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Low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type has a favorable outcome with radiation therapy alone, and the addition of chemotherapy shows no survival benefit. Nonetheless, a proportion of patients will relapse or progress, with a dismal outcome, highlighting the need for a novel therapeutic strategy. Promising preliminary findings indicate the efficacy of PD-1/PD-L1 inhibitors in extranodal natural killer/T-cell lymphoma, nasal type, with good toxicity profiles. Here we describe the design of a phase II study (CLCG-NKT-2101), which is evaluating the safety and efficacy of adding anti-PD-1 antibody to the current radiation therapy regimen in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type patients. Tislelizumab will be added in an inductive and concurrent way to radiation therapy. The primary end point will be the complete response rate after induction immunotherapy. Clinical trial registration: ClinicalTrials.gov (NCT05149170).

The present study aimed to investigate the clinical features, prognosis, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma (ENKTCL). This real-world study retrospectively reviewed 56 newly diagnosed advanced-stage non-nasal type ENKTCL patients from two large-scale Chinese cancer centers in the last 10-15 years and screened 139 newly diagnosed advanced-stage nasal type ENKTCLs admitted during the same period for comparison. The non-nasal type ENKTCLs exhibited significantly higher Ki-67 expression levels compared to nasal type disease (P = 0.011). With a median follow-up duration of 75.03 months, the non-nasal group showed slightly inferior survival outcomes without statistically significant differences compared to the nasal group (median overall survival (OS): 14.57 vs. 21.53 months, 5-year OS: 28.0% vs. 38.5%, P = 0.120). Eastern Cooperative Oncology Group (ECOG) score ≥ 2 (hazard ratio (HR) = 2.18, P = 0.039) and lactic dehydrogenase (LDH) elevation (HR = 2.44, P = 0.012) were significantly correlated with worse OS in the non-nasal group. First-line gemcitabine-based chemotherapy regimens showed a trend toward slightly improved efficacy and survival outcomes compared to non-gemcitabine-based ones in the present cohort of non-nasal ENKTCLs (objective response rate: 91.7% vs. 63.6%, P = 0.144; complete response rate: 50.0% vs. 33.3%, P = 0.502; median progression-free survival: 10.43 vs. 3.40 months, P = 0.106; median OS: 25.13 vs. 9.30 months, P = 0.125), which requires further validation in larger sample size studies. Advanced-stage non-nasal type patients could achieve comparable prognosis with nasal cases after rational therapy. The modified nomogram-revised index (including age, ECOG score, and LDH) and modified international prognostic index (including age, ECOG score, LDH, and number of extranodal involvement) functioned effectively for prognostic stratification in non-nasal type ENKTCLs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To analyze the differentiation characteristics of extranodal natural killer/T-cell lymphoma, nasal type, one nude mouse model, cell lines SNK6 and SNT8, and 16 fresh human samples were analyzed by flow cytometry immunophenotyping and immunohistochemistry staining; and 115 archived cases were used for phenotypic detection and prognostic analysis. We found that CD25 was expressed by most tumor cells in all samples, and CD56(+)CD25(+) cells were the predominant population in the mouse model, the 2 cell lines, and 10 of the 16 fresh tumor samples; in the other 6 fresh tumor samples, the predominant cell population was of the CD16(+)CD25(+) phenotype, and only a minor population showed the CD56(+)CD25(+) phenotype. The phenotype detected by immunohistochemistry staining generally was consistent with the phenotype found by flow cytometry immunophenotyping. According to the expression of CD56 and CD16, 115 cases could be classified into 3 phenotypic subtypes: CD56(-)CD16(-), CD56(+)CD16(-), and CD56(dim/-)CD16(+). Patients with tumors of the CD56(dim/-)CD16(+) phenotype had a poorer prognosis than patients with tumors of the other phenotypes. Differentiation of extranodal natural killer/T-cell lymphoma, nasal type apparently resembles the normal natural killer cell developmental pattern, and these tumors can be classified into 3 phenotypic subtypes of different aggressiveness. Expression of CD56(dim/-)CD16(+) implies a poorer prognosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To explore the clinical characteristics and prognosis of patients with angioimmunoblastic T cell lymphoma (AITL)., Methods: The clinical features and prognostic factors of 42 cases newly diagnosed as AITL at Peking University Cancer Hospital from January 2007 to August 2012 were retrospectively analyzed., Results: Their median age was 59(34-76) years. Among them, 97.6% cases (41/42) belonged to Ann Arbor stage III/IV, 73.8% (31/42) cases presented with B symptoms, 85.7% (36/42)cases had painless lymphadenopathy, 52.4% (22/42)cases extranodal involvement, 64.3% (27/42) cases elevated lactate dehydrogenase and 45.2% (19/42) cases elevated β2-microglobulin at diagnosis. And 40.5% (17/42) cases had 3 points of international prognostic index (IPI) score with the highest proportion.First-line chemotherapy was predominantly CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) or CHOP-like-based and complete response was achieved in 44.7% (17/38) of them. The median follow-up time was 40 (2-106) months The 1, 2, 5-year survival rates were 78%, 57% and 39% respectively.Statistical analysis showed that IPI was an independent prognostic factor (P = 0.009).Other factors included gender (P = 0.311), age (P = 0.263), with or without B symptoms (P = 0.102), Ki-67 index (P = 0.146) as well as the choice of first-line chemotherapy (P = 0.292) each had a tendency of affecting; the survival rate, but failed to reach statistical significance., Conclusions: Angioimmunoblastic T-cell lymphoma is a major type of peripheral T-cell lymphoma. Most AITL patients are elders with a late stage. The disease generally displays an aggressive clinical course and poor prognosis.

