Seems that none of my patients sleeps, or at least not very well. Indeed, population-based studies suggest that almost one-third of adults report difficulty initiating or maintaining sleep, waking up too early, and/or nonrestorative or poor quality of sleep.

Light-emitting electronic “e-readers” or “e-books” have exploded as a favorite medium for reading. Many of my patients tell me that when they are unable to sleep, they read. Much of this reading occurs on e-books. But artificial light can produce alerting effects and suppress melatonin. This might be causing or worsening the national insomnia epidemic.

Dr. Anne-Marie Chang and colleagues conducted a randomized, crossover study evaluating the impact of an e-book and a traditional book on sleep (PNAS 2014 Dec. 22 [doi:10.1073/pnas.1418490112]). In the study, 12 healthy young adults were randomized to two conditions: 1) reading an e-book for 4 hours before bedtime; or 2) reading a printed book for 4 hours before bedtime on 5 consecutive evenings. Participants then switched conditions.

The e-book suppressed evening levels of melatonin by 55%, whereas the printed book showed no suppression, and the e-book shifted the melatonin onset to more than 1.5 hours later. Compared with the printed book, the e-book also significantly increased sleep latency (10 minutes longer), decreased REM sleep by11 minutes, decreased evening sleepiness, and increased morning sleepiness.

But not all e-book readers are created equal. Screens of devices used in the current study emit blue light (wavelength 452 nm), the type of light most implicated in melatonin suppression. Newer “e-ink” readers do not emit this light and are “front lit,” with light cast inward rather than outward.

People struggling with insomnia should be encouraged to explore the e-ink options. The table included in the study can provide some guidance as to the type of e-book that may be most beneficial to our sleepy patients.

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.

Seems that none of my patients sleeps, or at least not very well. Indeed, population-based studies suggest that almost one-third of adults report difficulty initiating or maintaining sleep, waking up too early, and/or nonrestorative or poor quality of sleep.

Light-emitting electronic “e-readers” or “e-books” have exploded as a favorite medium for reading. Many of my patients tell me that when they are unable to sleep, they read. Much of this reading occurs on e-books. But artificial light can produce alerting effects and suppress melatonin. This might be causing or worsening the national insomnia epidemic.

Dr. Anne-Marie Chang and colleagues conducted a randomized, crossover study evaluating the impact of an e-book and a traditional book on sleep (PNAS 2014 Dec. 22 [doi:10.1073/pnas.1418490112]). In the study, 12 healthy young adults were randomized to two conditions: 1) reading an e-book for 4 hours before bedtime; or 2) reading a printed book for 4 hours before bedtime on 5 consecutive evenings. Participants then switched conditions.

The e-book suppressed evening levels of melatonin by 55%, whereas the printed book showed no suppression, and the e-book shifted the melatonin onset to more than 1.5 hours later. Compared with the printed book, the e-book also significantly increased sleep latency (10 minutes longer), decreased REM sleep by11 minutes, decreased evening sleepiness, and increased morning sleepiness.

But not all e-book readers are created equal. Screens of devices used in the current study emit blue light (wavelength 452 nm), the type of light most implicated in melatonin suppression. Newer “e-ink” readers do not emit this light and are “front lit,” with light cast inward rather than outward.

People struggling with insomnia should be encouraged to explore the e-ink options. The table included in the study can provide some guidance as to the type of e-book that may be most beneficial to our sleepy patients.

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.

Seems that none of my patients sleeps, or at least not very well. Indeed, population-based studies suggest that almost one-third of adults report difficulty initiating or maintaining sleep, waking up too early, and/or nonrestorative or poor quality of sleep.

Light-emitting electronic “e-readers” or “e-books” have exploded as a favorite medium for reading. Many of my patients tell me that when they are unable to sleep, they read. Much of this reading occurs on e-books. But artificial light can produce alerting effects and suppress melatonin. This might be causing or worsening the national insomnia epidemic.

Dr. Anne-Marie Chang and colleagues conducted a randomized, crossover study evaluating the impact of an e-book and a traditional book on sleep (PNAS 2014 Dec. 22 [doi:10.1073/pnas.1418490112]). In the study, 12 healthy young adults were randomized to two conditions: 1) reading an e-book for 4 hours before bedtime; or 2) reading a printed book for 4 hours before bedtime on 5 consecutive evenings. Participants then switched conditions.

The e-book suppressed evening levels of melatonin by 55%, whereas the printed book showed no suppression, and the e-book shifted the melatonin onset to more than 1.5 hours later. Compared with the printed book, the e-book also significantly increased sleep latency (10 minutes longer), decreased REM sleep by11 minutes, decreased evening sleepiness, and increased morning sleepiness.

But not all e-book readers are created equal. Screens of devices used in the current study emit blue light (wavelength 452 nm), the type of light most implicated in melatonin suppression. Newer “e-ink” readers do not emit this light and are “front lit,” with light cast inward rather than outward.

People struggling with insomnia should be encouraged to explore the e-ink options. The table included in the study can provide some guidance as to the type of e-book that may be most beneficial to our sleepy patients.

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.

Question: A patient alleges that an ophthalmologist was negligent in performing blepharoplasty. The surgical site became infected and left the patient with a disfigured eye. An infectious disease specialist was to testify as plaintiff’s expert, but the defense, relying on a state statute, objected that the expert-to-be had no specialized training in ophthalmology.

Correct statements about expert medical testimony include the following, except:

A. The federal Rules of Evidence require that an expert possess the relevant knowledge, skill, education, training, or experience.

B. Only a few states have enacted statutes specifying that an expert must be in the same or similar specialty as the defendant.

C. Advocates contend that such statutes reduce frivolous lawsuits by limiting expert shopping and the use of “hired guns.”

D. It is the sitting judge, not the jury, who interprets the statute and decides whether a witness qualifies as an expert.

E. In some cases, a nondoctor such as a nurse or pharmacist may be allowed to offer expert testimony against a doctor.

Answer: B. Lay testimony is usually insufficient to define the standard of care in a claim of medical malpractice, and “the question of negligence must be decided by reference to relevant medical standards of care for which the plaintiff carries the burden of proving through expert medical testimony” (Craft v. Peebles, 893 P.2d 138 [Haw.1995]). Court rules of evidence dictate that the expert must possess the knowledge, skill, experience, training, or education for establishing that standard.

In coming to an opinion, the expert may rely on external evidence in the form of a book, treatise, or article; and although these sources represent hearsay evidence, they are admissible to enable the expert witness to form his/her opinion.

The facts of the multiple-choice question above are taken from a recent case (Edwards v. Sunrise Ophthalmology ASC, LLC, 134 So. 3d 1056 [Fla. 4th DCA 2013]), whose appeal is yet to be heard by the Florida Supreme Court. The plaintiff alleged that the surgical site was infected with nocardia during a lower-lid blepharoplasty, which caused her to undergo additional surgery with resulting disfigurement of the eye.

A lower court disqualified the plaintiff’s expert, an infectious disease specialist, based on a Florida statute stipulating that expert medical opinion can be offered only by one in the “same or similar specialty” (Section 766.102, Florida Statutes (2009)). In the words of the court, “Simply put, the infectious disease doctor is not an eye surgeon, nor is the ophthalmologist an infectious disease doctor.”

More than half of all the states have a medical-expert law, many with language comparable to the Florida statute. The idea behind such a statute, frequently enacted as part of a state’s tort reform, is to limit expert shopping and the use of hired guns and “junk science.”

Unsurprisingly, litigation abounds over the statutory language.

For example, a Maryland court ruled that a vascular surgeon was qualified to set the standard of care when an orthopedic surgeon’s alleged negligence caused a patient to lose a leg following knee surgery. The court found the two specialties to be “related,” because the orthopedic complication was vascular in origin.

In some jurisdictions without strict statutory requirements, doctors are more likely to be allowed to testify outside their specialty.

Instances of professionals of unlike specialties qualifying as experts include a nephrologist testifying against a urologist, an infectious disease specialist offering an expert opinion in a stroke case, a pharmacist testifying on the issue of a medication side effect, and a nurse on bedsores. Georgia requires only that an expert show significant familiarity with the area of practice in which the expert opinion is to be given. Still, in a sleep apnea case (Nathans v. Diamond, 654 S.E.2d 121 [Ga. 2007]), the court held that a pulmonologist was not qualified to testify on the standard of surgical care provided by an otolaryngologist.

Besides arguing over the statutory language, litigants have also raised questions of constitutionality. For example, Arizona’s statute ARS §12-2604 (A) requires a medical expert to be a specialist who is actively practicing or teaching in that area of medicine. The state court of appeals held that this violated the separation of powers doctrine (conflicting with Arizona Rule of Evidence 702), but the Supreme Court of Arizona subsequently reversed and reinstated the law (Seisinger v. Siebel, 203 P.3d 483 [Ariz. 2009]).

More recently, the same court upheld the constitutionality of the requirement that an expert share “the same specialty” as the treating physician, and disqualified an adult hematologist from serving as an expert because the defendant was a pediatric hematologist, not an adult hematologist (Baker v. University Physicians Healthcare, 296 P.3d 42 [Ariz. 2013]).

Another issue deals with the locality rule. In an Illinois case, the court accepted an out-of-state plaintiff expert based on his qualifications, competency, and familiarity with standards in the defendant’s community. The case dealt with the development of a rectovaginal fistula that complicated an episiotomy during delivery (Purtill v. Hess, 489 N.E.2d 867 [Ill. 1986]).

The defense attempted to exclude the expert, alleging the lack of familiarity with the standards in the community (Rantoul, Ill.). However, the expert stated that he was familiar with the minimum standards of medical practice in relation to the diagnosis and treatment of rectovaginal fistulae, and those minimum standards were uniform throughout the country.

It is not necessary that the expert witness has the highest possible qualifications to testify about a particular matter. Still, in Domingo v. T.K. (289 F.3d 600 [9th Cir. 2002]), a federal court excluded the testimony of the plaintiff’s expert witness, because it lacked reliability. The plaintiff developed brain damage from fat embolism following hip surgery, and alleged that prolonged malleting of a hip prosthesis was the cause of the fat embolism syndrome (FES).

The court found that “there was no evidence of widespread acceptance of Dr. Harrington’s theory linking extended malleting to FES; indeed, no theory linking extensive malleting to FES had ever been published.” It also noted the lack of any objective source, peer review, clinical tests, establishment of an error rate or other evidence to show that Dr. Harrington followed a valid, scientific method in developing his theory.

Being disqualified as an expert is one thing, but a recent case goes further. In addition to dismissing an expert’s testimony, a state judge barred the expert from ever testifying in his courtroom after it was determined that the testimony was untruthful.

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected]

Question: A patient alleges that an ophthalmologist was negligent in performing blepharoplasty. The surgical site became infected and left the patient with a disfigured eye. An infectious disease specialist was to testify as plaintiff’s expert, but the defense, relying on a state statute, objected that the expert-to-be had no specialized training in ophthalmology.

Correct statements about expert medical testimony include the following, except:

A. The federal Rules of Evidence require that an expert possess the relevant knowledge, skill, education, training, or experience.

B. Only a few states have enacted statutes specifying that an expert must be in the same or similar specialty as the defendant.

C. Advocates contend that such statutes reduce frivolous lawsuits by limiting expert shopping and the use of “hired guns.”

D. It is the sitting judge, not the jury, who interprets the statute and decides whether a witness qualifies as an expert.

E. In some cases, a nondoctor such as a nurse or pharmacist may be allowed to offer expert testimony against a doctor.

Answer: B. Lay testimony is usually insufficient to define the standard of care in a claim of medical malpractice, and “the question of negligence must be decided by reference to relevant medical standards of care for which the plaintiff carries the burden of proving through expert medical testimony” (Craft v. Peebles, 893 P.2d 138 [Haw.1995]). Court rules of evidence dictate that the expert must possess the knowledge, skill, experience, training, or education for establishing that standard.

In coming to an opinion, the expert may rely on external evidence in the form of a book, treatise, or article; and although these sources represent hearsay evidence, they are admissible to enable the expert witness to form his/her opinion.

The facts of the multiple-choice question above are taken from a recent case (Edwards v. Sunrise Ophthalmology ASC, LLC, 134 So. 3d 1056 [Fla. 4th DCA 2013]), whose appeal is yet to be heard by the Florida Supreme Court. The plaintiff alleged that the surgical site was infected with nocardia during a lower-lid blepharoplasty, which caused her to undergo additional surgery with resulting disfigurement of the eye.

A lower court disqualified the plaintiff’s expert, an infectious disease specialist, based on a Florida statute stipulating that expert medical opinion can be offered only by one in the “same or similar specialty” (Section 766.102, Florida Statutes (2009)). In the words of the court, “Simply put, the infectious disease doctor is not an eye surgeon, nor is the ophthalmologist an infectious disease doctor.”

More than half of all the states have a medical-expert law, many with language comparable to the Florida statute. The idea behind such a statute, frequently enacted as part of a state’s tort reform, is to limit expert shopping and the use of hired guns and “junk science.”

Unsurprisingly, litigation abounds over the statutory language.

For example, a Maryland court ruled that a vascular surgeon was qualified to set the standard of care when an orthopedic surgeon’s alleged negligence caused a patient to lose a leg following knee surgery. The court found the two specialties to be “related,” because the orthopedic complication was vascular in origin.

In some jurisdictions without strict statutory requirements, doctors are more likely to be allowed to testify outside their specialty.

