ScienceDaily (May 9, 2012) For the first time, scientists at Fred Hutchinson Cancer Research Center have transplanted brain cancer patients' own gene-modified blood stem cells in order to protect their bone marrow against the toxic side effects of chemotherapy. Initial results of the ongoing, small clinical trial of three patients with glioblastoma showed that two patients survived longer than predicted if they had not been given the transplants, and a third patient remains alive with no disease progression almost three years after treatment.

"We found that patients were able to tolerate the chemotherapy better and without negative side effects after transplantation of the gene-modified stem cells than patients in previous studies who received the same type of chemotherapy without a transplant of gene-modified stem cells," said Hans-Peter Kiem, M.D., senior and corresponding author of the study published in the May 9 issue of Science Translational Medicine.

Kiem, a member of the Clinical Research Division at the Hutchinson Center, said that a major barrier to effective use of chemotherapy to treat cancers like glioblastoma has been the toxicity of chemotherapy drugs to other organs, primarily bone marrow. This results in decreased blood cell counts, increased susceptibility to infections and other side effects. Discontinuing or delaying treatment or reducing the chemotherapy dose is generally required, but that often results in less effective treatment.

In the current study, Kiem and colleagues focused on patients with glioblastoma, an invariably fatal cancer. Many of these patients have a gene called MGMT (O6-methylguanine-DNA-methyltransferase) that is turned on because the promoter for this gene is unmethylated. MGMT is a DNA repair enzyme that counteracts the toxic effect of some chemotherapy agents like temozolomide. Patients with such an unmethylated promoter status have a particularly poor prognosis.

A drug called benzylguanine can block the MGMT gene and make tumor cells sensitive to chemotherapy again, but when given with chemotherapy, the toxic effects of this combination are too much for bone marrow cells, which results in marrow suppression.

By giving bone marrow stem cells P140K, which is a modified version of MGMT, those cells are protected from the toxic effects of benzylguanine and chemotherapy, while the tumor cells are still sensitive to chemotherapy. "P140K can repair the damage caused by chemotherapy and is impervious to the effects of benzylguanine," Kiem said.

"This therapy is analogous to firing at both tumor cells and bone marrow cells, but giving the bone marrow cells protective shields while the tumor cells are unshielded," said Jennifer Adair, Ph.D., who shares first authorship of the study with Brian Beard, Ph.D., both members of Kiem's lab.

The three patients in this study survived an average of 22 months after receiving transplants of their own circulating blood stem cells. One, an Alaskan man, remains alive 34 months after treatment. Median survival for patients with this type of high-risk glioblastoma without a transplant is just over a year.

"Glioblastoma remains one of the most devastating cancers with a median survival of only 12 to 15 months for patients with unmethylated MGMT," said Maciej Mrugala, M.D., the lead neuro oncologist for this study.

As many as 50 percent to 60 percent of glioblastoma patients harbor such chemotherapy-resistant tumors, which makes gene-modified stem cell transplant therapy applicable to a large number of these patients. In addition, there are also other brain tumors such as neuroblastoma or other solid tumors with MGMT-mediated chemo resistance that might benefit from this approach.

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Gene-modified stem cell transplant protects patients from toxic side effects of chemotherapy, study suggests

Study is first to show feasibility and efficacy of a new use for autologous stem cell transplant

Newswise SEATTLE For the first time, scientists at Fred Hutchinson Cancer Research Center have transplanted brain cancer patients own gene-modified blood stem cells in order to protect their bone marrow against the toxic side effects of chemotherapy. Initial results of the ongoing, small clinical trial of three patients with glioblastoma showed that two patients survived longer than predicted if they had not been given the transplants, and a third patient remains alive with no disease progression almost three years after treatment.

We found that patients were able to tolerate the chemotherapy better and without negative side effects after transplantation of the gene-modified stem cells than patients in previous studies who received the same type of chemotherapy without a transplant of gene-modified stem cells, said Hans-Peter Kiem, M.D., senior and corresponding author of the study published in the May 9 issue of Science Translational Medicine.

Kiem, a member of the Clinical Research Division at the Hutchinson Center, said that a major barrier to effective use of chemotherapy to treat cancers like glioblastoma has been the toxicity of chemotherapy drugs to other organs, primarily bone marrow. This results in decreased blood cell counts, increased susceptibility to infections and other side effects. Discontinuing or delaying treatment or reducing the chemotherapy dose is generally required, but that often results in less effective treatment.

In the current study, Kiem and colleagues focused on patients with glioblastoma, an invariably fatal cancer. Many of these patients have a gene called MGMT (O6-methylguanine-DNA-methyltransferase) that is turned on because the promoter for this gene is unmethylated. MGMT is a DNA repair enzyme that counteracts the toxic effect of some chemotherapy agents like temozolomide. Patients with such an unmethylated promoter status have a particularly poor prognosis.

A drug called benzylguanine can block the MGMT gene and make tumor cells sensitive to chemotherapy again, but when given with chemotherapy, the toxic effects of this combination are too much for bone marrow cells, which results in marrow suppression.

By giving bone marrow stem cells P140K, which is a modified version of MGMT, those cells are protected from the toxic effects of benzylguanine and chemotherapy, while the tumor cells are still sensitive to chemotherapy. P140K can repair the damage caused by chemotherapy and is impervious to the effects of benzylguanine, Kiem said.

This therapy is analogous to firing at both tumor cells and bone marrow cells, but giving the bone marrow cells protective shields while the tumor cells are unshielded, said Jennifer Adair, Ph.D., who shares first authorship of the study with Brian Beard, Ph.D., both members of Kiems lab.

The three patients in this study survived an average of 22 months after receiving transplants of their own circulating blood stem cells. One, an Alaskan man, remains alive 34 months after treatment. Median survival for patients with this type of high-risk glioblastoma without a transplant is just over a year.

Glioblastoma remains one of the most devastating cancers with a median survival of only 12 to 15 months for patients with unmethylated MGMT, said Maciej Mrugala, M.D., the lead neuro oncologist for this study.

See the article here:
Transplanted Gene-Modified Blood Stem Cells Protect Brain Cancer Patients From Toxic Side Effects of Chemotherapy

LAS VEGAS, May 10, 2012 /PRNewswire/ -- An investigational therapyderived from a patient's own bone marrow stem cells improves heart function in some patients with progressive heart failure due to dilated cardiomyopathy (DCM), according to the results of a Phase 2a study presented today as a late-breaking clinical trial at the SCAI 2012 Scientific Sessions.