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 EBER1/2, 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, CD3ε, TIA-1 and GrB. Three cases were positive for CD3 and two cases were positive for CD30. Monoclonal TCRγ gene rearrangement was found in 7 of 18 cases. The positive rate of EBER1/2 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.

Hepatosplenic T-cell lymphoma is a highly aggressive tumor with a poor outcome. About 210 cases were identified through PubMed, of which fewer than 20 originated in Asia. We reviewed 17 Chinese cases of hepatosplenic T-cell lymphoma, including an unusual one with cutaneous pink papules, for clinicopathologic, immunophenotypic, and genotypic features; Epstein-Barr virus status; treatment; and outcome. The median age of the patients was 23 years. All patients had splenomegaly, and 88.2% of them had hepatomegaly as well. Bone marrow involvement was present in 53.3%. Eleven patients underwent splenectomy for diagnosis and treatment. Twelve specimens were collected by image-guided liver core biopsy or wedge resection. Histologically, the homogeneous small- to medium-size neoplastic lymphoid cells infiltrated the sinuses or sinusoids of the spleen, bone marrow, and liver. Diagnosis was based on image-guided core-needle biopsy of the liver alone in 41.2% of the cases. Immunohistochemically, 15 of the lesions were hepatosplenic γδ T-cell lymphoma, and the remaining 2 were hepatosplenic αβ T-cell lymphoma. Epstein-Barr virus was detected in both cases of hepatosplenic αβ T-cell lymphoma and one case of hepatosplenic γδ T-cell lymphoma. Most of the patients received cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or regimens similar to it. Follow-up data were available in 70.6% of the patients; half of them died of the tumor, and the median survival time was 6 months. The frequency of bone marrow involvement was lower than that reported in the literature. Image-guided core-needle biopsy of the liver is recommended for diagnosis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Extranodal nasal-type natural killer/T-cell lymphoma presenting in skin, either primary or secondary, is relatively rare in China, accounting for about 4.1% of tumors. The clinicopathologic features of the neoplasm are still poorly understood. Sixteen Chinese cases of cutaneous natural killer/T-cell lymphomas were investigated retrospectively by pathology, immunophenotype, genotype, Epstein-Barr virus status, and survival analysis. The mean age of the patients was 36.3 years; 81% of the patients presented with multiple cutaneous lesions. Angiocentricity and epidermotropism were observed in 43.7% and 25%, respectively; the average number of mitoses was 12 per 10 high-power fields. The neoplastic cells of all 16 cases were positive for CD3varepsilon/CD45RO and granzyme B and negative for CD4, CD5, CD8, and CD20; 87.5% of the tumors expressed CD56. Signals for EBER were detected in 81.3% of cases. No clonal TCRgamma/TCRbeta gene rearrangement was demonstrated. Thirteen of 15 patients received chemotherapy; a partial response was achieved in 10 patients; 10 (66.7%) of 15 patients died of the disease, and the average survival time was 6.6 months. In conclusion, both primary and secondary cutaneous natural killer/T-cell lymphomas are highly aggressive. The outcome is closely related to the number and distribution of the lesions as well as the stage. In patients with generalized skin lesions and extracutaneous involvement, the prognosis usually is poor.

Objective: To evaluate the practical values of PCR detectable T-cell receptor (TCR) gene rearrangement in paraffin embedded tissue samples in the diagnosis of T-cell malignancies using BIOMED-2 PCR multiplex tubes TCRgamma(A+B)., Methods: Traditional phenol-chloroform method was used to extract DNA from 55 cases of archival paraffin embedded tissues samples of T-cell malignancies and the DNA quality was evaluated by PCR-based amplification of housekeeping gene beta-globin. The selected BIOMED-2 PCR multiplex tubes TCRgamma(A+B) were used to detect TCR gene rearrangement and comparison with the results of universal TCR primers (T(VG)/T(JX)) was performed., Results: Positive detection rates by the BIOMED-2 multiplex tubes TCRgamma(A+B) and the universal primers (T(VG)/T(JX)) were 76.4% and 60.0%, respectively. There were not statistical difference between the methods (P > 0.05)., Conclusion: BIOMED-2 multiplex tubes TCRgamma(A+B) is suitable for detection of clonal rearrangements of TCR genes in current archival paraffin embedded tissue samples of T-cell malignancies.

