Dihydroartemisinin enhances cell apoptosis in diffuse large B cell lymphoma by inhibiting the STAT3 activity

Background:Dihydroartemisinin(DHA)is reported to be a potential anticancer agent,and the mechanisms underlying the effects of DHA on diffuse large B cell lymphoma however are still obscure.This study aimed to assess the antitumor effect of DHA on diffuse large B cell lymphoma cells and to determine the potential underlying mechanisms of DHA-induced cell apoptosis.Methods:Here,the Cell Counting Kit 8 assay was conducted to study cell proliferation.We performed Annexin V-FITC/propidium iodide staining,real-time polymerase chain reaction,and western blot analysis to analyze cell apoptosis and potential molecular mechanisms.Results:The results showed that DHA substantially suppressed cell proliferation and induced cell apoptosis in vitro in a time-and concentration-dependent fashion.Moreover,STAT3 activity could be inhibited after stimulation with DHA.Conclusion:These results imply that the underlying anti-tumoral effect of DHA may increase apoptosis in diffuse large B cell lymphoma cells via the STAT3 signaling pathway.In addition,DHA might be an effective drug for diffuse large B cell lymphoma therapy.

Efficacy of rituximab in gastric diffuse large B cell lymphoma patients

AIM:To evaluate retrospectively the efficacy of rituximab plus chemotherapy in gastric diffuse large B cell lymphoma(DLBCL).METHODS:Sixty patients(median age:58 years)with histologically confirmed gastric DLBCL treated at four Italian institutions between 2000 and 2007,were included in this analysis.Patients were selected by stage (Ⅰ-Ⅳ,Lugano staging system),European Cooperative Oncology Group performance status(0-2)and treatment strategies.Treatment strategies were chemotherapy alone(group A,n=30)[scheduled as cyclophosphamide,doxorubicin,vincristine and prednisone (CHOP)and CHOP-like],and chemotherapy combined with rituximab(group B,n=30).The primary end point of the study was complete response(CR)rate;the secondary end points were disease-free survival (DFS)at 5 years and overall survival(OS).RESULTS:Median follow-up was 62 mo(range:31102 mo).We observed a significant difference between the two groups(A vs B)in terms of CR[76.6%(23/30) vs 100%,P=0.04)and DFS at 5 years[73.3%(22/30) vs 100%,P=0.03).To date,19 group A(63.3%) patients are alive and 11 have died,while all group B patients are alive.No significant differences in toxicity were observed between the two groups.CONCLUSION:Rituximab in combination with chemotherapy improves CR rate,DFS and OS.Further prospective trials are needed to confirm our results.

Diffuse large B cell lymphoma originating from the maxillary sinus with skin metastases:A case report and review of literature

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is the most common type of malignant lymphoma(ML),accounting for 30%-40%of cases of non-Hodgkin’s lymphoma(NHL)in adults.Primary paranasal sinus lymphoma is a rare presentation of extranodal NHL that accounts for only 0.17%of all lymphomas.ML from the maxillary sinus(MS)is a particularly rare presentation,and is thus often difficult to diagnose.We have reported the first known case of DLBCL originating from the MS with rapidly occurrent multiple skin metastasis.CASE SUMMARY An 81-year-old Japanese man visited our hospital due to continuous pain for 12 d in the left maxillary nerve area.His medical history included splenectomy due to a traffic injury,an old right cerebral infarction from when he was 74-years-old,hypertension,and type 2 diabetes mellitus.A plain head computed tomography(CT)scan revealed a 3 cm×3.1 cm×3 cm sized left MS.On day 25,left diplopia and ptosis occurred,and a follow-up CT on day 31 revealed the growth of the left MS mass.Based on an MS biopsy on day 50,we established a definitive diagnosis of DLBCL,non-germinal center B-cell-like originating from the left MS.The patient was admitted on day 62 due to rapid deterioration of his condition,and a plain CT scan revealed the further growth of the left MS mass,as well as multiple systemic metastasis,including of the skin.A skin biopsy on day 70 was found to be the same as that of the left MS mass.We notified the patient and his family of the disease,and they opted for palliative care,considering on his condition and age.The patient died on day 80.CONCLUSION This case suggests the need for careful,detailed examination,and for careful follow-up,when encountering patients presenting with a mass.

