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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.

Rev1 has two important functions in the translesion synthesis pathway, including dCMP transferase activity, and acts as a scaffolding protein for other polymerases involved in translesion synthesis. However, the role of Rev1 in mutagenesis and tumorigenesis in vivo remains unclear. We previously generated Rev1-overexpressing (Rev1-Tg) mice and reported that they exhibited a significantly increased incidence of intestinal adenoma and thymic lymphoma (TL) after N-methyl-N-nitrosourea (MNU) treatment. In this study, we investigated mutagenesis of MNU-induced TL tumorigenesis in wild-type (WT) and Rev1-Tg mice using diverse approaches, including whole-exome sequencing (WES). In Rev1-Tg TLs, the mutation frequency was higher than that in WT TL in most cases. However, no difference in the number of nonsynonymous mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) genes was observed, and mutations involved in Notch1 and MAPK signaling were similarly detected in both TLs. Mutational signature analysis of WT and Rev1-Tg TLs revealed cosine similarity with COSMIC mutational SBS5 (aging-related) and SBS11 (alkylation-related). Interestingly, the total number of mutations, but not the genotypes of WT and Rev1-Tg, was positively correlated with the relative contribution of SBS5 in individual TLs, suggesting that genetic instability could be accelerated in Rev1-Tg TLs. Finally, we demonstrated that preleukemic cells could be detected earlier in Rev1-Tg mice than in WT mice, following MNU treatment. In conclusion, Rev1 overexpression accelerates mutagenesis and increases the incidence of MNU-induced TL by shortening the latency period, which may be associated with more frequent DNA damage-induced genetic instability., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

We conducted a hospital-based case-control study to explore the association between proximity to various land use types and childhood leukemia and lymphoma. This research involved 428 cases of childhood leukemia and lymphoma (2016-2021), along with a control group of 428 children aged 1-15 in Tehran. We analyzed the risk of childhood cancer associated with land use by employing logistic regression adjusted for confounding factors such as parental smoking and family history. The odds ratio (OR) for children with leukemia and lymphoma residing within 100 m of the nearest highway was 1.87 (95% CI = 1.00-3.49) and 1.71 (95% CI = 1.00-2.93), respectively, in comparison to those living at a distance of 1000 m or more from a highway. The OR for leukemia with exposure to petrol stations within 100 m was 2.15 (95% CI = 1.00-4.63), and for lymphoma it was 1.09 (95% CI = 0.47-2.50). A significant association was observed near power lines (OR = 3.05; 95% CI = 0.97-9.55) within < 100 m for leukemia. However, no significant association was observed between power lines and the incidence of childhood lymphoma. There was no association between bus stations, major road class 2, and the incidence of childhood leukemia and lymphoma. In conclusion, our results suggest a possible association between the incidence of childhood leukemia and proximity to different urban land uses (i.e., highways and petrol stations). This study is the first step in understanding how urban land use affects childhood leukemia and lymphoma in Tehran. However, comprehensive studies considering individual-level data and specific pollutants are essential for a more nuanced understanding of these associations., (© 2024. The Author(s).)

