G-CSF + plerixafor versus G-CSF alone mobilized hematopoietic stem cells in patients with multiple myeloma and lymphoma: a systematic review and meta-analysis.

AIM: The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), and Hodgkin's lymphoma (HL). This systematic review and meta-analysis aimed to determine the ability of G-CSF + plerixafor to mobilize peripheral blood (PB) CD34+ cells and examine its safety profile. METHODS: We performed a database search using the terms 'granulocyte colony stimulating factor', 'G-CSF', 'AMD3100', and 'plerixafor', published up to May 1, 2023. The methodology is described in further detail in the PROSPERO database (CRD42023425760). RESULTS: Twenty-three studies were included in this systematic review and meta-analysis. G-CSF + plerixafor resulted in more patients achieving the predetermined apheresis yield of CD34+ cells than G-CSF alone (OR, 5.33; 95%, 4.34-6.55). It was further discovered that G-CSF + plerixafor could mobilize more CD34+ cells into PB, which was beneficial for the next transplantation in both randomized controlled (MD, 18.30; 95%, 8.74-27.85) and single-arm (MD, 20.67; 95%, 14.34-27.00) trials. Furthermore, G-CSF + plerixafor did not cause more treatment emergent adverse events than G-CSF alone (OR, 1.25; 95%, 0.87-1.80). CONCLUSIONS: This study suggests that the combination of G-CSF and plerixafor, resulted in more patients with MM, NHL, and HL, achieving the predetermined apheresis yield of CD34+ cells, which is related to the more effective mobilization of CD34+ cells into PB.

Overcoming Barriers to Referral for Chimeric Antigen Receptor T Cell Therapy in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma. Although outcomes to frontline therapy are encouraging, patients who are refractory to or in relapse after first-line therapy experience inferior outcomes. A significant proportion of patients treated with additional lines of cytotoxic chemotherapy ultimately succumb to their disease, as established in the SCHOLAR-1 study. Chimeric antigen receptor (CAR) T cell therapy is a novel approach to cancer management that reprograms a patient's own T cells to better target and eliminate cancer cells. It was initially approved by the US Food and Drug Administration for patients with relapsed/refractory (r/r) DLBCL as a third line of treatment. Based on recently published randomized data, CAR-T therapy (axicabtagene ciloleucel and lisocabtagene maraleucel) also has been approved as a second line of treatment for patients who are primary refractory or relapse within 12 months of first-line therapy. Despite the proven efficacy in treating r/r DLBCL with CD19-directed CAR-T therapy, several barriers may prevent eligible patients from receiving treatment. Barriers to CAR-T therapy include cost of therapy, patient hesitancy, required travel to academic treatment centers, nonreferrals, poor understanding of CAR-T therapy, lack of caregiver support, knowledge of available resources, and timely patient selection by referring oncologists. In this review, we provide an overview of the FDA-approved CD19-directed CAR-T cell therapies (tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel) from pivotal clinical trials and supporting real-world evidence from retrospective studies. In both clinical trials and real-world settings, CAR-T therapy has been shown to be safe and efficacious for treating patients with r/r DLBCL: however, several barriers prevent eligible patients from accessing these therapies. Barriers to referrals for CAR-T therapy are described, along with recommendations to improve collaboration between community oncologists and physicians from CAR-T therapy treatment centers and subsequent long-term care of patients in community treatment centers.

Myocardial work-A new tool for early detection of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy induced-cardiotoxicity in hematological patients.

BACKGROUND: Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP) chemotherapy in non-Hodgkin's lymphoma (NHL) has risk of cardiotoxicity. PURPOSE: To determine the role of myocardial work and biomarkers in subclinical diagnosis and prediction of cardiotoxicity. METHODS: The 130 NHL patients (52 ± 9 years, 62% men) scheduled for RCHOP, with LVEF>50%, were evaluated at baseline, after third cycle and chemotherapy completion for 3D LVEF, 2D myocardial deformation (longitudinal, radial, circumferential strain - LS, RS, CS) and myocardial work (global constructive work, waste work, work index and work efficiency - GCW, GWW, GWI, GWE). NT-pro-BNP and troponin I were determined. RESULTS: After chemotherapy ended, 37 patients (28%) (group I) developed asymptomatic cardiotoxicity (8 mild form, 25 moderate form, 4 severe form); 93 patients (group II) did not. After third cycle, all patients had decreased LS, CS, RS, GCW, GWI, GWE and increased GWW, persistent after chemotherapy completion, with significant changes in group I. After third cycle, GWE and GCW were the best independent predictors for LVEF reduction; GWE decrease with>5% after third cycle predicted cardiotoxicity after chemotherapy completed (91% sensitivity, 94% specificity). CONCLUSIONS: In NHL, myocardial work can diagnose subclinical cardiotoxicity and predict LVEF decline. These parameters should be used for sensitive evaluation of myocardial function during chemotherapy.

