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Showing posts with label Dr. Shaf Keshavjee. Show all posts
Showing posts with label Dr. Shaf Keshavjee. Show all posts
TEDMED is one of the most prestigious annual events where leaders in the medical field discuss their ideas and I'm pleased to see that Dr. Shaf Keshavjee was an invited speaker. The first speaker of the event, he followed double-lung transplant recipient soprano Charity Tillemann-Dick's opening song “I Could Have Danced All Night” Dr. Keshavjee is my lung transplant surgeon and it's been my privilege to see the development of the Toronto EXVIVO Lung Perfusion System from it's early beginnings. Click here for a video of the system.
TEDMED celebrates conversations that demonstrate the intersection and connections between all things medical and healthcare related: from personal health to public health, devices to design and Hollywood to the hospital. TMED was held Oct 26-29 in San Diego.
Last night at view video, Shaf Keshavjee, director of the Toronto Lung Transplant Program, asked for volunteers to come onstage and touch a breathing pig lung, which was hooked up to a machine that kept it essentially “alive.”
Martha Stewart, seated up front, raised her hand, so minutes later she — and a handful of other conference participants — had donned rubber gloves and were grasping the lung as the machine helped it “breathe.” (We halfway expected her to offer up a really good offal recipe to the crowd.)
The tool Keshavjee had brought with him was essentially a mini heart-lung machine but in reverse. It permits the lung to stay at room temperature and function as usual — removing carbon dioxide from blood (a cellular solution, in this demonstration) and adding oxygen. When a human lung retrieved from a deceased donor is hooked up to the machine, physicians get the luxury of time to assess its condition and then treat it using targeted methods, including gene and cellular therapy, before transplanting it into the recipient. At that point, it’s become a “super organ,” as Keshavjee says.
Using conventional methods, transplanted lungs are cooled to slow deterioration and then transplanted, with little time to assess their condition or repair damage. Keshavjee says this new method has allowed some 30 patients to receive donated and repaired lungs that wouldn’t have ordinarily been used.
He says the holy grail for the pre-op repair process would be to treat donated lungs while they’re outside the body to avoid rejection by the host, to “make it like self.”
Your generosity can save or enhance the lives of up to fifty people with heart, kidneys, liver, lungs, pancreas and small intestine transplants (see allotransplantation). One tissue donor can help by donating skin, corneas, bone, tendon, ligaments and heart valves
Has your life been saved by an organ transplant? "Pay it forward" and help spread the word about the need for organ donation - In the U.S. another person is added to the national transplant waiting list every 11 minutes and 18 people die each day waiting for an organ or tissue transplant. Organs can save lives, corneas renew vision, and tissue may help to restore someone's ability to walk, run or move freely without pain. Life Begins with You
I've had the pleasure of visiting the labs in Toronto where this groundbreaking research is taking place and the results as described here offer great promise in having a global impact, with the potential to double the number of lungs available for transplant. Here is a video describing the EX Vivo Lung system:
April 28, 2010 (Chicago, Illinois) — Assessment and reconditioning of extended or initially rejected donor lungs using ex vivo lung perfusion (EVLP) is safe and leads to favorable outcomes after transplantation, according to results from the HELP trial — the largest clinical experience of EVLP to date — conducted at the University of Toronto in Ontario.
The trial results were presented here at the International Society for Heart & Lung Transplantation 30th Anniversary Meeting. The study employed the normothermic acellular Toronto XVIVO system (Vitrolife). "In the HELP trial, we aimed to determine the safety of transplanting initially rejected donor lungs after ex vivo re-assessment and reconditioning," said principal investigator Marcelo Cypel, MD, from the Toronto Lung Transplant Program of the University of Toronto, who presented the results.
The early outcomes of transplant after EVLP are at least equivalent to those using conventionally assessed and preserved donor lungs, said Dr. Cypel.
