Moe,Quote:
Originally Posted by Moe
be nicer! :nono:
you can experess your desagreement with what I post, but you can also ignore what I post.
Paolo
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Moe,Quote:
Originally Posted by Moe
be nicer! :nono:
you can experess your desagreement with what I post, but you can also ignore what I post.
Paolo
[QUOTE=Wise Young;1623654]Thank you Wise,Quote:
Originally Posted by paolocipolla
I hope that when you will publish the data you will make available also videos of the people "walking".
Paolo
Even contusions have often a cavity that many researchers agree that needs to be filled in with something.Quote:
Originally Posted by havok
There are many scaffolds under development that could do the job or periferial nerve transpant seems to be a very good (if not better) option as well.
Paolo
Dr. Wise,
Have the researchers investigated the safety/efficacy of the UCBMC+MP and lithium treatment in the lab on animals with incomplete injuries?
Your right it would be better if he or anyone else would ignore you but since you have done it 1000000000000000 times it becomes hard to do so. Also since Wise is nice enough he amazingly responds to what you say so you are going to see your stuff quoted in his posts.Quote:
Originally Posted by paolocipolla
Wise can you consider lumbar injury patients in your phase3 trial or for lumbosacral you have separate trial? If you can see some white growth then why dont u try lumbosacral patients?
If a volunteer of a clinical trial receive the placebo treatment, will he receive at the end of the trial the "real" treatment, the same for example if a volunteer of the planned us trial receive ucbmc+lthium+mp can he receive at the end the treatment with cethrin?
Other question, the period of phase 1 for safety is sufficiently long to see if there is no risk of tumors if the cells continue to proliferate?
Dr.Young - I'm curious about muscle spasms.
Have the patients noticed any difference in their tone/muscle spasms? Enough to ween off of baclofen or any kind of muscle relaxers?
Lately My spasms have been getting so bad (currently on 80mg a day) that I'm considering a baclofen pump. If I do get one. will that affect my chances of being chosen for upcoming trials?
Quote:
Originally Posted by Wills77
Good question. I have a baclofan pump... Does that make any difference?
I didnt think much progress was being made with scaffolds? Also who was doing periferial nerve transplants?Quote:
Originally Posted by paolocipolla
"We get too little from medical innovation because we expect too much."
The Daily BeastQuote:
The New York Times reports on a remarkable trial of a new gene-based therapy for leukemia, which reprograms the patient's own immune system to fight the rogue cells. The results have been nothing short of remarkable:
"Despite the mixed results," the story goes on, "cancer experts not involved with the research say it has tremendous promise, because even in this early phase of testing it has worked in seemingly hopeless cases."Quote:
Three adults with chronic leukemia treated at the University of Pennsylvania have also had complete remissions, with no signs of disease; two of them have been well for more than two years, said Dr. David Porter. Four adults improved but did not have full remissions, and one was treated too recently to evaluate. A child improved and then relapsed. In two adults, the treatment did not work at all. The Pennsylvania researchers were presenting their results on Sunday and Monday in Atlanta at a meeting of the American Society of Hematology.
"Mixed results?" These are fantastic results. Twelve people were treated for end-stage, multi-drug resistant leukemia; one third are in full remission. More than one third have at least slowed the progress of their disease. These are people who had one foot, and the toes on the other foot, in the grave. Even if this is only a temporary respite, it's a major success.
It strikes me that medical research is haunted by the memory of penicillin, and the other antibiotics that immediately followed. For a period of ten or fifteen years, "miracle cures" were the stuff of everyday life rather than television movies and late night infomercials: you took a pill, and something that had previously been fatal, like pneumonia or tuberculosis, simply went away. Often, you went from death's door to the picture of health in hours or days.
As a consequence, people think that this is how medical discoveries are supposed to work: you find a cure for a fatal or crippling disease, everyone gets better instantly, and the world is a better place. I suspect that this is Big Pharma critic Marcia Angell's mental model. The reason she's decided that drug companies are about as useful as a third buttock is that they're no longer delivering the miracle pills on schedule.
But this is not how innovation works most of the time. Innovation is not "Problem solved forever!" Instead it's mostly "We've reduced the incidence of this problem by 11.3%." But if you do that over and over again, eventually you can produce a pretty good fascimile of the miracle cure you thought you were supposed to get in the first place.
Unfortunately, Penicillin Envy can make it difficult to achieve those lesser innovations. A while back, Michael Mandel pointed out that the FDA frequently makes the perfect the enemy of the "needs improvement"--and thereby kills promising technologies. A company that developed a computer system for diagnosing melanoma was turned down on the grounds that it didn't do as good a job as the best dermatologists. Of course, not everyone has access to the best dermatologists--and more importantly, there's no reason to think that the first-generation system will do as good a job as the eighth generation. But if you kill the first generation, you also kill the eighth.
The FDA eventually reversed itself, but the mentality remains. We expect too many miracle cures, and as a result, we get fewer medical miracles.
An interesting point of view. Thanks for posting.Quote:
Originally Posted by crabbyshark
Clayton
There are two reasons for excluding ASIA B and C patients from the trials. The first is that transplanting cells into the spinal cord may jeopardize surviving axons that are crossing the injury site. The second is that ASIA B and C subjects have better prognoses for recovery than ASIA A subjects. The second reason is not applicable to people with chronic spinal cord injury. I may be able to convince my colleagues to include patients with sacral sparing and no other motor or sensory function in the lower limbs. We shall see
I was under the impression the surgery required was already proven safe in China and "better prognoses" is a good thing. Aren't those two factors enough to expand the inclusion criteria in at least a few people who understand the risk?
Brad
"Cells Harvested From Human Urine Used To Make Stem Cells"
Anyone recall Dr. Wise mentioning this in the June open house? via Wired
Prediction: When the Kunming results are finally released to the public this month they will be a headline story on the evening news, front page of cnn.com, trending on Twitter, upvoted on reddit, and covered by sites like Huffington Post.Quote:
Biologists in China have published a study detailing how they transformed common cells found in human urine into neural stem cells that can be used to create neurons and glial brain cells. The find holds huge potential for the rapid testing and development of new treatments for neurodegenerative disorders.
[QUOTE=Wise Young;1623654]Dear Wise,Quote:
Originally Posted by paolocipolla
One more question: if I understood correctly, there was a comparison between people who got the treatment only, and some other group who received both the treatment + locomotor training in Kunming.
What about comparing people who had treatment only to people who received locomotor training only? has this been done ?
If I remember well, you have always been quite positive about the intensive locomotor training given in Kunming. What I am trying to figure out through this question is whether the treatment has (so far) influenced the ambulation capabilities of patients in combination with locomotor training, or whether that progress was only or mainly due to intensive locomotor training itself.
I understand it is too early for any conclusion and further functional progress might still happen should the white matter growth lead to actual new connections and regained motor control, but I am just trying to understand the current results better.
thanks a lot in advance for your explanations. Corinne
Lets hope so!!!Quote:
Originally Posted by crabbyshark
For the latest results using periferial nerve see the second presentation of Jerry Silver at W2W as soon as it comes on line.Quote:
Originally Posted by havok
For biodegrdable scaffolds here are some random examples:
http://www.nanotope.com/
http://www.invivotherapeutics.com/
http://www.eni-net.org/organization/...of-eva-sykova/
http://pubs.acs.org/action/doSearch?...ation=40025957
I wonder why Wise doesn't seem to consider any scaffold for future clinical trials in ChinaSCINet :thinking:
Paolo
Actually another good presentation that will come up online shortly is byQuote:
Originally Posted by paolocipolla
Ravi Bellamkonda, PhD, Walter H. Coulter Dept. of Biomedical Engineering, Georgia Institute of Technology. Dr. Bellamkonda’s lab focuses on peripheral nerve regeneration and interfacing, as well as overcoming the CSPG (Chondroitin Sulfate Proteoglycan) contribution to regenerative failure in the central nervous system. He also looks at interfacing technologies that might better integrate electronics into the nervous system.
Ravi has worked on the delivery of a thermostabilized Ch'ase via scaffolding.
Do you know for a fact he hasn't considered this as a possible future avenue?Quote:
Originally Posted by paolocipolla
I said "doesn't seem", so what does that mean to you?Quote:
Originally Posted by cripwalk
In other words "no", I hope Wise can comment.
Paolo
Do researchers implant a biodegradable scaffold every time they inject a paralyzed rat with stem cells and it starts walking again?Quote:
Originally Posted by paolocipolla
If the researchers inject a paralyzed rat with stem cells and leave the scaffold out, does the rat fail to walk again?
Perhaps there isn't enough preclinical safety/efficacy data available yet to justify bringing scaffolds to human trial when there are other therapies showing more promise?
Perhaps evidence suggests a scaffold isn't necessary? :thinking:
Which evidece? :thinking:Quote:
Originally Posted by crabbyshark
Scaffolds could be usefull in many ways to repair the spinal cord. As far as I know at this stage of research I see it difficult to say for sure if they will be needed or if they will not be needed.
If you know that for sure, it would be good if you could provide real convincing evidence to support what you say.
Paolo
Here we go again... let's find some little thing to pick at and then make Wise waste his precious time responding to your continued aggression.Quote:
Originally Posted by paolocipolla
I'm sure Wise and his colleagues are analyzing all treatment possibilities and moving forward on the ones that show the greatest potential.
Scaffolds could be useful, but scaffolds could also not be useful. If axons are growing across the injury site without scaffolds, that might indicate scaffolds may not be as useful, and that other therapies would be more useful.Quote:
Originally Posted by paolocipolla
I believe Dr. Wise saying his "data suggests that many axons are growing across the injury" is convincing evidence. I believe him when he says some people are beginning to walk again, too.
Paolo, if you are so confident that axons are not growing across the injury site, or that people from the Kunming study are not beginning to walk again, would you like to place a wager on it and take advantage of my naivety?
We could transfer the funds via PayPal. $100? $200? Even odds?
I am very serious about this.
