RPRD1B/CREPT facilitates the progression of diffuse large B-cell lymphoma by inhibiting apoptosis through the NF-κB signaling pathway

Objective:To investigate the role of RPRD1B in the progression of diffuse large B-cell lymphoma(DLBCL)and its potential as a therapeutic target.Methods:This study analyzed RPRD1B expression in DLBCL and normal tissues using public databases and assessed its prognostic impact through survival analysis.In vitro and in vivo experiments were conducted to explore the mechanisms by which RPRD1B influences tumor growth and apoptosis.Results:RPRD1B expression was significantly elevated in DLBCL compared to normal tissues and was associated with poor prognosis.In vitro and in vivo experiments demonstrated that RPRD1B promoted lymphoma cell proliferation and inhibited apoptosis through the NF-κB signaling pathway.Conclusions:RPRD1B plays a critical role in the progression of DLBCL by modulating apoptosis and cellular proliferation.Targeting RPRD1B may offer a novel therapeutic strategy for DLBCL,suggesting its potential as a prognostic marker and therapeutic target in hematological malignancies.

Identifying relevant factors influencing cancer-related fatigue in patients with diffuse large B-cell lymphoma during chemotherapy

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a rapidly growing malignant tumor,and chemotherapy is one of the treatments used to combat it.Although advancements of science and technology have resulted in more and more patients being able to receive effective treatment,they still face side effects such as fatigue and weakness.It is important to thoroughly investigate the factors that contribute to cancer-related fatigue(CRF)during chemotherapy.AIM To explore the factors related to CRF,anxiety,depression,and mindfulness levels in patients with DLBCL during chemotherapy.METHODS General information was collected from the electronic medical records of eligible patients.Sleep quality and mindfulness level scores in patients with DLBCL during chemotherapy were evaluated by the Pittsburgh Sleep Quality Index and Five Facet Mindfulness Questionnaire-Short Form.The Piper Fatigue Scale was used to evaluate the CRF status.The Self-Rating Anxiety Scale and Self-Rating Depression Scale were used to evaluate anxiety and depression status.Univariate analysis and multivariate regression analysis were used to investigate the factors related to CRF.RESULTS The overall average CRF level in 62 patients with DLBCL during chemotherapy was 5.74±2.51.In 25 patients,the highest rate of mild fatigue was in the cognitive dimension(40.32%),and in 35 patients the highest moderate fatigue rate in the behavioral dimension(56.45%).In the emotional dimension,severe fatigue had the highest rate of occurrence,34 cases or 29.03%.The CRF score was positively correlated with cancer experience(all P<0.01)and negatively correlated with cancer treatment efficacy(all P<0.01).Tumor staging,chemotherapy cycle,self-efficacy level,and anxiety and depression level were related to CRF in patients with DLBCL during chemotherapy.CONCLUSION There was a significant correlation between CRF and perceptual control level in patients.Tumor staging,chemotherapy cycle,self-efficacy level,and anxiety and depression level influenced CRF in patients with DLBCL during chemotherapy.

Design of manganese ion coated Prussian blue nanocarrier for the therapy of refractory diffuse large B-cell lymphoma based on a comprehensive analysis of ferroptosis regulators from clinical cases

Diffuse large B-cell lymphoma(DLBCL)is a prevalent human malignancy,and understanding its biology will help identify problems in refractory patients and customize alternative therapies for them.We found that DLBCL can be stratified into two independent subtypes with different clinical characteristics and outcomes by consensus clustering of expression of ferroptosis regulatory genes,which proves that ferroptosis is effective in treating refractory cases.In this work,we constructed a novel ferroptosis nanocarrier(PBPMn@PEG)by coating Prussian blue nanoparticles with manganese ions and encapsulating them with poly(ethyleneglycol).The low efficiency of the Fenton reaction of Prussian blue nanoparticles can be improved greatly by manganese coating,and can effectively generate hydroxyl radicals,and induce ferroptosis of lymphoma cells(SU-DHL-10 cells)by down-regulating ferroptosis suppressor genes and up-regulating ferroptosis driver genes.It also induces effective cell apoptosis,which is synergistic with ferroptosis for DLBCL therapy.In vivo experiments also prove that PBPMn@PEG achieved a better anti-tumor effect by up-regulating COX2,HO-1/hemeoxygenase-1(HMOX1),and NADPH oxidase-4(NOX4),and downregulating FSP1 and GPX4,with lower biotoxicity.As a novel and potential DLBCL drug carrier,our discovery served as a foundation for the treatment of the refractory DLBCL by inducing ferroptosis for DLBCL treatment in addition to the therapeutic effect of drugs.

