质子束放疗在肿瘤中的研究进展

肿瘤放疗的基本准则是提高肿瘤靶区的放射剂量,同时更好地保护肿瘤周围的正常组织器官。质子束治疗（PBT）是目前全球最先进的放疗技术之一,其能更好地体现这一准则。理论上,质子束以其特有的Bragg峰和优越的相对生物学效应,可给予肿瘤靶区最大剂量,同时降低肿瘤周围正常组织器官的接受剂量,实现对肿瘤靶区的“定向爆破”,提高肿瘤的局部治疗率和控制率,优于传统光子治疗。目前已应用于临床的研究包括黑色素瘤、肺癌、食管癌、乳腺癌、肝癌、前列腺癌和儿童恶性肿瘤等多种病变,但多为回顾性研究,而且建立和维护质子设备的成本巨大,因此用PBT治疗恶性肿瘤尚存争议。PBT面临的挑战是缺乏足够的临床证据和不明确的生物学效应等,克服这些不足可能会更好地促进PBT的快速发展。笔者详细论述了PBT的物理、生物学特性及其在肿瘤治疗中的研究和应用进展。     

Effects of Selenium on Radiation Responses of Tumor Cells and Tissue

PURPOSE: This review summarizes information about modulation of radiation effects in tumor cells and tissues by selenium. RESULTS: In vitro, clonogenic survival to ionizing radiation was found to be reduced, depending on selenite concentration and duration of administration, by a factor of 1.5-4.4. In experimental animal tumors, a positive effect of selenium was observed with chemotherapy. The only available study in combination with irradiation did not show any benefit of selenium with clinically relevant radiotherapy protocols in R1H tumors. None of the investigations demonstrated a negative effect on the tumor response to therapy. CONCLUSION: The only study with fractionated irradiation was performed in a rat R1H tumor, which does not show accelerated repopulation. Therefore, interaction of selenium with such repopulation processes, potentially resulting in increased tumor tolerance, could not be detected. For local administration of normal tissues with selenium, potential tumor effects may be of less importance, but these may be relevant for systemic administration. Therefore, well-designed studies with relevant tumor models and endpoints, and with clinically relevant fractionation protocols are recommended.     

组蛋白去乙酰化酶抑制剂用于放疗增敏的分子机制研究进展

放射治疗是目前临床上最常用的治疗癌症的手段之一，但其仍存在辐射剂量高、正常组织不良反应大，以及肿瘤细胞的放疗耐受等缺点。因此，寻求安全有效的放疗增敏剂以提高肿瘤细胞对辐射的敏感性一直是放疗研究的热点。组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitors，HDACIs）是一类表观遗传学修饰剂，除了其固有的抗癌特性外，还能调节肿瘤细胞对电离辐射和紫外线辐射敏感性。本文在查阅文献基础上，重点阐述了HDACIs增强肿瘤细胞辐射敏感性的不同分子机制以及对肿瘤细胞的选择性杀伤作用。     

Magnetic resonance imaging evaluation of radiation-induced changes in experimentally implanted renal cell carcinoma

The effect of radiation on the magnetic resonance imaging appearance and relaxation parameters of human renal cell tumors implanted in male white-Swiss athymic nude mice was evaluated. Twenty-three mice were treated with external beam radiation, receiving a total dose of 2,500 rads administered in a single treatment limited to subcutaneous tumor. Twenty-two tumor-bearing mice served as control animals. Experimental and control mice were studied with MRI at four (n = 9), seven (n = 20), 14 (n = 8), and 28 (n = 8) days following experimental radiotherapy. A 0.35 tesla superconductive MRI system was employed. Images were generated using spin-echo technique with repetition times (TR) of 500 and 2,000 ms and echo-delay times (TE) of 28 to 30 and 56 to 60. Relaxation time calculations were made on the basis of tumor signal-intensity measurements in assigned regions of interest. The MRI appearances and relaxation times of irradiated tumors that decreased in size following treatment, irradiated tumors that grew, and control tumors were similar, as were their histologic features. No statistically significant differences could be detected in relaxation times of the four experimental and four control groups. Statistical evaluation was performed using analysis of variance. Further investigation of MRIs potential in tissue characterization following radiotherapy is warranted, but evaluation of change in tumor dimensions remains the most reliable indicator of therapeutic response.     

