Clare Wilson over at the NewScientist has reported the case of a woman given an experimental stem cell treatment in Portugal for a spinal cord injury who later developed a strange tumor consisting of nose tissue. I highly recommend going over to that site and reading her excellent article.
What’s the deal with this case?
The woman was treated with nasal stem cells eight years earlier. Her condition did not improve and now eight years later the tumor was removed in the US from her spine. The 3-cm tumor fortunately was benign, but was secreting mucous and causing her pain.
More generally, providers are injecting thousands of patients each year with all different kinds of stem cells into all different kinds of places in the body. Often the stem cells have nothing to do with the place of the injury such as in this case the use of nasal stem cells for a spine injury.
There are several things to point out about this case that are particularly important.
First, there is so much we do not know about how stem cells behave when transplanted and, as George Daley is quoted in this piece, our knowledge is relatively primitive. Great caution is warranted and there are a host of risks. Professor Leigh Turner, who has been closely following emerging stem cell treatments for years, is quoted related to this point:
“But the case shows that even patients who feel they have nothing to lose should be cautious, says Leigh Turner of the University of Minnesota in Minneapolis, who tracks lawsuits involving stem cell therapies. “We still need to think in terms of risks and benefits.”
Second, long-term follow up of stem cell treatments is crucial and most of the follow up done by stem cell clinics is too short. Usually follow up outside of academic clinical trials only lasts months. This case of a benign, but harmful tumor showing up eight years after treatment shows that follow up should be measured in decades.
Third, clinical trials have risks. This was not some rogue clinic, but rather a clinical trial in Europe at the Hospital de Egas Moniz in Lisbon. Any kind of experimental treatment, even within the context of a clinical trial, has a host of risks both known and unknown.
Wilson quotes my favorite cell therapy expert, Alexey, on this point:
“The case shows that even when carried out at mainstream hospitals, experimental stem cell therapies can have unpredictable consequences, says Alexey Bersenev, a stem cell research analyst who blogs at Cell Trials. “We have to realise complications can also happen in a clinical trial,” he says.”
This case also brings to mind the case of the woman who grew bone in her eye after a fat stem cell-based interventions a few years back and also the strange, but interesting report of a doctor growing a nose intentionally on a man’s forehead to use as a replacement nose (See image above).
Stem cells are exciting and powerful, but we must do our best to understand and respect that power as clinical applications using stem cells are advanced more quickly and widely. Patients must also be made aware of the risks they are taking and the limits of current knowledge as well as alternative treatment options.
This article leaves it unclear as to wether the nasal tissue was reinjected at the same operative session or wether the cells were implanted after culture expansion. As you know the cell population would become much more homogenous and dedifferentiated towards msc lineage with each subsequent culture passage.
As it stands, I doubt whether they could have obtained enough nasal mucosa to derive significant number of stromal cells from the sample specimen. My hunch is that they culture expanded the cells.
Even then, there are questions as to how they expanded the cells. What kind of factors were introduced to speed up the growth curve so as to treat a patient who flew in from US to Portugal?
If they did inject nasal tissue directly into the spine, it is not surprising at all the patient had a few clusters of acinar cells growing. The fact the tumor was benign and took so long to grow (remember the spinal canal is very tight thus intolerant of rapid growth) leads me to believe this is also a possibility.
As a clinician, the article seems very scant on information, but it appears the tumor was a teratoma with some acinar cells in the mix producing mucous tissue. As such it would be a reportable case of autologous stem cells causing teratoma and worth calling attention to
I feel I should also point out that the “bone formation” in the case Dr. Wu reported had many other contributing factors that cast doubt as to whether it was truly a case of stem cells “growing bone” or heterotopic calcifications. Heterotopic calcifications can happen as a consequence of fat necrosis. Fat necrosis with calcifications is not uncommon with poorly processed fat grafts. Secondly, the patient had also been injected in the eyelid with a calcium hydroxy apatite based filler, which is a stupendous misjudgment by a clinician injecting stem cells, as the calcium hydroxy apatite is a terrific matrix for bone formation, and indeed has been used as bone filler. By injecting Stromal Vascular Fraction (which is what I think was used in the case you cite) the surgeon was literally creating a bioreactor for ectopic calcification. The miracle is she did not have more ectopic calcification.
The case of the nose on the man’s forehead does not belong in this article or discussion.There is a time honored and proven technique of reconstructing noses using forehead flaps. Because of the uninjured area’s good vascularity you can reconstruct patiently the complicated and anatomically intricate nasal structures with good vascular supply. And this is the key differentiator- is not creating new tissue, it is “borrowing from Paul (forehead skin, cartilage from other ares) to pay Peter”. The nostrils are pointing up because the entire nasal construct will be rotated into place on a vascular leash. It was not reconstructed “in situ” because the poor vascularity and scar tissue in the recipient bed (the nose) would have doomed the effort to certain failure.
I share your belief in rigorous scientific verification of stem cell therapies, but by the same token, claims of clinical autologous stem cell disasters deserve the same attention to detail. In my experience, such disasters in AUTOLOGOUS therapies are usually the result of clinical misapplications rather than cellular misbehavior. In the use of nasal mucosa case you cite, there are too many questions. In the case of the heterotopic eyelid calcification, it is a clinical blunder with an expected result to any clinician with a clue, and in the case of the ectopic nose, well it doesn’t belong here.
This is very interesting not least for the gruesome image it conjures. Next a sneezing spine!?
However, reading the New Scientist article, it seems the Portugese hospital did the transplant as it were direct from the nasal area, without isolating the cells prior to implant, so at a very deeply level of amateur supposition on my part, I expect the cues from the associated cells were such that they thought they were still in the nasal environment?
Maybe there will be some evolution of pre-transplant steps that will serve to ensure any such ‘cues’ are eradicated.
In the interests of balance, one should note the following article which reports a very substantive set of data — showing no teratoma or other such nasty things when autologous bone marrow derived MSC were used to treat orthopaedic conditions:
http://www.ncbi.nlm.nih.gov/pubmed/24352775
This is exactly what one would expect from evolutionary considerations…
Keep in mind that the stem cells used in this case were adult stem cells derived from the nose, likely a heterogeneous mix of neuroepithelial stem cells, respiratory stem cells, and MSCs too. The power/multipotency of any kind of stem cell brings the potential with it to grow unwanted tissue types depending on context and probably some degree of chance too.
When you say “any kind of stem cell…” you generalize. That is why I point to the above publication — to counter undue generalization.