Occurrence of MYD88L265P and CD79B mutations in diffuse large b cell lymphoma with bone marrow infiltration:A case report

BACKGROUNDOver the past 20 years,we have gained a deep understanding of the biologicalheterogeneity of diffuse large B cell lymphoma(DLBCL)and have developed arange of new treatment programs based on the characteristics of the disease,bringing us to the era of immune-chemotherapy.However,the effectiveness andmolecular mechanisms of targeted-immunotherapy remain unclear in DLBCL.Targeted-immunotherapy may be beneficial for specific subgroups of patients,thus requiring biomarker assessment.CASE SUMMARYHere,we report a case of MCD subtype DLBCL with MYD88L265P and CD79Bmutations,considered in the initial stage as lymphoplasmic lymphoma(LPL)orWaldenstrom macroglobulinemia(WM).Flow cytometry supported this view;however,the immunohistochemical results of the lymph nodes overturned theabove diagnosis,and the patient was eventually diagnosed with MCD subtypeDLBCL.The presence of a monoclonal IgM component in the serum and infiltrationof small lymphocytes with a phenotype compatible with WM into the bonemarrow led us to propose a hypothesis that the case we report may have transformedfrom LPL/WM.CONCLUSIONThis highlights the possible transformation from WM to DLBCL,CD79B mutationmay be a potential biomarker for predicting this conversion.

Guillain-Barrésyndrome and hemophagocytic syndrome heralding the diagnosis of diffuse large B cell lymphoma:A case report

BACKGROUND Central nervous system(CNS)lesions and peripheral neuropathy are rare among patients with non-Hodgkin’s lymphoma(NHL).Lymphomatous infiltration or local oppression usually accounts for CNS or peripheral nerve lesions.The incidence of peripheral neuropathy was 5%.Guillain-Barrésyndrome(GBS)is rare and may occur in less than 0.3%of patients with NHL.Hemophagocytic syndrome(HPS)is a rare complication of NHL.It has been reported that 1%of patients with hematological malignancies develop HPS.Diffuse large B-cell lymphoma(DLBCL)combined with GBS has been reported in 10 cases.CASE SUMMARY We report the case of a 53-year-old man who was initially hospitalized because of abnormal feelings in the lower limbs and urinary incontinence.He was finally diagnosed with DLBCL combined with GBS and HPS after 16 d,which was earlier than previously reported.Immunoglobulin pulse therapy,dexamethasone,and etoposide were immediately administered.The neurological symptoms did not improve,but cytopenia was relieved.However,GBS-related clinical symptoms were relieved partially after one cycle of rituximab-cyclophosphamide,hydroxydaunorubicin,vincristine,and prednisone(R-CHOP)chemotherapy and disappeared after six cycles of R-CHOP.CONCLUSION GBS and HPS heralding the diagnosis of Epstein-Barr virus DLBCL are rare.Herein,we report a rare case of DLBCL combined with GBS and HPS,and share our clinical experience.Traditional therapies may be effective if GBS occurs before lymphoma is diagnosed.Rapid diagnosis and treatment of DLBCL are crucial.

New risk factors and new tendency for central nervous system relapse in patients with diffuse large B-cell lymphoma:a retrospective study

