Primecuts – This Week In The Journals

November 28, 2011

By Rachel Bond, MD

Faculty Peer Reviewed

A Gift…From Yourself? Stem Cells.

With Thanksgiving just passing, it is hard not to comment on all one can be thankful for. Now, with ‘Frosty the Snowman’ and ‘Let it Snow’ blasting at the retail stores, it is also not too hard to succumb to the holiday cheer. With the holidays close in sight, why not start talking about gift giving? As physicians, we have a lot to be thankful for, and the ultimate gift we can provide to someone is life.

 A report published online first by The Lancet [1] and brought to my attention by Yahoo Health News, perfectly-enough on Thanksgiving, described the world’s first ‘successful’ transplant of a synthetic trachea seeded with stem cells. The patient, a 36-year-old African-born man, now residing in Iceland, was the first person in the world to receive this type of transplant at the Karolinska University Hospital in Stockholm, Sweden. The transplant was required secondary to a tracheal malignancy obscuring his airway and making it difficult, if not impossible at times for the patient to breath. The procedure was performed under the care of a multidisciplinary team run by Professor Macchiarini. The procedure, involving the complete removal of the affected area of the tumor and trachea, also included replacing the removed tissue with a tailor-made artificial structure.

The Karolinska University Hospital, in collaboration with the University College of London used three-dimensional imaging to scan the patient in order to create the synthetic scaffold needed to be perfectly tailored to the patient’s specific body size and shape. After scanning the patient, scientists first constructed a glass model of the affected trachea to be replaced. The glass was then used to shape the synthetic scaffold, a bioartificial nanocomposite. Once that was done, it was shipped to the Karolinska Institute. The scaffold was populated using the patient’s autologous bone-marrow mononuclear cells, a process that took a total of 36 hours. Post-operatively, the patient was given two weeks of granulocyte colony-stimulating factor and epoetin beta to enhance the regenerative process.

According to Professor Macchiarini in a press release, his method provided advantages over other techniques in transplantation and regenerative medicine because lack of concern of rejection as the scaffold is populated with the patient’s own cells. As such, immunosuppressive drugs are not required. Prior transplants have required donors, which not only increases the rejection rate but also involves long waiting periods. Another key advantage is that the implant can be tailored to the patient’s body habitus as it is artificially constructed. With this in mind, the patient continues to do well with no complications reported as of yet.

Since this first successful surgery in June of 2011, the transplant team has performed another transplant on a second patient from Maryland with cancer of the airway. This patient’s bioartificial scaffold, however, was made from nanofibers; considered to be an upgrade from those used in the initial operation. The team plans to soon treat a 13-month-old South Korean infant also using this method, showing how it can be extended and shaped to any particular body size. With such success, Professor Macchiarini hopes to extend the research to include other organ systems such as the lungs, heart and the gastrointestinal tract.

Although this truly sounds promising and the techniques represent huge medical advances, I concur with the editorial review provided by Dr. Harald C. Ott and Dr. Douglas J. Mathisen, from Massachusetts General Hospital and Harvard Medical School in Boston. Both physicians caution that more research is needed to fully evaluate its safety and effectiveness [2]. As stated on Yahoo Health News and concluded in a news release by Drs. Ott and Mathisen, “to be adjudged successful, bioartificial organs must function over a long time — short-term clinical function is an important achievement, but is only one measure of success. Choice of ideal scaffold material, optimum cell source, well-defined tissue culture conditions, and perioperative management pose several questions to be answered before the line to broader clinical application of any bioartificial graft can be crossed safely and confidently.” Hence, it’s just a matter of having more time to explore these areas to perfect the process.

Another study that made headlines on a CBS News segment in mid-November showed for the first time that researchers were able to use a patient’s very own cardiac stem cells (not bone marrow cells which have typically been used) to attempt at repair of the patient’s damaged cardiac cells. The segment focused on Ken Miles, a 39 year old male who experienced a massive heart attack one year prior and was left with only 30% of his heart functioning and constant symptoms including reduced exercise tolerance and shortness of breath. On a June day in 2009, Mr. Miles underwent an infusion of stem cells, grown from cells taken from his own heart a few weeks earlier at Cedar Sinai Hospital in Los Angeles, California. He was the first patient to undergo this procedure initiated by Dr. Eduardo Marban and his research team. A few weeks later in Kentucky, a patient named Mike Jones underwent a similar procedure at the University of Louisville’s Jewish Hospital, lead by Dr. Roberto Bolli. Jones suffered from advanced heart failure, the result of a heart attack years earlier. Like Miles, he received an infusion of cardiac stem cells, grown from his own heart tissue. The findings of the later study by Bolli were reported at the American Heart Association’s scientific sessions meeting in Orlando, Florida, and in the November 14th online edition of The Lancet [3].

