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Gao XD, Zhang J, Li A, Ding Y, Zhao B, Li L. Analysis of anxiety and depression and influencing factors in non-Hodgkin's lymphoma of the nasal cavity and paranasal sinus. World J Psychiatry 2025; 15:99346. [DOI: 10.5498/wjp.v15.i4.99346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/13/2025] [Accepted: 02/17/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Natural killer (NK)/T-cell non-Hodgkin's lymphoma (NHL) in the nasal cavities and paranasal sinuses accounts for approximately 10% of all lymphomas, and the occurrence of nasal NHL is related to Epstein-Barr virus infection.
AIM To explore the anxiety and depression status of patients with NK/T-cell NHL in the nasal cavities and paranasal sinuses and analyzes the relevant influencing factors.
METHODS A retrospective analysis was performed, which included 30 patients with primary nasal NK/T-cell NHL treated in Shaanxi Provincial People’s Hospital from January 2017 to January 2023. An additional 50 healthy volunteers were selected as the control group. Both groups were assessed using the self-rating anxiety scale (SAS) and Self-rating (SDS). SDS and SAS scores of patients with NHL at different disease stages were analyzed, and they were further grouped into negative emotion (NE) (n = 19) and non-NE (n = 11) groups based on their depression and anxiety. Factors affecting the occurrence of NEs in patients with NHL were analyzed using univariate and multivariate logistic regression models.
RESULTS Patients with NHL exhibited higher SDS and SAS scores than healthy controls. Moreover, patients with NHL at stages III and IV had higher SDS and SAS scores than those in stage I. Among the 30 patients, there were 13 patients with depression (43.3%), 16 patients with anxiety (53.3%), and 10 patients with both anxiety and depression (33.3%). Univariate analysis identified a higher proportion of people in the NE group with stage III-IV NHL, an educational level ≤ high school, and a monthly household income < 5000 yuan compared with the non-NE group. Multiple logistic regression analysis further revealed that stage III-IV was a risk factor for NEs in patients with NHL.
CONCLUSION The stage of NK/T-cell NHL in nasal cavities and paranasal sinuses is closely related to patient anxiety and depression. The higher the staging, the greater the incidence of anxiety and depression.
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Affiliation(s)
- Xu-Dong Gao
- Department of Otolaryngology Head and Neck Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - Jin Zhang
- Department of Otolaryngology Head and Neck Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - An Li
- Department of Otolaryngology Head and Neck Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - Yu Ding
- Department of Otolaryngology Head and Neck Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - Bo Zhao
- Department of Otolaryngology Head and Neck Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - Lan Li
- Department of Hematology, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
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Al-Mansour M, Aga SS, O’Connor OA. Perspectives on the Mature T-Cell Lymphomas in the Middle East: A Comprehensive Review of the Present Status. Cancers (Basel) 2024; 16:4131. [PMID: 39766031 PMCID: PMC11674585 DOI: 10.3390/cancers16244131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
Background: T-cell lymphomas (TCLs) are rare and aggressive malignancies associated with poor outcomes, often because of the development of acquired drug resistance as well as intolerance to the established and often toxic chemotherapy regimens in elderly and frail patients. The many subtypes of TCL are well established to exhibit marked geographic variation. The epidemiology, clinical presentation, diagnosis, prognosis, and treatment of TCLs in the Middle East (ME) are yet to be explored; hence, limited data are available about these entities in this part of the world. Aim: Therefore, in this review article, we aim to discuss the available data regarding the T-cell neoplasms in the ME, including the incidence of specific subtypes of peripheral T-cell lymphoma (PTCL), as well as the trends in survival and treatment, all in an effort to understand the natural history of these complex entities across the ME.
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Affiliation(s)
- Mubarak Al-Mansour
- Adult Medical Oncology, Princess Noorah Oncology Centre, Ministry of National Guard Health Affairs-Western Region (MNGHA-WR), King Saud Bin Abdul Aziz University for Health Sciences (KSAU-HS), King Abdullah International Medical Research Centre (KAIMRC), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia;
- College of Medicine, King Abdullah International Medical Research Centre (KAIMRC), King Saud Bin Abdul Aziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs-Western Region (MNGHA-WR), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia
| | - Syed Sameer Aga
- College of Medicine, King Abdullah International Medical Research Centre (KAIMRC), King Saud Bin Abdul Aziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs-Western Region (MNGHA-WR), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia
| | - Owen A. O’Connor
- University of Virginia Comprehensive Cancer Center, Translational Orphan Blood Cancer Research Center, Charlottesville, VA 22903, USA;
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Jin J, Mao X, Zhang D. A differential diagnosis method for systemic CAEBV and the prospect of EBV-related immune cell markers via flow cytometry. Ann Med 2024; 56:2329136. [PMID: 38502913 PMCID: PMC10953786 DOI: 10.1080/07853890.2024.2329136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 02/23/2024] [Indexed: 03/21/2024] Open
Abstract
Chronic active Epstein-Barr virus (CAEBV) infection of the T-cell or Natural killer (NK)-cell type, systemic form (systemic CAEBV or sCAEBV) was defined by the WHO in 2017 as an EBV-related lymphoproliferative disorder and is listed as an EBV-positive T-cell and NK-cell proliferation. The clinical manifestations and prognoses are heterogeneous. This makes systemic CAEBV indistinguishable from other EBV-positive T-cell and NK-cell proliferations. Early diagnosis of systemic CAEBV and early hematopoietic stem cell transplantation can improve patient prognosis. At present, the diagnosis of systemic CAEBV relies mainly on age, clinical manifestations, and cell lineage, incurring missed diagnosis, misdiagnosis, long diagnosis time, and inability to identify high-risk systemic CAEBV early. The diagnostic methods for systemic CAEBV are complicated and lack systematic description. The recent development of diagnostic procedures, including molecular biological and immunological techniques such as flow cytometry, has provided us with the ability to better understand the proliferation of other EBV-positive T cells and NK cells, but there is no definitive review of their value in diagnosing systemic CAEBV. This article summarizes the recent progress in systemic CAEBV differential diagnosis and the prospects of flow cytometry.
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Affiliation(s)
- Jie Jin
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xia Mao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Donghua Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Wu C, Shi L, Shi K, Wang Z, Zhang Y. A Case Report of Extranodal NK/T-Cell Lymphoma Misdiagnosed as Meibomitis. Ocul Immunol Inflamm 2024; 32:1124-1127. [PMID: 37186811 DOI: 10.1080/09273948.2023.2201326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 04/05/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023]
Abstract
INTRODUCTION Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare type of non-Hodgkin's lymphoma. This report presents a patient with the right lower eyelid ENKTL misdiagnosed as meibomitis repeatedly. CASE PRESENTATION A 48-year-old woman developed recurrent redness and swelling in right eyelid for 2 years. Three eyelid mass removal operations were performed in local hospitals, and the pathological examination suggested meibomitis. Physical examination showed an induration in the lateral lower eyelid of the right eye, local defect of the eyelid margin, mild entropion, redness and swelling of the surrounding tissues, and temporal bulbar conjunctiva hyperemia. The eyelid lesion was resected and ENKTL was diagnosed by specific immunohistochemical staining and in situ hybridization. The lymphoma resolved with chemotherapy and radiotherapy. The patient was still alive forty-one months after the last operation. CONCLUSION Our report demonstrates that recurrent eyelid redness and swelling might be a malignant tumor, and clinicians should be vigilant.
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Affiliation(s)
- Chao Wu
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, China
| | - Lu Shi
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, China
| | - Ke Shi
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Zhiqiang Wang
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, China
| | - Yulan Zhang
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, China
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Xiao Y, Zhang X, Gao Y, Lin K, Chi W, Zhou K, Ma J, Zhang T. Extranodal natural killer/T-cell lymphoma with tonsil involvement: a case report. BMC Oral Health 2024; 24:867. [PMID: 39080655 PMCID: PMC11290306 DOI: 10.1186/s12903-024-04452-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 06/06/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND Extranodal natural killer/T-cell lymphoma (ENKTL) with tonsil involvement is not common, especially in children. CASE PRESENTATION A 13-year-old girl presented with an unexplained sore throat for more than 2 months, together with intermittent fever and suppurative tonsilitis. Nasopharyngoscopy revealed a pharyngeal mass. Enhanced computed tomography (CT) scan showed tonsillar hypertrophy and punctate calcification. Chronic pyogenic granulomatous inflammation with pseudoepithelial squamous epithelial hyperplasia was observed in left tonsil, and pyogenic granulomatous inflammation and a small number of T-lymphoid cells were detected in the right tonsil. The immunohistochemical results showed CD2+, CD3+, CD4+, CD5+, CD8+, granzyme B+, and TIA-1+. The Ki-67 proliferation index was 20%. The case showed T cell receptor gene rearrangement. Finally, the case was diagnosed as ENKTL of stage II with tonsil involvement. The patient received 6 cycles of chemotherapy with SMILE regimen, and showed complete response with no recurrence in the follow-up. CONCLUSION We presented a rare case of ENKTL with tonsil involvement in a child. The patient showed complete response to the SMILE chemotherapy with no recurrence.
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Affiliation(s)
- Yang Xiao
- Department of Otolaryngology, Head and Neck Surgery, Children's Hospital Affiliated to Kunming Medical University (Kunming Children's Hospital), Kunming, China
| | - Xing Zhang
- Department of Cardiology, Children's Hospital Affiliated to Kunming Medical University (Kunming Children's Hospital), Kunming, China
| | - Yingqin Gao
- Department of Otolaryngology, Head and Neck Surgery, Children's Hospital Affiliated to Kunming Medical University (Kunming Children's Hospital), Kunming, China
| | - Ken Lin
- Department of Otolaryngology, Head and Neck Surgery, Children's Hospital Affiliated to Kunming Medical University (Kunming Children's Hospital), Kunming, China
| | - Wenyue Chi
- Department of Otolaryngology, Head and Neck Surgery, Children's Hospital Affiliated to Kunming Medical University (Kunming Children's Hospital), Kunming, China
| | - Kaijian Zhou
- Kunming Medical University Haiyuan College, Kunming, China
| | - Jing Ma
- Department of Otolaryngology, Head and Neck Surgery, Children's Hospital Affiliated to Kunming Medical University (Kunming Children's Hospital), Kunming, China.
| | - Tiesong Zhang
- Department of Otolaryngology, Head and Neck Surgery, Children's Hospital Affiliated to Kunming Medical University (Kunming Children's Hospital), Kunming, China.
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Nejjari H, Ait Zine I, Ammouri W, Bernousssi Z, Kabbaj H. Primary Testicular Extranodal NK/T-cell Lymphoma Nasal Type Associated With Epstein-Barr Virus Infection: A Moroccan Case Report. Cureus 2024; 16:e63361. [PMID: 39070361 PMCID: PMC11283753 DOI: 10.7759/cureus.63361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 07/30/2024] Open
Abstract
Epstein-Barr virus (EBV) is a ubiquitous and potentially oncogenic human herpesvirus. In this article, we discuss a rare case of primary testicular NK/T-cell lymphoma, nasal type, associated with high plasma Epstein-Barr virus DNA load. The patient, a 45-year-old man, presented with painful testicular swelling, fever, and weight loss. An orchiectomy revealed tumor proliferation, which was diagnosed as testicular NK/T cell lymphoma, nasal type, confirmed by immunohistochemistry, and classified as stage IV according to the Ann Arbor classification. The patient was treated with SMILE chemotherapy. After treatment, a PET scan showed complete remission with negative EBV DNA levels. The discussion focused on the role of EBV in the development of this malignant lymphoproliferation and the importance of quantifying EBV DNA load by real-time PCR in assessing prognosis, patient follow-up, and response to treatment.
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Affiliation(s)
- Hanaa Nejjari
- Central Laboratory of Virology, Ibn Sina Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
| | - Intissar Ait Zine
- Internal Medecine Department, Ibn Sina Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
| | - Wafa Ammouri
- Internal Medecine Department, Ibn Sina Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
| | - Zakia Bernousssi
- Pathology Department, Ibn Sina Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
| | - Hakima Kabbaj
- Central Laboratory of Virology, Ibn Sina Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
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He Y, Luo Z, Chen H, Ping L, Huang C, Gao Y, Huang H. A Nomogram Model Based on the Inflammation-Immunity-Nutrition Score (IINS) and Classic Clinical Indicators for Predicting Prognosis in Extranodal Natural Killer/T-Cell Lymphoma. J Inflamm Res 2024; 17:2089-2102. [PMID: 38595337 PMCID: PMC11001545 DOI: 10.2147/jir.s452521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 03/19/2024] [Indexed: 04/11/2024] Open
Abstract
Background Systemic inflammation, immunity, and nutritional status are closely related to patients' outcomes in several kinds of cancers. This study aimed to establish a new nomogram based on inflammation-immunity-nutrition score (IINS) to predict the prognosis of extranodal natural killer/T-cell lymphoma (ENKTL) patients. Methods The clinical data of 435 patients with ENTKL were retrospectively reviewed and randomly assigned to training cohort (n=305) and validation cohort (n=131) at a ratio of 7:3. Cox regression analysis was employed to identify independent prognostic factors and develop a nomogram in the training cohort. Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) curve were employed to assess the performance of the nomogram and compare it with traditional prognostic systems (PINK, IPI, KPI). Internal validation was performed using 1000 bootstrap resamples in the validation cohort. Kaplan-Meier survival analyses were conducted to compare the overall survival (OS) of patients in different risk groups. Results In the training cohort, in addition to several classic parameters, IINS was identified as an independent prognostic factor significantly associated with the OS of patients. The nomogram established based on the independent prognostic indicators showed superior survival prediction efficacy, with C-index of 0.733 in the training cohort and 0.759 in the validation cohort compared to the PINK (0.636 and 0.737), IPI (0.81 and 0.707), and KPI (0.693 and 0.639) systems. Furthermore, compared with PINK, IPI, and IPI systems, the nomogram showed relatively superior calibration curves and more powerful prognostic discrimination ability in predicting the OS of patients. DCA curves revealed some advantages in terms of clinical applicability of the nomogram compared to the PINK, IPI, and IPI systems. Conclusion Compared with traditional prognostic systems, the nomogram showed promising prospects for risk stratification in ENKTL patient prognosis, providing new insights into the personalized treatment.