"Worldwide, only about 15% of donor lungs are accepted for transplantation. EVLP is a new technique that allows time to accurately assess the lung and to optimize function of injured donor lungs that would otherwise not be used," Dr. Cypel explained.
HELP was a prospective nonrandomized trial that included donor lungs that were considered unacceptable on the basis of current clinical criteria and that met study inclusion criteria. Donors were required to have a partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio of 300 mm Hg or less, or of more than 300 mm Hg with additional donor risk factors (multiple blood transfusions, pulmonary edema, donor cardiac death). Poor oxygenation or poor lung compliance was the primary reason for unsuitability.
The lungs were subjected to EVLP at 37 °C with Steen solution for 4 hours. The assessment of transplantability was made after examining lung function in the system. Organs with a partial pressure of oxygen (pO2)/FiO2 ratio of more than 400 mm Hg during EVLP were transplanted. The primary end point was a primary graft dysfunction (PGD) score of 2 to 3 within 72 hours of transplantation. Secondary end points were 30-day mortality, length of stay in the intensive care unit (ICU), length of stay in the hospital, length of intubation, proportional survival, and biomarkers in perfusate and lung tissue.
Between September 2008 and January 2009, there were 309 donors, and 129 lungs (41%) were used for 136 transplants. Of these, 25 were enrolled in the HELP trial and 22 went to transplant. These patients were compared with 114 conventionally treated control subjects. Of the 22 patients in the EVLP group, 19 had extended criteria — "no EVLP available and transplanted with concerns" — or were outright rejected.
Of the 25 lungs treated with EVLP, 22 improved sufficiently to be transplanted, and all functioned well after transplantation, the investigators reported.
Donor characteristics were similar between the HELP and control groups, except the HELP group had significantly more donors from cardiac deaths, and more patients with abnormal bronchoscopy, lower PaO2, and positive cultures. The donor score was also significantly higher in the HELP group (6 vs 4; P < .0001). Recipient demographics were similar between the groups.
The total preservation time (time to implantation) was 10 hours (range, 6 to 17 hours) for the EVLP group, after which a significant improvement in lung function was observed in the treated organs, Dr. Cypel reported.
In the majority of cases, PGD grade after EVLP was 0 to 1. "A few with good lung function after EVLP had PGD grade 3 upon ICU arrival, but this quickly improved to 0 or 1 within 24 hours," he said. PGD grade 2 was more common in the control group. More than 30% of these patients had PGD grade 2 at 24 hours, compared with 10% of the HELP group. By 72 hours, PGD grade 2 was observed in approximately 25% of the control group and 15% of the HELP group.
"For recipient outcomes, we saw no significant differences between the HELP population and controls," Dr. Cypel reported. This included 30-day mortality, time to extubation, ICU and hospital length of stay, PaO2/FiO2 ratio upon ICU arrival, and need for extracorporeal mechanical oxygenation.
Thirty-day mortality was 10.5% in the HELP group and 5.2% for other transplantations. No patients required extracorporeal mechanical oxygenation after EVLP, compared with 3.5% with conventional transplant. At 560 days posttransplant, survival was 80% for each group, he reported.
"Our system was able to discriminate between the lungs that were acceptable, and therefore transplanted (n = 22), and those that were rejected (n = 3), Dr. Cypel noted. In general, the rejected lungs had lower gas exchange, higher pulmonary vascular resistance, and higher airway pressure. Interestingly, the rejected lungs also had higher levels of inflammatory cytokines, he said.
"Using the inflammatory chip (Xceed), we are exploring the inflammatory gene profile before and after EVLP, trying to identify what these changes mean," he said. Dr. Cypel added that identification of biological predictors of donor lung quality during EVLP, perhaps through a genetic profile, would be helpful in the evolution of this technology.
Future May Be "Personalized" Organ Transplant
Dr. Cypel's presentation was followed by an invited lecture by Shaf Keshavjee, MD, the F.G. Pearson–R.J. Ginsberg Chair in Thoracic Surgery and director of the Toronto Lung Transplant Program. Dr. Keshavjee was involved in the HELP study, but he expanded upon the study's findings to provide a broader picture of EVLP.
