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Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous malignancy with distinct Germinal Center B-Cell Like (GCB) and non-GCB subtypes. Accurate subtyping is crucial due to differences in prognosis and treatment response. While gene expression profiling is the gold standard, it is often unavailable in low-resource settings. Inflammatory and nutritional biomarkers such as Systemic Immune-Inflammation Index (SII), Prognostic Nutritional Index (PNI), and Advanced Lung Cancer Inflammation Index (ALI) offer a practical alternative. This study aims to evaluate their diagnostic potential in early-stage DLBCL subtypes. A cross-sectional analysis was conducted on 60 early stage DLBCL patients (30 GCB, 30 non-GCB) at Dr Hasan Sadikin General Hospital Bandung. Clinical characteristics, hematological parameters, and inflammation-based indices (SII, PNI, and ALI) were evaluated. Differences between subtypes were analyzed using the Mann-Whitney -test, and Receiver Operating Characteristic (ROC) analysis was used to determine diagnostic performance. The median SII was significantly higher in non-GCB compared with GCB (982,575; IQR: 609,112-2,239,917 vs 575,598; IQR: 454,578-886,426, p = 0.014). Conversely, PNI was higher in GCB compared to non-GCB group (49.18; IQR: 46.38-56.38 vs 45.96; IQR 40.05-52.28, p = 0.011). ALI values were also higher in the GCB than non-GCB (44.14; IQR: 27.69-67.18 vs 24.51; IQR: 14.34-42.47,p=0.003). ROC analysis revealed that ALI had the highest diagnostic accuracy (AUC = 0.724; 95% CI: 0.593-0.831), followed by SII (AUC = 0.685, 95% CI: 0.552-0.799) and PNI (AUC = 0.691 95% CI: 0.558-0.804). Optimal cut-off values were ≤1,234,133 for SII, >43.27 for PNI, and >27.41 for ALI. ALI demonstrated the best balance between sensitivity (76.7%) and specificity (63.3%), making it the most reliable marker for distinguishing DLBCL subtypes. SII, PNI, and ALI differ significantly between DLBCL subtypes. These findings suggest that integrating these indices into a diagnostic model could enhance risk stratification and guide therapeutic decision-making in DLBCL. Further studies with larger cohorts are warranted to validate these findings.

BackgroundRelapsed or refractory (R/R) non–germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL) shows poor clinical outcomes. Bruton tyrosine kinase (BTK) inhibitors have established therapeutic activity by targeting B-cell receptor signaling, with promising results in treating DLBCL. The monotherapy of zanubrutinib, a selective BTK inhibitor, or second-line salvage chemotherapy has shown limited efficacy in patients with R/R DLBCL. Thus, the present study evaluated the efficacy and safety of zanubrutinib-combined therapy in heavily treated patients with non-GCB DLBCL.MethodsThis retrospective study consists of 27 heavily treated patients with non-GCB DLBCL who received zanubrutinib-combined therapy between January 2021 and February 2024 in Shanghai Tongji Hospital and Zhejiang Second Affiliated Hospital. Efficacy outcomes included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), whereas safety outcomes included incidence of adverse events.ResultsOf all the 27 enrolled patients’ baseline,24 patients (88.9%) showed a high IPI score (≥3), 23 patients (85.2%) had a high proliferation score (Ki 67≥80%) and 20 patients (74.1%) were heavily treated with ≥3 lines of previous treatments. The ORR in all patients was 74.1% (95%CI, 53.7%-88.9%), the partial response (PR) was 66.7% (95%CI, 46.0%-83.5%). With a median follow-up of 36.6 months, the median PFS was 10.6 months (95%CI 7.3-14) and median OS was 19.6 months (95%CI 12.3-not reached). The grade ≥3 hematologic toxicities included neutropenia (85.1%, 23/27) and thrombocytopenia (37%, 10/27). The grade ≥3 nonhematologic AEs were hypokalemia (11.1%, 3/27) and pulmonary infection (11.1%, 3/27). No treatment-related deaths occurred. Subgroups stratified by gender, age, and presence/absence of extranodal lesions all maintained an ORR of over 70%. The efficacy of the combined therapy seemed to be not affected by most baseline characteristics and was associated with high response even in high-risk subgroups. Of all the evaluated 27 patients, 2 patients got complete response (CR) received autologous stem cell transplantation and lenalidomide maintenance therapy respectively. 19 patients got no CR were bridged to CD19 chimeric antigen receptor (CAR)-T cell therapy, while the other 6 patients received additional salvage chemotherapy. In the CAR-T cohort, the ORR was 89.5% (95%CI: 67.0%~98.2%) and CR was 57.9% (95%CI: 34.5%~78.9%), the median PFS was 14 months (95% CI: 5.2-37.9) and median OS was 27.7 months (95% CI: 10.1- not reached). The CAR-T group was associated with improved overall survival relative to the non-CAR-T group (HR = 0.21, 95% CI: 0.05–0.79, P = 0.02). In the landmark analysis, the survival probability of CART group was 80% at 12 months post-landmark, the non-CAR-T group exhibited an earlier initial drop with survival decreasing to 57.1% at 12 months.ConclusionZanubrutinib-combined therapy was effective and safe for the treatment of heavily treated patients with non-GCB DLBCL. It offers a promising treatment option and serving as an effective bridge to CAR-T therapy, with manageable toxicity. Future prospective studies with larger cohorts are needed to validate these findings.