Leukemia and lymphoma are the two most common forms of hematologic malignancy, and their etiology is largely unknown. Pathophysiological mechanisms suggest a possible association with air pollution, but little empirical evidence is available. We aimed to investigate the association between long-term residential exposure to outdoor air pollution and risk of leukemia and lymphoma. We pooled data from four cohorts from three European countries as part of the "Effects of Low-level Air Pollution: a Study in Europe" (ELAPSE) collaboration. We used Europe-wide land use regression models to assess annual mean concentrations of fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), black carbon (BC) and ozone (O 3 ) at residences. We also estimated concentrations of PM 2.5 elemental components: copper (Cu), iron (Fe), zinc (Zn); sulfur (S); nickel (Ni), vanadium (V), silicon (Si) and potassium (K). We applied Cox proportional hazards models to investigate the associations. Among the study population of 247,436 individuals, 760 leukemia and 1122 lymphoma cases were diagnosed during 4,656,140 person-years of follow-up. The results showed a leukemia hazard ratio (HR) of 1.13 (95% confidence intervals [CI]: 1.01-1.26) per 10 μg/m 3 NO 2 , which was robust in two-pollutant models and consistent across the four cohorts and according to smoking status. Sex-specific analyses suggested that this association was confined to the male population. Further, the results showed increased lymphoma HRs for PM 2.5 (HR = 1.16; 95% CI: 1.02-1.34) and potassium content of PM 2.5 , which were consistent in two-pollutant models and according to sex. Our results suggest that air pollution at the residence may be associated with adult leukemia and lymphoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the risk of malignancy (overall, breast, lung, and lymphoma) in patients with rheumatoid arthritis treated with abatacept, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), and other biologic/targeted synthetic (b/ts)DMARDs in clinical practice., Methods: Four international observational data sources were included: ARTIS (Sweden), RABBIT (Germany), FORWARD (USA), and BC (Canada). Crude incidence rates (IRs) per 1000 patient-years of exposure with 95% confidence intervals (CIs) for a malignancy event were calculated; rate ratios (RRs) were estimated and adjusted for demographics, comorbidities, and other potential confounders. RRs were then pooled in a random-effects model., Results: Across data sources, mean follow-up for patients treated with abatacept (n = 5182), csDMARDs (n = 73,755), and other b/tsDMARDs (n = 37,195) was 3.0-3.7, 2.9-6.2, and 3.1-4.7 years, respectively. IRs per 1000 patient-years for overall malignancy ranged from 7.6-11.4 (abatacept), 8.6-13.2 (csDMARDs), and 5.0-11.8 (other b/tsDMARDs). IRs ranged from: 0-4.4, 0-3.3, and 0-2.5 (breast cancer); 0.1-2.8, 0-3.7, and 0.2-2.9 (lung cancer); and 0-1.1, 0-0.9, and 0-0.6 (lymphoma), respectively, for the three treatment groups. The numbers of individual cancers (breast, lung, and lymphoma) in some registries were low; RRs were not available. There were a few cases of lymphoma in some of the registries; ARTIS observed an RR of 2.8 (95% CI 1.1-6.8) with abatacept versus csDMARDs. The pooled RRs (95% CIs) for overall malignancy with abatacept were 1.1 (0.8-1.5) versus csDMARDs and 1.0 (0.8-1.3) versus b/tsDMARDs., Conclusions: This international, post-marketing observational safety study did not find any statistically significant increase in the risk of overall malignancies in pooled data in patients treated with abatacept compared with csDMARDs or with other b/tsDMARDs. Assessment of larger populations is needed to further evaluate the risks for individual cancers, especially lymphoma., Competing Interests: Declaration of Competing Interest TAS and AG were employees of (at the time of the analysis), and are shareholders in, Bristol Myers Squibb. SS has attended scientific advisory committee meetings for Atara, Boehringer Ingelheim, Merck, Pfizer, and Seqirus; received speaking fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and received grant/research support from Boehringer Ingelheim. MB has received speaker fees from Novartis and Pfizer and provides expert testimony for Celltrion. MCH has received personal fees from Bristol Myers Squibb (advisory board member) and is Editor-in-Chief of Seminars in Arthritis and Rheumatism. MLS is an employee of, shareholder in, and consultant for Bristol Myers Squibb. JA has received grant/research support from and has served as a PI for AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB. AS has received grant/research support from a consortium of 14 companies (AbbVie, Bristol Myers Squibb, Celltrion, Fresenius Kabi, Gilead/Galapagos, Hexal, Lilly, Mylan/Viatris, Merck Sharp & Dohme, Pfizer, Roche, Samsung, Sanofi-Aventis, and UCB); and has received honoraria from AbbVie, Bristol Myers Squibb, Celltrion, Merck Sharp & Dohme, Pfizer, and Roche. YM (for the German RABBIT register) is supported by a joint, unconditional grant from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Fresenius Kabi, Hexal, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, UCB, and Viatris; and has received honoraria from Pfizer. AD is an employee of, and shareholder in, Bristol Myers Squibb. No other disclosures relevant to this article were reported., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Cancer and cardiovascular diseases both have adverse effects on each other. We aim in the current study to investigate cardiac dysfunction including its prevalence, and associated factors in patients treated for breast cancer and lymphoma in a unique cardiac oncology center., Methods: A single-center retrospective study included 180 patients with cancer breast and lymphoma who presented and were treated at our oncology center from January 2019 to February 2022., Result: Out of 180 consecutive patients, 155 patients (86 %) were diagnosed with cancer breast and 25 patients (14 %) were diagnosed with lymphoma. Patients with lymphoma were older age, less obese, and showed more prevalence of diabetes mellitus (DM) (P = 0.026, 0.05, and 0.04 respectively). They also showed more post-therapy left ventricular (LV) dilatation and lower values of global longitudinal strain (GLS); however, they did not develop more LV dysfunction compared to cancer breast patients. Moreover, lymphoma patients showed poor in-hospital outcomes (P = 0.04, 0.001, and 0.015 for infection, pericardial effusion, and mortality respectively). Cancer therapy-related cardiac dysfunction (CTRCD) was observed in 41 patients (23 %) of our population. The independent predictors of CTRCD in the current study were DM, low body mass index (BMI), and the use of trastuzumab., Conclusions: Some patients treated for breast cancer and lymphoma develop LV dysfunction. Lymphoma patients showed more subclinical LV dysfunction and poor in-hospital outcomes compared to patients with cancer breast. DM, low body mass index (BMI), and the use of trastuzumab were the independent predictors of cardiac dysfunction among our patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Brentuximab vedotin (BV) was approved as a therapy for patients with CD30-positive lymphoma in China in 2020 based on the results of multiple clinical trails. Few Chinese real-world data of its use are yet available. Herein, we present the application situation of BV in patients with lymphoma among different hospitals in Henan province in China under real-world conditions., Methods: This was a multicenter and retrospective study in 104 patients with lymphoma who received BV for the first time between August 2020 and September 2022 across eight centers in Henan province. Data on the clinical use, effectiveness and adverse events (AEs) of BV were extracted from patient medical records. Short-term effectiveness was assessed based on objective response rate (ORR), complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier method. Safety was also evaluated in our study., Results: 104 lymphoma patients were enrolled in our study, who had completed a median of two cycles (range,1-8) of BV-based treatment. A total of 72.1% of patients were relapsed/refractory (R/R) lymphoma, and only 27.9% were previously untreated lymphoma who received BV in frontline treatment settings. Among them who received effectiveness evaluation, the ORR achieved 64.5% (CR 25.8%, PR 38.7%). After a median follow-up of 11 months, the 6-month PFS rate and OS rate achieved 77.2% and 90.1% respectively, and the 12-month PFS rate and OS rate achieved 77.2% and 79.9% respectively. In general, BV-based treatment was well-tolerated, with 38.5% incidence of grade ≥3 AEs. The most commonly reported AEs were hematologic disorders, especially neutropenia, with the incidence reaching 50.0%., Conclusions: BV-based regimens could be a promising therapeutic option with remarkable effectiveness and moderate toxicity in treating Chinese lymphoma patients with CD30 expression., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The background status and the current treatment options of patients with rheumatoid arthritis (RA) who develop malignant lymphoma (ML) and other malignancies are unclear. This study investigated the differences in background factors between ML and other malignancies that occur in RA patients and post-malignancy treatment., Methods: We identified 935 RA patients with new-onset malignancies among 110,571 person-years registered in the National Database of Rheumatic Disease in Japan from 2012 to 2018. Analysis cohorts 1 and 2 included 597 and 490 patients with available data for 1 year before and after the development of malignancies, respectively. Factors associated with the development of ML were longitudinally evaluated by multiple logistic regression analyses., Results: Of the 935 patients (mean age 70.5, standard deviation 9.9), 15.5% had ML; this was comparable to the rate of lung cancer (14.3%). In cohort 1, methotrexate (MTX), biological disease-modifying anti-rheumatic drugs (bDMARDs), and non-steroidal anti-inflammatory drugs (NSAIDs) were used in 74.4%, 23.4%, and 56.7% of ML and in 56.8%, 25.4%, and 35.3% of other malignancies 1 year before the occurrence of malignancies. Clinical disease activity index (CDAI) and C-reactive protein were similar between the two groups. Multivariable analysis showed that MTX use (odds ratio [OR]: 2.22, 95% CI [confidence interval]: 1.32-3.73, p=0.003) and NSAID use (OR: 2.51, 95% CI: 1.58-3.98, p <0.001) were significantly associated with the development of ML versus other malignancies. However, this association was not observed with bDMARDs. In cohort 2, one year after the development of malignancies, MTX was used in none of ML and 41.8% of patients who developed other malignancies. In both malignancy groups, approximately 15% of patients received bDMARDs and 50% received glucocorticoids. IL-6 inhibitors were preferentially prescribed in patients with ML versus those with other malignancies. At year 1, CDAI remission was achieved in 37.3% and 31.1% of patients in the ML and other malignancy groups, respectively., Conclusion: Patients receiving long-term treatment with MTX and NSAIDs may be at a relatively high risk of developing ML. The treatment landscape after developing malignancies differed considerably between patients with ML and other malignancies, and different treatment strategies should be established., Competing Interests: Declaration of Competing Interest TS has received research grants and/or honoraria from Abbvie Japan Co., Ltd., AsahiKASEI Co., Ltd., Astellas Pharma Inc., Ayumi Pharmaceutical, Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo., Eli Lilly Japan K.K., Mitsubishi-Tanabe Pharma Co., Ono Pharmaceutical, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., and UCB Japan Co. Ltd. TM has received grants and/or honoraria from Abbvie Japan Co., Ltd., AsahiKASEI Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo., Eli Lilly Japan K.K., Mitsubishi-Tanabe Pharma Co., Ono Pharmaceutical, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Taisho Pharmaceutical Co. Ltd., and UCB Japan Co. Ltd. YU has received honoraria from AsahiKASEI Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Gilead Sciences, Inc., Pfizer Japan Inc., and Sanofi K.K. KK has received grants and/or honoraria from Abbvie Japan Co., Ltd., AsahiKASEI Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Mitsubishi-Tanabe Pharma Co., Ayumi Pharmaceutical, Bristol Myers Squibb K.K., Taisho Pharmaceutical Co. Ltd., and UCB Japan Co. Ltd, Pfizer Japan Inc., Eisai Co., Ltd., and Gilead Sciences, Inc. All other authors have declared no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

