High infiltration of CD20+ B lymphocytes in extranodal natural killer/T-cell lymphoma is associated with better prognosis

Immune cells have an uncertain function during the progression of extranodal natural killer/T-cell lymphoma (ENKTL). The present study determined the distribution, phenotype, and clinical significance of B lymphocytes in ENKTL. Immunohistochemistry indicated high infiltration of CD20⁺ B lymphocytes in the tumour tissues of 40% of the patients, and that a high infiltration correlated with better overall survival. Moreover, B lymphocytes had an active mature phenotype in situ and suppressed the proliferation of ENKTL cells in vitro. These results suggest that tumour infiltration of CD20⁺ B lymphocytes may be a new prognostic indicator for patients with ENKTL.     

High-dose chemotherapy with autologous stem cell transplantation in extranodal NK/T-cell lymphoma: a retrospective comparison with non-transplantation cases

To determine the role of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in extranodal NK/T-cell lymphoma patients, we conducted a retrospective analysis. In our previous study, we searched for patients who had received HDC/ASCT and identified 16 eligible patients and compared the treatment outcome with historical control group (n=246). Nine patients received HDC/ASCT in the first (CR1) or second complete remission (CR2), while seven patients received HDC/ASCT as salvage. Twelve of 16 patients achieved or maintained CR after HDC/ASCT. Among the 12 patients, five patients relapsed. Estimated 2-year overall survival (OS) and relapse-free survival (RFS) rates were 71.3+/-12.4% and 25.8+/-14.3%, respectively. There was a tendency of better survival in patients who received HDC/ASCT as compared to those who did not (P=0.091). In subset analysis, patients who underwent HDC/ASCT at CR (P=0.049) and patients with stage III or IV (P=0.001) had a favorable outcome. Patients with NKIPI 3,4 or EUNKTL, who underwent HDC/ASCT had more prolonged survival without statistical significance (P=0.055 and 0.056). In conclusion, HDC/ASCT may be considered as a treatment option for patients with extranodal NK/T-cell lymphoma, especially those in CR, with advanced disease (stage III/IV or EUNKTL) and high NKIPI scores.     

Sustained remission of multi-line relapsed extranodal NK/T-cell lymphoma,nasal type,following sintilimab and chidamide: A case report

Introduction:There is currently no optimal treatment modality for refractory or relapsed Extranodal NK/T-cell lymphoma, nasal type (ENKTL). In recent years, programmed cell death protein 1 (PD-1)/programmed cell – ligand 1 pathway blockade and histone deacetylase inhibitors have emerged as promising strategies for refractory or relapsed ENKTL. Accumulating evidence has shown that therapeutic effects of anti-PD-1 antibody could be enhanced by histone deacetylase inhibitors.Patient Concerns:A 52-year-old male patient was diagnosed with stage I ENKTL by biopsy on February 2010.Diagnosis:positron emission tomography–computed tomography (PET-CT) and biopsy were used to diagnose relapsed ENKTL in 2014.Interventions:The patient was treated with radiotherapy and six cycles of etoposide, prednisone, vincristine (Oncovin), cyclophosphamide and doxorubicin hydrochloride and achieved complete remission (CR) by PET-CT in August 2010. In November 2014, the patient was diagnosed with relapsed stage IV ENKTL and was treated with six cycles of alternative chemotherapy with the regimen of steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide and pegaspargase plus Gemcitabine, Oxaliplatin along with radiotherapy. The patient achieved remission and was placed on thalidomide maintenance treatment. Upon suspicion of relapse suggested by PET-CT, Autologous stem cell transplant was performed after BCNU, etoposide, Ara-C, and melphalan preconditioning on February 2016. Following relapse again in December 2016, the lesions of left femur were treated with radiotherapy and he received anti-PD-1 antibody. He was treated with 4 cycles of pegaspargase plus Gemcitabine, Oxaliplatin on August 2017. The patient''s condition improved. He received maintenance and consolidation therapy including lenalidomide, radiotherapy of the right nasal cavity and paranasal sinuses and antigen-specific reactive T cell infusions. PET-CT imaging showed there was high metabolic activity signal in the distal end of right femoral on August 2018 and the treatment regimen was adjusted to radiotherapy of the distal end of right femoral and systemic treatment of PD-1 antibody Sintilimab and chidamide 30 mg. After 5 months post-treatment, biopsy of nasopharynx showed no lymphoma cells. The patient continued the treatment of Sintilimab and chidamide 20 mg.Outcomes:PET-CT imaging showed his lesions obtained remission after 8 months post-treatment.Conclusion:Thus, combination of sintilimab and chidamide can be used to treat relapsed ENKTL following treatment failure from chemo-, radio-, and immuno-therapy. A clinical trial has been launched.     