Diagnostic Efficacy of^(18)F-FDG PET/CT in Detecting Bone Marrow Infiltration in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

Objective Diffuse large B-cell lymphoma(DLBCL)is often associated with bone marrow infiltration,and 2-deoxy-2-(18F)fluorodeoxyglucose positron emission tomography/computed tomography(^(18)F-FDG PET/CT)has potential diagnostic significance for bone marrow infiltration in DLBCL.Methods A total of 102 patients diagnosed with DLBCL between September 2019 and August 2022 were included.Bone marrow biopsy and^(18)F-FDG PET/CT examinations were performed at the time of initial diagnosis.Kappa tests were used to evaluate the agreement of^(18)F-FDG PET/CT with the gold standard,and the imaging features of DLBCL bone marrow infiltration on PET/CT were described.Results The total detection rate of bone marrow infiltration was not significantly different between PET/CT and primary bone marrow biopsy(P=0.302)or between the two bone marrow biopsies(P=0.826).The sensitivity,specificity,and Youden index of PET/CT for the diagnosis of DLBCL bone marrow infiltration were 0.923(95%CI,0.759-0.979),0.934(95%CI,0.855-0.972),and 0.857,respectively.Conclusion^(18)F-FDG PET/CT has a comparable efficiency in the diagnosis of DLBCL bone marrow infiltration.PET/CT-guided bone marrow biopsy can reduce the misdiagnosis of DLBCL bone marrow infiltration.

Diffuse large B-cell lymphoma successfully treated with amplified natural killer therapy alone: A case report

BACKGROUND The prognosis of patients with advanced diffuse large B-cell lymphoma(DLBCL)is poor,with a 5-year survival rate of approximately 50%.The mainstay of treatment is multidrug combination chemotherapy,which has been associated with serious side effects.Amplified natural killer(ANK)cell therapy amplifies and activates natural killer(NK)cells to attack only malignant tumors.As ANK cells attack programmed death ligand 1(PD-L1)-positive tumor cells,ANK therapy is considered effective against adult T-cell lymphoma and malignant lymphoma.CASE SUMMARY Herein,we report a case of an older patient with advanced DLBCL who was successfully treated with ANK immunotherapy.A 91-year-old female visited our hospital with sudden swelling of the right axillary lymph node in April 2022.The patient was diagnosed with stage II disease,given the absence of splenic involvement or contralateral lymphadenopathy.ANK therapy was administered.Six rounds of lymphocyte sampling were performed on July 28,2022.To reduce the occurrence of side effects,the six samples were diluted by half to obtain 12 samples.Cultured NK cells were administered twice weekly.The treatment efficacy was evaluated by performing computed tomography and serological tests every 1 or 2 mo.The treatment suppressed lesion growth,and the antitumor effect persisted for several months.The patient experienced mild side effects.PD-L1 immunostaining was positive,indicating that the treatment was highly effective.CONCLUSION ANK therapy can be used as a first-line treatment for malignant lymphoma;the PD-L1 positivity rate can predict treatment efficacy.

Rituximab combined with Bruton tyrosine kinase inhibitor to treat elderly diffuse large B-cell lymphoma patients: Two case reports

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHLs.This report aims to explore the efficacy and safety of rituximab combined with Bruton tyrosine kinase inhibitors(BTKis)in the treatment of elderly patients with DLBCL.CASE SUMMARY The clinical data of two elderly patients with DLBCL who received rituximab combined with BTKi in our hospital were retrospectively analyzed,and the literature was reviewed.The patients were treated with chemotherapy using the R-miniCHOP regimen for two courses.Then,they received rituximab in combination with BTKi.CONCLUSION The treatment experience in these cases demonstrates the potential efficacy of rituximab combined with BTKi to treat elderly DLBCL patients,thus providing a new treatment strategy.

