Analysis of treatment results of concurrent and asynchronous radiochemotherapy for early extranodal NK/T cell lymphoma / 中华放射肿瘤学杂志

Objective:To compare the efficacy of concurrent and asynchronous radiochemotheray for early extranodal nasal natural killer/T-cell lymphoma (NKTCL).Methods:From 2007 to 2020, 278 patients with early NKTCL treated with comprehensive treatment in the Affiliated Tumor Hospital of Guizhou Medical University were recruited. According to the adjusted Nomogram-revised risk index (NRI) prognostic model, there were 49 cases in the good prognostic group without adverse prognostic factors (age>60 years old, increased serum lactate dehydrogenase (LDH), ECOG score ≥2, primary tumor invasion (PTI), Ann Arbor stage Ⅱ, and 229 cases in the poor prognostic group with any adverse prognostic factors. 145 of these cases were treated with concurrent radiochemotherapy, and 133 of them were treated with asynchronous radiochemotherapy.Results:The 5-year overall survival (OS) rate of the whole group was 71.0%, and the progression-free survival (PFS) rate was 67.6%. The 5-year OS rate in the good prognostic group was 95.6%, and 65.4% in the poor prognostic group ( P<0.001). In the poor prognostic group, the 5-year OS rates of patients with NRI=1(low-and moderate-risk group), NRI=2(moderate-and high-risk group), NRI≥3(high-risk group) were 72.1%, 61.1% and 47.7%, respectively ( P=0.007). There was no significant difference in curative effect between the concurrent and asynchronous radiochemotherapy groups. The 5-year OS rates were 70.6% and 69.8%( P=0.783), and the 5-year PFS rates were 67.6% and 65.2%( P=0.631). Further stratified analysis showed that the 5-year OS rates of patients with NRI=1 receiving concurrent and asynchronous radiochemotherapy were 73.1% and 76.5%( P=0.576), 62.6% and 69.3%( P=0.427) for those with NRI=2, and 58.1% and 42.3% for those with NRI≥3( P=0.954). Conclusions:Comprehensive treatment can significantly improve the prognosis of early NKTCL in the poor prognostic group. In the sequence of radiotherapy and chemotherapy, there is no significant difference in 5-year OS and PFS rates between concurrent and asynchronous radiochemotherapy. Sequential treatment with better tolerance can be adopted for early NKTCL with poor prognosis.

Prognostic analysis of early stage extranodal natural-killer/T cell lymphoma treated with induced chemotherapy combined with radiotherapy / 中华放射肿瘤学杂志

Objective:To analyze the efficacy and prognostic factors of induced chemotherapy combined with radiotherapy in the treatment of early stage extranodal natural-killer/T cell lymphoma (ENKTCL).Methods:Two hundred and eighty-seven early stage NKTCL patients were treated in Affiliated Cancer Hospital of Guizhou Medical University from October 2003 to October 2021. All patients were aD ministrated with short courses of induced chemotherapy combined with radiotherapy. Clinical prognostic factors of early stage NKTCL were analyzed. The overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan- Meier method, log-rank test was conducted for univariate analysis and Cox models were performed for multivariate analysis. Results:The 5-year OS and PFS were 72.8% and 68.9% in all patients. According to Nomogram risk index (NRI) prognostic model, 286 patients were divided into the low risk (NRI=0), intermediate low risk (NRI=1), intermediate high risk (NRI=2), high risk (NRI=3) and very high risk (NRI≥4) groups. In these 5 groups, the 5-year OS were 95.6%, 76.3%, 69.5%, 61.0% and 23.3%(all P<0.001), and the 5-year PFS were 93, 2%, 69.8%, 64.6%, 60.2% and 23.3%(all P<0.001), respectively. In the radiotherapy with a dose of ≥50 Gy and<50 Gy groups, the 5-year OS were 73.8% and 65.9%( P=0.123) and the 5-year PFS were 72.8% and 45.3%( P=0.001). According to the response to induced chemotherapy of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD), the 5-year OS were 85.4%, 74.0%, 61.8% and 28.5%(all P<0.001), and the 5-year PFS were 83.7%, 66.8%, 65.7% and 27.4%(all P<0.001), respectively. Univariate analyses showed that stage Ⅱ, ECOG≥2, primary tumor invasion, radiotherapy dose<50 Gy and short-term efficacy of induced chemotherapy were poor prognostic factors for the 5-year OS and PFS (all P<0.05). Multivariate analyses demonstrated that primary tumor invasion, ECOG≥2 and stage Ⅱ were poor prognostic factors for OS (all P<0.05), and primary tumor invasion and ECOG≥2 were poor prognostic factors for PFS (all P<0.05). Conclusions:Early stage NKTCL patients can obtain high efficacy after induced chemotherapy combined with radiotherapy. Complete response to induced chemotherapy is associated with favorable prognosis.

