Thread: ChinaSCINet Update

  1. #1501
    Quote Originally Posted by Leif View Post
    I would strongly support to not be posting the China data on CC until it is published in a journal. By that one will avoid the constant negative whining from non-productive people like Paolo.
    I agree 100% with you Leif. Posting it here prior to it being published will only lead to even more of Doctor Young's valuable time being wasted explaining the obvious, or what is obvious to us that bother to thoroughly read what he has already written.


  2. #1502
    Another question whenever you have a chance Dr. Young (and I apologize if this has been answered but its a 150 page thread!): do you have any ideas regarding injuries longer than two segments? My medical documents state an acute care MRI showed "extensive spinal cord contusion with micro bleeding associated with edema that extends from the level of T5 to T10-11"... So I'm guessing I'd be excluded from these trials. If and when a therapy is shown to be beneficial would the use of the therapy be for those only satisfying the exclusion criteria? Would individuals like me have to wait another several years for a trial to show the beneficial effects in lesions of 3,4,5,etc. segments? All hypothetical but do you have any thoughts? Thanks so much and happy new year (and birthday!).

  3. #1503
    Senior Member Cspine's Avatar
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    Am I correct in my understanding that "improved locomotor scores" do not necessarily mean functional or voluntary movement?
    Death and taxes

  4. #1504
    Quote Originally Posted by Cspine View Post
    Am I correct in my understanding that "improved locomotor scores" do not necessarily mean functional or voluntary movement?
    Cspine,

    this is a concept that Wise has tried to sell after he runned out of arguments to answer some questions..
    I don't believe it.
    I have asked Wise to post videos of a person with a T SCI with no voluntary movements below the level of injury who can just voluntarely activated the CPG (I don't think this can happen too) to see how he/she can walk...

    I am confident he will do that sometimes in his life time.. but I expect the subject/s will not meet the specifics above.

    Paolo
    In God we trust; all others bring data. - Edwards Deming

  5. #1505
    It is so frustrating writing to you because you twist what I said. Please, do not rephrase what I said. Let me emphasize what I said both in answer to your specific comments and below:

    • It is not true that the contusion model that we use to test therapies cause injuries equivalent to ASIA C lesions. We typically use the 25-mm weight drop that causes a severe contusion and 90% of rats DO NOT recover weight supporting locomotion from this injury.

    • While surgeons often expose spinal cords to remove tumors, few surgeons have opened the dura and seen chronically injured human spinal cords. Our study exposed 28 spinal chronically injured human spinal cords. For some surgeons in Hong Kong, this was their first view of chronically injured spinal cords. These are all patients with severe injuries and had recovered little or no function and have remained ASIA A for many years.

    Finally, your answer to C-spine regarding "improved locomotor scores" not necessarily meaning functional or voluntary movement is not only wrong but insulting. You suggest that I tried to sell the concept of locomotor scores improving after I had "runned [sic] out of arguments to answer some questions". That is not true. I presented the findings of improved locomotor scores without changes in motor or sensory scores to an audience of scientists. You just happened see a webcast of my presentation. In that workshop, I hypothesized that this was because regrowing axons are activating the central pattern generators, allowing patients to walk even though they cannot activate the individual muscles. Activation of walking through the CPG is an idea that has long been held by many scientists, i.e. that locomotion can be indirectly activated through the central pattern generator without direct activation of individual muscles. You heard what I said in the workshop but you were ignorant of the concept. I tried hard to explain it to you but you continue to misunderstand. Please, don't foist your ignorance on me.

    In the quotation below, I changed your comments to blue. Mine are in red.

    Wise.

    Quote Originally Posted by paolocipolla View Post
    Quote Originally Posted by Wise Young View Post
    Paolo,

    Yes, cutting into the spinal cord will damage some tissue. In the early stages, a contused spinal cord is filled with dead tissue that is under pressure. The pressure results with the breakdown of the blood brain barrier and swelling of cells at the injury site. If you cut the spinal cord too early after injury, the spinal cord will "mushroom" out of the opening and the results may even be worse. Reginald Allen in 1911 and 1914 reported that a myelotomy and removal of necrotic tissues from a contused cord will restore function in dogs. Several attempts were made to test this claim in humans in the 1970's but these were usually done shortly at 8-24 hours after injury. We have tried this in animals and found that a myelotomy done during the first 24 hours will allow the spinal cord to swell out of the dura so that we cannot stitch it close. To see the beneficial effects, we must go in at a week or longer, when the spinal cord is not under pressure. When we do a myelotomy at 10 days, the spinal cord does not swell out of the dural opening and the animals show less tissue damage when we look at the spinal cord 6 weeks later.

