A multimodal contrast agent for preoperative MR Imaging and intraoperative tumor margin delineation

We have constructed a multimodal contrast agent suitable for near-infrared, NIR, fluorescent imaging as well as magnetic resonance imaging, MRI. This class of agents may be useful for preoperative tumor localization and tumor functional evaluation and for intraoperative delineation of tumor margins. We have covalently attached dyes of the cyanine family to a previously described polymeric contrast agent, Gd-DTPA-polylysine, of an extended, uncoiled conformation. The dual modality agent is as effective in imaging tumors by MRI as the parent compound provided that the dye loading on the polymer is such that it does not eliminate all the available free-lysine groups on the parent Gd-DTPA-polylysine polymers. NIR fluorescence from preclinical subcutaneous and orthotopic mammary gland tumors could be detected with a signal to background ratio of as high as 4.5 at 12 hours post agent injection at a dye dose of 125 nmole/kg. For intraoperative delineation of tumor margins, a wide-field illumination camera system was devised giving high signal to background NIR fluorescent images of surgically exposed orthotopic mammary gland tumors. Histologic microscopy confirmed the location of the dual modality agent at the boundary of the tumor with a margin distance of about 0.3 mm from labeled tumor cells.     

Fluorescent Nanoparticle Uptake for Brain Tumor Visualization

Accurate delineation of tumor margins is vital to the successful surgical resection of brain tumors. We have previously developed a multimodal nanoparticle CLIO-Cy5.5, which is detectable by both magnetic resonance imaging and fluorescence, to assist in intraoperatively visualizing tumor boundaries. Here we examined the accuracy of tumor margin determination of orthotopic tumors implanted in hosts with differing immune responses to the tumor. Using a nonuser-based signal intensity method applied to fluorescent micrographs of 9L gliosarcoma green fluorescent protein (GFP) tumors, mean overestimations of 2 and 24 µm were obtained using Cy5.5 fluorescence, compared to the true tumor margin determined by GFP fluorescence, in nude mice and rats, respectively. To resolve which cells internalized the nanoparticle and to quantitate degree of uptake, tumors were disaggregated and cells were analyzed by flow cytometry and fluorescence microscopy. Nanoparticle uptake was seen in both CD11b⁺ cells (representing activated microglia and macrophages) and tumor cells in both animal models by both methods. CD11b⁺ cells were predominantly found at the tumor margin in both hosts, but were more pronounced at the margin in the rat model. Additional metastatic (CT26 colon) and primary (Gli36 glioma) brain tumor models likewise demonstrated that the nanoparticle was internalized both by tumor cells and by host cells. Together, these observations suggest that fluorescent nanoparticles provide an accurate method of tumor margin estimation based on a combination of tumor cell and host cell uptake for primary and metastatic tumors in animal model systems and offer potential for clinical translation.     

Low grade gliomas: comparison of intraoperative ultrasound characteristics with preoperative imaging studies

Thirty-three patients with low grade gliomas were evaluated with preoperative computed tomography (CT), magnetic resonance (MR) and intraoperative ultrasound (IOUS). Six patients had undergone previous surgical exploration. Tumor borders were marked with cortical letters and corresponding depths calculated. Resection of tumor corresponded to these ultrasound dimensions. The histology of biopsy specimens from tumor and ultrasound determined margins was studied on formalin fixed permanent sections using hematoxylin and eosin (H&E) and immunocytochemistry (GFAP).Tumors were all seen on preoperative MR studies and most commonly showed a decreased T₁ and increased T₂ signal. Seven tumors showed variable enhancement with gadolinium. On CT two tumors were not seen, twenty-three tumors were hypodense and eight hyperdense. Three tumors showed variable CT contrast enhancement. All tumors were hyperechoic on ultrasound. Twenty-five (75%) tumors were well defined with distinct margins compared to adjacent brain. Eight tumors had poorly defined borders on ultrasound; five (62%) of these lesions had previously undergone surgeery. Eight tumors invaded functional brain identified by stimulation mapping techniques (e.g., speech cortex), thus limiting the resection. Five resections were limited because of involvement of important anatomical structures (e.g., corpus callosum). Of the remaining 20 tumors, seventeen (85%) had ultrasound defined margins that were histologically free of solid tumor (normal brain or sparse atypical cells only).Low grade gliomas are readily identified and their margins well defined by intraoperative ultrasound regardless of preoperative imaging patterns. The results suggest that IOUS may enhance intraoperative delineation and extent of resection for low grade gliomas.     