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Affiliation(s)
- Yanxia He
- Department of Oncology, The Third People’s Hospital of Chengdu, Sichuan, People’s Republic of China
| | - Zhumei Luo
- Department of Oncology, The Third People’s Hospital of Chengdu, Sichuan, People’s Republic of China
| | - Haoqing Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Liqing Ping
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Cheng Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Yan Gao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Huiqiang Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
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Yang P, Cai M, Cao Y, Fan S, Tang W, Ji M, Huang L, Wang F, Zhao W, Niu T, Mo X. Up-front autologous stem cell transplant in peripheral T-cell lymphoma patients achieving complete response after first-line treatment: A multicentre real-world analysis. Br J Haematol 2024; 204:1414-1421. [PMID: 38272453 DOI: 10.1111/bjh.19317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/05/2024] [Accepted: 01/15/2024] [Indexed: 01/27/2024]
Abstract
We conducted a retrospective, multicentre study to compare consolidation therapy with or without first-line autologous stem cell transplant (ASCT) for peripheral T-cell lymphoma (PTCL) patients in a real-world setting. We enrolled 347 PTCL patients who achieved complete response after first-line treatment. Of these, 257 received consolidation chemotherapy (non-ASCT group) and 90 received ASCT (ASCT group). Clinical outcomes were comparable between ASCT and non-ASCT groups. After propensity score matching, the 2-year cumulative incidence of treatment-related mortality and relapse remained similar between groups (1.9% vs. 2.0%, p = 0.985; 24.7% vs. 47.1%, p = 0.021). However, significant differences emerged in progression-free survival and overall survival probabilities. Within the T-cell lymphoma subgroup, ASCT patients exhibited favourable outcomes compared to non-ASCT patients: 2-year progression-free survival (73.4% vs. 50.8%, p = 0.024) and overall survival (92.1% vs. 73.5%, p = 0.021). Notably, no significant differences were observed for patients with NK/T-cell lymphoma. These real-world data suggest that up-front ASCT is a safe and effective consolidation option for PTCL patients in remission, particularly those with T-cell lymphoma.
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Affiliation(s)
- Peipei Yang
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
| | - Mingci Cai
- State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Cao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Fan
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Wei Tang
- State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengmeng Ji
- State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liang Huang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fengrong Wang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Weili Zhao
- State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting Niu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaodong Mo
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences (2019RU029), Beijing, China
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Zhang YH, Tao Q, Zhang WY, Zhao S, Liu WP, Gao LM. Histone methyltransferase KMT2D inhibits ENKTL carcinogenesis by epigenetically activating SGK1 and SOCS1. Genes Genomics 2024; 46:203-212. [PMID: 37523130 DOI: 10.1007/s13258-023-01434-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 07/19/2023] [Indexed: 08/01/2023]
Abstract
BACKGROUND Epigenetic alteration plays an essential role in the occurrence and development of extranodal natural killer/T cell lymphoma (ENKTL). Histone methyltransferase (HMT) KMT2D is an epigenetic regulator that plays different roles in different tumors, but its role and mechanism in ENKTL are still unclear. METHODS We performed immunohistochemical staining of 112 ENKTL formalin-fixed paraffin-embedded (FFPE) samples. Then, we constructed KMT2D knockdown cell lines and conducted research on cell biological behavior. Finally, to further investigate KMT2D-mediated downstream genes, ChIP-seq and ChIP -qPCR was performed. RESULTS The low expression of KMT2D was related to a decreased abundance in histone H3 lysine 4 mono- and trimethylation (H3K4me1/3). In KMT2D knockdown YT and NK-YS cells, cell proliferation was faster (P < 0.05), apoptosis was decreased (P < 0.05), the abundance of S phase cells was increased (P < 0.05), and the level of H3K4me1 was decreased. Notably, ChIP-seq revealed two crucial genes and pathways downregulated by KMT2D. CONCLUSIONS KMT2D is a tumor suppressor gene that mediates H3K4me1 and influences ENKTL proliferation and apoptosis by regulating the cell cycle. Moreover, in ENKTL, serum- and glucocorticoid-inducible kinase-1 (SGK1) and suppressor of cytokine signaling-1 (SOCS1) are downstream genes of KMT2D.
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Affiliation(s)
- Yue-Hua Zhang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Qing Tao
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Wen-Yan Zhang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Sha Zhao
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Wei-Ping Liu
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China.
| | - Li-Min Gao
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China.
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Sato S, Ishii M, Tachibana K, Furukawa Y, Toyota T, Kinoshita S, Azusawa Y, Ando J, Ando M. Establishment of ganglioside GD2-expressing extranodal NK/T-cell lymphoma cell line with scRNA-seq analysis. Exp Hematol 2024; 130:104132. [PMID: 38029851 DOI: 10.1016/j.exphem.2023.11.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 11/14/2023] [Accepted: 11/19/2023] [Indexed: 12/01/2023]
Abstract
Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL), is characterized by Epstein-Barr virus infection and poor prognosis. We established a novel cell line, ENKL-J1, from bone marrow cells of an ENKL patient. We found that ENKL-J1 cells express the ganglioside GD2 (GD2) and that GD2-directed chimeric antigen receptor T cells exhibit cytotoxicity against ENKL-J1 cells, indicating that GD2 would be a suitable target of GD2-expressing ENKL cells. Targeted next-generation sequencing revealed TP53 and TET2 variants in ENKL-J1 cells. Furthermore, single-cell RNA sequencing in ENKL-J1 cells showed high gene-expression levels in the oncogenic signaling pathways JAK-STAT, NF-κB, and MAPK. Genes related to multidrug resistance (ABCC1), tumor suppression (ATG5, CRYBG1, FOXO3, TP53, MGA), anti-apoptosis (BCL2, BCL2L1), immune checkpoints (CD274, CD47), and epigenetic regulation (DDX3X, EZH2, HDAC2/3) also were expressed at high levels. The molecular targeting agents eprenetapopt, tazemetostat, and vorinostat efficiently induced apoptosis in ENKL-J1 cells in vitro. Furthermore, GD2-directed chimeric antigen receptor T cells showed cytotoxicity against ENKL-J1 cells in vivo. These findings not only contribute to understanding the molecular and genomic characteristics of ENKL; they also suggest new treatment options for patients with advanced or relapsed ENKL.
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Affiliation(s)
- Shoko Sato
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Midori Ishii
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Kota Tachibana
- Division of Cell Therapy & Blood Transfusion Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Yoshiki Furukawa
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Tokuko Toyota
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Shintaro Kinoshita
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Yoko Azusawa
- Division of Cell Therapy & Blood Transfusion Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Jun Ando
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; Division of Cell Therapy & Blood Transfusion Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Miki Ando
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
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Yu J, Jin S, Yin X, Du H. Expression of the immune checkpoint molecules PD‑L1 and PD‑1 in EBV‑associated lymphoproliferative disorders: A meta‑analysis. Exp Ther Med 2024; 27:7. [PMID: 38223325 PMCID: PMC10785044 DOI: 10.3892/etm.2023.12294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 08/31/2023] [Indexed: 01/16/2024] Open
Abstract
Epstein-Barr virus (EBV) has been implicated in the development of a wide range of lymphoproliferative disorders. In this process, the role of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) has remained to be clarified. A meta-analysis of 20 studies was performed and risk ratios (RRs) with 95% confidence intervals (CIs) were used to evaluate the association between PD-L1/PD-1 expression and the status of EBV infection. The results showed that the expression level of PD-L1 in tumor cells was significantly higher in EBV+ cases with a pooled RR of 2.26 (95% CI, 1.63-3.14; P<0.01), particularly in subtypes of diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma. Similarly, EBV infection increased the expression of PD-L1 in immune cells with a pooled RR of 2.20 (95% CI, 1.55-3.12; P<0.01). In subtypes of DLBCL and post-transplant lymphoproliferative disorder, the expression of PD-L1 in immune cells is increased in EBV+ cases. Regarding the expression level of PD-1 in tumor-infiltrating lymphocytes (TILs), no significance was found between EBV infection and PD-1 expression, with a pooled RR of 1.10 (95% CI, 0.81-1.48; P>0.05). The present meta-analysis demonstrated that in EBV-associated lymphoproliferative disorders, EBV infection was associated with the expression level of PD-L1 in tumor cells and immune cells but was not associated with the expression of PD-1 in TILs.
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Affiliation(s)
- Junyao Yu
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Shenhe Jin
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Xiufeng Yin
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Huaping Du
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
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Rivera-Francia VM, Failoc-Rojas VE, Villacorta-Carranza R, Leon Garrido-Lecca A, Calle-Villavicencio A, Torres-Mera A, Valladares-Garido MJ, Huerta-Collado Y, Motta-Guerrero R, Casanova Marquez L. Use of PD-1 blockade in refractory/relapsed natural killer T-cell lymphomas: a systematic review and synthesis of case reports. Leuk Lymphoma 2024; 65:37-47. [PMID: 37794819 DOI: 10.1080/10428194.2023.2264431] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 09/20/2023] [Indexed: 10/06/2023]
Abstract
Natural killer/T-cell lymphoma (NK/T-cellL) is an aggressive non-Hodgkin's lymphoma with limited treatment options for patients who experience disease progression or recurrence after second-line treatment. The use of new therapies, such as pembrolizumab, which involves immune checkpoint blockade mechanisms, is proposed. This systematic review followed the MOSE guidelines and searched PUBMED/MEDLINE, EMBASE, and Scopus databases. Fourteen articles were found, reporting on the use of pembrolizumab anti PD-1 in NK/T-cellL patients. The objective response rate was 84.50%, with disease-free survival ranging from two to 48 months. The complete response rate was 61.6%, and the quality of the reported studies was evaluated to be of high and moderate confidence bias levels in case reports and high bias in clinical trials. Pembrolizumab and others anti PD-1 are treatment options for refractory/recurrent NK/T-cellL, regardless of PD-L1 expression, with good short- and long-term results and low adverse events.
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Nakamura T, Tatetsu H, Higuchi Y, Endo S, Shiraishi S, Kawanaka K, Imakane D, Sonoda M, Furuta R, Shichijo T, Honda Y, Karube K, Mikami Y, Nosaka K, Matsuoka M, Yasunaga JI. Extranodal NK/T-cell lymphoma with localized relapse in bone marrow of lower leg detected using PET-CT. J Clin Exp Hematop 2024; 64:45-51. [PMID: 38538318 PMCID: PMC11079990 DOI: 10.3960/jslrt.23046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/27/2023] [Accepted: 12/27/2023] [Indexed: 05/12/2024] Open
Abstract
Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma (NHL) with poor prognosis, particularly in relapsed or refractory patients. Thus, timely detection of relapse and appropriate disease management are crucial. We present two patients with ENKTL, wherein positron emission tomography-computed tomography (PET-CT) with total-body coverage after induction therapy, detected newly relapsed regions in the bone marrow of the lower leg prior to progression. Case 1: A 47-year-old woman with nasal obstruction, showing 18F-fluoro-deoxyglucose (FDG) uptake in the nasal cavity (Lugano stage IE). After induction therapy (RT-2/3 DeVIC), PET-CT revealed abnormal uptake only in the right fibula. Case 2: A 68-year-old man with a skin nodule/ulcer and an enlarged right inguinal lymph node was diagnosed with advanced ENKTL. A PET-CT scan revealed abnormal uptake in the subcutaneous mass of the right medial thigh, lymph nodes, and descending colon (Lugano stage IV). After induction therapy, PET-CT revealed new abnormal uptake only in the left tibia. In both patients, CT-guided biopsy confirmed ENKTL recurrence. Moreover, PET-CT with whole-body coverage was useful for the timely assessment of relapse and detection of asymptomatic bone involvement. This approach allowed for modifications to treatment strategies in certain patients.
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14
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Shen Z, Chen X, Sun C, Lu T, Shi Y, Zhang H, Ye J, Wang L, Zhu T, Miao Y, Zhang X, Wang L, Cai G, Sang W. Comparative analysis of clinicopathologic characteristics and prognosis between nasal and nonnasal extranodal NK/T-cell lymphoma. Cancer Med 2023; 12:21138-21147. [PMID: 37902266 PMCID: PMC10726883 DOI: 10.1002/cam4.6674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/04/2023] [Accepted: 10/04/2023] [Indexed: 10/31/2023] Open
Abstract
BACKGROUND The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the underlying features responsible for these differences are not well clarified especially in the era of asparaginase therapy. METHODS In total, 1007 newly diagnosed ENKTL patients from 11 medical centers were included in this study. Clinicopathologic characteristics and survival data were collected. The chi-squared test and Kruskal-Wallis test were utilized for the comparison of different groups. Univariable and multivariable Cox proportional hazards models were used to screen prognostic factors. RESULTS Overall, 869 (86.3%) patients were nasal forms. Compared to patients with nasal ENKTL, nonnasal patients were at more advanced stages and had poor performance status, bone marrow involvement, elevated serum lactate dehydrogenase (LDH), and CD56-negative status (p < 0.05). The 5-year overall survival (OS) for nasal and nonnasal patients were 65.6% and 45.0%, respectively. The OS of nasal forms patients were superior to nonnasal patients, especially in Eastern Cooperative Oncology Group performance status (ECOG PS) (≥2), advanced stage, KPI (HIR/HR), IPI (HIR/HR), PINK (HR), and high EBV DNA load groups. In patients treated with pegaspargase/L-asparaginase-based regimens, the OS of nasal patients was better than that of nonnasal patients. After adjusting the covariates of age, stage, ECOG PS score, LDH, B symptoms, and BM involvement, results showed that the nonnasal site was associated with poor survival of ENKTL. CONCLUSIONS The clinicopathologic characteristics and prognosis of nasal and nonnasal ENKTL patients are different. Nasal forms patients had superior OS than nonnasal patients, especially in the era of asparaginase.