    Has this animal study been published?
    No, this study has not yet been published. We are submitting it for publication.

    I don't know where you got the "understanding" that more than 50% of human spinal cord injuries are much worse than the typical spinal contusions done in the laboratory. In fact, over 64% of spinal cord injuries admitted to hospital in the U.S. are incomplete injuries (ASIA B, C, D).

    That confirms what I said, thank you Wise.
    In fact with the contusion models used in labs currently animals recover some movements usually above BBB 10 which makes the animals like an ASIA C human. That does not happens in real life with all human SCIs.

    • Please, what I said does not confirm what you said. In the laboratory, we typically use the 25 mm weight drop injury, which results in an average BBB score of 8. Over 90% of rats do not recover weight-supported locomotion (which require a BBB score of >10) and a 25 mm weight drop contusion causes what is equivalent to an ASIA A at T11. In contrast, the 12.5 mm weight drop injury is a moderate spinal cord injury that usually result in a BBB score of 13-14, an ASIA C at T11.


    Of those with "complete" spinal cord injuries, almost all involve contusions or crush without penetration of the dura. In ChinaSCINet, I have now seen chronic injured spinal cords in the operating room.

    I am happy you are finally seeing human chronic spinal cords (I am surprised to learn you have not seen human spinal cords before), but remeber these are selected SCI according to the inclusion criteria as you specify below which exclude severe SCI etc., so they do not rapresent the SCI population.

    Most clinicians and scientists HAVE NOT seen a chronically injured spinal cord before. I have seen many spinal cords but not chronically injured human spinal cords exposed in the operating room before. Why are you saying these exclude severe SCI? You are wrong. All the subjects that we saw had severe SCI, resulting in ASIA A classification. We excluded ASIA B and C's. The only subjects that we excluded was one or two who had loss of white matter for more than 3 segments.

    You would be astonished by how intact the spinal cord looks. The concept of cutting a chunk of that spinal cord out is, in my opinion, is totally unjustified.

    We are currently testing the hypothesis that umbilical cord blood cells injected into the surrounding cord will migrate into the injury site and produce a bridge of cells. These are of course phase II studies assessing feasibility and safety of the injections. Our studies have shown that the procedure is feasible and safe, that the cells seem to allow bundles of fibers to grow across the injury site and possibly go long distances up and down the spinal cord, and that some of the subjects are recovering locomotor function at 6 or more months after treatment.

    I don't believe you here, but I hope you'll present scientific evidence, so that I will change my mind.
    • What is it that you don't believe?

    We are not using any biomaterials in our chronic spinal cord injury study. However, there may be an opportunity to use some biomaterials in subacute spinal cord injury. Several groups have approached us with a variety of biomaterials for this purpose. We are still evaluating these materials before we make a decision.

    That's interesting you never said before, that I remember, that you are evaluating biomaterials.
    • We have been evaluating a variety of materials from several companies and made by the Biomaterials Center of New Jersey at Rutgers.


    As I said, we are planning a phase III trial of the lateral myelotomy treatment of subacute spinal cord injury in ChinaSCINet. If this trial shows that the myelotomy is beneficial, this will open up an opportunity to do a multicenter trial where some type of biomaterial and cells can be placed into the cavity opened up by the myelotomy.

    I do not believe that umbilical cord blood mononuclear cells (UCBMC) will be beneficial for all types of spinal cord injuries. As I have already indicated, this therapy is designed to improve long tract regeneration and may not be effective for some types of spinal cord injuries.
    For example, UCBMC+lithium, without neuronal replacement therapy, is not likely to help people with lower lumbosacral injuries where substantial gray matter have been damaged. That is why we are now developing a lumbosacral spinal cord injury model and testing neural stem cells in that model with different approaches to attracting axons to grow into the ventral roots.

