Phase II study of pegaspargase, etoposide, gemcitabine (PEG) followed by involved-field radiation therapy in early-stage extranodal natural killer/T-cell lymphoma.

OBJECTIVE: The prognosis of extra-nodal NK/T cell lymphoma (ENKTL) is poor, and the optimal therapy remains controversial. This study aims to evaluate the safety and efficacy of a new combined modality therapy. METHODS: Phase-2 study of pegaspargase, etoposide and gemcitabine (PEG) combined with involved field radiation therapy (IFRT) in newly-diagnosed patients with early-stage ENKTL. Patients received 4 course of PEG followed by IFRT. The primary endpoints were complete response (CR), partial response (PR), and objective response rate (ORR) after IFRT. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: 34 consecutive patients with Ann Arbor stage I/II were enrolled. 3 patients progressed on PEG, while the remaining 31 received IFRT. The ORR was 88.2% (30/34), included 28 (82.4%) complete and 2 (5.8%) partial responses. With a median follow-up of 56.0 months (Interquartile Range [IQR], 36.0-66.9 months), the estimated 5-year PFS and OS were 87.4% (95% Confidence Interval [CI],69.5%-94.8%) and 97.1% (95%CI, 80.1%-99.6%), respectively. Most adverse events were hematological and easily managed. CONCLUSIONS: PEG followed by IFRT is a safe and effective initial therapy for early-stage ENKTL, demonstrating impressive PFS and OS rates. This promising approach warrants further validation in a randomized controlled trial (Registered at Clinicaltrials.gov NCT02705508).Trial registration: ClinicalTrials.gov identifier: NCT02705508.

Lipid profile as a novel prognostic predictor for patients with acute myeloid leukemia.

Purpose: This study investigated the relationship between serum lipid levels and clinical outcomes in acute myeloid leukemia (AML) by establishing a predictive risk classification model. Method: A total of 214 AML patients who were pathologically diagnosed and treated with standard induction chemotherapy at Sun Yat-Sen University Cancer Center were included. The patients were randomly divided into the training (n = 107) and validation (n=107) cohorts. Univariate and multivariate Cox analyses were used to assess the value of triglyceride (TG), Apolipoprotein B (Apo B), Apo Apolipoprotein A-I (Apo A-I), cholesterol (CHO), and high-density lipoprotein (HDL) as prognostic factors for AML. Results: After a series of data analyses, a five-factor model was established to divide the patients into high- and low-risk groups. Kaplan-Meier survival analysis showed that the high-risk group had a poor prognosis (P<0.05). The area under the curve of the novel model for five-year OS was 0.737. A nomogram was constructed to integrate the model with age and the 2017 ELN cytogenetic classification, with the merged model showing improved accuracy with an area under the curve of 0.987 for five-year OS. Conclusion: A novel model was constructed using a combination of the serum lipid profile and clinical characteristics of AML patients to enhance the predictive accuracy of clinical outcomes. The nomogram used the lipid profile which is routinely tested in clinical blood biochemistry and showed both specific prognostic and therapeutic potential.

Integrated assessment of the clinical and biological value of ferroptosis-related genes in multiple myeloma.

BACKGROUND: Ferroptosis is an iron-dependent mode of cell death that could be induced by erastin and exert antitumor effects. However, the clinical and biological roles of ferroptosis-related gene (FRG) signature and the therapeutic value of erastin in multiple myeloma (MM) remained unknown. METHODS: Clinical and gene expression data of MM subjects were extracted from the Gene Expression Omnibus (GEO) public database. Univariable cox analysis was applied to determine FRGs related to survival and the least absolute shrinkage and selection operator (LASSO) regression analysis was used to develop a prognostic model. Prediction accuracy of the model was estimated by receiver operating characteristic (ROC) curves. Functional pathway enrichments and infiltrating immune status were also analyzed. We conducted in vitro experiments to investigate the combination therapy of erastin and doxorubicin. RESULTS: 17 FRGs were strongly associated with patient survival and 11 genes were identified to construct the prognostic model. ROC curves indicated great predictive sensitivity and specificity of the model in all cohorts. Patients were divided into low- and high-risk groups by median risk score in each cohort and the survival of the low-risk group was significantly superior than that of the high-risk group. We also observed a close relevance between functional pathways and immune infiltration with risk scores. Moreover, we combined erastin and doxorubicin in our in vitro experiments and found synergetic antitumor effects of the two agents, and the underlying mechanism is the overgeneration of intracellular Reactive Oxygen Species (ROS). CONCLUSIONS: We demonstrated the important value of ferroptosis in patient prognosis and as a potential antitumor target for MM.

CircKIF4A Is a Prognostic Factor and Modulator of Natural Killer/T-Cell Lymphoma Progression.

