儿科恶性血液病化疗期间的综合护理

恶性血液病是儿童最常见的恶性肿瘤,常见的有急性白血病和恶性淋巴瘤。化疗是延长甚至治愈这些恶性血液病患儿生命的重要手段之一,但目前的化疗药物作用选择性不高,在杀伤肿瘤细胞的同时,对机体的正常组织细胞也具有杀伤作用［１］。故在化疗的诱导缓解期、巩固治疗期...     

自体免疫免疫细胞治疗技术之CIK细胞治疗癌症

近年来:自体免疫细胞治疗技术越来越广泛地被应用到临床治疗中。自体免疫细胞治疗技术是指从患者自身外周血等中分离单个核细胞,经过专项实验室进行细胞的活化与增殖后,回输入患者体内,直接杀伤肿瘤细胞或被病毒感染的细胞,同时起到调节和增强机体免疫功能的作用。随着自体免疫细胞治疗技术的发展,应用细胞因子诱导的杀伤细胞(cytokine induced killer cell,CIK细胞)进行恶性肿瘤治疗的临床试验也陆续开展。     

《科学》：药物组合帮巨噬细胞“吃掉”肿瘤

在合成SIRPα蛋白（CV1单核细胞）和抗癌药物利妥昔单抗的双重打击下。小鼠体内的肿瘤在29天后被清除。 为了避免被免疫系统破坏,癌细胞耍了一些小手段。当它们分裂形成肿瘤时,会避免让巨噬细胞察觉到,巨噬细胞是从事消灭死亡细胞和危险入侵者的免疫细胞。现在,许多癌症患者都在利用抗体药物进行治疗,这些抗体药物的部分作用是标识肿瘤细胞以便让巨噬细胞消灭它们。尽管这些药物可以延长患者的生命,但它们并不总是非常有效一部分原因在于癌细胞会通过给免疫细胞发送一个“别吃我”的信号进行反击。     

肿瘤细胞回击免疫系统

肿瘤细胞回击免疫系统癌症患者的免疫系统为何不能清除肿瘤细胞一直是个谜,人们曾怀疑是肿瘤细胞逃脱了免疫监视或阻抑了免疫应答。新的研究证实,黑色素瘤细胞表面有一种可引起免疫细胞凋亡的分子,提示肿瘤细胞能杀灭攻击他们的免疫细胞。在启动凋亡的过程中,传递死亡...     

体内致敏的树突状细胞诱导特异性抗肿瘤免疫的基础研究

目的证实树突状细胞（dendritic cells,DC）可在体内通过吞噬凋亡肿瘤细胞获取抗原物质,探讨其在肿瘤免疫治疗中的意义.方法以615小鼠的前胃癌细胞株造模,在体外用rmGM-CSF和rmIL-4从荷瘤小鼠骨髓细胞分化、诱导未成熟树突状细胞.分为4组：小剂量化疗组、树突状细胞组、小剂量化疗＋树突状细胞组和对照组,以BAX试剂盒检测肿瘤细胞凋亡.在瘤体内注射树突状细胞,观察给药侧瘤体及对侧瘤体体积,生存期,和特异性细胞毒性T淋巴细胞（CTLs）对肿瘤细胞的特异性杀伤作用.结果小剂量化疗能诱导肿瘤细胞凋亡.小剂量化疗后瘤内应用树突状细胞,给药侧瘤体及对侧瘤体体积明显缩小（P＜0.05）,小鼠的生存率提高,体内凋亡肿瘤细胞致敏的DC诱导的CTL对MFC有显著的杀伤作用,在效靶比为40：1、20：1、10：1和5：1时72 h的杀伤率分别为87.64%、70.32%、34.63%和13.87%.并能特异性杀伤小鼠前胃癌细胞MFC（P＜0.01）.结论体外诱导分化的未成熟DC,能于体内捕获小剂量化疗诱导的凋亡肿瘤细胞所携带的肿瘤抗原,诱导机体特异性抗肿瘤免疫反应.     

