Physician-defined patient complexity differs from current diagnosis-based measures

As Americans live longer with multiple medical conditions, managing their care is becoming increasingly challenging. Being able to define and measure patient complexity has important implications for how care is organized, how physicians and health care systems are paid, and how resources are allocated. In an article in the Dec. 20 Annals of Internal Medicine, a team of Massachusetts General Hospital (MGH) researchers report finding that primary care physicians define patient complexity using a broader range of factors — including mental health, social factors and financial issues — than do commonly used approaches based only on diagnoses and prior costs.

“Simply counting the number of co-morbid conditions does not really capture whether a patient is complex,” explains Richard W. Grant, MD, MPH, the paper’s lead author. “All primary care physicians can point to patients of theirs with very complicated medical histories who are relatively straightforward to manage, whereas other patients can be a real challenge despite relatively few medical diagnoses. Our results emphasize the importance of social and behavioral contexts that can create important barriers to delivering high-quality primary care.”

The study enrolled 40 primary care physicians from 12 MGH-affiliated practices and community health centers. Participating physicians used a web-based tool to review a list of 120 of their own patients and indicated those who, in their view, were complex. For those complex patients, they were asked to indicate which of five domains — medical decision-making, coordinating care, mental health or substance abuse problems, health-related behaviors, and social or economic circumstances — were involved in that determination.

The authors found that primary care physicians designated about one-quarter of their patients as complex — with older, more experienced physicians and those working in community health centers reporting higher proportions of complex patients. Compared to non-complex patients, complex patients were older, more often women, and had more clinic visits to many different providers. Complex patients were also prescribed more medicines — including prescriptions for anti-psychotic medicines — were more likely to miss appointments, and were more likely to live in neighborhoods with lower income and educational levels. The authors then found that the results of physician assessment differed substantially from those of other common methods for assessing complexity.

“Managing complex patients requires greater clinician effort, increased health care resources, and substantial family and community support,” says Grant, who recently joined the division of Research at Kaiser Permanente Northern California (http://www.dor.kaiser.org). “In order to redesign our health care systems to more effectively care for complex patients, we need a better handle on exactly who they are. By asking primary care physicians about their experiences with their own patients in a systematic and quantitative way, we were able to bring out the importance of social and behavioral factors, in addition to specific medical problems. This work may help guide efforts to redesign health care systems so that we can deliver high quality, cost-effective care tailored to individual patient needs.”

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On the Net:

• Massachusetts General Hospital
• Annals of Internal Medicine

Increased risk of inflammatory bowel disease in women with endometriosis: a nationwide Danish cohort study

Women with endometriosis are up to twice as likely to develop inflammatory bowel disease as those without this reproductive disorder, suggests a large study published online in Gut.

And the effect can last for up to 20 years after their diagnosis of endometriosis–a condition in which cells from the womb lining implant in other areas of the body.

Endometriosis is relatively common, and thought to affect as many as one in 10 women during their child bearing years.

The researchers tracked the long term health of more than 37,000 Danish women who had been admitted to hospital with endometriosis between 1977 and 2007.

During a monitoring period, which lasted an average of 13 years, 320 of these women developed inflammatory bowel disease–228 ulcerative colitis and 92 Crohn’s disease. These figures equate to an increased risk of developing inflammatory bowel disease of 50% compared with women in the general population.

When the analysis was restricted to women whose endometriosis was verified surgically, the risk increased further to 80%, and the effect persisted for more than 20 years after the initial diagnosis.

The average time lag between a diagnosis of endometriosis and the development of inflammatory bowel disease was around 10 years.

Both inflammatory bowel disease and endometriosis are chronic inflammatory disorders, which typically begin in young adulthood, affect the bowel, and cause abdominal pain.

The authors conclude that the explanation for the link between the two disorders may lie in common causes or the effects of treatment for endometriosis.

Some research suggests that long term use of oral contraceptives, which are frequently used to treat endometriosis, may increase the risk of developing inflammatory bowel disease.

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On the Net:

• BMJ-British Medical Journal
• Gut

The identification of genes that contribute to a susceptibility to complex neuropsychiatric disorders such as schizophrenia, major depression and bipolar disorders has been not very successful using conventional genetic approach. There are several problems associating with this conventional approach including carriers of genes cannot be identified in the absence of manifest symptoms and the heterogeneity of neuropsychiatric disorders. A new direction that appears encouraging is the identification of neurobiological or neurobehavioral characteristics associated with these complex neuropsychiatric disorders, or endophenotypes, that may be more closely linked to gene expression. Endophenotype is a biomarker associating with genetic components as well as the clinical symptoms of neuropsychiatric disorders. It plays an important role to bridge the gap between microscopic level and macroscopic level of neuropsychiatric disorders. The identification of endophenotype, along with the advanced genetic analysis such genomewise association studies, is very crucial to the identification of genes that predispose someone to neuropsychiatric disorders. Therefore, the study of endophenotype is of particular useful for us to understand the underlying mechanism of the illness process of neuropsychiatric disorders, aiding the clinicians to make accurate diagnosis and for early detection purposes.

With the supported from the National Basic Research Programme of China (973 Progamme) (2007CB512302), The Key Laboratory of Mental Health of the Institute of Psychology, Chinese Academy of Sciences has organized a strategic symposium for endophenotypes, titled “”Endophenotype strategy for psychotic disorders and summit meeting of Key Laboratory of Mental Health, Institute of Psychology, CAS”. International renowned scholars of this field presented their updated findings on endophenotypes. Professor Irving Gottesman, the founder of the endophenotype for neuropsychiatric disorders, was also giving a video lecture to all the participants. Their work was published in the special issue of Chinese Science Bulletin, 2011, Vol. 56(32).

Cognitive deficits have been widely recognized as core features of schizophrenia, and as major contributors to the clinical outcome of the disorder. They are also studied widely as ‘endophenotypes’, reflecting a growing consensus that schizophrenia is a broader, more multidimensional illness than the diagnostic criteria required for its formal diagnosis. Stone and Hsi adopted this evolving view of cognition underlying its utilization in recent initiatives for intervention and assessment in schizophrenia, and illustrated it with the use of the MATRICS Cognitive Consensus Battery, a standardized battery of neuropsychological tests developed to assess the effectiveness of cognitive enhancing treatments in schizophrenia. They then further provided evidence to show the utilization of neuropsychological deficits in the identification, validation and remediation of a liability syndrome for schizophrenia (‘schizotaxia’). Taken together, the inclusion of cognition in broader consortium and other collaborative efforts to assess interrelationships across multiple dimensions of function will provide important catalysts for progress in each individual dimension. Utilization of cognition underscores its functional importance in the clinical outcome of schizophrenia. Moreover, it helps to illuminate indicators of liability for schizophrenia that might be amenable to remediation.

On the other hand, Prof. Pak Sham and colleagues have addressed the statistical issues and approaches in endophenotype research. In this paper, they argued that in reality, a putative endophenotype is unlikely to be a perfect representation of the genetic component of disease liability. The magnitude of the correlation between a putative endophenotype and the genetic component of disease liability can be estimated by fitting multivariate genetic models to twin data. A number of statistical methods have been developed for incorporating endophenotypes in genetic linkage and association analyses with the aim of improving statistical power. The most recent of such methods can handle multiple endophenotypes simultaneously for the greatest increase in power. In addition to increasing statistical power, endophenotype research plays an important role in helping to understand the mechanisms which connect the associated genetic variants with disease occurrence. The causal pathways are likely to be very complicated and involve endophenotypes at multiple levels: from RNA expression profiles and patterns of protein expression, through neuronal and synaptic properties, to neurophysiological and neurocognitive function. Novel statistical approaches may be required for the analysis of the complex relationships between endophenotypes at different levels and how they converge to cause the occurrence of disease.

In the paper of Consortium for the Human Information and Neurocognitive Endophenotype (CHINE) in mainland China: An example from neurological soft signs for neuropsychiatric disorders, Chan made a strategic paper on endophenotypes and argued the need for establishing a central consortium for neuropsychiatric disorders in mainland China, namely the CHINE. The CHINE is intentionally established to pave the roadmap for neuropsychiatric disorders research. It not only identifies the biosignatures for neuropsychiatric disorders but also serves as the central databank for examining the etiologies of major complex neuropsychiatric disorders as well as serving as the main basis for corresponding treatment development. The CHINE emphasizes on two main features, i.e., the supposedly universal basic cognitive functioning such as attention, and the supposedly culturally specific social cognitive functioning such as emotion perception and expression. In this consortium, data collected highlights the genetic level (susceptibility genes associating with major neuropsychiatric disorders, neuroanatomical level (structural and functional imaging data), and behavioral level (neurocognitive function performances, social cognitive functioning, neurological and clinical manifestations). Target groups include both the clinically diagnosed patients suffering from neuropsychiatric disorders (mainly schizophrenia and bipolar disorders at the current moment, but will be extended to other clinical groups later), non-psychotic first-degree relatives of the patients, and healthy controls. Chan specifically illustrated an example of a promising endophenotype for schizophrenia, namely neurological soft signs, in detailing the steps for building the consortium. It is also noteworthy that the potential translational usage of neurological soft signs as a quick, quantifiable, sensitive and user-friendly bedside early detection and screening tool for clinical practice.

