Unique endoscopic features of primary biliary diffuse large B-cell lymphoma: A case report with literature review (with video).

A 67-year-old man visited our hospital complaining of dark-colored urine and upper abdominal pain. Magnetic resonance cholangiopancreatography showed stricture of the distal bile duct, and contrast-enhanced computed tomography showed irregular thickening of the distal bile duct wall. However, no enlarged lymph nodes, pancreatic tumors, or other neoplastic lesions were apparent around the bile duct. Endoscopic ultrasonography and intraductal ultrasonography showed irregular thickening of the inner hypoechoic layer without the disappearance of the innermost thin hyperechoic layer. On the basis of these findings, we considered that the bile duct lesion was of non-epithelial origin. Thus, we repeatedly performed bile duct biopsies from the same site under fluoroscopy to obtain a sample of the submucosal tissue. The pathological diagnosis was diffuse large B-cell lymphoma, and the patient received systemic chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). After six courses of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, positron emission tomography-computed tomography showed the disappearance of 18-fluorodeoxyglucose uptake in the bile duct and endoscopic retrograde cholangiography showed improvement of the bile duct stricture. Endoscopic findings and repeated biopsies were useful in making the diagnosis of primary biliary diffuse large B-cell lymphoma.

Vertical targeting of the PI3K/AKT pathway at multiple points is synergistic and effective for non-Hodgkin lymphoma.

The phosphatidylinositol 3­kinase/protein kinase B (PI3K/AKT) signaling pathway is critically active in many cell types, both normal and neoplastic. Many small-molecule inhibitors targeting different levels of the PI3K/AKT pathway have been developed for cancer therapy, but their efficacy is reduced by compensatory pathway re-activation mechanisms, and their tolerability by toxic side effects. We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT). Half-maximal (IC50) concentrations of these inhibitors for AKT activity inhibition at 1 h, when used individually, were much lower than their IC50 values for reduction of viable cell number after 4 days. Time-course studies explained this discrepancy: AKT activity in the continuous presence of the inhibitors returned to normal after 24 h, and was supranormal after inhibitor removal. Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin. Moreover, combined PDPK1 and AKT inhibition showed synergy with multiple different PI3K inhibitors. In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers.

Real-world efficacy of chidamide plus R-CHOP in newly diagnosed double-expressor diffuse large B-cell lymphoma.

Background: Approximately 20%-30% of diffuse large B-cell lymphoma (DLBCL) cases are classified as double-expressor lymphoma (DEL), characterized by the co-expression of the MYC and BCL2 proteins. However, the most effective therapeutic strategy for DEL remains unidentified. Objectives: To evaluate the efficacy of a novel histone deacetylase inhibitor, chidamide, in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (CR-CHOP) in the treatment of DEL. Design: This was a retrospective study. Methods: This study included 62 DEL patients from December 2016 to December 2020. All patients were administered a first-line treatment with CR-CHOP. The short-term efficacy, survival status, and adverse reactions in this population were observed, and the prognostic factors were analyzed. Results: The median age was 53.9 years (range, 19-77). All patients received a median of six cycles (range, 1-8) of treatment, with 79.0% achieving complete response (CR) and an overall response rate of 88.7%. With a median follow-up of 45.5 months (range, 1-82), the median progression-free survival (PFS) and median overall survival (OS) had not yet been reached. However, the 3-year PFS rate was 71% (95% CI: 61-83), the 3-year OS rate was 87% (95% CI: 79-96), the 5-year PFS rate was 67% (95% CI: 55-80), and the 5-year OS rate was 85% (95% CI: 77-95). Age and autologous stem cell transplantation after CR or partial response were independent prognostic factors for PFS, while various clinical factors were not associated with OS outcomes. The most common grades 3-4 hematologic and nonhematologic toxicity were leukopenia (46.7%) and infection (21%), respectively. Conclusion: This long-term follow-up study indicates that CR-CHOP in untreated DLBCL with the DEL phenotype demonstrates high short-term efficacy and safety as well as promising survival outcomes.

Co-occurrence of Primary Tracheal Diffuse Large B-Cell Lymphoma and Pulmonary AA Amyloidosis: A Unique Case Report.

