WASHINGTON - A transcatheter pulmonary valve system that provides a new right ventricle to pulmonary artery conduit to congenital heart disease patients without the need for open heart surgery performed a little better in a real-world registry at 10 U.S. centers than it had in the pivotal trial that led to the system's 2010 FDA approval.

The new results "confirm the strong performance of the Melody transcatheter pulmonary valve achieved by real-world providers with results comparable to the U.S. investigational device exemption [IDE] trial," Dr. Aimee K. Armstrong said at the annual meeting of the American College of Cardiology. The "high level" of 97% freedom from transcatheter pulmonary valve (TPV) dysfunction at 1 year "was better than in the IDE trial," where the level reached 94%, noted Dr. Armstrong of the University of Michigan in Ann Arbor.

Mitchel L. Zoler/Frontline Medical News

The registry study, which the FDA mandated when it approved the Melody valve in 2010, ran during July 2010 to July 2012 at 10 U.S. centers that had not participated in the pivotal trial. The 99 patients who received an implant that stayed in place for at least 1 day ranged from 5 to 45 years old, with an average age of 20 years. Although patient follow-up averaged 22 months, the study's primary endpoint was acceptable hemodynamic function within the conduit at 6 months, with a prespecified performance goal of 75% of patients achieving this outcome. The outcome actually occurred in 97% of the 90 evaluable patients at 6 months, and in 88% of all 99 patients who received a conduit. The difference between each of these rates and the performance goal was statistically significant, Dr. Armstrong said.

The transcatheter valve showed excellent performance by other criteria as well. Acceptable hemodynamic function continued through 1 year in 94% of the 87 implanted patients with evaluable data at 12 months, which translated to 83% of the entire 99 patients in the implanted group. Severe or moderate pulmonary valve regurgitation existed in 85% of the patients before treatment; after treatment no patient had severe or moderate regurgitation, and after 1 year 63% had no regurgitation, 24% had trace, and 12% had mild regurgitation (figures total 99% because of rounding). The 1-year rate of 97% of patients free from dysfunction of their implanted valve appeared to surpass the 94% rate seen in the pivotal trial (Circulation 2010;122:507-16).

The results also showed that high right ventricular pressure prior to valve placement was the only variable independently associated with subsequent valve dysfunction. "Patients who go into the procedure with a very stenotic conduit are probably at higher risk for transcatheter pulmonary valve dysfunction down the road," she said.

The study was sponsored by Medtronic, which markets the Melody transcatheter pulmonary valve. Dr. Armstrong said she has received research funding from Medtronic and Edwards Lifesciences.

[email protected]

WASHINGTON - A transcatheter pulmonary valve system that provides a new right ventricle to pulmonary artery conduit to congenital heart disease patients without the need for open heart surgery performed a little better in a real-world registry at 10 U.S. centers than it had in the pivotal trial that led to the system's 2010 FDA approval.

The new results "confirm the strong performance of the Melody transcatheter pulmonary valve achieved by real-world providers with results comparable to the U.S. investigational device exemption [IDE] trial," Dr. Aimee K. Armstrong said at the annual meeting of the American College of Cardiology. The "high level" of 97% freedom from transcatheter pulmonary valve (TPV) dysfunction at 1 year "was better than in the IDE trial," where the level reached 94%, noted Dr. Armstrong of the University of Michigan in Ann Arbor.

Mitchel L. Zoler/Frontline Medical News

The registry study, which the FDA mandated when it approved the Melody valve in 2010, ran during July 2010 to July 2012 at 10 U.S. centers that had not participated in the pivotal trial. The 99 patients who received an implant that stayed in place for at least 1 day ranged from 5 to 45 years old, with an average age of 20 years. Although patient follow-up averaged 22 months, the study's primary endpoint was acceptable hemodynamic function within the conduit at 6 months, with a prespecified performance goal of 75% of patients achieving this outcome. The outcome actually occurred in 97% of the 90 evaluable patients at 6 months, and in 88% of all 99 patients who received a conduit. The difference between each of these rates and the performance goal was statistically significant, Dr. Armstrong said.

The transcatheter valve showed excellent performance by other criteria as well. Acceptable hemodynamic function continued through 1 year in 94% of the 87 implanted patients with evaluable data at 12 months, which translated to 83% of the entire 99 patients in the implanted group. Severe or moderate pulmonary valve regurgitation existed in 85% of the patients before treatment; after treatment no patient had severe or moderate regurgitation, and after 1 year 63% had no regurgitation, 24% had trace, and 12% had mild regurgitation (figures total 99% because of rounding). The 1-year rate of 97% of patients free from dysfunction of their implanted valve appeared to surpass the 94% rate seen in the pivotal trial (Circulation 2010;122:507-16).

