BACKGROUND:Antinuclear antibody (ANA) is important for the diagnosis of autoimmune diseases. When ANA is positive, further specific autoantibody tests are needed to make a definite diagnosis. METHODS:This article reports a case of a patient with an autoimmune disease who had inconsistent results in the detection of antinuclear antibodies by indirect immunofluorescence assay (IIFA) and linear immunoblotting assay (LIA). RESULTS:This patient presented with negative ANA and positive anti-SSA/Ro52. CONCLUSIONS:IIF-ANA negative and LIA-ANAS positive exists in clinical tests. The combination of IIFA and LIA is important.

Bispecific antibodies engaging CD3 have transformed the treatment landscape of B-cell malignancies but remain constrained by T-cell overactivation and cytokine release. Here, we describe PSB202, a first-in-class bifunctional antibody co-targeting CD20 and CD37 to deplete malignant B cells independently of T-cell engagement. In this multicenter, open-label phase Ia trial (NCT05003141), adults with relapsed or refractory (R/R) CD20⁺ B-cell non-Hodgkin lymphoma (B-NHL) received escalating doses of PSB202 from 12 to 300 mg. Primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary endpoints were safety, pharmacokinetics, pharmacodynamics, and efficacy. Fifteen heavily-pretreated patients were enrolled, with a median age of 67.7 years (range, 54–78). One DLT of grade 4 neutropenia occurred at 100 mg. MTD was not reached. PSB202 showed a manageable safety profile, with grade ≥ 3 neutropenia and leukopenia both occurring in 60

ABSTRACT:Older patients with diffuse large B-cell lymphoma (DLBCL) present unfavorable genetic and microenvironmental alterations. In this phase 2 trial, we assessed the efficacy and safety of zanubrutinib in combination with rituximab and lenalidomide (ZR2) in patients with de novo DLBCL aged ≥75 years. Forty patients were enrolled, and the primary end point was the complete response rate, which was 65.0% (95% confidence interval [CI], 48.3-78.9) at the end of induction treatment. The 2-year progression-free and overall survival rates were 67.1% (95% CI, 50.1-79.4) and 82.4% (95% CI, 66.5-91.2). The most common grades 3 and 4 hematologic adverse event (AE) was neutropenia (n = 14 [35.0%]). The most common grades 3 and 4 nonhematologic AEs were increased alanine transaminase (n = 5 [12.5%]) and aspartate transaminase levels (n = 5; 12.5%), and pulmonary infection (n = 5 [12.5%]). No events of atrial fibrillation were observed. Importantly, the efficacy of ZR2 was more dependent on tumor microenvironmental than genetic alterations, and was associated with upregulation of class I and II human leukocyte antigen and increased number and function of conventional type 1 dendritic cells. Preexisting expansion of intratumoral CD8+ T cells and treatment-induced clonal T-cell receptor (TCR) repertoire contributed to better clinical outcome. TCR sequencing of the peripheral blood mononuclear cell samples from patients with durable remission detected the expanded T-cell clones 3 years after treatment. These findings thus improve the understanding of the effect of T-cell immunological memory on ZR2-based immunotherapy, and support a paradigm shift toward mechanism-based targeted therapy of aggressive lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT04460248.

