CAR-T cells targeting CD38 and LMP1 exhibit robust antitumour activity against NK/T cell lymphoma.

BACKGROUND: Natural killer/T cell lymphoma (NKTCL) is an aggressive lymphoma with a poor prognosis. Chimeric antigen receptor-transduced T (CAR-T) cell therapy has become a promising immunotherapeutic strategy against haematologic malignancies. METHODS: In this study, four CAR-T cell lines (CD38-CAR, LMP1-CAR, CD38-LMP1 tandem CAR 1 and CD38-LMP1 tandem CAR 2) were generated. The effect of CAR-T cells against NKTCL cells was evaluated both in vitro and in vivo. Expression of T cell activation markers and cytokines produced by CAR-T cells were detected by flow cytometry. RESULTS: The four CAR-T cell lines could effectively eliminate malignant NKTCL cells. They could be activated and produce inflammatory cytokines in a target-dependent manner. In vivo tests showed that the CAR-T cells exhibited significant antitumour effects in a xenotransplanted NKTCL mouse model. CONCLUSIONS: In summary, four CAR-T cell lines exhibited significant cytotoxicity against NKTCL cells both in vitro and in vivo. These results indicated the effective therapeutic promise of CD38 and LMP1 CAR-T cells in NKTCL.

Enhanced efficacy of combined fluzoparib and chidamide targeting in natural killer/T-cell lymphoma.

The treatment of natural killer/T-cell lymphoma (NKTCL) presents an onerous challenge, and a search for new therapeutic targets is urgently needed. Poly ADP-ribose polymerase inhibitors (PARPi) were initially used to treat breast and ovarian cancers with BRCA1/2 mutations. Their excellent antitumor efficacy led to a series of clinical trials conducted in other malignancies. However, the exploration of PARPi and their potential use in combination treatments for NKTCL remains unexplored. We treated NKTCL cell lines with fluzoparib (a novel inhibitor of PARP) and chidamide (a classical inhibitor of HDACs) to explore their cytotoxic effects in vitro. Then, their antitumor efficacy in vivo was confirmed in YT-luciferin xenograft mouse models. Fluzoparib or chidamide alone inhibited NKTCL cell proliferation in a dose-dependent manner. Cotreatment with both drugs synergistically induced excessive accumulation of DNA double-strand breaks and massive apoptotic cell death by inhibiting the DNA damage repair pathway, as shown by the decreased protein levels of p-ATM, p-BRCA1, p-ATR, and Rad51. Moreover, the combination treatment apparently increased the level of intracellular reactive oxygen species (ROS) to enhance apoptosis, and pretreatment with an ROS scavenger reduced the proapoptotic effect by 30-60% in NKTCL cell lines. In vivo, this combined regimen also showed synergistic antitumor effects in xenograft mouse models. The combination of fluzoparib and chidamide showed synergistic effects against NKTCL both in vitro and in vivo and deserves further exploration in clinical trials.

Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells.

BACKGROUND: Extranodal natural killer/T cell lymphoma (NKTCL) is a highly aggressive type of non-Hodgkin lymphoma that facing the treatment challenges. Natural compounds are important sources for drug development because of their diverse biological and chemical properties, among which terpenoids have strong anticancer activities. METHODS: The human NK/T cell lymphoma cell line YT and peripheral blood lymphocytes isolated from NKTCL patients were treated with different concentrations of kayadiol. Then, the following experiments were performed: CCK-8 assay for cell viability, reactive oxygen species (ROS) and glutathione (GSH) assay and co-treatment with NAC, reduced GSH, or ferrostatin-1 for ferroptosis, the proteome profiling for elucidating signaling pathways, and western blot for the expression of p53, SCL7A11, and GPX4. siRNA and CRISPR/Cas9 plasmid for p53 knockout was designed and transfected into YT cells to evaluate the causal role of p53 in kayadiol-induced ferroptosis. The synergistic effect was evaluated by CCK8 assay after co-treatment of kayadiol with L-asparaginase or cisplatin. RESULTS: In this study, we found that kayadiol, a diterpenoid extracted from Torreya nucifera, exerted significant killing effect on NKTCL cells without killing the healthy lymphocytes. Subsequently, we observed that kayadiol treatment triggered significant ferroptosis events, including ROS accumulation and GSH depletion. ROS scavenger NAC, GSH, and ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed kayadiol-induced cell death in NKTCL cells. Furthermore, kayadiol decreased the expression of SLC7A11 and GPX4, the negative regulatory proteins for ferroptosis. We then demonstrated that p53 was the key mediator of kayadiol-induced ferroptosis by SLC7A11/GPX4 axis through p53 knockout experiments. In addition, kayadiol exerted a synergistic effect with L-asparaginase and cisplatin in NKTCL cells. CONCLUSION: Taken together, our results suggested that the natural product kayadiol exerted anticancer effects through p53-mediated ferroptosis in NK/T cell lymphoma cells. Hence, it can serve as an effective alternative in the treatment of NK/T cell lymphoma, especially for patients exhibiting chemoresistance.

