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Many studies have demonstrated that tumor-associated macrophages (TAMs) were a prognostic indicator in patients with B cell lymphoma. But, we know little about the clinical significance of TAMs in extranodal natural killer/T cell lymphoma(ENKTL), nasal type. CD68 expression was detected using immunohistochemistry to determine the numbers of TAMs in 70 ENKTL patients, and the data were used to evaluate its relationship with clinicopathological features, treatment response, and prognosis. Patients with high number of infiltrated CD68+ TAMs (>60/hpf) at diagnosis tended to have more adverse clinical characteristics. Patients with low CD68+ TAM content (<60/hpf) at diagnosis had better overall survival ( P = 0.003) and progression-free survival ( P = 0.002) and achieved higher complete remission rates ( P = 0.008). Multivariate analysis revealed that CD68 + TAM content, Ki-67 index, and stage III and IV were independent prognostic factors for both OS and PFS. Using the International Prognostic Index or Korean Prognostic Index for extranodal NK/T cell lymphoma, nasal type, the majority of patients were in the low-risk category. CD68 + TAM content was helpful to differentiate the low-risk patients with different survival outcomes. Our data suggest that CD68+ TAM content at diagnosis is a powerful predictor of prognosis for ENKTL, which suggests a role for TAMs in the pathogenesis of this disease and offers new insight into potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

13-Methyltetradecanoic acid (13-MTD), a saturated branched-chain fatty acid purified from soy fermentation products, induces apoptosis in human cancer cells. We investigated the inhibitory effects and mechanism of action of 13-MTD on T-cell non-Hodgkin’s lymphoma (T-NHL) cell lines both in vitro and in vivo. Growth inhibition in response to 13-MTD was evaluated by the cell counting kit-8 (CCK-8) assay in three T-NHL cell lines (Jurkat, Hut78, EL4 cells). Flow cytometry analyses were used to monitor the cell cycle and apoptosis. Proteins involved in 13-MTD-induced apoptosis were examined in Jurkat cells by western blotting. We found that 13-MTD inhibited proliferation and induced the apoptosis of T-NHL cell lines. 13-MTD treatment also induced a concentration-dependent arrest of Jurkat cells in the G1-phase. During 13-MTD-induced apoptosis in Jurkat cells, the cleavage of caspase-3 and poly ADP-ribose polymerase (PARP, a caspase enzymolysis product) were detected after incubation for 2 h, and increased after extending the incubation time. However, there was no change in the expression of Bcl-2 or c-myc proteins. The appearance of apoptotic Jurkat cells was accompanied by the inhibition of AKT and nuclear factor-kappa B (NF-κB) phosphorylation. In addition, 13-MTD could also effectively inhibit the growth of T-NHL tumors in vivo in a xenograft model. The tumor inhibition rate in the experimental group was 40%. These data indicate that 13-MTD inhibits proliferation and induces apoptosis through the down-regulation of AKT phosphorylation followed by caspase activation, which may provide a new approach for treating T-cell lymphomas. [ABSTRACT FROM AUTHOR]

Targeted therapy with Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of patients with various B-cell malignancies. BTK inhibitors such as ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib have shown good clinical efficacy and better safety profiles than those of traditional chemotherapy and chemoimmunotherapy regimens. Multiple studies on new BTK inhibitors are ongoing, which may provide more therapeutic options for the treatment of B-cell malignancies. Considering the unmet need of evidence on BTK inhibitors in all clinical settings and to standardize the use of BTK inhibitors available in mainland China, Taiwan, Hong Kong, and Macau regions, this consensus has been formulated for the treatment of various B-cell malignancies based on the clinical practice and available evidences on the use of BTK inhibitors. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective treatment of B-cell malignancies with BTK inhibitors. [ABSTRACT FROM AUTHOR]

Summary: Anti‐PD‐1 antibody has shown certain effects in patients with newly diagnosed extranodal NK/T‐cell lymphoma (ENKTL). Here, we evaluated the clinical efficacy and safety of first‐line anti‐PD‐1 antibody for the treatment of patients with ENKTL and explored biomarkers for treatment response. The clinical data of 107 patients with newly diagnosed ENKTL were retrospectively analysed. Patients received either first‐line anti‐PD‐1 antibody induction treatment or anti‐PD‐1 antibody combined with asparaginase‐based chemotherapy (immunochemotherapy). We found that immunochemotherapy was an independent prognostic factor for longer PFS (p < 0.001). The overall response rate and complete remission rate of immunochemotherapy group was higher than immunotherapy induction group (86.11% vs. 62.86% and 72.22% vs. 52.29%, respectively, p = 0.013). We also observed pretreatment CD4/CD8 ratio >0.83 was significant associated with better response and longer PFS in ENKTL patients received first‐line anti‐PD1‐antibody. Plasma copy number of EBV decreased more significantly in patients with CD4/CD8 ratio >0.83 after treatment. PD‐L1 expression was associated with better response and PFS, while elevated plasma IL‐6, IL‐10 and IFN‐γ were associated with poor prognosis. Anti‐PD‐1 antibody treatment showed promising results in newly diagnosed ENKTL patients. The assessment of pretreatment CD4/CD8 ratio in ENKTL seems feasible for identifying responders to anti‐PD‐1 antibody treatment. [ABSTRACT FROM AUTHOR]