Comparative analysis of conventional ultrasound and shear wave elastography features in primary breast diffuse large B-cell lymphoma

BACKGROUND Primary breast diffuse large B-cell lymphoma(PB-DLBCL)is a rare subtype of non-Hodgkin lymphoma that accounts for<3%of extranodal lymphomas and 1%of breast tumors.Its diagnosis and management are challenging because of its rarity,heterogeneity,and aggressive behavior.Conventional ultrasound(US)is the first-line imaging modality for breast lesions;however,it has limited specificity and accuracy for PB-DLBCL.Shear wave elastography(SWE)is a novel US technique that measures tissue stiffness and may reflect the histological characteristics and biological behavior of breast lesions.AIM To compare the conventional US and SWE features of PB-DLBCL and evaluate their diagnostic performance and prognostic value.METHODS We retrospectively reviewed the clinical data and US images of 32 patients with pathologically confirmed PB-DLBCL who underwent conventional US and SWE before treatment.We analyzed conventional US features(shape,margin,orientation,echo,posterior acoustic features,calcification,and vascularity)and SWE features(mean elasticity value,standard deviation,minimum elasticity value,maximum elasticity value,and lesion-to-fat ratio)of the PB-DLBCL lesions.Using receiver operating characteristic curve analysis,we determined the optimal cutoff values and diagnostic performance of conventional US and SWE features.We also performed a survival analysis to assess the prognostic value of conventional US and SWE features.RESULTS The results showed that the PB-DLBCL lesions were mostly irregular in shape(84.4%),microlobulated or spiculated in margins(75%),parallel in orientation(65.6%),hypoechoic in echo(87.5%),and had posterior acoustic enhancement(65.6%).Calcification was rare(6.3%)and vascularity was variable(31.3%avascular,37.5%hypovascular,and 31.3%hypervascular).The mean elasticity value of PB-DLBCL lesions was significantly higher than that of benign breast lesions(113.4±46.9 kPa vs 27.8±16.4 kPa,P<0.001).The optimal cutoff value of the mean elasticity for distinguishing PB-DLBCL from benign breast lesions was 54.5 kPa,with a sensitivity of 93.8%,specificity of 92.9%,positive predictive value of 93.8%,negative predictive value of 92.9%,and accuracy of 93.3%.The mean elasticity value was also significantly correlated with Ki-67 expression level(r=0.612,P<0.001),which is a marker of tumor proliferation and aggressiveness.Survival analysis showed that patients with higher mean elasticity values(>54.5 kPa)had worse overall survival(OS)and progression-free survival(PFS)than those with lower mean elasticity values(<54.5 kPa)(P=0.038 for OS and P=0.027 for PFS).CONCLUSION Conventional US and SWE provide useful information for diagnosing and forecasting PB-DLBCL.SWE excels in distinguishing PB-DLBCL from benign breast lesions,reflects tumor proliferation and aggressiveness,and improves disease management.

Effect of T-regulatory cells and interleukin-35, interleukin-10, and transforming growth factor-beta on diffuse large B-cell lymphoma