    On the other hand, I think that the method that we have developed for injecting cells into the spinal cord above and below the injury site will be useful even for severely injured spinal cords, as long as there is no separation of the two ends of the cord.

    Does that mean that if there is separation there is no hope in your opinion?
    No, a separation between the two ends of the spinal cord does not mean that there is no hope. However, transected spinal cords are very rare. I have seen only a few in my lifetime. It can occur when a spinal cord has been shot and the bullet is still in the canal. I have seen several cases where a knife was used to cut the spinal cord but the spinal cord were only partly cut. There have been a few published anecdotal cases of severed spinal cords.

    We excluded patients who have long lesion sites where there is a gap of white matter than extends over two segments. This is because we don't want to do a laminectomy that is longer than 2 segments.

    I suspect also because you consider harder to see some recovery in these cases.
    • Your suspicions are wrong. As I explained, the reason why we exclude these subjects is because we do not want to do a long laminectomy.

    We have also excluded patients that have T11 and lower injuries or C4 and higher injuries. So, our trial will not shed any light on the efficacy of the therapy for those conditions.

    Wise.
    Last edited by Wise Young; 01-02-2013 at 04:46 AM.

  6. #1506
    Quote Originally Posted by Cspine View Post
    Am I correct in my understanding that "improved locomotor scores" do not necessarily mean functional or voluntary movement?
    Cspine,

    We observed that patients showed improved locomotor scores but did not improve their motor or sensory scores. Motor scores represent voluntary activation of muscles on a scale of 0-5, where 0 indicates no movement when the subject is asked to move the muscle, 1 indicates trace or flicker movement, 2 indicates muscle movement only when the influence of gravity is removed, 3 indicates ability to counteract the effects of gravity, 4 indicates ability to move muscle against resistance but not normal, 5 indicates normal muscle strength.

    The walking is voluntary in the sense that the subjects are initiating and maintaining walking. Many of the subjects are supporting most of their weight (they are leaning on a device that has wheels on it). The walking is also functional in the sense that some subjects taking steps and moving around with devices, something that they could not before the therapy. People are stepping with their legs even though they may not show improvements in their ability to wiggle their toes (extensor hallucis longus), move their ankles (anterior tibialis/gastrocnemius), straighten their knees (quadriceps), or flex their hips (psoas) on command.

    Many people who have recovered walking after spinal cord injury will tell you that they can walk but they don't have good control of the individual muscles or have feelings in their feet. This is common.

    Wise.

  7. #1507
    Quote Originally Posted by ay2012 View Post
    Another question whenever you have a chance Dr. Young (and I apologize if this has been answered but its a 150 page thread!): do you have any ideas regarding injuries longer than two segments? My medical documents state an acute care MRI showed "extensive spinal cord contusion with micro bleeding associated with edema that extends from the level of T5 to T10-11"... So I'm guessing I'd be excluded from these trials. If and when a therapy is shown to be beneficial would the use of the therapy be for those only satisfying the exclusion criteria? Would individuals like me have to wait another several years for a trial to show the beneficial effects in lesions of 3,4,5,etc. segments? All hypothetical but do you have any thoughts? Thanks so much and happy new year (and birthday!).
    ay2012,

    I don't know what our therapy would do for people with lesions that are over 2 segments long. I don't think that you would be necessarily excluded from our trials at all. We are using diffusion tensor imaging to see the loss of long spinal tracts at the injury site. In all cases, we saw a gap between the white matter above and below the injury site. That gap ranged from 1-2 segments. In one patient (I believe), we excluded the subject because he did not show any DTI-imageable fibers in a 3-segment stretch of the cord. Our protocol called for injecting the cells at the edges of the white matter. We did not want to do a laminectomy that is over 2 segments long.

    Just because you have some microbleeding and a report suggesting extensive contusion does not mean that you have a wide white matter gap of greater than 2 segments. Edema often extends long distances above and below the injury site. We did not excluded subjects based on this criterion. It is possible that we may find that patients with long white matter gaps will not respond as well to this therapy but there is not enough data to support this possibility. In our first trials, we are doing what we think is safest for the patient and our surgeons thought that a three segment laminectomy poses additional risk. If the treatment does regenerate the spinal cord, most surgeons may consider the benefit to be worth the risk.

    Wise.