Instances of professionals of unlike specialties qualifying as experts include a nephrologist testifying against a urologist, an infectious disease specialist offering an expert opinion in a stroke case, a pharmacist testifying on the issue of a medication side effect, and a nurse on bedsores. Georgia requires only that an expert show significant familiarity with the area of practice in which the expert opinion is to be given. Still, in a sleep apnea case (Nathans v. Diamond, 654 S.E.2d 121 [Ga. 2007]), the court held that a pulmonologist was not qualified to testify on the standard of surgical care provided by an otolaryngologist.

Besides arguing over the statutory language, litigants have also raised questions of constitutionality. For example, Arizona’s statute ARS §12-2604 (A) requires a medical expert to be a specialist who is actively practicing or teaching in that area of medicine. The state court of appeals held that this violated the separation of powers doctrine (conflicting with Arizona Rule of Evidence 702), but the Supreme Court of Arizona subsequently reversed and reinstated the law (Seisinger v. Siebel, 203 P.3d 483 [Ariz. 2009]).

More recently, the same court upheld the constitutionality of the requirement that an expert share “the same specialty” as the treating physician, and disqualified an adult hematologist from serving as an expert because the defendant was a pediatric hematologist, not an adult hematologist (Baker v. University Physicians Healthcare, 296 P.3d 42 [Ariz. 2013]).

Another issue deals with the locality rule. In an Illinois case, the court accepted an out-of-state plaintiff expert based on his qualifications, competency, and familiarity with standards in the defendant’s community. The case dealt with the development of a rectovaginal fistula that complicated an episiotomy during delivery (Purtill v. Hess, 489 N.E.2d 867 [Ill. 1986]).

The defense attempted to exclude the expert, alleging the lack of familiarity with the standards in the community (Rantoul, Ill.). However, the expert stated that he was familiar with the minimum standards of medical practice in relation to the diagnosis and treatment of rectovaginal fistulae, and those minimum standards were uniform throughout the country.

It is not necessary that the expert witness has the highest possible qualifications to testify about a particular matter. Still, in Domingo v. T.K. (289 F.3d 600 [9th Cir. 2002]), a federal court excluded the testimony of the plaintiff’s expert witness, because it lacked reliability. The plaintiff developed brain damage from fat embolism following hip surgery, and alleged that prolonged malleting of a hip prosthesis was the cause of the fat embolism syndrome (FES).

The court found that “there was no evidence of widespread acceptance of Dr. Harrington’s theory linking extended malleting to FES; indeed, no theory linking extensive malleting to FES had ever been published.” It also noted the lack of any objective source, peer review, clinical tests, establishment of an error rate or other evidence to show that Dr. Harrington followed a valid, scientific method in developing his theory.

Being disqualified as an expert is one thing, but a recent case goes further. In addition to dismissing an expert’s testimony, a state judge barred the expert from ever testifying in his courtroom after it was determined that the testimony was untruthful.

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected]

Question: A patient alleges that an ophthalmologist was negligent in performing blepharoplasty. The surgical site became infected and left the patient with a disfigured eye. An infectious disease specialist was to testify as plaintiff’s expert, but the defense, relying on a state statute, objected that the expert-to-be had no specialized training in ophthalmology.

Correct statements about expert medical testimony include the following, except:

A. The federal Rules of Evidence require that an expert possess the relevant knowledge, skill, education, training, or experience.

B. Only a few states have enacted statutes specifying that an expert must be in the same or similar specialty as the defendant.

C. Advocates contend that such statutes reduce frivolous lawsuits by limiting expert shopping and the use of “hired guns.”

D. It is the sitting judge, not the jury, who interprets the statute and decides whether a witness qualifies as an expert.

E. In some cases, a nondoctor such as a nurse or pharmacist may be allowed to offer expert testimony against a doctor.

Answer: B. Lay testimony is usually insufficient to define the standard of care in a claim of medical malpractice, and “the question of negligence must be decided by reference to relevant medical standards of care for which the plaintiff carries the burden of proving through expert medical testimony” (Craft v. Peebles, 893 P.2d 138 [Haw.1995]). Court rules of evidence dictate that the expert must possess the knowledge, skill, experience, training, or education for establishing that standard.

In coming to an opinion, the expert may rely on external evidence in the form of a book, treatise, or article; and although these sources represent hearsay evidence, they are admissible to enable the expert witness to form his/her opinion.

The facts of the multiple-choice question above are taken from a recent case (Edwards v. Sunrise Ophthalmology ASC, LLC, 134 So. 3d 1056 [Fla. 4th DCA 2013]), whose appeal is yet to be heard by the Florida Supreme Court. The plaintiff alleged that the surgical site was infected with nocardia during a lower-lid blepharoplasty, which caused her to undergo additional surgery with resulting disfigurement of the eye.

A lower court disqualified the plaintiff’s expert, an infectious disease specialist, based on a Florida statute stipulating that expert medical opinion can be offered only by one in the “same or similar specialty” (Section 766.102, Florida Statutes (2009)). In the words of the court, “Simply put, the infectious disease doctor is not an eye surgeon, nor is the ophthalmologist an infectious disease doctor.”

More than half of all the states have a medical-expert law, many with language comparable to the Florida statute. The idea behind such a statute, frequently enacted as part of a state’s tort reform, is to limit expert shopping and the use of hired guns and “junk science.”

Unsurprisingly, litigation abounds over the statutory language.

For example, a Maryland court ruled that a vascular surgeon was qualified to set the standard of care when an orthopedic surgeon’s alleged negligence caused a patient to lose a leg following knee surgery. The court found the two specialties to be “related,” because the orthopedic complication was vascular in origin.

In some jurisdictions without strict statutory requirements, doctors are more likely to be allowed to testify outside their specialty.

Instances of professionals of unlike specialties qualifying as experts include a nephrologist testifying against a urologist, an infectious disease specialist offering an expert opinion in a stroke case, a pharmacist testifying on the issue of a medication side effect, and a nurse on bedsores. Georgia requires only that an expert show significant familiarity with the area of practice in which the expert opinion is to be given. Still, in a sleep apnea case (Nathans v. Diamond, 654 S.E.2d 121 [Ga. 2007]), the court held that a pulmonologist was not qualified to testify on the standard of surgical care provided by an otolaryngologist.

Besides arguing over the statutory language, litigants have also raised questions of constitutionality. For example, Arizona’s statute ARS §12-2604 (A) requires a medical expert to be a specialist who is actively practicing or teaching in that area of medicine. The state court of appeals held that this violated the separation of powers doctrine (conflicting with Arizona Rule of Evidence 702), but the Supreme Court of Arizona subsequently reversed and reinstated the law (Seisinger v. Siebel, 203 P.3d 483 [Ariz. 2009]).

More recently, the same court upheld the constitutionality of the requirement that an expert share “the same specialty” as the treating physician, and disqualified an adult hematologist from serving as an expert because the defendant was a pediatric hematologist, not an adult hematologist (Baker v. University Physicians Healthcare, 296 P.3d 42 [Ariz. 2013]).

Another issue deals with the locality rule. In an Illinois case, the court accepted an out-of-state plaintiff expert based on his qualifications, competency, and familiarity with standards in the defendant’s community. The case dealt with the development of a rectovaginal fistula that complicated an episiotomy during delivery (Purtill v. Hess, 489 N.E.2d 867 [Ill. 1986]).

The defense attempted to exclude the expert, alleging the lack of familiarity with the standards in the community (Rantoul, Ill.). However, the expert stated that he was familiar with the minimum standards of medical practice in relation to the diagnosis and treatment of rectovaginal fistulae, and those minimum standards were uniform throughout the country.

It is not necessary that the expert witness has the highest possible qualifications to testify about a particular matter. Still, in Domingo v. T.K. (289 F.3d 600 [9th Cir. 2002]), a federal court excluded the testimony of the plaintiff’s expert witness, because it lacked reliability. The plaintiff developed brain damage from fat embolism following hip surgery, and alleged that prolonged malleting of a hip prosthesis was the cause of the fat embolism syndrome (FES).

The court found that “there was no evidence of widespread acceptance of Dr. Harrington’s theory linking extended malleting to FES; indeed, no theory linking extensive malleting to FES had ever been published.” It also noted the lack of any objective source, peer review, clinical tests, establishment of an error rate or other evidence to show that Dr. Harrington followed a valid, scientific method in developing his theory.

Being disqualified as an expert is one thing, but a recent case goes further. In addition to dismissing an expert’s testimony, a state judge barred the expert from ever testifying in his courtroom after it was determined that the testimony was untruthful.

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected]

Embryogenesis is an incredible phenomenon. It begins with fertilization and implantation of the blastocyst into the uterine wall, followed by development of the extraembryonic membrane which gives rise to the placenta, which is, literally, the lifeblood of the fetus. Although physicians often focus on the health of the placenta during pregnancy, the umbilical cord is an equally important organ.

The umbilical cord acts as a conduit through which metabolic products and biproducts, such as nutrients, antibodies, iron, and blood, pass bidirectionally between a mother and her baby. Many problems can arise if the cord becomes altered. For example, true umbilical cord knot is associated with small-for-gestational-age fetuses, premature birth, neonatal intensive care unit admissions, and fetal death (Int. J. Gynaecol. Obstet. 2013;122:18-21). In addition, short or long cord length may lead to fetal heart rate anomalies and higher risk for birth asphyxia (J. Obstet. Gynaecol. India. 2012;62:520-5).

While the health of the umbilical cord during pregnancy closely correlates to successful outcomes, the cord’s functions conclude at birth. Physicians clamp the umbilical cord at parturition as a routine part of the delivery process. Many ob.gyns. may not even stop to think about cord clamping. To borrow the phrase from the old Nike slogan, they “just do it.”

However, exactly when physicians should clamp the umbilical cord remains a topic for debate. Should ob.gyns. clamp the cord immediately or shortly after birth? Proponents of immediate clamping might argue that waiting too long could cause an influx of placental* blood in the neonate, leading to risk for jaundice. Those on the side of delayed cord clamping might say that waiting to terminate the cord prevents the baby’s oxygen supply from being prematurely cut off. Also, how long should the delay last: One minute? Two minutes? More? Less?

Clearly, the issue of cord clamping requires discussion. Therefore, we have devoted the first Master Class of 2015 to this important topic. We have invited Dr. George A. Macones, the Mitchell and Elaine Yanow Professor and Chair, and director of the division of maternal-fetal medicine and ultrasound in the department of obstetrics and gynecology at Washington University, St. Louis, to explore the debate. As the recent vice chair for the Committee on Practice Bulletins – Obstetrics for the American College of Obstetricians and Gynecologists, Dr. Macones has a unique perspective on the arguments for and against immediate or delayed cord clamping, as well as significant experience as a practicing ob.gyn. and leader at a vibrant academic medical center.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Correction, 4/14/15: An earlier version of this article misstated the potential consequences of waiting too long to clamp the umbilical cord.

Embryogenesis is an incredible phenomenon. It begins with fertilization and implantation of the blastocyst into the uterine wall, followed by development of the extraembryonic membrane which gives rise to the placenta, which is, literally, the lifeblood of the fetus. Although physicians often focus on the health of the placenta during pregnancy, the umbilical cord is an equally important organ.

The umbilical cord acts as a conduit through which metabolic products and biproducts, such as nutrients, antibodies, iron, and blood, pass bidirectionally between a mother and her baby. Many problems can arise if the cord becomes altered. For example, true umbilical cord knot is associated with small-for-gestational-age fetuses, premature birth, neonatal intensive care unit admissions, and fetal death (Int. J. Gynaecol. Obstet. 2013;122:18-21). In addition, short or long cord length may lead to fetal heart rate anomalies and higher risk for birth asphyxia (J. Obstet. Gynaecol. India. 2012;62:520-5).

While the health of the umbilical cord during pregnancy closely correlates to successful outcomes, the cord’s functions conclude at birth. Physicians clamp the umbilical cord at parturition as a routine part of the delivery process. Many ob.gyns. may not even stop to think about cord clamping. To borrow the phrase from the old Nike slogan, they “just do it.”

However, exactly when physicians should clamp the umbilical cord remains a topic for debate. Should ob.gyns. clamp the cord immediately or shortly after birth? Proponents of immediate clamping might argue that waiting too long could cause an influx of placental* blood in the neonate, leading to risk for jaundice. Those on the side of delayed cord clamping might say that waiting to terminate the cord prevents the baby’s oxygen supply from being prematurely cut off. Also, how long should the delay last: One minute? Two minutes? More? Less?

Clearly, the issue of cord clamping requires discussion. Therefore, we have devoted the first Master Class of 2015 to this important topic. We have invited Dr. George A. Macones, the Mitchell and Elaine Yanow Professor and Chair, and director of the division of maternal-fetal medicine and ultrasound in the department of obstetrics and gynecology at Washington University, St. Louis, to explore the debate. As the recent vice chair for the Committee on Practice Bulletins – Obstetrics for the American College of Obstetricians and Gynecologists, Dr. Macones has a unique perspective on the arguments for and against immediate or delayed cord clamping, as well as significant experience as a practicing ob.gyn. and leader at a vibrant academic medical center.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Correction, 4/14/15: An earlier version of this article misstated the potential consequences of waiting too long to clamp the umbilical cord.

Embryogenesis is an incredible phenomenon. It begins with fertilization and implantation of the blastocyst into the uterine wall, followed by development of the extraembryonic membrane which gives rise to the placenta, which is, literally, the lifeblood of the fetus. Although physicians often focus on the health of the placenta during pregnancy, the umbilical cord is an equally important organ.

