Managing Patients with Cutaneous B-Cell and T-Cell Lymphomas Other Than Mycosis Fungoides

Cutaneous lymphomas (CL) are a heterogeneous group of neoplasms characterized with clinical and histopathological variation, as well as overlap with benign dermatoses. Diagnosis and treatment of CLs is challenging and often requires a multidisciplinary approach. However, prognostic knowledge of these conditions and awareness of treatment options can help optimize appropriate use of available regimens, thereby improving care for patients. Here, we review the most recent literature and outline treatment themes for managing patients with cutaneous B-cell and T-cell lymphomas other than mycosis fungoides.     

趋化因子受体CCR7在T细胞淋巴瘤播散中的作用

目的：探讨趋化因子受体CCR7在T细胞淋巴瘤播散中的作用; 旨在为T细胞淋巴瘤靶点治疗的新方向提供一定的实验基础及理论依据。方法： 皮肤T细胞淋巴瘤Hut78和成人T淋巴细胞白血病/淋巴瘤Jurkat细胞株培养, 通过Transwell小室检测了细胞体外侵袭能力并进行比较; 通过RT-PCR和Western-blot技术对两种细胞株的CCR7和PI3K/Akt信号转导通路的表达进行了检测。结果： 1） Hut78细胞体外侵袭能力较强; 两种T细胞淋巴瘤细胞经过CCL21共培养后, 侵袭能力均有所增强, 且均呈现与CCL21浓度的正相关趋势; 2） Hut78细胞中CCR7mRNA, PI3KmRNA、 AktmRNA均高于Jurkat细胞, 差异均有显著性 （P<0.001）;CCR7、 pAkt蛋白在Hut78细胞中的表达也明显高于Jurkat细胞 （P<0.05）。结论： T细胞淋巴瘤中高表达的CCR7与肿瘤的侵袭性有关, 可能通过PI K/Akt信号通路促进肿瘤的侵袭和播散。     

CXCL12/CXCR4轴与乳腺癌研究进展

趋化因子CXCL12与其受体CXCR4信号通路与乳腺癌细胞的定向播散和器官特异性转移密切相关,研究CXCL12/CXCR4轴在乳腺癌生长及转移中的重要作用,有望为乳腺癌靶向治疗提供新的策略。     

趋化因子受体CCR7及配体对肿瘤生物学行为的影响

在正常和非正常的生理状况下，趋化因子受体通过与其配体的结合在体内发挥着多种生物学作用。全文就新近发现的趋化因子受体CCR7及其配体CCL21和CCLl9的研究进展作一综述。     

趋化因子受体CXCR4在甲状腺癌中的表达

目的探讨趋化因子受体CXCR4在甲状腺癌中的表达及临床意义,为临床治疗甲状腺癌寻求新的治疗靶点提供依据。方法采用免疫组化SP染色法检测甲状腺癌、结节性甲状腺肿、甲状腺腺瘤及正常甲状腺组织中CXCR4表达差异,以及CXCR4在甲状腺癌中的表达与患者肿瘤病理类型、淋巴结转移状态、年龄及性别的关系。结果CXCR4在甲状腺癌组织中高表达,与结节性甲状腺肿、甲状腺腺瘤及正常甲状腺组织中表达差异有统计学意义,而且与患者淋巴结转移状态、病理类型密切相关,与患者年龄、性别无关。结论CXCR4在甲状腺癌的发生发展中可能起到重要作用,CXCR4在甲状腺癌中高表达,与患者淋巴结转移状态、病理类型密切相关,可作为甲状腺癌患者预后的指标,本研究为临床寻找新的甲状腺癌治疗靶点提供了重要依据。     

Cutaneous T-Cell Lymphomas: Prognosis and Quality-of-Life Issues

Cutaneous lymphomas (CL) include lymphocytic malignancies derived from B cells, T cells, or other cell types such as natural killer cells. Cutaneous T-cell lymphomas are the most common CL, especially mycosis fungoides, Sézary syndrome, and the spectrum of large-cell CD30⁺ lymphoproliferative disorders. It is important to understand that these diseases have a much better prognosis than their nodal counterparts; therefore, treatment has to be stage adapted and palliative. Due to the anatomical localization, these lymphomas have significant impact on the quality of life of the patient.     

