Nasal NK/T-cell Lymphoma Research Articles

Nasal NK/T Cell Lymphoma (NKTL): A Reported Case

Nasal NK/T cell lymphoma (NKTL), is an aggressive malignancy associated with Epstein Barr virus infection. Nasal NK/T cell lymphoma (NKTL), manifests as a necrotic process affecting nasal or upper aerodigestive structures and, rarely, extra nasal sites such as skin, and the gastrointestinal tract. The diagnosis is confirmed by histological and immunohistochemical analysis of the biopsy. Overall prognosis is poor. However, during the last two decades, advances in its clinicopathologic, genetic and molecular characterization have been achieved, as have changes in the chemotherapy regimens that, in combination with radiotherapy, are significantly improving the survival of these patients, especially in initial stages.

A Phase I/II Study (JACKPOT8) of DZD4205, a Selective JAK1 Inhibitor, in Refractory or Relapsed Peripheral T- Cell Lymphoma

Background: Peripheral T-Cell Lymphoma (PTCL) is an aggressive malignancy which lacks effective treatment. Emerging data suggests that the JAK-STAT pathway may play an important role in mediating pathogenesis of PTCL. DZD4205 (AZD4205) is an orally available, potent and highly selective JAK1 inhibitor. In T-cell lymphoma cell lines, DZD4205 modulates pSTAT3 pathway and suppresses cell proliferation, and in tumor xenograft models, DZD4205 exhibits dose-dependent anti-tumor activities, with good correlation with drug exposure and modulations of pSTAT3 in tumor tissues. A phase I/II study (JACKPOT8) was initiated to assess the safety, tolerability, pharmacokinetics and anti-tumor efficacy of DZD4205 in patients with refractory/relapsed (r/r) PTCL. Methods: The JACKPOT8 study (ClinicalTrials.gov Identifier: NCT04105010) included two parts: Part A, dose escalation and Part B, dose expansion. In Part A, patients with r/r PTCL who have progressed on or were refractory to systemic therapy will be enrolled and treated with DZD4205 at two different dose levels, 150 mg or 250 mg once daily. In Part B, patients will receive DZD4205 treatment at a defined dose. The primary objective is to assess the safety and tolerability of DZD4205, and the secondary objectives include anti-tumor efficacy and pharmacokinetics. Evaluation of safety/tolerability and tumor response will be based on the CTCAE version 5.0 and 2014 Lugano classification, respectively. Patients will be treated until disease progression, intolerance to adverse events, or withdrawal of consent. Results: As of June 30, 2020, a total of 23 patients with r/r PTCL were enrolled and received DZD4205 at 150 mg (n = 19) or 250 mg (n = 4) once daily. Patient characteristics: median age (range): 65.0 years (34-79); median prior systemic therapies (range): 2 lines (1-8). Four patients had undergone prior hematopoietic stem cell transplantation (HSCT). Six patients had bone marrow involvement at the study entry. Histological subtypes included peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (n = 10, 43.5%), angioimmunoblastic T-cell lymphoma (AITL) (n = 10, 43.5%), ALK-negative anaplastic large cell lymphoma (ALCL ALK-) (n = 2, 8.7%) and extra-nodal nasal NK/T-cell lymphoma (NKTCL) (n = 1, 4.3%) . Preliminary data showed that 20 patients experienced treatment emergent adverse events (TEAEs), among whom 13 (56.5%) had ≥ grade 3 TEAEs. Based on local investigators' assessment, eight patients (34.8%) had ≥ grade 3 TEAEs which were considered to be related to DZD4205. The most common (> 5% incidence) DZD4205-related TEAEs (any grade) included thrombocytopenia (n = 6, 26.1%), neutropenia (n = 4, 17.3%), decreased appetite (n = 3, 13.0%), nausea (n = 2, 8.7%), interstitial lung disease (n = 2, 8.7%) and pneumonia (n = 2, 8.7%). Most TEAEs were manageable with dose interruption and reduction. Preliminary PK data is available in 20 patients (n = 19 at 150 mg, n = 1 at 250 mg). Exposure at 250 mg is higher than 150 mg following a single and multiple dose. As expected from long t1/2 of DZD4205, accumulation of about 3 folds in AUC was observed. DZD4205 had flat PK profile with small difference between Css,max and Css,min after 22 days of once daily dosing, which is an optimal PK profile to maintain DZD4205 concentrations above effective levels throughout the dosing interval. As of June 30, 2020, 22 patients (n = 19 at 150 mg, n = 3 at 250 mg) had at least one post-treatment Lugano assessment. In 150 mg cohort, 8 out of 19 patients showed tumor response, with objective response rate (ORR) of 42%, among whom 4 (21%) had complete response (CR) and another 4 (21%) partial response (PR). In 250 mg cohort, 1 out of 3 patients showed tumor response, with ORR of 33%. Tumor response was observed in subtypes including AITL, PTCL-NOS, ALCL (ALK-) and NKTCL. At the data cut-off date, the longest duration on treatment was > 8 months. Patient enrolment is ongoing. Updated clinical data will be shared at the meeting. Conclusion: DZD4205 shows good tolerability, pharmacokinetic profiles and promising anti-tumor efficacy in patients with r/r PTCL, indicating its potential as a therapeutic option for this unmet medical need. Disclosures Kim: Donga: Research Funding; Kyowa-Kirin: Research Funding; Roche: Research Funding; Johnson&Johnson: Research Funding; Celltrion: Research Funding; Mundipharma: Research Funding. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Wang:Dizal Pharmaceuticals: Current Employment. Li:Dizal Pharmaceuticals: Current Employment. Huang:Dizal Pharmaceuticals: Current Employment. Deng:Dizal Pharmaceuticals: Current Employment. Chen:Dizal Pharmaceuticals: Current Employment. Yang:Dizal Pharmaceuticals: Current Employment.