Primary pleural epithelioid angiosarcoma treated successfully with anti-PD-1 therapy: A rare case report

Rationale:Primary pleural angiosarcoma (PPA) is an extremely rare malignancy for which there is no consensus on treatment. The clinical course of PPA is usually quickly fatal, regardless of the treatment used.Patient concerns:We describe the rare case of a 52-year-old man who presented initially with hemoptysis and received emergency surgery for the primary.Diagnoses:He received a confirmed diagnosis of primary pleural angiosarcoma (PPA) by postoperative pathology and was subsequently treated with radiotherapy and chemotherapy, but had failed and was intolerant to chemotherapy.Interventions:The patient had 5% tumor PD-L1 positivity with 22C3 pharmDx and received pembrolizumab (200 mg every 21 days) for 13 cycles.Outcomes:The disease remained well controlled according to the RECIST 1.1. criteria. He is currently under observation and waiting to start the next cycle of immunotherapy.Lesson:Our case report suggests that the use of anti-PD-1 therapy does show efficacy in the treatment of PPA and may provide a viable treatment option for patients.     

Clinical significance of Th1/Th2 ratio in patients with myelodysplastic syndrome

In this study, we attempted to evaluate the clinical significance of T helper 1 (Th1)/T helper 2 (Th2) ratio in patients with myelodysplastic syndrome (MDS), five refractory anaemia (RA), four refractory anaemia with ringed sideroblasts (RARS), 31 refractory cytopenia with multilineage dysplasia (RCMD), nine refractory anaemia with excess blast-1 (RAEB-1) and seven refractory anaemia with excess blast-2 (RAEB-2). Intracellular interleukin-4 (Th2 cytokine) and interferon-gamma (Th1 cytokine) production was assessed in CD4+ T lymphocytes activated by phorbol 12-myristate 13-acetate and ionomycin using flow cytometry. Mean Th1/Th2 ratios in each MDS group were as follows: RA/RARS, 8.8 (95% CI, 5.8-11.8), RCMD, 14.7 (95% CI, 9.5-19.9), RAEB-1, 10.6 (95% CI, 4.6-16.6), RAEB-2, 12.8 (95% CI, 3.0-22.7) and control 12.8 (95% CI, 9.6-16.1). There were no significant differences in Th1/Th2 ratio in the RA/RARS, RCMD, RAEB-1 and RAEB-2 subgroups when compared to controls. Because Th1/Th2 ratio in the RCMD group was widely distributed, we divided RCMD patients according to Th1/Th2 ratio into three groups (low, normal and high Th1/Th2 groups). There were no differences in severity of cytopenia among the three above groups. However, the percentage of CD8 cells in the low Th1/Th2 group was significantly lower than those in the high group (P < 0.01). These data suggest that Th1/Th2 imbalance induces CD4/CD8 imbalance, and serves as a marker of the biological interplay in immune regulation.     

Successful treatment with cyclosporin A for myelodysplastic syndrome with erythroid hypoplasia associated with T-cell receptor gene rearrangements

Myelodysplastic syndrome (MDS) with erythroid hypoplasia, a rare form of MDS, has not yet been clearly defined. We report four patients with MDS with erythroid hypoplasia who received immunosuppressive therapy. All were elderly, had severe transfusion-dependent anaemia, morphological evidence of myelodysplasia and a low percentage (3.2-13.6%) of erythroid precursors. Administration of cyclosporin A (CsA) improved their anaemia; all transfusion-dependent patients achieved transfusion-independence. An inverted CD4/8 ratio was seen in three patients who also demonstrated T-cell receptor (TCR)-beta and -gamma gene rearrangements by Southern blotting and clonality by polymerase chain reaction. Treatment with CsA can be an attractive alternative treatment for patients with MDS with erythroid hypoplasia, which may be associated with a clonal abnormality in T cells.     