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Affiliation(s)
- Ziyuan Shen
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
| | - Xicheng Chen
- Department of HematologyAffiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Cai Sun
- Department of HematologyAffiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Tianyi Lu
- Department of HematologyAffiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Yuye Shi
- Department of HematologyThe First People's Hospital of Huai'anHuai'anJiangsuChina
| | - Hao Zhang
- Department of HematologyThe Affiliated Hospital of Jining Medical UniversityJiningShandongChina
| | - Jingjing Ye
- Department of HematologyQilu Hospital of Shandong UniversityJinanShandongChina
| | - Ling Wang
- Department of HematologyTai'an Central HospitalTai'anShandongChina
| | - Taigang Zhu
- Department of HematologyThe General Hospital of Wanbei Coal‐Electric GroupSuzhouAnhuiChina
| | - Yuqing Miao
- Department of HematologyYancheng First People's HospitalYanchengJiangsuChina
| | - Xudong Zhang
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Liang Wang
- Department of Hematology, Beijing Tongren HospitalCapital Medical UniversityBeijingChina
| | - Guoqi Cai
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
| | - Wei Sang
- Department of HematologyAffiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
- Blood Diseases Institute, Xuzhou Medical UniversityXuzhouJiangsuChina
- Key Laboratory of Bone Marrow Stem CellXuzhouJiangsuChina
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15
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Tachita T, Takahata T, Yamashita S, Ebina T, Kamata K, Yamagata K, Tamai Y, Sakuraba H. Newly diagnosed extranodal NK/T-cell lymphoma, nasal type, at the injected left arm after BNT162b2 mRNA COVID-19 vaccination. Int J Hematol 2023; 118:503-507. [PMID: 37093551 PMCID: PMC10124685 DOI: 10.1007/s12185-023-03607-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 04/25/2023]
Abstract
Anti-SARS-CoV-2 vaccines were developed in response to the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the BNT162b2 mRNA vaccine is effective, adverse effects have been reported. Here, we report a case of extranodal NK/T-cell lymphoma, nasal type (ENKL), of the left arm following BNT162b2 mRNA vaccination. A 73-year-old male presented with a lump in the left arm, which was the site where he received the BNT162b2 mRNA vaccine 3 months prior. He was treated with topical corticosteroids and debridement, but the tumor progressed. Additionally, fever, night sweats, and general fatigue were observed. Laboratory findings included thrombocytopenia, elevated lactate dehydrogenase, and soluble interleukin-2 receptor levels. Skin biopsy led to a diagnosis of ENKL. The patient was treated with a 50% dose of SMILE therapy and radiotherapy, resulting in regression of the tumor. It seems that latent Epstein-Barr virus (EBV)-infected NK/T cells were reactivated by vaccination and contributed to the onset of ENKL. This is the first report of ENKL after BNT162b2 mRNA vaccination. The present case highlights the possible risk of development of malignant lymphoma, including ENKL at the injection site, after BNT162b2 COVID-19 vaccination.
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Affiliation(s)
- Takuto Tachita
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-Cho, Hirosaki, , Aomori, 036-8562, Japan.
| | - Takenori Takahata
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-Cho, Hirosaki, , Aomori, 036-8562, Japan
| | - Satoru Yamashita
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-Cho, Hirosaki, , Aomori, 036-8562, Japan
| | - Toru Ebina
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-Cho, Hirosaki, , Aomori, 036-8562, Japan
| | - Kosuke Kamata
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-Cho, Hirosaki, , Aomori, 036-8562, Japan
| | - Kazufumi Yamagata
- Department of Bioscience and Laboratory Medicine, Hirosaki University Graduate School of Health Sciences, Hirosaki, Japan
| | - Yoshiko Tamai
- Department of Transfusion and Cell Therapy Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-Cho, Hirosaki, , Aomori, 036-8562, Japan
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16
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Huang W, Liu X, Li L, Zhang Y, Gao Y, Gao J, Kang L. Multimodality imaging evaluation of primary testicular extranodal natural killer/T-cell lymphoma: two case reports. Front Med (Lausanne) 2023; 10:1183564. [PMID: 37324131 PMCID: PMC10267869 DOI: 10.3389/fmed.2023.1183564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/11/2023] [Indexed: 06/17/2023] Open
Abstract
Background Extranodal natural killer/T-cell lymphoma (ENKTCL) is a distinct pathological entity and accounts for ~10% of T-cell lymphomas. The histological features of ENKTCL include angiodestruction and coagulative necrosis and the association with EBV infection. ENKTCL is typically aggressive and mainly affects the nasal cavity and nasopharyngeal region. However, some patients can present with distant nodal or extranodal involvement such as the Waldeyer ring, gastrointestinal tract, genitourinary organs, lung, thyroid, skin, and testes. Compared to ENKTCL of nasal type, primary testicular ENKTCL is very rare and has a lower age of onset and faster clinical progression, with tumor cell dissemination occurring early in the disease. Case report Case 1: A 23-year-old man presented with 1 month of right testicular pain and swelling. Enhancement CT revealed increased density in the right testis, uneven increased enhancement, discontinuity of the local envelope, and multiple trophoblastic vessels in the arterial phase. Testicular ENKTCL was diagnosed by post-operative pathology. The patient underwent a follow-up 18F-FDG PET/CT imaging 1 month later and found elevated metabolism in the bilateral nasal, left testicular, and right inguinal lymph nodes. Unfortunately, the patient received no further treatment and died 6 months later. Case 2: A 2-year-old male child presented with an enlarged right testicle, MRI showed a mass in the right epididymis and testicular area, which showed low signal on T1WI, high signal on T2WI and DWI, and low signal on ADC. Meanwhile, CT showed soft tissue in the lower lobe of the left lung and multiple high-density nodules of varying sizes in both lungs. Based on the post-operative pathology, the lesion was diagnosed with primary testicular ENKTCL. The pulmonary lesion was diagnosed as hemophagocytic lymphohistiocytosis associated with EBV infection. The child was given SMILE chemotherapy, but pancreatitis was induced during chemotherapy, then he died 5 months later after chemotherapy. Conclusion Primary testicular ENKTCL is very rare in clinical practice, typically presenting as a painful testicular mass, which can mimic inflammatory lesions and cause diagnostic challenges. 18F-FDG PET/CT plays pivotal roles in the diagnosis, staging, evaluation of treatment outcomes and prognosis evaluation in patients with testicular ENKTCL, and it is helpful to assist clinical practice to better formulate individualized treatment plans.
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Affiliation(s)
- Wenpeng Huang
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Xiaonan Liu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Liming Li
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yongbai Zhang
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Yuan Gao
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Jianbo Gao
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lei Kang
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
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17
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Feng X, Meng M, Li H, Gao Y, Song W, Di R, Li Z, Zhang X, Zhang M. T-cell dysfunction in natural killer/T-cell lymphoma. Oncoimmunology 2023; 12:2212532. [PMID: 37250921 PMCID: PMC10210841 DOI: 10.1080/2162402x.2023.2212532] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 05/03/2023] [Accepted: 05/08/2023] [Indexed: 05/31/2023] Open
Abstract
Natural killer/T-cell lymphoma (NKTCL) is an incurable aggressive T-cell lymphoma closely correlated with Epstein‒Barr virus (EBV) infection. Chronic and consistent viral infection induces T-cell exhaustion. Herein, we describe T-cell dysfunction in NKTCL patients for the first time. Peripheral blood mononuclear cells (PBMCs) from age-matched healthy donors (HDs) and NKTCL patients were collected, and lymphocyte distributions, multiple surface inhibitory receptors (IRs), effector cytokine production and cell proliferation were determined by flow cytometry. PBMCs from HDs were cocultured with NKTCL cell lines to verify the clinical findings. IR expression was further assessed in NKTCL tumor biopsies using multiplex immunohistochemistry (mIHC). NKTCL patients have higher frequencies than HDs of inhibitory T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). T-cell distribution also varies between NKTCL patients and HDs. T cells from NKTCL patients demonstrated higher expression levels of multiple IRs than HDs. Meanwhile, T-cell proliferation and interferon-γ production was significantly reduced in NKTCL patients. More importantly, the number of EBV-specific cytotoxic cells was lower in NTKCL patients, and these cells demonstrated upregulation of multiple IRs and secreted fewer effector cytokines. Interestingly, NKTCL cells caused normal PBMCs to acquire T-cell exhaustion phenotypes and induced generation of Tregs and MDSCs. In line with ex vivo finding, mIHC results showed that CD8+ T cells from NKTCL tumor biopsies expressed much higher level of IRs compared with reactive lymphoid hyperplasia individuals. The immune microenvironment of NKTCL patients exhibited T-cell dysfunction and accumulation of inhibitory cell components, which may contribute to impaired antitumor immunity.
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Affiliation(s)
- Xiaoyan Feng
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
- Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou, Henan, China
| | - Miaomiao Meng
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
- Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou, Henan, China
| | - Hongwen Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou, Henan, China
| | - Yuyang Gao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou, Henan, China
| | - Wenting Song
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
- Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou, Henan, China
| | - Ruiqing Di
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Nursing Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou, Henan, China
| | - Xudong Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou, Henan, China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou, Henan, China
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18
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Zhong H, Cheng S, Zhang X, Xu B, Chen J, Jiang X, Xiong J, Hu Y, Cui G, Wei J, Qian W, Huang X, Hou M, Yan F, Wang X, Song Y, Hu J, Liu Y, Ma X, Li F, Wu C, Chen J, Yu L, Bai O, Xu J, Zhu Z, Liu L, Zhou X, Huang L, Tong Y, Niu T, Wu D, Zhang H, Wang C, Ouyang B, Yi H, Song Q, Cai G, Li B, Liu J, Li Z, Xiao R, Wang L, Jiang Y, Liu Y, Zheng X, Xu P, Huang H, Wang L, Chen S, Zhao W. Etoposide, dexamethasone, and pegaspargase with sandwiched radiotherapy in early-stage natural killer/T-cell lymphoma: A randomized phase III study. Innovation (N Y) 2023; 4:100426. [PMID: 37181228 PMCID: PMC10173773 DOI: 10.1016/j.xinn.2023.100426] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 04/10/2023] [Indexed: 05/16/2023] Open
Abstract
Methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma, nasal type (NKTCL). We explored the efficacy and safety of reduced-intensity, non-intravenous etoposide, dexamethasone, and pegaspargase (ESA) with sandwiched radiotherapy. This multicenter, randomized, phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China. Patients were randomly assigned (1:1) to receive ESA (pegaspargase 2,500 IU/m2 intramuscularly on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4) or MESA (methotrexate 1 g/m2 intravenously on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4, and pegaspargase 2,500 IU/m2 intramuscularly on day 5) regimen (four cycles), combined with sandwiched radiotherapy. The primary endpoint was overall response rate (ORR). The non-inferiority margin was -10.0%. From March 16, 2016, to July 17, 2020, 256 patients underwent randomization, and 248 (ESA [n = 125] or MESA [n = 123]) made up the modified intention-to-treat population. The ORR was 88.8% (95% confidence interval [CI], 81.9-93.7) for ESA with sandwiched radiotherapy and 86.2% (95% CI, 78.8-91.7) for MESA with sandwiched radiotherapy, with an absolute rate difference of 2.6% (95% CI, -5.6-10.9), meeting the non-inferiority criteria. Per-protocol and sensitivity analysis supported this result. Adverse events of grade 3 or higher occurred in 42 (33.6%) patients in the ESA arm and 81 (65.9%) in the MESA arm. ESA with sandwiched radiotherapy is an effective, low toxicity, non-intravenous regimen with an outpatient design, and can be considered as a first-line treatment option in newly diagnosed early-stage nasal NKTCL.
