肿瘤突变负荷对结直肠癌患者免疫治疗疗效的预测价值

目前,结直肠癌的治疗已经从"外科为主、放化疗为辅"的固有治疗模式转向了精准化、个体化的治疗理念,免疫治疗越来越受到重视。然而,并不是所有的患者都对免疫检查点抑制剂有反应。因此,预测治疗反应的可能性将有助于对可获益的患者进行筛选。较多研究表明,肿瘤突变负荷与免疫检查点抑制剂的疗效呈正相关,可以成为免疫治疗的独立生物标记物。本研究对肿瘤突变负荷在结直肠癌患者免疫治疗疗效中的预测价值及应用现状进行综述。     

免疫检查点抑制剂治疗晚期非小细胞肺癌的预后标志物动态监测研究进展

免疫检查点抑制剂在晚期非小细胞肺癌中的应用显著提高了患者的生存获益,但存在治疗反应率低等临床问题.免疫检查点抑制剂治疗是肿瘤-免疫系统交互对话、动态变化的过程,纵向监测生物标志物变化,有助于消除个体间的差异,提供肿瘤时空异质性信息.本文将从肿瘤细胞源性、免疫微环境源性及多指标联合三方面对免疫检查点抑制剂治疗晚期非小细胞...     

长链非编码RNA在结直肠癌中的研究进展

结直肠癌的发生、发展是一个多步骤、多阶段、多基因参与的细胞遗传性疾病。长链非编码RNA(long non-coding RNA,lncRNA)是一类长度超过200 bp核苷酸,不具备蛋白质编码功能,但具有广泛的基因表达调控作用的非编码RNA分子。研究显示,lncRNA在多种肿瘤中异常表达,其在结直肠癌的发生、发展过程中具有重要的作用,可作为结直肠癌诊断和预后的特异性分子标志物以及有效的治疗靶点。该文就lncRNA在结直肠癌中的研究进展作一综述,以期为其临床研究结直肠癌的诊断和治疗提供依据。     

DC-CIK联合化疗对晚期结直肠癌患者免疫功能及B7-H4蛋白表达的影响

目的探讨树突状细胞联合细胞因子诱导的杀伤细胞(DC-CIK)免疫治疗联合常规化疗对晚期结直肠癌患者免疫功能及B7-H4蛋白表达的影响。方法选取2012年10月至2014年9月收治的晚期结直肠癌患者110例,随机分为两组,每组各55例。其中对照组接受常规化疗,观察组患者接受DC-CIK联合化疗。对比分析两组患者治疗后的免疫功能及B7-H4蛋白表达情况。结果对照组患者接受治疗后其外周血中CD4~+、CD8~+和CD4~+/CD8~+无显著差异(P0.05);而观察组患者接受治疗后外周血中CD4~+和CD4~+/CD8~+显著升高,与对照组患者相比有显著差异(P0.05);观察组患者的肿瘤促进分子CD168、CD133、CD151的含量与对照组患者相比明显降低,肿瘤抑制分子CD9和CD63的含量明显高于对照组患者,而干扰素γ(IFN-γ)显著升高,差异有显著性(P0.05);此外,观察组患者治疗后的可溶性B7-H4蛋白表达明显低于对照组患者(P0.05)。结论与单纯化疗相比,DC-CIK联合化疗治疗晚期结直肠癌患者有助于提高患者的免疫功能,降低B7-H4蛋白表达,抑制肿瘤生长,在临床治疗晚期结直肠癌的过程中值得推广应用。     

MTT法测定大肠癌化疗药物敏感性

目的　运用MTT法测定大肠癌体外对化疗药物的敏感性及其适用价值。方法　采用改良的噻唑兰 (MTT)法测定 84例结直肠癌标本对 9种化疗药物的体外敏感性 ,并运用免疫组化法检测 30例肿瘤细胞的多药耐药基因 (MDR1)。结果　 84例结直肠癌细胞对化疗药物的敏感性 ,从高到低依次为 5 Fu >MMC >Ara C >HCPT >CBP >CDDP >MXT >MTX >ADM。 30例患者中 14例MDR1阳性。结论　以MTT法检测结直肠癌细胞对化疗的敏感性有助于指导临床选择肿瘤敏感的化疗药物 ,并可避免盲目选用肿瘤非敏感性化疗药对机体造成的毒性反应。在检测肿瘤对化疗药物敏感性的同时 ,建议检测多药耐药基因 ,及时发现耐药病人 ,以便采用其它有效的治疗方法。     