Targeted proteomic scan identifies alteration of serum proteins among workers occupationally exposed to low levels of trichloroethylene.

Occupational exposure to trichloroethylene (TCE) has been associated with alterations in B-cell activation factors and an increased risk of non-Hodgkin's lymphoma (NHL). Here, we aimed to examine the biological processes influenced by TCE exposure to understand the underlying molecular mechanisms. This cross-sectional molecular epidemiology study included data of 1317 targeted proteins in the serum from 42 TCE exposed and 34 unexposed factory workers in Guangdong, China. We used multivariable linear regressions to identify proteins associated with TCE exposure and examined their exposure-response relationship across categories of TCE exposure (unexposed, low exposed: <10 ppm, high exposed: ≥10 ppm). We further examined pathway enrichment of TCE-related proteins to understand their biological response. Occupational exposure to TCE was associated with lower levels of tumor necrosis factor receptor superfamily member 17 (TNFRSF17; ß = -.08; p-value = .0003) and kynureninase (KYNU; ß = -.10, p-value = .002). These proteins also showed a significant exposure-response relation across the unexposed, low exposed, and high exposed workers (all p-trends < .001, false discovery rate [FDR] < 0.20). Pathway analysis of TCE-related proteins showed significant enrichment (FDR < 0.05) for several inflammatory and immune pathways. TCE exposure was associated with TNFRSF17, a key B-cell maturation antigen that mediates B-cell survival and KYNU, an enzyme that plays a role in T-cell mediated immune response. Given that altered immunity is an established risk factor for NHL, our findings support the biological plausibility of linking TCE exposure with NHL.

Herbicide use in farming and other jobs in relation to non-Hodgkin's lymphoma (NHL) risk.

OBJECTIVES: Given mixed evidence for carcinogenicity of current-use herbicides, we studied the relationship between occupational herbicide use and risk of non-Hodgkin's lymphoma (NHL) in a large, pooled study. METHODS: We pooled data from 10 case-control studies participating in the International Lymphoma Epidemiology Consortium, including 9229 cases and 9626 controls from North America, the European Union and Australia. Herbicide use was coded from self-report or by expert assessment in the individual studies, for herbicide groups (eg, phenoxy herbicides) and active ingredients (eg, 2,4-dichlorophenoxyacetic acid (2,4-D), glyphosate). The association between each herbicide and NHL risk was estimated using logistic regression to produce ORs and 95% CIs, with adjustment for sociodemographic factors, farming and other pesticides. RESULTS: We found no substantial association of all NHL risk with ever-use of any herbicide (OR=1.10, 95% CI: 0.94 to 1.29), nor with herbicide groups or active ingredients. Elevations in risk were observed for NHL subtypes with longer duration of phenoxy herbicide use, such as for any phenoxy herbicide with multiple myeloma (>25.5 years, OR=1.78, 95% CI: 0.74 to 4.27), 2,4-D with diffuse large B-cell lymphoma (>25.5 years, OR=1.47, 95% CI: 0.67 to 3.21) and other (non-2,4-D) phenoxy herbicides with T-cell lymphoma (>6 years, lagged 10 years, OR=3.24, 95% CI: 1.03 to 10.2). An association between glyphosate and follicular lymphoma (lagged 10 years: OR=1.48, 95% CI: 0.98 to 2.25) was fairly consistent across analyses. CONCLUSIONS: Most of the herbicides examined were not associated with NHL risk. However, associations of phenoxy herbicides and glyphosate with particular NHL subtypes underscore the importance of estimating subtype-specific risks.

