I’ve often said in my writings that I have yet to encounter a for-profit stem cell clinic that is not a predatory quack clinic selling unproven treatments for serious diseases at high prices. Although I’ve been writing about this phenomenon and how these clinics continue to operate for quite a long time now, my interest was particularly piqued when a hometown hero, Gordie Howe, went to Mexico for an infusion of stem cells to treat his serious stroke. As a result, even though he was hardly ever shown, he became a de facto celebrity pitch man for Stemedica Cell Technologies, the San Diego company that made the stem cell product that he received at the Mexican clinic and had provided it to Howe at no cost other than his travel. Never mind that there was no good evidence that the stem cell infusion improved Howe’s neurologic function. More recently, William Shatner touted an “anti-aging” stem cell infusion that he had undergone. Meanwhile, there have been reports of spinal cord tumors as a result of dubious stem cell treatments. As the FDA tries to crack down on the most egregious offenders selling stem cell quackery, there comes another reminder that, contrary to what stem cell entrepreneurs tell us, these treatments are not without risk—in some cases, significant risk, in the form of a case report from Newfoundland in Canada of a man with a cervical spine mass after a stem cell treatment. The mass turned out to be an olfactory mucosa stem cell tumor.
Here’s the case history:
A 38-year-old man was referred to the neurosurgical clinic with a 3- to 4-year history of deteriorating neurologic function in his arms (sensory disturbance with some subjective weakness) and gradual loss of bladder function. The patient’s medical history included a C5/C6 fracture-dislocation secondary to trauma at 20 years of age. Despite having had posterior spinal fusion and rehabilitation, he had partial paralysis of his arms, and severe paralysis of his legs and trunk. According to the American Spinal Injury Association (ASIA) Impairment Scale (AIS) (https://asia-spinalinjury.org/wp-content/uploads/2019/04/ASIA-ISCOS-IntlWorksheet_2019.pdf), which grades impairment after spinal cord injury from A (complete motor and sensory deficits) to E (neurologically intact), he had sustained an ASIA D injury (i.e., motor incomplete). This means that half or more of the key muscles below the neurologic level of injury were active against gravitational resistance. At 26 years of age, the patient had undergone experimental stem cell transplantation. Using a nasal approach, the surgical team harvested an olfactory mucosa graft that was transplanted to his spinal cord lesion on the next day. Although the patient could not provide an operative report, the surgical team (Lima and colleagues) published their transplantation and surgical procedure.1 Fusion hardware was removed and he again underwent rehabilitation. Although he hoped to walk again and have resolution of his chronic pain, he never regained clinically significant motor function, and he experienced additional pain.
This is, of course, a horrific injury. This man had very severe neurologic deficits and was, in essence, a quadriplegic. Now, here’s the interesting thing. This procedure appears not to have been performed at a for-profit quack stem cell clinic. Rather, it was performed in Portugal at Hospital de Egas Moniz in Lisbon and the clinical trial protocol approved by the hospital’s ethics committee and published by Carlos Lima
I was intrigued by the procedure; so I looked up the clinical trial protocol. The timeline fits, because the operations for the clinical trial were carried out between 2001 and 2003. The trial itself enrolled seven patients ranging from 18 to 32 years of age with spinal cord injury (four men and three women). All had suffered serious spinal cord injury with paralysis, and all injuries had resulted from motor vehicle collisions save one, which had resulted from a fall.
The authors described the rationale for using olfactory mucosa grafts:
There are several potential advantages of olfactory mucosa transplants. The olfactory mucosa is a structural unit with embryonic features that offer the possibility of promoting regeneration and reconstruction. Removing part of the olfactory mucosa does not permanently damage olfaction because it is a continuously regenerating system. By using the olfactory mucosa to fill the spinal cord cavity with solid tissue as opposed to using cell suspensions, there is decreased risk of individual cells entering the cerebrospinal fluid (CSF) circulation. In an experimental transplant study, tissue (as opposed to cell suspensions derived from that tissue) was more effective and showed greater cell viability (12). During the period of adaptation to the new environment, cells may be supported by their original surrounding cell types. Olfactory mucosa transplants avoid the artificial environment of tissue culture, which also reduces the risks of the procedure. Instead, olfactory mucosa grafts preserve the CSF environment, because CSF also bathes the olfactory mucosa through the olfactory route of CSF drainage (13). The autologous olfactory mucosa graft would not be an additional burden to the immune system, because the grafted material was previously exposed to the contemporary immunological state of the central nervous system.