Lack of Expression of MTAP in Uncommon T-Cell Lymphomas

BackgroundT-cell lymphomas, in particular peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL), have only limited and noncurative treatment options.Patients and MethodsWe report here that a high percentage of PTCL, AITL, and ALCL lack the enzyme methylthioadenosine phosphorylase (MTAP), as do T-cell leukemia and T-cell lymphoblastic leukemia. MTAP-deficient cells cannot cleave endogenous methylthioadenosine to adenine and 5-methylthioribose-1-phosphate, a precursor of methionine, and as a result have enhanced sensitivity to inhibitors of de novo purine biosynthesis. A recently introduced antifolate, pralatrexate, which has been shown to inhibit de novo purine biosynthesis, has been approved for treatment of PTCL and may have an increasing role in therapy. An alternative strategy involving coadministration of methylthioadenosine and high-dose 6-thioguanine has been proposed and may prove to be selectively toxic to MTAP-deficient uncommon lymphomas.ConclusionThus the consequences of MTAP deficiency suggest that new therapeutic interventions for T-cell lymphoma may be feasible.     

The Role of High-Dose Therapy in Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of non-Hodgkin's lymphomas. With few exceptions (eg, anaplastic large-cell lymphoma expressing the anaplastic lymphoma kinase), PTCLs have generally been reported to have a worse prognosis compared with B-cell lymphomas. Despite the poor outcome after conventional therapy, the impact of high-dose therapy with autologous or allogeneic stem cell transplantation (SCT) in these rare diseases is poorly defined mainly because of the lack of prospective PTCL-restricted studies. Most data exist for high-dose therapy with autologous SCT in relapsing or refractory disease. Because most studies showed similar results for PTCL compared with aggressive B-cell lymphomas in which high-dose therapy with autologous SCT is accepted as standard therapy, this approach seems appropriate in relapsing or refractory PTCL. Results for high-dose therapy with autologous SCT as first-line therapy mainly rely on studies on aggressive lymphomas that also included lymphomas of the T-cell phenotype. Our own recently published PTCL-restricted prospective study confirmed the feasibility with only moderate toxicity and a good response rate. Overall, patients with a good remission status after induction therapy exhibited a high complete response rate after transplantation, and at least a subgroup of patients remained in long-term remission. The greatest uncertainty exists for the impact of allogeneic SCT after high-dose therapy. In refractory or relapsing PTCL, this approach might improve the outcome for eligible patients, especially when using reduced-intensity conditioning. Overall, because data on high-dose therapy for PTCL are limited, larger and randomized studies are necessary to definitely confirm the preliminary results.     

CXC Chemokine Receptor 4 Expression,CXC Chemokine Receptor 4 Activation,and Wild-Type Nucleophosmin Are Independently Associated With Unfavorable Prognosis in Patients With Acute Myeloid Leukemia

BackgroundCXC chemokine receptor 4 (CXCR4) is activated by phosphorylation and essential for migration of hematopoietic precursors to bone marrow. CXCR4 overexpression predicts unfavorable prognosis in patients with acute myeloid leukemia (AML). Nucleophosmin (NPM1) mutation is the most frequent genetic abnormality in patients with AML and predicts a favorable prognosis. In vitro studies have suggested that mutant nucleophosmin (NPM) decreases CXCR4-mediated chemotaxis by downregulating CXCR4, thereby linking the NPM and CXCR4 pathways.Patients and MethodsIn a group of 117 untreated adults with AML, we used immunohistochemistry to assess bone marrow specimens for CXCR4 and phosphorylated CXCR4 (pCXCR4) expression. All cases also were analyzed for NPM1 mutations using polymerase chain reaction–based methods.ResultsCXCR4 expression was detected in 75 patients (64%), and pCXCR4 expression was detected in 31 patients (26%). NPM1 mutations were detected in 63 patients (54%). NPM1 mutations did not correlate with CXCR4 (P = .212) or pCXCR4 (P = .355) expression. The median 5-year overall survival was 27% (95% confidence interval, 19-36), with a median follow-up of 8 months (95% confidence interval, 6-15). In a multivariate Cox proportional hazards model, reduced overall and progression-free survival rates were associated with a history of antecedent hematologic disorder, failure to achieve complete remission, thrombocytopenia, unfavorable cytogenetics, CXCR4 expression, and wild-type NPM1. pCXCR4 expression was independently associated with shorter progression-free survival.ConclusionsThere is no correlation between NPM1 mutations and CXCR4 or pCXCR4 expression, suggesting that the CXCR4 and NPM pathways act independently in adult AML.     