结直肠癌患者血清可溶性E-选择素及细胞黏附分子-1水平及临床意义

目的探讨结直肠癌患者血清可溶性E-选择素和细胞黏附分子-1水平及其临床意义。方法采用酶联免疫吸附试验（ELISA）检测220例结直肠癌患者E-选择素和细胞黏附分子-1的血清浓度,并以200名健康体检者作为对照组,比较结直肠癌患者手术前后血清E-选择素和细胞黏附分子-1水平的变化。结果结直肠癌患者血清E-选择素和细胞黏附分子-1水平显著高于对照组（P〈0.05）;术后2周结直肠癌患者血清E-选择素和细胞黏附分子-1水平较术前明显下降（P〈0.05）;随着临床分期的上升,E-选择素和细胞黏附分子-1水平显著升高,其水平与淋巴结转移和Dukes分期相关（P〈0.05）;E-选择素和细胞黏附分子-1水平与年龄、性别及肿瘤部位无明显相关。结论血清E-选择素和细胞黏附分子-1水平在一定程度上反映了结直肠癌的侵袭转移过程,是预测结直肠癌发展及预后的重要指标。     

结直肠癌组织Rab27A的表达及意义

目的： 在基因和蛋白水平检测结直肠癌组织及相应的癌旁组织中Rab27A表达情况，并探讨其与结直肠癌患者临床特点的相关性及临床意义。方法： 回顾性分析2005年1月至2019年1月在上海市浦东新区人民医院普通外科和上海交通大学医学院附属仁济医院胃肠外科接受手术治疗的125例结直肠癌患者的结直肠癌病理标本及其临床病理资料。采用实时定量聚合酶链反应（qRT-PCR）和Western印迹法分别检测其中32对和8对结直肠癌患者的肿瘤组织和相应的癌旁组织（距癌组织边缘>5 cm）中Rab27A mRNA和蛋白表达情况。免疫组织化学检测125例结直肠癌组织中Rab27A表达情况，计算Rab27A染色强度，并分析其与临床特点之间的关系。结果： 在32对结直肠癌肿瘤组织和癌旁组织中，肿瘤组织中Rab27A mRNA表达水平明显高于癌旁正常临床组织（P=0.001）。在8对结直肠癌肿瘤组织和癌旁组织中，肿瘤组织中蛋白表达水平明显高于癌旁正常组织。肿瘤大小和临床分期在Rab27A蛋白高表达组和低表达组差异有统计学意义（P=0.037、0.017）。生存分析结果显示，Rab27A表达水平越高，结直肠癌患者预后越差。同时，多因素分析表明，Rab27A在结直肠癌患者中可作为独立的预后分子标志物。结论： Rab27A在结直肠癌的发生发展中起重要作用，可作为反映结直肠癌生物学行为的潜在有效指标。     

结直肠癌中B7-H1表达的意义

共刺激信号是1970年由Bretscher和Cohn在T细胞活化双信号模型的基础上提出并证实的［1］,属于免疫球蛋白超家族（IgSF）的B7家族中的共刺激分子有些是激发或增强免疫应答,有些是下调或终止免疫应答。B7-H1是新发现的 B7家族成员之一,它在诱导初始T 细胞的增殖,抑制活化T细胞的增殖分化和分泌细胞因子,促进活化T细胞的凋亡中发挥重要作用。研究发现,B7-H1分子可在人类多种肿瘤组织中表达,促进效应性CTL（细胞毒T淋巴细胞）的凋亡,参与肿瘤的免疫逃逸过程［2］。本研究应用免疫组织化学法检测 B7-H1在结直肠癌组织和正常结直肠组织中的表达,并探讨该分子与肿瘤发生、发展及预后等方面的关系。     