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Affiliation(s)
- Huijuan Zhong
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Shu Cheng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xi Zhang
- Department of Hematology, Xinqiao Hospital, Chongqing 400037, China
| | - Bing Xu
- Department of Hematology, First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361009, China
| | - Jiayi Chen
- Department of Radiation Oncology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xufeng Jiang
- Department of Nuclear Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jie Xiong
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Guohui Cui
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Juying Wei
- Department of Hematology, First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Wenbin Qian
- Department of Hematology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Xiaobing Huang
- Institute of Hematology, Department of Hematology, Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China
| | - Ming Hou
- Department of Hematology, Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China
| | - Feng Yan
- Department of Hematology, Third Affiliated Hospital of Suzhou University, First People’s Hospital of Changzhou, Changzhou, Jiangsu 213004, China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China
| | - Yongping Song
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450003, China
| | - Jianda Hu
- Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350401, China
| | - Yuanhua Liu
- Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Xuejun Ma
- Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Fei Li
- Department of Hematology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Chongyang Wu
- Department of Hematology, Second Hospital of Lanzhou University, Lanzhou, Gansu 730030, China
| | - Junmin Chen
- Department of Hematology and Rheumatology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350004, China
| | - Li Yu
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, China
| | - Ou Bai
- Department of Hematology, First Hospital of Jilin University, Changchun, Jilin 130061, China
| | - Jingyan Xu
- Department of Hematology, Nanjing Drum Tower Hospital, Nanjing, Jiangsu 210008, China
| | - Zunmin Zhu
- Department of Hematology, Henan Province People’s Hospital, Zhengzhou, Henan 450003, China
| | - Li Liu
- Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shanxi 710032, China
| | - Xin Zhou
- Department of Hematology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, China
| | - Li Huang
- Department of Oncology and Hematology, Hospital Affiliated to Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yin Tong
- Department of Hematology, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, China
| | - Ting Niu
- Department of Hematology, Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Depei Wu
- First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Hao Zhang
- Department of Otolaryngology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chaofu Wang
- Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Binshen Ouyang
- Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hongmei Yi
- Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qi Song
- Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Gang Cai
- Department of Radiation Oncology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Biao Li
- Department of Nuclear Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jia Liu
- Department of Hematology, Xinqiao Hospital, Chongqing 400037, China
| | - Zhifeng Li
- Department of Hematology, First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361009, China
| | - Rong Xiao
- Institute of Hematology, Department of Hematology, Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China
| | - Luqun Wang
- Department of Hematology, Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China
| | - Yujie Jiang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China
| | - Yanyan Liu
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450003, China
| | - Xiaoyun Zheng
- Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350401, China
| | - Pengpeng Xu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hengye Huang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Li Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Saijuan Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai 200025, China
| | - Weili Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai 200025, China
- Corresponding author
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He Y, Gao Y, Ping L, He H, Huang C, Bai B, Wang X, Li Z, Cai Q, Huang Y, Pan X, Zeng W, Liu Y, Huang H. The emerging role of anti-PD-1 antibody-based regimens in the treatment of extranodal NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis. J Cancer Res Clin Oncol 2023; 149:2017-2027. [PMID: 35809114 DOI: 10.1007/s00432-022-04147-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/13/2022] [Indexed: 11/11/2022]
Abstract
PURPOSE Anti-PD-1 antibody (anti-PD-1 mAb) showed favorable outcomes in some patients with relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL). However, the role of anti-PD-1 antibody in NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHS) remains unclear. Here, we evaluated the efficacy and toxicity of anti-PD-1 antibody-based treatment in NK/T-LAHS patients. METHODS The clinical data of 98 patients diagnosed with NK/T-LAHS at Sun Yat-sen University Cancer Center and the First Affiliated Hospital of Guangdong Pharmaceutical University from May 2014 to November 2021 were retrospectively analyzed. All patients received anti-HLH [HLH-2004 (etoposide, dexamethasone, cyclosporine A) or DEP-based (liposomal doxorubicin, etoposide, methylprednisolone)] regimen and sequential anti-ENKTL chemotherapy (ChT) combined with anti-PD-1 antibody or not. RESULTS The overall response rate (ORR) of the anti-PD-1 mAb plus ChT regimens was higher than that of the ChT regimens (73.3% vs. 45.5%, P = 0.041). The toxicity of the anti-PD-1 mAb plus ChT regimens was tolerable. Except for higher rate of neutropenia, no significant difference in adverse events (AEs) was observed between the two groups. When the optimal response to anti-ENKTL was achieved, the median EBV DNA levels in patients who received anti-PD-1 mAb plus ChT were significantly lower than patients who received ChT only (878 copies/mL vs. 18,600 copies/mL, P = 0.001). With a median follow-up of 26.6 months (range 0-65.9 months), the median overall survival (mOS) was 3.5 months (95% CI：2.3-4.7 months). Patients treated with anti-PD-1 mAb plus ChT experienced a longer mOS than those who received ChT only [5.2 months (95% CI: 2.5-7.8 months) vs. 1.5 months (95% CI: 0.5-2.6 months), P = 0.002]. Cox multivariate analysis found that anti-PD-1 mAb was an independent prognostic factor for all NK/T-LAHS patients. CONCLUSION In conclusion, anti-PD-1 mAb combined with ChT regimens seemed to be associated with prolonged survival in NK/T-LAHS patients and may represent a potentially promising treatment strategy for this population.
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Affiliation(s)
- Yanxia He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yan Gao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Liqin Ping
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Haixia He
- Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Cheng Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Bing Bai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiaoxiao Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhiming Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qingqing Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yuhua Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xueyi Pan
- Department of Hematology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Wenbin Zeng
- Department of Hematology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yanan Liu
- Department of Hematology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Huiqiang Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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20
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Zhou J, Toh SHM, Tan TK, Balan K, Lim JQ, Tan TZ, Xiong S, Jia Y, Ng SB, Peng Y, Jeyasekharan AD, Fan S, Lim ST, Ong CAJ, Ong CK, Sanda T, Chng WJ. Super-enhancer-driven TOX2 mediates oncogenesis in Natural Killer/T Cell Lymphoma. Mol Cancer 2023; 22:69. [PMID: 37032358 PMCID: PMC10084643 DOI: 10.1186/s12943-023-01767-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 03/24/2023] [Indexed: 04/11/2023] Open
Abstract
BACKGROUND Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL. METHODS We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo. RESULTS SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2, were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis. CONCLUSIONS Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic.
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Affiliation(s)
- Jianbiao Zhou
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- NUS Centre for Cancer Research (N2CR), 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore
| | - Sabrina Hui-Min Toh
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore
| | - Tze King Tan
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore
| | - Kalpnaa Balan
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore
| | - Jing Quan Lim
- Division of Cellular and Molecular Research, Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
- Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Tuan Zea Tan
- Genomics and Data Analytics Core (GeDaC), Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore
| | - Sinan Xiong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Yunlu Jia
- Department of Medical Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Siok-Bian Ng
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore
| | - Yanfen Peng
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore
| | - Anand D Jeyasekharan
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- NUS Centre for Cancer Research (N2CR), 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore
| | - Shuangyi Fan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore
| | - Soon Thye Lim
- Director's office, National Cancer Centre, Singapore, 168583, Singapore
- Office of Education, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Chin-Ann Johnny Ong
- Department of Sarcoma, Peritoneal and Rare Tumours (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre, Singapore, 168583, Singapore
- Department of Sarcoma, Peritoneal and Rare Tumours (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Singapore, 168583, Singapore
- Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Centre, Singapore, 168583, Singapore
- SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore, 169857, Singapore
- SingHealth Duke-NUS Surgery Academic Clinical Program, Duke-NUS Medical School, Singapore, 169857, Singapore
- Institute of Molecular and Cell Biology, A*STAR Research Entities, Singapore, 138673, Singapore
| | - Choon Kiat Ong
- Division of Cellular and Molecular Research, Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
- Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
| | - Takaomi Sanda
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore.
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
| | - Wee-Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore.
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
- NUS Centre for Cancer Research (N2CR), 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore.
- Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228, Singapore.
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Yap DRY, Lim JQ, Huang D, Ong CK, Chan JY. Emerging predictive biomarkers for novel therapeutics in peripheral T-cell and natural killer/T-cell lymphoma. Front Immunol 2023; 14:1068662. [PMID: 36776886 PMCID: PMC9909478 DOI: 10.3389/fimmu.2023.1068662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Peripheral T-cell lymphoma (PTCL) and natural killer/T-cell lymphoma (NKTCL) are rare subtypes of non-Hodgkin's lymphoma that are typically associated with poor treatment outcomes. Contemporary first-line treatment strategies generally involve the use of combination chemoimmunotherapy, radiation and/or stem cell transplant. Salvage options incorporate a number of novel agents including epigenetic therapies (e.g. HDAC inhibitors, DNMT inhibitors) as well as immune checkpoint inhibitors. However, validated biomarkers to select patients for individualized precision therapy are presently lacking, resulting in high treatment failure rates, unnecessary exposure to drug toxicities, and missed treatment opportunities. Recent advances in research on the tumor and microenvironmental factors of PTCL and NKTCL, including alterations in specific molecular features and immune signatures, have improved our understanding of these diseases, though several issues continue to impede progress in clinical translation. In this Review, we summarize the progress and development of the current predictive biomarker landscape, highlight potential knowledge gaps, and discuss the implications on novel therapeutics development in PTCL and NKTCL.
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Affiliation(s)
- Daniel Ren Yi Yap
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Jing Quan Lim
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Dachuan Huang
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Choon Kiat Ong
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Jason Yongsheng Chan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
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22
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Thawani R, Kim MS, Arastu A, Feng Z, West MT, Taflin NF, Thein KZ, Li R, Geltzeiler M, Lee N, Fuller CD, Grandis JR, Floudas CS, Heinrich MC, Hanna E, Chandra RA. The contemporary management of cancers of the sinonasal tract in adults. CA Cancer J Clin 2023; 73:72-112. [PMID: 35916666 PMCID: PMC9840681 DOI: 10.3322/caac.21752] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 05/21/2022] [Accepted: 06/27/2022] [Indexed: 01/25/2023] Open
Abstract
Sinonasal malignancies make up <5% of all head and neck neoplasms, with an incidence of 0.5-1.0 per 100,000. The outcome of these rare malignancies has been poor, whereas significant progress has been made in the management of other cancers. The objective of the current review was to describe the incidence, causes, presentation, diagnosis, treatment, and recent developments of malignancies of the sinonasal tract. The diagnoses covered in this review included sinonasal undifferentiated carcinoma, sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, and esthesioneuroblastoma, which are exclusive to the sinonasal tract. In addition, the authors covered malignances that are likely to be encountered in the sinonasal tract-primary mucosal melanoma, NUT (nuclear protein of the testis) carcinoma, and extranodal natural killer cell/T-cell lymphoma. For the purpose of keeping this review as concise and focused as possible, sarcomas and malignancies that can be classified as salivary gland neoplasms were excluded.
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Affiliation(s)
- Rajat Thawani
- Division of Hematology and Oncology, Knight Cancer Institute, Oregon Health and Science University
| | - Myung Sun Kim
- Division of Hematology and Oncology, Knight Cancer Institute, Oregon Health and Science University
| | - Asad Arastu
- Department of Internal Medicine, Oregon Health and Science University
| | - Zizhen Feng
- Division of Hematology and Oncology, Knight Cancer Institute, Oregon Health and Science University
| | - Malinda T. West
- Division of Hematology and Oncology, Knight Cancer Institute, Oregon Health and Science University
| | | | - Kyaw Zin Thein
- Division of Hematology and Oncology, Knight Cancer Institute, Oregon Health and Science University
| | - Ryan Li
- Department of Otolaryngology, Division of Head and Neck Surgery, Oregon Health and Science University
| | - Mathew Geltzeiler
- Department of Otolaryngology, Division of Head and Neck Surgery, Oregon Health and Science University
| | - Nancy Lee
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center
| | | | - Jennifer R. Grandis
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco
| | | | - Michael C. Heinrich
- Division of Hematology and Oncology, Knight Cancer Institute, Oregon Health and Science University
| | - Ehab Hanna
- Department of Head and Neck Surgery, MD Anderson Cancer Center
| | - Ravi A. Chandra
- Department of Radiation Medicine, Oregon Health and Science University
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23
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Kang S, Cho H, Kim S, Lee K, Kang EH, Park JS, Lee YS, Park CS, Go H, Huh J, Ryu JS, Lee SW, Kim SJ, Kim WS, Yoon SE, Ko YH, Suh C. A New Prognostic Index for Extranodal Natural Killer/T-Cell Lymphoma:Incorporation of Serum β-2 Microglobulin to PINK. Cancer Res Treat 2023; 55:314-324. [PMID: 35381163 PMCID: PMC9873344 DOI: 10.4143/crt.2022.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/30/2022] [Indexed: 02/04/2023] Open
Abstract
PURPOSE Prognostic Index for Natural Killer Lymphoma (PINK) is the most widely accepted prognostic model for patients withextranodal natural killer/T-cell lymphoma (ENKTL) treated with non-anthracycline-based therapy. We aimed to evaluate the prognostic implications of serum β-2 microglobulin (β2M) in the context of PINK and proposed a new prognostic model. MATERIALS AND METHODS A total of 138 patients who were newly diagnosed with ENKTL and treated with non-anthracycline-based chemotherapy were identified. The cut-off value of high serum β2M was calculated by maximal-chi square methods (4.1 mg/L). A new prognostic model incorporating serum β2M into PINK was proposed and validated in an independent validation cohort (n=88). RESULTS The patients' median age was 53.5 years (range, 19 to 80 years). Patients with high serum β2M levels had significantly worse overall survival (OS) and progression-free survival (PFS). In multivariate analysis, high serum β2M was an independent adverse prognostic factor for OS. A new PINK-B (Prognostic Index for Natural Killer Lymphoma-serum β-2 microglobulin) model stratifiedpatients into three groups with distinct OS and PFS in the training cohort (3-year OS, 84.1% [95% confidence interval, 75.1 to 94.2], 46.8% [36.1 to 60.8] and 17.6% [6.3 to 49.2] for the low-, intermediate, and high-risk groups, respectively; 3-year PFS, 70.6% [59.4 to 83.8], 35.9% [25.9 to 49.8], and 7.35% [1.1 to 46.7] for the low-, intermediate-, and high-risk groups, respectively). The PINK-B model was further validated in an independent cohort. CONCLUSION Serum β2M is an independent prognostic factor for ENKTL patients. The new serum β2M-based prognostic model may be useful for identifying ultra-high-risk patients, and it can easily be adopted into daily clinical practice.
