International Circulation: Could you talk about your some of your personal experiences in translational research?
《国际循环》：请您谈谈您在转化医学研究中的个人经验？
Dr. Fisher: I have been doing this for a long time. The first memorable experience was in 1985. We did the first tPA experiment in an animal model and showed that it was effective in rabbits. I would like to say that translational research is a very rewarding experience. You start with a hypothesis and， through the process of experimentation， you can make a novel discovery. This is especially true for me， because I started doing animal modeling from the perspective of a clinician. For me there has been a few “ah-ha” moments over the course of the last 30 years， and the tPA was one of them.
Another was in the in the early 90s， when we started using MRI as an assessment tool to evaluate therapeutic responses. The first drug we tested was a neuroprotective agent and we demonstrated that it effected the evolution of the diffusion lesion in vivo. As there was one prior study， we were the second group to show the evolution of an ischemic lesion in a living animal. The first neuroprotective drug we tested worked.
In the early 2000s， we started combining the effusion and perfusion images to look at the evolution of the ischemic penumbra. We mapped the evolution of the penumbra over time and watched the mismatch of the two disappear. Then we tried various treatments. We tried a whole series of different agents and we could see that different drugs could slow down the diffusion lesion evolution and prolong the penumbra.
The most recent moment was a couple a years ago， when we published a paper on high flow oxygen treatment. We were able to extend the therapeutic time window of tPA in the animal model. I think an interesting future application of this research would be to give this as a pre-hospital treatment. This may allow for the extended survival of the penumbra. By having more penumbra， we will be able to treat with reperfusion.
Dr. Fisher: 我做转化医学研究已经有很长时间了。令人难忘的经历最早开始于1985年。我们首次在动物模型上进行了tPA实验并证实它在兔子体内是有效的。我认为转化医学研究是非常有意义的。你从一个假设开始，通过实验得到一个新的发现。对我而言尤其如此，因为我从临床医生的角度来设计并开展动物实验。对于我来说在过去的30年里有一些取得重大发现的时候，tPA就是其中之一。
另一个就是在90年代早期的时候，那时我们开始用MRI作为一种评估工具来评价治疗的反应。我们检测的第一个药物是一种神经保护剂，我们的研究显示这种药物影响了弥散性病变在体内的进展。在先前的一项研究中，我们是第二个显示在活体动物中缺血性病变进展的研究小组。我们检测的第一种神经保护药物在实验中是有效的。
在2000年早期，我们开始把渗出和灌注影像相结合来观察缺血的半暗带的进展。我们描绘出在一段时间内半暗带的变化并观察两种影像的差异。然后我们尝试了各种治疗方法。我们尝试了一系列不同的药物并且发现不同的药物能减缓弥散病灶的进展并延长半暗带。
最近的一次发现是在2年前，我们发表了一篇关于高流量氧治疗的文章。我们在动物实验中能延长tPA的治疗时间窗。我认为这项研究将来可能作为一种入院前的治疗方法而得到应用。这意味着半暗带处组织存活的几率增加。当存在更多的半暗带时，我们将可能进行再灌注治疗。
IC: Given your track record with MRI-based research， could you please tell our readers about your latest progress in this field?
《国际循环》：根据您以往在MRI方面的研究，您能跟读者谈谈您在这方面最近取得的成果吗？
We are currently performing imaging experiments where we inject labeled clots into our animals. These clots are radio-opaque and are obvious on T1 imaging， allowing us to perform serial imaging every 15 minutes for a couple of hours. In doing so， we could compare the rapidity and extent of clot lysis with different therapies. We compared tPA and tPA plus annexin II and we were able to show that the combination worked more rapidly and completely than tPA alone. We plan to continue this research. The first experiment will be to find a maximized dose of the combination. Basically， if you want new lytic， it has to be an improvement over tPA. An improvement would dissolve clots more completely and faster. Now， we have a new assessment tool to watch real time clot dissolution in vivo. Downstream from there， we are able to image the hypoperfuse plane and compare how much of that is restored to normal perfusion， as well as the ultimate effects of the reperfusion on the size of the infarct.
This research is part of a translational grant we have with Massachusetts General Hospital. The basic idea of this whole program is to investigate this combination treatment as a new drug application， so that it can undergo clinical trials. Funding translational research is a relatively new initiative of the NIH. Their goal is to bring new therapies， based on a complete data package from animals， to the point of clinical trials. This used to be in the domain of the drug companies， but the NIH is now funding some treatments that drug companies would be willing to develop for various reasons.
