77例T细胞非霍奇金淋巴瘤的临床病理特点和免疫表型分析

目的探讨T细胞非霍奇金淋巴瘤的临床病理特点和免疫表型。方法对77例T细胞非霍奇金淋巴瘤进行苏木素和伊红染色(HE)和免疫组织化学检查,按WHO 2008年《造血和淋巴组织肿瘤的病理学和遗传学》标准进行分类。结果 77例T细胞非霍奇金淋巴瘤中,鼻型结外NK/T细胞淋巴瘤32例(41.6%),非特异性外周T细胞淋巴瘤20例(26.0%),间变性大细胞淋巴瘤11例(14.3%),前驱T淋巴细胞淋巴瘤9例(11.7%)。结论 T细胞非霍奇金淋巴瘤中,最常发生的亚型是鼻型结外NK/T细胞淋巴瘤,其次为非特异性外周T细胞淋巴瘤、间变性大细胞淋巴瘤和前驱T淋巴细胞淋巴瘤。其中,鼻型结外NK/T细胞淋巴瘤预后较差,而间变性大细胞淋巴瘤预后相对较好。     

The clinicopathologic features and immunophenotypes of T-cell non-Hodgkin's lymphoma: an analysis of 77 cases

目的 探讨T细胞非霍奇金淋巴瘤的临床病理特点和免疫表型.方法 对77例T细胞非霍奇金淋巴瘤进行苏木素和伊红染色(HE)和免疫组织化学检查,按WHO 2008年《造血和淋巴 组织肿瘤的病理学和遗传学》标准进行分类.结果 77例T细胞非霍奇金淋巴瘤中,鼻型结外NK/T细胞淋巴瘤32例(41.6％),非特异性外周T细胞淋巴瘤20例(26.0％),间变性大细胞淋巴瘤11例(14.3％),前驱T淋巴细胞淋巴瘤9例(11.7％).结论 T细胞非霍奇金淋巴瘤中,最常发生的亚型是鼻型结外NK/T细胞淋巴瘤,其次为非特异性外周T细胞淋巴瘤、间变性大细胞淋巴瘤和前驱T淋巴细胞淋巴瘤.其中,鼻型结外NK/T细胞淋巴瘤预后较差,而间变性大细胞淋巴瘤预后相对 较好.     

CD56在非霍奇金淋巴瘤中的表达和意义

目的探讨CD56在非霍奇金淋巴瘤中NK/T细胞淋巴瘤的表达和意义。方法应用组织形态学及免疫组织化学分析对29例我院既往诊断的恶性淋巴瘤组织进行HE、PSA染色,同时作CD56的免疫表型分析。结果10例弥漫性大B淋巴瘤和6例外周T细胞淋巴瘤肿瘤细胞CD56表达均阴性,12例NK/T细胞淋巴瘤CD56表达阳性,1例NK/T细胞淋巴瘤可疑。结论CD56可作为非霍奇金淋巴瘤中NK/T细胞淋巴瘤分类鉴别的重要指标。     

高强度化疗治疗T淋巴母细胞淋巴瘤完全缓解后合并急性单核细胞白血病1例

淋巴母细胞淋巴瘤（1ymphoblastic lymphoma,LBL）是一种少见的,来源于不成熟的前体淋巴细胞的高度侵袭性的肿瘤,约占非霍奇金淋巴瘤（Non—HodgkinLymphomas,NHL）的2％～8．5％。在WHO分类中LBL被认为是前体B／T细胞肿瘤,是急性淋巴细胞白血病（ALL）的淋巴结或结外表现,其中约80％为T细胞表型,     

非霍奇金淋巴瘤细胞白血病的免疫表型

选用抗人白细胞分化抗原单克隆抗体，采用ＡＰＡＡＰ桥联免疫酶标染色方法分析１４例非霍奇金淋巴瘤细胞白血病免疫表型。结果表明：１０例起源于Ｔ淋巴细胞（７１．４％），其中６例为早期胸腺细胞；４例起源于Ｂ淋巴细胞（２８．６％），其中３例为成熟Ｂ细胞。免疫表型分析具有判断预后价值。     