脑肿瘤治疗后磁共振质子波谱评价

目的：评估脑肿瘤手术后、放疗后的多体素^1H MRS的临床应用价值。方法：21例脑肿瘤手术后、放疗后行多体素^1H MRS检查。结果：^1H MRS显示脑肿瘤内Cho升高5例，其中4例手术证实为肿瘤复发，1例为胶质增生。放射治疗后肿瘤生长抑制。^1H MRS表现为Cho降低，NAA、Cr明显下降。放射性坏死^1H MRS表现为肿瘤坏死区出现乳酸-脂质峰。结论：^1H MRS可评估脑肿瘤术后复发和监测肿瘤放疗后的病理变化，是一种有价值的检查方法。     

电离辐射对淋巴管的影响研究进展

电离辐射会造成淋巴管内皮细胞死亡,导致淋巴管结构破坏、功能紊乱和数量减少,对放疗产生负面影响,但也会诱导肿瘤细胞和肿瘤浸润性免疫细胞等细胞分泌多种细胞因子,促进肿瘤相关淋巴管生成,增强抗肿瘤免疫,有利于抗肿瘤治疗。研究电离辐射后淋巴管变化可能是探索放疗与免疫治疗协同抗肿瘤作用的一个途径。本综述从电离辐射后淋巴管形态学改变、电离辐射影响淋巴管分子机制和电离辐射后淋巴管变化在临床中的价值3个角度进行了归纳分析,以期为开展电离辐射对淋巴管影响的研究提供思路。     

无机纳米材料介导的肿瘤放疗增敏的研究进展

放疗作为一种肿瘤治疗手段,可通过电离辐射对肿瘤细胞造成直接或间接的损伤,但电离辐射对正常组织的损伤和肿瘤的放疗抵抗等问题会影响放疗的疗效。肿瘤放疗增敏是近年来的研究热点,其旨在增强肿瘤对放疗的敏感性,从而克服放疗的缺陷,提高放疗的疗效。无机纳米材料介导的肿瘤放疗增敏主要通过增加细胞内的辐射能量沉积、催化产生活性氧自由基和调控肿瘤微环境等方式提高放疗的疗效。笔者就无机纳米材料介导的肿瘤放疗增敏的研究进展进行综述。     

Potential use of in vivo proton spectroscopy for head and neck lesions

Early experience with in vivo MRS has shown its potential for obtaining biochemical information, thus enhancing the diagnostic sensitivity of MRI studies. Further work on combined MRI and in vivo MRS is needed, with the goal of characterization and abnormal conditions according to their spectral patterns and for identification of tumor markers. We presented in this communication our preliminary results. It seems that the resonance from melanin can be used as a marker for melanotic tumors.     

Assessment of radiotherapeutic effect on brain tumors by dynamic susceptibility contrast MR imaging: a preliminary report.

PURPOSE: The purpose of this study was to assess tumor vascularity of the brain by dynamic susceptibility contrast (DSC) MR imaging and to determine whether this method is clinically useful for monitoring radiation effects on brain tumors. We, furthermore, compared DSC MR imaging with single-photon emission computed tomography (SPECT) using technetium-99m diethylene-triamine-pentaacetic acid human serum albumin (99mTc-HSA-D) in the assessment of tumor vascularity in a limited numbers of cases. METHODS: Twelve patients with various kinds of brain tumors were studied. DSC MRI was performed on all patients before and after radiation therapy. SPECT using 99mTc-HSA-D was also performed in five patients. The rate of change in tumor blood volume in response to radiation therapy was evaluated with DSC MRI and SPECT. The rate of change in tumor volume in response to radiation was also measured. RESULTS: Ten patients were successfully studied. The rate of change in tumor blood volume correlated well between DSC MRI and SPECT. There was no significant correlation between the rates of change for tumor blood volume and tumor volume. Changes in tumor vascularity preceded the reduction in tumor volume seen following radiotherapy. CONCLUSION: DSC MRI provides information regarding radiation effects on tumor vessels that is not available with conventional MRI.     

Radioluminescent nanoparticles and deep-tissue photodynamic therapy to enhance radiotherapy efficacy