This study aimed to investigate a stratified approach based on hepatitis B virus (HBV) surface antibody (anti-HBs) for managing HBV reactivation (HBVr) in lymphoma patients with serological protection against HBV. A retrospective analysis was conducted on 209 lymphoma patients with a baseline anti-HBs titre of ≥10 iu/L, who were either positive or negative for HBV core antibody (anti-HBc). The results revealed that 15.7% of patients lost serological protection following 6-month anti-lymphoma therapy. With a median follow-up of 28.1 months, the cumulative rates of HBVr at 6 months, 2 years and 4 years were 2.9%, 4.7% and 6.3% respectively. Without intervention, the overall rate of reactivation was 2.0% for patients with isolated anti-HBs and 10.5% for those with positive anti-HBs and anti-HBc. To identify patients at high risk of losing seroprotection and susceptible to HBVr, a predictive model was developed. The high-risk group had significantly higher rates of serological protection loss (27.8% vs. 2.2%) and cumulative incidence of HBVr (22.0% vs. 0%) compared to the low-risk group. Overall, this study highlights the risk of HBVr in lymphoma patients with positive anti-HBs, with or without positive anti-HBc, and recommends periodic monitoring for low-risk patients and early intervention for high-risk patients., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: The risk of malignancy in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) and biological disease-modifying antirheumatic drug (bDMARD) combination therapy is unknown. This study aimed to clarify the incidence of malignancy and the recommended monitoring period in patients receiving this combination therapy., Materials and Methods: A retrospective, observational study based on a large Japanese medical claims database was conducted between April 2013 and February 2020. Patients with RA were classified into MTX-alone and combination therapy groups, and the standardized incidence rates (SIR) of malignancy were calculated. The time of onset of malignancy in both groups was calculated., Results: In total, 2,052 patients received MTX-alone and 782 received combination therapy. The incidence of malignant lymphoma was significantly higher with MTX-alone therapy (SIR: 6.09, 95% confidence interval (CI): 1.58 - 10.61) and combination therapy (SIR: 20.86, 95% CI: 8.53 - 33.19) than in the general Japanese population. Furthermore, the combination therapy had a significantly higher risk of malignant lymphoma than the MTX-alone therapy (adjusted odds ratio: 4.27, 95% CI: 1.64 - 11.12). The median time from MTX prescription to the onset of malignant lymphoma was 3.58 years (interquartile range (IQR): 2.00 - 5.34 years) for MTX-alone and 3.42 years (IQR: 1.25 - 4.92 years) for combination therapy., Conclusion: The incidence of malignant lymphoma in the combination therapy group was extensively higher than that in the general Japanese population. Special attention is required for early symptoms of malignant lymphoma, particularly in the 3 rd - 4 th year after initiating MTX therapy.

Background: Haemolymphoreticular neoplasias (HLRNs) from the Ramazzini Institute (RI) carcinogenicity studies on Aspartame (APM) in rats and mice were heterogeneously grouped over the years and different statistical methods were applied., Objective: We report all the detailed HLRN diagnoses of all the RI rats and mice studies on APM and the related statistics., Methods: Histological subtypes and lineage (myeloid or lymphoid) are reported in males (MM) and females (FF) in line with the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions (INHAND) for rodents and the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues. Statistical analyses included Fisher's Exact test and Cochran-Armitage trend test., Findings: Results from the post-natal bioassay on Sprague-Dawley (SD) rats (BT6008) showed statistically significant increases in lymphomas (all types) (MM, FF), leukemias (all types) (FF), immunoblastic lymphomas (MM, FF), total lymphoid tumours (MM, FF), monocytic leukemia (FF), myeloid leukemia (FF), histiocytic sarcoma (FF), and total myeloid tumours (FF). Results from the prenatal experiment on SD rats (BT6009), showed statistically significant increases in lymphomas (all types) (FF), leukemias (all types) (FF), total lymphoid tumours (FF), myeloid leukemia (FF), and total myeloid tumours (FF). Finally, results from the prenatal bioassay on Swiss mice (BT6010) showed statistically significant increases in leukemias (all types) (MM, FF), lymphoblastic leukemia (MM, FF), monocytic leukemia (MM) and total myeloid tumours (MM)., Conclusions: Our analyses, performed in line with international recommended guidelines for statistics and pathology, confirm and reinforce our previous findings of statistically significant increases of HLRNs in rodents exposed to APM., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

COVID-19 infection and vaccination may be associated with a wide variety of cutaneous and immune manifestations. Here, we describe two patients who presented with monoclonal cutaneous T-cell infiltrates that showed cytologic and immunophenotypic features concerning for lymphoma shortly following COVID-19 vaccination. In one case, the eruption completely resolved. The second patient showed initial resolution, but her disease recurred and progressed following a breakthrough SARS-CoV-2 infection. These cases suggest that immune stimulation following exposure to SARS-Cov-2 protein(s) in vaccine or infection may facilitate the development of a lymphoma or lymphoproliferative disorder in susceptible individuals. Moreover, they show that separating these cases from pseudolymphomatous reactive conditions is often challenging and requires close clinical correlation., (© 2022 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal infection of the central nervous system caused by reactivation of John Cunningham virus (JCV). The case of a 59-year-old woman presenting with neurological disorders after treatment of her relapsed lymphoma with rituximab, among others, is reported. Magnetic resonance imaging showed fast-growing white matter lesions of both hemisphere and cerebellar that were neither space-consuming nor enhancing contrast media. Clinical and radiological suspicion of PML was confirmed by detection of JCV-DNA in cerebrospinal fluid. The patient died from devastating neurological decline only 11 days after the diagnosis was made. Due to the wider indication of monoclonal antibodies in almost every medical specialty we must always consider iatrogenic PML in addition to classic PML associated with acquired immunodeficiency syndrome (AIDS)., (© 2022. The Author(s).)

Objective: To analyze the value of 3-dimensional speckle tracking echocardiograghy (3D-STE) derived strain parameters on the detection of subclinical myocardial deformation alterations in patients with lymphoma treated with anthracycline agents. Methods: This study was a retrospective study. A total of 37 patients with newly diagnosed diffuse large B cell non-Hodgkin lymphoma between December 2012 and December 2014 in Cancer Center, Fudan university were included. 3D-STE strain measurements were performed at baseline (T0),after the completion of two therapy circles (T1) and at the end of anthracycline regimen chemotherapy (Te). Echocardiography images were analyzed on the TTA workstation, and the indexes included left atrial minimum volume (LAVmin), left atrial emptying index (LAEF), left atrial active emptying index (LAAEF), as well as the left ventricular global longitudinal strain (LVGLS), left ventricular global circumferential strain (LVGCS), left atrial global longitudinal strain (LAGLS). The overall left atrioventricular longitudinal strain (LAVGLS) was calculated, which was the sum of the absolute values of LVGLS and LAGLS. The changes of left ventricular strain indexes measured by 3D-STE at different time points of patients were evaluated. Results: Thirty-seven patients with DLBCL, aged (48.3±12.1)years, including 23 males (63.9%), were enrolled. Compared with baseline, LVGLS (T1: (-18.63±4.73)% vs. (-22.13±4.40)%, P =0.001; Te:(-18.26±4.64)% vs. (-22.13±4.40)%, P <0.001), LAGLS (T1: (20.41±5.56)% vs. (23.98±5.59)%, P =0.003; Te: (17.60±3.96)% vs. (23.98±5.59)%, P <0.001) and LAVGLS (T1: (39.05±7.60)% vs. (46.11±7.77)%, P <0.001; Te: (40.34±8.55)% vs. (46.11±7.77)%, P <0.001) were all deteriorated at the T1 and Te. While LVGCS ((-21.98±5.82)% vs. (-26.15±7.51)%, P =0.010), LAVmin ((23.93±7.29)ml vs. (20.33±7.03)ml, P =0.029), LAEF ((28.94±11.16)% vs. (35.79±11.12)%, P =0.002) and LAAEF ((11.93±10.00)% vs. (18.10±9.96)%, P =0.013) were decreased only until Te. Conclusions: 3D-STE strain measurements could detect early myocaridial function alteration in patients receiving anthracycline regimen chemotherapy, thus may provide a novel approach to monitor anthracycline caused myocardial toxicity.