I have moved some posts that were off topic. This topic should be about ChinaSCINet and the trials that it is conducting. Thank you. Wise.
havok,Quote:
Originally Posted by havok
Our current trials do not rule out penetrating injuries of the spinal cord. We do leave it to the discretion of surgeons to exclude patients whom they think may present difficulties to expose or to transplant. This include lesions that exceed 2 vertebral segments in length and transected spinal cords.
Wise.
Paolo,Quote:
Originally Posted by paolocipolla
This decision will be up to the investigators. My own feeling is that showing selected videos of a study often have undue influence on public perception of trial results. If one chooses to show videos of the best walkers in a study, this will create a perception (no matter how many caveats are given) that all the patients will recover to this extent. There is no easy way to choose a video of an "average" walker in the study. So, if one video is shown, videos of all the patients should be shown but this is often impractical and the temptation is for authors to make the results of the study more impressive. However, if the videos clarify what is meant by "walking", I do favor showing videos. So, whether I would support such videos will depend on the videos that the investigators want to present.
Wise.
[QUOTE=corinne4cure;1624831]Corinne,Quote:
Originally Posted by Wise Young
Let me first say that we are doing phase II trials. People are expecting too much of these trials. These are not intended to prove or disprove efficacy. Rather, they are intended to provide information concerning the best and safe dose, route of treatment, and hopefully indicate some trend towards efficacy. Pivotal trials (Phase III) will be the trials that will resolve questions such as the one that you ask. The question and problem is how we can do this in a convincing way. Let me explain.
Our phase III trials will be evaluating three therapies: umbilical cord blood mononuclear cells, lithium, and intensive locomotor training. All three may have strong placebo effects. To rule out placebo effects, the trial should be double-blinded, i.e. neither the subjects nor the evaluators know what therapies the subjects have received. Unfortunately, two of the therapies are difficult to blind. Both the subjects and evaluating doctors can easily tell whether the subjects have had surgery or are undergoing intensive locomotor training. So double blinding will be difficult, if not impossible.
If we don't do a double-blinded study, critics will say that surgery alone or locomotor training alone can make people walk. By the way, these are often the same critics who claim that no therapy can restore function to "complete" chronic spinal cord injury but consistency is not a hobgloblin of critics. Millions of patients have had surgery in the chronic stage of after complete ASIA A spinal cord injury and very few have recovered substantial locomotor function after surgery. So, even though surgery alone is very unlikely to restore function, the clinical trial must somehow prove that it does not.
Likewise, there is little evidence that people who have chronic "complete" (ASIA A) spinal cord injury will recover walking after intensive locomotor training. Yes, some people such as Patrick Rummerfield recover walking years after severe spinal cord injury and is running marathons. To my knowledge, he has not received experimental regenerative therapies other than exercise. However, while not quite as rare as hen's teeth, people like Pat are rare. Suzy Harkema and many investigators have been studying treadmill locomotor training of people with chronic ASIA A injuries. They find that training seldom results in people achieving unassisted locomotion. My own observations of the Kunming locomotor training program suggests that intensive 6:6:6 overground locomotor training is not sufficient for locomotor recovery in people with chronic "complete" (ASIA A) spinal cord injury.
What is our solution to this problem in ChinaSCINet? Because we really cannot blind subjects to the placebo effects of intensive 6:6:6 locomotor program, we decided to encompass the placebo and the physical effects in the ChinaSCINet. After all, who cares if the mechanism is placebo or physical as long as it works. In the ChinaSCINet trial, we are planning to randomize a subpopulation of subjects and send them to Kunming for locomotor training. In the other centers, we plan to monitor the number of hours that the subjects engage in locomotor training (using pedometers and daily diaries). This will tell us whether or not locomotor training restores function in people and the intensity of training that is necessary.
In the U.S., we are planning a phase II trial to compare subjects that are randomized to 6:6:6 (i.e. 6 hours a day, 6 days a week, for 6 months) to 3:3:3 (i.e. 3 hours a day, 3 days a week, for 3 months) training programs. This is supposed to establish feasibility. Each participating center will have a rehabilitation only group, consisting of 3:3:3 training and encouragement for the subjects to "walk to tolerance" in the remaining time. In the phase III trials, we plan to compare rehab only, UCBMC transplant only, lithium only, and UCBMC+lithium. I am worried that if we don't have a intensive locomotor training program in the U.S., we will not see any locomotor recovery.
Wise.
[QUOTE=Wise Young;1626637]Wise, I can only assume that double blind/blind trials are being utilized over simple mathematical significance because of the limited number of patients available to test. Is this correct? Presumably a higher 'n' would give clearer and more convincing results but pragmatics (time/money/availability of subjects) prevent this from happening?Quote:
Originally Posted by corinne4cure
Cripwalk. It’s not so much about pragmatics. Randomized, double blind, placebo-controlled clinical trials are the gold standard.
[QUOTE=Wise Young;1626637]Quote:
Originally Posted by corinne4cure
Wise,
Where in the US are you planning on doing these studies? Will it include all ASIA classifications? Has there been any "non-formal" research on the 3:3:3 vs. 6:6:6 research? I've heard that some researchers feel that locomotive training is more effective by assisted walking, if possible, rather than using a body weighted treadmill (Therastride, Locomat), due to limited side gait mobility in the hips and other things, whats your take on this? What type of locomotive training or exercise regiment is part of this routine? Does this involve other excersizes such as FES and strength workouts? What do you feel would be the difference and requirements from "intensive" locomotive training to "normal" locomotive training?
Thank you!
There is no "routine" protocol for locomotor training. NRN utilizes the manual treadmill, the Lokomat utilizes robotic motion and once you advance the Zero G can be utilized to simulate over ground more realisticly while preventing falls.
NRN for 1.5 hours 5 days a week is hugely expensive from a labor standpoint. The data is not yet complete for Zero G or overground. One can utilize a swimming pool for chest deep walking once there is volitional control and get very good results.
:running:
[QUOTE=cripwalk;1626663]cripwalk,Quote:
Originally Posted by Wise Young
I am not sure that I understand your assumption or question. Double blind trials are not being utilized because of any change in mathematical significance. The standard statistical significance tests will be utilized. The reason that treatments are double-blinded is to avoid placebo effects and evaluator bias. Double blind refers a trial in which both the subjects and evaluators do not knowing what therapies they have received.
Obviously, one cannot double-blind locomotor training because both the subjects and the evaluators would know that the training is or has occurred. Cell transplants can be double blinded by comparison of the treated group with a group that received sham surgery but no transplants were placed (as you can probably imagine, this is difficult to do and considered unethical by some people). Drugs can be relatively easily double-blinded by having the subjects take a pill that has the active ingredient or a "placebo" pill that has only inert ingredients.
A generally accepted probability is 0.05 for significance, i.e. 1 in 20 chance of error. The preferred statistical test is ANOVA (analysis of variance) for comparison of two or more treatment groups. The number of subjects per treatment group (n) can be calculated based on an assumption of 0.05 p-value (alpha) and an assumed effect size (see http://www.math.yorku.ca/SCS/Online/power/)
Wise.
Paolo,Quote:
Originally Posted by paolocipolla
I am not sure where you get your information concerning scaffolding but I don't find much credible data supporting their use for repairing spinal cord injury in clinical trials for the following reasons:
- There is no easy way of putting scaffolding inside a contused spinal cord without damaging the cord further. Most of the studies that I know have used transected spinal cords and placed the scaffold between two cut ends of the spinal cord. As you know, transected spinal cords are exceedingly rare.
- Regeneration of axons through a scaffold faces two difficult obstacles. The first is to get the axons to grow into the scaffold. As Xu Xia-ming showed, this can be done by filling the scaffold with Schwann cells. The next obstacle is to get the axons to grow out of the scaffold into the surrounding cord. A few treatments (such as combination neurotrophins) seem to do this but the results have been modest, at best.
- Some investigators have proposed that the spinal cord can be transected and the scaffold be put between the cut ends. I am not convinced that this is better than injecting cells into the spinal cord surrounding the injury site. The cells migrate into the injury site and form a continuous living bridge across the injury site.
So, perhaps you can tell us where you have gotten the impression that scaffolding is so promising. What studies are you referring to?
Wise.
[QUOTE=Skipow;1626799]Skipow,Quote:
Originally Posted by Wise Young
We were planning to do the studies at Brackenridge Hospital in Austin, TX. Unfortunately, our principal investigator moved to another hospital and we are still raising money for that study. We are still hoping to go ahead with this study but we need to recruit another investigator and raise the funds for the study at Brackenridge.
Yes, there have been many informal studies but what we need are formal controlled studies. Our investigators in Kunming believe that assisted walking on body weight supported treadmill systems is not only ineffective but may teach the body bad habits regarding weight support and balance. Likewise, they do not favor FES. They prefer intensive overground walking over treadmill.
The evidence that treadmill training is superior to overground walking is very limited. Likewise, there is little or no evidence that FES (stimulation of leg muscles) improve unassisted walking to any significant degree. Of course, there are lots of claims by manufacturers of various walking systems, including Locomat and Therastride, but the evidence that these expensive systems have restored walking to people, particularly those with "complete" (ASIA A) spinal cord injury, is very limited.
I have posted on this subject many times, including descriptions of the walking program in Kunming, where they do overground walking with a rolling device that the people lean on and use for partial weight support. They use this walking program extensively in people with acute spinal cord injury. They have published a paper showing that as many as 50% of patients with ASIA A complete spinal cord injuries, who then received a lateral myelotomy within several weeks after injury and participated in this intensive walking training, recover unassisted walking. Since this paper was published, they have treated several hundred patients with similar results.