Primary tracheal diffuse large B-cell lymphoma (DLBCL) is a rare, aggressive, but potentially curable malignancy that is difficult to diagnose and treat. We herein report a 93-year-old Japanese man diagnosed with primary tracheal DLBCL after presenting with progressive dyspnea due to severe upper tracheal stenosis during follow-up for pulmonary amyloidosis. Following the diagnosis, the patient was treated with corticosteroids, followed by R-CHOP chemotherapy, resulting in a therapeutic response. The patient's history of pulmonary amyloidosis may have contributed to the development of tracheal DLBCL. An evaluation of the risks and benefits of various therapeutic interventions is crucial for providing optimal patient-specific care.

Flow cytometry identifies changes in peripheral and intrathecal lymphocyte patterns in CNS autoimmune disorders and primary CNS malignancies.

BACKGROUND: Immune dysregulation is a hallmark of autoimmune diseases of the central nervous system (CNS), characterized by an excessive immune response, and primary CNS tumors (pCNS-tumors) showing a highly immunosuppressive parenchymal microenvironment. METHODS: Aiming to provide novel insights into the pathogenesis of CNS autoimmunity and cerebral tumor immunity, we analyzed the peripheral blood (PB) and cerebrospinal fluid (CSF) of 81 autoimmune limbic encephalitis (ALE), 148 relapsing-remitting multiple sclerosis (RRMS), 33 IDH-wildtype glioma, 9 primary diffuse large B cell lymphoma of the CNS (CNS-DLBCL), and 110 controls by flow cytometry (FC). Additionally, an in-depth immunophenotyping of the PB from an independent cohort of 20 RRMS and 18 IDH-wildtype glioblastoma patients compared to 19 controls was performed by FC combined with unsupervised computational approaches. RESULTS: We identified alterations in peripheral and intrathecal adaptive immunity, mainly affecting the T cell (Tc) but also the B cell (Bc) compartment in ALE, RRMS, and pCNS-tumors compared to controls. ALE, RRMS, and pCNS-tumors featured higher expression of the T cell activation marker HLA-DR, which was even more pronounced in pCNS-tumors than in ALE or RRMS. Glioblastoma patients showed signs of T cell exhaustion that were not visible in RRMS patients. In-depth characterization of the PB revealed differences mainly in the T effector and memory compartment between RRMS and glioblastoma patients and similar alterations in the Bc compartment, including atypical Bc, CD19+CD20- double negative Bc, and plasma cells. PB and CSF mFC together with CSF routine parameters could reliably differentiate ALE and RRMS from pCNS-tumors facilitating early diagnosis and treatment. CONCLUSIONS: ALE, RRMS, and pCNS-tumors show distinct but partially overlapping changes mainly in HLA-DR+ Tc, memory Tc, exhausted Tc, and Bc subsets providing insights into disease pathogenesis. Moreover, mFC shows diagnostic potential facilitating early diagnosis and treatment.

Rituximab induces ferroptosis and RSL3 overcomes rituximab resistance in diffuse large B-cell lymphoma cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common malignant lymphoma in adults, and the use of rituximab has greatly improved the survival of DLBCL patients. Currently, the first-line treatment regimen for DLBCL is still rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), which significantly improves outcomes for DLBCL patients. However, a percentage of patients still experience refractory or relapsed disease. Since Dr. Brent R Stockwell proposed ferroptosis in 2012, Roudkenar, M. H. Roushandeh, A. M. Valashedi, M. R. and others proved the importance of ferroptosis in cancer drug resistance. The purpose of this study was to elucidate whether rituximab could exert anticancer effects on DLBCL cells by promoting ferroptosis. Cell viability was assessed using the Cell Counting Kit-8. The results showed that rituximab exposure induced ferroptosis in OCI-LY1 cells. However, combination with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, indicating that ferroptosis plays a key role in rituximab-induced cell death. Western blotting was performed to detect the levels of specific ferroptosis-associated proteins in DLBCL. Moreover, GSH depletion and MDA upregulation was assessed using GSH assays and MDA assay kits in rituximab-treated OCI-LY1 cells. In addition, rituximab failed to induce ferroptosis in rituximab-resistant cell lines. Treatment with RSL3 enhanced the effects of rituximab on DLBCL cells by inhibiting cell viability. In conclusion, we report for the first time that rituximab induces ferroptosis in lymphoma cells, at least partially through the SLC7A11/GPX4 axis. We also identify targeting ferroptosis as a promising therapeutic option for both sensitive cells and resistant cells in the treatment of DLBCL.