The umbilical cord acts as a conduit through which metabolic products and biproducts, such as nutrients, antibodies, iron, and blood, pass bidirectionally between a mother and her baby. Many problems can arise if the cord becomes altered. For example, true umbilical cord knot is associated with small-for-gestational-age fetuses, premature birth, neonatal intensive care unit admissions, and fetal death (Int. J. Gynaecol. Obstet. 2013;122:18-21). In addition, short or long cord length may lead to fetal heart rate anomalies and higher risk for birth asphyxia (J. Obstet. Gynaecol. India. 2012;62:520-5).

While the health of the umbilical cord during pregnancy closely correlates to successful outcomes, the cord’s functions conclude at birth. Physicians clamp the umbilical cord at parturition as a routine part of the delivery process. Many ob.gyns. may not even stop to think about cord clamping. To borrow the phrase from the old Nike slogan, they “just do it.”

However, exactly when physicians should clamp the umbilical cord remains a topic for debate. Should ob.gyns. clamp the cord immediately or shortly after birth? Proponents of immediate clamping might argue that waiting too long could cause an influx of placental* blood in the neonate, leading to risk for jaundice. Those on the side of delayed cord clamping might say that waiting to terminate the cord prevents the baby’s oxygen supply from being prematurely cut off. Also, how long should the delay last: One minute? Two minutes? More? Less?

Clearly, the issue of cord clamping requires discussion. Therefore, we have devoted the first Master Class of 2015 to this important topic. We have invited Dr. George A. Macones, the Mitchell and Elaine Yanow Professor and Chair, and director of the division of maternal-fetal medicine and ultrasound in the department of obstetrics and gynecology at Washington University, St. Louis, to explore the debate. As the recent vice chair for the Committee on Practice Bulletins – Obstetrics for the American College of Obstetricians and Gynecologists, Dr. Macones has a unique perspective on the arguments for and against immediate or delayed cord clamping, as well as significant experience as a practicing ob.gyn. and leader at a vibrant academic medical center.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Correction, 4/14/15: An earlier version of this article misstated the potential consequences of waiting too long to clamp the umbilical cord.

When technology is mentioned in the context of health care, it is often received as an impersonal, profit- or regulatory-driven interface between a provider and patient. If designed – hopefully with a clinician involved – with the purpose of actually solving a problem, digital technology will ultimately gain favor. Examples of such tools include links and apps which provide reference information. Epocrates and doximity on the provider side and WebMD on the consumer/patient side are prime examples. There are increasingly more digital tools for patients and caregivers to help them improve self-participation in their health care as well as to navigate the system. The challenge in the health care technology space is to make people (both providers and patients) aware of them, to facilitate use, and to incorporate relevant and actionable data seamlessly into the patient’s electronic record. Technology needs to be designed in a way in which it conforms to the clinical work flow between the patient and provider. I will give examples of available tools that can improve a patient’s daunting journey. I do not have any financial or other affiliation with any companies mentioned.

1. They can help prepare for the office visit.

I don’t know why, but patients have evolved a belief that they need to present a self-diagnosed condition at the office visit. They often feel guilty not providing the diagnosis. I believe firmly (and tell patients) that their responsibility is to know when something isn’t right and to call the provider. Notwithstanding this, I encourage patients to do online research into their symptoms. Tools found at FamilyDoctor.org, the Mayo Clinic Symptom Checker, or iTriage can help frame thoughts or prompt a discussion with a caregiver prior to a visit, which can then serve as a foundation for the office encounter.

2. Patient education content.

The term “patient engagement” is used commonly today. It implies the active participation of the patient in health care and disease management. Many believe that patient engagement should be focused on medication adherence. While this is critical, it remains a reflection of a patient’s understanding of diagnosis; long-term treatment goals (which need be personalized per a discussion about them); and the components of the treatment itself, which include lifestyle changes and nontraditional pharmacologic therapies as well. Seeing disease through a patient’s eyes (empathy) is the key to good relationships that in turn promote engagement. Excellent digital patient education tools are now available for download and review by patients and caregivers. They explain diagnoses, tests, procedures, and medications. Some are proprietary and made by pharmaceutical and medical device companies, while others are produced by third-party companies that allow the provider to white label the product or even customize the content. One excellent example is Liberate Health. (Ed. note: This publication’s parent company has a relationship with Liberate Health.)

3. Social media.

This is where the patients and caregivers are. It follows then that social media is where providers should be. There are some excellent online patient communities that contain disease-specific groups. Examples are Smart Patients and Treatment Diaries. Social media is a big part of motivating patients and giving support to them and to caregivers. It allows for information exchange in a convenient, relaxing, and nonthreatening setting. While skeptics might question the validity of medical information and advice on these sites, I would say that encouraging patients to participate shows empathy. If a disclaimer is offered stating that this is not a substitute for a health care provider, it can be a significant source of support.

4. Connections to caregivers.

Caregivers are left out of many digital health tools. A good working definition of a caregiver is “an unpaid individual (a spouse, partner, family member, friend, or neighbor) involved in assisting others with activities of daily living and/or medical tasks.” About 29% of the U.S. adult population (65.7 million) provides care to someone who is ill, disabled, or aged. Other statistics about caregivers are more impressive. Health and medical apps are promising tools that can be offered to patients. The rubber has yet to fully meet the road in this arena for a few reasons, many of which are tied to the reputation, usability, and priorities of present electronic health record vendors who represent the face of digital health technology to most physicians and other health care providers. However, there is little denial that they (and other mobile health tools) will play an important role in health care’s future. Both patients and caregivers have expressed what is desired in a mobile app. As aging at home becomes a necessary goal of health care from social, financial, and societal standpoints, caregivers will assume an even greater portion of care.

5. Provide for better continuity of care.

Lack of continuity of care leading to medical errors is not a new topic of discussion. This is relevant in both the inpatient and the outpatient setting. Mobile digital technologies can reduce errors by improving communication to both providers and patients as well as among providers themselves. Use of digital tablets at the bedside by patients can improve provider-patient communication and decrease errors. Handoff of patients among providers is another opportunity for mobile health tools to decrease errors. One such app is Smart Sign Out. Ultimately, any tool that decreases errors is a patient advocate tool.

While some physicians believe that patient advocacy is distinct from patient care, I submit that patient advocacy is something any good physician does every day with every patient, including conveying empathy, providing easy to understand explanations of conditions, and offering advice to be considered in a shared decision-making process. We all enter the field of medicine because we want to contribute to the well-being of others. Let’s not lose sight of that, and let’s look to available and emerging technologies to assist us in this mission.

Dr. Scher is an electrophysiologist with the Heart Group of Lancaster (Pa.) General Health. He is also director of DLS Healthcare Consulting, Harrisburg, Pa., and clinical associate professor of medicine at the Pennsylvania State University, Hershey.

When technology is mentioned in the context of health care, it is often received as an impersonal, profit- or regulatory-driven interface between a provider and patient. If designed – hopefully with a clinician involved – with the purpose of actually solving a problem, digital technology will ultimately gain favor. Examples of such tools include links and apps which provide reference information. Epocrates and doximity on the provider side and WebMD on the consumer/patient side are prime examples. There are increasingly more digital tools for patients and caregivers to help them improve self-participation in their health care as well as to navigate the system. The challenge in the health care technology space is to make people (both providers and patients) aware of them, to facilitate use, and to incorporate relevant and actionable data seamlessly into the patient’s electronic record. Technology needs to be designed in a way in which it conforms to the clinical work flow between the patient and provider. I will give examples of available tools that can improve a patient’s daunting journey. I do not have any financial or other affiliation with any companies mentioned.

1. They can help prepare for the office visit.

I don’t know why, but patients have evolved a belief that they need to present a self-diagnosed condition at the office visit. They often feel guilty not providing the diagnosis. I believe firmly (and tell patients) that their responsibility is to know when something isn’t right and to call the provider. Notwithstanding this, I encourage patients to do online research into their symptoms. Tools found at FamilyDoctor.org, the Mayo Clinic Symptom Checker, or iTriage can help frame thoughts or prompt a discussion with a caregiver prior to a visit, which can then serve as a foundation for the office encounter.

2. Patient education content.

The term “patient engagement” is used commonly today. It implies the active participation of the patient in health care and disease management. Many believe that patient engagement should be focused on medication adherence. While this is critical, it remains a reflection of a patient’s understanding of diagnosis; long-term treatment goals (which need be personalized per a discussion about them); and the components of the treatment itself, which include lifestyle changes and nontraditional pharmacologic therapies as well. Seeing disease through a patient’s eyes (empathy) is the key to good relationships that in turn promote engagement. Excellent digital patient education tools are now available for download and review by patients and caregivers. They explain diagnoses, tests, procedures, and medications. Some are proprietary and made by pharmaceutical and medical device companies, while others are produced by third-party companies that allow the provider to white label the product or even customize the content. One excellent example is Liberate Health. (Ed. note: This publication’s parent company has a relationship with Liberate Health.)

3. Social media.

This is where the patients and caregivers are. It follows then that social media is where providers should be. There are some excellent online patient communities that contain disease-specific groups. Examples are Smart Patients and Treatment Diaries. Social media is a big part of motivating patients and giving support to them and to caregivers. It allows for information exchange in a convenient, relaxing, and nonthreatening setting. While skeptics might question the validity of medical information and advice on these sites, I would say that encouraging patients to participate shows empathy. If a disclaimer is offered stating that this is not a substitute for a health care provider, it can be a significant source of support.

4. Connections to caregivers.

Caregivers are left out of many digital health tools. A good working definition of a caregiver is “an unpaid individual (a spouse, partner, family member, friend, or neighbor) involved in assisting others with activities of daily living and/or medical tasks.” About 29% of the U.S. adult population (65.7 million) provides care to someone who is ill, disabled, or aged. Other statistics about caregivers are more impressive. Health and medical apps are promising tools that can be offered to patients. The rubber has yet to fully meet the road in this arena for a few reasons, many of which are tied to the reputation, usability, and priorities of present electronic health record vendors who represent the face of digital health technology to most physicians and other health care providers. However, there is little denial that they (and other mobile health tools) will play an important role in health care’s future. Both patients and caregivers have expressed what is desired in a mobile app. As aging at home becomes a necessary goal of health care from social, financial, and societal standpoints, caregivers will assume an even greater portion of care.

5. Provide for better continuity of care.

Lack of continuity of care leading to medical errors is not a new topic of discussion. This is relevant in both the inpatient and the outpatient setting. Mobile digital technologies can reduce errors by improving communication to both providers and patients as well as among providers themselves. Use of digital tablets at the bedside by patients can improve provider-patient communication and decrease errors. Handoff of patients among providers is another opportunity for mobile health tools to decrease errors. One such app is Smart Sign Out. Ultimately, any tool that decreases errors is a patient advocate tool.

While some physicians believe that patient advocacy is distinct from patient care, I submit that patient advocacy is something any good physician does every day with every patient, including conveying empathy, providing easy to understand explanations of conditions, and offering advice to be considered in a shared decision-making process. We all enter the field of medicine because we want to contribute to the well-being of others. Let’s not lose sight of that, and let’s look to available and emerging technologies to assist us in this mission.

Dr. Scher is an electrophysiologist with the Heart Group of Lancaster (Pa.) General Health. He is also director of DLS Healthcare Consulting, Harrisburg, Pa., and clinical associate professor of medicine at the Pennsylvania State University, Hershey.

When technology is mentioned in the context of health care, it is often received as an impersonal, profit- or regulatory-driven interface between a provider and patient. If designed – hopefully with a clinician involved – with the purpose of actually solving a problem, digital technology will ultimately gain favor. Examples of such tools include links and apps which provide reference information. Epocrates and doximity on the provider side and WebMD on the consumer/patient side are prime examples. There are increasingly more digital tools for patients and caregivers to help them improve self-participation in their health care as well as to navigate the system. The challenge in the health care technology space is to make people (both providers and patients) aware of them, to facilitate use, and to incorporate relevant and actionable data seamlessly into the patient’s electronic record. Technology needs to be designed in a way in which it conforms to the clinical work flow between the patient and provider. I will give examples of available tools that can improve a patient’s daunting journey. I do not have any financial or other affiliation with any companies mentioned.

1. They can help prepare for the office visit.

I don’t know why, but patients have evolved a belief that they need to present a self-diagnosed condition at the office visit. They often feel guilty not providing the diagnosis. I believe firmly (and tell patients) that their responsibility is to know when something isn’t right and to call the provider. Notwithstanding this, I encourage patients to do online research into their symptoms. Tools found at FamilyDoctor.org, the Mayo Clinic Symptom Checker, or iTriage can help frame thoughts or prompt a discussion with a caregiver prior to a visit, which can then serve as a foundation for the office encounter.

2. Patient education content.

The term “patient engagement” is used commonly today. It implies the active participation of the patient in health care and disease management. Many believe that patient engagement should be focused on medication adherence. While this is critical, it remains a reflection of a patient’s understanding of diagnosis; long-term treatment goals (which need be personalized per a discussion about them); and the components of the treatment itself, which include lifestyle changes and nontraditional pharmacologic therapies as well. Seeing disease through a patient’s eyes (empathy) is the key to good relationships that in turn promote engagement. Excellent digital patient education tools are now available for download and review by patients and caregivers. They explain diagnoses, tests, procedures, and medications. Some are proprietary and made by pharmaceutical and medical device companies, while others are produced by third-party companies that allow the provider to white label the product or even customize the content. One excellent example is Liberate Health. (Ed. note: This publication’s parent company has a relationship with Liberate Health.)

