Analysis of CCND3 mutations in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), accounts for 30-40% of newly diagnosed lymphomas, has an overall cure rate of approximately 60%. Despite previous reports suggesting a negative prognostic association between CCND3 mutations and Burkitt lymphoma, their prognostic implications in DLBCL remain controversial. To investigate this, we evaluated CCND3 mutation status in 2059 DLBCL patient samples from four database (integrated cohort) and additional 167 DLBCL patient samples in our center (JSPH cohort). The mutation was identified in 5.5% (113/2059) of the cases in the integrated cohort, with 86% (97/113) found in exon 5. Furthermore, P284, R271, I290 and Q276 are described as CCND3 mutation hotspots. CCND3 mutation was associated with decreased overall survival (OS) in the integrated cohort (P = 0.0407). Further subgroup analysis revealed that patients diagnosed as EZB subtype DLBCL by LymphGen algorithm with CCND3 mutations had poorer OS than patients diagnosed as EZB subtype without CCND3 mutations (P = 0.0140). Using the next-generation sequencing (NGS) in the JSPH cohort, it was found that both cell cycle and DNA replication pathways were highly upregulated in patients with CCND3 mutations. Our results suggest that CCND3 mutations can serve as a novel prognostic factor in DLBCL pathogenesis. Consequently, the development of personalized therapeutic strategies for DLBCL patients with CCND3 mutations might enhance their prognosis.

Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma.

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundred ND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

PRMT5 activates lipid metabolic reprogramming via MYC contributing to the growth and survival of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable and aggressive subtype of non-Hodgkin B-cell lymphoma. Increased lipid uptake, storage, and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. However, no data has been explored for the roles of lipid metabolism reprogramming in MCL. Here, we identified aberrant lipid metabolism reprogramming and PRMT5 as a key regulator of cholesterol and fatty acid metabolism reprogramming in MCL patients. High PRMT5 expression predicts adverse outcome prognosis in 105 patients with MCL and GEO database (GSE93291). PRMT5 deficiency resulted in proliferation defects and cell death by CRISPR/Cas9 editing. Moreover, PRMT5 inhibitors including SH3765 and EPZ015666 worked through blocking SREBP1/2 and FASN expression in MCL. Furthermore, PRMT5 was significantly associated with MYC expression in 105 MCL samples and the GEO database (GSE93291). CRISPR MYC knockout indicated PRMT5 can promote MCL outgrowth by inducing SREBP1/2 and FASN expression through the MYC pathway.

Low T3 syndrome as a predictor of poor prognosis in peripheral T-cell lymphomas

Purpose The purpose of the study was to evaluate the prognostic value of low T3 syndrome in peripheral T-cell lymphomas (PTCLs). Methods One hundred and seventy-four patients of newly diagnosed PTCLs were enrolled in the study. We performed statistical analysis based on the clinical data collected. Results Thirty-Six (20.69%) patients had low T3 syndrome at first admission. Results suggested that the patients with higher score of ECOG PS, International Prognostic Index (IPI) and Prognostic Index for T-cell lymphoma (PIT), bone marrow involvement and lower level of albumin tended to develop low T3 syndrome. The median progression-free survival (PFS) and overall survival (OS) were 10 months and 36 months, respectively, for all patients. Pre-existing low T3 syndrome was in correlation with worse PFS and OS. Patients with low T3 syndrome showed worse PFS (4 months vs 13 months, P = 0.0001) and OS (7 months vs 83 months, P < 0.0001) than patients without low T3 syndrome. IPI and PIT, respectively, combined with low T3 syndrome improved the ability to predict OS and PFS of PTCLs. Conclusions The study indicated that low T3 syndrome may be a good candidate for predicting prognosis of peripheral T-cell lymphomas (AU)

Prognostic value of POD18 combined with improved IELSG in primary central nervous system lymphoma