Analysis of Key Factors Associated with Response to Salvage High-Dose Methotrexate Rechallenge in Primary Central Nervous System Lymphoma with First Relapse.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin's lymphoma that occurs in the central nervous system. Although sensitive to chemotherapy, 35-60% of PCNSL patients still relapse within 2 years after the initial treatment. High-dose methotrexate (HD-MTX) rechallenge is generally used in recurrent PCNSL, especially for patients who have achieved a response after initial methotrexate (MTX) treatment. However, the overall remission rate (ORR) of HD-MTX rechallenge is about 70-80%. Additionally, the side effects of HD-MTX treatment endanger the health of patients and affect their quality of life. METHODS: This is a retrospective study of patients with first relapse PCNSL at Huashan Hospital, Fudan University between January 2000 and November 2020. By comparing the clinical characteristics and radiological manifestations of first relapsed PCNSL patients with remission and non-remission after receiving HD-MTX rechallenge, we screened out the key factors associated with HD-MTX rechallenge treatment response, to provide some help for the selection of salvage treatment strategies for patients with recurrent PCNSL. Additionally, patients with remission after HD-MTX rechallenge were followed up to identify the factors related to progression-free survival of the second time (PFS2) (time from the first relapse to second relapse/last follow-up). The Kruskal-Wallis and Pearson chi-square tests were performed to examine the univariate association. Further, multivariable logistic regression analysis was used to study the simultaneous effect of different variables. RESULTS: A total of 207 patients were enrolled in the study based on the inclusion criteria, including 114 patients in the remission group (RG) and 81 patients in the non-remission group (nRG), and 12 patients were judged as having a stable disease. In Kruskal-Wallis and Pearson chi-square tests, progression-free survival rates for first time (PFS1) and whether the initial treatment was combined with consolidated whole brain radiotherapy (WBRT) were related to the response to HD-MTX rechallenge treatment, which was further validated in regression analysis. Further, after univariate analysis and regression analysis, KPS was related to PFS2. CONCLUSIONS: For PCNSL patients in their first relapse, HD-MTX rechallenge may be an effective salvage treatment. PFS1 and whether initial treatment was combined with consolidation WBRT were associated with HD-MTX rechallenge treatment response. In addition, patients with higher KPS at the time of the first relapse had a longer PFS2 after HD-MTX rechallenge treatment.

Incidence and Risk Factors for Acute Kidney Injury After Chimeric Antigen Receptor T-Cell Therapy.

OBJECTIVE: To evaluate the association of baseline and postinfusion patient characteristics with acute kidney injury (AKI) in the month after chimeric antigen receptor T-cell (CAR-T) therapy. METHODS: We retrospectively reviewed records of 83 patients with non-Hodgkin lymphoma undergoing CAR-T therapy (axicabtagene ciloleucel) between June 2016 and November 2020. Patients were followed up to 1 month after treatment. Post-CAR-T AKI was defined as a more than 1.5-fold increase in serum creatinine concentration from baseline (on the day of CAR-T infusion) at any time up to 1 month after CAR-T therapy. RESULTS: Of 83 patients, 14 (17%) developed AKI during follow-up. At 1 month after CAR-T infusion, 10 of 14 (71%) AKI events had resolved. Lower baseline estimated glomerular filtration rate, use of intravenous contrast material, tumor lysis prophylaxis, higher peak uric acid and creatine kinase levels during follow-up, and change in lactate dehydrogenase from baseline to peak level within 1 month after initiation of CAR-T therapy were significantly associated with AKI incidence during follow-up. Incidence of AKI was also higher in patients who received higher doses of corticosteroids and tocilizumab. CONCLUSION: Acute kidney injury occurred in approximately 1 in 6 patients who received axicabtagene ciloleucel for non-Hodgkin lymphoma. Patients with high tumor burden receiving higher total doses of corticosteroids or tocilizumab should be closely monitored for development of AKI. Lower baseline kidney function at CAR-T initiation, exposure to contrast material, and progressive increase in levels of tumor lysis markers (uric acid, lactate dehydrogenase, creatine kinase) after CAR-T infusion may predict risk of AKI during the 1 month after infusion.

Asparaginase Erwinia chrysanthemi for acute lymphoblastic leukemia and lymphoblastic lymphoma.