3. Social media.

This is where the patients and caregivers are. It follows then that social media is where providers should be. There are some excellent online patient communities that contain disease-specific groups. Examples are Smart Patients and Treatment Diaries. Social media is a big part of motivating patients and giving support to them and to caregivers. It allows for information exchange in a convenient, relaxing, and nonthreatening setting. While skeptics might question the validity of medical information and advice on these sites, I would say that encouraging patients to participate shows empathy. If a disclaimer is offered stating that this is not a substitute for a health care provider, it can be a significant source of support.

4. Connections to caregivers.

Caregivers are left out of many digital health tools. A good working definition of a caregiver is “an unpaid individual (a spouse, partner, family member, friend, or neighbor) involved in assisting others with activities of daily living and/or medical tasks.” About 29% of the U.S. adult population (65.7 million) provides care to someone who is ill, disabled, or aged. Other statistics about caregivers are more impressive. Health and medical apps are promising tools that can be offered to patients. The rubber has yet to fully meet the road in this arena for a few reasons, many of which are tied to the reputation, usability, and priorities of present electronic health record vendors who represent the face of digital health technology to most physicians and other health care providers. However, there is little denial that they (and other mobile health tools) will play an important role in health care’s future. Both patients and caregivers have expressed what is desired in a mobile app. As aging at home becomes a necessary goal of health care from social, financial, and societal standpoints, caregivers will assume an even greater portion of care.

5. Provide for better continuity of care.

Lack of continuity of care leading to medical errors is not a new topic of discussion. This is relevant in both the inpatient and the outpatient setting. Mobile digital technologies can reduce errors by improving communication to both providers and patients as well as among providers themselves. Use of digital tablets at the bedside by patients can improve provider-patient communication and decrease errors. Handoff of patients among providers is another opportunity for mobile health tools to decrease errors. One such app is Smart Sign Out. Ultimately, any tool that decreases errors is a patient advocate tool.

While some physicians believe that patient advocacy is distinct from patient care, I submit that patient advocacy is something any good physician does every day with every patient, including conveying empathy, providing easy to understand explanations of conditions, and offering advice to be considered in a shared decision-making process. We all enter the field of medicine because we want to contribute to the well-being of others. Let’s not lose sight of that, and let’s look to available and emerging technologies to assist us in this mission.

Dr. Scher is an electrophysiologist with the Heart Group of Lancaster (Pa.) General Health. He is also director of DLS Healthcare Consulting, Harrisburg, Pa., and clinical associate professor of medicine at the Pennsylvania State University, Hershey.

SAN FRANCISCO – Use of intraoperative nerve monitoring during thyroidectomy to avoid injuring the recurrent laryngeal nerve is counterintuitively associated with a higher risk of vocal cord paralysis, in a cohort study of data from the Nationwide Inpatient Sample.

“We do caution against perhaps the broad adoption of nerve monitoring until we can really study this further,” said Dr. Thomas K. Chung, a research fellow in the department of surgery, division of otolaryngology, at the University of Alabama at Birmingham, and the study’s lead investigator.

He and his colleagues compared outcomes between 12,742 patients who had nerve monitoring and 230,433 patients who did not (the conventional practice) while undergoing thyroidectomy between 2008 and 2011.

The proportion of patients who developed vocal cord paralysis was significantly higher with monitoring than without it (1.9% vs. 1.4%), he reported at the annual clinical congress of the American College of Surgeons. The findings were essentially the same in propensity-adjusted analyses that took into account differences between groups in preoperative factors (1.8% vs. 1.3%).

There was no evidence that the difference was related to differences in the use of laryngoscopy to check for paralysis, in hospitals’ coding and billing for monitoring, or in payers’ coverage of this surgical adjunct.

Stratified analyses looking at the extent of surgery showed total thyroidectomy with neck dissection to be the exception, as patients monitored during these more complex operations were significantly less likely to develop vocal cord paralysis than were nonmonitored counterparts (2.8% vs. 4.5%).

The more often hospitals used nerve monitoring as indicated by the volume of thyroidectomy cases, the lower the rate of vocal cord paralysis – with the exception of cases of partial thyroidectomy, in which more frequent use was associated with a counterintuitive increase in the rate of this complication, according to Dr. Chung, who disclosed that he had no relevant conflicts of interest.

“Nerve monitoring demonstrates a significant benefit particularly in complex cases such as total thyroidectomy with neck dissection,” he said. “Low nerve monitoring and utilization with partial thyroidectomy appears to be associated with higher vocal cord paralysis; with respect to the partial thyroidectomies, this may be due to the fact that the burden of complication is already so low, with vocal cord paralysis rates of about 0.8%, that additional use of nerve monitoring may not confer any benefit.”

Dr. Chung offered several possible reasons as to why monitoring may be associated with a higher risk of vocal cord paralysis, including presence of a learning curve, substitution of monitoring for direct visualization of the nerve, and false-negatives whereby a lack of signal from the monitor may lead to more aggressive ablation when the nerve is in fact nearby.

The study had its limitations, he acknowledged. “Nerve monitoring may not be coded all the time,” he said. Information about prior neck radiation and surgery, which increase the risk of vocal cord paralysis, was unavailable. “In the group with thyroidectomy with neck dissection, there is no code for central neck dissection. And even if it is a partial thyroidectomy with neck dissection, the central neck dissection would put both nerves at risk and therefore certainly increase the risk of vocal cord paralysis,” he noted.

Invited discussant Julie Ann Sosa, chief of endocrine surgery at the Duke Cancer Institute in Durham, N.C., said, “I would like to congratulate you and your whole group for tackling what is perhaps one of the most highly contested and contentious issues within endocrine surgery and otolaryngology. It’s also I think a very important area for study because there is a relative paucity of data demonstrating for or against the use of this technology as an adjunct. Current guidelines basically say it’s a wash: We can’t say one way or the other whether folks should be using it. And the anticipated guidelines, those coming out from the American Thyroid Association, similarly will say that more data are needed. So I think you are filling a clear vacuum.”

Dr. Sosa questioned the generalizability of the findings, noting that nearly two-thirds of thyroid procedures are now done in the ambulatory setting. “You used the Nationwide Inpatient Sample, so I think you are looking at a minority of cases and highly complex cases, with a length of stay on the order of 2-3 days, which is really exceptional. Most of us send home patients the same day. So how generalizable do you think your conclusions are, and have you thought about potentially using some of the ambulatory surgery databases to try to ask similar questions?” she queried.

The investigators plan to repeat analyses using the Nationwide Inpatient Sample’s ambulatory data set next, according to Dr. Chung. “Being able to see whether or not this still holds true in an outpatient setting is definitely worthwhile,” he agreed.

Dr. Sosa further wondered about the roles of bilateral versus unilateral monitoring, and continuous versus intermittent monitoring, saying, “I think the approach an individual surgeon takes could definitely result in different outcomes. So I wonder, were you able to address at a more granular level the specific technologies employed?”

The Nationwide Inpatient Sample unfortunately does not capture information on these aspects of monitoring, said Dr. Chung. However, “with respect to continuous versus intermittent, we do think that that’s actually an important variable. It is possible that those who are using nerve monitoring are doing this in a continuous fashion, so when they perhaps injure the first side of the vocal cords, they may stop. So what was originally planned to be a total thyroidectomy from the get-go that had an intraoperative nerve injury may be aborted so as to not create any disastrous airway complications. That may also artificially increase the partial thyroidectomy results, thereby increasing vocal cord paralysis complications in the partial thyroidectomy group.”

SAN FRANCISCO – Use of intraoperative nerve monitoring during thyroidectomy to avoid injuring the recurrent laryngeal nerve is counterintuitively associated with a higher risk of vocal cord paralysis, in a cohort study of data from the Nationwide Inpatient Sample.

“We do caution against perhaps the broad adoption of nerve monitoring until we can really study this further,” said Dr. Thomas K. Chung, a research fellow in the department of surgery, division of otolaryngology, at the University of Alabama at Birmingham, and the study’s lead investigator.

He and his colleagues compared outcomes between 12,742 patients who had nerve monitoring and 230,433 patients who did not (the conventional practice) while undergoing thyroidectomy between 2008 and 2011.

The proportion of patients who developed vocal cord paralysis was significantly higher with monitoring than without it (1.9% vs. 1.4%), he reported at the annual clinical congress of the American College of Surgeons. The findings were essentially the same in propensity-adjusted analyses that took into account differences between groups in preoperative factors (1.8% vs. 1.3%).

There was no evidence that the difference was related to differences in the use of laryngoscopy to check for paralysis, in hospitals’ coding and billing for monitoring, or in payers’ coverage of this surgical adjunct.

Stratified analyses looking at the extent of surgery showed total thyroidectomy with neck dissection to be the exception, as patients monitored during these more complex operations were significantly less likely to develop vocal cord paralysis than were nonmonitored counterparts (2.8% vs. 4.5%).

The more often hospitals used nerve monitoring as indicated by the volume of thyroidectomy cases, the lower the rate of vocal cord paralysis – with the exception of cases of partial thyroidectomy, in which more frequent use was associated with a counterintuitive increase in the rate of this complication, according to Dr. Chung, who disclosed that he had no relevant conflicts of interest.

“Nerve monitoring demonstrates a significant benefit particularly in complex cases such as total thyroidectomy with neck dissection,” he said. “Low nerve monitoring and utilization with partial thyroidectomy appears to be associated with higher vocal cord paralysis; with respect to the partial thyroidectomies, this may be due to the fact that the burden of complication is already so low, with vocal cord paralysis rates of about 0.8%, that additional use of nerve monitoring may not confer any benefit.”

Dr. Chung offered several possible reasons as to why monitoring may be associated with a higher risk of vocal cord paralysis, including presence of a learning curve, substitution of monitoring for direct visualization of the nerve, and false-negatives whereby a lack of signal from the monitor may lead to more aggressive ablation when the nerve is in fact nearby.

The study had its limitations, he acknowledged. “Nerve monitoring may not be coded all the time,” he said. Information about prior neck radiation and surgery, which increase the risk of vocal cord paralysis, was unavailable. “In the group with thyroidectomy with neck dissection, there is no code for central neck dissection. And even if it is a partial thyroidectomy with neck dissection, the central neck dissection would put both nerves at risk and therefore certainly increase the risk of vocal cord paralysis,” he noted.

Invited discussant Julie Ann Sosa, chief of endocrine surgery at the Duke Cancer Institute in Durham, N.C., said, “I would like to congratulate you and your whole group for tackling what is perhaps one of the most highly contested and contentious issues within endocrine surgery and otolaryngology. It’s also I think a very important area for study because there is a relative paucity of data demonstrating for or against the use of this technology as an adjunct. Current guidelines basically say it’s a wash: We can’t say one way or the other whether folks should be using it. And the anticipated guidelines, those coming out from the American Thyroid Association, similarly will say that more data are needed. So I think you are filling a clear vacuum.”

Dr. Sosa questioned the generalizability of the findings, noting that nearly two-thirds of thyroid procedures are now done in the ambulatory setting. “You used the Nationwide Inpatient Sample, so I think you are looking at a minority of cases and highly complex cases, with a length of stay on the order of 2-3 days, which is really exceptional. Most of us send home patients the same day. So how generalizable do you think your conclusions are, and have you thought about potentially using some of the ambulatory surgery databases to try to ask similar questions?” she queried.

The investigators plan to repeat analyses using the Nationwide Inpatient Sample’s ambulatory data set next, according to Dr. Chung. “Being able to see whether or not this still holds true in an outpatient setting is definitely worthwhile,” he agreed.

Dr. Sosa further wondered about the roles of bilateral versus unilateral monitoring, and continuous versus intermittent monitoring, saying, “I think the approach an individual surgeon takes could definitely result in different outcomes. So I wonder, were you able to address at a more granular level the specific technologies employed?”

The Nationwide Inpatient Sample unfortunately does not capture information on these aspects of monitoring, said Dr. Chung. However, “with respect to continuous versus intermittent, we do think that that’s actually an important variable. It is possible that those who are using nerve monitoring are doing this in a continuous fashion, so when they perhaps injure the first side of the vocal cords, they may stop. So what was originally planned to be a total thyroidectomy from the get-go that had an intraoperative nerve injury may be aborted so as to not create any disastrous airway complications. That may also artificially increase the partial thyroidectomy results, thereby increasing vocal cord paralysis complications in the partial thyroidectomy group.”

SAN FRANCISCO – Use of intraoperative nerve monitoring during thyroidectomy to avoid injuring the recurrent laryngeal nerve is counterintuitively associated with a higher risk of vocal cord paralysis, in a cohort study of data from the Nationwide Inpatient Sample.

“We do caution against perhaps the broad adoption of nerve monitoring until we can really study this further,” said Dr. Thomas K. Chung, a research fellow in the department of surgery, division of otolaryngology, at the University of Alabama at Birmingham, and the study’s lead investigator.

He and his colleagues compared outcomes between 12,742 patients who had nerve monitoring and 230,433 patients who did not (the conventional practice) while undergoing thyroidectomy between 2008 and 2011.

The proportion of patients who developed vocal cord paralysis was significantly higher with monitoring than without it (1.9% vs. 1.4%), he reported at the annual clinical congress of the American College of Surgeons. The findings were essentially the same in propensity-adjusted analyses that took into account differences between groups in preoperative factors (1.8% vs. 1.3%).