Ixmyelocel-T is developed by culturing a patient's bone marrow for 12 days to increase the numbers of immune cells including macrophages and monocytes, as well as mesenchymal cells, stem cells that can differentiate into several different cell types. The resulting cell treatment is then injected into the patient's heart muscles to encourage growth of new tissue and improve inflammation.

"An increasing number of patients have progressive heart failure due to dilated cardiomyopathy, even after treatment with drug therapy and surgical intervention," said Timothy Henry, MD, FSCAI, director of research and an interventional cardiologist at the Minneapolis Heart Institute at Abbott Northwestern Hospital, and the study's principal investigator. "In this study, patients treated with ixmyelocel-T showed repair in damaged heart muscle and some reversal in heart failure symptoms."

The trial included 22 ischemic (IDCM) and non-ischemic (NIDCM) patients with a New York Heart Association (NYHA) heart failure class of III or IV, or moderate to severe heart failure, and a left ventricular ejection fraction of 30 percent or less, which is a measure of how much blood leaves the heart with each pump. Patients were randomized to receive an injection of the treatment into their heart muscles or to a control group, and were followed at 3, 6 and 12 months.

After 12 months, no procedural complications and no difference in adverse events were reported among patients who received the treatment and the control group. IDCM patients who received the cell treatment had a lower mean number of major adverse clinical events (0.33 compared to 1.67 in the control group). IDCM patients who received the treatment were more likely to see improvement in NYHA class, six-minute walking distance and ejection fraction, compared to NIDCM patients who received the treatment and those in the control group.

"Treatment with ixmyelocel-T was well-tolerated and patients who received the cell therapy showed improved symptoms after one year," said Dr. Henry. "The results provide a strong basis for a larger clinical trial of this treatment in patients with dilated cardiomyopathy."

The study was sponsored by Aastrom Biosciences.

Dr. Henry will present "Safety and Efficacy ofIxmyelocel-T, An Expanded Patient-Specific Mixed Cell Therapy, in Dilated Cardiomyopathy" on Thursday, May 10, 2012, in the Late-Breaking Clinical Trials Session beginning at 12:00 p.m. (Pacific Time).

About SCAI

Headquartered in Washington, D.C., the Society for Cardiovascular Angiography and Interventions is a 4,000-member professional organization representing invasive and interventional cardiologists in approximately 70 nations. SCAI's mission is to promote excellence in invasive and interventional cardiovascular medicine through physician education and representation, and advancement of quality standards to enhance patient care. SCAI's patient education program, Seconds Count, offers comprehensive information about cardiovascular disease. For more information about SCAI and Seconds Count, visit http://www.scai.org or http://www.SecondsCount.org.

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Treatment with Ixmyelocel-T Shown to Improve Outcomes in Heart Failure Patients

HAIFA, Israel, May 9, 2012 (GLOBE NEWSWIRE) -- Pluristem Therapeutics, Inc. (Nasdaq:PSTI - News) (TASE:PLTR) today announced that a seven year-old girl suffering from an aplastic bone marrow whose condition was rapidly deteriorating is now experiencing a reversal of her condition with a significant increase in her red cells, white cells and platelets following the intramuscular injection of the company's PLacental eXpanded (PLX) cells. Aplastic bone marrow is a disease where the patient has no blood-forming hematopoietic stem cells in the bone marrow.

"With her body rejecting all possible treatment -- and with no other options -- we finally turned to Pluristem's PLX cells, which literally saved her life," said Professor Reuven Or, Director of Bone Marrow Transplantation, Cell Therapy and Transplantation Research Center at Hadassah Medical Center and the child's physician. "The results of this unique case indicate that PLX cells may be effective in treating other diseases that affect the bone marrow."

The patient has been hospitalized at the Hadassah Hebrew University Medical Center, Jerusalem since August 2011. Her aplastic bone marrow had been refractory to treatment and, therefore, she underwent allogeneic stem cell transplantation from a matched unrelated donor. The first transplant was unsuccessful and the patient remained with bone marrow failure. Therefore, the patient underwent a second allogeneic stem cell transplantation from a second donor. Unfortunately, the bone marrow function was very poor and the patient suffered from recurrent infections. Approximately two months after the patient's second bone marrow transplant, the child received PLX cells intramuscularly in two doses approximately one week apart. Approximately 10 days after the last administration of PLX cells, the patient's hematological parameters began to significantly increase, an effect that has persisted to date. Additionally, the patient's general clinical status has improved. Subsequent analysis has indicated that the PLX cells worked by stimulating the recovery of the hematopoietic stem cells contained in the second bone marrow transplant that she had received over two months earlier. Finally, after nine months of hospitalization, the child will be discharged from the hospital.

"Pluristem is extremely happy that our PLX cells have helped this little girl," said Zami Aberman, Chairman and CEO of Pluristem. "Remarkably, these beneficial effects were seen in the patient after our PLX cells were administered intramuscularly and correlates with the positive effects on the bone marrow when we administered our PLX cells intramuscularly (IM) in animals exposed to toxic levels of radiation. Pluristem now has several data points to indicate that our PLX cells may work for systemic diseases when given locally, away from the target organ, and without a need to give cells intravenously."

In February 2012, Pluristem announced the results of animal studies suggesting PLX cells can be potentially effective in treating the life threatening hematopoietic complications associated with Acute Radiation Syndrome (ARS). In these experiments, animals given PLX cells IM up to 24 hours post irradiation demonstrated a recovery of their red cells, white cells, platelets and bone marrow to almost normal levels. It was that announcement, and the significant deterioration of the patient following two bone marrow transplants, that led Professor Reuven Or to contact Pluristem about the possible compassionate use of PLX cells to treat his young patient.

Pluristem recently received U.S. FDA Clearance to begin a Phase II clinical trial using the company's proprietary PLX-PAD cell product candidate intramuscularly for the treatment of Intermittent Claudication (IC), a subset of peripheral artery disease (PAD). In April, the Company was awarded a $3.1 Million grant by the Israeli Government, which will be used to help fund R&D and clinical trials.