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is an aggressive non-Hodgkin lymphoma that affects B lymphocytes.It can develop in the lymph nodes and can be localized or generalized.Despite DLBCL being considered potentially curable,little research has been conducted on the relationship between the body's immune response and DLBCL.AIM To study the expression and significance of T-regulatory cells(Tregs)interleukin(IL)-35,IL-10,and transforming growth factor-beta(TGF-β)in DLBCL.METHODS Data from 82 patients with DLBCL who were initially admitted to The First Affiliated Hospital of Ningbo University(Zhejiang Province,China)between January 2017 and June 2022 and treated with standard first-line regimens were reviewed.Three patients were lost to follow-up;thus,79 patients were included in the statistical analysis and then divided into three groups according to the evaluation of clinical efficacy:Incipient(new-onset and treatment-naïve),effectively treated,and relapsed-refractory.Thirty healthy individuals were included in the control group.The expression of peripheral blood T lymphocytes and their associated factors IL-35,IL-10,and TGF-βin the four groups were observed.RESULTS In contrast to the successfully treated and normal control groups,both the incipient and relapse-refractory groups exhibited greater proportions of CD4-positive(+)Tregs(P<0.05),whereas the proportion of CD8+Tregs did not differ substantially between the groups.Serum levels of IL-35 and IL-10 in the incipient and relapsed-refractory groups were higher than those in the effectively treated and normal control groups(P<0.05).There was no statistically significant distinction in the expression level of TGF-βbetween the groups(P>0.05).The correlation between IL-35 and IL-10 concentrations was significantly positive,with a correlation coefficient of 0.531(P<0.05).The correlation between IL-35 and TGF-βconcentration was significantly positive,with a correlation coefficient of 0.375(P<0.05).The correlation between IL-10 and TGF-βconcentration was significantly positive,with a correlation coefficient of 0.185(P<0.05).The expression concentrations of IL-35,IL-10 and TGF-βwere apparently and positively correlated(P<0.05).CONCLUSION Tregs IL-35,and IL-10 may be closely associated with the occurrence and development of DLBCL and the detection of related indices may be helpful in the analysis of disease prognosis.

Helicobacter pylori eradication treatment for primary gastric diffuse large B-cell lymphoma:A single-center analysis

BACKGROUND Unlike the already established effect of Helicobacter pylori(H.pylori)eradication on gastric mucosa-associated lymphoid tissue(MALT)lymphoma,its therapeutic effect on primary gastric diffuse large B-cell lymphoma(DLBCL)is still unclear.AIM To clarify the efficacy of H.pylori eradication treatment for primary gastric DLBCL.METHODS We reported on 3 new cases,and added them to 3 previously reported cases.We analyzed the usefulness of H.pylori eradication treatment for gastric DLBCL for a total of 6 cases at our center.RESULTS Of the 6 patients(27-90 years old,3 males and 3 females),all 3 patients with single lesions(one transformed from MALT lymphoma)achieved complete remission(CR)after H.pylori eradication.Regarding the 2 newly reported cases,CR was maintained for more than 6 years with eradication treatment alone.In contrast,none of the 3 patients with 2 lesions achieved CR.In 1 newly reported case,endoscopic CR was achieved in one lesion,while stable disease was obtained in the other lesion.Two patients with progressive disease responded to standard chemo therapy±radiation and remained in CR for more than 6 years.CONCLUSION We believe it is worthwhile to attempt H.pylori eradication for elderly patients with primary gastric DLBCL in a single lesion with a small tumor burden.

Coexistence of diffuse large B-cell lymphoma,acute myeloid leukemia,and untreated lymphoplasmacytic lymphoma/waldenström macroglobulinemia in a same patient:A case report

BACKGROUND The Coexistence of myeloid and lymphoid malignancies is rare.Myeloid leukemia occurs more frequently as a secondary event in patients receiving chemotherapy agents for lymphoid malignancies.Synchronous diagnoses of diffuse large B-cell lymphoma(DLBCL),acute myeloid leukemia(AML),and untreated lymphoplasmacytic lymphoma/Waldenström macroglobulinemia(LPL/WM)in the same patient have not been reported.Here we report one such case.CASE SUMMARY An 89-year-old man had a chest wall mass histopathologically diagnosed as DLBCL.The bone marrow and peripheral blood contained two groups of cells.One group of cells fulfilled the criteria of AML,and the other revealed the features of small B lymphocytic proliferative disorder,which we considered LPL/WM.Multiple chromosomal or genetic changes were detected in bone marrow mononuclear cells,including ATM deletion,CCND1 amplification,mutations of MYD88(L265P)and TP53,WT1 overexpression,and fusion gene of BIRC2-ARAP1,as well as complex chromosomal abnormalities.The patient refused chemotherapy because of old age and died of pneumonia 1 mo after the final diagnosis.CONCLUSION The coexistence of DLBCL,AML,and untreated LPL/WM in the same patient is extremely rare,which probably results from multiple steps of genetic abnormalities.Asymptomatic LPL/WM might have occurred first,then myelodysplastic syndromerelated AML developed,and finally aggressive DLBCL arose.Therefore,medical staff should pay attention to this rare phenomenon to avoid misdiagnoses.