Prognostic analysis of early stage extranodal natural-killer/T cell lymphoma / 中华放射肿瘤学杂志

Objective:To analyze the efficacy and prognostic factors of radiotherapy combined with asparaginase/peaspartase-based chemotherapy regimen in the treatment of early stage extranodal natural-killer/T cell lymphoma of the upper aerodigestive tract (UADT ENKTCL).Methods:267 early stage UADT ENKTCL patients were treated in Guizhou Cancer Hospital from October 2003 to February 2020. Among them, 229 patients received radiotherapy or radiotherapy combined with menpartaminase/permenidase-based chemotherapy regimen and 38 patients were treated with radiotherapy or chemotherapy alone. The overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan- Meier method, log-rank test was conducted for univariate analysis and Cox regression model was performed for multivariate analysis. Results:The 5-year OS and PFS were 67.2% and 61.5% in all patients. The 5-year OS and PFS in patients treated with radiotherapy combined with chemotherapy, radiotherapy alone and chemotherapy alone were 71.7%, 35% and 49%(all P<0.001), and 66.4%, 35% and 28%(all P<0.001), respectively. According to the NRI risk stratification, 246 patients treated with radiotherapy and chemotherapy were divided into the favourable and the unfavourable prognosis groups. The 5-year OS was 93.3% and 64.3%( P<0.001) and the 5-year PFS was 91.1% and 56.7%( P<0.001) in two groups. For patients receiving radiotherapy with a dose ≥50 Gy and<50 Gy, the 5-year OS was 72.4% and 55.7%( P<0.001), and the 5-year PFS was 68.3%, and 36.5%( P<0.001). In the unfavourable prognosis group, the 5-year OS of patients receiving ≥ 4 and<4 cycles of chemotherapy was 65.5% and 59.2%( P=0.049), and the 5-year PFS was 60.7% and 50.6%( P=0.018). Univariate analysis showed that stage Ⅱ, ECOG≥2, primary tumor invasion, radiotherapy alone, NRI≥1(Nomogram-revised risk index), EBV-DNA≥2 750 copies/ml, radiotherapy dose < 50 Gy, and<4 cycles of chemotherapy were associated with unfavorable 5-year OS and PFS (all P<0.05), and CHOP-like regimen was the risk factor of unfavorable 5-year PFS ( P<0.05). Multivariate analysis demonstrated that primary tumor invasion, ECOG≥2, and radiotherapy dose <50 Gy were associated with unfavorable OS and PFS (all P<0.05), and stage Ⅱ was the risk factor of unfavorable 5-year OS ( P<0.05). Conclusions:The prognosis of early stage low-risk UADT ENKTCL of is favourable. Sufficient dose of extended involved-field radiotherapy is an important curative modality in early stage UADT ENKTCL. Compared with radiotherapy alone, radiotherapy combined with chemotherapy can significantly improve the prognosis of early stage UADT ENKTCL patients in the unfavourable prognosis group. Full-course chemotherapy can significantly prolong the long-term survival in the unfavorable prognosis group. The chemotherapy containing asparaginase can significantly enhance the prognosis of patients with early stage UADT ENKTCL.

Detection of high-frequency mutant genes in extranodal NK/T cell lymphoma by next-generation sequencing technology and its clinical significance / 中国肿瘤生物治疗杂志

@# Objective: To analyze the mutation of target genes in extranodal natural killer/T-cell lymphoma (ENKTL) by using nextgeneration sequencing, and to explore its relationship with prognosis and clinical characteristics, as to provide evidence for the pathogenesis, clinical diagnosis and targeted therapy of ENKTL. Methods: According to previous literature reports, the genes whose mutations can affect the development of lymphoma were selected as the target genes for this study. 29 patients with ENKTL, who were newly diagnosed at the Fourth Hospital of Hebei Medical University from August 2010 to October 2018, were selected for this study. The mutation of 9 target genes in the specimen was detected by thenext-generationsequencingtechnology.Therelationshipsamongclinicalfeatures,diseaseprognosisandmutationofthetargetgeneswereanalyzedbySPSS21.0statisticalsoftware.Results： ：Ninetargetgenes were were screened. AT-rich interactive-domain 1A(ARID1A) gene showed the highest mutation rate in ENKTL (10 cases, 34.48%) followedbylysinemethyltransferase2D(KMT2D)gene(31.03%)andtumorprotein P53 (TP53) gene (24.13%). Kaplan-Meier survival analysis showed that the overall survival of ENKTL patients with KMT2D gene wild type was significantly better than patients with KMT2D gene mutation (P=0.006). The KMT2D gene mutation was found to besignificantlyrelatedtoclinicalstage,CRP,albumin,lymphocyte count and Ki67 expression in ENKTL patients (all P<0.05). COX regression analysis showed that KMT2D gene mutation was an independent adverse prognostic factor (P<0.05). Conclusion: The KMT2D gene has a high mutant frequency in ENKTL and is associated with patients’prognosis, suggesting that KMT2D gene plays an important role in the initiation and development of ENKTL. It could be used as a clinical therapeutic target for ENKTL.