The prognosis of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. The efficacy of salvage therapy with ICE (ifosfamide, carboplatin, and etoposide) is limited. DLBCL can evade immune surveillance by upregulating programmed cell death ligand 1 (PD-L1). The purpose of this study was to explore the efficacy and safety of programmed cell death 1 (PD-1) blockade combined with ICE regimen (P-ICE) in the treatment of R/R DLBCL patients. In this study, we retrospectively explored efficacy and toxicity in R/R DLBCL patients treated with P-ICE. Prognostic biomarkers, including clinical features and molecular markers related to efficacy, were explored. From February 2019 to May 2020, a total of 67 patients treated with the P-ICE regimen were analyzed. The median follow-up time was 24.7 months (range: 1.4–39.6 months), with an objective response rate (ORR) of 62.7% and a complete response rate (CRR) of 43.3%. The 2-year progression-free survival (PFS) and overall survival (OS) rates were 41.1% (95% CI: 35.0–47.2%) and 65.6% (95% CI: 59.5–71.7%), respectively. Age, Ann Arbor stage, international prognostic index (IPI) score, and response to first-line chemotherapy were correlated with the ORR. Grade 3 and 4 adverse events (AEs) related to the P-ICE regimen were reported in 21.5% of patients. The most common AE was thrombocytopenia (9.0%). No treatment-related deaths occurred. In patients with R/R DLBCL, the P-ICE regimen has promising efficacy and mild toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Anti-PD-1 antibody (anti-PD-1 mAb) showed favorable outcomes in some patients with relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL). However, the role of anti-PD-1 antibody in NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHS) remains unclear. Here, we evaluated the efficacy and toxicity of anti-PD-1 antibody-based treatment in NK/T-LAHS patients. Methods: The clinical data of 98 patients diagnosed with NK/T-LAHS at Sun Yat-sen University Cancer Center and the First Affiliated Hospital of Guangdong Pharmaceutical University from May 2014 to November 2021 were retrospectively analyzed. All patients received anti-HLH [HLH-2004 (etoposide, dexamethasone, cyclosporine A) or DEP-based (liposomal doxorubicin, etoposide, methylprednisolone)] regimen and sequential anti-ENKTL chemotherapy (ChT) combined with anti-PD-1 antibody or not. Results: The overall response rate (ORR) of the anti-PD-1 mAb plus ChT regimens was higher than that of the ChT regimens (73.3% vs. 45.5%, P = 0.041). The toxicity of the anti-PD-1 mAb plus ChT regimens was tolerable. Except for higher rate of neutropenia, no significant difference in adverse events (AEs) was observed between the two groups. When the optimal response to anti-ENKTL was achieved, the median EBV DNA levels in patients who received anti-PD-1 mAb plus ChT were significantly lower than patients who received ChT only (878 copies/mL vs. 18,600 copies/mL, P = 0.001). With a median follow-up of 26.6 months (range 0–65.9 months), the median overall survival (mOS) was 3.5 months (95% CI：2.3–4.7 months). Patients treated with anti-PD-1 mAb plus ChT experienced a longer mOS than those who received ChT only [5.2 months (95% CI: 2.5–7.8 months) vs. 1.5 months (95% CI: 0.5–2.6 months), P = 0.002]. Cox multivariate analysis found that anti-PD-1 mAb was an independent prognostic factor for all NK/T-LAHS patients. Conclusion: In conclusion, anti-PD-1 mAb combined with ChT regimens seemed to be associated with prolonged survival in NK/T-LAHS patients and may represent a potentially promising treatment strategy for this population. [ABSTRACT FROM AUTHOR]

