lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells

PURPOSE: Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin's lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro. EXPERIMENTAL DESIGN: An in vitro ADCC system was used to assess the ability of lenalidomide to enhance human NK cell and monocyte function in response to rituximab. RESULTS: Lenalidomide directly enhanced IFN-gamma production via Fc-gamma receptor-mediated signaling in response to IgG. It was also a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro, an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Lenalidomide also enhanced the ability of NK cells to kill primary tumor cells derived from three patients with B-CLL who have been treated previously with fludarabine plus cyclophosphamide. Enhanced NK cell ADCC was associated with enhanced granzyme B and Fas ligand expression and could be inhibited by a granzyme B inhibitor and partially inhibited by antibody to FasL. Enhanced NK cell Fc-gamma receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function. CONCLUSIONS: These findings suggest that lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro, providing a strong rationale for the combination of lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer.     

早期鼻咽非霍奇金淋巴瘤:不同免疫表型的预后差异和治疗对策分析

背景与目的:鼻咽是淋巴瘤较常见的发病部位之一,但对于不同病理免疫表型(B细胞与NK/T细胞)鼻咽淋巴瘤的临床特点和预后以及相应的治疗对策的区别,临床报道较少。本研究的目的在于探讨不同免疫表型的早期鼻咽非霍奇金淋巴瘤的临床表现和治疗效果,评估B细胞和NK/T细胞表型之间的预后差异,为治疗方案的相应调整提供依据。方法:回顾性分析1987年5月至2003年12月间80例初治的早期鼻咽非霍奇金淋巴瘤患者的临床资料,病理和免疫表型检查显示48例为B细胞来源(B组),32例为T和NK细胞来源(T组)。42例患者接受化放疗综合治疗,31例单纯化疗,7例单纯放疗。化疗多数采用标准CHOP方案,1～10周期(中位数5周期);放射治疗采用高能光子射线配合高能电子线,常规分割,照射剂量DT30～70Gy(中位数52Gy)。两组患者的治疗方式相近,但B组的化疗周期数大于后者。结果:B组和T组的5年总生存(OS)率分别为69.5%和35.5%(P=0.003),5年无疾病进展生存(PFS)率分别为53.3%和28.9%(P=0.032)。多因素分析显示,B细胞免疫表型、无全身症状、局部控制是OS有利的独立预后影响因素;B细胞免疫表型、治疗反应好(CR/PR)是PFS有利的独立预后因素。治疗方法影响OS的单因素分层分析显示:B组患者单纯化疗(19例)和放化疗综合治疗(25例)的5年OS分别为68.1%、61.7%,单纯放射治疗的4例随访期间全部生存(P=0.311);而T组患者单纯化疗(12例)和放化疗综合治疗(17例)的5年OS分别为0、44.1%,单纯放射治疗的3例中2例生存4、10个月后死亡,1例随访60个月生存(P=0.020)。结论:早期鼻咽非霍奇金淋巴瘤病例中,虽然B细胞表型患者的年龄偏大、颈淋巴结受侵比例偏高,其预后却优于NK/T细胞表型患者。后者全身症状多见,单纯化疗的缓解率和生存率较低,在综合治疗中应该更积极配合放射治疗。     

Early locoregional high-dose radiotherapy is associated with long-term disease control in localized primary angiocentric lymphoma of the nose and nasopharynx.

Nasal NK/T cell is a rare form of usually localized non-Hodgkin's lymphoma (NHL) which generally carries a poor prognosis when treated with conventional NHL chemotherapy protocols. We reviewed 20 consecutive localized stage I/II nasal NK/T cell lymphomas treated at our institution over a 29 year period. Median age was 44 (range 23-71). Front-line therapy was generally radiotherapy alone (35-70 Gy) before 1980 and combination chemotherapy after 1980. Six patients were treated with first-line radiotherapy and they achieved complete remission (CR). Two subsequently received combination chemotherapy. Five of those patients remained in complete remission, after 97+ to 277+ months. Twelve patients were treated with first-line chemotherapy including CHOP or CHOP-like regimen in seven cases, and COP in five cases. Only three of them achieved CR, five had partial response and four had progressive disease. Five of the seven patients treated with CHOP did not achieve complete remission. The nine patients who failed to achieve CR with chemotherapy subsequently received salvage radiotherapy but only two of them obtained CR. Finally, two patients were treated with alternated chemotherapy and radiotherapy and achieved CR, which persisted after 14+ and 26+ months. Median survival was not reached in patients who received front-line radiotherapy, and was 35 months in patients who received front-line chemotherapy. These findings confirm that chemotherapy gives a low complete remission rate in localized nasal NK/T cell lymphoma. By contrast, first-line radiotherapy seems to give favorable results, whereas its results are poorer when administered after resistance to chemotherapy. Whether the use of chemotherapy after radiotherapy, or alternated chemotherapy-radiotherapy regimens give better clinical results than radiotherapy alone will have to be evaluated prospectively in this type of NHL.     

