miRNA-155 Modulates the Malignant Biological Characteristics of NK/T-Cell Lymphoma Cells by Targeting FOXO3a Gene

This study investigated the effects of miRNA-155 on malignant biological characteristics of NK/T-cell lymphoma cell lines and the possible mechanism. The expression of miRNA-155 was detected in lymphoma cell lines from different sources （SNK-6, YTS, Jurkat and DOHH2） by real-time PCR. Lentiviral vectors （pLL3.7） that could overexpress or downexpress miRNA-155 were constructed. Recombinant lentiviral particles were prepared and purified, and their titers determined. The expression of miRNA-155 in the infected SNK-6 cells and the cell proliferation were detected by PCR and CCK-8, respectively. Flow cytometry was used to determine the apoptosis of infected SNK-6 cells. The target of miRNA155 was predicted from Targetscan website. The effect of miRNA155 on FOXO3a expression was examined by Western blotting. The results showed that among the human NK/T-cell lymphoma cell lines SNK-6, YTS, Jurkat and DOHH2, the expression of miRNA-155 was highest in SNK-6. The infection efficiency of the recombinant lentivirns in SNK-6 was more than 70% at multiplicity of infection （MOI） of 100. The expression of miRNA-155 was significantly increased in SNK-6 cells infected by lentivirus vectors with high expression of miRNA-155 （4 times higher than the control group）, and profoundly decreased in those infected with lentivirnses with low expression of miRNA-155. The proliferation of letivirns-infected SNK-6 cells was decreased as the expression of miRNA-155 reduced. The apoptosis rate was increased with the reduction in the expression of miRNA-155. FOXO3a was found to be a possible target of miRNA155, as suggested by Targetscan website. Western blotting showed that the expression of FOXO3a was significantly elevated in SNK-6 cells with miRNA-155 inhibition. It was concluded that reduction in miRNA-155 expression can inhibit the proliferation of SNK-6 lymphoma cells and promote their apoptosis, which may be associated with regulation of FOXO3a gene.

Gastrosplenic fistula occurring in lymphoma patients: Systematic review with a new case of extranodal NK/T-cell lymphoma

AIM To provide the overall spectrum of gastrosplenic fistula(GSF) occurring in lymphomas through a systematic review including a patient at our hospital.METHODS A comprehensive literature search was performed in the MEDLINE database to identify studies of GSF occurring in lymphomas. A computerized search of our institutional database was also performed. In all cases, we analyzed the clinicopathologic/radiologic features, treatment and outcome of GSF occurring in lymphomas. RESULTS A literature search identified 25 relevant studies with 26 patients. Our institutional data search added 1 patient. Systematic review of the total 27 cases revealed that GSF occurred mainly in diffuse, large B-cell lymphoma(n = 23), but also in diffuse, histiocytic lymphoma(n = 1), Hodgkin's lymphoma(n = 2), and NK/T-cell lymphoma(n = 1, our patient). The common clinical presentations are constitutional symptoms(n = 20) and abdominal pain(n = 17), although acute gastrointestinal bleeding(n = 6) and infection symptoms due to splenic abscess(n = 3) are also noted. In all patients, computed tomography scanning was very helpful for diagnosing GSF and for evaluating the lymphoma extent. GSF could occur either post-chemotherapy(n = 10) or spontaneously(n = 17). Surgical resection has been the most common treatment. Once patients have recovered from the acute illness status after undergoing surgery, their long-term outcome has been favorable. CONCLUSION This systematic review provides an overview of GSF occurring in lymphomas, and will be helpful in making physicians aware of this rare disease entity.

Primary Testicular NK/T-Cell Lymphoma:A Study of Two Cases and Review of Literature

Primary testicular NK/T-cell lymphoma is an extremely rare entity progressed rapidly.The aim of this study was to examine clinical and pathological features of primary testicular NK/T-cell lymphoma and to investigate the effective diagnosis and prognosis.In this paper,the two cases of primary testicular NK/T-cell lymphoma were observed by light microscopy,immunohistochemistry and examined by in situ hybridization for Epstein-Barr Virus（EBV） DNA and the literatures were reviewed.The two patients respectively present with bilateral and right-side painless testicular enlargement.The morphology of neoplastic cells of case 1 were small to medium,tumor cells of case 2 were small,medium and large mixed.The tumor cells grew diffusely with irregular and distort nuclear,destructed the organizational structure of the normal testis,and damaged blood vessels,meanwhile,coagulation necrosis was exist.Immunohistochemical staining of neoplastic cells showed positive for CD45,CD2,CD56,CD3ε（cytoplasm staining pattern）,CD45RO and Granzyme B,and negative for CD57,CD20,CD79α,CD30,CK,MPO,TdT,Bcl-2 and PLAP were negative.In addition,the EBV DNA was detected in the lymphoma by In situ hybridization.In conclusion,the expression of CD56,CD3ε,and Granzyme B associated proteins and EBV examination by in situ hybridization play a vital role in diagnosis and differential diagnosis of primary testicular NK/T-cell lymphoma.