Background: After several cases of peculiar hematological malignancies following introduction of new oral anti-hepatitis C virus (HCV) treatments in our recent practice, we aimed to systematically identify all cases of hematological malignancies (HM) in patients with chronic HCV infection and to compare them according to the prescription of oral anti-HCV Direct Acting Antivirals (DAA) treatment or not., Material/methods: In this single-center retrospective observational study, we included all patients with confirmed HM and chronic HCV infection managed between 2010 and 2019 in the Pitié-Salpêtrière hospital, Paris. Non-inclusion criteria were a benign hematological disorder, an HM preceding chronic HCV infection and HCV acute infection. We compared characteristics of patients who received DAA before HM diagnosis to those with no DAA before HM., Results: Over the 10 years, 61 cases of HM among HCV infected patients were identified (female 29%, median age of 58.0 years [IQR 17]). Twenty-one received DAA before the onset of HM (Group DAA+) and 40 did not (Group DAA-) including 22 having received DAA after HM. In the DAA+ group, oral NS5B, NS5A and NS3A inhibitors were used in 90, 76 and 29% respectively. HM developed in the two years following DAA initiation in 76%. Eight (38%) had Non-Hodgkin Lymphoma, 5 (24%) had an Acute Myeloid Leukaemia (AML) including two with a mixed phenotype, 2 each had Hodgkin Lymphoma, Multiple Myeloma or a myeloproliferative disorder and one each had a chronic Lymphocytic Leukaemia or AL Amyloidosis. In the Group DAA-, HM were NHL in 20(50%) patients, Myeloproliferative neoplasms in 7 (17%), Multiple Myeloma in 5, Hodgkin Lymphoma in 3, Myelodysplastic syndrome and AML in 2 (5%) each and Acute Lymphoblastic Leukaemia in one. No significant difference between the groups DAA + and - was found according to age, sex, HCV genotype, viral load, co-infection or type and exposition of previous HCV treatments. AML, liver transplantation and cirrhosis were significantly more frequent in the DAA+ group (p = 0.020, 0.045 and 0.032, respectively)., Conclusion: AML seemed more frequent after using DAA treatments, notably in severe HCV patients including cirrhotic and/or liver transplanted patients. A multicentric observational study is ongoing to confirm and explore the results., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background and Aim: Thiopurines are widely used to maintain remission in both ulcerative colitis (UC) and Crohn's disease (CD). Reported effectiveness and tolerability rates have been variable across studies. There are only sparse data in Asian population regarding the long-term efficacy and safety of thiopurines., Methods: Records of 5351 patients followed up at inflammatory bowel disease (IBD) clinic, All India Institute of Medical Sciences, New Delhi from 2004 to 2020 were evaluated retrospectively. Safety was evaluated in terms of long-term adverse events and development of malignancy., Results: Of 5351 patients with IBD, 1093 who received thiopurine for > 3 months (UC = 788 [proctitis-1.9%, left-sided colitis-44.9%, & pancolitis-53.1%] & CD = 305 [inflammatory-42.6%, stricturing-46.9%, & fistulizing-10.5%]) were included (60.8%-male patients). Follow up and treatment duration on thiopurine were 7 (4-12) years and 39.4 ± 40.3 months, respectively, with 254 (23.2%) patients receiving thiopurines for more than 5 and 68 (6.2%) receiving for more than 10 years. Three hundred and fifty-nine (UC: 249 [31.6%]; CD: 110 [36.1%]; P = 0.1) patients developed adverse events; commonest was myelosuppression (23.4%) followed by gastrointestinal intolerance (3%), flu-like illness (1.7%), and arthralgia/myalgia (1.4%). Myelosuppression was the commonest cause of thiopurine withdrawal. No patient (including 254 patients on thiopurine for ≥ 5 years) developed lymphoma or non-melanoma skin cancer. The cumulative probability of staying free from adverse events in overall IBD cohort at 1, 2, and 5 years was 78.6%, 71.9%, and 68.4%, respectively, and this was comparable between UC and CD (P = 0.09)., Conclusion: Long-term follow up of patients with IBD from northern India on thiopurine monotherapy demonstrated minimal risk of development of lymphoma as well as non-melanoma skin cancer., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Due to the high prevalence of HIV, HIV-associated lymphoma (HAL) is a common malignancy in South Africa. However, there is a paucity of literature on HAL from this region. The objective of this study was to profile the clinical characteristics and outcome of CD20-positive HAL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), with or without rituximab (R), from a single center in KwaZulu -Natal, South Africa., Methods: Retrospective chart review of adult patients treated from 2006 to 2018 for HIV-associated CD20-positive lymphoma. The clinical characteristics, complete response (CR), and 2-year overall survival (OS) are described., Results: The analysis included 102 patients, 54% females, median age of 39 years, and median CD4 cell count of 196 cells/μL. Bone marrow involvement was noted in 5%. Eighty-six percent of the cohort received concomitant antiretroviral therapy and chemotherapy, 76% of the CHOP group, and 92% of the R-CHOP group. Overall, a CR was seen in 55% (95% CI 45%; 65%), with a 2-year OS of 59% (95% CI 50%, 69%). A CR was attained in 46% on CHOP and 64% on R-CHOP, with a 2-year disease-free survival (DFS) for CHOP of 42% and 50% for R-CHOP., Conclusion: Although the clinical characteristics and laboratory findings are similar to other higher-income cohorts, there was a difference in gender and incidence of marrow involvement. The low incidence of marrow involvement has prompted more routine use of immunohistochemistry and flow cytometry in staging marrows of HAL locally. Further randomized studies are required for the establishment of locally validated, cost-effective treatment guidelines., (© 2022. The Author(s).)

No cigarette smoke test matrix is without limitation, due to the complexity of the starting aerosol and phase to phase dynamics. It is impossible to capture all chemicals at the same level of efficiency, therefore, any test matrix will inadvertently or by design fractionate the test aerosol. This case study examines how four different test matrices derived from cigarette smoke can be directly compared. The test matrices assessed were as follows, total particulate matter (TPM), gas vapour phase (GVP), a combination of TPM + GVP and whole aerosol (WA). Here we use an example assay, the mouse lymphoma assay (MLA) to demonstrate that data generated across four cigarette smoke test matrices can be compared. The results show that all test matrices were able to induce positive mutational events, but with clear differences in the biological activity (both potency and toxicity) between them. TPM was deemed the most potent test article and by extension, the particulate phase is interpreted as the main driver of genotoxic induced responses in the MLA. However, the results highlight that the vapour phase is also active. MLA appeared responsive to WA, with potentially lower potency, compared to TPM approaches. However, this observation is caveated in that the WA approaches used for comparison were made on a newly developed experimental method using dose calculations. The TPM + GVP matrix had comparable activity to TPM alone, but interestingly induced a greater number of mutational events at comparable relative total growth (RTG) and TPM-equivalent doses when compared to other test matrices. In conclusion, this case study highlights the importance of understanding test matrices in response to the biological assay being assessed and we note that not all test matrices are equal., (Copyright © 2022. Published by Elsevier B.V.)

Human urothelial cell carcinoma (UCC) and non-Hodgkin lymphoma are considered environmental cancers in people, but less is known about environment risk for UCC and lymphoma in dogs. The objective of this study was to determine whether dogs with these cancers, compared to unaffected control dogs, live in counties with higher tap water contaminants or higher levels of air pollution as measured by the Environmental Protection Agency (EPA) and by National Air Toxics Assessment chemical exposure risk estimates. Dogs with available home addresses from two previously published case-control populations were included: 66 dogs with UCC and 70 unaffected controls; and 56 boxer dogs with lymphoma and 84 unaffected boxer controls. Tap water total trihalomethanes, which are water disinfection by-products, were more than threefold higher in UCC case counties of residence compared to controls (p < .0001), and a higher proportion of dogs with UCC lived in counties exceeding EPA ozone limits (41.8%) compared to controls (13.6% p = .0008). More boxers with lymphoma lived in counties exceeding EPA ozone limits (52.1%) compared to controls (29.0%; p = .018), with higher exposure risk estimates for airborne 1,3-butadiene and formaldehyde (p = .004-.005). These data support the hypothesis that tap water contaminants and airborne environmental pollutants contribute to the risk of both urothelial carcinoma and lymphoma in dogs. If these findings reflect causal relationships, then it is possible that tap water filtration units and more effective air pollution controls could decrease the overall incidence of these cancers in dogs., (© 2021 John Wiley & Sons Ltd.)