《自然-生物技术》:科学家可用干细胞制造大量免疫细胞

<正>近日在线出版的《自然-生物技术》报道了一种利用干细胞制造出大量可杀死小鼠体内肿瘤细胞的人免疫细胞的技术。该技术或能让癌症免疫疗法这种通过激活免疫系统来消灭肿瘤的治疗方法更容易获得实施。大多数癌症免疫疗法需要从病人血液中分离出T细胞这种免疫细胞。但是,能够杀死特定肿瘤细胞而不伤害正常细胞的T细胞的数量非常     

树突状细胞对小剂量化疗疗效影响的基础研究

目的 研究树突状细胞对小剂量化疗疗效的影响,探讨小剂量化疗的可能机制.方法 以615小鼠的前胃癌细胞株(MFC)造模,在体外用rmGM-CSF和rmIL-4从荷瘤小鼠骨髓细胞分化、诱导未成熟树突状细胞.分为4组:小剂量化疗组、树突状细胞组、小剂量化疗+树突状细胞组、对照组,以BAX试剂盒检测肿瘤凋亡情况.在瘤体内注射树突状细胞,计算抑瘤率、特异性细胞毒性T淋巴细胞(CTL)的增殖及其对肿瘤细胞的特异性杀伤作用.结果 小剂量化疗能诱导肿瘤细胞凋亡,BAX 基因产物表达增多.注射侧抑瘤率小剂量化疗+DC组、小剂量化疗组、DC组分别为100%、67.22%和57.98%.对侧抑瘤率小剂量化疗+DC组、小剂量化疗组、DC组分别为87.58%、59.69%和48.24%.体内凋亡肿瘤细胞致敏的DC能显著刺激T淋巴细胞增殖,其诱导的CTL对MFC有显著的杀伤作用,在效靶比为40∶ 1、20∶ 1、10∶ 1和5∶ 1时72 h杀伤率分别为87.64%、70.32%、34.63%和13.87%.并能特异性杀伤小鼠前胃癌细胞MFC(P<0.01).结论 小剂量化疗的机制与肿瘤细胞凋亡及免疫促进有一定的相关.     

三维细胞培养与肿瘤细胞恶性表型研究

了解肿瘤细胞与微环境的相互作用,对研究肿瘤的发生、发展及抗癌药物的筛选具有重要意义。三维细胞培养技术近年被用于研究肿瘤细胞恶性表型,与传统二维细胞培养相比．它可以模拟体内细胞生长的微环境,是研究肿瘤细胞恶性表型、细胞与细胞外基质信号传递的有力工具。     

树突状细胞与CIK细胞共培养诱生的DCCIK细胞群对肿瘤的杀伤作用

由树突状细胞(DC)与细胞因子诱导的同源杀伤细胞(CIK)的共培养诱生的细胞群(DCCIK)对肿瘤细胞的细胞毒活性的研究。DCCIK细胞体外杀伤肿瘤靶细胞A549(MTT法),效靶比为10∶1、5∶1时杀伤率分别为61%、52%。DCCIK细胞诱导培养3周后,效靶比为10∶1、5∶1时杀伤率分别为64%和56%。数据亦表明DCCIK细胞对靶细胞的杀伤优于CIK细胞。动物体内实验分荷瘤A549、BEL7404和A375三组,每组分(A)DCCIK 化疗、(B)单用化疗。治疗20天、35天后测量各组肿瘤消失率。结果显示:DCCIK 化疗的抑瘤效果明显好于单纯化疗。提示DCCIK细胞有临床应用前景。     

VIP族激素调节人类大颗粒淋巴细胞的自然杀伤活力

NK细胞是一类重要的大颗粒免疫细胞,能杀灭肿瘤细胞和病毒,并参与机体造血的调节。NK细胞受多种因素调节,近来认为一些脑肠肽如VIP、SS等也参与了NK细胞的功能调节,且已积累了不少体内、体外试验证据。作者利用新合成的VIP拮抗剂VIP 4Cl-D-Phe~6-Leu~(17)进一步观察了VIP族激素对人类外周血NK细胞活力的调节作用。     

Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma.

Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting.     

肠内营养联合复方氨基酸在恶性肿瘤患者化疗中的应用

为了观察肠内营养(EN)支持治疗联合复方氨基酸在恶性肿瘤化疗患者中的临床疗效及并建立相关护理方法,将68例恶性肿瘤化疗患者随机分为治疗组和对照组,每组34例,治疗组给予肠内营养支持治疗联合复方氨基酸治疗,对照组给予常规处理。对两组病人治疗前后进行生化指标监测、记录不良反应以及进行营养评估。研究结果显示,治疗组与对照组比较,人体测量值增加,血清清蛋白升高,两组比较有显著性差异(p<0.05)。本研究表明,肠内营养(EN)支持治疗联合复方氨基酸对于改善恶性肿瘤化疗病人的营养状况效果明显,并且可以提高患者对化疗的耐受力、增强免疫功能。     

Model of Tumor Dormancy/Recurrence after Short-Term Chemotherapy

Although many tumors regress in response to neoadjuvant chemotherapy, residual tumor cells are detected in most cancer patients post-treatment. These residual tumor cells are thought to remain dormant for years before resuming growth, resulting in tumor recurrence. Considering that recurrent tumors are most often responsible for patient mortality, there exists an urgent need to study signaling pathways that drive tumor dormancy/recurrence. We have developed an in vitro model of tumor dormancy/recurrence. Short-term exposure of tumor cells (breast or prostate) to chemotherapy at clinically relevant doses enriches for a dormant tumor cell population. Several days after removing chemotherapy, dormant tumor cells regain proliferative ability and establish colonies, resembling tumor recurrence. Tumor cells from “recurrent” colonies exhibit increased chemotherapy resistance, similar to the therapy resistance of recurrent tumors in cancer patients. Previous studies using long-term chemotherapy selection models identified acquired mutations that drive tumor resistance. In contrast, our short term chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that can resume growth after drug removal. Studying unique signaling pathways in dormant tumor cells enriched by short-term chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence.     

Homeostasis of adult human stem cells and carcinogenesis

Treatment of malignant diseases with radiation therapy, chemotherapy, and immunodepressants requires subsequent restoration of bone marrow by the use of transplantation of donor bone marrow or separated adult stem cells to the body. During the next 1–15 years, in these patients, the risk of malignant neoplasia substantially increases as compared to healthy persons. This was previously considered as the effect of treatment. However, it has been found that part of cells and the stroma of a secondary tumor consist of progenies of transplanted stem cells. This demonstrates an important role of stem cells in tumorigenesis. Numerous studies also show that adult mouse or human stem cells cultured in vitro can form foci of sarcoma, cancer or other types of malignant growth. Malignant growth is more intense when chronic inflammation is present in the body. A lot of experimental data including studies in humans demonstrated that, after transplantation, stem cells actively occupy the tumor stroma, stimulate tumorigenesis and its metastasis. An important condition of human life is the presence of strong homeostatic mechanisms that control the number of stem cells in the body and limit their division even in regeneration foci. After transplantation of stem cells, their number in the blood and, correspndingly, in a pathological regeneration location increases by the dozens. This level of cells in the body cannot be reached spontaneously. This significantly enhances the rate of tissue regeneration, which creates conditions for malignant growth.     

Activation of local and systemic anti-tumor immune responses by ablation of solid tumors with intratumoral electrochemical or alpha radiation treatments