Photodynamic therapy (PDT) is an anticancer therapy that relies on the light activation of non-toxic photosensitizers to generate reactive oxygen species (ROS) to damage tumor cells. As the excitation light for PDT lies in the visible range, it can only penetrate up to a few mm in tissues. Therefore, the application of PDT is limited to superficial or optic-fiber accessible tumors. In order to overcome this major limitation, it has been proposed to leverage the particular properties of scintillating nanoparticles, which down-convert ionizing radiation into visible light. Scintillating nanoparticles can therefore act as internal light sources remotely activated by the penetrating X-rays used in radiotherapy to activate deep tissue PDT¹, or X-ray induced PDT (XPDT). Proof-of-concept studies have been published, yet the therapeutic mechanisms remain to be fully understood. When using nanoscintillators in combination with radiotherapy, mechanisms other than PDT can also be activated. For example, as nanoscintillators are typically made of high-Z elements, we hypothesized the existence of the purely physical radiation dose-enhancement effect. This effect is initiated by a higher photoelectric absorption of orthovoltage X-rays (< 250 keV) by high-Z elements compared to soft tissues, which leads to a higher production of photo- and Auger electrons that enhance the damage to cancer tissues for a given dose of radiotherapy². In this communication, we will present the results we recently obtained with Lu₃Al₅O₁₂:Pr nanoscintillators conjugated to the photosensitizer protoporphyrin IX. More specifically, we will present the ability of these nanoconjugates to enhance the efficacy of radiotherapy through different mechanisms, such as radiation dose enhancement and XPDT, against pancreatic cancer cells cultured both as 2D monolayers and 3D spheroids.     

Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications

Purpose: Cancer treatment is one of the most challenging diseases in the present era. Among a few modalities for cancer therapy, radiotherapy plays a pivotal role in more than half of all treatments alone or combined with other cancer treatment modalities. Management of normal tissue toxicity induced by radiation is one of the most important limiting factors for an appropriate radiation treatment course. The evaluation of mechanisms of normal tissue toxicity has shown that immune responses especially inflammatory responses play a key role in both early and late side effects of exposure to ionizing radiation (IR). DNA damage and cell death, as well as damage to some organelles such as mitochondria initiate several signaling pathways that result in the response of immune cells. Massive cell damage which is a common phenomenon following exposure to a high dose of IR cause secretion of a lot of inflammatory mediators including cytokines and chemokines. These mediators initiate different changes in normal tissues that may continue for a long time after irradiation. In this study, we reviewed the mechanisms of inflammatory responses to IR that are involved in normal tissue toxicity and considered as the most important limiting factors in radiotherapy. Also, we introduced some agents that have been proposed for management of these responses.

Conclusions: The early inflammation during the radiation treatment is often a limiting factor in radiotherapy. In addition to the limiting factors, chronic inflammatory responses may increase the risk of second primary cancers through continuous free radical production, attenuation of tumor suppressor genes, and activation of oncogenes. Moreover, these effects may influence non-irradiated tissues through a mechanism named bystander effect.     

MR波谱在鼻咽癌放疗后颅底复发与放射性脑病鉴别诊断中的应用

目的 应用MR波谱(MRS)对鼻咽癌颅底复发与放射性脑病进行对比研究,探讨MRS对两者的鉴别诊断价值.方法 选择鼻咽癌根治性放射治疗后经常规MRI怀疑鼻咽癌颅底复发或放射性脑病患者50例行MRS,其中男44例,女6例,经临床及MRI复查综合诊断,26例为鼻咽癌颅底复发,24例为颞叶放射性脑病.对比分析放疗后复发与放射性脑病之间及其与相对"正常"脑组织之间胆碱(Cho)、N-乙酰天冬氨酸(NAA)、肌酸(Cr)、乳酸-脂质(LL)等主要代谢物含量的异同.采用秩和检验对所得数据进行统计分析.结果 复发组的Cho/Cr、Cho/NAA、LL/Cr中位数分别为2.22、2.13、1.77,放射性脑病组分别为1.40、1.31、0.57,两者间差异有统计学意义(P值均<0.01),复发组高于放射性脑病组.肿瘤复发组Cho、Cr、NAA的中位数分别为3366.00、1023.00、1930.00,放射性脑病组分别为2469.50、1864.50、1734.00,3个代谢产物的含量在肿瘤复发与放射性脑病之间差异均无统计学意义(P值均>0.05).在取得了"正常"脑组织对比的14个肿瘤复发病例中,复发灶的Cr、NAA、LL、Cho/Cr、Cho/NAA、LL/Cr的中位数分别为1023.00、1930.00、2090.00、3.76、2.13、3.39,"正常"区域分别为2370.00、3012.00、1680.00、1.64、1.17、0.75,两组各参数间差异均有统计学意义(P值均<0.05),复发灶的LL、Cho/Cr、Cho/NAA、LL/Cr高于"正常"区域,而NAA、Cr低于"正常"区域;在取得了"正常"脑组织对照的12个放射性脑病病例中,放射性脑病的Cho、Cr、NAA、LL、Cho/Cr、LL/Cr的中位数分别为390.00、217.50、427.50、39.00、1.30、0.40,而"正常"脑组织分别为680.00、360.00、610.00、30.00、1.54、0.09,上述参数在放射性脑病与其"正常"区域之间差异有统计学意义,放射性脑病的Cho(P<0.01)、Cr(P<0.01)、NAA(P<0.01)、Cho/Cr(P<0.05)低于"正常"区域,而放射性脑病的LL(P<0.05)、LL/Cr(P<0.01)高于"正常"组织.结论 鼻咽癌放疗后复发与放射件脑病在MRS上主要代谢物的变化各有特点,尤其是Cho/Cr、Cho/NAA、LL/Cr等指标复发灶明显高于放射性脑病,对于两者的鉴别诊断具有很高的价值.     