Risk-based,response-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: A China Lymphoma Collaborative Group study

We aimed to determine the survival benefits of chemotherapy (CT) added to radiotherapy (RT) in different risk groups of patients with early-stage extranodal nasal-type NK/T-cell lymphoma (ENKTCL), and to investigate the risk of postponing RT based on induction CT responses. A total of 1360 patients who received RT with or without new-regimen CT from 20 institutions were retrospectively reviewed. The patients had received RT alone, RT followed by CT (RT + CT), or CT followed by RT (CT + RT). The patients were stratified into different risk groups using the nomogram-revised risk index (NRI). A comparative study was performed using propensity score-matched (PSM) analysis. Adding new-regimen CT to RT (vs RT alone) significantly improved overall survival (OS, 73.2% vs 60.9%, P < .001) and progression-free survival (PFS, 63.5% vs 54.2%, P < .001) for intermediate-risk/high-risk patients, but not for low-risk patients. For intermediate-risk/high-risk patients, RT + CT and CT + RT resulted in non-significantly different OS (77.7% vs 72.4%; P = .290) and PFS (67.1% vs 63.1%; P = .592). For patients with complete response (CR) after induction CT, initiation of RT within or beyond three cycles of CT resulted in similar OS (78.2% vs 81.7%, P = .915) and PFS (68.2% vs 69.9%, P = .519). For patients without CR, early RT resulted in better PFS (63.4% vs 47.6%, P = .019) than late RT. Risk-based, response-adapted therapy involving early RT combined with CT is a viable, effective strategy for intermediate-risk/high-risk early-stage patients with ENKTCL in the modern treatment era.     

An unusual extranodal natural killer/T-cell lymphoma presenting as chronic laryngitis: A case report

Rationale:Nasal-type, extranodal natural killer (NK)/T-cell lymphoma is a rare lymphoma. The tumor usually shows ulcerative and necrotic lesions in the nasal cavities and sinuses. Tissue involvement outside the nasal cavity is uncommon.Patient concern:We describe a 30-year-old man with a 2-month history of hoarseness, weight loss, and dyspnea.Diagnosis:Magnetic resonance image (MRI) showed edema of the larynx with obliteration of the airway. Laryngoscopic examination described necrotic tissue in the glottis and larynx. The biopsy showed chronic, necrotizing laryngitis, with no granulomas, vasculitis, or atypical cells. The immunologic and microbiologic study was negative. Later, after immunosuppressive therapy, the patient presented erythema and diffuse enlargement of the right arm. MRI showed myositis of the biceps and brachial muscles. Infection was rule out, and direct microscopy showed an extensive muscle infiltration by mononuclear cells and abundant mitosis. Immunohistochemistry was positive for CD3, CD8, Ki 67 (90%), and CD56 compatible with extranodal NK/T cell lymphoma.Interventions:The patient initially received immunosuppression treatments (corticoids, cyclofosfamide, and Rituximab) with relapsing episodes. When lymphoma was diagnosed, chemotherapy was started.Outcomes:The patient died during chemotherapy.Lessons:Nasal-type, extranodal NK/T-cell lymphoma should be suspected even when there are no classical findings of neoplasms on histology. Immunohistochemistry is mandatory to rule it out.     

CD4:CD8 ratio in children with perinatally acquired HIV‐1 infection

Objectives

In adults with horizontally acquired HIV infection, an inverted CD4:CD8 ratio is associated with persistent immune activation, size of HIV reservoir and predicts an increased risk of non‐AIDS‐defining adverse events. Normalization of this ratio with antiretroviral therapy (ART) is suboptimal in adults, despite viral suppression, and is less well described in paediatric populations. We investigated rates of CD4:CD8 ratio recovery in children with perinatally acquired HIV infection (PaHIV) on ART.