非霍奇金淋巴瘤100例病理形态和免疫表型的观察

目的 根据WHO(2001年)淋巴瘤的新分类,对贵州省部分以往诊断的非霍奇金淋巴瘤(Non-Hodgkin's Lymphoma)重新进行形态学和免疫表型研究并分类,以探讨新的WHO分类在我省淋巴瘤分类中的适应性.方法 应用组织形态学观察及免疫组织化学分析对100例以往诊断的恶性淋巴瘤组织重新诊断分型,并根据新的WHO分类进行分类和回顾性分析.结果 100例NHL,B-NHL55例(55%),T-NHL44例(44%),有1例未明确诊断(1%).根据新的WHO分类,在B-NHL中,以弥漫性大B细胞性淋巴瘤(DLBCL)居多,共27例(47.2%).CD20表达94.5%(52/55).未能进一步分类3例(5.5%).在T-NHL,以外周T细胞淋巴瘤(PTCL)居多,共17例(38.6%),其次NK/T细胞淋巴瘤(NK/TCL)13例(29.5%).CD45RO表达86.3%(38/44).单纯HE染色的诊断结果符合率达78%,结合免疫组化符合率达96%.非霍奇金淋巴瘤Ki-67增值指数平均率为73.7%.结论 在病理形态的基础上,结合免疫表型,非霍奇金淋巴瘤绝大多数可明确诊断.WHO关于非霍奇金淋巴瘤的新分类是较为统一而又明确的分类方案,具有较强的实用性.     

B小细胞淋巴瘤患者化疗期间自尊及生活质量相关性研究

恶性淋巴瘤包括霍奇金淋巴瘤和非霍奇金淋巴瘤[1],非霍奇金淋巴瘤绝大多数为B细胞来源[2].由于肿瘤对机体的影响及化疗对机体的副作用,患者较易形成一系列的异常心理状态,常表现为不同程度的负性情绪,继而引起自尊及生活质量的改变.本研究通过对89例B小细胞淋巴瘤化疗患者自尊及生活质量进行调查,探讨其临床意义,旨在为临床合理治疗及干预提供理论依据.     

肠病型T细胞淋巴瘤(附6例报告)

目的探讨肠病型T细胞淋巴瘤的临床病理特征、免疫表型及鉴别诊断要点。方法对6例肠病型T细胞淋巴瘤复习其临床资料,并行病理学检查、免疫组化染色及结合文献进行分析。结果6例均诊断为非霍奇金淋巴瘤T细胞型,其中2例为中大细胞型,4例为小细胞型。结论肠道T细胞淋巴瘤较少见,尤其是中大细胞型T细胞淋巴瘤,其临床病理表现较特殊,预后差,可能与EB病毒密切相关,临床诊断较困难,其诊断和鉴别诊断主要依靠病理组织学及免疫组织化学。     

1例睾丸非霍奇金淋巴瘤病理诊断及鉴别诊断特点(附文献复习)

目的:分析1例睾丸非霍奇金淋巴瘤,了解本病病理诊断和鉴别诊断特点。方法:完善患者临床资料,描述肿瘤光学显微镜下病理特点,辅助特征性免疫组化标记检测,复习相关文献后做出临床病理诊断。结果:该患者门诊拟诊右侧睾丸炎收治入院,单侧睾丸全切术后,进行病理诊断,根据镜下特点及免疫组化标记,诊断为睾丸非霍奇金淋巴瘤弥漫大B细胞型。结论:睾丸非霍奇金淋巴瘤弥漫大B细胞型在临床上较少见,预后差,易误诊。     

循环DNA中TP53基因多态性与非霍奇金淋巴瘤的关系研究

目的探讨和研究循环DNA中TP53基因多态性与非霍奇金淋巴瘤的关系。方法施行PCR-单链构象多态性分析法(PCR-SSCP对所选取的45例非霍奇金淋巴瘤组织进行TP53基因外显子5～8的多态性测验:①检测TP53基因多态性的方法 :施行PCR-单链构象多态性分析法(PCR-SSCP)对所选取的45例非霍奇金淋巴瘤组织进行TP53基因外显子5～8的多态性测验,扩增后形成的产物可以通过单链构象多态性分析(SSCP)的方式进行分析和研究。②成像研究方法 :运用全自动凝胶成像系统进行分析和研究。结果 TP53基因发生突变的具体情况:在45例非霍奇金淋巴瘤患者中,其中有20例患者的TP53基因组的DNA具有异常迁移率带,这充分显示出这类肿瘤很可能具有TP53基因多态性,总多态率为56.3%。其中按照肿瘤组织细胞源头进行分组:B细胞组与T-NK细胞组的多态率分别为57.4%、36.8%,二者之间进行差异比较,结果均没有统计学意义(P>0.05);按照肿瘤生物学行为进行分组:侵袭性、惰性组以及高侵袭性组之间进行差异比较,结果均有统计学意义(P<0.05)。结论 TP53基因多态性存在于非霍奇金淋巴瘤中,TP53基因的多态性在非霍奇金淋巴瘤的发展过程中起着非常重要的作用。     