A female patient in her 60s was going to get treatment for rheumatoid arthritis(RA). Considering the possibility of using biologics, CT examination was performed for screening of malignant diseases. A mass shadow in the left lobe of the thyroid gland was detected. The patient was followed up, and ultrasonography did not reveal any malignant findings. She was treated with methotrexate(MTX), and 1 year later, the thyroid mass was enlarged on CT. Ultrasonography revealed an enlarged hypoechoic region. Fine needle aspiration cytology revealed malignant lymphoma. Excisional biopsy was performed to determine the treatment plan. The pathological diagnosis was follicular lymphoma, and the possibility of methotrexate- associated lymphoproliferative disorders(MTX-LPD)persisted. It was difficult to discontinue MTX because of the high activity of RA. She was treated with rituximab for malignant lymphoma and concurrently with MTX for RA. The thyroid tumor disappeared for 3 months. Four years later, there is no sign of tumor recurrence.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Recently, there has been increased concern about a risk of secondary malignancies (SM) occurring in myelofibrosis (MF) patients receiving ruxolitinib (RUX). In polycythemia vera (PV), on the other hand, only limited data on the risk of SM under RUX treatment are available. To investigate the association between RUX therapy in PV and SM, we conducted a retrospective, single-center study that included 289 PV patients. RUX was administered to 32.9% (95/289) of patients for a median treatment duration of 48.0 months (range 1.0-101.6). Within a median follow-up of 97 months (1.0-395.0) after PV diagnosis, 24 SM occurred. Comparing the number of PV patients with RUX-associated SM (n = 10, 41.7%) with the 14 (58.3%) patients who developed SM without RUX, no significant difference (p = 0.34, chi square test) was found. No increased incidences of melanoma, lymphoma, or solid "non-skin" malignancies were observed with RUX (p = 0.31, p = 0.60, and p = 0.63, respectively, chi square test). However, significantly more NMSC occurred in association with RUX treatment (p = 0.03, chi-squared test). The "SM-free survival" was not significantly different by log rank test for all 289 patients (p = 0.65), for the patients (n = 208; 72%) receiving cytoreductive therapy (p = 0.48) or for different therapy sequences (p = 0.074). In multivariate analysis, advanced age at PV diagnosis (HR 1.062 [95% CI 1.028, 1.098]) but not administration of RUX (HR 1.068 [95% CI 0.468, 2.463]) was associated with an increased risk for SM (p = 0.005). According to this retrospective analysis, no increased risk of SM due to RUX treatment could be substantiated for PV., (© 2021. The Author(s).)

Methotrexate-associated lymphoproliferative disorder is recognized as a lymphoma that occurs following methotrexate administration. The lesion of the spine is extremely rare, and only one case of lesion in the lumbar spine has been reported so far. Here, we present a case of methotrexate-associated lymphoproliferative disorder of the thoracic spine in a 54-year-old woman with rheumatoid arthritis. The lesion formed an extra-skeletal tumor mass from lateral to the vertebral body to the paravertebral muscle extending posterior to the epidural space without bone destruction. Magnetic resonance imaging showed low signal intensities on both T1- and T2-weighted images and high signal intensity with short-tau inversion recovery. These radiological findings were similar to those for primary spinal lymphoma. The lesion rapidly paralyzed the patient, forcing her to be treated with posterior spinal decompression. The lesion could not be resected because it adhered to the dura. Following the histopathological diagnosis as methotrexate-associated lymphoproliferative disorder, methotrexate administration was terminated. The remaining mass lesion showed complete regression within 6 months. Methotrexate-associated lymphoproliferative disorder, which could be cured by the discontinuation of methotrexate, should be considered a differential diagnosis in spinal lesion cases showing lymphoma-like appearance with methotrexate treatment to avoid unnecessary treatments., (© 2021. The Author(s).)

The topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus have been used widely as corticosteroid-sparing agents in treating various cutaneous diseases. However, the association between TCIs and risk of malignancy remains controversial. By systematic review and meta-analysis, we aimed to investigate the association between TCIs and lymphoma. Eligible studies in online databases were identified from the date of inception to August 30, 2020. To assess the outcome of TCI-related risk of lymphoma, analysis of cohort studies comparing the incidence of lymphoma with and without treatment with TCIs was performed. Furthermore, the subgroup analyses of Hodgkin lymphoma and non-Hodgkin lymphoma were also conducted. The pooled results revealed that using topical tacrolimus (RR 1.68, 95 % CI 1.39-2.04) or pimecrolimus (RR 1.40, 95 % CI 1.13-1.74) significantly increased the risk of lymphoma. TCI users also showed higher incidence of lymphoma in the range of 0.02-0.09 %, compared to that of 0.02-0.06 % in the control group. Additionally, subgroup analyses showed both tacrolimus (RR 1.89; 95 % CI 1.53-2.32) and pimecrolimus (RR 1.38; 95 % CI 1.09-1.74) had significantly higher risk of non-Hodgkin lymphoma, but no increased risk of Hodgkin lymphoma. In conclusion, TCI-exposed patients have a significantly increased risk of lymphoma, especially non-Hodgkin lymphoma., (© 2021 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

BMS-986251 is a retinoid-related orphan receptor γt (RORγt) inverse agonist that was in development for the treatment of autoimmune diseases. RORγt is a nuclear hormone receptor and transcription factor that is involved in the differentiation and function of T helper 17 cells. RORγt-deficient (constitutive or conditional) mice develop thymic lymphomas with >50% mortality at 4 months, whereas heterozygous mice are normal. A 6-month study was conducted in rasH2-Tg hemizygous mice to assess the potential carcinogenicity of BMS-986251. BMS-986251 was administered once daily by oral gavage to groups of 27 mice/sex at doses of 0 (water control), 0 (vehicle control), 5, 25, or 75 mg/kg. The positive control, N-methyl-N-nitrosourea, was administered by a single intraperitoneal injection to 15 mice/sex at a dose of 75 mg/kg. There were no tumors attributed to BMS-986251 except for thymic lymphomas. Thymic lymphoma was observed in 1 male (3.7%) and 3 females (11.1%) at the mid dose, and 6 females (22.2%) at the high dose. No lymphomas were observed in the negative control groups whereas the incidence of lymphomas in the positive control group was 47-60%. The incidence of thymic lymphomas in the BMS-986251-treated groups was higher than published literature and test facility historical control data. Furthermore, increased thymic lymphoid cellularity (lymphoid hyperplasia) was observed at the mid dose in males and at all doses in females. Since lymphoid hyperplasia may represent a preneoplastic change, a no-effect dose for potential tumor induction was not identified in this study. These results led to the discontinuation of BMS-986251 and underscore the challenges in targeting RORγt for drug development., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Formal requirements for genotoxicity testing of drug candidates to support clinical entry have been in place since the issue of initial regulatory guidance over 25 years ago and subsequent update a decade ago. An evaluation of such testing, supporting first clinical entry of 108 small molecule drug candidates over the last decade, showed that the most common approach (75 % of tested compounds) was for a Good Laboratory Practice test battery in the form of 2 in vitro (a bacterial reverse mutation and a mammalian cell) assays and one in vivo assay. The majority of other tested compounds involved in vitro testing only in bacterial reverse mutation and mammalian cell assays. Testing using a bacterial reverse mutation assay and an in vivo assessment of genotoxicity with 2 different tissues was limited to 2 occasions. For in vitro mammalian cell testing, the chromosome aberration test was most commonly used (70 % occasions), followed by a micronucleus test (16 % occasions) or a mouse lymphoma assay (14 % occasions). For in vivo evaluation, the most common test was a rodent bone marrow micronucleus test (87 % occasions). A positive in vitro mammalian cell assay result was seen on 13 % occasions but was not confirmed with further in vivo testing and the drug candidates were taken into the clinic. In conclusion, the present evaluation showed that the current test battery paradigm for genotoxicity testing has an integral part in supporting clinical entry to confirm candidate drugs taken into the clinic are unlikely to have genotoxic activity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-cell lymphoblastic leukemia/lymphoma. Here we aimed to identify key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53 +/- , and Kras LA1 mice were not observed to harbor significantly higher numbers of nonsynonymous somatic mutations compared with thymic lymphomas from unirradiated p53 -/- mice. However, distinct patterns of recurrent mutations arose in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Reporter mice for activation of Notch1 signaling revealed that total-body irradiation (TBI) enriched Notch1 hi CD44 + thymocytes that could propagate in vivo after thymocyte transplantation. Mechanistically, genetic inhibition of Notch1 signaling in immature thymocytes prevented formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, these results demonstrate a critical role of activated Notch1 signaling in driving multistep carcinogenesis of thymic lymphoma following TBI in p53 WT mice. SIGNIFICANCE: These findings reveal the mutational landscape and key drivers in murine radiation-induced thymic lymphoma, a classic animal model that has been used to study radiation carcinogenesis for over 70 years., (©2021 American Association for Cancer Research.)