恶性血液病患者化疗前后淋巴细胞亚群测定及其意义

 目的 研究恶性血液病患者化疗前后淋巴细胞亚群的变化及其意义。方法 采用流式细胞术对21例急性淋巴细胞白血病（ALL）／非霍奇金淋巴瘤（NHL）患者和23例急性髓系白血病（AML）患者化疗前后淋巴细胞亚群（包括CD+4细胞、CD+8细胞、CD+4／CD+8比值、NK细胞）进行检测。结果 CR组白血病、淋巴瘤的CD+4／CD+8与NK细胞比例均明显高于初诊组和化疗后未缓解组白血病、淋巴瘤（P＜0.05）;CR组ALL／NHL的CD+4／CD+8明显低于CR组AML（P＜0.05）。结论 CD+4／CD+8与NK细胞比例可以作为判断恶性血液病患者病情严重程度和预后的指标,与AML相比,ALL／NHL的细胞免疫功能受损更为严重。     

Interleukin-2 in neuroblastoma: clinical perspectives based on biological studies

Stage IV neuroblastoma (NB) is a disease with a poor prognosis. Chemotherapeutical intensification and hematological rescue with autologous bone marrow transplantation (ABMT) achieve some complete remissions (CR), but most patients relapse during the first year. Immunotherapy could be an alternative in this situation of high risk of relapse due to residual disease and ABMT-related immunodepression. Ten stage IV NB patients in CR or very good partial remission have been treated with recurrent 5-day cycles of high doses of Interleukin-2 (IL2) after ABMT throughout one year (usually 5-6 cycles). Natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic activities, as well as phenotype and number of circulating NK cells were determined, before and after each course of IL2 treatment. The effects promoted by IL2 varied during treatment: early cycles of IL2 induced a great extent of cell expansion, mainly on CD3-/CD16-/CD56+bright and CD8+dim cell phenotypes; conversely, late courses of IL2 promoted higher NK cytotoxic activity but a lesser increase on circulating NK cells. The induction of LAK activity did not significantly differ from early and late IL2 treatments. Clinical results are still inconclusive due to the small number of patients. The median follow-up of patients treated with IL2 is 24 months and the disease free survival (DFS) probability is 0.80 +/- 0.12 vs 0.16 +/- 0.15 from a historical control with identical treatment, but in the absence of IL2 treatment (p < 0.005). IL2 treatment-related toxicity was mild and no interruption of the treatment was required. Extremely accurate hydric control was carried out to avoid, as much as possible, the consequences of vascular leak syndrome, one of the most important toxic effects of IL2 treatment. The results presented here suggest an evolution of NK activity during IL2 treatment after ABMT, which should be taken into account for the designing of new immunotherapeutical protocols and opens a promising perspective in treatment of stage IV neuroblastoma.     

Clinical significance of nm23-H1 proteins expressed on cell surface in non-Hodgkin's lymphoma.

The nm23 gene was isolated as a metastasis suppressor gene that exhibits low expression in high-level metastatic cancer cells. Its gene is related to the prognosis of acute myelogenous leukemia (AML) and non-Hodgkin's lymphoma (NHL). In this study, we examined the expression of nm23-H1 protein on the lymphoma cell surface of NHL. In 28 of 108 cases (25.9%), we observed > or = 20% of cell surface nm23-H1 protein expression and expression was especially high in peripheral T cell lymphomas and extranodal NK/T cell lymphomas. We also observed a significant correlation between serum nm23-H1 level and cell surface nm23-H1 expression levels. In patients with high levels of cell surface nm23-H1 expression, overall and progression-free survival rates were significantly lower than those in patients with low surface nm23-H1 expression levels. When surface nm23-H1 and serum nm23-H1 were combined, patients with high levels of both exhibited a poorer prognosis than patients with a high level of one or the other. These results indicate that in addition to serum nm23-H1, cell surface nm23-H1 may be used as a prognostic factor in planning a treatment strategy. The nm23-H1 protein appears to be intimately related to biological aggressiveness of lymphoma and, therefore, might be a molecular target of NHL treatment.     