Results of irradiation using different radiation sources in the treatment of malignant parotid tumors

Patients with malignant parotid tumors were treated at two different centres with slightly ionizing radiation (110 patients) and neutron therapy (15 patients). The treatment results are compared. The principles of comparison applied in this analysis are identical. The histologic classification was made according to the W.H.O. recommendation of 1972 and the staging according to Becske. Local tumor control is the criterion applied in the comparative assessment of both methods. The analysis has shown that there is no significant difference in the treatment results within the individual stages of tumor's advancement after application of an orthovolt therapy and a telecobalt therapy. Patients treated in early stages (stages I and III) had a substantially higher rate of local tumor control (72%) than patients in advanced stages (46%, stages III and IV). A more favorable treatment results was achieved by neutron therapy in all stages of tumor's advancement. In this case the rate of patients with local tumor control (87%) was significantly higher than after radiotherapy with slightly ionizing radiation (46%).     

The role of magnetic resonance imaging in early detection of recurrent breast cancer

Purpose

The purpose of this work was the evaluation of new advances of magnetic resonance imaging (MRI) in diagnosis of recurrent breast cancer after conservative surgery, chemotherapy and radiotherapy.

Preoperative proton MR spectroscopic imaging of brain tumors: correlation with histopathologic analysis of resection specimens

BACKGROUND AND PURPOSE: Tumor progression is often difficult to distinguish from nonneoplastic treatment response on the basis of MR images alone. This study correlates metabolite levels measured by preoperative MR spectroscopic (MRS) imaging with histologic findings of biopsies, obtained during image-guided resections of brain mass lesions, to clarify the potential role of MRS in making this distinction. METHODS: Twenty-nine patients with brain tumors underwent high-resolution (0.2-1 cc) 3D proton MRS imaging and MR imaging before undergoing surgery; 11 had a newly diagnosed neoplasm, and 18 had recurrent disease. Surgical biopsies were obtained from locations referenced on MR images by guidance with a surgical navigation system. MR spectral voxels were retrospectively centered on each of 79 biopsy locations, and metabolite levels were correlated with histologic examination of each specimen. RESULTS: All mass lesions studied, whether attributable to tumor or noncancerous effects of previous therapy, showed abnormal MR spectra compared with normal parenchyma. When the pattern of MRS metabolites consisted of abnormally increased choline and decreased N-acetyl aspartate (NAA) resonances, histologic findings of the biopsy specimen invariably was positive for tumor. When choline and NAA resonances were below the normal range, histologic findings were variable, ranging from radiation necrosis, astrogliosis, and macrophage infiltration to mixed tissues that contained some low-, intermediate-, and high-grade tumor. CONCLUSION: This study demonstrated that 3D MRS imaging can identify regions of viable cancer, which may be valuable for guiding surgical biopsies and focal therapy. Regions manifesting abnormal MR spectra had a mixture of histologic findings, including astrogliosis, necrosis, and neoplasm.     

Magnetic resonance imaging of head and neck tumors

Magnetic resonance imaging (MRI) provides several advantages over computed tomography (CT) in the evaluation of head and neck region tumors. The improved soft-tissue contrast among normal and abnormal tissues provided by MRI now permits the exact delineation of tumor margins in the nasopharynx, oropharynx, and skull base regions. In addition, the ability to depict cross-sectional anatomy and pathology in three planes without intravenous contrast, patient manipulation, or ionizing irradiation is a distinct advantage of MRI over CT scanning. Drawbacks of MRI include the detection of subtle osseous abnormalities, patient motion, and artifacts introduced by ferromagnetic dental appliances. These drawbacks appear minimal when compared to the benefits of improved soft-tissue contrast and the ability to image exact tumor volumes.     

放疗联合免疫治疗的抗肿瘤免疫机制研究进展

作为恶性肿瘤的重要治疗方法之一,放疗通常被认为是一种局部治疗手段。然而,近年来越来越多的研究提示合理的放疗剂量和分割模式可改善肿瘤微环境,诱导肿瘤细胞免疫原性死亡,形成原位疫苗,激活全身的抗肿瘤免疫效应。同时,免疫治疗可有效增强放疗的抗肿瘤免疫作用,已在临床前研究中得到证实,正在临床研究中进行广泛探索。该文对放疗的抗肿瘤免疫效应及相关机制、放疗与免疫治疗联合应用的研究进展进行了综述。     

Role of short TE 1H-MR spectroscopy in monitoring of post-operation irradiated patients.