Abstract: We present here a 72-year-old man with mantle cell lymphoma who has completed chemotherapy and achieved complete metabolic response to the therapy 10 months ago. Series follow-up FDG PET/CT scans have been negative for lymphoma. Current FDG PET/CT scan showed a new cluster of subcentimeter left axillary lymphadenopathy with avid FDG uptake. There was also focal FDG uptake in the left upper arm deltoid muscle and adjacent subcutaneous soft tissue, with no other abnormal FDG-avid lesion or suspicious CT image findings. The medical history revealed that the patient received COVID-19 mRNA vaccine 2 days before the FDG PET/CT examination., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To estimate the association between biological DMARDs (bDMARDs; overall and by drug) as used in RA and the risk of malignant lymphomas including subtypes., Methods: By linking nationwide Swedish registers we identified cohorts of patients with RA initiating treatment with a bDMARD (n = 16 392), bDMARD-naïve (n = 55 253), an age- and sex-matched general population comparator cohort (n = 229 047), and all incident lymphomas 2001-16. We used Cox regression to calculate hazard ratios (HRs) of lymphoma taking calendar period and other factors into account., Results: There were 82 lymphomas among the bDMARD-treated patients with RA, crude incidence rate 76/100 000 person-years, and 310 lymphomas among the bDMARD-naïve patients with RA, crude incidence rate 90/100 000 person-years. This resulted in an adjusted HR (aHR) associated with bDMARD treatment (vs not) of 1.08 (95% CI: 0.83, 1.41). The corresponding aHR for bDMARD-treated and bDMARD-naïve vs the general population was 1.65 (95% CI: 1.31, 2.08) and 1.56 (95% CI: 1.37, 1.78) respectively. Restricting follow-up period to after 2006, the aHR of lymphoma for patients with RA starting a first bDMARD vs bDMARD-naïve was 0.69 (95% CI: 0.47, 1.00), and for bDMARD treated vs patients with RA switching from one conventional synthetic DMARDs to another, aHR was 0.46 (95% CI: 0.28, 0.73). There were no signals of different risks with any particular TNF inhibitor (TNFi) agent. We found no different lymphoma subtype pattern following bDMARD therapy., Conclusion: Treatment with bDMARDs, including both TNFi and non-TNFi bDMARDs, does not further increase the lymphoma risk in RA; instead, bDMARD treatment may actually reduce the excess lymphoma risk in RA., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents remains unclear., Aim: To assess the comparative risk of lymphoma with anti-TNF agents and/or thiopurines in IBD METHODS: We searched PubMed, EMBASE and Cochrane Library to identify studies that evaluated lymphoproliferative disorders associated with anti-TNF agents with or without thiopurines. The risk of lymphoma was assessed through four comparator groups: combination therapy (anti-TNF plus thiopurine), anti-TNF monotherapy, thiopurine monotherapy and control group. Pooled incidence rate ratios (IRR) were estimated through Poisson-normal models., Results: Four observational studies comprising 261 689 patients were included. As compared with patients unexposed to anti-TNF and thiopurines, those exposed to anti-TNF monotherapy, thiopurine monotherapy or combination therapy had pooled IRR (per 1000 patient-years) of lymphoma of 1.52 (95% CI: 1.06-2.19; P = 0.023), 2.23 (95% CI: 1.79-2.79; P < 0.001) and 3.71 (95% CI: 2.30-6.00; P ≤ 0.01), respectively. The risk of lymphoma associated with combination therapy was higher than with thiopurines or anti-TNF alone with pooled IRR of 1.70 (95% CI: 1.03-2.81; P = 0.039) and 2.49 (95% CI: 1.39-4.47; P = 0.002), respectively. The risk did not differ between anti-TNF monotherapy and thiopurine monotherapy with pooled IRR of 0.72 (95% CI: 0.48-1.07; P = 0.107). All observational studies were of high quality according to the Newcastle-Ottawa scale., Conclusions: There is an increased risk of lymphoma in IBD patients treated with anti-TNF agents, either alone or when combined with thiopurines., (© 2020 John Wiley & Sons Ltd.)

Background: Few studies have assessed the relation between maternal prenatal pesticides use and childhood lymphoma risk, some reporting a positive association with non-Hodgkin lymphoma (NHL). We investigated the association between maternal exposure to pesticides during pregnancy and childhood Hodgkin (HL) and non-Hodgkin lymphoma., Methods: We pooled data from the two French national population-based case-control studies ESCALE (2003-2004) and ESTELLE (2010-2011). Data on domestic and occupational exposures to pesticides during pregnancy were obtained through standardised maternal interviews. Logistic regression models were used to compute odds ratios (OR) and 95% confidence intervals (CI) for HL and NHL, by pesticide category adjusted for potential confounders. Analyses by histological subtypes were also performed., Results: We included 328 H L, 305 non-Hodgkin NHL and 2,415 controls. Around 40% of control mothers reported having used pesticides during index pregnancy, of whom 95% reported insecticides use. Maternal use of herbicides and fungicides occurred mostly in combination with insecticides. Insecticides use was more frequently reported in cases than controls (OR NHL  = 1.6 [95%CI 1.3-2.1], p = 0.0001; OR HL  = 1.3 [95%CI 1.0-1.7], p = 0.03). This association appeared more marked for Burkitt lymphoma and mixed cellularity classical HL. No obvious association was observed with occupational pesticides exposure during pregnancy., Conclusion: These results suggest that maternal domestic use of insecticides during pregnancy might be related to both childhood NHL and HL. Further larger studies are urgently needed., (Copyright © 2020. Published by Elsevier Ltd.)

