Tislelizumab monotherapy in patients with previously untreated early-stage classical Hodgkin lymphoma: a real-world study.

The anti-PD-1 antibodies have been reported to show a striking effect in relapsed and refractory(R/R) classical Hodgkin lymphoma (cHL), however, there is still limited real-world data assessing the role of anti-PD-1 antibody monotherapy in early-stage cHL. In this retrospective analysis, we reported the effectiveness and safety of tislelizumab monotherapy in the first-line therapy of early-stage cHL. Twenty-three consecutive patients (10 males and 13 females) with previously untreated stage I A-II B cHL were included. At interim evaluation after 2 doses of tislelizumab monotherapy, 11 of 23 patients (47.8%) achieved complete response (CR). At the end of tislelizumab monotherapy (EOTM), objective response was observed in 22 of 23 patients (95.7%), with CR in 16 patients (69.6%). Among six patients with PR-EOTM, two patients underwent 4 cycles of ABVD chemotherapy and one patient underwent 4 cycles of tislelizumab plus AVD. One patient who developed progressive disease (PD) after 4 doses of tislelizumab subsequently underwent 4 cycles of ABVD chemotherapy. Except for four patients with CR-EOTM, consolidative radiotherapy was given to 19 patients. All patients obtained CR at the end of all treatments. With a median follow-up time of 21.3 months (range, 6.9-32.7 months), the estimated 2-year PFS rate and 2-year OS rate were 95.65% and 100%, respectively. Except for grade 3 lymphocyte count decreased, no other grade 3/4 TRAE was observed. In addition, no serious AE was reported. Our preliminary data observed that tislelizumab monotherapy was safe and highly effective in previously untreated early-stage cHL.

Acidity Scale in a Choline Chloride- and Ethylene Glycol-Based Deep Eutectic Solvent and Its Implication on Carbon Dioxide Absorption.

An equilibrium acidity (pKa) scale that comprises 16 Brönsted organic acids, including phenols, carboxylic acids, azoles, and phenylmalononitriles, was established in a choline chloride/EG-based deep eutectic solvent (DES) ([Ch][Cl]:2EG) by ultraviolet-visible (UV-Vis) spectroscopic methods. The established acidity scale spans about 6 pK units in the DES, which is similar to that for these acids in water. The acidity comparisons and linear correlations between the DES and other solvents show that the solvent property of [Ch][Cl]:2EG is quite different from those of amphiphilic protic and dipolar aprotic molecular solvents. The carbon dioxide absorption capabilities as well as apparent absorption kinetics for a series of anion-functionalized DESs ([Ch][X]:2EG) were measured, and the results show that the basicity of comprising anion [X] of choline salt is essential for the maximum carbon dioxide absorption capacity, i.e., a stronger basicity leads to a greater absorption capacity. The possible absorption mechanisms for carbon dioxide absorption in these DESs were also discussed based on the spectroscopic evidence.

Adjuvant Chemotherapy for Gastric Cancer Patients with Mismatch Repair Deficiency or Microsatellite Instability: Systematic Review and Meta-Analysis.