Background: CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T‐cell‐mediated immunity. However, the role of CD70 in B‐cell malignancies remains controversial. Methods: We investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B‐cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD‐L1 inhibitor in a murine lymphoma model. Results: We showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0%) than in the Swedish cohort (9/84, 10.8%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over‐expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8+ T cells were furthermore identified in CD70 high‐expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD‐L1 interactions could reduce CD70+ lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells. Conclusions: Our findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno‐therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Ibrutinib has revolutionized the treatment of mantle cell lymphoma (MCL). Both ibrutinib monotherapy and ibrutinib‐based combination therapy are important salvage options for patients with relapsed/refractory (R/R) MCL. The real‐world efficacy and safety profile of the two strategies in Chinese patients with R/R MCL remain unclarified. Methods: In the present study, data of 121 R/R MCL patients who received either ibrutinib monotherapy (N = 68) or ibrutinib combination therapy (N = 53) in 13 medical centers in China were retrospectively reviewed. Results: With a median follow‐up of 20.5 months, the overall response rate was 60.3% versus 84.9% (p = 0.003), complete remission rate was 16.2% versus 43.4% (p < 0.001), and median progression‐free survival (PFS) was 18.5 months (95% confidence interval [CI], 12.1–21.8) vs. 30.8 months (95% CI, 23.5‐NR) (hazard ratio, 0.53 [95% CI, 0.30–0.93]; p = 0.025), with ibrutinib monotherapy and ibrutinib‐based combination therapy, respectively. Subgroup analysis showed that patients with male gender, no refractory disease, Ki67 <30%, previous line of therapy = 1, non‐blastoid subtype, and the number of extranodal sites involved <2 might benefits more from the combination therapy. Treatment‐emergent adverse events were similar, except for a higher incidence of all grade neutropenia in the ibrutinib combination group (12.7% vs. 32.0%, p = 0.017). Conclusions: Ibrutinib combination therapy demonstrated potentially superior efficacy and comparable tolerability to ibrutinib monotherapy. Ibrutinib‐based combination therapy could be one of the prominent treatment options for R/R MCL patients. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is the most prevalent type of lymphoma that is potentially curable by chemotherapy. Immunogenic cell death (ICD) is regarded as an essential process for the clearance of residual tumor cells. However, the impact of ICD on DLBCL remains unknown. Here, we tried to explore the prognostic role of ICD in DLBCL. Methods: A gene expression microarray of DLBCL was downloaded from the Gene Expression Omnibus (GEO). The genes involved in ICD were obtained via literature reviews. Then, based on univariate, multivariate, and LASSO Cox regression analysis, the ICD-related gene signature was identified. The effect of the ICD-related gene signature on DLBCL was explored. The chi-square test was used to compare complete response rate (CRR) and recurrence rate between high- and low-risk groups. Results: The signature based on 12 ICD-related genes could independently predict the overall survival of DLBCL. Furthermore, high risk was linked to lower CRR and higher recurrence rate. Then, a nomogram based on the ICD-related gene signature was established. The area under the curve of the prediction model reached 0.820 in the training set and 0.780 in the validation set. Conclusions: This study suggested that the ICD-related gene signature could be a novel prognostic indicator for DLCBL. [ABSTRACT FROM AUTHOR]

It is estimated that over 10,000,000 occupational injuries occur in China each year. This study explored the relationships between four dimensions of safety climate (management commitment, safety supervision, coworker support, and safety training), three dimensions of safety behavior (safety compliance, personal protective equipment, and safety initiatives), and occupational injuries among Chinese manufacturing workers. A cross-sectional survey was conducted using a sample of 3970 manufacturing workers from 42 companies in Zhongshan City, China. A structured questionnaire was used to capture participants’ socio-demographic characteristics, occupational safety climate, occupational safety behavior, and occupational injuries in the previous year. Path analysis was used to test the relationships between safety climate, safety behavior and injuries at each workplace. The results revealed significant associations between different safety climates, safety behavior, and unintentional injuries, and provided evidence that safety behavior strongly mediates the relationship between safety climate and unintentional injuries. Our study reinforces the empirical association of occupational safety climate and safety behavior with occupational injuries and identifies some effective measures to prevent and control injuries in Chinese workplaces. [ABSTRACT FROM AUTHOR]

Studies comparing the efficacy and safety of R-CHOP and modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-90 (NHL-BFM-90) regimens in children and adolescents with diffuse large B-cell lymphoma (DLBCL) are lacking. Thus, we retrospectively analyzed 85 DLBCL patients aged ≤18 years from 2000 to 2020; 74 patients received the modified NHL-BFM-90 regimen, and 11 received the R-CHOP regimen. The 5-year OS and event-free survival (EFS) rates between the modified NHL-BFM-90 and R-CHOP regimens were 91.0% vs. 90.9% (P = 0.466) and 89.8% vs. 68.6% (P = 0.055), respectively. In the stratified analysis, the survival outcome of pediatric patients treated with the modified NHL-BFM-90 regimen was not significantly different from that of adolescent patients. The OS and EFS rates of patients with early-stage disease were both 100%. Patients in the advanced-stage group who were treated with the modified NHL-BFM-90 regimen had superior EFS rates (P < 0.05). The frequency of severe adverse events from the two regimens was similar. There were no treatment-related deaths. We concluded that the modified NHL-BFM-90 regimen has better efficacy than R-CHOP in DLBCL patients with advanced-stage disease. However, the R-CHOP regimen might be an option for early-stage DLBCL. Further prospective studies are needed to guide clinical decisions about treatment. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare but devastating event. Intravenous high-dose methotrexate (HD-MTX) is recommended as CNS prophylaxis, but the optimal timing and dose has not been elucidated. Here, we report a multicenter analysis of prophylactic HD-MTX administration for DLBCL. Two hundred eighty-four patients receiving HD-MTX either concurrent with each induction chemotherapy cycle (n = 221) or at the end of induction therapy (EOI, n = 63) were included. Patients with CNS-IPI scoring 4–6, and/or testicular involvement, and/or double/triple hit lymphoma, were stratified into the high-risk group and the others into the moderate-risk group. Concurrent HD-MTX was associated with increased risk of grade 3/4 treatment-related toxicity (OR,1.49; P = 0.006) and subsequent chemotherapy delays (OR, 1.87; P = 0.003) in multivariate analysis. With a median follow-up of 36.0 months, no significant difference in CNS relapse rate was identified between the concurrent and EOI groups (3.2% vs 4.8%, P = 0.34), even in the high-risk group. Analysis on systemic MTX dose suggested that high-dose MTX (≥ 2 g/m2) was associated with better CNS relapse control only in the high-risk group, but not in the moderate-risk group. This study may elucidate the superiority of EOI HD-MTX to some extent. High MTX dose (≥ 2 g/m2) may not be necessary for the moderate-risk patients. [ABSTRACT FROM AUTHOR]