Interferon-Inducible Protein-10 and the Pathogenesis of Cutaneous T-Cell Lymphomas

Human interferon-g inducible protein-10 (IP-10), a small basic protein secreted by interferon (INF)-g stimulated keratinocytes, is chemotactic for normal CD4-positive lymphocytes and inhibits early normal and leukemic hemopoietic progenitor proliferation. Cutaneous T-cell lymphoma (CTCL) is an indolent CD4-positive lymphoma characterized by multiple skin relapses before visceral dissemination. We investigated the role of IP-10 in the biology of CTCL by using immunocytochemistry to define IP-10 expression in normal and CTCL skin biopsies. Using purified recombinant (r) IP-10, we generated a rabbit antiserum that recognized and neutralized rIP-10 but did not cross-react with any keratinocyte proteins or any other chemokine. Immunoperoxidase staining of normal epidermis demonstrated that IP-10 was expressed by basal but not by differentiated keratinocytes. The epidermis overlying CTCL lesions was often hyperplastic, IP-10 immunostaining was enhanced compared to normal skin, and extended to the suprabasal keratinocytes in 25 of 26 patients for a frequency of 96%; and 95% confidence interval (CI) of 80% to 100%. However, IP-10 was detectable in the dermal or epidermal lymphoid infiltrates in only three of these 26 patients (12%; 95% Cl, 2% to 39%). Skin clinically free of CTCL demonstrated normal IP-10 immunostaining. In one patient who had matching biopsies performed before and after treatment, IP-10 was initially overexpressed before treatment but was normally expressed when he achieved remission. These results suggest that IP-10 may play a role in the epidermotropism of CTCL. More work is required to determine whether IP-10 stimulates or inhibits CTCL proliferation. A better understanding of the growth controls operating in CTCL may be used to develop curative therapies for this disorder.     

趋化因子受体CXCR4在鼻咽癌中的表达及意义

目的探讨趋化因子受体CXCR4在人鼻咽癌中的表达及临床意义。方法采用Real-timeRT-PCR法检测鼻咽癌细胞株中CXCR4mRNA的表达,应用免疫组织化学法并结合组织阵列检测正常鼻咽组织、鼻咽癌和鼻咽癌淋巴结转移石蜡组织标本中CXCR4蛋白的表达情况。结果在7种鼻咽癌细胞株中,CXCR4基因在高成瘤、高转移潜能的5-8F细胞中表达水平最高,在无转移能力的610B细胞中表达最低。CXCR4蛋白在正常鼻咽组织、鼻咽癌和鼻咽癌淋巴结转移组织中表达差异具有统计学意义（P=0．002）;鼻咽癌组织中CXCR4表达高于正常鼻咽组（P=0．029）;伴发转移的鼻咽癌组织比未发生转移的鼻咽癌组织CXCR4表达增强,差异具有统计学意义（P=0．008）;淋巴结转移癌组织CX-CR4表达比鼻咽癌组织高（P=0．013）。结论本研究提示CXCR4表达与鼻咽癌转移存在密切关系,CXCR4表达可作为鼻咽癌转移过程中一个有价值的指标。     

Cutaneous T-Cell Lymphomas: A Review of New Discoveries and Treatments

Treatment regimens of patients with CTCL vary widely based on clinician preference and patient tolerance. Skin directed therapies are recommended for patients with early stage IA and IB MF, with combinations used in refractory cases. While no regimen has been proven to prolong survival in advanced stages, immunomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment efforts should strive for palliation and improvement of quality of life. With many new therapies and strategies on the horizon, the future looks promising for CTCL patients. Unfortunately, other than allogeneic HCT, there are no potential curative therapies for CTCL. Clinical trials are currently underway to identify new therapies to improve quality of life for patients, and researchers are hard at work to identify novel pathways and genes for prognostication and as targets for therapies. Importantly, collaborative clinical trials to enhance rates of accrual need to be conducted, and improved interpretation of data via standardizing end points and response criteria should be an emphasis. Recently, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) met to develop consensus guidelines to facilitate collaboration on clinical trials. These proposed guidelines consist of: recommendations for standardizing general protocol design; a scoring system for assessing tumor burden in skin, lymph nodes, blood, and viscera; definition of response in skin, nodes, blood, and viscera; a composite global response score; and a definition of end points. Although these guidelines were generated by consensus panels, they have not been prospectively or retrospectively validated through analysis of large patient cohorts.     