Quote:
[*] Zhu H, Feng YP, Young W, You SW, Shen XF, Liu YS and Ju G (2008). Early neurosurgical intervention of spinal cord contusion: an analysis of 30 cases. Chin Med J (Engl) 121: 2473-8. Clinical Center for Spinal Cord Injury, PLA Kunming General Hospital, Kunming,Yunnan 650032, China. BACKGROUND: The incidence of spinal injury with spinal cord contusion is high in developed countries and is now growing in China. Furthermore, spinal cord injury happens mostly in young people who have a long life expectance. A large number of patients thus are wheelchair bound for the rest of their lives. Therefore, spinal cord injury has aroused great concern worldwide. Despite great efforts, recovery from spinal cord injury remains unsatisfactory. Based on the pathology of spinal cord contusion, an idea of early neurosurgical intervention has been formulated in this study. METHODS: A total of 30 patients with "complete" spinal cord injury or classified as American Spinal Injury Association (ASIA)-A were studied. Orthopedic treatment of the injured vertebra (e), internal fixation of the vertebral column, and bilateral laminectomy for epidural decompression were followed directly by neurosurgical management, including separation of the arachnoid adhesion to restore cerebrospinal fluid flow and debridement of the spinal cord necrotic tissue with concomitant intramedullary decompression. Rehabilitation started 17 days after the operation. The final outcome was evaluated after 3 months of rehabilitation. Pearson chi-square analysis was used for statistical analysis. RESULTS: All the patients recovered some ability to walk. The least recovered patients were able to walk with a wheeled weight support and help in stabilizing the weight bearing knee joint (12 cases, 40%). Thirteen patients (43%) were able to walk with a pair of crutches, a stick or without any support. The timing of the operation after injury was important. An optimal operation time window was identified at 4 - 14 days after injury. CONCLUSIONS: Early neurosurgical intervention of spinal cord contusion followed by rehabilitation can significantly improve the locomotion of the patients. It is a new idea of a therapeutic approach for spinal cord contusion and has been proven to be very successful.
Wise.
Dr. Young,
I have a couple questions that I'm sure will show the layman in me but I was wondering if you could help. You've said that it might be too early, even at six months or a year, to gauge the functional benefits that could occur with these treatments, as the white matter would have to grow up and down the cord. Wouldn't it just be sufficient for growth across the injury site? Also, if we're banking on continued growth for functional return, beyond six months to a year, shouldn't we also be wary of jumping to conclusions regarding safety at these time frames? Or is that just a risk that appears not that great? Thanks as always.
This kind of reminded me of my weary thoughts i get when i hear "white matter growing UP the cord to the brain". Sounds scary to me.Quote:
Originally Posted by ay2012
"I am worried that if we don't have a intensive locomotor training program in the U.S., we will not see any locomotor recovery." Wise, I know a place real close to home where I met you that has a system you speak of :beer2: Also the question about the baclofen pump any input for that ? Thanks
Thanks for the reply, I really do appreciate it. Hopefully it is only penetrating. Is there any way to tell if it was transected because when I asked the doctor they couldn't even tell me what happened other than it was a burst fracture. My mom had to tell me about when they did the surgery they said an exploded inward. And also is there any plan for those with "long" injuries? I know mines over 3 segments long. Thanks again, and thanks again for everything your doingQuote:
Originally Posted by Wise Young
Seconded, on the question regarding segmental length. Would applying a potential therapy to a longer injury be the same as that with a higher injury i.e. a separate trial would be needed? I thought these may be treated differently given the concern with higher level of injury was safety, given it could impact breathing function for example.Quote:
Originally Posted by havok
Dr. Wise - 5 questions , please disregard if answered already.
- How many days till we see results published?
- Is US Trial totally jeopardized with 1 doctor / investigator absence?
(aside from that we know for financing issue and FDA approval)
- Trial in Norway on schedule?
- Kunming paper is huge - how to convince world to adopt procedure fast?
- How about Incomplete injuries inclusion in trial or ...?
thanks!
ay2012,Quote:
Originally Posted by ay2012
Sensory axons must grow from below the injury site to the brainstem before they can restore function. Motor axons must grow from above the injury site to the lumbosacral spinal cord before they can restore movement. If recovery occurs any faster, it would be because there are existing axons that are crossing the injury site that have sprouted.
Regarding safety, we are looking for complications due to surgery and the transplanted cells. If the cells have grown into a tumor, we expect to see an effect within 6 months. Of course, we would have to wait longer to see any slow effect but we can safely conclude that we see no evidence of any tumor induced or other significant neurological loss associated with the surgery.
Wise.
That is what regeneration is. White matter are myelinated spinal tracts. Wise.Quote:
Originally Posted by Barrington314mx
I don't know (and don't think) that intensive locomotor training alone will help. I am referring to locomotor training after regenerative therapy. Regarding the baclofen pump, I am not sure. We have no experience with transplanting the cells in people with baclofen pump. I would think that we would want to keep it in but to check it regularly to make sure that the spasticity is not declining and the dose can be reduced.Quote:
Originally Posted by allenstevens
Wise.
Comad,Quote:
Originally Posted by comad
1. The publication will not be for months. We are planning to submit the papers in January. Even in the unlikely case that it is accepted by the first journal that we submit to, it is likely to take 3-4 months. If we have to get it to other journals, it would take 6 months.
2. Are you referring to the Phase 3 trial? If so, the loss of one center would not be a problem. However, in the case of the Phase II trial in Brackenridge, we have to find another principal investigator. Of course, we still have to raise th funds.
3. The trial is Norway is the Phase III trial which is scheduled for Q3 2013. We still have to submit the IND and get the commitment of th Norwegian government to cover the costs. But, yes, I hope and believe that we are on schedule.
4. Kunming paper will be published separately from the Hong Kong paper, which focuses on DTI. The Kunming paper will focus on neurological and locomotor recovery. I myself do not know the results yet. I will find out when I get to Hong Kong shortly after Christmas.
5. I suspect that we will not be including motor incomplete patients in the trials in 2013. The reason is because their inclusion will increase the size of the trial, which we cannot afford at the present.
Wise.
We will not be able to see any of the information I results until it is officially published?Quote:
Originally Posted by Wise Young
What is the cost per patient? What is the total that needs to be raised for ASIA A only? What would it take to see a few C's included? Dollar wise?
Yes, I was under the impression that we would hear results sometime this month... Is that correct?Quote:
Originally Posted by Lyerly
But what stops them from growing? Or how do they know when to stop? Maybe i watch too many weird movies. I get a picture of over grown ivy taking over my brain. :medusa:Quote:
Originally Posted by Wise Young
dr wise
i though axons only need to connect on each side of the lesion,sensory or motor to establish function?
Dr. Young,Quote:
Originally Posted by Wise Young
Thanks for the response and sorry to press the issue, but could you provide some reasoning or even just literature as to why you would assume that the six month time frame would be sufficient to tell if a tumor would grow. I'm sure you've thought that through, but its the most common response I hear from people, even people in the rehab community, top physiatrists, heck even my main doctors in acute care as to why one should be weary for participating in trials and stem cell therapies more generally. Obviously these people aren't at the forefront of the research but it'd be nice to have a response to them.
Lyerly,Quote:
Originally Posted by Lyerly
I have not yet decided whether or not to release the 6-month data. I have not seen the data yet but I am not sure that pre-release of the data serves any purpose.
Regarding cost per patient, I have indicated several times now that we estimate the cost to be $100,000 per subject. So, a 20-subject Phase II study plus organization and insurance costs adds up to about $2.1 million. A 120-subject Phase III study would cost about $12 million. We may achieve some savings here and there.
One cannot not just include "a few C's" in a clinical trial, just for curiosity sake. If we include ASIA C subjects in a phase III trial, we would need to include sufficient subjects to determine whether outcome of A's differ significantly from C's. Since C's are more variable than A's, we will need more subjects than just doubling the number of subjects. Thus, adding C's to the U.S. phase III trial would more than double the cost of the trial. We were originally planning to include B's and C's in the ChinaSCINet trial because the cost of trials is about one fifth of the cost in the U.S. I had earlier estimated that inclusion of A, B, and C's in China would require a study of about 400 subjects. To save money, we are considering studying only 120 ASIA A subjects in China as well.
Wise.
ay2012,Quote:
Originally Posted by ay2012
Umbilical cord blood cells have been transplanted into many thousands of people over the past 20 years. To my knowledge, no case of tumor of the transplanted umbilical cord blood cells has ever been reported. The cells that we are using have not been genetically modified, expanded, or altered.
In our trials, we have transplanted umbilical cord blood cells into 41 subjects. Several of the subjects are a year and half after injury. Over 10 of the subjects are more than one year after transplantation. All are over 6 months. If we do not see any safety issues at this point, there are unlikely to be any. I hope that the FDA will accept our data.
The risk is not zero, of course. But, the risk is very low. Are you sure you want to insist on more stringent safety criteria, like a year or two? If so, this guarantees delays of 2 or more years between trials.
Wise.
Stacyd,Quote:
Originally Posted by stacyd
Let me explain it first in words and then with a diagram. Two sensory tracts bring sensory information to the brain. One is situated in the posterior columns of the spinal cord and makes synapses (connections) with neurons in the brain stem called nucleus gracilis (for sensations coming from the legs) and nucleus cuneatus) for sensations coming from the arms). These nuclei in turn sends axons to the thalamus which is at the center of the brain and distributes the information to the cortex. The second tract is located in the lateral column and is called the spinothalamic tract. It travels all the way from below the injury site to the thalamus.
Several motor tracts carry motor information for movement. One is called corticospinal tract, carrying axons directly from neurons in the cortex to the lower spinal cord. Others include rubrospinal tract (which runs from the red nucleus in the midbrain to the spinal cord below the injury site), the cerebellospinal tract (which runs from the cerebellum to the lower spinal cord), the vestibulospinal and reticulospinal tract (which runs from the brainstem to the lower spinal cord), and the propriospinal tract (which runs from the upper spinal cord to the lower spinal cord). These motor axons must grow from above the injury site to the lower spinal cord.
The central pattern generator (CPG) is located in the upper portion of the lumbosacral spinal cord (where the L2 cord is). Axons that are growing down the spinal cord are likely to get to the CPG first before they reach the motoneurons that operate the legs. Activation of the CPG can activate the legs to do stepping. In the picture below, I show the sensory tracts (red) and the motor tracts (blue). The spinal cord injury site is depicted by the grayish red area. The solid lines indicate where the axons are still intact below (sensory) and above (motor) the injury site. The dotted line indicates the path that the axons must grow.
Wise.
Wise, that asymmetry is interesting. If I read that correctly a person with a C level injury would regain sensation below their injury site before movement and the reverse for people L injuries. Someone like me (T8) would regain them about the same time period. Is that correct?