Natural killer cytotoxic factor induction by K562 cells in patients with advanced cancer: correlation with production of interferon

Advanced cancer patients were studied for their ability to produce natural killer cytotoxic factor (NKCF). Of 23 patients with advanced epithelial cancers, 8 showed deficient natural killer (NK) activity, as measured in a standard 51Cr release assay. Lymphocytes from these patients did not generate NKCF (nonproducers) in the presence of K562 cells. In addition, 7 other patients whose NK activity was in the normal range did not generate NKCF. Thus the deficiency in NKCF production was only partially correlated with the level of NK activity. Supernatants generated for NKCF were also assayed for antiviral activity. Mean interferon (IFN) titer of supernatants generated from peripheral blood lymphocytes (PBL) of cancer patients was significantly lower than that of supernatants generated by PBL from normal donors. Supernatants from 10 of 15 NKCF nonproducers contained no detectable IFN, whereas the remaining 5 contained up to 100 U IFN. NKCF was never generated in the absence of IFN. The defect in NKCF production by PBL from cancer patients could be corrected by the incubation of effector cells with exogenous IFN-alpha or IFN-alpha inducers, such as other tumor cells or viruses. The relationship among NKCF, IFN, and NK activities is discussed.     

Treatment of T-cell non-hodgkin’ lymphoma

Opinion statement T-cell non-Hodgkin’s lymphoma (NHL) represents approximately 10% to 15% of all lympho-mas in Western countries. Patients with T-cell NHL are often treated similarly to patients with intermediate grade B-cell NHL, although many reports have demonstrated lower overall survival rates in patients with T-cell NHL compared to patients with B-cell NHL. Updated classifications have recognized specific clinical and pathologic T-cell entities, such as peripheral T-cell lymphoma, not otherwise characterized, angioimmunoblastic lymphoma, systemic anaplastic T-cell lymphoma, adult T-cell leukemia/lymphoma, subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal natural killer (NK)/T-cell lymphoma nasal type, and enteropathy-type intestinal T-cell lymphoma. Furthermore, these distinct T-cell NHL subtypes often warrant individual-ized diagnostic and therapeutic strategies, such as the associated cytophagic histiocytic panniculitis and hemophagocytic syndrome with subcutaneous panniculitis-like T-cell lymphoma, the chromosomal translocation t(2;5), leading to the nucleophosmin anaplastic lymphoma kinase fusion protein, viral pathogenesis of Epstein-Barr virus, human T-cell lymphotropic virus type-1 associated with extranodal NK/T-cell lymphoma nasal type and adult T-cell leukemia/lymphoma, respectively, and the role of radiation therapy in extra-nodal NK/T-cell lymphoma nasal type. Other active therapeutic agents in T-cell NHL include purine and pyrimidine antimetabolite agents eg, nucleoside analogues and gemcitabine, respectively), denileukin diftitox, and antinucleoside or retinoic acid with interferon-α combination treatment. The exact role of transplantation in patients with T-cell NHL is unknown, but several case series have documented the feasibility of autologous and allogeneic transplant with reported long-term survival rates similar to transplanted B-cell NHL. Identification of relevant proto-oncogenes and tumor suppressor genes involved in the pathogenesis of T-cell NHL, such as the nucleophosmin anaplastic lymphoma kinase fusion protein, p53 and retinoblastoma gene, cyclin-dependent kinase inhibitors, histone deacetylation inhibitors, and infectious etiologies (eg, Epstein-Barr virus and Helicobacter pylori), in addition to their interplay with the various regulatory pathways of cell-cycle progression and apoptosis, represent potential candidates for molecular-based therapy. Prospective multi-institution clinical trials are critically important to determine the most effective treatment regimens that will continue to improve cure rates in these aggressive, yet treatable and often curable, diseases.     