NK/T-Cell Lymphomas: Pathobiology, Prognosis and Treatment Paradigm

The current World Health Organization (WHO) classification includes two types of natural killer (NK)-cell lymphomas: extranodal NK/T-cell lymphoma, nasal type (ENKL), and aggressive NK-cell leukemia (ANKL). These diseases are mostly endemic to East Asia and Latin America. The Epstein-Barr virus (EBV) is usually detected in tumor cells, suggesting that EBV plays an important role in lymphomagenesis. At the site of origin, ENKL can be divided into two major subtypes: nasal and extranasal diseases. The advanced disease presentation, highly aggressive clinical course, and poor prognosis of the latter are analogous to ANKL. It is well known that P-glycoprotein, which is a product of the multi-drug resistance (MDR1) gene, is expressed on neoplastic cells of ENKL or ANKL. This is a major cause of the refractoriness of malignant lymphoma to conventional chemotherapeutic regimens containing anthracycline. Recent studies, however, have identified that L-asparaginase-containing regimens, such as SMILE (steroid, methotrexate, ifosfamide, L-asparaginase and etoposide), are effective for ENKL. Considering the myelotoxicity of SMILE, its use in the treatment of ANKL needs some modifications, but this treatment scheme is promising in improving the prognosis of NK-cell lymphomas.     

趋化因子受体CXCR4和VEGF-C蛋白在食管癌组织中的表达及临床意义

[目的]探讨趋化因子受体（CXCR4）和血管内皮生长因子（VEGF-C）在食管癌组织中的表达情况,及其在食管癌发生、浸润、转移中的作用。[方法]应用免疫组织化学方法检测82例食管癌组织、20例正常食管组织中CXCR4、VEGF-C表达情况,并分析其与临床病理参数的关系。[结果]CXCR4在82例食管癌组织中的阳性表达率为64.6%,CXCR4表达与食管癌患者年龄、性别无关（P〉0.05）,而与分化程度、病理类型、TNM分期、浸润深度和淋巴结转移有相关性（P〈0.05）。VEGF-C在82例食管癌组织中的阳性表达率为74.4%,VEGF-C表达与食管癌患者年龄、性别、分化程度和病理类型无关（P〉0.05）,而与TNM分期、浸润深度和淋巴结转移有相关性（P〈0.05）。[结论]CXCR4和VEGF-C在食管癌组织中呈高表达,且与食管癌细胞侵袭、转移和淋巴结转移相关,在促进食管癌侵袭和转移中可能存在协同作用。     

HIF-1α和HIF-2α上调非小细胞肺癌中CCR7的表达

背景与目的CCR7与非小细胞肺癌的淋巴结转移密切相关,但CCR7的上调机制却不是很清楚。本研究通过观察趋化因子受体CCR7和缺氧诱导因子1α(HIF-1α)、缺氧诱导因子2α(HIF-2α)在非小细胞肺癌组织中的表达及相互关系,探讨非小细胞肺癌CCR7上调机制。方法应用免疫组织化学染色(SP法)检测94例非小细胞肺癌组织中CCR7、HIF-1α和HIF-2α的表达,并联合运用RNAi技术沉默人肺腺癌A549细胞中HIF-1α、HIF-2α表达,采用RT-PCR和免疫荧光方法观察CCR7的变化情况,分析CCR7表达与HIF-1α、HIF-2α之间的关系。结果免疫组织化学结果显示:CCR7主要表达于癌细胞质和(或)胞膜,HIF-1α、HIF-2α主要表达于癌细胞核和(或)细胞质,非小细胞肺癌中CCR7、HIF-1α和HIF-2α的表达率分别为75.53%(71/94)、54.25%(51/94)和70.21%(66/94),χ2检验显示CCR7表达与非小细胞肺癌的临床病理分期(P<0.001)和淋巴结转移(P=0.001)有密切关系,而与年龄、性别、组织学类型无关(P>0.05)。此外,CCR7和HIF-1α、HIF-2α表达正相关(r=0.272,P<0.01)(r=0.225,P<0.05)。向A549细胞中转染HIF-1α、HIF-2α特异性siRNA,分别抑制HIF-1α、HIF-2α表达后发现CCR7的mRNA和蛋白水平均下调(P<0.05)。结论CCR7表达与非小细胞肺癌侵袭转移密切相关,CCR7在NSCLC中过表达受HIF-1α和HIF-2α调控。     