Yes. For example, Christopher Reeve regained sensation in 3/4 of his body since by about 2 years. He had a C1/2 injury.Quote:
Originally Posted by t8burst
Somebody with a mid-thoracic spinal cord injury (like you) should get motor function back if the tracts are regenerating.
Wise.
Dr Wise Young
Thank you! I have a better understanding now.
Sorry, does this mean there won't even be an update on the trials after you take a look at this data (as was originally suggested....as in you won't broadly comment on the results) or that the detailed data won't be released (which I'm assuming it wouldn't given it'll be pending publication)?Quote:
Originally Posted by Wise Young
As I said, I have not yet decided. Wise.Quote:
Originally Posted by ay2012
Was your mind changed because of the backlash/questioning that came when you provided the last personal observations? The fact that you keep us in the loop and the access you give of yourself to our questions and concerns is, as you note, not common....but its also a reason, among others, why so many throw our support behind your work.Quote:
Originally Posted by Wise Young
Quote:
Originally Posted by Wise Young
Really :argue: ?
Couldn't releasing or not releasing information impact the ability of you or others to raise funds for the trials?Quote:
Originally Posted by Wise Young
ay2012, I simply have not decided.Quote:
Originally Posted by ay2012
Let me review what happened. I had earlier provided general comments about the results when I announced that we will go ahead to do Phase III trials because our phase I/II trials indicate that the therapy is safe and some patients have shown improved locomotor function. This was greeted with great interest by many people and disbelief by some people, who went as far as to suggest that I am providing confusing information in order to raise more money for the trials.
Last month, I was giving a talk to other scientists in the New Bedford workshop about the obstacles and lessons we have learned from clinical trials. I pointed out two interesting findings in our trial, i.e. that we are seeing white matter regrowth in some patients and that improved locomotor function can occur without significant changes in motor and sensory scores. This led to a spirited discussion that I hope helped the community understand some of the mechanisms of recovery from regeneration.
I have stated many times that I will not provide detailed trial data and that people would have to wait until publication for such data. In addition, I also said many times that I did not believe that even the 6-month data would be sufficient to show that umbilical cord blood cell transplants is effective or not. Despite my repeated assertions that it is too early to say anything definitive about efficacy of umbilical cord blood transplants, many people have been jumping to unwarranted conclusions that umbilical cord blood mononuclear cell transplants are not effective.
Some people have dismissed the therapy because people are not walking at 6-12 weeks. So, clearly, releasing the 6-month data can lead to misconceptions by the community. At the present, I am unsure that the benefits of releasing the 6-month data are sufficient to counter the misconceptions.
Lyerly, are you suggesting that people would stop supporting the trial if the information suggests that the treatment seem to be ineffective at 6 months? Or, if the results seem positive, people would give more money? If so, that would be a terrible shame for the following reasons:
1. The 6-month outcomes are still too early to say whether the treatment is or is not effective.
2. "Negative" results are as important as "positive" results.
3. People should be supporting the trials regardless of the results.
Wise.
Lyerly, are you suggesting that people would stop supporting the trial if the information suggests that the treatment seem to be ineffective at 6 months? Or, if the results seem positive, people would give more money? If so, that would be a terrible shame for the following reasons:
1. The 6-month outcomes are still too early to say whether the treatment is or is not effective.
2. "Negative" results are as important as "positive" results.
3. People should be supporting the trials regardless of the results.
Wise.[/QUOTE]
I was thinking that positive results would lead to increased donations with possibly positive press. I think it would be easier to gain support for something that is known to potentially have significant and maybe even visible improvement.
I think it would be easier to convince people to donate to something they have expectations for as opposed to just donating to research in general.
Lyerly,
In my opinion, people should support clinical trials. Their support should not depend on whether the trials are trending positive or negative. They should not be fair-weather friends who support trials only when they think that it is showing positive results and drop their support when the trials are not showing positive results. Negative results are important also.
Lest somebody think that I am suggesting that our trial results are negative, let me say that I am sufficiently optimistic that the trials will show positive results to have committed to doing a phase III trial in 2013. By the way, if anybody thinks that I am willing to spend the next several years working my butt off and raising millions of dollars to do clinical trials on a therapy that I don't believe will work, they are absolutely wrong.
I am undecided about whether and how to present the 6-month data on CareCure. For example, if I say that patients are walking, people will demand that I present videos. If I showed videos of walking patients, I will likely be severely criticized for presenting anecdotal data to raise money for the trials, which would be true. If I presented the detailed data and the analyses, it may jeopardize publication of the data in a good journal. It is not an easy decision.
Wise.
Quote:
Originally Posted by Lyerly
Wise:
Please hold on to the data and keep it from this site. Publication is much too important to worry about what some on this forum will think or wonder. That is all that they have is time to wait for the publication. If you detail that info here you will be bombarded with question and what if's that will take your time away from the goal.
Seems like a no-brainer. You need millions in funding which would be much more contingent on a well received article in a peer-reviewed journal than presenting any form of the results to people who either see your dedication and will support you regardless of if you present the data or people who for some reason have a personal grudge against you and will find fault with whatever you post.
As a researcher you are in a very unusual position in that you have a large website related to your work. if people can google and see even partial results of your trials they may see no point in publishing them in their journal.
Quote:
Originally Posted by Wise Young
I know that if I was raising money for something that has a good chance that will benefit me or even a proven or documented chance that it would be easier. It gives the donor something to see that there investment lead towards and would make them more comfortable and generous knowing the chances of improvement are high as opposed to just giving in general.
Quote:
Originally Posted by Wise Young
While people should support clinical trials in general, good results or bad, this is probably an idealistic viewpoint relative to how people react. Then, the question becomes, where will the majority of the funding come from moving forward? If from outside institutions, agencies, corporations (as I would assume) then, as some above have suggested, if telling us anything jeopardizes the chances of publishing, forget about us. If the risk is not too much, and a lot of the funding will end up coming from Justadollarplease then perhaps it's beneficial to keep the community engaged with updated information. Sorry, but I'm an economist by trade and we always look at incentives!
I think the issue here is that Wise is trying to help us out by keeping us informed of the trial's progress, not for the purpose of soliciting funding as some suggest, but because he understands the position we're in, how it helps us get by each day knowing that we're a step (or push) closer. But some on this site, who are not from the medical profession (and obviously don't understand the protocols and procedures of scientific reporting), feel that it's their role to peer reveiw his work and question his integrity for the sake of self gratification, rather than ask geniune questions to improve our understanding, and this does nothing but waste his time (and our's as we have to plough through all of the rubbish lately to find the real info). I totaly understand where Wise is coming from regarding this. As a sceintist I would do the same if I was in a similar position with my work.
Clayton
Definitely agree with the above and would like to point out that I'm not suggesting that Wise is reporting or not reporting for funds; he's explicitly stated that he is not doing this and feels uneasy at the prospect. I was just pointing out that, regardless of how he feels, people in the community are likely to react by supporting a "front-runner". Although this isn't how science truly works, in the absence of understanding everything in these trials and in the subsequent papers people will likely feel that those with the "best" results are doing the "best" work. It's the publication bias and it's present in all fields....
Agreed.Quote:
Originally Posted by ay2012
I totally agree with the above. Had a feeling that these wanabees and so called BS meters were going to ruin things for us.Quote:
Originally Posted by Geoman
Two important quotes from Wise are reproduced below.
“Last month, I was giving a talk to other scientists in the New Bedford workshop about the obstacles and lessons we have learned from clinical trials. I pointed out two interesting findings in our trial, i.e. that we are seeing white matter regrowth in some patients and that improved locomotor function can occur without significant changes in motor and sensory scores. This led to a spirited discussion that I hope helped the community understand some of the mechanisms of recovery from regeneration”.
“What I believe we are seeing in our trial now is regeneration. Long fiber tracts are regrowing long distances in the spinal cords and they appear to be making some synaptic connections with distal motor structures at 6-18 months after umbilical cord blood transplants. At least in initial stages, subjects are showing improved walking without much change in motor and sensory scores.”
These purported findings, especially the report of long distance regeneration (and now with evidence of synaptic connections) in a chronically injured human, could be extremely important to the spinal cord injury field. It is also important to point out that when one makes extremely bold statements about ones research or clinical trial findings at a conference (ie., the New Bedford Workshop) that is being widely disseminated via the web, that the information is now in the public domain and is deserving, indeed, crying out for answers to critical questions. I’ve watched the New Bedford video twice and I have lots of questions that I wish had been asked by those in your audience. I also believe that public disclosure of scientific findings here at Care Cure should be subject to the same level of scrutiny. I think both Paolo and I share this viewpoint, not because we wish to assault anybody, but because we are passionate about getting to the truth about what may or may not be a viable strategy to improve the lives of people with chronic SCI.
Because of the unprecedented nature of Wise’s claims, I’d really like him to present what he believes to be the solid and convincing evidence that functional regeneration has occurred in his patients.
Here are just a few of the myriad of questions:
What is your evidence in vitro that umbilical cord cells are preferred surfaces for axonal regeneration? I have not seen this presented. If they are not good surfaces for growth in vitro how can they form a growth bridge in vivo?
When axons truly regenerate in animal models they always take meandering trajectories. Indeed, this characteristic is a hallmark of acceptable evidence for regeneration. Yet, in your presentation you suggest that axon regeneration in humans occurs in tight, rectilinear bundles. Why would the human be different than all other animal species?
You state that you see “white matter regrowth”. I have never heard of regeneration being described this way before. As stated above, axons always wander around as they regenerate and they completely lack myelin. Indeed, lack of myelin is another hallmark of true regeneration. Are you also suggesting that regenerating axons in your patients become re-myelinated? What is your evidence for this?
You mention in your presentation that you saw no correlation between patients with purported regeneration and functional recovery. Yet you now suggest that you see evidence for synaptic reformation and imply that such recovery is correlated with regeneration. Could you explain the change in interpretation? Could you present your evidence that new synapses have formed? It seems impossible to conclude this solely from DTI data.
You describe a patient in whom you saw a long “regenerated” bundle of axons that totally degenerated and then remarkably regenerated again. What is your convincing evidence for this spectacularly amazing finding?