Primary testicular NK/T cell lymphoma: a clinicopathologic analysis of six cases

Objective: To evaluate the clinicopathological features, diagnosis and management of primary testicular NK/T cell lymphoma (NKTCL). Methods: Six cases of primary testicular NKTCL at Beijing Friendship Hospital, Capital Medical University from January 2007 to December 2016 were retrospectively analyzed for the morphology, immunephenotype and outcome, and relevant literature was reviewed. Results: The median age of patients at diagnosis was 45 years(range 32-65 years). All patients presented with testicular masses as initial symptoms (6/6), five cases (5/6) were on the right. The lesions were confined to the testis. All patients were classified as Ann Arbor stage Ⅰ but the tumors exhibited aggressive clinical behavior. Two patients died of the disease within two months, three (3/6) had clinical remission, and one (1/6) was lost to follow-up. Morphologically, the lymphoma cells showed a diffuse growth pattern that largely effaced the interstitial tissues, and surrounded seminiferous tubules in all cases. There was also a prominent angioinvasive pattern, with focal necrosis and karyorrhexis(4/6). Cytologically, the medium-sized neoplastic cells showed scanty to moderate amount of cytoplasm and irregular folded nuclei. The immunophenotype was similar to that of nasal NKTCL: the neoplastic cells were positive for cytoplasmic CD3, CD56, cytotoxic molecules and EBV-encoded small RNA, the loss of CD5 antigen was seen in all cases. Conclusions: Primary testicular NKTCL is extremely rare, highly aggressive and is associated with a poor prognosis. There is no unified standard of treatment. Thus, at the time of diagnosis of testicular lymphoma, NKTCL should be included in the differential diagnosis.

Unusual Cause of Bradycardia: Cardiac Metastasis From Pancreatic NK/T Cell Lymphoma

Extranodal NK/T cell lymphoma (NKTL) is a rare malignancy, accounting for 5-10% of all NHL. A majority of patients with NKTL present with nasal/sinus involvement. About 30% present with extranasal disease involving the upper airway, gastrointestinal tract, lungs, or soft tissues. Cardiac metastasis, in particular, is rare and difficult to diagnose given the lack of symptoms in most cases. Here we present a case of primary pancreatic NKTL with a metastatic right atrial mass. A 34 year-old previously healthy male presented with epigastric pain, jaundice, clay-colored stool, and dark urine for 1 week. He also complained of increasing dyspnea on minimal exertion without chest pain. On exam, he was jaundiced, bradycardic, with epigastric tenderness. Labs showed ALP 907, total bilirubin 10.2, AST 250, ALT 452, and lipase 381. Hepatitis and HIV serologies were negative. EKG showed junctional bradycardia at 42 bpm. CT showed a dilated common bile duct (CBD), pancreatic head and tail masses, and a filling defect in the right atrium. TTE showed a 2x4 cm mass in the right intra-atrial septum. CT guided biopsy of the pancreatic tail mass revealed EBV positive, nasal type NKTL. PET scan revealed hyper-metabolic foci consistent with lymphoma involving the right atrium, pancreas, spleen, and left adrenal gland. ERCP showed a high grade stricture in the distal CBD requiring a sphincterotomy with 2 stents placed in the CBD. The patient was then treated with chemotherapy. Repeat TTE after one cycle showed decrease in the right atrial mass size. Despite that, the patient developed atrial flutter with variable block, which was ultimately controlled with metoprolol. He was subsequently discharged with appropriate follow-up. We presented a rare case of primary pancreatic NKTL with cardiac metastasis. NKTL is a highly aggressive malignancy which rarely involves the heart. Our case emphasizes the point that clinicians should have a high index of suspicion for cardiac metastasis in a patient who presents with a pancreatic mass and cardiac symptoms such as arrhythmias, chest pain or dyspnea. Following the first round of chemotherapy, our patient's arrhythmia evolved to atrial flutter with variable block. This suggests that myocardium infiltrated with lymphoma cells may be susceptible to the development of potentially life-threatening arrhythmias. Thus, particular attention should be made to patients with NKTL and cardiac involvement to avoid arrhythmias post-chemotherapy.

