Wednesday, October 31, 2012

Smoking Bans Cut MI Rate

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: October 29, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Indoor smoking bans substantially cut heart attack rates in communities and may have an impact on sudden cardiac death as well, a population-based study showed.
Myocardial infarction (MI) incidence dropped 33% after implementation of ordinances banning smoking in restaurants and the workplace, Richard D. Hurt, MD, of the Nicotine Dependence Center at the Mayo Clinic in Rochester, Minn., and colleagues found.
Sudden cardiac death incidence declined by 17% in Olmsted County -- where Mayo Clinic is located -- with the laws, though not statistically significant at P=0.13 with the relatively low number of events, the group reported online in the Archives of Internal Medicine.
Other than the expected decline in smoking prevalence from making it less convenient, cardiovascular risk factors remained largely stable in the population there, supporting an effect of the bans themselves, they pointed out.
"Exposure to second-hand smoke should be considered a modifiable risk factor for MI," they wrote. "All people should avoid second-hand smoke exposure as much as possible, and those with coronary heart disease should have no exposure to second-hand smoke."
These additional data supporting smoke-free policies should encourage more locales to adopt them, Hurt and colleagues added.
"Second-hand smoke does matter, and the results of this study will help us to be able to move forward with policies and guidelines to be able to minimize second-hand smoke," Lauren Whitt, PhD, of the University of Alabama at Birmingham, agreed in an interview with MedPage Today.
Other studies of smoke-free workplace and public place laws have pointed to declines in acute MI rates and hospitalizations, fewer asthma admissions among children, and improved quality of life, Sara Kalkhoran, MD, and Pamela M. Ling, MD, MPH, both of the University of California San Francisco, pointed out in an invited commentary.
"Moving forward, we should prioritize the enforcement of smoke-free policies, eliminating loopholes in existing policies as well as encouraging expansion of smoke-free policies to include multi-unit housing, motor vehicles, casinos, and outdoor locations," they wrote.
"Clean air laws encompassing larger portions of the population will help to establish a cleaner bill of health for all."
Olmsted County enacted a smoke-free restaurant law in 2002 and extended the ban to include all workplaces, including bars, in 2007.
Hurt's group compared outcomes through records of the Mayo Clinic and the one other medical center serving the county in the Rochester Epidemiology Project.
The incidence of MI fell from 151 per 100,000 population in the 18-month period before either ordinance to 101 per 100,000 in the 18 months after both were into effect (P<0.001).
Incidence of sudden cardiac death went from 109 to 92 per 100,000 population over the same period (P=0.13).
The researchers cited CDC data for Minnesota from the Behavioral Risk Factor Surveillance System showing a decline in smoking prevalence among adults from 20% in 2000 to 15% in 2010.
However, no other risk factors moved in a direction expected to reduce MI rates. Diabetes and obesity rose, while hypertension and high cholesterol prevalence stayed relatively flat.
"As trends in other risk factors do not appear explanatory, smoke-free workplace laws seem to be ecologically related to these favorable trends," Hurt's group wrote.
They noted, though, that these trends occurred against a backdrop of declining incidence of sudden cardiac death over the past 30 years and other tobacco control efforts in the state.
Other limitations included lack of data on self-reported or biochemical markers of second-hand smoke exposure, and the primarily white population studied.

Read more and view video MedPage Today

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Monday, October 29, 2012

Hurricane Sandy poses problems for patients and doctors

There are about 60 million people in the path of hurricane Sandy and undoubtedly many of these will be organ transplant recipients who must take anti-rejection and other meds daily. For these patients, it is extremely important to plan ahead to make sure their drugs are in supply, safe and dry. 

