Extranodal NK/T-cell lymphoma is a rare pathological type, incidence of which is 2% - 10% of the primary NHL cases, showing a broad morphologic spectrum with frequent necrosis. Extranodal NK/T-cell lymphoma occurs more frequently in Asian population, especially in Southern China and Southeast Asian population. It is reported that the incidence of ENKL among lymphomas (1314 cases) in Asian countries was 4 times as much as the Western countries (22% vs. 5%) by the International Peripheral T-cell Lymphoma Project. Nasal NK/T-cell lymphoma most commonly occurred in the nasal cavity or other parts of the upper aerodigestive tract, and is highly associated with EBV (Epstein-Barr virus) infection, which is highly aggressive and its prognosis generally is poor. The mean survival time is about 12-38 months. It is important to accurately assess the patients prognosis for an optimal treatment. Localized disease (stage I and II) often has a relatively good prognosis through local radiation or combined therapy. There is a paucity of data to guide therapy in advanced disease. Generally, combining therapy is the most commonly selected approach for advanced disease. The conditions of the patients with advanced, relapsed or refractory diseases have been improved by high-intensity chemotherapy combined with radiation, and a regimen containing L-asparaginase L-Asp. Recently some studies have demonstrated promising outcomes in the selected cases by high-dose chemotherapy supplemented with auto-or allo-HSCT. Targeting therapy is also developing quickly. This current review mainly focuses on the advance of treatment for extranodal NK/T-cell lymphoma.
Antineoplastic Combined Chemotherapy Protocols ; Hematopoietic Stem Cell Transplantation ; Humans ; Lymphoma, Extranodal NK-T-Cell ; drug therapy ; radiotherapy ; therapy

Objective: To explore the molecular mechanisms of 14-3-3ζ in gemcitabine resistance in extranodal NK/T-cell lymphoma, nasal type (ENKTL) . Methods: The effects of cell proliferation and invasion were detected by cell counting kit-8 (CCK-8) assay and transwell assay. YTS cells were exposed to gradually increased concentrations of gemcitabine to establish gemcitabine-resistant YTS cells (YTS-gem) in vitro. 14-3-3ζ specific siRNA lentiviral vector was transfected into YTS and YTS-gem cells to downregulate 14-3-3ζ expression, and stable transfected cell clones were screened. The protein expression was determined by Western blot. Results: ①14-3-3ζ expression was significantly up-regulated in gemcitabine resistant YTS-gem cells, comparing with that of YTS cells (P<0.05) . ②The results of CCK-8 and transwell assay showed that downregulation of 14-3-3ζ significantly reduced the cell proliferation and invasion abilities (P<0.05) . ③Downregulation of 14-3-3ζ could restore gemcitabine sensitivity in gemcitabine resistant YTS-gem cells (P<0.05) . ④Western blotting results showed that knockdown of 14-3-3ζ significantly upregulated pro-apoptotic Bax, and downregulated anti-apoptotic Bcl-2, Caspase-3, cleaved caspase-3, Cyclin D1 in gemcitabine-resistant YTS-gem cells (P<0.05) . There was no significant difference in p53 ang P-gp expression levels. Conclusions: 14-3-3ζ was upregulated in gemcitabine resistant YTS cells. Overexpression of 14-3-3ζ promoted cell proliferation and enhanced cell migration. 14-3-3ζ contributed to gemcitabine resistance to ENKTL through anti-apoptosis.
14-3-3 Proteins/metabolism* ; Cell Line, Tumor ; Deoxycytidine/therapeutic use* ; Drug Resistance, Neoplasm ; Humans ; Lymphoma, Extranodal NK-T-Cell/drug therapy* ; Gemcitabine

OBJECTIVE: To explore the curative effect of nasal type extranodal NK/T-cell lymphoma by sequential chemotherapy combined radiotherapy compared with chemtherapy. METHOD: Fifty-seven cases of nasal type extranodal NK/T-cell lymphoma confirmed by pathological morphology and immuno-histochemistry were divided into chemotherapy combined radiotherapy group (34 cases) or chemotherapy group (23 cases). Twenty-three patients in the chemotherapy group alternately applied CHOP, VDLP and MEOP regimen after each two treatments into the clinical observation; Chemotherapy combined radiotherapy group of 34 patients, in addition to the above chemotherapy, applied three-dimensional conformal radiation therapy of the primary site by linear accelerators. Then all of patients were ceased treatment and followed up 3-5 years. RESULT: (1) After treatment, effective rate of two groups was 91.2% and 87.0%, there was no obvious difference (P > 0.05); After follow up about 1 year, effective rate of two groups was 76.5% and 73.9%, there was no obvious difference (P > 0.05); (3) After follow up about 3 years and 5 years, disease free survival (DFS) of two groups was 61.3%, 47.6% and 43.5%, 21.4%, there was obvious difference (P < 0.05). (4) Long-term survival is closely related to treatment mode. (5) B symptoms, advanced (III, IV) stage, the International Prognostic Index (IPI), KPS scores were correlated with prognosis, and were independent prognostic factors. CONCLUSION Treatment with chemotherapy and radiotherapy for nasal type extranodal NK/T-cell lymphoma had obvious curative effect and may improve long-term survival efficiently compared with chemotherapy alone.
Adult ; Antineoplastic Combined Chemotherapy Protocols ; Combined Modality Therapy ; Female ; Humans ; Lymphoma, Extranodal NK-T-Cell ; drug therapy ; radiotherapy ; therapy ; Male ; Middle Aged ; Radiotherapy ; methods ; Treatment Outcome ; Young Adult

