High-risk subtypes of chronic lymphocytic leukemia are detectable as early as 16 years prior to diagnosis.

Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.

Pre-existing sleep problems as a predictor of post-acute sequelae of COVID-19.

Several months after COVID-19 many individuals still report persisting symptoms, the so-called 'post-COVID-19 syndrome'. An immunological dysfunction is one of the main pathophysiological hypotheses. As sleep is central to the functioning of the immune system, we investigated whether self-reported pre-existing sleep disturbance might be an independent risk factor for the development of post-COVID-19 syndrome. A total of 11,710 participants of a cross-sectional survey (all tested positive for severe acute respiratory syndrome coronavirus-2) were classified into probable post-COVID-19 syndrome, an intermediate group, and unaffected participants at an average of 8.5 months after infection. The case definition was based on newly occurring symptoms of at least moderate severity and ≥20% reduction in health status and/or working capacity. Unadjusted and adjusted odds ratios were calculated to investigate the association between pre-existing sleep disturbances and subsequent development of post-COVID-19 syndrome while controlling for a variety of demographic, lifestyle, and health factors. Pre-existing sleep disturbances were found to be an independent predictor of subsequent probable post-COVID-19 syndrome (adjusted odds ratio 2.7, 95% confidence interval 2.27-3.24). Sleep disturbances as part of the post-COVID-19 syndrome were reported by more than half of the participants and appeared to be a new symptom and to occur independent of a mood disorder in most cases. Recognition of disturbed sleep as an important risk factor for post-COVID-19 syndrome should promote improved clinical management of sleep disorders in the context of COVID-19. Further, it may stimulate further research on the effect of improving sleep on the prognosis of COVID-19 long-term sequelae and other post-viral conditions.

Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP).

BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

The GAIN Registry - a New Prospective Study for Patients with Multi-organ Autoimmunity and Autoinflammation.

Patient registries are a very important and essential tool for investigating rare diseases, as most physicians only see a limited number of cases during their career. Diseases of multi-organ autoimmunity and autoinflammation are especially challenging, as they are characterized by diverse clinical phenotypes and highly variable expressivity. The GAIN consortium (German multi-organ Auto Immunity Network) developed a dataset addressing these challenges. ICD-11, HPO, and ATC codes were incorporated to document various clinical manifestations and medications with a defined terminology. The GAIN dataset comprises detailed information on genetics, phenotypes, medication, and laboratory values. Between November 2019 and July 2022, twelve centers from Europe have registered 419 patients with multi-organ autoimmunity or autoinflammation. The median age at onset of symptoms was 13 years (IQR 3-28) and the median delay from onset to diagnosis was 5 years (IQR 1-14). Of 354 (84.5%) patients who were genetically tested, 248 (59.2%) had a defined monogenetic cause. For 87 (20.8%) patients, no mutation was found and for 19 (4.5%), the result was pending. The most common gene affected was NFkB1 (48, 11.5%), and the second common was CTLA4 (40, 9.5%), both genetic patient groups being fostered by specific research projects within GAIN. The GAIN registry may serve as a valuable resource for research in the inborn error of immunity community by providing a platform for etiological and diagnostic research projects, as well as observational trials on treatment options.

Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways.

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

Early and Rapid Identification of COVID-19 Patients with Neutralizing Type I Interferon Auto-antibodies.

PURPOSE: Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable strategy for early identification of IFN-AAB-positive patients for potential subsequent clinical interventions. METHODS: We analyzed sera of 430 COVID-19 patients from four hospitals for presence of IFN-AABs by ELISA. Binding specificity and neutralizing activity were evaluated via competition assay and virus-infection-based neutralization assay. We defined clinical parameters associated with IFN-AAB positivity. In a subgroup of critically ill patients, we analyzed effects of therapeutic plasma exchange (TPE) on the levels of IFN-AABs, SARS-CoV-2 antibodies and clinical outcome. RESULTS: The prevalence of neutralizing AABs to IFN-α and IFN-ω in COVID-19 patients from all cohorts was 4.2% (18/430), while being undetectable in an uninfected control cohort. Neutralizing IFN-AABs were detectable exclusively in critically affected (max. WHO score 6-8), predominantly male (83%) patients (7.6%, 18/237 for IFN-α-AABs and 4.6%, 11/237 for IFN-ω-AABs in 237 patients with critical COVID-19). IFN-AABs were present early post-symptom onset and at the peak of disease. Fever and oxygen requirement at hospital admission co-presented with neutralizing IFN-AAB positivity. IFN-AABs were associated with lower probability of survival (7.7% versus 80.9% in patients without IFN-AABs). TPE reduced levels of IFN-AABs in three of five patients and may increase survival of IFN-AAB-positive patients compared to those not undergoing TPE. CONCLUSION: IFN-AABs may serve as early biomarker for the development of severe COVID-19. We propose to implement routine screening of hospitalized COVID-19 patients for rapid identification of patients with IFN-AABs who most likely benefit from specific therapies.