Doctors Urged to prepare for Patient Surge After Hurricane Sandy, Says Expert

By Robert Lowes
Physicians in the path of Hurricane Sandy, which is expected to make landfall tonight on the New Jersey shore, should open up their office schedules later this week for a surge of patients with chronic illnesses, according to an expert on healthcare emergency preparedness.
"People lose their medicine, or it gets wet," said Linda Landesman, MD, author of Public Health Management of Disasters: The Practice Guide. "They lose power, and there goes the medicine in their refrigerator. They lose their glasses. Dampness exacerbates their asthma. You can't imagine all the possibilities.
"Physician practices might want to consider postponing some of their noncritical appointments so they have the capacity to see the emergency walk-ins."
Although attention has centered on New York City, which has ordered evacuation of low-lying areas, including portions of Manhattan, much of the eastern seaboard is at risk of flooding, power outages, and massive property damage. Nine states already have declared states of emergency.
Hospitals in the Mid-Atlantic states and New England are taking familiar precautions — cancelling elective surgeries; stocking up on food, water, and emergency generator fuel; instructing entire shifts to bring toothbrushes and pajamas for indefinite stays; rescheduling appointments in outpatient facilities; and closing physician offices.
The drill also includes discharging as many patients as safely as possible and evacuating others who are critically ill. The North Shore–Long Island Jewish Health System, for example, transferred dozens of patients dependent on ventilators and other mechanical devices from its flood-prone Staten Island University Hospital and Southside Hospital in Bayshore, New York, to other facilities in its system.
"The good news is we've had almost a week of warning, so people have had time to get prepared," said Dr. Landesman, a former assistant vice president of the New York City Health and Hospitals Corporation. Another plus, she said, is that East Coast hospitals have fresh memories of this drill from when they executed it last fall for Hurricane Irene.
Dr. Landesman, who now teaches at the University of Massachusetts–Amherst, said the 1000-mile-wide Hurricane Sandy threatens to strain emergency resources more than smaller storms. When a state or area is beset by a natural disaster, she said, hospitals and public health authorities typically take advantage of mutual-aid agreements with their neighbors, bringing in ambulances and extra medical personnel, for example. However, when their neighbors face the same natural disaster, those resources become unavailable.
"That's why the federal [emergency response] system is so important as a backup," said Dr. Landesman.
Already, the US Department of Health and Human Services has deployed two 50-member medical disaster crews to New Jersey, the department said in a press release today, and another such team is ready to go into action if needed.

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Sunday, October 28, 2012

Women who quit smoking by 40 can live an extra decade

The Telegraph

Women who stop smoking by the age of 40 dramatically cut risk of early death, enjoying up to ten more years of life, a major new study has found.

The study of 1.3 million women found that quitting smoking by the age of 30 allowed women to avoid up to 97 per cent of the extra risk of premature death.
The results, which are published in The Lancet medical journal, showed that lifelong smokers died a decade earlier than those who did not smoke at all.
Those who stopped at thirty lost an average of a month of life and if they stopped at 40 they died a year younger.
Most of the increased death rate resulted from smoking-related diseases such as lung cancer, chronic lung disease, heart disease or stroke.
The risk rose steeply with the quantity of tobacco smoked, but even light smokers who puffed fewer than 10 cigarettes a day doubled their likelihood of dying.

The authors of the Million Women Study wrote: "Smokers lose at least 10 years of lifespan. Although the hazards of smoking until age 40 years and then stopping are substantial, the hazards of continuing are 10 times greater."
Women aged 50 to 65 were enrolled into the study, designed to investigate links between health and lifestyle, from 1996 to 2001.
Participants completed a questionnaire about living habits, medical and social factors and were re-surveyed three years later. Women were monitored for a total of 12 years on average, during which there were 66,000 deaths.
Initially, 20% of the women were smokers, 28% were ex-smokers, and 52% had never smoked.
Those who still smoked at the three year re-survey were almost three times more likely than non-smokers to die over the next nine years.
Both the hazards of smoking and the benefits of quitting were greater than previous studies had suggested, said the researchers.
Professor Sir Richard Peto, one of the co-authors at Oxford University, said: "If women smoke like men, they die like men - but, whether they are men or women, smokers who stop before reaching middle age will on average gain about an extra 10 years of life."
He added: "Both in the UK and in the USA, women born around 1940 were the first generation in which many smoked substantial numbers of cigarettes throughout adult life.
"Hence, only in the 21st century could we observe directly the full effects of prolonged smoking, and of prolonged cessation, on premature mortality among women."
Professor Rachel Huxley, from the University of Minnesota, said: "In most of Europe and the USA, the popularity of smoking among young women reached its peak in the 1960s, decades later than for men.
"Hence, previous studies have underestimated the full eventual impact of smoking on mortality in women, simply because of the lengthy time lag between smoking uptake by young women and disease onset in middle and old age."

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Saturday, October 27, 2012

Jehovah's Witness who needed bloodless transplant dies

By Brad Cooper The Kansas City Star

A western Kansas woman who forced the state to honor her religion and agree to provide a Medicaid-funded bloodless liver transplant has died.

Mary Stinemetz, 66, passed away Sunday at the University of Colorado Hospital, roughly three years after she first learned she needed a liver transplant.

A Jehovah’s Witness from the western Kansas town of Hill City, Stinemetz got a Kansas appeals court to find that the state violated her constitutional right to exercise her religious faith when it denied Medicaid coverage for an out-of-state liver transplant.

Stinemetz refused to undergo a liver transplant at the University of Kansas Hospital because she would need a blood transfusion - something she couldn’t accept as a Jehovah’s Witness. She wanted to receive a special bloodless transplant in Nebraska instead.

State officials had argued in court that there was no medical necessity for a bloodless transplant, and that her religious preference shouldn’t determine insurance coverage.