MR and iron magnetic nanoparticles. Imaging opportunities in preclinical and translational research

Ultrasmall superparamagnetic iron oxide nanoparticles and magnetic resonance imaging provide a non-invasive method to detect and label tumor cells. These nanoparticles exhibit unique properties of superparamagnetism and can be utilized as excellent probes for magnetic resonance imaging. Most work has been performed using a magnetic resonance scanner with high field strength up to 7 T. Ultrasmall superparamagnetic iron oxide nanoparticles may represent a suitable tool for labeling molecular probes that target specific tumor-associated markers for in vitro and in vivo detection by magnetic resonance imaging. In our study, we demonstrated that magnetic resonance imaging at 1.5 T allows the detection of ultrasmall superparamagnetic iron oxide nanoparticle conjugated antibody specifically bound to human tumor cells in vitro and in vivo, and that the magnetic resonance signal intensity correlates with the concentration of ultrasmall superparamagnetic iron oxide nanoparticle antibody used and with the antigen density at the cell surface. The experiments were performed using two different means of targeting: direct and indirect magnetic tumor targeting. The imaging of tumor antigens using immunospecific contrast agents is a rapidly evolving field, which can potentially aid in early disease detection, monitoring of treatment efficacy, and drug development. Cell labeling by iron oxide nanoparticles has emerged as a potentially powerful tool to monitor trafficking of a large number of cells in the cell therapy field. We also studied the labeling of natural killer cells with iron nanoparticles to a level that would allow the detection of their signal intensity with a clinical magnetic resonance scanner at 1.5 T. Magnetic resonance imaging and iron magnetic nanoparticles are able to increase the accuracy and the specificity of imaging and represent new imaging opportunities in preclinical and translational research.     

多模态脑功能定位在胶质瘤中的临床应用

目的:探讨术前多模态磁共振弥散张量成像（diffusion tensor imaging，DTI）脑功能定位技术在脑胶质瘤手术中的应用价值。方法:选择2016年1月至2017年3月在我院接受手术治疗的25例脑胶质瘤患者作为研究对象，所有患者术前均利用核磁共振DTI技术在导航工作站将肿瘤、神经纤维束及肿瘤周边的结构进行重建，并进行3D打印，术前根据3D打印出来的模型进行模拟手术，术中避开重要结构切除肿瘤，手术入路设计上可以避免损伤脑功能区及肿瘤周边的重要结构，通过多模态定位技术进行脑胶质瘤手术。结果:术前导航定位准备工作13～19 min，平均（15.2±1.4） min；iMRI扫描准备时间4～7 min，平均（5.8±0.8） min。25例患者全切21例，占84％；次全切或部分全切4例，占16％。术后KPS评分与术前相比较显著升高（P<0.05）。术后1年生存23例，生存率92％。结论:术前多模态磁共振DTI脑功能定位技术用于脑胶质瘤的手术治疗可通过影像融合和重建，提供准确的肿瘤与功能区结构的关系，准确显示肿瘤位置，为肿瘤的精准切除提供了保障。     

Presurgical mapping with magnetic source imaging: comparisons with intraoperative findings

We compare noninvasive preoperative mapping with magnetic source imaging to intraoperative cortical stimulation mapping. These techniques were directly compared in 17 patients who underwent preoperative and postoperative somatosensory mapping of a total of 22 comparable anatomic sites (digits, face). Our findings are presented in the context of previous studies that used magnetic source imaging and functional magnetic resonance imaging as noninvasive surrogates of intraoperative mapping for the identification of sensorimotor and language-specific brain functional centers in patients with brain tumors. We found that magnetic source imaging results were reasonably concordant with intraoperative mapping findings in over 90% of cases, and that concordance could be defined as “good” in 77% of cases. Magnetic source imaging therefore provides a viable, if coarse, identification of somatosensory areas and, consequently, can guide and reduce the time taken for intraoperative mapping procedures.     