Acute lymphoblastic leukemia (ALL) is a neoplastic disease characterized by the malignant proliferation of lymphoid cells in the blood and bone marrow. It accounts for approximately 75% of childhood leukemia. Lymphoblastic lymphoma (LBL) is a type of non-Hodgkin's lymphoma characterized by rapid growth and highly aggressive characteristics that occurs most commonly in adolescents and young adults. Asparaginase is primarily used to treat patients with ALL or LBL. Because allergic reactions occur in patients treated with bacterial-derived asparaginase, it is important to develop an alternative asparaginase preparation for patients allergic to asparaginase. Recombinant asparaginase Erwinia chrysanthemi-rywn (JZP-458) is a recombinant Erwinia asparaginase that uses a novel Pseudomonas fluorescens expression platform in the production process. JZP-458 has the same amino acid sequence as E. chrysanthemi-derived asparaginase (ERW) and its in vitro activity is similar to that of ERW. JZP-458 is highly efficacious in patients allergic to asparaginase. Data from a phase I clinical trial indicated that following the intramuscular or intravenous administration of JZP-458 to volunteers, serum asparaginase activity ≥ 0.1 IU/mL was observed in 100% of the volunteers 72 hours after administration. In this review, we summarize the mechanism of action and the related research data obtained with JZP-458 for the treatment of ALL or LBL.

Environmental pesticide exposure and non-Hodgkin lymphoma survival: a population-based study.

BACKGROUND: There is evidence indicating that pesticide exposure is a risk factor for non-Hodgkin lymphoma (NHL) development. However, the association between pesticide exposure and NHL survival is not well-established. METHODS: Using the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010 to 2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state-mandated Pesticide Use Reporting (PUR) by census tract from 2012 to 2014. In addition, data from PUR was integrated into a geographic information system that employs land-use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. Multivariable Cox proportional hazards regression models were used to evaluate the association between total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data and lymphoma-specific and overall survival. RESULTS: Among 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt exposure was observed in 34.1%, 26.0%, 10.6%, 14.0%, and 12.8% of NHL patients, respectively. Total pesticide exposure at the time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival. CONCLUSIONS: Although we found no consistent associations between agricultural pesticide exposure at the neighborhood level and worse survival, these results provide a platform for designing future studies to determine the association between pesticide and NHL.

Impact of occupational pesticide exposure assessment method on risk estimates for prostate cancer, non-Hodgkin's lymphoma and Parkinson's disease: results of three meta-analyses.

Assessment of occupational pesticide exposure in epidemiological studies of chronic diseases is challenging. Biomonitoring of current pesticide levels might not correlate with past exposure relevant to disease aetiology, and indirect methods often rely on workers' imperfect recall of exposures, or job titles. We investigated how the applied exposure assessment method influenced risk estimates for some chronic diseases. In three meta-analyses the influence of exposure assessment method type on the summary risk ratio (sRR) of prostate cancer (PC) (25 articles), non-Hodgkin's lymphoma (NHL) (29 articles) and Parkinson's disease (PD) (32 articles) was investigated. Exposure assessment method types analysed were: group-level assessments (eg, job titles), self-reported exposures, expert-level assessments (eg, job-exposure matrices) and biomonitoring (eg, blood, urine). Additionally, sRRs were estimated by study design, publication year period and geographic location where the study was conducted. Exposure assessment method types were not associated with statistically significant different sRRs across any of the health outcomes. Heterogeneity in results varied from high in cancer studies to moderate and low in PD studies. Overall, case-control designs showed significantly higher sRR estimates than prospective cohort designs. Later NHL publications showed significantly higher sRR estimates than earlier. For PC, studies from North America showed significantly higher sRR estimates than studies from Europe. We conclude that exposure assessment method applied in studies of occupational exposure to pesticides appears not to have a significant effect on risk estimates for PC, NHL and PD. In systematic reviews of chronic health effects of occupational exposure to pesticides, epidemiological study design, publication year and geographic location, should primarily be considered.

Evaluation of Medication Instruction Sheets for Patients Undergoing R-CHOP Therapy in Non-Hodgkin's Lymphoma.

BACKGROUND/AIM: High-dose chemotherapy is frequently administered to patients with hematologic malignancies, thereby causing severe adverse drug reactions (ADRs) at a relatively high frequency. To precisely monitor ADRs, we developed a medication instruction sheet (MIS) for patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) combination therapy for non-Hodgkin's lymphoma (NHL). Herein, we evaluated the usefulness of the MIS for managing ADRs in patients who received R-CHOP therapy. PATIENTS AND METHODS: We included patients aged ≥20 years who received R-CHOP therapy as first-line treatment for NHL at the Department of Hematology, Kyushu University Hospital, between August 2014 and December 2018. Medical professionals evaluated the possible occurrence of ADRs according to the present MIS and ADRs were graded according to the Common Toxicity Criteria, version 4.0 (National Cancer Institute, Bethesda, MD, USA). Finally, the accuracy of the MIS in predicting the occurrence of ADRs of different grades and during definite periods was evaluated. RESULTS: Seventy-five patients with NHL were included in the present study. Overall, 359 ADR events were monitored, which were predicted ADR items listed in the MIS. Among these, 254 (71%) events occurred during the same period as those listed in the MIS. The onset timing of any grade of an infusion reaction and peripheral neuropathy precisely matched those listed in the MIS. However, the accuracy of the MIS was reduced in patients with thrombocytopenia (42%). CONCLUSION: The present MIS could be useful for monitoring ADRs in patients with cancer undergoing R-CHOP therapy.