Background This study aimed to identify the prognostic value of interim 18 F-FDG PET/CT (I-PET) for germinal center B-cell-like (GCB) and non-GCB diffuse large B-cell lymphoma (DLBCL), respectively. Methods Baseline 18 F-FDG PET/CT (B-PET) and I-PET scans were performed in 112 patients with DLBCL. The prognostic value of I-PET using the Deauville five-point scale (D-5PS) criteria or percentage decrease in SUVmax (∆SUVmax) for GCB and non-GCB DLBCL were evaluated. Results A significant difference in progression-free survival (PFS) was found between GCB and non-GCB DLBCL patients ( P  < 0.05). Based on D-5PS criteria, I-PET was divided into positive (score > 3) and negative (score ≤ 3) subgroups. Results indicated that I-PET using D-5PS criteria was an independent predictor for PFS of GCB DLBCL ( P  < 0.05), but not for overall survival (OS) ( P  > 0.05). For non-GCB DLBCL, PFS and OS were significantly higher in I-PET negative group than I-PET positive group ( P  < 0.05). Receiver operating characteristic (ROC) curve analysis proved that I-PET using ΔSUVmax can also effectively predict PFS and OS of non-GCB DLBCL ( P  < 0.05), but not for GCB DLBCL ( P  > 0.05). Based on the optimal threshold found by ROC curve analysis, patients were dichotomized into ∆SUVmax high and low groups. Log-rank test and Cox regression demonstrated that the layered ∆SUVmax was predictive of PFS and OS in non-GCB DLBCL ( P  < 0.05). Conclusions I-PET may have different prognostic values for GCB and non-GCB DLBCL. Thus, the pathology type of DLBCL may be considered while using I-PET as a prognostic tool in the future.

IntroductionTreatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) shows poor response rates in non–germinal center B cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL) patients with multiple extranodal involvement. This study aims to evaluate anti-tumor activity and safety of zanubrutinib with R-CHOP (ZR-CHOP) in treatment naïve non-GCB DLBCL with extranodal involvement.MethodsIn this single-arm, phase 2, prospective, single-center study, patients with newly diagnosed non-GCB DLBCL with extranodal involvement enrolled between October 2020 to March 2022 received ZR-CHOP for 6 cycles followed by 2 cycles of maintenance treatment with rituximab and zanubrutinib. The primary endpoint included progression-free survival (PFS) in the intent-to-treat (ITT) population whereas the secondary endpoints included overall response rate (ORR), complete response (CR), and duration of response. Further, next-generation sequencing (NGS) was used for detection of different oncogenic mutations closely related to DLBCL pathogenesis.ResultsFrom October 2020 to March 2022, 26 patients were enrolled, and 23 of them were evaluated for efficacy after receiving 3 cycles of ZR-CHOP treatment. 1-year PFS and OS were 80.8% and 88.5% respectively while expected PFS and OS for 2-years are 74.0% and 88.5% respectively with median follow-up of 16.7 months and ORR was 91.3% (CR: 82.61%; PR: 8.70%). Oncogenic mutations closely related to DLBCL pathogenesis were assessed in 20 patients using NGS. B-cell receptor and NF-κB pathway gene mutations were detected in 10 patients, which occurred in MYD88 (7/19), CD79B (4/19), CARD11 (5/19), and TNFAIP3 (2/19). Hematological adverse events (AEs) ≥ grade 3 included neutropenia (50%), thrombocytopenia (23.1%), and anemia (7.7%) whereas non-hematological AEs ≥ grade 3 included pulmonary infection (19.2%).ConclusionZR-CHOP is safe and effective for treating treatment naïve non-GCB DLBCL patients with extranodal involvement.Clinical Trial RegistrationClinicaltrials.gov, NCT04835870

