Stem cell tourism is here. It exists and, apparently, it’s a good business. But does it really help patients? What are the results and long-term outcomes? Professionals (physicians and scientists) are staying skeptical and referring to lack of any reported data about “stem cell treatments” abroad. There are stories of many cases you can read online, but almost all of them are advertised on clinic web-sites, “told by patients” and positive. Sorry, but I don’t believe in this magic, I don’t buy it. Absence of any “no effect” cases or “unsuccessful treatments”, actually makes me cautious and even scared. I think that such innovative intervention as cell therapy can not avoid negative results or complications. What we really need right now is that observational studies. What is it? These studies do the following:

1. evaluation of the patients who have returned from “stem cell tourism” trip by physicians;
2. collection of data about all patients who went through such treatments;
3. unbiased analysis (not by clinic-providers and not subjectively by patients);
4. evaluation and analysis of published cases and phases I-II of clinical trials;
5. publish in peer-reviewed professional scientific and medical journals.

It is needless to say how badly we need this kind of studies in cell therapy. Until observational studies and conclusive clinical trials, professionals will consider all magical cases of cure as anecdotal and speculation. Well, the good news is that we have got some observational studies right now. I’ll quote one of them below.

The study, evaluating cellular therapies for amyotrophic lateral sclerosis (ALS), is published by our Spanish colleagues in September’s issue of Cytotherapy journal. This is the best observational study I have ever read! Strikingly, unlike advertisements online, data is negative!

The increasing availability of stem cells in many countries, together with straightforward laws of supply and demand, makes it imperative that clinical trials demonstrating the effectiveness of these treatments be undertaken, before ‘stem-cell tourism’ becomes more widespread and ends all opportunities for this promising new treatment. Therefore we present the results from a series of 12 patients who decided to seek cell therapy of their own accord in the clinics mentioned above.

They evaluated three groups of patients:

1. Three patients treated with fetal olfactory ensheathing cells by intracerebral injection in China by published methodology;
2. Two patients received mesenchymal stromal cells by intrathecal and intravenous routes in Greece;
3. Seven patients received intrathecal enriched CD34+ cells in Germany.

None of the three centers providing treatment maintained a specific follow-up protocol after TX. No information about the anticipated result of the treatment was offered in writing at any of the centers except for the one in Israel. We have no information regarding the expectations of success given verbally to the patients by the medical teams.

The authors evaluated patients by commonly used in neurology functional scales - ALS functional rating scale (ALSFRS-R) and forced vital capacity (FVC). Data were compared with scores, reported for natural progression of ALS. The study showed no difference in the progression of the disease and was no changes observed in comparison with pre-treatment status. Some adverse effects were noticed:

There were two adverse effects reported during the TX procedures. Patient 1, who received intracerebral ensheathing olfactory cells, presented with fever and deterioration in consciousness, lasting 5 days, 48 h after surgery. One of the patients that received intrathecal MSC presented with intense back pain 4 h after the lumbar puncture, which required morphine derivatives for 72 h. No late complications attributable to the TX were observed during the follow-up period.

Importantly, authors retrospectively analysed all available data about current ALS clinical trials. 550 patients underwent cell therapeutic treatments and outcome was reported. All possible cell types were injected (hematopoietic, mesenchymal stromal cell, total mononuclear, fetal neural), mostly autologous. None of these trials and cases were found positive. Authors conclude that current cell therapy can not cure or even offer better life for patients with ALS.

I like the last 2 columns of their trials summary table. First one showed that outcome judged by subjective impression of the authors is mostly positive (6 out of 8 reports). Second one showed the opposite - objective evaluation in all reports is negative.