Diesel exhaust exposure and risk of non-Hodgkin lymphoma: a meta-analysis.

OBJECTIVE: We aimed at carrying out a systematic review and meta-analysis of epidemiological studies on the association between occupational and non-occupational exposures to diesel exhaust and risk of non-Hodgkin lymphoma. METHODS: We conducted a systematic search of the literature and identified 16 cohort studies and 7 case-control studies that analyzed non-Hodgkin lymphoma alone or combined with Hodgkin lymphoma or multiple myeloma, from which we extracted 29 independent risk estimates. We performed random-effects meta-analyses for ever-exposure to diesel exhaust, overall and after stratification for outcome and study design. RESULTS: The meta-relative risk of non-Hodgkin lymphoma was 0.97 (95% confidence interval, 0.93-1.01; P -heterogeneity = 0.43). The meta-relative risk of results of cohort studies was 0.97 (95% confidence interval, 0.94-1.01) that of case-control studies was 1.00 (95% confidence interval, 0.84-1.17). Similar results were obtained when the meta-analysis was restricted to studies that analyzed only non-Hodgkin lymphoma. There was no indication of publication bias. CONCLUSION: Our meta-analysis provided no overall evidence of an increased risk of non-Hodgkin lymphoma in subjects exposed to diesel exhausted.

No Association Observed between Coffee Intake and Risk of Non-Hodgkin Lymphoma among Postmenopausal Women.

BACKGROUND: Some preliminary studies indicate that components in coffee may have anticarcinogenic effects. However, the association between coffee-drinking habits and the risk of non-Hodgkin lymphoma (NHL) remain controversial. OBJECTIVE: To examine the relationship between coffee intake and NHL incidence in a large prospective study of postmenopausal US women. DESIGN AND PARTICIPANTS/SETTING: The participants included 74,935 women from the Women's Health Initiative Observational Study who were recruited from 1993 through 1998. Information about coffee-drinking habits was collected at baseline via self-administered questionnaires. MAIN OUTCOME MEASURES: Newly diagnosed NHL was validated by medical records and pathology records. Separate analyses were performed for the following three subtypes of NHL: diffuse large B-cell lymphoma (n = 244), follicular lymphoma (n = 166), and chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 64). STATISTICAL ANALYSES PERFORMED: Age-adjusted and multivariable-adjusted Cox proportional hazards models were used to determine associations of coffee intake (specifically, the total amount of coffee consumed daily, coffee types, and coffee preparation methods) with risk of NHL. RESULTS: A total of 851 women developed NHL during a median 18.34 years of follow-up (range = 0.01 to 24.30 years; ± 6.63 years). Overall, no associations were observed between coffee intake and risk of NHL regardless of the total amount of daily coffee intake (P value for trend = 0.90), caffeinated (P = 0.55) or decaffeinated coffee intake (P = 0.78), and filtered or unfiltered coffee intake (P = 0.91) after controlling for sociodemographic factors, lifestyle risk factors, and clinical risk factors/current medical conditions. No significant associations were observed between coffee intake with specific subtypes of NHL. A statistically significant interaction was found between alcohol intake, coffee intake, and incident NHL (P value for interaction = 0.02) based on the adjusted analysis. Specifically, among women who frequently consumed alcohol (> 7 drinks/week), those who had moderate coffee intake (2 to 3 c coffee/day) had a significantly reduced risk of developing NHL (hazard ratio 0.61, 95% CI 0.36 to 0.98), compared with those who did not drink coffee. CONCLUSIONS: The findings from this study do not support an association between coffee consumption and NHL risk, irrespective of the total amount of daily coffee intake, coffee types, or coffee preparation methods.

Benzene exposure and non-Hodgkin lymphoma: a systematic review and meta-analysis of human studies.

