MTHFD1 regulates the NADPH redox homeostasis in MYCN-amplified neuroblastoma.

MYCN amplification is an independent poor prognostic factor in patients with high-risk neuroblastoma (NB). Further exploring the molecular regulatory mechanisms in MYCN-amplified NB will help to develop novel therapy targets. In this study, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) was identified as the differentially expressed gene (DEG) highly expressed in MYCN-amplified NB, and it showed a positive correlation with MYCN and was associated with a poor prognosis of NB patients. Knockdown of MTHFD1 inhibited proliferation and migration, and induced apoptosis of NB cells in vitro. Mouse model experiments validated the tumorigenic effect of MTHFD1 in NB in vivo. In terms of the mechanism, ChIP-qPCR and dual-luciferase reporter assays demonstrated that MTHFD1 was directly activated by MYCN at the transcriptional level. As an important enzyme in the folic acid metabolism pathway, MTHFD1 maintained the NADPH redox homeostasis in MYCN-amplified NB. Knockdown of MTHFD1 reduced cellular NADPH/NADP+ and GSH/GSSG ratios, increased cellular reactive oxygen species (ROS) and triggered the apoptosis of NB cells. Moreover, genetic knockdown of MTHFD1 or application of the anti-folic acid metabolism drug methotrexate (MTX) potentiated the anti-tumor effect of JQ1 both in vitro and in vivo. Taken together, MTHFD1 as an oncogene is a potential therapeutic target for MYCN-amplified NB. The combination of MTX with JQ1 is of important clinical translational significance for the treatment of patients with MYCN-amplified NB.

Efficacy and safety comparison between R-CHOP and modified NHL-BFM-90 regimens in children and adolescents with diffuse large B-cell lymphoma.

Studies comparing the efficacy and safety of R-CHOP and modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-90 (NHL-BFM-90) regimens in children and adolescents with diffuse large B-cell lymphoma (DLBCL) are lacking. Thus, we retrospectively analyzed 85 DLBCL patients aged ≤18 years from 2000 to 2020; 74 patients received the modified NHL-BFM-90 regimen, and 11 received the R-CHOP regimen. The 5-year OS and event-free survival (EFS) rates between the modified NHL-BFM-90 and R-CHOP regimens were 91.0% vs. 90.9% (P = 0.466) and 89.8% vs. 68.6% (P = 0.055), respectively. In the stratified analysis, the survival outcome of pediatric patients treated with the modified NHL-BFM-90 regimen was not significantly different from that of adolescent patients. The OS and EFS rates of patients with early-stage disease were both 100%. Patients in the advanced-stage group who were treated with the modified NHL-BFM-90 regimen had superior EFS rates (P < 0.05). The frequency of severe adverse events from the two regimens was similar. There were no treatment-related deaths. We concluded that the modified NHL-BFM-90 regimen has better efficacy than R-CHOP in DLBCL patients with advanced-stage disease. However, the R-CHOP regimen might be an option for early-stage DLBCL. Further prospective studies are needed to guide clinical decisions about treatment.

Influence of MTHFR C677T and A1298C polymorphisms on the survival of pediatric patients with non-Hodgkin lymphoma.

This study evaluated the influence of MTHFR C677T/A1298C polymorphisms on the survival of pediatric NHL. We enrolled 374 patients including 283 males and 91 females between 2014 and 2020. The median age was 9 years. The tumor types included Burkitt lymphoma (n = 180), lymphoblastic lymphoma (n = 95), anaplastic large cell lymphoma (n = 64), and diffuse large B cell lymphoma (n = 35). A subgroup of 158 patients were genotyped concerning C677T/A1298C polymorphisms. Neither C677T nor A1298C polymorphism was a significant factor in multivariate analysis. However, Kaplan-Meier analysis revealed that patients carrying 677 T allele had a significantly higher 5-year EFS rate in the whole group (n = 158), and higher 5-year EFS/OS rates in the subgroup of BL/DLBCL than those with wild type. In conclusion, the C677T polymorphism could be used for survival prediction and potential risk stratification for further treatment protocols for Chinese pediatric NHL, especially for BL/DLBCL.

Identification of prognostic immune-related genes in rhabdoid tumor of kidney based on TARGET database analysis.