BACKGROUND: Mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) status serves as a predictor of a poor response to adjuvant chemotherapy among stage 2 colon cancer patients. This study aimed to investigate the efficacy of adjuvant chemotherapy in dMMR/MSI-H gastric cancer (GC). METHODS: Clinical studies comparing adjuvant chemotherapy and surgery alone in dMMR/MSI-H GCs through June 2021 were retrieved to assess the survival of patients managed with both treatments. Two approaches were used to pool the hazard ratio (HR) of survival: (1) if Kaplan-Meier curves and number of patients at risk were provided, individual patient data were extracted. Cox models were used to calculate the HR with its 95% confidence interval (CI); (2) for study-level data, pooled HR was estimated using fixed/random-effects models. RESULTS: Seven clinical studies were assessed. For dMMR/MSI-H versus mismatch repair-proficient (pMMR)/microsatellite stable (MSS)/microsatellite instability-low (MSI-L) status, the estimated 5-year disease-free survival (DFS) rate was 74.2% versus 51.5% (HR, 0.44; 95% CI, 0.32-0.62; P < 0.001) and the estimated 5-year OS rate was 60.5% versus 49.1% (HR, 0.71; 95% CI, 0.60-0.85; P < 0.001). The study-level data showed pooled HRs of 0.42 for DFS (95% CI, 0.31-0.57; P < 0.001) and 0.65 for OS (95% CI, 0.38-1.11; P = 0.114). For adjuvant chemotherapy versus observation of dMMR/MSI-H, the estimated 5-year DFS rate was 76.1% versus 73.3% (HR, 0.72; 95% CI, 0.45-1.15; P = 0.171) and the estimated 5-year OS rate was 73.5% versus 59.7% (HR, 0.62; 95% CI, 0.46-0.83; P = 0.001). Significant survival differences also were observed at study level. CONCLUSIONS: The study findings confirm the benefit of adjuvant chemotherapy for dMMR/MSI-H GC patients.

Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma.

Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg+]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.

Effect of rituximab on adult Burkitt's lymphoma: a systematic review and meta-analysis.

The treatment of Burkitt's lymphoma with rituximab is controversial, and studies that compared the efficacy of chemotherapy alone with chemotherapy plus rituximab have not been powered to test differences in overall survival (OS). We conducted this systematic review and meta-analysis to identify the value of rituximab for the treatment of BL to guide treatment decisions. Based on the PubMed, Web of Science, and Cochrane library online electronic databases, all retrospective and randomized clinical trial studies that compared the aforementioned two regimens were included. The pooled hazard ratio and odds ratio were analyzed using Review Manager 5.3. The primary outcome was the 2-year OS. A total of 581 publications were identified using a predetermined search strategy. One randomized controlled trial (RCT) and five retrospective studies, which included 646 cases (351 cases for the chemotherapy with rituximab group and 295 cases for the chemotherapy alone group), fulfilled the selection criteria and were included in the meta-analysis. The chemotherapy with rituximab group was associated with a higher 2-year OS (hazard ratio 0.62, 95 % CI 0.45-0.85, P = 0.003), 2-year progression-free survival (hazard ratio 0.46, 95 % CI 0.43-0.50, P < 0. 001), and complete remission rate (odds ratios 3.26, 95 % CI 1.22-8.66, P = 0.02). In addition, the treatment-related mortality did not significantly differ between the two treatment regimens (odds ratio 1.16, 95 % CI 0.55-2.45, P = 0.69). The meta-analysis indicates that the addition of rituximab to the treatment regimen for Burkitt's lymphoma may be associated with a significant survival benefit and did not increase the mortality compared with chemotherapy alone.

Anti-Helicobacter pylori Treatment in Patients With Gastric Cancer After Radical Gastrectomy.