The relationship of chemotherapeutic and endocrine intervention on natural killer cell activity in human breast cancer

Peripheral blood natural killer (NK) activity against K562 target tumor cells was monitored in patients with breast cancer receiving no treatment, combination chemotherapy, and/or endocrine therapy. NK activity in untreated Stage I patients with no evidence of disease (ned) was significantly higher than in healthy controls. NK activity was shown to decline in individuals with cytotoxic drug therapy (P equals 0.036). There also were reduction in lymphocyte recoveries concomitant with chemotherapeutic intervention (P less than 0.001). Lymphocyte counts were incorporated in a calculation of absolute NK activity that more accurately reflected the significant reduction in NK activity that occurred in patients with localized and systemic disease on chemotherapy. Different chemotherapeutic agents were found to selectively affect NK activity. Stage II patients on phenylalanine mustard (P)/5-fluorouracil (F) (PF) and cyclophosphamide (C)/methotrexate (M)/5-fluorouracil (F) (CMF) protocols showed significant reductions in overall NK activity relative to healthy controls and Stage I patients with ned. Patients on P/doxorubicin (A)/F/tamoxifen (Tx) (PAFT) protocols showed reduced NK activity relative to Stage I patients. Patients on the short-dose C/A (CA) protocol showed normal levels of overall NK activity. High-risk Stage I patients on methotrexate (M)/F (MF)with sequential leucovorin rescue and patients with metastatic disease on endocrine therapy, i.e., Tx or megestrol acetate (Meg) showed overall NK activities in the range of healthy controls. Patients with systemic disease on CMF, CMF/vincristine/prednisone (CMFVP), vinblastine/A/thiotepa/fluoxymesterone (VATH), mitomycin/mitoxantrone (MtMx), and A regimens showed overall levels of absolute NK that were significantly less than either healthy controls or metastatic patients undergoing endocrine therapy. NK cytolytic data, monitored at multiple effector to target ratios, were subjected to exponential regression analysis. The elevation of NK cell responses in Stage I patients with ned and the decline of NK cell responses with cytotoxic chemotherapy were due to alterations in the maximal plateau levels of NK cell cytotoxicity represented by the A (asymptote) values. The k values obtained on regression analysis and indices of the relative killing capacities of individual NK cells remained unaltered in all populations. These results suggest that the cytolytic lymphocyte NK pool, elevated in Stage I patients with cancer, selectively declines as a result of cytotoxic therapy.     

原发鼻腔非霍奇金淋巴瘤的治疗选择和疗效

目的 分析原发鼻腔非霍奇金淋巴瘤（NHL）放疗和化疗的近期疗效以及治疗方法对预后的影响。方法 129例经病理证实的原发鼻腔NHL患者中,经形态学诊断为鼻腔NK／T细胞淋巴瘤者116例。做免疫组化57例,其中52例为NK／T细胞来源,占91．2％;5例为B细胞来源,占8．8％。根据Ann Arbor分期,ⅠE期102例,ⅡE期22例,ⅣE期5例,ⅠE和ⅡE期患者中,单纯放疗22例,单纯化疗7例,综合治疗95例,ⅣE期以化疗为主。结果 5年总生存率（OS）和无病生存率（DFS）分别为68．0％和55．8％,ⅠE期和ⅡE期患者的5年OS分别为71．7％和70．6％（P=0．77）,DFS分别为60．9％和47．0％（P=0．09）。首程治疗后达CR患者的5年OS为83．1％,而未达CR患者的5年OS为18．0％（P=0．000）,相应5年DFS分别为68．0％和15．5％（P=0．000）。124例ⅠE和ⅡE期患者中,67例患者接受单纯放疗或放疗后化疗,放疗后完全缓解率（CR）为74．7％,其余57例为化疗后放疗或单纯化疗,化疗后CR率仅19．3％（P=0．000）,46例化疗后未达CR的患者中,42例仍局限于局部区域,31例经放疗达到CR,ⅠE和ⅡE期患者中,先放疗组（放疗＋化疗或单纯放疗）、化疗后放疗组的5年OS分别为76．0％和74．4％,DFS分别为65．0％和56．2％（P〉0．05）,ⅠE和ⅡE期单纯化疗7例,3例存活,4例死亡,中位生存时间15个月,1年生存率为26．7％。结论 中国人原发鼻腔NHL主要为NK／T细胞来源,放疗的近期疗效显著优于化疗,化疗加入放疗并未改善生存率,ⅠE和ⅡE期患者应以放射治疗为主要治疗手段。     