Methods

A cross‐sectional, retrospective analysis of routine clinical data in children with PaHIV (5–18 years old) attending a single UK centre was carried out.

Results

CD4:CD8 normalization was seen in 62% of children on suppressive ART. A negative correlation was found between current CD4:CD8 ratio and age at start of ART. Positive correlations were found between current CD4:CD8 ratio and total time with suppressed HIV viral load and nadir CD4 counts. Multiple linear regression analysis showed that age at start of ART was significantly associated with current CD4:CD8 ratio (standardized β = ?0.680; P < 0.001). Patient sex, ethnicity and antiretroviral regimen did not affect ratio recovery.

Conclusions

We found higher rates of CD4:CD8 ratio normalization compared with previous adult studies. Children who started ART at a younger age were more likely to recover a normal ratio. The current policy of universal treatment for all HIV‐positive adults and children will enhance immunological normalization.

     

鼻型结外NK/T细胞淋巴瘤患者血清潜伏膜蛋白1/EB病毒核抗原1检测的临床意义

目的 检测鼻型结外NK/T细胞淋巴瘤(ENKL)患者血清EB病毒核抗原1(EBNA1)、潜伏膜蛋白1(LMP1),探讨其与ENKL的关系.方法 选取首都医科大学北京同仁医院2010年8月到2013年8月新诊断ENKL患者36例、健康对照者20例,以EBNA1、LMP1为目的基因,采用实时定量PCR方法分别检测ENKL患者治疗前后和健康对照者外周血EBNA1、LMP1.结果 治疗前,ENKL患者血清EBNA1中位数为1.9×104(0 ～ 11.0×104)拷贝/μl,健康对照组为8.0(0 ～43.8)拷贝/μl;ENKL患者LMP1中位数为3.9 ×103(118.3 ～24.0×103)拷贝/μl,健康对照组为3.3(0～33.3)拷贝/μl.治疗前ENKL患者EBNA1、LMP1均显著高于健康对照组(P均＜0.01).治疗后,ENKL患者血清EBNA1中位数为1.0×103(0 ～2.0×103)拷贝/μl,LMP1为300.8(0 ～825.7)拷贝/μl,两者较治疗前均显著降低(P＜0.05).治疗有效患者的治疗后EBNA1、LMP1中位数均低于治疗无效的患者(P＜0.05).治疗前ENKL患者EBNA1、LMP1与血清乳酸脱氢酶水平呈正相关(r=0.364、0.546,P=0.040、0.012).EBNA1、LMP1低于临界值(EBNA1:1.3×104拷贝/μl; LMP1:3.0×103拷贝/μl)患者的2年总生存率和无进展生存率优于EBNA1、LMP1高于临界值者,但差异无统计学意义(P均＞0.05).结论 (1)检测ENKL患者血清EBNA1和LMP1对评判治疗效果具有一定价值;(2)ENKL患者血清EBNA1、LMP1可反映肿瘤负荷.     

Primary extranodal natural Killer/T-cell lymphoma in a child in the colon: A case report