Post-surgical radiation therapy is a routine procedure in the treatment of primary malignant brain tumors. Along with modest therapeutic effects conventional fractionated radiotherapy, in spite of any modifications, produces damage to non-malignant brain tissues lying within the treatment volume, the extent of which depends on radiation dose. Serial 1H-MRS allows non-invasive investigation of tissue metabolic profiles. In the present study the ratios of resonance signals assigned to the major 1H-MRS-visible metabolites (N-acetylaspartate, choline, creatine, inositol, lactate and lipid methylene group) were evaluated before, during and after post-surgical fractionated radiotherapy in brain regions close to and more distant from the tumor bed, receiving different radiation exposures (60 and < 40 Gy, respectively). The study group consisted of ten patients (aged 28-51). A MRI/MRS system (Elscint 2T Prestige) operating at the field strength of 2 T and the proton resonance frequency of 81.3 MHz has been used and the 1H-MR spectra were acquired using single voxel double-spin-echo PRESS sequence with a short TE. The spectra were post-processed with automatic fitting in the frequency domain. It was found that although the metabolite profiles depend on the dose obtained, but other stress factors (like surgery) seem to contribute to the overall picture of the metabolic status of the brain as well. In studies of early irradiation injuries, an increase of choline related ratios may serve rather as cell proliferation indictors than as cell injury ones, whereas the mI/Cr ratio appears as one of the first indicators of local irradiation injury. In order to establish the prognostic marker for early radiation damage, however, it seems necessary to analyze all visible metabolites as well. None of the metabolites separately may serve as such an indicator due to the complexity of tissue metabolism. Interestingly, MRI reveals no changes during the therapy process, whereas the metabolite ratios are being affected in the course of time, thus supporting the presumption that the 1H-MRS is a valuable method of radiation therapy monitoring.     

大鼠肝肿瘤细胞灶性凋亡MRI表现

目的:建立大鼠肝肿瘤细胞凋亡模型并研究其磁共振成像表现.方法:选取45只肝肿瘤大鼠,随机分成放疗组,酒精注射组及对照组,每组15只,分1d、3d、7d共3个时间点观察;每组大鼠每个时间点均采集磁共振MRI、DWI、~1H-MRS图像,分析磁共振图像,并测量ADC值及~1H-MRS各代谢物波峰下面积,进行统计学处理;磁共振检查后取标本送病理学(HE,TUNEL,PCNA)及电镜检查;将病理学检查结果与磁共振图像对照分析.结果:①病理学检查结果证实放疗组肝肿瘤细胞发生凋亡;酒精注射组肝肿瘤细胞以发生坏死为主;②放疗组同未治疗组比较肿瘤体积减小,T_1 WI信号等低,T_2 WI信号稍减低,DWI信号下降,呈等高信号,内见条片状等低信号区,ADC值增加,Lip、Cho、Lae、Glx峰下降,Cr峰变化不大;③酒精治疗组体积缩小,病灶中央信号强度明显减低,旱条片状,T_1 WI等低信号,T_2 WI低信号;DWI信号不均匀片状减低,ADC值介于正常组织与残留肿瘤组织之间;Lip、Cho、Lac、Glx、Cr各峰明显下降.结论:大鼠肝肿瘤放疗可诱导细胞凋亡,凋亡后磁共振检查有特异性表现.特别是T_2WI、DWI、~1H-MRS,活体检测肿瘤细胞凋亡成为可能.     

PI3K/Akt与胶质瘤辐射抗性

恶性脑胶质瘤的术后治疗是患者预后生存期延长的关键,如何提高肿瘤组织的辐射敏感性,增强正常组织的辐射抗性是当前肿瘤放射生物学及临床放疗研究的热点。研究资料表明,PI3K/Akt抗细胞凋亡通路的激活提高了部分细胞的辐射抗性,特别在表皮细胞受紫外线照射的研究中提示,辐射产生的活性氧可能是该通路激活的原因之一;电离辐射可能诱导相关的细胞因子通过激活PI3K/Akt通路介导胶质瘤细胞的辐射抗性;PI3K及其相关酶可能通过DNA修复途径发挥抗辐射作用。PI3K/Akt通路的研究可为放射治疗胶质瘤提供新型的增敏药。