Background: We aimed to establish a predictive prognostic risk-stratification model for diffuse large B-cell lymphoma (DLBCL) in the rituximab era.Methods: The data of 1406 primary DLBCL patients from the Sun Yat-Sen University Cancer Center were analysed to establish a nomogram prognostic index (NPI) model for predicting overall survival (OS) based on pre-treatment indicators. An independent cohort of 954 DLBCL patients from three other hospitals was used for external validation.Results: Age, performance status, stage, lactate dehydrogenase, number of extranodal sites, BCL2, CD5 expression, B symptoms and absolute lymphocyte and monocyte count were the main factors of the NPI model and could stratify the patients into four distinct categories based on their predicted OS. The calibration curve demonstrated satisfactory agreement between the predicted and actual 5-year OS of the patients. The concordance index of the NPI model (0.794) was higher than the IPI (0.759) and NCCN-IPI (0.750), and similar results were obtained upon external validation. For CD5 + DLBCL patients, systemic treatment with high-dose methotrexate was associated with superior OS compared to R-CHOP-based immunochemotherapy alone.Conclusions: We established and validated an accurate prediction model, which performed better than IPI and NCCN-IPI for prognostic stratification of DLBCL patients. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to estimate the health preference–based index scores of the population of patients with lymphoma using the EQ-5D in China. Methods: A cross-sectional online survey was conducted to examine the health and well-being of patients with lymphoma in China. Their health-related quality of life (HRQoL; using the EQ-5D), demographic and socioeconomic characteristics, and health conditions were assessed. The data were analyzed using Pearson's χ2 test, analysis of variance, and binary logistic and Tobit regression models. Results: A total of 3261 patients (sex: men = 58.5%, age: < 30 years = 9.5% and > 60 years = 24.6%) participated in the study. The mean EQ-5D-5L index and EQ-VAS scores were 0.83 and 68.8, respectively. Binary logistic regression analysis revealed that women reported more pain-related problems than men did. Unemployed participants were substantially more likely to report health problems on all the five dimensions of the EQ-5D than their employed counterparts. The Tobit regression model revealed that respondents who were older, unemployed, with low income, received chemotherapy, and with short durations reported a low index score. Conclusion: Using the EQ-5D, the preference-based scores of different subpopulations of patients with lymphoma may support economic evaluation by promoting the simultaneous consideration of both the reasonable use of resources and satisfactory achievement of health outcomes. [ABSTRACT FROM AUTHOR]

We have systematically investigated the effect of deep cryogenic treatment (DCT) and intercritical annealing (IA) on the microstructural evolution and mechanical properties of a hot rolled medium-manganese transformation-induced plasticity (TRIP) steel. By intercritical annealing of DCT-treated steel in the fully martensitic state, ultra-fine-grained (UFG) austenite with different morphologies, namely lath-like and granular, was obtained. It is interesting that carbon segregation caused by DCT promoted the formation of carbide which can be additional nucleation sites for austenite besides the boundary of lath-martensite during austenite revision treatment (ART). Furthermore, the process of austenite growth was simulated by DICTRA and it revealed that austenite nucleated at the boundary of lath-martensite and carbide, and then grew into different morphologies, i.e. lath-like and globular, respectively. Moreover, the dissolution of cementite and finite diffusion distance of Mn limited austenite growth and partitioning of Mn, which resulted in refined grain size and high degree of Mn-enrichment. Consequently, enhanced mechanical-stability of austenite was obtained by DCT+IA, which ensured outstanding combination of mechanical properties, i.e. yield strength of 807 MPa, tensile strength of 1650 MPa and total elongation of 25.3%. The improved strength and ductility was attributed to stabilized austenite that enabled the moderate evolution of TRIP-related work hardening. [ABSTRACT FROM AUTHOR]