Importance: Whether anti-Helicobacter pylori treatment can provide survival benefits for patients with gastric cancer who are diagnosed with H pylori infection is an area with limited research. Objective: To explore the potential survival benefits of anti-H pylori treatment after radical gastrectomy in patients with gastric cancer and presurgical confirmation of H pylori infection. Design, Setting, and Participants: This retrospective cohort study was conducted using data from patients with gastric cancer treated between January 1, 2010, and December 31, 2018, and followed up for outcome ascertainment until May 19, 2021. Propensity score matching was performed in patients treated with or without anti-H pylori treatment. This study involved a single institute in a comprehensive cancer treatment and research center located in Guangzhou, Guangdong Province, China. The study included patients with gastric or esophagogastric junction adenocarcinoma who underwent curative gastrectomy with D2 lymphadenectomy and tested positive for H pylori infection. Data were analyzed from March to June 2023. Exposure: Anti-H pylori treatment, which primarily includes triple therapy regimens consisting of amoxicillin, clarithromycin, and omeprazole for 14 days. Main Outcomes and Measures: Clinical outcomes, including overall survival (OS) and disease-free survival (DFS), were analyzed by Kaplan-Meier method, log-rank test, and Cox proportional hazards regression model. Subgroup analysis based on crucial clinical information was also conducted. Results: All 1293 patients (median [IQR] age, 59 [50-65] years; 860 [66.5%] male) were divided into 2 groups, with 125 patients in the anti-H pylori treatment group and 1168 patients in the non-anti-H pylori treatment group based on whether they received anti-H pylori treatment during the perioperative period and the follow-up. Survival analysis showed that the 5-year OS rates were 94.1% (95% CI, 89.3%-99.2%) in the anti-H pylori group and 73.8% (95% CI, 70.7%-77.0%) in the non-anti-H pylori group, and the hazard ratio (HR) of these 2 groups was 0.33 (95% CI, 0.18-0.60; P < .001). The survival benefit remained after propensity score matching (HR, 0.50; 95% CI, 0.26-0.99; P = .048). Multivariable analysis for OS and DFS further showed the survival benefit of anti-H pylori treatment, with HRs of 0.38 (95% CI, 0.17-0.87; P = .02) and 0.48 (95% CI, 0.28-0.83; P = .008), respectively. Among patients with TNM stage II/III disease who received adjuvant chemotherapy, anti-H pylori treatment was associated with survival benefits (OS: HR, 0.49; 95% CI, 0.24-0.99; P = .046), whereas among those who did not receive adjuvant chemotherapy, anti-H pylori treatment was not associated with survival benefits (OS: HR, 0.29; 95% CI, 0.04-2.08; P = .22). Conclusions and Relevance: This cohort study indicates that anti-H pylori treatment may be associated with improved survival in patients with gastric cancer who have H pylori infections. The study reinforces the importance of including H pylori screening and treatment in the surgical treatment of these patients.

Outcomes of COVID-19 in patients with lymphomas participating in registered clinical trials: A real-world study from China in the Omicron outbreak era.

BACKGROUND: This real-world study investigated the outcome of COVID-19 in lymphoma patients participating in registered clinical trials and explored potential risk factors with the outcome of COVID-19 during the first wave of the Omicron outbreak in China. METHODS: One hundred and ten patients participating in registered clinical trials and diagnosed with COVID-19 in our center between December 1, 2022, and January 31, 2023, were included. RESULTS: Four (3.6%) patients were identified as severe COVID-19 and 2 (1.8%) as critical COVID-19, respectively. The mortality rate observed was 2.73% for the entire cohort, 33.3% for the severe/critical COVID-19 group, and 18.8% for the hospitalized group. The 90-day OS was 98.2% for the entire cohort, 66.7% for the severe/critical COVID-19 group, and 87.5% for the hospitalized group. Advanced age (≥70 years), comorbidities, and PI3K inhibitor-containing regimen were significantly associated with the severity of COVID-19. Patients with indolent B-cell non-Hodgkin lymphomas were less likely to be hospitalized for COVID-19. CONCLUSION: This study reported similar clinical features of COVID-19 in our cohort with that of non-hematological malignancy (HM) patients, while the proportion of severe/critical COVID-19 and the mortality rate were relatively higher than non-HM patients. Our findings provided valuable experience to aid clinical researchers with managing lymphoma patients participating in registered clinical trials during the ongoing pandemic of the Omicron variant.

The combination treatment strategy of lenvatinib for hepatocellular carcinoma: a real-world study.