Patterns of Primary Tumor Invasion and Regional Lymph Node Spread Based on Magnetic Resonance Imaging in Early-Stage Nasal NK/T-cell Lymphoma: Implications for Clinical Target Volume Definition and Prognostic Significance

This study aimed to determine the pathways of primary tumor invasion (PTI) and regional lymph node (LN) spread based on magnetic resonance imaging (MRI) in early-stage nasal NK/T-cell lymphoma (NKTCL), to improve clinical target volume (CTV) delineation and evaluate the prognostic value of locoregional extension patterns. A total of 105 patients with newly diagnosed early-stage nasal NKTCL who underwent pretreatment MRI were retrospectively reviewed. All patients received radiation therapy with or without chemotherapy. The incidences of PTI and regional LN involvement were 64.7% and 25.7%, respectively. Based on the incidence of PTI, involved sites surrounding the nasal cavity were classified into 3 risk subgroups: high-risk (>20%), intermediate-risk (5%-20%), and low-risk (<5%). The most frequently involved site was the nasopharynx (35.2%), followed by the maxillary (21.9%) and ethmoid (21.9%) sinuses. Local disease and regional LN spread followed an orderly pattern without LN skipping. The retropharyngeal nodes (RPNs) were most frequently involved (19.0%), followed by level II (11.4%). The 5-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) rates for all patients were 72.8%, 65.2%, and 90.0%, respectively. The presence of PTI and regional LN involvement based on MRI significantly and negatively affected PFS and OS. Early-stage nasal NKTCL presents with a high incidence of PTI but a relatively low incidence of regional LN spread. Locoregional spread followed an orderly pattern, and PTI and regional LN spread are powerful prognostic factors for poorer survival outcomes. CTV reduction may be feasible for selected patients.

MiRNA expression profiling of Epstein-Barr virus-associated NKTL cell lines by Illumina deep sequencing.

The aim of this work was to establish the microRNA profile of SNK6 and SNT16, two Epstein–Barr virus (EBV)‐infected cell lines derived from nasal NK/T‐cell lymphoma (NKTL). The oncogenic EBV is strongly associated with the pathogenesis of nasal and extranodal NK/T‐cell lymphoma and expresses 44 mature microRNAs and two noncoding EBV‐encoded RNAs (EBERs). miRNAs are 19‐25nt noncoding RNAs that affect host and viral gene expression post‐transcriptionally. Deregulated miRNA patterns are frequently linked to a variety of human cancers including lymphomas. miRNA profiling of the two NK/T cell lines vs. primary cells revealed 10 and 4 up‐regulated and 10 and 12 down‐regulated miRNAs in SNK6 and SNT16 cells respectively. The results were validated by qRT‐PCR for selected miRNAs. Target gene analyses confirmed cullin 5 (CUL5) and sphingosin‐1‐phosphate receptor 1 (S1PR1) as targets for the down‐regulated hsa‐miR‐148a and viral ebv‐miR‐BART16 respectively. As recently demonstrated for the regulation of IL1‐alpha by miR‐142‐3p, coexpression of the EBERs selectively exerted corepression of S1PR1 by BART16 but not of CUL5 by miR‐148a, indicating selective corepression by the EBERs.