About Pluristem Therapeutics Inc.

Pluristem Therapeutics Inc. (Nasdaq:PSTI - News) (TASE:PLTR) is a leading developer of placenta-based cell therapies. The Company's patented PLX (PLacental eXpanded) cells are a drug delivery platform that releases a cocktail of therapeutic proteins in response to a host of local and systemic inflammatory and ischemic diseases. PLX cells are grown using the company's proprietary 3D micro-environmental technology and are an "off-the-shelf" product that requires no tissue matching prior to administration. Pluristem is focusing on the use of PLX cells administered locally to treat systemic diseases and potentially obviating the need to use the intravenous route.

Data from two phase I/II studies indicate that Pluristem's first PLX product candidate, PLX-PAD, is safe and potentially effective for the treatment of end stage peripheral artery disease when given locally. Additionally, Pluristem is developing PLX-PAD for cardiac ischemia, PLX-BMP for Acute Radiation Exposure, Bone Marrow Transplant Failure and Chemotherapy induced Bone Marrow Aplasia, PLX-ORTHO for orthopedic indications and PLX-PAH for Pulmonary Hypertension in collaboration with United Therapeutics. Pluristem's pre-clinical animal models have demonstrated PLX cells are also potentially effective in other inflammatory/ischemic indications, including diastolic heart failure, inflammatory bowel disease, neuropathic pain and pulmonary fibrosis.

Pluristem has a strong patent portfolio, GMP certified manufacturing and research facilities as well as strategic relationships with major research institutions.

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Compassionate Use of Pluristem's PLX Cells Saves the Life of a Child After Bone Marrow Transplantation Failure

(CBS News) Patients with brain cancer may face devastating side effects from chemotherapy, but a new study offers a possible solution: stem cells.

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The stem cells form a shield of sorts against the toxic side effects from chemo, according to the researchers behind the study. It was a small trial that involved only three patients with glioblastoma, the most aggressive and common form of a malignant brain tumor that's usually fatal.

Two of the patients survived longer than predicted with help from the stem cell treatment - an average of 22 months - and a third man from Alaska remains alive today with no disease progression almost three years following treatment.

How does it work?

Many patients with the deadly form of brain cancer possess a gene called MGMT. The MGMT gene is typically turned on and counters the effects from some chemotherapy agents, such as temozolomide, rendering them less effective. As such, people with such a gene often have a particularly poor prognosis.

A drug called benzylguanine can block the MGMT gene, thus making tumors more receptive to chemotherapy, but the combination of the drug and chemo are often too toxic for healthy bone marrow cells.

That's where the new stem cell treatment comes in. By combining bone marrow stem cells with a modified version of MGMT in the form of the new treatment, patients' cells were protected from the toxic effects of the cancer drugs and chemotherapy while keeping the tumor cells targeted.

"This therapy is analogous to firing at both tumor cells and bone marrow cells, but giving the bone marrow cells protective shields while the tumor cells are unshielded," study author Dr. Jennifer Adair, a researcher at the Fred Hutchinson Cancer Research Center in Seattle, said in a news release.

Read more:
Stem cells boost brain tumor treatments for some patients, study finds

After half a year of blood transfusions to treat life-threatening anemia, 9-year-old Ricky Martinez was running out of time.

The Murrieta boy needed a bone marrow transplant to save his life. Although his parents had held numerous drives seeking a match for their son, the perfect donor eluded them.

Then another option appeared ---- doctors found Ricky's own blood from his umbilical cord, banked at birth, and stored in a medical facility.

"I had donated it at birth, when I delivered," said Ricky's mother, Cynthia Martinez. "I had no idea that I'd be using it for him nine years later."

The cord blood discovery represents a "godsend" for the family, Martinez said, because Ricky's body began rejecting the transfusions that keep him alive.

Cord blood contains stem cells ---- undifferentiated cells that can spur production of healthy tissue to help treat various diseases. Doctors believe it could jump-start Ricky's bone marrow, allowing his body to resume normal blood production.

But it's not a guarantee.

Ricky's condition, aplastic anemia, is an extremely rare disease, and cord blood transplantation is an experimental procedure for the condition, said David Buchbinder, a hematologist and transplant physician who is treating Ricky at Children's Hospital Orange County, in the city of Orange.

Although the procedure offers few risks of complications, it also pushes the boundaries of medical practice, placing Ricky in a realm of mixed medical opinions and uncertain results, Buchbinder said.

His parents say they're willing to go there to save their son's life.

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REGION: Surprise cord-blood find is 'godsend' for ailing boy

Latest Senior Health News

THURSDAY, May 3 (HealthDay News) -- Researchers who found a way to rejuvenate aged blood-forming cells in mice say their achievement offers clues about how it may be possible to combat health problems associated with old age.

The study by scientists at Cincinnati Children's Hospital Medical Center and Ulm University Medicine in Germany appeared online May 3 in the journal Cell Stem Cell.

Hematopoietic (meaning "to make blood") stem cells, which originate in the bone marrow, produce all of the body's red and white blood cells and platelets. As people age, these cells increase in number but become but less effective at generating new blood cells and immune cells. This makes older people more susceptible to infections and diseases, including leukemia.

In laboratory experiments with mouse cells, the researchers found that a specific protein that regulates cell aging also controls a process that causes blood-making stem cells to age. Using drugs to inhibit the action of this protein (called Cdc42) reversed aging of the hematopoietic stem cells and restored their function to a level similar to that of younger stem cells.

It had been believed that the aging of hematopoietic stem cells was locked in by nature and could not be reversed by using drugs, according to a hospital news release.

"Our findings suggest a novel and important role for Cdc42, and identify its activity as a target for ameliorating natural [hematopoietic stem cell] aging," principal investigator Hartmut Geiger, of the University of Ulm, said in the release. "We know the aging of [these stem cells] reduces in part the response of the immune system response in older people, which contributes to diseases such as anemia and may be the cause of tissue attrition in certain systems of the body."

Researchers say the next step is to test a protein inhibitor in mice to see how hematopoietic stem cells and various tissues respond. The researchers also are gathering samples of human blood-making stem cells for future lab tests.

Although studies involving animals can be useful, they frequently fail to produce similar results in humans.

