Introduction

Both the medical and lay press have directed a lot of attention lately to the treatment of children and adolescents with antipsychotic medications. The literature is clear that the number of children taking this class of medications has risen sharply since their release (Arch. Gen. Psychiatry 2006;63:679-85). What is much less clear is the degree to which this increase represents a reasonable intervention for patients in significant need versus an overuse when other strategies are more appropriate.

Case Summary

Cody is a 6-year-old boy who lives with his younger sister and single mother. The family struggles financially, and the father, who has never had much contact with his son, is currently incarcerated. Since he was a toddler, Cody has been prone to high levels of aggressive behavior and frequent, intense angry outbursts. He was asked to leave his preschool due to his behavior and now is commonly disruptive at school. His pediatrician diagnosed him with attention-deficit/hyperactivity disorder a year ago and began a trial of a psychostimulant, which made him even more irritable, and was discontinued. Cody and his mother now present with concerns that there is “something more” affecting his behavior. The pediatrician now considers whether or not treatment with an antipsychotic medication is reasonable at this point.

Discussion

The above clinical scenario represents a critical and often antagonizing moment in treatment for both the family and the treating physician, yet it is hardly uncommon. The situation often is made more complicated by the fact that what is often the first plan of action, namely referral or consultation with a child psychiatrist, can be very difficult to access.

The American Academy of Child and Adolescent Psychiatry has published online guidelines for the use of antipsychotic medication in youth (http://bit.ly/1eat7e9). Key recommendations and points from this 27-page document and 19 recommendations include the following:

• Patients being considered for treatment with an antipsychotic medication should receive a “meticulous diagnostic assessment” with any medication prescribed being part of a “multidisciplinary” treatment plan (Recommendation 1).

• Prescribers should “regularly check the current literature” regarding the scientific evidence for antipsychotic medication use (Recommendation 2).

• Antipsychotic medications are considered first-line medication treatment for bipolar disorder, schizophrenia, tics/Tourette’s, and autism. (Recommendation 2).

• Antipsychotic medications are not first-line treatment for several other diagnoses and behaviors, including disruptive behavior disorders such as ADHD, aggression, eating disorders, and post-traumatic stress disorder (PTSD). Their use should be considered only after other pharmacologic and nonpharmacologic interventions have failed (Recommendation 2).

• Antipsychotic medications are not advised for preschool-aged patients. (Recommendation 2).

• Dosing should be as low as possible and not exceed the maximum recommended dose for adults (Recommendation 4).

• Simultaneous treatment with multiple antipsychotic medications is not recommended (Recommendation 8).

• Patients should receive regular metabolic monitoring, including lab work, both before and during treatment (Recommendations 11-13).

These are rigorous guidelines that challenge even those who regularly assess and treat children with serious psychiatric disorders. The clinical and legal implications of prescribing antipsychotic medications without adhering to these guidelines will, and probably should, give many physicians pause. Further, the specific point about the need for a thorough psychiatric evaluation underlies the commonly heard recommendation that this class of medicines generally should be avoided by primary care physicians. At the same time, many pediatricians are acutely aware of how dire the clinical situation often is for these families. At this point, it can easily begin to feel very much like a “no-win” situation.

Here are some thoughts that may be useful to consider in these moments:

• Remember that many non-MD mental health professionals can offer a lot of help. Although they can’t do the prescribing themselves, referral to a psychologist or another type of therapist can be useful in getting information about a patient’s diagnosis and the degree to which nonpharmacologic options have been exhausted. If the patient is already seeing a therapist, it is certainly worthwhile to seek their advice as to whether or not antipsychotic medications are now reasonable to consider.

• Look for opportunities to talk “curbside” to a child psychiatrist. Most of us are keenly aware of how inadequate access is to child psychiatry and want to help. Indeed, many states now have specific brief consultation programs in place.

• Get the lab work. A recent study in Pediatrics reported that a baseline glucose was obtained in only 11% of youth receiving antipsychotic medication treatment (Pediatrics 2014;134:e1308-14). In addition to providing important information, this step signals to everyone involved that the decision to use these medications is not something to be taken lightly.

Case follow-up

Cody’s pediatrician decides to get a diagnostic evaluation from a psychologist, who confirms the ADHD diagnosis without associated conditions such as bipolar disorder. The psychologist recommends a course of therapy to build regulatory skills for Cody and provide the mother with some parent behavioral guidance about how to best manage Cody’s challenges and encourage health-promoting behaviors such as physical activity, reading, and a regular sleep routine. The pediatrician decides to try a second line ADHD medication, guanfacine, and the school also begins to institute an incentive plan to reinforce positive behavior. In combination, these efforts significantly reduce the level of aggression and dysregulated behavior.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Dr. Rettew said he has no relevant financial disclosures. Follow him on Twitter @pedipsych.

Introduction

Both the medical and lay press have directed a lot of attention lately to the treatment of children and adolescents with antipsychotic medications. The literature is clear that the number of children taking this class of medications has risen sharply since their release (Arch. Gen. Psychiatry 2006;63:679-85). What is much less clear is the degree to which this increase represents a reasonable intervention for patients in significant need versus an overuse when other strategies are more appropriate.

Case Summary

Cody is a 6-year-old boy who lives with his younger sister and single mother. The family struggles financially, and the father, who has never had much contact with his son, is currently incarcerated. Since he was a toddler, Cody has been prone to high levels of aggressive behavior and frequent, intense angry outbursts. He was asked to leave his preschool due to his behavior and now is commonly disruptive at school. His pediatrician diagnosed him with attention-deficit/hyperactivity disorder a year ago and began a trial of a psychostimulant, which made him even more irritable, and was discontinued. Cody and his mother now present with concerns that there is “something more” affecting his behavior. The pediatrician now considers whether or not treatment with an antipsychotic medication is reasonable at this point.

Discussion

The above clinical scenario represents a critical and often antagonizing moment in treatment for both the family and the treating physician, yet it is hardly uncommon. The situation often is made more complicated by the fact that what is often the first plan of action, namely referral or consultation with a child psychiatrist, can be very difficult to access.

The American Academy of Child and Adolescent Psychiatry has published online guidelines for the use of antipsychotic medication in youth (http://bit.ly/1eat7e9). Key recommendations and points from this 27-page document and 19 recommendations include the following:

• Patients being considered for treatment with an antipsychotic medication should receive a “meticulous diagnostic assessment” with any medication prescribed being part of a “multidisciplinary” treatment plan (Recommendation 1).

• Prescribers should “regularly check the current literature” regarding the scientific evidence for antipsychotic medication use (Recommendation 2).

• Antipsychotic medications are considered first-line medication treatment for bipolar disorder, schizophrenia, tics/Tourette’s, and autism. (Recommendation 2).

• Antipsychotic medications are not first-line treatment for several other diagnoses and behaviors, including disruptive behavior disorders such as ADHD, aggression, eating disorders, and post-traumatic stress disorder (PTSD). Their use should be considered only after other pharmacologic and nonpharmacologic interventions have failed (Recommendation 2).

• Antipsychotic medications are not advised for preschool-aged patients. (Recommendation 2).

• Dosing should be as low as possible and not exceed the maximum recommended dose for adults (Recommendation 4).

• Simultaneous treatment with multiple antipsychotic medications is not recommended (Recommendation 8).

• Patients should receive regular metabolic monitoring, including lab work, both before and during treatment (Recommendations 11-13).

These are rigorous guidelines that challenge even those who regularly assess and treat children with serious psychiatric disorders. The clinical and legal implications of prescribing antipsychotic medications without adhering to these guidelines will, and probably should, give many physicians pause. Further, the specific point about the need for a thorough psychiatric evaluation underlies the commonly heard recommendation that this class of medicines generally should be avoided by primary care physicians. At the same time, many pediatricians are acutely aware of how dire the clinical situation often is for these families. At this point, it can easily begin to feel very much like a “no-win” situation.