Significance of cytotoxic activity of peripheral blood lymphocytes against autologous tumor cells in patients with bladder cancer

Cell-mediated immunity is an important and central mechanism of host resistance to cancer. Most reported studies have used cultured tumor cell lines as targets to assess antitumor cell-mediated cytotoxicity. However, it is difficult to translate the data generated from the cytotoxic activity against cultured tumor cell lines to cytotoxicity against autologous tumors. In a recent study, we have reported on the prognostic significance of circulating cytotoxic lymphocytes against autologous tumor cells in patients with bladder cancer. In this study, we examined whether established bladder cancer cell line like T24 or NK-sensitive K562 target cells can be substituted for autologous bladder cancer cells. The cytotoxic activity of peripheral blood lymphocytes (PBL) against freshly isolated autologous tumor cells, the T24 human bladder cancer cell line and the NK-sensitive K562 human myelogenous leukemia cell line was studied in 63 patients with primary initial bladder cancer by a 12-h 51Cr release assay. The mean percent cytotoxic activity of PBL directed against autologous tumor cells, T24 cells and K562 cells were 11.3%, 18.2% and 29.4%, respectively, using an E:T of 40:1. The cytotoxic activity against T24 cells in patients with bladder cancer was higher than that in normal individuals. The anti-K562 and the anti-T24 cytotoxic activities in patients with low-stage or low-grade bladder cancer were relatively higher than those in patients with high-stage or high-grade cancer, but not statistically significant. There was no correlation between the anti-autologous tumor cytotoxic activity and either the histologic grade or stage in patients with bladder cancer. The extent of the anti-autologous tumor cytotoxic activity was not paralleled with that of either the anti-K562 or the anti-T24 cytotoxic activity. In contrast, the anti-K562 cytotoxic activity correlated positively with the anti-T24 cytotoxic activity. Separation of PBL revealed that the anti-K562 and the anti-T24 cytotoxic activities were mediated mainly by the NK cells, whereas the anti-autologous tumor cytotoxic activity was mediated by both the NK cells and the T lymphocytes. These findings demonstrate that cytotoxicity against T24 or K562 cells is not of prognostic value. The magnitude of the anti-autologous tumor cytotoxic activity of PBL derived from bladder cancer patients might represent an independent and important immunological parameter to monitor disease progression.     

In vivo augmentation of natural killer cell activity with a deoxyribonucleic acid fraction of BCG

A fraction extracted from BCG and designated MY-1, which was composed of 70.0% DNA and 28.0% RNA, was previously reported to possess strong antitumor activities against various syngeneic mouse and guinea pig tumors. An intraperitoneal injection of MY-1 (100 micrograms) 1 day before rendered mouse peritoneal cells cytotoxic to YAC-1 cells. The effector cells were nonadherent to plastic dishes, and the activity was destroyed by treatment with anti-asialo GM1 antiserum plus complement or carrageenan in vitro, but not with carbonyl-iron or anti-Thy 1.2, suggesting that the cells are natural killer (NK) cells. In vivo augmentation of NK activity was dependent on MY-1 dose, and reached the peak 1 day after MY-1 injection. Since NK activity in lipopolysaccharide (LPS)-nonresponder mice could be augmented by MY-1, the possibility that LPS contaminated the MY-1-augmented NK was excluded. MY-1 digested preliminarily with DNase lost its NK-inducing activity, suggesting that the DNA entity of MY-1 was essential for the activity. When mice were pretreated with anti-asialo GM1 or carrageenan, MY-1 could not render the peritoneal cells cytotoxic. Antitumor activities of MY-1 were also abolished if the animals were pretreated with anti-asialo GM1 antiserum or carrageenan, suggesting that the activities can be ascribed mainly to activated NK cells.     