CircADARB1 serves as a new biomarker in natural killer T-cell lymphoma and a potential regulator of p-Stat3.

BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is a rare and aggressive subtype of Non-Hodgkin's Lymphoma. CircRNA has shown great potential to become a biomarker in plasma. In this study, we aimed to determine circRNA for its diagnostic and prognostic value and biological function in NKTCL. METHOD: The circRNA microarray of plasma from NKTCL patients and healthy donors were conducted. The relative expressions of target circRNA were verified by qRT-PCR. We conducted function experiments in vitro and in vivo. Bioinformatics predicted the target miRNA of the target circRNA and the binding site was detected by the dual luciferase report assay. Downstream target protein was predicted and detected by western blot in vitro and immunohistochemistry in vivo. RESULT: By analyzing the plasma circRNA microarrays in NKTCL, 6137 circRNAs were up-regulated and 6190 circRNAs were down-regulated. The relative expressions of circADARB1 were significantly higher in NKTCL patients. The knockdown of circADARB1 inhibited proliferation of NKTCL cells in vitro and in vivo. CircADARB1 could bind to miR-214-3p in the downstream and regulate the expression of p-Stat3. In nude mice tumor tissue, p-Stat3 was under-expressed in the circADARB1 knockdown group. CONCLUSION: CircADARB1 was highly expressed in NKTCL plasma and circADARB1 was a potential biomarker to assist diagnosis and predict the response in NKTCL. CircADARB1 bound up to miR-214-3p and regulated p-Stat3.

Diagnostic approach to T- and NK-cell lymphoproliferative disorders in the gastrointestinal tract.

Most gastrointestinal NK and T cell lymphomas are aggressive in behavior, although in recent years a subset of indolent lymphoproliferative disorders have been described, which must be distinguished from their more malignant mimics. Intestinal T-cell lymphomas may arise from intra-epithelial lymphocytes and display epitheliotropism, such as enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. They are both aggressive in behavior but differ in their clinic-pathological features. On the other hand, intra-epithelial lymphocytes are not prominent in intestinal T-cell lymphoma, NOS, which is a diagnosis of exclusion and probably represents a heterogeneous group of entities. Indolent lymphoproliferative disorders of NK- and T-cells of both CD8 and CD4 subsets share a chronic, recurring clinical course but display differences from each other. CD8+ T-cell lymphoproliferative disorder of GI tract has a low proliferative fraction and does not progress nor undergo large cell transformation. Whilst NK-cell enteropathy runs an indolent clinical course, it may display a high proliferation fraction. On the other hand, CD4+ indolent T-cell lymphoproliferative disorder displays variable proliferation rates and may progress or transform after a number of years. In Asia and South America, it is not uncommon to see involvement of the gastrointestinal tract by EBV-associated extranodal NK/T cell lymphoma, nasal type, which must be distinguished from NK cell enteropathy and EBV-associated mucocutaneous ulcers.

PEG-L-CHOP treatment is safe and effective in adult extranodal NK/T-cell lymphoma with a low rate of clinical hypersensitivity.