Here are some thoughts that may be useful to consider in these moments:

• Remember that many non-MD mental health professionals can offer a lot of help. Although they can’t do the prescribing themselves, referral to a psychologist or another type of therapist can be useful in getting information about a patient’s diagnosis and the degree to which nonpharmacologic options have been exhausted. If the patient is already seeing a therapist, it is certainly worthwhile to seek their advice as to whether or not antipsychotic medications are now reasonable to consider.

• Look for opportunities to talk “curbside” to a child psychiatrist. Most of us are keenly aware of how inadequate access is to child psychiatry and want to help. Indeed, many states now have specific brief consultation programs in place.

• Get the lab work. A recent study in Pediatrics reported that a baseline glucose was obtained in only 11% of youth receiving antipsychotic medication treatment (Pediatrics 2014;134:e1308-14). In addition to providing important information, this step signals to everyone involved that the decision to use these medications is not something to be taken lightly.

Case follow-up

Cody’s pediatrician decides to get a diagnostic evaluation from a psychologist, who confirms the ADHD diagnosis without associated conditions such as bipolar disorder. The psychologist recommends a course of therapy to build regulatory skills for Cody and provide the mother with some parent behavioral guidance about how to best manage Cody’s challenges and encourage health-promoting behaviors such as physical activity, reading, and a regular sleep routine. The pediatrician decides to try a second line ADHD medication, guanfacine, and the school also begins to institute an incentive plan to reinforce positive behavior. In combination, these efforts significantly reduce the level of aggression and dysregulated behavior.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Dr. Rettew said he has no relevant financial disclosures. Follow him on Twitter @pedipsych.

Introduction

Both the medical and lay press have directed a lot of attention lately to the treatment of children and adolescents with antipsychotic medications. The literature is clear that the number of children taking this class of medications has risen sharply since their release (Arch. Gen. Psychiatry 2006;63:679-85). What is much less clear is the degree to which this increase represents a reasonable intervention for patients in significant need versus an overuse when other strategies are more appropriate.

Case Summary

Cody is a 6-year-old boy who lives with his younger sister and single mother. The family struggles financially, and the father, who has never had much contact with his son, is currently incarcerated. Since he was a toddler, Cody has been prone to high levels of aggressive behavior and frequent, intense angry outbursts. He was asked to leave his preschool due to his behavior and now is commonly disruptive at school. His pediatrician diagnosed him with attention-deficit/hyperactivity disorder a year ago and began a trial of a psychostimulant, which made him even more irritable, and was discontinued. Cody and his mother now present with concerns that there is “something more” affecting his behavior. The pediatrician now considers whether or not treatment with an antipsychotic medication is reasonable at this point.

Discussion

The above clinical scenario represents a critical and often antagonizing moment in treatment for both the family and the treating physician, yet it is hardly uncommon. The situation often is made more complicated by the fact that what is often the first plan of action, namely referral or consultation with a child psychiatrist, can be very difficult to access.

The American Academy of Child and Adolescent Psychiatry has published online guidelines for the use of antipsychotic medication in youth (http://bit.ly/1eat7e9). Key recommendations and points from this 27-page document and 19 recommendations include the following:

• Patients being considered for treatment with an antipsychotic medication should receive a “meticulous diagnostic assessment” with any medication prescribed being part of a “multidisciplinary” treatment plan (Recommendation 1).

• Prescribers should “regularly check the current literature” regarding the scientific evidence for antipsychotic medication use (Recommendation 2).

• Antipsychotic medications are considered first-line medication treatment for bipolar disorder, schizophrenia, tics/Tourette’s, and autism. (Recommendation 2).

• Antipsychotic medications are not first-line treatment for several other diagnoses and behaviors, including disruptive behavior disorders such as ADHD, aggression, eating disorders, and post-traumatic stress disorder (PTSD). Their use should be considered only after other pharmacologic and nonpharmacologic interventions have failed (Recommendation 2).

• Antipsychotic medications are not advised for preschool-aged patients. (Recommendation 2).

• Dosing should be as low as possible and not exceed the maximum recommended dose for adults (Recommendation 4).

• Simultaneous treatment with multiple antipsychotic medications is not recommended (Recommendation 8).

• Patients should receive regular metabolic monitoring, including lab work, both before and during treatment (Recommendations 11-13).

These are rigorous guidelines that challenge even those who regularly assess and treat children with serious psychiatric disorders. The clinical and legal implications of prescribing antipsychotic medications without adhering to these guidelines will, and probably should, give many physicians pause. Further, the specific point about the need for a thorough psychiatric evaluation underlies the commonly heard recommendation that this class of medicines generally should be avoided by primary care physicians. At the same time, many pediatricians are acutely aware of how dire the clinical situation often is for these families. At this point, it can easily begin to feel very much like a “no-win” situation.

Here are some thoughts that may be useful to consider in these moments:

• Remember that many non-MD mental health professionals can offer a lot of help. Although they can’t do the prescribing themselves, referral to a psychologist or another type of therapist can be useful in getting information about a patient’s diagnosis and the degree to which nonpharmacologic options have been exhausted. If the patient is already seeing a therapist, it is certainly worthwhile to seek their advice as to whether or not antipsychotic medications are now reasonable to consider.

• Look for opportunities to talk “curbside” to a child psychiatrist. Most of us are keenly aware of how inadequate access is to child psychiatry and want to help. Indeed, many states now have specific brief consultation programs in place.

• Get the lab work. A recent study in Pediatrics reported that a baseline glucose was obtained in only 11% of youth receiving antipsychotic medication treatment (Pediatrics 2014;134:e1308-14). In addition to providing important information, this step signals to everyone involved that the decision to use these medications is not something to be taken lightly.

Case follow-up

Cody’s pediatrician decides to get a diagnostic evaluation from a psychologist, who confirms the ADHD diagnosis without associated conditions such as bipolar disorder. The psychologist recommends a course of therapy to build regulatory skills for Cody and provide the mother with some parent behavioral guidance about how to best manage Cody’s challenges and encourage health-promoting behaviors such as physical activity, reading, and a regular sleep routine. The pediatrician decides to try a second line ADHD medication, guanfacine, and the school also begins to institute an incentive plan to reinforce positive behavior. In combination, these efforts significantly reduce the level of aggression and dysregulated behavior.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Dr. Rettew said he has no relevant financial disclosures. Follow him on Twitter @pedipsych.

The recent rise of specialty hospitalists, particularly in the surgery and oncology fields, has benefitted hospitals and patients alike. Consider the growing ranks of oncology hospitalists, a small but quickly expanding HM specialty that has applied hospitalist principles to inpatient cancer and end-of-life care.

One such program at M.D. Anderson Cancer Center in Houston has attracted nine hospital-based physicians, four advanced-practice nurses, and two pharmacists since its launch in 2006. More doctors and nurse practitioners are being recruited, and the group is piloting an observation unit geared toward symptom management for an average of five oncology patients per day.

Although most inpatients cared for M.D. Anderson hospitalists are being treated for cancer, many have general medical needs, such as managing diabetes or high blood pressure, explains hospitalist Maria-Claudia Campagna, MD, FHM, assistant professor in the division of internal medicine at MD Anderson. Other patients, including those who don't yet have a confirmed cancer diagnosis, and family members of cancer patients may also be seen by the hospitalists. MD Anderson also has an established palliative-care service.

Increasingly, hospitals have employed specialty hospitalist teams, staffed by general oncologists or internal medicine hospitalists skilled at complex cancer care to care for inpatients with cancer, and the trend shows no signs of slowing.

Likewise, the practice of employing surgical hospitalists in non-trauma centers is gaining steam. Some non-trauma hospitals have reported improved patient outcomes and greater  efficiency with surgical hospitalists.

A retrospective review of emergency surgical operations performed over five years at Sutter Medical Center, in Sacramento, Calif., found that an acute-care surgery model resulted in fewer overall complications, shorter lengths of stay, and lower hospital costs.

This approach by Surgical Affiliates Management Group, Inc. of Sacramento—the group contracted to perform the surgeries at SMC—combines elements of trauma, critical care, emergency surgical medicine, and elective general surgery, and it could be applied to emergency general surgeries at other hospitals that lack a trauma service without jeopardizing quality of care, the authors state.

Visit our website for more information on specialty hospitalist programs.