Purpose The International Extranodal Lymphoma Study Group (IELSG) score is widely used in clinical practice to stratify the risk of primary central nervous system lymphoma (PCNSL) patients. Our study aims to confirm and improve the IELSG score in PCNSL patients based on Chinese populations. Materials and methods A total of 79 PCNSL patients were retrospectively analyzed. All patients treated with high-dose methotrexate (HD-MTX)-based therapy collected clinical data. The receiver-operating characteristic (ROC) curve was used to determine the optimal cut-off values for the factors in IELSG score. Progression of disease (POD) at the most landmark time point was determine by Epanechnikov kernel and the area under the ROC curve (AUROC). Kaplan–Meier and multivariable regression methods were used to analyze survival data. Nomogram was generated for calculating the weight of each selected factor. Results The traditional IELSG score had no significant difference on OS and PFS except ECOG ≥ 2 and could not stratify the risk groups in PCNSL. The improved IELSG scoring system was established, which incorporated age ≥ 54 years, ECOG ≥ 2, deep brain structure, elevated CSF protein, and LDH/ULN > 0.75. On the other hand, POD18 was identified as a new powerful prognostic factor for PCNSL. In multivariate analysis, POD18 and the improved IELSG scoring system were independent prognostic factors for OS. Nomogram including the two significant variables showed the best performance (C-index = 0.828). Conclusions In this study, the IELSG score was improved and a new prognostic indicator POD18 was incorporated to construct a nomogram prognostic model, thereby further improving the predictive ability of the model (AU)

Cause-specific mortality in a population-level cohort of diffuse large B-cell lymphoma following chemotherapy in the early 21st century.

Diffuse large B-cell lymphoma (DLBCL) is a severe non-Hodgkin's lymphoma. Life expectancy has improved with rituximab, but cause-specific mortality data is lacking. Using the Surveillance, Epidemiology, and End Results (SEER) database to study 27,449 individuals aged 20-74 years diagnosed with primary DLBCL who received chemotherapy between 2000 and 2019, we calculated standardized mortality rate (SMR) and excess absolute risk (EAR) and examined the connection between age, sex, time after diagnosis, and cause of death. Based on 12,205 deaths, 68.7% were due to lymphoma, 20.1% non-cancer causes, and 11.2% other cancers. Non-cancer mortality rates (SMR 1.2; EAR, 21.5) increased with DLBCL compared to the general population. The leading non-cancer death causes were cardiovascular (EAR, 22.6; SMR, 1.6) and infectious (EAR, 9.0; SMR, 2.9) diseases with DLBCL. Risks for non-cancer death and solid neoplasms are highest within the first diagnosis year, then decrease. Among socioeconomic factors, being white, being married, and having a higher income were favorable factors for reducing non-cancer mortality. To improve survival, close surveillance, assessment of risk factors, and early intervention are needed.

CD30 protects EBV-positive diffuse large B-cell lymphoma cells against mitochondrial dysfunction through BNIP3-mediated mitophagy.

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (EBV+ DLBCL) predicts poor prognosis and CD30 expression aggravates the worse consequences. Here, we reported that CD30 positivity was an independent prognostic indicator in EBV+ DLBCL patients in a retrospective cohort study. We harnessed CRISPR/Cas9 editing to engineer the first loss-of-function models of CD30 deficiency to identify that CD30 was critical for EBV+ DLBCL growth and survival. We established a pathway that EBV infection mediated CD30 expression through EBV-encoded latent membrane protein 1 (LMP1), which involved NF-κB signaling. CRISPR CD30 knockout significantly repressed BCL2 interacting protein 3 (BNIP3) expression and co-IP assay indicated a binding between CD30 and BNIP3. Moreover, silencing of CD30 induced mitochondrial dysfunction and suppressed mitophagy, resulting in the accumulation of damaged mitochondria by depressing BNIP3 expression. Additionally, CRISPR BNIP3 knockout caused proliferation defects and increased sensitivity to apoptosis. All the findings reveal a strong relationship between mitophagy and adverse prognosis of EBV+ DLBCL and discover a new regulatory mechanism of BNIP3-mediated mitophagy, which may help develop effective treatment regimens with anti-CD30 antibody brentuximab vedotin to improve the prognosis of CD30+ EBV+ DLBCL patients.

Low T3 syndrome as a predictor of poor prognosis in peripheral T-cell lymphomas.

PURPOSE: The purpose of the study was to evaluate the prognostic value of low T3 syndrome in peripheral T-cell lymphomas (PTCLs). METHODS: One hundred and seventy-four patients of newly diagnosed PTCLs were enrolled in the study. We performed statistical analysis based on the clinical data collected. RESULTS: Thirty-Six (20.69%) patients had low T3 syndrome at first admission. Results suggested that the patients with higher score of ECOG PS, International Prognostic Index (IPI) and Prognostic Index for T-cell lymphoma (PIT), bone marrow involvement and lower level of albumin tended to develop low T3 syndrome. The median progression-free survival (PFS) and overall survival (OS) were 10 months and 36 months, respectively, for all patients. Pre-existing low T3 syndrome was in correlation with worse PFS and OS. Patients with low T3 syndrome showed worse PFS (4 months vs 13 months, P = 0.0001) and OS (7 months vs 83 months, P < 0.0001) than patients without low T3 syndrome. IPI and PIT, respectively, combined with low T3 syndrome improved the ability to predict OS and PFS of PTCLs. CONCLUSIONS: The study indicated that low T3 syndrome may be a good candidate for predicting prognosis of peripheral T-cell lymphomas.