Regarding secondary effects, one of the patients who underwent treatment with olfactory ensheathing cells presented with serious central nervous system (CNS) complications. Three cases of meningitis were identified in an observational study of seven patients with chronic spinal cord injuries treated at the same center. Of the nine patients receiving intrathecal stem cells, one presented with back pain lasting 3 days that required morphine, and two complained of sensory symptoms in their legs. A similar prevalence and intensity of adverse events were found in the English- and Chinese-language literature. Of the groups using intracerebral injection, 4.9% of patients in a Chinese group experienced complications including headache, short-term fever, seizures, CNS infection, pneumonia, respiratory failure, urinary tract infection, heart failure and possible pulmonary embolism; 25% of this group experiencing complications died.

As you can guess, conclusions are the following:

In view of these negative results for cell therapy in humans, further insufficiently controlled clinical trials should be avoided. Furthermore, these treatments are often offered by ‘for profit’ clinics, which raises ethical implications. ALS experts could prevent the worrying new type of medical ‘tourism’ arising from patients’ desperate searches for effective treatment. The ever-increasing range of fraudulent procedures provides therapies that are not proven and that may cause serious psychologic and economic distress to the patients concerned, and endanger the legitimate progress made by scientists in the field of stem cells. In conclusion, the results obtained to date in these clinical trials suggest that cell therapy in ALS has not been shown to be sufficiently effective in curing or halting the disease, and its presumed ability to slow down the disease’s progression has yet to be proven.

I love this study! Very well done and unbiased. Extremely important for community! Based on this data we can design better trials and avoid possible complications. We can answer to patients seeking treatments, if they ask for advice.

Of course, it is very sad news for desperate ALS patients, but it’s how it is. Cell therapy is not a magic. Stem cells are not a panacea.

**********
PS: I’m ready to send this paper out to everyone who is interested. Contact me.

I’d like to highlight the importance of collecting data dedicated to cell therapy activity. First of all, analysis of scientific literature, indexed in PubMed can capture very small part of all activities in clinical cell therapy field. Collecting such data will allow us to define some trends, estimate potential market and navigate the community to work in right direction. Collecting the data about cell therapy activities is a hard work and our efforts should be collaborative.

There are a number of professional organizations and societies which started to do it. For example, European group for Blood and Marrow Transplantation (EBMT), in 2007 included a “novel cellular therapy” category in their annual activity survey for transplant centers. The first report about cell therapy activity in Europe, was published with annual 2007 EBMT survey. They define “novel cellular therapy” as cell transplants of non-hematopoietic cells or hematopoietic stem cells (HSCs) for non-hematopoietic use. For 2008 report, data were collected in collaboration with 4 other professional organizations: TERMIS-EU, ISCT-EU, ICRS and EULAR. This collaborative effort led to creation of comprehensive database of nearly all patients, legally treated in Europe by different cell types.

Center for International Blood and Marrow Transplant Research (CIBMTR) is the organization collecting cell therapy activity data mainly in US. They have listed a few research projects dedicated to cell therapy, but didn’t release any reports yet. I have never heard anything like that from Asia, but I suspect that they have done a lot. I’m happy to share some published data below.

2008 EBMT cell therapy activity report you can download from TERMIS web-site under “patient survey” (.pdf).

Cell therapy activity in Europe 2008 in numbers:

Members of the 4 participating societies from 47 countries (39 European and 8 affiliated countries) were contacted for the 2008 report (EBMT survey). The non-European countries affiliated with the EBMT were Algeria, Iran, Israel, Jordan, Lebanon, Saudi Arabia, South Africa, and Tunisia. Thirty three teams in 16 countries (14 European and 2 affiliated countries) reported novel cellular therapies using the survey form, with detailed information on indication, cell source and type, donor type, processing, and delivery mode.

1040 patients were treated with novel cellular therapies, 376 (36%) with allogeneic and 664 (64%) with autologous cells.
Main indications were cardiovascular disorders (29%; 100% autologous), musculoskeletal disorders (18%; 97% autologous), neurological disorders (9%; 39% autologous), epithelial disorders (9%; 18% autologous), autoimmune diseases (12%; 77% autologous), and graft-versus-host disease (23%; 13% autologous).