In addition, it is known that the two cell types in the olfactory mucosa known to be useful in the repair of the nervous system are stem-like progenitor cells and olfactory ensheathing cells (OECs). The stem-like progenitor cells divide rapidly and can develop into neurons or supporting cells. There are also a number of promising animal studies that suggest that these cells can contribute to the repair of damaged neurons. As a result, it was thought that there was sufficient preclinical evidence to do a pilot study.
The surgical procedure itself involved multiple teams and three steps. The first step involved neurosurgeons exposing the damaged spinal cord and removing as much scar tissue as possible to expose the gross viable nervous tissue in both stumps of the severed cord. This wound was temporarily closed, and then the otolaryngologists went into action to harvest the olfactory mucosa graft. Finally, the graft was implanted into the site of injury. The graft was immersed in saline or cerebrospinal fluid and cut into small pieces, after which the graft was placed at the site of injury. Patients were transferred to the surgical intensive care unit.
Six months after transplantation, MRI showed filling of the defect in the spinal cord in all patients but one, with no evidence of tumor overgrowth. There was some improvement in every patient, but reading the report, I couldn’t see the results as anything more than mildly promising and worth following up, which the same team of investigators did in a prospective, uncontrolled pilot study of olfactory mucosal autograft implantation in 20 patients who had sustained traumatic spinal cord injury 18 to 189 months previously (mean 49 months). The AIS scores improved in 11 of 20 patients and declined only in 1 patient.
However, as promising as these results might sound, we must be cautious, as the authors of the case report of the spinal mass suggest:
Studies involving transplantation using olfactory mucosal autografts notably carry several limitations. To date, patient enrollment is small, making the generalizability of results difficult. The studies are neither randomized nor blinded. The relative contributions of intensive postoperative rehabilitation and olfactory mucosa transplantation to recovery are unclear given the lack of large control groups. Some studies with questionable rehabilitation intensity and compliance showed no postoperative improvement in ASIA motor score. Although these studies claim that olfactory mucosal autograft transplantation is feasible and safe given the few adverse events encountered, their follow-up periods are limited.
Now, at a followup of around 17 years, this patient presented with a cervical spine mass, as seen on this MRI:
The mass is best seen in A as an irregular area against the vertebral bones. Don’t worry if you can’t read the MRI; I included it for those who can. The mass extends from the C4 to C7 vertebrae. You don’t need to be able to read MRIs to see the the mass in this surgical photo from the exploration and resection of the mass:
The suction catheter shows very thin mucinous material that was expressed from the mass (white arrow). Solid components were adherent to and infiltrating the spinal cord, resulting in the surgeons not being able resect the entire mass. So they did a subtotal resection. This is what pathology found:
Pathologic examination of the samples found mucinous material and tissue consistent with ectopic olfactory mucosa. The sections showed tissue and small cysts lined by a pseudostratified columnar epithelium (Figure 3A). Nerve twigs and submucosa glands were seen in the underlying connective tissue, with 1 slide showing bone. Results from examination of tissue using immunohistochemistry showed neurofilaments and S100 proteins within the nerve twigs, and perineurial cells that were positive for epithelial membrane antigen and glial fibrillary acidic protein positivity in some areas, likely representing gliotic spinal tissue (Figure 3B).
Translation: This was a mass with mucus in it and tissue consistent with olfactory mucosa and thus deriving from the olfactory mucosa graft. The prognosis after surgery is basically unknown. The authors report:
Between discharge and follow-up at 6 weeks, the patient became severely deconditioned because of admissions to hospital for urinary tract infection and acute pancreatitis. His injury remained classified as ASIA D, but a physical examination found either stability or slight loss of power in the myotomes of his arms and legs. Given the subtotal resection of the mass, radiotherapy was offered after consultation with colleagues in other centres in Canada to try to sterilize any residual cells in the hope of slowing regrowth of the mass. The benefit of radiation in this setting is unknown; however, further surgical resection was not possible, and there was no role for chemotherapy. Treatment with radiotherapy and rehabilitation and surveillance are ongoing.