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Affiliation(s)
- Sora Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Hyungwoo Cho
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Shin Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Kyoungmin Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Eun Hee Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Jung Sun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Yoon Sei Lee
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Chan-Sik Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Heounjeong Go
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Jooryung Huh
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Jin Sook Ryu
- Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Sang-Wook Lee
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
| | - Seok Jin Kim
- Division of Hematology and Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Won Seog Kim
- Division of Hematology and Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Sang Eun Yoon
- Division of Hematology and Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Young Hyeh Ko
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Cheolwon Suh
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
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24
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The Novel Prognostic Index Model of Combining Circulating Tumor DNA and PINK-E Predicts the Clinical Outcomes for Newly Diagnosed Extranodal NK/T-cell Lymphoma. Hemasphere 2022; 7:e822. [PMID: 36570690 PMCID: PMC9771254 DOI: 10.1097/hs9.0000000000000822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/21/2022] [Indexed: 12/27/2022] Open
Abstract
Extranodal NK/T-cell lymphoma (ENKTL) is a highly aggressive and heterogeneous disease with poor clinical outcome. Our previous work had demonstrated that circulating tumor DNA (ctDNA) analyses were feasible in ENKTL, and dynamic tracing of ctDNA could be used to monitor the disease status. However, the prognostic value of ctDNA in ENKTL has not been fully investigated. Patients with newly diagnosed ENKTL from February 2017 to December 2021 (n = 70) were enrolled. The pretreatment ctDNA concentration (hGE/mL) was measured. The prognostic value of ctDNA, international prognostic index (IPI), Korean prognostic index (KPI), PINK-E, and the combination of PINK-E and ctDNA (PINK-EC) were investigated in our cohort. The IPI and PINK-E risk categories had a significant difference in progression-free survival (PFS) and overall survival (OS) between the low-risk and intermediate-risk groups. The KPI risk category had a difference in PFS and OS between the intermediate-risk and high-risk groups. Furthermore, integrating ctDNA into the PINK-E model could overcome the shortcomings of other prognostic models, which could significantly distinguish the different-risk groups. Overall, our results demonstrated that PINK-EC showed a superior prognostic prediction value and stability compared with IPI, KPI, and PINK-E. The integration of molecular features of the tumor into classic risk categories might better characterize a high-risk group where novel treatment approaches are most needed.
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25
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Xiang Y, Lin X, Cai X, Qu S, Lin KY. Extranodal natural killer/T-cell lymphoma invading a patient's heart: A rare case report and literature review. Front Oncol 2022; 12:1011894. [PMID: 36568165 PMCID: PMC9768479 DOI: 10.3389/fonc.2022.1011894] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Extranodal NK/T-cell lymphoma (ENKTL) is a rare but aggressive subtype of non-Hodgkin lymphoma, which is derived from NK cells or T cells. There are very few cases of ENKTL invading the heart. Only 12 cases of ENKTL invading the heart have been reported in the English literature. Due to the rarity of this lymphoma, an effective therapeutic strategy has not been defined. Here, we present a case of a 51-year-old Chinese male with extranodal NK/T-cell lymphoma invading the heart and review the literature. The patient received a chemotherapy regimen of PD1 monoclonal antibody (Sintilimab) in combination with first-line P-Gemox. The patient survived for 2 months after diagnosis.
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Affiliation(s)
- Yifei Xiang
- Department of Cardiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China,Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Cardiovascular Institute, Fujian Provincial Center for Geriatrics, Fujian Clinical Medical Research Center for Cardiovascular Diseases, Fuzhou, China
| | - Xueqin Lin
- Department of Cardiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China,Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Cardiovascular Institute, Fujian Provincial Center for Geriatrics, Fujian Clinical Medical Research Center for Cardiovascular Diseases, Fuzhou, China
| | - Xiaoling Cai
- Department of Cardiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China,Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Cardiovascular Institute, Fujian Provincial Center for Geriatrics, Fujian Clinical Medical Research Center for Cardiovascular Diseases, Fuzhou, China
| | - Shuang Qu
- Department of Hematology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China,*Correspondence: Shuang Qu, ; Kai-Yang Lin,
| | - Kai-Yang Lin
- Department of Cardiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China,Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Cardiovascular Institute, Fujian Provincial Center for Geriatrics, Fujian Clinical Medical Research Center for Cardiovascular Diseases, Fuzhou, China,Department of Hematology, Fujian Heart Failure Center Alliance, Fuzhou, China,*Correspondence: Shuang Qu, ; Kai-Yang Lin,
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Samad MA, Mahboob E, Shafiq A, Ur Rehman MH, Sheikh A, Tharwani ZH. Types of T-cell lymphoma-a cytogenetic perspective. Ann Med Surg (Lond) 2022; 84:104844. [PMID: 36536747 PMCID: PMC9758356 DOI: 10.1016/j.amsu.2022.104844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/25/2022] [Accepted: 10/30/2022] [Indexed: 11/11/2022] Open
Abstract
T cell lymphoma, a type of non-Hodgkin lymphomas is a rare form of malignancy with poor outcomes. TCLS are a heterogeneous group of lymphoid malignancies that occur in nodal and extranodal sites. There are two main types of TCLs namely T-lymphoblastic lymphoma/leukemia and Peripheral T-cell lymphomas classified based on clinical manifestations and cytogenetic mutations. The use of advance technology like karyotyping, fluorescent in situ hybridization (FISH), comparative genomic hybridization (CGH) has allowed us to study TCLs in detail and to observe a different biochemical change that occurs in different TCLs allowing us to classify and treat them differently. This review focuses on the different mutations occurring in different TCLs and how they help us distinguish one type from another.
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Affiliation(s)
- Muhammad Ammar Samad
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Eman Mahboob
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Aimen Shafiq
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | | | - Ayesha Sheikh
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Zoaib Habib Tharwani
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
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High-dose extended-field radiotherapy plus chemotherapy improved survival in extranodal NK/T-cell lymphoma in a real-life setting: results from the multicenter T-Cell Brazil Project. Sci Rep 2022; 12:20557. [PMID: 36446856 PMCID: PMC9709053 DOI: 10.1038/s41598-022-25034-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022] Open
Abstract
Extranodal natural-killer/T-cell lymphoma (ENKTL) is a rare and aggressive Epstein-Barr virus related mature T-cell and natural-killer malignancy. Although highly prevalent in South America, few studies covering data from this geographic location have been published. Therefore, this study aims to report clinical characteristics, prognostic factors, and outcomes in a multicenter cohort of ENKTL patients from Brazil. This retrospective, observational and multicenter study included 98 ENKTL patients treated during two decades in Brazil. Data were extracted from the T-Cell Brazil Project database. In our cohort, 59/98 patients (60.2%) were male, with a median age of 50 years. Sixty-two patients (63.3%) had B-symptoms, 26/98 (26.5%) had Eastern Cooperative Oncology Group scale ≥ 2; 16/98 (16.3%) presented extranasal disease and 34.7% (34/98) were advanced-stage (Ann Arbor/Cotswolds III/IV). The median follow-up for the whole cohort was 49 months, with an estimated 2-year overall survival (OS) and progression-free survival (PFS) of 51.1% and 17.7%, respectively. In early-stage disease (IE/IIE), the median OS was 21.8 months for patients treated with concurrent radiotherapy plus chemotherapy (CCRT-VIPD [etoposide/vp-16, ifosfamide, cisplatin and dexamethasone), 16.2 months for sequential chemoradiotherapy (SCRT) followed by asparaginase-based regimens, and 56.7 months for SCRT followed by CHOP-like (cyclophosphamide, doxorrubicin, vincristine and prednisone) treatments, p = 0.211. CCRT was associated with higher rates of early-mortality, hematological toxicity, and mucositis. Median OS was 8.2 months for patients with advanced-stage disease receiving regimens containing asparaginase compared to 3.2 months for anthracycline-based therapy, p = 0.851. Chemo-radiotherapy (CRT) regimens demonstrated better OS (p = 0.001) and PFS (p = 0.007) than chemotherapy alone. Multivariate analysis revealed anemia, relapsed/refractory (R/R) disease and radiotherapy omission as poor outcome predictors for OS. Lymphopenia and radiotherapy omission adversely affected PFS. Concerning progression of disease within 24-months (POD-24), clinical stage III/IV was a poor outcome predictor. In this real-life Brazilian cohort, ENKTL presented dismal outcomes. Radiation therapy was an independent factor for increased OS and PFS, but CCRT regimens were associated with higher toxicities. Polychemotherapy based on anti-multi drug resistant agents was not associated with survival benefit in either early or advanced-stage disease in our patient cohort.
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28
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Eriksen PRG, Clasen-Linde E, Brown PDN, Haunstrup L, Christoffersen M, Asdahl P, Thomsen TM, von Buchwald C, Heegaard S. NK- and T-cell lymphoma of the nasal cavity and paranasal sinuses in Denmark 1980-2017: a nationwide cohort study. Leuk Lymphoma 2022; 63:2579-2588. [PMID: 35699970 DOI: 10.1080/10428194.2022.2087069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 10/18/2022]
Abstract
Compared to Asian and Latin American populations, sinonasal NK- or T-cell lymphoma is rare in Europe. All patients with sinonasal NK- or T-cell lymphoma in Denmark from 1980 to 2017 were validated histologically, and the disease behavior and demographics were extracted from medical records and national registries. Prognostic factors associated with mortality were determined using survival statistics. We included 56 patients: 40 extranodal NK/T-cell lymphoma (nasal type) (ENKTCL) and 16 peripheral T-cell lymphoma (not otherwise specified) (PTCL). The median age was 66, and most patients were male (72%). The ENKTCL and PTCL 5-year overall survival was 48% and 50%, respectively; progression-free survival was 38% for both. With ENKTCL, stage and performance status increased mortality significantly (HR = 8.6; p < 0.001 and HR = 4.23; p = 0.04). In conclusion, disseminated disease had a dismal outcome and the onset of ENKTCL in this ethnically homogeneous European cohort was about a decade later than reported in Asian populations.
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Affiliation(s)
- Patrick R G Eriksen
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Erik Clasen-Linde
- Hematopathology Section, Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Peter de Nully Brown
- Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Laura Haunstrup
- Department of Hematology, Aalborg University Hospital, Aalborg, Denmark
| | | | - Peter Asdahl
- Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Christian von Buchwald
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Steffen Heegaard
- Eye Pathology Section, Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Chung J, Jee SR, Choi E, Yu SJ, Yoon JS, Lee HS, Lee SH, Park SJ, Park HY. Gastric CD56-negative Extranodal Natural Killer/T-cell Lymphoma: A Case Report. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2022; 80:190-194. [DOI: 10.4166/kjg.2022.076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 06/28/2022] [Accepted: 08/01/2022] [Indexed: 11/05/2022]
Affiliation(s)
- Joohong Chung
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Sam Ryong Jee
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Eunjeong Choi
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Seung Jung Yu
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Jun Sik Yoon
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Hong Sub Lee
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Sang Heon Lee
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Sung Jae Park
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Ha Young Park
- Department of Pathology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
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30
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Li LJ, Zhang JY. Treatment of refractory/relapsed extranodal NK/T cell lymphoma with decitabine plus anti-PD-1: A case report. World J Clin Cases 2022; 10:10193-10200. [PMID: 36246799 PMCID: PMC9561561 DOI: 10.12998/wjcc.v10.i28.10193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/24/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Extranodal natural killer/T cell lymphoma, nasal type (ENKL) is a highly aggressive malignancy characterized by its association with Epstein-Barr virus (EBV) and extranodal involvement, which shows a poor clinical outcome. Although L-asparaginase-based chemotherapy has improved the response rates of relapsed/refractory (R/R) ENKL, relapse occurs in up to 50% of patients with disseminated disease.
CASE SUMMARY Immune evasion has emerged as a critical pathway for survival in ENKL and may be effectuated via STAT3-driven upregulation of programmed cell death ligand 1 (PD-L1) or other molecular pathways. Anti-PD-1 is effective for R/R ENKL with EBV-driven upregulation of PD-L1 expression. Anti-PD-1 combined with decitabine showed positive preliminary results in a patient with R/R ENKL and resistance to anti-PD-1.
CONCLUSION The treatment experience, in this case, demonstrated the potential ability of decitabine combined with PD-1 inhibitor to treat R/R ENKL, thus providing a new treatment strategy for this tumor.
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Affiliation(s)
- Lin-Jie Li
- Department of Hematology, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
| | - Jun-Yu Zhang
- Department of Hematology, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
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31
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Mao S, Diao C, Cao L. Primary small intestinal extranodal NK/T cell lymphoma, nasal type with kidney involvement: a rare case report and literature review. Diagn Pathol 2022; 17:75. [PMID: 36199094 PMCID: PMC9533626 DOI: 10.1186/s13000-022-01254-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/22/2022] [Accepted: 09/15/2022] [Indexed: 11/10/2022] Open
Abstract
Background Extranodal NK/T cell lymphoma, nasal type (EN-NK/T-NT) is a rare and aggressive type of non-Hodgkin’s lymphoma. EN-NK/T-NT seldom occurs in the gastrointestinal tract, and renal involvement is relatively rare. Case presentation Here we report a case of primary small intestinal EN-NK/T-NT with kidney involvement. We present the case of a 71-year-old female who was admitted to our hospital for coronary heart disease with a fever of unknown origin. Laboratory examination showed renal impairment and PET/CT showed a locally thickened wall of the small intestine, abnormally increased FDG metabolism in the right lower abdomen, and multiple slightly high-density masses with abnormal increased FDG metabolism in the right kidney. The gross specimen showed a grayish-white lump located in the ileum approximately 15 cm away from the ileocecum, and two grayish-white lumps located in the upper and lower poles of the right kidney, respectively. The pathological diagnosis was EN-NK/T-NT. The patient died approximately 10 months after the operation. Conclusion EN-NK/T-NT is a rare type of non-Hodgkin’s lymphoma and may develop insidiously, with fever as the only clinical manifestation. The disease was found to be difficult to diagnose in the early stage, resulting in a highly aggressive clinical course and short survival time.