BACKGROUND: Malignant rhabdoid tumor of the kidney (RTK) is a rare and highly aggressive pediatric malignancy. Immune system dysfunction is significantly correlated with tumor initiation and progression. METHODS: We integrated and analyzed the expression profiles of immune-related genes (IRGs) in 65 RTK patients based on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Prognostic related IRGs in RTK patients were analyzed using univariate and multivariate analysis, based on which a prognostic model with IRGs was constructed. Correlation analysis between the risk score of our model and tumor-infiltrating cell were also investigated. RESULTS: Twenty two IRGs were significantly associated with the clinical outcomes of RTK patients. Gene ontology (GO) analysis revealed that inflammatory pathways were most frequently implicated in RTK. A prognostic model was constructed using 7 IRGs (MMP9, SERPINA3, FAM19A5, CCR9, PLAUR, IL1R2, PRKCG), which were independent prognostic indices that could differentiate patients based on their survival outcomes. Furthermore, the risk scores from our prognostic model was positively associated with cancer-associated fibroblasts (CAFs). CONCLUSIONS: We screened seven IRGs of clinical significance to distinguish patients with different survival outcomes. This may enhance our understanding of the immune microenvironment of RTK, and could use to design individualized treatments for RTK patients. BACKGROUND: Malignant rhabdoid tumor of the kidney (RTK) is a rare and highly aggressive pediatric malignancy. Immune system dysfunction is significantly correlated with tumor initiation and progression. METHODS: We integrated and analyzed the expression profiles of immune-related genes (IRGs) in 65 RTK patients based on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Prognostic related IRGs in RTK patients were analyzed using univariate and multivariate analysis, based on which a prognostic model with IRGs was constructed. Correlation analysis between the risk score of our model and tumor-infiltrating cell were also investigated. RESULTS: Twenty two IRGs were significantly associated with the clinical outcomes of RTK patients. Gene ontology (GO) analysis revealed that inflammatory pathways were most frequently implicated in RTK. A prognostic model was constructed using 7 IRGs (MMP9, SERPINA3, FAM19A5, CCR9, PLAUR, IL1R2, PRKCG), which were independent prognostic indices that could differentiate patients based on their survival outcomes. Furthermore, the risk scores from our prognostic model was positively associated with cancer-associated fibroblasts (CAFs). CONCLUSIONS: We screened seven IRGs of clinical significance to distinguish patients with different survival outcomes. This may enhance our understanding of the immune microenvironment of RTK and could use to design individualized treatments for RTK patients.

Venous thromboembolic events in T-cell lymphoma patients: Incidence, risk factors and clinical features.

INTRODUCTION: Patients with hematologic malignancies are prone to developing thromboembolism. The incidence, risk factors and clinical features for developing venous thromboembolism (VTE) are not well-elucidated in patients with T-cell lymphoma. MATERIALS AND METHODS: The present study retrospectively analyzed 668 patients with VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), who were admitted to Tianjin Medical University Cancer Institute and Hospital and Sun Yat-sen University Cancer Center from January 2006 to December 2018. All patients were diagnosed with T-cell lymphoma, and all episodes of symptomatic VTE were confirmed by imaging and ultrasound. The follow-up results were obtained through telephone communication and outpatient visits. RESULTS: A total of 668 patients were analyzed. Thirty-three (4.94%) patients had at least one episode of VTE, and all of which were deep vein thrombosis alone. All VTEs occurred in patients who received chemotherapy, while no VTE occurred in patients who did not receive chemotherapy. By univariate analysis, central venous catheter (CVC) (odds ratio [OR] 6.63, confidence interval [CI] 2.24-19.57, P = 0.001), Eastern Cooperative Oncology Group (ECOG) performance status 2, 3, or 4 (OR: 62.15, CI: 15.42-250.48, P = 0.000), and stage III or IV (OR: 4.06, CI: 1.00-16.40, P = 0.049) were identified as risk factors for developing VTE. By multivariate analysis, CVC (OR: 3.23, CI: 1.49-7.23, P = 0.003) and stage III or IV (OR: 2.30, CI: 1.06-4.97, P = 0.035) were still significant risk factors for developing VTE. CONCLUSION: The incidence of VTE in the present study population was comparable to that of lymphoma patients, other than T-cell lymphoma, and VTE was associated with CVC and advanced stage.