The state chose not to appeal the case and agreed to cover the procedure. But by the time Stinemetz could get on a transplant list, her condition had worsened to a point where she was no longer eligible for a liver transplant.

For 20 years, Stinemetz had suffered from primary biliary cirrhosis, a chronic disease that causes the liver to deteriorate and malfunction over time.

By this summer, Stinemetz had acknowledged in an interview that she was terminally ill with the disease.

Her survivors include her husband, Merlyn, six children and their spouses and 24 grandchildren.

Her memorial service will be at 2 p.m. Saturday at the Kingdom Hall of Jehovah Witnesses in Hill City.

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Friday, October 26, 2012

EMS learn how to treat LVAD patients with no pulse

I know several people who are either wearing or wore an LVAD prior to their heart transplant, but I never thought about whether or not they had a pulse and the implications of this in the event of an emergency. As the article notes it can be deadly if people try to do CPR on these patients.

"EMS personnel say when a patient doesn't have a pulse, their first instinct is to start CPR, but doing chest compressions on an LVAD patient can kill them. In fact, two Floridians have died because first responders did just that."

WINK News Now
NORTH NAPLES, Fla - A ventricular assist device or VAD is designed for people who are waiting for a heart transplant.
But, as the technology becomes more popular, local first responders are learning VAD patients present a unique challenge. They don't have a pulse.
That's why this week, the North Naples Fire District is hosting a special training session for first responders across Southwest Florida so they can learn exactly how to treat VAD patients.
Robert Abba has had two heart attacks since 2006. "I'm still on the list, waiting for a phone call. It's a tough thing because there aren't enough donors."
In the meantime, Abba has turned to the LVAD, a left ventricular assist device, that helps the heart pump blood through the body and while the LVAD has given him his life back he says, "I have no pulse because it's a constant pressure through the heart with the pump."
EMS personnel say when a patient doesn't have a pulse, their first instinct is to start CPR, but doing chest compressions on an LVAD patient can kill them. In fact, two Floridians have died because first responders did just that.
"Doing chest compressions could dislodge the device," says Jorge Aguilera, Deputy Chief at the North Naples Fire District. "Since it's connected directly to the heart, they can bleed to death internally."
The LVAD isn't just for elderly patients. A young person who is too overweight for a transplant can use the LVAD so they can exercise.
Breast cancer patients with heart conditions, aren't eligible for a heart transplant until they're cancer free for five years. They can now also use the LVAD to keep their blood flowing.
"We are definitely taking what we consider the lead on this," says Aguilera. "We want to be advocates for our patients. They need to be comfortable and know if they come to Collier County, the first responders know what it is."
The training wraps up Thursday at North Naples fire station 45.