PURPOSE: Lenvatinib is recommended as a first-line therapy in unresectable hepatocellular carcinoma (HCC). Combination therapy with local therapy (LT) or PD-1/PD-L1 inhibitors (PI) might improve the antitumor effect of lenvatinib. The objective of this study was to investigate the antitumor effect of lenvatinib-based combination therapies. METHODS: The study retrospectively analyzed 215 HCC patients who received lenvatinib therapy. The outcomes of patients treated with lenvatinib monotherapy as well as combination strategies were compared. Progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was the primary endpoint, while PFS by mRECIST, overall survival (OS), objective response rate (ORR) and safety were the secondary endpoints. Propensity score matching (PSM) analysis was performed to overcome the bias of baseline characteristics. RESULTS: Compared with lenvatinib monotherapy, combination therapy prolonged PFS (by RECIST v1.1, 7.77 vs. 4.43 months, P = 0.045; by mRECIST, 6.97 vs. 5.27 months, P = 0.067). A higher ORR was also recorded in the combined-therapy group, according to both RECIST v1.1 (37 vs. 5%, P < 0.001) and mRECIST (53 vs. 11%, P < 0.001). Similar outcomes were obtained after PSM. Moreover, triple therapy (combined with both PI and LT) was significantly superior to dual therapy (combined with either PI or LT) in terms of better PFS according to RECIST v1.1 (8.90 vs. 6.43 months, P = 0.023). However, adverse events occurred in more patients receiving combined therapy and triple therapy. No difference was observed in OS between groups. CONCLUSION: Combination therapies based on lenvatinib were associated with significantly better PFS and tumor response rates than lenvatinib monotherapy in HCC patients.

Evaluating relapse-free survival as an endpoint for overall survival in adjuvant immunotherapy trials.

BACKGROUND: Relapse-free survival (RFS) has been considered a primary endpoint to assess the effects of immunotherapy in the adjuvant setting among patients with early-stage disease. However, it is not clear whether RFS is a valid surrogate endpoint for overall survival (OS) in this clinical context. METHODS: Phase II or III clinical trials of adjuvant immunotherapy that reported hazard ratios on OS and RFS were identified. We used a weighted regression analysis at the arm and trial levels to assess the efficacy of RFS as a surrogate for OS, quantified by the weighted coefficient of determination (R2). Strong correlations (R2 ≥ 0.7) at the arm and trial levels indicated valid surrogacy. The surrogate threshold effect was also evaluated. RESULTS: Fifteen high-quality randomized clinical trials involving 13 715 patients were included. At the arm level, moderate and strong associations were observed between RFS2-year and OS3-year (R2 = 0.58, 95% confidence interval [CI] = 0.25 to 0.92) and RFS3-year and OS5-year (R2 = 0.72, 95% CI = 0.38 to 1.00), respectively. At the trial level, a moderate association was observed between effect of treatment on RFS and OS (R2 = 0.63, 95% CI = 0.33 to 0.94). The surrogate threshold effect for RFS was 0.86. Consistent results were confirmed in several sensitivity analyses based on different trial phases, experimental arms, cancer types, and treatment strategies. CONCLUSIONS: Our meta-analysis failed to find a clinically strong association between RFS and OS in randomized clinical trials of adjuvant immunotherapy. Our findings challenge the use of RFS as the primary efficacy endpoint and suggest the use of OS in this clinical context.

A single-cell atlas of diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is one of the most common yet aggressive types of B cell lymphoma and remains incurable in 40% of patients. Herein, we profile the transcriptomes of 94,324 cells from 17 DLBCLs and 3 control samples using single-cell RNA sequencing. Altogether, 73 gene expression programs are identified in malignant cells, demonstrating high intra- and intertumor heterogeneity. Furthermore, 2,754 pairs of suggestive cell-cell interactions are predicted, indicating a complex and highly dynamic tumor microenvironment. Especially for B cell lymphomas, a strong costimulatory CD70-CD27 interaction is predicted between malignant and T cells. Furthermore, coinhibitory signals mediated by TIM3 or TIGIT seem to be the main driving force for T cell exhaustion. Finally, we find that chronic hepatitis B virus infection may have a significant impact on tumor cell survival and immune evasion in DLBCL. Our results provide insights into B cell lymphomagenesis and may facilitate the design of targeted immunotherapy strategies.

