笔形探测器手术中只需10秒就可知道是不是癌组织

  • 2017-09-14 11:43:47 来源:奇点网

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9月6日著名期刊《科学转化医学》杂志发表研究成果:德克萨斯大学奥斯汀分校的研究人员开发了一种方便快速的笔形探测器,能在10秒之内确定手术切缘组织的良恶性状况,用时是现行病理诊断手段的1/150[1]!

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手术切除实体肿瘤时,对切缘性质的判断是非常关键的。

但到底切除范围多大,才能实现完整切除不留后患呢?临床实践中并没有统一的标准,手术中更多要依靠术者根据术前检查结果、肿瘤形态、切除组织量对正常生理功能的影响等因素进行判断,这就为癌症复发留下了可乘之机。

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当然,医生们也并非全靠着经验和感觉行事,冰冻切片检查可以在手术过程中快速提供病理诊断,但这一方法也存在明显的局限性。

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智能手术刀iKnife

Livia Ebervin带领的德克萨斯大学奥斯汀分校研究团队也许找到了答案。她们开发出了一种实时组织学诊断设备,命名为MasSpec Pen。这支“神笔”是多学科共同努力的结晶。

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Livia Eberlin教授(左)和论文第一作者张佳玲博士(右)

MasSpec Pen的整套设备主要由三个部分组成:一台微量注射泵、双向活瓣导管和形状与一支笔相似的手持探测器。当然,旁边的质谱分析仪也是必不可少。相信看过示意图,很多外科医生会对它的控制方式感到颇为亲切。这不就像整天握在手中的电刀嘛!

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用Eberlin教授自己的话来简单介绍一下MasSpec Pen的工作原理:“随着生长失控,肿瘤细胞的代谢会出现明显失调,与正常细胞的差异极大,因此我们用MasSpec Pen对组织进行像采集指纹一样的提取和分析。通过简洁和平缓的化学过程,MasSpec Pen就能在不造成组织损伤的状况下迅速提供给我们诊断所需的分子信息。[7]”

探测器注入极微量的水,提取出病人体内的小分子物质

提取物传递到质谱分析仪,进行良恶性的判断

整个过程中,探测器接触组织的时间仅需3秒,而判断可在10秒钟之内完成。

当然,为了实现良恶性的判断,还需要首先收集到用来判断的数据。研究人员先从正常的组织中获取了相关的数据图谱,并与DESI-MSI法的结果进行了比对,结果基本一致。再用同样的手段进行对癌组织的检测,标定出与正常组织明显不同的图谱表现,就让“神笔”有了判断的基础。

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在实现快速判断的同时,MasSpec Pen的损伤也是极小,相比大手术时动辄十几公分的切口,下图里400微米的取样,基本可以称为完全无创了。

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是时候把“神笔”投入实战了。使用MasSpec Pen,研究人员对包括肺、卵巢、甲状腺、乳腺在内的253份人体组织样本进行检查,其中近半为癌症组织,而这些癌症每种都会出现不同的质谱图。MasSpec Pen的表现没有让人失望,数据分析的结果显示,它的诊断特异性达到了96.2%,敏感性为96.4%!

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研究人员随后对MasSpec Pen能否准确区分组织学上的良恶性区域边界进行了测试,同样得到了令人满意的结果,MasSpec Pen的判断与病理诊断结果几乎完全相同。

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为继续验证MasSpec Pen的准确性,研究人员决定在小鼠模型上进行进一步的活体试验。在向小鼠植入乳腺癌细胞并培养后进行手术切除,再用MasSpec Pen进行取样检测,分析的结果也清晰地显示出了正常组织与癌组织的不同。

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Eberlin教授希望,这一研究成果能在2018年进入临床开展初步的验证[8]。不过只研发出“神笔”,并不能解决投入临床实践面临的所有问题,首当其冲的拦路虎就是质谱分析仪的配备问题。

MasSpec Pen的功能或许不仅限于判断肿瘤的切除程度。在获取更多数据建立大规模的数据库后,研究人员还希望将它与腹腔镜手术系统、机器人手术系统等微创技术和可视化技术结合,从而促进更广泛的临床应用。希望,这样一种简洁、快速、准确的诊断手段能尽快进入临床,帮助外科和肿瘤医生。

Is the pen mightier than the scalpel?

Although a surgeon’s goal is to remove cancer in its entirety during excision surgery, achieving negative margins (absence of cancer cells at the outer edge of the excised tumor specimen) can be challenging. To facilitate intraoperative diagnosis, Zhang et al. developed a handheld pen-like device that rapidly identifies the molecular profile of tissues using a small volume water droplet and mass spectrometry analysis. After 3 s of gentle physical contact with a tissue surface, the water droplet is transported to a mass spectrometer, which characterizes diagnostic proteins, lipids, and metabolites. The pen could be used to rapidly distinguish tumor from healthy tissue during surgery in mice, without requiring specific labeling or imaging and without evidence of tissue destruction.

Abstract

Conventional methods for histopathologic tissue diagnosis are labor- and time-intensive and can delay decision-making during diagnostic and therapeutic procedures. We report the development of an automated and biocompatible handheld mass spectrometry device for rapid and nondestructive diagnosis of human cancer tissues. The device, named MasSpec Pen, enables controlled and automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules. We used the MasSpec Pen for ex vivo molecular analysis of 20 human cancer thin tissue sections and 253 human patient tissue samples including normal and cancerous tissues from breast, lung, thyroid, and ovary. The mass spectra obtained presented rich molecular profiles characterized by a variety of potential cancer biomarkers identified as metabolites, lipids, and proteins. Statistical classifiers built from the histologically validated molecular database allowed cancer prediction with high sensitivity (96.4%), specificity (96.2%), and overall accuracy (96.3%), as well as prediction of benign and malignant thyroid tumors and different histologic subtypes of lung cancer. Notably, our classifier allowed accurate diagnosis of cancer in marginal tumor regions presenting mixed histologic composition. Last, we demonstrate that the MasSpec Pen is suited for in vivo cancer diagnosis during surgery performed in tumor-bearing mouse models, without causing any observable tissue harm or stress to the animal. Our results provide evidence that the MasSpec Pen could potentially be used as a clinical and intraoperative technology for ex vivo and in vivo cancer diagnosis.

Here, we demonstrated that the MasSpec Pen is effective for in vivo diagnosis of cancer regions during murine oncologicalsurgery.Theentireprocedure from triggering the system to data analysis is performed under10s, and further improvements are envisioned. Compared with the time necessary for intraoperative pathologic frozen section analysis of excised species (~30 min) or postoperative final pathologic evaluation(severaldays), the time required for the MasSpec Pen analysis could expedite surgical procedures, diagnosis, and treatment. Our results demonstrate that the molecular information obtained using a 1.5-mm sampling size allows accurate identification of cancer in marginal tumor regions of mixed histologic composition, although further validation of these results with larger independent sample sets is needed. We are currently exploring other machining methods to increase sampling resolution; however, the 1.5-mm sampling size relates well with the degree of precision achieved during surgical resection.

参考资料:

1.http://stm.sciencemag.org/content/9/406/eaan3968

2.Buchholz T A, Somerfield M R, Griggs J J, et al. Journal of clinical oncology, 2014, 32(14): 1502-1506.

3.Stummer W, Pichlmeier U, Meinel T, et al. The lancet oncology, 2006, 7(5): 392-401.

4.Jermyn M, Mok K, Mercier J, et al.. Science translational medicine, 2015, 7(274): 274ra19-274ra19.

9.Li A, Zi Y, Guo H, et al. Nature Nanotechnology, 2017, 12(5): 481-487.