Objective: To explore the diagnostic implication of immunophenotyping and gene rearrangement in subcutaneous panniculitis-like T-cell lymphoma (SPTL)., Methods: According to the selection criteria of 2005 WHO-EORTC classification for cutaneous lymphomas, 20 SPTL patients were enrolled in this study. A 10-antibody panel was used for immunophenotyping and in addition, polymerase chain reaction for TCR gamma and IgH gene rearrangement and in situ hybridization for EBER1/2 were also employed., Results: There were 9 males and 11 female with a mean age of 29.5 years. Immunophenotypic study showed that all the patients expressed one to three T-cell associated antigens (CD2, CD3 or CD45RO), 18 patients were positive for beta F1, 18 for CD8, 20 for TIA-1 and 16 for granzyme B. None of the patients expressed CD4, CD20 and CD56. TCR gamma gene rearrangement was found in 16 of 20 cases (80.0%) and none for IgH gene rearrangement. The positive rate of EBER1/2 was 25.0% (5/20)., Conclusions: Since the majority of SPTL patients show clonal TCR gene rearrangements, correlations among clinical presentation, histological features, immunophenotype and gene rearrangement data are considered important in confirming a diagnosis of SPTL.

Objective: To investigate the expression of CYR61 and VEGF in extranodal nasal-type NK/T cell lymphoma and its significance., Methods: CYR61 mRNA and VEGF mRNA were detected by real-time fluorescence quantitative PCR method in 20 cases of extranodal nasal-type NK/T cell lymphoma. Expressions of CYR61 and VEGF were studied by immunohistochemistry in 40 cases of the tumor., Results: (1) Over-expression of CYR61 mRNA and VEGF mRNA was found in 19/20(95.0% ) and 15/20(75.0% ) cases, respectively. (2)Tumor cells expressing CYR61 protein and VEGF protein were detected in 38(95.0% ) and 25 (62. 5% ) of the 40 cases respectively, being no significant difference from the control. Co-expression of CYR61 and VEGF at both the mRNA and protein levels was 95.0% and 65.0% , respectively. Over-expression of CYR61 and VEGF at both mRNA and protein levels was found in 8 of the 40 cases. (3) The prognosis of the patients over-expressing CYR61 and VEGF was worse., Conclusion: In extranodal nasal-type NK/T cell lymphoma, the expression level of CYR61 and VEGF was changed and it may be of prognostic implication of

Objective: To quantitatively detect the expression level of ribosome protein S13 (RPS13) in NK/T cell lymphoma., Methods: The total RNA isolated from the parafin-embedded tissue of NK/T cell lymphoma was reversely transcribed into cDNA. The real-time fluorescence quantitative PCR technology method was used to analyze the expression level of RPS13 gene., Results: The real-time fluorescence quantitative PCR technology was successfully performed to precisely detect the mRNA level. The expression level of RPS13 gene in tumor tissue of 20 cases of NK/T cell lymphoma was dramatically lower than that in normal peripheral blood lymphocyte of healthy controls., Conclusion: The RPS13 gene has lower expression level in tumor tissue cells of NK/T cell lymphoma than in normal lymphocyte, indicating that it plays an role in the development of the NK/T cell lymphoma.

