A 54-year-old man diagnosed with chronic lymphocytic leukemia (CLL) was admitted in our department in June 2014. After one cycle of FC chemotherapy, a bone marrow examination revealed normalized lymphocyte count and another acute myeloid leuke-mia (AML)-M5 clone. The patient refused sequential treatment and only received follow-up examination. He had continuous hemato-logically stable disease and died of pulmonary infection on July 2015. After a multidisciplinary team discussion, we confirmed the si-multaneous diagnosis of CLL and AML-M5. Through this discussion,tumor second hit model,tumor evolution model,andtumor heterogeneitywere further defined.

Objective:To illustrate the effect and mechanism of ibrutinib,a Bruton's tyrosine kinase(BTK)inhibitor that inhibits diffuse large B-cell lymphoma(DLBCL)cell survival.Methods:DLBCL cell lines SUDHL-10 and HBL-1 were treated with ibrutinib at different concentrations.A MTT assay was used to detect the inhibition of cell proliferation.Cell apoptosis was analyzed by Annexin V-binding assay,as well as flow cytometry and DAPI staining.The expression of phosphorylated BTK,AKT and ERK was detected by Western blot. DLBCL cells were co-cultured with MSC.The inhibitory effect of ibrutinib on DLBCL cells in tumor microenvironment was assessed in clonogenicity in vitro and in a tumor-bearing non-obese diabetic/severe combined immunodeficient mice in vivo.Results:Up to 2.5 μmol/L and high concentrations of ibrutinib significantly inhibited the proliferation of DLBCL cells in a dose-dependent manner.Approx-imately 1 and 2.5 μmol/L ibrutinib was added on SUDHL-10 cells for 24 h,and the cell apoptotic rates were(21.73±3.64)% and(34.71± 2.36)%,respectively.Both were superior to that of the control group(3.55±1.89)%(P<0.05).Both two DLBCL cell lines pretreated with 5 and 10 μmol/L ibrutinib for 24 h and exhibited nuclear shrinkage at 5 μmol/L and nuclear fragmentation at 10 μmol/L.The expres-sion of phosphorylated BTK,AKT,and ERK decreased significantly after ibrutinib treatment.Ibrutinib inhibited clonogenicity in vitro(P<0.01)and cell proliferation and growth in vivo of DLBCL cells in co-culture system.The differences were statistically significant.Conclu-sion:Ibrutinib can inhibit the proliferation and induce apoptosis of SUDHL-10 and HBL-1 cell lines through a mechanism of blocking the AKT and ERK signaling pathways,as well as the proliferation of DLBCL cells in tumor microenvironment.This finding can significant-ly benefit DLBCL treatment.

Objective:This study aims to investigate the clinical features and prognostic factors of patients with diffuse large B-cell lymphoma (DLBCL) and assess the prognostic value of diabetes mellitus (DM) and hyperglycemia during DLBCL treatment in DLBCL.Methods:The clinical data of 481 newly diagnosed DLBCL patients from January 1, 2009 to December 31, 2019 at Tianjin Medical University Cancer Institute and Hospital and Sun Yat-sen University Cancer Center were retrospectively collected, focusing on their blood glucose levels before and during treatment. Cox regression method was used for univariate analysis to assess prognostic factors, and the Kaplan-Meier method was used to draw survival curves to assess the prognostic value of DM and hyperglycemia during DLBCL treatment in patients with DLBCL.Results:Eighty-two (17.0%) patients had DM before DLBCL diagnosis and treatment, and 88 (18.3%) patients had at least one blood glucose increase during DLBCL treatment. Cox univariate analysis showed that age, Ann Arbor stage, international prognostic index, and DM were associated with overall survival (OS) and progression-free survival (PFS) (all P<0.05) . The pairwise comparison between the two groups showed that the OS ( P=0.001) and PFS ( P<0.001) of patients with pre-existing DM were significantly worse than those of patients without abnormal blood glucose. Moreover, the OS ( P=0.003) and PFS ( P<0.001) of patients with hyperglycemia during DLBCL treatment were significantly worse than those of patients without abnormal blood glucose. No significant difference exists between patients with DM and patients with hyperglycemia during DLBCL treatment (OS, P=0.557; PFS, P=0.463) . Additionally, patients with adequate glycemic control during chemotherapy had a better prognosis compared with patients with poor glycemic control (OS, P=0.037; PFS, P=0.007) . Conclusion:DM is an important factor affecting the prognosis of patients with DLBCL. Moreover, hyperglycemia during treatment is related to the poor prognosis of patients with DLBCL.