Image-guided tumor resection using real-time near-infrared fluorescence in a syngeneic rat model of primary breast cancer

Tumor involvement of resection margins is found in a large proportion of patients who undergo breast-conserving surgery. Near-infrared (NIR) fluorescence imaging is an experimental technique to visualize cancer cells during surgery. To determine the accuracy of real-time NIR fluorescence imaging in obtaining tumor-free resection margins, a protease-activatable NIR fluorescence probe and an intraoperative camera system were used in the EMR86 orthotopic syngeneic breast cancer rat model. Influence of concentration, timing and number of tumor cells were tested in the MCR86 rat breast cancer cell line. These variables were significantly associated with NIR fluorescence probe activation. Dosing and tumor size were also significantly associated with fluorescence intensity in the EMR86 rat model, whereas time of imaging was not. Real-time NIR fluorescence guidance of tumor resection resulted in a complete resection of 17 out of 17 tumors with minimal excision of normal healthy tissue (mean minimum and a mean maximum tumor-free margin of 0.2 ± 0.2 mm and 1.3 ± 0.6 mm, respectively). Moreover, the technique enabled identification of remnant tumor tissue in the surgical cavity. Histological analysis revealed that the NIR fluorescence signal was highest at the invasive tumor border and in the stromal compartment of the tumor. In conclusion, NIR fluorescence detection of breast tumor margins was successful in a rat model. This study suggests that clinical introduction of intraoperative NIR fluorescence imaging has the potential to increase the number of complete tumor resections in breast cancer patients undergoing breast-conserving surgery.     

多参数MRI及基于MRI的放射组学在膀胱癌诊断中的价值

膀胱癌发病率居全球恶性肿瘤前列,其诊断和分期主要依靠膀胱镜取病理活检,因其有创性及取材范围局限性,膀胱癌术前分期困难及预后差等问题仍然是临床诊疗的难点。目前,临床缺乏对膀胱癌术前精准分期及术后评估的无创的影像学方法。多模态磁共振技术包括T2加权、动态对比增强（dynamic contrast enhanced,DCE）和弥散加权成像（diffusion weighted imaging,DWI）被探索性地应用于肿瘤分期、阳性淋巴结的检出、复发预测等方面。同时,基于多模态磁共振技术的放射组学能对肿瘤内部信息进行挖掘,为肿瘤诊断提供更多影像学依据。     

Novel strategies in glioblastoma surgery aim at safe,supra-maximum resection in conjunction with local therapies

The biggest challenge in neuro-oncology is the treatment of giioblastoma, which exhibits poor prognosis and is increasing in incidence in an increasing aging population. Diverse treatment strategies aim at maximum cytoreduction and ensuring good quality of life. We discuss multimodal neuronavigation, supra-maximum tumor resection, and the postoperative treatment gap. Multimodal neuronavigation allows the integration of preoperative anatomic and functional data with intraoperative information. This approach includes functional magnetic resonance imaging （MRI） and diffusion tensor imaging in preplanning and ultrasound, computed tomography （CT）, MRI and direct （sub）cortical stimulation during surgery. The practice of awake craniotomy decreases postoperative neurologic deficits, and an extensive supra- maximum resection appears to be feasible, even in eloquent areas of the brain. Intraoperative MRI- and fluorescence-guided surgery assist in achieving this goal of supra-maximum resection and have been the subject of an increasing number of reports. Photodynamic therapy and local chemotherapy are properly positioned to bridge the gap between surgery and chemoradiotherapy. The photosensitizer used in fluorescence-guided surgery persists in the remaining peripheral tumor extensions. Additionally, blinded randomized clinical trials showed firm evidence of extra cytoreduction by local chemotherapy in the tumor cavity. The cutting-edge promise is gene therapy although both the delivery and efficacy of the numerous transgenes remain under investigation. Issues such as the choice of （cell） vector, the choice of therapeutic transgene, the optimal route of administration, and biosafety need to be addressed in a systematic way. In this selective review, we present various evidence and promises to improve survival of glioblastoma patients by supra-maximum cytoreduction via local procedures while minimizing the risk of new neurologic deficit.     