Background Patients with non–germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) often exhibit suboptimal responses to standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Methods This multicenter, phase II study evaluated the safety and efficacy of zanubrutinib, lenalidomide, and R-CHOP (ZR2-CHOP) in newly diagnosed non-GCB DLBCL. Patients received oral zanubrutinib (160 mg twice daily), lenalidomide (25 mg once daily on Days 1–7), and standard R-CHOP every 21 days for up to six cycles. Results A total of 34 patients were enrolled. The median age was 55 years, with 29.4% over 60 years. Double-expressor lymphoma (DEL) was present in 64.7%, and 39.3% were classified as the MCD genetic subtype. The best overall response rate was 100%. Complete response (CR) was achieved in 70.6% of patients at mid-treatment and 94.1% at end-of-treatment. With a median follow-up of 28 months, the 2-year progression-free survival (PFS) rate was 84.8%, and the 2-year overall survival (OS) rate was 96.8%. In this small cohort, PFS benefit appeared consistent across high-risk subgroups, including those with DEL and MCD subtypes. Plasma ctDNA negativity was achieved in 84% (21/25) of evaluable patients during treatment. Grade 3–4 adverse events occurred in 67.6% of patients, primarily hematologic toxicities. Conclusions ZR2-CHOP demonstrated promising efficacy and manageable toxicity in newly diagnosed non-GCB DLBCL. Trial registration ClinicalTrials.gov Identifier: NCT05200312 (registered January 20, 2022).

Background Primary cardiac lymphoma (PCL) is a rare malignancy, representing a small fraction of primary cardiac tumors. Non-germinal center B-cell (non-GCB) diffuse large B-cell lymphoma (DLBCL), a subtype of PCL, often presents with severe symptoms due to its cardiac involvement, and poses diagnostic and therapeutic challenges. This case highlights the use of an innovative surgical approach in managing a non-GCB primary cardiac DLBCL. Case presentation We report the case of a 68-year-old woman presenting with palpitations, dizziness, and obstructive cardiac symptoms. Diagnostic imaging revealed a large mass in the right atrium near the superior vena cava. A novel “zongzi”-shaped endoscopic gauze folding technique was employed to facilitate complete tumor resection while preserving cardiac structure. Pathology confirmed double expressor DLBCL with BCL2 and MYC co-expression, indicating a high-risk profile. The patient’s postoperative course was uneventful, and she was discharged in stable condition. However, follow-up imaging at six months revealed local disease progression. Conclusions This case underscores the challenges in managing primary cardiac DLBCL and highlights the potential of novel surgical techniques to improve resection outcomes while minimizing structural damage to the heart. Further research is essential to optimize multimodal approaches, particularly for aggressive PCL subtypes like double expressor lymphoma.

Objectives Standard treatment with a thiotepa-based regimen in countries with a limited resource is less feasible. Aims of the study were to evaluate the treatment outcome, and identify the prognostic factors in patients with primary central nervous system lymphoma (PCNSL). Methods We conducted a retrospective study of 43 patients diagnosed with PCNSL, DLBCL subtype, who were treated with either HDMTX-based regimen, whole brain radiotherapy (WBRT), or both between 2010 and 2017. Results There were 43 patients with a median age of 65 years (range 34–89 years). Protein expression of CD10, Bcl6, MUM1, Bcl2 and MYC were found in 19, 86, 91, 91 and 23%, respectively. Both germinal center B cell (GCB) and double-expressor (MYC+/Bcl2+) lymphomas were found in 21%. Multiple brain lesions and maximum tumor diameter (MTD) ≥5 cm were seen in 27 and 10 patients, respectively. Chemotherapy combined with WBRT, chemotherapy and WBRT were given to 20, 14 and 9 patients, respectively. Overall complete remission (CR) rate was 55.8%. Those receiving a combined-modality therapy had a higher CR rate than those treated with either chemotherapy (75% versus 36%, p =  0.036) or WBRT (75% versus 44%, p =  0.109). Median follow-up time was 17 months, and a 7-year overall survival (OS) was 40%. Features associated with a prolonged OS were an ECOG score ≤ 2 ( p  = 0.001), multiple brain lesions ( p  = 0.010), multiple area of brain involvement ( p  = 0.023), MTD < 5 cm ( p  = 0.004), GCB subtype ( p  = 0.003) and positive CD10 staining ( p  = 0.007). Expression of Bcl2 protein was associated with a significantly worse OS in the non-GCB DLBCL patients. Discussion The factors affecting treatment outcomes in PCNSL were cell of origin of DLBCL, lesion characteristics, patients’ status and treatment regimen.