Background: Intestinal T-cell lymphoma (ITCL) is a heterogeneous lymphoid neoplastic group with variable clinical and pathological features. ITCL in oriental countries is different from enteropathy-type intestinal T-cell lymphoma (ETCL) in relation to celiac disease and Epstein-Barr virus (EBV). The objective of this study was to investigate the clinicopathological features, immunophenotype, expression of cytotoxic molecule (TIA-1), T-cell receptor (TCR)-gamma gene rearrangement, and Epstein-Barr virus (EBV) latent infection in primary ITCL without celiac disease in Chinese., Methods: The clinical data of 42 patients were analyzed, and the patients were followed up. Compared with human reactive lymphoid tissues, in situ hybridization for EBER1/2, polymerase chain reaction for TCR-gamma gene rearrangement, and immunohistochemical staining for immunophenotypes, TIA-1 and EBV latent membrane proteins (LMP-1) were investigated. Survival curves of different clinicopathological features, immuno-phenotypes, expression of LMP1, TCR-gamma gene rearrangement and therapy were analyzed., Results: Three fourths of the patients suffered from ITCL in China were men with a peak age incidence in the 4th decade. Common presenting features included fever and hemotochezia. The prognosis was poor with a median survival of 3.0 months. The lesions were mostly localized in the ileocecum and colon. About 38/42 (90.5%) patients demonstrated pleomorphic medium-sized on large cells. Histological features of celiac disease were rarely seen. All 42 patients with ITCL revealed CD45RO positive. Neoplastic cells partially expressed T-cell differentiated antigens (CD3epsilon, CD4, CD8) and NK cell associated antigen (CD56). The positive frequency of CD3epsilon, CD4, CD8 and CD56 was 28/42 (66.7%), 7/42 (16.7%), 10/42 (23.8%) and 12/42 (28.6%) respectively. Thirty-nine cells (92.9%) expressed TIA-1, but none expressed CD20 and CD68. More than half of the patients (64.3%, 64.3% and 59.5%) revealed TCR-gamma gene rearrangement by three different TCR-gamma primers respectively. EBER1/2 was detected in 41 (97.6%) of the 42 patients. The expression frequency of LMP-1 was 38.1% (16/42)., Conclusions: Primary ITCL without celiac disease in Chinese is a special highly EBV-associated clinicopathological entity. There are few similarities in patients with celiac disease in western countries. A small proportion of primary ITCLs in Chinese and extranodal NK/T-cell lymphoma of nasal type belong to the same spectrum.

Objective: To assess the stability and variability of the LMP1 gene and protein in nude-mice transplanted tumor models of extranodal nasal type NK/T-cell lymphoma., Methods: PCR and Western Blot were performed to detect the full-length LMP1 gene and protein expression in the established extranodal nasal type NK/ T-cell lymphoma transplanted tumor models and the tissues of donor tumors. Then the sequence of full-length LMP1 gene in transplanted tumor models and donor were compared with the sequence of wild-type B95. 8 and deletion-type CAO cell strains., Results: LMP1 gene and protein were detected in all the extranodal nasal type NK/T-cell lymphoma transplanted tumor models, and the full-length LMP1 nucleotide sequence homology with the donor tumor was 99. 76%. It was found in sequencing analysis that LMP1 gene sequence possessed both conservative character and specificity, similar to that of CAO cell strains., Conclusion: LMP1 gene and protein existed stably in the extranodal nasal type NK/T-cell lymphoma transplanted tumor models, which implied that LMP1 might relate to the maintenance and development of this lymphoma. The nude-mice transplanted tumor models provided an important experimental platform for further studies on the correlation of LMP1 and extranodal nasal type NK/T-cell lymphoma.

Unlabelled: To investigate the expression and prognostic significance of Epstein-Barr virus latent membrane protein 1 in extranodal nasal type NK/T-cell lymphoma in the Chengdu area., Methods: The expression of latent membrane protein-1 (LMP1) was detected by immunohistochemistry (IHC) and DNA-PCR in 67 cases of extranodal nasal type NK/T-cell lymphoma, and the differences in survival rate between positive and negative expression groups of LMP1-protien and LMP1-DNA were analyzed respectively., Results: Ten (14.93%) cases were positive at LMP1-protein level, and fifty-six (83.58%) were positive at LMP1-DNA level. The total expression rate of LMP1 was 83.58%. No statistically significant difference was observed between the expression of LMP1 and prognosis (P = 0.678) and between the expression of LMP1-DNA and prognosis (P = 0.943)., Conclusion: LMP1 was shown to be closely associated with extranodal nasal type NK/T-cell lymphoma in Chengdu. The expression rate of LMP1 at protein level was different from that at DNA level. No relationship was found between the prognosis and the LMP1 expression in extranodal nasal type NK/T-cell lymphoma.

Objective: To evaluate the status of cell differentiation in nasal NK/T cell lymphomas., Methods: The clinical data of 88 cases of NK/T cell lymphomas were collected. Antibodies to the following antigens were used in the immunohistochemical study: T cell differentiation antigens (CD3epsilon, CD5 and CD1a); NK cell associated antigens (CD56, CD57) and antibodies of CD34 and CD38., Results: (1) Clinicopathology: clinically, frequently involved sites were the nasal cavity and the pharynx. Ulceration and erosion of the mucosa were common signs. Pathologically, diffuse infiltration of the tumor cells was observed in 68 of 88 (70.45%) cases of nasal NK/T cell lymphomas. In 71 (80.68%) cases infiltrated cells were predominantly medium to large sized; (2) Differentiation status of tumor cells: the tumor cells expressed CD3epsilon in 78/88 (88.64%); CD5 in 56/88 (63.63%), CD56 in 25/88 (28.41%) and no positivity for CD1a, CD57, CD34 and CD38., Conclusion: Status of tumor cell differentiation in nasal NK/T cell lymphoma may have passed the stage of progenitor cell differentiation but not yet to the stage of mature T or NK cells.