Objective·To analyze the clinicopathologic characteristics, gene mutation profile, and prognostic factors of patients with adrenal diffuse large B-cell lymphoma (DLBCL).Methods·From March 2002 to December 2022, a total of 105 patients with adrenal DLBCL admitted to Ruijin Hospital, Shanghai Jiao Tong University School of Medicine were retrospectively analyzed for their clinicopathological data, survival outcomes, and prognostic factors. Patients' gene mutation profiles were evaluated by targeted sequencing of 152 lymphoma-related genes.Results·The median age of the patients was 62 (15‒82) years and the male-to-female ratio was 2.3∶1. Among them, 63 patients (60.0%) were over 60 years old, 22 patients (21.0%) had an Eastern Cooperative Oncology Group (ECOG) performance status of two or higher, 87 patients (82.9%) were staged Ann Arbor Ⅲ‒Ⅳ, 92 patients (87.6%) had elevated serum lactate dehydrogenase (LDH) levels (above the upper limit of reference), 84 patients (80.0%) had extranodal invasion in at least two organs, 67 patients (63.8%) were of non-germinal center B-cell (non-GCB) origin, and 95 patients (90.5%) had an international prognosis index (IPI) scored over 2. With a median follow-up of 28.3 (0.7‒191.9) months, the estimated 2-year overall survival (OS) rate and progression-free survival (PFS) rate were 68.3% and 53.1%, respectively. The estimated 5-year OS rate and PFS rate were 52.6% and 44.0%, respectively. Among 93 patients who could be evaluated for clinical outcomes, 62 (66.7%) got a complete response (CR). Univariate analysis and multivariate Cox analysis revealed that age over 60 years was an adverse prognostic factor for PFS, and ECOG performance status of two or higher was an adverse prognostic factor for both OS and PFS. Targeted gene sequencing in 46 adrenal diffuse DLBCL patients showed high mutation frequencies in lysine methyltransferase 2D (KMT2D; n=17, 37%), Pim-1 proto-oncogene, serine/threonine kinase (PIM1; n=17, 37%), MYD88 innate immune signal transduction adaptor (MYD88; n=15, 33%), CD79b molecule (CD79B; n=13, 28%), and BTG anti-proliferation factor 2 (BTG2; n=10, 22%).Conclusion·Age over 60 years is an adverse prognostic factor for PFS, and ECOG performance status of two or higher is an adverse prognostic factor for both OS and PFS in patients with adrenal DLBCL. Patients exhibited high frequencies of KMT2D, PIM1, MYD88, CD79B, and BTG2 mutations, as well as an increased proportion of the MCD-like subtype.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous B cell neoplasm with variable clinical outcomes influenced by both tumor-derived and lymphoma microenvironment (LME) alterations. A recent transcriptomic study identifies four DLBCL subtypes based on LME characteristics: germinal center (GC)-like, mesenchymal (MS), inflammatory (IN), and depleted (DP). However, integrating this classification into clinical practice remains challenging. Here, we utilize deconvolution methods to assess microenvironment component abundance, establishing an LME classification of DLBCL using immunohistochemistry markers and digital pathology based on CD3, CD8, CD68, PD-L1, and collagen. This staining-based algorithm demonstrates over 80% concordance with transcriptome-based classification. Single-cell sequencing confirms that the immune microenvironments distinguished by this algorithm align with transcriptomic profiles. Significant disparities in overall and progression-free survival are observed among LME subtypes following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP with targeted agents (R-CHOP-X) immunochemotherapy. LME subtypes differed from distinct immune escape mechanisms, highlighting specific immunotherapeutic targets and supporting application of this classification in future precision medicine trials.

This study aims to conduct a comprehensive bibliometric analysis of global research trends and hotspots related to the biological activities of d-limonene, a prominent monoterpene compound found in essential oils, that warrant attention. We performed a bibliometric analysis of 1928 publications sourced from the Web of Science core database, covering the period from 1994 to 2024. Utilizing CiteSpace and VOSviewer software, we analyzed publication trends, collaboration networks among countries, institutions, and authors, and explored the evolution of research themes and current hotspots through keyword analysis. Our findings indicate a rapid increase in research on d-limonene activities since 2017, with China and Brazil leading in publication output. Italy and the USA play central roles within the collaboration network. Notably, a core group of authors has yet to emerge in this field. The biological activities of d-limonene, particularly its antibacterial, antioxidant, anti-inflammatory, and antitumor properties, are widely studied. Recent research hotspots focus on its neuroprotective effects and its potential role in inhibiting antibiotic resistance. The study highlights the growing interest in d-limonene and suggests that its use as an adjuvant to enhance therapeutic efficacy through synergistic interactions with other drugs may represent a significant research direction for the future. This analysis provides valuable insights for researchers and practitioners in pharmacology and related fields, emphasizing the importance of d-limonene in advancing health-related applications.

[18F]-Fluorodeoxyglucose (FDG)-PET/CT is essential for staging and evaluating treatment response in diffuse large B-cell lymphoma (DLBCL). The prognostic potential of PET-derived biomarkers requires efficient extraction and analysis of biological signatures. In this study, 18F-FDG-PET scans of 839 newly diagnosed DLBCL patients were analyzed, with DNA sequencing performed on 710 patients. Using the nnUNet deep learning framework, trained on both AutoPET public and in-house datasets, enabled precise PET scan segmentation and biomarker extraction. Key biomarkers, including total metabolic tumor volume (TMTV), Max MTV (MAX_MTV), standardized maximum tumor dissemination (SDmax_patient), and standardized maximum distance between the largest and another lesion (SDmax_bulk), showed significant prognostic value. Integrating LymphPlex genetic subtypes with PET biomarkers and clinical risk factors, we identified critical prognostic indicators: EZB-like-MYC+, MCD-like, TP53Mut subtypes, high TMTV, and elevated lactate dehydrogenase (LDH). Consequently, the ClinicalPET LymphPlex model was developed, effectively differentiating survival rates across various treatments. Additionally, combined with transcriptomic data, we revealed that risk factors within the ClinicalPET LymphPlex like high TMTV and LDH were notably associated with immune-suppressive tumor microenvironments.