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Immunotoxins do not only bind to cancer-specific receptors to mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. The plant glycoside SO1861 was previously reported to enhance the endolysosomal escape of antibody-toxin conjugates in non-hematopoietic cells, thus increasing their cytotoxicity manifold. Here we tested this technology for the first time in a lymphoma in vivo model. First, the therapeutic CD20 antibody obinutuzumab was chemically conjugated to the ribosome-inactivating protein dianthin. The cytotoxicity of obinutuzumab-dianthin (ObiDi) was evaluated on human B-lymphocyte Burkitt’s lymphoma Raji cells and compared to human T-cell leukemia off-target Jurkat cells. When tested in combination with SO1861, the cytotoxicity for target cells was 131-fold greater than for off-target cells. In vivo imaging in a xenograft model of B-cell lymphoma in mice revealed that ObiDi/SO1861 efficiently prevents tumor growth (51.4% response rate) compared to the monotherapy with ObiDi (25.9%) and non-conjugated obinutuzumab (20.7%). The reduction of tumor volume and overall survival was also improved. Taken together, our results substantially contribute to the development of a combination therapy with SO1861 as a platform technology to enhance the efficacy of therapeutic antibody-toxin conjugates in lymphoma and leukemia.     

Antiangiogenic therapies in non-Hodgkin's lymphoma

The tumor microenvironment is critical in the initiation and progression of cancerous growth, which is dependent on the establishment of a functional vascular network supporting neoplastic proliferation. While the precise role of tumor angiogenesis in lymphoma pathogenesis remains under active investigation, emerging data on the proangiogenic properties of the neoplastic lymphoma cells and mechanism of vascular assembly suggest that angiogenesis is highly relevant to the biology and therapy of non-Hodgkin's lymphoma. Antiangiogenic therapies in non-Hodgkin's lymphoma are in various stages of clinical development aiming at distinct angiogenic pathways operative in endothelial cells and perivascular stromal cells. The major classes of available antiangiogenics include anti-VEGF, small molecule inhibitors targeting proangiogenic receptor tyrosine kinases and their downstream signal transduction pathways, as well as immunomodulatory compounds with antiangiogenic properties. Preliminary clinical data indicate therapeutic advantages associated with strategies targeting dual compartments of vascular cells and tumor cells, as well as multiple angiogenic pathways within the tumor microenvironment. This review summarizes recent applications of antiangiogenic strategies in non-Hodgkin's lymphoma based on current understanding of the biology of lymphoma angiogenesis.     

CpG oligodeoxynucleotide-induced immunity prevents growth of germinal center-derived B lymphoma cells

Therapeutic efficacy of CpG oligodeoxynucleotide (ODN) ISS 1018 was tested in a murine B cell lymphoma model. Previous studies showed that the B lymphoma cells of SJL mice stimulate vigorous proliferation of host CD4(+) TH cells that is unaccompanied by development of tumor-specific CTL. In the presence of ISS 1018, however, tumor cells stimulated high levels of CTL activity in vitro, and this cytotoxic activity was inhibited when anti-IL-12 mAb was added to the cultures. Tumor cells pre-incubated with ISS 1018 were also able to generate CTL without addition of exogenous ODN, and FACS analysis revealed that following incubation with ISS 1018 for 24 h, tumor cells exhibited upregulation of MHC I, MHC II, and co-stimulatory molecule CD80. Finally, tumor-injected mice treated with ISS 1018 showed significantly less growth of tumor cells in lymph nodes and spleen, and exhibited prolonged survival compared to mice treated with a control ODN. The documented effects of CpG ODNs to stimulate cytokines, such as IL-12, from antigen presenting cells, and to upregulate expression of MHC Class I and Class II, as well as co-stimulatory molecules on tumor cells, are also the likely mechanisms by which CTL are generated by ISS 1018 in the SJL B cell lymphoma model.     

Tumor senescence as a determinant of drug response in vivo.