Dr. Fisher: 我们最近正在进行在动物体内注射标记凝块的影像学实验。这些凝块是X线不透明的并且在T1加权相下清晰可见，使我们能在几个小时内每隔15分钟采集一次并获得一系列影像。在这个过程中，我们能对比在不同治疗下凝块溶解的速度和程度。我们把tPA和tPA联合膜联蛋白II治疗进行了对比，我们的结果显示联合治疗比tPA单独治疗的起效更迅速作用更完全。我们计划继续进行这项实验。首先需要进行实验找到联合用药的最大剂量。从基本上来讲，如果你想要一种新的溶栓药物，它的作用就必须优于tPA。效果的增强会更快更有效的溶解血栓。现在我们有了一种新的评估工具来实时观察血栓在体内的溶解。接下来，我们就能通过影像显示低灌注阶段并对灌注恢复到正常水平的程度进行对比，同时还能观察梗死区域再灌注的最终效果。
这项研究是我们在马萨诸塞总医院转化医学基金的一部分。这项研究的主要目的是为了探索这种联合治疗作为一种新的药物治疗的应用，因此它还会继续进行临床试验。资助转化医学研究是NIH相对新的项目。转化医学的目的是通过从动物实验中获得的完整资料来探索新的治疗方法，并最终进行临床试验。这在以前都是药物公司的研究领域，但是NIH现在开始资助一些药物公司由于各种原因愿意开发的治疗方法。
IC: Given the role of penumbral imaging in the expansion of the time window for acute stroke therapy， do you think that the time window should be extended to more than 6 hours?
《国际循环》：根据半影成像在急性中风治疗时间窗延长中的作用，您认为时间窗应该被延长至6小时以上吗？
Obviously we want to try to successfully treat as many people as possible and minimize potential harm. With tPA， it was initially developed to be given very early， within 3 hours of stroke onset. The idea behind acute stroke therapy is to treat or preserve parts of the brain that are at risk of dying. On average， a smaller infarct means there should be less functional deficit in the patient and the tissue most at risk is the penumbra. If you treat early， most patients will have extensive amounts of penumbra. As time elapses， there are certainly patients that will still have salvageable penumbra， but there are a lot of other patients that will not have penumbra. If you limit yourself to clinical criteria in these later time window trials， you are going to have a lot of uninformative patients that cannot respond to any treatment， because the whole ischemic lesion is already dead. Therefore it would be difficult to demonstrate that there is a clinical benefit for the patients enrolled in the trial. If we want to help those that can still benefit from treatment， then it makes sense to identify the target tissue of the treatment， which is the penumbra. That is the only way that I can see of extending the time window. This does not have to be six hours， you can treat people much longer. There are some patients that have extensive penumbra many hours after the stroke onset. However， by just using clinical criteria， you cannot identify them.
Right now， the EXTEND trail from Australia and the ECAS 4 trial from Europe are taking patients with substantial mismatch for up to 9 hours. Instead of basic treatment enrolment criteria， where decisions are based on time， you can hopefully prove penumbral imaging identifies patients who can respond for many hours after stroke onset. This is going to be a whole paradigm shift in how we approach treating people.
I personally think that the benefits of tPA in the 3 to 4.5 hour window are pretty modest. About a month ago， the FDA refused Genentech’s request to extend tPA’s time window of approval to after 4.5 hours in the United States. Apparently they did this because they felt that the data in ECAS 4 were not robust enough to persuade them to extend the time window. A study that I’d like to see done， and maybe the FDA’s lack of approval will move this forward， is to treat everybody in a 3-4.5 hour window， and obtain advanced imaging either just before treatment starts or while it is being infused. Then， they could look at the patterns on images to predict the responders and the non-responders. I am confident that we will be able to identify patterns in response.
Diffuse data from Gregory Albers has identified patterns that actually predict harm， such as increased risk of bleeding and poor outcomes. My analogy for this is the beginning of the antibiotic era in the 1940s， when penicillin was first used. Back then， they were just treating everybody because they did not have other options. They assumed that many people would benefit， but over time， they realized that doing cultures and sensitivities made sense because then you could target your specific antibiotic for those who had responsive bacteria. In a gross analogy， advanced imaging is like microbiology for antibiotic therapy: we need to move it to the next phase where everybody agrees that the target of acute stroke therapy is to salvage some of the penumbra. If we have ways to approximately identify the penumbra， then why not try to identify patients who have a target tissue.
