Science up to January 1, 2017. We calculated summary odds ratio (OR) estimates for the association between one natural log increase in concentration of each biomarker and NHL using random-effects models for NHL as a composite outcome and for several histological subtypes of NHL.ResultsSeventeen nested case control studies were included. Elevated levels of several biomarkers were more strongly associated with increased odds of NHL: TNF-α, OR = 1.18 (95% confidence interval [CI] = 1.04 to 1.34); CXCL13, OR = 1.47 (95% CI = 1.03 to 2.08); sCD23, OR = 1.57 (95% CI = 1.21 to 2.05); sCD27, OR = 2.18 (95% CI = 1.20 to 3.98); sCD30, OR = 1.65 (95% CI = 1.22 to 2.22). In stratified analyses, IL-6, TNF-α, sCD27, and sCD30 were more strongly associated with NHL in HIV-infected individuals compared to HIV-uninfected individuals. Between-study heterogeneity was observed across multiple biomarkers for overall NHL and by subtypes.ConclusionThis meta-analysis provides evidence that elevated circulating levels of TNF-α, CXCL13, sCD23, sCD27, and sCD30 are consistently associated with an increased risk of NHL, suggesting the potential utility of these biomarkers in population risk stratification and prediction.

HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.

Risk of pancreatic cancer and non-Hodgkin lymphoma associated with healthy lifestyle behaviors in the EPIC study

Introduction Pancreatic cancer (PC) and non-Hodgkin lymphoma (NHL) are both rare cancers which are particularly prevalent in Western countries and for which increasing incidence rates have been observed for the past decades. Moreover, both of them have unclear etiology and only few risk factors identified so far. While PC has been firmly associated with cigarette smoking, type II diabetes, obesity, as well as chronic pancreatitis, NHL has been mainly related to immune disorders and occupational exposure like benzenes. Roles of lifestyle factors in PC and NHL etiologies are still largely undefined, but recent evidences suggested that lifestyle, as well as high levels of alcohol consumption may be related to PC and NHL risks. Therefore, associations between modifiable lifestyle factors and either PC risk or NHL risk were investigated using an index expressing healthy lifestyle behaviors in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods Within 14 years of follow-up, 1113 incident PC cases and 2244 incident NHL cases (1845 B-NHL, 372 DLCBL, 415 CLL/SLL, 278 FL, and 535 PCN/MM) were diagnosed in the EPIC study. A score named the Healthy Lifestyle Index (HLI) ranging from 0 to 20 was built combining lifestyle factors assessed at baseline, i.e. a score for diet, physical activity, smoking habits, alcohol intake, and BMI. A score of 20 corresponding to the highest level of adherence to primary prevention recommendations was meant to reflect a healthy lifestyle. HLI was modelled in categories ( 15) and in continuous for a 1-category increase. Cox proportional hazard models with age as primary time variable were used to estimate PC and NHL hazard ratios (HR) and their 95% confidence intervals (95% CI) in relation to the HLI, adjusting for potential confounding factors. Results The combination of healthy lifestyle behaviors into an increasing HLI was inversely associated with PC with a 29% (95% CI: 0.64, 0.78) decreasing risk for a 1-category increase of HLI among EPIC participants. Modifiable lifestyle factors driving PC risk's reduction were smoking abstinence (pWald Conclusions Findings from the EPIC study suggested that the risk of PC was inversely associated with healthy lifestyle profiles, whereas no association was found in relation to NHL risk among EPIC participants. The results support adhering to primary prevention guidelines in order to decrease PC incidence and should encourage policy makers to promote healthy lifestyle in general population, in particular for cancers with no available screening strategy. In addition, they provide more evidence in favor of investigating non-modifiable risk factors to further understanding NHL's etiology.

Anthropometric factors and non-Hodgkin's lymphoma risk: systematic review and meta-analysis of prospective studies.