The recent rise of specialty hospitalists, particularly in the surgery and oncology fields, has benefitted hospitals and patients alike. Consider the growing ranks of oncology hospitalists, a small but quickly expanding HM specialty that has applied hospitalist principles to inpatient cancer and end-of-life care.

One such program at M.D. Anderson Cancer Center in Houston has attracted nine hospital-based physicians, four advanced-practice nurses, and two pharmacists since its launch in 2006. More doctors and nurse practitioners are being recruited, and the group is piloting an observation unit geared toward symptom management for an average of five oncology patients per day.

Although most inpatients cared for M.D. Anderson hospitalists are being treated for cancer, many have general medical needs, such as managing diabetes or high blood pressure, explains hospitalist Maria-Claudia Campagna, MD, FHM, assistant professor in the division of internal medicine at MD Anderson. Other patients, including those who don't yet have a confirmed cancer diagnosis, and family members of cancer patients may also be seen by the hospitalists. MD Anderson also has an established palliative-care service.

Increasingly, hospitals have employed specialty hospitalist teams, staffed by general oncologists or internal medicine hospitalists skilled at complex cancer care to care for inpatients with cancer, and the trend shows no signs of slowing.

Likewise, the practice of employing surgical hospitalists in non-trauma centers is gaining steam. Some non-trauma hospitals have reported improved patient outcomes and greater  efficiency with surgical hospitalists.

A retrospective review of emergency surgical operations performed over five years at Sutter Medical Center, in Sacramento, Calif., found that an acute-care surgery model resulted in fewer overall complications, shorter lengths of stay, and lower hospital costs.

This approach by Surgical Affiliates Management Group, Inc. of Sacramento—the group contracted to perform the surgeries at SMC—combines elements of trauma, critical care, emergency surgical medicine, and elective general surgery, and it could be applied to emergency general surgeries at other hospitals that lack a trauma service without jeopardizing quality of care, the authors state.

Visit our website for more information on specialty hospitalist programs.

The recent rise of specialty hospitalists, particularly in the surgery and oncology fields, has benefitted hospitals and patients alike. Consider the growing ranks of oncology hospitalists, a small but quickly expanding HM specialty that has applied hospitalist principles to inpatient cancer and end-of-life care.

One such program at M.D. Anderson Cancer Center in Houston has attracted nine hospital-based physicians, four advanced-practice nurses, and two pharmacists since its launch in 2006. More doctors and nurse practitioners are being recruited, and the group is piloting an observation unit geared toward symptom management for an average of five oncology patients per day.

Although most inpatients cared for M.D. Anderson hospitalists are being treated for cancer, many have general medical needs, such as managing diabetes or high blood pressure, explains hospitalist Maria-Claudia Campagna, MD, FHM, assistant professor in the division of internal medicine at MD Anderson. Other patients, including those who don't yet have a confirmed cancer diagnosis, and family members of cancer patients may also be seen by the hospitalists. MD Anderson also has an established palliative-care service.

Increasingly, hospitals have employed specialty hospitalist teams, staffed by general oncologists or internal medicine hospitalists skilled at complex cancer care to care for inpatients with cancer, and the trend shows no signs of slowing.

Likewise, the practice of employing surgical hospitalists in non-trauma centers is gaining steam. Some non-trauma hospitals have reported improved patient outcomes and greater  efficiency with surgical hospitalists.

A retrospective review of emergency surgical operations performed over five years at Sutter Medical Center, in Sacramento, Calif., found that an acute-care surgery model resulted in fewer overall complications, shorter lengths of stay, and lower hospital costs.

This approach by Surgical Affiliates Management Group, Inc. of Sacramento—the group contracted to perform the surgeries at SMC—combines elements of trauma, critical care, emergency surgical medicine, and elective general surgery, and it could be applied to emergency general surgeries at other hospitals that lack a trauma service without jeopardizing quality of care, the authors state.

Visit our website for more information on specialty hospitalist programs.

Sound Physicians' recent acquisition of Cogent Healthcare creates the largest hospitalist management group in the country, which may or may not be a good thing, one hospitalist expert notes.

The deal, which closed last month, creates a company with more than 1,750 hospitalists in 180 hospitals nationwide. Reuters estimated the sale price at more than $375 million.

"We certainly don't care so much about biggest," says Robert Bessler, MD, chief executive officer of Sound Physicians, which will be the merged firms' name moving forward. "We're focused on trying to be the practice of choice for docs and provider of choice for hospitals—and really focus on performance as a business model to drive results."

John Nelson, MD, MHM, a principal in Nelson Flores Hospital Medicine Consultants and regular columnist for The Hospitalist, says he believes the impact of the merger will vary by market.

"Hospitalists in competing groups could benefit, for example, by being seen as a more attractive alternative for candidates in the market to join a practice, and large companies may be able to invest in innovation that might benefit all of us," Dr. Nelson says in an email. "But for others, it may seem to make things worse, for example, by influencing the local market toward lower compensation or higher workload. It will be very market-dependent."

Dr. Bessler says he believes the merger "creates incredible synergy." For example, Cogent has The Intensivist Group, which operates full-service intensivist programs, and it can now potentially expand to hospitals where Sound hospitalists work.

Conversely, Sound’s post-acute-care program can be expanded to hospitals where Cogent has a presence.

Dr. Bessler understands that being the largest group can be seen as a good or a bad thing by industry watchers. "I think it leads to further innovation," he says. "It pools resources to do better things for hospital medicine, for hospitals, for patients, and for docs. And the reality is that even on a combined basis, we have less than 5% of the market. It's a massive market."

Visit our website for more information on mergers in hospital medicine.

Sound Physicians' recent acquisition of Cogent Healthcare creates the largest hospitalist management group in the country, which may or may not be a good thing, one hospitalist expert notes.

The deal, which closed last month, creates a company with more than 1,750 hospitalists in 180 hospitals nationwide. Reuters estimated the sale price at more than $375 million.

"We certainly don't care so much about biggest," says Robert Bessler, MD, chief executive officer of Sound Physicians, which will be the merged firms' name moving forward. "We're focused on trying to be the practice of choice for docs and provider of choice for hospitals—and really focus on performance as a business model to drive results."

John Nelson, MD, MHM, a principal in Nelson Flores Hospital Medicine Consultants and regular columnist for The Hospitalist, says he believes the impact of the merger will vary by market.

"Hospitalists in competing groups could benefit, for example, by being seen as a more attractive alternative for candidates in the market to join a practice, and large companies may be able to invest in innovation that might benefit all of us," Dr. Nelson says in an email. "But for others, it may seem to make things worse, for example, by influencing the local market toward lower compensation or higher workload. It will be very market-dependent."

Dr. Bessler says he believes the merger "creates incredible synergy." For example, Cogent has The Intensivist Group, which operates full-service intensivist programs, and it can now potentially expand to hospitals where Sound hospitalists work.

Conversely, Sound’s post-acute-care program can be expanded to hospitals where Cogent has a presence.

Dr. Bessler understands that being the largest group can be seen as a good or a bad thing by industry watchers. "I think it leads to further innovation," he says. "It pools resources to do better things for hospital medicine, for hospitals, for patients, and for docs. And the reality is that even on a combined basis, we have less than 5% of the market. It's a massive market."

Visit our website for more information on mergers in hospital medicine.

Sound Physicians' recent acquisition of Cogent Healthcare creates the largest hospitalist management group in the country, which may or may not be a good thing, one hospitalist expert notes.

The deal, which closed last month, creates a company with more than 1,750 hospitalists in 180 hospitals nationwide. Reuters estimated the sale price at more than $375 million.

"We certainly don't care so much about biggest," says Robert Bessler, MD, chief executive officer of Sound Physicians, which will be the merged firms' name moving forward. "We're focused on trying to be the practice of choice for docs and provider of choice for hospitals—and really focus on performance as a business model to drive results."

John Nelson, MD, MHM, a principal in Nelson Flores Hospital Medicine Consultants and regular columnist for The Hospitalist, says he believes the impact of the merger will vary by market.