BACKGROUND: The combination of chemotherapy and L-asparaginase (L-ASP) treatment significantly increased survival rate in an adult patient with extranodal natural killer (NK)/T-cell lymphoma (NKTCL). However, hypersensitivity reactions of L-ASP in some patients limited its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and longer circulating half-life than unconjugated L-ASP, and has been reported to be effective and well-tolerated in children with acute lymphoblastic leukemia. Cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and prednisolone (CHOP) is the most common chemotherapy for non-Hodgkin lymphoma. In this report, we sought to study the efficacy and safety of PEG-L- CHOP in NKTCL in adult Chinese patients. METHODS: Our study is a prospective, multi-center, open-label clinical trial. Patients with newly diagnosed adult NKTCL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included six cycles of PEG-L-CHOP regimen. Radiotherapy was scheduled after 2-4 cycles of PEG-L-CHOP regimen, depending on the stage and primary anatomic site. RESULTS: We enrolled a total of 33 eligible patients. All 33 patients completed 170 cycles of chemotherapy combined with radical radiotherapy. The overall response rate was 96.9% (32/33) with 75.8% (25/33) achieving complete responses and 21.2% (7/33) achieving partial responses. The overall survival (OS) at 1, 2, 3-year were 100, 90.61 and 80.54%, respectively. The major adverse effects were bone marrow suppression, reduction of fibrinogen level, liver dysfunction, and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded. CONCLUSIONS: PEG-L-CHOP chemotherapy in combination radiotherapy is safe and durably effective treatment for adult extranodal NK/T-cell lymphoma with fewer allergic reactions. This study was approved by the Peking University Beijing Cancer Hospital Ethics Review Committee (reference number: 2011101104). The clinical trial registration number ChiCTR1800016940 was registered on July 07, 2018 at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ). The clinical trial was registered retrospectively.

Successful treatment with anti-programmed-death-1 antibody in a relapsed natural killer/T-cell lymphoma patient with multi-line resistance: a case report.

BACKGROUND: Extranodal natural killer/T-cell lymphoma (NKTCL), nasal type, is an aggressive malignancy with poor prognosis. Currently, there is no recommended standard therapy for relapsed NKTCL. CASE PRESENTATION: A 37-year-old woman with lymphadenopathy was diagnosed with NKTCL by biopsy of an enlarged lymph node on the right side of her neck. Enhanced computed tomography revealed no metastasis. For this patient, we performed continuous chemotherapy followed by radiotherapy; however, nodule biopsy showed metastases in her lower limbs 3 months after radiotherapy, which confirmed disease progression. Unfortunately, the patient' s temperature was persistently high and her skin ulcers could not be controlled well using multi-line treatment. Therefore, we attempted treatment with the anti-programmed-death-1 (PD-1) antibody, pembrolizumab. Surprisingly, the patient achieved clinical complete remission (CR) after four cycles of pembrolizumab treatment, despite having persistent detectable Epstein-Barr virus (EBV) DNA. Other molecular monitoring techniques were unavailable for this patient owing to the retrospective nature of the study. The only adverse event was soreness of the upper limb joints and muscles. CONCLUSION: This relapsed NKTCL case treated with pembrolizumab showed that multimodal therapy including pembrolizumab would be partially or totally effective for relapsed NKTCL.

EBV DNA methylation profiles and its application in distinguishing nasopharyngeal carcinoma and nasal NK/T-cell lymphoma.

BACKGROUND: As an oncovirus, EBV is associated with multiple cancers, including solid tumors and hematological malignancies. EBV methylation plays an important role in regulating tumor occurrence. However, the EBV methylation profiles in EBV-associated tumor tissues are poorly understood. RESULTS: In this study, EBV methylation capture sequencing was conducted in several different tumor tissue samples, including NPC, EBVaGC, lung LELC and parotid LELC. Besides, EBV capture sequencing and following qMSP were performed on nasopharyngeal brushing samples from NPC and nasal NKTCL patients. Our results showed that the EBV genome among different types of tumors displayed specific methylation patterns. Among the four types of tumors from epithelial origin (NPC, EBVaGC, lung LELC and parotid LELC), the most significant differences were found between EBVaGC and the others. For example, in EBVaGC, all CpG sites within 1,44,189-1,45,136 bp of the EBV genome sequence on gene RPMS1 were hyper-methylated compared to the others. Differently, significant differences of EBV CpG sites, particularly those located on gene BILF2, were observed between NPC and nasal NKTCL patients in nasopharyngeal brushing samples. Further, the methylated level of BILF2 was further detected using qMSP, and a diagnostic model distinguishing NPC and nasal NKTCL was established. The AUC of the model was 0.9801 (95% CI 0.9524-1.0000), with the sensitivity and specificity of 98.81% (95% CI 93.63-99.94%) and 76.92% (95% CI 49.74-91.82%), respectively. CONCLUSIONS: Our study reveals more clues for further understanding the pathogenesis of EBV, and provides a possibility for distinguishing EBV-related tumor by detecting specific EBV CpG sites.