非霍奇金淋巴瘤1012例临床病理分析

目的:了解我院近10年来非霍奇金淋巴瘤(NHL)的发病特点,分析影响NHL预后的相关因素.方法:回顾性分析了近10年来我院收治的1012例NHL患者的临床病理特点,对影响新疆地区NHL生存率及预后的临床病理因素进行分析.结果:1012例NHL中以40～60岁汉族男性发病多见,最主要病理类型依次为弥漫性大B细胞淋巴瘤(DLBCL)346例(34.1%),外周T细胞淋巴瘤(PTCL)185例(18.3%),滤泡淋巴瘤(FL)97例(9.6%),黏膜相关淋巴组织淋巴瘤(MALT)94例(9.3%),NK/T细胞淋巴瘤62例(6.1%),T-淋巴母细胞淋巴瘤(T-LBL)47例(4.6%).结性起病的淋巴瘤619例(61.2%),结外起病的淋巴瘤393例(38.8%).本组维吾尔族女性FL淋巴瘤患者人数比例较汉族女性患者高(P=0.002),汉族男性PTCL患者人数比例高于维吾尔族男性患者(P=0.015).5年总生存率为45.8%.单因素分析显示临床分期,行为状态评分(PS),B症状,年龄,肿块大小,血清乳酸脱氢酶(LDH),结外器官受侵数目及IPI是NHL的预后因素(P＜0.05).多因素分析提示T细胞来源,Ⅲ～Ⅳ临床分期,IPI评分3～5分及LDH增高是NHL独立的预后不良因素(P＜0.05).结论:新疆地区NHL发病以中年多见,结性起病者多于结外起病,B细胞淋巴瘤多于T细胞淋巴瘤.免疫分型、临床分期、IPI、血清LDH水平与NHL预后相关.     

HNK-1+ cells in non-Hodgkin's lymphoma: lack of relation with transferrin receptor expression on malignant cells

It has been proposed that Natural Killer (NK) cell activity is involved in host defence against neoplasia, and that NK cells react with or recognize the transferrin receptor (TrR) on target cells. HNK-1 expression has been related to NK cell function. Therefore, in 118 cases of non-Hodgkin's lymphoma (NHL) we studied the occurrence and distribution of HNK-1+ cells by immunohistochemistry, and simultaneously assessed the expression of TrR on malignant cells. In NHL of intermediate or high grade malignancy there was uniform expression of TrR on malignant cells. In low grade malignancy NHL, only lymphocytic and lymphoplasmacytoid lymphomas were TrR negative, except for faint staining of proliferation centres. In 23 cases of follicular lymphoma, 9 showed the absence of HNK-1+ cells in neoplastic follicles. In 16/23 cases HNK-1+ cells were present around follicles or in interfollicular areas: 8 of these cases revealed a higher density of HNK-1+ cells at this site than inside the follicles. In 22/26 cases with high grade malignancy NHL, HNK-1+ cells were absent or present in small density, which is different from the presence in higher density in low grade malignancy NHL. We conclude that (i) TrR expression on NHL cells is not obligatory related with histological class or malignancy grade of the tumour, and that (ii) HNK-1+ cells are not universally present in areas of malignant cells, in particular in follicular lymphoma and in NHL of high grade malignancy.     

129例原发鼻腔非霍奇金淋巴瘤的预后分析

背景与目的：原发鼻腔非霍奇金淋巴瘤（non-Hodgkin’s lymphoma,NHL）预后较差．远处转移和局部复发率均较高．目前本病尚无标准治疗原则。本研究主要探讨影响原发鼻腔NHL的预后因素。方法：1996年1月至2002年12月共收治129例经病理证实的原发鼻腔NHL。116例经病理形态学诊断为鼻腔NK／T细胞淋巴瘤。根据Ann Arbor分期,ⅠE期102例,ⅡE期22例,ⅣE期5例。124例ⅠE／ⅡE期患者单纯放疗22例,单纯化疗7例,45例放疗后化疗,50例化疗后放疗。5例ⅣE期以化疗为主。结果：全组5年总生存率（overall survival,OS）和无病生存率（disease-freely survival,DFS）分别是68．0％和55．8％。ⅠE期和ⅡE期患者的5年OS分别是71．7％和70．6％（P=0．77）,DFS分别是60．9％和47．0％（P=0．09）。首程治疗后完全缓解（complete response,CR）的患者5年OS为83．1％,而未达CR患者的5年OS为18．0％（P〈0．01）,相应5年DFS分别为68．0％和15．5％（P〈0．01）。国际预后指数（international prognostic index,IPl）评分为0,1和≥2的5年OS分别为81．1％、60．1％和14．3％（P〈0．01）,DFS分别为68．8％、44．6％和22．5％（P〈0．01）。38例患者治疗中进展或疗后复发,远处结外器官复发占78．9％,是治疗失败主要原因。单因素分析显示,首程治疗后的CR率、一般状态评分（performance status,PS）、IPI和修订后IPI与预后相关。多因素分析显示仅治疗后的CR率是独立预后因素。结论：治疗后的CR率是影响原发鼻腔NHL的重要预后因素,原因以远处病灶治疗失败为主。     