Rationale:Primary extranodal natural killer (NK)/T-cell lymphoma (ENKTL) rarely occurs in childhood and adolescence. To the best of our knowledge, ENKTL of childhood in the gastrointestinal (GI) tract has not been reported yet.Patient concerns:A 12-year-old Chinese boy complained of abdominal pain and persistent fever for 1 month.Diagnosis:Grossly an ulcerated tumor with perforation was located at the proximal ascending colon, 5 cm × 4 cm × 1.5 cm in diameter. The tumor was poorly circumscribed, tan-white and solid. Histological evaluation revealed medium-sized atypical lymphoid cells with large areas of necrosis distributed throughout all layers of the colon. Small blood vessels with destroyed walls were surrounded by lymphoid cells. Immunohistochemistry (IHC) highlighted tumor cells as strongly positive for CD3, CD56, CD5, CD2, CD8, CD4, CD43, T-cell restricted intracellular antigen 1 (TIA-1) and granzyme B. The proliferation index, measured by Ki-67 expression was high with 60%. The In situ hybridization (ISH) for EBER was positive. TCR was negative. Therefore, the final diagnosis was ENKTL of childhood in the colon.Interventions:The patient underwent right hemicolectomy and ileocolostomy.Outcomes:We recommended further evaluation and treatment, but the patient and patient family rejected further treatment of his condition. The patient died within 1 month after being discharged from hospital as a result of his disease.Lessons:ENKTL of childhood in the GI tract is extremely rare. Due to the non-specific clinical symptoms, it is easy it is easy not to think of this differential diagnosis at early stage. If patients have GI symptoms, ENKTL cannot easily be ignored. It is necessary to diagnose ENKTL of childhood in the GI tract by morphology and immunohistochemistry, and to differentiate from the GI T-cell lymphomas. We hope this case may serve as a reference improving clinical diagnosis and treatment.     

A novel monoclonal antibody specific for human pre-B cell leukemia/lymphoma

A novel monoclonal antibody, designated WH14-antibody (WH14-Ab), was produced by using a non-T ALL cell line (HBL-3) as an immunogen. 35S-labelled immunoprecipitate revealed that the antigen reacting with WH14-Ab was estimated to be 30 Kd. Immunoglobulin isotype of WH14-Ab was IgG1. In the normal hematopoietic tissue, WH14-Ab reacted with a small number of monocytes (less than 30%) in the peripheral blood, but neither with the lymphocytes nor granulocytes. WH14-Ab reacted with HBL-3 and REH, but not with other B-cell leukemia/lymphoma and EBV-transformed cell lines. In addition, WH14-Ab reacted with most non-T ALL and pre-B lymphoblastic lymphoma. WH14-Ab did not react with all T-cell lymphomas. These findings indicate that the WH14-Ab may recognize the cell surface determinant shared by immature B cells, especially pre-B cells, in the B-cell lineage. WH14-Ab may be useful not only for the detection of pre-B cell leukemia/lymphomas but also for the investigation of maturation and differentiation of B-cell lineage.     

Identification of biclonal (duplex) leukaemic cells expressing either CD4+/CD8- or CD4-/CD8+ from a patient with adult T-cell leukaemia/lymphoma

A 24-year-old Japanese woman was admitted to our hospital in 1987 with a chief complaint of skin eruptions, and was diagnosed as having chronic ATLL. In 1993 the leucocyte count increased gradually to 126.0x10⁹/l with 91.5% abnormal lymphocytes expressing two different types of antigenicity, either CD4⁺/CD8^- or CD4^-/CD8⁺. Monoclonal integration of human T-cell lymphotropic virus type-I proviral DNA was detected at different sites of the genomic DNA in each cell type. These studies clearly indicate that CD4⁺/CD8^- and CD4^-/CD8^- leukaemic cells originated from two independent clones.     

HIV/AIDS患者机会性感染特点分析

目的探讨HIV／MDS患者机会性感染疾病谱及其与CD4^＋及CD8^＋T细胞间的关系,从而为临床防治机会性感染提供依据。方法对北京佑安医院感染科2002—2005年收治的181例HIV／AIDS患者的临床资料进行回顾性分析。结果181例患者中,有104例发生了机会性感染,部分患者同时有多种机会性感染。本组最常见的机会性感染是口腔念珠菌感染（52．9％）,其他依次为卡氏肺孢子菌肺炎（PCP）（31．7％）、结核（21．2％）、食管或肠道真菌感染（15．4％）、疱疹病毒感染（12．5％）及肺部感染（6．7％）等;各种机会性感染中,结核组与PCP组间CD4／CD8比值差异具有统计学意义;按同时伴有机会性感染的种类数分组,机会性感染各组的平均CD4^＋、CD8^＋T细胞计数及CD4／CD8比值均显著低于无机会性感染组;随着机会性感染种类的增加,CD4^＋T细胞数逐渐降低,CD4／CD8比值亦逐渐降低。结论HIV／MDS患者机会性感染多见于消化和呼吸系统,发生频率与CD4^＋T细胞计数及CD4／CD8比值有着非常密切的关系,CD4^＋T细胞计数小于200个／μl、CD4／CD8比值小于0．20,机会性感染明显增加,且随着病情进展同时发生多种机会性感染的几率也明显增加,此可作为开展机会性感染预防的参照指标。     