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Affiliation(s)
- Shuyan Mao
- Department of Pathology, Shanghai Pudong New Area People's Hospital, No.490, Chuanhuan South Road, Chuansha town, 200120, Shanghai, China
| | - Changying Diao
- Department of Pathology, Xuzhou Central Hospital, No.199, Jiefang South Road, 221009, Xuzhou, Jiangsu, China.
| | - Lei Cao
- Department of Pathology, Shanghai Pudong New Area People's Hospital, No.490, Chuanhuan South Road, Chuansha town, 200120, Shanghai, China
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32
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Muacevic A, Adler JR. Extranodal Natural Killer/T-cell Lymphoma With an Unusual Presentation: A Case Report and Literature Review. Cureus 2022; 14:e30734. [PMID: 36447707 PMCID: PMC9699802 DOI: 10.7759/cureus.30734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2022] [Indexed: 01/25/2023] Open
Abstract
The Epstein-Barr virus is closely linked to a lymphoproliferative disease known as natural killer/T-cell lymphoma (NKTL). Early identification of NKTL might be challenging because it can resemble other nasopharyngeal pathologies. Contrary to the presented case, T-cell lymphoma often develops in the nasal canal and spreads to the oral cavity. Here, we present the case of a 45-year-old man with an unusual presentation of NKTL presenting initially as acute follicular tonsillitis.
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High plasma EBV-DNA load and positive EBER status associated with viral recurrence and persistent infection in early treatment of lymphoma. Clin Exp Med 2022:10.1007/s10238-022-00900-6. [PMID: 36168074 DOI: 10.1007/s10238-022-00900-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/17/2022] [Indexed: 11/03/2022]
Abstract
The relationship between plasma EBV-DNA load (PEDL) and Epstein-Barr virus (EBV)-encoded small RNA (EBER) during the early treatment of lymphoma remains unclear. We explored discrepancies in PEDL and variables associated with EBER and evaluated the consistency between EBER and qualitative analysis of PEDL (qPEDL). Serial measurements of PEDL were performed to determine the dynamic changes of PEDL in early treatment of lymphoma. As a result, the median PEDL of non-Hodgkin's lymphoma NKT cell subtype (NHL-NKT) was higher than that of non-Hodgkin's lymphoma B cell subtype (NHL-B), the median PEDL of extranodal NK/T cell lymphoma (ENKTCL) was higher than that of diffuse large B cell lymphoma (DLBCL), and the median PEDL of EBER positive was higher than that of EBER negative. Age, Ki-67 ≧ 80%, Bcl-2 ≧ 80%, p53, and qPEDL were related to EBER. The PEDL could distinguish NHL-B, DLBCL, NHL-NKT, and ENKTCL from other lymphoma subtypes. EBER-positive patients spent more time with viral "turn negative (TN)" and "continuous positive (CP)" and less time with viral "continuous negative (CN)." The median PEDL of CP was higher than that of TN. In conclusion, although EBER affects the levels of PEDL in general, it has poor concordance with qPEDL. Our results show, for the first time, that high PEDL and positive EBER present a strong association with viral recurrence and persistent infection in the early treatment of lymphoma.
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Herek TA, Bouska A, Lone W, Sharma S, Amador C, Heavican TB, Li Y, Wei Q, Jochum D, Greiner TC, Smith L, Pileri S, Feldman AL, Rosenwald A, Ott G, Lim ST, Ong CK, Song J, Jaffe ES, Wang GG, Staudt L, Rimsza LM, Vose J, d'Amore F, Weisenburger DD, Chan WC, Iqbal J. DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS. Blood 2022; 140:1278-1290. [PMID: 35639959 PMCID: PMC9479030 DOI: 10.1182/blood.2021015019] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 04/08/2022] [Indexed: 11/20/2022] Open
Abstract
Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.
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Affiliation(s)
- Tyler A Herek
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Alyssa Bouska
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Waseem Lone
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Sunandini Sharma
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Catalina Amador
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Tayla B Heavican
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Yuping Li
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - Qi Wei
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - Dylan Jochum
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Timothy C Greiner
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Lynette Smith
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE
| | - Stefano Pileri
- Division of Diagnostic Hematopathology, European Institute of Oncology-IEO IRCCS, Milan, Italy
| | - Andrew L Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Andreas Rosenwald
- Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany
| | - German Ott
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany
| | - Soon Thye Lim
- Division of Medical Oncology, National Cancer Centre Singapore/Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore
| | - Choon Kiat Ong
- Division of Medical Oncology, National Cancer Centre Singapore/Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore
| | - Joo Song
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - Elaine S Jaffe
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Gang Greg Wang
- Lineberger Comprehensive Cancer Center and
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Louis Staudt
- Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Lisa M Rimsza
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ
| | - Julie Vose
- Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE; and
| | - Francesco d'Amore
- Department of Haematology, Aarhus University Hospital, Aarhus N, Denmark
| | | | - Wing C Chan
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - Javeed Iqbal
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
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35
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Zhang L, Shangguan C, Li X, Li L, Wang X, Fu X, Sun Z, Shi Y, Wu J, Zhang X, Yu H, Nan F, Yan J, Chang Y, Zhou Z, Wu X, Feng X, Liu X, Xue H, Zou L, Lu Y, Wang J, Wang G, Li W, Zhang M. DDGP followed by radiotherapy vs VIPD followed by radiotherapy in newly diagnosed early NK/T-cell lymphoma. Leuk Res 2022; 118:106881. [DOI: 10.1016/j.leukres.2022.106881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/15/2022] [Accepted: 05/28/2022] [Indexed: 10/18/2022]
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36
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Lim JQ, Huang D, Chan JY, Laurensia Y, Wong EKY, Cheah DMZ, Chia BKH, Chuang WY, Kuo MC, Su YJ, Cai QQ, Feng Y, Rao H, Feng LN, Wei PP, Chen JR, Han BW, Lin GW, Cai J, Fang Y, Tan J, Hong H, Liu Y, Zhang F, Li W, Poon MLM, Ng SB, Jeyasekharan A, Ha JCH, Khoo LP, Chin ST, Pang WL, Kee R, Cheng CL, Grigoropoulos NF, Tang T, Tao M, Farid M, Puan KJ, Xiong J, Zhao WL, Khor CC, Hwang W, Kim WS, Campo E, Tan P, Teh BT, Chng WJ, Rötzschke O, Tousseyn T, Huang HQ, Rozen S, Lim ST, Shih LY, Bei JX, Ong CK. A genomic-augmented multivariate prognostic model for the survival of Natural-killer/T-cell lymphoma patients from an international cohort. Am J Hematol 2022; 97:1159-1169. [PMID: 35726449 DOI: 10.1002/ajh.26636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 05/17/2022] [Accepted: 06/16/2022] [Indexed: 11/09/2022]
Abstract
With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK) and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; P<0.001) and overall survival (OS, HR: 5.23, 95% CI 2.57-10.65; P=0.001) with known risk-features of these indices. When we assign an additional risk-score to samples, which are mutant for the GPM, the Harrell's C-indices of GPM-augmented IPI, PINK and PINK-E improved significantly (P<0.001, χ2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer towards better prognostication of NKTCL patients. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Jing Quan Lim
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore.,ONCO-ACP, Duke-NUS Medical School, 8 College Road, Singapore
| | - Dachuan Huang
- Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore.,ONCO-ACP, Duke-NUS Medical School, 8 College Road, Singapore
| | - Jason Yongsheng Chan
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Yurike Laurensia
- Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Esther Kam Yin Wong
- Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Daryl Ming Zhe Cheah
- Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Burton Kuan Hui Chia
- Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Wen-Yu Chuang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,Chang Gung University, Taoyuan, Taiwan
| | - Ming-Chung Kuo
- Chang Gung University, Taoyuan, Taiwan.,Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yi-Jiun Su
- Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Qing-Qing Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yanfen Feng
- Guangdong Provincial People's Hospital.,Guangdong Academy of Medical Sciences
| | - Huilan Rao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Li-Na Feng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Pan-Pan Wei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jie-Rong Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Bo-Wei Han
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guo-Wang Lin
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jun Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yu Fang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jing Tan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore.,Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Huangming Hong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yanhui Liu
- Guangdong Provincial People's Hospital.,Guangdong Academy of Medical Sciences
| | - Fen Zhang
- Guangdong Provincial People's Hospital.,Guangdong Academy of Medical Sciences
| | - Wenyu Li
- Guangdong Provincial People's Hospital.,Guangdong Academy of Medical Sciences
| | - Michelle L M Poon
- Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore
| | - Siok-Bian Ng
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Anand Jeyasekharan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Department of Haematology-Oncology, National University Health System, Singapore
| | - Jeslin Chian Hung Ha
- Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Lay Poh Khoo
- Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Suk Teng Chin
- Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Wan Lu Pang
- Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Rebecca Kee
- Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Chee Leong Cheng
- Department of Pathology, Singapore General Hospital, 20 College Road, Academia, Singapore
| | | | - Tiffany Tang
- ONCO-ACP, Duke-NUS Medical School, 8 College Road, Singapore
| | - Miriam Tao
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Mohamad Farid
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
| | - Kia Joo Puan
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, Singapore, Singapore
| | - Jie Xiong
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei-Li Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chiea Chuen Khor
- Genome Institute of Singapore, 60 Biopolis Street Genome, Singapore
| | - William Hwang
- Director's office, National Cancer Centre, Singapore
| | - Won Seog Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
| | - Elias Campo
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain
| | - Patrick Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Genome Institute of Singapore, 60 Biopolis Street Genome, Singapore.,Division of Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore
| | - Bin Tean Teh
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Division of Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore
| | - Wee-Joo Chng
- Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Olaf Rötzschke
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, Sinagpore, Singapore
| | - Thomas Tousseyn
- KU Leuven, Department of Imaging and Pathology, Translational Cell and Tissue Research Lab, Herestraat 49, Leuven, Belgium.,UZ Leuven, Department of Pathology, Leuven, Belgium
| | - Hui-Qiang Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Steve Rozen
- Division of Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore.,Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, Singapore
| | - Soon Thye Lim
- Director's office, National Cancer Centre, Singapore.,Office of Education, Duke-NUS Medical School, Singapore
| | - Lee-Yung Shih
- Chang Gung University, Taoyuan, Taiwan.,Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jin-Xin Bei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Choon Kiat Ong
- Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore.,Genome Institute of Singapore, 60 Biopolis Street Genome, Singapore.,Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore
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Gao LM, Zhang YH, Shi X, Liu Y, Wang J, Zhang WY, Liu WP. The Role of PD-L1 Expression in Prediction and Stratification of Recurrent or Refractory Extranodal Natural Killer/T-Cell Lymphoma. Front Oncol 2022; 12:821918. [PMID: 35619907 PMCID: PMC9128790 DOI: 10.3389/fonc.2022.821918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/29/2022] [Indexed: 02/05/2023] Open
Abstract
Background and Aims The clinical outcome of relapsed and refractory (RR) extranodal natural killer/T-cell lymphoma (ENKTL) is poor. It is necessary to identify RR patients in ENKTL and find novel therapeutic targets to improve the prognosis of patients with RR ENKTL. Methods A total of 189 ENKTL patients with effective clinical characteristics were enrolled. Paraffin specimens were collected for PD-L1 expression identification. Kaplan-Meier curve analysis was performed for survival analysis. Whole exome sequencing (WES) was performed for identifying the mutational characterization of RR and effective treatment (ET) patients. Results Univariate and multivariate Cox proportional hazards regression analysis showed that negative PD-L1 expression (HR = 1.132, 95% CI = 0.739-1.734, P = 0.036) was an independent predictor of poor prognosis in patients with ENKTL. The overall survival (OS) of PD-L1 positive patients was significantly higher than that of PD-L1 negative patients (P = 0.009). Then, we added PD-L1 expression as a risk factor to the model of Prognostic Index of Natural Killer Lymphoma (PINK), and named as PINK+PD-L1. The PINK+PD-L1 model can significantly distinguish RR patients, ET patients, and the whole cohort. Moreover, our data showed that PD-L1 expression was lower than 25% in most RR patients, suggesting that RR subtypes may be associated with low expression of PD-L1 (P = 0.019). According to the whole exome sequencing (WES), we found that the mutation frequencies of JAK-STAT (P = 0.001), PI3K-AKT (P = 0.02) and NF-kappa B (P < 0.001) pathways in RR patients were significantly higher than those in ET patients. Conclusion Patients tend to show RR when PD-L1 expression is lower than 25%. The model of PINK+PD-L1 can stratify the risk of different groups and predict OS in ENKTL patients. The mutational profile of ENKTL patients with RR is different from that of patients with ET.