The prognostic significance of MYC/BCL2 double expression in DLBCL in the genetic classification era.

Double expression (DE) is a World Health Organization-recognized adverse prognostic factor in diffuse large B-cell lymphoma (DLBCL). However, the prognostic value of DE in the genetic subtyping era and potential mechanisms remain to be explored. We enrolled 246 DLBCL patients diagnosed between December 2021 and September 2023 in a Jiangsu Province Hospital cohort and included 930 DLBCL patients from three published studies in an external cohort. Double-expression DLBCL (DEL) in the external cohort was mainly distributed in the OTHER subtype (42.0%), EZB subtype (28.3%), and MCD subtype (15.0%), whereas the MCD subtype exhibited the highest ratio of DEL. DEL was significantly related to unfavorable overall survival (OS) and progression-free survival (PFS) in DLBCL, but only in EZB and OTHER subtypes that DEL retained remarkably adverse impacts on survivals compared to non-DEL. We explored the prognostic value of clinical and genetic parameters in DEL patients and found only ST2 showed better OS than A53 in DEL patients, whereas the other subtypes showed no significant difference. DEL showed similarities with the MCD subtype in mutation profiles. Furthermore, RNA-sequencing analyses exhibited upregulation in tumor proliferation-related pathways in DEL patients, but downregulation in extracellular matrix organization, T-cell activation and proliferation, type II interferon production, and pathways associated with cell death might contribute to the poor outcomes of DEL patients.

A rare case of splenic marginal zone lymphoma with MYD88 mutation transformed into diffuse large B-cell lymphoma: case report and literature review.

In indolent lymphomas, histological transformation (HT) often results in a poor prognosis and presents a significant challenge in the management of these lymphomas. Previous studies have indicated that MYD88 mutations are associated with transformation in certain haematologic malignancies. We report a rare case of splenic marginal zone lymphoma (SMZL) harbouring an MYD88 mutation, which was transformed into diffuse large B-cell lymphoma (DLBCL) and accompanied by newly emerging genetic abnormalities. The role of the MYD88 gene in SMZL is currently unclear. Through this case, we reviewed relevant studies, which indicated that MYD88 mutations, along with other genetic anomalies, may play a significant role in this process. In the future, it is essential to collect more of these rare cases for further research.

Identification of ferroptosis-related genes associated with diffuse large B-cell lymphoma via bioinformatics and machine learning approaches.

Ferroptosis has emerged as a critical mechanism in the development and progression of various tumors, particularly diffuse large B-cell lymphoma (DLBCL). However, the thorough characterization of ferroptosis-related genes in DLBCL remains inadequately explored. We retrieved datasets associated with DLBCL and ferroptosis gene sets from the Gene Expression Omnibus (GEO) database and the Ferroptosis Database (FerrDb), resulting in the identification of 27 differentially expressed ferroptosis-related genes (DE-FRGs) linked to DLBCL. Utilizing the LASSO and Support Vector Machine Recursive Feature Elimination (SVW-RFE) algorithms, we identified 10 genes-MT1G, MTOR, BRD4, ACO1, SAT1, PEBP1, LPIN1, ATM, SRXN1, and PRDX1-as key biomarker candidates with significant diagnostic potential. Functional enrichment analyses revealed that these biomarker genes are likely involved in regulating several critical biological pathways implicated in DLBCL pathogenesis, including immune response, oxidative phosphorylation, and cell cycle regulation. Moreover, we identified 246 potential therapeutic agents targeting these 10 biomarker genes. Concurrently, competitive endogenous RNA (ceRNA) network analysis uncovered a complex regulatory network centered on the identified biomarker genes. Additionally, CIBERSORT analysis highlighted notable alterations in the immune microenvironment of DLBCL patients. We propose a diagnostic strategy that provides novel insights into the molecular mechanisms underlying DLBCL. Nevertheless, further validation of the practical value of this strategy for DLBCL diagnosis is necessary before its clinical application.

Identification of miR-451 target genes as prognostic markers in diffuse large B-cell lymphoma.