You mention repeatedly here at Care Cure that regenerating axons in your chronic patients is occurring at 1MM per day and, therefore, is going to take a long time for the axons to reach their targets. What is your evidence that in your patients the axons are continuing to elongate and at a given rate? Also, related to this, why do you suggest that axons have to grow all the way to their motor neuron targets before you might get functional recovery? All of us in the regeneration/SCI field appreciate that in animal models, axons can link up with distant targets via interneuronal connections. Why couldn’t that happen in humans?
What is your evidence that the long strands of whatever they might be that pass through and beyond the lesion in your DTI images (those that were not especially visible in your presentation) are truly axonal and not something else? Might it be possible that such strands of tissue were at one time spared bundles of axons that may have degenerated (and had become DTI invisible) but then became intensely gliotic (DTI visible)? I think Dr. Tansey was getting at this with his question. In other words what is your evidence that there are, in fact, viable axons in these newly formed structures if, indeed, they are really newly formed? With only simple snapshots of these bundles at one timepoint and a claim that they were not there at an earlier stage, I suggest that one is hard pressed to conclude the remarkable conclusion that white matter “regrowth” is occurring. I am not an expert on all of the caveats that revolve around DTI imaging but I know they exist and it might be a good thing to discuss this.
I think that showing that the distal tip of the bundle continues to elongate weekly would be your most compelling evidence, using DTI only, for ongoing regeneration. It would also surely be nice if you could show convincing long distance regeneration using these same strategies in an animal model of long chronic cord injury. Given that this has never before been shown in an animal model you can surely understand why one might be legitimately skeptical and why your claims are so profound.
jsilver and paolo should really change the focus of their questions. On want side you claim what you seek is knowledge, yet when I read your questions all I see is cynicism, meaning you care more about proving that there is not gonna be a cure within our life time than actually leaving anything positive to us.
I don't see anything wrong with what Wise have said so far. All the data needed to make an accurate statement is not yet ready. Wise IMO express what seems to be happening and what that could lead to. If it not, understanding why not is gonna help future researches.
It had been said before, but all this labeled "doubts" are starting to become annoying for some of us. You may or may not know more than us, but I swear I don't see anything positive with the way some of you rise questions. Actually feels like a POS attitude towards our situation and people on the research field who tries to help
To be fair, none of us know enough about the science to determine how fair or unfair Dr. Silver's questions are. Let Dr. Young respond...and it would likely be helpful for a "third-party" scientist to post some comments on these issues, so as to deescalate the emotions, help the community understand, and allow everyone to find some common ground. Good questions should be encouraged.... Unless we're all content to just sit on the sidelines while these things are discussed...
You are of course correct that showing positive clinical trial results will encourage more donations. On the other hand, we are not talking about "giving in general". It is giving specifically for the purpose of supporting chronic spinal cord injury clinical trials. It should not depend on whether the trials are showing positive or negative results. Both are important. I know that I am being idealistic but think about the cancer field. There has yet to be a cure for glioblastoma or pancreatic cancer but people continue to give for clinical trials, knowing that it is the only path to a cure.Quote:
Originally Posted by Lyerly
Yes, positive results will help raise money. Success is the most powerful of incentives. Everybody loves winners. Once we have had our first success, funding for more clinical trials will be easier to get. Not only private donors but also many companies will flock to ChinaSCINet, SCINetUSA, SCINetIndia, and SCINetNorway to offer therapies and money.Quote:
Originally Posted by ay2012
I am under constant pressure to show "positive" results not only to potential donors, supporters, and spectators but also to doctors, nurses, and subjects who are working their hearts out in these trials. In Kunming, for example, the nurses have given up their weekends to examine subjects in their homes, often after many hours of travel. The subjects are walking every day. They all need incentives.
We must be careful not to raise expectations too high. We cannot count on being lucky and getting a homerun on the first pitch. There will be failures, disappointments, and errors. The trials may not go the way we hope. We must weather the disappointments and continue to play. We are here to win the game and not just the first inning.
Keep up the great work and effort Wise!
Jerry,
Thank you very much for your questions.
Let me first put the talk that I gave into context. It was at a workshop on obstacles to clinical trials. So, I chose to talk about two surprising findings that we have found in our clinical trials to date. The first is that MRI/DTI show spinal fiber bundles that cross the injury site at 6-12 months after transplanting HLA-matched umbilical cord blood mononuclear cells. The second is improved locomotor scores that do not correspond to improvements in motor or sensory scores.
I did not disclose these findings on CareCure. My colleagues at the Chinese University of Hong Kong had presented these results at two recent professional meetings. I was presenting these two findings for colleagues to discuss in the workshop. People had seen the video of the workshop and were asking me questions about the findings. I answered the questions as best as I could. From that discussion, I realized that people are having difficulty understanding how regenerating spinal tracts restore function and the concept of indirect motor activation. I did my best to explain.
You point out one issue with my language that I agree should be corrected. I had used the words "white matter regrowth" to describe the phenomenon that we observed. Since white matter implies myelinated tracts and I have no idea whether these fibers are myelinated or not, the proper term probably should be simply "fiber bundles". Diffusion tensor tractography traces bundles of fibers that have similar anisotropy. They may or may not be myelinated.
Before treatment, all patients had a clear gap at the injury site. In one patient who did not receive a transplant, there was no growth over a 2 year period. At 6-12 months after treatment, two subjects showed fiber bundles that grew across the injury site and extended many cm into the rostral and caudal spinal cord. We observed this phenomenon in two of five subjects. In my opinion, this finding is worth presenting for discussion at the workshop.
We had used a 3T clinical MRI to do DTI so that we could see the border of the injury site for injection purposes. The fiber tracts that we saw were typically >1 mm thick. I agree that it would be of interest to do weekly or monthly tractography to see the fiber bundles elongating. It may allow us to calculate the rate of growth. In the upcoming Phase III trial, we are planning to do repeated tractography in subjects that show fibers growing across the injury site, as well electrophysiology.
I am not sure that you and I disagree on the subject of indirect activation of motor activity. We observed improved locomotor scores without changes in motor scores. This is actually quite common. Many people who can walk after spinal cord injury cannot activate individual muscles as well as one would expect. This is consistent with descending axons activating the central pattern generator rather than direct activation of motoneurons.
Wise.
Quote:
Originally Posted by jsilver
I agree. If you don't ask, you cannot know the answers.Quote:
Originally Posted by ay2012
ResidentBio,Quote:
Originally Posted by ResidentBio
I want a cure in my life time, I don't know if that will happen, but I am doing what I can to make it happen, including questioning things that don't seem right and and that might drive in the wrong direction money and advocacy effort.
Then I just express my opinions supported by arguments that you and others may consider not valid, if so you can provide your opinions with your arguments.
In this way the discussion can be usefull and educative also for people that just read. That in the end will affect positively SCI research, I believe.
Paolo
Marcus,Quote:
Originally Posted by Marcus
you are free to think that, but you are wrong.
I am just a person with SCI that has been following SCI research with diligence for 8 years now including attending SCI scientific meetings etc., That just with the intention to be a person with SCI as informed as possible so that I can possibly provide useful inputs for a faster progress toward a cure.
Questionable things must be questioned if we want a faster progress toward a cure.
Just read the story of the AIDS movments as an example:
http://www.fastercures.org/documents...asicsFinal.pdf
Paolo
I see a contradiction here, but maybe it's just me.Quote:
Originally Posted by Wise Young
Perhaps it would be better to say "try to walk every day" rather than "are walking every day.
Just my personal opinion.
Paolo
For the love of God. Is there anyone else here confused by what Wise means by "walking"? Has he not explained the 6-6-6 regimen of the trial enough times for anyone else? Anyone?Quote:
Originally Posted by paolocipolla
Psst: It's just you.
I moved posts to Members that I thought were off-track, while leaving what I thought was important. If you think I removed to much, PM me.
While I acknowledge the need for robust scientific debate, particularly where new ground is being broken, why is it that we see so much negativity towards Wise's work from some here? Perhaps this is how it's done in the medical profession and we just happen to be able to witness it here on a public forum. I've been an environmental geochemistry consultant for over 25 years and while much of my work requires peer review, it has never been in such a negative manner as witnessed on this site. I'm not saying this to defend Wise, I know he's more than capable of looking after himself on that front, I would just like to get rid of all the rubbish so that we can get back to the central role of this forum, to educate and empower us with knowledge. We're all in this together to fix this thing, sure ask questions if you don't understand (but not over and over again because you don't hear what you want to hear, or you couldn't be bothered doing you're own research) and let someone know if and why you disagree with what they're saying, but there is no need for negativity toward someone for presenting something that you don't agree with.Quote:
Originally Posted by Geoman
Just to clarify my earlier post. Many people on this site have been asking Wise for an update on the progress and preliminary findings from ChinaSCINet, and Wise has accomodated these requests, where possible, with the required provisos. It is my understanding that he has provided us with the preliminary data with the intent of keeping us informed of progress for our benefit, not for critical review or for our approval (or funding). The time for critical peer review will happen once all of the results are in and reported, and this will be done by adequately trained people, not us. I appreciate that Wise has provided the preliminary data in the past and while I'm dissappointed that he may have to discontinue this in the future, I understand his reasoning. I also understand that this is a bit of a gray area because it may be beneficial to the cause to get feedback from likes of Jerry Silver and it is also very interesting for us to watch how it's played out, hence Wise's indecision regarding this. But the crux of the matter is that because some people on this site are latching on to the preliminary data and trying to analyse it prematurely without the required medical or sceintific expertise, after many warnings from people who saw it coming, it is no longer in the best interest of the trial for Wise to release any of the data until it has been all been collected, reveiwed and reported, as required, and unfournately this means that we will need to wait a lot longer for any results (Wise, please correct me if I'm wrong). If only those responsible could take heed!
Clayton
I request my all CC friends not to be personal and negative here on CC. I know we being SCI patients have lot of hopes but it does not mean that we become so much negative on others. Let us pray and watch progress from Wise and Jerry and few others.
Jerry can you just tell that how far ch'ase and ur peptide away from human trials now?