VLA-4 suppression by senescence signals regulates meningeal immunity and leptomeningeal metastasis.

Leptomeningeal metastasis is associated with dismal prognosis and has few treatment options. However, very little is known about the immune response to leptomeningeal metastasis. Here, by establishing an immunocompetent mouse model of breast cancer leptomeningeal metastasis, we found that tumor-specific CD8+ T cells were generated in deep cervical lymph nodes (dCLNs) and played an important role in controlling leptomeningeal metastasis. Mechanistically, T cells in dCLNs displayed a senescence phenotype and their recruitment was impaired in mice bearing cancer cells that preferentially colonized in leptomeningeal space. Upregulation of p53 suppressed the transcription of VLA-4 in senescent dCLN T cells and consequently inhibited their migration to the leptomeningeal compartment. Clinically, CD8+ T cells from the cerebrospinal fluid of patients with leptomeningeal metastasis exhibited senescence and VLA-4 downregulation. Collectively, our findings demonstrated that CD8+ T cell immunosenescence drives leptomeningeal metastasis.

Combination of Anti-PD-1 Antibody, Anlotinib and Pegaspargase "Sandwich" With Radiotherapy in Localized Natural Killer/T Cell Lymphoma.

Asparaginase/pegaspargase containing regimens combined with radiotherapy are highly effective and considered the cornerstone of localized Natural killer/T-cell lymphoma (NKTL) treatment. However, these chemotherapy regimens inevitably cause relatively high incidence of treatment-related adverse events (TRAEs). Herein we retrospectively evaluated the efficacy and safety of the combined regimen of anti-PD-1 antibody, anlotinib and pegaspargase "sandwich" with radiotherapy in localized NKTL. Anti-PD-1 antibody and pegaspargase at 2500 U/m2 were administered on day 1, while anlotinib (12 mg once a day) was orally administered on days 1-14. The treatment was repeated every 3 weeks. All the eight patients included received 3 cycles of the regimen followed by radiotherapy and an additional 3 cycles. The overall response rate was 100%, and the complete response rate was 87.5%. With a median follow-up time of 35.5 months (range, 34.03-40.90 months), median PFS and OS times were not reached. The 3-year PFS and OS rates were 100% and 100%, respectively. All patients were alive at the last follow-up. No treatment-related death and no grade 4 TRAE was reported. No grade 3/4 hematological toxicity was detected, and half of the patients didn't report any hematological toxicity. This study indicates that anti-PD-1 antibody combined with anlotinib and pegaspargase is a promising chemoradiotherapy regimen for localized NTKL, with mild toxicity and good tolerance.

LAG3-PD1 or CTLA4-PD1 Inhibition in Advanced Melanoma: Indirect Cross Comparisons of the CheckMate-067 and RELATIVITY-047 Trials.

Objective: To compare the inhibition of LAG3-PD1 versus the inhibition of CTLA-4-PD1 in patients with previously untreated advanced melanoma. Methods: The individual participant data (IPD) were extracted from the KM plots using a graphical reconstructive algorithm. Log-rank, Cox proportional hazard model, Bayesian hierarchical model with time-varying hazard ratio (HR) effect, and restricted mean survival time (RMST) were performed to estimate survival benefits. Results: The CheckMate-067 (n = 630) and RELATIVITY-047 (n = 714) trials were included for analysis. The graphical reconstructive algorithm showed that IPD had similar HRs and log-rank values as the original plots. The HR of nivolumab plus relatlimab (LAG3 inhibitor) versus nivolumab plus ipilimumab (CTLA4 inhibitor) was 1.19 (95% confidence interval [CI] 0.96 to1.48). The 24-months RMST of nivolumab plus relatlimab versus nivolumab was 2.35 (95% CI 0.77-3.94) months, compared with 1.87 (95% CI, 0.25-3.49) months for nivolumab plus ipilimumab versus nivolumab. The Bayesian hierarchical model showed that patients treated with nivolumab plus relatlimab had earlier PFS benefits than those with nivolumab plus ipilimumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients using nivolumab plus relatlimab and 55.0% of patients using nivolumab plus ipilimumab. Conclusions: These findings suggest that the PFS of LAG3-PD1 and CTLA4-PD1 inhibition were similar and LAG3-PD1 inhibition exhibited earlier survival benefit and lesser TRAEs.