Prognostic value of POD18 combined with improved IELSG in primary central nervous system lymphoma.

PURPOSE: The International Extranodal Lymphoma Study Group (IELSG) score is widely used in clinical practice to stratify the risk of primary central nervous system lymphoma (PCNSL) patients. Our study aims to confirm and improve the IELSG score in PCNSL patients based on Chinese populations. MATERIALS AND METHODS: A total of 79 PCNSL patients were retrospectively analyzed. All patients treated with high-dose methotrexate (HD-MTX)-based therapy collected clinical data. The receiver-operating characteristic (ROC) curve was used to determine the optimal cut-off values for the factors in IELSG score. Progression of disease (POD) at the most landmark time point was determine by Epanechnikov kernel and the area under the ROC curve (AUROC). Kaplan-Meier and multivariable regression methods were used to analyze survival data. Nomogram was generated for calculating the weight of each selected factor. RESULTS: The traditional IELSG score had no significant difference on OS and PFS except ECOG ≥ 2 and could not stratify the risk groups in PCNSL. The improved IELSG scoring system was established, which incorporated age ≥ 54 years, ECOG ≥ 2, deep brain structure, elevated CSF protein, and LDH/ULN > 0.75. On the other hand, POD18 was identified as a new powerful prognostic factor for PCNSL. In multivariate analysis, POD18 and the improved IELSG scoring system were independent prognostic factors for OS. Nomogram including the two significant variables showed the best performance (C-index = 0.828). CONCLUSIONS: In this study, the IELSG score was improved and a new prognostic indicator POD18 was incorporated to construct a nomogram prognostic model, thereby further improving the predictive ability of the model.

25-Hydroxy vitamin D deficiency is an inferior predictor of peripheral T-cell lymphomas.

The aim of the study was to explore the significance and prognostic value of 25-hydroxy vitamin D (25-(OH) D) deficiency in peripheral T-cell lymphomas (PTCLs). One hundred fifty-six patients of newly diagnosed PTCLs were enrolled in the study. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curves were plotted, and corresponding areas under the curve (AUC) were calculated to estimate the accuracy of International Prognostic Index (IPI) plus 25-(OH) D deficiency and Prognostic Index for T-cell lymphoma (PIT) plus 25-(OH) D deficiency respectively in PTCL risk stratification. Our results showed that the 25-(OH) D deficiency was an independent inferior prognostic factor for both PFS (P = 0.0019) and OS (P = 0.005) for PTCLs, especially for AITL and PTCL-not otherwise specified (PTCL-NOS). Additionally, adding 25-(OH) D deficiency to PIT indeed has a superior prognostic significance than PIT alone for PFS (P = 0.043) and OS (P = 0.036). Multivariate COX regression analysis revealed that PIT 2‒4, albumin (ALB) ≤ 35 g/L, and 25-(OH) D deficiency were regarded as independent risk factors of PFS and OS. Our results showed that 25-(OH) D deficiency was associated with inferior survival outcome of PTCLs, especially for AITL and PTCL-NOS. PIT plus 25-(OH) D deficiency could better indicate the prognosis for PFS and OS of PTCLs than PIT.

Spatially Selective Solvation Structure by Electronegative Micro-Arrays for Stable Lithium-Metal Anode Interface.

For electrolytes with conventional lithium salt concentration, it is not easy to generate sufficient anion-derived beneficial inorganic components to stabilize the electrolyte-lithium metal anode interface due to the repulsion of the free-state anions by the anode. In this study, the above issues are solved through the strong interaction between electronegative materials and lithium ions (Li+ ). A locally high Li+ concentration strategy is proposed by preparing micro-arrays of electronegative nano-hydroxyapatite (nHA) on the Cu foil. It is found that the oxygen atoms in the phosphate group (-PO4 ) of the nHA can strongly adsorb Li+ to form a locally Li+ -rich region, which increases the probability of anions interacting with Li+ . The formation of more Li+ -coordinated anions at the electrolyte-anode interface can reduce the Li+ de-solvation energy barrier, and enable the anions to completely decompose into lithium fluoride (LiF) and lithium nitride (Li3 N) on the Li metal anode. The interfacial transfer dynamics is accelerated and the Li dendrites are effectively suppressed. Under high current density, the anode exhibits a long lifespan with high Coulombic efficiency and small polarization voltage. The nHA micro-arrays achieve the targeted solvation structure at the electrolyte-anode interface while ensuring conventional lithium salt concentration in the bulk electrolyte.