He said that the concept of donor organ management is changing toward a paradigm that focuses on "regeneration, not death" of the organ. "The focus has been on slowing down death, rather than facilitating recovery and regeneration," Dr. Keshavjee said. "Currently, we only find out how the organ works after we implant it."
Currently, assessment of organ function is impossible at procurement, leading to the rejection of questionable organs that might be accepted in the setting of ex vivo evaluation. Going beyond assessment, ex vivo optimization of organs would increase the percentage of transplantable organs, with very few organs rejected in the end, Dr. Keshavjee explained.
"How do we get there? We need to develop a stable, reliable ex vivo maintenance perfusion technique and treatment platform," he said, "and develop a 'treatment arsenal' that is capable of injury-specific repair and immunological preparation for tolerance."
A number of questions remain with regard to organ-specific needs (heart, lung, liver) and approaches, mechanical and engineering factors, perfusate composition, and so forth. "Different resuscitation objectives will require different perfusion strategies," Dr. Keshavjee pointed out.
There are short-term issues, he added, such as thrombolysis and metabolic support, intermediate needs that might be addressed by gene therapy and immunomodulation, and long-term needs that call for regenerative medicine approaches. Functional repair of human donor lungs by interleukin-10 gene therapy has already been reported by the Toronto group, he noted (Sci Transl Med. 2009;1:4ra9).
The HELP study was funded by Vitrolife. Dr. Cypel has disclosed no relevant financial relationships. Dr. Keshavjee reports receiving grants and research support from Vitrolife and Astellas Canada, and holding the Chair in Transplantation Research, which is funded by Wyeth (Pfizer).
International Society for Heart & Lung Transplantation (ISHLT) 30th Anniversary Meeting: Abstract 258. April 23, 2010.
“You Have the Power to Save Lives – Register to be an organ and tissue donor & Tell Your Loved Ones of Your Decision”
Your generosity can save up to eight lives with heart, kidneys, liver, lungs, pancreas and small intestine transplants (see allotransplantation). One tissue donor can help 75 to 100 other people by donating skin, corneas, bone, tendon, ligaments and heart valves
Has your life been saved by an organ transplant? "Pay it forward" and help spread the word about the need for organ donation - In the U.S. another person is added to the national transplant waiting list every 11 minutes and 18 people die each day waiting for an organ or tissue transplant. Organs can save lives, corneas renew vision, and tissue may help to restore someone's ability to walk, run or move freely without pain. Life Begins with You
This ground-breaking research in lung transplantation will have a global impact and I am very fortunate to have had the opportunity to see the initial lung perfusion technique being perfected using pig lungs. The senior scientist leading this research, Dr. Shaf Keshavjee, is the surgeon that performed my lung transplant more than 7 years ago and I am very pleased to report on this outstanding success.
Scientistshope to reduce inflammation in lungs donated for transplantationby maintaining them in a special perfusion chamber and usinggene therapy to administer interleukin-10. (Photocredit: NathanSulyma, RN/Toronto General Hospital)
FOR the first time in the world, transplant surgeons at Toronto General Hospital, University Health Network, Canada, used a new technique to repair an injured donor lung that was unsuitable for transplant, and then successfully transplanted it into a patient. They said the use of this technique could significantly expand the lung donor organ pool and improve outcome after transplantation. CHUKWUMA MUANYA writes with agency reports. Chukwuma Muanya The Guardian
FOR the first time, scientists in the McEwen Centre for Regenerative Medicine, University Health Network, Canada, have successfully used gene therapy to repair injured human donor lungs, making them potentially suitable for transplantation into patients. This technique could significantly expand the number of donor lungs by using organs that are currently discarded, and improve outcomes after transplantation.