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On the Net:

• Science in China Press
• Chinese Science Bulletin

A series of unfortunate events? Morbidity and mortality in a Borsetshire village

With a risk of traumatic death far higher than the national average, rural life may not be so idyllic in Ambridge, the fictitious village in the BBC radio series, The Archers, finds research in the Christmas issue published on bmj.com today.

However, the study also shows that the overall mortality rate in Ambridge is slightly lower than the country as a whole, so characters should not worry unduly. Those who do not perish in a hideous accident have a good chance of living for a long time.

The author, Rob Stepney, wanted to investigate whether The Archers was any more true to life (and death) than TV soap operas. Established research has concluded that characters in Coronation Street and EastEnders have a higher risk of death than bomb disposal experts and racing drivers.

Could life on a radio soap opera be safer wondered Stepney? He reviewed deaths, childbirth and episodes of serious illness over a 20 year period in the series (1991 to September 2011).

Of the 15 deaths recorded in Ambridge over the 20 years, nine were of male characters and six of female characters. This equates to a mortality rate of 7.8 per 1,000 population per year for men compared with 8.5 per 1,000 in England and Wales mid-way through the study period. For women in Ambridge, the mortality rate was 5.2 deaths per 1,000 compared with 5.8 per 1,000 nationally.

However the chance of accidental death or suicide in Ambridge is worryingly high. During the study period there was a road traffic accident, a death when a tractor overturned, Nigel Pargetter fell from a roof, and there was a suicide from a self-inflicted gunshot wound.

These figures translate into 27% of the total mortality in Ambridge. But in real life, in the year 2000, accidents accounted for only 4% of deaths in men.

To compensate for the 15 deaths in the past 20 years, 13 children have been born to the 115 characters. The annual live birth rate in Ambridge in 1992-2011 was 5.6 per 1,000 compared with 11.4 per 1,000 in England and Wales.

Access to healthcare appears to be good in Ambridge, however. One character, Elizabeth Archer, who was born with a heart defect, recently had a life-saving implant operation. She was lucky as nationally fewer than 100 such implants were carried out in 2009.

In conclusion, Stepney says that, if characters in The Archers steer clear of accidents, Ambridge appears to be a safe place to live.

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On the Net:

• BMJ-British Medical Journal

Study to see if walking and/or memory training may prevent memory problems in people with Parkinson’s disease

Researchers from the University of Maryland School of Medicine and the Baltimore VA Medical Center have launched a study of exercise and computerized memory training to see if those activities may help people with Parkinson’s disease prevent memory changes. The type of memory that will be examined is known as “executive function;” it allows people to take in information and use it in a new way. Many Parkinson’s patients develop problems with executive function, which can prevent them from working and may eventually require a caregiver to take over more of the complex cognitive tasks of daily living.

“Studies of normal aging show that memory and executive function can be improved with exercise, such as walking several days a week,” explains Karen Anderson, M.D., principal investigator and an assistant professor of neurology and psychiatry at the University of Maryland School of Medicine. Dr. Anderson is also a neuro-psychiatrist at the Maryland Parkinson’s Disease and Movement Disorders Center at the University of Maryland Medical Center and a clinician in mental health at the Baltimore VA Medical Center.

She adds, “We want to see if exercise can slow or reverse some of these memory changes in Parkinson’s patients. We will also investigate whether a computer game designed to improve executive function may make a difference as well. The other question is, what happens when you put the two interventions together — if there is memory improvement, will it be even better than with one of the interventions? Or is it more efficient to do just one or the other? We really do not know.”

The researchers, who received funding through a VA Merit Award, plan to enroll about 90 patients who will be divided randomly into three groups: exercisers walking on a treadmill, memory game players and those doing both exercise and memory games. Participants in each group will receive a memory assessment at the beginning of the study. They will come in three times a week for their training for three months and will be then be tested again. Three months after that, the researchers will test the participants again to see if there may be longer term benefits to the training.

With both the treadmill walking and the memory game, the exercise or video game will become more challenging as the participant improves. The memory training works like a video game with players advancing to a higher level of difficulty. For the exercisers, trainers may increase the speed or slope of the treadmill to make it more aerobically challenging.

“This new study builds on our experience from a previous study of exercise for gait and mobility in Parkinson’s disease. Since both motor function and cognitive function are important for mobility and performance of daily activities, this new study will investigate the individual and combined effects of treadmill training and cognitive training,” explains Lisa Shulman, M.D., co-investigator and professor of neurology at the University of Maryland School of Medicine.

“Parkinson’s patients are eager to know if there is anything they can do to give them greater control over their condition. Mobility and memory are the two key components to preserve independence. If these treatment strategies are found to be effective, we will learn important new approaches to delaying disability,” says Dr. Shulman who is co-director of the Maryland Parkinson’s Disease and Movement Disorders Center.

The treadmill training will take place at the Baltimore VA Medical Center in the Maryland Exercise and Robotics Center of Excellence, a gym facility with specialized equipment for people with physical limitations or balance issues. For safety, participants will wear a safety harness while walking on the treadmill. Experienced exercise physiologists will supervise each training session.

The computerized memory training game will take place both at the VA and University of Maryland School of Medicine.

“This study shows the commitment of our University of Maryland faculty to exploring new approaches, such as exercise and memory training, to help patients with illnesses such as Parkinson’s disease around the world,” says E. Albert Reece, M.D., Ph.D., M.B.A, vice president for medical affairs, University of Maryland, and dean, University of Maryland School of Medicine.

The Maryland researchers expanded the exercise studies to Parkinson’s patients after first finding success with treadmill training for stroke patients. This research, also conducted at the University of Maryland School of Medicine and the VA Maryland Health Care System, found that regular exercise on a treadmill can improve stroke patients’ walking ability even years after they’ve had a stroke.

Co-investigator Richard Macko, M.D., says, “With stroke patients, we have seen that the consistent, repetitive motion of walking may help the brain to develop new connections to compensate for the damaged ones. This new Parkinson’s study takes the concept of exercise training for neurology patients in a new direction. We will be interested to see if this consistent training will produce benefits to memory.” Dr. Macko is director of the Maryland Exercise and Robotics Center of Excellence at the VA Maryland Health Care System and professor of neurology at the University of Maryland School of Medicine.

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On the Net:

• University of Maryland Medical Center

Young infants and toddlers with sickle cell anemia who received the drug hydroxyurea were no more likely to have cellular genetic damage than those who received a placebo or inactive medicine, said researchers from Baylor College of Medicine in Houston and St. Jude Children’s Research Hospital in Memphis, Tenn., yesterday at the American Society of Hematology’s annual meeting in San Diego, Calif.

These findings provide further evidence of the safety of hydroxyurea for children with sickle cell anemia, said the study’s lead author Dr. Patrick T. McGann, a clinical fellow of pediatric hematology and oncology at BCM and the Texas Children’s Hematology Center. There is some concern that hydroxyurea therapy would lead to genetic damage at the cellular level and could increase the risk of developing cancer.

Inherited blood disorder

Sickle cell anemia is an inherited blood disorder caused by a gene mutation in the beta-globin gene. The red blood cells of individuals affected with the disorder are shaped like a sickle or crescent, unlike normal red blood cells that are disc—shaped. Normal, healthy red blood cells move through blood vessels easily, carrying hemoglobin, the critical protein necessary for the delivery of oxygen, throughout the body. The stiff, sickle-shaped red blood cells do not flow as easily and often get stuck in small blood vessels, decreasing oxygen delivery to legs, arms and other organs and resulting in severe pain, increased risk of infection and chronic organ damage.

Hydroxyurea was approved by the U.S. Food and Drug Administration as a treatment for adults with sickle cell disease in 1998, but it has not yet been approved for use in children. Hydroxyurea reduces the amount of sickle hemoglobin by stimulating the production of fetal hemoglobin, which results in healthier red blood cells and a reduction in the frequency and severity of the complications associated with the disorder.

“It is important to demonstrate the low genotoxic risks associated with hydroxyurea for children with sickle cell anemia given that hydroxyurea was historically used as a chemotherapeutic treatment for cancer,” said McGann, working under the mentorship of Dr. Russell E. Ware, professor of pediatrics at BCM and director of the Texas Children’s Center for Global Health and of the Texas Children’s Hematology Center.

The research team used data collected from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a multi-center study whose primary goal was to investigate the ability of hydroxyurea to prevent chronic organ damage in very young patients with sickle cell anemia.

A total of 193 infants (average 13.6 months) were assigned at random to receive hydroxyurea or placebo for two years. After studying the effect of the drug, the researchers found no evidence of increased genetic damage in the children who received hydroxyurea than in those who received placebo.