BACKGROUND:Papillary thyroid microcarcinoma (PTMC) incidence has significantly increased, and some cases still exhibit invasive traits. The entire molecular landscape of PTMC, which can offer hints for the etiology of cancer, is currently absent. METHODS:We compared our findings with those for PTMC in the TCGA by analyzing the largest study at the current stage of whole exome sequencing and RNA-sequencing data from 64 patients with PTMC. Then, we systematically demonstrated the differences between the two PTMC subtypes based on multi-omics analyses. Additionally, we created a molecular prediction model for the PTMC subtypes and validated them among TCGA patients for individualized integrative assessment. RESULTS:In addition to the presence of BRAF mutations and RET fusions in the TCGA cohort, we also discovered a new molecular signature named PTMC-inflammatory that implies a potential response to immune intervention, which is enriched with AFP mutations, IGH@-ext fusions, elevated immune-related genes, positive peroxidase antibody, and positive thyroglobulin antibody. Additionally, a molecular prediction model for the PTMC-inflammatory patients was created and validated among TCGA patients, while the prognosis for these patients is poor. CONCLUSIONS:Our findings comprehensively define the clinical and molecular features of PTMC and may inspire new therapeutic hypotheses.

Dear Editor, Hepatitis B virus (HBV) is an oncogenic virus and a major risk factor for developing hepatocellular carcinoma.1 Growing evidence also suggests that HBV infection is linked to an increased incidence of diffuse large B-cell lymphoma (DLBCL).1 Among 1925 newly diagnosed DLBCL patients (Figure S1), we revealed that DLBCLs with current HBV infection (HBV-surface-antigen [HBsAg]+), instead of those with previous HBV infection (HBsAg- and antibodies against HBV-core-antigen+), correlated with high-risk clinical features (Table S1), as previously reported.2, 3 The prognostic impact of HBV infection in DLBCL remained controversial in the rituximab era,2, 3 largely due to the relatively small sample size of patients receiving rituximab-containing treatment. Here, among 1490 patients with R-CHOP treatment, we observed that the progression-free survival (PFS) and overall survival (OS) of DLBCLs with current HBV infection were significantly worse than those of non-HBV infection (Figure 1A,B). Moreover, current HBV infection independently predicted adverse PFS and OS when other prognostic variables were adjusted (Figure S2). More elderly patients were observed in the previous HBV infection group, probably due to the universal infant HBV vaccination in China since 2002. HBV indirectly promotes DLBCL tumorigenesis by inducing B-cell hyperactivation.2 Accordingly, in DLBCLs of current HBV infection, transcriptional factors for germinal center (GC) initiation and maintenance4 were upregulated, while transcriptional factor for B-cell differentiation was downregulated, as compared to those of non-HBV infection (Figure 1C). Besides, B-cell surface markers for B-cell development5 were significantly higher in DLBCLs of current HBV infection than in non-HBV infection (Figure 1D). Moreover, DLBCLs of current HBV infection presented upregulated B-cell-related signaling pathways as revealed by single sample Gene Set Enrichment Analysis (GSEA) (Figure 1E, Table S2), and increased major histocompatibility complex class II molecules (Figure S3A, Table S3), which play an essential role in B cell-T cell co-stimulation.4 However, no significant difference was detected between previous HBV infection and non-HBV infection. Upon B-cell activation, B cells enter into the GC to generate high-affinity antibodies through activation-induced cytidine deaminase (AID).6 In pathological conditions, enhanced AID activity induces aberrant generation of genetic mutations and chromosomal translocations.6 Indeed, DLBCLs with current HBV infection exhibited significantly increased BCL6 translocation by fluorescence in situ hybridization (Figure 1F), as well as increased gene mutations, including BTG2, FAS, CD70, TNFRSF14, PTPN6, STAT3, EBF1, and NOTCH1 (Figure 1G). However, no significant difference in chromosomal translocations or gene mutations was detected between previous and non-HBV infection. Moreover, no significant difference of the genetic subtypes (Other, BN2, EZB, MCD, A53, N1, ST2, or genetically composite) was observed among three groups (Figure S3B, Table S4). Together, HBV virus may increase genomic alterations through B-cell hyperactivation under persistent HBV antigen stimulation, contributing to DLBCL development. Based on the similar clinical and molecular patterns, patients with previous and non-HBV infection were grouped as non-current HBV infection. GSEA revealed that current HBV infection was significantly associated with enriched signaling pathways involving B-cell activation and immune regulation (Figure 2A), with CD70 having the highest fold change among the significantly overexpressed genes in current HBV infection group (Figure 2B). By immunohistochemistry, DLBCLs with current HBV infection showed aberrant higher CD70 expression on B-lymphocytes (Figure 2C), indicating association between B-cell activation and CD70 expression. By RNA sequencing, enrichment of B-cell activation positively correlated with CD70 expression (Figure 2D). To confirm the role of B-cell activation on CD70 upregulation, we cultured OCI-LY10 and SU-DHL4 cells with anti-IgG, and observed significantly increased CD70 expression in both cell lines induced by anti-IgG (Figure 2E). T cells play essential roles in chronic HBV infection. As revealed by tumor immunophenotyping, DLBCLs with current HBV infection exhibited significantly increased