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More than two years ago, in the first post of “Stem Cell Autopsy” series, I’ve linked to the 1996 Neurology report about the complication of intra-cerebral transplantation of fetal tissues. Recently, the story behind of this bizzare case, was described in the book “When Scientists Go Wrong” by Simon LeVay. You can read the ” neuroscience chapter” for free here. I was really thrilled by the story when was reading this chapter. There were a lot of interesting details. It turns out that It was the first and the only one case of teratoma development in cell tranplantation history. Today I’m sharing more details on this case and quotes from the book.

The author described a development of clinical fetal cell neurotransplantation and interviewed the key people, who was involved in the case of Parkinson’s Disease patient – Max Truex. Neurotransplantation of fetal brain tissue in Parkinson’s Disease was pioneered in 1987 in Sweden.

Then, in November 1988, the first American foetal transplant was performed by a team led by neuroscientist Curt Freed of the University of Colorado. Freed had researched the technique for years, first in rats (like the Swedes) and then in monkeys. This research was funded by federal grants, but when he began the human work Freed had to turn to private funds because the Reagan administration, concerned about the abortion issue, had banned the use of federal grants to support transplantations involving human foetal tissue.
For the first transplant, Freed selected a volunteer by the name of Don Nelson, a 51-year-old Denver man who had been suffering from Parkinson’s disease for 19 years. As with Max Truex, Nelson was deteriorating fast and he was desperate to try some new therapy. Freed obtained foetal tissue from an abortion clinic in the Denver area, dissected out the substantia nigra and (with the collaboration of a neurosurgeon) injected the foetal cells into the striatum on one side of Nelson’s brain.
If the Swedes were publicity-shy almost to the point of secretiveness, Freed was the very opposite: he held a news conference to announce the transplant just two days after the operation, long before he could know whether Nelson would experience any benefit from the procedure.

Years after diagnosis, Max was under observation of their family’s friend – neurosurgeon Paul Iacono (link). Dr. Iacono was brave enough to decide to take him in China and transplant fetal tissues into Max’s brain. It was 1989. The technique was pioneered in 1987. Very few physicians were able to perform this procedure around the world and all of them have rejected Max Truex. China was the only country which agreed to provide them a hospital bed and abundance of aborted fetuses.

In any event, Iacono said that he made great efforts to find a place where Truex could get a foetal transplant. ‘I tried all my friends all over the world – Sweden, Britain, Japan. I tried and tried. And eventually, after two or three years of following Max, I realised I had to do it myself.’

Another surprise had to do with money. According to Kay, the doctors, at the Zhengzhou hospital, or the hospital administrators, demanded a substantial fee – she thought it was in the range of $20,000 to $25,000 – to let the operation go ahead. Don said that Max told him the fee was close to the annual operating budget for the hospital.

Max’s parkinsonism symptoms improved after the transplant and he was fine during almost two years. But in March of 1991, he started to feel something strange and became concerned about his death.

Rebecca Folkerth is a pathologist who performed Truex’s brain autopsy. She was the only available neuropathologist on Sunday at New England Medical Center:

‘I answered my page on the Sunday night and I said, “OK, I’ll come and do this autopsy.” It sounded like Durso was having trouble getting anyone to help him.’

Folkerth reached the hospital around 9pm. ‘Once I got there, I got a call from Dr. Iacono,’ she says. ‘He told me the whole history and said, “Can I ask you to take some of the tissue fresh and freeze it?” I said, “OK, fine.”

Up to now, Folkerth hadn’t noticed anything unusual about Truex’s brain. ‘But as I was cutting it,’ she told me, ‘I made this observation, “Gee, look at this strange stuff in the ventricles, in the third and fourth ventricles, and in the lateral ventricles also.” I thought, “Isn’t that odd?” and I took a bunch of pictures. And I thought, “That looks like cartilage; isn’t that weird!” Even to the naked eye it looked like cartilage, and there were hairs – you could see them, just eyeballing it – the gross pictures are extremely dramatic.’

Brains don’t usually contain cartilage or hair, of course. Nor bone or skin, which she later discovered were also present. ‘You could see the hair shafts,’ she went on. ‘So I knew there was something very strange about this right away. Oh, this was the most strange thing I’d ever seen, and at this point it was the middle of the night. I was the only one there, looking at this case and thinking, “What the hell is this?” It was creepy. So here I am taking these pictures and thinking this is some mistake; this is a tumour – a teratoma.’