"Hospitalists in competing groups could benefit, for example, by being seen as a more attractive alternative for candidates in the market to join a practice, and large companies may be able to invest in innovation that might benefit all of us," Dr. Nelson says in an email. "But for others, it may seem to make things worse, for example, by influencing the local market toward lower compensation or higher workload. It will be very market-dependent."

Dr. Bessler says he believes the merger "creates incredible synergy." For example, Cogent has The Intensivist Group, which operates full-service intensivist programs, and it can now potentially expand to hospitals where Sound hospitalists work.

Conversely, Sound’s post-acute-care program can be expanded to hospitals where Cogent has a presence.

Dr. Bessler understands that being the largest group can be seen as a good or a bad thing by industry watchers. "I think it leads to further innovation," he says. "It pools resources to do better things for hospital medicine, for hospitals, for patients, and for docs. And the reality is that even on a combined basis, we have less than 5% of the market. It's a massive market."

Visit our website for more information on mergers in hospital medicine.

While typing this column, I could not recall the last time I saw a patient with “tennis elbow” (lateral epicondylitis) from actual tennis. Lateral epicondylitis peaks between the ages of 30 and 65 years and affects about 1.3% of this group – the vast majority of whom, I am quite suddenly convinced, do not play tennis. Pain is worse with wrist extension and typically affects the dominant hand. The most likely etiology is repeated microtrauma.

The examination is straightforward and about 90% will recover by 1 year without a surgical procedure. The unhappy customers who darken our doorways with worsening or nonimproving symptoms are the ones who make us wonder if we gave them effective conservative measures to begin with.

So what conservative measures are effective?

Sims and colleagues published a meta-analysis evaluating nonsurgical treatments for lateral epicondylitis. The review involved 58 studies (Hand 2014.9:419-46).

The investigators concluded that steroid injections provide relief only for the short term. The authors suggest that this may related to lateral epicondylitis being caused by repeated microtrauma rather than inflammation (perhaps this is why NSAIDs are not always beneficial either). Botulinum A, which works by paralyzing the extensor muscles, thereby allowing them to heal, is comparable to steroids. But patients may not love the experience of extensor muscle paralysis. Prolotherapy, injection of osmotics or irritants to promote inflammation in the target tissue, is also comparable to steroids. Platelet-rich plasma or autologous blood injections have uncertain relative benefit compared to steroids. Bracing with a counterforce brace (i.e., “tennis elbow strap”) or wrist extension splint, physical therapy, and shock wave therapy do not lessen pain or improve function in a dependable way.

This review leaves primary care clinicians who are uncomfortable injecting steroids into the arm with not much in the way of clearly effective evidence-based therapies. Personally, I ask my Ortho Hand colleagues to help me with the injection part. But only when patients fail to respond to what I give them.

So if this is a self-limited disease that gets better in 12-18 months, should we just be offering nothing more than activity modification? Patients will not accept this. My read on the data Sims collected is that there weren’t any quality studies comparing the elbow strap to offering nothing and patients tended to improve with it – although admittedly not clearly more than other therapies such as strengthening exercises. So for now, I will continue to recommend: 1) the elbow strap; 2) home exercises, and 3) lots and lots of reassurance. It’s all I got to give.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

While typing this column, I could not recall the last time I saw a patient with “tennis elbow” (lateral epicondylitis) from actual tennis. Lateral epicondylitis peaks between the ages of 30 and 65 years and affects about 1.3% of this group – the vast majority of whom, I am quite suddenly convinced, do not play tennis. Pain is worse with wrist extension and typically affects the dominant hand. The most likely etiology is repeated microtrauma.

The examination is straightforward and about 90% will recover by 1 year without a surgical procedure. The unhappy customers who darken our doorways with worsening or nonimproving symptoms are the ones who make us wonder if we gave them effective conservative measures to begin with.

So what conservative measures are effective?

Sims and colleagues published a meta-analysis evaluating nonsurgical treatments for lateral epicondylitis. The review involved 58 studies (Hand 2014.9:419-46).

The investigators concluded that steroid injections provide relief only for the short term. The authors suggest that this may related to lateral epicondylitis being caused by repeated microtrauma rather than inflammation (perhaps this is why NSAIDs are not always beneficial either). Botulinum A, which works by paralyzing the extensor muscles, thereby allowing them to heal, is comparable to steroids. But patients may not love the experience of extensor muscle paralysis. Prolotherapy, injection of osmotics or irritants to promote inflammation in the target tissue, is also comparable to steroids. Platelet-rich plasma or autologous blood injections have uncertain relative benefit compared to steroids. Bracing with a counterforce brace (i.e., “tennis elbow strap”) or wrist extension splint, physical therapy, and shock wave therapy do not lessen pain or improve function in a dependable way.

This review leaves primary care clinicians who are uncomfortable injecting steroids into the arm with not much in the way of clearly effective evidence-based therapies. Personally, I ask my Ortho Hand colleagues to help me with the injection part. But only when patients fail to respond to what I give them.

So if this is a self-limited disease that gets better in 12-18 months, should we just be offering nothing more than activity modification? Patients will not accept this. My read on the data Sims collected is that there weren’t any quality studies comparing the elbow strap to offering nothing and patients tended to improve with it – although admittedly not clearly more than other therapies such as strengthening exercises. So for now, I will continue to recommend: 1) the elbow strap; 2) home exercises, and 3) lots and lots of reassurance. It’s all I got to give.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

While typing this column, I could not recall the last time I saw a patient with “tennis elbow” (lateral epicondylitis) from actual tennis. Lateral epicondylitis peaks between the ages of 30 and 65 years and affects about 1.3% of this group – the vast majority of whom, I am quite suddenly convinced, do not play tennis. Pain is worse with wrist extension and typically affects the dominant hand. The most likely etiology is repeated microtrauma.

The examination is straightforward and about 90% will recover by 1 year without a surgical procedure. The unhappy customers who darken our doorways with worsening or nonimproving symptoms are the ones who make us wonder if we gave them effective conservative measures to begin with.

So what conservative measures are effective?

Sims and colleagues published a meta-analysis evaluating nonsurgical treatments for lateral epicondylitis. The review involved 58 studies (Hand 2014.9:419-46).

The investigators concluded that steroid injections provide relief only for the short term. The authors suggest that this may related to lateral epicondylitis being caused by repeated microtrauma rather than inflammation (perhaps this is why NSAIDs are not always beneficial either). Botulinum A, which works by paralyzing the extensor muscles, thereby allowing them to heal, is comparable to steroids. But patients may not love the experience of extensor muscle paralysis. Prolotherapy, injection of osmotics or irritants to promote inflammation in the target tissue, is also comparable to steroids. Platelet-rich plasma or autologous blood injections have uncertain relative benefit compared to steroids. Bracing with a counterforce brace (i.e., “tennis elbow strap”) or wrist extension splint, physical therapy, and shock wave therapy do not lessen pain or improve function in a dependable way.

This review leaves primary care clinicians who are uncomfortable injecting steroids into the arm with not much in the way of clearly effective evidence-based therapies. Personally, I ask my Ortho Hand colleagues to help me with the injection part. But only when patients fail to respond to what I give them.

So if this is a self-limited disease that gets better in 12-18 months, should we just be offering nothing more than activity modification? Patients will not accept this. My read on the data Sims collected is that there weren’t any quality studies comparing the elbow strap to offering nothing and patients tended to improve with it – although admittedly not clearly more than other therapies such as strengthening exercises. So for now, I will continue to recommend: 1) the elbow strap; 2) home exercises, and 3) lots and lots of reassurance. It’s all I got to give.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

[email protected]

SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

[email protected]

SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

[email protected]

Sutures, hemoclips, and electrocautery are the primary means of achieving hemostasis during gynecologic surgery. When these are inadequate or infeasible, topical hemostatic agents can be employed. Use of these agents has increased by 10%-21% since 2000, yet studies evaluating their use in gynecologic surgery are limited (J. Surg. Res. 2014;186:458-66).