There was no evidence that the difference was related to differences in the use of laryngoscopy to check for paralysis, in hospitals’ coding and billing for monitoring, or in payers’ coverage of this surgical adjunct.

Stratified analyses looking at the extent of surgery showed total thyroidectomy with neck dissection to be the exception, as patients monitored during these more complex operations were significantly less likely to develop vocal cord paralysis than were nonmonitored counterparts (2.8% vs. 4.5%).

The more often hospitals used nerve monitoring as indicated by the volume of thyroidectomy cases, the lower the rate of vocal cord paralysis – with the exception of cases of partial thyroidectomy, in which more frequent use was associated with a counterintuitive increase in the rate of this complication, according to Dr. Chung, who disclosed that he had no relevant conflicts of interest.

“Nerve monitoring demonstrates a significant benefit particularly in complex cases such as total thyroidectomy with neck dissection,” he said. “Low nerve monitoring and utilization with partial thyroidectomy appears to be associated with higher vocal cord paralysis; with respect to the partial thyroidectomies, this may be due to the fact that the burden of complication is already so low, with vocal cord paralysis rates of about 0.8%, that additional use of nerve monitoring may not confer any benefit.”

Dr. Chung offered several possible reasons as to why monitoring may be associated with a higher risk of vocal cord paralysis, including presence of a learning curve, substitution of monitoring for direct visualization of the nerve, and false-negatives whereby a lack of signal from the monitor may lead to more aggressive ablation when the nerve is in fact nearby.

The study had its limitations, he acknowledged. “Nerve monitoring may not be coded all the time,” he said. Information about prior neck radiation and surgery, which increase the risk of vocal cord paralysis, was unavailable. “In the group with thyroidectomy with neck dissection, there is no code for central neck dissection. And even if it is a partial thyroidectomy with neck dissection, the central neck dissection would put both nerves at risk and therefore certainly increase the risk of vocal cord paralysis,” he noted.

Invited discussant Julie Ann Sosa, chief of endocrine surgery at the Duke Cancer Institute in Durham, N.C., said, “I would like to congratulate you and your whole group for tackling what is perhaps one of the most highly contested and contentious issues within endocrine surgery and otolaryngology. It’s also I think a very important area for study because there is a relative paucity of data demonstrating for or against the use of this technology as an adjunct. Current guidelines basically say it’s a wash: We can’t say one way or the other whether folks should be using it. And the anticipated guidelines, those coming out from the American Thyroid Association, similarly will say that more data are needed. So I think you are filling a clear vacuum.”

Dr. Sosa questioned the generalizability of the findings, noting that nearly two-thirds of thyroid procedures are now done in the ambulatory setting. “You used the Nationwide Inpatient Sample, so I think you are looking at a minority of cases and highly complex cases, with a length of stay on the order of 2-3 days, which is really exceptional. Most of us send home patients the same day. So how generalizable do you think your conclusions are, and have you thought about potentially using some of the ambulatory surgery databases to try to ask similar questions?” she queried.

The investigators plan to repeat analyses using the Nationwide Inpatient Sample’s ambulatory data set next, according to Dr. Chung. “Being able to see whether or not this still holds true in an outpatient setting is definitely worthwhile,” he agreed.

Dr. Sosa further wondered about the roles of bilateral versus unilateral monitoring, and continuous versus intermittent monitoring, saying, “I think the approach an individual surgeon takes could definitely result in different outcomes. So I wonder, were you able to address at a more granular level the specific technologies employed?”

The Nationwide Inpatient Sample unfortunately does not capture information on these aspects of monitoring, said Dr. Chung. However, “with respect to continuous versus intermittent, we do think that that’s actually an important variable. It is possible that those who are using nerve monitoring are doing this in a continuous fashion, so when they perhaps injure the first side of the vocal cords, they may stop. So what was originally planned to be a total thyroidectomy from the get-go that had an intraoperative nerve injury may be aborted so as to not create any disastrous airway complications. That may also artificially increase the partial thyroidectomy results, thereby increasing vocal cord paralysis complications in the partial thyroidectomy group.”

T cells

Credit: NIAID

SAN FRANCISCO—CTL019, a chimeric antigen receptor (CAR) T cell targeting CD19, is not the only CAR in the production line.

Investigators at the National Cancer Institute in Bethesda, Maryland, and Memorial Sloan Kettering Cancer Center (MSKCC) in New York City are also pursuing CAR T-cell therapy.

These groups are using a retroviral platform to transduce the T cells rather than a lentiviral one, as is the case with CTL019.

Investigators reported progress to date on these makes of CARs at the 2014 ASH Annual Meeting.

Daniel W. Lee III, MD, of the National Cancer Institute, reported on a phase 1 study of CD19 CAR T cells in children and young adults with CD19+ acute lymphoblastic leukemia or non-Hodgkin lymphoma.

And Jae H. Park, MD, of MSKCC, presented data from a trial of JCAR015—autologous T cells genetically modified to express a 19-28z CAR targeting CD19—in patients with B-cell acute lymphoblastic leukemia.

The study is sponsored by MSKCC, but JCAR015 is a product of Juno Therapeutics.

T cells

Credit: NIAID

SAN FRANCISCO—CTL019, a chimeric antigen receptor (CAR) T cell targeting CD19, is not the only CAR in the production line.

Investigators at the National Cancer Institute in Bethesda, Maryland, and Memorial Sloan Kettering Cancer Center (MSKCC) in New York City are also pursuing CAR T-cell therapy.

These groups are using a retroviral platform to transduce the T cells rather than a lentiviral one, as is the case with CTL019.

Investigators reported progress to date on these makes of CARs at the 2014 ASH Annual Meeting.

Daniel W. Lee III, MD, of the National Cancer Institute, reported on a phase 1 study of CD19 CAR T cells in children and young adults with CD19+ acute lymphoblastic leukemia or non-Hodgkin lymphoma.

And Jae H. Park, MD, of MSKCC, presented data from a trial of JCAR015—autologous T cells genetically modified to express a 19-28z CAR targeting CD19—in patients with B-cell acute lymphoblastic leukemia.

The study is sponsored by MSKCC, but JCAR015 is a product of Juno Therapeutics.

T cells

Credit: NIAID

SAN FRANCISCO—CTL019, a chimeric antigen receptor (CAR) T cell targeting CD19, is not the only CAR in the production line.

Investigators at the National Cancer Institute in Bethesda, Maryland, and Memorial Sloan Kettering Cancer Center (MSKCC) in New York City are also pursuing CAR T-cell therapy.

These groups are using a retroviral platform to transduce the T cells rather than a lentiviral one, as is the case with CTL019.

Investigators reported progress to date on these makes of CARs at the 2014 ASH Annual Meeting.

Daniel W. Lee III, MD, of the National Cancer Institute, reported on a phase 1 study of CD19 CAR T cells in children and young adults with CD19+ acute lymphoblastic leukemia or non-Hodgkin lymphoma.

And Jae H. Park, MD, of MSKCC, presented data from a trial of JCAR015—autologous T cells genetically modified to express a 19-28z CAR targeting CD19—in patients with B-cell acute lymphoblastic leukemia.

The study is sponsored by MSKCC, but JCAR015 is a product of Juno Therapeutics.

ALL patient

Credit: Bill Branson

SAN FRANCISCO—A chimeric antigen receptor (CAR) T-cell therapy is feasible in 90% of heavily pretreated or transplanted patients with acute lymphoblastic leukemia (ALL) and can serve as a bridge to transplant, according to investigators.

Daniel W. Lee III, MD, of the National Cancer Institute in Bethesda, Maryland, reported on a phase 1 study of this CD19 CAR T-cell therapy in children and young adults with CD19+ ALL or non-Hodgkin lymphoma at the 2014 ASH Annual Meeting (abstract 381*).

Twenty-one patients were enrolled on the trial. They had a preparative regimen of fludarabine and cyclophosphamide and were infused with CAR T cells 11 days after the peripheral blood mononuclear cells were collected.

Dose levels were 1 x 10⁶ CAR+ T cells/kg, 3 x 10⁶ CAR+ T cells/kg, or the maximum number of cells generated if below either one of these levels. Two patients received less than the dose assigned and were not evaluated for toxicity.

Patients were a median age of 13 years (range, 5 to 27). Fourteen were male, 20 had ALL, and 1 had diffuse large B-cell lymphoma.

All had detectable disease, and 2 were CNS2 at the time of T-cell infusion. Six had primary refractory disease, 8 had at least 1 prior stem cell transplant, and 4 had prior immunotherapy.

The investigators determined that the maximally tolerated dose was 1 x 10⁶ CAR+ T cells/kg. The dose-limiting toxicities were related to cytokine release syndrome (CRS), which was reversible if managed appropriately with tocilizumab, with or without steroids.

Grade 3 adverse events possibly related to therapy included fever (47%), febrile neutropenia (37%), electrolyte disturbance (29%), CRS (16%), hypotension (11%), transaminitis (16%), and 5% each for hypertension, prolonged QTc, dysphasia, LV systolic dysfunction, multiorgan failure, hypoxia, and pulmonary edema.

Grade 4 events possibly related to treatment included electrolyte disturbance (5%), CRS (16%), hypotension (11%), cardiac arrest (5%), and hypoxia (5%). There was no evidence of graft-vs-host disease.

The complete response (CR) rate was 67% in the intent-to-treat population and 70% in patients with ALL.

“Those patients who responded tended to have some degree of cytokine release syndrome, whereas those patients who did not respond or had stable disease did not have any CRS,” Dr Lee said. “But, also, it’s important to note that you don’t have to have severe grade 3 or grade 4 CRS in order to have significant response.”

Dr Lee also pointed out that in vivo CAR T-cell expansion significantly correlated with response (P=0.0028). And CRS severity correlated with IL-6 (P=0.0002), INF-γ (P=0.0002), C-reactive protein (P=0.0015), and CAR (P=0.0011).

At a median follow-up of 10 months, minimal residual disease-negative patients had a 79% leukemia-free survival. Overall survival was 52% for all patients enrolled. Two patients had CD19-negative relapses.

The investigators also found that CAR T cells can eliminate CNS leukemia, with 11 of 17 patients (65%) having CAR T cells detectable in their cerebrospinal fluid.

The team concluded that this therapy is feasible in 90% of heavily pretreated or transplanted ALL patients and can serve as a bridge to transplant.

*Information in the abstract differs from that presented at the meeting.

ALL patient

Credit: Bill Branson

SAN FRANCISCO—A chimeric antigen receptor (CAR) T-cell therapy is feasible in 90% of heavily pretreated or transplanted patients with acute lymphoblastic leukemia (ALL) and can serve as a bridge to transplant, according to investigators.

Daniel W. Lee III, MD, of the National Cancer Institute in Bethesda, Maryland, reported on a phase 1 study of this CD19 CAR T-cell therapy in children and young adults with CD19+ ALL or non-Hodgkin lymphoma at the 2014 ASH Annual Meeting (abstract 381*).

Twenty-one patients were enrolled on the trial. They had a preparative regimen of fludarabine and cyclophosphamide and were infused with CAR T cells 11 days after the peripheral blood mononuclear cells were collected.

Dose levels were 1 x 10⁶ CAR+ T cells/kg, 3 x 10⁶ CAR+ T cells/kg, or the maximum number of cells generated if below either one of these levels. Two patients received less than the dose assigned and were not evaluated for toxicity.

Patients were a median age of 13 years (range, 5 to 27). Fourteen were male, 20 had ALL, and 1 had diffuse large B-cell lymphoma.

All had detectable disease, and 2 were CNS2 at the time of T-cell infusion. Six had primary refractory disease, 8 had at least 1 prior stem cell transplant, and 4 had prior immunotherapy.

The investigators determined that the maximally tolerated dose was 1 x 10⁶ CAR+ T cells/kg. The dose-limiting toxicities were related to cytokine release syndrome (CRS), which was reversible if managed appropriately with tocilizumab, with or without steroids.

Grade 3 adverse events possibly related to therapy included fever (47%), febrile neutropenia (37%), electrolyte disturbance (29%), CRS (16%), hypotension (11%), transaminitis (16%), and 5% each for hypertension, prolonged QTc, dysphasia, LV systolic dysfunction, multiorgan failure, hypoxia, and pulmonary edema.

Grade 4 events possibly related to treatment included electrolyte disturbance (5%), CRS (16%), hypotension (11%), cardiac arrest (5%), and hypoxia (5%). There was no evidence of graft-vs-host disease.

The complete response (CR) rate was 67% in the intent-to-treat population and 70% in patients with ALL.

“Those patients who responded tended to have some degree of cytokine release syndrome, whereas those patients who did not respond or had stable disease did not have any CRS,” Dr Lee said. “But, also, it’s important to note that you don’t have to have severe grade 3 or grade 4 CRS in order to have significant response.”

Dr Lee also pointed out that in vivo CAR T-cell expansion significantly correlated with response (P=0.0028). And CRS severity correlated with IL-6 (P=0.0002), INF-γ (P=0.0002), C-reactive protein (P=0.0015), and CAR (P=0.0011).

At a median follow-up of 10 months, minimal residual disease-negative patients had a 79% leukemia-free survival. Overall survival was 52% for all patients enrolled. Two patients had CD19-negative relapses.

The investigators also found that CAR T cells can eliminate CNS leukemia, with 11 of 17 patients (65%) having CAR T cells detectable in their cerebrospinal fluid.