recruiting activity of regulatory T (Treg) cells (Figure 3A). Treg cells have been recognized to promote immune evasion by controlling the immune activity of T cells.7 Indeed, as compared to the Treg-low group according to the median recruiting score of Treg cells, the Treg-high group showed significantly downregulated signaling pathways related to T-cell immune response (Figure S3C). Treg cell increase in patients with current HBV infection was further confirmed by immunohistochemistry (Figure 3B) and multi-color flow cytometry (Figure 3C, Figure S3D). CD27-CD70 interaction induces critical survival factors for Treg cells, thereby promoting Treg cell differentiation and inhibiting Treg cell apoptosis.8 Consistently, elevated CD70 expression (CD70-high group based on the median CD70 level) was significantly related to higher recruiting activity of Treg cells (Figure S3E). Additionally, key chemokines and chemokine receptors involved in Treg recruitment activity were significantly upregulated in CD70-high group, as compared to CD70-low group (Figure S3F). With ectopic expression of CD70 through transfecting with CD70-vector in OCI-LY10 and SU-DHL4 cells (Figure 3D,E), CD70 facilitated lymphoma cell proliferation in both cell lines (Figure 3F), in consistent with previous study that CD70 may induce a growth advantage of B cells.9 Under co-culture system with peripheral blood mononuclear cells, CD70 overexpression on OCI-LY10 and SU-DHL4 cells significantly promoted Treg cell increasing (Figure 3G) and tumor cell proliferation as well (Figure 3H). Therefore, HBV infection may increase Treg cells via CD70, thereby inducing tumor escape from immune surveillance and subsequent DLBCL progression. Lenalidomide is an effective immunomodulatory agent in treating DLBCL and exerts anti-tumor activity through targeting Treg cells.10 Upon lenalidomide treatment, both co-culture systems elicited significantly decreased Treg cells (Figure 4A) and tumor cells (Figure 4B). We next treated 52 relapsed/refractory patients with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE), and observed DLBCLs with current HBV infection displayed significantly shorter PFS and OS than those of non-current HBV infection (Figure 4C). When relapsed/refractory patients received lenalidomide plus R-ICE, lenalidomide significantly improved the PFS and OS of DLBCLs with current HBV infection (Figure 4D). Of note, Treg cells remained unchanged upon R-ICE treatment (Figure 4E), but were significantly decreased upon lenalidomide plus R-ICE treatment in patients with current HBV infection (Figure 4F). In conclusion, DLBCLs with current HBV infection may refer as a specific entity with aggressive disease course and resistance to immunochemotherapy. Targeting tumor microenvironment could be promising approaches for mechanism-based treatment on virus-related B-cell malignancies. We appreciate the effort of the physicians for enrolling patients, the bioinformatic support of Computational Biology Group from Network & Information Center at Shanghai Jiao Tong University, and thank all the patients involved for allowing us to analyze their clinical data. Graphical Abstract was created with BioRender. This study was supported by the National Natural Science Foundation of China (82130004, 81830007, and 82070204), Shanghai Municipal Education Commission Gaofeng Clinical Medicine (20152206 and 20152208), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Clinical Research Plan of Shanghai Hospital Development Center (SHDC2020CR1032B), Chang Jiang Scholars Program, Samuel Waxman Cancer Research Foundation, and the Foundation of National Facility for Translational Medicine (Shanghai, TMSK-2020-115). The authors declare that they have no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background Previously studies shown a potential risk of antihypertensive medicines in relation to cancer susceptibility, which creating significant debate in the scientific community and public concern. We sought to investigate the relationship between antihypertensive medicines and cancer risk, by drug type and class. Methods We conducted a population-based cohort study and enrolled patients diagnosed with hypertension from community healthcare centers in Changning District, Shanghai, China. Antihypertensive drug administration were classified as five common antihypertensive drugs. The main outcomes were incidence of total cancer and by major cancer type. Results Between January 2013 and December 2017, a total of 101,370 hypertensive patients were enrolled in this cohort. During a mean follow-up of 5.1 (SD 1.3) years, 4970 cancer cases were newly diagnosed in the cohort. CCBs were the most frequently used antihypertensives which were associated with a moderately increased risk of total cancer (hazard ratio, HR = 1.11, 95% CI: 1.05–1.18). The second commonly used drug ARBs were also associated with increased risk of total cancer (HR = 1.10, 95%CI: 1.03–1.17) as well as lung and thyroid cancers (HR = 1.21, 95%CI: 1.05–1.39; HR = 1.62 95%CI: 1.18–2.21, respectively). No significant association was found between cancer and other antihypertensives. Hypertensive patients who use more than one class of antihypertensives drugs had a higher risk of total cancer (HR: 1.22, 95%CI: 1.10–1.35 for two classes; HR: 1.22, 95%CI: 1.03–1.45 for three or more classes), and a possible dose–response relationship was suggested ( P for trend < 0.001). The risk of thyroid cancer was higher in hypertensive patients prescribed with three or more antihypertensive classes. Conclusions Use of ARBs or CCBs may be associated with an increased risk of total cancer. Taking more than one class of antihypertensives drugs appeared to have a higher risk for total cancer.