Background: While international agreement supports a causal relationship of benzene exposure with acute myeloid leukemia, there is debate about benzene and lymphoid neoplasm risks., Methods: In a case-cohort study with follow-up of 110 631 Chinese workers during 1972-1999, we evaluated benzene exposure-response for non-Hodgkin lymphoma (NHL), lymphoid leukemias (LL), acute lymphocytic leukemia (ALL), and total lymphoid neoplasms (LN). We estimated benzene exposures using state-of-the-art hierarchical modeling of occupational factors calibrated with historical routine measurements and evaluated cumulative exposure-response using Cox regression., Results: NHL and other specified LN were increased in exposed vs unexposed workers. However, there was no evidence of exposure-response for NHL or other specified LN. Based on a linear exposure-response, relative risks at 100 parts per million-years (RR at 100 ppm-years) for cumulative benzene exposure using a 2-year lag (exposure at least 2 years before the time at risk) were 1.05 for NHL (95 percent confidence interval (CI) = 0.97, 1.27; 32 cases), 1.11 for LL (95% CI < 0, 1.66; 12 cases), 1.21 for ALL (95% CI < 0, 3.53; 10 cases), and 1.02 for total LN (95% CI < 0, 1.16; 49 cases). No statistically significant exposure-response trends were apparent for these LN for 2 to <10-year or ≥10-year lags. NHL risks were not significantly modified by sex, age, or year at first exposure, attained age, or time since exposure., Conclusion: Given the study strengths and limitations, we found little evidence of exposure-response for benzene and NHL, LL, ALL, or total LN, although NHL and other specified LN were increased in exposed vs unexposed individuals., (© 2020 Wiley Periodicals LLC.)

Background: Pesticide exposure is a suspected risk factor for childhood cancer. We investigated the risk of developing childhood cancer in relation to parental occupational exposure to pesticides in Switzerland for the period 1990-2015., Methods: From a nationwide census-based cohort study in Switzerland, we included children aged < 16 years at national censuses of 1990 and 2000 and followed them until 2015. We extracted parental occupations reported at the census closest to the birth year of the child and estimated exposure to pesticides using a job exposure matrix. Cox proportional hazards models, adjusted for potential confounders, were fitted for the following outcomes: any cancer, leukaemia, central nervous system tumours (CNST), lymphoma, non-CNS solid tumours., Results: Analyses of maternal (paternal) exposure were based on approximately 15.9 (15.1) million-person years at risk and included 1891 (1808) cases of cancer, of which 532 (503) were leukaemia, 348 (337) lymphomas, 423 (399) CNST, and 588 (569) non-CNS solid tumours. The prevalence of high likelihood of exposure was 2.9% for mothers and 6.7% for fathers. No evidence of an association was found with maternal or paternal exposure for any of the outcomes, except for "non-CNS solid tumours" (High versus None; Father: adjusted HR [95%CI] =1.84 [1.31-2.58]; Mother: 1.79 [1.13-2.84]). No evidence of an association was found for main subtypes of leukaemia and lymphoma. A post-hoc analysis on frequent subtypes of "non-CNS solid tumours" showed positive associations with wide CIs for some cancers., Conclusion: Our study suggests an increased risk for solid tumours other than in the CNS among children whose parents were occupationally exposed to pesticides; however, the small numbers of cases limited a closer investigation of cancer subtypes. Better exposure assessment and pooled studies are needed to further explore a possible link between specific childhood cancers types and parental occupational exposure to pesticides.

This work investigates a completely novel and experimental concept of exposing L5178Y cells at the air-agar-interface to mainstream cigarette smoke aerosol (Kentucky reference 3R4F). This study highlights the associated challenges of combining a suspension cell line alongside an in vitro aerosol exposure system. To achieve a monolayer, cells were 'seeded' in a concentrated cell super-mix suspension onto an RPMI/agar-matrix -base. The resulting cell suspension media was adsorbed into the agar base leaving the L5178Y cells lightly suspended on the agar surface, approximating a monolayer. Cells were deemed supportable on the agar-matrix, viable and recoverable. Using Vitrocell VC 10 exposure system and the Ames 4 exposure module, L5178Y cells were successfully exposed to a dynamic cigarette smoke aerosol, recovered and assessed for mutant frequencies, using standard assay procedures. Method development included assessment of flowing air conditions, plating efficiency and recovery of L5178Y cells from the agar-matrix surface. Positive controls MMS and B[a]P were successfully incorporated into the agar-matrix and metabolic activation was achieved by S-9 incorporation into the same agar-base-matrix. B[a]P demonstrated metabolic activation and positive response, suggesting a clear cellular interaction with the agar-matrix. Whole smoke exposed cells in the presence of metabolic activation showed a clear dose response and increasing mutant frequencies, well in excess of the controls (air and incubator) and the global evaluation factor following a 2 or 3 day expression period. This experimental concept demonstrates that L5178Y cells can be exposed to cigarette smoke aerosol, using a completely novel and a previously untested approach. Although this work successfully demonstrates the approach is viable and cells can be plated and maintained on an agar-matrix, more optimisation and robustness assessment is required before it can be considered fully adapted and used alongside other whole aerosol methodologies for the assessment of cigarette smoke and other inhaled aerosols., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Lymphomas and leukaemias involving the lung have in some cases been hard to distinguish from respiratory tract infection in Sprague-Dawley (SD) rats from long-term bioassays. In order to differentiate between tumours and immune cell infiltrates, updated pathological criteria and nomenclature were used and immunohistochemistry (IHC) was applied to haematopoietic and lymphoid tissue tumours (HLTs) in the original prenatal long-term Aspartame (APM) study performed by the Ramazzini Institute (RI). All 78 cases of HLTs from treated and control groups were re-examined based on light microscopic morphological characteristics and subjected to a panel of IHC markers including Ki67, CD3, PAX5, CD20, CD68, TdT, CD45, CD14 and CD33. The analysis confirmed the diagnoses of HLTs in 72 cases, identified 3 cases of preneoplastic lesions (lymphoid hyperplasia), and categorized 3 cases as inflammatory lesions. A statistically significant increase in total HLTs (p = 0.006), total lymphomas (p = 0.032) and total leukaemias (p = 0.031) in treated female rats was confirmed (high dose vs control), and a statistically significant linear trend for each HLT type was also observed. After the HLT cases re-evaluation, the results obtained are consistent with those reported in the previous RI publication and reinforce the hypothesis that APM has a leukaemogenic and lymphomatogenic effect., (Copyright © 2020. Published by Elsevier GmbH.)

Rationale: Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a serious complication in patients treated using methotrexate. It occasionally develops in extra-nodal sites, but rarely in the central nervous system (CNS) or in 2 different sites at the same time. We present the rare case of a patient with rheumatoid arthritis who developed lymphoma in the CNS and stomach during MTX therapy., Patient Concerns: A 75-year-old Japanese man with rheumatoid arthritis who received methotrexate was admitted to our hospital because of gait ataxia and anorexia., Diagnoses: Imaging findings and biopsy led to a diagnosis of 2 different types of MTX-LPD in the central nervous system and stomach., Interventions: The lesion in his stomach improved after methotrexate withdrawal, whereas the cerebellar mass required high-dose methotrexate and rituximab therapy., Outcomes: Complete remission has been maintained for the 2 years following the initiation of chemotherapy., Lessons: In patients with RA who receive MTX and develop new neurological symptoms, CNS lymphoma as an MTX-LPD may be considered as a differential diagnosis.

We review approaches for characterizing "peak" exposures in epidemiologic studies and methods for incorporating peak exposure metrics in dose-response assessments that contribute to risk assessment. The focus was on potential etiologic relations between environmental chemical exposures and cancer risks. We searched the epidemiologic literature on environmental chemicals classified as carcinogens in which cancer risks were described in relation to "peak" exposures. These articles were evaluated to identify some of the challenges associated with defining and describing cancer risks in relation to peak exposures. We found that definitions of peak exposure varied considerably across studies. Of nine chemical agents included in our review of peak exposure, six had epidemiologic data used by the U.S. Environmental Protection Agency (US EPA) in dose-response assessments to derive inhalation unit risk values. These were benzene, formaldehyde, styrene, trichloroethylene, acrylonitrile, and ethylene oxide. All derived unit risks relied on cumulative exposure for dose-response estimation and none, to our knowledge, considered peak exposure metrics. This is not surprising, given the historical linear no-threshold default model (generally based on cumulative exposure) used in regulatory risk assessments. With newly proposed US EPA rule language, fuller consideration of alternative exposure and dose-response metrics will be supported. "Peak" exposure has not been consistently defined and rarely has been evaluated in epidemiologic studies of cancer risks. We recommend developing uniform definitions of "peak" exposure to facilitate fuller evaluation of dose response for environmental chemicals and cancer risks, especially where mechanistic understanding indicates that the dose response is unlikely linear and that short-term high-intensity exposures increase risk., (© 2019 The Authors. Risk Analysis published by Wiley Periodicals, Inc. on behalf of Society for Risk Analysis.)