Imatinib mesylate in combination with pembrolizumab in patients with advanced KIT-mutant melanoma following progression on standard therapy: A phase I/II trial and study protocol

Introduction:Genetic alterations of KIT gene are known to be one of the major causes of melanoma. Those are more common in the mucous and acral subtypes and KIT is regarded as major oncogene in Asian melanomas, where the prevalence of these subtypes is high. Up to date, several clinical trials have been conducted to target KIT gene alterations in melanoma with unsatisfied efficacies. Imatinib mesylate, a small-molecule inhibitor of the KIT tyrosine kinase, provides a rapid but not durable clinical response in KIT-mutant melanoma. Meanwhile, recent basic and clinical evidence have revealed another aspect of KIT-targeted therapy, namely the enhancement of antitumor activity of immune checkpoint inhibitors. Herein, we designed clinical trial of co-administrating imatinib mesylate and pembrolizumab (anti-PD-1 antibody) to evaluate its safety and efficacy.Methods and analysis:This is an open-label, single-arm, phase I/II clinical trial involving Japanese patients with metastatic KIT-mutant melanoma that are refractory to standard therapy including anti-PD-1 therapy. Phase I study is a dose-escalation study comprising two dose levels of imatinib mesylate (200 and 400 mg/day, respectively) with fixed dose of pembrolizumab (200 mg every 3 weeks) to evaluate safety and tolerability and determine recommended phase II dose. The primary endpoint of the phase II study is the objective response rate after 4 cycles (3 weeks/cycle) of pembrolizumab and imatinib mesylate at the dose determined in phase I, based on RECIST version 1.1. A Simon''s minimax two-stage design is employed to test the null hypothesis of a 5% response rate vs 30% alternative, which will be rejected when a lower confidence limit of two-sided 90% confidence interval of true response rate is over than threshold response rate. The secondary endpoints include progression free survival, overall survival, best overall response and incidence of adverse events. Totally, a target size of 22 patients will be expected.Discussion:If this study shows efficacy and acceptable safety profile, it will contribute to the development of novel treatment option for patients with KIT-mutant melanoma that are refractory to standard therapy.Trial registration:{"type":"clinical-trial","attrs":{"text":"NCT04546074","term_id":"NCT04546074"}}NCT04546074. Date of Registration: September 11, 2020 (https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT04546074","term_id":"NCT04546074"}}NCT04546074). Date of First Participant Enrollment: December 23, 2020.     

A longitudinal study of immunological status in Chinese Haemophiliacs: importance of the heat viral inactivation of factor concentrates. II. Improvements of CD4/CD8 ratio after treatments with heat-inactivated factor concentrates

Screened and heated clotting factor concentrates of intermediate purity have been used in Taiwanese Haemophiliacs since the end of 1986. A significant improvement of CD4/CD8 ratio during the years 1987–1989 as compared with those during the years 1984–1986 was observed in Haemophilia A patients [mean±SD (median), 1.191±0.495 (1.163) vs. 0.880±0.325 (0.838), P =0.0020] who were seronegative for human immunodeficiency virus. Almost all patients received an increased amount of factor VIII concentrates and total plasma products since 1987. Multiple linear regression analysis for the association of CD4/CD8 ratio with changes in dosage of plasma products revealed that there was a significant positive association of CD4/CD8 ratio measured during 1987–1989 with dosage of factor VIII concentrate administered during 1984–1986 ( P =0.0230), which is an indicator for changes in viral load, but not with changes in dosage of plasma products, which are indicators for changes in plasma protein intake. Our data indicate that immunological abnormalities after replacement therapy observed in Haemophiliacs are mainly attributed to virus infection through infusion of factor concentrates, not to allogeneic proteins existing in plasma products.