结直肠癌分子分型及分子标志物的研究进展

结直肠癌(colorectal cancer, CRC)是生物学高度异质性的肿瘤,对其进行分子分型有助于识别肿瘤组织来源、预测肿瘤进展或转移复发风险,且是个体化精准治疗的必要前提。分子标志物RAS、BRAF、PI3KCA和HER-2能协助CRC的诊断、临床分期、判断预后和指导临床治疗。本文就近年来CRC分子分型及其分子标志物的研究作一综述。     

ceRNAs在结直肠癌中的研究进展

结直肠癌在我国乃至全球范围发生率和死亡率都居于前列,严重危害着人体的健康,虽然结直肠癌的诊断和治疗技术不断提高,但中晚期结直肠癌患者的生存期仍然不佳,因此需要深入理解结直肠癌的发生发展机制,竞争内源性RNA理论的提出加深了对肿瘤形成机制的理解。竞争内源性RNA理论认为假基因转录本、长链非编码RNA、环状RNA、mRNA能作为竞争性内源性RNA,它们拥有编码蛋白mRNA相同microRNA反应元件,能竞争结合microRNA的结合位点,影响功能蛋白的表达而发挥促癌或抑癌的作用。近来大量研究表明竞争性内源性RNA分子在结直肠癌恶性行为中发挥重要功能,因此有必要对这些研究进行归纳梳理,本文目的在于将这些在结直肠癌中研究的竞争性内源性RNA分子进行归类,并阐述这些分子在结直肠癌中的作用。      

膜联蛋白在肿瘤凋亡显像中的研究进展

目前的影像学检查方法尚不能在肿瘤治疗早期即对疗效进行有效判断,而活体凋亡显像能在细胞水平对肿瘤组织的改变进行早期、无创、动态监测,从而准确判断肿瘤细胞对化疗药物的反应。磷脂酰丝氨酸(PS)由细胞膜内侧翻转到细胞膜表面是细胞凋亡早期最具特征性的改变之一,这使得PS成为细胞凋亡显像的有效靶点。放射性核素标记的膜联蛋白可选择性与翻转到细胞膜表面的PS结合,从而可在体内对早期疗效进行判断。由于在有效的抗肿瘤治疗开始24 h后即可观察到大量的肿瘤细胞发生凋亡,因此活体凋亡显像有助于为临床个体化治疗方案的制订提供指导性意见。本文在临床前研究和临床试验两方面对膜联蛋白凋亡显像在抗肿瘤治疗早期疗效评价中的机制、应用、局限性及未来发展前景作一综述。     

脂肪酸代谢在恶性肿瘤发生机制及分子影像中的应用

恶性肿瘤的增殖需要多种能量物质包括糖、脂肪和蛋白质。代谢重编程为恶性肿瘤提供能量,促进肿瘤的发生发展。沃伯格效应被认为是肿瘤代谢的主要方式,在这个过程中葡萄糖利用增加,为肿瘤代谢提供能量;利用此特性18F-FDG显像因能准确反应肿瘤生物学特征、位置、进展和对治疗的反应,PET等分子影像已广泛应用于肿瘤诊断和治疗并发挥不可替代作用。此外,肿瘤还需要脂肪酸代谢产物调控蛋白质翻译后修饰,提供脂质信号分子及膜磷脂以抵抗化疗药物的作用等。利用肿瘤细胞脂肪酸合成增加这一特性,放射性核素标记短链脂肪酸可用于肿瘤显像。本文对肿瘤脂肪酸代谢及其分子影像学相关研究做一综述。      