And for my last example， the June issue of Stoke featured an analysis of the desmoteplase trials . They showed that in patients with no documented occlusion， on CT angiograms or MR angiograms， there was absolutely no benefit for the treatment of this other lytic. This illustrates that if you cannot observe a clot， then the lytic was not working because the patient either did not have a clot or it was so far distal that it had little benefit. This is where I see future progress， we went through an initial era of showing the we actually had a functional treatment and now we need to find ways to include more people and to maximize treatment benefits.
Dr. Fisher: 很明显我们希望治疗尽可能多的患者并同时把潜在的危险最小化。在使用tPA时，最初的设计是很早期就给药，即在发生中风后的3小时内给药。急性中风的治疗目的是挽救那些即将坏死的脑组织。平均来讲，更小面积的梗死意味着患者功能缺失的程度更少，并且更容易进展为坏死的组织大部分都在半暗带内。如果你及早的进行治疗，大部分患者的半暗带面积会明显增大。随着时间的延长，肯定还有患者存在可挽救的半暗带，但是很多其他患者的半暗带是消失的。如果你在这些晚时间窗试验中完全依赖于临床标准，你就会纳入很多资料不清并对任何治疗都没有反应的患者，因为这些患者的整个缺血病变部位已经全部死亡了。因此就很难在试验纳入患者中显示出治疗的临床获益。如果我们想帮助那些仍然可能从治疗中获益的患者，就必须明确治疗的靶组织，也就是半暗带。这是我认为能延长时间窗的唯一办法。这个时间限制并非必须是6小时，你也可以治疗超过这一时间的患者。有些患者在中风发生很多个小时后依然存在很大的半暗带。然而，你不能仅仅通过临床标准来确定这种情况。
现在，澳大利亚的EXTEND试验和欧洲的ECAS 4试验都纳入了最长时间为9小时的较大影像差异患者。这些决定基于时间而非基础治疗纳入标准，你能通过半暗带影像来识别那些在中风发生很多个小时后依然对治疗有反应的患者。这将是我们治疗患者方法的一种根本性改变。
我个人认为tPA的3至4.5小时有效时间窗是非常适当的。大约在一个月前，FDA拒绝了Genentech公司的请求，他们希望把tPA在美国应用的时间窗延长至4.5小时以后。很明显，FDA拒绝了这一请求是因为他们认为ECAS 4中的试验数据并不足以说服他们延长时间窗。我希望看到的试验是，也许缺少FDA的批准会促进这些试验的完善，使他们能在3-4.5小时的时间窗内治疗所有的患者，并获得在治疗前或在给药同时的进一步的影像资料。那时，他们就能通过影像的特征来预测对治疗有反应或没有反应的患者。我坚信我们将会明确那些对治疗有反应患者的特征。
Gregory Albers获得的弥散数据已经确定出了实际上能预测危害的特征，比如增加出血风险和不良后果的情况。我把这比喻为1940年的抗生素时代的开始时期，当青霉素首次被使用的时候。那时，青霉素被用来治疗每个患者，因为别无选择。人们假定很多人会从中获益，但是随着时间的流逝，人们认识到进行病原体培养和抗生素敏感性实验更合理，因为通过这些手段能靶向应用特殊的抗生素来治疗那些携带有反应的细菌的患者。从总体上来比喻，先进的成像就像微生物的抗生素治疗：我们需要跨越到下一阶段，在这一阶段所有的人都认为急性中风治疗的目标是半暗带的挽救。如果我们有粗略确定半暗带的方法，那我们为什么不试着确定哪些患者存在靶向组织呢？
最后我再举个例子，Stoke杂志的六月刊发表了一项去氨普酶的分析。研究表明在那些没有CT或MR血管造影显示存在明确闭塞的患者中，明显也是没有溶栓治疗获益的。这也表明如果你不能观察到血栓，那么溶栓就不会起效，因为患者可能没有血栓或血栓在血管远端，获益太小。这就是我认为将来的进展，我们经历的最初时代显示我们确实有很有效的治疗，而现在我们需要发现扩大受益患者的方法来最大化治疗的获益。
采访稿整理
延长r-tPA治疗时间窗时机尚未成熟
——麻省大学医学院Marc Fisher教授专访
延长时间窗，明确半影区
我们希望治疗尽可能多的患者并将潜在危险最小化。如果及早进行治疗，大部分患者的半影区面积会明显增大。随时间延长，肯定还有患者存在可挽救的半影带。如果我们想帮助那些仍然可能从治疗中获益的患者，就必须明确治疗的靶组织，即半影带，这是我认为能延长时间窗的唯一办法。这个时间限制并非必须是6小时。有些患者在卒中发生很多个小时后依然存在很大的半影区。
现在，澳大利亚的EXTEND试验和欧洲的ECAS 4试验都纳入了最长时间为9小时的较大影像差异患者。这些决定基于时间，而非基础治疗纳入标准，你能通过半影区影像来识别那些在卒中发生很多个小时后依然对治疗有反应的患者。这将是治疗方法的一种根本性改变。
扩大受益者范围，最大化治疗获益
对于r-tPA，我个人认为3~4.5小时的有效时间窗是非常恰当的。大约在1个月前，FDA拒绝了Genentech公司将tPA时间窗延长至4.5小时以上的请求，因为他们认为ECAS 4中的试验数据并不足以说服他们延长时间窗。
我们的工作需要跨越到下一阶段：确定哪些患者存在治疗靶组织。Stoke 6月刊发表的一项去氨普酶的分析表明，在CT或磁共振血管造影显示无明确血管闭塞的患者中，溶栓治疗是没有获益的。我们将来的研究方向应是发现扩大受益患者的方法，以使治疗获益最大化。
Obviously， we want to try to successfully treat as many people as possible and minimize potential harm. r-tPA was initially developed to be given very early， within 3 hours of stroke onset. The idea behind acute stroke therapy is to treat or preserve parts of the brain that are at risk of dying. On average， a smaller infarct means there should be less functional deficit in the patient and the tissue most at risk is the penumbra. If you treat early， most patients