Intestinal T-cell lymphomas:A retrospective analysis of 68 cases in China

AIM: To investigate the clinical features, diagnosis, treatment and prognosis of intestinal T-cell lymphomas (ITCL) by retrospective analysis.

EB病毒在结外NK/T细胞淋巴瘤中的预后价值:一项淮海淋巴瘤协作组的多中心回顾性研究

目的 基于倾向性评分逆处理概率加权(IPTW)法评估EB病毒(EBV)在结外NK/T细胞淋巴瘤患者中的预后价值。方法 收集2012年10月—2021年4月淮海淋巴瘤协作组中8家医疗机构初诊为结外NK/T细胞淋巴瘤且具有全血EBV-DNA数据的468例患者的临床资料。采用IPTW法分析EBV载量对结外NK/T细胞淋巴瘤患者生存期的影响;采用Cox比例风险模型进行多因素分析;绘制Kaplan-Meier曲线,组间比较采用Log rank χ~2检验。结果 468例结外NK/T细胞淋巴瘤患者中,EBV-DNA阳性266例,EBV-DNA阴性202例。EBV-DNA阳性组和阴性组患者的5年OS分别为62.5%和89.2%,两组比较,经Log rank χ~2检验,差异有统计学意义(χ~2=42.900,P=0.000)。IPTW前,两组的美国东部肿瘤协作组(ECOG)活动状态(PS)评分(ECOG PS评分)、原发部位、CA分期、Ann Arbor分期、白蛋白、乳酸脱氢酶、治疗方案比较,差异均有统计学意义(P<0.05)。IPTW后,EBV-DNA阳性组和阴性组组间均衡,EBV-DNA阴性组患者5年OS为90.7%,而EBV-DNA阳性组患者5年OS为63.5%。Cox比例风险模型分析结果 显示,EBV-DNA阳性[■=4.244(95%CI:2.457,7.332)]、ECOG PS≥2分[■=2.020(95%CI:1.171,3.483)]是结外NK/T细胞淋巴瘤患者预后的不良影响因素(P<0.05)。结论 经IPTW法平衡混杂因素后,EBV-DNA阴性患者生存情况明显优于EBV-DNA阳性患者。

Extranodal natural killer/T-cell lymphoma,nasal type:epidemiology study

Extranodal natural killer （NK）IT-cell lymphoma, nasal type （ENKTCL） is a rarely kind of non-Hodgkin lymphoma （NHL）. It is much more frequent in Asian and Latin American countries than other part of the world. It typically affects nasal cavity. In China, one of its endemically places, ENKTCL accounts for 74%-96% of nasal NHL. Patients with ENKTCL usually show a highly aggressive clinical course, and its etiology is unclear. However, it is already proved that ENKTCL is associated with Epstein-Barr virus （EBV） infection, regardless patients＇, ethnicity and areas. Some studies show that the risk will increase among several occupations, such as farmer, who are frequently exposure to pesticides and chemical solvent and risk can be cut down if taking some protective measures.

Three-dimensional conformal radiotherapy plus concurrent DICE chemotherapy for early-stage nasal-type natural killer/T-cell lymphoma of Waldeyer's ring: A single-institution study