  8. #1508
    Quote Originally Posted by paolocipolla View Post
    Wise,

    in my opinion you are being unfair with ay2012, he is just reading with common sense. Perhaps you should be more careful not to post misunderstandable info and contradicting info.

    Paolo
    I disagree. I don't think that I am being unfair with ay2012. I was clear in both my statement and my interpretation. When ay2012 tried to ask whether I meant more than I wrote, I told him no and that he should not over-read what I wrote.

    Wise.
    Last edited by Wise Young; 01-02-2013 at 05:02 AM.

  9. #1509
    There are two trials. One is on chronic spinal cord injury. We transplanted 8 subjects in Hong Kong and 20 subjects in Kunming with chronic spinal cord injury. The other is on subacute spinal cord injury. We transplanted 13 subjects in Kunming (and there are 13 other subjects that did not receive transplants but received intradural decompression). I do not have the data on the subacute trial (because that is double-blind). Whenever I have talked about MR/DTI imaging or locomotor/motor/sensory scores, I have been referring to the chronic trial.

    Wise.



    Quote Originally Posted by ay2012 View Post
    sorry I posted this in the other thread but it belongs here:
    Subacute? Which trial is this? I was under the impression that of the patients in both the Hong Kong and Kunming trials were chronics....I went back and saw you mention these subacute patients a few times and also checked clinicaltrials.gov which seems to have a separate trial for acutes and subacutes (NCT01471613)... Is it right to assume then that you were talking about the improved locomotor, sensory, motor scores in terms of chronic patients? If not, are the subacutes getting the intradural decompression? I'm sorry if you've clarified before but suddenly I'm very confused....and I think it would just be nice to know if your personal observations from before were from chronics or subacutes. Thanks!
    So, I just would like to know (if you're aware) whether these improvements, in sensory, motor and locomotor scores are from chronics or subacute? I'm assuming the former if these observations form the basis to move forward with the Phase III trials and sorry to labour the point but I think it's pretty relevant...

  10. #1510
    Quote Originally Posted by Sue Pendleton View Post
    "We are not using any biomaterials in our chronic spinal cord injury study. However, there may be an opportunity to use some biomaterials in subacute spinal cord injury."

    So, only chronics are not blindly sent to one of the 3 therapies? Do chronics only get PT or lithium no cells at all? Isn't that a rather biased trial? And feel free to tell me I read this wrong. I just have seen few studies of high T low cervical injuries getting volitional walking back using lokomotor traing only. Trunk mucles need to hook up too and that requires intervention.
    Sue, sorry that I didn't answer to your post earlier. The chronic spinal cord injury subjects in Kunming were randomized to five treatment groups (n=4 per group):
    A Four 4-µliter injections into dorsal root entry zones above and below the injury site, each µliter containing 100,000 umbilical cord blood mononuclear cells per µliter. This adds up to 1.6 million cells.
    B Four 8-µliter injections into the same sites, adding up to 3.2 million cells.
    C Four 16-µliter injections into the same sites, adding up to 6.4 million cells.
    D The same as group C except that a bolus of 30 mg/kg of methylprednisolone is given intravenously at the time of surgery.
    E The same as group D except that the subjects received oral lithium titrated to so that venous blood has 0.6-0.8 mM of lithium.

    In Hong Kong, only 8 subjects were randomized to group A or B.

    In the Kunming study, only 5 of the 20 subjects had cervical spinal cord injury. In Hong Kong, 4 of the 8 subjects had cervical spinal cord injury. In the chronic study, we did not do a concurrent control group that received only rehabilitation. However, in Hong Kong, none of the subjects received intensive locomotor training whereas all but 2 of the subjects in the Kunming study received at least three months of locomotor training. These two subjects had possible fractures of their legs (which in retrospect turned out to be also present in x-rays before the surgery) that shortened the amount of time they spent doing locomotor training.

    This is only a phase II trial, escalating dose trial to assess the safety and efficacy of increasing doses of umbilical cord blood mononuclear cells, as well the effect of a single bolus of methylprednisolone, and the effects of a 6-week course of oral lithium carbonate therapy. The phase III trial is necessary to show efficacy.

    Wise.
    Last edited by Wise Young; 01-02-2013 at 04:58 AM.

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