The results also showed that high right ventricular pressure prior to valve placement was the only variable independently associated with subsequent valve dysfunction. "Patients who go into the procedure with a very stenotic conduit are probably at higher risk for transcatheter pulmonary valve dysfunction down the road," she said.

The study was sponsored by Medtronic, which markets the Melody transcatheter pulmonary valve. Dr. Armstrong said she has received research funding from Medtronic and Edwards Lifesciences.

[email protected]

WASHINGTON - A transcatheter pulmonary valve system that provides a new right ventricle to pulmonary artery conduit to congenital heart disease patients without the need for open heart surgery performed a little better in a real-world registry at 10 U.S. centers than it had in the pivotal trial that led to the system's 2010 FDA approval.

The new results "confirm the strong performance of the Melody transcatheter pulmonary valve achieved by real-world providers with results comparable to the U.S. investigational device exemption [IDE] trial," Dr. Aimee K. Armstrong said at the annual meeting of the American College of Cardiology. The "high level" of 97% freedom from transcatheter pulmonary valve (TPV) dysfunction at 1 year "was better than in the IDE trial," where the level reached 94%, noted Dr. Armstrong of the University of Michigan in Ann Arbor.

Mitchel L. Zoler/Frontline Medical News

The registry study, which the FDA mandated when it approved the Melody valve in 2010, ran during July 2010 to July 2012 at 10 U.S. centers that had not participated in the pivotal trial. The 99 patients who received an implant that stayed in place for at least 1 day ranged from 5 to 45 years old, with an average age of 20 years. Although patient follow-up averaged 22 months, the study's primary endpoint was acceptable hemodynamic function within the conduit at 6 months, with a prespecified performance goal of 75% of patients achieving this outcome. The outcome actually occurred in 97% of the 90 evaluable patients at 6 months, and in 88% of all 99 patients who received a conduit. The difference between each of these rates and the performance goal was statistically significant, Dr. Armstrong said.

The transcatheter valve showed excellent performance by other criteria as well. Acceptable hemodynamic function continued through 1 year in 94% of the 87 implanted patients with evaluable data at 12 months, which translated to 83% of the entire 99 patients in the implanted group. Severe or moderate pulmonary valve regurgitation existed in 85% of the patients before treatment; after treatment no patient had severe or moderate regurgitation, and after 1 year 63% had no regurgitation, 24% had trace, and 12% had mild regurgitation (figures total 99% because of rounding). The 1-year rate of 97% of patients free from dysfunction of their implanted valve appeared to surpass the 94% rate seen in the pivotal trial (Circulation 2010;122:507-16).

The results also showed that high right ventricular pressure prior to valve placement was the only variable independently associated with subsequent valve dysfunction. "Patients who go into the procedure with a very stenotic conduit are probably at higher risk for transcatheter pulmonary valve dysfunction down the road," she said.

The study was sponsored by Medtronic, which markets the Melody transcatheter pulmonary valve. Dr. Armstrong said she has received research funding from Medtronic and Edwards Lifesciences.

[email protected]

TORONTO – Routine EEG monitoring after surgery with cardiopulmonary bypass in neonates revealed a seizure incidence of 8% in a recent study. In most cases (85%), seizure activity was detectable only on EEG and would not have been identified or treated without EEG monitoring, reported Dr. Maryam Y. Naim, of Children’s Hospital of Philadelphia, during the AATS Annual Meeting.

Of concern, status epilepticus was noted in 62% of neonates with seizures, and mortality was higher in babies with seizures versus those without (38% vs. 3%; P less than .01). "Postoperative seizures are associated with worse neurological outcomes," said Dr. Naim. In addition to being a biomarker of underlying brain injury, there is some evidence that the seizures themselves may cause secondary brain injury.

A total of 161 neonates had 48-hours of EEG monitoring begun within 6 hours of cardiac surgery with CPB. The median gestational age of the cohort was 39 weeks, 16% were premature, and 13% had identified genetic defects. The median age at surgery was 5 days. Deep hypothermic circulatory arrest was used in 48% of surgeries (median time, 48 minutes), 16% had open chest with delayed sternal closure, and 9% had a cardiac arrest.

Seizures were detected in 13 (8%), with a median onset of 20 hours after return to the cardiac ICU (CICU) from surgery. Seizures were subclinical, or EEG only, in 11 patients (85%), electroclinical in the other 2 (15%), and status epilepticus was seen in 8 (62%). When seizures occurred, the patient was treated with antiseizure medications. Abnormal vital signs or movements suggestive of seizure activity were noted at the bedside; although such events were recorded in 32 patients (22%), none had EEG correlates consistent with seizure activity.

"Neonates with all types of heart disease had seizures ... " said Dr. Naim. " ... with a highest percentage occurring in those with single ventricles and arch obstruction."