Lumps of glistening cartilage lined the floor of one of the ventricles. Part of one of the lateral ventricles was completely filled with a waxy, skin-like tissue. The fourth ventricle, which is located in the brainstem near nerve centres concerned with breathing and other vital functions, was packed full of hair and other tissues, so much so that some of the surrounding brain structures were compressed and discoloured.

There was no doubt that the teratoma originated from transplanted fetal brain tissue.

This whole experience left a big impression on Folkerth, and so over the next few months she devoted a lot of her free time to analysing the tissue samples from Truex’s brain. In the left and right striatum, where Iacono had deposited the tissue from the two 16-week-old foetuses, she found no surviving cells from the transplant, only scar tissue. This was consistent with findings from other research groups, who have reported that tissue from foetuses this old has a very low chance of surviving the transplantation procedure. Folkerth concluded that the reported improvement that Truex had experienced was not due to the presence of any transplanted nerve cells in his brain. Either just the damage caused by the injections had a beneficial effect, which didn’t seem terribly likely, or some other factor, such as the new drug that Truex received, was the reason.
What about all the weird tissues in the ventricles? These presumably arose from the tissue that Iacono had dissected from the very young, five- to six-week-old foetus and had injected into the left lateral ventricle. Folkerth believes that Iacono mistakenly included some tissue that was not from the embryo’s brain at all – tissue from just outside the brain that normally would have developed into the overlying bone, cartilage, skin, and hair.

Later on, Folkerth decided to proceed with publication, but without Iacono:

Iacono had been the initial driving force behind the autopsy, and it would have been natural for him to participate in publishing the findings that emerged from it. In fact, at a scientific meeting three months after Truex’s death, he announced that the results of the autopsy were ‘pending’. But later, Iacono seemed to lose interest in having the results published.

In the publication Folkerth did not mention American physician, who traveled in China with his patient. She also didn’t use a term “teratoma” to describe a cell mass from Max Truex’s brain. The story about publication is quite interesting:

After more than a year’s delay, they sent their manuscript to the New England Journal of Medicine, because that journal had already published several articles about foetal-cell transplantation for Parkinson’s disease. But the manuscript was rejected. ‘That was funny,’ says Folkerth. ‘I thought this was something that was definitely worthy of being in that particular journal.There seemed to be kind of a pro-transplant point of view in the other articles they had published.’
What Folkerth didn’t know was that her manuscript was reviewed by Curt Freed, a major enthusiast for foetal-cell transplantation and an author of one of those ‘pro-transplant’ articles in the NEJM.
The rejection of the manuscript caused another delay, but in 1995 Folkerth and Durso sent the manuscript to another, less prestigious journal,Neurology. It was accepted, and it appeared in 1996, five years after the autopsy it described.

Iacono didn’t respond to the Neurology article, or if he did his response didn’t get published. But the journal did publish a response from a research team that had begun to do foetal-cell transplants at the University of South Florida in 1993. Evidently, this team, like Curt Freed, was worried that Folkerth’s article would throw the field of foetal-cell transplantation into disrepute, and they expressed their feelings about what Iacono had done in unusually strong language. ‘This is a case of extremely poor tissue dissection,’ they wrote. ‘One wonders why this transplant was performed in China,’ they added, ‘outside of State and Federal regulations, Institutional Review Board oversight, and peer review scrutiny.’ ‘We should not be surprised,’ they concluded, ‘that poor science leads to poor outcomes.’

Finally, what Iacono thought about Truex’s death:

Iacono never abandoned his conviction that Truex was greatly helped by his transplants, and he rejected the idea that the tissue in his ventricular system caused his death. ‘There weren’t any signs of increased intracerebral pressure,’ he told me. ‘He wasn’t having urinary incontinence, he wasn’t showing signs of dementia, he wasn’t complaining of headaches. He was acting normally, and his wife said he came in and sat down and died. That just doesn’t sound like [ventricular blockage]. His death was officially signed out as a heart attack.’ (Kay says that Max’s death certificate lists only ‘Parkinson’s disease’ and does not mention any immediate cause for his death.)