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered. RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years. CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 in Households with Children, Southwest Germany, May-August 2020.

Resolving the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in households with members from different generations is crucial for containing the current pandemic. We conducted a large-scale, multicenter, cross-sectional seroepidemiologic household transmission study in southwest Germany during May 11-August 1, 2020. We included 1,625 study participants from 405 households that each had ≥1 child and 1 reverse transcription PCR-confirmed SARS-CoV-2-infected index case-patient. The overall secondary attack rate was 31.6% and was significantly higher in exposed adults (37.5%) than in children (24.6%-29.2%; p = <0.015); the rate was also significantly higher when the index case-patient was >60 years of age (72.9%; p = 0.039). Other risk factors for infectiousness of the index case-patient were SARS-CoV-2-seropositivity (odds ratio [OR] 27.8, 95% CI 8.26-93.5), fever (OR 1.93, 95% CI 1.14-3.31), and cough (OR 2.07, 95% CI 1.21-3.53). Secondary infections in household contacts generate a substantial disease burden.

Association between anthropometry and lifestyle factors and risk of B-cell lymphoma: An exposome-wide analysis.

To better understand the role of individual and lifestyle factors in human disease, an exposome-wide association study was performed to investigate within a single-study anthropometry measures and lifestyle factors previously associated with B-cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2402 incident BCL cases were diagnosed from 475 426 participants that were followed-up on average 14 years. Standard and penalized Cox regression models as well as principal component analysis (PCA) were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, diet and BCL and/or the subtypes. PCAs confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B-cell lymphoma (DLBCL) and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL.

Altered Spectrum of Lymphoid Neoplasms in a Single-Center Cohort of Common Variable Immunodeficiency with Immune Dysregulation.

PURPOSE: Common variable immune deficiency (CVID) confers an increased risk of lymphoid neoplasms, but reports describing the precise WHO specification of the lymphoma subtypes and their immunological environment are lacking. We therefore classified lymphomas-occurring in a cohort of 21 adult CVID patients during a 17-year period at our center-according to the 2016 WHO classification and characterized the local and systemic immunological context RESULTS: The median time between the onset of CVID and lymphoma was 14 years. Patients showed a high prevalence of preceding immune dysregulation: lymphadenopathy (n = 13, 62%), splenomegaly (n = 18, 86%), autoimmune cytopenia (n = 14, 67%), and gastrointestinal involvement (n = 15, 71%). The entities comprised extranodal marginal zone lymphoma (n = 6), diffuse large B cell lymphoma (n = 7), plasmablastic lymphoma (n = 1), classic Hodgkin lymphoma (n = 4, including three cases with germline CTLA4 mutations), T cell large granular lymphocytic leukemia (n = 2), and peripheral T cell lymphoma, not otherwise specified (n = 1), but no follicular lymphoma. An Epstein-Barr virus association was documented in eight of 16 investigated lymphomas. High expression of PDL1 by tumor cells in five and of PDL1 and PD1 by tumor-infiltrating macrophages and T cells in 12 of 12 investigated lymphomas suggested a tolerogenic immunological tumor environment. CONCLUSION: In summary, a diverse combination of specific factors like genetic background, chronic immune activation, viral trigger, and impaired immune surveillance contributes to the observed spectrum of lymphomas in CVID. In the future, targeted therapies, e.g., PD1/PDL1 inhibitors in CVID associated lymphomas with a tolerogenic environment may improve therapy outcome.

[Development of an Intervention to Enhance Health Literacy of Patients with Common Variable Immunodeficiency (CVID)]. / Entwicklung einer Schulung zur Förderung der Gesundheitskompetenz von Patienten mit variablem Immundefekt (CVID).