Evaluation of Efficacy and Toxicity of Helical Tomotherapy in the Treatment of Patients with Nasal NK/T-Cell Lymphoma

Purpose: Nasal lymphoma created dosimetric challenges in radiotherapy due to the complex anatomical structures. This study was to evaluate the efficacy and toxicity of helical Tomotherapy (HT) in the treatment of nasal NK/T-cell lymphoma (NKTCL) patients. Methods and Materials: Between August 2008 and April 2013, a total of 25 NKTCL patients were treated with HT in our department; Among them, three patients have not received chemotherapy, one patient has received concurrent chemo-radiation with CHOP plus L-ASP, two patients have received the sequential chemotherapy regimen following irradiation, and all the others have received 1 - 2 cycles of induction chemotherapy followed by irradiation and then with sequential chemotherapy. CHOP-L with 1 - 7 cycles (median: 4 cycles) was utilized as the main chemotherapy regimen. As for HT, the gross tumor volume (GTV) received target doses (TD) ranging from 50 to 56 Gy (median: 50 Gy) at 2 - 2.78 Gy per fraction; and the clinical target volume (CTV) from 36 to 50 Gy (median: 40 Gy) at 1.6 - 2 Gy per fraction. Results: For those patients who had received irradiation, thirteen achieved complete remission (CR), four partial responses (PR); four had progressive disease (PD), two were lost to follow-up, two died within one month after irradiation and were not followed. In 21 patients with follow-up records, the overall response (CR + PR) was 81.0% with the 3-year survival rate of 87.2%, and the mean survival time was 52.8 months [95% confidence interval (CI): 45.2 - 60.4 months]. After radiotherapy the majority of patients had dry mouth and taste changes in varying degrees, and a small portion of patients had compromised hearing or vision functions. No brain injury symptoms occurred during radiation radiotherapy. Conclusions: As compared with conventional three-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiation therapy (IMRT) performed with HT, HT appears to have more favorable efficacy and toxicity profiles in the treatment of NKTCL. Further systematic and randomized clinical research is under investigation.

Nasal NK-T cell lymphoma: 10-year experience of a single institute in India.

e19536 Background: Nasal NK –T cell lymphoma accounts for 5% of all NHLs at our centre. Methods: We reviewed data of 38 patients treated between January 2002 and August 2013. Results: Patients’ med...

An A91V SNP in the Perforin Gene Is Frequently Found in NK/T-Cell Lymphomas

NK/T-cell lymphoma (NKTCL) is the most frequent EBV-related NK/T-cell disease. Its clinical manifestations overlap with those of familial haemophagocytic lymphohistiocytosis (FHLH). Since PERFORIN (PRF1) mutations are present in FHLH, we analysed its role in a series of 12 nasal and 12 extranasal-NKTCLs. 12.5% of the tumours and 25% of the nasal-origin cases had the well-known g.272C>T(p.Ala91Val) pathogenic SNP, which confers a poor prognosis. Two of these cases had a double-CD4/CD8-positive immunophenotype, although no correlation was found with perforin protein expression. p53 was overexpressed in 20% of the tumoral samples, 80% of which were of extranasal origin, while none showed PRF1 SNVs. These results suggest that nasal and extranasal NKTCLs have different biological backgrounds, although this requires validation.

Prognostic Value Of LMP1, CLA, NK-Cell Origin, and Pretreatment Bone Marrow EBER-ISH In Localized NK/T-Cell Lymphoma Prospectively Treated With Concurrent Chemoradiotherapy: An Ancillary Study Of Japan Clinical Oncology Group (JCOG) 0211