Of the 406 HSC treatments, 84% were autologous transplants and 70% were used to treat cardiovascular diseases. All 48 chondrocyte and 16 myoblast transplants were autologous. Of the 491 mesenchymal stromal cell-based therapies, 49% were allogeneic.

Of all the grafted products reported in detailed form, 51% were based on expanded cells and in 5% of the cases cells were transduced. About one-third (31%) of the products was given intravenously, 45% intraorgan, 14% on a membrane or gel, and 10% using a three-dimensional scaffold.

Nonexpanded cells were used to treat 93% of cardiovascular, 50% of musculoskeletal, and 19% of neurological disorders, whereas epithelial/parenchymal and autoimmune diseases were exclusively treated with expanded cells.

High cellular therapy rates were reported in Belgium, the Netherlands, Slovenia, Switzerland, and Turkey.

This report is impressive! In appendix they listed all centers performed cell therapy procedures in 47 countries with name of doctors. Please let me know if you have fresh information about 2008-2009 cell therapy activities in US, Europe and Asia. Stay tuned for 2009 reports.

Many people predict that unrelated allogeneic cord blood (CB) cell transplantation could be “the next big thing” in regenerative medicine. A few obvious questions arise here:

1. Can we transplant HLA-mismatched CB cells into the patient with degenerative disease without fear of adverse immune reactions such as graft-versus-host (GVH) and host-mediated immune clearance? How many cells would be safe?
2. Can we transplant allogeneic CB cells with a regenerative purpose without myeloablative or immunosuppressive conditioning?
3. What therapeutic benefit would we expect after allogeneic CB cell therapy in immunocompetent (non-conditioned) patient?

All of these questions were addressed in the 2007 review - Cord blood in regenerative medicine: do we need immune suppression?

The possibility of using cord blood in absence of host preconditioning would open up the door for a multitude of stem cell therapeutic applications. The currently dogma amongst cord blood transplanters is that administration of allogeneic cord blood, even if HLA-matched, would in the best case scenario lead to immunologically-mediated rejection or the graft, and in the worst case cause GVHD. Here we provide rationale for the preliminary clinical exploration of cord blood administration in a non-preconditioned host.

The authors cite a lot of historical facts showing that CB cell transplant like a blood transfusion was done safely even in the 1930s, when HLA matching was not introduced. Reported data shows that even in myeloablative setting in leukemia clinic HLA-matching in CB transplant does not play a significant role in the outcome. The role of HLA-matching in CB cell transplantation for purposes of regenerative medicine has not been tested and reported. Now we have the first evidence, that mismatched allogeneic CB cell therapy can be done safely in different non-hematological conditions, which do not required immunosupressive conditioning.

The authors evaluated safety of allogeneic mismatched umbilical CB mononuclear cell therapy in 114 patients mostly with neurodegenerative diseases, which was performed in Nanshan Affiliated Hospital of Guangdong Medical College (China):

Doses of 1-3 x 107 cord blood mononuclear cells per treatment, with 4-5 treatments both intrathecal and intravenously were performed. Adverse events and hematological, immunological, and biochemical parameters were analyzed for safety evaluation.

Results: No serious adverse effects were reported. Hematological, immunological, and biochemical parameters did not deviate from normal ranges as a result of therapy.

and conclusion:

In summary, these data support the safety and freedom from immunologically-mediated adverse effects of allogeneic cord blood therapy in absence of immune suppression/myeloablation. This study presents for the first time a detailed safety analysis of using non-matched, allogeneic cord blood cells to treat non-hematopoietic degenerative conditions. The longest follow-up with this protocol was 4 years with no evidence of immune reactivity or GVHD. Evaluation of therapeutic benefit is currently in progress.

