Blood and Lymphatic Cancer-Targets and Therapy最新文献

Background: The heterogeneity in the health burden and non-infectious risk factors of Burkitt lymphoma (BL) across sex, age, and geographic distribution remain inadequately understood.

Methods: Based on Global Burden of Disease study 2021, we estimate the health burden of BL from four metrics: incidence, mortality, prevalence, and disability-adjusted life years. Subgroups were stratified by age, sex, region, and socio-demographic index (SDI). Joinpoint regression was used to evaluate the average annual percentage change (AAPC) to quantify trends in the health burden. Predictions were performed using the Bayesian age-period-cohort model. Non-infectious risk factors were identified and analyzed utilizing summary exposure values (SEVs) to assess their impact on BL incidence and mortality.

Results: The estimated global incident number of BL was 19,073 (95% CI: 9651 to 32,509) in 2021, nearly threefold that of 1990. The health burden of BL was markedly higher in males than females, especially among individuals aged under 20 years. From 1990 to 2021, the most significant increasing trend in BL health burden was observed in Cabo Verde, while Georgia exhibited the most notable decline. From 2021 to 2040, the global age-standardized incidence and mortality rates were projected to decline by 14.7% and 24.7%, respectively. Conversely, the health burden on individuals aged 20 to 54 years was anticipated to rise through 2040. In our study, low bone mineral density was found to be linked with elevated risk for males aged over 54 years, while childhood sexual abuse exhibited a paramount positive association with BL risk for females, regardless of age. Notably, tobacco use, particularly secondhand smoking, were inversely associated with BL risk across all age groups and sexes.

Conclusion: Burkitt lymphoma demonstrated unique distribution patterns in terms of age, sex, and region. Further investigations into the heterogeneity of the risk factors for BL are essential for the development of more effective health policies and clinical practices.

Background: BNIP3L regulates mitophagy and apoptosis, and its dysregulation is closely linked to the development and progression of cancers. Studies have shown that BNIP3L is valuable for assessing tumor progression and prognosis. This study aims to investigate the diagnostic and prognostic significance of serum BNIP3L levels in multiple myeloma (MM).

Methods: The serum level of BNIP3L were measured in 152 MM patients and 158 healthy controls by Enzyme-Linked Immunosorbent Assay (ELISA). Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic ability of MM. The prognostic relevance of serum BNIP3L levels in MM patients was assessed using Kaplan-Meier survival analysis and Cox regression.

Results: Serum BNIP3L levels were significantly elevated in MM patients compared to healthy controls (P < 0.001) and demonstrated significant diagnostic value (Area Under the Curve (AUC) = 0.744). Higher BNIP3L levels correlated negatively with serum calcium (P = 0.02) and M protein (P = 0.03). MM patients with extramedullary infiltration (EMI) or high-risk cytogenetic abnormalities had higher serum BNIP3L levels compared to those without these features (all P < 0.05). BNIP3L levels were significantly higher in non-transplant patients compared to autologous stem cell transplant (ASCT) patients (P = 0.01). And patients achieving Very Good Partial Response (VGPR) efficacy had significantly lower serum BNIP3L levels than those who achieving only Partial Response (PR) (P = 0.04). Compared to patients with low serum BNIP3L levels, those with high levels exhibited a trend toward poorer overall survival (Hazard Ratio (HR) = 1.40, 95%Confidence Interval (CI): 0.47-4.19).

Conclusion: This study identified serum BNIP3L as a potential diagnostic biomarker for active MM. Elevated BNIP3L levels were significantly associated with adverse clinical characteristics, suboptimal treatment response, and a trend toward inferior survival. Consequently, measuring serum BNIP3L could be valuable for monitoring disease progression and prognostic evaluation in MM patients.

Background: Acute myeloid leukemia (AML) remains clinically challenging due to its molecular heterogeneity and poor outcomes, highlighting the urgent need for novel biomarkers and therapeutic targets.

Purpose: This study aims to identify and characterize the role of leucine-rich α-2-glycoprotein 1 (LRG1) in AML, evaluating its potential as both a prognostic biomarker and a therapeutic target.

Methods: We conducted an integrated basic and clinical investigation of LRG1 in AML. Methods included analysis of LRG1 expression in patient samples versus controls and pre- versus post-treatment, assessment of its clinical correlations with mutations and subtypes, and evaluation of its prognostic impact. Functional validation was performed using LRG1 knockdown models to assess effects on colony formation, apoptosis, and differentiation. Single-cell RNA profiling was utilized to identify LRG1-enriched cell populations and explore its role in microenvironmental crosstalk.