will have extensive amounts of penumbra. As time elapses， there are certainly patients that will still have salvageable penumbra， but there will also be some without any. If you limit yourself to clinical criteria in these later time window trials， you are going to have a lot of uninformative patients that cannot respond to any treatment， as the whole ischemic lesion is already dead. Therefore it would be difficult to demonstrate that there is a clinical benefit for the patients enrolled in the trial. If we want to help those that can still benefit from treatment， then it makes sense to identify the target tissue of the treatment， which is the penumbra. That is the only way that I can see of extending the time window. This does not have to be six hours: you can treat people much longer. There are some patients that have extensive penumbra many hours after the stroke onset. However， by just using clinical criteria， you cannot identify them.
Right now， the EXTEND trail from Australia and the ECAS 4 trial from Europe are taking patients with substantial mismatch for up to 9 hours. Instead of basic treatment enrolment criteria， where decisions are based on time， you can hopefully prove that penumbral imaging identifies patients who can respond for many hours after stroke onset. This is going to be a whole paradigm shift in how we approach treating people.
I personally think that the benefits of r-tPA in the 3 to 4.5 hour window are pretty modest. About a month ago， the FDA refused Genentech’s request to extend r-tPA’s time window of approval to after 4.5 hours in the United States. Apparently they did this because they felt that the data in ECAS 4 were not robust enough to persuade them to extend the time window. A study that I’d like to see done， and maybe the FDA’s lack of approval will move this forward， is to treat everybody in a 3-4.5 hour window， and obtain advanced imaging either just before treatment starts or while it is being infused. Then， they could look at the patterns on images to predict the responders and the non-responders. I am confident that we will be able to identify patterns in response.
The next phase will be where everybody agrees that the target of acute stroke therapy is to salvage some of the penumbra. If we have ways to approximately identify the penumbra， then why not try to identify patients who have a target tissue. The June issue of Stoke featured an analysis of the desmoteplase trials. They showed that in patients with no documented occlusion， on CT angiograms or MR angiograms， there was absolutely no benefit for the treatment of this other lytic. This illustrates that if you cannot observe a clot， then the lytic was not working， because the patient either did not have a clot or it was so far distal that it had little benefit. This is where I see future progress， we went through an initial era of showing that we actually had a functional treatment and now we need to find ways to include more people and to maximize treatment benefits.
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