Effective treatment

“We found that young children treated with hydroxyurea for two years did not demonstrate evidence of increased DNA damage when compared to children receiving placebo” said McGann. “These data represent another important piece of evidence that this very effective treatment is safe for young children.”

Other investigators at BCM who contributed to this study include Ware, Dr. Jonathan Flanagan, assistant professor of pediatrics at BCM and Thad Howard.

Other investigators include Dr. Stephen Dertinger of Litron Laboratories in Rochester, New York; Dr. Jin He of St. Jude Children’s Research Hospital in Memphis, Tenn.; Dr. Anita Kulharya of the Georgia Health Sciences University in Augusta and Dr. Bruce Thompson of Clinical Trials and Surveys Corp. in Owings Mills, M.D.

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On the Net:

• BCM

Three experts discuss the rising influence of neuroscience in the courtroom, how advances in neuroscience are posing new challenges for the judicial system, and the use of therapeutic solutions for reforming criminals.

Increasingly what we know about the brain is affecting what happens during and after criminal trials. Recently, for instance, the U.S. Supreme Court decided that adolescents could not be eligible for the death penalty partially based on neuroscience evidence that indicated the teen brain is not fully mature. Defense attorneys have also used brain scans to suggest their clients’ actions were influenced by brain damage or abnormalities, as part of an argument for modified sentences. And the recent view of drug addiction as a brain disorder has raised questions about how drug addicts should be held accountable for their criminal behavior.

The rising influence of neuroscience in the courtroom was the focus of the Fred Kavli Public Symposium, held in November at the Society for Neuroscience’s “Neuroscience 2011.” Titled “The Brain on Trial: Neuroscience and the Law,” the symposium was chaired by Alan Leshner, Chief Executive Officer of the American Association for the Advancement of Science and former head of the National Institute of Drug Abuse. One of the key issues this symposium explored was how advances in neuroscience are posing serious challenges for the judicial system, as well as possible solutions for the treatment of criminals.

The Kavli Foundation held a teleconference to discuss this topic. Along with Dr. Leshner, the participants included cognitive neuroscientist and neuroethics expert Martha Farah, director of the Center for Neuroscience and Society, University of Pennsylvania. Also joining the dialogue was neuropsychiatrist Jay Giedd, MD, an expert in adolescent brain development at the National Institute of Mental Health and chief of NIMH’s Unit on Brain Imaging in the Child Psychiatry Branch.

Together, they discussed what role neuroscience should have in determining legal policies and judgments, innovative brain-based treatments for certain pathological behavior, and how we are easily fooled by colorful brain scans. They also shared opinions on whether “painting a picture of the neural processes that give rise to criminal behavior” as Dr. Farah put it, can excuse that behavior or mandate lighter sentencing. Below is the edited transcript of that discussion.

THE KAVLI FOUNDATION: Dr. Leshner, to begin, in the context of neuroscience and the law, what does your field reveal about personal responsibility that you feel is not well understood?

ALAN LESHNER: There´s been a lot of controversy around the increased understanding that addiction is a brain disease and the implications of that for personal responsibility or law. The fact that you have a brain disease means that biologically, change in your brain has led to compulsive repeated drug use. But it doesn´t mean that you have no responsibility for any of your behavior. Are you less responsible? In a way you are, and that should be taken into account in sentencing; but more to the point, it means we should require treatment while we have drug addicts under criminal justice control because that would decrease significantly the probability they would commit crimes again. Although people may not want treatment initially, they become more involved in it as they are required to participate in drug treatment programs and the treatment is ultimately effective. So I believe drug addicts should be required to go into treatment if they commit an act against society. More criminal justice institutions are implementing treatment while people are under criminal justice control.

TKF: Dr. Giedd, as an expert in adolescent brain development, what is the proper use of your insights into the brain for determining in a courtroom whether a person is responsible for his or her actions?

JAY GIEDD: What the neuroscientist is often asked is, “Was it the person, or was it his or her brain, that made them commit a crime?” To me this is a false dichotomy because the person and the brain are inseparable–everything we think, feel or do, all of our motivations, urges, and our ability to act or not act upon those urges is ultimately a product of our brain activity. This means that, even if we can trace the person´s actions back to the brain, for the most part that doesn´t change the personal responsibility for the crime, which is more of a social, moral, or philosophical issue. There are some rare but remarkable exceptions where someone might have brain damage or a brain tumor that dramatically affects their capacity to make decisions. But most often, it´s not a matter of the brain being qualitatively different from that of other people, and more of the brain reflecting a lifelong accumulation of experiences in which genes interact with the environment in very complex ways. In general, people overvalue the ability of brain imaging or neuroscience to cut through that complexity.

TKF: What about the sentencing of a convicted criminal. Does neuroscience have a role in determining or tempering the legal consequences of a crime, particularly among teenagers?

JAY GIEDD: There currently is debate about whether adolescent brain maturity should be considered in sentencing for a crime or help determine what would be the proper deterrent for future adverse behavior. On average, the 15-year-old brain is different than the 25-year-old brain. What´s difficult is applying this to individuals, as there are so many exceptions to the rule — there are many mature teens, and likewise immature people in their twenties and thirties. So the real challenge is going from group averages to individual prediction or characterization. One pretty strong group phenomenon is that teenagers don´t really think about the future the same way that older people do, so long-term consequences are less of a deterrent to their behavior. Teens are less likely to weigh long-term consequences over the immediate consequences. The other strong adolescent phenomenon is heightened sensitivity to peer pressure. The judicial system could focus on both of these adolescent phenomena when determining deterrents and interventions for adolescent criminal behavior.

TKF: Dr. Farah, what are your thoughts on this topic?

MARTHA FARAH: I agree with Jay and Alan. The mere fact that brain processes give rise to the behavior isn´t enough to excuse it. The fact that your behavior had causes doesn´t diminish your responsibility for it in the eyes of the law. But the law does recognize some psychological conditions that diminish responsibility, and if neuroscience knows something about the neural processes underlying these conditions, it can aid in their diagnoses. If the kind of neuroimaging research that Jay does continues for a few more decades, we may well get to the point where we can point to a brain signature in the brain scans of people who have not yet developed an ability to think about the future. Then it would be really reasonable for an attorney to bring in that kind of a brain scan and say, “This young person was developmentally incapable of thinking about the consequences of what he just did.” That would be a case of neuroscience appropriately helping to excuse someone, but it wouldn´t be doing it just by showing there´s a brain basis to the behavior. It would be doing it by showing that a certain psychological ability wasn´t there.

TKF: So is it ever a valid defense to simply say, “My brain made me do it”?

JAY GIEDD: The Charles Whitman case of 1966 comes to mind–he was the Texas tower shooter who killed 16 people and wounded 32 others. Brain scans revealed he had a brain tumor, which may have led to these aggressive, uncontrolled actions. Those cases are so rare, in which there is blatant damage to the brain that is obviously linked to the behavior that occurred, but it certainly can happen. What´s more difficult to discern are the much more subtle brain differences that may not necessarily be linked to the behavior. In these cases, the colorful brain scans introduced in courts can be almost irrationally persuasive. One study showed that if you put in an image into a scientific paper that had nothing to do with the content, other scientists will rate the paper as being more logical and better written, as being more persuasive.

TKF: A picture says a thousand words.

JAY GIEDD: Yes, but not necessarily true words. It´s very seductive to have an aesthetically beautiful brain scan that brings a sense of certainty to something that really isn´t certain. Human behavior is much more nuanced and complex than what some of these images are showing. There are several reasons why brain scans are often misinterpreted and can´t be counted on. One is that you´d really have to be scanning the person at the time of the crime to accurately capture what their brain was like then, because brain states change second-by-second. Another reason is that there´s always the danger of making reverse inferences. An example of a reverse inference is “All dogs have four legs, a chair has four legs, therefore a chair is a dog.” People will look at a brain scan and say “Aha, there´s a bright color indicating heightened activity in this area of the brain that is involved in impulsivity,” even though there are thousands of other activities besides impulsivity that would also cause that same bright color in that spot of the brain. People notoriously overestimate our ability to go from the pictures, aesthetically pleasing as they are, to predicting behavior, to being useful.

TKF: What has been your experience in how neuroimaging plays out in the courtroom?

JAY GIEDD: In the court situations I´ve been involved in, attorneys present me with case histories of incredibly impulsive behavior–of young children hopping into police cars and driving them off without thinking about the consequences, and ask me to do brain scans to see if these kids are impulsive, but that´s a backwards way to approach this. Everything they´ve just said clearly demonstrates that indeed these kids are very impulsive, and if their brain scans show heightened activity in an area that´s involved in impulsivity, okay, but if they didn´t show that, I just wouldn´t believe the images. We can use imaging to tell if someone can do long division just by showing them a problem while they´re in the scanner for about $600, or we can get the same information for three cents just by pulling out a pencil and paper and asking them what´s the answer to a long division problem. It´s a fundamental misconception that the imaging can confirm certain behavioral realities.