-- Robert Preidt

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Researchers Rejuvenate Blood-Forming Stem Cells in Mice

Earlier this spring, Jets defensive coordinator Mike Pettine spent more than an hour on the phone with Villanova coach Andy Talley. But they weren't talking about football.

Instead, Pettine needed advice on a cause that Talley has championed in Philadelphia: bone marrow donation.

The topic hit close to home for Pettine last month, when he learned through a close friend about Michael Manganiello, a long-time Jets fan from Wayside who was diagnosed with acute myelofibrosis Easter weekend.

The rare condition -- which causes the bone marrow to progressively scar and become unable to produce blood cells -- is aggressively advancing in Manganiello's body, and his survival depends on quickly finding a matching bone marrow donor.

"It was a no-brainer to step in and help," Pettine said last night. "We dont get a lot of opportunities to do something like this, when you have a chance to have such a great impact on a life."

Pettine served as a co-host for the "Match for Michael" event held last night in Eatontown, which raised funds for the Manganiello family and the National Marrow Donor Program, but more importantly added more than 400 new people to the national bone marrow registry. Registering is as easy as taking a cheek swab, and bone marrow donation is now a less invasive procedure, the majority of the time being done via a non-surgical peripheral blood stem cell donation. Donors can usually resume normal activities within two to seven days.

Talley, who founded a non-profit organization two years ago to add donors to the national registry, gave Pettine advice on running such an event. Jets coach Rex Ryan and players Mark Sanchez, Sione Pouha and Aaron Maybin lent their support by attending the event last night, signing autographs and posing for pictures with the newly registered donors.

Manganiello, whose wife described him as the No. 1 Jets fan, was at the Robert Wood Johnson Hospital, where he is currently undergoing chemotherapy, but the Jets coaches and players were trying to reach him in his hospital room by phone.

"He's very selfless -- he would be embarrassed to know we are all here for him, he'd probably feel funny," Margo Manganiello, Michael's wife, said. "I just know were going to get through this together as a family, and I just feel like this must have happened for a reason, for us to give back to other families that are in similar situations, to help them find a cure. Because I'm very optimistic that were going to get there."

In a matter of weeks, the Manganiello family's life has been turned upside down. The 44-year-old father of three had been experiencing fatigue while running and an irregular heartbeat earlier this spring, so his wife forced him to go to the emergency room the day before Easter. It was there that blood tests confirmed the scary diagnosis.

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Jets support one fan's quest for a life-saving bone-marrow transplant

PLATTSBURGH Lois Wenger cites her faith in God as the underlying factor in her ability to help others in need, and she has never faltered in lending a helping hand.

Or in this case some much-needed bone marrow.

Wenger, who works as a support specialist in CVPH Medical Center's Information Services and Support Department, has been donating blood for years. Her blood type is O-negative, which is the universal blood type and can be used by most people in need of a transfusion.

"My older sister is a medical technologist, so it's always been a regular practice (to give blood)," Wenger said.

That practice expanded a few years ago when Wenger heard that the CVPH Blood Donor Center was working with the Rhode Island Blood Donor Center on a plan to increase the national database for bone-marrow donations.

"Only about 5 million people (nationally) were in the database at that time," said Nancy Roberts, a registered nurse at the CVPH Blood Donor Center. "We thought it would be a good idea to send out the word (for needed donors) in our region."

During the past few years, the Donor Center has hosted a bone-marrow registration at the annual Relay for Life fundraising program for the American Cancer Society.

Those successful drives, along with registrations made through the Blood Donor Center, have resulted in about 700 people from the North Country now being listed on the bone-marrow donation registry.

Those potential donors remain anonymous while their specific tissue type (collected by a simple cheek swab when registering) is recorded via bar code.

There is nothing else for the potential donor to do unless they are notified of a potential match anywhere in the country and even across the globe.

Continued here:
Local woman donates stem cells through national registry

A startup has set out to create a biobank of stem cell-rich tissues collected during surgery with the idea that customers can use their own stored biomaterials for use in future bone graft procedures and stem cell therapies.

Cleveland-based CellBank Technologies is modeling parts of its business on the cord blood bank industry, but instead of blood, it plans to store stem cells and bone-grafting tissues harvested from patients during knee and hip replacement surgeries.

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The problem with harvesting autologous bone graft tissue is that doing so requires a second painful surgery so doctors can obtain the patients own cells. And that additional surgery is just another opportunity for the patient to develop postoperative pain or other complications. Grafting tissue can be taken from several different body parts, including the iliac crest at the hip.

Other options for bone-graft patients include allograft (human tissue harvested from someone besides the patient), synthetic materials and growth factors, which are substances that stimulate cell growth. Controversy has recently engulfed Medtronics bone growth factor Infuse, with allegations of off-label use that contributed to the company paying $85 million to settle a class-action securities fraud lawsuit.

Autograft, which involves harvesting your own bone-grafting tissue, is the gold standard, but its so hard to get, Uram said.

CellBanks plan is to collect bone, marrow and stem cells that would otherwise be discarded during knee and hip surgeries. CellBank customers would then have access to their grafting materials, a product the company has labeled GoldGraft, for future bone graft surgery. The company would also store patients stem cells for use in future stem cell therapies.

Companies that store stem cells for patients include NeoStem and ViaCord.Uram said shes not aware of any other company today that stores both autograft tissue and stem cells for a patients future use.

Thats the beauty of our offering, she said. Were playing in the stem cell collect-and-store industry, but were giving our customers a way to use that collected tissue before the stem cell industry even takes off, if they need it, through use of bone-grafting tissue. With one collection our products solve multiple health needs.

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Biobank aims to collect stem cells and tissues for use in future bone grafts

ScienceDaily (Apr. 24, 2012) Although people generally talk about cancer, it is clear that the disease occurs in a bewildering variety of forms. Even single groups of cancers, such as those of the white blood cells, may show widely differing properties. How do the various cancers arise and what factors determine their progression? Clues to these two issues, at least for leukemias, have now been provided by Boris Kovacic and colleagues at the University of Veterinary Medicine, Vienna (Vetmeduni Vienna). The results are published in the current issue of the journal EMBO Molecular Medicine and have extremely important consequences for the treatment of a particularly aggressive type of leukemia.