In their pioneering work, a team of researchers led by Dr. Shaf Keshavjee, above, Senior Scientist at the McEwen Centre for Regenerative Medicine, University Health Network and Director of the Lung Transplant Program, University Health Network developed a technique of ex vivo gene delivery to donor lungs, before they are implanted into a recipient's body.
The technique was shown to be simple and effective in improving lung function. Their results, "Functional Repair of Human Donor Lungs by IL-10 Gene Therapy," are published in the October 28, 2009 edition of the journal Science Translational Medicine.
"This work is a big step in using regenerative strategies to repair injured lungs," says Keshavjee, who is also Director, Latner Thoracic Research Laboratories and Professor and Chair, Division of Thoracic Surgery at the University of Toronto. "For the first time, we hope to improve the health of donor lungs that we could not have used before by using gene therapy to decrease inflammation and repair cells before transplantation."
Keshavjee also emphasizes that clinical trials on humans would be the next step in testing this promising approach before it could be used on patients waiting for lung transplants. In these future clinical trials, lungs repaired with the gene therapy will be offered to patients waiting for a life-saving lung transplant.
The process of gene therapy used on injured lungs will be carefully explained to the patients and, if they consent, the patients will be potentially transplanted with the repaired lungs should no other suitable donor lungs become available.
"This work opens the door for a variety of therapies that could potentially be applied to repair various injuries in other donor organs to improve the safety and outcome of transplants," adds Keshavjee.
Using a novel approach to overcome some of the challenges of gene therapy, the researchers first developed a strategy to preserve lungs at normal body temperature, with the lungs kept outside the body in a protective dome.
The Toronto XVIVO Lung Perfusion System continuously pumps a bloodless solution of oxygen, proteins and nutrients into injured donor lungs, mimicking normal physiological conditions. This makes it possible for the injured cells to begin repairing themselves, and also sets the stage for more sophisticated repair techniques to be applied to donor lungs.
Working with pig and then human donor lungs, which were unsuitable for transplantation, the researchers first placed the lungs on the Toronto XVIVO Lung Perfusion System to warm them to normal body temperature. Then, using a specially engineered adenovirus vector -- a common cold virus -- the researchers used a bronchoscope to inject the vector with an added IL-10 gene through the windpipe into the human lungs.
The study found that lungs maintained on the Toronto Lung Perfusion System alone, the control group, did not deteriorate and remained stable. However, the donor lungs that received the gene therapy, in addition to the ex vivo perfusion, significantly improved their function with regards to blood flow throughout the lungs and their ability to take in fresh oxygen and get rid of carbon dioxide. The boosted IL-10 effect lasts for up to 30 days in the lung.
The authors state that transplanting lungs which function better from the start would lead to more predictable, safer outcomes, shorter periods of mechanical ventilation and shorter intensive care unit stays for patients.
"It's as if gene therapy turbocharges each individual cell to manufacture many more proteins in its own IL-10 factory," explains Keshavjee, "This protein down-regulates or decreases the inflammatory potential of cells injured before and during the transplant process. It also has the capacity to turn down the recipient's immune system which rejects the transplanted organ."
The IL-10 gene is found normally in animal and human cells, and plays a role in inhibiting the immune response to infection or foreign materials such as transplanted organs. The researchers found that the lungs begin producing the new IL-10 anti-inflammatory proteins about six hours after insertion.
More than 80 per cent of potential donor lungs are injured and show inflammation during the process of brain death and intensive care related complications, and cannot be used for transplantation. Moreover, inflammation and organ rejection are the two main complications after transplant surgery.
"Everything we can do to prevent lung injury, especially in the first 72 critical hours after surgery, would have a significant impact on survival and quality of life after transplantation," notes Dr. Marcelo Cypel, a transplant surgical fellow at Toronto General Hospital who is the first author of the paper. Cypel adds that patients who have severe early lung injury are at greater risk of dying after surgery, and have higher rates of organ rejection later on.