Diffuse large B-cell non-Hodgkin lymphomas: the clinical relevance of histological subclassification

In the REAL classification the diffuse large B-cell non-Hodgkin lymphomas (NHL) are grouped together, because subclassifications are considered to lack both reproducibility and clinical significance. Others, however, claim that patients with an immunoblastic NHL have a worse prognosis than patients with other types of diffuse large B-cell NHL. Therefore, we investigated the prognostic and clinical significance of histological subclassification of diffuse large B-cell NHL in a uniformly treated series of patients. For this retrospective study, all patients diagnosed as having an immunoblastic (IB) B-cell NHL by the Lymphoma Review Panel of the Comprehensive Cancer Center Amsterdam (CCCA) between 1984 and 1994, and treated according to the guidelines of the CCCA, were analysed. Patients with a centroblastic polymorphic subtype (CB-Poly) or centroblastic (CB) NHL by the Lymphoma Review Panel who were treated in the Netherlands Cancer Institute during the same period according to CCCA guidelines were used as reference groups. All patients' records were reviewed. Clinical parameters at presentation, kind of therapy and clinical outcome were recorded. All available histological slides were separately reviewed by two haemato-pathologists. One hundred and seventy-seven patients were included in the study: 36 patients (20.3%) with an IB NHL, 69 patients (39%) with a CB-Poly NHL and 72 patients (40.7%) with a CB NHL. The patients with an IB NHL tended to be older and presented more often with stage I or II and one extranodal site than patients with a CB and CB-Poly NHL. None of the subtypes showed a clear preference for localization in a particular site. The patients with IB or CB-Poly NHL showed a significantly worse prognosis than patients with CB NHL, with a 5-year overall survival for patients with CB NHL of 56.3% and for patients with IB or CB-Poly NHL 39.1% and 41.6% respectively. The 5-year disease free survival was 53.2% for the patients with CB, 32% for the patients with CB-Poly and 26.9% for the patients with IB NHL. A multivariate analysis showed that histological subtyping was of prognostic significance independent of the International Prognostic Index. This finding merits further exploration in prospective studies in order to judge the value of subclassification of large B-cell NHL as a guideline in therapy choice.     

What signals are generated by anti-CD20 antibody therapy?

Immunotherapy with rituximab (a chimeric anti-CD20 monoclonal antibody), alone or in combination with chemotherapy, has improved the treatment outcome of patients with non-Hodgkin’s lymphoma (NHL), but the in vivo mechanisms by which rituximab exerts its effects have not been elucidated. The mechanisms underlying resistance are not known. In addition to the proposed actions mediated by rituximab (such as complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and apoptosis), rituximab may signal the tumor cells and inhibit constitutively activated survival signaling pathways (Raf-1-MEK1/2-ERK1/2, p38 MAPK, NF-κB, and Akt), resulting in inhibition of cell growth and of selectively anti-apoptotic gene products such as Bcl-2 and Bcl-_xL. The inhibition of these anti-apoptotic gene products by rituximab sensitizes drug-resistant tumor cells to apoptosis induced by a variety of cytotoxic chemotherapeutic drugs. Also, rituximab sensitizes NHL cells to apoptosis resulting from upregulation of death receptors, implicating a novel in vivo role of host involvement in rituximab-mediated effects. We have developed rituximab-resistant clones that do not respond to rituximab-mediated cell signaling. The clones exhibited hyperactivated cell survival pathways and overexpression of anti-apoptotic gene products and could not be chemosensitized by rituximab. Inhibitors of the survival signaling pathways reverse drug resistance in both wildtype cells and resistant clones. These findings identify several novel intracellular pathways modifyed by rituximab that sensitize NHL cells to both chemotherapy and immunotherapy, as well as several therapeutic targets whose modifications reverse resistance. These findings have clinical relevance for both prognosis and novel treatment strategies for patients with NHL.     