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Wednesday, October 24, 2012

Presumed consent discussion continues in Canada

By Laura Eggertson,Canadian Medical Association Journal
Testing presumed consent for organ donation in a province or region where residents support the notion could help resolve the debate over whether a national "opt-out" system would improve Canada's chronic organ shortage, an expert says.
"From a national point of view, because consent to organ and tissue donation laws are provincially based, we would welcome having a province take a lead on this to demonstrate whether it is effective," says Dr. Sam Shemie, medical director for organs and tissues donation at Canadian Blood Services (CBS) and a pediatric intensive care physician in the Division of Pediatric Critical Care at Montreal Children's Hospital in Quebec. "If Atlantic Canada decides to pursue this, good on them. It would be an example for the rest of us."
A recent survey indicated that a majority of people in Nova Scotia, New Brunswick and Newfoundland and Labrador would support an "opt-out" approach to organ donation. Such programs presuppose the presumed consent of residents to be organ donors unless they take proactive steps to indicate their objections.
Currently, the converse is true. Canadians can "opt in" to donate after they die by either signing the form on their driver's license, or through the explicit consent of surviving family. Traditionally, even if a person has signed a donor card, the final decision has typically been left to families, although consideration is being given to adopting the concept of "first person consent," i.e., automatically harvesting organs when a donor card has been signed ( As part of its recent plan to create an "integrated inter-provincial organ donation and transplantation system," CBS proposes to craft strategies that would substantially increase organ donation rate (
Although it's long been held that Canadians find an "opt-out" approach somewhat anathema, a Corporate Research Associates Sept. 12 survey of 1200 adults in Atlantic Canada suggests that opinion on the issue is shifting. Some 60% of Nova Scotians support the proposition of presumed consent, as do 56% of people in Newfoundland and Labrador, and 55% of people in New Brunswick (The survey's accuracy was reported at ± 4.9 percentage points, 95 times out of 100).
Although Prince Edward Island residents were not surveyed, the province indicated the findings are cause for a discussion on presumed consent.
PEI, as well as the other Atlantic provinces, "is in the preliminary stages of looking at that," says Dr. Richard Wedge, executive director of medical affairs for Health PEI. "We haven't got any concrete plans at this point to do anything like this. … The people who work on different policies within organ donation and transplantation programs have been discussing this, along with an inter-provincial initiative that's under way to try to improve organ donation in Canada."
CBS and the various provincial agencies responsible for organ donation and transplantation have been discussing approaches to improving organ donation rates in Canada for 20 years, says Shemie. Over the past five years, national public opinion surveys have been evenly split between those who support and oppose presumed consent, he says, adding that if popular opinion is shifting in favour of such a program in a particular region, then it's appropriate for that province to discuss that option.
As part of its new national strategic plan, CBS will advocate for more investment in front-line donation and transplant services, improved training and support for hospital personnel in all departments, and better education for the Canadian public, before considering a controversial approach such as presumed consent, Shemie says. "The conclusion certainly from a national perspective is — not now. Maybe later, but not now. But we would welcome provinces taking the lead. This is the way innovation in health care and health policy occurs. One place tries it and it demonstrates to the rest of the country how controversial it is, what the problems with it are, and what the successes are."
Reaction to presumed consent in Ontario was mixed in the findings of a 2007 survey, says Ronnie Gavsie, president and chief executive officer of the Trillium Gift of Life Network. "It is clear people feel organ donation is a gift — a step that is positive and taken proactively, rather than it being a reactive assumption that someone would be a donor."
Ontario is not prepared to become the province that steps out to test the presumed consent waters, because most residents believe people should register their consent to be donors at and have the discussion with their families, Gavsie adds.
Countries that have presumed consent policies in place, such as Spain, have "told us categorically that they do not believe their donation rates are a reflection of presumed consent," she says. Gavsie also notes that presumed consent did not increase donation rates in Singapore and that even when such approaches are in place, family consent is typically required and people often deny permission because they do not believe their loved one made an informed decision.
"So there's simply no evidence that we have, even when we look internationally, that presumed consent is the silver bullet," Gavsie says.
According to CBS, Canada's donation rate in 2010 was 13.9 deceased organ donations per million population, a rate which lagged well behind that of the United Kingdom (15.5), the United States (26.1) and Spain (32.1). There were 2153 organ transplants in Canada in 2010, including 1234 kidneys, 443 livers, 167 hearts and 178 lungs, according to the Canadian Organ Replacement Register. There were 4529 Canadians on the waiting lists, 511 people who withdrew their names from a waiting list and 247 people who died while on a list.
Although the United Kingdom recently rejected the presumed consent model as a way of increasing organ donation rates in England, Wales is looking at the option "very seriously," says Shemie.

Tuesday, October 23, 2012

UCLA's heart transplant program ranked among nation's best

Medical center also recognized for efforts to improve organ donation rates
The heart transplant program at Ronald Reagan UCLA Medical Center has again been recognized as one of highest ranking in the nation by an agency of the U.S. Department of Health and Human Services.

UCLA's program is one of only seven heart transplant centers nationwide — and the only one in California — to be ranked at the silver level by the Health Resources and Services Administration (HRSA), which has federal oversight of the nation's organ donation and transplantation network.

The HRSA survey measures the performance of organ transplant centers by assessing transplant rates, post-transplant survival rates and mortality rates for patients after they are placed on organ-donation waiting lists. To earn silver status, a program must achieve better-than-expected performance in at least two of those categories. Only one center — a liver transplant program in Florida — earned a gold ranking for achievements in all three.  

UCLA, which also earned silver status in 2010, when the HRSA organ transplant center survey was inaugurated, is the only heart transplant program in the U.S. to have earned a silver ranking twice.

"As the only two-time silver-level heart transplant program, we are incredibly proud of our team's hard work in providing the very best care for our patients who undergo this lifesaving treatment," said Dr. Abbas Ardehali, a professor of cardiothoracic surgery and director of UCLA's heart transplant program. "This recognition acknowledges that patients in the UCLA heart transplant program have a better chance of survival."

The HRSA awards were presented Oct. 4 at ceremony held in Grapevine, Texas.

In addition, Ronald Reagan UCLA Medical Center received the Department of Health and Human Services' Bronze Medal of Honor for Organ Donation for achieving and sustaining national goals for organ donation, including a donation rate of 75 percent or more of eligible donors.

"We are so proud of our health care professionals who reach out with great compassion and sensitivity to explain and inspire individuals and families to save lives as organ and tissue donors during emotionally difficult times," said Dr. J. Thomas Rosenthal, the medical center's chief medical officer. "Every life touched by organ and tissue donation crosses a bridge between death and life, grief and meaning, hope and healing. This award is a true honor."

The Medal of Honor awards were presented for work done between April 1, 2010, and March 31, 2012.