BACKGROUND: Non-Hodgkin lymphoma comprises a heterogeneous group of cancers with unresolved aetiology, although risk factors include environmental exposures to toxic chemicals. Although the ubiquitous pollutant benzene is an established leukemogen, its potential to cause non-Hodgkin lymphoma has been widely debated. We aimed to examine the potential link between benzene exposure and risk of non-Hodgkin lymphoma in humans by evaluating a wide array of cohort and case-control studies using electronic systematic review. METHODS: We did a comprehensive systematic review and meta-analysis of all qualified human epidemiological studies that assessed the relationship between benzene exposure and non-Hodgkin lymphoma. We queried the PubMed and Embase databases for relevant articles published before June 5, 2019, and applied the SysRev platform for study selection. All peer-reviewed human cohort and case-control studies that reported non-Hodgkin lymphoma risk estimates specifically for benzene exposure were eligible for inclusion. Studies that calculated relative risks (RRs) for industries or job types without identifying those specifically exposed to benzene, that combined non-Hodgkin lymphoma with other cancer types, or that reported many different solvent exposures together were excluded. From each study, two investigators independently extracted information on the study design, location, years, sample size, participation rates, age, sex, sources of cases and controls, diagnosis, histological verification, exposure assessment, results, adjustment, and statistical analysis, and subsequently assessed study quality. We calculated the meta-analysis relative risk (meta-RR) and CIs using the fixed effect and random effect models, as well as assessing publication bias. FINDINGS: Our search yielded 2481 articles. After screening and removal of duplicates, 20 case-control studies and eight cohort studies were included in our meta-analysis, which included a total of 9587 patients with non-Hodgkin lymphoma. We reported an increased meta-relative risk (meta-RR) of 33% in highly exposed groups, when data were available (meta-RR 1·33 [95% CI 1·13-1·57], n=28). The meta-RR rose to 1·51 (1·22-1·87, n=18) in the studies that provided results specifically for highly exposed individuals. In particular, we reported a doubling of this risk for diffuse large B-cell lymphoma, a major non-Hodgkin lymphoma subtype (1·67 [1·01-2·77]). We also detected increased risks for follicular lymphoma (1·47 [0·95-2·27]) and hairy cell leukaemia (1·77 [0·99-3·16]), though they were not statistically significant. Funnel plot, Egger's test (p=0·77) and Begg's test (p=0·98) did not show evidence of publication bias. We evaluated the major aspects of causal inference and found evidence to support all the Hill considerations for assigning causation. INTERPRETATION: Our findings suggest a causal link between benzene exposure and non-Hodgkin lymphoma, especially for diffuse large B-cell lymphoma. FUNDING: National Institute of Environmental Health Sciences.

Exposure to glyphosate and risk of non-Hodgkin lymphoma: an updated meta-analysis.

OBJECTIVE: We updated a recent systematic review and meta-analysis of epidemiologic studies to help clarifying the association between exposure to glyphosate and risk of non-Hodgkin lymphoma (NHL). METHODS: We conducted an updated search of the literature, and identified a total of 15 relevant publications, from which we extracted results from six non-overlapping studies. We performed random-effects meta-analyses for ever-exposure to glyphosate, dose-response, and risk of specific NHL subtypes Results: The meta-RR for ever-exposure to glyphosate was 1.05 (95% confidence interval [CI] 0.90-1.24; I2 = 0%). The meta-RR for the highest category of exposure was 1.15 (95% CI 0.72-1.83; 3 studies). The meta-RR for diffuse large B-cell lymphoma (DLBCL) was 1.29 (95% CI 1.02-1.63; 4 studies), that for follicular lymphoma was 0.84 (95% CI 0.61-1.17), and that for chronic lymphocytic leukemia/small lymphocytic lymphoma was 1.33 (95% CI 0.65-2.70). There was indication of publication bias. CONCLUSIONS: This updated meta-analysis reinforces our previous conclusion of a lack of an association between exposure to glyphosate and risk of NHL overall, although an association with DLBCL cannot be ruled out.

A Review and Update with Perspective of Evidence that the Herbicide Glyphosate (Roundup) is a Cause of Non-Hodgkin Lymphoma.