Objective Nasal-type natural killer/T-cell lymphoma of Waldeyer＇s ring （WR-NK/TL） has different clinico- pathological characteristics from those of other subtypes of NK/T lymphoma; thus, the optimal treatment remains unclear. To find a more effective treatment model for WR-NK/TL, we conducted a single-center study of concurrent radiochemotherapy. Methods Forty-five patients with newly diagnosed stage IE to liE WR-NKTL were randomly divided into two groups. The 23 cases in the concurrent radiochemotherapy group were treated with three-dimensional conformal radiotherapy （48-52 Gy） and 2 courses of DICE （dexamethasone, ifosfamide, cisplatin, and etoposide） synchronous chemotherapy. The 22 cases in the radiotherapy group only received three-dimen- sional conformal radiotherapy （50-54 Gy）. The primary end points were overall survival （OS）, progression- free survival （PFS）, and toxicity. Results The 1-, 3-, and 4-year OS and PFS rates were 95.5%, 65.6%, and 45.9%, and 86.4%, 56.0%, and 46.7% in the radiotherapy group, and 100%, 88.5%, and 88.5%, and 100%, 82.0%, and 73.8% in the concurrent radiochemotherapy group, respectively. The OS （P = 0.0477） and PFS rates （P = 0.0488） were higher in the concurrent radiochemotherapy group than in the radiotherapy group. The overall re- sponse rate was 100% in both the radiotherapy group [complete response （CR）, 18 cases] and concurrent radiochemotherapy group （CR, 22 cases）. The concurrent radiochemotherapy group had more severe side effects, especially grade 3 ＋ 4 events, such as leukopenia, anorexia, and stomatitis. However, side effects benefiting from excellent oral care were endurable. Conclusion Radiotherapy plus concurrent DICE chemotherapy may be an effective and safe compre- hensive treatment for patients with WR-NKTL.

原发皮肤的儿童结外NK/T细胞淋巴瘤-鼻外型1例及文献复习

目的报道1例原发皮肤的儿童结外NK/T细胞淋巴瘤,鼻外型,并回顾文献,学习该病的临床特征、组织病理、免疫组化及治疗预后特点,以提高临床医生对该病的认识。方法分析本例原发皮肤的儿童结外NK/T细胞淋巴瘤-鼻外型患者的临床表现、辅助检查、病理组化及治疗预后,并复习近年国内外相关文献。结果 11岁男性患儿表现为皮肤结节、斑块伴乏力,肝脾淋巴结明显肿大。实验室检查示白细胞和血小板降低,肝酶升高,乳酸脱氢酶升高,凝血时间延长,血液EBV-PCR高度复制。组织病理提示局部或弥漫大小不一淋巴细胞浸润,可见核碎裂,部分细胞核大深染。免疫组化:CD3(+)、CD20(-)、CD56(+++)、颗粒酶B(+)、T细胞胞浆内抗原-1(+)、Ki-67约30%~40%(+);EB病毒编码RNA原位杂交(+++)。诊断:原发皮肤的结外NK/T细胞淋巴瘤,鼻外型。告知病情后家属放弃治疗。结论不同于鼻型,本病的临床表现特异性不高,易误诊为脂膜炎等,多合并系统受累,确诊依靠组织病理、免疫组化、EBV病原学检验及结合临床表现。尽管采用强势化疗,本病仍预后不良。

Clinicopathology, immunophenotype, T cell receptor gene rearrangement, Epstein-Barr virus status andp53 gene mutation of cutaneous extranodal NK/T-cell lymphoma, nasal-type

Background Extranodal natural killer/T-cell （NK/T cell） lymphoma, nasal-type, is a rare lymphoma. Skin is the second most common site of involvement after the nasal cavity/nasalpharynx. The aim of this study was to investigate the clinicopathologic features, immunophenotype, T cell receptor （TCR） gene rearrangement, the association with Epstein-Barr virus （EBV） infection and p53 gene mutations of the lymphoma. Methods The clinicopathologic analysis, immunohistochemistry, in situ hybridization for EBERI/2, TCR gene rearrangement by polymerase chain reaction （PCR）, mutations of p53 gene analyzed by PCR and sequence analysis were employed in this study. Results In the 19 cases, the tumor primarily involved the dermis and subcutaneous layer. Immunohistochemical staining showed that most of the cases expressed CD45RO, CD56, CD3E, TIA-1 and GrB. Three cases were positive for CD3 and two cases were positive for CD30. Monoclonal TCRy gene rearrangement was found in 7 of 18 cases. The positive rate of EBERI/2 was 100%. No p53 gene mutation was detected on the exon 4-9 in the 18 cases. Fifteen cases showed Pro （proline）/Arg （arginine） single nucleotide polymorphisms （SNPs） on the exon 4 at codon 72. The expression of p53 protein was 72% （13/18）immunohistochemically. Conclusions Cutaneous NK/T-cell lymphoma is a rare but highly aggressive lymphoma with poor prognosis. No p53 gene mutation was detected on the exon 4-9, and Pro/Arg SNPs on p53 codon 72 were detected in the cutaneous NK/T-cell lymphoma. The overexpression of p53 protein may not be the result of p53 gene mutation.