Oxidized regenerated cellulose

Oxidized regenerated cellulose (Surgicel) is made from dissolved oxidized cellulose woven into a dry gauze sheet (J. Urol. 2006;176:2367-74). It is applied directly to tissue, creating a scaffold for platelet aggregation and decreasing tissue pH, further activating the clotting cascade (Surg. Infect. (Larchmt.) 2003;4:255-62). It is absorbed in 14 days, but can persist for 1 year.

Oxidized regenerated cellulose (ORC) is easily passed through laparoscopic trocars. One study found ORC efficacious in controlling tubal hemorrhage during laparoscopic sterilization (Int. J. Gynaecol. Obstet. 2003;82:221-2). It has also been shown to have bactericidal activity (Surg. Infect. (Larchmt.) 2003; 4:255-62) and prevent development of peritoneal adhesions (Acta. Chir. Scand. 1978;144:375-8).

Microfibrillar collagen

Microfibrillar collagen (Avitene) is made from bovine collagen in a powder or sponge sheet, and acts as a scaffold for platelet aggregation. It is applied directly to tissue and is absorbed in 3 months. One study found microfibrillar collagen (MC) use during cold knife conization resulted in nonsignificant reduction in operative time and similar hemostatic results compared to Sturmdorf suture (Obstet. Gynecol. 1978;51:118-22). MC also has been used to treat bleeding following uterine perforation and during laparoscopic hysterectomy.

Gelatins

Gelatins (Gelfoam, Surgifoam) are made of porcine collagen in a powder or foam (J. Urol. 2006;176:2367-74). It is applied directly to tissue, acting as a sponge to absorb blood. Pressure for several minutes is necessary for optimal hemostasis. Some surgeons moisten gelatins with topical thrombin prior to use, though no trials exist evaluating the efficacy of this maneuver.

Gelatin is absorbed in 4-6 weeks (J. Urol. 2006;176:2367-74) and can be passed through laparoscopic trocars. No studies have evaluated gelatins in gynecologic surgery so its applications are extrapolated from vascular and urologic surgery (J. Urol. 2006;176:2367-74).

Microporous polysaccharide spheres

Microporous polysaccharide spheres (Arista) form a polysaccharide powder made from potato starch. It absorbs water, concentrating platelets and other proteins to accelerate clot formation. It is applied to a dry surgical field and followed with gentle pressure. MPS is absorbed in 48 hours. No studies specifically evaluate the use of MPS in gynecologic surgery.

Topical thrombins

Thrombin (Thrombin-JMI, Evithrom, Recothrom) is derived from bovine, human, or recombinant sources. It converts fibrinogen to fibrin and activates factor XIII, platelets, and smooth muscle constriction (Biologics 2008;2:593-9). Thrombin is a spray or syringe, and is often used with gelatin foam (Thrombi-Gel) or matrix (FloSeal) (Biologics 2008;2:593-9). FloSeal use has been reported during ovarian cystectomy (J. Minim. Invasive. Gynecol. 2009;16:153-6), hysterotomy repair (J. Obstet. Gynaecol. 2012;32:34-5). During myomectomy, it was associated with decreased blood loss, transfusions, and shorter length of stay (Fertil. Steril. 2009;92:356-60).

Fibrin sealants

Fibrin sealants (Tisseel, TachoSil) are made of thrombin and concentrated fibrinogen from human plasma. They must be mixed prior to application and act by forming a fibrin clot. Tisseel can reduce hemorrhage after loop electrosurgical excision procedure (Gynecol. Obstet. Invest. 2012;74:1-5) and decreases operative time, time to hemostasis, and blood loss during laparoscopic myomectomy (Surg. Endosc. 2012;26:2046-53). Case reports describe the use of fibrin sealants in the management of obstetrical hemorrhage and hysterotomy repair.

Cost and complications

Hemostatic agents vary significantly in cost, but no comparative cost analyses exist. One study found that commercial insurance was associated with topical hemostatic agent use during gynecologic surgery (J. Surg. Res. 2014;186:458-66).

Use of ORC has been associated with postoperative abscess and imitation of abscess without true infection, and MC and gelatins can also increase infection risk. The dry hemostatic agents have been associated with thromboembolism. The complications of thrombins and fibrins are related to immune responses or transmission of pathogens. Recombinant thrombin is believed to be the safest option (J. Am. Coll. Surg. 2007;205:256-65). Floseal has been reported to cause diffuse pelvic inflammation and postoperative small bowel obstruction. Because of possible complications, it is important to use only the needed amount of product, and to dictate use in the operative note.

Despite widespread use of topical hemostatic agents in gynecologic surgery, studies are limited and these agents should be recommended only as adjuncts to conventional methods of achieving hemostasis.

Topical hemostatic agents are recommended for surgical fields that are less amenable to electrocautery, including denuded areas on peritoneal surfaces, and around important heat-sensitive structures such as nerves. The dry matrix agents (ORC, MC, gelatin, and MPS) are most useful in slowly bleeding areas or in patients with a bleeding diathesis. Thrombin and fibrin can be useful in situations when more significant bleeding is encountered. Complications arising from topical hemostatic agents are few.

Given current limited studies, the choice of product continues to depend on patient characteristics and surgeon preference.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at UNC-Chapel Hill. Dr. Soper is a professor of gynecologic oncology at UNC-Chapel Hill.

Sutures, hemoclips, and electrocautery are the primary means of achieving hemostasis during gynecologic surgery. When these are inadequate or infeasible, topical hemostatic agents can be employed. Use of these agents has increased by 10%-21% since 2000, yet studies evaluating their use in gynecologic surgery are limited (J. Surg. Res. 2014;186:458-66).

Oxidized regenerated cellulose

Oxidized regenerated cellulose (Surgicel) is made from dissolved oxidized cellulose woven into a dry gauze sheet (J. Urol. 2006;176:2367-74). It is applied directly to tissue, creating a scaffold for platelet aggregation and decreasing tissue pH, further activating the clotting cascade (Surg. Infect. (Larchmt.) 2003;4:255-62). It is absorbed in 14 days, but can persist for 1 year.

Oxidized regenerated cellulose (ORC) is easily passed through laparoscopic trocars. One study found ORC efficacious in controlling tubal hemorrhage during laparoscopic sterilization (Int. J. Gynaecol. Obstet. 2003;82:221-2). It has also been shown to have bactericidal activity (Surg. Infect. (Larchmt.) 2003; 4:255-62) and prevent development of peritoneal adhesions (Acta. Chir. Scand. 1978;144:375-8).

Microfibrillar collagen

Microfibrillar collagen (Avitene) is made from bovine collagen in a powder or sponge sheet, and acts as a scaffold for platelet aggregation. It is applied directly to tissue and is absorbed in 3 months. One study found microfibrillar collagen (MC) use during cold knife conization resulted in nonsignificant reduction in operative time and similar hemostatic results compared to Sturmdorf suture (Obstet. Gynecol. 1978;51:118-22). MC also has been used to treat bleeding following uterine perforation and during laparoscopic hysterectomy.

Gelatins

Gelatins (Gelfoam, Surgifoam) are made of porcine collagen in a powder or foam (J. Urol. 2006;176:2367-74). It is applied directly to tissue, acting as a sponge to absorb blood. Pressure for several minutes is necessary for optimal hemostasis. Some surgeons moisten gelatins with topical thrombin prior to use, though no trials exist evaluating the efficacy of this maneuver.

Gelatin is absorbed in 4-6 weeks (J. Urol. 2006;176:2367-74) and can be passed through laparoscopic trocars. No studies have evaluated gelatins in gynecologic surgery so its applications are extrapolated from vascular and urologic surgery (J. Urol. 2006;176:2367-74).

Microporous polysaccharide spheres

Microporous polysaccharide spheres (Arista) form a polysaccharide powder made from potato starch. It absorbs water, concentrating platelets and other proteins to accelerate clot formation. It is applied to a dry surgical field and followed with gentle pressure. MPS is absorbed in 48 hours. No studies specifically evaluate the use of MPS in gynecologic surgery.