Phase Ⅰ study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large B-cell lymphoma in Chinese patients

Anti-CD 19 chimeric antigen receptor(CAR)T cell therapy has shown impressive efficacy in treating B-cell malignancies.A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR,a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule,for the treatment of patients with refractory diffuse large B-cell lymphoma(DLBCL).Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell(C-CAR011)treatment.The overall response rate was 20%and 50%at 4 and 12 weeks after the infusion of C-CAR011,respectively,and the disease control rate was 60%at 12 weeks after infusion.Treatment-emergent adverse events occurred in all patients.The incidence of cytokine release syndrome in all grades and grade^3 was 90%and 0,respectively,which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel.Neurotoxicity or other dose-limiting toxicides was not observed in any dose cohort of C-CAR011 therapy.Antitumor efficacy was apparent across dose cohorts.Therefore,C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL,and further large-scale clinical trials are warranted.

Outcomes in refractory diffuse large B-cell lymphoma:results fromamulticenter real-world study in China

Background:Diffuse large B-cell lymphoma(DLBCL)patients refractory to rituximab-based immunochemotherapy have a dismal prognosis.However,the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries.To validate the definition and outcomes of refractory DLBCL in China,we conducted a multicenter,retrospective cohort study.Methods:The REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL(REAL-TREND)study was performed using real-world data from 8 centers in China.DLBCL patients with curative intent were included in the REAL-TREND dataset.Overall survival(OS)was estimated using the Kaplan-Meier method and compared by the log-rank test.Due to heterogeneity in response rates among different centers,the response rates of refractory patients were pooled using random-effect models.Multivariate survival analysis was performed using the Cox regression model.Results:A total of 2778 DLBCL patients diagnosed between January,2010 and December,2015 were enrolled to this study.After validating previous definitions,the SCHOLAR-1 study was most suitable to define refractory DLBCL.The estimated 5-year cumulative incidence of refractory patients was 20%(95% confidence Interval[CI]=18%-22%).After the determination of refractory disease,overall response rate and complete remission rate were 30%(95%CI=22%-38%)and 9%(95%CI=4%-15%),respectively.Patients with either no response to immunochemotherapy or relapse within 12 months after stem-cell transplantation had inferior survival with a median OS of 5.9 months(95%CI=5.5-7.1 months)and 2-year OS rate of 16%(95%CI=12%-20%).International prognostic index score 4-5(hazard ratio[HR]=2.22;95%CI=1.47-3.35),central nervous systemrelapse(HR=1.43;95%CI=1.04-1.97),and best response status(HR=2.68;95%CI=1.42-5.03 for partial remission.HR=5.97,95%CI=3.21-11.11 for stable disease/progressive disease)were independent unfavorable prognostic factors.Conclusions:This is the first large-scale Asian cohort study focusing on outcomes of refractory DLBCL.The definition of the SCHOLAR-1 study identifies patients with homogenously inferior survival,thus is appropriate to select refractory DLBCL.Due to poor clinical outcomes in the rituximab era,patients with refractory DLBCL may be potential candidates for novel treatment modalities.

Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin:Analysis of 1,085 WHO classified cases in a single institution in China

Objective: To explore the clinicobiologic features and outcomes of diffuse large B-cell lymphoma(DLBCL)patients in China according to the primary site.Methods: A total of 1,085 patients diagnosed with DLBCL in National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College during a 6-year period were enrolled. Their clinical characteristics and outcomes were analyzed according to the primary site.Results: In the 1,085 patients, 679(62.6%) cases were nodal DLBCL(N-DLBCL) and 406 cases(37.4%) were extranodal DLBCL(EN-DLBCL). The most common sites of N-DLBCL were lymphonodus(64.8%), Waldeyer's ring(19.7%), mediastinum(12.8%) and spleen(2.7%), while in EN-DLBCL, stomach(22.4%), intestine(16.0%),nose and sinuses(8.9%), testis(8.4%), skin(7.9%), thyroid(6.9%), central nervous system(CNS)(6.4%), breast(5.7%), bone(3.4%), and salivary gland(2.7%) were most common. N-DLBCL patients tend to present B symptoms, bulky disease, and elevated LDH more often, while age >60 years, extranodal sites >1, Ann Arbor stage I or II, bone marrow involvement, and Ki-67 index >90% were usually seen in EN-DLBCL. The 5-year overall survival(OS) rate and progression-free survival(PFS) rate for all patients were 62.5% and 54.2%. The 5-year OS rate for patients with N-DLBCL and EN-DLBCL were 65.5% and 56.9%(P=0.008), and the 5-year PFS were57.0% and 49.0%(P=0.020). Waldeyer's ring originated DLBCL possessed the highest 5-year OS rate(83.6%) and PFS rate(76.9%) in N-DLBCL. The top five EN-DLBCL subtypes with favorable prognosis were stomach,breast, nose and sinuses, lung, salivary gland, with 5-year OS rate: 70.3%, 69.6%, 69.4%, 66.7% and 63.6%,respectively. While CNS, testis, oral cavity and kidney originated EN-DLBCL faced miserable prognosis, with 5-year OS rate of 26.9%, 38.2%, and 42.9%.Conclusions: In our study, primary sites were associated with clinical characteristics and outcomes. Compared with EN-DLBCL, N-DLBCL had better prognosis.

Prognostic Value of D-Dimer in Patients with Diffuse Large B-cell Lymphoma:A Retrospective Study

This study evaluated the significance of serum D-Dimer for predicting survival of patients with diffuse large B-cell lymphoma(DLBCL).We analyzed the clinical data from 113 patients who were newly diagnosed with DLBCL at Tongji Hospital from January 2012 to January 2016.The results indicated that there were higher levels of D-Dimer in DLBCL patients with the following characteristics:stage HI/IV,lymphocyte monocyte ratio(LMR)<2.27,lactate dehydrogenase(LDH)>upper limit of normal(ULN),albumin(ALB)<35 g/L,and anemia.After the first chemotherapeutic regimen,D-Dimer was significantly decreased concomitantly with LDH.Cox univariate regression analysis showed that the overall survival(OS)was negatively affected by the following factors:age>60 years,stage m/IV,LDH>ULN,LMR<2.27,anemia and D-Dimer>0.92.Multivariate analysis showed that only LDH>ULN(P=0.038)and age>60 years(P=0.047)were independent adverse prognostic factors.However,it was suggested that D-Dimer could be regarded as a marker of high tumor burden and a potential prognostic screening tool for patients with DLBCL,not otherwise specified(NOS).

Composite diffuse large B-cell lymphoma and classical Hodgkin's lymphoma of the stomach:Case report and literature review

The combination of classical Hodgkin’s lymphoma(cHL)and non-Hodgkin lymphoma coexisting in the same patient is not common,especially in one extranodal location.Here we present a rare case of composite diffuse large B-cell lymphoma(DLBCL)and cHL occurring simultaneously in the stomach of a 53-year-old female who presented with upper abdominal discomfort and gas pain.Surgery was performed and the disease was diagnosed pathologically as composite lymphoma of DLBCL and cHL using hematoxylin-eosin and immunohistochemical staining.Epstein-Barr virus(EBV)infection was not detected by in situ hybridization for EBV-encoded RNA or immunohistochemistry for EBV latent membrane protein-1.Polymerase chain reaction analysis from the two distinct components of the tumor demonstrated clonal immunoglobulinκlight chain gene rearrangements.The patient died approximately 11 mo after diagnosis in spite of receiving eight courses of the CHOP and two courses of the rituximab-CHOP(RCHOP) chemotherapy regimen.This case report showed that the two distinct components,DLBCL and cHL,appeared to originate from the same clonal progenitor cell,and that EBV infection was not essential for transformation during the course of tumorigenesis.