Background: Natural killer/T-cell lymphoma (NKTL) is difficult to treat. Circular RNAs (circ RNAs) have been implicated in tumorigenesis. However, the function of circKIF4A in NKTL has not been investigated. Methods: QPCR analysis was used to compare circKIF4A levels in NKTL cell lines versus normal cell lines. Kaplan-Meier survival analysis was used to assess the effect of circKIF4A on the prognosis of NKTL. The correlation between clinicopathological features and circKIF4A expression was examined using cox regression analysis. Luciferase reporter, RNA immunoprecipitation and immunohistochemistry assays were also used to investigate the mechanisms of circKIF4A in NKTL. Results: Our analyses revealed that circKIF4A is significantly upregulated in NKTL cell lines and that its upregulation correlates with the poor prognosis of NKTL. The silencing of circKIF4A significantly suppressed glucose uptake and lactate production in NKTL cells. Moreover, we showed that circKIF4A, PDK1, and BCL11A bind miR-1231 and that circKIF4A regulates PDK1 and BCL11A expressions by sponging miR-1231. Conclusions: During NKTL progression, circKIF4A regulated PDK1 and BCL11A levels by sponging miR-1231. Our data indicated that circKIF4A is oncogenic in NKTL and that it is a predictor of poor prognosis of NKTL.

Integrative analysis identifies CXCL11 as an immune-related prognostic biomarker correlated with cell proliferation and immune infiltration in multiple myeloma microenvironment.

PURPOSE: The interaction between tumor cells and tumor microenvironment (TME) has an important impact on progression and prognosis of multiple myeloma (MM), and has been proven to be promising therapeutic targets. This study intended to explore the relationship between TME and prognosis and identify valuable biomarkers of MM. METHODS: The transcriptomic and clinical information of MM retrieved from the Gene Expression Omnibus (GEO) were used to establish the model. The curve of Kaplan-Meier survival and the time-dependent receiver operating characteristic (ROC) were used to appraise the predictive ability. A nomogram was established for clinical application. Furthermore, the CIBERSORT algorithm was used to investigate the relation between IRGPI with the infiltration of immune cells. We also used histology, as well as in vitro and in vivo experiments to validate these findings. RESULTS: The results demonstrated an immune-related gene-based prognostic index (IRGPI) combined with clinical information. Patients were separated into high- and low-risk groups based on risk score, which had significantly difference in survival status and immune infiltrations. Furthermore, we identified CXCL11 as a key factor, which positively promotes the progression of MM and correlate with macrophage M2-like polarization and tumor immune cells infiltration. CONCLUSION: Our findings suggest the IRGPI significantly demonstrate the differential prognosis and prediction of immune cells infiltration. It provides some insights into the complex interaction between myeloma tumor cells and the TME, as well as in the development of a novel biomarker target for anti-MM therapy.

Integrative Analysis of a Pyroptosis-Related Signature of Clinical and Biological Value in Multiple Myeloma.

Purpose: Pyroptosis is an inflammation-based programmed cell death that holds great potential as a novel cancer therapeutic target in patients with multiple myeloma (MM). However, thus far, the function of pyroptosis-related genes (PRGs) in MM and their prognostic relevance remains undetermined. Methods: The model was established by the LASSO analysis, based on the Gene Expression Omnibus (GEO) dabatase, and its efficacy was verified using two external datasets. The model's predictive ability was assessed by the Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) curves. Finally, a nomogram was established for clinical application. We also confirmed the validity of our model using specimens and in vitro experiments. Results: We established an 11-PRG signature profile, and verified its efficacy using two validation cohorts (VCs). In both cohorts, patients were separated into two subpopulations, according to their median risk scores (RS). Our analysis revealed that high-risk (HR) patients experienced considerably lower overall survival (OS), compared to the low-risk (LR) patients. Using functional enrichment and immune infiltration analyses, we demonstrated that the immunologic status was strongly related to RS. Furthermore, using a pyroptosis inhibitor Q-VD-OPh, we revealed that MM cell proliferation and progression was drastically suppressed and the doxorubicin (DOX)-induced apoptosis was reversed. Conclusion: Based on our analysis, pyroptosis not only serves as a measure of MM treatment efficiency and patient prognosis, but is also a possible target for anti-MM therapy.

NK-/T-cell lymphomas.

Natural killer/T-cell lymphoma (NKTL) is a sub-type of Epstein-Barr virus (EBV)-related non-Hodgkin lymphomas common in Asia and Latin America but rare elsewhere. Its pathogenesis is complex and incompletely understood. Lymphoma cells are transformed from NK- or T-cells, sometimes both. EBV-infection and subsequent genetic alterations in infected cells are central to NKTL development. Hemophagocytic syndrome is a common complication. Accurate staging is important to predict outcomes but there is controversy which system is best. More than two-thirds of NKTL lympohmas are localized at diagnosis, are frequently treated with radiation therapy only and have 5-year survival of about 70 percent. Persons with advanced NKTLs receive radiation therapy synchronously or metachronously with diverse multi-drug chemotherapy typically including L-asparginase with 5-year survival of about 40 percent. Some persons with widespread NKTL receive chemotherapy only. There are few data on safety and efficacy of high-dose therapy and a haematopoietic cell autotransplant. Immune therapies, histone deacetylase (HDAC)-inhibitors and other drugs are in early clinical trials. There are few randomized controlled clinical trials in NKTLs and no therapy strategy is clearly best; more effective therapy(ies) are needed. Some consensus recommendations are not convincingly evidence-based. Mechanisms of multi-drug resistance are considered. We discuss these issues including recent advances in our understanding of and therapy of NKTLs.