The HRSA leads federal efforts to increase organ and tissue donation and transplantation and supports the Donation and Transplantation Community of Practice, which brings together donation and transplantation professionals, hospital staff and other professionals involved in the donation process to identify and share best practices. For more information,

One of the nation's busiest transplant centers, Ronald Reagan UCLA Medical Center offers heart, lung, liver, kidney, intestinal, pancreas, cornea, auto islet, bone marrow, hand and face transplant services.

For more information, visit
For more news, visit the UCLA Newsroom and follow us on Twitter.

Monday, October 22, 2012

Fred Hutch Nobel laureate established BMT as a life-saving treatment for blood cancers

SEATTLE – E. Donnall Thomas, M.D., who won the 1990 Nobel Prize in physiology or medicine for his pioneering work in bone-marrow transplantation to cure leukemias and other blood cancers, died today.  He was 92.
Editor's note: A multi-media news release with photos and broadcast-quality b-roll can be downloaded here:
Dr. E. Donnall Thomas
Dr. E. Donnall Thomas

Thomas joined the faculty of Fred Hutchinson Cancer Research Center in 1974 as its first director of medical oncology. He later became associate director and eventually director of the Center's Clinical Research Division. He stepped down from that position at age 70 in 1990 and officially retired from the Hutchinson Center in 2002.

Thomas, along with his wife and research partner, Dottie – a trained medical technologist – and a small team of fellow researchers stubbornly pursued transplantation throughout the 1960s and 1970s despite doubts by many prominent physicians of the day.

"To the world, Don Thomas will forever be known as the father of bone marrow transplantation, but to his colleagues at Fred Hutch he will be remembered as a friend, colleague, mentor and pioneer," said Larry Corey, M.D., president and director of Fred Hutchinson Cancer Research Center. "The work Don Thomas did to establish marrow transplantation as a successful treatment for leukemia and other otherwise fatal diseases of the blood is responsible for saving the lives of hundreds of thousands of people around the globe."

His groundbreaking work is among the greatest success stories in cancer treatment. Bone marrow transplantation and its sister therapy, blood stem cell transplantation, have had worldwide impact, boosting survival rates from nearly zero to up to 90 percent for some blood cancers. This year, approximately 60,000 transplants will be performed worldwide.

Thomas edited the first two editions of the seminal bone marrow transplantation reference book, "Hematopoietic Cell Transplantation," in 1994 and 1999, which became recognized as the "bible in the field." He also contributed a chapter to the third edition, published in 2004, at which time the book's title was changed to "Thomas' Hematopoietic Cell Transplantation."

"Don quite literally wrote the book on marrow transplantation," said Fred Appelbaum, M.D., director of the Hutchinson Center's Clinical Research Division, a friend of Thomas' and an editor of the book. "Don was a hero. He was, by far, the most influential person in my career, and I know that many others would say the same thing."

Thomas was a member of 15 medical societies, including the National Academy of Sciences. He also received more than 35 major honors and awards, including the Gairdner Foundation International Award and the Presidential Medal of Science. He was past president of the American Society of Hematology and served on the editorial boards of eight medical journals.

Thomas came to Seattle in 1963 to be the first head of the Division of Oncology at the University of Washington School of Medicine. Continuing work begun in Cooperstown, N.Y., Thomas led a small team that labored in the basement of temporary facilities at the former U.S. Public Health Hospital. They sought to do what others were convinced would never work: to cure leukemia and other cancers of the blood by destroying a patient's diseased bone marrow with near-lethal doses of radiation and chemotherapy and then rescuing the patient by transplanting healthy marrow. The goal was to establish a fully functioning and cancer-free blood and immune system.

"We moved to Seattle … at a time when it seemed that marrow transplantation would never be successful," Thomas recalled in a 2000 interview. "So we focused our attention on laboratory experiments." As chief of medicine at the Mary Imogene Bassett Hospital in Cooperstown, N.Y., Thomas began studies of marrow grafts, treating relatively few human patients. After moving to Seattle, Thomas and his colleagues worked almost exclusively in the laboratory well into 1967, postponing work on patients until treatment complications could be resolved.

It took almost 20 years after Thomas's seminal paper on bone-marrow transplantation was published in The New England Journal of Medicine in September 1957 for the procedure to become an accepted therapy. During that time most medical professionals dismissed the idea.

"In the 1960s in particular and even into the 1970s, there were very responsible physicians who said this would never work," Thomas said. "Some suggested it shouldn't go on as an experimental thing."

The early success was enough to convince Seattle surgeon William Hutchinson, M.D., to support Thomas and his team and build the group a permanent home. In 1972, ground broke for the construction of the original Fred Hutchinson Cancer Research Center building in Seattle's First Hill neighborhood, and its doors opened in 1975.