Glyphosate-based formulations (GBFs), such as Roundup, are the most heavily used herbicides in the world. In 2015, the International Agency for Research on Cancer (IARC) concluded that glyphosate and GBFs are probably carcinogenic to humans (group 2A), mainly for non-Hodgkin lymphoma (NHL). However, this finding has been controversial, and most pesticide regulatory agencies have not followed their lead. The purpose of this review was to examine the scientific literature linking exposure to glyphosate and GBFs to the development of NHL, with emphasis on new findings since publication of the IARC report. The epidemiologic studies provide ample evidence for an association between exposure to GBFs and an increased risk of NHL. Animal studies have shown that glyphosate is carcinogenic in rodents and causes NHL in mice. Mechanistic studies have demonstrated that glyphosate and GBFs are genotoxic to human lymphocytes, the normal cell of origin of NHL, both in vitro and in vivo. Genotoxic and other biological effects have also been shown in various animal and cell models with these agents even at low doses. A novel mechanism underlying the specificity of glyphosate for NHL, that is upregulation of the B-cell genome mutator enzyme activation-induced cytidine deaminase, has recently been demonstrated. These findings were evaluated holistically using the guidelines for evaluation of general causation set forth by Bradford Hill. This evaluation provides coherent and compelling evidence that glyphosate and GBFs are a cause of NHL in humans exposed to these agents. These findings should prompt new reviews by pesticide regulatory agencies around the world.

Development of a Questionnaire for the Search for Occupational Causes in Patients with Non-Hodgkin Lymphoma: The RHELYPRO Study.

Non-Hodgkin lymphoma (NHL), multiple myeloma and chronic lymphocytic leukemia are possibly related to environmental and/or occupational exposure. The primary objective of this study was to develop a questionnaire for screening patients with these blood disorders who might benefit from a specialized consultation for possible recognition of the disease as an occupational disease. The study included 205 subjects (male gender, 67.3%; mean age, 60 years; NHL, 78.5%). The questionnaire performed very satisfactorily in identifying the exposures most frequently retained by experts for their potential involvement in the occurrence of NHL. Its sensitivity and specificity in relation to the final expertise were 96% and 96% for trichloroethylene, 85% and 82% for benzene, 78% and 87% for solvents other than trichloroethylene and dichloromethane, 87% and 95% for pesticides, respectively. Overall, 15% of the subjects were invited to ask National Social Insurance for compensation as occupational disease. These declarations concerned exposure to pesticides (64%), solvents (trichloroethylene: 29%; benzene: 18%; other than chlorinated solvents: 18%) and sometimes multiple exposures. In conclusion, this questionnaire appears as a useful tool to identify NHL patients for a specialized consultation, in order to ask for compensation for occupational disease.

Dietary exposure to polychlorinated biphenyls (PCB) and risk of Non-Hodgkin's lymphoma: Evidence from the French E3N prospective cohort.

INTRODUCTION: Polychlorinated biphenyls (PCB) are persistent and bioaccumulative lipophilic substances, mostly used in the past by industry. Known to be cancerogenic, PCB are suspected to increase Non-Hodgkin's Lymphoma (NHL) risk in the general population mainly due to evidence from cases-controls studies. Since their interdiction in 1987, diet represents the main route of exposure for the general population, nevertheless no study has assessed the relationship between PCB dietary exposure and NHL risk. The aim of this study was to analyze the association between dietary exposures to dioxin like PCB (DL PCB) and non-dioxin like PCB (NDL PCB) and NHL risk in the E3N prospective cohort of French women. MATERIALS AND METHODS: Among 67,879 women included in this study, 457 cases of NHL were confirmed during 21 years of follow-up. Dietary exposure to PCB was estimated combining food consumption data collected in E3N and food contamination data provided by French Agency for Food, Environmental and Occupational Health & Safety (ANSES) in the second French total diet study. Cox regression models, adjusted for potential confounders, were used to estimate hazard ratio (HR) and 95% confidence intervals (CI). RESULTS: Average age at diagnosis was 67 years. The median dietary exposure to DL PCB and NDL PCB was, 18.5 pg TEQ/d and 138,843.2 pg/d, respectively. While no association was found between dietary exposure to DL PCB or NDL PCB and overall NHL risk, analyses by NHL histological subgroups showed a positive association between dietary exposures to DL PCB and Diffuse Large B Cell Lymphoma (OR3vs1 1.90, 95%CI [1.03-3.51], ptrend 0.02). Nevertheless these findings were no longer statistically significant when the models were adjusted for fish and dairy products consumption. In addition, an inverse association was found between dietary exposure to NDL PCB and the risk of follicular lymphoma (OR3vs1 0.46, 95%CI [0.24-0.87], ptrend 0.01). CONCLUSION: This is the first study to evaluate the association between dietary exposure to DL and NDL PCB and the risk of NHL in a prospective cohort study. Overall, the findings suggest a lack of association between dietary exposure to DL or NDL PCB and NHL risk. Additional studies are needed to reproduce these findings.