BACKGROUND: B-cell lymphoma, a diverse malignancy, is intricately regulated by multiple factors. MicroRNAs (miRNAs) have been demonstrated to be important regulators of the initiation and progression of human B-cell lymphoma, but their functions need to be further explored. RESEARCH DESIGN AND METHODS: Two B-cell lymphoma cell lines, Romas and HBL-1, were engineered to overexpress miR-451, with cell proliferation assessed via cell counting assays. Flow cytometry was used to study the effects of miR-451 on cell cycle and apoptosis. Bioinformatics analyses were performed using GEO datasets (GSE181063, GSE32918, GSE56315) to identify DEGs, and potential miR-451 target genes were predicted using tools like ENCORI, TargetScan, and R packages. A risk model for DLBCL prognosis was developed using Cox and LASSO regression. qRT-PCR validated the expression of these target genes. RESULTS: This study revealed that miR-451 inhibited cell proliferation, arrested the cell cycle, and induced apoptosis in human DLBCL cell lines. Bioinformatics analysis identified 9 target genes (MMP9, AQP9, RIN2, EOMES, LCP2, SELPLG, MAL, SOCS5, S1PR3) significantly associated with DLBCL prognosis, suggesting a potential mechanism by which miR-451 suppresses DLBCL development. CONCLUSIONS: Our study indicates that a specific set of miR-451 target genes may significantly influence DLBCL patient outcomes.

Baseline and interim 18F-FDG PET/CT metabolic parameters predict the efficacy and survival in patients with diffuse large B-cell lymphoma.

Introduction: The prognostic value of 18F-FDG PET/CT metabolic parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), in diffuse large B-cell lymphoma (DLBCL) remains inadequately explored. This study aims to assess the correlation between these parameters and patient outcomes. Methods: A cohort of 156 DLBCL patients underwent 18F-FDG PET/CT imaging at baseline and after 3-4 cycles of R-CHOP or CHOP-like regimen. The third quartiles of liver uptake values were used as thresholds for calculating MTV and TLG. Patient outcomes were analyzed based on Ann Arbor staging and the 5-PS score. A nomogram was developed to predict overall survival (OS). Results: Patients with low baseline TLG exhibited significantly better outcomes compared to those with high baseline TLG in both Ann Arbor stages I-II and III-IV (1-year PFS: 78.9% vs. 40%, p=0.016; OS: 94.7% vs. 40%, p=0.005 for stage I-II; 1-year PFS: 74.1% vs. 46.8%, p=0.014; OS: 85.4% vs. 71.8%, p=0.007 for stage III-IV). In interim PET/CT patients with a 5-PS score >3, the high ΔTLG group had superior prognosis (1-year PFS: 82.3% vs. 35.7%, p=0.003; OS: 88.2% vs. 85.7%, p=0.003). The nomogram achieved a C-index of 0.9 for OS prediction. Discussion: The findings suggest that baseline TLG is a robust prognostic indicator for patients with DLBCL, particularly in early stages, while ΔTLG effectively distinguishes those with favorable outcomes in higher-risk groups. These metabolic parameters from 18F-FDG PET/CT could enhance treatment decision-making and patient management strategies.

Survival outcomes of patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation in Germany: real-world evidence from an administrative database between 2010 and 2019.

Background: Limited real-world evidence is available for patients with diffuse large B-cell lymphoma (DLBCL) who received an autologous stem cell transplantation (ASCT) in Germany. Objectives: This study aims to describe the real-world survival outcomes of patients with DLBCL who received ASCT in Germany after diagnosis. Design: This study is a retrospective database analysis covering the period between 2010 and 2019. Methods: Unadjusted overall survival (OS) was plotted using the Kaplan-Meier estimator for the overall population and stratified by relapse status. A Cox regression was run to identify factors that influence OS. Results: A total of 112 patients received an ASCT, with the average time from first-line treatment to ASCT being 11.7 months. The median OS estimated by Kaplan-Meier was 83.4 months for the entire cohort. The only variable that significantly reduced the OS was the presence of subsequent treatment after ASCT in a time-dependent model. Conclusion: OS after ASCT for DLBCL patients in Germany is higher than previously reported and may still be considered a valid option for carefully selected patients with relapsed/refractory DLBCL.

Non-linear relationship between soluble interleukin-2 receptor and prognosis of diffuse large B-cell lymphoma.