The associations between anthropometric factors and non-Hodgkin's lymphoma (NHL) risk remain inconclusive. A meta-analysis was performed to clarify these associations. PubMed and Web of Science were searched for relevant prospective observational studies. A random-effects model was used to generate the summary relative risks (RRs) with 95% confidence intervals (CIs). A total of 22 prospective cohort studies, with over 20,000 NHL cases, were included in the present meta-analysis. The summary RRs of NHL risk were 1.06 (95% CI 1.03, 1.09) for each 5 kg/m2 increase in body mass index (BMI), 1.11 (95% CI 1.07, 1.16) for each 5 kg/m2 increase in BMI in early adulthood (age 18-21 years), 1.05 (95% CI 1.01, 1.09) for each 10 kg increase in weight, 1.21 (95% CI 1.15, 1.28) for each 10 kg increase in weight in early adulthood (age 18-21 years), and 1.13 (95% CI 1.10, 1.17) for each 10 cm increase in height. No association was found for waist circumference (WC) and waist-to-hip ratio. By subtypes, all anthropometric factors (but not WC) were associated with an increased risk of diffuse large B-cell lymphoma. Chronic lymphocytic leukemia/small lymphocytic lymphoma was positively associated with BMI in early adulthood and with height, whereas follicular lymphoma was only positively associated with height. In summary, BMI and weight in early adulthood may be more relevant to NHL development than current BMI and weight. These findings emphasize the importance of maintaining a healthy weight throughout the life-course, starting from early life, for NHL prevention. Increased NHL risk with taller stature, which may reflect cumulative exposure to hormones/growth factors and nutrition status in early life, further supports the relevance of early life exposure in the etiology of NHL.

SNP variants associated with non-Hodgkin lymphoma (NHL) correlate with human leukocyte antigen (HLA) class II expression

Large consortia efforts and genome-wide association studies (GWASs) have linked a number of genetic variants within the 6p21 chromosomal region to non-Hodgkin lymphoma (NHL). Complementing these efforts, we genotyped previously reported SNPs in the human leukocyte antigen (HLA) class I (rs6457327) and class II (rs9271100, rs2647012 and rs10484561) regions in a total of 1,145 subjects (567 NHL cases and 578 healthy controls) from two major ethnic groups in Malaysia, the Malays and the Chinese. We identified a NHL-associated (PNHL_add = 0.0008; ORNHL_add = 0.54; 95% CI = 0.37–0.77) and B-cell associated (PBcell_add = 0.0007; ORBcell_add = 0.51; 95% CI = 0.35–0.76) SNP rs2647012 in the Malaysian Malays. In silico cis-eQTL analysis of rs2647012 suggests potential regulatory function of nearby HLA class II molecules. Minor allele rs2647012-T is linked to higher expression of HLA-DQB1, rendering a protective effect to NHL risk. Our findings suggest that the HLA class II region plays an important role in NHL etiology.

Associations between genetic variants in immunoregulatory genes and risk of non-Hodgkin lymphoma in a Chinese population.

We undertook a hospital-based case-control study to examine the associations between single nucleotide polymorphisms (SNPs) in selected immunoregulatory genes and non-Hodgkin lymphoma (NHL) risk in a Chinese population. One hundred and sixty-nine NHL patients diagnosed according to the World Health Organization (WHO) 2001 standard and 421 controls were recruited. Nine SNPs in three genes (IL-10, IL-1RN, and TNF-α) were selected based on predicted functions and previous study findings. Genetic association analysis was performed using the Cochran-Armitage trend test and multiple logistic regression. Four SNPs were associated with an increased risk of overall NHL: odds ratio per minor allele [ORper-minor-allele] and 95% confidence interval [CI] were 2.64 (1.75-3.98) for IL-10 rs1800893, 2.67 (1.72-4.16) for IL-1RN rs4251961, 1.80 (1.24-2.63) for TNF- α rs1800630, and 1.55 (1.02-2.37) for TNF- α rs2229094. These SNPs were also associated with an increased risk of diffuse large B-cell lymphoma (DLBCL). In addition, another SNP (TNF- α rs1041981) was associated with an increased risk of DLBCL (ORper-minor-allele=1.73, 95% CI 1.14-2.61). The findings provide evidence on the role of these immunoregulatory gene variants in NHL etiology.

Hyperglycemia is associated with poor survival in primary central nervous system lymphoma patients.