A systematic review and meta-analysis of occupational exposures and risk of follicular lymphoma.

BACKGROUND: The etiology of follicular lymphoma (FL), a common non-Hodgkin lymphoma subtype, is largely unknown. OBJECTIVE: We performed a systematic review and meta-analysis of observational studies examining the relationship between occupational exposures and FL risk. METHODS: We searched Ovid MEDLINE, Ovid EMBASE, and Web of Science for eligible observational studies examining job titles or occupational exposures prior to January 1, 2020. We performed a narrative synthesis and used random-effects models to generate meta-estimates of relative risk (RR) with 95% confidence intervals (95%CI) for exposures reported by three or more studies. RESULTS: Fifty-eight studies were eligible. Ten cohort and 37 case-control studies quantified FL risk in relation to any exposure to one or more occupational groups or agents. Eight cohort and 19 case-control studies examined dose-response relationships. We found evidence of a positive association with increasing plasma concentration of dichlorodiphenyldichloroethylene (DDE; meta-RR = 1.51, 95%CI = 0.99, 2.31; I2 = 0.0%) and polychlorinated biphenyls (PCBs; meta-RR = 1.47, 95%CI = 0.97, 2.24; I2 = 8.6%). We observed a positive association with exposure to any solvent (meta-RR = 1.16, 95%CI = 1.00, 1.34; I2 = 0.0%) and chlorinated solvents (meta-RR = 1.35, 95%CI = 1.09, 1.68; I2 = 0.0%). Single studies reported a significant positive dose-response association for exposure to any pesticide, hexachlorobenzene, any organophosphate, diazinon, metolachlor, carbaryl, lindane, trichloroethylene, oils/greases, and extremely low-frequency magnetic fields. Job title-only analyses suggested increased risk for medical doctors and spray painters, and decreased risk for bakers and teachers. Overall, studies demonstrated low risk of bias, but most studies examined small numbers of exposed cases. CONCLUSIONS: Current evidence indicates a positive association between FL and occupational exposure to DDE, PCBs, any solvent and chlorinated solvents. Our findings may help guide policies and practices on the safe use of solvents and inform models of lymphomagenesis. Future studies with larger sample sizes and comprehensive quantitative exposure measures may elucidate other avoidable carcinogenic exposures.

Residential Exposure to PM2.5 Components and Risk of Childhood Non-Hodgkin Lymphoma in Denmark: A Nationwide Register-Based Case-Control Study.

In a recent study, we observed an increased risk of childhood non-Hodgkin lymphoma (NHL) associated with exposure to fine atmospheric particulate matter (PM2.5) and black carbon (BC). In this nationwide register-based case-control study, we focus on specific components of PM2.5 in relation to childhood NHL in Denmark (1981-2013) by identifying all incidents of childhood NHL cases in the Danish Cancer Registry (n = 170) and four (cancer-free) randomly selected controls matched by date of birth and sex. We applied PM2.5 concentrations and the following sub-components: secondary organic aerosols (SOA), secondary inorganic aerosols (SIA; i.e., NO3-, NH4+ and SO42-), BC, organic carbon (OC) and sea salt. We calculated a time-weighted exposure average from birth to index-date at all addresses. Odds ratios (ORs) were adjusted for register-based socio-demographic variables. We observed adjusted ORs and 95% confidence intervals (95% CI) of 2.05 (1.10, 3.83) per interquartile range (IQR, 4.83 µg/m3) PM2.5 and 1.73 (0.68, 4.41) per IQR (3.71 µg/m3) SIA, 0.95 (0.71, 1.29) per IQR (0.05 µg/m3) SOA, 1.22 (1.02, 1.46) per IQR (0.39 µg/m3) BC, 1.02 (0.83, 1.26) per IQR (0.56 µg/m3) OC and 1.01 (0.79, 1.30) per IQR (0.87 µg/m3) sea salt, respectively. The estimates were attenuated after adjustment for PM2.5, whereas the OR for PM2.5 remained increased regardless of adjustment for specific components. The findings indicate that the previously observed relation between PM2.5 and childhood NHL may be related to BC (as reported in our previous study) but also partly to SIA, but the role of specific chemical components of PM2.5 remains ambiguous.