Hepatitis C virus and diffuse large B-cell lymphoma: Pathogenesis, behavior and treatment

A significant association between hepatitis C virus (HCV) infection and B-cell lymphoma has been reported by epidemiological studies, most of them describing a strong relationship between indolent lymphomas and HCV. Furthermore, the curative potential of antiviral therapy on HCV related indolent lymphomas supports a specific role for the virus in lymphomagenesis. These observations are reinforced by numerous laboratory experiments that led to several hypothetical models of B-cell transformation by HCV. Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype in the western countries, has been associated to HCV infection despite its aggressive nature. This association seems particularly prominent in some geographical areas. Clinical presentation of HCV-associated DLBCL has consistently been reported to differ from the HCV-negative counterpart. Nevertheless, histopathology, tolerance to standard-of-care chemo-immunotherapy (R-CHOP or CHOP-like regimens) and final outcome of HCV-positive DLBCL patients is still matter of debate. Addition of rituximab has been described to enhance viral replication but the probability of severe hepatic complications remains low, with some exceptions (i.e., hepatitis B virus or immune immunodeficiency virus co-infected patients, presence of grade &#x0003e; 2 transaminases elevation, cirrhosis or hepatocarcinoma). HCV viral load in this setting is not necessarily directly associated with liver damage. Overall, treatment of HCV associated DLBCL should be performed in an interdisciplinary approach with hepatologists and hematologists with close monitoring of liver function. Available reports reveal that the final outcome of HCV-positive DLBCL that receive standard immunochemotherapy is not inferior to their HCV-negative counterpart. This review summarizes data on epidemiology, pathogenesis and therapeutic approach on HCV-associated DLBCL. Several issues that are matter of debate like clinical management of patients with transaminase elevation, criteria for discontinuing or starting immuno-chemotherapy, as well as the exact role of monoclonal antibodies will be analyzed.

Clinical features, survival and prognostic factors of primary testicular diffuse large B-cell lymphoma

Objective： To assess the clinical features, survival and prognostic factors of primary testicular diffuse large B-cell lymphoma （DLBCL）. Methods： A retrospective study of 37 patients with primary testicular DLBCL was carried out from November 2003 to May 2012. Their clinical features, survival and prognostic factors were analyzed. Results： During a median follow-up period of 39.8 months （5.4-93.0 months）, the median progression-free survival （PFS） was 26.2 months （95% CI：0-65 months） and the 3-year overall survival （OS） rate was 78.4%. Within the whole cohort, the factors significantly associated with a superior PFS were limited stage （stage Ⅰ/Ⅱ）, lactate dehydrogenase （LDH） ≤245 U/L, international prognostic index （IPI） ≤1, primary tumor diameter 〈7.5 cm, and patients who had complete response （CR） and received doxoruhicin-contained chemotherapy （P〈0.05）. There was a trend toward superior outcome for patients who received combined therapy （surgery/ chemotherapy/radiotherapy） （P=0.055）. Patients who had CR, primary tumor diameter 〈7.5 cm and IPI score ≤1 were significantly associated with longer PFS at multivariate analysis. Conclusions： Primary testicular DLBCL had poorer survival. CR, primary tumor diameter and IPI were independent prognostic factors. The combined therapy of orchectomy, doxorubicin-contained chemotherapy and contralateral testicular radiotherapy （RT） seemed to improve survival.