It is well known that many types of cancer arise as a result of a mutation within a cell and prevailing wisdom has held that the stage of differentiation of this cell determines exactly what form of cancer develops. For example, it was believed that so-called chronic myeloid leukemia or CML arises from bone marrow stem cells, while a different type of leukemia, known as B-cell acute lymphoid leukemia or B-ALL, results from B-cell precursors. This belief has been spectacularly refuted by the latest results from Boris Kovacic and colleagues in the Vetmeduni Viennas institutes of Animal Breeding and Genetics and of Pharmacology and Toxicology.

The researchers have now shown that both CML and B-ALL arise from the most primordial kind of blood cell (long-term haematopoietic stem cells), although the pathways by which the diseases progress are different. The usual causes of CML and B-ALL are two highly related versions of the same oncogene, BCR/ABL. If the primordial blood cells are transformed or made potentially cancerous by a particular version of BCR/ABL, for technical reasons termed BCR/ABLp210, the result is chronic myeloid leukemia or CML. The long-term haematopoietic stem cells remain and act as the dreaded cancer stem cells, or CSCs, which ensure that the disease persists. Curing chronic myeloid leukemia requires the complete elimination of the CSCs. However, if the long-term haematopoietic stem cells are transformed by a related version of BCR/ABL, BCR/ABLp185, the result is a highly aggressive form of leukemia, B-ALL. The finding that B-ALL actually originates from the same stem cells as CML was both unexpected and highly provocative.

Kovacic and colleagues have shown further that B-ALL only develops if the transformed stem cell is exposed to a particular growth factor, interleukin-7. If interleukin-7 is present (it usually is), the transformed long-term haematopoietic stem cells undergo a differentiation step to CSCs, which in this case correspond to pro-B cells. If interleukin-7 is absent during the initial phase of transformation, B-ALL cannot develop.

In other words, two distinct types of cell are involved in leukemia development, the primordial cells (also termed the cells of origin of cancer) and the cancer stem cells that cause the disease to progress. Unless the CSCs are eliminated, fresh cancer cells can arise at any time and the leukemia will recur. The problem is that current leukemia therapies are not designed to target CSCs. The primordial CSCs in CML are highly quiescent and thus difficult to target. In contrast, the CSCs in B-ALL are abundant and have a high turnover rate, which makes them susceptible to treatment. Treatment of B-ALL may thus succeed in eliminating most CSCs but if even a single cell remains intact it is likely that the patient will relapse, possibly with an even more aggressive form of leukemia. A therapy that targets the bulk of tumour cells will not work, as Kovacic succinctly summarizes his results. To treat B-ALL successfully it will be necessary for us to learn much more about the development of the disease. A combined therapy is required, so future work should aim at developing drugs that target the long-term haematopoietic stem cells from which B-ALL is derived.

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Originally posted here:
Leukemia cells have a remembrance of things past

Public release date: 24-Apr-2012 [ | E-mail | Share ]

Contact: Dr Boris Kovacic Boris.Kovacic@vetmeduni.ac.at 43-125-077-5622 University of Veterinary Medicine -- Vienna

Although people generally talk about "cancer", it is clear that the disease occurs in a bewildering variety of forms. Even single groups of cancers, such as those of the white blood cells, may show widely differing properties. How do the various cancers arise and what factors determine their progression? Clues to these two issues, at least for leukaemias, have now been provided by Boris Kovacic and colleagues at the University of Veterinary Medicine, Vienna (Vetmeduni Vienna). The results are published in the current issue of the journal EMBO Molecular Medicine and have extremely important consequences for the treatment of a particularly aggressive type of leukaemia.

It is well known that many types of cancer arise as a result of a mutation within a cell and prevailing wisdom has held that the stage of differentiation of this cell determines exactly what form of cancer develops. For example, it was believed that so-called chronic myeloid leukaemia or CML arises from bone marrow stem cells, while a different type of leukaemia, known as B-cell acute lymphoid leukaemia or B-ALL, results from B-cell precursors. This belief has been spectacularly refuted by the latest results from Boris Kovacic and colleagues in the Vetmeduni Vienna's institutes of Animal Breeding and Genetics and of Pharmacology and Toxicology.

The researchers have now shown that both CML and B-ALL arise from the most primordial kind of blood cell (long-term haematopoietic stem cells), although the pathways by which the diseases progress are different. The usual causes of CML and B-ALL are two highly related versions of the same oncogene, BCR/ABL. If the primordial blood cells are transformed or made potentially cancerous by a particular version of BCR/ABL, for technical reasons termed BCR/ABLp210, the result is chronic myeloid leukaemia or CML. The long-term haematopoietic stem cells remain and act as the dreaded cancer stem cells, or CSCs, which ensure that the disease persists. Curing chronic myeloid leukaemia requires the complete elimination of the CSCs. However, if the long-term haematopoietic stem cells are transformed by a related version of BCR/ABL, BCR/ABLp185, the result is a highly aggressive form of leukaemia, B-ALL. The finding that B-ALL actually originates from the same stem cells as CML was both unexpected and highly provocative.

Kovacic and colleagues have shown further that B-ALL only develops if the transformed stem cell is exposed to a particular growth factor, interleukin-7. If interleukin-7 is present (it usually is), the transformed long-term haematopoietic stem cells undergo a differentiation step to CSCs, which in this case correspond to pro-B cells. If interleukin-7 is absent during the initial phase of transformation, B-ALL cannot develop.

In other words, two distinct types of cell are involved in leukaemia development, the primordial cells (also termed the cells of origin of cancer) and the cancer stem cells that cause the disease to progress. Unless the CSCs are eliminated, fresh cancer cells can arise at any time and the leukaemia will recur. The problem is that current leukaemia therapies are not designed to target CSCs. The primordial CSCs in CML are highly quiescent and thus difficult to target. In contrast, the CSCs in B-ALL are abundant and have a high turnover rate, which makes them susceptible to treatment. Treatment of B-ALL may thus succeed in eliminating most CSCs but if even a single cell remains intact it is likely that the patient will relapse, possibly with an even more aggressive form of leukaemia. "A therapy that targets the bulk of tumour cells will not work," as Kovacic succinctly summarizes his results. "To treat B-ALL successfully it will be necessary for us to learn much more about the development of the disease. A combined therapy is required, so future work should aim at developing drugs that target the long-term haematopoietic stem cells from which B-ALL is derived."