光声成像在肿瘤诊断和治疗中的研究进展

癌症一直是困扰人类的一大难题，常规成像方法在肿瘤的诊断上存在一定的局限。光声成像作为目前医学影像研究的新热点，相比于常规影像方法，它可以利用内源性对比剂如黑色素和血红蛋白，实时且无创地监测与肿瘤血管生成相关物质的浓度，或者通过分子靶向性外源性造影剂与抗体或多肽结合，提供关于肿瘤结构及其分子信息，从而实现形态及功能成像。近年来，光声成像为癌症的早期诊断、肿瘤血管生成的研究、肿瘤微环境的探测，以及癌症进展和治疗反应的监测做出了有价值的贡献。根据光声成像在肿瘤成像上展示出的独特优势，本文就此种医学成像方法在癌症诊断、分期和治疗指导中的应用进展进行综述。      

Tumor markers.

The past decade has seen many advances in the detection, characterization, and clinical applications of tumor markers. Although cancer screening applications have been limited by low disease prevalences in asymptomatic populations, tumor markers may be of diagnostic value in specific situations. The major use of tumor markers in primary care is in monitoring disease recurrence and the response to therapy. These uses may obviate the need for second-look surgery as it has with CA 125 elevations in ovarian carcinoma. On the other hand, tumor markers may indicate a need for second-look surgery as when CEA levels are elevated in colorectal carcinoma. Despite the apparent usefulness of markers in detecting cancer recurrence, the clinician is reminded of the conditions justifying treatment with the discovery of an abnormal laboratory value as put forth by Fries and Holman: (1) the treatment should be known to be effective, (2) early treatment should be known to be more effective than therapy given after the disease is clinically apparent (or early treatment carry the risk of less toxicity), and (3) prediction of impending deterioration must be consistently accurate. When these criteria are met, the planning of therapeutic regimens on the basis of marker levels may be rationally considered. Until these criteria are met, elevated markers can only stimulate the clinician to be more vigilant in the search for response to therapy or recurrence. Exciting developments are on the horizon with respect to the use of tumor markers in radionuclide imaging, radioimmunoguided surgery, and development of drug delivery systems. Further research into the structure and function of these substances may provide further insights into the phenomena of malignant transformation, tumor invasion, metastasis, and the development of new therapeutic options. With new advances in molecular biology and with the identification of oncogenes, it may be possible in the future to detect mutant oncoproteins that are specific for early cancers and premalignant conditions. Delecting these oncoproteins may provide a basis for development of truly sensitive and specific markers that can be used to detect cancer at an early and curable stage.     

影像学生物标志物评估肝癌局部区域治疗的研究现状与进展

原发性肝癌局部区域治疗通过相关物理或化学方法使肿瘤细胞变性坏死,然而肝癌L R T s后早期肿瘤大小改变不明显,甚至肿瘤广泛坏死会导致肿瘤体积的增加,这限制了形态学影像用于评估肝癌对LRTs的治疗反应。随着影像学技术的进步与发展,提供更多微观组织学信息的影像学生物标志物被提出与研究,突破了形态学影像的局限性,给临床治疗提供了及时有效的疗效与预后信息。本文就影像学生物标志物在肝癌LRTs疗效评估中的应用现状及进展予以综述。     

How molecular imaging is speeding up antiangiogenic drug development

Drug development is a long process that generally spans about 10 to 15 years. The shift in recent drug discovery to novel agents against specific molecular targets highlights the need for more robust molecular imaging platforms. Using molecular probes, molecular imaging can aid in many steps of the drug development process, such as providing whole body readout in an intact system, decreasing the workload and speeding up drug development/validation, and facilitating individualized anticancer treatment monitoring and dose optimization. The main focus of this review is the recent advances in tumor angiogenesis imaging, and the targets include vascular endothelial growth factor and vascular endothelial growth factor receptor, integrin alpha(v)beta(3), matrix metalloproteinase, endoglin (CD105), and E-selectin. Through tumor angiogenesis imaging, it is expected that a robust platform for understanding the mechanisms of tumor angiogenesis and evaluating the efficacy of novel antiangiogenic therapies will be developed, which can help antiangiogenic drug development in both the preclinical stage and the clinical settings. Molecular imaging has enormous potential in improving the efficiency of the drug development process, including the specific area of antiangiogenic drugs.     