In other words, if the radiation doesn’t work and the mass recurs, options will be very limited. Nor is this the only case of a mass following an olfactory bulb mucosa graft for spinal cord injury. The authors review several other cases of mass lesions following olfactory mucosal autografting in the medical literature, one who underwent surgery by the same medical team as the patient in this case report. Two other cases involving patients who developed similar spinal masses 5 and 7 years after autologous olfactory mucosa transplantation have been reported.
One thing that should be noted is that these patients underwent stem cell grafting procedures at a public hospital under an ethics panel-approved clinical trial protocol, and they suffered serious complications in the form of masses growing where their grafts were implanted and causing more damage to the spinal cord. Given the gap of many years between surgery and growth of the mass to the point where it caused symptoms, it’s quite possible that additional masses will be detected. Even so, I saw an additional red flag that might not have been picked up on in reports of these cases. The man in the case report I discussed is a Canadian citizen, and the woman who also developed a mass after this procedure is an American:
At a hospital in Portugal, the unnamed woman, a US citizen, had tissue containing olfactory stem cells taken from her nose and implanted in her spine. The hope was that these cells would develop into neural cells and help repair the nerve damage to the woman’s spine. The treatment did not work – far from it. Last year the woman, then 28, underwent surgery because of worsening pain at the implant site. The surgeons removed a 3-centimetre-long growth, which was found to be mainly nasal tissue, as well as bits of bone and tiny nerve branches that had not connected with the spinal nerves. The growth wasn’t cancerous, but it was secreting a “thick copious mucus-like material”, which is probably why it was pressing painfully on her spine, says Brian Dlouhy at the University of Iowa Hospitals and Clinics in Iowa City, the neurosurgeon who removed the growth. The results of the surgery have now been published.
OK, so reputable public hospital or not, this is stem cell tourism. Now, putting it together, there are two additional observations that got my skeptical antennae twitching. Her’s the first one, from the Canadian case report:
Olfactory mucosal autograft surgery costs about $50 000; with patients facing additional expenses for travel, accommodations, caregiver support and recuperation, this price can easily double. The subsequent cost for managing any complications in Canada can be the same because these patients require ongoing multidisciplinary care.
This got me thinking: Did the patients pay for the surgery? It seems rather likely that the foreign participants in this clinical trial, at the very least, paid for their surgery. Hmmm.
Now here’s the second observation, from a New Scientist story about the woman who developed a mass on her spine after this procedure:
was unable to reach the Lisbon team members, but Jean Peduzzi-Nelson, a stem cell researcher at Wayne State University in Detroit, Michigan, who advised the team on their surgical technique – she had previously tested it on rodents – claims the clinic has given the therapy to about 140 people in total. Peduzzi-Nelson adds that most of the recipients of the nasal tissue who received the right kind of rehabilitation after their surgery experienced improvement. “I am saddened to learn of this adverse event, however, the incidence of this problem is less than 1 per cent,” she says. “Many patients receiving this treatment have had remarkable recovery.”New Scientist
My first reaction was: “Less than one percent”? That’s quite a lot, actually, given the potential morbidity and even mortality when this complication occurs. Partial paralysis could easily become complete paralysis, and pain can become unbearable.
They have? Or should I say: They had? After all, the above article is five years old. Funny, but the Canadian researchers who just published the case report I discussed did a literature review, and they didn’t mention any later studies encompassing hundreds of patients. So I hit PubMed. Nope, nothing more to see there. The last clinical trial by Carlos Lima involving olfactory mucosal autografts dates back to 2010 and was the pilot trial of 20 patients. Peduzzi-Nelson appears to have suggested that Lima’s group has done way more than 20 olfactory mucosa autografts than just 27 (the seven from the first pilot study and the 20 from the second). Which is true? Has Lima only done 27 under his clinical trial protocols, or has he gone beyond that and continued to treat patients? Does he charge for the procedure? You see where I’m going with this? Is he becoming, for all intents and purposes, no different than the for-profit stem cell clinics I regularly castigate for their unethical practices? If he is continuing to do the procedure, why hasn’t he published further about it in nine years? Is the hospital charging patients the $50,000 or more for the procedure, even though it is, by any stretch of the imagination,
I definitely smell something fishy here.