Topical thrombins

Thrombin (Thrombin-JMI, Evithrom, Recothrom) is derived from bovine, human, or recombinant sources. It converts fibrinogen to fibrin and activates factor XIII, platelets, and smooth muscle constriction (Biologics 2008;2:593-9). Thrombin is a spray or syringe, and is often used with gelatin foam (Thrombi-Gel) or matrix (FloSeal) (Biologics 2008;2:593-9). FloSeal use has been reported during ovarian cystectomy (J. Minim. Invasive. Gynecol. 2009;16:153-6), hysterotomy repair (J. Obstet. Gynaecol. 2012;32:34-5). During myomectomy, it was associated with decreased blood loss, transfusions, and shorter length of stay (Fertil. Steril. 2009;92:356-60).

Fibrin sealants

Fibrin sealants (Tisseel, TachoSil) are made of thrombin and concentrated fibrinogen from human plasma. They must be mixed prior to application and act by forming a fibrin clot. Tisseel can reduce hemorrhage after loop electrosurgical excision procedure (Gynecol. Obstet. Invest. 2012;74:1-5) and decreases operative time, time to hemostasis, and blood loss during laparoscopic myomectomy (Surg. Endosc. 2012;26:2046-53). Case reports describe the use of fibrin sealants in the management of obstetrical hemorrhage and hysterotomy repair.

Cost and complications

Hemostatic agents vary significantly in cost, but no comparative cost analyses exist. One study found that commercial insurance was associated with topical hemostatic agent use during gynecologic surgery (J. Surg. Res. 2014;186:458-66).

Use of ORC has been associated with postoperative abscess and imitation of abscess without true infection, and MC and gelatins can also increase infection risk. The dry hemostatic agents have been associated with thromboembolism. The complications of thrombins and fibrins are related to immune responses or transmission of pathogens. Recombinant thrombin is believed to be the safest option (J. Am. Coll. Surg. 2007;205:256-65). Floseal has been reported to cause diffuse pelvic inflammation and postoperative small bowel obstruction. Because of possible complications, it is important to use only the needed amount of product, and to dictate use in the operative note.

Despite widespread use of topical hemostatic agents in gynecologic surgery, studies are limited and these agents should be recommended only as adjuncts to conventional methods of achieving hemostasis.

Topical hemostatic agents are recommended for surgical fields that are less amenable to electrocautery, including denuded areas on peritoneal surfaces, and around important heat-sensitive structures such as nerves. The dry matrix agents (ORC, MC, gelatin, and MPS) are most useful in slowly bleeding areas or in patients with a bleeding diathesis. Thrombin and fibrin can be useful in situations when more significant bleeding is encountered. Complications arising from topical hemostatic agents are few.

Given current limited studies, the choice of product continues to depend on patient characteristics and surgeon preference.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at UNC-Chapel Hill. Dr. Soper is a professor of gynecologic oncology at UNC-Chapel Hill.

Sutures, hemoclips, and electrocautery are the primary means of achieving hemostasis during gynecologic surgery. When these are inadequate or infeasible, topical hemostatic agents can be employed. Use of these agents has increased by 10%-21% since 2000, yet studies evaluating their use in gynecologic surgery are limited (J. Surg. Res. 2014;186:458-66).

Oxidized regenerated cellulose

Oxidized regenerated cellulose (Surgicel) is made from dissolved oxidized cellulose woven into a dry gauze sheet (J. Urol. 2006;176:2367-74). It is applied directly to tissue, creating a scaffold for platelet aggregation and decreasing tissue pH, further activating the clotting cascade (Surg. Infect. (Larchmt.) 2003;4:255-62). It is absorbed in 14 days, but can persist for 1 year.

Oxidized regenerated cellulose (ORC) is easily passed through laparoscopic trocars. One study found ORC efficacious in controlling tubal hemorrhage during laparoscopic sterilization (Int. J. Gynaecol. Obstet. 2003;82:221-2). It has also been shown to have bactericidal activity (Surg. Infect. (Larchmt.) 2003; 4:255-62) and prevent development of peritoneal adhesions (Acta. Chir. Scand. 1978;144:375-8).

Microfibrillar collagen

Microfibrillar collagen (Avitene) is made from bovine collagen in a powder or sponge sheet, and acts as a scaffold for platelet aggregation. It is applied directly to tissue and is absorbed in 3 months. One study found microfibrillar collagen (MC) use during cold knife conization resulted in nonsignificant reduction in operative time and similar hemostatic results compared to Sturmdorf suture (Obstet. Gynecol. 1978;51:118-22). MC also has been used to treat bleeding following uterine perforation and during laparoscopic hysterectomy.

Gelatins

Gelatins (Gelfoam, Surgifoam) are made of porcine collagen in a powder or foam (J. Urol. 2006;176:2367-74). It is applied directly to tissue, acting as a sponge to absorb blood. Pressure for several minutes is necessary for optimal hemostasis. Some surgeons moisten gelatins with topical thrombin prior to use, though no trials exist evaluating the efficacy of this maneuver.

Gelatin is absorbed in 4-6 weeks (J. Urol. 2006;176:2367-74) and can be passed through laparoscopic trocars. No studies have evaluated gelatins in gynecologic surgery so its applications are extrapolated from vascular and urologic surgery (J. Urol. 2006;176:2367-74).

Microporous polysaccharide spheres

Microporous polysaccharide spheres (Arista) form a polysaccharide powder made from potato starch. It absorbs water, concentrating platelets and other proteins to accelerate clot formation. It is applied to a dry surgical field and followed with gentle pressure. MPS is absorbed in 48 hours. No studies specifically evaluate the use of MPS in gynecologic surgery.

Topical thrombins

Thrombin (Thrombin-JMI, Evithrom, Recothrom) is derived from bovine, human, or recombinant sources. It converts fibrinogen to fibrin and activates factor XIII, platelets, and smooth muscle constriction (Biologics 2008;2:593-9). Thrombin is a spray or syringe, and is often used with gelatin foam (Thrombi-Gel) or matrix (FloSeal) (Biologics 2008;2:593-9). FloSeal use has been reported during ovarian cystectomy (J. Minim. Invasive. Gynecol. 2009;16:153-6), hysterotomy repair (J. Obstet. Gynaecol. 2012;32:34-5). During myomectomy, it was associated with decreased blood loss, transfusions, and shorter length of stay (Fertil. Steril. 2009;92:356-60).

Fibrin sealants

Fibrin sealants (Tisseel, TachoSil) are made of thrombin and concentrated fibrinogen from human plasma. They must be mixed prior to application and act by forming a fibrin clot. Tisseel can reduce hemorrhage after loop electrosurgical excision procedure (Gynecol. Obstet. Invest. 2012;74:1-5) and decreases operative time, time to hemostasis, and blood loss during laparoscopic myomectomy (Surg. Endosc. 2012;26:2046-53). Case reports describe the use of fibrin sealants in the management of obstetrical hemorrhage and hysterotomy repair.

Cost and complications

Hemostatic agents vary significantly in cost, but no comparative cost analyses exist. One study found that commercial insurance was associated with topical hemostatic agent use during gynecologic surgery (J. Surg. Res. 2014;186:458-66).

Use of ORC has been associated with postoperative abscess and imitation of abscess without true infection, and MC and gelatins can also increase infection risk. The dry hemostatic agents have been associated with thromboembolism. The complications of thrombins and fibrins are related to immune responses or transmission of pathogens. Recombinant thrombin is believed to be the safest option (J. Am. Coll. Surg. 2007;205:256-65). Floseal has been reported to cause diffuse pelvic inflammation and postoperative small bowel obstruction. Because of possible complications, it is important to use only the needed amount of product, and to dictate use in the operative note.

Despite widespread use of topical hemostatic agents in gynecologic surgery, studies are limited and these agents should be recommended only as adjuncts to conventional methods of achieving hemostasis.

Topical hemostatic agents are recommended for surgical fields that are less amenable to electrocautery, including denuded areas on peritoneal surfaces, and around important heat-sensitive structures such as nerves. The dry matrix agents (ORC, MC, gelatin, and MPS) are most useful in slowly bleeding areas or in patients with a bleeding diathesis. Thrombin and fibrin can be useful in situations when more significant bleeding is encountered. Complications arising from topical hemostatic agents are few.