Despite an emphasis on the prognostic impact of serum soluble interleukin-2 receptor (sIL-2R) at diagnosis in patients with diffuse large B-cell lymphoma (DLBCL), whether the prognostic impact of elevated sIL-2R is linear remains unclear. To verify the presence of a non-linear association between sIL-2R level at diagnosis and overall survival (OS) in patients with newly diagnosed DLBCL, we conducted a multi-center, observational retrospective study. Among 488 analyzable patients, Cox proportional hazards modeling identified serum sIL-2R level at diagnosis as an independent predictor of OS. Multivariate Cox hazard modeling with restricted cubic spline model demonstrated that the relationship between serum sIL-2R level and OS was clearly non-linear (P for effect of sIL-2R = 0.002; P for non-linearity = 0.015). Mortality risk increased gradually as sIL-2R levels increased and plateaued at approximately 5,000 U/mL. Segmented regression analysis revealed that the trend in negative prognostic impact from a gradual increase in serum sIL-2R level changed significantly, with a breakpoint at approximately 2,000 U/mL. Multivariate receiver operating characteristic curves showed a significant improvement in prediction ability when serum sIL-2R level was added to the International Prognostic Index (IPI). Serum sIL-2R level at diagnosis was not only a prognostic factor, but also improved predictive accuracy for OS when incorporated with the IPI. However, the negative correlation between increasing sIL-2R and prognosis was non-linear.

Serum concentrations of per- and polyfluorinated substances and risk of B-cell non-Hodgkin lymphoma.

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that are detectable in the serum of most U.S. adults. Some studies of highly-exposed individuals have suggested positive associations between PFAS and B-cell non-Hodgkin lymphoma (B-NHL). To investigate whether associations exist at lower exposure levels, we conducted a nested case-control study investigating serum PFAS concentrations and B-NHL within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We measured pre-diagnostic serum concentrations of five PFAS among 706 cases (age at diagnosis = 55-93 years, median 73 years) and 706 controls individually matched on age at blood draw, sex, self-reported race and ethnicity, study center, and year of blood collection (the median follow-up years = 10). We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) for PFAS concentrations in relation to B-NHL, both overall and for selected histologic subtypes [diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL)] using conditional logistic regression. We found no evidence of a positive association with B-NHL for any of the five PFAS. In analyses of histologic subtypes, perfluorohexane sulfonate (PFHxS) was significantly associated with DLBCL in a model adjusting for all other PFAS (OR for highest vs. lowest quintile = 2.19, 95 % CI = 1.21, 3.95; Ptrend = 0.02), but not in a model without mutual adjustment (OR = 1.37, 95 % CI = 0.82, 2.29; Ptrend = 0.26). We also observed an inverse association between perfluorononanoate and DLBCL (mutually-adjusted OR = 0.83, 95 % CI = 0.69, 0.99 per doubling in concentration), although the association was null among participants with blood drawn prior to 1997 (OR<1997 = 1.00, 95 % CI = 0.82, 1.21; OR≥1997 = 0.65, 95 % CI = 0.53, 0.79; Pinteraction = 0.0003). In conclusion, our findings from a prospective cohort study with PFAS serum concentrations comparable to that of the general population do not support an association with increased risk of B-NHL overall. The suggestive evidence of a positive association between PFHxS and DLBCL warrants further investigation.

Exploring Differentially Expressed Genes and Immune Modulation in Diffuse Large B-Cell Lymphoma through RNA Sequencing Analysis.