Leaving that aside, though, the most important thing to remember from this case report, the author’s conclusion:
Given the vulnerability of patients who are chronically ill, especially those with spinal cord injury or neurologic disorders who may be targets of Internet-based marketing for stem cell therapy), physicians in Canada should be aware of the rationale behind stem cell therapy as well as the reported adverse events. Both family physicians and specialists may need to counsel patients on stem cell transplantation or diagnose complications in those who have had these procedures.
Precisely. Even under the auspices of a properly designed clinical trial approved by an institutional review board, there is the potential for serious adverse reactions from stem cells. Now just imagine what could happen as a result of the unregulated sale of unproven stem cell therapies.
ADDENDUM: I just discovered that Carlos Lima died in 2012, although apparently his work still goes on. His group also claimed to have done over 120 of these procedures.
42 replies on “Olfactory mucosa tumors: Another complication of stem cell treatments”
How likely is it, given the time gap you describe, that in unregulated stem cell clinics there are many cases of this that are never tracked back to the original treatment? I mean, it sounds like one rason this was caught was that – as fishy as this seems, and you made a powerful case of it – there actually is patient follow up and monitoring and available records here?
This is scary–so is that picture! As a skeptic, I guess I’d wonder what Portugal knows that we, or Canada, doesn’t? People tend to wonder what they have to lose when they are in these conditions, but they need to actually answer that question before they take these risks.
It’s really difficult to assess risk without knowing the denominator. Is it 27 or 120? Even if it’s 120, there seems to be significant risk here, probably with no benefit. I would advise any potential patients to stay away from this procedure.
ASIA? Oh not that ASIA. Getting that confused with another quakronym.
I love their first album! Carl Palmer is one of the greatest drummers ever.
Is it possible more proceedures were done and only the 20 were included in the study?
Yes, but why leave those out unless they change the results of the study in an unfavorable way? If that’s what happened, I would classify that behavior as misconduct.
The one image of that mass included with the paper looks benign (I am a pathologist). I would be doubtful about the efficacy of radiation, and I agree that chemotherapy is not indicated.
Also, since this seems to be overgrowth of benign mucosa, lag times of many years between treatment and presentation of a mass is not surprising.
Are you saying that radiotherapy focussed on the benign tumour would not slow its growth? Just asking – I don’t know the answer.
What’s the C3–C7 distance? Naively, that and the depth of the tumor seem like considerations for trying to zap the thing.
Radiotherapy, like chemotherapy, works best on rapidly growing tumors. Since this is not a neoplasm, just misplaced benign mucosa, it will be growing very slowly, making standard cancer treatments doubtful at best.
I think what’s happening is that someone assumed that because olfactory mucosa regenerates readily, placing some in an injured spinal cord would induce the spinal cord to regenerate. The result seems to be transplantation of olfactory mucosa instead.
mdfinfer: ” The result seems to be transplantation of olfactory mucosa instead.”
There is snot in his spine. There is snot in his spine.
Boogers on his neruons.
That’s just a new and totally different level of gross and horrifying. I don’t know how to process this.
Oh, good. It’s not just me . . . .
Regarding the patients paying for the procedure, I do not see it as fleecing the patients because, well, this is the EU.
To put it very simply, each of the EU countries have their system of compulsory health insurance and within each country, the local regulations state what is covered from this health insurance and what is not (and the extras can be covered by non-compulsory insurance). The extent of coverage differs between the EU countries.
By the general EU law, any citizen of any European Union country will be treated within the EU without travel insurance or any other sort based on them having paid that compulsory health insurance in their home country – but the local laws and regulations may and do limit it to an extent – my state mandated insurance would cover only the amount the treatment would cost in my home country and since we are one of the cheaper ones, I still do get travel insurance.