Investigation of fatty acid metabolism in chronic lymphocytic leukemia to guide clinical outcome and therapy.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the West. With CLL's heterogeneity, some people still develop disease refractory and relapse despite advances in treatment. Thus, early diagnosis and treatment of high-risk CLL patients is critical. Fatty acid (FA) metabolism contributes to tumorigenesis, progression, and therapy resistance through enhanced lipid synthesis, storage, and catabolism. In this study, we aimed to construct a prognostic model to improve the risk stratification of CLL and reveal the link between FA metabolism and CLL. The differentially expressed FA metabolism-related genes (FMGs) in CLL were filtered through univariate Cox regression analysis based on public databases. Functional enrichment was examined using prognostic FA metabolism-related gene enrichment analysis. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) estimated immune infiltration score and immune-related pathways. Pearson's correlation analysis investigated FA metabolism-related genes and drug sensitivity. A novel prognostic model was built using least absolute shrinkage and selection operator (LASSO) Cox algorithms. This validation cohort included 36 CLL patients from our center. We obtained CLL RNA microarray profiles from public databases and identified 15 prognostic-related FMGs. CLL patients were divided into two molecular clusters based on the expression of FMGs. The Kaplan-Meier analysis revealed a significant difference in TFS (P < 0.001) and OS (P < 0.001) between the two clusters. KEGG functional analysis showed that several pathways were enriched, including the chemokine and immune-related signaling pathways. In the training and validation cohorts, patients with higher FA metabolism-related prognostic index (FAPI) levels had worse outcomes. Finally, a novel nomogram prognostic model including CLL international prognostic index (CLL-IPI) was constructed, exhibiting reliable effectiveness and accuracy. In conclusion, we established a reliable predictive signature based on FA metabolism-related genes and constructed a novel nomogram prognostic model, supporting the potential preclinical implications of FA metabolism in CLL research.

m6A-Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a hematological malignancy with high metabolic heterogeneity. N6-methyladenosine (m6A) modification plays an important role in metabolism through regulating circular RNAs (circRNAs). However, the underlying mechanism is not yet fully understood in CLL. Herein, an m6A scoring system and an m6A-related circRNA prognostic signature are established, and circTET2 as a potential prognostic biomarker for CLL is identified. The level of m6A modification is found to affect the transport of circTET2 out of the nucleus. By interacting with the RNA-binding protein (RBP) heterogeneous nuclear ribonucleoprotein C (HNRNPC), circTET2 regulates the stability of CPT1A and participates in the lipid metabolism and proliferation of CLL cells through mTORC1 signaling pathway. The mTOR inhibitor dactolisib and FAO inhibitor perhexiline exert a synergistic effect on CLL cells. In addition, the biogenesis of circTET2 can be affected by the splicing process and the RBPs RBMX and YTHDC1. CP028, a splicing inhibitor, modulates the expression of circTET2 and shows pronounced inhibitory effects. In summary, circTET2 plays an important role in the modulation of lipid metabolism and cell proliferation in CLL. This study demonstrates the clinical value of circTET2 as a prognostic indicator as well as provides novel insights in targeting treatment for CLL.

Chidamide plus prednisone, cyclophosphamide, and thalidomide for relapsed or refractory peripheral T-cell lymphoma: A multicenter phase II trial.