Thomas and his team persisted because they believed transplantation was the key to saving the lives of people with leukemia, lymphoma, multiple myeloma and other fatal blood diseases.
"I've said in the past that I have two attributes: one is I'm stubborn to keep doing it and other is I attracted some good people to work with me," Thomas told an interviewer in 2006.

Today, bone marrow transplants are a proven success for treating leukemia and other cancers as well as blood disorders such as aplastic anemia.
Thomas is survived by his wife, Dottie, two sons and a daughter.

To make a donation in Thomas' memory and continue the legacy of his lifesaving research, visit here. Gifts will be directed to the Clinical Research Division, of which Thomas was the founding director. 

Saturday, October 20, 2012

UC to Study Generic vs. Brand-Name Transplant Drugs with a $2.7M FDA Grant

I've been concerned about the efficacy of generic drugs vs brand name since my lung transplant over ten years ago. When renewing prescriptions I've often been given a different generic drug than the one I received previously and I look forward to the results of this study.

Press release

CINCINNATI—A new study at the University of Cincinnati (UC) seeks to end the questions over generic-vs.-brand for a common immunosuppressive drug for transplant patients, tacrolimus.

Rita Alloway, PharmD, UC research professor of medicine and director of transplant clinical research within the UC Department of Internal Medicine, has received a $2.7 million U.S. Food and Drug Administration grant to run a clinical trial studying the immunosuppressant tacrolimus (Prograf) against two other generic manufacturers in liver and kidney transplant patients. 

Tacrolimus is a "cornerstone drug” in post-transplant immunosuppression, used after transplant to reduce the activity of the patient’s immune system and lower the risk of rejection. It’s also a critical dose drug—a medication in which the dosage level between efficacy and unwanted side effects is very close.

"Most immunosuppressant drugs require individualized dosing and careful management to ensure the proper blood concentrations are maintained,” says Alloway. "Too high exposure to these drugs increases the risk of toxicity, over-immunosuppression and cancer in patents. Too low exposure may lead to rejection of the organ by the patient’s immune system.”

Alloway says these conditions have led transplant physicians and their patients to be wary of using generic immunosuppressants—concerned that the quality, pharmacokinetics and therapeutic efficacy of these new drugs may differ from the branded, or innovator, product.

Her study aims to address these concerns in a prospective, blinded, six-way crossover study in kidney and liver transplant patients testing whether the two most disparate generics, based on potency, purity, and dissolution ( "Generic Hi” and "Generic Lo”), are bioequivalent to the innovator version in stable transplant patients. 

"Currently more than 50 percent of transplant patients are dispensed generic tacrolimus,” says Alloway. "The largest concern for clinicians is the switchability between various generics. When patients receive their prescription, they could be getting medication from different manufacturers each month. We’re investigating whether even the most disparate generics have the same efficacy in healthy post-transplant patients.”

Collaborators in the study include Uwe Christians, MD, PhD, professor of anesthesiology at the University of Colorado, and Sander Vinks, PharmD, PhD, UC professor of pediatrics and director of the Division of Clinical Pharmacology at Cincinnati Children’s Hospital Medical Center.

"These collaborators provide expertise in tacrolimus level analysis and pharmacokinetic data analysis,” says Alloway. "The study design will incorporate the most sensitive and specific tacrolimus level analysis while evaluating different methods of bioequivalence data analysis.

"In addition, we plan to evaluate patients designated genetically as 'poor absorbers' or 'high metabolizers,' patients at a greater risk of receiving lower or higher concentrations of the medication than desired. That will allow us to further characterize unique factors which may affect tacrolimus levels of different manufacturers.”
The trial will enroll 72 transplant patients—36 kidneys and 36 livers—transplanted in the UC Health University Hospital and Christ Hospital transplant programs starting early 2013.

Alloway is an internationally recognized expert on generic immunosuppressive drug development and FDA approval standards. She will present the grant to a meeting of the FDA, the American Society of Transplantation and American Society of Transplant Surgeons Monday, Oct. 22, in Washington, D.C.

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Friday, October 19, 2012

Transplanted Neural Stem Cells Produced Myelin, UCSF Study Shows

UCSF Press Release

Phase I Investigation Demonstrates Signs of Engraftment and Safety at One Year

headline image
David Rowitch, MD, PhD, professor and chief of neonatology, in the Neuro-Intensive Care Nursery.
By Jennifer O'Brien on October 10, 2012
A Phase I clinical trial led by investigators from the University of California, San Francisco (UCSF) and sponsored by Stem Cells Inc., showed that neural stem cells successfully engrafted into the brains of patients and appear to have produced myelin.
The study, published in Wednesday's issue of Science Translational Medicine, also demonstrated that the neural stem cells were safe in the patients’ brains one year post transplant.