I’m really glad to see the first report like this. I think it’s very important and a good study. But I’d like to see at least one more independent report without any author’s conflict of interest. Also, the question of ABO-matching needs to be address further in regenerative medicine settings. I’d like to hear comments from hematologists and bone marrow transplantation physicians especially.

full text is freely available online (.pdf)

This is re-blog from Stem Cell Assays

I wrote an article about blogging and some online tools that I use. I’m sharing my experience and presenting a model of how scientific blogging can be used for professional networking online. I’d like to welcome everyone to read and comment. Article in open access. Some excerpts below.

*************

I have been blogging for 7 years and stayed tightly in my area of expertise (niche). When I started blogging in English (my first language is Russian), I set up a few goals:

* Practice tight and productive networking with scientists and medical professionals in the same niche of interest from around the world.
* Transform professional connections online into real connections and collaborations.
* Get a sense of what is science online, and what web tools I can use to increase my scientific productivity.
* Summarize all of my notes, bookmarks and thoughts in the area of my interest and put them in one place online (database), where I can easily find them at any time.
* Improve my language (English) and writing skills.
* Monetize and possibly earn some money from blogging.
* Acquire professional value, peer recognition and my “authority” for advancement in career.

It turns out that the networking part has worked especially wonderfully for me. I’ll share my experience in this essay.

Blogging analytical content
Because now there are a lot of tools available for information management, I decide to fill my blog with analytical content. I pick and summarize the most exciting and controversial work in my field — adult stem cell research. I’m writing about current trends in the field with a translational focus. My content is based not only on publications, but also on information from conferences that I attend and personal communication. It makes the content quite distinctive in my niche. Each of my posts contains links to a few papers, all connected by a particular topic. I put some of my thoughts into it and try to provoke reader discussion. I also try to incorporate some online tools in the blog that could be very useful for scientists.

I think with the variety of tools available right now, there is no need to have a blog just for quick sharing of some links or news or videos or fresh papers with your peers.

Finally, I came up with the idea that nothing can replace a blog post if it’s made in the format of a unique analytical thoughtful mini-article. You can even consider scientific blog posts as a small online publication judged by your peers from networking. I think blogging will be widely accepted in the scientific mainstream only if it can bring some professional value, i.e., unique trusted information with the possibility of real time discussion in informal settings.

The blog as a professional networking tool
So I’m using a blog as a hub for gathering information picked from my bookmarks, and its analysis. In this case, high quality analytical information is an input, but what is the output? I consider a blog as a part of an online project, which connects the shared information with professionals working in the same field. In order to get the output I share links to my blog posts in professional networking web-services, such as LinkedIn.

So, discussion about my blog posts can occur anywhere: comments under the post itself, comments in LinkedIn groups, replies on Twitter, comments on FriendFeed, and personal communication via email. I think that using a few tools together makes your networking online more productive and valuable.

read full text
*************

How to cite: Bersenev A. Scientific blogging as a model for professional networking online. Cellular Therapy and Transplantation. 2010;2(7). 10.3205/ctt-2010-en-000084.01

Adult stem cells a are non-dividing or slow cycling cell population, which reside in the organs largely in G-0 phase of cell cycle (quiescent). Currently, there is a general assumption that quiescence serves as a protective mechanism that saves stem cells from environmental stress and DNA damaging agents. Also, there is an assumption that quiescence protects cancer stem cells from radiation and chemotherapy, making them resistant. New findings, which came out from the Emmanuelle Passegue laboratory, demonstrate that stem cell quiescence also has a dark side due to intrinsic vulnerability to mutations.

Nonhomologous recombination end joining DNA repair coupled with stem cell quiescence
The authors showed that quiescent hematopoietic stem cells (HSCs), in response to damage (irradiation), use different mechanism of DNA repair compared to cycling HSCs and myeloid progenitors. Nonhomologous recombination end joining (NHEJ) is a mechanism of DNA repair in quiescent HSCs, coupled with acquisition of errors and mutations. Unlike quiescent HSCs, cycling HSCs and progenitors use a different and effective mechanism of DNA repair - homologous recombination (HR). But no wonder here, it is known that NHEJ is a common mechanism of DNA repair for any type of quiescent cells in mammals:

Interestingly, repair of DSBs by homologous recombination is downregulated during G0, G1 and early S phases in the somatic cells of multicellular eukaryotes 5. This means that NHEJ is the predominant - if not exclusive - mechanism for the repair of DSBs during G0, G1 and early S phases, and NHEJ continues to repair a minority of breaks during late S and G2 phases.