Currently, more than 50 patients are waiting for either a lung or heart-lung transplant in Ontario, Canada. About 20 per cent of those on the wait list will die before they receive a lung transplant. In Canada, the number of people waiting for a lung transplant has doubled in the past 10 years, with 252 Canadians waiting to receive a lung transplant in 2006, compared to 119 in 1997. Two hundred and ninety-nine (299) Canadians died while waiting for a lung transplant between 1997 and 2006.
It is estimated that the number of donor organs available for lung transplants could easily be doubled with this technique to treat and improve donor lungs.
Other members of the team who contributed to this study include: Mingyao Liu, Matt Rubacha, Jonathan Young, Shin Hirayama, Masaki Anraku, Masaaki Sato, Marc de Perrot, Thomas Waddell of the McEwen Centre for Regenerative Medicine and the University of Toronto; Jeffrey Medin, Ontario Cancer Institute, Princess Margaret Hospital; and Arthur Slutsky, St. Michael's Hospital.
The study was supported by grants from the Canadian Institutes of Health Research and the Center for Gene Therapy, National Institutes of Health, U.S.
“You Have the Power to Save Lives – Register to be a donor & Tell Your Loved Ones of Your Decision”
Your generosity can save up to eight lives with heart, kidneys, liver, lungs, pancreas and small intestine transplants. One tissue donor can help up to 100 other people by donating skin, corneas, bone, tendon, ligaments and heart valves
Has your life been saved by an organ transplant? "Pay it forward" and help spread the word about the need for organ donation - In the U.S. another person is added to the national transplant waiting list every 11 minutes and 18 people die each day waiting for an organ or tissue transplant.
Congratulations to Dr. Shaf Keshavjee and his team at Toronto General Hospital, University Health Network, for their success in the use of gene therapy to repair injured lungs that were previously unsuitable for transplant. This breakthrough has the potential for global impact in the effort to provide more organs for transplant.
Researchers used the Toronto XVIVO Lung Perfusion System to continuously pump a bloodless solution of oxygen, proteins and nutrients into injured donor lungs, mimicking normal physiological conditions and warming the lungs to normal body temperatures. This makes it possible for the injured cells to begin repairing themselves, and also sets the stage for gene therapy repair techniques to be applied to donor lungs. The technique was shown to be simple and effective in improving lung function. Their results, “Functional Repair of Human Donor Lungs by IL-10 Gene Therapy,” are published in the October 28, 2009 edition of the journal SCIENCE Translational Medicine: http://stm.sciencemag.org.
Toronto, Ontario - Breakthrough: For the first time, scientists in the McEwen Centre for Regenerative Medicine at University Health Network have successfully used gene therapy to repair injured human donor lungs, making them potentially suitable for transplantation into patients. This technique could significantly expand the number of donor lungs by using organs that are currently discarded, and improve outcomes after transplantation.
In their pioneering work, a team of researchers led by Dr. Shaf Keshavjee, Senior Scientist at the McEwen Centre for Regenerative Medicine, University Health Network and Director of the Lung Transplant Program, and the Latner Thoracic Surgery Research Laboratories, developed a technique of ex vivo gene delivery to donor lungs, before they are implanted into a recipient's body. The technique was shown to be simple and effective in improving lung function.
To find out more about this research milestone,click here.
click here for video of breathing lung click here for enhanced view of an ex vivo lung
Clinical trials on humans would be the next step in testing this promising approach before it could be used on patients waiting for lung transplants. In these future clinical trials, lungs repaired with the gene therapy will be offered to patients waiting for a life-saving lung transplant. Currently, more than 50 patients are waiting for either a lung or heart-lung transplant in Ontario. About 20% of those on the wait list will die before they receive a lung transplant. In Canada, the number of people waiting for a lung transplant has doubled in the past 10 years, with 252 Canadians waiting to receive a lung transplant in 2006, compared to 119 in 1997. Two hundred and ninety-nine (299) Canadians died while waiting for a lung transplant between 1997 and 2006. It is estimated that the number of donor organs available for lung transplants could easily be doubled with this technique to treat and improve donor lungs.