OBJECTIVE: To investigate the clinical characteristics, diagnosis, and treatment of one patient with primary adrenal natural killer/T-cell lymphoma (PANKTCL), and to strengthen the understanding of this rare type of lymphoma. METHODS: The clinical manifestations, diagnosis and treatment process, and prognosis of the patient admitted in our hospital were retrospectively analyzed. RESULTS: Combined with pathology, imaging, bone marrow examination， etc, the patient was diagnosed with PANKTCL (CA stage, stage II; PINK-E score 3, high-risk group). Six cycles of "P-GemOx+VP-16" regimen（gemcitabine 1 g/m² d1 + oxaliplatin 100 mg/m² d 1 + etoposide 60 mg/m² d 2-4 + polyethylene glycol conjugated asparaginase 3 750 IU d 5） was performed, and complete response was assessed in 4 cycles. Maintenance therapy with sintilimab was administered after the completion of chemotherapy. Eight months after the complete response, the patient experienced disease recurrence and underwent a total of four courses of chemotherapy, during which hemophagocytic syndrome occurred. The patient died of disease progression 1 month later. CONCLUSION PANKTCL is rare, relapses easily, and has a worse prognosis. The choice of the "P-GemOx+VP-16" regimen combined with sintilimab help to improve the survival prognosis of patient with non-upper aerodigestive tract natural killer /T-cell lymphoma.
Humans ; Treatment Outcome ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Retrospective Studies ; Etoposide ; Neoplasm Recurrence, Local/drug therapy* ; Asparaginase ; Deoxycytidine ; Lymphoma, T-Cell, Peripheral/drug therapy* ; Lymphoma, Extranodal NK-T-Cell/therapy* ; Oxaliplatin/therapeutic use*

PURPOSE: Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is a rare subtype of non-Hodgkin lymphoma, and asparaginase-based regimens are the best first-line treatments. Data on the role of specific circulating lymphocyte subsets in the progression of ENKTL are limited. The aim of this study was to investigate the clinical correlation and distribution of circulating absolute CD4+ T-cell counts (ACD4Cs) in ENKTL. MATERIALS AND METHODS: We retrospectively searched medical records for 70 newly diagnosed ENKTL patients treated with pegaspargase-based regimens. Comparison of ACD4Cs as a continuous parameter in different groups was calculated. Univariate and multivariate analyses were used to assess prognostic factors for overall survival (OS) and progression-free survival (PFS). RESULTS: Stage III/IV, B symptoms, elevated lactate dehydrogenase, monocytopenia, high-intermediate and high risk International Prognostic Index (IPI) and Korean Prognostic Index (KPI), high risk Prognostic Index of Natural Killer Lymphoma (PINK), and lower lymphocytes were significantly associated with low ACD4C at diagnosis. With a median follow-up time of 32 months, patients who had an ACD4C < 0.30×109/L had a worse OS. Median OS was 11 months and median PFS was 5 months in the low ACD4C cohort. There were significant differences in both OS and PFS between the two cohorts. Moreover, multivariate Cox analysis identified ACD4Cs as an independent predictor for OS and PFS. CONCLUSION: Low ACD4Cs were associated with poorer survival and could act as a negative predictor for ENKTL patients treated with asparaginase-based regimens.
Cell Count* ; Cohort Studies ; Diagnosis ; Disease-Free Survival ; Drug Therapy* ; Follow-Up Studies ; Humans ; L-Lactate Dehydrogenase ; Lymphocyte Subsets ; Lymphocytes ; Lymphoma* ; Lymphoma, Extranodal NK-T-Cell ; Lymphoma, Non-Hodgkin ; Medical Records ; Multivariate Analysis ; Prognosis* ; Retrospective Studies ; T-Lymphocytes

As the chemotherapeutic resistance of extranodal NK/T-cell lymphoma (ENKTL) rises year by year, searching for novel chemoprevention compounds has become imminent. Gambogic acid (GA) has recently been shown to have anti-tumor effects, but its role and underling mechanism in ENKTL are rather elusive. In the present study, we showed that GA inhibited the cell growth and potently induced the apoptosis of ENKTL cells in vitro in a time- and concentration-dependent manner. Furthermore, GA induced cell death through endoplasmic reticulum stress (ERS) mediated suppression of Akt signaling pathways and finally the release of the caspase-3 proteases. Overall, our data provided evidences supporting GA as a potential therapeutic agent for ENKTL, which may facilitate further preclinical development of anti-tumor drugs.
Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Endoplasmic Reticulum Stress ; drug effects ; Humans ; Lymphoma, Extranodal NK-T-Cell ; drug therapy ; genetics ; metabolism ; physiopathology ; Proto-Oncogene Proteins c-akt ; genetics ; metabolism ; Signal Transduction ; drug effects ; Xanthones ; pharmacology