Background: In patients with difuse large B?cell lymphoma(DLBCL), central nervous system(CNS) relapse is uncom?mon but is nearly always fatal. This study aimed to determine the risk factors for CNS relapse in DLBCL patients and to evaluate the eicacy of rituximab and intrathecal chemotherapy prophylaxis for CNS relapse reduction.Methods: A total of 511 patients with newly diagnosed DLBCL treated at the Sun Yat?sen University Cancer Center between January 2003 and December 2012 were included in the study. Among these patients, 376 received R?CHOP regimen(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment, and 135 received CHOP regimen(cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment. Intrathe?cal chemotherapy prophylaxis(methotrexate plus cytarabine) was administered to those who were deemed at high risk for CNS relapse. In the entire cohort and in the R?CHOP set in particular, the Kaplan–Meier method coupled with the log?rank test was used for univariate analysis, and the Cox proportional hazards model was used for multivariate analysis. Diferences were evaluated using a two?tailed test, and P < 0.05 was considered signiicant.Results: At a median follow?up of 46 months, 25(4.9%) patients experienced CNS relapse. There was a trend of reduced occurrence of CNS relapse in patients treated with rituximab; the 3?year cumulative CNS relapse rates were 7.1% in CHOP group and 2.7% in R?CHOP group(P = 0.045). Intrathecal chemotherapy prophylaxis did not confer much beneit in terms of preventing CNS relapse. Bone involvement [hazard ratio(HR) = 4.21, 95% conidence interval(CI) 1.38–12.77], renal involvement(HR = 3.85, 95% CI 1.05–14.19), alkaline phosphatase(ALP) >110 U/L(HR = 3.59, 95% CI 1.25–10.34), serum albumin(ALB) <35 g/L(HR = 3.63, 95% CI 1.25–10.51), treatment with rituxi?mab(HR = 0.34, 95% CI 0.12–0.96), and a time to complete remission ≤ 108 days(HR = 0.22, 95% CI 0.06–0.78) were independent predictive factors for CNS relapse in the entire cohort. Bone involvement(HR = 4.44, 95% CI 1.08–18.35), bone marrow involvement(HR = 11.70, 95% CI 2.24–60.99), and renal involvement(HR = 10.83, 95% CI 2.27–51.65) were independent risk factors for CNS relapse in the R?CHOP set.Conclusions: In the present study, rituximab decreased the CNS relapse rate of DLBCL, whereas intrathecal chemo?therapy prophylaxis alone was not suicient for preventing CNS relapse. Serum levels of ALB and ALP, and the time to complete remission were new independent predictive factors for CNS relapse in the patients with DLBCL. In the patients received R?CHOP regimen, a trend of increased CNS relapse was found to be associated with extranodal lesions.

Disseminated soft tissue diffuse large B-cell lymphoma involving multiple abdominal wall muscles:A case report

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is the most common subtype of non�Hodgkin lymphoma,and patients with DLBCL typically present rapidly growing masses.Lymphoma involving muscle is rare and accounts for only 5%;furthermore,multiple muscles and soft tissue involvement of DLBCL is unusual.Due to unusual clinical manifestation,accurate diagnosis could be delayed.CASE SUMMARY A 61-year-old man complained of swelling,pain and erythematous changes in the lower abdomen.Initially,soft tissue infection was suspected,however,skin lesion did not respond to antibiotics.18Fluoro-2-deoxy-D-glucose(18F-FDG)positron emission tomography-computed tomography demonstrated FDG uptake not only in the skin and subcutaneous tissue of the abdomen but also in the abdominal wall muscles,peritoneum,perineum,penis and testis.DLBCL was confirmed by biopsy of the abdominal wall muscle and subcutaneous tissue.After intensive treatment including chemotherapy with rituximab,cyclophosphamide,doxorubicin,vincristine and prednisolone,central nervous system prophylaxis(intrathecal injection of methotrexate,cytarabine and hydrocortisone)and orchiectomy,he underwent peripheral blood stem cell mobilization for an autologous hematopoietic stem cell transplantation.Despite intensive treatment,the disease progressed rapidly and the patient showed poor outcome(overall survival,9 mo;disease free survival,3 mo).CONCLUSION The first clinical manifestation of soft tissue DLBCL involving multiple muscles was similar to the infection of the soft tissue.

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy

Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation.A multi-center phase I/II trial of anti-CD19 CD28z CAR-T(FKC876,ChiCTR1800019661)was conducted.Among 22 evaluable DLBCL patients,seven achieved complete remission,10 experienced partial remissions,while four had stable disease by day 29.Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients,and compared at different stages of treatment.M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells,leading to CAR-T cell therapy failure and disease progression in DLBCL.Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy,during both cell expansion and disease progression,which could not be altered by infiltrating CAR-T cells.Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments.Thus,our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

Rituximab Treatment Strategy for Patients with Diffuse Large B-Cell Lymphoma after First-Line Therapy： A Systematic Review and Meta-Analysis