Immunodeficiency in Preclinical Smoldering Adult T-Cell Leukemia

We treated two Japanese patients with Pneumocystis carinii pneumonia.Inclusion bodies in both adrenal glands of patient no. 1 indicateda herpesvirus infection. The patient no. 2 recovered from thepneumonia upon sulfametoxazole-trimethoprim medication and high-dosemethylprednisolone therapy. In both patients, anti-human T-cellleukemia virus type I (HTLV-I) antibodies were positive andanti-human immunodeficiency virus antibodies were negative.Peripheral leukocytes in patient no. 1 numbered 13.6 x 10³/µlwith 25% morphologically normal lymphocytes and 4% abnormal.Lymphocyte surface markers were 72.6%, CD4+, 13.6% CD8+ and46.4% CD3+. In patient no. 2, leukocytes numbered 13.8 x 10³/µl,including 18% lymphocytes, although no morphologically abnormallymphocyte was evident. Lymphocyte markers were 36.6% CD4+,16.8% CD8+ and 46.6% CD3+. Monoclonal integration HTLV-I proviralDNA in lymphocytes of patient no. 2 was demonstrated by Southernblotting. Thus, both patients must have had smoldering adultT-cell leukemia (ATL) without any cutaneous involvement, whereasthe morphological diagnosis from peripheral blood smears wasone of HTLV-I carrier status with a few atypical lymphocytes,i.e., the preclinical state of smoldering ATL. Pneumocystiscarinii infectious, a viral infection of the adrenals (no. 1),negative purified protein derivatives of the tuberculin reactionand suppressed blastogenesis of the peripheral lymphocytes indicatedHTLV-I-induced impairment of the immune mechanism to have alreadyoccurred in both patients without there being a vast proliferationof ATL cells.     

趋化因子受体CXCR4在食管癌中的表达及临床意义

[目的]探讨CXCR4在食管癌中的表达及意义。[方法]应用免疫组织化学方法检测82例食管癌组织、20例癌旁食管组织中CXCR4的表达。[结果]CXCR4在癌旁食管组织无表达,在82例食管癌组织中的阳性表达率为64.6%(53/82)。CXCR4表达与食管癌患者的年龄、性别无关,而与分化程度、TNM分期、浸润深度、组织学类型和淋巴结转移有关。[结论]CXCR4在食管癌中高表达,CXCR4可能是促进食管癌侵袭和转移的一个重要分子。     

趋化因子受体CCR7与PI3K/Akt通路在胃癌组织中的表达及意义

目的 观察趋化因子受体CCR7和磷脂酰肌醇-3-激酶（PI3K）、蛋白激酶B（PKB或Akt）在胃癌组织中的表达情况,探讨CCR7与PI3K/Akt通路的关系。方法 采用RT-PCR法检测32例胃癌及相应癌旁对照组织中CCR7mRNA、PI3KmRNA、AktmRNA的表达;Western Blotting法检测CCR7、p-Akt蛋白的表达。结果 胃癌组织中CCR7mRNA、PI3KmRNA、AktmRNA与癌旁对照组织的表达水平相比,差异均有显著性（P〈0.001）,且CCR7mRNA与PI3KmRNA、AktmRNA表达呈正相关（P〈0.05）。CCR7、P-Akt蛋白在胃癌组织中的表达水平明显高于癌旁对照组织（P〈0.05）,两者表达与肿瘤TNM分期、浸润深度、分化程度、淋巴结转移与远处转移有关（P〈0.05）,并且CCR7、P-Akt表达水平呈正相关（P〈0.05）。结论 胃癌组织中高表达的CCR7可能通过PI3K/Akt通路促进胃癌的侵袭转移。     

Targeting IRAK1 in T-Cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) represents expansion of cells arrested at specific stages of thymic development with the underlying genetic abnormality often determining the stage of maturation arrest. Although their outcome has been improved with current therapy, survival rates remain only around 50% at 5 years and patients may therefore benefit from specific targeted therapy. Interleukin receptor associated kinase 1 (IRAK1) is a ubiquitously expressed serine/threonine kinase that mediates signaling downstream to Toll-like (TLR) and Interleukin-1 Receptors (IL1R). Our data demonstrated that IRAK1 is overexpressed in all subtypes of T-ALL, compared to normal human thymic subpopulations, and is functional in T-ALL cell lines. Genetic knock-down of IRAK1 led to apoptosis, cell cycle disruption, diminished proliferation and reversal of corticosteroid resistance in T-ALL cell lines. However, pharmacological inhibition of IRAK1 using a small molecule inhibitor (IRAK1/4-Inh) only partially reproduced the results of the genetic knock-down. Altogether, our data suggest that IRAK1 is a candidate therapeutic target in T-ALL and highlight the requirement of next generation IRAK1 inhibitors.