In Bolli’s study, sixteen patients with severe heart failure (defined by the study as a left ventricular ejection fraction (LVEF) of less than 40%) received a batch of autologous cardiac stem cells obtained during a scheduled coronary artery bypass graft (CABG) operation. Within a year, their heart function markedly improved. When the study began, Bolli’s patients had an average LVEF of 30.3%. Four months after undergoing CABG and receiving stem cells, it was 38.5% (In 14 of the 16 patients given cardiac stem cells). Among eight patients who were followed for a full year the EF improved to an astounding 42.5%. Infarct size was also found to decrease in a portion of the treated group. A control group of seven patients only provided standard maintenance medications, showed no improvement at all (LVEF of 30.1% at four months after CABG and 30.2% at eight months after CABG). This was an open-label trial. As such, patients knew when they were allocated in the treatment wing of the study as were required by the FDA. This mere fact can affect the validity of the trial. Not to mention, the study makes it very hard to assimilate the results to a larger population, given such the small sample size used. Regardless, the patients have shown improved performance ability in their daily activities and exercise capabilities. In addition, they have shown improvement in the cardiac function evaluated through blinded echocardiography technicians performing the study and physicians reading the echo report.

In the Cedars-Sinai study, 17 patients, including Mr. Miles, were given stem cells approximately six weeks after suffering a moderate to severe myocardial infarction (MI) [4]. All had lost enough cardiac tissue to put them at risk for future chronic heart failure (CHF), according to Dr. Eduardo Marban, with LVEF ranging from 25-45%. As such, unlike Bolli’s study that treated patients with a diagnosis already of CHF, Marban’s study aimed to treat patients before they developed heart failure. As such, the focus was more on regression of the actual scar. The study showed that not only did scar tissue retreat — shrinking a reportedly 40% in Ken Miles, and between 30% and 47% in other test subjects — but the patients actually generated new heart tissue. On average, the stem cell recipients grew the equivalent of 600 million new heart cells, according to Marban, who used MRI imaging to measure the changes. Interestingly, unlike Bolli’s study, in Marber’s, there were no changes in ejection fraction; however, this was not a major focus as the patient’s did not have CHF.

Of even greater interest is the fact that the cardiac stem cells were not derived from the bone marrow, but instead were harvested, in both studies, from stem cells taken from the patients’ own hearts during bypass surgery. With this, no adverse events to the study population were noted. Of course, just like with the tracheal regeneration a larger patient population is needed.

The findings are a boost to the notion that the heart contains the seeds of its own rebirth. For years, it was believed that heart cells, once destroyed, were gone forever. This may be a thing of the past with this new data suggesting otherwise. After all, Marber showed the competency of the cardiac stem cells soon after an MI, and Bolli was able to show that the patient’s cardiac stem cells were still capable of multiplying and turning into useful muscle and blood vessel walls several years after a heart attack. As such, timing from the initial event (i.e. MI) to the point one uses the cardiac stem cells did not matter much. This is ground breaking, especially for a chronic disease such as end-stage heart failure!

With bone marrow stem cells supplying a whole new trachea and cardiac stem cells improving and even regenerating the beating heart, science is truly advancing by the minute. Regenerative medicine is steadily improving and is no longer a thing of the future, but a thing of here and now. There will come a time when we can realize the commonality of having the ability to make use of our bone marrow cells or preferably obtain tissue from the actual diseased organ itself to help cure a disease. Of course, more research studies are needed; however, I am very much impressed, optimistic and see great promise in possible cures of a variety of diseases to help continue to provide the ultimate gift to our patients…life.

 Dr. Rachel Bond is a  3rd year resident at NYU Langone Medical Center

Peer reviewed by Michael Poles, MD, Section Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Jungebluth P, Alici E, Baiguera S, Le Blanc K, Blomberg P, Bozoky B, Crowley C, Einarsson O, Grinnemo KH, Gudbjartsson T, Le Guyader S, Henriksson, G, Hermanson O, Juto JE, Leidner B, Lilja T, Liska J, Luedde T, Lundin V, Moll G, Nilsson B, Roderburg C, Stromblad S, Sutlu T, Teixeira AI, Eatz E,Seifalian A, Macchiarini P. Tracheobronchial transplantation with stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. The Lancet,Early Online Publication, November 24, 2011. DOI: 10.1016/S0140- 6736(11)61715-7. Available from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61715-7/fulltext

2. Ott HC, Mathisen DJ. Bioartificial tissues and organs: are we ready to translate? The Lancet, Early Online Publication, November 24, 2011. DOI: 10.1016/S0140-6736(11)61791-1. Available at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61791-1/fulltext

3. Bolli R, Chugh AR, D’Amario D, Loughran J, Stoddard MF, Ikram S, Beache G, Wagner SG, Leri A, Hosoda T, Sanada F, Elmore JB, Goichberg P, Cappetta D, Solankhi NK, Fahsah I, Rokosh DG, Slaughter MS, Kajstura J, Anveersa P. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomized phase 1 trial. The Lancet, Volume 378, Issue 9806: 1847-1857. Published Online: November 14, 2011. Available at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61590-0/fulltext

4. Marban E. The CADUCEUS (CArdiosphere-Derived aUtologous stem Cells to reverse ventricular dysfunction) Trial. Published Online on American Heart Website. Available at: http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_433695.pdf

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