This study investigated the epidemiological and clinical peculiarities of BCL2 and BCL6 rearrangement in patients with high grade B-cell lymphoma (HGBL) from Taiwan, compared with data from Western countries. Two hundred and eighty-two DLBCL cases from Taipei Medical University-affiliated hospitals (n = 179) and Tri-Service General Hospital (n = 103) were enrolled for this study. From the 282, 47 (16.7%) had MYC translocation; 24 of these harbored concurrent BCL2 and/or BCL6 translocation (double-hit, DH or triple-hit, TH). Twelve DH-HGBL cases had simultaneous MYC and BCL6 translocations, 8 harbored MYC and BCL2 rearrangement, while the remaining 4 patients exhibited TH. Together, 66.7% of DH/TH-HGBL patients were BCL6 rearrangement positive. Among these BCL6-rearranged DH/TH-HGBL patients, only 6 (37.5%) overexpressed MYC and BCL6 proteins simultaneously, indicating that MYC-BCL6 co-overexpression may not be plausible surrogate biomarker for screening BCL6-rearranged DH-HGBL. By the end of year 5, all patients with TH-HGBL, BCL2 DH-HGBL and all but one BCL6 DH-HGBL cases had expired or were lost to follow-up. Progression-free survival (PFS) was longer for the non-DH/TH-HGBL group compared with the DH/TH-HGBL group. While the patients with BCL2 DH-HGBL were lost to follow-up by day 800, their remaining TH-HGBL and BCL6 DH-HGBL peers exhibited very poor PFS, regardless of age strata. More so, patients with BCL6 rearrangement were 5.5-fold more likely associated with extranodal involvement compared with their BCL2-rearranged peers. Moreover, ~60.0% of the BCL6-rearranged DH-HGBL cases were non-GCB, suggesting that including screening for BCL6 rearrangement in patients with the non-GCB phenotype may aid medical decision-making and therapeutic strategy. Contrary to contemporary data from western countries, 2 in every 3 patients with DH/TH-HGBL in Taiwan harbor BCL6 rearrangement. Consistent with present findings, we recommend mandatory screening for BCL6 rearrangement in patients with aggressive HGBL in Taiwan.

Diffuse Large B-cell lymphoma (DLBCL) is an aggressive disease with heterogeneous outcome and marked variable response to chemotherapy. We assessed promoter hypermethylation (PM) for a panel of tumor suppressor genes in 75 DLBCLs compared to 20 lymphoid hyperplasia (LH) and 30 normal control, using methylation specific PCR. Results were correlated to patients’ clinic-pathological characteristics, immunophenotyping, and patients’ outcome. DAPK1, RUNX3, MT1G, MGMT, CDH1 and p16 PM were detected in 38.7% (29/75), 49.3% (37/75), 46.7% (35/75), 44% (33/75), 49.3% (37/75) and 42.7% (32/75);respectively, of DLBCL patients compared to LH group (P < 0.05). Aberrant PM of RUNX3, MGMT, CDH1 and p16 was significantly higher in non-germinal central B-cell like (non-GCB) compared to GCB (58.3% vs. 33.3%, 56.2% vs. 22.2, 62.5% vs. 25.9, and 56.2% vs. 18.5%, respectively). PM of studies genes in DLBCL associated significantly with worse survival outcome and resistance to chemotherapy (P ≤ 0.01). In non-GCB group, DAPK1, MT1G, RUNX3, CDH1 and p16 PM associated significantly with reduced DFS (P ≤ 0.004) and OS (P ≤ 0.015). Multivariate analysis indicated that RUNX3 and CDH1 PM were independent prognostic factors for OS (P = 0.03 and 0.04; respectively), while DAPK1, RUNX3 and MT1G PM were independent prognostic factors for DFS (P = 0.002, 0.037& 0.007; respectively). DAPK1, RUNX3, MT1G, CDH1 and p16 PM are promising prognostic and/or predictive markers for non-GCB independent of IPI. Upregulation of those genes using new demethylating agents is a promising approach that sensitize chemoresistant DLBCL patients, especially the non-GCB subtype.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognised variability in molecular aetiology and clinical outcome. Though the use of agents such as rituximab significantly improves outcome, intrinsic genetic and morphological factors greatly affect the response to treatment. The objective of this study was to evaluate the prognostic value of immunohistochemical subtyping and the International Prognostic Index (IPI) for predicting treatment outcome in Chinese DLBCL patients. We followed 108 cases of DLBCL and performed prognostic analyses based on molecular subtyping of the disease through immunostaining of tissue samples. The use of rituximab conferred a clinical benefit to DLBCL patients regardless of disease subtype. Importantly, this treatment regimen also improved outcomes in patients with the non-germinal centre B-cell-like (GCB) DLBCL subtype, frequently associated with poorer prognosis. Our results suggest that IPI was the best tool for the prediction of treatment outcome in our patient cohort, regardless of treatment regimen. Furthermore, the use of rituximab alongside classical chemotherapy regimens can improve the outcomes for DLBCL patients who exhibit both GCB and non-GCB subtypes of the disease.