TKF: It seems like you are being asked to make a distinction between normal and abnormal behavior based on neuroimaging or other neuroscience evidence. The determination that drug addiction is a disease also suggests we have clear diagnostic endpoints that really distinguish normal from abnormal behavior. But is the evidence ever clear cut in certain cases? Is it really obvious when someone is drug addicted?

ALAN LESHNER: It´s easily determined whether someone is addicted with current diagnostic tools, such as the addiction severity index. But all this knowledge of brain involvement in addiction helps you put the issue in the right box. Traditionally we have thought of addiction only as a criminal justice issue and therefore everything we did related to it had to do with a criminal justice approach. But once you understand that it´s a brain disease and therefore a health issue, you realize the only effective policies in modern society are those that recognize both the health aspect of drug addiction–that drug addicts commit crimes like burglary in order to secure drugs–and that society feels they ought be held responsible for those crimes. The issue for me is not so much what´s the appropriate punitive approach, but what will work best for society. If you don´t deal with the illness or the brain part of drug addiction, you have much less chance of actually reducing the behavior you don´t like, whether it´s drug using or committing crimes. By combining the health approach to the criminal justice approach, I think you have a better chance of having effective and acceptable public policy.

TKF: Do prosecutors ever argue that a brain scan proves a person is hopelessly addicted or has some other problem that suggests they shouldn´t be allowed to join society?

ALAN LESHNER: It does happen, but when that happens it´s a misrepresentation. In fact, we have quite effective treatments for drug addiction that are equally effective as those for other chronic relapsing disorders. It´s not the same as taking penicillin for your strep throat, but there are very effective treatments that can help bring the addiction under control.

MARTHA FARAH: Where the strategy of presenting brain scans as evidence in a trial can backfire is for psychopaths. Psychopaths are likely to commit crimes and, unlike drug addicts, there are no effective treatments for them. So the defense could show a brain scan of a psychopath and say, “Look; this guy´s brain doesn´t work like a normal person´s brain–he´s wired up wrong and couldn´t have shown empathy and moral judgment,” with the aim of getting a lighter sentence. But the judge or jury can hear this and decide it makes him more dangerous and incorrigible so they had better lock him up and throw away the key.

TKF: What role do you think science should have in helping society or the courtroom determine when and how much someone should be held responsible for his or her actions?

ALAN LESHNER: Policy, including criminal justice policy, is always made on the basis of both scientific facts and societal values and we´re never in a situation where you can expect that science will drive the development of policy all by itself. Having said that, I would want to be assured that the science has been fully considered, and that we´re not denying it by diluting or distorting it in the process of making public policy, including criminal justice policy.

TKF: You´re saying that science can provide the facts, but society still has to put a value judgment on top of it?

ALAN LESHNER: Absolutely. It doesn´t have to, it will. You need to recognize that that´s a part of the way the world works.

JAY GIEDD: There are several ways neuroscience can help shape judicial or other social policies, including influencing determinations of appropriate punishments for adolescent crimes or legal age minimums for certain behaviors or political offices. One of the things in the neuroscience of adolescence that is getting more accepted is the importance of learning by example, by modeling. The brain is well suited to learn by example, modeling, and from experience. So incarcerating people in the second decade of their lives will mean their learning will come from other criminals and the judicial system. We have to be aware of the lifelong consequences of having people locked up at this time of life when their brains are specializing based on their experience. The danger is we might have them specialize in being criminals. Also, around the world people are struggling with what should be the appropriate age minimums for voting, driving, becoming a Congressman or president, or having other privileges in society. I think the neuroscience could help with those kinds of policy decisions or laws. Neuroscience findings on adolescents, for example, led to many states adopting graduated driving licenses, which have saved a lot of lives. So neuroscience can be helpful in creating policies related to keeping teens safe and healthy, more so than determining punishment and retribution after they´ve done crimes. Neuroscience may have a place at the table for helping us understand these ideas of competency in major life decisions.

TKF: It sounds like you´re more comfortable making scientific judgments about adolescents as a group as opposed to determining from an individual adolescent´s brain scan whether he or she is prone to abnormal behavior.

JAY GIEDD: Exactly, and that´s really been our greatest challenge, not just for the judicial system, but clinically as well. We can say the average schizophrenic brain is different than that of the average person without schizophrenia, but we can´t put an individual in a scan and tell if they have schizophrenia, or depression, ADHD, autism, etc. There´s a lot of group effort trying to improve our ability to go from the group average to the individual level. The amount of progress we make on that will affect how much neuroimaging findings should influence judicial proceedings.

MARTHA FARAH: Some of the most interesting implications of the neuroscience findings are for how criminals should be punished, as opposed to the question of how responsible they should be for their behavior. We punish for a variety of reasons: for retribution, to incentivize good behavior, and in some cases, to improve the offender. This last one is sometimes called “therapeutic justice”–we send someone to anger management therapy or parenting classes. A lot of good could come from getting society more strongly behind the idea of therapeutic justice. If people´s brains are causing them to do bad things and if we can fix their brains or foster healthier development of their brains, we´ll all be safer. The individual offender is better off and society is better off. So, by putting crime within that public health framework, it makes the idea of therapeutic justice more appealing. As clinical neuroscience advances, it´s actually going to give us ways of accomplishing therapeutic justice.

TKF: So along with being punished, someone´s sentence might include drug therapy to alter how they think and behave?

MARTHA FARAH: The therapy could actually be the sole punishment, or be part of someone´s sentence. We already sentence sex offenders to anti-androgen therapy–chemical castration. And that treatment works on the brain in addition to other parts of the body. It is a central nervous system intervention that´s supposed to help curb their antisocial urges and keep people safer. We may have more such therapies available as neuroscience goes forward.

TKF: So in the future, people might be incarcerated less and instead treated for behavioral offenses.

MARTHA FARAH: Yes, although it does raise the specter of Brave New World and state control of brain processes. The science can tell us what we can do, but society´s values will tell us whether we should do it.

ALAN LESHNER: I agree. And I do believe that people should be required to go into treatment, whether they want it or not, if they are addicted and commit an act against society. You´re not totally controlling the individual with that treatment–it´s not like they are turned into zombies. They go through treatment programs that don´t do away with their free will. It´s important to have a perspective on the degree of mind control that´s being exerted here–it´s not very great. So to second what Martha said, both from a societal standpoint and an individual standpoint, they´re better off getting that treatment.

TKF: What would a therapeutic punishment be for an adolescent whose brain is just not mature enough? There´s no treatment that can speed up that maturity.

JAY GIEDD: The adolescent brain is very plastic and there are things you can do to improve it, from modeling more healthy behaviors to working on impulse control. Brain-based interventions do not have to be deterministic. It´s not like one morning you wake up and your brain´s mature–it´s a very protracted process. But a lot can be done to help adolescents make better choices and have different peer systems. I completely agree with Martha and Alan that it could be a very good thing for that adolescent if they are mandated to get these services that they might not otherwise get because of finances or peer pressures. If we really want to make society safer and better, it would be a very good investment. You can´t move the clock to fast forward, in terms of brain development. But just because someone is an adolescent doesn´t mean you can´t improve their decision-making.

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On the Net:

• The Kavli Foundation

Research assessing the safety and efficacy of hydroxyurea therapy in pediatric patients with sickle cell disease (SCD) and the use of pre-operative transfusions for patients with SCD who undergo low- and moderate-risk elective surgery will be presented today at the 53rd Annual Meeting of the American Society of Hematology.

An estimated 90,000 to 100,000 Americans are affected each year by SCD, a serious disorder that causes normal red blood cells to become rigid and form in a crescent “sickle” shape. The abnormal shape of these cells causes them to clump together and become embedded in the blood vessels of organs, causing pain, infection, potential organ damage, and stroke. Even with advancements in drug therapies and prevention methods, safe and effective treatment options remain limited, especially for children and patients facing surgery who have an increased risk for complications.

“The studies presented today underscore the need to assess the quality and effectiveness of therapy for sickle cell disease, particularly in the pediatric population, and investigate the strategic use of pre-operative transfusion for sickle cell patients,” said Susan B. Shurin, MD, moderator of the press conference and Acting Director of the National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Md.

Dr. Shurin, who has been instrumental in the U.S. Department of Health and Human Services´ (HHS) recent initiative to promote research advances in SCD, stated, “I am hopeful that discoveries like these, combined with continuing efforts to develop new treatments, share public health data, and provide evidence-based guidelines, will soon lead to significant improvement in the lives of patients with SCD.”

This press conference will take place on Sunday, December 11, at 10:00 a.m. PST.

Hydroxyurea Treatment of Young Children with Sickle Cell Anemia: Safety and Efficacy of Continued Treatment — the BABY HUG Follow-up Study [Abstract 7]

Hydroxyurea is the only federally approved therapy to prevent sickle cell complications in adults with sickle cell anemia (SCA). However, based on positive results from previous trials assessing clinical benefits for use in children, specialists are increasingly considering the use of hydroxyurea in their pediatric patients. Results from the BABY HUG Follow-up Study I suggest that continued use of hydroxyurea is both safe and effective in infants with SCA.