Folks from outside the EU either have commercial insurance which can limit the coverage as they please, or, well, they pay for healthcare. And it is mostly the state, be it directly or via funding the hospitals, universities or research groups which pays for the experimental treatments. So in this context, I would see charging for the treatment perfectly normal – one is not a part of the system, doesn’t add any money to the system (the mandatory health insurance is usually a certain percentage of one’s income so it’s a tax in anything but a name) so they are not allowed to take anything away from the system. Should a US or Canadian citizen come to Europe to have their appendix or broken hand dealt with, they would pay for it as well.
So in this context, I see it as perfectly normal that should someone come to EU to get a treatment of any sort, they pay for it.
I’ll go and ask my doc friends whether they have a clue about non-EU nationals being enrolled in clinical trials because I got curious. I guess that nobody would want such participants because it would mean too much paperwork.
I think what Dr. Gorski means is that they shouldn’t be paying for a procedure that is being done as part of a clinical trial. Also insurance often doesn’t cover experimental treatments.
Exactly. If a person is participating in a clinical trial (where the outcome is unknown), ethically, they should not pay for the procedure. They might pay for things like transportation, housing, food, and maybe for other medical expenses not directly related to the trial, but they should not pay for the trial itself.
It’s wrong to charge people thousands of dollars for something that everyone involved knows might not work. (If you knew it worked you wouldn’t need a trial.)
People from outside the US come here all the time for clinical trials and aren’t charged for the treatment.
I can totally see not wanting to enroll patients who you might lose to followup because of borders and oceans and travel, but that’s a bigger concern than who pays for their medical treatment.
Although I do not do any stem cells treatment, I am following development of this pretty fresh branch of medicine. In fact, at least theoretically, it looks to be a future of medicine, together with immunotherapy. There is plenty of evidence that stem cells therapy can help people, especially the mesenchymal ones (like in OA, neurology etc)). It is also relatively simple method of treatment so I am not surprised that so many “easy money” clinics had opened up, especially in the US. After all, all private clinics, also these ones offering well established treatments are also pro-profit. I guess we need time to say which SC treatment works, which do not. The example presented above is classic experimental treatment with potential high risk of complications. I am pretty sure that this risk was explained to the patient together with experimental character of the treatment. When you are tetraplegic you take everything. Also it seems, it was the first case like this (hence their complications rate below 1% – 1of 120) so they had no idea this kind of complications can happen before). It would be interesting to check the real improvement of rehabilitation of previous patients though. I also don’t blame the hospital to charge the overseas patient for a treatment. I guess the American hospital would do the same with EU citizen – probably charging even more. I guess it is wrong to name stem cells medicine quackery as it limits the development of medicine in general. Just, let’s hope the market is just better regulated.
Benign is not the same as harmless. There are plenty of benign neoplasms and non-neoplastic processes that harm patients. Benign and malignant are technical terms with specific meanings.
Benign and malignant are both terms that have been used far far longer than they have been part of medical argot, which is why I specifically said “in the general sense.”
e.g. The White House is occupied by a malignant entity whose deeds are rarely benign.
I think something we all need to realize, both with stem cells and with immunotherapy is that the thing that makes these treatments desirable is also the thing that makes them dangerous. Immunotherapy can be very powerful. Stem cells can become many kinds of cells!
The problem is that, right now, we have very, very little control over what these things do when they’re let loose. Several cell-based immunotherapies have terrifying side effects (potentially fatal), not because they’re badly made, but because when you fuss with the immune system that much (CAR-Ts specifically), you take off the brakes and let if go full bore, something the rest of the immune system spends all its time preventing.
Sure, stem cells can become many different types of cells. But right now it’s clear that we have little to no control over which specific types of cells come out of the stem cells. The reason that bone marrow transplants work (generally) is because they’re pretty far down the differentiation path, so they only want to be blood cells in the bone marrow, rather than bone cells or nerve cells or snot-making cells or whatever.
To give an engineering analogy, we’ve made rockets, but not the guidance systems yet. (Except that it won’t be nearly as simple and easy as rockets.)
“I guess the American hospital would do the same with EU citizen – probably charging even more.”
No. American hospitals are not flea markets; they do not charge patients more for being from Europe or any other country. They don’t care where you’re from.
Is this even legitimately “stem cell” work?
It appears to me that the transplanted cells must have already been too far along their normal developmental path to be coerced into becoming something else. One of the quotations refers to “tissue” – can something legitimately called tissue also be sufficiently “stemmy?”