Given current limited studies, the choice of product continues to depend on patient characteristics and surgeon preference.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at UNC-Chapel Hill. Dr. Soper is a professor of gynecologic oncology at UNC-Chapel Hill.

He has aged a year since President Obama nominated him for U.S. Surgeon General in November 2013, but on Monday Boston hospitalist Vivek Murthy, MD, was confirmed as the highest physician in America.

According to multiple sources, Dr. Murthy’s outspoken support for stricter gun laws and belief that guns are a public health issue delayed his confirmation due to opposition from the National Rifle Association (NRA), which in a letter to Senate leadership in February said Dr. Murthy’s confirmation would be a “prescription for disaster for America’s gun owners.”

Despite this, Senate Democrats approved his four-year appointment in a 51-43 vote that cut along party lines. In his confirmation hearing in February, Dr. Murthy said he does not “intend to use the surgeon general’s office as a bully pulpit for gun control.”

Dr. Murthy, 37, earned his medical and business degrees from Yale and for the last decade has worked as both an internist and a hospitalist at Brigham and Women’s Hospital in Boston. He is the youngest Surgeon General ever, and the first of Indian-American descent.

"On behalf of America's 44,000 hospitalists, I congratulate Dr. Murthy, a fellow hospitalist and one of our SHM members, on his historic appointment to U.S. Surgeon General," says Society of Hospital Medicine President Burke Kealey, MD, SFHM. "Being America’s doctor requires many of the same traits required of hospitalists: leadership, sharp clinical skills, and the ability to engage with patients. And, like hospitalists in thousands of hospitals across the country, I am confident Dr. Murthy will become an agent of change to improve delivery of care in our country."

In 2008, Dr. Murthy founded Doctors for Obama, a non-profit, grassroots organization of 16,000 physicians and medical students dedicated to transforming the healthcare system. After the election, he changed the name of the organization to Doctors for America. He also started the software company TrialNetworks in 2007 to aid in drug development, and, in 1995, he started an HIV and AIDS education non-profit in India called VISIONS Worldwide.

In a statement from the White House Monday, President Obama applauded the Senate for Dr. Murthy’s confirmation, saying: “Vivek’s confirmation makes us better positioned to save lives around the world and protect the American people here at home.”

Dr. Murthy replaces acting Surgeon General Boris Lushniak, who took over when Regina Benjamin resigned in July 2013. The surgeon general is the U.S.’ top spokesperson on all matters of public health and oversees the 6,700 members of the U.S. Public Health Service Commissioned Corps.

Kelly April Tyrrell is a freelance writer in Madison, Wis.

 Information for this report was published online at cnn.com and usatoday.com.

He has aged a year since President Obama nominated him for U.S. Surgeon General in November 2013, but on Monday Boston hospitalist Vivek Murthy, MD, was confirmed as the highest physician in America.

According to multiple sources, Dr. Murthy’s outspoken support for stricter gun laws and belief that guns are a public health issue delayed his confirmation due to opposition from the National Rifle Association (NRA), which in a letter to Senate leadership in February said Dr. Murthy’s confirmation would be a “prescription for disaster for America’s gun owners.”

Despite this, Senate Democrats approved his four-year appointment in a 51-43 vote that cut along party lines. In his confirmation hearing in February, Dr. Murthy said he does not “intend to use the surgeon general’s office as a bully pulpit for gun control.”

Dr. Murthy, 37, earned his medical and business degrees from Yale and for the last decade has worked as both an internist and a hospitalist at Brigham and Women’s Hospital in Boston. He is the youngest Surgeon General ever, and the first of Indian-American descent.

"On behalf of America's 44,000 hospitalists, I congratulate Dr. Murthy, a fellow hospitalist and one of our SHM members, on his historic appointment to U.S. Surgeon General," says Society of Hospital Medicine President Burke Kealey, MD, SFHM. "Being America’s doctor requires many of the same traits required of hospitalists: leadership, sharp clinical skills, and the ability to engage with patients. And, like hospitalists in thousands of hospitals across the country, I am confident Dr. Murthy will become an agent of change to improve delivery of care in our country."

In 2008, Dr. Murthy founded Doctors for Obama, a non-profit, grassroots organization of 16,000 physicians and medical students dedicated to transforming the healthcare system. After the election, he changed the name of the organization to Doctors for America. He also started the software company TrialNetworks in 2007 to aid in drug development, and, in 1995, he started an HIV and AIDS education non-profit in India called VISIONS Worldwide.

In a statement from the White House Monday, President Obama applauded the Senate for Dr. Murthy’s confirmation, saying: “Vivek’s confirmation makes us better positioned to save lives around the world and protect the American people here at home.”

Dr. Murthy replaces acting Surgeon General Boris Lushniak, who took over when Regina Benjamin resigned in July 2013. The surgeon general is the U.S.’ top spokesperson on all matters of public health and oversees the 6,700 members of the U.S. Public Health Service Commissioned Corps.

Kelly April Tyrrell is a freelance writer in Madison, Wis.

 Information for this report was published online at cnn.com and usatoday.com.

He has aged a year since President Obama nominated him for U.S. Surgeon General in November 2013, but on Monday Boston hospitalist Vivek Murthy, MD, was confirmed as the highest physician in America.

According to multiple sources, Dr. Murthy’s outspoken support for stricter gun laws and belief that guns are a public health issue delayed his confirmation due to opposition from the National Rifle Association (NRA), which in a letter to Senate leadership in February said Dr. Murthy’s confirmation would be a “prescription for disaster for America’s gun owners.”

Despite this, Senate Democrats approved his four-year appointment in a 51-43 vote that cut along party lines. In his confirmation hearing in February, Dr. Murthy said he does not “intend to use the surgeon general’s office as a bully pulpit for gun control.”

Dr. Murthy, 37, earned his medical and business degrees from Yale and for the last decade has worked as both an internist and a hospitalist at Brigham and Women’s Hospital in Boston. He is the youngest Surgeon General ever, and the first of Indian-American descent.

"On behalf of America's 44,000 hospitalists, I congratulate Dr. Murthy, a fellow hospitalist and one of our SHM members, on his historic appointment to U.S. Surgeon General," says Society of Hospital Medicine President Burke Kealey, MD, SFHM. "Being America’s doctor requires many of the same traits required of hospitalists: leadership, sharp clinical skills, and the ability to engage with patients. And, like hospitalists in thousands of hospitals across the country, I am confident Dr. Murthy will become an agent of change to improve delivery of care in our country."

In 2008, Dr. Murthy founded Doctors for Obama, a non-profit, grassroots organization of 16,000 physicians and medical students dedicated to transforming the healthcare system. After the election, he changed the name of the organization to Doctors for America. He also started the software company TrialNetworks in 2007 to aid in drug development, and, in 1995, he started an HIV and AIDS education non-profit in India called VISIONS Worldwide.

In a statement from the White House Monday, President Obama applauded the Senate for Dr. Murthy’s confirmation, saying: “Vivek’s confirmation makes us better positioned to save lives around the world and protect the American people here at home.”

Dr. Murthy replaces acting Surgeon General Boris Lushniak, who took over when Regina Benjamin resigned in July 2013. The surgeon general is the U.S.’ top spokesperson on all matters of public health and oversees the 6,700 members of the U.S. Public Health Service Commissioned Corps.

Kelly April Tyrrell is a freelance writer in Madison, Wis.

 Information for this report was published online at cnn.com and usatoday.com.

SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.

Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).

Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*

CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.

“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”

“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”

More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.

Updated results

At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019.  He and his colleagues previously reported results in children and adults with ALL in NEJM.

Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19⁺ and 5 were CD19^-.

Dr Grupp explained that CD19⁺ relapses represent waning T cells, and CD19^- relapses represent true antigen escape. The latter patients still have CTL019 cells.

Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.

The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.

Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.

“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”

Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.

To date, there has been no graft-vs-host disease.

In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.

Persistence and proliferation

“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”

Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.

Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19⁺ recurrence is overrepresented, Dr Grupp noted.

Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.

Toxicity

Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.

Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.

The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).

“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.

Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.

Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.

“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.

B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.

Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.

Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.

CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.

*Data in the presentation differ from the abstract.

SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.

Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).

Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*

CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.

“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”

“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”

More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.

Updated results

At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019.  He and his colleagues previously reported results in children and adults with ALL in NEJM.

Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19⁺ and 5 were CD19^-.

Dr Grupp explained that CD19⁺ relapses represent waning T cells, and CD19^- relapses represent true antigen escape. The latter patients still have CTL019 cells.

Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.

The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.

Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.

“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”

Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.

To date, there has been no graft-vs-host disease.

In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.

Persistence and proliferation

“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”

Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.

Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19⁺ recurrence is overrepresented, Dr Grupp noted.

Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.

Toxicity

Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.

Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.

The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).

“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.

Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.

Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.

“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.

B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.

Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.

Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.

CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.

*Data in the presentation differ from the abstract.

SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.

Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).

Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*

CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.

“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”

“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”

More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.

Updated results

At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019.  He and his colleagues previously reported results in children and adults with ALL in NEJM.

Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19⁺ and 5 were CD19^-.

Dr Grupp explained that CD19⁺ relapses represent waning T cells, and CD19^- relapses represent true antigen escape. The latter patients still have CTL019 cells.

Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.

The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.

Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.

“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”

Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.

To date, there has been no graft-vs-host disease.

In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.

Persistence and proliferation

“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”

Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.

Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19⁺ recurrence is overrepresented, Dr Grupp noted.

Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.

Toxicity

Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.

Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.

The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).

“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.

Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.

Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.

“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.

B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.

Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.

Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.

CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Smiling baby

Credit: Petr Kratochvil

Young children who undergo total body irradiation (TBI) in preparation for hematopoietic stem cell transplant (HSCT) are at a higher risk for a decline in IQ, according to research published in the Journal of Clinical Oncology.

The study showed that most young patients don’t experience lasting effects on their IQ following HSCT.

However, patients who underwent HSCT at 3 years of age or younger and received TBI had a greater risk of intellectual decline after transplant.

“For the great majority of patients, these findings provide reassurance that transplantation will not have a significant negative impact on cognitive development,” said study author Sean Phipps, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

“We have also identified a high-risk group of younger patients who may benefit from more intensive interventions, including developmental stimulation and other rehabilitative therapies designed to prevent a decline in intellectual functioning and aid in recovery.”

Dr Phipps and his colleagues tracked the IQ scores of 170 St Jude patients before HSCT and for 5 years after the procedure. The patients were 4 months to 23 years of age when their transplants occurred.

Before HSCT, the average IQ scores of all patients were in the normal range. One year after transplant, average IQ scores of patients aged 5 and younger had declined sharply.

But the scores of most patients rebounded in subsequent years. Five years after the procedure, IQ scores for most patients, even the youngest survivors, had largely recovered and fell within the range of normal intelligence.

Patients in the high-risk group were the lone exception. The IQ scores of patients who were both aged 3 or younger when their transplants occurred and who received TBI failed to recover from the first-year decline.

Five years after HSCT, these survivors had average IQ scores in the low-normal range of intelligence. Their scores were more than 16 points lower than the scores of patients who were just as young when their transplants occurred but did not receive TBI.

Furthermore, of the 72 patients in this study whose transplants included TBI, there was a long-term impact on intellectual functioning only for patients who were 3 or younger at transplant.

“The significant first-year decline reflects the intensity of transplantation, which our results suggest leads to greater disruption in development in the youngest children than was previously recognized,” said study author Victoria Willard, PhD, also of St Jude.

The researchers said these findings are good news for most parents whose children must undergo HSCT and provide another reason for hope of good long-term outcomes.

For those whose children are in the newly recognized high-risk group, increased attention and activities designed to stimulate cognitive development may help to prevent reduced IQ following transplant, according to Dr Phipps.

Smiling baby

Credit: Petr Kratochvil

Young children who undergo total body irradiation (TBI) in preparation for hematopoietic stem cell transplant (HSCT) are at a higher risk for a decline in IQ, according to research published in the Journal of Clinical Oncology.

The study showed that most young patients don’t experience lasting effects on their IQ following HSCT.

However, patients who underwent HSCT at 3 years of age or younger and received TBI had a greater risk of intellectual decline after transplant.

“For the great majority of patients, these findings provide reassurance that transplantation will not have a significant negative impact on cognitive development,” said study author Sean Phipps, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

“We have also identified a high-risk group of younger patients who may benefit from more intensive interventions, including developmental stimulation and other rehabilitative therapies designed to prevent a decline in intellectual functioning and aid in recovery.”

Dr Phipps and his colleagues tracked the IQ scores of 170 St Jude patients before HSCT and for 5 years after the procedure. The patients were 4 months to 23 years of age when their transplants occurred.

Before HSCT, the average IQ scores of all patients were in the normal range. One year after transplant, average IQ scores of patients aged 5 and younger had declined sharply.

But the scores of most patients rebounded in subsequent years. Five years after the procedure, IQ scores for most patients, even the youngest survivors, had largely recovered and fell within the range of normal intelligence.

Patients in the high-risk group were the lone exception. The IQ scores of patients who were both aged 3 or younger when their transplants occurred and who received TBI failed to recover from the first-year decline.

Five years after HSCT, these survivors had average IQ scores in the low-normal range of intelligence. Their scores were more than 16 points lower than the scores of patients who were just as young when their transplants occurred but did not receive TBI.

Furthermore, of the 72 patients in this study whose transplants included TBI, there was a long-term impact on intellectual functioning only for patients who were 3 or younger at transplant.

“The significant first-year decline reflects the intensity of transplantation, which our results suggest leads to greater disruption in development in the youngest children than was previously recognized,” said study author Victoria Willard, PhD, also of St Jude.

The researchers said these findings are good news for most parents whose children must undergo HSCT and provide another reason for hope of good long-term outcomes.

For those whose children are in the newly recognized high-risk group, increased attention and activities designed to stimulate cognitive development may help to prevent reduced IQ following transplant, according to Dr Phipps.

Smiling baby

Credit: Petr Kratochvil

Young children who undergo total body irradiation (TBI) in preparation for hematopoietic stem cell transplant (HSCT) are at a higher risk for a decline in IQ, according to research published in the Journal of Clinical Oncology.

The study showed that most young patients don’t experience lasting effects on their IQ following HSCT.

However, patients who underwent HSCT at 3 years of age or younger and received TBI had a greater risk of intellectual decline after transplant.

“For the great majority of patients, these findings provide reassurance that transplantation will not have a significant negative impact on cognitive development,” said study author Sean Phipps, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

“We have also identified a high-risk group of younger patients who may benefit from more intensive interventions, including developmental stimulation and other rehabilitative therapies designed to prevent a decline in intellectual functioning and aid in recovery.”

Dr Phipps and his colleagues tracked the IQ scores of 170 St Jude patients before HSCT and for 5 years after the procedure. The patients were 4 months to 23 years of age when their transplants occurred.

Before HSCT, the average IQ scores of all patients were in the normal range. One year after transplant, average IQ scores of patients aged 5 and younger had declined sharply.

But the scores of most patients rebounded in subsequent years. Five years after the procedure, IQ scores for most patients, even the youngest survivors, had largely recovered and fell within the range of normal intelligence.

Patients in the high-risk group were the lone exception. The IQ scores of patients who were both aged 3 or younger when their transplants occurred and who received TBI failed to recover from the first-year decline.

Five years after HSCT, these survivors had average IQ scores in the low-normal range of intelligence. Their scores were more than 16 points lower than the scores of patients who were just as young when their transplants occurred but did not receive TBI.

Furthermore, of the 72 patients in this study whose transplants included TBI, there was a long-term impact on intellectual functioning only for patients who were 3 or younger at transplant.

“The significant first-year decline reflects the intensity of transplantation, which our results suggest leads to greater disruption in development in the youngest children than was previously recognized,” said study author Victoria Willard, PhD, also of St Jude.

The researchers said these findings are good news for most parents whose children must undergo HSCT and provide another reason for hope of good long-term outcomes.

For those whose children are in the newly recognized high-risk group, increased attention and activities designed to stimulate cognitive development may help to prevent reduced IQ following transplant, according to Dr Phipps.