The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) was a multicenter, randomized clinical trial that assessed the clinical benefits of hydroxyurea in very young patients with SCA. Results from the study demonstrated that hydroxyurea administered to infants with SCA provided substantial clinical benefit over placebo.

Researchers launched the BABY HUG Follow-Up Study I in 2008 to assess the safety and efficacy of continued treatment with hydroxyurea in infants with SCA. The Follow-Up Study I included 163 children between the ages of 28 and 44 months who had participated in the BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. Investigators collected clinical and laboratory data every six months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

At Follow-Up Study entry, families enrolling their children did not know their child´s randomized study treatment assignment in BABY HUG; 82 percent initially chose clinical prescription of open-label hydroxyurea, demonstrating a high acceptance rate for the drug. Through the 36 months of follow-up, acceptance remained high, with 68 to 75 percent of the participating families reporting that their children continued to take hydroxyurea.

Follow-Up Study I data indicate that children who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency room visits, episodic transfusions, and hospital admissions for any reason when compared to those taking placebo. These clinical benefits are similar to those demonstrated by the drug in BABY HUG, the results of which were published earlier this year and are consistent with previously published trials that detail the therapy´s benefits in older children and adults.

“Our study data reveal not only that the clinical benefits of hydroxyurea continue with ongoing administration, but also the wide acceptance of the treatment by the families of our patients, demonstrated by the high percentage of families that continued their children on hydroxyurea after the randomized trial ended,” said lead author Zora R. Rogers, MD, Professor of Pediatrics at UT Southwestern Medical Center Dallas and Clinical Director of the Bone Marrow Failure and General Hematology Program at Children´s Medical Center Dallas. “Analysis of growth and development assessments obtained in the Follow-Up Study along with these clinical results will further enhance our understanding of the benefits of the use of starting hydroxyurea in children with sickle cell disease at a very young age.”

The BABY HUG Follow-Up Study I is funded by the National Heart, Lung, and Blood Institute (NHLBI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Dr. Rogers will present this study in an oral presentation on Sunday, December 11, at 4:30 p.m. PST at the Manchester Grand Hyatt in the Elizabeth Ballroom AB.

Genotoxicity Associated with Hydroxyurea Exposure in Infants with Sickle Cell Anemia: Results From the BABY-HUG Phase III Clinical Trial [Abstract 8]

Using data from the largest clinical trial to date to assess the use of hydroxyurea in pediatric patients with sickle cell anemia (SCA), researchers have provided further evidence that the therapy likely does not cause long-term genetic damage (known as genotoxicity) in young patients with SCA.

To assess whether hydroxyurea potentially causes genotoxic effects in infants with SCA, researchers analyzed patient data from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). This multicenter, randomized clinical trial assessed the clinical benefits of hydroxyurea in infants with SCA.

In this study, 193 infants between the ages of nine and 18 months were randomized to receive either hydroxyurea or placebo over the course of two years. An important secondary objective of the study was the in vivo measurement of acquired genotoxic effects of hydroxyurea, which was obtained by tracking the frequency of several laboratory-based measures of DNA damage. These markers include breaks in chromosomes or chromatids (DNA double-strands), abnormal recombination of DNA in cells of the immune system, and the formation of micronucleated reticulocytes (abnormal young red blood cells).

At the conclusion of the study, children receiving hydroxyurea did not show any significant differences in the numbers of any of the damage markers when compared with children on placebo. These data suggest that conventional doses of hydroxyurea do not appear to cause DNA damage as suggested by laboratory-based experiments that have used higher concentrations of the drug, providing reassurance that hydroxyurea presents low genotoxic risk to children.

“Although the clinical benefits of hydroxyurea for children with sickle cell disease are well recognized, treatment in young patients is limited due to concerns about potential long-term genotoxic effects,” said lead author Patrick T. McGann, MD, Fellow in the Department of Pediatrics in the Hematology-Oncology Section at Baylor College of Medicine in Houston. “Results from this study contribute to a growing body of evidence suggesting that in vivo genotoxicity of hydroxyurea in sickle cell anemia appears to be low. Taken together with the clinical benefits demonstrated in the BABY HUG study, hydroxyurea may be considered as a potential therapeutic option for even very young, asymptomatic children with sickle cell anemia.”

Dr. McGann will present this study in an oral presentation on Sunday, December 11, at 4:45 p.m. PST at the Manchester Grand Hyatt in the Elizabeth Ballroom AB.

Pre-Operative Transfusion Reduces Serious Adverse Events in Patients with Sickle Cell Disease (SCD): Results From the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) Randomised Controlled Multicentre Clinical Trial [Abstract 9]

New research suggests that patients with sickle cell disease (SCD) who are undergoing surgeries, such as abdominal surgery or tonsillectomy, should receive pre-operative transfusions to reduce their risk of post-operative complications.

Pre-operative blood transfusions have been used to reduce complications after surgery for SCD patients, who are at higher risk for these complications than the general population. However, some experts have claimed that the procedure is not necessary and can be safely omitted prior to surgery.

To assess the clinical benefit of pre-operative transfusion to alleviate perioperative complications in patients with SCD undergoing low- or medium-risk surgery, researchers embarked on the multicenter, randomized controlled Transfusion Alternatives Pre-Operatively in Sickle Cell Disease (TAPS) Trial. The trial was carried out between November 2007 and March 2011 at 22 clinical sites in the United Kingdom, the Netherlands, and Canada.

Patients with HbSS and HbSbo thalassemia, the most severe forms of SCD, were randomized to two treatment arms: patients in Arm A received a pre-operative blood transfusion, while patients in Arm B did not. The primary outcome of the TAPS trial was the proportion of patients experiencing any significant complication between time of randomization into the study and 30 days post-surgery.

Of the 343 patients screened for the trial, 70 were randomized into treatment arms at time of study termination. The trial was closed early because of an excess of serious adverse events (SAEs), which were a subset of complication reports, in the untransfused arm (Arm A). Thirty-three patients in Arm A and 34 patients in Arm B were included in the final analysis. Researchers found that 39 percent of patients who did not receive pre-operative transfusions experienced a perioperative complication, compared to 15 percent of patients in the transfusion arm. There was also a difference in the rate of SAEs between the two arms; 30 percent of patients who did not receive a transfusion experienced an SAE, compared to only 3 percent of patients who received one prior to surgery. The majority of SAEs reported were acute chest syndrome, a life threatening complication of SCD.

“Currently, many patients with SCD are not receiving pre-operative transfusions, which may be putting them at risk of serious complications. The results from our trial demonstrate a striking increase in the total number of complications, both common and life-threatening, in patients who did not receive a blood transfusion before surgery,” said lead author Jo Howard, MD, Consultant Hematologist at Guy´s and St. Thomas Hospital in London. “Moving forward, we recommend that clinicans take these results into consideration when deciding on pre-operative transfusion and suggest that patients with HbSS and HbSbo thalassaemia receive a blood transfusion before surgery.”

The TAPS trial and was sponsored and funded by NHS Blood and Transplant in the United Kingdom.

Dr. Howard will present this study in an oral presentation on Sunday, December 11, at 5:00 p.m. PST at the Manchester Grand Hyatt in the Elizabeth Ballroom AB.

1Sickle Cell Disease: Data & Statistics. http://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed October 18, 2011

American Society of Hematology 53rd Annual Meeting

The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on new treatment techniques for patients with bleeding and clotting disorders, targeted therapies for acute and chronic leukemia, improving recovery and outcomes in transplantation, and emerging treatments for lymphoma and myeloma. For the complete annual meeting program and abstracts, visit www.hematology.org/2011abstracts. Get up-to-date information about the annual meeting by following ASH on Twitter @ASH_hematology.

The American Society of Hematology is the world´s largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems by promoting research, clinical care, education, training, and advocacy in hematology. The official journal of ASH is Blood, the most cited peer-reviewed publication in the field, which is available weekly in print and online.