Gambogic acid induces cell apoptosis through endoplasmic reticulum stress triggered inhibition of Akt signaling pathways in extranodal NK/T-cell lymphoma cells

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.

MiRNAs and lncRNAs in NK cell biology and NK/T-cell lymphoma

The important role of lncRNAs and miRNAs in directing immune responses has become increasingly clear.Recent evidence conforms that miRNAs and lncRNAs are involved in NK cell biology and diseases through RNAeprotein,RNAeRNA,or RNAeDNA interactions.In this view,we summarize the contribution of miRNAs and lncRNAs to NK cell lineage devel-opment,activation and function,highlight the biological significance of functional miRNAs or lncRNAs in NKTL and discuss the potential of these miRNAs and lncRNAs as innovative bio-markers/targets for NKTL early diagnosis,target treatment and prognostic evaluations.

Progress in the treatment of NK-cell lymphoma/leukemia

Natural killer(NK)/T cell lymphoma includes two major subtypes of disease,specifically extranodal NK/T cell lymphoma,nasal type(ENKL)and aggressive NK cell leukemia(ANKL).Both are strongly associated with Epstein Barr virus and are prevalent in East Asia and Latin America.Except for that of limited-stage ENKL,the prognosis of both diseases was poor in the previous decade.The advent of non-anthracycline-based chemoradiotherapy has contributed to an improvement in ENKL prognosis,but there is still room for further treatment progress.Recently,the high efficacy of PD-1 antibody was reported in relapsed or refractory ENKL patients.This was later supported by the finding that PD-L1/PD-L2 genetic alterations are frequently observed in ENKL and ANKL patients.Due to the rarity of the disease,a standard treatment for ANKL remains to be established.Currently,allogeneic stem cell transplantation is the only curative treatment,and this is even applicable to chemo-resistant ANKL patients.In this review,we focus on recent treatment approaches for NK/T cell lymphomas including novel agents.

鼻外NK/T细胞淋巴瘤21例临床特征及预后分析

目的 探讨鼻外NK/T细胞淋巴瘤的临床特征与预后.方法 对21例鼻外NK/T细胞淋巴瘤的病例资料进行回顾性分析,并复习相关文献.结果 患者以晚期、有B症状、体能状态（ECOG评分）2～4分、国际预后指数（IPI）3～5分和乳酸脱氢酶（LDH）升高者为多,除1例放弃治疗外,20例患者中,完全缓解5例,部分缓解1例,总生存率为30.0％.早期患者疗效较好,2例晚期合并噬血细胞综合征和弥散性血管内凝血的患者预后最差.结论 鼻外NK/T细胞淋巴瘤患者的预后较差,临床分期、ECOG、IPI和LDH是影响预后的主要因素.

14-3-3ζ蛋白在晚期NK／T细胞淋巴瘤患者中的表达及其意义

结外NK／T细胞淋巴瘤，鼻型（extranodal natural killer／T-cell lymphoma，nasal—type，ENKTL）是一类高度侵袭性，具有特殊形态、免疫表型和生物学行为的非霍奇金淋巴瘤（NHL），其在亚洲多发而西方国家少见。

鼻型结外NK/T细胞淋巴瘤诊治进展

鼻型结外NK/T细胞淋巴瘤临床常见且治疗效果不佳、预后差，早期、正确的诊断以及有效的治疗对于提高患者的预后有重要作用。本文对近年来鼻型结外NK/T细胞淋巴瘤在诊断及治疗方面的进展做一综述。

P-GEMOX方案一线治疗原发鼻外鼻型NK/T细胞淋巴瘤临床观察

目的探讨以P-GEMOX(培门冬酶、吉西他滨、奥沙利铂)方案作为一线方案治疗原发鼻外鼻型NK/T细胞淋巴瘤(NKTCL)的临床疗效。方法回顾性分析深圳市人民医院2015年9月至2018年10月收治的一线接受P-GEMOX方案化疗的7例原发鼻外鼻型NKTCL患者的临床表现、治疗反应及预后。结果7例原发鼻外鼻型NKTCL患者中位发病年龄41岁(27~74岁),男性多见(6例);原发及侵犯的鼻外部位包括回盲部、淋巴结、皮肤、睾丸、肾上腺、中枢神经系统等。患者一线采用P-GEMOX方案化疗,虽部分患者能获得短暂疗效,但最终所有患者均快速进展并死亡,总生存期2周至21个月。结论P-GEMOX方案一线治疗原发鼻外的鼻型NKTCL近期疗效尚可,但远期疗效较差。