PURPOSE: To evaluate radiotherapy (RT) and chemotherapy (CT) treatments of early-stage extranodal natural killer/T-cell lymphoma (ENKTL). MATERIALS AND METHODS: Fifty-five patients with stage I or II ENKTL [n=39 (71%) and 16 (29%) patients, respectively] who were treated with RT between 1999 and 2013 were analyzed retrospectively. The median age was 54 years (range, 24-81). Patients were grouped by treatment modality as RT alone [n=19 (35%)], upfront CT plus RT [CT+RT, n=16 (29%)], and concurrent chemoradiotherapy [CCRT, n=20 (36%)]. The median RT dose was 48 Gy. Patient characteristics between each treatment group were well balanced. Patterns of failure and survival were analyzed. RESULTS: The overall response rate after RT was 94.6%. Ten patients experienced distant failure, and seven experienced local failure comprising five in-field and two out-field failures. The local and distant failure rates in the RT-alone group were the same (16%). In the CT+RT group, the most common failure sites were local (19%). In the CCRT group, the most common failures were distant (25%). At a median follow-up of 56 months (range, 1-178 months), the 5-year overall survival (OS) and progression-free survival rates were 66% and 54%, respectively. The 5-year OS rate for the RT-alone and CT+RT groups were 76% and 69%, respectively, and the 2-year OS rate for the CCRT group was 62% (p=0.388). CONCLUSION: In the era of multimodal treatment for ENKTL, RT alone using advanced techniques should be considered for local disease control, whereas maintenance CT regimens should be considered for distant disease control.
Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Chemoradiotherapy ; Combined Modality Therapy ; Disease-Free Survival ; Female ; Humans ; Lymphoma, Extranodal NK-T-Cell/*drug therapy/mortality/*radiotherapy ; Male ; Middle Aged ; Retrospective Studies ; Survival Rate ; Treatment Outcome ; Young Adult

CD4 Antigens ; metabolism ; CD56 Antigen ; metabolism ; Dendritic Cells ; pathology ; Diagnosis, Differential ; Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor ; Hematologic Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; surgery ; Humans ; Immunohistochemistry ; Leukemia, Myeloid ; pathology ; Lymphoma, Extranodal NK-T-Cell ; pathology ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; pathology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; pathology ; Skin Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; surgery

Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Cisplatin ; administration & dosage ; Dexamethasone ; administration & dosage ; Diagnosis, Differential ; Female ; Follow-Up Studies ; Humans ; Immunohistochemistry ; Lymphoma, Extranodal NK-T-Cell ; pathology ; Lymphoma, Primary Cutaneous Anaplastic Large Cell ; pathology ; Lymphoma, T-Cell, Cutaneous ; drug therapy ; pathology ; Lymphomatoid Granulomatosis ; pathology ; Male ; Middle Aged ; Natural Killer T-Cells ; pathology ; Neoplasm Recurrence, Local ; Skin Neoplasms ; drug therapy ; pathology ; Young Adult

Objective: To explore the prognostic factors of extracellular NK/T cell lymphoma (ENKTL) treated with pegaspargase/L-asparaginase. Methods: The clinical data of 656 ENKTL patients diagnosed at 11 medical centers in the Huaihai Lymphoma Working Group from March 2014 to April 2021 were retrospectively analyzed. The patients were randomly divided into two groups: a training set (460 cases) and a validation set (196 cases) at 7∶3, and the prognostic factors of the patients were analyzed. A prognostic scoring system was established, and the predictive performance of different models was compared. Results: Patients' median age was 46 (34, 57) years, with 456 males (69.5% ) and 561 nasal involvement (85.5% ). 203 patients (30.9% ) received a chemotherapy regimen based on L-asparaginase combined with anthracyclines, and the 5-year overall survival rate of patients treated with P-GEMOX regimen (pegaspargase+gemcitabine+oxaliplatin) was better than those treated with SMILE regimen (methotrexate+dexamethasone+cyclophosphamide+L-asparaginase+etoposide) (85.9% vs 63.8% ; P=0.004). The results of multivariate analysis showed that gender, CA stage, the Eastern Cooperative Oncology Group performance status (ECOG PS) score, HGB, and EB virus DNA were independent influencing factors for the prognosis of ENKTL patients (P<0.05). In this study, the predictive performance of the prognostic factors is superior to the international prognostic index, Korean prognostic index, and prognostic index of natural killer lymphoma. Conclusion: Gender, CA stage, ECOG PS score, HGB, and EB virus DNA are prognostic factors for ENKTL patients treated with pegaspargase/L-asparaginase.
Male ; Humans ; Middle Aged ; Asparaginase/therapeutic use* ; Prognosis ; Retrospective Studies ; Lymphoma, Extranodal NK-T-Cell/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Etoposide ; Cyclophosphamide ; Methotrexate/therapeutic use* ; DNA/therapeutic use* ; Treatment Outcome