So, we have confirmed case of teratoma development after fetal tissue transplantation in human brain. According the patients observation in clinical trials, this case is unique and only the one. Nevertheless, it’s well documented. I was really surprised by the fact that human embryonic tissues (5-6 weeks of gestation) still retain the pluripotency. What do you think?

Download 1996 Neurology report

PS: Special thanks to Doug Sipp for the link to the book chapter!

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More than 200 clinical trials assessing safety and efficacy of mesenchymal stem cells (MSC) are currently ongoing around the world. Now we have many reports about safety of MSC infusions, but we still have no idea what is really going on with cells after infusion. Autopsy material can provide valuable information about cells fate, the mechanism of therapeutic action and long-term complications of cell therapy. Unfortunately, we are lacking reports about pathological finding from autopsies of patients, who underwent MSC-based therapies.

Katarina Le Blanc‘s group from Karolinska Institutet has published a very very important analysis of autopsy material from patients, who underwent MSC infusions. This report is not available in open access, so I’m going to summarize some very important points here.

The authors analyzed 18 patients with hematological malignancies and solid tumors, which underwent HLA-matched allogeneic MSC infusions to treat/ prevent complications of hematopoietic stem cell transplantation (GVHD, hemorrhagic cystitis and some others). All patients died in 3 – 408 days (median 21 days) after the last MSC infusion. Donor’s MSC’s DNA was detected by PCR in multiple tissues. The results of this analysis are the following:

1. No solid tumors (of any origin) or ectopic tissue formation was observed.
Lymphoproliferative disorder was diagnosed in two patients, but no link to infused MSC was found.

2. Tissues from 8 out of 18 patients (44%) were positive for MSC donor DNA. Quantative analysis was done in 6 cases. Only one patient had MSC donor DNA > 1/1000 cells. Positive MSC were found mostly in the lungs, lymph nodes and intestine. MSC donor DNA in bone marrow was detected only in one case.

Histological examination of engrafted MSCs was not possible due to the scarcity of the cells. We can therefore not conclude that the DNA detected represents true MSC engraftment.

3. There were no correlation found between MSC engraftment (donor DNA) and treatment response:

… of the fifteen patients available for PCR analysis, three had shown a complete response to MSC therapy, six a partial response and six were classified as non-responders.

4. Detection of MSC donor DNA was negatively correlated with time after infusion and autopsy/ biopsy.

The bottom line: Intravenous infusion of matched allogeneic MSC does not cause severe complications, such as tumor or ectopic tissue formation due to rapid clearance from the recipient. More likely, allogeneic MSC act as “medicinal cells” shortly after infusion and do not engraft in the tissues. The persistence of donor’s MSC in recipient does not correlate with treatment efficacy:

The function of MSCs appears to be mediated through a “hit and run” mechanism rather than through sustained engraftment in the injured tissues.

Overall, this remarkable study is very unique and well done! Highly recommended to read and cite!

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Today, I’d like to introduce a guest post by Frances Verter. Dr. Verter is a Founder and a Director of Parent’s Guide to Cord Blood Foundation.

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

This is a guest post by Frances Verter

This table is an effort to capture a snapshot of all the current clinical trials that are using stem cells from blood or tissues harvested at birth.

The primary research source for this table was searches of ClinicalTrials.gov between Dec. 2011 and Mar. 2012. I have also relied on Lee Buckler’s posts to his Cell Therapy Blog.

Emerging Therapies with Perinatal Tissues and Stem Cells

Indication Occurance in USA Cell Source Donor Type Stage of Use Trial or Product
Cartilage
Repair
9.6% men >
age 60 and 18% women >
age 60
cord
blood
allogeneic approved by KFDA
Cartistem