Latent membrane protein 1 (LMP1), cutaneous lymphocyte antigen (CLA), NK-cell origin, and pretreatment bone marrow Epstein-Barr virus - encoded RNA by in situ hybridization (EBER-ISH) have been reported as prognostic biomarkers in patients with extranodal NK/T-cell lymphoma (NKTCL), nasal type when treated with conventional therapy (Kanemitsu N, et al. Clin Cancer Res 2012; Yoshino T, et al. Br J Haematol 2002; Kim GE, et al. Head Neck 2004; Lee J, et al. Clin Cancer Res 2007). Recently, concurrent chemoradiotherapy has become a standard management approach for newly diagnosed, localized, nasal NKTCL (Yamaguchi M, et al. J Clin Oncol 2009; Kim SJ, et al. J Clin Oncol 2009). Because it is a new treatment modality for lymphoma, little data are available on the prognostic biomarkers of NKTCL among patients treated with concurrent chemoradiotherapy. To evaluate the prognostic significance of known immunophenotypic biomarkers among patients treated with concurrent chemoradiotherapy, we conducted an ancillary clinicopathologic study of JCOG0211, which was a phase I/II trial of concurrent chemoradiotherapy (RT-DeVIC) for newly diagnosed, localized, nasal NKTCL (Yamaguchi M, et al. J Clin Oncol 2009 & 2012).The histological diagnoses of all 33 patients who were enrolled in JCOG0211 were confirmed as extranodal NKTCL, nasal type, by the Central Pathology Review. Pathological samples from 32 patients were available for the study. Patients received concurrent chemoradiotherapy comprising RT of 50 Gy and 3 cycles of DeVIC. The expression of LMP1 and CLA in tumor cells was examined using immunohistochemistry with paraffin sections of pretreatment lymphoma samples. Two monoclonal antibodies for TCRβ (βF1) and TCRγ (CγM1) were used to evaluate the cell of origin of lymphoma cells. Preliminary examination revealed that βF1 and CγM1 specifically recognized αβ and γδ T cells, respectively. Cases were considered to be of NK-cell origin if both TCRβ and TCRγ were negative. Cases showing positive staining for one or both of the antibodies (TCRβ and TCRγ) were determined to be of T-cell origin. Pretreatment bone marrow specimens from patients were examined for EBER-ISH.LMP1 and CLA were positive in 66% (19/29) and 29% (9/31) of the cases, respectively. Among 32 cases examined for cell lineage, 27 (84%) cases were of NK-cell origin. Two (6%) cases were of αβ T-cell origin on the basis of positivity for TCRβ but not TCRγ, and 3 (9%) cases were of γδ T-cell origin on the basis of positivity for TCRγ but not TCRβ. Pretreatment bone marrow EBER-ISH was positive in 2 (7%) out of 29 cases examined.The median follow-up was 68 months (range, 61-94). The overall survival (OS) was better in the LMP1-positive (LMP1+) group than in the LMP1-negative (LMP1-) group [hazard ratio (HR), 0.240; 95% confidence interval (CI), 0.057-1.013; 80% CI, 0.093-0.615; P=0.035]. The OS at 5 years was 84% (95% CI, 59-95%) in the LMP1+ patients and 50% (95% CI, 18-75%) in the LMP1- patients. The progression-free survival (PFS) at 5 years was 74% (95% CI, 48-88%) in the LMP1+ patients and 50% (95% CI, 18-75%) in the LMP1- patients. The HR of PFS in the LMP1+ patients was 0.421 (95% CI, 0.121-1.463; 80% CI, 0.187-0.950). There were no significant differences in the OS and PFS between the CLA+ and CLA- patients (5-yr OS, 56% vs. 77%; 5-yr PFS, 56% vs. 68%). All 5 patients of T-cell origin achieved complete response by RT-DeVIC and were alive without relapse at the last follow-up. The OS and PFS at 5 years in the 27 patients of NK-cell origin were 67% (95% CI, 46-81%) and 59% (95% CI, 39-75%), respectively. Two patients who were positive for pretreatment bone marrow EBER-ISH survived more than 5 years without disease progression (5-yr OS and PFS, 100%).Our current study, for the first time, validated a favorable impact on the OS of LMP1 expression in newly diagnosed, localized, nasal NKTCL in a cohort uniformly treated with concurrent chemoradiotherapy. Further evaluation with a larger number of patients is warranted. (Supported in part by The National Cancer Center Research and Development Funds #21-6-3 & #23-A-17) Disclosures:Ishizuka:Sanofi: Employment. Oshimi:Eisai: Employment.

Downregulation of miR‐15a due to LMP1 promotes cell proliferation and predicts poor prognosis in nasal NK/T‐cell lymphoma