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Affiliation(s)
- Li-Min Gao
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Yue-Hua Zhang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoliang Shi
- Department of Medical Product, OrigiMed, Inc., Shanghai, China
| | - Yang Liu
- Department of Medical Product, OrigiMed, Inc., Shanghai, China
| | - Junwei Wang
- Department of Medical Product, OrigiMed, Inc., Shanghai, China
| | - Wen-Yan Zhang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Wei-Ping Liu
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
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38
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Hue SSS, Ng SB, Wang S, Tan SY. Cellular Origins and Pathogenesis of Gastrointestinal NK- and T-Cell Lymphoproliferative Disorders. Cancers (Basel) 2022; 14:2483. [PMID: 35626087 PMCID: PMC9139583 DOI: 10.3390/cancers14102483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/08/2022] [Accepted: 05/13/2022] [Indexed: 11/25/2022] Open
Abstract
The intestinal immune system, which must ensure appropriate immune responses to both pathogens and commensal microflora, comprises innate lymphoid cells and various T-cell subsets, including intra-epithelial lymphocytes (IELs). An example of innate lymphoid cells is natural killer cells, which may be classified into tissue-resident, CD56bright NK-cells that serve a regulatory function and more mature, circulating CD56dim NK-cells with effector cytolytic properties. CD56bright NK-cells in the gastrointestinal tract give rise to indolent NK-cell enteropathy and lymphomatoid gastropathy, as well as the aggressive extranodal NK/T cell lymphoma, the latter following activation by EBV infection and neoplastic transformation. Conventional CD4+ TCRαβ+ and CD8αβ+ TCRαβ+ T-cells are located in the lamina propria and the intraepithelial compartment of intestinal mucosa as type 'a' IELs. They are the putative cells of origin for CD4+ and CD8+ indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and intestinal T-cell lymphoma, NOS. In addition to such conventional T-cells, there are non-conventional T-cells in the intra-epithelial compartment that express CD8αα and innate lymphoid cells that lack TCRs. The central feature of type 'b' IELs is the expression of CD8αα homodimers, seen in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), which primarily arises from both CD8αα+ TCRαβ+ and CD8αα+ TCRγδ+ IELs. EATL is the other epitheliotropic T-cell lymphoma in the GI tract, a subset of which arises from the expansion and reprograming of intracytoplasmic CD3+ innate lymphoid cells, driven by IL15 and mutations of the JAK-STAT pathway.
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Affiliation(s)
- Susan Swee-Shan Hue
- Department of Pathology, National University Hospital, Singapore 119074, Singapore; (S.S.-S.H.); (S.W.)
| | - Siok-Bian Ng
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
| | - Shi Wang
- Department of Pathology, National University Hospital, Singapore 119074, Singapore; (S.S.-S.H.); (S.W.)
| | - Soo-Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
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39
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Daines BS, Varman RM, Nguyen TQ. Extranodal natural killer/T-cell lymphoma nasal type. Proc AMIA Symp 2022; 35:672-674. [PMID: 35991731 PMCID: PMC9373771 DOI: 10.1080/08998280.2022.2071074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 10/18/2022] Open
Abstract
Extranodal natural killer/T-cell lymphoma nasal type (ENKL) is a rare neoplasm uncommon in the US. Diagnosis is complicated by low incidence and rapid tissue necrosis preventing timely histologic confirmation. We report the case of a 55-year-old woman with ENKL who faced a challenging diagnostic workup due to widespread nasal tissue necrosis and nonspecific sinus-related complaints. While ENKL is significantly more common in Asia and South America, clinicians worldwide should maintain a high level of suspicion for patients presenting with nonspecific nasopharyngeal complaints who have signs of tissue necrosis. Early recognition and treatment with combined radiotherapy and chemotherapy can improve survival.
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Affiliation(s)
- Benjamin S. Daines
- Department of Otolaryngology–Head and Neck Surgery, Texas Tech University Health Sciences Center, Lubbock, Texas
| | - Rahul M. Varman
- Department of Otolaryngology–Head and Neck Surgery, Texas Tech University Health Sciences Center, Lubbock, Texas
| | - Tam Q. Nguyen
- Department of Otolaryngology–Head and Neck Surgery, Texas Tech University Health Sciences Center, Lubbock, Texas
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40
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Chai Y, Chen B, Qi F, Fang H, Qi SN, Guo RY, Li N, Yang Y, Wang SL, Song YW, Yang JL, Zhang D, Wei YC, Li YX, Dong M. First-line chemoradiation with or without chidamide (tucidinostat) in patients with early stage intermediate- and high-risk early-stage extranodal nasal-type natural killer/T-cell lymphoma: a randomized phase 2 study in China. Int J Radiat Oncol Biol Phys 2022; 113:833-844. [PMID: 35452752 DOI: 10.1016/j.ijrobp.2022.04.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/20/2022] [Accepted: 04/01/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE We investigated the safety and efficacy profile of intensity-modulated radiation therapy (IMRT) followed by gemcitabine, dexamethasone, cisplatin (GDP), plus chidamide in the first-line setting for intermediate- and high-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTCL). METHODS This was an open-label, randomized phase 2 trial performed at two centers in China. Patients were eligible if they were newly-diagnosed with intermediate- and high-risk early-stage ENKTCL with at least one risk factor based on a nomogram-revised risk index:> 60 years old, elevated serum lactate dehydrogenase, invasion of the primary tumor, stage II or Eastern Cooperative Oncology Group performance status > 1 or stage II disease. Patients were treated with IMRT followed by GDP, with or without chidamide, in the first-line setting. Two-year progression-free survival (PFS) comprised the primary endpoint. Toxicities, the 2-year overall survival (OS), and the response rate comprised the secondary endpoints. RESULTS Eligible patients (n = 74) were enrolled between May 2015 and December 2019. Among them, 37 patients were treated with IMRT+GDP+chidamide (chidamide group), while 37 cases were treated with IMRT+GDP (control group). Follow-up comprised a median of 43.4 months (range, 1.0-74.6 months). The objective response rate was 86.5% in the chidamide group and 78.4% in the control group (P = 0.359) at the end of treatment completion. The 2-year OS and PFS rates were 89.2% and 75.2% in the chidamide group versus 83.8% (P = 0.388) and 70.2% (P = 0.821) in the control group. The main adverse events were hematological toxicities and mucositis, with similar rates in the two groups (P > 0.05). CONCLUSIONS The addition of chidamide to IMRT + GDP as first-line treatment achieved similar treatment outcomes and tolerable toxicities in patients with intermediate- and high-risk ENKTCL.
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Affiliation(s)
- Yue Chai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Chen
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fei Qi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hui Fang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shu-Nan Qi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ru-Yuan Guo
- Department of Radiation Oncology, Shanxi provincial cancer hospital, Shanxi, China
| | - Ning Li
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong Yang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shu-Lian Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong-Wen Song
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jian-Liang Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Di Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu-Ce Wei
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ye-Xiong Li
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Mei Dong
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Gao Y, Feng X, Song W, Li H, Shi C, Jin M, Li Z, Zhang L, Zhang M. The potential efficacy and mechanism of bendamustine in entra-nodal NK/T cell lymphoma. Hematol Oncol 2022; 40:678-688. [PMID: 35439335 DOI: 10.1002/hon.3007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/17/2022] [Accepted: 04/18/2022] [Indexed: 01/10/2023]
Abstract
Bendamustine has been shown to have anti-tumor activities in hematological malignancies, but the role of bendamustine in natural killer (NK)/T cell lymphoma (NKTCL) treatment is unclear. Our study has shown that bendamustine had potent growth-inhibitory and apoptosis-inducing effects on NKTCL cells. Interestingly, we noticed that the combination of either gemcitabine or etoposide results in additive or synergistic cytotoxicity. Bendamustine induced mitochondria-mediated apoptosis in concentration- and time-dependent manners in NKTCL cells, shown as down-regulation of Bcl-2 and activation of cleavage of caspases 3, 7, 9 and poly adenosinediphosphate-ribose polymerase (PARP). Bendamustine arrested NKTCL cells in G2/M phase, with downregulation of expression of cyclin B1 and upregulation of expression of p-cdc2, p-cdc25c and p-P53. Furthermore, we confirmed that bendamustine activated DNA damage response (DDR) directly or through Ataxia Telangiectasia Mutated Protein (ATM)/Chk2 and ATR/Chk1 pathway and increased the intracellular reactive oxygen species (ROS) level in NKTCL cells, which caused G2/M phase arrest and apoptosis. Bendamustine also inhibited phosphorylation of transcriptional factor STAT3, contributing to cell apoptosis and proliferation inhibition. Finally, we verified the effect of bendamustine on NKTCL cells in vivo. It showed that bendamustine dramatically inhibited the growth of the subcutaneous tumor, with no obvious impact on mice weight. These findings demonstrate that bendamustine activates DDR pathway, induces the accumulation of intracellularROS level as well as inhibition of STAT3, leading to cell apoptosis and G2/M cell cycle arrest in NKTCL cells, which indicates that bendamustine dramatically suppressed NKTCL both in vitro and in vivo and provides a potential therapeutic strategy in the treatment of NK/T lymphoma.
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Affiliation(s)
- Yuyang Gao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Xiaoyan Feng
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Wenting Song
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China.,Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
| | - Hongwen Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Cunzhen Shi
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Mengyuan Jin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Lei Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China.,State Key Laboratory of Esophageal Cancer Prevention & Treatment and Henan Key Laboratory for Esophageal Cancer Research, Zhengzhou, Henan, China
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Lei T, Chang Y, Zhang L, Zhang M. The Effect of Chronic Rhinosinusitis on the Staging and Prognosis of Extranodal Natural Killer/T-Cell Lymphoma: A Single-Center Retrospective Analysis. Front Oncol 2022; 12:878559. [PMID: 35449572 PMCID: PMC9016184 DOI: 10.3389/fonc.2022.878559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/03/2022] [Indexed: 11/25/2022] Open
Abstract
Clinically, extranodal natural killer/T-cell lymphoma (ENKTL) patients frequently had a history of chronic rhinosinusitis (CRS) before onset, and the correlation between the two diseases has not been systematically reported at present. In this study, we applied the method-retrospective analysis-to explore the relationship between CRS and ENKTL. We collected clinical data and the length of CRS history before onset in 214 patients diagnosed with ENKTL and found that the length of CRS history was correlated with the stage of 182 ENKTL patients whose primary sites were upper aerodigestive tract (UAT) (χ 2 = 21.317, p = 0.046, n = 182); the Spearman correlation coefficient was 0.162 (p = 0.029). There was no significant difference in stage of the non-UAT-ENKTL patients (χ 2 = 18.910, p = 0.091, n = 32). The COX multivariate regression analysis showed that CRS history was an independent prognostic predictor for PFS of the UAT-ENKTL patients (p = 0.004), and patients without CRS had significantly better PFS than the more than 15 years CRS history group (p = 0.001). Our findings suggested that we should not ignore the existence of chronic inflammation of the nasal cavity in ENKTL patients. It is better to treat CRS as soon as possible in clinical practice to reduce the possibility of the occurrence or progression of UAT-ENKTL.
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Yang J, Guo X, Guo S, Yan H, Chai L, Guo Y, Li Z, Hao Z, Su L. Management of adverse effects associated with pegylated Escherichia coli asparaginase on coagulation in the treatment of patients with NK/T-cell lymphoma. Medicine (Baltimore) 2022; 101:e25578. [PMID: 35451376 PMCID: PMC8913082 DOI: 10.1097/md.0000000000025578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 03/31/2021] [Indexed: 01/04/2023] Open
Abstract
Natural killer/T-cell lymphoma (NK/TL) is a chemotherapy-sensitive disease, and asparaginase-based chemotherapy has become the standard primary treatment for patients with this malignancy recently. The objective of this study was to evaluate the adverse reactions on blood coagulation of the administered pegylated Escherichia coli (E coli) asparaginase (PEG-ASP) to the NK/TL patients. Clinical data of 71 NK/TL patients (range 13-73 years), who received 239 cycles of chemotherapy treatment containing PEG-ASP in the Hematology Department of Shanxi Province Cancer Hospital of China from January 2016 to December 2019 were analyzed retrospectively. Data of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FBG), and antithrombinIII (ATIII) were obtained at the time points routinely and statistically analyzed. There were statistical differences between the monitored parameters of baseline day0 (the day before use of PEG-ASP, named day0) and those of day3 (the 3rd day after treatment) to day6, and data showed all of the indicators could recover within 21 days. The events included PT prolonged in 33 patients (46.5%), APPT prolonged in 41 patients (57.7%, 20 patients with APTT >60 seconds), FBG decreased in 49 patients (69.0%, 12 patients with FBG <1 g/L), and ATIII decreased in 52 patients (73.2%). The patients' average number of cycles received was 2.3 for PT (>14 seconds), 2.5 for APTT (>35 seconds), 2.7 for FBG (<2 g/L), and 2.6 for D-dimer (>550 ng/mL). Compared with those at day0, PT and APTT prolonged sharply at day3 (P < .05), reached the peak at day12, maintained the prolonged level from day3 to day15, and gradually recovered at day 21. FBG and ATIII significantly decreased at day6 and day3 respectively (P < .05), both of them fell to the minimum at day12, and then returned the normal. The D-dimer levels were no significantly change during the whole treatment course. The APTT >60 seconds or FBG <1 g/L side effects were improved by symptomatic treatment of supplementation of fresh frozen plasma or cryoprecipitate infusion, no concomitant bleeding or thrombotic events emerging. Our data suggested although chemotherapy including PEG-ASP impacted moderately on the coagulation function of NK/TL patients, clinically monitored regularly were necessary and most NK/TL patients can complete the chemotherapy cycles successfully.