OBJECTIVE: The aim of the article was to describe the development of a training program to enhance the health literacy of patients with immunodeficiency. In addition, patient satisfaction and acceptance of the training will be evaluated. METHODS: Patients' needs were identified with a questionnaire (N=238). Additionally, interviews with clinical immunologists (N=5) and patients with common variable immunodeficiency (CVID) (N=9) were conducted. On this basis, the authors developed a manual for the intervention. It focuses on active communication with physicians as well as health-related communication at the workplace. The evaluation of patient satisfaction with the intervention was based on a questionnaire (N=49). RESULTS: The results show that the ratings of the patients were in the good to very good range (M=1.77; SD=0.38). From the analysis of the free text, hints for training improvement could be derived. CONCLUSION: Evaluation of the intervention showed that the new training was accepted and patients considered it comprehensible and relevant.

Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes.

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Risk Factors for Complicated Lymphadenitis Caused by Nontuberculous Mycobacteria in Children.

Nontuberculous mycobacteria (NTM) are an emerging cause of infections, including chronic lymphadenitis in children. To identify risk factors for NTM lymphadenitis, particularly complicated disease, we collected epidemiologic, clinical, and microbiological data on 138 cases of NTM lymphadenitis in children across 13 centers in Germany and Austria. We assessed lifestyle factors but did not identify specific risk behaviors. We noted that more cases of NTM lymphadenitis occurred during cold months than during warm months. Moreover, we noted female sex and age <5.5 years as potential risk factors. Complete extirpation of the affected lymph node appeared to be the best therapeutic measure. We integrated the study data to develop a simple risk score to predict unfavorable clinical outcomes for NTM lymphadenitis.

Serum levels of hsa-miR-16-5p, hsa-miR-29a-3p, hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-223-3p and subsequent risk of chronic lymphocytic leukemia in the EPIC study.

Chronic lymphocytic leukemia (CLL) is an incurable disease accounting for almost one-third of leukemias in the Western world. Aberrant expression of microRNAs (miRNAs) is a well-established characteristic of CLL, and the robust nature of miRNAs makes them eminently suitable liquid biopsy biomarkers. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), the predictive values of five promising human miRNAs (hsa-miR-16-5p, hsa-miR-29a-3p, hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-223-3p), identified in a pilot study, were examined in serum of 224 CLL cases (diagnosed 3 months to 18 years after enrollment) and 224 matched controls using Taqman based assays. Conditional logistic regressions were applied to adjust for potential confounders. The median time from blood collection to CLL diagnosis was 10 years (p25-p75: 7-13 years). Overall, the upregulation of hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-29a-3p was associated with subsequent risk of CLL [OR1∆Ct-unit increase (95%CI) = 1.42 (1.18-1.72), 1.64 (1.31-2.04) and 1.75 (1.31-2.34) for hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-29a-3p, respectively] and the strongest associations were observed within 10 years of diagnosis. However, the predictive performance of these miRNAs was modest (area under the curve <0.62). hsa-miR-16-5p and hsa-miR-223-3p levels were unrelated to CLL risk. The findings of this first prospective study suggest that hsa-miR-29a, hsa-miR-150-5p and hsa-miR-155-5p were upregulated in early stages of CLL but were modest predictive biomarkers of CLL risk.

Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study.

Limited evidence exists on the role of modifiable lifestyle factors on the risk of lymphoma. In this work, the associations between adherence to healthy lifestyles and risks of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) were evaluated in a large-scale European prospective cohort. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 2,999 incident lymphoma cases (132 HL and 2,746 NHL) were diagnosed among 453,808 participants after 15 years (median) of follow-up. The healthy lifestyle index (HLI) score combined information on smoking, alcohol intake, diet, physical activity and BMI, with large values of HLI expressing adherence to healthy behavior. Cox proportional hazards models were used to estimate lymphoma hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses were conducted by excluding, in turn, each lifestyle factor from the HLI score. The HLI was inversely associated with HL, with HR for a 1-standard deviation (SD) increment in the score equal to 0.78 (95% CI: 0.66, 0.94). Sensitivity analyses showed that the association was mainly driven by smoking and marginally by diet. NHL risk was not associated with the HLI, with HRs for a 1-SD increment equal to 0.99 (0.95, 1.03), with no evidence for heterogeneity in the association across NHL subtypes. In the EPIC study, adherence to healthy lifestyles was not associated with overall lymphoma or NHL risk, while an inverse association was observed for HL, although this was largely attributable to smoking. These findings suggest a limited role of lifestyle factors in the etiology of lymphoma subtypes.

Infectious mononucleosis, immune genotypes, and non-Hodgkin lymphoma (NHL): an InterLymph Consortium study.