A plea for the biopsy marker: how,why and why not clipping after breast biopsy?

In the last decade, percutaneous breast biopsies have become a standard for the management of breast diseases. Biopsy clips allow for precise lesion localization, thus minimizing the volume of breast to be resected at the time of surgery. With the development of many imaging techniques (including mammography, sonography, and breast magnetic resonance imaging), one of the challenges of the multidisciplinary became to synthesize all informations obtained from the various imaging procedures. The use of biopsy markers after percutaneous biopsy is one of the keys for optimal patient management, helping the radiologist to deal with multiple lesions, to insure correlation across different imaging modalities and to follow-up benign lesions, helping the oncologist by marking a tumor prior to neoadjuvant chemotherapy, helping the surgeon by facilitating preoperative needle localization, to precisely mark the margins of extensive disease and to guide intraoperative tumor resection, and helping the pathologist to insure the lesion of interest has been removed and to identify the region of interest in a mastectomy specimen. We believe biopsy clip markers should be deployed after all percutaneous interventions and present in this review the arguments to support this statement. Minimal indications for clip deployment will also be detailed.     

Vascular targeted nanoparticles for imaging and treatment of brain tumors.

PURPOSE: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. EXPERIMENTAL DESIGN: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents. RESULTS: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. CONCLUSIONS: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.     

Surgical considerations in early-stage breast cancer: lessons learned and future directions

Emerging evidence regarding the relationship between local failure and outcome in breast cancer has placed increased emphasis on the surgeon's role in reducing local recurrence after breast-conserving surgery. This includes both improving patient selection and optimizing the procedure. Proper patient selection, selective use of magnetic resonance imaging, and better patient-physician communication including the use of decision aids can optimize both local control and patient satisfaction without unnecessarily increasing the mastectomy rate. Neoadjuvant systemic therapy can increase both the number of patients eligible for breast-conservation surgery as well as the likelihood of success. Adequate surgical margins are crucial and can be achieved without excessive re-excision rates with detailed preoperative planning, consideration of oncoplastic resections. and intraoperative margin analysis. This article reviews several areas in which the surgeon can help ensure the success of breast-conservation therapy.     

Real-time multi-modality imaging of glioblastoma tumor resection and recurrence

The lack of relevant pre-clinical animal models incorporating the clinical scenario of Glioblastoma multiforme (GBM) resection and recurrence has contributed significantly to the inability to successfully treat GBM. A multi-modality imaging approach that allows real-time assessment of tumor resection during surgery and non-invasive detection of post-operative tumor volumes is urgently needed. In this study, we report the development and implementation of an optical imaging and magnetic resonance imaging (MRI) approach to guide GBM resection during surgery and track tumor recurrence at multiple resolutions in mice. Intra-operative fluorescence-guided surgery allowed real-time monitoring of intracranial tumor removal and led to greater than 90 % removal of established intracranial human GBM. The fluorescent signal clearly delineated tumor margins, residual tumor, and correlated closely with the clinically utilized fluorescence surgical marker 5-aminolevulinic acid/porphyrin. Post-operative non-invasive optical imaging and MRI confirmed near-complete tumor removal, which was further validated by immunohistochemistry (IHC). Longitudinal non-invasive imaging and IHC showed rapid recurrence of multi-focal tumors that exhibited a faster growth rate and altered blood-vessel density compared to non-resected tumors. Surgical tumor resection significantly extended long-term survival, however mice ultimately succumbed to the recurrent GBM. This multi-modality imaging approach to GBM resection and recurrence in mice should provide an important platform for investigating multiple aspects of GBM and ultimately evaluating novel therapeutics.     

Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment

Malignant glioma is a common and severe primary brain tumor with a high recurrence rate and an extremely high mortality rate within 2 years of diagnosis, even when surgical, radiological, and chemotherapeutic interventions are applied. Intravenously administered drugs have limited use because of their adverse systemic effects and poor blood–brain barrier penetration. Here, we combine 2 methods to increase drug delivery to brain tumors. Focused ultrasound transiently permeabilizes the blood–brain barrier, increasing passive diffusion. Subsequent application of an external magnetic field then actively enhances localization of a chemotherapeutic agent immobilized on a novel magnetic nanoparticle. Combining these techniques significantly improved the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea to rodent gliomas. Furthermore, the physicochemical properties of the nanoparticles allowed their delivery to be monitored by magnetic resonance imaging (MRI). The resulting suppression of tumor progression without damaging the normal regions of the brain was verified by MRI and histological examination. This noninvasive, reversible technique promises to provide a more effective and tolerable means of tumor treatment, with lower therapeutic doses and concurrent clinical monitoring.     

Pseudotumoral demyelination: a diagnosis pitfall (report of three cases)

Rare forms of demyelinating disease such as Balò's concentric sclerosis or Schilder's disease may simulate brain tumors, both clinically and on the computed tomography (CT) and magnetic resonance imaging (MRI). Even the histopathological diagnosis after a biopsy is not entirely reliable. We report three cases of pseudotumoral demyelinating disorders having required a stereotaxic biopsy, one of which was erroneously diagnosed as a malignant astrocytoma. We describe MRI especially the intense contrast enhancement with ill-defined margins, and the mild mass effect. We then detail the histopathological processes upon which differential diagnosis with a tumor can be based.     

The role of diffusion tensor imaging in establishing the proximity of tumor borders to functional brain systems: implications for preoperative risk assessments and postoperative outcomes

Diffusion Tensor Imaging (DTI) is a new MRI imaging technique sensitive to directional movements of water molecules, induced by tissue barriers. This provides a new form of contrast that allows the identification of functional white matter tracts within the brain, and has been proposed as a technique suitable for presurgical planning in brain tumor patients. Resection of primary brain tumors improves survival, functional performance, and the effectiveness of adjuvant therapies, provided that surgically-induced neurological deficits can be avoided. Diffusion Tensor Imaging (DTI) has the potential to establish spatial relationships between eloquent white matter and tumor borders, provide information essential to preoperative planning, and improve the accuracy of surgical risk assessments preoperatively. We present our experience in a series of 28 brain tumor patients where the integration of functional magnetic resonance imaging (fMRI) and DTI data was used to determine key anatomic spatial relationships preoperatively. Twice as many functional systems were localized to within 5 mm of tumor borders when DTI and fMRI were utilized for preoperative planning, compared to that afforded by fMRI alone. Our results show that the combined use of fMRI and DTI can provide a better estimation of the proximity of tumor borders to eloquent brain systems sub-serving language, speech, vision, motor and premotor functions. Additionally, a low regional complication rate (4%) observed in our series suggests that preoperative planning with these combined techniques may improve surgical outcomes compared to that previously reported in the literature. Larger studies specifically designed to establish the accuracy and predictive value of DTI in brain tumor patients are warranted to substantiate our preliminary observations.     