In my opinion, there are two challenges in getting other people to care about funding spinal cord injury therapies:
1. The perception that once injured, a person doesn't get worse. Contrast with ALS, MS, Parkinson's, Alzheimer's, etc. After stabilization, SCI is not considered by most to be imminently lethal.
2. Conventional wisdom says that spinal cord injury will just simply never be fixed. In cancer cases, patients receive bone marrow transplants, surgery, radiation, etc. and survive. HIV/AIDS patients receive drug cocktails that lengthen life and sometimes make the virus undetectable in the body. Pancreatic cancer people have hope because some breast cancer people get better. A major breakthrough for ANY neurological disease (i.e.: if a brain injury person got stem cells, began to make limited eye contact 9 months later) would help change the spinal cord injury conversation.
I'm probably ignorant on this, but in terms of moving therapies forward, what is the importance of published studies if they aren't necessary to apply for and receive FDA approval for the Phase III clinical trials? Is purported data/outcomes categorically dismissed by researchers if not yet published in a journal? Would any researchers support the trial's findings despite not being published in a journal?
What happens if you put the info out there and an official study confirming the data was published later? Truth is confirmed either way.
It feels a little like a reliable scout who sees an invading army and doesn't tell his fellow soldiers about it until first receiving the necessary permission from his commander to do so. Time that could've been used preparing a defense is wasted because of inefficient bureaucracy.
Paolo,Quote:
Originally Posted by paolocipolla
I know you have good intentions, but getting bogged down with this is just semantics and not helpful in any way, and in fact may be detrimental due to the fact that Wise is now considering whether or not he will be providing us with any of the preliminary findings of the trial/s. It really just comes across that you're just feeding your own ego rather than genuinely trying to help the cause. If it's your "personal opinion" and it doesn't help our understanding, in future it's probably best to keep it that way..."personal" that is.
Clayton
I wish that someone really could explain to Paolo that these therapies are not for him. I wish that for example Wise Young and Jerry Silver could explain to Paolo that due to the complexity of injuries like the one Paolo has where big areas and networks of the spinal cord is damaged including lower motoneurons, systems connected to the CPG and other generators including large areas of segmental interneurons and ascending and descending axon pathways, - that it will be impossible to threat Paolo’s injury. As of today there are just some scattered proof in animal models that some axon sprouting can occur for any research in the SCI field, and to take it from there to humans is a huge step, let alone to cure injuries like the one Paolo has. It will be impossible in his lifetime. And like it is now I feel that scientists are fooling Paolo and giving him false hope. Someone should be realistic and explain all this in a good way to Paolo. It’s fine that Paolo is working for cures for others, but one should not fool Paolo letting him believing that there will be therapies for him in the near future.
It's clear that there is a variance of definitions for "Cure" and "walking". And this is part of the reason why this thread is so hot right now.
Activating the CPG with or without a pharmacological way of boosting plasticity may see some improvements in primitive functions for chronic SCI. Definitely a win for most of us but this is not walking as many of you will have known it before your injuries. Will we take it? Of course. But ask incomplete walkers as to how incredibly difficult this is and for many a return to the wheelchair becomes a must! We will want more than this (not in an ungrateful way - just a realist ;).
Whether activating the CPG will have any effect on functional recovery after regeneration of CST axons is yet to be known. The outcomes of this trial will go some way to confirming this. So let's see.
My hunch is (please note it's a hunch) that for regenerative strategies a different mode of training will be required here with less focus on autonomic functions and more focus on finer motor movement training. You would expect overground training with kinematic errors, proprioceptive prompts, functional training modalities and activity-based rehabilitation will be a better fit for regenerative strategies than just locomotor training alone. However, this variety of modalities will no doubt confuse researchers who are trying to simplify the parameters of the rehabilitation components of a potential therapy when clearly variety is important.
Is that an informed opinion Leif or just that you are worried that you may have to abdicate your comfortable throne in Norway if someone comes up with a Cure in your lifetime? :nono:Quote:
Originally Posted by Leif
Paolo,Quote:
Originally Posted by paolocipolla
Walking is a continuum. To me, a person who is taking weight-supporting steps, with or without help, is walking. It may not be normal walking but the people who are doing it call it walking and I agree with them.
Wise.
Leif,Quote:
Originally Posted by Leif
We have now been spending the past year working on the problem to replacing motoneurons in contused rat lumbosacral spinal cord. Our first task has been to create a model of lumbosacral injury. It is actually quite a beautiful model. Contusions of different levels of the lumbosacral spinal cord produce very specific locomotor deficits associated with particular patterns of neuronal loss. The model includes upper lumbar, mid-lumbar, lumbosacral, and conus injuries.
So, we will be transplanting neural stem cells from various sources to replace neurons in the lumbosacral spinal cord in the coming months. One of the most interesting problems that we have had to solve is how to get the motoneurons to extend their axons out into the ventral roots and to reinnervate muscles. I think that we may have developed a way to do so.
I use to be quite discouraging to people who have lumbosacral spinal cord injuries or ischemic spinal cord injuries that frequently damage gray matter, saying that I don't know how to fix the problem and that regeneration of spinal tracts alone will not restore function. To me the solution to the problem require four fairly difficult steps but we have accomplished at least two of these and have been working on the second two.
• development of a reliable lumbosacral spinal cord injury model with specific behavioral deficits with which to judge efficacy of therapies.
• identification of a source of immunocompatible neural stem cells that can be transplanted to replace neurons that have been lost.
• find a way to attract axons of the new motoneurons to send their axons into the ventral roots and grow all the way to muscles.
• getting interneurons from the central pattern generator and descending spinal tracts to make synapses with the motoneurons.
If we work hard and are lucky, we might have the therapies ready for trial by 2015.
Wise.
I just wanted to comment, that I really appreciate this dialogue. It is very helpful, informative and does provide context to our problem. As a passive viewer, I value this discussion and wish many therapies could be discussed in this manner (without any personal attacks). Thanks to all for their contributions.
Wise it means no trials for lumbosacral even in 2014?
Long wait bit discouraging
Wise,
The important thing is that you and your team know the results, not us. I personally would love to hear any news you have and I won't be too terribly upset no matter how vague and reserved that news may be. We are all so desperate for even a sliver of hope that we at times act like a pack of hungry dogs.
Whoa, Wise, first I have to agree with Paolo because I did take a few steps on my own in the parallel bars and many more with help. That was exercising and trying to get to independent, no help needed 'walking'. As in ASIA normals.
As far as comparing complicated and large lumbrosacral complete injuries and incomplete ischemia injuries as saying they are equally difficult to fix, um, I'm confused. I know I'm rusty on my science after a few years of other things to brush up on but won't getting the cortico-spinal tract regenerated lead to 'walking' in the future? Yes, I do remember the 1mm a day pace but with PT and a CST fix I assumed we were looking at the fix that someone who didn't know us wouldn't see a person who had had a SCI. I do not extend that to my contracted hand because of fusion of joints, etc.
Oh, and Merry Christmas!
Pelican,Quote:
Originally Posted by Fly_Pelican_Fly
I am not sure what you mean by "locomotor training" but I use the term locomotor training to refer to overground walking. Perhaps you are thinking of locomotor training as weight-supported treadmill training. If so, let me emphasize none of the subjects in our studies have had any treadmill training. They start with overground walking.
There are two serious limitations to weight-supported treadmill training. First, weight support harnesses place significant pressure on certain body parts, such as the straps that go between the legs) and carry a significant risk of pressure sores and walking time must be limited to an hour or less at a time. Second, due of the weight support, the walking is abnormal and the sensory cues for the legs are incorrect. It is like teaching the person to walk on the moon and then having to reteach the person how to walk on the earth when transferring to overground walking. The group in Kunming believes that walking should be done with full-weight bearing from the beginning.
When I first visited Kunming in 2004, I am surprised by how fast the people start to step and walk without assistance when they get the training starting 2 weeks after their spinal cord injury. Many (particularly incomplete or complete patients who received the intradural decompression) recovered walking within 3 months. However, people with chronic spinal cord injury do not recover as fast and almsot all reach a plateau within 3 months.
To the best of my knowledge, our current trial is the first time that the Kunming group has been systematically training a significant cohort of patients with chronic spinal cord injury with their 6:6:6 overground walking program after cell transplants. Incidentally, several of the patients currently in Kunming are training but without having received any transplants, so they constitute a form of control.
While some of the subjects (about 25%) in our study showed improvements during the first 3 months, we are now seeing subjects that showed little improvement during the first 3-6 months but are getting locomotor function late at 6-12 months. Please withhold judgment on the walking until you have actually seen the data and the walking. I cannot present the detailed data or videos here without attracting criticism from people like Jerry Silver but I think that you will be surprised. We will get the work published as soon as we can.
I have been observing spinal-injured people doing locomotor training for several decades. In the 1980's, for example, Barbara Devine headed a group that trained people with spinal cord injury to walk 7 or more hours every day. She had dozens of people walking in her facility in Cottonwood, Alabama and then later in Galveston, Texas. In my opinion, very few got functional walking back.
Wise.
Dr. Wise,
According to the model of nerve regeneration you provided, wouldn't the clinical trials show improved arm and hand function in cervical level injury subjects (C5 and below) at this point? What motor scores are being used to test upper level extremities? Is there arm therapy being used in this trial as well, or is this a consideration for phase 3 studies?
Is this model for nerve regrowth a disagreed topic for SCI researchers as well, where the nerves just need to jump across the injury site or to the location of the nerve root?
Everyone,
I am really appreciative of top researchers discussing results on this web site and allowing open questions and discussion, but we should try to be more polite to one another. Critical questions are important and are great for understanding what is going on, but when people get negative towards one another and then talk about it more. It removes focus of why we even come to this forum. Both sides of the fence are not innocent here either. Lets stick to the point.
It would be really interesting to go to a thread that is limited to researchers to discuss their opinions, ideas, and findings among one another, without the clutter of the general public, so it is condensed and easier to page through. Does this exist? Some of the best ideas are formed during the after hours of conventions where a bunch of researchers collaborate and debate their ideas, why not do this every day?! I'm sure it would speed up the rate of progress for SCI research. This would be really interesting to observe as well.