Single-Cell Analysis Reveals Malignant Cells Reshape the Cellular Landscape and Foster an Immunosuppressive Microenvironment of Extranodal NK/T-Cell Lymphoma.

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive type of lymphoma associated with Epstein-Barr virus (EBV) and characterized by heterogeneous tumor behaviors. To better understand the origins of the heterogeneity, this study utilizes single-cell RNA sequencing (scRNA-seq) analysis to profile the tumor microenvironment (TME) of NKTCL at the single-cell level. Together with in vitro and in vivo models, the study identifies a subset of LMP1+ malignant NK cells contributing to the tumorigenesis and development of heterogeneous malignant cells in NKTCL. Furthermore, malignant NK cells interact with various immunocytes via chemokines and their receptors, secrete substantial DPP4 that impairs the chemotaxis of immunocytes and regulates their infiltration. They also exhibit an immunosuppressive effect on T cells, which is further boosted by LMP1. Moreover, high transcription of EBV-encoded genes and low infiltration of tumor-associated macrophages (TAMs) are favorable prognostic indicators for NKTCL in multiple patient cohorts. This study for the first time deciphers the heterogeneous composition of NKTCL TME at single-cell resolution, highlighting the crucial role of malignant NK cells with EBV-encoded LMP1 in reshaping the cellular landscape and fostering an immunosuppressive microenvironment. These findings provide insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.

High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma.

NK/T-cell lymphoma (NKTCL) and γδ T-cell non-Hodgkin lymphomas (γδ T-NHL) are highly aggressive lymphomas that lack rationally designed therapies and rely on repurposed chemotherapeutics from other hematological cancers. Histone deacetylases (HDACs) have been targeted in a range of malignancies, including T-cell lymphomas. This study represents exploratory findings of HDAC6 inhibition in NKTCL and γδ T-NHL through a second-generation inhibitor NN-429. With nanomolar in vitro HDAC6 potency and high in vitro and in cellulo selectivity for HDAC6, NN-429 also exhibited long residence time and improved pharmacokinetic properties in contrast to older generation inhibitors. Following unique selective cytotoxicity towards γδ T-NHL and NKTCL, NN-429 demonstrated a synergistic relationship with the clinical agent etoposide and potential synergies with doxorubicin, cytarabine, and SNS-032 in these disease models, opening an avenue for combination treatment strategies.

The clinical characteristics and prognostic factors of 410 patients with natural killer/T-cell lymphoma.

PURPOSE: To investigate the clinical characteristics and prognostic factors of natural killer/T-cell lymphoma (NKTCL). METHODS: We retrospectively reviewed 410 NKTCL patients admitted to our lymphoma center from 2000 to 2019. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method, and the differences between the study groups were compared by the log-rank test. RESULTS: The median age of the 410 patients was 44 (range 8-84), and the 5-year OS and PFS were 61.2% and 38.4%, respectively. For patients with stage I/II, the 5-year PFS rate was 57.5%, and the 5-year OS rate was 77.2%. For patients with stage III/IV, the 5-year PFS rate was 17.4%, and the 5-year OS rate was 43.7%. Compared to the patients who received radiotherapy alone or chemotherapy alone as their initial treatment, the patients who received combined chemoradiotherapy had longer PFS (P = 0.013). Independent prognostic factors for OS were stage III/IV (P = 0.001), elevated IPI/aaIPI score (P = 0.019), elevated PINK score (P < 0.001) and elevated plasma EBV-DNA (P = 0.003). An elevated PINK score (P < 0.001) was an independent prognostic factor for PFS. CONCLUSION: Stage III/IV, elevated IPI/aaIPI score, elevated PINK score and elevated plasma EBV-DNA were independent prognostic factors for OS. Elevated PINK score was an independent prognostic factor for PFS. In stage III/IV patients, the patients who received combined chemoradiotherapy had significantly longer PFS.

Icaritin inhibits PLK1 to activate DNA damage response in NK/T cell lymphoma and increases sensitivity to GELOX regime.