• PBMC EBV-DNA poorly correlated with imaging-based disease assessment and plasma EBV-DNA in patients with ENKTCL, while Plasma EBV-DNA strongly correlated with disease status. • Plasma EBV-DNA was more sensitive than PET/CT and CT/MRI in response evaluation and relapse monitoring. Regardless of imaging-based assessment, a substantial increase of plasma EBV-DNA indicated disease progression during treatment, and relapse was almost inevitable in patients with positive plasma EBV-DNA at the end of treatment. • When imaging-based disease assessment was discordant with plasma EBV-based assessment, the kinetic patterns of EBV-DNA were helpful to identify at-risk patients. Relapse occurred only in patient with intermittently or persistently positive plasma EBV-DNA, and occasionally positive EBV-DNA did not correlate with relapse. Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related hematological malignancy. The presence of EBV-DNA in peripheral blood is a widely used ENKTCL tumor marker. However, there is no consensus on the preferred blood specimen type for EBV testing. Furthermore, discordance between EBV-based and imaging-based disease assessments is common, and how to interpret this discordance is important. We retrospectively analyzed the data of ENKTCL patients in the Affiliated Cancer Hospital of Zhengzhou university and Sun Yat-sen University Cancer Center. All EBV-DNA and imaging-based disease assessment data were collected at diagnosis, during treatment, at the end of treatment, and during follow-up. We compared matched plasma EBV-DNA and peripheral blood mononuclear cell (PBMC) EBV-DNA and matched EBV-based and imaging-based assessments to uncover their clinical relevance. A total of 450 patients with adequate data were included, of whom 278 had plasma EBV-DNA data, 250 had PBMC EBV-DNA data, and 78 had matched plasma and PBMC EBV-DNA data. No significant correlations were found between PBMC and plasma EBV-DNA and between PBMC EBV-DNA and imaging-based assessment, but patients with positive PBMC EBV-DNA at diagnosis or intermittently/persistently positive PBMC EBV-DNA during follow-up had poorer survival. In contrast, plasma EBV-DNA strongly correlated with lymphoma status. Detectable pre- and post-treatment plasma EBV-DNA was associated with significantly worse survival. Patients with early-stage disease who had detectable plasma EBV-DNA at the end of treatment shared similar survival to those with advanced-stage disease, even if their imaging-based assessments were negative. For disease relapse monitoring, 78 (55.7%) episodes of relapse were detected by both imaging and plasma EBV-DNA; 58 (41.4%) detected by plasma EBV-DNA earlier than imaging, with a median time of 9.3 (0.3 - 37.8) months; and only 4 (2.9%) detected by plasma EBV-DNA later than imaging. The sensitivities of plasma EBV-DNA, PET/CT, and CT/MRI were 97.1%, 76.8%, and 45.1%, respectively, and their specificities were 91.7%, 84.2%, and 96.7%, respectively. Analysis of EBV kinetic patterns in EBV+/imaging- episodes revealed that relapse occurred only in patients with intermittently/persistently positive plasma EBV-DNA. Persistent plasma EBV+ was also seen in patients after autologous hematopoietic stem cell transplantation. Occasional EBV+ was not associated with relapse. Plasma and PBMC EBV-DNA have different clinical relevance in ENKTCL patients. PBMC EBV-DNA does not correlate with imaging-based disease assessment. PBMC or even whole blood should not be used for response evaluation and relapse monitoring. However, PBMC EBV-DNA still has prognostic value. Plasma EBV-DNA is strongly related to tumor status and is not only a prognosticator at diagnosis and end of treatment, but also a sensitive marker in relapse monitoring compared to PET/CT and CT/MRI. The specificity of plasma EBV-DNA is relatively low, but when EBV-DNA kinetic patterns are considered, it can identify at-risk patients. [ABSTRACT FROM AUTHOR]

• Chidamide + ChT brought PFS benefit to R/R PTCL patients with good tolerability. • Chidamide-contained regimens prolonged PFS of patients with high second-line IPI. • Young patients may benefit more from the combination of chemotherapy and chidamide. • Chemotherapy combined with chidamide brought PFS benefit to CD30-negative patients. Peripheral T-cell lymphoma (PTCL) is characterized by an aggressive clinical behavior. Chidamide has been approved for the treatment of relapsed/refractory (R/R) PTCL in China. We compared the efficacy of chidamide-contained regimens with chemotherapy (ChT) in R/R PTCL. Based on the second-line treatments, patients were divided into three groups, including ChT, ChT combined with chidamide (chidamide + ChT) and chidamide combined with or without other targeted agents (targeted therapy) group. Chidamide + ChT group had a better progression-free survival (PFS) compared with targeted therapy group (p = 0.013), and showed a trend towards superior PFS compared with ChT group (p = 0.079). Among patients with high second-line International Prognostic Index (IPI) (3-5), chidamide+ChT group had a longer PFS than ChT group(p = 0.018), and PFS in targeted therapy group was not inferior to that in chidamide+ChT group (p = 0.200). Among patients younger than 60 years, chidamide+ChT group demonstrated a PFS benefit over targeted therapy group (p = 0.010). Among CD30-negative patients, PFS was superior in the chidamide+ChT group compared with ChT group (p < 0.001). Conversely, results observed above were absent in patients with low second-line IPI or patients older than 60 years or CD30-positive patients. Overall, the combination of chidamide and ChT may be an effective treatment strategy for R/R PTCL. [ABSTRACT FROM AUTHOR]