[7] Hydroxyurea Treatment of Young Children with Sickle Cell Anemia: Safety and Efficacy of Continued Treatment — the BABY HUG Follow-up Study

Zora R. Rogers, MD1, Billie Fish, CCRP2*, Zhaoyu Luo, PhD2*, Rathi V. Iyer, MD3, Courtney D. Thornburg, MD, MS4, Sharada A. Sarnaik, MD5, Sohail R. Rana, MD6*, Lori Luchtman-Jones, MD7, Sherron M. Jackson, MD8*, Thomas H. Howard, MD9, James F. Casella, MD10, R. Clark Brown, MD, PhD11, Ofelia A. Alvarez, MD12, Jonathan C. Goldsmith, MD13, Scott T. Miller, MD14 and Winfred C. Wang, MD15

1Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
2Clinical Trials & Surveys Corporation , Owings Mills, MD
3University if Mississippi, Jackson, MS
4Duke University Medical Center, Durham, NC
5Children’s Hosp. of Michigan, Detroit, MI
6Howard University, Washington, DC
7Children’s National Medical Center, Washington, DC
8Medical University of South Carolina, Charleston, SC
9University of Alabama at Birmingham, Birmingham, AL
10The Johns Hopkins University School of Medicine, Baltimore, MD
11Emory University / Children’s Healthcare of Atlanta, Atlanta, GA
12Univ. of Miami School of Med., Miami, FL
13National Heart Lung and Blood Institute, NIH, Bethesda, MD
14SUNY – Brooklyn, Brooklyn, NY
15St. Jude Children’s Research Hospital, Memphis, TN

BABY HUG [Clinical Trials #NCT00006400], an NIH-NICHD sponsored randomized placebo-controlled trial showed that hydroxyurea (HU) administered to 9-18 month old children with sickle cell anemia (SCA) provides substantial clinical benefit. Benefits include a decrease in pain crises, acute chest syndrome events, need for transfusion and hospital admission; hematologic improvement include higher total and fetal hemoglobin concentration, larger red cell size, and lower WBC counts with toxicity limited to transient reduction in absolute neutrophil count (ANC) [Lancet 2011; 377:1663-72]. The parent or guardian of all 176 children who completed at least 18 months of randomized treatment were offered participation in an initial observational BABY HUG Follow-Up Study and 163 (93%) consented to participate. Clinical and laboratory data were collected every 6 months by structured abstraction of the medical record regarding use of clinically prescribed HU (dose escalation recommended), blood counts, clinical imaging, and sickle cell-related events. At the time of enrollment the family did not know their child’s randomized study treatment assignment; 133 (82%) initially chose clinical prescription of open-label HU. Acceptance of HU has remained high through 36 months of follow-up; during each 6 month data collection period 68-75% of participants reported having taken HU.

Only 2 patients have left the study (due to relocation) and more than 93% of expected data have been collected. Preliminary analyses as of May 2011, including 417 patient years (pt-yrs) of follow up, demonstrate that in comparison to participants not taking HU, children who continue to take HU have statistically lower rates of pain crises requiring emergency department (ED) visits, episodic transfusions, and hospital admissions for any reason, including acute chest syndrome or febrile illness (see table). The substantial decrease in acute chest syndrome episodes is similar to the effect demonstrated with HU use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of HU therapy in older children and adults. The decrease in the rate of admission for febrile events in HU-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain. There was no difference in hospitalization rates for painful events including dactylitis. Two patients in the non-HU group had a stroke. There were no differences between groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up children taking HU had persistently higher hemoglobin and MCV, and lower WBC and ANC than those not taking HU.

Results of these analyses including growth and development assessments will enhance our understanding of the impact of HU use in children with SCA starting at a very young age. The accruing data from the BABY HUG Follow-Up Study demonstrate a continuation of the substantial benefits of early HU therapy with no discernable additional toxicities. Ongoing follow up of this cohort is essential to fully define these benefits as children grow, and to observe for late toxicity.

Disclosures: Off Label Use: Hydroxyurea is not indicated for treatment of children with sickle cell disease. Use of this medication was for clinical indications and not mandated by this observational study.

[8] Genotoxicity Associated with Hydroxyurea Exposure in Infants with Sickle Cell Anemia: Results From the BABY-HUG Phase III Clinical Trial

Patrick T. McGann, MD1, Jonathan M Flanagan, PhD2, Thad A Howard, MS2*, Stephen D Dertinger, PhD3*, Jin He, MD4*, Anita S Kulharya, PhD5*, Bruce W Thompson, PhD6* and Russell E. Ware, MD, PhD2

1Texas Children’s Hospital Hematology Center, Baylor College of Medicine, Houston, TX
2Baylor College of Medicine, Houston, TX
3Litron Laboratories, Rochester, NY
4St. Jude Children’s Research Hospital, Memphis, TN
5Pathology, Georgia Health Sciences University, Augusta, GA
6Clinical Trials and Surveys Corp., Owings Mills, MD

The laboratory and clinical benefits of hydroxyurea therapy for children with sickle cell anemia (SCA) are well recognized, but treatment in young patients is limited in part by concerns about long-term genotoxicity, and specifically possible carcinogenicity. To date, few prospective data have been available to assess the mutagenic and carcinogenic potential of hydroxyurea in young patients with SCA. The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) was a multi-center double-blinded placebo-controlled randomized clinical trial (NCT00006400) testing whether hydroxyurea could prevent chronic organ damage in very young patients with SCA. BABY HUG was conducted across 14 centers and was approved by the local institutional review boards of all participating centers. A total of 193 infants (mean 13.6 months) with SCA (HbSS or HbS/ß0-thalassemia) were randomized to receive hydroxyurea (fixed dose of 20 mg/kg/day) or placebo for two years. An important secondary objective of the study was the in vivo measurement of acquired genotoxicity using three laboratory assays: chromosomal karyotype including quantitation of chromosomal breaks, chromatid breaks, and fusion events; illegitimate VDJ recombination events representing inversion events on chromosome 7 with juxtaposition of T-cell receptor Vg and Jb and gene loci; and micronucleated reticulocyte formation signifying aberrant erythroid production. Subjects in both the hydroxyurea and placebo groups had significantly increased numbers of total chromosome breaks and similar numbers of chromatid breaks at study exit compared to study entry. However, at study exit, subjects with hydroxyurea exposure had similar numbers of chromosome and chromatid breaks as subjects receiving placebo (0.5 ± 1.4 chromosome breaks per 100 metaphases vs. 0.4 ± 2.5, p=NS; 0.6 ± 1.1 chromatid breaks per 100 metaphases vs.0.8 ± 3.4, p=NS). There were no changes in the number of illegitimate VDJ recombination events observed, comparing study entry and exit samples either in the hydroxyurea or the placebo treatment group. At study exit, subjects treated with hydroxyurea had similar numbers of illegitimate VDJ recombination events as subjects receiving placebo (0.7 ± 0.5 events per µg of DNA versus 0.7 ± 0.4 events, p=NS). Subjects treated with hydroxyurea had a similar number of early reticulocytes containing micronuclei at study exit compared to subjects receiving placebo (0.3 ± 0.2% versus 0.3 ± 0.2%, p=NS). Together, these data indicate that hydroxyurea treatment in very young patients with SCA was not associated with any significant increases in genotoxicity compared to placebo treatment. These data provide evidence of cytogenetic stability in this susceptible population of young children and contribute to a growing body of evidence to suggest that in vivo genotoxicity of hydroxyurea in patients with SCA appears to be low.

Disclosures: Dertinger: Litron Laboratories: Employment.

[9] Pre-Operative Transfusion Reduces Serious Adverse Events in Patients with Sickle Cell Disease (SCD): Results From the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) Randomised Controlled Multicentre Clinical Trial

Jo Howard, MB, BChir, MRCP, FRCPath1*, Moira Malfroy, RN2*, Llewelyn Charlotte, PhD2*, Louise Choo, PhD3*, David Rees, FRCPath4*, Isabeau Walker, FRCA5*, Tony Johnson, PhD3*, Louise Tillyer, FRCPath6*, Karin Fijnvandraat, MD, PhD7, Melanie Kirby-Allen, MD8*, Renate Hodge, MSc2*, Shilpi Purohit2*, Sally C. Davies, FRCP, FMedSci9 and Lorna M Williamson, FRCPath2*

1Haematology, Guy’s and St Thomas’ NHS Foundation Trust, LONDON, United Kingdom
2NHSBT/MRC Clinical Studies Unit, NHS Blood and Transplant
3Clinical Trials Unit, Medical Research Council
4Haematology, Kings College Hospital NHS Foundtion Trust
5Great Ormond Street Hospital NHS Trust
6Haematology, Royal Brompton and Harefield NHS Foundation Trust
7Academic Medical Center (AMC), Amsterdam, Netherlands
8Hospital for Sick Children Toronto
9Department of Health, London

Introduction: The rate of complications after surgery is increased in patients with Sickle Cell Disease (SCD) and pre-operative blood transfusion has historically been used to decrease this risk. Observational studies and one limited Randomised Controlled Trial (RCT) have suggested that in some patients, transfusion can safely be omitted. Since transfusion is associated with complications including alloimmunisation and increased post-operative infections, we performed a RCT to address whether overall peri-operative complications in SCD are reduced by pre-operative transfusion.