Natural killer/T cell lymphoma (NKTCL) is a highly aggressive subtype of non-Hodgkin lymphoma. Gemcitabine, oxaliplatin, and L-asparaginase (GELOX) is one of the first-line chemotherapy regimens of NKTCL. Yet, the prognosis of NKTCL is poor. Icaritin is an herb-derived monomer from icariin with antitumor effects. We found that icaritin induced proliferation inhibition and apoptosis of NKTCL both in vitro and in vivo. Moreover, icaritin inhibited the dissemination of NKTCL in vivo. RNA sequencing revealed the Polo-like kinase 1 (PLK1) gene and DNA damage response (DDR) as the targets of icaritin. Mechanistically, icaritin inhibited PLK1 to promote checkpoint kinase 2 (Chk2) homodimerization and its T387 phosphorylation, which further activated p53, leading to the activation of the DDR pathway. Moreover, inhibiting PLK1 increased Forkhead box O3a nuclear localization, the latter of which activated ataxia telangiectasia mutated (ATM), an early sensor of DNA damage. Then ATM phosphorylated Chk2 T68 and initiated Chk2 activation. Remarkably, the combined treatment of icaritin and GELOX achieved better antitumor efficacy than single treatment in vivo. In summary, our results proved the efficacy of icaritin treating NKTCL, provided insights into its antitumor molecular mechanism, and revealed the application value of icaritin in facilitating clinical NKTCL treatment.

MiR-363 suppresses the tumor growth of natural killer/T-cell lymphoma via the SIRT6/PI3K/AKT axis.

Background: Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive tumor of non-Hodgkin's lymphoma. The role of micro ribonucleic acid (RNA) (miR)-363 in NKTCL has not yet been elucidated. The present study aimed to investigate the potential role of miR-363 in NKTCL. Methods: The expression of the top five differentially expressed microRNAs (miRNAs) as well as sirtuin 6 (SIRT6) in NK normal cells and its tumor cell lines were explored. The clinical tissues of NKTCL patients were collected and analyzed for expression of miR-363 and SIRT6. In addition, human NK/T-cell lymphoma cells (SNK-6) were transfected into different groups to detect cell proliferation and apoptosis abilities through cell counting kit 8 (CCK-8) experiment and flow cytometry analysis. Western blot assay was employed to examine protein expression. NKTCL nude mice models were constructed by subcutaneous injection of stably transfected SNK-6 cells to validate the mechanism of miR-363 in NKTCL via SIRT6 in vivo. Results: MiR-363 was down-regulated in NKTCL tissues and cell lines. Overexpression of miR-363 inhibited cell proliferation and promoted cell apoptosis. In contrast, SIRT6 was up-regulated in NKTCL and proved to be a downstream target of miR-363. SIRT6 could activate the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Also, miR-363 mimic could suppress the proliferation and induce the apoptosis of NKTCL via the SIRT6/PI3K/AKT axis both in vitro and in vivo. Conclusions: MiR-363 suppresses the SIRT6/PI3K/AKT pathway to restrain cell proliferation and accelerate cell apoptosis during NKTCL progression.

Integrated driver mutations profile of chinese gastrointestinal-natural killer/T-cell lymphoma.

Background: One of the most common nasal external sites in extranodal Natural Killer/T-cell lymphoma (NKTCL) is in the gastrointestinal (GI) system. Despite this, reports on gastrointestinal-Natural Killer/T-cell lymphoma (GI-NKTCL) are very few. To obtain a better understanding of this manifestation of NKTCL, we conducted a retrospective study on GI-NKTCL to analyze its clinical features, genomic changes and immune infiltration. Methods: We retrospectively collected patients diagnosed with GI-NKTCL in the Sixth Affiliated Hospital of Sun Yat-sen University from 2010 to 2020. From this cohort we obtained mutation data via whole exome sequencing. Results: Genomic analysis from 15 patients with GI-NKTCL showed that the most common driving mutations were ARID1B(14%, 2/15), ERBB3(14%, 2/15), POT1(14%, 2/15), and TP53(14%, 2/15). In addition, we found the most common gene mutation in patients with GI-NKTCL to be RETSAT(29%, 4/15) and SNRNP70(21%, 3/15), and the most common hallmark pathway mutations to be G2M checkpoint pathway (10/15, 66.7%), E2F targets (8/15, 53.3%), estrogen response late (7/15, 46.7%), estrogen response early (7/15, 46.7%), apoptosis (7/15, 46.7%) and TNFA signaling via NFKB (7/15, 46.7%). In the ICIs-Miao cohort, SNRNP7-wild-type (WT) melanoma patients had significantly prolonged overall survival (OS) time compared with SNRNP7 mutant type (MT) melanoma patients. In the TCGA-UCEC cohort, the patients with RETSAT-MT or SNRNP7-MT had significantly increased expression of immune checkpoint molecules and upregulation of inflammatory immune cells. Conclusions: In this study, we explored GI-NKTCL by means of genomic analysis, and identified the most common mutant genes (RETSAT and SNRNP70), pathway mutations (G2M checkpoint and E2F targets) in GI-NKTCL patients. Also, we explored the association between the common mutant genes and immune infiltration. Our aim is that our exploration of these genomic changes will aid in the discovery of new biomarkers and therapeutic targets for those with GI-NKTCL, and finally provide a theoretical basis for improving the treatment and prognosis of patients with GI-NKTCL.

