研究者发明一种脑手术辅助工具

shumufeng 翻译

2013年1月10日讯—根据普渡大学和布里格姆妇产医院的研究显示，一个在术中可以更快更全面检测脑组织的工具成功确定了五名脑外科手术患者的癌症类型、级别和浸润范围。该工具将微量电荷溶剂投放到脑组织表面，从而获得组织分子组成的信息，并产生有关肿瘤细胞性质和含量的彩色编码图像。

普渡大学的R. Graham Cooks教授共同领导了该研究团队。他说研究人员分析了取自患者的标本，但我们的目标是在一天内就能分析术中未受损的脑组织。Henry Bohn Hass著名的化学教授提到，我们希望最终能在术中进行这种分析，以便指导脑外科医生确定手术界限，同时在切除任何组织前就可以确定该区域肿瘤的性质。我们在实际操作中并非如此，但这是关键的一步。这表明我们能够很容易得找到诊断肿瘤细胞类型和含量的分子模式。

普渡大学的研究人员与（哈佛大学医学院）布里格姆妇女医院的研究人员和医生共同设计了这个工具进行研究。脑外科手术可在先进的多模式图像引导手术室或AMIGO和布里格姆妇女医院的标准手术室进行。详述研究结果的论文发表在即将出版的一期《国家科学研究院学报》上，并同时在线发表。

Nathalie Agar博士（布里格姆妇产医院神经外科系的外科分子图像试验室主任）提到，这些发现显示了该分析方法的潜力，并且在评估其改善患者护理价值方面迈出了重要一步。Agar共同领导了这项研究，他说这种方式将会导致实时图像引导手术的出现，并且无手术护理和使用标记药物的干扰。外科医生以前不能使用有关组织的大量且详细信息，这将使肿瘤的切除更为精确。此外，在手术日进行详细诊断将帮助肿瘤科医生设计更为有效的辅助治疗方案。Alexandra Golby博士（布里格姆妇女医院神经外科部的图像引导神经外科学主任）和这篇论文的合作作者认为切除脑组织极富挑战性。AMIGO的临床合作导师Golby提到，脑肿瘤组织与正常脑组织极为相似且边界不清，所以很难区分正常脑组织和肿瘤的界限。尤其是当肿瘤处于支持运动、言语、视力的关键区域时，我们希望尽可能多得保留有功能的脑组织。

目前的外科手术依赖于医生训练有素的眼睛，并且借助于外科显微镜和术前进行成像扫描技术。布里格姆妇女医院的Sandro Santagata博士参与这项研究，他提到手术中切除的脑组织样本病理检测提供的有关癌症组织和诊断的信息更为具体。然而，组织冰冻切片检测需要半小时，这就不能用于检测多个标本和指导手术。这项新工具能在几秒钟之内对胶质瘤和脑膜瘤进行分类并确定肿瘤级别。该工具可以建立相同类型的病理分析，但是用于外科手术尚有距离。 外科医生在术中切除了32名患者的标本，随后用新工具进行了分析，并用标准病理方法测试了其精确性。Cooks说这些患者样本的分析结果与标准病理方法高度一致。

这项工具依赖于Cooks和他的同事们开发的环境质谱分析技术，该技术称为电喷雾解吸电离，或DESI。质谱分析首先将分子转化成中子，或是通过电流改变其性质，从而确定它们的质谱，即对样本组织中的中子进行质谱分析。常规质谱需要化学分离、操纵样本和在电离室内进行电离和分析。DESI技术不必进行上述步骤，它是在质谱仪表面直接进行电离，这使得这项技术对手术操作而言更为简单、快捷和实用。研究人员使用DESI评估了脑组织中类脂（脂肪物质）的分布和数量。研究团体开发的软件程序使用这些结果对脑肿瘤进行描述，并探测健康组织和癌症组织的边界。研究人员通过对脑肿瘤组织进行研究，发现类脂与癌症的不同类型和级别以及肿瘤细胞的含量相对应。

参与这项研究的普渡大学研究生Livia Eberlin说，这个研究团队通过在开展研究之前增加脑膜瘤这一类型，从而扩展和改善了脑肿瘤的分级系统。斯坦福大学的博士后研究生Eberlin说，这个分级包涵了两种最常见的脑肿瘤----胶质瘤和脑膜瘤,它们占所有脑肿瘤的大约65%。对这种图像技术获得的分子信息进行分析可知，它比其他技术可提供的信息更为详细。我们希望有朝一日这种方法可以帮助每年数千名脑肿瘤患者。验证研究中的脑肿瘤类型分级结果与标准病理方法完全符合。研究人员发现虽然术中取自患者的样本复杂且具有异质性，但是其质谱分析结果与病理差别不大。取自肿瘤不同部位的样本其成分不同，肿瘤细胞的含量差异极大。