Background: Diffuse large B-cell lymphoma (DLBCL) is globally recognized as the most prevalent and aggressive subtype of non-Hodgkin lymphoma. While conventional treatments are effective initially, the disease can become resistant or relapse over time. This study aimed to examine the differentially expressed genes at the transcriptome level and molecular pathways in DLBCL patients. Methods: This investigation utilized RNA sequencing analysis to compare differentially expressed gene samples from five diffuse large B-cell lymphoma patients with two healthy volunteers. These participants were admitted to UKM Medical Center, Kuala Lumpur between 2019 and 2020. The differentially expressed genes were identified using the DESeq2 R package (version 1.10.1) using a negative binomial distribution model. The obtained P values were corrected with the Benjamin and Hochberg method and identified using a False Discovery Rate threshold of <0.05, with log2 fold change (FC) of ≥2 or ≤-2. Results: Results showed 73 differentially expressed genes between the two groups, among which 70 genes were downregulated, and three genes were upregulated. The differentially expressed genes analyzed with the Reactome pathway were significantly associated with the downregulation of antimicrobial humoral response (P<0.001), neutrophil degranulation (P<0.001), chemokine receptors bind chemokines (P=0.028), defensins (P=0.028) and metabolism of angiotensinogen (P=0.040). Conclusion: These findings suggest that the identified pathways may contribute to cancer progression and weaken the immune response in diffuse large B-cell lymphoma patients. This study offers fresh insights into previously undiscovered downstream targets and pathways modulated by diffuse large B-cell lymphoma.

Diffuse Large B Cell Lymphoma: Immunohistochemical Classification According to Hans Algorithm and Association With Outcome in A Moroccan Institution.

Background: The most prevalent subtype of non-Hodgkin lymphoma is diffuse large B-cell lymphoma (DLBCL). Germinal center B-cell (GCB) and non-germinal center B-cell (non GCB) are the two main biologically different molecular subtypes identified utilizing an immunohistochemistry-based approach. Aim: Our objective in this study is to analyze the impact of immunohistochemical subtypes of DLBCL (GCB or non GCB) on demographic and clinicopathological parameters, response to chemotherapy and survival outcomes. Subjects and methods: This is a retrospective study including 106 cases of DLBCL collected in the department of pathology, Hassan II university hospital, Fez (Morocco), over a period of 12 years (January 2010-September 2022). The subtypes of DLBCLs were defined according to Hans algorithm, using immunohistochemistry by three biomarkers (CD10, BCL6, MUM1). Statistical analysis used: Independent t tests and analyses of variance were used for the comparison of mean values. We employed the SPSS 26.0 program to achieve this. A statistically significant value was set at P < .05. Results: Seventy-five patients (71%) were non-GCB subtype, while thirty-one patients (29%) had the GCB immunosubtype. We have found a significant (P < .05) correlations between DLBCL immunosubtypes and treatment responses on one hand and survival in the other hand. In the GCB subtype, the response rate and survival were significantly improved. A significant association was found between Ki 67 expression and survival on univariate analysis. On multivariate analysis, we note a correlation between Ki 67 expression, DLBCL immunohistochemical subtypes and survival outcome. Conclusion: Non GCB subtype is associated with poor response to treatment and inferior survival outcome compared to GCB subtype in Moroccan context, especially when combined with high expression of Ki 67 marker.

A Biphasic Presentation of Diffuse Large B-cell Lymphoma Metastasis to the Hypothalamus-pituitary Axis: A Case Report and Literature Review.

The Hypothalamus-Pituitary axis (HPA) is a rare location for metastasis of non-Hodgkin's lymphoma. Lymphomas constitute less than 0.5% of reported HPA metastasis. This case is unique in that, in addition to the noted panhypopituitarism; initial diagnostics demonstrated marked hyponatremia, consistent with syndrome of inappropriate antidiuretic hormone (SIADH), which was subsequently complicated by sudden diabetes insipidus (DI), suggesting hypothalamic/stalk infiltration. Despite low sensitivity, CSF cytology/flow cytometry may serve as a less invasive diagnostic measure. Treatment includes systemic chemotherapy with agents that cross the blood-brain barrier. Surgical resection alone or associated radiotherapy did not show an increase in survival. The prognosis remains poor.

Sphingosine kinase 1 counteracts chemosensitivity and immune evasion in diffuse large B cell lymphoma cells via the PI3K/AKT/PD-L1 axis.