Results: Integrated analysis revealed significantly elevated LRG1 expression in AML patients compared to controls (P<0.001), with levels decreasing post-treatment (P<0.001). High LRG1 expression correlated with FLT3 mutations (P<0.01), M3-M5 AML subtypes (M0&M1&M2 VS M3, P<0.001; M0&M1&M2 VS M4, P<0.01; M0&M1&M2 VS M5, P<0.001; M3 VS M5, P<0.05; M4 VS M5, P<0.05), and worse survival (P<0.01). Functionally, LRG1 knockdown impaired colony formation (P<0.001), increased apoptosis (P<0.001), and disrupted differentiation (P<0.01). Single-cell profiling identified LRG1 enrichment in hematopoietic stem and progenitor cells (HSPCs) and myeloid progenitors, where it facilitated microenvironmental crosstalk via Macrophage Migration Inhibitory Factor (MIF), Galactoside-binding lectin (GALECTIN), and Cyclophilin A (CypA) signals.

Conclusion: Our findings establish LRG1 as a robust prognostic biomarker and a key functional regulator of AML maintenance through myeloid progenitor dysregulation, presenting it as a promising target for new therapeutic strategies.

Background: Dual-expression lymphoma (DEL) is an aggressive subtype with concurrent MYC and BCL2 overexpression. This disease exhibits a poor prognosis and responds poorly to standard R-CHOP therapy,highlighting the urgent need for novel treatments. Alantolactone (ALA), a natural compound, has shown anticancer potential, but its efficacy and mechanism in DEL remain unclear. This study aimed to investigate the anti-tumor effects of ALA against DEL and its underlying dual-targeting mechanism.

Methods: The cytotoxic activity of ALA was assessed in lymphoma cell lines and a normal lymphocyte line. Apoptosis was evaluated by flow cytometry and Western blotting. Network pharmacology, molecular docking, dynamics simulations, and cellular thermal shift assays (CETSA) were utilized to identify and validate direct targets of ALA. The anti-tumor efficacy of ALA was further examined in a DEL xenograft mouse model using PET-CT imaging and survival analysis.

Results: In the present study, the anticancer activity of ALA in DEL was explored in vivo and in vitro. ALA was shown to inhibit DEL growth in vivo with little toxicity to normal tissues. Mechanistically, ALA stabilized active glycogen synthase kinase 3β (GSK3β) (binding affinity: -15.66 kcal/mol; ΔTm +9°C), enhancing β-catenin degradation and suppressing Wnt-driven oncogenesis. Simultaneously, ALA directly bound BCL2 (-22.22 kcal/mol), triggering both intrinsic and extrinsic apoptotic pathways. Simultaneously, ALA directly bound BCL2 (binding affinity: -22.22 kcal/mol), triggering both intrinsic and extrinsic apoptotic pathways. ALA exhibited robust anti-DEL activity across preclinical models. While in vivo it significantly suppressed tumor progression (SUVmax reduction >50%, p<0.01) and extended survival (median 50 vs 80 days, p<0.01) in DEL xenografts. The therapeutic relevance was underscored by clinical correlation showing DEL patients with high GSK3β expression had superior survival outcomes.

Conclusion: ALA exerts potent anti-DEL activity by simultaneously targeting GSK3β in the Wnt pathway and directly inhibiting BCL2, leading to suppressed tumor proliferation and induced apoptosis. Our findings highlight ALA as a promising multi-targeting therapeutic candidate for DEL and propose a novel strategy against this refractory lymphoma.

Purpose: Primary central nervous system lymphoma (PCNSL) is a rare, yet highly aggressive non-Hodgkin lymphoma confined to the central nervous system (CNS). High-dose methotrexate (HD-MTX) remains the baseline chemotherapy for newly-diagnosed PCNSL. Intensive chemotherapies combined with HD-MTX have improved patient outcomes. However, the substantial toxicities limited their applicability, especially among elderly patients with poor physical status. Optimal composition of induction and consolidation treatment are still warranted.

Patients and methods: In this prospective single-arm phase II trial (ChiCTR2200061485), we evaluated the efficacy and safety of HD-MTX combined with rituximab and orelabrutinib, a second-generation BTK inhibitor with high CNS penetration, as induction therapy in newly diagnosed PCNSL. Twenty-two patients received up to six cycles of the combined induction therapy. Patients who achieved remission proceeded to non-randomized consolidation therapies with ASCT (autologous hematopoietic stem cell transplantation), WBRT (whole-brain radiotherapy), or orelabrutinib maintenance, based on patient eligibility and physician discretion. The primary endpoint was the centrally assessed response post-induction. Secondary endpoints included progression free survival (PFS), overall survival (OS), and safety.