NK/T-cell non-Hodgkin lymphoma: Case report and review of the literature.

Natural killer (NK)/T-cell lymphomas represent a rare type of lymphoid malignancy with mostly extranodal involvement, having NK cell or (rare) T cell lineage, classified by the World Health Organization into several subtypes which can involve the head and neck region, with the most frequent one being the nasal type. This article presents the case of a 31-year-old patient who presented at the Emergency Unit of Saint Andrew Emergency Clinical Hospital of Galati suffering from mycosis fungoides-like cutaneous lesions, associated with partial left eyelid ptosis of unknown etiology, as well as a poor health status with fever and respiratory failure. The final diagnosis was NK/T-cell non-Hodgkin lymphoma, possibly nasal type with medium sized T cells. The complexity of the rare diagnosis, associated with the unusual rapid patient evolution towards exitus 3 months after diagnosis, the intra-orbital metastatic involvement and the absence of a standardized treatment are case peculiarities, some of which are consistent with current literature data.

The exact Deauville score, NABS score and high SUVmax predicts outcome in extranodal natural killer/T-cell lymphoma.

OBJECTIVE: Natural killer T-cell lymphoma (NKTCL) is an aggressive type of non-Hodgkin's lymphoma. While FDG-PET/CT imaging has been increasingly utilized for disease assessment, its prognostic value and potential utility in NKTCL patient stratification remain controversial. We aim to investigate the prognostic utility of FDG-PET/CT and its role in complementing clinical indices. METHODS: We conducted a retrospective review of 72 patients from a tertiary National Cancer Centre with biopsy-proven NKTCL and available FDG-PET/CT data (either baseline, end of treatment or both). Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional regression. RESULTS: High initial SUVmax was significantly associated with advanced Ann-Arbor stage (p = 0.0352), elevated LDH levels (p = 0.0059) and plasma EBV DNA detection (p = 0.0278). SUVmax correlated with worse progression-free survival (PFS) (HR 3.68, 95% CI 1.56-8.69, p = 0.0030) and a trend toward worse overall survival (OS) (HR 2.06, 95% CI 0.95-4.45, p = 0.0676). End of treatment Deauville scores of 4-5, as compared to scores of 1-3, was associated with worse PFS (HR 2.72, 95% CI 1.04-7.12, p = 0.0419). Notably, while all patients with scores of 5 developed progressive disease, only 2 of 5 patients with scores of 4 eventually relapsed. Clinical indices (NABS score) were still able to stratify survival outcomes regardless of end-of-treatment Deauville scores. CONCLUSIONS: A Deauville score of 5 is more diagnostic of true disease progression than a score of 4, and NABS score may be used in patients who achieve Deauville scores of 1-3 for further risk stratification. A higher SUVmax at baseline portends a worse prognosis in NKTCL.

Nasal-type T-cell lymphoma referred as fungal rhinosinusitis: Case report.

NKTCL is a rare and destructive midline tumor that can be easily misdiagnosed as other more common inflammatory processes. The differential diagnosis of NKTCL should always be kept in mind for any lesion of the paranasal sinuses with atypical presentation and nonresponsive to conventional treatments.

Characteristics and Clinical Implications of the Nasal Microbiota in Extranodal NK/T-Cell Lymphoma, Nasal Type.