The team concluded that this therapy is feasible in 90% of heavily pretreated or transplanted ALL patients and can serve as a bridge to transplant.

*Information in the abstract differs from that presented at the meeting.

ALL patient

Credit: Bill Branson

SAN FRANCISCO—A chimeric antigen receptor (CAR) T-cell therapy is feasible in 90% of heavily pretreated or transplanted patients with acute lymphoblastic leukemia (ALL) and can serve as a bridge to transplant, according to investigators.

Daniel W. Lee III, MD, of the National Cancer Institute in Bethesda, Maryland, reported on a phase 1 study of this CD19 CAR T-cell therapy in children and young adults with CD19+ ALL or non-Hodgkin lymphoma at the 2014 ASH Annual Meeting (abstract 381*).

Twenty-one patients were enrolled on the trial. They had a preparative regimen of fludarabine and cyclophosphamide and were infused with CAR T cells 11 days after the peripheral blood mononuclear cells were collected.

Dose levels were 1 x 10⁶ CAR+ T cells/kg, 3 x 10⁶ CAR+ T cells/kg, or the maximum number of cells generated if below either one of these levels. Two patients received less than the dose assigned and were not evaluated for toxicity.

Patients were a median age of 13 years (range, 5 to 27). Fourteen were male, 20 had ALL, and 1 had diffuse large B-cell lymphoma.

All had detectable disease, and 2 were CNS2 at the time of T-cell infusion. Six had primary refractory disease, 8 had at least 1 prior stem cell transplant, and 4 had prior immunotherapy.

The investigators determined that the maximally tolerated dose was 1 x 10⁶ CAR+ T cells/kg. The dose-limiting toxicities were related to cytokine release syndrome (CRS), which was reversible if managed appropriately with tocilizumab, with or without steroids.

Grade 3 adverse events possibly related to therapy included fever (47%), febrile neutropenia (37%), electrolyte disturbance (29%), CRS (16%), hypotension (11%), transaminitis (16%), and 5% each for hypertension, prolonged QTc, dysphasia, LV systolic dysfunction, multiorgan failure, hypoxia, and pulmonary edema.

Grade 4 events possibly related to treatment included electrolyte disturbance (5%), CRS (16%), hypotension (11%), cardiac arrest (5%), and hypoxia (5%). There was no evidence of graft-vs-host disease.

The complete response (CR) rate was 67% in the intent-to-treat population and 70% in patients with ALL.

“Those patients who responded tended to have some degree of cytokine release syndrome, whereas those patients who did not respond or had stable disease did not have any CRS,” Dr Lee said. “But, also, it’s important to note that you don’t have to have severe grade 3 or grade 4 CRS in order to have significant response.”

Dr Lee also pointed out that in vivo CAR T-cell expansion significantly correlated with response (P=0.0028). And CRS severity correlated with IL-6 (P=0.0002), INF-γ (P=0.0002), C-reactive protein (P=0.0015), and CAR (P=0.0011).

At a median follow-up of 10 months, minimal residual disease-negative patients had a 79% leukemia-free survival. Overall survival was 52% for all patients enrolled. Two patients had CD19-negative relapses.

The investigators also found that CAR T cells can eliminate CNS leukemia, with 11 of 17 patients (65%) having CAR T cells detectable in their cerebrospinal fluid.

The team concluded that this therapy is feasible in 90% of heavily pretreated or transplanted ALL patients and can serve as a bridge to transplant.

*Information in the abstract differs from that presented at the meeting.

CHICAGO – Implementation of preoperative venous thromboembolism prophylaxis requires a highly individualized approach and a little boost from information technology, one expert suggested.

“What may not be appreciated by some vascular surgeons is that for certain procedures we do, our patients actually have a high VTE [venous thromboembolism] risk. I know people think, ‘We use heparin, so our patients aren’t at high risk,’ but they actually are,” Dr. Melina Kibbe said at a symposium on vascular surgery sponsored by Northwestern University.

The VTE risk is 4.2% for open thoracoabdominal aortic aneurysm repair and 2.2% for thoracic endovascular aortic repair in the American College of Surgeons National Surgical Quality Improvement Program database. That may be an underestimation, however, because the NSQIP database captures only symptomatic events documented by imaging and those events occurring in the first 30 days after surgery.

Patrice Wendling/Frontline Medical News

Smaller studies looking at the problem prospectively suggest the VTE risk is closer to 2%-12% after open aortic surgery and 5.3% after endovascular aortic repair, she said.

Add to that the U.S. Surgeon General’s 2008 call to action to prevent VTE and the Institute of Medicine’s stance that failure to provide VTE prophylaxis qualifies as a medical error, and it would be tempting for vascular surgeons to prescribe pharmacologic prophylaxis for all of their patients, or at least do so based on the type of procedure.

“But VTE formation is really secondary to patient-specific and procedure-related factors,” said Dr. Kibbe, a professor of vascular surgery at Northwestern University in Chicago.

She highlighted five current VTE risk assessment models (RAMs) and the potential returns when RAMs are incorporated into clinical decision support systems.

• Kucher model. One of the earlier and most straightforward RAMs is the Kucher model. It assessed eight weighted risk factors (advanced age, obesity, bed rest, hormone replacement therapy/oral contraceptives, major surgery, cancer, prior VTE, and hypercoagulability) and provided surgeons with electronic alerts regarding prophylaxis.

VTE rates dropped from 8.2% to 4.9% in the high-risk category (score ≥ 4) with the use of the simple physician reminders (N. Engl. J. Med. 2005;352:969-77). Prospective validation showed that VTE increased proportionally with higher scores, Dr. Kibbe said. On the other hand, the model lacked sensitivity at low VTE risk, because 20% of patients with a score of 4 or less actually had VTEs.

“So, while it was simple, it only works well for the high-risk category,” she said.

• Rogers model. One of the most vigorously studied and developed RAMs is the Rogers model (J. Am. Coll. Surg. 2007;204:1211-21). It identified 15 variables (including lab values, patient characteristics, disease states, work relative-value unit, and type of operation) that were independently associated with VTE formation among 183,609 patients undergoing general, vascular, or thoracic procedures at 142 Veterans Health Administration and private hospitals. Each variable is assigned a value from 0 to 9 and added together to create a Rogers score.

Validation showed that VTE risk correlates with the Rogers score, rising from 0.11% for patients with a low score (< 7) to 1.32% for those with a high score (> 10), Dr. Kibbe said. Criticisms of the model are that it is complex, VTE incidence in the entire cohort was low at just 0.63%, the type of VTE prophylaxis used was unclear, and the model lacks prospective validation in a vascular surgery cohort.

• Caprini model. The most commonly used RAM is the 2005 Caprini model (Dis. Mon. 2005;51:70-8), which assigns a weighted score based on more than 30 VTE risk factors compiled by the authors. It has been prospectively validated in numerous studies and shown to accurately stratify 30-day VTE risk at 0.5% for patients at very low risk, 1.5% for low risk, 3% for moderate risk, and 6% for high risk.

The Caprini model, however, was not developed with the same rigor as the Rogers RAM, some of the risk factors have been shown not to be a risk for VTE, and it is complex, Dr. Kibbe observed.

• Pannucci model. The Pannucci model was created specifically to counteract the complexity of the Rogers and Caprini RAMs and incorporates only seven risk factors (personal history of VTE, current cancer, age ≥ 60 years, body mass index ≥ 40 kg/m², male sex, sepsis/septic shock/systemic inflammatory response syndrome, and family history of VTE) into a weighted index for 90-day VTE risk (Chest 2014;145:567-73). The model was developed using a statewide database and a derivation cohort made up of 20% vascular surgery patients.

Both the derivation and validation cohorts identified an 18-fold variation in VTE risk from the lowest- to highest-risk surgical population, showing that the model stratifies patients correctly. Further prospective validation is needed, Dr. Kibbe said.

• Scarborough model. Finally, in an attempt to develop a RAM specific to vascular surgery patients, Dr. John Scarborough and colleagues examined 6,035 patients undergoing open AAA repair in the NSQIP database. The 30-day VTE rate was 2.4% for the entire cohort. Eight independent perioperative risk factors were identified and used to create a nonweighted scoring system (J. Am. Coll. Surg. 2012;214:620-6).

Overall, 65% of patients had 0-1 risk factor and a VTE incidence of 1.5%, while 15% had 3 or more risk factors and a VTE incidence of 6.1%. The Scarborough model has good risk stratification, Dr. Kibbe said, but it is limited by the aforementioned criticisms regarding the NSQIP database, and it also needs prospective validation.

“We all know that proper VTE prophylaxis is very important for our patients; but we need mechanisms by which the attention given to this need for prophylaxis, which is a lot, is turned into proper implementation,” she said.

For Dr. Kibbe and her colleagues, proper implementation meant developing a RAM that was incorporated into the electronic medical record system for all surgical patients at the Jesse Brown VA Medical Center in Chicago. Clinicians were prompted to complete the RAM upon placing orders for preanesthesia testing clearance, and the clinical decision support system would provide a recommended prophylaxis regimen and easily selected electronic orders that could be signed.

A pre- and postimplementation analysis involving 400 consecutive patients revealed an 82% increase in patients with preoperative VTE prophylaxis ordered (22% vs. 40%), a 75% decrease in inappropriate cancellation of orders more than 12 hours before surgery (37% vs. 9%), and a nearly sevenfold increase in the number of patients receiving pharmacologic and mechanical prophylaxis (5% vs. 32%), she said. There was an 80% and 36% decline in DVT rates at 30 and 90 days postoperative, but event rates were too low to detect a significant difference (J. Vasc. Surg. 2010;51:648-54).

Dr. Kibbe reported having no financial disclosures.

[email protected]

CHICAGO – Implementation of preoperative venous thromboembolism prophylaxis requires a highly individualized approach and a little boost from information technology, one expert suggested.

“What may not be appreciated by some vascular surgeons is that for certain procedures we do, our patients actually have a high VTE [venous thromboembolism] risk. I know people think, ‘We use heparin, so our patients aren’t at high risk,’ but they actually are,” Dr. Melina Kibbe said at a symposium on vascular surgery sponsored by Northwestern University.

The VTE risk is 4.2% for open thoracoabdominal aortic aneurysm repair and 2.2% for thoracic endovascular aortic repair in the American College of Surgeons National Surgical Quality Improvement Program database. That may be an underestimation, however, because the NSQIP database captures only symptomatic events documented by imaging and those events occurring in the first 30 days after surgery.

Patrice Wendling/Frontline Medical News

Smaller studies looking at the problem prospectively suggest the VTE risk is closer to 2%-12% after open aortic surgery and 5.3% after endovascular aortic repair, she said.

Add to that the U.S. Surgeon General’s 2008 call to action to prevent VTE and the Institute of Medicine’s stance that failure to provide VTE prophylaxis qualifies as a medical error, and it would be tempting for vascular surgeons to prescribe pharmacologic prophylaxis for all of their patients, or at least do so based on the type of procedure.

“But VTE formation is really secondary to patient-specific and procedure-related factors,” said Dr. Kibbe, a professor of vascular surgery at Northwestern University in Chicago.

She highlighted five current VTE risk assessment models (RAMs) and the potential returns when RAMs are incorporated into clinical decision support systems.

• Kucher model. One of the earlier and most straightforward RAMs is the Kucher model. It assessed eight weighted risk factors (advanced age, obesity, bed rest, hormone replacement therapy/oral contraceptives, major surgery, cancer, prior VTE, and hypercoagulability) and provided surgeons with electronic alerts regarding prophylaxis.

VTE rates dropped from 8.2% to 4.9% in the high-risk category (score ≥ 4) with the use of the simple physician reminders (N. Engl. J. Med. 2005;352:969-77). Prospective validation showed that VTE increased proportionally with higher scores, Dr. Kibbe said. On the other hand, the model lacked sensitivity at low VTE risk, because 20% of patients with a score of 4 or less actually had VTEs.

“So, while it was simple, it only works well for the high-risk category,” she said.

• Rogers model. One of the most vigorously studied and developed RAMs is the Rogers model (J. Am. Coll. Surg. 2007;204:1211-21). It identified 15 variables (including lab values, patient characteristics, disease states, work relative-value unit, and type of operation) that were independently associated with VTE formation among 183,609 patients undergoing general, vascular, or thoracic procedures at 142 Veterans Health Administration and private hospitals. Each variable is assigned a value from 0 to 9 and added together to create a Rogers score.

Validation showed that VTE risk correlates with the Rogers score, rising from 0.11% for patients with a low score (< 7) to 1.32% for those with a high score (> 10), Dr. Kibbe said. Criticisms of the model are that it is complex, VTE incidence in the entire cohort was low at just 0.63%, the type of VTE prophylaxis used was unclear, and the model lacks prospective validation in a vascular surgery cohort.

• Caprini model. The most commonly used RAM is the 2005 Caprini model (Dis. Mon. 2005;51:70-8), which assigns a weighted score based on more than 30 VTE risk factors compiled by the authors. It has been prospectively validated in numerous studies and shown to accurately stratify 30-day VTE risk at 0.5% for patients at very low risk, 1.5% for low risk, 3% for moderate risk, and 6% for high risk.

The Caprini model, however, was not developed with the same rigor as the Rogers RAM, some of the risk factors have been shown not to be a risk for VTE, and it is complex, Dr. Kibbe observed.