Nasal NK/T-cell lymphoma (NNKTL) is an Epstein-Barr virus (EBV)-associated malignancy and has distinct clinical and histological features. However, its genetic features are hitherto unclear. MicroRNAs (miRNAs) play a crucial role in the pathogenesis of several malignancies via regulating gene expression. In this study, we investigated whether the specific microRNAs were related to the tumor behaviors in NNKTL. MiRNA array and Quantitative RT-PCR analyses revealed that miR-15a was expressed at a much lower level in NNKTL cells (SNK-1, SNK-6, and SNT-8) than in normal peripheral NK cells and EBV-negative NK cell line KHYG-1. Quantitative PCR and western blot analyses showed that the expression of MYB and cyclin D1, which are validated targets of miR-15a, was higher in NNKTL cells. Transfection of NNKTL cells (SNK-6 and SNT-8) with a miR-15a precursor decreased MYB and cyclin D1 levels, thereby blocking G1/S transition and cell proliferation. Knockdown of EBV-encoded latent membrane protein 1 (LMP1) significantly increased miR-15a expression in SNK-6 cells. In NNKTL tissues, we found that reduced miR-15a expression, which correlated with MYB and cyclin D1 expression, was associated with poor prognosis of NNKTL patients. These data suggest that downregulation of miR-15a, possibly due to LMP1, implicates in the pathogenesis of NNKTL by inducing cell proliferation via MYB and cyclin D1. Thus, miR-15a could be a potential target for antitumor therapy and a prognostic predictor for NNKTL.

Epstein-Barr Virus–Encoded miR-BART20-5p Inhibits T-bet Translation with Secondary Suppression of p53 in Invasive Nasal NK/T-Cell Lymphoma

Nasal NK/T-cell lymphoma (NNL) is an Epstein-Barr virus (EBV)-associated lymphoma derived from cytotoxic NK or T cells of the nasal mucosa. NNLs are noninvasive in the earliest stage, and become invasive with disease progression. The EBV encodes at least 44 miRNAs, whose functions in the pathogenesis of NNL are mostly unknown. We evaluated the levels of 39 EBV-encoded miRNAs with quantitative real-time RT-PCR in a series of 20 noninvasive NNLs and 20 invasive NNLs. miR-BART20-5p was associated most strongly with invasion (P ≤ 0.001), and lack of T-bet, the master transcription factor for cytotoxic NK cells. However, we identified T-bet (official symbol, TBX21) transcripts in T-bet-negative NNLs, implying a block in the translation of T-bet by miR-BART20-5p. In co-transfection experiments, miR-BART20-5p inhibited T-bet translation in both non-Hodgkin and Hodgkin lymphoma cell lines. Endogenous mir-BART20-5p also inhibited translation of T-bet in EBV-infected YT lymphoma cells of NK-cell origin. Induction of T-bet in YT cells up-regulated p53, leading to increased sensitivity in response to doxorubicin. Finally, YT cells transplanted into severe combined immunodeficiency mice had an invasive behavior. Taken together, we conclude that EBV-encoded miR-BART20-5p inhibits T-bet translation with secondary suppression of p53 in invasive nasal NK/T-cell lymphoma. An antagomir to miR-BART20-5p might be an effective therapeutic agent through induction of T-bet and p53.

Patterns of Local Extension and Regional Spread in Early Stage Nasal NK/T-cell Lymphoma Based on Magnetic Resonance Imaging

Patterns of Local Extension and Regional Spread in Early Stage Nasal NK/T-cell Lymphoma Based on Magnetic Resonance Imaging

Long-term follow-up results of a phase I/II study of concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma (NKTCL): JCOG0211.

8050 Background: Concurrent chemoradiotherapy has been regarded as one of the standard management for localized nasal NKTCL. However, its long-term efficacy and toxicity is not known. Methods: The JCOG0211 trial is a phase I/II study of concurrent chemoradiotherapy consisting of radiotherapy (RT) of 50 Gy and 3 cycles of DeVIC (carboplatin, etoposide, ifosfamide, dexamethasone) for newly diagnosed, localized nasal NKTCL (JCO 2009). Patients (Pts) with newly diagnosed, localized diseases (IE &amp; contiguous IIE with cervical node involvement) who were 20-69 yrs of age with PS 0-2 were eligible. 3-D conformal RT planning with a wide margin (+ 2 cm to the gross tumor, the entire nasal cavity and the nasopharynx) and a 2-step cone down were required. 33 pts were enrolled in the study, 27 of whom were treated with RT and a 2/3-dose of DeVIC, which was selected as the recommended phase II dose in the preceding phase I portion of the trial. All pts completed RT without any protocol violations. Long-term follow-up results on overall survival (OS), progression-free survival (PFS) and toxicity were evaluated. Results: The median follow-up was 69 months (range, 62-96). The pt (N=33) characteristics were as follows: median age 54 yrs (range, 21-68); stage IIE 33%; B symptom (+) 36%; elevated serum LDH 21%. %5-yr OS and PFS were 73% (95%CI, 54-85%) and 67% (95%CI, 48-80%), respectively. 11 pts (33%) experienced disease recurrence. Two achieved a 2nd CR by salvage chemotherapies followed by allogeneic stem cell transplantation, and the remaining 9 pts died of disease. There was no observed death and disease progression after 34 and 31 months, respectively. One pt experienced Grade 3 irregular menstruation for 3 years. No other Grade 3 or 4 late non-RT-associated adverse events (AEs) were observed. One pt received plastic surgery due to Grade 4 RT dermatitis. No other Grade 3 or greater RT-associated late AEs were encountered. Conclusions: Both survival benefit and disease control from concurrent chemoradiotherapy with RT and DeVIC are maintained during a 5-yr follow-up, indicating the excellent efficacy of this approach as a first-line therapy for localized nasal NKTCL. Long-term toxicity is acceptable.

