BACKGROUND: Extranodal natural killer/T‐cell lymphoma, nasal type (ENKTL) is a distinct subtype of non‐Hodgkin lymphoma in which the upper aerodigestive tract is the most commonly involved site. To date, optimal treatment strategies and prognosis for patients with ENKTL have not been fully defined. METHODS: This prospective study was conducted to evaluate the efficacy and safety profiles of first‐line combined gemcitabine, oxaliplatin, and L‐asparaginase (GELOX) followed by involved‐field radiation therapy for patients with stage IE/IIE ENKTL. The primary endpoints were the complete response rate, the objective response rate, and toxicities. Secondary endpoints were overall survival and progression‐free survival. RESULTS: Twenty‐seven patients with newly diagnosed ENKTL were enrolled and completed the entire course of treatment. At the end of treatment, the overall response rate was 96.3%, including 20 patients (74.1%) who attained a complete response and 6 patients (22.2%) who attained a partial response. No patients developed disease progression during therapy. Grade 1 and 2 toxicities were frequent during GELOX, but grade 3 and 4 toxicities were few, and no treatment‐related deaths occurred. At a median follow‐up of 27.37 months, 7 patients (25.9%) experienced disease progression, and 4 of those patients died of disease. The rates of 2‐year overall and progression‐free survival were both 86%, and patients who attained a complete response at the end of treatment had significantly longer progression‐free survival (P = .012) and overall survival (P = .021) than patients who did not attain a complete response. CONCLUSIONS: The current results indicated that GELOX followed by involved‐field radiation therapy can be an effective and feasible treatment strategy for patients with stage IE/IIE ENKTL of the upper aerodigestive tract. These results will require further investigation in larger prospective trials. Cancer 2013. © 2012 American Cancer Society.
BackgroundNatural killer/T-cell lymphoma (NKTCL) is an Epstein–Barr virus (EBV)-associated, highly aggressive lymphoma. Treatment outcome remains sub-optimal, especially for advanced-stage or relapsed diseases. Programmed cell death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have become promising therapeutic targets for various malignancies, but their role in the pathogenesis and their interactions with EBV in NKTCL remains to be investigated.MethodsExpression of PD-L1 was measured in NK-92 (EBV-negative) and SNK-6 (EBV-positive) cells by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay, and flow cytometry, respectively. Latent membrane protein 1 (LMP1)-harboring lentiviral vectors were transfected into NK-92 cells to examine the correlation between LMP1 and PD-L1 expression. Proteins in the downstream pathways of LMP1 signaling were measured in NK-92 cells transfected with LMP1-harboring or negative control vectors as well as in SNK-6 cells. PD-L1 expression on tumor specimens and serum concentration of soluble PD-L1 were collected in a retrospective cohort of patients with Ann Arbor stage I~II NKTCL, and their prognostic significance were analyzed.ResultsExpression of PD-L1 was significantly higher in SNK-6 cells than in NK-92 cells, at both protein and mRNA levels. Expression of PD-L1 was remarkably upregulated in NK-92 cells transfected with LMP1-harboring lentiviral vectors compared with those transfected with negative control vectors. Proteins in the MAPK/NF-κB pathway were upregulated in LMP1-expressing NK-92 cells compared with the negative control. Selective inhibitors of those proteins induced significant downregulation of PD-L1 expression in LMP1-expressing NK-92 cells as well as in SNK-6 cells. Patients with a high concentration of serum soluble PD-L1 (≥3.4 ng/ml) or with a high percentage of PD-L1 expression in tumor specimens (≥38 %) exhibited significantly lower response rate to treatment and remarkably worse survival, compared with their counterparts. A high concentration of serum soluble PD-L1 and a high percentage of PD-L1 expression in tumor specimens were independent adverse prognostic factors among patients with stage I~II NKTCL.ConclusionsPD-L1 expression positively correlated LMP1 expression in NKTCL, which was probably mediated by the MAPK/NF-κB pathway. PD-L1 expression in serum and tumor tissues has significant prognostic value for early-stage NKTCL.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0341-7) contains supplementary material, which is available to authorized users.
Immune checkpoint signaling plays an important role in immunosuppression in multiple myeloma (MM). Blood levels of soluble programmed death-ligand 1 (sPD-L1), a checkpoint-relevant protein, might predict treatment response and survival outcomes in MM patients. We used an enzyme-linked immunosorbent assay to measure serum sPD-L1 levels in 81 newly diagnosed MM patients. We found that myeloma patients had higher sPD-L1 concentrations than healthy controls. The best sPD-L1 cutoff value for predicting disease progression risk was 2.783 ng/mL. The overall response rate to treatment was higher in low sPD-L1 patients than in high sPD-L1 patients. The 3-year progression free survival (PFS) and overall survival (OS) rates for all patients were 16% and 64%, respectively. Multivariate survival analysis including Eastern Cooperative Oncology Group performance status score, treatment response, and sPD-L1 level showed that a less than partial treatment response (PR) and higher sPD-L1 levels (>2.783 ng/ml) were independent prognostic factors for shorter PFS; neither factor was predictive of OS. The serum sPD-L1 level is a valuable biomarker for predicting treatment response and an independent prognostic factor for PFS. PD-1/PD-L1 blockade may be a promising novel immune-based therapeutic strategy in MM.
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