以纳米分子探针为基础的分子影像技术在肿瘤早期检测中的应用

包含纳米材料、纳米器件以及纳米表征测量等的纳米技术,对生物、医学的进步产生了巨大影响.尤其利用纳米材料独特的颗粒及光学、电学等特性,结合现代医学影像技术,如光学成像、CT、PET/SPECT、MRI及超声成像(US)等,有可能在肿瘤发生初期进行早期特异性检测和有效的靶向治疗,使影像医学从对传统的解剖和生理功能的研究进展到分子水平成像,实现靶向分子成像,探索疾病的分子水平变化,在疾病早期做出明确诊断.     

A review of micro- and macrovascular analyses in the assessment of tumor-associated vasculature as visualized by MR

There is currently no noninvasive, reliable method of assessing brain tumor malignancy or of monitoring tumor treatment response. Monitoring changes to tumor vasculature might provide an effective means of assessing both tumor aggressiveness and treatment efficacy. To date, most such research has concentrated upon tumor "microvascular" imaging, with permeability and/or perfusion imaging used to assess vessel changes at the subvoxel level. An alternative approach assesses tumor vasculature at the "macroscopic" level, calculating the numbers and shapes of the larger vessels discriminable by magnetic resonance angiography. This paper provides an overview of magnetic resonance (MR) vascular imaging at both the microscopic (dynamic MR perfusion and permeability) and macroscopic (MR angiographic) levels. The two approaches provide different, complementary information and together could provide important insights into cancer growth as well as new methods of assessing malignancy and tumor treatment response.     

Contrast ultrasound imaging for identification of early responder tumor models to anti-angiogenic therapy

Agents targeting vascular endothelial growth factor (VEGF) have been validated as cancer therapeutics, yet efficacy can differ widely between tumor types and individual patients. In addition, such agents are costly and can have significant toxicities. Rapid noninvasive determination of response could provide significant benefits. We tested if response to the anti-VEGF antibody bevacizumab (BV) could be detected using contrast-enhanced ultrasound imaging (CEUS). We used two xenograft model systems with previously well-characterized responses to VEGF inhibition, a responder (SK-NEP-1) and a non-responder (NGP), and examined perfusion-related parameters. CEUS demonstrated that BV treatment arrested the increase in blood volume in the SK-NEP-1 tumor group only. Molecular imaging of α(V)β(3) with targeted microbubbles was a more sensitive prognostic indicator of BV efficacy. CEUS using RGD-labeled microbubbles showed a robust decrease in α(V)β(3) vasculature following BV treatment in SK-NEP-1 tumors. Paralleling these findings, lectin perfusion assays detected a disproportionate pruning of smaller, branch vessels. Therefore, we conclude that the response to BV can be identified soon after initiation of treatment, often within 3 days, by use of CEUS molecular imaging techniques. The use of a noninvasive ultrasound approach may allow for earlier and more effective determination of efficacy of antiangiogenic therapy.     

In vivo fluorescence molecular imaging of the vascular endothelial growth factor in rats with early diabetic retinopathy

Anti-vascular endothelial growth factor (anti-VEGF) therapy is effective for reducing the severity level of diabetic retinopathy (DR). However, it is difficult to determine the in vivo spatial and temporal expression of VEGF in the DR retina at an early stage. Here, we report a quantitatively fluorescence molecular imaging and image analysis method by creating a VEGF targeted fluorescence imaging probe, which can potentially detect and predict anti-VEGF treatment response. Moreover, the ex vivo multiscale fluorescence imaging demonstrated the spatial correlation between VEGF relative expression and vascular abnormalities in two and three dimensions. It revealed that VEGF was mainly abnormally expressed at the bifurcation of the microvessels, which advances the knowledge of the DR progression by molecular fluorescence imaging. Our study has the potential to achieve early detection of DR disease, provide more insight into understanding anti-VEGF treatment, and may help stratify patients based on the molecular imaging of retinal VEGF.