Results: Among the 22 enrolled patients, the overall response rate (ORR) at the end of induction therapy was 91.0%, including 9 patients (41.0%) with complete remissions (CRs), and 11 patients (50.0%) with partial remissions (PRs). With a median follow-up of 22.3 months (range 2.3-42.4 months), the 1-year and 2-year PFS rates were 66.6% and 59.2%, respectively; OS rates were 81.8% and 66.3%, respectively. Consolidation was performed in 15 patients: 5 underwent ASCT, 4 received WBRT, and 6 received maintenance orelabrutinib. The most common adverse effects were grade 1 anemia (45.5%). Grade ≥ 3 events included neutropenia (13.6%) and pneumonia (9.0%).

Conclusion: The combination of HD-MTX, rituximab, and orelabrutinib demonstrates high response rates and manageable toxicity in newly diagnosed PCNSL, supporting further evaluation in randomized trials.

Purpose: This study evaluated the efficacy and safety of a 14-day blinatumomab-venetoclax (BV) regimen as induction therapy for newly diagnosed Ph-negative B-cell acute lymphoblastic leukemia (B-ALL), focusing on rapid remission and tolerability in unfit patients.

Patients and methods: Thirteen patients received venetoclax (100 mg on day 1, 200 mg on day 2, 300 mg on day 3, and 400 mg from days 4 to 14) with blinatumomab (9 to 28 ug/day) for 14 days. Bone marrow assessments were performed at days 14-21. Primary endpoints were complete remission (CR) rate, minimal residual disease (MRD) negativity by flow cytometry, and adverse events.

Results: The CR rate after one cycle of BV regimen was 92.3% (12/13), and all patients achieved MRD-negativity; 91.7% (11/12) achieved MRD clearance by day 21. Grade 1-2 cytokine release syndrome occurred in 46.2% (6/13; 1 grade 3). Hematologic toxicity included grade 3-4 neutropenia (92.3%) and thrombocytopenia (46.2%), with only 30.8% febrile neutropenia. All AEs resolved rapidly with supportive care, allowing therapy to continue without interruption. At median follow-up of 283 days, 1-year relapse-free survival rate and overall survival rate were 60.6% and 83.3%.

Conclusion: The 14-day BV regimen induced rapid deep remission (91.7% MRD-negative by day 21) with manageable toxicity in Ph-negative B-ALL. Synergistic T-cell activation by venetoclax may explain enhanced efficacy.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm that is felt to arise from somatic mutations with hematopoietic stem and progenitor cells (HSPC's), leading to the development of atypical megakaryocytic hyperplasia. Associated dysregulated cytokine signaling and the trafficking of fibroblasts to the marrow compartment then leads to the deposition of collagen in the marrow compartment. On a molecular level, several well-established driver mutations in JAK2, CALR or MPL activate signaling through JAK/STAT, producing the proliferative phenotype of myelofibrosis. JAK inhibition, accordingly, has been and remains a mainstay in MF-directed therapy. In patients whose disease becomes refractory to Jak inhibitors or in those who experience intolerable adverse effects, however, options from different therapeutic classes are available. Despite this broad availability that includes erythropoiesis-stimulating agents, androgens and TGF-β inhibitors, one of the major challenges in management remains the implementation and successful long-term use of agents to treat cytopenic myelofibrosis. Research into alternative drivers has now led not only to the identification of alternative signaling mechanisms in MF but also to the development and now approval of new therapies outside of Jak inhibitors.

Introduction: The tumor microenvironment (TME) influences diffuse large B-cell lymphoma (DLBCL) progression, but the prognostic roles of tumor-infiltrating T-lymphocytes (TIL-T), tumor-associated macrophages (TAMs), and PD-L1 remain undefined. This study investigates the clinicopathological associations and prognostic impacts of TIL-T, TAMs, and PD-L1 expression in DLBCL.

Methods: This retrospective study evaluated 89 primary DLBCL cases, integrating clinicopathological data with automated immunohistochemical quantification of CD3, CD8, FOXP3, CD163, and PD-L1 expression in tumor hotspots and microenvironmental compartments. Prognostic associations of TIL-T, TAMs, and PD-L1 expression with PFS and OS were analyzed via Kaplan-Meier methods and Cox regression.