Immunohistochemistry of Programmed Cell Death in Archival Human Pathology Specimens

Immunohistochemistry (IHC) for detecting key signal molecules involved in programmed cell death (PCD) in archival human pathology specimens is fairly well established. Detection of cleaved caspase-3 in lymphocytes in rheumatoid arthritis (RA) and gastric surface foveolar glandular epithelia but not in synoviocytes in RA, gastric fundic glandular epithelia, or nasal NK/T-cell lymphoma (NKTCL) cells suggests anti-apoptotic mechanisms in cell differentiation and in oncogenesis such as the induction of survivin. Enzymatically pretreated and ultra-super sensitive detection of beclin-1 in synoviocytes in RA and gastric fundic glandular epithelia suggests enhanced autophagy. The deposition of beclin-1 in fibrinoid necrosis in RA and expression of beclin-1 in detached gastric fundic glandular cells suggest that enhanced autophagy undergoes autophagic cell death (ACD). NKTCL exhibited enhanced autophagy through LC3 labeling and showed densely LC3 labeled cell-debris in regions of peculiar necrosis without deposition of beclin-1, indicating massive ACD in NKTCL and the alternative pathway enhancing autophagy following autophagic vesicle nucleation. Autophagy progression was monitored by labeling aggregated mitochondria and cathepsin D. The cell-debris in massive ACD in NKTCL were positive for 8-hydroxydeoxyguanosine, suggesting DNA oxidation occurred in ACD. Immunohistochemical autophagy and PCD analysis in archival human pathology specimens may offer new insights into autophagy in humans.

A combination of methotrexate and irradiation promotes cell death in NK/T-cell lymphoma cells via down-regulation of NF-κB signaling

Nasal NK/T-cell lymphoma (NKTL) is a highly aggressive disease. Although radiotherapy is the first-line of treatment for NKTL, the clinical outcome is poor. Thus, there is a need for an effective radiosensitizer to improve the survival rate of patients. NF-κB activation contributes to cell survival as well as chemo- and radio-resistance in various cancer cells. In NKTL, the constitutive activation of NF-κB is also a critical factor. In the present study, we used two EBV-expressing NKTL cell lines (Hank-1 and NK-92) to evaluate the radiosensitizing effect of methotrexate (MTX), highlighting the role of NF-κB. Combined treatment of MTX and IR significantly induced apoptosis and growth inhibition in both NKTL cells. The synergistic cytotoxicity was correlated with blocking nuclear NF-κB and suppressing expression of NF-κB-mediated anti-apoptotic proteins. These data suggest that the combined treatment with MTX and IR can inhibit IR-induced NF-κB activation in NKTL cells. Taken together, co-treatment with MTX and IR may provide a therapeutic advantage for patients with NKTL.

EBV-encoded miRNAs

The Epstein–Barr virus (EBV) is an oncogenic Herpes virus involved in the induction of a variety of human tumours. It was the first virus found to encode microRNAs (miRNAs). MiRNAs are short, non-coding RNAs that in most cases negatively regulate gene expression at the post-transcriptional level. EBV-transformed cells express at least 44 mature viral miRNAs that target viral and cellular genes. In addition, EBV-infection severely deregulates the miRNA profile of the host cell. The presently available information indicates that the virus uses its miRNAs to inhibit the apoptotic response of the infected cell as a means to establish a latent infection. Likewise, EBV-encoded miRNAs interfere in the expression of viral genes in order to mask the infected cell from the immune response. Cellular targets of viral miRNAs are involved in protein traffic within the cell and regulate innate immunity. MiRNA profiling of diffuse large B-cell lymphoma (DLBCL) and nasal NK/T-cell lymphoma (NKTL) showed that only 2% of the miRNAs are derived from the virus, while viral miRNAs comprise up to 20% of the total miRNA in nasopharyngeal carcinoma (NPC) and probably contribute to the formation or maintenance of NPC. The presence of viral miRNAs in exosomes raises the fascinating possibility that virus-infected cells regulate gene expression in the surrounding tissue to avert destruction by the immune system. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.