Thanks! Merry Christmas!
Wise, I agree that overground walking training will be much more effective than weight assisted treadmill training.Quote:
Originally Posted by Wise Young
But, from what I have seen so far a walking programme alone will not really be enough for unassisted walking - no matter how how intensive. Surely there is more than just walking in the programme in Kunming? For example how are the trunk muscles, glutes and hamstrings being stimulated and conditioned appropriately? Maybe there is more to the programme that you havent described because unassisted walking needs a hell of lot of conditioning - something that you dont get by simply walking.
Let me give you an example. I know a number of incomplete walkers who walk with crutches and canes very well. They walk all day long. Not just at home but everywhere. However, without stimulating, strengthening and some serious conditioning of the trunk, hamstrings and glutes they can never progress to unassisted walking.
Is there perhaps more to the programme in Kunming than 6 hours of walking?
Cheers
Pelican,Quote:
Originally Posted by Fly_Pelican_Fly
I share your view. Most people with ASIA A spinal cord injuries reach a low plateau in their walking and more walking, no matter how intensive, will not get them beyond that plateau. Of course, you get an occasional person who never seriously tried walking and may even be incomplete that will show dramatic improvement with training. But, in general, intensive locomotor training does not restore unassisted walking to people with chronic ASIA A spinal cord injury.
We don't have a non-transplanted group of chronic spinal cord injury patients in this study. However, there are some patients at Kunming now who are not part of the study but are training without having received any cell transplnats. Also, this is an escalating dosing study where dose of cells injected increased. When we complete analysis of the data, we will correlate recovery with the dose and HLA-matching of cells.
In our study, the subjects averaged 12 years after injury and none were able to walk without assistance before the treatment. All were ASIA A. Although some (25%) showed improved locomotor scores without motor score changes within 6 months, most (75%) of them showed only slight or no improvements in locomotor scores after 3 months of training. Now, some subjects are showing delayed locomotor recovery at 6-12 months.
I want to emphasize that this is a phase II study. It was designed to ascertain whether the treatment is safe, feasible, and improves recovery of some patients. So far, the study results indicate that the therapy is safe. It certainly appears to be feasible. Finally, it improves recovery in some of the subjects, even though it was only 3 months after treatment.
The study showed several unexpected findings. First, MR/DTI showed fiber bundles growing across the injury site at 6-18 month after cell transplants. Second, even by 3 months some subjects (25%) showed improved locomotor scores. Third, at 6-12 months, we are seeing delayed locomotor recovery in some subjects.
The data suggest that the bundles of fibers and the improvements in locomotor scores result from the transplants. None of the subjects has had bundles of fibers crossing the injury site before transplantation. None showed such bundles <6 months after the treatment. At least in two subjects, the fiber bundles were growing longer between 6-18 months.
Only a Phase III trial, a true double-blind randomized controlled trial will prove this. That is why we are pushing forward to do that trial in 2013.
Wise.
While I agree with your general point, I think you're doing the same thing on another level. Who cares if Wise gives us preliminary results? The important thing is that the data gets published in a peer reviewed journal. Giving us prelim results is pointless and gets us no where. You are missing the forest for the trees.Quote:
Originally Posted by Geoman
Great question about the arms. The picture that I showed in http://sci.rutgers.edu/forum/showpos...postcount=1403 applies to the arms as well as the legs. We are collecting ASIA motor and sensory scores from the arms and the legs. In the arms, the ASIA standard examination includes five muscles: deltoids, biceps, wrist extensors, triceps, and wrist flexors. We did not include other hand function measures but plan to include them in the Phase III trial. We are hoping that we will see some improvements in those scores but I want to emphasize that less than half of the subjects in the Hong Kong and Kunming trial have cervical spinal cord injuries.
Wise.
Quote:
Originally Posted by Skipow
Can you discuss preliminary outcomes in arm motor/ sensory improvement from this trial from the cervical subjects?Quote:
Originally Posted by Wise Young
Since the study seems to be safe in C5 subjects and below, will C4 or higher be considered for phase 3? Or does another phase 1 and 2 study need to be done to assess the safety of this procedure with C4 and higher?
Thanks!
I'm curious about hand and arm function as well. Walking is actually fairly low on my priority list. I have a little movement in my fingers and especially my thumbs, but it's more novel and not functional.
:applaud:Quote:
Originally Posted by Chaz19
We are planning a phase II trial on high cervical injuries (C1-C4) to assess a different protocol where the cells are injected into the injury site and below in the injury site, rather than above and below the injury site. The reason why we restricted the current trial to C5 is because a C4 injury would require the that the upper (above the injury) injection be done at C3.Quote:
Originally Posted by Skipow
We have not analyzed the data for recovery of the hand and arm function yet and so I don't know the results yet.
Wise.
Quote:
Originally Posted by Wise Young
I'm glad to learn that things are planned to move forward even for upper injuries. A read one of your posts regarding the safety for nerve fiber growth downwards and upwards for the c5 level… I’m glad that it has been proving good results on the safety data so far but my question to you is should we consider a much obvious higher risk for the c1-c2 level due to the location is much closer than a c5 to the brain? I’m curious and worried if somewhere up in the spinal cord there’s some kind of natural barrier preventing anything growing up in the skull… I understand that perhaps it’s too early to know but I’m curious of your point of view.
I thank you very much for your hard work and appreciate the time you share with us!
Cheers,
Moe
So.... For those of us seeking any new kind of information, is there anything on the horizon we should check back here in a couple months for? I.e. update on the publishing process, organization or fundraising for the Phase III (in China and the US)? Thanks again.
Moe, I don't think that there is a "natural barrier preventing anything growing up in the skull." The main reason why we have been reluctant to inject cells into the upper cervical spinal cord is that the phrenic nucleus (responsible for breathing) is located there (C2-C4). I think that surgeons would be willing to accept the risk of injecting cells into the injury site (since that has already been damaged). Injecting into non-traumatized C3 spinal cord is risk that most neurosurgeons are not willing to take.Quote:
Originally Posted by Moe
Wise.
When is the upper injury trial scheduled? Will it be in China?
ay2012, I am sorry to sound repetitive but I simply have not yet decided when and how to present further data from the phase II study.Quote:
Originally Posted by ay2012
Our goal is to provide information for the community concerning the progress of the trials but not at the risk of jeopardizing publication or drawing criticism to the trial. We have already seen some examples of the latter here. In general, it is all right to present unpublished results at scientific meetings for discussion but it is not acceptable to present detailed data or analyses on internet. Some journals may consider this to be prepublication. So, we have to be careful.
On the other hand, one of the purposes of CareCure is to improve the community's understanding of the science and clinical trials that are going on. When I see gross misunderstandings of not only clinical trials but mechanisms of therapy and recovery, I feel that it is worthwhile discussing some of our observations if it helps people understand the science and spinal cord injury better.
We are of course working very hard to collect all the data, completing and sending the manuscripts for publication. In addition, of course, we will be submitting IND's (applications for clinical trials) to regulatory agencies around the world. We may have changes of the protocol. In March, we are planning to have investigator's workshops in China, India, Norway, and the U.S. All these may be associated with information that we may release here. So, stay tuned.
Wise.
I think that we will do it in the U.S. I am not sure when. Wise.Quote:
Originally Posted by Scaper1
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.Quote:
Originally Posted by paolocipolla
Hey Doc, do you ever sleep? or do you have a 5 hour energy drink addiction? Seriously, thanks for the dedication.
Wise,Quote:
Originally Posted by Wise Young
about point 1, you have posted many times about doing a mielotomy (which you say it improves outcomes) which require cutting the spinal cord.
How do you do that without causing more damage and more scarring?
I think the same procedure might be used to insert a solid scaffold in the spinal cord, does that make sense?
BTW you suggested me this solution using solid scaffolds last time we met in Italy.
About point 2 would you have a look to this study?
http://pubs.acs.org/action/doSearch?...ation=40025957
It seems that axons have crossed the scaffold and functional recovery has been seen and documented by electrophisiology.
While I agree that it is not something ready for clinical trials tomorrow (but maybe sooner than Cethrin and Muse cells) I would look into it (if you haven't yet) also because it is something done on animals one month after SCI, which should be close to chronic, while Cethrin and Muse cells have been tested just on acute that I know.
About your point 3, what about people with a very severe SCI if not anatomically complete SCI, how do you bridge the gap in these people? Maybe a solid scaffold could help? Or a peripheral nerve bridge may work better?
One more question, InVivo is investing a lot in biomaterials and planning clinical trials, do you thing it is built just around "hot air"? .. and you know I am not super excited about InVivo, but I would think they should have something.
Paolo
Leif, thanks very much for the advice. I appreciate it and agree. Wise.Quote:
Originally Posted by Leif
I post late either from jet lag or from being on the other side of the world. But seriously, I frequently stay up late because I am skyping with my colleagues concerning the clinical trials. A myriad decisions are associated with clinical trials. I am thankful for Boeing 777's and Skype. They allow me to fly directly to China from Newark and to communicate with my staff in Hong Kong in real time. Without these two developments, I think that ChinaSCINet would not have been possible. To avoid criticism, I disclose that I have no stock and have received no consulting fees from United or Microsoft, the owners respectively of the Boeing 777's and Skye. Wise.Quote:
Originally Posted by muskie
My advice is to pay attention to the many who appreciate what you are doing and to ignore those few who criticize. Nobody ever did anything great without a few critical people following along. Happy Holidays!Quote:
Originally Posted by Wise Young
Paolo,
The myelotomy in Kunming is done from the side, usually at the dorsal root entry zone to keep from cutting through any of the long tracts. Most myelotomies are done at the midline, which cuts through the posterior column tracts for the legs. When the myelotomy is done during the first week or two after the injury, necrotic tissue is under pressure and comes out of the opening. This leaves a cavity in which scaffolding can be placed. Note that this is only possible during the first 2 weeks after injury. In the chronically injured spinal cord, the necrotic tissue has already consolidated and there may be axons crossing the injury site. In fact, Carlos Lima and his colleagues use to cut a chunk of spinal cord out of the injury site, saying that they are removing "scar". However, he showed picture of histology of the removed pieces of cord and there were axons running through them. That is one of the reasons why I think that it is not a good idea to remove chunks of spinal cord out and why I think very little of the cutting out "scar" idea. I don't think that it should be done on chronically injured spinal cords.