The nasal mucosa contains undifferentiated stem cells. My guess is that they are hoping that these stem cells will develop into neurones (instead of nasal mucosal cells) when they are transplanted into the spinal cord environment.
So it would appear, then, that they jammed in a chunk of tissue hoping for good luck with the desirable portion thereof and that the undesirable bits would just magically go away. If there were space for the mucosal cells to grow without causing problems, this would seem at least moderately non absurd. There isn’t really an abundance of available space where the ol’ spinal cord resides. I would call the undesired growth “malignant” in the general sense. It clearly isn’t “benign” in the general sense.
yes. That’s why they took olphactory mucosa – containing olphactory nerves. They did experiments on rats first and apparently were encouraged with results to start doing the same on humans. In one case things went not as expected, which unfortunately is a part of medicine. Bad outcome is common in “hopeless cases”.
There was bone in the cancerous growth. So stem cells were potent indeed, and differentiated randomly.
As an aside…
I’m not a doctor, nurse, PA, etc ( but have studied bio, physio, etc)
I am amazed that they went with this plan of action- as a few commenters said- “Were they just hoping that things would sort out correctly?” – put cells in a new place and hope that they’d do the right thing / grow into the type of cell needed? Weren’t they already “too far along” on their own path?
I mean, they were doing this ON PEOPLE! And an ethics committee let them?
Even though “olfactory mucosa regenerates readily” ( mdfinfer), it is quite a leap of imagination to assume that it would regenerate into exactly the type of cell needed in the spine- instead of regenerating into what it was
-btw- after listening to / reading the endless faux physio/ woo that I do, it is quite a treat to read commenters like mdfinfer, a few others here.
“There was bone in the cancerous growth. So stem cells were potent indeed, and differentiated randomly.”
Or the biopsy was contaminated with bits of bone from the surgical procedure.
At least there weren’t any teeth.
Heh, heh : I’ve seen those images too.
I think my ovary grew either teeth or an eyeball, but my surgeon wouldn’t tell me. It’s a long story but he was a fertility specialist and this was probably the first potentially lethal case he’d seen in a very long time.
My partner had a hair follicle growing in her brain.
From stems or as hamartoma?
How on earth was this detected?
The Human Nose Harbors a Niche of Olfactory Ectomesenchymal Stem Cells Displaying Neurogenic and Osteogenic Properties
Bruno Delorme, Emmanuel Nivet, Julien Gaillard, Thomas Häupl, Jochen Ringe, Arnaud Devèze, Jacques Magnan, Jérôme Sohier, Michel Khrestchatisky, François S. Roman, Pierre Charbord, Luc Sensebé, Pierre Layrolle, and François Féron
Stem Cells and Development VOL. 19, NO. 6
It goes without saying that olfactory stem cells have olfactory potential, which is main problem there
Horrifying. Thank you for this information. I had no idea but it makes perfect sense.
So they put some snot cells in the spinal cord and now the spinal cord is being crushed by excessive snot?
My wife received a really nice brochure in the mail today from Celltex. They will obtain your own cells using a simple one-time adipose tissue extraction. Then they will grow hundreds of millions of one’s own stable MSCs for therapeutic use. Then if you suffer from any one of 19 chronic conditions, you can “take back your life”.
If you are “among the 114 million Americans who suffer” from one of these conditions, “Celltex can help alleviate your symptoms” …
Their lab is “FDA-registered”!
And there’s a testimonial!
Oops. You have to go to Hospital Galenia in Cancun, Mexico.
Does this sound too good to be true? Of course it does.
Oy. I work in human cell stuff (immunotherapy) and I had a hell of a time talking my MIL out of having this done for her knee (though she found a place in San Diego rather than across the border).
She was also initially excited about the cell extraction, since it’s fat from around your midsection. She was sad when I explained that 100mL of tissue wasn’t exactly the liposuction of her dreams.
I’m trying to think of a counter-example to “if it says it does everything, it doesn’t do anything”. Aspirin? Water?
I would say “exercise,” but I’m sure there are a few things exercise isn’t touted as a cure/treatment for. I’m pretty sure nobody’s ever claimed that going for a little jog will cure paralysis.