Cooks说，这个研究团队计划继续增加和改善分级软件，以便开发一种可在手术中使用的微型质谱仪。该研究团队也会继续测试肿瘤组织的分子模式。环境电离质谱使我们能更加清楚得看到未切除的脑组织（这就如同外科医生亲手操作一般），并获得简单但极为有用的分子信息。这些分子不仅有助于辅助诊断，而且也有助于判断预后和了解这种破坏性疾病。Agar说，布里格姆妇女医院在AMIGO单元中设立了一台质谱分析仪，计划开始检测用于探测脑肿瘤和乳腺癌边界的方法。

除Cooks and Eberlin外，Purdue大学的论文合作作者包括研究生Alan Jarmusch。除了Agar and Golby，布里格姆妇女医院的合作作者包括神经科学部的IsaiahNorton、Daniel Orringer、Ian Dunn、 Xiaohui Liu and JenniferIde；病理科的Keith Ligon和Sandro Santagata；放射科的Ferenc Jolesz。 国家卫生研究院、杰姆斯·麦克唐奈基金会、脑科学基金会和丹尼尔·波顿神经科学基金和klarman家族基金会资助了这项研究。

布里格姆妇女医院是一个非营利性教**盟及Partners HealthCare的创始会员。虽然该医院的生物医学研究所进行研究并有所发现，但是布里格姆妇女医院是人类疾病基础、临床和转化研究的国际领导者。

New Tool to Help Brain Surgeons One Step Closer to Operating Room

http://www.sciencedaily.com/releases/2013/01/130110111723.htm?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+sciencedaily%2Fhealth_medicine%2Fcancer+%28ScienceDaily%3A+Health+%26+Medicine+News+--+Cancer%29&utm_content=Youdao+Reader

Jan. 10, 2013 — A new tool that could allow for faster, more comprehensive testing of brain tissue during surgery successfully identified the cancer type, grade and tumor margins in five brain surgery patients, according to a Purdue University and Brigham and Women's Hospital study.

The tool sprays a microscopic stream of charged solvent onto the tissue surface to gather information about its molecular makeup and produces a color-coded image that reveals the nature and concentration of tumor cells.

Researchers analyzed specimens removed from the patients, but the goal is to one day be able to perform the analysis on intact brain tissue during surgery, said R. Graham Cooks, the Purdue professor who co-led the research team.

'We hope to eventually be able to perform this analysis during surgery to help guide brain surgeons so that the borders of tumors can be identified and the cancer status of a site can be established before any tissue is removed,' said Cooks, who is the Henry Bohn Hass Distinguished Professor of Chemistry. 'We aren't there yet, but this was a critical step in the process. It shows we've found easily identifiable molecular patterns that can be used to diagnose the type and concentration of cancer cells.'

Purdue researchers designed the tool and collaborated with researchers and physicians at Brigham and Women's Hospital at Harvard Medical School to perform the study. The brain surgery was performed in the Advanced Multi-Modality Image Guided Operating suite, or AMIGO, and in standard operating rooms at Brigham and Women's Hospital. A paper detailing the results will be published in an upcoming issue of the Proceedings of the National Academy of Sciences and is published online.

Dr. Nathalie Agar, director of the Surgical Molecular Imaging Laboratory within the neurosurgery department at Brigham and Women's Hospital, said the findings showed the analysis method's potential and achieved an important step in the path to assessing its value in improving patient care.

'This approach could lead to real-time, image-guided surgery without interference with surgical care and without the administration of labeling agents,' said Agar, who co-led the study. 'Such extensive and detailed information about the tissue was previously unavailable to surgeons and could lead to more precise tumor removal. In addition, having access to a detailed diagnosis on the day of surgery could help the oncologist more efficiently design the course of adjuvant therapy.'

Dr. Alexandra Golby, director of Image-Guided Neurosurgery in Brigham and Women's Hospital's neurosurgery department and paper co-author, said brain tumors are particularly challenging to remove.