Objective: This study investigated whether using biological disease-modifying antirheumatic drugs (bDMARDs) further increases the risk of malignant lymphoma in patients with rheumatoid arthritis undergoing methotrexate therapy using spontaneous adverse reaction databases in different countries., Materials and Methods: Patient data were acquired from the US Food and Drug Administration's Adverse Event Reporting System (FAERS), the Japanese Adverse Drug Event Report (JADER), and the Canada Vigilance Adverse Reaction Online Database (CVARD) from the first quarter of 2004 to the end of 2015. Data subset analysis was performed to investigate whether the use of bDMARDs further increased the risk of malignant lymphoma in patients receiving methotrexate therapy., Results: The FAERS subset data indicated a significant association between Hodgkin lymphoma and methotrexate with infliximab (reporting odds ratio (ROR): 8.28. 95% CI: 5.70 - 12.02; information component (IC): 2.04, 95% CI: 1.59 - 2.49). In addition, signal scores suggested that methotrexate with infliximab (ROR: 3.26. 95% CI: 2.68 - 3.98; IC: 1.31, 95% CI: 1.04 - 1.58) was significantly associated with non-Hodgkin lymphoma (NHL). The CVARD subset data also indicated a significant association between NHL and methotrexate with infliximab (ROR: 22.82. 95% CI: 5.02 - 103.78; IC: 1.77, 95% CI: 0.13 - 3.41). However, the JADER subset data revealed no significant associations., Conclusion: The present study shows that using infliximab further increases the risk of malignant lymphoma in patients receiving methotrexate therapy.
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This study provides an overview of the epidemiology and secular trends of malignant lymphoma in Japan. Using data from clinics and hospitals throughout Japan, we analyzed 9426 cases of malignant lymphoma diagnosed in 2007-2014. We show that the proportion of follicular lymphoma and methotrexate-associated lymphoproliferative disorder increased during this time, as did the onset age for follicular lymphoma and diffuse large B-cell lymphoma. Significant increases in onset age for follicular lymphoma and diffuse large B-cell lymphoma were observed in both men and women (all P values <0.0001 except for P = 0.0448 for the latter disease in women). Further studies are required to determine the reasons for the higher proportion of and onset age for these lymphomas. Additionally, we believe that continued observation of these trends is necessary., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Pesticides are commonly used worldwide and almost every human is potentially exposed to these chemicals. Exposure to pesticides such as permethrin and malathion has been associated with hematological malignancies in epidemiological studies. However, biological evidence showing if these chemicals induce genetic aberrations involved in the etiology of leukemia and lymphoma is missing. In our previous work, we have shown that a single high exposure (200 μm, 24 hours) of permethrin and malathion induce damage in genes associated with hematological malignancies in peripheral blood mononuclear cells analyzed by interphase fluorescence in situ hybridization (FISH). In the present study, we assessed by FISH whether exposure to low concentrations (0.1 μm, 72 hours) of permethrin and malathion induce aberrations in KMT2A and IGH genes, which are involved in the etiology of leukemia and lymphoma. Peripheral blood mononuclear cells were exposed to the chemicals, and damage in these genes was assessed on interphases and metaphases. We observed that both chemicals at low concentration induced structural aberrations in KMT2A and IGH genes. A higher level of damage was observed in KMT2A gene with malathion treatment and in IGH gene with permethrin exposure. We also observed numerical aberrations induced by these chemicals. The most frequent aberrations detected on interphase FISH were also observed on metaphases. Our results show that permethrin and malathion induce genetic damage in genes associated with hematological cancer, at concentrations biologically relevant. In addition, damage was observed on dividing cells, which suggests that these cells maintain their proliferation capacity in spite of the genetic damage they possess., (Copyright © 2018 John Wiley & Sons, Ltd.)

Background: To describe a case of highly suspected primary intraocular lymphoma (PIOL) in a patient using etanercept for the treatment of rheumatoid arthritis., Case Presentation: A 50-year-old female patient presented with decreased vision in her left eye that lasted for a week. She had a 15-year history of seropositive rheumatoid arthritis (RA), and had been taking weekly etanercept for the preceding 8 months. Funduscopic examination and SD-OCT showed a swollen ellipsoid zone (EZ) and a retinal pigment epithelium (RPE) irregularity of the right eye. We also noted EZ disruption and a RPE irregularity in the left eye. As subretinal infiltration was aggravated in the right eye after the initial treatment, we completed a vitrectomy. Vitreous cytology revealed PIOL with positive CD20 immunostaining. She was treated with serial intravitreal methotrexate injections and systemic chemotherapy. After the treatment, subretinal infiltration and subRPE deposits were decreased in the right eye with no evidence of recurrence in either eye., Conclusions: This case suggests a potential relationship between immunosuppression with anti-TNFα medication, and increased risk for lymphoma, especially in patients with underlying rheumatologic disorders and especially in patients with suspected chronic refractory uveitis.

Background: Styrene is an important industrial chemical that the general population is exposed to at low levels. Previous research has suggested increased occurrence of leukemia and lymphoma among reinforced plastics workers exposed at high levels of styrene., Methods: We followed 73,036 workers of 456 small- and medium-sized Danish reinforced plastics companies from 1968 to 2011 and investigated the exposure-response relation between cumulative styrene exposure and incidence of lymphohematopoietic malignancies. We modeled styrene exposure from employment history, survey data, and historical styrene exposure measurements. We retrieved information on lymphohematopoietic malignancies from national cancer and patient registers., Results: We identified 665 cases overall of 21 different lymphohematopoietic malignancies or combinations thereof, each with at least 20 cases, during 1,581,976 person-years of follow-up. Initial analyses suggested higher age, sex, and calendar year-adjusted incidence rate ratios (RRs) for acute myeloid leukemia, Hodgkin lymphoma, and T-cell lymphoma with higher estimates of cumulative styrene exposure. Accounting for time since exposure showed a trend by cumulative styrene exposure (P = 0.01) and a doubled risk (RR = 2.4; 95% CI, 1.2, 4.6) of acute myeloid leukemia following estimated high compared with estimated low cumulative exposure during the prior 15-29 years. We observed no increased risk following exposure during more recent years and less consistent risk patterns for Hodgkin lymphoma and T-cell lymphoma., Conclusions: This study, to our knowledge the largest epidemiologic study to date of occupational styrene exposure, suggests increased risk of acute myeloid leukemia following high styrene exposure with a latency period of about 15 years.

The use of immunosuppressive agents is associated with an increased risk of the development of certain types of malignancies, particularly lymphoma. Many of these lymphomas are associated with Epstein-Barr virus (EBV), which might be reactivated under immunosuppression. We present the case of a patient with an autoimmune hepatitis who developed EBV-associated Hodgkin-like lymphoma under immunosuppressive treatment with azathioprine. The tumor regressed spontaneously after withdrawal of azathioprine. The development of an EBV-associated Hodgkin-like lymphoma under this immunosuppressive therapy, and especially the regression of the lymphoma after cessation of azathioprine, confirms the relationship between this immunosuppressant, EBV-infection, and the development of Hodgkin-like lymphoma.
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