Primary central nervous system lymphoma (PCNSL) is a type of non-Hodgkin lymphoma (NHL), and it has been postulated that metabolic disorder may contribute to NHL etiology. We retrospectively investigated the prognostic significance of hyperglycemia in patients with PCNSL. We evaluated glucose transporter type 1 (GLUT1) expression by immunohistochemistry and analyzed its association with hyperglycemia and survival. The medical and neuroradiologic records of 50 patients with PCNSL at our institution over the past 15 years were analyzed. Patients were divided into 3 groups based on mean fasting plasma glucose (FPG) levels: normal (<110 mg/dL), prediabetes (110-125 mg/dL), and diabetes (≥126 mg/dL). We defined prediabetes and diabetes groups as hyperglycemia. Forty-four percent of patients were in the prediabetes and diabetes groups. One-year survival rates were 73%, 66%, and 43% in normal, prediabetes, and diabetes groups, respectively. Univariate analysis revealed that high age, female sex, poor performance status, high mean FPG, and monotherapy were associated with shorter survival. Multivariable Cox regression analyses showed that high mean FPG and monotherapy were significant predictors of shorter survival (p = 0.036 and p = 0.000, respectively). The GLUT1 immunohistopathologic staining was performed in 34 cases, 20 of which (58%) showed variable levels of GLUT1 expression at the cell membrane and/or cytoplasm. Prediabetes and diabetes groups had a higher percentage of GLUT1-positive cells compared with the normal group (p = 0.015). These findings indicate that hyperglycemia is associated with poor survival. The putative biological mechanism might involve differential GLUT1 expression between hyperglycemic and normal states in patients with PCNSL.

Periodontal disease and risk of non-Hodgkin lymphoma in the Health Professionals Follow-Up Study.

Periodontal disease is a chronic inflammatory condition that has been associated with chronic diseases, including cancer. In an earlier prospective cohort analysis within the Health Professionals Follow-Up Study (HPFS), we observed a 31% higher risk of non-Hodgkin lymphoma (NHL) among participants with severe periodontal disease at baseline. Here, we extend the study with an additional 8 years of follow-up, and conduct analyses with updated periodontal disease status and NHL subtypes. The HPFS is an ongoing prospective cohort study of 51,529 men in the USA Between baseline in 1986 and 2012, 875 cases of NHL were diagnosed, including 290 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 85 diffuse large B-cell lymphomas and 91 follicular lymphomas. We performed multivariable Cox proportional hazards regression to evaluate associations of interest. History of periodontal disease at baseline was positively associated with risk of NHL overall (hazard ratio (HR) = 1.26, 95% confidence interval (CI): 1.06-1.49) and CLL/SLL (HR = 1.41, 95% CI: 1.04-1.90). With updated periodontal status, HRs were 1.30 (95% CI: 1.11-1.51) for NHL overall and 1.41 (95% CI: 1.08-1.84) for CLL/SLL. In contrast, after adjusting for periodontal disease, tooth loss was inversely associated with NHL, suggesting that other causes or consequences of tooth loss may have different implications for NHL etiology. Our findings suggest that periodontal disease is a risk factor for NHL. Whether periodontal disease is a direct or indirect cause of NHL, or is a marker of underlying systemic inflammation and/or immune dysregulation, warrants further investigation.

Abstract 867: Reproductive factors and risk of B-cell non-Hodgkin lymphoma among women in Los Angeles