Screening of a novel CRM1 targeting inhibitor and its effects on the proliferation and growth of extranodal NK/T cell lymphoma / 中国药科大学学报

@#The purpose of this study was to screen out the novel chromosome maintenance protein 1(CRM1)covalent targeting inhibitors by computer-assisted drug design(CADD), and to study their effects on the proliferation of extranodal nature killer/T cell lymphoma(ENKTL). A novel CRM1 inhibitor LFS-829 was designed based on the molecular structure of LFS-01 by means of ADME/T and covalent docking. The target binding of LFS-829 with CRM1 was analyzed by MALDI-TOF mass spectrometry. The effects of LFS-829 on the proliferation of extranodal NK/T cell lymphoma SNK6 and HANK-1 cells were detected by CCK-8. The cell morphology was observed by live cell workstation. Immunofluorescence experiments were used to analyze the effect of LFS-829 on nuclear export function of CRM1. The changes of NF-κB signaling pathway under different concentrations of LFS-829 were analyzed by Western blot, dual luciferase reporter gene assay and enzyme-linked immunosorbent assay. Apoptosis was detected by flow cytometry, and the expression of proteins related to apoptosis pathway was detected by Western blot. Tests of peripheral blood mononuclear lymphocyte(PBMC)toxicity, platelet toxicity and mouse acute toxicity were done to make sure that it is not harmful to human. LFS-829 could bind covalently to the cysteine residue of the hydrophobic active pocket of CRM1. LFS-829 could selectively kill SNK6 and HANK-1 cells, with IC50 of 366 nmol/L and 158 nmol/L in 72 h, respectively, and cell morphology was significantly changed. LFS-829 at 800 nmol/L significantly inhibited the nuclear export function of CRM1, promoted nuclear assembly of IκB-α, down-regulated the transcriptional activity of NF-κB signaling pathway, significantly up-regulated the expression of apoptotic pathway protein p53, cleaved Caspase 3 and cleaved Caspase 9 and induced apoptosis, with no obvious killing effect on PBMC or platelets. It did not cause substantial tissue damage to mice at the high dose of 300 mg/kg, which shows its great prospect of future application.

Linfoma NK/T extra nodal, tipo nasal, con compromiso cutáneo primario: reporte de un caso / Extranodal Natural Killer/T-Cell Lymphoma, nasal-type with primary cutaneous involvement: a case report

INTRODUCCIÓN: El linfoma extranodal natural killer/célula T (NK/T) de tipo nasal, es una neoplasia poco frecuente, con una alta letalidad, caracterizada por destrucción ósea alrededor de los senos paranasales, el septum nasal u obstrucción de la vía aérea. Puede presentar compromiso primario de la piel, vía aérea y otros órganos. OBJETIVO: Presentar un caso ilustrativo de una afección poco frecuente y de curso agresivo en población pediátrica, para facilitar la sospecha diagnóstica y el rápido reconocimiento por parte de los especialistas. CASO CLÍNICO: Adolescente de 14 años, que consultó por lesiones solevantadas en brazos y piernas, no dolorosas, sugerentes de paniculitis subcutánea, las cuales evolucionaron a máculas violáceas ulceradas. La biopsia de las lesiones fue compatible con linfoma NK/T de tipo nasal. Fue derivada a oncología pediátrica, donde recibió tratamiento quimioterápico. Pese a los esfuerzos médicos, la paciente falleció a los 8 meses producto de una infección pulmonar grave secundaria a inmunosupresión. CONCLUSIONES: El linfoma extranodal NK/T, tipo nasal es una neoplasia poco frecuente, que se comporta de forma agresiva, con una alta mortalidad sin tratamiento. Por lo que su reconocimiento es de gran relevancia para el diagnóstico precoz y rápida derivación a Hemato-Oncología.

INTRODUCTION: Extranodal natural killer/T-cell lymphoma (NK/T), nasal type, is an infrequent neoplasm with a high lethality, characterized by bone destruction around the sinus, nasal septum or obstruction of the airway. Also, may be primary skin involvement, airway and other organs. OBJECTIVE: Submit a rare condition in the pediatric population, in order to facilitate the diagnostic suspicion and quick recognition from specialists. CASE REPORT: a 14-year-old girl, who presented arm and leg lesions, painless, suggestive of subcutaneous panniculitis, which evolve to ulcerated purple maculae. Skin biopsy showed lesion compatible with NK/T lymphoma, nasal type. She was referred to pediatric oncology, where she received chemotherapy treatment. Despite medical efforts, the patient died eight months after due to a serious pulmonary infection secondary to immunosuppression. CONCLUSIONS: Extranodal NK/T-cell lymphoma, nasal type, is a rare neoplasm that behaves aggressively, with high mortality without treatment, therefore, its recognition has a high importance for early diagnosis and prompt referral to Hematology-Oncology.