It has become apparent in the last few years that induction of apoptosis is insufficient to account for the therapeutic effect of anticancer agents. Chemotherapy and radiation induce two other antiproliferative responses in tumor cells, cell death through mitotic catastrophe and terminal growth arrest through the program of senescence. Different types of tumor cells were found to develop the senescent phenotype upon drug treatment in vitro and in vivo. Cell culture studies demonstrated that this phenotype marks tumor cells that survive drug exposure but lose the ability to proliferate, and that such cells activate multiple growth-inhibitory genes. A recent study demonstrated that senescence, along with apoptosis, is a key determinant of in vivo response to chemotherapy in a transgenic mouse model of B-cell lymphoma. This review discusses the results of the latter study, as well as the differences between the genetic determinants of treatment-induced senescence in murine lymphoma and in human solid tumor cells.     

环磷酰胺作用B细胞非霍奇金淋巴瘤对抑癌基因PTEN的影响

目的 探索环磷酰胺作用非霍奇金淋巴瘤对抑癌基因PTEN的影响,为治疗B细胞非霍奇金淋巴瘤寻找新治疗途径提供实验依据.方法 免疫沉淀(IP)技术提取细胞中的PTEN蛋白,采用高效液相色谱(HPLC)法分别检测不同时间(10、30、60min)不同浓度的环磷酰胺(0、25、50 μmol·L-1)作用Namalwa细胞株时PTEN基因的活性;Western-blot技术检测PTEN,磷酸化PTEN,Akt及磷酸化Akt的表达;基因芯片技术筛选环磷酰胺作用Namalwa细胞后基因表达谱的改变;q-PCR技术检验基因谱表达的改变.结果 不同浓度的环磷酰胺作用Namalwa细胞后PTEN活性降低;Western-blot结果显出磷酸化PTEN及磷酸化Akt表达降低;基因芯片筛选发现上调的基因有13个,下调的基因有16个.环磷酰胺作用B细胞非霍奇金淋巴瘤Namalwa细胞后引起基因表达谱广泛改变.对差异基因的分析得出环磷酰胺作用Namalwa细胞引起基因表达谱重要信号通路上基因的改变.结论 环磷酰胺治疗B细胞非霍奇金淋巴瘤具有较低的缓解率,可能与环磷酰胺作用细胞使PTEN基因活性减弱,同时引起信号通路上基因表达改变有关.     

Effect of high cell density on the growth properties of tumor cells: a role in tumor cytotoxicity of chemotherapeutic drugs

The aim of this study was to understand the role of tumor progression in the growth properties of tumor cells and their susceptibility to the cytotoxicity of chemotherapeutic drugs. A murine transplantable T cell lymphoma of spontaneous origin, designated as Dalton's lymphoma, was used as a model tumor for this investigation. Tumor cells were harvested from the early (5 days after tumor transplantation) and late tumor-bearing stages (17 days after tumor transplantation), with or without in-vivo administration of the chemotherapeutic drugs, cisplatin or doxorubicin. Tumor cells harvested at the late tumor-bearing stages showed a higher proliferative ability in vitro. Tumor progression was found to be associated with a decline in the tumor cytotoxicity of the chemotherapeutic drugs. Similar results were also obtained when tumor cells were cultured at low (10(5) cells/ml) and high (10(9) cells/ml) cell densities in vitro in medium alone or in one containing the chemotherapeutic drugs. An increase in the expression of heat shock protein (Hsp70), vascular endothelial growth factor, interleukin-2 receptor and interleukin-2 proteins along with an inhibition in the expression of caspase-activated DNase and p53 proteins was observed during the late tumor-bearing stage and also in the Dalton's lymphoma cells when cultured in vitro at a higher cell density. The ascitic fluid obtained from the late tumor-bearing stage and the culture supernatant of tumor cells incubated in vitro at high cell density showed high levels of cell growth-regulating cytokines: interleukin-1, interleukin-2, interferon-gamma, vascular endothelial growth factor, tumor growth factor-beta and interleukin-10. In-vivo administration of cisplatin in tumor-bearing mice at the late tumor-bearing stage did not alter the level of these cytokines in the ascitic fluid. In view of the results of this investigation, it is suggested that under high cellular density-associated environmental conditions the tumor cells alter their growth properties depending on an alteration in the expression of cell growth and apoptosis-regulating proteins. Tumor cells, thus, switch to a high level of proliferation, which renders them resistant to the cytotoxicity of chemotherapeutic drugs.     