The donor-derived cell-free DNA (ddcfDNA) is found in the plasma and urine of kidney transplant recipients and displays notable potential in diagnosing rejection, specifically antibody-mediated rejection (ABMR). Nonetheless, the quantitative methods of ddcfDNA lacking standardization and diverse detection techniques can impact the test outcomes. Besides, both the fraction and absolute values of ddcfDNA have been reported as valuable markers for rejection diagnosis, but they carry distinct meanings and are special in various pathological conditions. Additionally, ddcfDNA is highly sensitive to kidney transplant injury. The various sampling times and combination with other diseases can indeed impact ddcfDNA detection values. This review comprehensively analyses the various factors affecting ddcfDNA detection in kidney transplantation, including the number of SNPs and sequencing depths. Furthermore, different pathological conditions, distinct sampling time points, and the presence of complex heterologous signals can influence ddcfDNA testing results in kidney transplantation. The review also provides insights into ddcfDNA testing on different platforms along with key considerations., Competing Interests: Authors CC, YW, HL, HH, HS, TJ were employed by AlloDx Biotech Shanghai, Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cao, Yuan, Wang, Liu, Cuello Garcia, Huang, Tan, Zhou, Shi and Jiang.)

XPO1 is an attractive and promising therapeutic target frequently overexpressed in multiple hematological malignancies. The clinical use of XPO1 inhibitors in natural killer/T-cell lymphoma (NKTL) is not well documented. Here, we demonstrated that XPO1 overexpression is an indicator of poor prognosis in patients with NKTL. The compassionate use of the XPO1 inhibitor selinexor in combination with chemotherapy showed favorable clinical outcomes in three refractory/relapsed (R/R) NKTL patients. Selinexor induced complete tumor regression and prolonged survival in sensitive xenografts but not in resistant xenografts. Transcriptomic profiling analysis indicated that sensitivity to selinexor was correlated with deregulation of the cell cycle machinery, as selinexor significantly suppressed the expression of cell cycle-related genes. CDK4/6 inhibitors were identified as sensitizers that reversed selinexor resistance. Mechanistically, targeting CDK4/6 could enhance the anti-tumor efficacy of selinexor via the suppression of CDK4/6-pRb-E2F-c-Myc pathway in resistant cells, while selinexor alone could dramatically block this pathway in sensitive cells. Overall, our study provids a preclinical proof-of-concept for the use of selinexor alone or in combination with CDK4/6 inhibitors as a novel therapeutic strategy for patients with R/R NKTL., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Accurate diagnosis and prognosis prediction are conducive to early intervention and improvement of medical care for natural killer/T cell lymphoma (NKTCL). Artificial intelligence (AI)-based systems are developed based on nasopharynx magnetic resonance imaging. The diagnostic systems achieve areas under the curve of 0.905-0.960 in detecting malignant nasopharyngeal lesions and distinguishing NKTCL from nasopharyngeal carcinoma in independent validation datasets. In comparison to human radiologists, the diagnostic systems show higher accuracies than resident radiologists and comparable ones to senior radiologists. The prognostic system shows promising performance in predicting survival outcomes of NKTCL and outperforms several clinical models. For patients with early-stage NKTCL, only the high-risk group benefits from early radiotherapy (hazard ratio = 0.414 vs. late radiotherapy; 95% confidence interval, 0.190-0.900, p = 0.022), while progression-free survival does not differ in the low-risk group. In conclusion, AI-based systems show potential in assisting accurate diagnosis and prognosis prediction and may contribute to therapeutic optimization for NKTCL., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population., (© 2024. The Author(s).)