BACKGROUND:Exposure to various metals has been reported to lead to lung cancer. However, few studies focused on the combined effects of metal mixture.OBJECTIVE:To explore the relationship between metal mixture and lung cancer patients.METHODS:Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentration of 8 heavy metals (V, Cr, Mn, Se, Mo, Cd, Ba and Pb) in serum samples of 86 cases and 105 controls in the Tianjin Lung Cancer Cohort. Logistic regression models were used to estimate the effect of each metal on the risk of lung cancer. The restricted cubic spline function was applied to describe the dose-response relationship between various metal concentrations and lung cancer risk. Bayesian Kernel Machine Regression (BKMR), Weighted Quantile Sum (WQS) and Quantile G-Computation (QGC) were employed to explore the effects of metal mixtures as a whole on lung cancer.RESULTS:An increased risk of lung cancer was associated with higher blood Mo concentration (adjusted OR = 2.94, 95% CI = 1.03-8.74 for tertile 2 vs. tertile 1). Higher Se concentration in blood may have protective effects on the risk of lung cancer (adjusted OR = 0.18, 95% CI = 0.06-0.51 for tertile 3 vs. tertile 1, p-trend <0.001). In addition, Se and Cd may have an antagonism effect on the occurrence of lung cancer (RERI and 95% CI = -0.95 [-31.77, -0.07]; AP and 95% CI = -0.95 [-5.16 -0.74]). Although the metal mixture did not show a significant effect on lung cancer as a whole, this may be due to the offsetting effect between positive and negative effects.CONCLUSIONS:Our research indicates that Se has a promising anti-cancer application, but it is necessary to prevent the role of Cd that antagonize Se in lung cancer.

目的·总结接受伊马替尼治疗后符合停药标准的慢性髓系白血病(chronic myeloid leukemia,CML)慢性期(chronic phase,CP)患者在规范监测下尝试无治疗缓解(treatment-free remission,TFR)的结局,并分析可能影响TFR的预后因素和微滴式数字聚合酶链式反应(droplet digital polymerase chain reaction,ddPCR)在TFR监测中的作用.方法·对入组CML-CP患者在停药后定期进行规范监测.通过定量聚合酶链式反应(quantitative polymerase chain reaction,QPCR)检测BCR-ABL转录本评估分子学反应和复发;采用流式细胞仪检测淋巴细胞亚群,分析其对TFR的影响;采用ddPCR检测BCR-ABL,分析其在TFR中的预示作用.结果·①42例符合停药标准的CML-CP患者,中位随访时间41(5～93)个月;32例(76.2％)患者仍维持TFR状态.12、24和48个月的预期TFR率分别为85.1％、75.1％和70.1％.中位TFR时间为41(2～93)个月.停药后最常见的不良反应为肌肉关节疼痛(31.0％),均为Ⅰ～Ⅱ级.可评估的8例重启治疗患者100％达深层次分子学反应(deep molecular response,DMR).②停药后持续ddPCR阳性的患者中,7例(58.3％)出现分子学复发,而ddPCR结果为阴性的患者均未出现复发(P＜0.01).③停药前复发组的CD8+CD28-细胞百分比低于TFR组(6.2％vs 12.6％,P=0.026),停药后复发组CD4+CD25+细胞百分比高于TFR组(3.2％vs 2.1％,P=0.021).结论·长期持续接受伊马替尼治疗,并符合停药标准的CML-CP患者可以获得持续的TFR;ddPCR有助于提示TFR的预后,并更早识别可能发生分子学复发的患者;不同的T细胞亚群可能在TFR过程中参与了免疫调节以防止CML疾病复发.