The dual role of CD70 in B-cell lymphomagenesis.

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.

The G199X and V157fs mutations in the TP53 gene promote malignancy in serous ovarian cancer: an analysis using whole-exome sequencing.

BACKGROUND: The carcinogenic mechanisms underlying serous ovarian cancer are not fully understood. METHODS: Whole-exome sequencing and targeted sequencing were performed in ovarian cancer samples to identify novel molecular markers involved in the process of cell malignancy in ovarian cancer. In vitro experiments, the oncogenic roles such as cell proliferation, migration and invasion of TP53 G199X and V157fs mutations were investigated deeply. RESULTS: The present study identified the G199X and V157fs point mutations in the tumor protein P53 gene (TP53). The rate of TP53 mutation was 59.2% in a cohort of 76 ovarian cancer patients, compared with 9.0% in a cohort of 156 healthy women. Kaplan-Meier analysis showed that patients with a TP53 mutation had a lower 5-year overall survival (OS) rate compared with patients harboring wild type TP53. In vitro experiments in an ovarian cancer cell line demonstrated that the G199X and V157fs mutants inhibited P53 protein expression, enhanced proliferation, promoted migration and increased invasion. CONCLUSIONS: This study identified two novel markers, TP53 G199X and V157fs mutations in TP53. Functional assays indicated that these mutations enhanced the malignant phenotype in ovarian cancer cells. These novel markers will assist in the diagnosis of ovarian tumors and represent potential targets for the treatment of TP53 mutant ovarian cancers.

R-split-EPOCH plus high dose methotrexate in untreated diffuse large B cell lymphoma with MYC rearrangement or double expression of MYC and BCL-2.

Purpose: Diffuse large B cell lymphoma (DLBCL) with MYC rearrangement or double expression of MYC and BCL-2 (DE DLBCL) has a relatively poor prognosis and does not respond well to standard R-CHOP. In the current study, we aimed to investigate the efficacy and safety of R-split-EPOCH plus high dose methotrexate (HD-MTX) in the particular patient population. Methods: A total of 28 patients diagnosed with DE DLBCL or DLBCL with MYC rearrangement between January 2015 and December 2018 were included and retrospectively analyzed. All the participants underwent R-split-EPOCH plus HD-MTX as introduction therapy, with split infusion of etoposide, doxorubicin, and vincristine for 48 hours on D1-2 and D10-11, respectively. Results: The overall objective response (ORR) rate was 100%, with 24 (85.7%) complete response (CR) and 4 (14.3%) partial response (PR). The CR rate was 76.9% and 93.3% for DLBCL patients with MYC rearrangement and DE DLBCL patients, respectively. The 1- and 3-year PFS rate was 100% and 74.9%, respectively. The 1- and 3-year OS rate was 100% and 92.9%, respectively. Grade 3/4 non-hematological toxicity and grade 3/4 hematological toxicity occurred in 50% and 85.7% of patients, respectively. No treatment-related death was reported. Conclusions: R-split-EPOCH plus HD-MTX regimen is an effective and feasible treatment option for DE DLBCL and DLBCL with MYC rearrangement.