###

The paper "Diverging fates of cells of origin in acute and chronic leukemia" by Boris Kovacic, Andrea Hoelbl, Gabriele Litos, Memetcan Alacakaptan, Christian Schuster, Katrin M. Fischhuber, Marc A. Kerenyi, Gabriele Stengl, Richard Moriggl, Veronika Sexl and the late Hartmut Beug is published in the current issue of the journal "EMBO Molecular Medicine" (2012, Vol. 4 pp. 283-297).

The work was initiated at the Research Institute of Molecular Pathology (IMP) and was performed together with groups at the Medical University of Vienna and the Ludwig Boltzmann Institute for Cancer Research in Vienna.

Originally posted here:
Leukaemia cells have a remembrance of things past

Arkansas State University-Newport will host a Bone Marrow Donor Drive on campus Thursday, March 29 from 10am until 7pm and Saturday, March 31 from 9am until 1pm in the Student/Community Center, Merchants & Planters Insurance and Investments room. A bone marrow transplant is a lifesaving treatment for people with leukemia, lymphoma and many other diseases. First, patients undergo chemotherapy and sometimes radiation to destroy their diseased marrow. Then a donor's healthy blood-forming stem cells are transfused directly into the patient's bloodstream, where they can begin to function and multiply. For a patient's body to accept these healthy cells, the patient needs a donor who is a close match. Seventy percent of patients cannot find a matching donor within their family and depend on the national registry to find an unrelated bone marrow donor. Even with a registry of millions, 6 out of 10 patients NEVER receive the lifesaving transplant they need. Donors of all ethnicities are needed to change this. To see if you can be a bone marrow donor and to read about the process of testing and donating, go to http://www.dkmsamericas.org and click on Get Educated.

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ASUN to host Bone Marrow Donor Drive

Displaying rare unanimity on an issue, the full U.S. 9th Circuit Court of Appeals on Tuesday rejected a request by the federal government thatit reconsidera rulingthat most bone marrow donors can be compensated for providing life-saving marrow stem cells from their blood.

A three-judge panel of the appeals court ruled on Dec. 1 that the process of harvesting marrow cells by filtering a donor's blood wasn't covered by the 1984 National Organ Transplant Act's prohibitionof payment for organs or organ parts.The statute was enacted by Congress before the blood-filtering process was developed and donors were subjected to painful and medically risky surgical extraction of marrow by insertion of a siphoning needle into the hip bone. Compensation for that form of donation remains illegal.

Atty. Gen. Eric H. Holder Jr., on behalf of the federal government, petitioned the court in Januaryfor a new hearing by an 11-judge panel. Department of Justice lawyers argued that the December ruling ignored the clear intent of Congress to prevent money from influencing donation decisions.

The 9th Circuit panel said in its latest ruling thatall 25 active judges on the court were informed of the government's request and none called for a vote on it, signaling their agreement with the December decision. That unusualaccord among the judges who span a broad ideological spectrum might also indicate that the U.S. Supreme Court will be unlikely to take the case for review.

The lawsuit challenging the ban on bone marrow compensation was brought by a group of cancer patients and their families, as well as a marrow transplant specialist and a California nonprofit organization, MoreMarrowDonors.org, aiming to expand the registry of available donors by offering up to $3,000 in housing assistance or scholarships for promising genetic matches.

Violation of the organ transplant act's prohibition on sales of organs or parts thereofcarries heavy fines and up to five years in prison.The 1984 act defined bone marrow as an organ part, while the 9th Circuit's ruling said it was a blood part and not subject to theban on compensation.

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Appeals court stands united on compensation for bone marrow donors

ScienceDaily (Mar. 26, 2012) A research network led by a Mayo Clinic physician found that stem cells derived from heart failure patients' own bone marrow and injected into their hearts improved the function of the left ventricle, the heart's pumping chamber. Researchers also found that certain types of the stem cells were associated with the largest improvement and warrant further study.

The results were presented March 26 at the 2012 American College of Cardiology Meeting in Chicago. They will also be published online in the Journal of the American Medical Association.

This Phase II clinical trial, designed to test this strategy to improve cardiac function, is an extension of earlier efforts in Brazil in which a smaller number of patients received fewer stem cells. For this new network study, 92 patients received a placebo or 100 million stem cells derived from the bone marrow in their hips in a one-time injection. This was the first study in humans to deliver that many bone marrow stem cells.

"We found that the bone marrow cells did not have a significant impact on the original end points that we chose, which involved reversibility of a lack of blood supply to the heart, the volume of the left ventricle of the heart at the end of a contraction, and maximal oxygen consumption derived through a treadmill test," says Robert Simari, M.D., a cardiologist at Mayo Clinic in Rochester, Minn. He is chairman of the Cardiovascular Cell Therapy Research Network (CCTRN), the network of five academic centers and associated satellite sites that conducted the study. The CCTRN is supported by the National Heart, Lung, and Blood Institute, which also funded the study.

"But interestingly, we did find that the very simple measure of ejection fraction was improved in the group that received the cells compared to the placebo group by 2.7 percent," Dr. Simari says. Ejection fraction is the percentage of blood pumped out of the left ventricle during each contraction.

Study principal investigators Emerson Perin, M.D., Ph.D., and James Willerson, M.D., of the Texas Heart Institute, explain that even though 2.7 percent does not seem like a large number, it is statistically significant and means an improvement in heart function for chronic heart failure patients who have no other options.

"This was a pretty sick population," Dr. Perin says. "They had already had heart attacks, undergone bypass surgery, and had stents placed. However, they weren't at the level of needing a heart transplant yet. In some patients, particularly those who were younger or whose bone marrows were enriched in certain stem cell populations, had even greater improvements in their ejection fractions."

The average age of study participants was 63. The researchers found that patients younger than 62 improved more. Their ejection fraction improved by 4.7 percent. The researchers looked at the makeup of these patients' stem cells from a supply stored at a biorepository established by the CCTRN. They found these patients had more CD34+ and CD133+ type of stem cells in their mixture.

"This tells us that the approach we used to deliver the stems cells was safe," Dr. Simari says. "It also suggests new directions for the next series of clinical trials, including the type of patients, endpoints to study and types of cells to deliver."