• Pannucci model. The Pannucci model was created specifically to counteract the complexity of the Rogers and Caprini RAMs and incorporates only seven risk factors (personal history of VTE, current cancer, age ≥ 60 years, body mass index ≥ 40 kg/m², male sex, sepsis/septic shock/systemic inflammatory response syndrome, and family history of VTE) into a weighted index for 90-day VTE risk (Chest 2014;145:567-73). The model was developed using a statewide database and a derivation cohort made up of 20% vascular surgery patients.

Both the derivation and validation cohorts identified an 18-fold variation in VTE risk from the lowest- to highest-risk surgical population, showing that the model stratifies patients correctly. Further prospective validation is needed, Dr. Kibbe said.

• Scarborough model. Finally, in an attempt to develop a RAM specific to vascular surgery patients, Dr. John Scarborough and colleagues examined 6,035 patients undergoing open AAA repair in the NSQIP database. The 30-day VTE rate was 2.4% for the entire cohort. Eight independent perioperative risk factors were identified and used to create a nonweighted scoring system (J. Am. Coll. Surg. 2012;214:620-6).

Overall, 65% of patients had 0-1 risk factor and a VTE incidence of 1.5%, while 15% had 3 or more risk factors and a VTE incidence of 6.1%. The Scarborough model has good risk stratification, Dr. Kibbe said, but it is limited by the aforementioned criticisms regarding the NSQIP database, and it also needs prospective validation.

“We all know that proper VTE prophylaxis is very important for our patients; but we need mechanisms by which the attention given to this need for prophylaxis, which is a lot, is turned into proper implementation,” she said.

For Dr. Kibbe and her colleagues, proper implementation meant developing a RAM that was incorporated into the electronic medical record system for all surgical patients at the Jesse Brown VA Medical Center in Chicago. Clinicians were prompted to complete the RAM upon placing orders for preanesthesia testing clearance, and the clinical decision support system would provide a recommended prophylaxis regimen and easily selected electronic orders that could be signed.

A pre- and postimplementation analysis involving 400 consecutive patients revealed an 82% increase in patients with preoperative VTE prophylaxis ordered (22% vs. 40%), a 75% decrease in inappropriate cancellation of orders more than 12 hours before surgery (37% vs. 9%), and a nearly sevenfold increase in the number of patients receiving pharmacologic and mechanical prophylaxis (5% vs. 32%), she said. There was an 80% and 36% decline in DVT rates at 30 and 90 days postoperative, but event rates were too low to detect a significant difference (J. Vasc. Surg. 2010;51:648-54).

Dr. Kibbe reported having no financial disclosures.

[email protected]

CHICAGO – Implementation of preoperative venous thromboembolism prophylaxis requires a highly individualized approach and a little boost from information technology, one expert suggested.

“What may not be appreciated by some vascular surgeons is that for certain procedures we do, our patients actually have a high VTE [venous thromboembolism] risk. I know people think, ‘We use heparin, so our patients aren’t at high risk,’ but they actually are,” Dr. Melina Kibbe said at a symposium on vascular surgery sponsored by Northwestern University.

The VTE risk is 4.2% for open thoracoabdominal aortic aneurysm repair and 2.2% for thoracic endovascular aortic repair in the American College of Surgeons National Surgical Quality Improvement Program database. That may be an underestimation, however, because the NSQIP database captures only symptomatic events documented by imaging and those events occurring in the first 30 days after surgery.

Patrice Wendling/Frontline Medical News

Smaller studies looking at the problem prospectively suggest the VTE risk is closer to 2%-12% after open aortic surgery and 5.3% after endovascular aortic repair, she said.

Add to that the U.S. Surgeon General’s 2008 call to action to prevent VTE and the Institute of Medicine’s stance that failure to provide VTE prophylaxis qualifies as a medical error, and it would be tempting for vascular surgeons to prescribe pharmacologic prophylaxis for all of their patients, or at least do so based on the type of procedure.

“But VTE formation is really secondary to patient-specific and procedure-related factors,” said Dr. Kibbe, a professor of vascular surgery at Northwestern University in Chicago.

She highlighted five current VTE risk assessment models (RAMs) and the potential returns when RAMs are incorporated into clinical decision support systems.

• Kucher model. One of the earlier and most straightforward RAMs is the Kucher model. It assessed eight weighted risk factors (advanced age, obesity, bed rest, hormone replacement therapy/oral contraceptives, major surgery, cancer, prior VTE, and hypercoagulability) and provided surgeons with electronic alerts regarding prophylaxis.

VTE rates dropped from 8.2% to 4.9% in the high-risk category (score ≥ 4) with the use of the simple physician reminders (N. Engl. J. Med. 2005;352:969-77). Prospective validation showed that VTE increased proportionally with higher scores, Dr. Kibbe said. On the other hand, the model lacked sensitivity at low VTE risk, because 20% of patients with a score of 4 or less actually had VTEs.

“So, while it was simple, it only works well for the high-risk category,” she said.

• Rogers model. One of the most vigorously studied and developed RAMs is the Rogers model (J. Am. Coll. Surg. 2007;204:1211-21). It identified 15 variables (including lab values, patient characteristics, disease states, work relative-value unit, and type of operation) that were independently associated with VTE formation among 183,609 patients undergoing general, vascular, or thoracic procedures at 142 Veterans Health Administration and private hospitals. Each variable is assigned a value from 0 to 9 and added together to create a Rogers score.

Validation showed that VTE risk correlates with the Rogers score, rising from 0.11% for patients with a low score (< 7) to 1.32% for those with a high score (> 10), Dr. Kibbe said. Criticisms of the model are that it is complex, VTE incidence in the entire cohort was low at just 0.63%, the type of VTE prophylaxis used was unclear, and the model lacks prospective validation in a vascular surgery cohort.

• Caprini model. The most commonly used RAM is the 2005 Caprini model (Dis. Mon. 2005;51:70-8), which assigns a weighted score based on more than 30 VTE risk factors compiled by the authors. It has been prospectively validated in numerous studies and shown to accurately stratify 30-day VTE risk at 0.5% for patients at very low risk, 1.5% for low risk, 3% for moderate risk, and 6% for high risk.

The Caprini model, however, was not developed with the same rigor as the Rogers RAM, some of the risk factors have been shown not to be a risk for VTE, and it is complex, Dr. Kibbe observed.

• Pannucci model. The Pannucci model was created specifically to counteract the complexity of the Rogers and Caprini RAMs and incorporates only seven risk factors (personal history of VTE, current cancer, age ≥ 60 years, body mass index ≥ 40 kg/m², male sex, sepsis/septic shock/systemic inflammatory response syndrome, and family history of VTE) into a weighted index for 90-day VTE risk (Chest 2014;145:567-73). The model was developed using a statewide database and a derivation cohort made up of 20% vascular surgery patients.

Both the derivation and validation cohorts identified an 18-fold variation in VTE risk from the lowest- to highest-risk surgical population, showing that the model stratifies patients correctly. Further prospective validation is needed, Dr. Kibbe said.

• Scarborough model. Finally, in an attempt to develop a RAM specific to vascular surgery patients, Dr. John Scarborough and colleagues examined 6,035 patients undergoing open AAA repair in the NSQIP database. The 30-day VTE rate was 2.4% for the entire cohort. Eight independent perioperative risk factors were identified and used to create a nonweighted scoring system (J. Am. Coll. Surg. 2012;214:620-6).

Overall, 65% of patients had 0-1 risk factor and a VTE incidence of 1.5%, while 15% had 3 or more risk factors and a VTE incidence of 6.1%. The Scarborough model has good risk stratification, Dr. Kibbe said, but it is limited by the aforementioned criticisms regarding the NSQIP database, and it also needs prospective validation.

“We all know that proper VTE prophylaxis is very important for our patients; but we need mechanisms by which the attention given to this need for prophylaxis, which is a lot, is turned into proper implementation,” she said.

For Dr. Kibbe and her colleagues, proper implementation meant developing a RAM that was incorporated into the electronic medical record system for all surgical patients at the Jesse Brown VA Medical Center in Chicago. Clinicians were prompted to complete the RAM upon placing orders for preanesthesia testing clearance, and the clinical decision support system would provide a recommended prophylaxis regimen and easily selected electronic orders that could be signed.

A pre- and postimplementation analysis involving 400 consecutive patients revealed an 82% increase in patients with preoperative VTE prophylaxis ordered (22% vs. 40%), a 75% decrease in inappropriate cancellation of orders more than 12 hours before surgery (37% vs. 9%), and a nearly sevenfold increase in the number of patients receiving pharmacologic and mechanical prophylaxis (5% vs. 32%), she said. There was an 80% and 36% decline in DVT rates at 30 and 90 days postoperative, but event rates were too low to detect a significant difference (J. Vasc. Surg. 2010;51:648-54).

Dr. Kibbe reported having no financial disclosures.

[email protected]

Blood collection

Credit: Charles Haymond

SAN FRANCISCO—JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, can produce durable responses in patients with B-cell acute lymphoblastic leukemia (ALL) who do not undergo subsequent hematopoietic stem cell transplant (HSCT), new research suggests.

JCAR015 consists of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19.

Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented data on JCAR015 at the 2014 ASH Annual Meeting (abstract 382).* The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.

JCAR015 was tested at a dose of 1 - 3 x 10⁶ CAR cells/kg in 33 adults with relapsed/refractory B-cell ALL. Twenty-eight patients were evaluable for toxicity, 27 for response, and 5 patients were too early in their treatment to evaluate at the time of data cutoff.

Twenty-one patients were male, and the median age was 55 (range, 23 to 74).

Thirteen patients (46%) had minimal disease (<5% blasts) immediately prior to T-cell infusion, and 15 patients (54%) had morphologic disease of 5% to 100% blasts (median 63%).

Eighteen patients (64%) had received 2 prior lines of therapy, and 5 (18%) each had 3 or more prior lines.

Eight patients (29%) underwent prior allogeneic HSCT, 9 patients (32%) were Philadelphia chromosome positive (Ph+), and 3 (11%) had the T315I mutation.

The overall complete response (CR) rate was 89%, and the minimal residual disease-negative CR rate was 88%. The median time to CR was 22.5 days (range, 9 to 33).

The investigators performed a subgroup analysis and found that 100% of the 13 patients with minimal disease before therapy achieved a CR, compared to 79% of patients with morphologic disease.

Eighty-six percent (6/7) of patients who had a prior HSCT and 90% (18/20) without a prior HSCT achieved a CR. Eighty-nine percent (8/9) of Ph+ patients achieved a CR, and 89% (16/18) of Philadelphia-negative patients (89%) achieved a CR.

At a median follow-up of 6 months (range, 1 to 38 months), 12 patients remained disease-free, including 7 patients who had more than a year of follow-up. Seven patients are disease-free without a subsequent HSCT.

Nine patients relapsed during a follow-up of 3 to 8 months, and 10 patients proceeded to HSCT. Two relapses occurred after HSCT, one in a patient who had CD19-negative blasts, and 7 relapses occurred without HSCT.

The overall survival rate at 6 months was 57%, and the median survival was 8.5 months.

For those patients who had a transplant after CAR therapy, the median survival was 10.8 months, and the survival rate at 6 months was 68%.

Dr Park pointed out that maximum T-cell expansion occurred between days 7 and 14 and correlated with the occurrence of cytokine release syndrome (CRS). The T cells persisted for 1 to 3 months following infusion.

The main adverse events were those associated with CRS and neurologic changes. Severe CRS requiring vasopressors or mechanical ventilation occurred in 5 patients (18%) overall and in 5 patients (33%) with morphologic disease before therapy. Severe CRS did not occur in any patient with minimal disease before therapy.

Grade 3 or 4 neurotoxicity occurred in 7 patients (25%) overall, in 6 patients (40%) with morphologic disease, and in 1 with minimal disease (8%) before therapy.

The investigators observed no graft-vs-host disease exacerbation, and CRS was managed with an IL-6R inhibitor, steroids, or both.

Dr Park noted that the neurologic symptoms are reversible and can occur independently of CRS.

He also pointed out that CR rates were similar regardless of different disease risk factors, and that durable responses have been achieved in patients who did not have a subsequent HSCT.

*Information in the abstract differs from that presented at the meeting.

Blood collection

Credit: Charles Haymond

SAN FRANCISCO—JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, can produce durable responses in patients with B-cell acute lymphoblastic leukemia (ALL) who do not undergo subsequent hematopoietic stem cell transplant (HSCT), new research suggests.

JCAR015 consists of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19.

Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented data on JCAR015 at the 2014 ASH Annual Meeting (abstract 382).* The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.

JCAR015 was tested at a dose of 1 - 3 x 10⁶ CAR cells/kg in 33 adults with relapsed/refractory B-cell ALL. Twenty-eight patients were evaluable for toxicity, 27 for response, and 5 patients were too early in their treatment to evaluate at the time of data cutoff.

Twenty-one patients were male, and the median age was 55 (range, 23 to 74).

Thirteen patients (46%) had minimal disease (<5% blasts) immediately prior to T-cell infusion, and 15 patients (54%) had morphologic disease of 5% to 100% blasts (median 63%).

Eighteen patients (64%) had received 2 prior lines of therapy, and 5 (18%) each had 3 or more prior lines.

Eight patients (29%) underwent prior allogeneic HSCT, 9 patients (32%) were Philadelphia chromosome positive (Ph+), and 3 (11%) had the T315I mutation.

The overall complete response (CR) rate was 89%, and the minimal residual disease-negative CR rate was 88%. The median time to CR was 22.5 days (range, 9 to 33).