The results of the investigation, designed to test safety and preliminary efficacy, are encouraging, said principal investigator David H. Rowitch, MD, PhD, a professor of pediatrics and neurological surgery at UCSF, chief of neonatology at UCSF Benioff Children’s Hospital and a Howard Hughes Medical Institute Investigator.
Nalin Gupta, MD, PhD
Nalin Gupta, MD, PhD
“For the first time, we have evidence that transplanted neural stem cells are able to produce new myelin in patients with a severe myelination disease,” said Nalin Gupta, MD, PhD, associate professor of neurological surgery and pediatrics and chief of pediatric neurological surgery at UCSF Benioff Children's Hospital, and co-principal investigator of the PMD clinical trial. 
“We also saw modest gains in neurological function, and while these can’t necessarily be attributed to the intervention because this was an uncontrolled trial with a small number of patients, the findings represent an important first step that strongly supports further testing of this approach as a means to treat the fundamental pathology in the brain of these patients.”
The study, one of the first neural stem cell trials ever conducted in the United States, is emblematic of UCSF’s pioneering role in the stem cell field. In 1981, Gail Martin, PhD, professor of anatomy, co-discovered embryonic stem cells in mice. In 2001, Roger Pedersen, PhD, professor emeritus of obstetrics, gynecology and reproductive sciences, derived two of the first human embryonic stem cell lines. On Monday, Shinya Yamanaka, MD, PhD, of the UCSF-affiliated Gladstone Institutes and Kyoto University, received the Nobel Prize in Physiology or Medicine for his discovery that adult cells can be reprogrammed to behave like embryonic stem cells. 

Landmark Study in Stem Cell Field

In the trial, human neural stem cells developed by Stem Cells, Inc., of Newark, California, were injected directly into the brains of four young children with an early-onset, fatal form of a condition known as Pelizaeus-Merzbacher disease (PMD). 
This image illustrates direct injection of human neural stem cells into the brai
This image illustrates direct injection of human neural stem cells into the brain's white matter, which is composed of bundles of nerve axons. There is lack of myelin, an insulating coating, in the severe pediatric condition Pelizaeus-Merzbacher disease (PMD). Over time, some stem cells become myelinating oligodendrocytes as reported in the papers from Uchida et al. and Gupta et al. Image by Kenneth Probst.
In PMD, an inherited genetic defect prevents brain cells called oligodendrocytes from making myelin, a fatty material that insulates white matter which serves as a conduit for nervous impulses throughout the brain. Without myelin sheathing, white matter tracts short-circuit like bare electrical wires and are unable to correctly propagate nerve signals, resulting in neurological dysfunction and neurodegeneration. Patients with early-onset PMD cannot walk or talk, often have trouble breathing and undergo progressive neurological deterioration leading to death between ages 10 and 15.The disease usually occurs in males.
Multiple sclerosis and certain forms of cerebral palsy also involve damage to oligodendrocytes and subsequent demyelination.
Before and after the transplant procedures in the children with PMD, which were conducted between 2010-2011, the patients were given standard neurological examinations and developmental assessments, and underwent magnetic resonance imaging (MRI). “MRI is the most stringent non-invasive method we have of assessing myelin formation,” said Rowitch.
The investigators found evidence that the stem cells had successfully engrafted, receiving blood and nutrients from the surrounding tissue and integrating into the brain, a process that Rowitch likened to “a plant taking root.”
This finding was particularly significant, he said, because the cells were not the patients’ own stem cells. “It would have been just as likely to expect that the patients would have rejected them,” he said.
The investigators also found indirect evidence that the stem cells had become oligodendrocytes and were producing myelin. “There is no non-invasive way to test this definitively,” cautioned Rowitch, “but our MRI findings suggest myelination in the regions that have been transplanted.”
Once transplanted and engrafted, neural stem cells have the potential to differentiate into a number of different brain cell types, depending on the area of the brain into which they are inserted. The sites chosen for the Phase I study were known from animal studies to be the most likely to result in the formation of oligodendrocytes.
In an animal study by another team of investigators, at Oregon Health & Science University's Papé Family Pediatric Research Institute, published in the same issue of Science Translational Medicine, Stem Cells Inc’s neural stem cells were injected into mouse models and became oligodendrocytes and formed myelin. “The animal study is consistent with the MRI findings from the clinical trial and further supports the possibility of donor-derived myelination in human patients,” said Rowitch.
“This is a landmark study for the field,” said Arnold R. Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. “Without such studies in human patients, we won’t really know how transplanted cells behave – whether they disperse or migrate, whether they engraft or degenerate and die, whether immune-suppressing regimens really work or not. It’s only through these investigations that we will be able to refine the necessary procedures and technologies and make progress toward cell-based therapies for this disease and related disorders.”
The Eli and Edythe Broad Center of Regeneration Medicine, one of the premier stem cell programs in the world, is focused on understanding the ways stem cells function, with the goal of developing therapies to treat a broad range of diseases, including cardiovascular disease, diabetes and neurological diseases.
Co-investigators of the clinical team are Jonathan Strober, MD, director of Clinical Services for Child Neurology and Director of the Muscular Dystrophy Clinic at UCSF Children's Hospital, and Nalin Gupta, MD, PhD, chief of Pediatric Neurological Surgery at UCSF Benioff Children's Hospital.
Other co-authors of the study are Roland G. Henry, PhD, Sang-Mo Kang, MD, Daniel Lim, MD, PhD, Monica Bucci, MD, Eduardo Caverzasi, MD, Laura Gaetano, PhD, Maria Luisa Mandelli, PhD, Tamara Ryan, RN, Rachel Perry, RN, Jody Farrell, RN, MSN, Rita J. Jeremy, PhD, Mary Ulman, RN and A. James Barkovitch, MD, of UCSF, and Stephen L. Huhn, MD, of StemCells, Inc.
The study was sponsored and supported by StemCells, Inc.
UCSF staff Tamara Ryan, Rachel Perry, Mary Ulman, and Drs. Barkovitch, Henry, Jeremy and Kang received partial salary support from the sponsor.