PURPOSE: We explored the interaction between non-Hodgkin lymphoma (NHL), infectious mononucleosis (IM) history, and immune-related genotypes in a pooled case-control analysis. METHODS: A total of 7,926 NHL patients and 10,018 controls from 12 case-control studies were included. Studies were conducted during various time periods between 1988 and 2008, and participants were 17-96 years of age at the time of ascertainment/recruitment. Self-reported IM history and immune response genotypes were provided by the InterLymph Data Coordinating Center at Mayo Clinic. Odds ratios (OR) were estimated using multivariate logistic regression, and interactions were estimated using the empirical Bayes method. PACT was used to account for multiple comparisons. RESULTS: There was evidence of an interaction effect between IM history and two variants on T-cell lymphoma (TCL) risk: rs1143627 in interleukin-1B (IL1B) (pinteraction = 0.04, ORinteraction = 0.09, 95% confidence interval [CI] 0.01, 0.87) and rs1800797 in interleukin-6 (IL6) (pinteraction = 0.03, ORinteraction = 0.08, 95% CI 0.01, 0.80). Neither interaction effect withstood adjustment for multiple comparisons. There were no statistically significant interactions between immune response genotypes and IM on other NHL subtypes. CONCLUSIONS: Genetic risk variants in IL1B and IL6 may affect the association between IM and TCL, possibly by influencing T-cell activation, growth, and differentiation in the presence of IM, thereby decreasing risk of immune cell proliferation.

Correction to: Infectious mononucleosis, immune genotypes, and non-Hodgkin lymphoma (NHL): an InterLymph Consortium study.

Unfortunately, the word "Group" is missed in the article title of the original publication. It has been corrected by this erratum.

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis.

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Inflammatory potential of diet and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition.

INTRODUCTION: Chronic inflammation plays a critical role in lymphomagenesis and several dietary factors seem to be involved its regulation. The aim of the current study was to assess the association between the inflammatory potential of the diet and the risk of lymphoma and its subtypes in the European Investigation into Cancer and Nutrition (EPIC) study. METHODS: The analysis included 476,160 subjects with an average follow-up of 13.9 years, during which 3,136 lymphomas (135 Hodgkin lymphoma (HL), 2606 non-Hodgkin lymphoma (NHL) and 395 NOS) were identified. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated using 28 dietary components and their corresponding inflammatory weights. The association between the ISD and lymphoma risk was estimated by hazard ratios (HR) and 95% confidence intervals (CI) calculated by multivariable Cox regression models adjusted for potential confounders. RESULTS: The ISD was not associated with overall lymphoma risk. Among lymphoma subtypes, a positive association between the ISD and mature B-cell NHL (HR for a 1-SD increase: 1.07 (95% CI 1.01; 1.14), p trend = 0.03) was observed. No statistically significant association was found among other subtypes. However, albeit with smaller number of cases, a suggestive association was observed for HL (HR for a 1-SD increase = 1.22 (95% CI 0.94; 1.57), p trend 0.13). CONCLUSIONS: Our findings suggested that a high ISD score, reflecting a pro-inflammatory diet, was modestly positively associated with the risk of B-cell lymphoma subtypes. Further large prospective studies on low-grade inflammation induced by diet are warranted to confirm these findings.

Occupational exposure to ionizing radiation and risk of lymphoma subtypes: results of the Epilymph European case-control study.

BACKGROUND: Evidence linking risk of lymphoma and B-cell lymphoma subtypes to ionizing radiation is inconclusive, particularly at low exposure levels. METHODS: We investigated risk of lymphoma (all subtypes), B-cell lymphomas, and its major subtypes, associated with low-level occupational exposure to ionizing radiation, in 2346 lymphoma cases and 2463 controls, who participated in the multicenter EpiLymph case-control study. We developed a job-exposure matrix to estimate exposure to ionizing radiation, distinguishing between internal and external radiation, and we applied it to the lifetime occupational history of study subjects, We calculated the Odds Ratio (OR) and its 95% confidence interval (95% CI) for lymphoma (all subtypes combined), B-cell lymphoma, and its major subtypes using unconditional, polytomous logistic regression adjusting for age, gender, and education. RESULTS: We did not observe an association between exposure metrics of external and internal radiation and risk of lymphoma (all subtypes), nor with B-cell lymphoma, or its major subtypes, at the levels regularly experienced in occupational settings. An elevated risk of diffuse large B cell lymphoma was observed among the most likely exposed study subjects with relatively higher exposure intensity, which would be worth further investigation. CONCLUSIONS: Further investigation is warranted on risk of B cell lymphoma subtypes associated with low-level occupational exposure to external ionizing radiation, and to clarify whether lymphoma should be included among the cancer outcomes related to ionizing radiation.