Background: Systemic inflammation, immunity, and nutritional status are closely related to patients' outcomes in several kinds of cancers. This study aimed to establish a new nomogram based on inflammation-immunity-nutrition score (IINS) to predict the prognosis of extranodal natural killer/T-cell lymphoma (ENKTL) patients., Methods: The clinical data of 435 patients with ENTKL were retrospectively reviewed and randomly assigned to training cohort (n=305) and validation cohort (n=131) at a ratio of 7:3. Cox regression analysis was employed to identify independent prognostic factors and develop a nomogram in the training cohort. Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) curve were employed to assess the performance of the nomogram and compare it with traditional prognostic systems (PINK, IPI, KPI). Internal validation was performed using 1000 bootstrap resamples in the validation cohort. Kaplan-Meier survival analyses were conducted to compare the overall survival (OS) of patients in different risk groups., Results: In the training cohort, in addition to several classic parameters, IINS was identified as an independent prognostic factor significantly associated with the OS of patients. The nomogram established based on the independent prognostic indicators showed superior survival prediction efficacy, with C-index of 0.733 in the training cohort and 0.759 in the validation cohort compared to the PINK (0.636 and 0.737), IPI (0.81 and 0.707), and KPI (0.693 and 0.639) systems. Furthermore, compared with PINK, IPI, and IPI systems, the nomogram showed relatively superior calibration curves and more powerful prognostic discrimination ability in predicting the OS of patients. DCA curves revealed some advantages in terms of clinical applicability of the nomogram compared to the PINK, IPI, and IPI systems., Conclusion: Compared with traditional prognostic systems, the nomogram showed promising prospects for risk stratification in ENKTL patient prognosis, providing new insights into the personalized treatment., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 He et al.)

Regimens based on Bruton's tyrosine kinase inhibitors (BTKi) have been increasingly used to treat mantle cell lymphoma (MCL). A real-world multicenter study was conducted to characterize treatment patterns and outcomes in patients with newly diagnosed MCL by Chinese Hematologist and Oncologist Innovation Cooperation of the Excellent (CHOICE). The final analysis included 1261 patients. Immunochemotherapy was the most common first-line treatment, including R-CHOP in 34%, cytarabine-containing regimens in 21% and BR in 3% of the patients. Eleven percent (n = 145) of the patients received BTKi-based frontline therapy. Seventeen percent of the patients received maintenance rituximab. Autologous hematopoietic stem cell transplantation (AHCT) was conducted in 12% of the younger (<65 years) patients. In younger patients, propensity score matching analysis did not show significant difference in 2-year progression-free survival and 5-year overall survival rate in patients receiving standard high-dose immunochemotherapy followed by AHCT than induction therapy with BTKi-based regimens without subsequent AHCT (72% vs 70%, P = .476 and 91% vs 84%, P = .255). In older patients, BTKi combined with bendamustine plus rituximab (BR) was associated with the lowest POD24 rate (17%) compared with BR and other BTKi-containing regimens. In patients with resolved hepatitis B at the baseline, HBV reactivation rate was 2.3% vs 5.3% in those receiving anti-HBV prophylaxis vs not; BTKi treatment was not associated with higher risk of HBV reactivation. In conclusion, non-HD-AraC chemotherapy combined with BTKi may be a viable therapeutic strategy for younger patients. Anti-HBV prophylaxis should be implemented in patients with resolved hepatitis B., (© 2023 UICC.)

Patients with relapsed/refractory (R/R) mature T- and natural killer (NK)-cell neoplasms lack effective treatments after failure of standard therapies. This phase 2 study evaluated the efficacy and safety of the programmed cell death protein 1 inhibitor tislelizumab in these patients. Seventy-seven patients were treated with 200 mg tislelizumab every 3 weeks. Twenty-two patients with extranodal NK-/T-cell lymphomas were enrolled in cohort 1; 44 patients with peripheral T-cell lymphoma (PTCL) were enrolled in cohort 2 (21 patients had PTCL not otherwise specified, 11 patients had angioimmunoblastic T-cell lymphoma, and 12 patients had anaplastic large-cell lymphoma). Cohort 3 comprised 11 patients with cutaneous T-cell lymphoma, of which 8 patients had mycosis fungoides (MF) and 3 had Sézary syndrome. Of the 77 patients, 76.6% had advanced-stage disease, 51.9% had refractory disease, and 49.4% received ≥3 prior systemic regimens. Promising efficacy was observed in cohort 3 (median follow-up [FU], 16.6 months; overall response rate [ORR], 45.5%; complete response [CR], 9.1%; median duration of response [DOR], 11.3 months; median progression-free survival, 16.8 months; median overall survival, not reached). Modest efficacy was observed in cohort 1 (median FU, 8.4 months; ORR, 31.8%; CR, 18.2%; median DOR, not reached) and cohort 2 (median FU, 9.3 months; ORR, 20.5%; CR, 9.1%; median DOR, 8.2 months). Most treatment-related adverse events were grade 1 or 2, and the safety profile was consistent with the known safety profile of tislelizumab. In conclusion, tislelizumab was well tolerated, achieving modest efficacy in R/R mature T- and NK-cell neoplasms, with some long-lasting remissions. This trial was registered at www.clinicaltrials.gov as #NCT03493451., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis. P21-activated kinase (PAK) is a component of the gene expression-based classifier that can predict the prognosis of T-LBL. However, the role of PAK in T-LBL progression and survival remains poorly understood. Herein, we found that the expression of PAK1 was significantly higher in T-LBL cell lines (Jurkat, SUP-T1, and CCRF-CEM) compared to the human T-lymphoid cell line. Moreover, PAK2 mRNA level of 32 relapsed T-LBL patients was significantly higher than that of 37 cases without relapse ( P = .012). T-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression (PAK1, P = .028; PAK2, P = .027; PAK1/2, P = .032). PAK inhibitors, PF3758309 (PF) and FRAX597, could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition. Besides, PF could enhance the chemosensitivity to doxorubicin in vitro and in vivo. Mechanistically, through western blotting and RNA sequencing, we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1, NF-κB and cell adhesion signaling pathways in T-LBL cell lines. These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin. Collectively, our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy., Competing Interests: Conflict of interest: The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS).)