'Tumor tissue within the brain often closely resembles normal brain tissue and may have indistinct boundaries, so it is difficult to determine where the tumor ends and the normal brain tissue begins,' said Golby, who also is the clinical co-director of AMIGO. 'We want to preserve as much functional brain tissue as possible, especially when a tumor is in a critical area of the brain, like that which supports movement, speaking or vision.'

Current surgical methods rely on the surgeon's trained eye with the help of an operating microscope and imaging from scans performed before surgery.

Pathological examination of specimens taken from the brain during surgery provides the most specific information about the tissue and diagnosis of the cancer. However, this examination of frozen sections takes about half an hour, which is too long for it to be useful in examining multiple samples and guiding surgery, said Dr. Sandro Santagata, a pathologist at Brigham and Women's Hospital who participated in the research.

'The new tool is able -- in a matter of seconds -- to identify and classify glioma and meningioma tumors and recognize the tumor grade,' Santagata said. 'It is able to establish the same type of assessment the pathology offers, but at a pace that is compatible with surgery.'

Surgeons removed 32 specimens from the patients during surgery, which were later analyzed by both the new tool and standard pathology methods to test its accuracy. The results for the patient samples were in very good agreement with standard pathology, Cooks said.

The tool relies on an ambient mass spectrometry analysis technique developed by Cooks and his colleagues called desorption electrospray ionization, or DESI.

Mass spectrometry works by first turning molecules into ions, or electrically charged versions of themselves, so that they can be identified by their mass. Through mass analysis of the ions the contents of a sample can be identified.

Conventional mass spectrometry requires chemical separations, manipulations of samples and containment in a vacuum chamber for ionization and analysis. The DESI technique eliminates these requirements by performing the ionization step directly on surfaces outside of the mass spectrometers, making the process much simpler, faster and more applicable to surgical settings.

The researchers used DESI to evaluate the distribution and amounts of fatty substances called lipids within the brain tissue. A software program the team developed then used the results to characterize the brain tumors and detect boundaries between healthy and cancerous tissue. The researchers identified lipid patterns that corresponded to the different types and grades of cancer and concentrations of tumor cells through earlier studies of banked brain tumor tissue.

Livia Eberlin, who was a graduate student at Purdue at the time of the study and participated in the research, said the team expanded and improved the classification system for brain cancers by adding the meningioma tumor type, prior to the study.

'The classifier includes the two most common types of brain tumors, gliomas and meningiomas, which combined account for about 65 percent of all brain tumors,' said Eberlin, who is now a postdoctoral researcher at Stanford University. 'The molecular information that is obtained from this kind of imaging technology allows for an analysis that is much more detailed than what other techniques can offer. We hope that it can one day help the thousands of people affected by brain cancer every year.'

The classification results for brain tumor type in the validation studies of banked tissue agreed with standard pathology methods 100 percent of the time. The researchers found that the results of the mass spectrometry analysis of samples taken from the patients during surgery agreed with pathology with very few exceptions, despite the complexity and heterogeneity of the surgical samples. The composition of samples taken from different regions of an individual tumor can differ and tumor cell concentrations are especially variable, Eberlin said.

The team plans to continue to add to and improve the classification software and to develop a miniature mass spectrometer that could be used during surgery, Cooks said. The team also will continue to examine the molecular patterns of cancerous tissue.

'Ambient ionization mass spectrometry allows us to look directly at unmanipulated tissue, just as a surgeon does, and get simple but extremely valuable molecular information,' Cooks said. 'These molecules have a story to tell not just in terms of aiding diagnosis, but also perhaps in terms of prognosis and our understanding of this devastating disease.'

Brigham and Women's Hospital has set up a mass spectrometer in the AMIGO suite and plans to begin testing the methodology for the detection of brain and breast cancer margins during surgery, Agar said.

In addition to Cooks and Eberlin, co-authors of the paper from Purdue include graduate student Alan Jarmusch. In addition to Agar and Golby, co-authors from Brigham and Women's Hospital include Isaiah Norton, Daniel Orringer, Ian Dunn, Xiaohui Liu and Jennifer Ide of the Department of Neurosurgery; Keith Ligon and Sandro Santagata of the Department of Pathology; and Ferenc Jolesz of the Department of Radiology.

The National Institutes of Health, James S. McDonnell Foundation, Brain Science Foundation and the Daniel E. Ponton Fund for the Neurosciences, and the Klarman Family Foundation funded this research.

Brigham and Women's Hospital is a nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. Through investigation and discovery conducted at its Biomedical Research Institute, the hospital is an international leader in basic, clinical and translational research on human diseases.