Genome-wide CRISPR screens reveal synthetic lethal interaction between CREBBP and EP300 in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoid malignancy and a highly heterogeneous disease. In this study, we performed whole-genome and transcriptome sequencing, and a genome-wide CRISPR-Cas9-knockout screen to study an activated B-cell-like DLBCL cell line (RC-K8). We identified a distinct pattern of genetic essentialities in RC-K8, including a dependency on CREBBP and MDM2. The dependency on CREBBP is associated with a balanced translocation involving EP300, which results in a truncated form of the protein that lacks the critical histone acetyltransferase (HAT) domain. The synthetic lethal interaction between CREBBP and EP300 genes, two frequently mutated epigenetic modulators in B-cell lymphoma, was further validated in the previously published CRISPR-Cas9 screens and inhibitor assays. Our study suggests that integration of the unbiased functional screen results with genomic and transcriptomic data can identify both common and unique druggable vulnerabilities in DLBCL and histone acetyltransferases inhibition could be a therapeutic option for CREBBP or EP300 mutated cases.

Expression of PD-L1 on Monocytes Is a Novel Predictor of Prognosis in Natural Killer/T-Cell Lymphoma.

Background: Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive lymphoma with a dismal prognosis, and novel therapeutic targets are urgently needed. Programmed death-ligand 1 (PD-L1) has become a promising therapeutic target for various cancers, but most of the studies have focused on expression of PD-L1 on tumor cells. Expression of PD-L1 on tumor-infiltrating non-malignant cells, especially monocytes, has not been studied in NKTCL, and its prognostic value remains unknown. Materials and Methods: Expression of PD-L1 on tumor-infiltrating stromal cells was measured in NKTert and HS5 cells when cultured alone or co-cultured with NKTCL cell lines. Clinical samples were collected from 42 patients with newly diagnosed NKTCL. Expression of PD-L1 on monocytes was analyzed in patients' peripheral blood and tumor tissues using flow cytometry and immunofluorescent staining, respectively. Survival data were retrospectively collected and the prognostic significance of PD-L1 expression on monocytes was analyzed. Results: PD-L1 expression on tumor-infiltrating stromal cells was remarkably elevated when co-cultured with NKTCL cells. The percentage of PD-L1+ monocytes among all monocytes in peripheral blood was significantly higher in NKTCL patients than that in healthy individuals. Among NKTCL patients, percentage of PD-L1+ monocytes in blood positively correlated with that in tumor tissues. Patients with a higher percentage (≥78.2%) of PD-L1+ monocytes in blood or with a higher percentage (≥24.2%) of PD-L1+ monocytes in tumor tissues exhibited a significantly inferior survival, compared with their counterparts. A higher percentage of PD-L1+ monocytes in blood or tumor tissues was an independent adverse prognostic factor. Conclusions: Expression of PD-L1 on monocytes is up-regulated and has significant prognostic value in patients with NKTCL.

In situ aluminium ions regulation for quantum efficiency and light stability promotion in white light emitting material.

In this study, we have proposed an in situ ion regulation strategy to assemble a white-light-emitting material with high stability and efficiency. A fluorescence tunable hybrid material was first fabricated by a "ship around the bottle" method in which the fluorescent dyes, disodium 2-naphthol-3,6-disulfonate (R) and ZnO Quantum Dots (QDs), were embedded into metal-organic frameworks (MOFs) in proportion. Then, the competition coordination of aluminium ions over zinc ions to R were utilized to subtly adjust the intensity of blue fluorescence, leading to an ideal white light with Commission Internationale de l'Eclairage (CIE) coordinates of (0.30, 0.33) and a high Color-Rendering Index (CRI) value of 93%. Compared with the material fabricated by the ratio tuning of the R salt and ZnO QDs directly, the in situ ions regulation strategy enabled the final product to have a higher quantum efficiency and light stability. Moreover, this strategy also settled the non-tunable problem of fluorescence due to the competition coordination effects of aluminium ions and zinc ions in the same synthetic system. This synthetic strategy and our new findings can provide more ideas for designing new white-light-emitting materials.