Methods: TAPS was a Phase III multicentre, pragmatic, randomised controlled trial with a parallel group sequential superiority design, carried out between November 2007 and March 2011 at 22 sites in the UK, Netherlands and Canada. Eligible patients had HbSS or HbSβ0thal, were aged one year or more and were having low risk (eg adenoidectomy, dental surgery) or medium risk (eg joint replacement, cholecystectomy, tonsillectomy) elective surgery. Patients were excluded if they had a haemoglobin (Hb) <6.5g/dl, had received a blood transfusion within the last 3 months or had severe SCD. Patients were randomly assigned to Arm A, which received no pre-operative transfusion, or Arm B, which received a top-up transfusion if Hb<9g/dl or a partial exchange if Hb9g/dl. Sites followed their own standards for all other aspects of peri-operative care, although guidance was provided. The primary outcome was all significant complications between randomisation and 30 days post surgery as defined in the protocol. These were sent blinded to the End-Point Review Panel for final classification. Complications which were life-threatening or resulted in death or persistent or significant incapacity/disability and other important medical events were also recorded as Serious Adverse Events (SAEs) and were reviewed by an Independent Data Monitoring Committee (IDMC). Due to a major imbalance in the number of SAEs between treatment groups, the trial was terminated early following an IDMC recommendation.

Results: 333 patients were screened for the trial and 70 patients were randomised at the time the trial was terminated. Thirty three completed 30 day follow up in Arm A and 34 in Arm B. Both groups were comparable with respect to age, gender, severity of SCD, type of surgery and baseline Hb. Only 13 patients had low risk surgery. The pre-operative (post-transfusion) Hb was higher in Arm B (9.7g/dl vs 7.7g/dl) and 5 patients in Arm B received partial exchange transfusion with a mean pre-operative HbS% of 47.2%. There were no differences in peri-operative management, including fluid support and oxygen therapy, between the two groups.

There were 11 SAEs (33%) in patients who did not receive a pre-operative transfusion, compared to only 1 SAE (3%) in patients who did receive a top-up transfusion or partial exchange. Eleven of the SAEs were Acute Chest Syndrome (ACS). Patients in the no pre-operative transfusion group also had more significant complications (13/33, 39%), which included SAEs, as compared to patients in the top-up/exchange group (5/34, 15%).

Type of surgery: 58% of patients underwent abdominal or ENT surgery. Four out of 13 patients (31%) who had abdominal surgery in Arm A had ACS events compared to none out of 10 patients in Arm B. Out of the 9 patients who had Tonsillectomy in Arm A, 3 patients had ACS events (33%) compared to none in 7 patients in Arm B.

Discussion: This RCT has shown a large increase in SAEs in un-transfused patients with HbSS and HbSβ0thal having low and moderate risk surgery. In particular there was a striking increase in ACS, a potentially life-threatening complication. We therefore recommend that pre-operative transfusion should be strongly considered for patients with HbSS and HbSβ0thal undergoing moderate risk surgery, in particular abdominal surgery and tonsillectomy. There was no evidence of increased benefit of exchange transfusion over top-up, although numbers were small, and exchange transfusions should be reserved for patients with a Hb>9g/dl. There is insufficient evidence to reach a conclusion on the role of pre-operative transfusion in other types of surgery or in patients with other sickle genotypes. Pre-operative transfusion in these patients should be decided on a case by case basis.

Acknowledgement: submitted on behalf of the TAPS Trial Investigators.

Disclosures: No relevant conflicts of interest to declare.

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On the Net:

• American Society of Hematology

Women who inherit the cancer genes BRCA1 or BRCA2 from their paternal lineage may get a diagnosis a decade earlier than those women who carry the cancer genes from their mother and her ancestors, according to a new study by researchers at the North Shore-LIJ Health System’s Monter Cancer Center in Lake Success, NY. The findings were reported on Thursday, Dec. 8, at the San Antonio Breast Cancer Symposium.

Iuliana Shapira, MD, North director of cancer genetics, and her colleagues conducted a retrospective review of 130 breast or ovarian cancer patients with the BRCA1 or BRCA2 mutations. They chose only those patients who knew the parent of origin. In other words, they could follow along their family tree to see where the breast cancer gene originated from. Some of their families had their own genetic tests done. For others, it was a matter of following the family pedigree.

As expected, a person had a 50-50 chance of getting a mutant BRCA gene from their mother or their father’s branch that carried the mutation. It is an autosomal dominant mutation. Looking at the family maps revealed some surprising findings. Contrary to the notion that the BRCA mutations are associated more commonly with Ashkenazi Jews, the scientists found that the BRCA mutations were also in families of Irish and Jamaican descent. “No one had ever conducted a study to look at the parent-of-origin effects,” said Dr. Shapira. “Genetic diseases may display parent-of-origin effects. In such cases, the risk depends on the specific parent or origin allele. Cancer penetrance in mutations carriers may be determined by the parent origin of BRCA mutation.”

They analyzed 1,889 consecutive (136 ovarian + 1753 breast) breast (BrCa) or ovarian cancer (OvCa) patients presenting for treatment at the Monter Cancer Center between 2007 and 2010. In 130 patients with BRCA 1 or 2 mutations the parent of origin for the mutation was known. Of the 130 patients, two had both BRCA1 and BRCA2 mutated paternally inherited disease and were excluded from this analysis. Of the breast cancer patients: 28 patients had paternal and 29 had maternal BRCA1 mutations, 24 had paternal and 21 had maternal BRCA 2 mutations. Of the ovarian cancer patients, six had paternal and 10 had maternal BRCA1 mutations; seven had paternal and three had maternal BRCA2 mutations.

In carriers of BRCA mutations, the mean age at diagnosis for ovarian cancer was 51 (range 21-70) and for breast cancer was 43 (range 24-78). But when they compared the mean age at diagnosis in the maternal versus paternal inheritance, they were surprised to find that breast cancer patients with a BRCA1 maternal inheritance, the age of diagnosis was on average around 45. By comparison, women with BRCA1 paternal inheritance were diagnosed around 38. For breast cancer BRCA2 maternal inheritance, the average age of diagnosis was 50 compared to 41 years old for those with a BRCA2 paternal inheritance.

There was no significant difference between paternal and maternal age of ovarian cancer diagnosis of BRCA1 or BRCA2 mutations.

“If this observation is duplicated in larger cohorts the results will have important implications for recommendation of surgical risk reduction in BRCA mutation carriers,” said Dr. Shapira. “That would mean that doctors might think about watching and waiting in young woman with BRCA mutations inherited from her mother’s family and being more aggressive in young women who inherited the mutation from their father’s side.”

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On the Net:

• North Shore-Long Island Jewish (LIJ) Health System

(Ivanhoe Newswire) — Women who work one night on, one night off, a day shift and then a night shift “¦ also known as rotating night shift work could be putting themselves at risk for type 2 diabetes. And furthermore, the longer you work, the more likely you are to gain weight. This new study sheds light on potential public health risk since a large portion of the working population is involved in some kind of permanent night and rotating night shift work.

The authors used data from the Nurses’ Health Study I (NHS I – established in 1976, and which included 121704 women) and the Nurses’ Health Study II (NHS II – established in 1989, and which included 116677 women), and found that in NHS I, 6,165 women developed type 2 diabetes and in NHS II 3,961 women developed type 2 diabetes. Using statistical models, the authors found that the duration of rotating night shift work was strongly associated with an increased risk of type 2 diabetes in both cohorts and that the risks of women developing type 2 diabetes, increased with the numbers of years working rotating shifts. However, these associations were slightly weaker after the authors took other factors into consideration.

Although these findings need to be confirmed in men and other ethnic groups, these findings show that additional preventative strategies in rotating night shift workers should therefore be considered.

“Recognizing that rotating night shift workers are at a higher risk of type 2 diabetes should prompt additional research into preventive strategies in this group,” the authors were quoted as saying.

“Some modifications to shift work itself might also be feasible. Rotating shift work comprises a range of alternative schedule patterns, such as backward- and forward-rotating shift systems, and the proportion of night and early morning shifts varies. Future studies should address these variations and identify patterns that minimize [type 2 diabetes] risk, ideally through large-scale randomized trials that would provide insights into causality,” the authors concluded.

SOURCE: PLoS Medicine, published online December 2011.

One study presented at the meeting, which is being held in Budapest, Hungary, 7 to 10 December, reports on an initiative using echocardiography to document early warning signs of adverse effects from trastuzumab (Herceptin ®)´, while the other uses echocardiography to evaluate the protective role of ACE inhibitors and statins on the hearts of cancer patients².

“These studies open the way for the early identification of myocardial damage at the subclinical level, thereby allowing clinicians to identify patients who might benefit from either changes in cancer therapy or the delivery of protective treatments,” says EAE president Dr Luigi Badano, from the University of Padua, Italy.

Already echocardiography is widely used to evaluating cardio toxicity, but the most commonly used parameter of left ventricular ejection fractions (LVEF), only identifies myocardial damage that has already occurred and fails to identify the early subtle alterations in left ventricular function that predict future functional decline.

Newer cancer therapies have improved the survival of patients with cancer and, in some cases, turned cancer into a chronic disease. The result is that patients are now surviving long enough for the adverse cardiovascular effects of some cancer therapies to become apparent. The anthracyclines and related compounds are the most frequently implicated agents, but other treatments such as 5—Fluoroouracil, its prodrug capecitabine, and trastuzumab, a tumor-specific antibody, have also been associated with cardio toxicity. Currently it is estimated that 17% of patients have to stop cancer therapy due to adverse effects on their hearts.