Background The optimal treatment for older adults with diffuse large B-cell lymphoma (DLBCL) needs to be further explored due to patient comorbidities, standard immunochemotherapy intolerance, and unfavourable genetic features. We did a phase 2 trial of ibrutinib, rituximab, and lenalidomide (iR2) to evaluate the efficacy and safety in older adult patients with de novo DLBCL. Methods In this phase 2, single-arm study, unfit or frail patients with de novo DLBCL aged 75 years or older were enrolled at Shanghai Ruijin Hospital, Shanghai, China. During the induction phase from cycle 1 to 6, 560 mg ibrutinib was given orally daily throughout each 21-day treatment cycle, 375 mg/m(2) rituximab was given intravenously on day 1, and 25 mg lenalidomide was given orally daily from day 1 to 10 in each cycle. Patients who had a complete response after induction were given another 6 cycles of lenalidomide maintenance (25 mg orally daily from day 1 to 10 every 21 days from cycle 7 to 12). The primary endpoint was complete response rate after 6 cycles or at the end of the induction treatment. This trial is registered with ClinicalTrials.gov, NCT03949062. Findings Between May 15, 2019, and May 8, 2020, a total of 30 patients were enrolled. The end of induction complete response rate was 56.7% (95% CI 37.4-74.5), and overall response rate was 66.7% (95% CI 47.2-82.7). With a median follow-up of 27.6 months (IQR 23.9-29.6), the 2-year progression-free survival rate was 53.3% (95% CI 34.3-69.1) and the 2-year overall survival rate was 66.7% (95% CI 46.9-80.5). The main grade 3-4 haematological adverse events were neutropenia (seven patients [23%]), thrombocytopenia (three patients [10%]), and anaemia (two patients [7%]). The most common grade 3-4 non-haematological adverse event was pulmonary infection (seven patients [23%]). Atrial fibrillation was observed in three (10%) patients, including one grade 2 and two grade 3. Interpretation A chemotherapy-free iR2 regimen is clinically effective and safe and warrants further investigation in phase 3 trials as first-line treatment in older adult patients with DLBCL. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.

PM2.5 exposure is associated with lung adenocarcinoma (LUAD), but the mechanism is unclear. The lack of understanding impedes our effort on prevention. This study examined a possible mechanism of lung cancer caused by PM2.5 exposure, and aimed to find a potential intervention for people living in PM2.5 polluted regions. Electron microscopy and oil-red staining were conducted to examine the lipid droplet accumulation. Masson’s trichrome staining, colony forming, scratch assay and transwell experiment were conducted to evaluate the effect of PM2.5 exposure and d-limonene intervention on the occurrence and progression of LUAD. Potential intervention targets were found by RNA-Seq and verified by luciferase reporter assay. MiR-195 KO mice constructed with CRISPR/Cas9 technology were used to investigate the pivotal role of d-limonene-miR-195-SREBP1/FASN axis. Cohort analysis of lung cancer patients, human LUAD tissues staining and human intervention trial were also conducted to validate the results of cell and animal experiments. Our results showed that PM2.5 exposure induced accumulation of lipid droplets in LUAD cells which accompanied by increased malignant cellular behaviors. PM2.5 exposure led to cleaved N-SREBP1 translocation into nucleus, which activated the de novo lipogenesis pathway. Same changes were also observed in normal lung epithelial cells and normal lung tissue, and mice developed pulmonary fibrosis after long-term exposure to PM2.5. Furthermore, in a cohort of 11,712 lung cancer patients, significant lipid metabolism disorders were observed in higher PM2.5 polluted areas. In view of that, d-limonene was found to inhibit the changes in lipid metabolism through upregulating the expression of miR-195, which inhibited the expression of lipogenic genes (SREBF1/FASN/ACACA) specifically. And a small human intervention trial showed that serum miR-195 was upregulated after oral intake of d-limonene. Our findings reveal a new mechanism of pulmonary fibrosis and LUAD that is related to PM2.5 exposure-induced lipid droplet accumulation. We also demonstrate that d-limonene-miR-195-SREBP1/FASN axis is a potential preventive intervention for mediating the progression and development of LUAD induced by PM2.5 exposure. Trial registration Chinese Clinical Trial Registry, ChiCTR2000030200. Registered 25 February 2020, http://www.chictr.org.cn/showproj.aspx?proj=48013