“You Have the Power to Save Lives – Sign Your Donor Card & Tell Your Loved Ones of Your Decision”
Your generosity can save up to eight lives with heart, kidneys, liver, lungs, pancreas and small intestine transplants. One tissue donor can help up to 100 other people by donating skin, corneas, bone, tendon, ligaments and heart valves
Has your life been saved by an organ transplant? "Pay it forward" and help spread the word about the need for organ donation - In the U.S. another person is added to the national transplant waiting list every 11 minutes and 18 people die each day waiting for an organ or tissue transplant.
Dr. Shaf Keshavjee (above), the surgeon that performed my lung transplant in 2002, is a world leader in lung transplantation and lung transplant research. His body of work is having a global impact and this article exemplifies that. The XVIVO Lung Perfusion Technique has the potential to double the number of lungs available for transplant, not only in Toronto, Canada but worldwide as other centers adopt the technique.
In a room at the Toronto General Hospital (TGH), a pair of human lungs is breathing inside a glass dome. As they breathe in and out, fed by a supply of gases and nutrients, the lungs are healing themselves from injury. This revolutionary technology promises to improve the fate of many patients waiting for lung transplants in Canada.
In Canada, nearly 300 patients with lung disease died between 1997 and 2006. These patients died because of a shortage of suitable lungs available for transplant. In fact, as few as one in 10 donated lungs available can be used. The new technology at TGH may allow doctors to more than double the number of lung transplants done worldwide, according to Dr. Shaf Keshavjee of TGH's Division of Thoracic Surgery.
"Lungs are very fragile as organs," says Dr. Keshavjee, who directs the Toronto Lung Transplant Program. "This new system allows you to assess the lungs, to diagnose what's wrong with them, and then repair them."
Dr. Keshavjee's team worked for years studying lung transplant and repair experiments on animal models. In December 2008 they announced a successful first use of the system in transplanting a pair of lungs into a patient. They have since completed twelve other successful transplants with the system, called The Toronto XVIVO System.
The work is being funded by the Canadian Institutes of Health Research's CIHR/Rx&D Collaborative Research Program, a partnership of CIHR and Canada's Research-Based Pharmaceutical Companies. Other collaborative partners include Astellas Canada, Wyeth Pharmaceuticals and Vitrolife Inc.
The Toronto XVIVO Lung Perfusion System was developed by Dr. Keshavjee's team and Virolife Inc., which specializes in lung preservation. The technique allows lungs to be kept at body temperature, outside the body. Fed with a bloodless solution containing nutrients, proteins and other medications, the organs exchange oxygen and carbon dioxide through a ventilator and can repair themselves while the researchers facilitate the recovery and check them. The lungs can be kept inside the device for up to 18 hours, though 12 hours is the current routine limit. A similar blood perfusion system developed in Sweden for short term assessment only works for about an hour before the lung becomes damaged.
"We've already successfully transplanted twelve* patients now using the XVIVO System, so those patients received lungs that couldn't have been used before," says Dr. Keshavjee. "They've all done superbly, every single one of them. We're now able to use lungs that we couldn't use before."
*As of today, Dr. Keshavjee tells me that 14 patients have now been transplanted - Merv.
The Canadian Institutes of Health Research (CIHR) is the Government of Canada's agency responsible for funding health research in Canada.
Your generosity can save up to eight lives with heart, kidneys, liver, lungs, pancreas and small intestine transplants. One tissue donor can help up to 100 other people by donating skin, corneas, bone, tendon, ligaments and heart valves
Has your life been saved by an organ transplant? "Pay it forward" and help spread the word about the need for organ donation
Diagnosed with pulmonary fibrosis (IPF) in 1999. Received a single-lung transplant in April, 2002. Am now an advocate for Organ & Tissue transplantation and research.
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