Cancer, the most devastating chronic disease affecting humankind, is treated primarily by surgery, chemotherapy, and radiation therapy. Surgery and radiotherapy are mainly used for debulking the primary tumor, while chemotherapy is the most efficient anti-metastatic treatment. To control better metastatic cancer, the host immune system should be stimulated. Yet, successful specific stimulation of the immune system against tumors was seldom achieved even in antigenic tumors. Our working hypothesis is that aggressive in situ tumor ablation can release tumor antigens and danger signals, which will enhance anti-tumor T cell responses resulting in the destruction of residual malignant cells in primary tumors and distant metastases. We developed two efficient in situ ablation treatments for solid cancer, which can be used to destroy the primary tumors and stimulate anti-tumor immune responses. The first treatment, electrochemical ablation, is applied through intratumoral electrodes, which deliver unipolar-pulsed electric currents. The second treatment, diffusing alpha-emitters radiation therapy (DaRT), is based on intratumoral ²²⁴Ra-loaded wire(s) that release by recoil its daughter atoms. These short-lived alpha-emitting atoms spread in the tumor and spray it with lethal alpha particles. It was confirmed that these treatments effectively destroy various malignant animal and human primary solid tumors. As a consequence of such tumor ablation, tumor-derived antigenic material was released and provoked systemic T cell-dependent anti-tumor immunological reactions. These reactions conferred protection against a secondary tumor challenge and destroyed remaining malignant cells in the primary tumor as well as in distant metastases. Such anti-tumor immune responses could be further amplified by the immune adjuvant, CpG. Electrochemical ablation or DaRT together with chemotherapy and immunostimulatory agents can serve as treatment protocols for solid metastatic tumors and can be applied instead of or in combination with surgery.     

肿瘤干细胞对恶性肿瘤辅助治疗的影响

放化疗是目前恶性肿瘤治疗的重要手段,但是迄今为止,除了手术以外,几乎没有能单独根治恶性肿瘤的治疗方法,甚至一些恶性肿瘤在手术、化疗或放疗后会出现再生和侵袭能力增强,被称为恶性肿瘤治疗后再增殖,这可能是恶性肿瘤治疗失败的主要原因,其主要机制可能是肿瘤干细胞(cancer stem cells,CSCs)对放化疗的耐受,以及放化疗导致肿瘤细胞的上皮细胞间质化,继而提高了肿瘤侵袭性。该文将从CSCs的角度重新探讨放化疗等辅助治疗对恶性肿瘤的影响。     

Homeostasis of adult stem cells and carcinogenesis

Treatment of malignant tumors using radiotherapy, chemotherapy, immunosuppressive drugs required to recover bone marrow transplant by the donor bone marrow or purified adult stem cells. During the next 1-15 years of follow up of these patients compared with healthy individuals of the same age increases the risk of multiple malignancies. It used to be attributed to the influence of therapeutic effects. However, it is revealed that some of the cells and the stroma of the secondary tumors are composed of descendants of transplanted stem cells. This indicates the important role of stem cells in tumor growth. This is also evidenced by numerous studies showing that adult stem cells from both mice and humans multiplied in vitro, after transplantation into the body give the sarcoma, cancer foci and other types of malignant growth. In this, malignant growth is most intense in the presence of focal chronic inflammation. No less than the experimental data, including those obtained in humans suggest that the transplanted stem cells actively colonize stroma of tumor tissue, stimulating the growth of the tumor and its metastasis. The human condition of survival is the presence of rigid homeostatic control mechanisms of low numbers of stem cells in the body and the limit their division, even in areas of regeneration. After the transplantation of stem cells their number in the bloodstream and, consequently, in the pathological foci of regeneration, increases in many dozens of times--this level can not be achieved by the organism itself. This leads to a sharp increase in the rate of regeneration of tissues, which creates conditions for amplification of malignant growth.     

Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal muramyl tripeptide (CGP 19835A lipid)

Summary We have recently begun a phase II trial in patients with osteosarcoma who developed pulmonary metastases during adjuvant chemotherapy or who presented with pulmonary metastases that persisted despite chemotherapy. Eligible patients were rendered free of visible disease by surgery. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (MTP-PE, CGP 19835A lipid) (2 mg/m²) was infused twice weekly for 3 months. In five patients, a single tumor nodule recurred within 6 weeks after completion of therapy. These lesions were resected and submitted for pathological examination. Tissue specimens obtained after therapy were compared to those obtained before therapy. All the patients showed a histological change in the characteristics of the pulmonary tumors. In three patients, peripheral fibrosis surrounded the tumor and inflammatory cell infiltration and neovascularization were present. This is in contrast to central necrosis, with viable peripheral tumor cells and no inflammatory response observed in lesions resected following chemotherapy. In a fourth case, evidence of early fibrotic changes was found. This and the fifth case showed a change in malignant characteristics, from high grade before liposomal therapy to low grade after therapy. The present study provides evidence for a biological effect of liposomal MTP-PE.     