OBJECTIVES:This study aimed to evaluate the effects of personalized nutrition intervention combined with telephone-based education on the nutritional status of colorectal cancer survivors and their quality of life. METHODS:In this randomized, parallel-controlled trial, 60 colorectal cancer survivors who met the eligibility criteria were recruited from a community in Shanghai and randomly assigned 1:1 into nutrition intervention and routine care groups. The routine care group received a follow up by telephoneafter 6 months. The nutrition intervention group received personalized nutritional interventions and telephone-based education through the WeChat app for 6 mo. Nutrition status, dietary intake, and quality of life were measured and compared between the groups. RESULTS:Of the enrolled participants, 56 participants were included in the modified intent-to-treat analysis for comparison. After the 6-mo intervention, the nutrition group had a statistically lower patient-generated subjective global assessment score and higher energy and protein intake compared with the routine care group. Moreover, the nutrition intervention group gained more weight (2.00 kg; 95% confidence interval, 0.25-3.00) than the routine care group (0.00 kg; 95% confidence interval, -1.75 to 0.00). Meanwhile, compared with the routine care group, the nutrition intervention group had significantly higher global health status, as well as physical, role, emotional, cognitive, and social functioning (P &lt; 0.05). CONCLUSIONS:Personalized nutrition interventions, combined with telephone-based education, provided by community health service centers can improve colorectal cancer survivors' nutritional status and quality of life. Personalized nutrition intervention for cancer survivors warrants further investigation in confirmatory studies.

Background: Lipid metabolism disorder, a new hallmark of cancer initiation, has been involved in lung adenocarcinoma (LUAD). However, few biomarkers about lipid metabolism-related genes (LMRGs) have been developed for prognosis prediction and clinical treatment of LUAD patients.Methods: In this study, we constructed and validated an effective prognostic prediction model for LUAD patients depending on LMRGs. Subsequently, we investigated the prediction model from immune microenvironment, genomic changes, and immunotherapy.Results: Then, eleven LMRGs were identified and applied to LUAD subtyping. In comparison with the high-risk group, the low-risk group exhibited a remarkably favorable prognosis, along with a higher immune score and lower tumor purity. Moreover, the low-risk group presented higher levels of immune checkpoint molecules, lower tumor immune dysfunction and exclusion (TIDE) score and tumor mutation burden (TMB), and higher likelihood of benefiting from immunotherapy. Furthermore, the genomic changes of six LMRGs (CD79A, HACD1, CYP17A1, SLCO1B3, ANGPTL4, and LDHA) were responsible for the difference in susceptibility to LUAD by greatly influencing B-cell activation.Conclusion: Generally speaking, the LMRG model is a reliable independent biomarker for predicting adverse outcomes in LUAD patients and has the potential to facilitate risk-stratified immunotherapy.

Lymphoma cells expressing CD5 (CD5+) confer inferior outcome of diffuse large B-cell lymphoma (DLBCL), especially in non-MYC/BCL2 double expressor (non-DE) patients. In tumor microenvironment, CD5+ non-DE tumor revealed increased proportion of immunosuppressive M2 macrophages and enhanced pathways related to macrophage activation and migration. In accordance to M2 activation, lipid metabolism was upregulated, including fatty acid uptake and fatty acid oxidation, which supplied energy for M2 macrophage polarization and activation. Meanwhile, CD36 expression was upregulated and strongly correlated to the proportion of M2 macrophages in CD5+ non-DE DLBCL. In vitro, a DLBCL cell line (LY10) overexpressing CD5 significantly increased M2 proportion in comparison with control when cocultured with peripheral blood mononuclear cells (PBMCs). The addition of metformin significantly decreased the M2 proportion and the CD36 expression level in the coculture systems, indicating that metformin could target altered lipid metabolism and decrease M2 macrophages in DLBCL, especially in CD5+ non-DE lymphoma. In conclusion, enhanced lipid metabolism and M2 macrophage activation contributed to the immunosuppressive tumor microenvironment and could be potential therapeutic targets in CD5+ non-DE DLBCL.