Results: High CD3+ infiltration correlated with lower Ki-67 expression, while elevated FOXP3+ levels linked to improved Eastern Cooperative Oncology Group Performance Status (ECOG). CD163+ TAMs varied by NCCN-IPI risk, ECOG, and cell of origin. Neoplastic PD-L1 (nPD-L1) positivity associated with higher NCCN-IPI scores, CD3+ T-cell infiltration, and CD163+ TAM enrichment. Microenvironmental PD-L1 (mPD-L1) correlated with age, ECOG, B symptoms, and infiltration of all T-cell subsets and TAMs. Survival analysis revealed prolonged overall survival (OS) with high CD3+, CD8+, FOXP3+ TIL-T, CD163+ TAMs, or mPD-L1 positivity, while progression-free survival (PFS) improved with CD3+ infiltration and mPD-L1. Univariate analysis identified B symptoms, extranodal involvement, and low TIL-T levels as OS risks, whereas ECOG 0 and mPD-L1+ were protective. Multivariate modeling confirmed B symptoms, extranodal disease, and CD3+ TIL-T as independent OS predictors; CD3+ TIL-T and B symptoms independently impacted PFS.

Discussion: The TME plays a crucial role in the biological behavior of DLBCL, particularly because TIL-T and TAMs are significantly associated with patient survival outcomes. These cell types may serve as critical biomarkers and provide novel immunotherapy targets in DLBCL.

Background: Drug-related problems (DRPs) are critical challenges in oncology practice, particularly among patients with non-Hodgkin lymphoma (NHL), due to complex regimens and high toxicity potential.

Purpose: This study aimed to identify, classify, and evaluate the prevalence of DRPs and associated factors, and explore the pattern of chemotherapy prescribing for NHL patients.

Methods: A cross-sectional study was conducted from November 2022 to September 2023 at National Oncology Centre (NOC), Al-Jomhouri Teaching Hospital. Adult NHL patients undergoing chemotherapy were enrolled, with a final sample of 279 patients. DRPs were identified and classified using the validated Pharmaceutical Care Network Europe (PCNE) and cross-checked against National Comprehensive Cancer Network (NCCN) guidelines. Potential drug-drug interactions (DDIs) were evaluated using the Lexicomp^® drug interactions database. Data was collected from patients' interviews, treatment charts and medical records. Descriptive statistics and linear regression were used for analysis.

Results: Among the 279 NHL patients included in the study, a total of 1870 DRPs were identified (average 6.7 per patient). Advanced-stage disease was observed in 79.6% of patients, and 63.4% received rituximab-containing regimens. The R-CHOP regimen being the most frequently used, which was associated with 52.7% of all DRPs. The most frequent DRPs involved dosing issues, including drug doses too low (26.5%) and incorrect or missing dose calculations (13.1%). DDIs contributed to 13% of the total identified DRPs, with the majority classified as mild interaction. Multivariate regression analysis identified comorbidities, lymphoma subtype, and number of chemotherapy cycles as significant predictors of DRP occurrence.

Conclusion: A high number of DRPs were identified among NHL patients in Yemen, with an average of 6.7 DRPs per patient, predominantly due to dosing issues. Integration of clinical pharmacy services, guideline-based prescribing, and systematic medication reviews are essential to minimize DRPs and improve treatment outcomes.

Purpose: The study was constructed for investigating the serum expression levels of ATIC with multiple myeloma (MM) patients and its potential clinical value as a biomarker, and analyzing its association with disease stage, treatment response, genetic characteristics and prognosis.

Patients and methods: The serum concentrations of ATIC were assessed in 186 MM patients and 201 healthy controls via ELISA, and the diagnostic efficacy was evaluated through ROC curve analysis. Correlation analysis was conducted based on clinical parameters, including common comorbidities, clinical stages, laboratory indicators, disease status, treatment response level, and pathological characteristics. The prognostic relevance of serum ATIC levels in MM patients was assessed using Kaplan-Meier survival analysis.

Results: Serum ATIC levels showed a significant upregulated in MM patients (median = 38.26 ng/mL) compared to healthy controls group (median = 16.98 ng/mL) (p < 0.0001). Newly diagnosed MM (NDMM) patients showed higher ATIC levels (median = 46.73 ng/mL). Results from ROC curve analysis showed that ATIC had a good diagnostic performance (AUC = 0.720, p < 0.0001). ATIC levels decreased with treatment response, and the Remission Group (R group) exhibited a notable decrease than the Active Disease Group (AD group) (p < 0.05). Higher R-ISS staging was associated with elevated ATIC levels (p < 0.05). Positive correlations were found between serum ATIC levels and ESR (p = 0.029), β2-MG (p = 0.035), GLO (p = 0.044), UA (p = 0.037), abnormal FISH results (p = 0.02), as well as poor prognosis. Notably, MM patients with diabetes had lower ATIC levels than those without diabetes (p = 0.004).

Conclusion: This study found that serum ATIC expression levels were significantly upregulated in MM patients, which is closely related to comorbidities, disease progression, renal dysfunction, and poor prognosis.