Use of human leukocyte antigen-mismatched allogeneic lymphokine-activated killer cells and interleukin-2 in the adoptive immunotherapy of patients with malignancies

Clinical effects and side effects were studied in the adoptive immunotherapy of patients bearing malignant diseases using human leukocyte antigen (HLA)-mismatched allogeneic lymphokine-activated killer (LAK) cells. Allogeneic LAK cells were induced from peripheral blood lymphocytes (PBL) of normal donors by means of initial stimulation with pokeweed mitogen (PWM). Six of 15 patients applied in the adoptive immunotherapy showed clinical effects such as partial or complete regression of pulmonary metastasis, pleural effusion and primary tumor. All pulmonary metastatic lesions were eliminated in one case by this adoptive immunotherapy combined with chemotherapy. Generally toxic effects were chillness, fever and general fatigue which were reversible, and no allergic side effects occurred even though allogeneic LAK cells were injected frequently except one patient who showed preshock like symptom accompanied with leukocytopenia and continuous hypotension immediately after infusion but was finally rescued. In the patients who received more than 10¹¹ of allogeneic LAK cells, anti-HLA class I antibodies appeared without any evidence of autoantibody. However, immunological side effects were never experienced after injection of allogeneic LAK cells even when the anti-HLA class I antibodies appeared in the patients. Taken together, allogeneic LAK cells could be considered as alternative therapy for patients with malignancies who could not supply sufficient materials of autologous LAK cells.Abbreviations PWM pokeweed mitogen - LAK lymphokine-activated killer - IL-2 interleukin 2 - PEL peripheral blood lymphocytes - TIL tumor-infiltrating lymphocytes - GVHD graft-versus-host disease - HLA human leukocyte antigen     

Biomarkers of Residual Disease,Disseminated Tumor Cells,and Metastases in the MMTV-PyMT Breast Cancer Model

Cancer metastases arise in part from disseminated tumor cells originating from the primary tumor and from residual disease persisting after therapy. The identification of biomarkers on micro-metastases, disseminated tumors, and residual disease may yield novel tools for early detection and treatment of these disease states prior to their development into metastases and recurrent tumors. Here we describe the molecular profiling of disseminated tumor cells in lungs, lung metastases, and residual tumor cells in the MMTV-PyMT breast cancer model. MMTV-PyMT mice were bred with actin-GFP mice, and focal hyperplastic lesions from pubertal MMTV-PyMT;actin-GFP mice were orthotopically transplanted into FVB/n mice to track single tumor foci. Tumor-bearing mice were treated with TAC chemotherapy (docetaxel, doxorubicin, cyclophosphamide), and residual and relapsed tumor cells were sorted and profiled by mRNA microarray analysis. Data analysis revealed enrichment of the Jak/Stat pathway, Notch pathway, and epigenetic regulators in residual tumors. Stat1 was significantly up-regulated in a DNA-damage-resistant population of residual tumor cells, and a pre-existing Stat1 sub-population was identified in untreated tumors. Tumor cells from adenomas, carcinomas, lung disseminated tumor cells, and lung metastases were also sorted from MMTV-PyMT transplant mice and profiled by mRNA microarray. Whereas disseminated tumors cells appeared similar to carcinoma cells at the mRNA level, lung metastases were genotypically very different from disseminated cells and primary tumors. Lung metastases were enriched for a number of chromatin-modifying genes and stem cell-associated genes. Histone analysis of H3K4 and H3K9 suggested that lung metastases had been reprogrammed during malignant progression. These data identify novel biomarkers of residual tumor cells and disseminated tumor cells and implicate pathways that may mediate metastasis formation and tumor relapse after therapy.