Top photo by Susan Merrell

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Thursday, October 18, 2012

Experience with the first 50 ex vivo lung perfusions in clinical transplantation

J Thorac Cardiovasc Surg 2012;144:1200-1207
© 2012 The American Association for Thoracic Surgery 

Cardiothoracic Transplantation

Experience with the first 50 ex vivo lung perfusions in clinical transplantation
Marcelo Cypel, MD, MScJonathan C. Yeung, MD, PhDTiago Machuca, MDManyin Chen, MDLianne G. Singer, MD,Kazuhiro Yasufuku, MD, PhDMarc de Perrot, MD, MScAndrew Pierre, MD, MScThomas K. Waddell, MD, PhD,Shaf Keshavjee, MD, MSc*
Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada

Read at the 92nd Annual Meeting of The American Association for Thoracic Surgery, San Francisco, California, April 28-May 2, 2012.

Received for publication April 25, 2012; revisions received July 8, 2012; accepted for publication August 1, 2012.
* Address for reprints: Shaf Keshavjee, MD, MSc, Toronto Lung Transplant Program, Toronto General Hospital, 200 Elizabeth St, 9N946, Toronto, ON, Canada. (

Objective: Normothermic ex vivo lung perfusion is a novel method to evaluate and improve the function of injured donor lungs. We reviewed our experience with 50 consecutive transplants after ex vivo lung perfusion.

Methods: A retrospective study using prospectively collected data was performed. High-risk brain death donor lungs (defined as PaO 2/FIO 2 <300 mm Hg or lungs with radiographic or clinical findings of pulmonary edema) and lungs from cardiac death donors were subjected to 4 to 6 hours of ex vivo lung perfusion. Lungs that achieved stable airway and vascular pressures and PaO 2/FIO 2 greater than 400 mm Hg during ex vivo lung perfusion were transplanted. The primary end point was the incidence of primary graft dysfunction grade 3 at 72 hours after transplantation. End points were compared with lung transplants not treated with ex vivo lung perfusion (controls).

Results: A total of 317 lung transplants were performed during the study period (39 months). Fifty-eight ex vivo lung perfusion procedures were performed, resulting in 50 transplants (86% use). Of these, 22 were from cardiac death donors and 28 were from brain death donors. The mean donor PaO 2/FIO 2 was 334 mm Hg in the ex vivo lung perfusion group and 452 mm Hg in the control group (P = .0001). The incidence of primary graft dysfunction grade 3 at 72 hours was 2% in the ex vivo lung perfusion group and 8.5% in the control group (P = .14). One patient (2%) in the ex vivo lung perfusion group and 7 patients (2.7%) in the control group required extracorporeal lung support for primary graft dysfunction (P = 1.00). The median time to extubation, intensive care unit stay, and hospital length of stay were 2, 4, and 20 days, respectively, in the ex vivo lung perfusion group and 2, 4, and 23 days, respectively, in the control group (P > .05). Thirty-day mortality (4% in the ex vivo lung perfusion group and 3.5% in the control group, P = 1.00) and 1-year survival (87% in the ex vivo lung perfusion group and 86% in the control group, P = 1.00) were similar in both groups.

Conclusions: Transplantation of high-risk donor lungs after 4 to 6 hours of ex vivo lung perfusion is safe, and outcomes are similar to those of conventional transplants. Ex vivo lung perfusion improved our center use of donor lungs, accounting for 20% of our current lung transplant activity.

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