Wise.
Quote:
Originally Posted by paolocipolla
This group is offering unproven mesenchymal stem cell therapies for spinal cord injury and charging for the therapies. They should not be doing this. If they are doing a clinical trial, I would be applauding but they are not. Actually, there are several groups in China offering this therapy and charging for the therapy. I would wait until there is convincing clinical trial evidence that this therapy is beneficial.Quote:
Originally Posted by td_trust
Beware of any place telling you that they have an effective cell transplant therapy and wanting to charge you money for the therapy. No cell transplant therapy has been shown to have beneficial effects or safe for chronic human spinal cord injury. So, if any place is telling you that they have an effective cell transplant therapy for spinal cord injury, please avoid them. If this were a legitimate clinical trial, they would not charge you for the therapy and they would post the trial on www.clinicaltrials.gov or similar trial website.
Regarding CT-guided cell transplants, we decided not to use this approach in ChinaSCINet because CT cannot show the presence of blood vessels. They are inserting the needle into the spinal cord without knowing that the needles may be penetrating some blood vessel and causing a catastrohic hemorrhage that may further damage the spinal cord. It is one of the reasons why the investigators of ChinaSCINet chose to expose the spinal cord and inject the cells under direct visual inspection of the spinal cord, to avoid any possibility of causing a hemorrhage.
Wise.
Will see how far ChinaSCINet will go. So far good news. By the end of phase III human trials, the others are still playing with rats...
Back to ChinaSCINet topic please...
I moved some of the discussion concerning scar tissue formation and discussion with Jerry Silver to its own thread:
http://sci.rutgers.edu/forum/showthread.php?t=211255
Hey guys new here wanted to know how many potential cures for sci
are in stage 3 clinical trials
Wise, You mean that it's not possible to do CT guided cell transplants because CT requires the person to be in the imaging equipment while the operation is ongoing? CT is the way anuerysms are monitored in my experience.Quote:
Originally Posted by Wise Young
I understand your reason for not cutting the scar tissue out.Quote:
Originally Posted by Wise Young
But is there any possiability of cutting slits into the scar tissue area and bridging the cord by that means or type of catalyst that might be able sofen for a better word the scare tussiue to allow better bridging or growth to occur.
Didn't the SCS work on this problem at one stage?
and when if some idea will both stage 3 and 4 be started and completed?
Leif,Quote:
Originally Posted by Leif
this is what I would do if the data I have indicate that the therapy does not work.
More in details... I would spend a year or so trying to get the data publisched in journals that likely would refuse the publication to gain time.
In the meantime I would do 10 more patients making sure they all get valid DTIs and electrophysiology exams (I would try also to include ASIA B and C) to make sure the therapy really does not work before giving up.
In parallel I would get another therapy ready for clinical trials to be announced the same day I will have to say UCB cells don't work.
That would mitigate the disappointment of the supporters.
Of course here above I am just anticipating the worst case scenario, if UCB cells will show some efficacy all will be easier.
Paolo
Quote:
Originally Posted by paolocipolla http://sci.rutgers.edu/forum/images/...s/viewpost.gif
Wise,
about point 1, you have posted many times about doing a mielotomy (which you say it improves outcomes) which require cutting the spinal cord.
How do you do that without causing more damage and more scarring?
I think the same procedure might be used to insert a solid scaffold in the spinal cord, does that make sense?
BTW you suggested me this solution using solid scaffolds last time we met in Italy.
About point 2 would you have a look to this study?
http://pubs.acs.org/action/doSearch?...ation=40025957
It seems that axons have crossed the scaffold and functional recovery has been seen and documented by electrophisiology.
While I agree that it is not something ready for clinical trials tomorrow (but maybe sooner than Cethrin and Muse cells) I would look into it (if you haven't yet) also because it is something done on animals one month after SCI, which should be close to chronic, while Cethrin and Muse cells have been tested just on acute that I know.
About your point 3, what about people with a very severe SCI if not anatomically complete SCI, how do you bridge the gap in these people? Maybe a solid scaffold could help? Or a peripheral nerve bridge may work better?
One more question, InVivo is investing a lot in biomaterials and planning clinical trials, do you thing it is built just around "hot air"? .. and you know I am not super excited about InVivo, but I would think they should have something.
Paolo
Wise,Quote:
Originally Posted by Wise Young
if I understand correctly what you say the myelotomy does some damage, but the benefits of getting the necrotic material out surpass the negative effects of cutting the spinal cord as necessary.
As I understand in real life probably more than 50% of traumatic SCI are much worse then the tipical contusion injury that is done in a lab on an animal. In fact penetrating bones in the spinal cord are not uncommon, that would cause signifinìcant fibrotic scar and not just gliosis, long gaps and sometimes even complete transactions of the spinal cord.
What would be your approach in these cases?
Sometimes I have had the impression that you consider just the kind of SCIs for which you believe UCB cells may do something and leave all the others behind, in fact, for example you have answered just partially to my questions which I think are of general interest. Hope you don't mind me beeing straightforward.
Paolo
Paolo,Quote:
Originally Posted by paolocipolla
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.
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). 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. 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.
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. 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. 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. 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.
The prevailing view is that regenerating axons take meandering courses as they regenerate. Can you speculate as to why the purported regenerating fibers in your patients are supposedly growing in tight bundles? What is your evidence that these structures are in fact axons?
Jerry,Quote:
Originally Posted by jsilver
That is why I think our finding is so significant. Scientists have been looking for and seeing single axons grow. During development, axons grow in bundles. They express the L1 cellular adhesion molecule and fasciculate into bundles. It is possible that the bundles of fibers are not axons although it is difficult to imagine what else they could be.
As I have described before, we have seen axons growing into the contusion site of animals. Our hope was that the treatment would increase the number of axons growing into and out of the contusion site. We did the DTI to see white matter ends at the contusion site so that we could identify the place for the cell injections. We were very surprised to see these bundles grow.
In the coming year, we will be assessing patients with DTI in a double-blind randomized clinical trial that will include rehabilitation alone, umbilical cord blood mononuclear cells alone (UCBMC), lithium alone, and UCBMC+lithium alone. Based on what we have seen to date, none of the patients have shown DTI evidence of the fiber bundles before 6 months.
Few of the patients show any motor or sensory score improvement before 6 months. About a quarter showed improved locomotor scores at 3 months. At 6 months, we are seeing more and better improvements of both motor and sensory scores, as well as locomotor scores. In my opinion, it is still too early to tell and we will need to do the phase III to come up with convincing results that the UCBMC with or without lithium is restoring function.
What we know so far is that people who don't do locomotor training do not recover locomotor function and people who don't get the UCMBC transplants do not show DTI images of fiber bundles crossing the injury site. The Phase III will tell us how many people who have undergone the intensive locomotor training without UCBMC±lithium recover unassisted walking and whether those treated with UCBMC±lithium recover more.
Wise.
I've been following news coming out of these studies with great interest. From time to time I've seen posts about research about chronic spinal cord injuries. It seems researchers have found acute injuries are easier to deal with than chronic injuries..especially with the changes, damage & creation of glial scar tissue that occurs at the site of an injured spinal cord over the course of weeks & months.
As a person who's injury happened on June 4, 1995, where does this leave those of us with "older" chronic injuries?? Am I wrong to at times to wonder if there will really be therapies/surgeries for chronic injuries in our lifetimes? I suppose I'm looking for reasons to be hopeful & optimistic about one day being more independent & getting out of this wheelchair.
Dr. Young, I know you think some people hang onto little things you say and sometimes misconstrue them, and I don't want to put words in your mouth or blow things out of proportion...but if this is what you really meant to say that is great news. You had mentioned both slight sensory and moderate locomotor recovery before, but improved motor scores would suggest controlled movements of muscles...fantastic!!Quote:
Originally Posted by Wise Young
Kyle, the average time after injury of subjects treated in our trial averaged 12 and 14 years in Kunming and Hong Kong. We have one patient who is more than 20 years after injury.Quote:
Originally Posted by KyleP2112
Wise.
ay2012, please don't over-read. In the immediately following sentence, I statedQuote:
Originally Posted by ay2012
Wise.Quote:
In my opinion, it is still too early to tell and we will need to do the phase III to come up with convincing results that the UCBMC with or without lithium is restoring function.
wise; when exactly will we get to hear the full 6 month follow-up data? I was sure it was this month? Whats going on?
Fair enough, I didn't want to attribute any observations you made to the therapy...I just wanted to clarify that bit on improved motor scores. Because, even though that would not prove anything, the observation is nonetheless not insignificant. I again just wanted to make sure you hadn't misspoke (err...miswrote), had a slip of the tongue, etc.Quote:
Originally Posted by Wise Young
"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.
Start reading post 1401 for explanation-Quote:
Originally Posted by lunasicc42
Quote:
Originally Posted by Wise Young
not directed at anyone, but.... General disappointment
Very understandable.Quote:
Originally Posted by Wise Young
Thank you Dr. Wise & ChinaSCINet for all your hard work.
Thanks for the reply & info Dr. Young.
sorry I posted this in the other thread but it belongs here:Quote:
Originally Posted by Wise Young
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...
ay2012, if you read back, all the info is in this thread.
This is good news,Quote:
Originally Posted by Wise Young
PaoloQuote:
Originally Posted by Wise Young
Wise,Quote:
Originally Posted by Wise Young
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
Originally Posted by Wise Young http://sci.rutgers.edu/forum/images/...s/viewpost.gif
Jerry,
At 6 months, we are seeing more and better improvements of both motor and sensory scores, as well as locomotor scores.
Wise.
beuty,Quote:
Originally Posted by beuty
please don't over-read. Wise in the immediately following sentence, stated
Quote:
In my opinion, it is still too early to tell and we will need to do the phase III to come up with convincing results that the UCBMC with or without lithium is restoring function.
Paolo
I can't imagine how exhausting your schedule is Doc, just remember to take care of yourself through it all.Quote:
Originally Posted by Wise Young