Abstract Background: Overall, non-Hodgkin lymphoma (NHL) incidence is higher in men than women, and the male to female ratio differs by NHL subtype. Historically, female reproductive characteristics and patterns have been inconsistently linked to NHL risk, though studies on this topic remain limited. Because a woman experiences changes in immune function during pregnancy, that permit her to establish and maintain a successful pregnancy, we hypothesize that such pregnancy-associated changes in immune function could affect the risk of NHL, a cancer of the immune cells. Methods: We conducted a population-based case-control study among women in Los Angeles County comprising 998 histologically confirmed B-cell NHL patients diagnosed 2004-2008 from the Los Angeles Cancer Surveillance Program and 998 individually matched controls (matched on age, race and socioeconomic status). Conditional logistic regression was used to calculate the associations [odds ratios (OR) and 95% confidence intervals (CI)] between female reproductive factors (e.g., ever pregnant; number of full-term pregnancies; breastfeeding) with B-cell NHL overall and unconditional logistic regression was used to calculate the associations with major NHL subtypes. Results: Compared to women who had never been pregnant, women who had full-term pregnancies had 17% decreased risk of B-cell NHL (OR = 0.83, 95% CI = 0.64-1.08); the decreased risk was most pronounced for the diffuse large B-cell lymphoma (DLBCL) subtype (OR = 0.68, 95% CI = 0.47-0.98). Increasing number of full-term pregnancies was inversely associated with B-cell NHL overall (P-trend = 0.02), DLBCL (P-trend = 0.03) and follicular lymphoma (P-trend = 0.04). Women who had reported breastfeeding also had decreased risk of B-cell NHL overall (OR = 0.80, 95% CI = 0.64-1.00) and follicular lymphoma (OR = 0.71, 95% CI = 0.50-1.00). Among women who had full-term pregnancies, women who breastfed for 60 weeks or more had 30% decreased risk of B-cell NHL overall (OR = 0.70, 95% CI = 0.52-0.93; P-trend = 0.06), which was consistent for follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Conclusions: Our results provide evidence for an association between female reproductive factors and decreased risk of B-cell NHL, supporting a role for hormonal factors in B-cell NHL etiology. Citation Format: Yani Lu, Jianning Luo, Sophia Wang, Jane Sullivan-Halley, Wendy Cozen, Leslie Bernstein. Reproductive factors and risk of B-cell non-Hodgkin lymphoma among women in Los Angeles. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 867. doi:10.1158/1538-7445.AM2015-867

Epidemiology and etiology of non-hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) consists of many histologically and biologically distinct lymphoid malignancies with poorly understood, but possibly distinct, etiologies. The patterns of incidence and time trend vary not only by age, sex, and race/ethnicity in the USA, but also show significant geographic differences, suggesting the potential role of infectious agents, environmental factors, and lifestyle factors in addition to host genetic status in the development of NHL. Important pathogenetic mechanisms include immune modulation and chronic antigen stimulation. Epidemiologic studies in the past two decades have provided intriguing new insights on the possible causes of lymphoma and support the idea that there is some mechanistic commonality of lymphomagenesis, but significant etiologic heterogeneity clearly exists. This review presents a summary of the current understanding of the descriptive epidemiology and etiology of NHL and suggests areas of focus for future epidemiologic research.

Polymorphic variation of inflammation-related genes and risk of non-Hodgkin lymphoma for Uygur and Han Chinese in Xinjiang.

Polymorphisms of inflammation-related genes have been found to be associated with non-Hodgkin lymphoma (NHL) or some of its subtypes, but only a few relevant data have been reported in China. In this study, the Snapshot method was used to assess genetic variation; a total of 14 single nucleotide polymorphisms (SNPs) for 6 inflammatory factors in 157 NHL cases (64 Uygur ethnic subjects, 93 Han Chinese) and 435 controls (231 Uygur and 204 Han Chinese) were studied from the Xinjiang province of China. Haplotype distribution was estimated using PHASE 2.3 software. Statistical differences in the genotype and haplotype frequencies between case and control groups were also considered and estimated. For the Han population, the geneotype distributions for TNF- αrs1800629, TNF-αrs1800630, IL-6 rs1800795, IL-6 rs1800797, NF-KB1 rs1585215 and TLR-4 rs4986790 showed significant differences between the case and control groups (p<0.05). The TNF-α gene frequencies of ACG and CCA haplotypes in the cases were higher than in the controls (OR=2.45, 95% CI: 1.55-3.89, p=0.0002, OR=2.53, 95% CI: 1.10-5.80, p=0.029, respectively), and the same findings were detected for TNF-β gene CA haplotype (OR=1.87, 95% CI: 1.21-2.90, p=0.0054). However, for the Uygur population, no such significant differences were detected within the gene-type distribution of the 14 SNPs. The TNF-α gene frequency of the CCA haplotype between the two groups (OR=1.98, 95% CI: 1.11-3.51, p=0.021) revealed a statistically significant difference. Our results showed that polymorphic variations of inflammation-related genes could be important to the NHL etiology of the Han population, and that these may only have limited influence on the Uygur population.