Other co-authors of the study are Guilherme Silva, M.D., Deirdre Smith, Lynette Westbrook; and James Chen, all of the Texas Heart Institute, St. Luke's Episcopal Hospital, Houston; Carl Pepine, M.D., R. David Anderson, M.D., Christopher Cogle, M.D., and Eileen Handberg, Ph.D., all of the University of Florida School of Medicine, Gainesville; Timothy Henry, M.D., Jay Traverse, M.D., and Rachel Olson, all of the Minneapolis Heart Institute at Abbott Northwestern Hospital; Doris Taylor, Ph.D., and Claudia Zierold, Ph.D., both of the University of Minnesota School of Medicine, Minneapolis; Stephen Ellis, M.D., James Thomas, M.D., and Carrie Geither, all of The Cleveland Clinic Foundation, Ohio; David Zhao, M.D., Marvin Kornenberg, M.D., Antonis Hatzopoulos, Ph.D., Sherry Bowman, and Judy Francescon, all of Vanderbilt University School of Medicine, Tennessee; Dejian Lai, Ph.D., Sarah Baraniuk, Ph.D., Linda Piller, M.D., Lara Simpson, Ph.D., Judy Bettencourt, Shelly Sayre, Rachel Vojvodic, and Lemuel Moye, M.D., Ph.D., all of The University of Texas School of Public Health, Houston; A. Daniel Martin, Ph.D., of the University of Florida College of Public Health and Health Professions, Gainesville; Marc Penn, M.D., Ph.D., of Northeast Ohio Medical University, Akron; Saif Anwaruddin, M.D., of Penn Heart and Vascular Hospital of the University of Pennsylvania, Philadelphia; Adrian Gee, Ph.D., and David Aguilar, M.D., of Baylor College of Medicine, Houston; Catalin Loghin, M.D., of The University of Texas Medical School, Houston; and Sonia Skarlatos, Ph.D., David Gordon, M.D., Ph.D., Ray Ebert, Ph.D., and Minjung Kwak, Ph.D., all of the National Heart, Lung and Blood Institute, Bethesda, MD.

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Bone marrow stem cells can improve heart function, study suggests

Public release date: 24-Mar-2012 [ | E-mail | Share ]

Contact: Traci Klein newsbureau@mayo.edu 507-284-5005 Mayo Clinic

CHICAGO -- A research network led by a Mayo Clinic physician found that stem cells derived from heart failure patients' own bone marrow and injected into their hearts improved the function of the left ventricle, the heart's pumping chamber. Researchers also found that certain types of the stem cells were associated with the largest improvement and warrant further study.

The results were presented today at the 2012 American College of Cardiology Meeting in Chicago. They will also be published online in the Journal of the American Medical Association.

This Phase II clinical trial, designed to test this strategy to improve cardiac function, is an extension of earlier efforts in Brazil in which a smaller number of patients received fewer stem cells. For this new network study, 92 patients received a placebo or 100 million stem cells derived from the bone marrow in their hips in a one-time injection. This was the first study in humans to deliver that many bone marrow stem cells.

"We found that the bone marrow cells did not have a significant impact on the original end points that we chose, which involved reversibility of a lack of blood supply to the heart, the volume of the left ventricle of the heart at the end of a contraction, and maximal oxygen consumption derived through a treadmill test," says Robert Simari, M.D., a cardiologist at Mayo Clinic in Rochester, Minn. He is chairman of the Cardiovascular Cell Therapy Research Network (CCTRN), the network of five academic centers and associated satellite sites that conducted the study. The CCTRN is supported by the National Heart, Lung, and Blood Institute, which also funded the study.

"But interestingly, we did find that the very simple measure of ejection fraction was improved in the group that received the cells compared to the placebo group by 2.7 percent," Dr. Simari says. Ejection fraction is the percentage of blood pumped out of the left ventricle during each contraction.

Study principal investigators Emerson Perin, M.D., Ph.D., and James Willerson, M.D., of the Texas Heart Institute, explain that even though 2.7 percent does not seem like a large number, it is statistically significant and means an improvement in heart function for chronic heart failure patients who have no other options.

"This was a pretty sick population," Dr. Perin says. "They had already had heart attacks, undergone bypass surgery, and had stents placed. However, they weren't at the level of needing a heart transplant yet. In some patients, particularly those who were younger or whose bone marrows were enriched in certain stem cell populations, had even greater improvements in their ejection fractions."

The average age of study participants was 63. The researchers found that patients younger than 62 improved more. Their ejection fraction improved by 4.7 percent. The researchers looked at the makeup of these patients' stem cells from a supply stored at a biorepository established by the CCTRN. They found these patients had more CD34+ and CD133+ type of stem cells in their mixture.

Go here to read the rest:
Bone marrow stem cells improve heart function, study finds

HOUSTON -

Doctors from the Texas Heart Institute at St. Luke's Episcopal Hospital have found that patients with heart failure may be able to repair the damaged areas of the heart with stem cells from the patient's own bone marrow.

Doctors presented the findings at the American College of Cardiologys 61st Annual Scientific Session Saturday.

The results are from a multi-center clinical study that measured the possible benefits of using a patients own bone marrow cells to repair damaged areas of the heart suffering from severe heart failure, a condition that affects millions of Americans.

The study, which was the largest such investigation to date, found that the hearts of the patients receiving bone marrow derived stem cells showed a small but significant increase in the ability to pump oxygenated blood from the left ventricle, the hearts main pumping chamber, to the body.

The expectation is that the study will pave the way for potential new treatment options and will be important to designing and evaluating future clinical trials.

This is exactly the kind of information we need to move forward with the clinical use of stem cell therapy, said Emerson Perin, MD, PhD, Director of Clinical Research for Cardiovascular Medicine at THI, and one of the studys lead investigators.

The bone-marrow derived stem cells are helpful to the injured heart when they are themselves biologically active, added Dr. James T. Willerson, the studys principal investigator and President and Medical Director of THI.

This study moves us one step closer to being able to help patients with severe heart failure who have no other alternatives.

The study was conducted by the Cardiovascular Cell Therapy Research Network, the national consortium to conduct such research funded by the National Institutes of Healths National Heart, Lung, and Blood Institute.