Background： Rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone （CHOP） significantly prolonged event-free survival in first-line chemotherapy for patients with diffuse large B-cell lymphoma （DLBCL）. But relapse and refractory DLBC L occur frequently. Although rituximab is effective, its role in salvage therapy after autologous transplant remains unclear. Maintenance therapy with rituximab in responding patients after first line chemotherapy may be a useful novel approach capable of eradicating minimal residual disease and to bring survival benefit. This systematic review and meta-analysis evaluated the effects of rituximab maintenance treatment and salvage therapy of patients with DLBCL. Methods： We performed a systematic review and meta-analysis of randomized controlled trials and compared rituximab maintenance or salvage therapy at relapse with observation. We searched the Cochrane Library, PubMed, EMBASE, conference proceedings, databases of ongoing trials, and references of published trials. Two reviewers independently assessed the quality of the trials and extracted data. Hazard ratios for time-to-event data were estimated and pooled. Results： Seven trials including 1470 DLBCL patients were included in this systematic review and recta-analysis. Patients treated with maintenance rituximab have better overall survival （OS） and event-tree survival （EFS） than patients in the observation arm, but there was no statistical significance. Patients who received rituximab salvage therapy for relapse or refractory DLBCL have statistically significantly better OS [HR of death = 0.72, 95% CI （0.55-0.94）, P - 0.02], progression-free survival （PFS） [HR - 0.61,95% CI（0.52-0.72）, P 〈 0.05], odds ratio （OR） [RR = 1.26, 95% CI（1.07-1,47）, P = 0.004] than patients in the observation arm. The rate of infection-related adverse events was higher with rituximab treatment [RR = 1.37, 95% CI = （ 1.14 - 1.65） P =0.001 ]. Conclusions： After first-line chemotherapy, the two rituximab-combined treatment strategies, including maintenance and salvage therapies can bring survival benefit. But due to the few studies, the low methodological quality assessment and the low outcome evidence quality, it＇s not confirmed that the two strategies are better than normal chemotherapy regimens. More high-quality randomized controlled trials are still needed to provide reliable evidence. The higher rate of infections after rituximab therapy should be taken into consideration when making treatment decisions.

Primary Cardiac Lymphoma: Three Case Reports and a Review of the Literature

Primary cardiac lymphoma (PCL) is a rare entity that comprises only 1% - 2% of all cardiac tumors. Due to their scarcity and variable clinical presentation, early diagnosis is challenging. In this series, three cases of PCL from a single institution are described, which highlight the spectrum of presenting features and emphasize common principles. In the first case, a 73-year-old male who presented with dyspnea was found to have a 12.1 cm mass in the right ventricle. Biopsy via cardiac catheterization revealed diffuse large B cell lymphoma (DLBCL). He was treated with chemoimmunotherapy and survived for two months. The second case describes a 55-year-old female who presented with chest pain. Imaging revealed a 3.1 cm right atrial mass and bilateral pleural effusions, with cytology from the latter demonstrating DLBCL. She was lost to follow up after three cycles of chemoimmunotherapy. In the last case, an 80-year-old female presented with weakness. A 4.0 cm mass was discovered in the right atrium and the patient expired shortly after admission. Autopsy confirmed the diagnosis of DLBCL. These case summaries are followed by a review of the clinical presentation, diagnostic approach, and treatment outcomes of PCL.

DPHL:A DIA Pan-human Protein Mass Spectrometry Library for Robust Biomarker Discovery

To address the increasing need for detecting and validating protein biomarkers in clinical specimens,mass spectrometry(MS)-based targeted proteomic techniques,including the selected reaction monitoring(SRM),parallel reaction monitoring(PRM),and massively parallel dataindependent acquisition(DIA),have been developed.For optimal performance,they require the fragment ion spectra of targeted peptides as prior knowledge.In this report,we describe a MS pipeline and spectral resource to support targeted proteomics studies for human tissue samples.To build the spectral resource,we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker.We then applied the workflow to generate DPHL,a comprehensive DIA pan-human library,from 1096 data-dependent acquisition(DDA)MS raw files for 16 types of cancer samples.This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer(PCa)patients.Thereafter,PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated.As a second application,the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma(DLBCL)patients and 18 healthy control subjects.Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM.These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery.DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000.