Medipost Co. Ltd.
Wound
dressing
Acute burn 450,000 hospital visits per year amnion

amnion
cord tissue

allogeneic

allogeneic

allogeneic

FDA

FDA

Beike trial: 2

BioDfactor

NuCel

NCT01443689

Eye surface repair corneal abrasion incidence 1.57% per year amion allogeneic FDA Prokera
Cerebral Palsy 2 per 1000 full term births cord blood autologous

autologous

autologous

allogeneic

Duke: 2

Georgia: 2

Monterrey:1

SunKwang:2

NCT01147653

NCT01072370

NCT01506258

NCT01528436

Hypoxic Ischemic Encephalopathy 2 per 1000 full term births cord blood autologous clinical trial:
phase 1
NCT00593242
Traumatic Brain Injury 435,000 per year ages 0-14,
#1 cause child death
cord blood autologous clinical trial:
phase 1
NCT01251003
Spinal Cord Injury 12,000 per year cord tissue allogeneic clinical trial:
phase 2
NCT01393977
Hearing loss, sensorineural 1 per 1000 births cord blood autologous clinical trial:
phase 1
NCT01343394
Hypoplastic Left Heart Syndrome 0.2 per 1000 births cord blood autologous clinical trial:
phase 1
NCT01445041
Type 1 Diabetes 1.7 per 1000 ages birth-19 cord blood autologous

autologous

allogeneic

Munchen: 1

U. FL: 2

China: 2

NCT00989547

NCT00873925

NCT01350219

Ischemic Stroke 8.1% adults over age 65 had stroke, #3 cause of adult death
cord blood

cord tissue

cord blood & placental cells

allogeneic


allogeneic



allogeneic
China: 1


Gen Hosp:2



Celgene: 2
NCT01438593


NCT01389453



NCT01310114
Critical Limb Ischemia 2.5 per 1000 people, >80% of them diabetics cord blood allogeneic Clinical trial:
phase 1
NCT01019681
Rheumatoid Arthritis 6 per 1000 people placental cells allogeneic Celgene trial:
phase 2
NCT01261403
Crohn’s Disease 1 per 10,000 people ages 10-19 placental cells allogeneic Celgene trial:
phase 2
NCT01155362

Table copyright Frances Verter, PhD 2012

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The definition of stem cell therapy

February 13, 2012

Today everyone is talking about stem cell therapy everywhere. It’s hot, it’s popular, it’s sexy. But nobody ask the very important question: “What is the real stem cell therapy and how can we define it?” I’ll try to answer this question and propose a definition. Background: It seems very simple to say “injection of stem […]

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The current status and the future of stem cell tourism – interview with Doug Sipp

January 18, 2012

In the last 3 weeks, we have witnessed some interesting moves against so-called “stem cell tourism”. Crackdown on “stem cell treatment” fraud in US, popularization of the problem via “60 Minutes” broadcast and start of reforms in China. I’ve asked Doug Sipp to comment on some recent events and on the problem in general. Here […]

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Cell therapy clinical trials in 2011

January 4, 2012

In April 2011 I’ve started a new project – Cell Therapy Trials. This is a prototype for tracking of clinical trials and cases in cell therapy field with publicizing it via Twitter. The big part of the project is collection of clinical data via tracking of published literature, conference reports and business press-releases. Today I’d […]

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Gene therapy is ready for prime time

December 28, 2011

I was not very optimistic about the future of gene therapy 3-4 years ago. Well, I was wrong about it. I was obsessed by cell therapy so much that underestimate the progress in gene therapy. Both fields have matured and so did I. Last two years brought us tremendous development in both fields. I realized […]

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Gene therapy drug approved on Russian market – Interview with Artur Isaev

December 19, 2011

The first gene therapy drug was approved on the Russian market on December 7. Neovasculogen (VEGF) will be used for treatment of peripheral arterial disease (PAD) and its complication critical limb ischemia (CLI). This drug is manufactured by Moscow’s company Human Stem Cell Institute (HSCI). The company’s CEO, Dr. Isaev kindly agreed to answer my […]

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Functional validation of human cancer stem cells

October 16, 2011

The cancer stem cell concept is evolving and causing great debate in the scientific and medical world. People are discussing these three most important questions: Do cancer stem cells (CSC) exist and is the concept valid? How can we identify and characterize them? What is the therapeutic relevance (for prognosis and therapeutic targeting)? In order […]

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What is the most promising method for targeting cancer stem cells?

September 13, 2011

cross-posted on StemCellAssays.com I wrote a lot about cancer stem cells in the last two years. You can track some of my posts here and here. It is very exciting and evolving field combining stem cell and cancer research. Currently, most professionals from both fields, are convinced in validity of cancer stem cell concept. But […]

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