The cardio toxic effects of cancer treatments encompass a heterogeneous group of disorders, says Dr Helder Dores, from Santa Cruz Hospital/São Francisco Xavier Hospital, Lisbon, Portugal, “They range from relatively benign arrhythmias, and hypertension, to potentially lethal conditions such as thromboembolism, myocardial infarction and cardiomyopathy with symptomatic heart failure.”

Cardiotoxicity can be acute, appearing in the first 10 days of treatment, late, or experienced 15 to 20 years later, as sometimes found with the survivors of childhood cancers. While the damage is well documented, the mechanisms are incompletely understood. “They appear to be multifactorial, with the production of oxygen free radicals considered the main cause of morphological alterations,” explains Liliana Radulescu, from Municipal Hospital, Cluj-Napoca, Romania.

In October 2011 the European Association of Echocardiograpy (EAE) announced that it is working with the American Society of Echocardiography (ASE) and American Society of Clinical Oncology (ASCO) to issue joint recommendations on the usefulness of echocardiographic evaluations in cancer patients, expected to be published in 2012. “The document should lay down guidance for the frequency of assessment with different chemotherapy agents, and also identify when patients should stop treatment or be prescribed protective treatments,” says Badano.

Study reveals early signs of myocardial damage

In the first study Helder Dores and colleagues, set out to identify early warning signs of adverse cardiac effects in women treated with trastuzumab for breast cancer. In the study 51 consecutive women, enrolled for treatment between May and September 2010, were assessed at baseline with echocardiography and then again at three months.

The investigators found that within the first three months no patients presented with overt signs of heart failure or significant left ventricular systolic function deterioration, although almost one-fifth developed impaired ventricular relaxation. Impaired ventricular relaxation occurs when pressure reduction in the left ventricle does not happen as fast as normal leading to abnormalities in the heart’s ability to fill properly.

“Patients with impaired ventricular relaxation are known to be at higher risk for progression to advanced stages of cardiac dysfunction (both systolic and diastolic), making it important for these patients to be subject to more frequent evaluations both during and after therapy,” says Dores.

Further studies are now needed, he says, to assess whether impaired ventricular relaxation occurs in larger populations of patients prescribed trastuzumab. “We need studies identifying the women who go on to develop overt cardiac dysfunction to see whether we can more accurately determine predictors of these adverse events at an earlier stage of treatment,” says Dores.

ACE inhibitors and statins deliver cardioprotection

In the second study Liliana Radulescu and colleagues used echo-Doppler echocardiography to investigate whether the ACE inhibitor lisinopril and the statin rosuvastatin might confer a cardio protective effect on patients treated with anthracyclines for a range of malignancies.

“While the exact mechanism of anthracycline related cardio toxicity is not fully understood, animal studies have pointed to oxidative stress and inflammation. Both ACE inhibitors and statins are known to play an important role in reducing oxidative stress and inflammation at the level of the heart muscle cells,”says Dr Andreea Parv.

In the prospective study left ventricular ejection fractions and LV diastolic function were compared for the study group of 26 patients treated with the anthracycline epirubicin who were also given the cardio protective treatments Lisinopril 10 mg and Rosuvastatin 10 mg, and a control group of 31 gender and age-matched patients who received epirubicin but had no accompanying cardioprotective treatments.

Results show that in comparison with patients receiving cardio protection the patients who receive no protection showed further deterioration of LV diastolic function, calculated as the ratio of early diastolic filling velocity(E) to filling velocity after atria contraction E/A (p<0.02).

“This is the first human prospective study documenting the cardioprotective effect of lisinopril and rosuvastatin in anthracycline induced cardio toxicity,” says Radulescu. Further studies, she adds, are now needed in larger numbers of patients, exploring a range of different types of malignancies.

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On the Net:

• European Society of Cardiology

Knowing biology of early or late recurring tumors could help extend survival by identifying interventions to delay or prevent recurrences after tamoxifen
An international research team led by Georgetown Lombardi Comprehensive Cancer Center has found biological differences in hormone-receptor positive breast cancer that are linked to the timing of recurrence despite endocrine therapy.
They say their findings, presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, may help oncologists find ways to individualize systemic therapy to delay or prevent recurrences, and to avoid excessive treatment of patients who will never recur.
“We found that, at the time of diagnosis, there are clear biological differences within the supposedly uniform group of hormone receptor positive breast cancers, and these differences distinguish subtypes relative to the time at which they recur,” says Minetta Liu, M.D., director of translational breast cancer research at Georgetown Lombardi Comprehensive Cancer Center.
“We need to exploit these differences and use our data to figure out what drives a tumor to never metastasize. Then we will try to manipulate the cancers that are programmed to recur to act like that of the non-recurrences,” she says.
Tamoxifen is credited with saving the lives of thousands of women with estrogen receptor-positive (ER+) breast cancer, which accounts for two-thirds of all diagnoses of invasive breast cancer in the United States. As the world’s leading breast cancer treatment and prevention drug, tamoxifen can stave off cancer recurrences for more than 10 years in some patients, but for others, the cancer returns much earlier.
To determine why some ER+ cancers treated with tamoxifen recur earlier rather than later, if at all, Liu and her Georgetown team collaborated with researchers at the University of Edinburgh and with engineers at Virginia Tech.
The Scottish collaborators shared high quality tumor biopsies collected from patients with different stages of breast cancer before they had started tamoxifen therapy. Critical clinical information was available to determine whether or not patients developed metastatic disease, and when the recurrence (if any) was found. The samples were processed and analyzed at Georgetown. Then scientists at Virginia Tech examined the gene expression patterns generated from the tumor biopsies relative to the known clinical outcomes to develop a predictive model of early, late or no disease recurrence.
The final analysis revealed distinct patterns in cancers that recurred early (up to three years from diagnosis) or late (more than ten years from diagnosis). Liu says that some of the genes that were identified were “expected and reassuring,” but others were “unexpected and novel.” Work is ongoing to validate selected genes as biological drivers of metastasis.
“Endocrine therapy and chemotherapy are not without toxicity,” Liu says. “The ability to predict which patients will recur early in their treatment course can lead to more appropriate recommendations for adjuvant chemotherapy. It might also identify those women who would benefit most from studies using investigational agents to enhance the effects of tamoxifen or aromatase inhibitors.”
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On the Net:

• Georgetown University Medical Center

Researchers may have discovered a series of genes that will help predict whether or not a woman with hormone receptor-positive invasive breast cancer will experience early, late or no recurrence of her disease.

Minetta C. Liu, M.D., associate professor of medicine and oncology and director of translational breast cancer research at Georgetown Lombardi Comprehensive Cancer Center, presented the findings at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, held Dec. 6-10, 2011.

“There are clear biological differences within the supposedly unified group of hormone receptor (HR)-positive breast cancers, and these differences distinguish subtypes relative to the time at which they recur,” Liu said. “Understanding what drives these distinctions will allow us to tailor treatment and improve patient outcomes.”

Women with HR-positive breast cancer are frequently treated with tamoxifen, which is credited with saving the lives of hundreds of thousands of women. Although tamoxifen prevents or delays cancer recurrence in many women, some will recur 10 years or more from their original diagnosis. Until now, the molecular basis for this recurrence pattern was unknown.

Liu and colleagues, in collaboration with investigators from the University of Edinburgh, evaluated high-quality frozen tumor samples obtained at the time of breast cancer diagnosis. These tissue samples were linked to data on treatment and clinical outcomes, allowing researchers to analyze gene expression patterns present before the initiation of any systemic therapy.

Together with engineers at Virginia Polytechnic Institute, Liu and colleagues identified significant gene expression patterns among the tumor samples. These patterns correlated strongly with the development of distant metastatic disease.

“We confirmed what many have already suspected,” said Liu. “There are biological drivers that define – at the time of tumor development – whether or not breast cancer will recur early, late or not at all. Now we need to validate these findings and take our knowledge to the next step.”

Liu hopes that this research can be used to help personalize treatment in day-to-day clinical practice. “Endocrine therapy and chemotherapy are not without toxicity,” she said. “The ability to predict which patients will recur early in their treatment course can lead to more appropriate recommendations for adjuvant chemotherapy. It might also identify those women who would benefit most from studies using investigational agents to enhance the effects of tamoxifen or aromatase inhibitors.”

She added: “At the other extreme are those patients with HR-positive tumors who recur long after completing five years of endocrine therapy. These are the patients for whom extended endocrine therapy and its related side effects are really worth it.”

The team’s next step is to validate their predictive model for the timing of recurrences on tamoxifen so that physicians and patients can make more informed decisions about the potential added benefits of adjuvant chemotherapy, extended endocrine therapy and involvement in clinical trials. They will also investigate combinations of molecular targets with the ultimate goal of delaying or preventing the development of metastatic breast cancer, Liu said.

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On the Net:

• American Association for Cancer Research