Prognostic value of BCL2 and TP53 genetic alterations for diffuse large B-cell lymphoma patients treated with R-CHOP

Objective:Limited data about the prognostic significance of BCL2 mutations and BCL2 copy number variations in diffuse large B-cell lymphoma(DLBCL)are available.This study aimed to comprehensively describe BCL2 genetic alterations in DLBCL patients,and examine correlation of BCL2,TP53 and other genetic alterations with outcomes in patients treated with R-CHOP.Methods:Probe capture-based high-resolution sequencing was performed on 191 patients diagnosed with de novo DLBCL.MYC,BCL2,and BCL6 protein expressions were detected by immunohistochemistry.Results:The presence of BCL2 alterations significantly correlated with poor progression-free survival(PFS)(5-year PFS:13.7%vs.40.8%;P=0.003)and overall survival(OS)(5-year OS:34.0%vs.70.9%;P=0.036).Importantly,patients who harbored BCL2 gain/amplifications(BCL2GA/AMP)also had a remarkably inferior 5-year PFS(11.1%vs.38.3%;P<0.001)and OS(22.1%vs.69.6%;P=0.009).In contrast,neither BCL2 mutations nor BCL2 translocations were significantly prognostic for survival.Multivariable analyses showed that the presence of BCL2 alterations,especially BCL2GA/AMP,TP53 mutations,and International Prognostic Index(IPI)were significantly associated with inferior PFS and OS.Novel prognostic models for OS were constructed based on 3 risk factors,including BCL2 alterations(Model 1)or BCL2GA/AMP(Model 2),TP53 mutations,and IPI,to stratify patients into 4 risk groups with different survival outcomes.Conclusions:This study showed that DLBCL patients treated with R-CHOP,BCL2 alterations,especially BCL2GA/AMP and TP53 mutations were significantly associated with inferior outcomes,which were independent of the IPI.The novel prognostic models we proposed predicted outcomes for DLBCL patients treated with R-CHOP,but further validation of the prognostic models is still warranted.

Case report of acute-on-chronic liver failure secondary to diffuse large B-cell lymphoma

Acute liver failure is a rare presentation of hematologic malignancy. Acute on chronic liver failure(ACLF) is a newly recognized clinical entity that describes acute hepatic decompensation in persons with preexisting liver disease. Diffuse large B-cell lymphoma(DLBCL) is an aggressive non-Hodgkin's lymphoma(NHL) with increasing incidence in older males, females and blacks. However, it has not yet been reported, to present with acute liver failure in patients with preexisting chronic liver disease due to human immunodeficiency virus(HIV)/hepatitis C virus(HCV) co-infection. We describe a case of ACLF as the presenting manifestation of DLBCL in an elderly black man with HIV/HCV coinfection and prior Hodgkin's disease in remission for three years. The rapidly fatal outcome of this disease is highlighted as is the distinction of ACLF from decompensated cirrhosis. Due to the increased prevalence of HIV/HCV co-infection in the African American 1945 to 1965 birth cohort and the fact that both are risk factors for chronic liver disease and NHL we postulate that the incidence of NHL presenting as ACLF may increase.

Extranodal involvement in young patients with diffuse large B-cell lymphoma： distribution, prognostic value and treatment options

Objective： Extranodal involvement represents a peculiar presentation of diffuse large B-cell lymphoma（DLBCL）. Previous studies have suggested that older patients are more prone to extranodal involvement. This study retrospectively addressed the distribution, prognostic value and treatment options of extranodal involvement in young patients with DLBCL.Methods： A total of 329 patients were enrolled according to the inclusion requirements. The effects of gender,extranodal involvement, age-adjusted international prognostic index（aa IPI）, rituximab infusion and radiotherapy on patient outcomes were evaluated.Results： Among these patients, 59% presented extranodal involvement in 16 anatomic sites. More than one instance was linked to many poorer clinical characteristics and poorer survival compared with either nodal disease or one instance. In patients with one extranodal lesion, multivariate analysis revealed that the site of extranodal involvement, but not the aa IPI or rituximab infusion, was independently related to the outcome, and radiotherapy had a negative influence on survival.Conclusions： Extranodal involvement is common in younger patients and exhibits a ubiquitous distribution.The site of extranodal involvement is of strong prognostic significance. Radiotherapy for extranodal lesions does not improve patient outcomes.