Treatment of primary progressive Hodgkin's and aggressive non-Hodgkin's lymphoma: is there a chance for cure?

PURPOSE: To determine differences in prognosis between primary progressive Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL), we retrospectively analyzed patients with progressive lymphoma who were treated with different salvage chemotherapy regimens including high-dose chemotherapy (HDCT) followed by autologous stem-cell support (ASCT). PATIENTS AND METHODS: One hundred thirty-one patients with primary progressive lymphoma (HD, n = 67; NHL, n = 64) were enrolled. Primary progressive disease was defined as disease progression during first-line chemotherapy or only transient response (complete or partial response lasting 相似文献   

Adult onset hemophagocytic lymphohistiocytosis prognosis is affected by underlying disease and coexisting viral infection: analysis of a single institution series of 35 patients

Adult onset hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome, which can develop as a complication of many disorders. Early diagnosis is essential in order to avoid a fatal outcome. To confirm the diagnosis of acquired HLH made in a single institution series of adult patients with HLH‐04 criteria, we applied the HScore and evaluated prognostic factors associated with clinical outcome. The median age of 35 patients was 54 (range 17–81), M/F ratio was 20/15. In 26/35 (74.3%) patients, an underlying haematological disease was present (2 Multicentric Castleman Disease, 10 B‐cell Non‐Hodgkin Lymphoma [NHL] and 14 T/NK‐cell NHL); an autoimmune disorder was observed in four (11.4%) patients (one Still Disease, one undifferentiated connective tissue disease and two haemolytic anaemia); in five (14.3%), no underlying disease was identified. A concomitant infection by EBV was observed in 10 patients (28.6%), CMV in 8 (22.9%), HHV8 in 6 (17.1%) and HIV in 1 (2.9%). Hyperferritinemia, fever and splenomegaly were present in more than 90% of patients, whereas bone marrow hemophagocytosis in 51% of cases only. According to HScore, 34/35 patients had a >75% and 32/35 >93% probability of HLH. Four‐year overall survival and HLH‐free survival were 17.8% (CI 1.9–33.8) and 23.8% (CI 7.3–40.3), respectively. By multivariate analysis, presence of oedema and hyperbilirubinemia were predictors of death, whereas there was a statistically significant trend for viral infection as predictor of poor prognosis. B‐NHL diagnosis was confirmed as associated to a better prognosis in comparison with T/NK lymphoma (4‐year HFS 53.3% vs. 0%, p = 0.09) and similar to other aetiologies. Copyright © 2016 John Wiley & Sons, Ltd.     

Release of natural killer cytotoxic factor in patients with lymphoproliferative disease of granular lymphocytes

To further investigate the mechanisms accounting for defective natural killer (NK) activity observed in the majority of patients with lymphoproliferative disease of granular lymphocytes (LDGL), we have studied the generation of natural killer cytotoxic factor (NKCF) from peripheral blood lymphocytes recovered from twelve LDGL patients. On the basis of their cytotoxic activity against the K-562 target cells, cases under study were separated in two groups. Cells from five patients, referred to as NK+, were found to exhibit high levels of NK-cell mediated cytotoxicity; cells from seven patients, referred to as NK-, despite their ability to bind to the K-562 targets, displayed a defective NK function. The coculture of cells from NK+ patients with NK sensitive K-562 cells triggered a significantly higher production of NKCF with respect to NK- patients (p less than 0.001 at 1:2 dilution). Using phytohemagglutinin (PHA) as the NKCF stimulator, differences between the groups were not significant, due to a recovery of NKCF generation in NK- patients. Furthermore, a consistent lectin (PHA) dependent cellular cytotoxicity (LDCC) was exhibited by both groups of patients. The addition of gamma-interferon (IFN-gamma) or interleukin-2 (IL-2) during NKCF generation did not significantly modify the production of this factor. Our data point out that (a) NKCF is involved in the lytic activity of LDGL patients' cells, (b) a constitutional impairment in the generation of NKCF is not present in NK- patients, since recovery of lytic function occurs after PHA stimulation, and (c) IL-2 and IFN-gamma do not play a relevant role in triggering NKCF production when added during the generation of this factor. These studies help to clarify the factors involved in the cytotoxic machinery of LDGL patients' cells, suggesting that the defect of the cytotoxic function observed in some LDGL patients could lie at the level of target recognition.