Cell density-dependent alterations in tumorigenic potential of a murine T-cell lymphoma: implication in the evolution of multidrug resistance in tumor cells

We have previously demonstrated that cells of murine T-cell lymphoma, when grown in vivo or in vitro in an environment of high cell density, undergo phenotypic alterations, providing them with survival benefits. However, it is unclear whether the acquisition of such growth-related phenotypic alterations is inheritable in successive cell generations and if these alterations are associated with an irreversible alteration in their tumorigenic ability and evolution of multidrug resistance. To investigate this, tumor cells of a murine model of a T-cell lymphoma, designated as Dalton's lymphoma, and obtained from high and low cell density environment in vitro and in vivo, were transplanted in mice with or without the administration of anticancer drugs followed by analysis of their phenotypic properties and tumorigenic potential as measured by kinetics of tumor growth and survival of the tumor-bearing host. Kinetics of tumor progression was comparatively rapid in tumor-bearing mice transplanted with tumor cells from a high cell density environment, causing an early death of the host. Moreover, under these conditions the antitumor response of anticancer drugs, cisplatin, doxorubicin, and methotrexate, was found to be less effective compared with mice transplanted with tumor cells from a low cell density environment. The tumor cells from a high cell density source showed a long-term alteration in their survival properties both in vitro and in vivo, indicating that such alterations were sustainable over successive cell cycles. The study also discusses the possible mechanisms indicating the role of MDR1, Hsp70 and 90, Bcl-2, IL-1, IL-6, IL-10, IFNgamma, and TGFbeta in the evolution of multidrug resistance in tumor cells obtained from a high cell density environment.     

Effective immunotherapy with local low doses of interleukin-2.

IL-2 treatment for metastatic tumors in man is usually given systemically with high doses, often in conjunction with large numbers of LAK-cells. Complete tumor regression is obtained in less than 10%, this treatment causes severe toxicity, and culturing of LAK-cells is laborious and expensive. In this paper we demonstrate that small amounts of locally applied rIL-2 alone, if given at the right time, can cure about 70% of DBA/2 mice with large metastasized syngeneic SL2 lymphoma comprising 4-10% of the total body weight, a tumor load hitherto considered fatal. Moreover, 3 out of 5 cows with ocular squamous cell carcinoma (BOSCC) of 1 x 1 up to 3 x 4 cm were cured with low doses of rIL-2 only. Taken together, we have now tested 11 tumors in animals. No antitumor effect was observed in EL4 lymphoma in C57BL mice. Partial antitumor effects were detected in RBL5 lymphoma in C57BL mice, stomach carcinoma in BALB/c mice, MOT-carcinoma in C3H mice, liver carcinoma in guinea pigs and bovine vulval papilloma/carcinoma. Complete tumor regression was obtained in SL2 lymphoma, L5178Y lymphoma, L1210 lymphoma, and P815 mastocytoma in DBA/2 mice and in bovine ocular squamous cell carcinoma. Low doses of locally injected IL-2 induce systemic immunity, as shown in DBA/2 mice bearing syngeneic SL2 lymphoma cells. We conclude that local low dose treatment can be effective and results in a high cure rate in several tumor models. In the DBA/2-SL2 lymphoma model this treatment is 100-1000 times more effective than any form of immunotherapy we have tested during 20 years in this model.(ABSTRACT TRUNCATED AT 250 WORDS)     

单细胞测序技术及其在结直肠癌中的应用

单细胞测序是一种新兴测序技术,能够对单个细胞的基因组、转录组和表观组进行分析。基于单细胞测 序探索结直肠癌中不同的分子和临床病理特征,可以揭示结直肠癌中存在的肿瘤内异质性,同时为结直肠癌的早期 诊断、治疗和预后分析提供新的思路。对单细胞测序技术及其在结直肠癌中的应用进展进行综述,为鉴定结直肠癌 预后标志物、寻找新的治疗靶点和个性化治疗方案提供参考。     

Nasal NK/T-cell lymphoma causing diagnostic difficulties

We present history, clinical presentation and anatomo-pathologic findings of a 24-year-old female patient with a nasal NK/T-cell lymphoma. This rare tumor is characterized by its angiocentric and angiodestructive growth, which results in extensive tumor necrosis. At the first encounter this tumor necrosis made it difficult to identify the nature of the tumor cells. However, this necrosis is a key feature: it is the result of the capacity of neoplastic NK/T-cells to invade vessels. The T-cell character of the neoplastic lymphoid has been shown by immunohistochemitry.