Natural killer/T-cell lymphoma (NKTL) is an uncommon malignancy with poor prognosis and limited therapeutic options. Activating mutations of signal transducer and activator of transcription 3 (STAT3) are frequently found in patients with NKTL, suggesting that targeted inhibition of STAT3 is a potential therapeutic option for this disease. Here, we have developed a small molecule drug WB737 as a novel and potent STAT3 inhibitor that directly binds to the STAT3-Src homology 2 domain with high affinity. In addition, the binding affinity of WB737 to STAT3 is 250-fold higher than STAT1 and STAT2. Interestingly, WB737 is more selective for NKTL with STAT3 -activating mutations in terms of growth inhibition and apoptotic induction when compared with Stattic. Mechanistically, WB737 inhibits both canonical and noncanonical STAT3 signaling via suppression of STAT3 phosphorylation at Tyr705 and Ser727, respectively, thereby inhibiting the expression of c-Myc and mitochondria-related genes. Moreover, WB737 inhibited STAT3 more potently than Stattic, resulting in a significant antitumor effect with undetectable toxicity, followed by almost complete tumor regression in an NKTL xenograft model harboring a STAT3 -activating mutation. Taken together, these findings provide preclinical proof-of-concept for WB737 as a novel therapeutic strategy for the treatment of NKTL patients with STAT3 -activating mutations., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Authors Mingyao Liu, Wenbo Zhou, and Huang Chen are employees from Shanghai Yuyao Biotech Co., Ltd., but have no financial and non‐financial interests to disclose., (© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Purpose: Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) is a rare and aggressive type of non-Hodgkin lymphoma with limited treatment options. This phase II study evaluated the efficacy and safety of sugemalimab, an anti-PD-L1 monoclonal antibody, in R/R ENKTL., Methods: Eligible patients received sugemalimab 1,200 mg intravenously once every 3 weeks for up to 24 months or until progression, death, or study withdrawal. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Key secondary end points included ORR assessed by the investigators, complete response rate, duration of response, and safety., Results: At the data cutoff (February 23, 2022), 80 patients were enrolled and followed for a median of 18.7 months. At baseline, 54 (67.5%) had stage IV disease and 39 (48.8%) had received ≥2 lines of prior systemic therapy. Independent radiologic review committee-assessed ORR was 44.9% (95% CI, 33.6 to 56.6); 28 (35.9%) patients achieved a complete response and seven (9.0%) achieved a partial response, with a 12-month duration of response rate of 82.5% (95% CI, 62.0 to 92.6). Investigator-assessed ORR was 45.6% (95% CI, 34.3 to 57.2), and 24 (30.4%) patients achieved a complete response. Most treatment-emergent adverse events were grade 1-2 in severity, and grade ≥ 3 events were reported in 32 (40.0%) patients., Conclusion: Sugemalimab showed robust and durable antitumor activity in R/R ENKTL. Treatment was well tolerated with expected safety profile for this drug class.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is strongly associated with Epstein-Barr virus (EBV) and has a high prevalence in Asian and in Central and South America. About 85% of ENKTLs derive from NK cells and 15% from T-cells. Various factors have been implicated in the development of ENKTL. Molecular pathogenesis of NK/T-cell lymphomas include mutations of genes, involving in the Janus Kinase/signal transducer and activator of transcription pathway, RNA helicase family, epigenetic regulation, and tumor suppression. The relationship between ENKTL and human leukocyte antigen has been demonstrated. Radiotherapy plays a key role in the first-line treatment of early-stage. In stage III/IV diseases, non-anthracycline-regimens-containing L-asparaginase are recommended. Although clinical remission after L-asparaginase-based combination therapy has been achieved in the majority of patients with advanced-stage or relapsed/refractory extranodal NK/T-cell lymphoma-nasal type, the long-term overall survival is still poor. Recently, immunotherapy and new therapeutic targets have gained much attention. In this article, we discuss the pathogenesis, diagnosis, prognostic models and management options of ENKTL., (© 2021 John Wiley & Sons Ltd.)