Natural killer/T cell lymphoma (NKTCL) most frequently affects the nasal cavity and upper aerodigestive tract (UAT) and is often mistaken for reactive disease processes, such as chronic rhinosinusitis (CRS). Recently, alterations of the nasal resident microbiota have been found in CRS. However, nasal microbial features in NKTCL have never been reported. This case-control study collected 46 NKTCL patients, 25 CRS patients and 24 matched healthy controls (HCs) to analyze nasal microbial profiles via 16S rRNA sequencing technology to improve our understanding of changes in the nasal microbiota in NKTCL. We found that alpha diversity was significantly decreased, while beta diversity was significantly increased in NKTCL compared with those in CRS and HCs. The genus Corynebacterium was significantly depleted in CRS and NKTCL versus that in HCs, while genus Staphylococcus was the most abundant in the NKTCL compared to that in the other two groups. The nasal microbial community was significantly different between UAT-NKTCL and non-UAT NKTCL patients. Importantly, based on a panel of taxa, excellent classification power with an AUC of 0.875 between UAT-NKTCL and CRS was achieved. Furthermore, the alpha diversity of the nasal microbiota was associated with several clinical covariates of NKTCL. Finally, PICRUSt analysis implicated an array of distinct functions in NKTCL that might be involved in the pathogenesis of the disease. In conclusion, the nasal microbial profile was unique in NKTCL. The nose-microbiota-UAT NKTCL axis represents a panel of promising biomarkers for clinical practice and contributes to revealing the potential pathogenesis of this malignancy.

Survival trends for extranodal NK/T-cell lymphoma, nasal type from different anatomical sites: a population-based study.

BACKGROUND: Extranodal natural killer/T-cell lymphoma (NKTCL), nasal type mostly involves the upper aerodigestive tract (UAT). NKTCLs derived from the UAT are referred to as nasal NKTCLs, while those without UAT involvement are referred to as extra-nasal NKTCLs. In this study, we aimed to investigate the outcomes and survival trends of NKTCLs from different anatomical sites. METHODS: Data from the US Surveillance, Epidemiology, and End Results (SEER) database on NKTCL (diagnosed between 1987 and 2016) were retrospectively analyzed. RESULTS: A total of 714 patients with NKTCL were included. The median overall survival (OS) and cancer-specific survival (CSS) were 36 and 57 months, respectively. For the entire cohort, the OS was improved from era 1 to era 2 with marginal significance (P=0.0595), however, no improvement was shown in CSS. For nasal NKTCLs, the OS of patients from era 2 was significantly improved compared to that of patients from era 1 (P=0.0244). The OS was significantly improved in non-cavity nasal NKTCLs (P=0.031) but not in nasal cavity NKTCLs (P=0.2982). Significant improvements in OS (P=0.0025) and CSS (P=0.0176) were found in stage I/II non-cavity nasal NKTCLs. For patients with extra-nasal NKTCLs, no difference was found in survival outcomes between the 2 eras. CONCLUSIONS: We have demonstrated that the outcomes of non-cavity nasal NKTCLs, especially those in stage I/II, have improved in the new era, while the outcomes of nasal cavity NKTCLs and extra-nasal NKTCLs have not improved. Our study highlights the heterogeneity in clinical outcomes and biology among NKTCLs from different sites. More studies are warranted to define the optimal treatments for patients with NKTCLs.

Epigenetic aberrations in natural killer/T-cell lymphoma: diagnostic, prognostic and therapeutic implications.

Natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that usually presents in the upper aerodigestive tract. This malignancy shows substantial geographic variability in incidence, and is characterized by Epstein-Barr virus (EBV) infections. Epigenetic aberrations may dysregulate the expression of genes involved in different hallmarks of cancer. A growing body of evidence underscores the importance of epigenetic aberrations in the pathogenesis of NKTCL. Promoter hypermethylation is a common epigenetic mechanism for the inactivation of tumour suppressor genes. Several epigenetically silenced tumour suppressor candidates (e.g. PRDM1, BIM) were identified in this aggressive cancer using locus-specific and genome-wide promoter methylation analyses. Importantly, genes involved in epigenetic modifications were identified to be mutated (e.g. KMT2D) or methylated (e.g. TET2) in NKTCL patients, which may contribute to pathogenesis through global alterations in chromatin states. Cancer-associated microRNAs, some of which are expressed by EBV, and long noncoding RNAs have been observed to be dysregulated in NKTCL. This review focuses on studies investigating epigenetic aberrations in NKTCL to bolster our overall understanding of the role of these abnormalities in disease pathobiology. We also discuss the potential of these epigenetic aberrations to improve diagnosis and prognosis as well as reveal novel targets of therapy for NKTCL.