Now it was discovered in adult stem cells. Most importantly, authors demonstrated that DNA mutations can persist or expanded in aberrant clone during HSC serial transplantation from primary to secondary recipients.

Taken together, these results demonstrate that quiescence dramatically restricts HSPCs’ ability to use the high-fidelity HR-mediated repair and instead forces them to rely on the more error-prone NHEJ mechanism to repair DSBs.

Our transplantation experiments directly demonstrate that damaged HSCs, which have undergone DNA repair and acquired mutation(s) during this process, can persist in vivo at relatively high frequencies and contribute either to the clonal expansion of aberrant cells or to the maintenance of cells with genomic alterations.

What is strange to me is that they didn’t get leukemia in mice after serial transplantation of mutated expanded HSC clones. Seem like protection mechanisms are very strong and disease onset requires additional hit mutations.

Radioresistance is uncoupled of quiescence
We know that stem cells in our organs are extreme survivers. They survive high doses of irradiation, exposure to DNA damaging agents and many chemotherapeutic drugs. The authors showed that active (cycling) HSCs magically retain radioresistance (by unknown mechanisms), even using HR mechanism for DNA repair. So, active cycling HSCs - that’s what we need! They are good guys! The consequence of this finding can put under question the assumption that cancer stem cell radioresistance could be explained by quiescence. Seem like it’s not true. Something else, different from quiescence make stem cells radioresistant.

The first puzzle is the evidence that NHEJ are actually coupled with radio- and chemoresistance. How can active cycling HSCs using the HR mechanism be radioresistant but myeloid progenitors are not? Yet another puzzle is the whole way of comparing quiescent HSCs and cycling HSCs. I don’t think authors did phenotype control of quiescent HSC and active (cycling) HSCs. Maybe a significant part of HSCs turned into multipotent progenitors, even after one day of stimulation protocol? More than that, what about nearly 50% of quiescent fraction of multipotent progenitors (LSK/Flk2+)? How are they resistant to irradiation? Well, we need to do more work to find some answers.

Aging, chemotherapy and some translational points
I like the point that authors make in discussion about how their findings can explain loss of HSCs function with age:

Our findings suggest that accumulation of NHEJ-mediated mutation(s) over a lifetime could dramatically hinder HSC performance and be a major contributor to the loss of function observed in aged HSCs and the development of age-related hematological disorders.

Another good point is the possible explanation of increased rate of chemotherapy-related malignancies (solid cancer or leukemia) after treatment with DNA damaging agents:

…cytotoxic therapies might inadvertently mutate the patient’s own quiescent HSCs by forcing them to undergo DNA repair using a mutagenic mechanism. Specifically, we show that proliferating HSCs have significantly decreased mutation rates, with no observed changes in their radioresistance, suggesting that it might be beneficial to induce HSCs to cycle prior to therapy with DNA damaging agents to enhance DNA repair fidelity and reduce the risk of leukemia development. Although this possibility remains to be tested…

Even though the possibility of this mechanism should be tested further, I wonder if it is universal for all adult stem cells in our organs? If all adult stem cells reside mostly in quiescent state, why not? It gives us some ideas about how we can play with chemotherapeutic drug combinations and therapeutic irradiation in clinical oncology. If your drug targets cycling cells, the approach mentioned above is not going to work. But what could work is the following sequence: 1 - drug killing cycling cells, but not causing severe DNA damage; 2 - drug which targets quiescent cells causing them to enter into cell cycle; 3 - DNA damaging drug. What do you think?

pre-published abstract