Epidemiology and Pathogenesis of Nasal NK/T-Cell Lymphoma: A Mini-Review

Nasal NK/T-cell lymphoma (NKTCL) frequently presents with necrotic, granulomatous lesions in the upper respiratory tract, and usually shows a highly aggressive clinical course. Thus, it was initially included in the clinical condition of lethal midline granuloma. Recently, the disease has been recognized as a neoplastic proliferation of NK/T cells. The disease is much more frequent in Asian and Latin American countries than in Western countries, and is universally associated with Epstein-Barr virus (EBV) infection. Analyses of gene mutations, especially p53 and c-kit, revealed the different frequencies by district. Abnormalities of other genes have also been reported. Case-control studies showed that the exposure to pesticides and chemical solvents could be causative of NKTCL. Further studies including HLA antigen typing of patients is necessary to further clarify the disease mechanism.

Treatment outcome of radiotherapy alone versus radiochemotherapy in early stage nasal natural killer/T-cell lymphoma

This study aims to investigate the prognostic factors and long-term treatment outcome in patients with early stage nasal natural killer (NK)/T-cell lymphoma. Sixty-four patients were recruited in this study, whose clinical and laboratory data were collected from hospital records. Early stage (stage IE: 51, stage IIE: 13) nasal NK/T-cell lymphoma (NNTCL) was established according to Ann Arbor staging classification. Among these patients, 23 received radiotherapy (RT) alone, the remaining 41 cases were treated with radiochemotherapy (RCT) comprised of 1-6 cycles of anthracycline-based chemotherapeutic regimens. Results show that the median overall survival (OS) time was 41 months. The 5-year OS and progression-free survival rates were 59.2 and 52.3%, respectively. The 5-year OS rate for patients who received RT alone was 57.9%, whereas that for patients who received RCT was 61.5% (P = 0.47). There is no significant difference between two treatment modalities. Multivariate analysis showed that Eastern Cooperative Oncology Group performance status (PS) score > or = 2, local tumor invasion out of nasal cavity, and lower complete remission (CR) rates in the initial treatment were significant unfavorable independent prognostic factors. Taken together, our study suggests that RCT did not improve the survival rate of patients with early stage NNTCL. PS score before treatment, local tumor invasion out of nasal cavity, and CR rate of the primary treatment may be independent prognostic factors among the subtype lymphoma entity.

Expression of the multidrug resistance protein MRP and the lung-resistance protein LRP in nasal NK/T cell lymphoma: further exploring the role of P53 and WT1 gene

Nasal NK/T-cell lymphoma (NKTL) is relatively common in the adult men of Asia. Many patients with nasal NKTL have poor response to therapy. Some of them show P-glycoprotein over-expression. To investigate the expression of other multidrug resistance proteins (MDR) and possible regulatory factors in nasal NKTL, the clinical and pathological features are described. Thirty Chinese adults with nasal NKTL are presented. Immunohistochemical study was carried out to detect multidrug resistance-associated protein 1 (MRP) and lung resistance-related protein (LRP). The association between possible regulatory proteins (P53 and WT1) and MDR were explored. In situ hybridisation for Epstein-Barr virus (EBV) detection, polymerase chain reaction assay for T-cell receptor gene and direct sequencing for the P53 gene were performed. Seven (23.3%) and eight (26.7%) patients showed immunoreactivity of MRP and LRP, respectively. Positive staining for both markers was identified in 6.7% (2 cases). The EBV was detected in most cases (97%). Twenty-six (86.7%) cases expressed positive nuclear staining of P53. However, of the cases analysed for P53 mutation, none showed a mutaion at the hot spots studied. WT1 protein was not detected in the nasal NKTL. Our study reports expression of MRP and LRP in nasal NKTL. The over-expression of P53 is probably associated with high incidence of EBV infection and unlikely a regulatory protein for the expression of MRP and LRP. Further studies are necessary to validate the association between P53 mutation and expression of MRP and LRP in nasal NKTL.