The investigators performed a subgroup analysis and found that 100% of the 13 patients with minimal disease before therapy achieved a CR, compared to 79% of patients with morphologic disease.

Eighty-six percent (6/7) of patients who had a prior HSCT and 90% (18/20) without a prior HSCT achieved a CR. Eighty-nine percent (8/9) of Ph+ patients achieved a CR, and 89% (16/18) of Philadelphia-negative patients (89%) achieved a CR.

At a median follow-up of 6 months (range, 1 to 38 months), 12 patients remained disease-free, including 7 patients who had more than a year of follow-up. Seven patients are disease-free without a subsequent HSCT.

Nine patients relapsed during a follow-up of 3 to 8 months, and 10 patients proceeded to HSCT. Two relapses occurred after HSCT, one in a patient who had CD19-negative blasts, and 7 relapses occurred without HSCT.

The overall survival rate at 6 months was 57%, and the median survival was 8.5 months.

For those patients who had a transplant after CAR therapy, the median survival was 10.8 months, and the survival rate at 6 months was 68%.

Dr Park pointed out that maximum T-cell expansion occurred between days 7 and 14 and correlated with the occurrence of cytokine release syndrome (CRS). The T cells persisted for 1 to 3 months following infusion.

The main adverse events were those associated with CRS and neurologic changes. Severe CRS requiring vasopressors or mechanical ventilation occurred in 5 patients (18%) overall and in 5 patients (33%) with morphologic disease before therapy. Severe CRS did not occur in any patient with minimal disease before therapy.

Grade 3 or 4 neurotoxicity occurred in 7 patients (25%) overall, in 6 patients (40%) with morphologic disease, and in 1 with minimal disease (8%) before therapy.

The investigators observed no graft-vs-host disease exacerbation, and CRS was managed with an IL-6R inhibitor, steroids, or both.

Dr Park noted that the neurologic symptoms are reversible and can occur independently of CRS.

He also pointed out that CR rates were similar regardless of different disease risk factors, and that durable responses have been achieved in patients who did not have a subsequent HSCT.

*Information in the abstract differs from that presented at the meeting.

Blood collection

Credit: Charles Haymond

SAN FRANCISCO—JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, can produce durable responses in patients with B-cell acute lymphoblastic leukemia (ALL) who do not undergo subsequent hematopoietic stem cell transplant (HSCT), new research suggests.

JCAR015 consists of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19.

Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented data on JCAR015 at the 2014 ASH Annual Meeting (abstract 382).* The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.

JCAR015 was tested at a dose of 1 - 3 x 10⁶ CAR cells/kg in 33 adults with relapsed/refractory B-cell ALL. Twenty-eight patients were evaluable for toxicity, 27 for response, and 5 patients were too early in their treatment to evaluate at the time of data cutoff.

Twenty-one patients were male, and the median age was 55 (range, 23 to 74).

Thirteen patients (46%) had minimal disease (<5% blasts) immediately prior to T-cell infusion, and 15 patients (54%) had morphologic disease of 5% to 100% blasts (median 63%).

Eighteen patients (64%) had received 2 prior lines of therapy, and 5 (18%) each had 3 or more prior lines.

Eight patients (29%) underwent prior allogeneic HSCT, 9 patients (32%) were Philadelphia chromosome positive (Ph+), and 3 (11%) had the T315I mutation.

The overall complete response (CR) rate was 89%, and the minimal residual disease-negative CR rate was 88%. The median time to CR was 22.5 days (range, 9 to 33).

The investigators performed a subgroup analysis and found that 100% of the 13 patients with minimal disease before therapy achieved a CR, compared to 79% of patients with morphologic disease.

Eighty-six percent (6/7) of patients who had a prior HSCT and 90% (18/20) without a prior HSCT achieved a CR. Eighty-nine percent (8/9) of Ph+ patients achieved a CR, and 89% (16/18) of Philadelphia-negative patients (89%) achieved a CR.

At a median follow-up of 6 months (range, 1 to 38 months), 12 patients remained disease-free, including 7 patients who had more than a year of follow-up. Seven patients are disease-free without a subsequent HSCT.

Nine patients relapsed during a follow-up of 3 to 8 months, and 10 patients proceeded to HSCT. Two relapses occurred after HSCT, one in a patient who had CD19-negative blasts, and 7 relapses occurred without HSCT.

The overall survival rate at 6 months was 57%, and the median survival was 8.5 months.

For those patients who had a transplant after CAR therapy, the median survival was 10.8 months, and the survival rate at 6 months was 68%.

Dr Park pointed out that maximum T-cell expansion occurred between days 7 and 14 and correlated with the occurrence of cytokine release syndrome (CRS). The T cells persisted for 1 to 3 months following infusion.

The main adverse events were those associated with CRS and neurologic changes. Severe CRS requiring vasopressors or mechanical ventilation occurred in 5 patients (18%) overall and in 5 patients (33%) with morphologic disease before therapy. Severe CRS did not occur in any patient with minimal disease before therapy.

Grade 3 or 4 neurotoxicity occurred in 7 patients (25%) overall, in 6 patients (40%) with morphologic disease, and in 1 with minimal disease (8%) before therapy.

The investigators observed no graft-vs-host disease exacerbation, and CRS was managed with an IL-6R inhibitor, steroids, or both.

Dr Park noted that the neurologic symptoms are reversible and can occur independently of CRS.

He also pointed out that CR rates were similar regardless of different disease risk factors, and that durable responses have been achieved in patients who did not have a subsequent HSCT.

*Information in the abstract differs from that presented at the meeting.

Inadequate evaluation of a mole has costly consequences

A 53-year-old woman went to her physician for treatment of a mole on her upper right arm, which she stated had grown and changed color. The physician burned it off without conducting a biopsy or follow-up. Fifteen months later, the patient returned to her physician because the scar was raised with small bumps. He referred her to a surgeon, who diagnosed malignant melanoma (Clark’s level V), with a satellite lesion but negative lymph nodes. The patient underwent surgery and adjuvant interferon-alpha therapy, which caused significant adverse effects.

The patient now has anxiety related to fears of recurrence or death, and must undergo regular positron emission tomography and computed tomography scans to evaluate her for recurrence.

PLAINTIFF’S CLAIM The melanoma should have been diagnosed at the patient’s initial presentation. If it had been diagnosed at that time, the patient would have had an 85% to 90% chance of survival, but because it wasn’t, her survival rate dropped to 60%.

THE DEFENSE No information about the defense is available.

VERDICT $750,000 Virginia settlement.

COMMENT When there is any doubt—by patient or physician—cut it out and send it out (for biopsy).

A higher index of suspicion for PE could have been lifesaving

A 37-year-old morbidly obese man was recovering in a rehabilitation facility from spinal surgery performed 2 weeks earlier. On the day he was to be discharged, he was transported by ambulance to the emergency department (ED) complaining of “a syncopal episode” with weakness, lightheadedness, dizziness, and sweatiness. This was followed by a second episode with similar symptoms. The patient had no wheezes or rales and his heart rhythm was normal, with no murmurs or gallop. In the ED his pulse rose from 94 to 116 and his blood pressure (BP) rose from 106/82 to 145/102. An electrocardiogram (EKG) was abnormal.

The ED physician felt the likelihood of PE was low, despite the fact that the patient was obese and had recent back surgery and an abnormal EKG. The ED physician felt that the likelihood of pulmonary embolism (PE) was low; he suspected, instead, that it was “likely vagal syncope.” The patient returned to the rehab facility, stayed overnight, and was discharged the next day. Two days later, he became short of breath, passed out, and was taken by ambulance to the hospital, where resuscitation efforts were unsuccessful. Autopsy revealed the cause of death was pulmonary thromboemboli from deep vein thrombosis.

PLAINTIFF’S CLAIM The ED physician failed to rule out PE, which should have been considered because of the patient’s obesity, recent back surgery, immobilization, syncope, tachycardia, elevated BP, and abnormal EKG.

THE DEFENSE No information about the defense is available.

VERDICT $1.25 million Massachusetts settlement.

COMMENT Why the physician decided that this patient, who died of a PE, was at low risk for one is puzzling. I count at least 4 risk factors for PE: obesity, postoperative status, abnormal EKG, and tachycardia.

Inadequate evaluation of a mole has costly consequences

A 53-year-old woman went to her physician for treatment of a mole on her upper right arm, which she stated had grown and changed color. The physician burned it off without conducting a biopsy or follow-up. Fifteen months later, the patient returned to her physician because the scar was raised with small bumps. He referred her to a surgeon, who diagnosed malignant melanoma (Clark’s level V), with a satellite lesion but negative lymph nodes. The patient underwent surgery and adjuvant interferon-alpha therapy, which caused significant adverse effects.

The patient now has anxiety related to fears of recurrence or death, and must undergo regular positron emission tomography and computed tomography scans to evaluate her for recurrence.

PLAINTIFF’S CLAIM The melanoma should have been diagnosed at the patient’s initial presentation. If it had been diagnosed at that time, the patient would have had an 85% to 90% chance of survival, but because it wasn’t, her survival rate dropped to 60%.

THE DEFENSE No information about the defense is available.

VERDICT $750,000 Virginia settlement.

COMMENT When there is any doubt—by patient or physician—cut it out and send it out (for biopsy).

A higher index of suspicion for PE could have been lifesaving

A 37-year-old morbidly obese man was recovering in a rehabilitation facility from spinal surgery performed 2 weeks earlier. On the day he was to be discharged, he was transported by ambulance to the emergency department (ED) complaining of “a syncopal episode” with weakness, lightheadedness, dizziness, and sweatiness. This was followed by a second episode with similar symptoms. The patient had no wheezes or rales and his heart rhythm was normal, with no murmurs or gallop. In the ED his pulse rose from 94 to 116 and his blood pressure (BP) rose from 106/82 to 145/102. An electrocardiogram (EKG) was abnormal.

The ED physician felt the likelihood of PE was low, despite the fact that the patient was obese and had recent back surgery and an abnormal EKG. The ED physician felt that the likelihood of pulmonary embolism (PE) was low; he suspected, instead, that it was “likely vagal syncope.” The patient returned to the rehab facility, stayed overnight, and was discharged the next day. Two days later, he became short of breath, passed out, and was taken by ambulance to the hospital, where resuscitation efforts were unsuccessful. Autopsy revealed the cause of death was pulmonary thromboemboli from deep vein thrombosis.

PLAINTIFF’S CLAIM The ED physician failed to rule out PE, which should have been considered because of the patient’s obesity, recent back surgery, immobilization, syncope, tachycardia, elevated BP, and abnormal EKG.

THE DEFENSE No information about the defense is available.

VERDICT $1.25 million Massachusetts settlement.

COMMENT Why the physician decided that this patient, who died of a PE, was at low risk for one is puzzling. I count at least 4 risk factors for PE: obesity, postoperative status, abnormal EKG, and tachycardia.

Inadequate evaluation of a mole has costly consequences

A 53-year-old woman went to her physician for treatment of a mole on her upper right arm, which she stated had grown and changed color. The physician burned it off without conducting a biopsy or follow-up. Fifteen months later, the patient returned to her physician because the scar was raised with small bumps. He referred her to a surgeon, who diagnosed malignant melanoma (Clark’s level V), with a satellite lesion but negative lymph nodes. The patient underwent surgery and adjuvant interferon-alpha therapy, which caused significant adverse effects.

The patient now has anxiety related to fears of recurrence or death, and must undergo regular positron emission tomography and computed tomography scans to evaluate her for recurrence.

PLAINTIFF’S CLAIM The melanoma should have been diagnosed at the patient’s initial presentation. If it had been diagnosed at that time, the patient would have had an 85% to 90% chance of survival, but because it wasn’t, her survival rate dropped to 60%.

THE DEFENSE No information about the defense is available.

VERDICT $750,000 Virginia settlement.

COMMENT When there is any doubt—by patient or physician—cut it out and send it out (for biopsy).

A higher index of suspicion for PE could have been lifesaving

A 37-year-old morbidly obese man was recovering in a rehabilitation facility from spinal surgery performed 2 weeks earlier. On the day he was to be discharged, he was transported by ambulance to the emergency department (ED) complaining of “a syncopal episode” with weakness, lightheadedness, dizziness, and sweatiness. This was followed by a second episode with similar symptoms. The patient had no wheezes or rales and his heart rhythm was normal, with no murmurs or gallop. In the ED his pulse rose from 94 to 116 and his blood pressure (BP) rose from 106/82 to 145/102. An electrocardiogram (EKG) was abnormal.

The ED physician felt the likelihood of PE was low, despite the fact that the patient was obese and had recent back surgery and an abnormal EKG. The ED physician felt that the likelihood of pulmonary embolism (PE) was low; he suspected, instead, that it was “likely vagal syncope.” The patient returned to the rehab facility, stayed overnight, and was discharged the next day. Two days later, he became short of breath, passed out, and was taken by ambulance to the hospital, where resuscitation efforts were unsuccessful. Autopsy revealed the cause of death was pulmonary thromboemboli from deep vein thrombosis.

PLAINTIFF’S CLAIM The ED physician failed to rule out PE, which should have been considered because of the patient’s obesity, recent back surgery, immobilization, syncope, tachycardia, elevated BP, and abnormal EKG.

THE DEFENSE No information about the defense is available.

VERDICT $1.25 million Massachusetts settlement.

COMMENT Why the physician decided that this patient, who died of a PE, was at low risk for one is puzzling. I count at least 4 risk factors for PE: obesity, postoperative status, abnormal EKG, and tachycardia.