BACKGROUND: Although the treatment of peripheral T-cell lymphoma (PTCL) has undergone advancements during the past several years, the response rate and long-term effects with respect to patients with PTCL remain unsatisfactory-particularly for relapsed or refractory (R/R) patients. This phase II trial was designed to explore the efficacy and safety of an all-oral regimen of chidamide plus prednisone, cyclophosphamide, and thalidomide (CPCT) for R/R PTCL patients who could not tolerate the standard chemotherapy for a variety of reasons. METHODS: We conducted a multicenter phase II clinical trial in which we combined chidamide (30 mg twice weekly) with prednisone (20 mg daily after breakfast), cyclophosphamide (50 mg daily after lunch), and thalidomide (100 mg daily at bedtime) (the CPCT regimen) for a total of fewer than 12 cycles as an induction-combined treatment period, and then applied chidamide as single-drug maintenance. Forty-five patients were ultimately enrolled from August 2016 to April 2021 with respect to Chinese patients at nine centers. Our primary objective was to assess the overall response rate (ORR) after the treatment with CPCT. RESULTS: Of the 45 enrolled patients, the optimal ORR and complete response (CR)/CR unconfirmed (CRu) were 71.1% (32/45) and 28.9% (13/45), respectively, and after a median follow-up period of 56 months, the median progression-free survival (PFS) and overall survival (OS) were 8.5 months and 17.2 months, respectively. The five-year PFS and OS rates were 21.2% (95% confidence interval [CI], 7.9-34.5 %) and 43.8% (95% CI, 28.3-59.3 %), respectively. The most common adverse event was neutropenia (20/45, 44.4%), but we observed no treatment-related death. CONCLUSION: The all-oral CPCT regimen was an effective and safety regimen for R/R PTCL patients who could not tolerate standard chemotherapy for various reasons. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02879526.

Dynamic changes in circulating EBV-DNA load during treatment have prognostic values in EBV+ DLBCL-NOS: a Chinese cohort study.

EBV-positive diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL-NOS), is an EBV-positive clonal B-cell lymphoid proliferation and circulating EBV-DNA is a great indicator for prognosis among EBV associated disease. In this retrospective study, we report 66 EBV+ DLBCL cases among 2137 DLBCL-NOS cases diagnosed from 2013 to 2021 (prevalence of 6.0%). After a median follow-up of 27 months, progression-free survival (PFS) and overall survival (OS) at 2 years were 39.5% ± 6.2% and 53.6% ± 6.4%, respectively. Multivariate analysis showed that only the biomarker of the positivity of post treatment EBV-DNA had a borderline correlation with shorter PFS and OS (PFS: P = 0.053; OS: P = 0.065). Patients were divided into three subgroups according to dynamic changes of EBV-DNA status: EBV-DNA persistently negative group, EBV-DNA persistently positive group, and EBV-DNA transformed from positive to negative group; among the three groups, patients of the persistently positive group had worst PFS and OS (P = 0.0527 and P = 0.0139, respectively). Decline in EBV copies correlated significantly with treatment response as well. In conclusion, circulating EBV-DNA level played a vital role in prognostic and monitoring marker for EBV+ DLBCL-NOS.

Directing Highly Ordered and Dense Li Deposition to Achieve Stable Li Metal Batteries.

Li metal anode is promising to achieve high-energy-density battery. However, it has rapid capacity fading due to the generation of inactive Li (dead Li), especially at high current density. This study reveals that the random distribution of Li nuclei leads to large uncertainty for the further growth behavior on Cu foil. Here, periodical regulation of Li nucleation sites on Cu foil by ordered lithiophilic micro-grooves is proposed to precisely manipulate the Li deposition morphology. The management of Li deposits in the lithiophilic grooves can induce high pressure on the Li particles, leading to the formation of dense Li structure and smooth surface without dendrite growth. Li deposits comprising tightly packed large Li particles largely reduce the side reaction and the generation of isolated metallic Li at high current density. Less dead Li accumulating on the substrate significantly prolongs the cycling life of full cells with limited Li inventory. The precise manipulation of the Li deposition on Cu is promising for high-energy and stable Li metal batteries.

Low T3 syndrome as a predictor of poor outcomes in patients with follicular lymphoma.

The aim of this study was to investigate the prognostic value of low T3 syndrome in follicular lymphoma (FL). A total of 221 FL patients with detailed serum thyroid hormone levels and other complete clinical data were enrolled. Baseline features associated with low T3 syndrome were analyzed and balanced by propensity score matching. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). A receiver operating characteristic (ROC) curve was plotted, and the area under the curve (AUC) was calculated to assess the predictive accuracy of FL international prognostic index FLIPI-1/FLIPI-2 and low T3 syndrome. A total of 22 patients (10.0%) had low T3 syndrome at diagnosis, which was associated with poor PFS and OS in the rituximab era. It is an independent prognostic factor for PFS and OS. Low T3 syndrome and FLIPI-1/FLIPI-2 significantly increased the AUC of PFS and OS compared to FLIPI-1/FLIPI-2 alone. Low T3 is a risk factor for POD24. In conclusion, low T3 syndrome may be a good candidate for predicting the prognosis of CLL in future clinical practice. Our study demonstrates that low T3 syndrome is associated with poorer survival outcomes in FL patients.