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive neoplasm of lymphatic system that represent 38-58 % of non-Hodgkin lymphoma. Chemoresistance and immune escape constitute the major obstacles to the treatment of patients. Sphingosine kinase 1 (SphK1) is involved in multiple processes of cancer. Up to now, little research focuses on its function in DLBCL. In the current research, GEPIA and human Protein Atlas databases confirmed high expression of SphK1 in DLBCL tissues. Analogously, increased expression of SphK1 were determined in DLBCL tissues and cells. Intriguingly, knockdown of SphK1 suppressed DLBCL cell viability and increased chemosensitivity to doxorubicin by decreasing cell viability and increasing caspase-3 activity. Reversely, SphK1 elevation facilitated cancer cell resistance to doxorubicin. Furthermore, loss of SphK1 increased the productions of inflammatory cytokine IFN-γ and TNF-α, but reduced IL-10 levels in co-culture model of CD8 + T cells and DLBCL cells. Importantly, SphK1 knockdown enhanced T cell cytotoxicity to DLBCL cells, while its elevation restrained the ability of T cells to kill cancer cells. Concomitantly, targeting SphK1 enhanced the percentage of CD8 + T cells and attenuated co-culture-evoked CD8 + T cell apoptosis, indicating the important roles in T cell escape. Mechanically, SphK1 overexpression enhanced and its knockdown suppressed activation of the PI3K/AKT/PD-L1 pathway. After blockage of this pathway by its antagonist, the beneficial effects of SpHK1 on chemoresistance and immune escape were abrogated. In vivo, targeting SphK1 inhibited tumor growth and enhanced the anti-tumor efficacy of doxorubicin in DLBCL xenograft tumor, concomitant with the inhibition of the PI3K/AKT/PD-L1 signaling. Collectively, SphK1 knockdown counteracted chemoresistance and immune escape from T cell killing by inhibiting the PI3K/AKT/PD-L1 pathway. Therefore, targeting SphK1 may represent a promising therapeutic strategy for overcoming chemoresistance and immune escape in DLBCL.

Single center, real-world retrospective study of CAR-T cell therapy for relapsed/refractory large B-cell lymphoma beyond second line: five-year results at the University Hospitals Leuven.

INTRODUCTION: Large B-cell lymphomas (LBCL) are the most frequently aggressive B-cell non-Hodgkin lymphomas. Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has emerged as a new, powerful treatment for relapsed or refractory (R/R) disease. Two CAR-T cell products, tisagenlecleucel (tisa-cel,) and axicabtagene ciloleucel (axi-cel), are reimbursed in Belgium for R/R LBCL beyond second line. OBJECTIVES AND METHODS: We conducted a retrospective cohort study to report the outcome with tisa-cel and axi-cel for R/R LBCL beyond second line in the years 2019-2023 at the University Hospitals Leuven for 79 patients selected for apheresis and CAR-T infusion. RESULTS: Eleven patients (14%) did not proceed to CAR-T cell infusion. For infused patients (n = 68), the best overall response rate (ORR)/complete response (CR) rate was 64%/49% for tisa-cel and 88%/66% for axi-cel (p = 0.04 for ORR). After a median follow-up of 13.8 months, progression-free survival (PFS) and overall survival (OS) at 1 year were 30% and 43% for tisa-cel and 48% and 62% for axi-cel. Cytokine release syndrome (CRS) (all grades/grade ≥3) occurred in 82%/9% after tisa-cel and in 97%/0% after axi-cel. Immune effector cell-associated neurotoxicity syndrome (ICANS) (all grades/grade ≥3) occurred in 24%/18% after tisa-cel and in 54%/40% after axi-cel. The non-relapse mortality in the infusion cohort was 13%. CONCLUSION: Our real-world data show high and durable response rates, with a non-significant trend towards a higher efficacy and higher toxicity for axi-cel compared to tisa-cel. Our results are in line with other real-world registries except for a shorter median OS and more high-grade ICANS.

[Recent advances in the treatment of DLBCL].

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of all malignant lymphomas, making it the most common subtype. Molecular genetic studies have elucidated the pathogenesis of DLBCL and the causes of its poor prognosis. This basic research has led to the development of novel molecularly targeted therapies that target molecules and cellular antigens in relevant signaling pathways or epigenetic enzymes. Treatment with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone has become the standard of care for newly diagnosed CD20-positive DLBCL with an International Prognostic Index score of 2 to 5, based on its reported efficacy for this indication. In addition, the development of immunotherapy such as anti-CD19-chimeric antigen receptor (CAR)-T therapy and bispecific antibodies such as epcoritamab, mosunetuzumab, and glofitamab has led to a paradigm shift in treatment of relapsed/refractory DLBCL. This review summarizes the evolution of treatment development for DLBCL, as well as the results of the current clinical standard of care and new therapies that are expected to become the standard of care.