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Stem cell, heart heath study

By Prue Salasky

3:48 p.m. EDT, March 23, 2012

UVA recently performed the first two stem cell transplants in Virginia, using non-embryonic stem cells from umbilical cord blood. The Stem Cell Transplant Program offers both bone marrow and stem cell transplants, with a focus on cord blood, to treat leukemia, lymphoma, Hodkin's disease and other blood diseases.

The outcome isn't known yet, but in both patients the stem cells began producing new cells 14 days after the transplant instead of the 24 to 28 days it usually takes.

The cord blood comes from placentas that otherwise would be discarded following childbirth; its benefits include sidestepping ethical issues of embryonic stem cells; they're easier and faster to collect than stem cells from other sources; and they are immune tolerant (this means that they won't attack other cells in the body and match doesn't have to be exact).

Speed is important because there is a narrow window of opportunity to perform a transplant when a patient's disease is in remission.

The program is led by Mary Laughlin, who heads up a team of 29, including 4 other transplant physicians who started seeing patients in September. The program had anticipated doing 15 transplants in first year; now expects to do 100.

Link:
Health Notes: UVA performs first stem cell transplants in Virginia

Public release date: 24-Mar-2012 [ | E-mail | Share ]

Contact: Jade Waddy Jade.Waddy@uth.tmc.edu 713-500-3030 JAMA and Archives Journals

Use of a patient's bone marrow cells for treating chronic ischemic heart failure did not result in improvement on most measures of heart function, according to a study appearing in JAMA. The study is being published early online to coincide with its presentation at the American College of Cardiology's annual scientific sessions.

Cell therapy has emerged as an innovative approach for treating patients with advanced ischemic heart disease, including those with heart failure. "In patients with ischemic heart disease and heart failure, treatment with autologous [derived from the same individual] bone marrow mononuclear cells (BMCs) has demonstrated safety and has suggested efficacy. None of the clinical trials performed to date, however, have been powered to evaluate specific efficacy measures," according to background information in the article.

Emerson C. Perin, M.D., Ph.D., of the Texas Heart Institute and St. Luke's Episcopal Hospital, Houston and colleagues conducted a study to examine the effect of transendocardial administration (use of a special catheter and injection procedure to deliver stem cells to the heart muscle) of BMCs to patients with chronic ischemic heart disease and left ventricular (LV) dysfunction with heart failure and/or angina. The patients in the phase 2 randomized trial were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institutesponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 2009 and April 2011. Patients were randomized to receive transendocardial injection of BMCs or placebo. The primary outcomes measured for the study, assessed at 6 months, were changes in left ventricular end-systolic volume (LVESV) assessed by echocardiography, maximal oxygen consumption, and reversibility of perfusion (blood flow) defect on single-photon emission tomography (SPECT). Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group).

Analysis of data indicated no statistically significant differences between the groups for the primary end points of changes in LVESV index, maximal oxygen consumption, and reversible defect. There were also no differences in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion (the movement of the wall of the heart during contraction), and clinical improvement.

In an exploratory analysis, the researchers did find that when LVEF was assessed, patients age 62 years or younger showed a statistically significant effect of therapy. Patients in the BMC group demonstrated an average increase in LVEF of 3.1 percent from baseline to 6 months, whereas patients in the placebo group showed a decrease of 1.6 percent.

"In the largest study to date of autologous BMC therapy in patients with chronic ischemic heart disease and LV dysfunction, we found no effect of therapy on prespecified end points. Further exploratory analysis showed a significant improvement in LVEF associated with treatment. Our findings provide evidence for further studies to determine the relationship between the composition and function of bone marrow product and clinical end points. Understanding these relationships will improve the design and interpretation of future studies of cardiac cell therapy," the authors write.

###

(JAMA. 2012;307(16):doi:10.1001/jama.2012.418. Available pre-embargo to the media at http://www.jamamedia.org)

View post:
Study examines treatment of heart failure with bone marrow cells

ScienceDaily (Mar. 24, 2012) Use of a patient's bone marrow cells for treating chronic ischemic heart failure did not result in improvement on most measures of heart function, according to a study appearing in JAMA. The study is being published early online to coincide with its presentation at the American College of Cardiology's annual scientific sessions.

Cell therapy has emerged as an innovative approach for treating patients with advanced ischemic heart disease, including those with heart failure. "In patients with ischemic heart disease and heart failure, treatment with autologous [derived from the same individual] bone marrow mononuclear cells (BMCs) has demonstrated safety and has suggested efficacy. None of the clinical trials performed to date, however, have been powered to evaluate specific efficacy measures," according to background information in the article.

Emerson C. Perin, M.D., Ph.D., of the Texas Heart Institute and St. Luke's Episcopal Hospital, Houston and colleagues conducted a study to examine the effect of transendocardial administration (use of a special catheter and injection procedure to deliver stem cells to the heart muscle) of BMCs to patients with chronic ischemic heart disease and left ventricular (LV) dysfunction with heart failure and/or angina. The patients in the phase 2 randomized trial were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 2009 and April 2011. Patients were randomized to receive transendocardial injection of BMCs or placebo. The primary outcomes measured for the study, assessed at 6 months, were changes in left ventricular end-systolic volume (LVESV) assessed by echocardiography, maximal oxygen consumption, and reversibility of perfusion (blood flow) defect on single-photon emission tomography (SPECT). Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group).

Analysis of data indicated no statistically significant differences between the groups for the primary end points of changes in LVESV index, maximal oxygen consumption, and reversible defect. There were also no differences in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion (the movement of the wall of the heart during contraction), and clinical improvement.

In an exploratory analysis, the researchers did find that when LVEF was assessed, patients age 62 years or younger showed a statistically significant effect of therapy. Patients in the BMC group demonstrated an average increase in LVEF of 3.1 percent from baseline to 6 months, whereas patients in the placebo group showed a decrease of -1.6 percent.

"In the largest study to date of autologous BMC therapy in patients with chronic ischemic heart disease and LV dysfunction, we found no effect of therapy on prespecified end points. Further exploratory analysis showed a significant improvement in LVEF associated with treatment. Our findings provide evidence for further studies to determine the relationship between the composition and function of bone marrow product and clinical end points. Understanding these relationships will improve the design and interpretation of future studies of cardiac cell therapy," the authors write.

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The above story is reprinted from materials provided by JAMA and Archives Journals.

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Treatment of ischemic heart failure with bone marrow cells does not show improvement for certain heart function measures