磁共振功能成像在脑肿瘤诊断中的应用

目前,MRI因软组织分辨率高、无辐射及多平面成像等优势已成为脑肿瘤疾病的一种常规检查手段。近年来,随着磁共振技术的发展及磁场强度的增加,一些新的MR功能成像技术已开始越来越多的应用于临床,如磁共振波谱、脑功能成像、灌注成像、磁敏感加权成像、弥散张量成像等,主要用于脑肿瘤之间及脑肿瘤与非肿瘤性疾病的鉴别、肿瘤的分级、指导外科术式的选择、放疗方案的制订等。     

胶质瘤BOLD-fMRI临床应用研究现状

目的：总结国内外血氧水平依赖性功能磁共振（blood oxygenation level dependant functional magnetic resonance imaging,BOLD-fMRI）在胶质瘤患者治疗中的应用。方法：应用PubMed及CNKI期刊全文数据库检索系统,以“血氧水平依赖性功能磁共振、胶质瘤、治疗”为关键词,检索2008-01-2014-01的中英文相关文献。纳入标准：1）BOLD-fMRI在胶质瘤外科手术中的应用;2）BOLD-fMRI在胶质瘤放疗中的价值。符合分析的文献41篇。结果：BOLD-fMRI立体功能成像所获得结果与术中对大脑皮层进行电刺激所获得的结果具有较高的一致性,能够在术前能准确直观的显示运动及语言等功能区位置,评估手术的可行性。并且通过术中解剖和功能定位联合神经外科手术导航仪进行术中导航,在治疗过程中有效的避开重要的脑部功能区,提高了手术方案的准确性,缩短了手术时间并同时最大化切除胶质瘤。根据胶质瘤患者手术前后无创的BOLD-fMRI图像对比,能够全面评估手术效果及判断其预后,为术后放疗靶区的勾画及计划的制定提供重要的参考信息。结论：BOLD-fMRI是一种能够灵敏、准确评价脑局部区域血氧水平的磁共振功能影像技术,在胶质瘤手术治疗的选择、放疗计划的制定以及判断预后等方面具有潜在的临床意义。     

Progress in magnetic resonance imaging of brain tumours

PURPOSE OF REVIEW: Advances in magnetic resonance based techniques have yielded improvements in both high-resolution anatomical imaging and methods to evaluate physiology and function. This review focuses on recent developments in these techniques as applied to pretreatment staging and post-treatment evaluation of brain tumours. RECENT FINDINGS: High-resolution spectroscopic imaging may contribute to pre-therapeutic grading and characterization of gliomas, as can diffusion techniques. The latter also hold promise in predicting survival in malignant supratentorial astrocytoma and could help to define areas for biopsy. Both methods can differentiate recurrent tumour from radiation injury. Perfusion-weighted magnetic resonance techniques offer potential markers of tumour angiogenesis and capillary permeability, and correlate well with vascular endothelial growth factor expression in grade II and grade III tumours. Functional magnetic resonance imaging can assess whether surgical treatment is feasible and select patients for intraoperative cortical stimulation. Combining multiple parameters in a magnetic resonance based diagnostic strategy could improve overall performance. SUMMARY: Magnetic resonance imaging provides insights into the physiology of human tumours in a way that is both noninvasive and radiation free. We may expect from these new imaging methods greater specificity in diagnosis and useful tools with which to predict and assess response to therapy.     

基于氧化铁的磁性纳米颗粒在肿瘤诊疗中的应用进展

将治疗性药物和成像组件集成于一个纳米平台内，构建兼具诊断和治疗功能的纳米颗粒（nanoparticles，NPs），实现肿瘤诊疗一体化是近年来纳米肿瘤学领域的研究热点。基于氧化铁（iron oxide，IO）的磁性纳米颗粒（magnetic nanoparticles，MNPs）是一种典型的诊治一体化性NPs，具有生物安全性高、超顺磁性及表面易于修饰和功能化等优点。MNPs不仅具有良好的载药能力，还具有T2W MR成像、磁靶向和磁热疗等功能，目前已广泛应用于肿瘤诊治一体化的研究中。本文对MNPs的结构，及其在肿瘤成像（T2W MRI成像联合T1W MRI、CT、光学、PET/SPECT和超声等双/多模态成像）以及肿瘤治疗[化疗、光动力治疗（photodynamic therapy，PDT）、光热治疗和磁热疗]等方面的研究进行综述。