Background Routine health checkup is an essential strategy for monitoring population health and maintaining healthy workforces. However, there was a lack of cancer screening tests among routine health checkups due to high costs and unreliable methods.Methods We conducted a two-stage study to evaluate the value of a blood test, Cancer Differentiation Analysis (CDATM), which is developed to differentiate the blood samples of healthy individuals from those of cancer patients through measuring and analyzing multiple biophysical properties.Results The first stage of a cross-sectional study included 75,942 healthy individuals in routine health checkup, and the second stage of a prospective population-based cohort included 1,957 healthy community members. Forty-eight and ten cancer cases were identified among cross-sectional study and prospective population-based cohort, respectively. Using a pre-determined cutoff, we found that the CDA™ test could differentiate blood samples between healthy and cancer individuals with >93% specificity and >55% sensitivity in both studies.Conclusions With high specificity and moderate sensitivity of CDA™ test, our study indicates that we can analyze biophysical properties in the blood to rapidly and reliably screen healthy individuals from cancer patients in a health checkup setting where most individuals are healthy or with average risk of cancer.

BACKGROUND:The mechanism of rapidly increased non-small cell lung cancer (NSCLC) among never-smoking Chinese women has not been elucidated. Ovarian sex steroid hormones have been suggested to counteract lung cancer development, and sex hormone-binding globulin (SHBG) is essential in sex hormones regulation. This study aims to exploring single nucleotide polymorphisms (SNPs) in genomic regions associated with SHBG concentrations that contributed to never-smoking female NSCLC. METHODS:Candidate genes were selected by a genome-wide association (GWAS) meta-analysis and gene expression profiles of never-smoking NSCLC of Chinese women. The candidate SNPs limited to common minor allele frequency (MAF), missense variant, ethnic heterogeneous distribution, and SNPs were genotyped using the TaqMan method. A two-stage case-control design was adopted for exploration and validation of associations between candidate SNPs and risk of NSCLC. All participants were never-smoking Chinese women. Chi-square test and multivariate logistic regression were applied. RESULTS:Beginning with 12 genomic regions associated with circulating SHBG concentrations and gene expression profiles from never-smoking NSCLC in Chinese women, candidate SNP rs12233719 and rs7439366 both located in candidate gene UGT2 B7, which may be related to circulating SHBG concentrations and cancer risk, were identified. A two-stage case-control study was conducted in Shenyang and Tianjin represented as the training stage and validation stage, respectively. Under the dominant model, compared to individuals with the wild G/G genotype, the adjusted OR of those with the T allele was 1.58 (95% CI: 1.15-2.16) in Chinese Shenyang training set, and was 1.49 (95% CI: 1.02-2.18) in Chinese Tianjin validation set, both accompanied with a significant trend relationship consistently. UGT2B7 was upregulated in female NSCLC patients' tumor tissues and was associated with a poor prognosis in NSCLC. CONCLUSION:Our findings indicated that a sex hormones regulation-related SNP rs12233719 was associated with never-smoking female lung cancer risk, which might partially explain NSCLC-susceptibility in Chinese women.

BACKGROUND:There is tremendous interest in the development of liquid biopsy techniques, but the potential role of liquid biopsy for the early detection of cancer has not yet been elucidated. We aim to explore the performance of liquid biopsy in the early diagnosis of cancer.METHODS:A systematic review was conducted of liquid biopsy in cancer early detection. Meta-regression was carried out to explore the source of heterogeneity and publication bias was also evaluated.RESULTS:Overall, there were six types of biomarkers and 17 studies focusing on liquid biopsy in the early detection of cancer, 7 studies in ctDNA, 5 studies in cfDNA, 2 studies in CTC, and the other three studies used circulating nucleosome, microRNA, and multiple biomarkers, respectively. Pooled sensitivity and specificity of liquid biopsy in cancer early detection was 0.76 (95%CI:0.67-0.83) and 0.92 (95%CI:0.86-0.96) and the area under the SROC curve was 0.91 (95%CI:0.88-0.93).CONCLUSIONS:The current evidence shows that liquid biopsy has relatively low sensitivity and high specificity in cancer early detection. Among all these biomarkers, cfDNA may have potentially promising value in cancer early detection, thereby supporting further study of cancer early detection.STUDY REGISTRATION:The study is registered at PROSPERO (Identifier number: CRD42020137205).