The prognostic value of 18F-FDG PET/CT in patients with extranodal natural killer/T-cell lymphoma / 中国肿瘤临床

Extranodal natural killer/T-cell lymphoma(ENKTL)is an Epstein-Barr virus-associated aggressive non-Hodgkin's lymphoma (NHL).It is prevalent in Asia and South America with an aggressive clinical course and a dismal prognosis.Currently,the prognostic models that are commonly used for ENKTL include the International Prognostic Index(IPI),Korean Prognostic Index(KPI),Prognostic In-dex of Natural Killer Cell Lymphoma(PINK),and Prognostic Index of Natural Killer Cell Lymphoma with Epstein-Barr virus DNA(PINK-E), all of which have some limitations.Positron emission tomography/computed tomography(PET/CT)is a new imaging technique combin-ing anatomical and functional imaging,with the advantages of high sensitivity and specificity,which is essential for diagnosis,staging, efficacy evaluation,and prognosis prediction of various malignant lymphomas.However,the prognostic value of PET/CT in ENKTL re-mains controversial.Therefore,in this article,we review relevant studies on the prognostic value of pretreatment,interim,and end-of-treatment PET/CT in patients with ENKTL.

Preliminary results of a phase Ⅱ prospective clinical study of early-stage nasal NK/T-cell lymphoma with extended involved-field intensity-modulated radiotherapy / 中华放射肿瘤学杂志

Objective To investigate the feasibility of the scheme of target volume delineation with extended involved?field intensity?modulated radiotherapy (IMRT) for patients with early?stage nasal NK/ T?cell lymphoma (NC?NKTL). Methods Twenty?one patients with stage IE?IIE NC?NKTL were treated with short?course chemotherapy combined with radiotherapy from 2011 to 2013. The majority of patients received the GELOX regimen. All patients received extended involved?field IMRT with a dose of 54?? 6 Gy in 26 fractions for gross tumor volume, 50?? 7 Gy in 26 fractions for high?risk clinical target volume (CTV), and 45?? 5 Gy in 26 fractions for low?risk CTV. The dose distribution, short?term treatment outcomes, and adverse reactions were analyzed. Results The 2?year sample size was 12. The 2?year follow?up rate was 100%. The 2?year local control rate ( LRC) was 100%. The 2?year overall and progression?free survival rates were 90?? 5% and 90?? 5%, respectively. The median coverage rates of planning target volumes with 90% of the prescribed doses of 54?? 6 Gy, 50?? 7 Gy, and 45?? 5 Gy were 99?? 8%, 99?? 6%, and 99?? 7%, respectively. No grade 3 or 4 adverse reactions were observed in patients. Conclusions The scheme of target volume delineation and dose configuration in our study not only achieves excellent target volume coverage, but also reduces adverse reactions in patients, which achieves a 2?year LRC ideal for patients with early?stage NC?NKTL.

Detecting EB virus to determine curative effect in extranodal natu-ral killer/T-cell lymphoma / 中国肿瘤临床

Objective:To investigate the clinical significance of detecting Epstein Barr virus (EBV) infection in evaluating recent curative and long-term effects in patients with extranodal natural killer (NK)/T-cell lymphoma. Methods:The EBV-DNA copies in the plasma of 109 patients, who were pathologically and immunohistochemically diagnosed with extranodal natural killer/T-cell lymphoma in the First Affiliated Hospital of Zhengzhou University between January 2011 and April 2014, were monitored via quantitative re-al-time polymerase chain reaction. Subsequently, the difference in recent curative and long-term effects between EBV positive and EBV negative patients was compared. Results:Among the 109 patients with extranodal NK/T-cell lymphoma, 34 (64.2%) cases of EBV posi-tive patients were at the advanced stage (Ⅲ~Ⅳ stages), and 22 (39.3%) cases of EBV negative patients were at the terminal stage (Ⅲ~Ⅳstages). EBV positive patients who accompanied by B symptoms were 33 (62.3%) , and there were 21 (37.5%) cases with B symptoms in EBV negative patients, the differences between stages and B symptoms were statistically significant. The attained objec-tive response rate of the EBV-DNA negative patients (34, 60.7%) was significantly higher than that of the EBV-DNA positive patients (22, 41.5%) (P<0.05). Similarly, the 2-year progression-free survival (PFS) rate of EBV negative patients was better than that of EBV positive patients (P<0.05). Conclusion:Detecting EBV in plasma has clinical significance in evaluating the recent curative effect and the 2-year PFS rate in patients diagnosed with extranodal NK/T-cell lymphoma.