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Affiliation(s)
- Jing Yang
- Department of Pharmacy, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, PR China
| | - Xiangyun Guo
- Department of Molecular Biology, Taiyuan, Shanxi, PR China
| | - Sutang Guo
- Department of Molecular Biology, Taiyuan, Shanxi, PR China
| | - Hongxia Yan
- Department of Pharmacy, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, PR China
| | - Limin Chai
- Department of Pharmacy, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, PR China
| | - Yimeng Guo
- Department of Pharmacy, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, PR China
| | - Zhenhua Li
- Department of Hematology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, PR China
| | - Zhiying Hao
- Department of Pharmacy, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, PR China
| | - Liping Su
- Department of Hematology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, PR China
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Terro K, Sharrouf L, El Cheikh J. Progress of Hematopoietic Stem Cell Transplantation and Radiotherapy in the Treatment of Extranodal NK/T Cell Lymphoma. Front Oncol 2022; 12:832428. [PMID: 35252002 PMCID: PMC8888904 DOI: 10.3389/fonc.2022.832428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/25/2022] [Indexed: 11/21/2022] Open
Abstract
Extranodal Natural Killer/T-cell lymphoma (ENKTL) is an extremely rare type of lymphoma which is highly lethal. It mainly affects the midline area unfolding as a necrotic granulomatous and extremely disfiguring lesion. There are two subtypes of (NKTL); the most common one is nasal which appears in the nasal cavity including the nasopharynx, oropharynx, parts of the aero digestive tract and Waldeyer’s ring. While the other rarer subtype, appears in sites like the skin, testis, gastrointestinal tract, salivary glands and muscle. ENKTL is popular for the expression of multidrug resistance-associated P-glycoprotein, which not only plays the main role at exporting many antitumor agents outside tumor cells, but also makes the disease hard to treat. It is commonly associated with Epstein-Barr virus (EBV) infection and commonly occurs in Asian populations. However, there is no single unified consensus yet as to what is the standardized treatment for ENKTL. Radiotherapy alone treatment, has been considered as a first-line therapy for localized ENKTL, which later on was found to be insufficient for improving survival rates. Thus, the combination of chemotherapy and radiotherapy has been recommended as a therapeutic modality for localized ENKTL. Several combination modalities of radiotherapy and chemotherapy have been advised in clinical practice including concurrent, sequential and sandwich chemo radiotherapy. For the best treatment outcome, only patients with localized nasal ENKTL and low risk of treatment failure are eligible for radiotherapy. Both radiotherapy and hematopoietic stem cell transplantation (HSCT) have been used as treatment modalities in ENKTL patients. Upfront HSCT was performed for ENKTL, but it was associated with a very poor prognosis even for the limited-stage disease. The evidence supporting the use of HSCT to treat ENKTL was derived from the results of a series of phase 1 and 2 trials along with retrospective studies. The end result was a unified consensus that consolidative HSCT is not necessary in patients with newly diagnosed localized ENKTL who achieved complete response after treatment with any of the modern chemo radiotherapy regimens. Hence, HSCT is solely advised for advanced and relapsed NKTL. The main debate remains over which HSCT is the most suitable for patients with newly diagnosed advanced NKTL and relapsed NKTL.
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Affiliation(s)
- Khodr Terro
- Hematology-Oncology Division, Naef K. Basile Institiute-NKBCI, American University of Beirut, Beirut, Lebanon
| | - Layal Sharrouf
- Hematology-Oncology Division, Naef K. Basile Institiute-NKBCI, American University of Beirut, Beirut, Lebanon
| | - Jean El Cheikh
- Hematology-Oncology Division, Naef K. Basile Institiute-NKBCI, American University of Beirut, Beirut, Lebanon
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Sun KH(M, Wong YT(H, Cheung KM(C, Yuen C(M, Chan YT(T, Lai WY(J, Chao C(D, Fan WS(K, Chow YK(K, Law MF, Tam HC(T. Update on Molecular Diagnosis in Extranodal NK/T-Cell Lymphoma and Its Role in the Era of Personalized Medicine. Diagnostics (Basel) 2022; 12:diagnostics12020409. [PMID: 35204500 PMCID: PMC8871212 DOI: 10.3390/diagnostics12020409] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/23/2022] [Accepted: 01/28/2022] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK)/T-cell lymphoma (NKTCL) is an aggressive malignancy with unique epidemiological, histological, molecular, and clinical characteristics. It occurs in two pathological forms, namely, extranodal NKTCL (ENKTCL) and aggressive NK leukemia, according to the latest World Health Organization (WHO) classification. Epstein–Barr virus (EBV) infection has long been proposed as the major etiology of lymphomagenesis. The adoption of high-throughput sequencing has allowed us to gain more insight into the molecular mechanisms of ENKTCL, which largely involve chromosome deletion and aberrations in Janus kinase (JAK)-signal transducer and activator of transcription (STAT), programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) pathways, as well as mutations in tumor suppressor genes. The molecular findings could potentially influence the traditional chemoradiotherapy approach, which is known to be associated with significant toxicity. This article will review the latest molecular findings in NKTCL and recent advances in the field of molecular diagnosis in NKTCL. Issues of quality control and technical difficulties will also be discussed, along with future prospects in the molecular diagnosis and treatment of NKTCL.
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Affiliation(s)
- Ka-Hei (Murphy) Sun
- Division of Hematopathology, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Hong Kong; (K.-H.S.); (C.Y.)
| | | | - Ka-Man (Carmen) Cheung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Carmen (Michelle) Yuen
- Division of Hematopathology, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Hong Kong; (K.-H.S.); (C.Y.)
| | - Yun-Tat (Ted) Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Wing-Yan (Jennifer) Lai
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Chun (David) Chao
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Wing-Sum (Katie) Fan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Yuen-Kiu (Karen) Chow
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Man-Fai Law
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
- Correspondence:
| | - Ho-Chi (Tommy) Tam
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
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Tse E, Kwong YL. Recent Advances in the Diagnosis and Treatment of Natural Killer Cell Malignancies. Cancers (Basel) 2022; 14:cancers14030597. [PMID: 35158865 PMCID: PMC8833626 DOI: 10.3390/cancers14030597] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Natural killer (NK)/T-cell lymphomas are aggressive extranodal Epstein–Barr virus (EBV)-positive malignancies. They can be divided into three subtypes: nasal (involving the nose and upper aerodigestive tract), non-nasal (involving skin, gastrointestinal tract, testis and other organs) and disseminated (involving multiple organs). Lymphoma cells are positive for CD3ε, CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asians. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial at diagnosis and follow-up. Stage I/II patients receive non-athracycline asparaginse-containing regimens, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients receive asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT). Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches include PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial. Abstract Natural killer (NK)/T-cell lymphomas are aggressive malignancies. Epstein–Barr virus (EBV) infection in lymphoma cells is invariable. NK/T-cell lymphomas are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nasal cavity and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other extranodal sites. Disseminated NK/T-cell lymphoma involves multiple organs, rarely presenting with a leukaemic phase. Lymphoma cells are positive for CD3ε (not surface CD3), CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asian patients. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial evaluations at diagnosis and follow-up. Stage I/II patients typically receive non-athracycline regimens containing asparaginse, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients are treated with asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable cases. Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches are needed, involving PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial in selected patients. Future strategies may include targeting of signalling pathways and driver mutations.
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He X, Gao Y, Li Z, Huang H. Review on natural killer /T-cell lymphoma. Hematol Oncol 2021; 41:221-229. [PMID: 34731509 DOI: 10.1002/hon.2944] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/26/2021] [Indexed: 11/06/2022]
Abstract
Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is strongly associated with Epstein-Barr virus (EBV) and has a high prevalence in Asian and in Central and South America. About 85% of ENKTLs derive from NK cells and 15% from T-cells. Various factors have been implicated in the development of ENKTL. Molecular pathogenesis of NK/T-cell lymphomas include mutations of genes, involving in the Janus Kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway, RNA helicase family, epigenetic regulation, and tumor suppression. The relationship between ENKTL and human leukocyte antigen (HLA) has been demonstrated. Radiotherapy (RT) plays a key role in the first-line treatment of early-stage. In stage III/IV diseases, non-anthracycline-regimens-containing L-asparaginase are recommended. Although clinical remission after L-asparaginase-based combination therapy has been achieved in the majority of patients with advanced-stage or relapsed/refractory(r/r) ENKL, the long-term overall survival is still poor. Recently, immunotherapy and new therapeutic targets have gained much attention. In this article, we discuss the pathogenesis, diagnosis, prognostic models and management options of ENKTL. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Xiaohua He
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Yan Gao
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Zhiming Li
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Huiqiang Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
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SLC1A1 mediated glutamine addiction and contributed to natural killer T-cell lymphoma progression with immunotherapeutic potential. EBioMedicine 2021; 72:103614. [PMID: 34628354 PMCID: PMC8511843 DOI: 10.1016/j.ebiom.2021.103614] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Metabolic reprogramming plays an essential role on lymphoma progression. Dysregulation of glutamine metabolism is implicated in natural-killer T-cell lymphoma (NKTCL) and tumor cell response to asparaginase-based anti-metabolic treatment. METHODS To understand the metabolomic alterations and determine the potential therapeutic target of asparaginase, we assessed metabolomic profile using liquid chromatography-mass spectrometry in serum samples of 36 NKTCL patients, and integrated targeted metabolic analysis and RNA sequencing in tumor samples of 102 NKTCL patients. The biological function of solute carrier family 1 member 1 (SLC1A1) on metabolic flux, lymphoma cell growth, and drug sensitivity was further examined in vitro in NK-lymphoma cell line NK-92 and SNK-6, and in vivo in zebrafish xenograft models. FINDINGS In NKTCL patients, serum metabolomic profile was characterized by aberrant glutamine metabolism and SLC1A1 was identified as a central regulator of altered glutaminolysis. Both in vitro and in vivo, ectopic expression of SLC1A1 increased cellular glutamine uptake, enhanced glutathione metabolic flux, and induced glutamine addiction, leading to acceleration of cell proliferation and tumor growth. Of note, SLC1A1 overexpression was significantly associated with PD-L1 downregulation and reduced cytotoxic CD3+/CD8+ T cell activity when co-cultured with peripheral blood mononuclear cells. Asparaginase treatment counteracted SLC1A1-mediated glutamine addiction, restored SLC1A1-induced impaired T-cell immunity. Clinically, high EAAT3 (SLC1A1-encoded protein) expression independently predicted superior progression-free and overall survival in 90 NKTCL patients treated with asparaginase-based regimens. INTERPRETATION SLC1A1 functioned as an extracellular glutamine transporter, promoted tumor growth through reprogramming glutamine metabolism of NKTCL, while rendered tumor cells sensitive to asparaginase treatment. Moreover, SLC1A1-mediated modulation of PD-L1 expression might provide clinical rationale of co-targeting metabolic vulnerability and immunosuppressive microenvironment in NKTCL. FUNDING This study was supported, in part, by research funding from the National Natural Science Foundation of China (82130004, 81830007 and 81900192), Chang Jiang Scholars Program, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Clinical Research Plan of SHDC (2020CR1032B), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Shanghai Chenguang Program (19CG15), Shanghai Sailing Program (19YF1430800), Medical-Engineering Cross Foundation of Shanghai Jiao Tong University (ZH2018QNA46), and Shanghai Yi Yuan Xin Xing Program.
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Tvedten E, Richardson J, Motaparthi K. What Effect Does Epstein-Barr Virus Have on Extranodal Natural Killer/T-Cell Lymphoma Prognosis? A Review of 153 Reported Cases. Cureus 2021; 13:e17987. [PMID: 34540511 PMCID: PMC8445857 DOI: 10.7759/cureus.17987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2021] [Indexed: 11/09/2022] Open
Abstract
The primary aim of this review is to identify the relationship between Epstein-Barr virus (EBV) and prognosis in extranodal natural killer/T-cell lymphoma (ENKTL). Additionally, a literature review of ENKTL was carried out. The investigators designed and implemented a 21-year literature review using the online databases PubMed and Google Scholar. The total number of cases analyzed was 153 (64 case reports; one comparative study; one systematic review). Information related to ENKTL from July 1999 to February 2021 was included in the study. Study variables included: patient demographics, tumor classification, screening modalities, tumor characteristics, symptomatology, treatment, and prognosis. The average age at diagnosis was 50.9 years (range: 4-90 years). Patients of Asian ethnicity were most commonly affected, and there was a 1.6:1 male to female ratio. ENKTL was most frequently detected in the head and neck region, and 53.1% of cases metastasized. Of all head and neck cases, the nose was the most affected location. Immunohistochemistry positivity included: EBV (32.0%), CD2 (96.6%), CD3ϵ (81.7%), CD43 (91.7%), CD56 (86.4%), Granzyme (97.1%), Perforin (90.9%), TIA-1 (97.8%), p53 (33.3%). The most frequently employed single treatment modality was chemotherapy alone, and 34.2% of patients expired within five years of diagnosis. The average follow-up period was 16.51 months (range: 0.25-66 months). EBV was significantly associated with metastatic ENKTL (χ2 = 4.36; CV = 3.84; p = 0.037). We found no association between EBV and ENKTL prognosis (χ2 = 17.2; CV = 21.0; p = 0.14).
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Affiliation(s)
- Erika Tvedten
- Department of Dermatology, Michigan State University, Detroit, USA
| | | | - Kiran Motaparthi
- Department of Dermatology, University of Florida, Gainesville, USA
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Beltrán BE, Marques-Piubelli ML, Quiñones MP, Cotrina E, Palomino EA, Morales J, Ramos W, Sotomayor EM, Chavez JC, Castillo JJ, Miranda RN. Extranodal NK/T-cell lymphoma, nasal type presenting as primary intestinal lymphoma vs intestinal T-cell lymphoma: A borderline diagnostic category in the revised WHO classification. HUMAN PATHOLOGY: CASE REPORTS 2021. [DOI: 10.1016/j.ehpc.2021.200534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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