Neuroimaging studies were reviewed by a neurologist to determine any association between injury and seizure location. Although neonates with and without seizures had similar CICU lengths of stay, mortality was higher in those with seizures (38% vs. 3%; P less than .01). No predictors of seizures were identified on multivariable analysis.

"Based on these data, we are continuing routine postoperative EEG monitoring in all neonates following surgery with CPB," she said.

While not discredited in any way, Dr. Naim’s data were met with a fair amount of pushback from the gathered group of pediatric cardiothoracic surgical experts. An informal poll of the audience showed that 80%-90% do not routinely monitor neonates for seizures post-CPB despite ACNS recommendations, and several of the comments questioned the technical and financial feasibility of routine EEG monitoring.

Said the invited discussant, Dr. Frank Pigula, a cardiac surgeon from Boston Children’s Hospital, "In all the groups that have studied this, in all patients who have had a seizure, there were documented brain abnormalities. So, the ways I picture these data are that a seizure is a sign of an underlying brain injury, much like a fever is a sign of an underlying infection.

"And you’ve made a good case for the routine postoperative surveillance for seizures; I’m sure everyone would agree that treating seizures is a good thing, but is there any evidence showing us that the early identification and treatment of seizures improves outcomes, either developmental delays or mortality?

In response, Dr. Naim noted that all the CHOP seizure sufferers were treated, whether they had EEG only or clinical seizures, and, at the 4-year mark, they are showing fewer neurodevelopmental issues than previous cohorts of untreated neonates.

"I think one thing that is very concerning is emerging evidence that the seizures themselves cause secondary brain injury," she said.

Dr. Naim and Dr. Pigula reported having no financial disclosures.

TORONTO – Routine EEG monitoring after surgery with cardiopulmonary bypass in neonates revealed a seizure incidence of 8% in a recent study. In most cases (85%), seizure activity was detectable only on EEG and would not have been identified or treated without EEG monitoring, reported Dr. Maryam Y. Naim, of Children’s Hospital of Philadelphia, during the AATS Annual Meeting.

Of concern, status epilepticus was noted in 62% of neonates with seizures, and mortality was higher in babies with seizures versus those without (38% vs. 3%; P less than .01). "Postoperative seizures are associated with worse neurological outcomes," said Dr. Naim. In addition to being a biomarker of underlying brain injury, there is some evidence that the seizures themselves may cause secondary brain injury.

A total of 161 neonates had 48-hours of EEG monitoring begun within 6 hours of cardiac surgery with CPB. The median gestational age of the cohort was 39 weeks, 16% were premature, and 13% had identified genetic defects. The median age at surgery was 5 days. Deep hypothermic circulatory arrest was used in 48% of surgeries (median time, 48 minutes), 16% had open chest with delayed sternal closure, and 9% had a cardiac arrest.

Seizures were detected in 13 (8%), with a median onset of 20 hours after return to the cardiac ICU (CICU) from surgery. Seizures were subclinical, or EEG only, in 11 patients (85%), electroclinical in the other 2 (15%), and status epilepticus was seen in 8 (62%). When seizures occurred, the patient was treated with antiseizure medications. Abnormal vital signs or movements suggestive of seizure activity were noted at the bedside; although such events were recorded in 32 patients (22%), none had EEG correlates consistent with seizure activity.

"Neonates with all types of heart disease had seizures ... " said Dr. Naim. " ... with a highest percentage occurring in those with single ventricles and arch obstruction."

Neuroimaging studies were reviewed by a neurologist to determine any association between injury and seizure location. Although neonates with and without seizures had similar CICU lengths of stay, mortality was higher in those with seizures (38% vs. 3%; P less than .01). No predictors of seizures were identified on multivariable analysis.

"Based on these data, we are continuing routine postoperative EEG monitoring in all neonates following surgery with CPB," she said.

While not discredited in any way, Dr. Naim’s data were met with a fair amount of pushback from the gathered group of pediatric cardiothoracic surgical experts. An informal poll of the audience showed that 80%-90% do not routinely monitor neonates for seizures post-CPB despite ACNS recommendations, and several of the comments questioned the technical and financial feasibility of routine EEG monitoring.

Said the invited discussant, Dr. Frank Pigula, a cardiac surgeon from Boston Children’s Hospital, "In all the groups that have studied this, in all patients who have had a seizure, there were documented brain abnormalities. So, the ways I picture these data are that a seizure is a sign of an underlying brain injury, much like a fever is a sign of an underlying infection.

"And you’ve made a good case for the routine postoperative surveillance for seizures; I’m sure everyone would agree that treating seizures is a good thing, but is there any evidence showing us that the early identification and treatment of seizures improves outcomes, either developmental delays or mortality?

In response, Dr. Naim noted that all the CHOP seizure sufferers were treated, whether they had EEG only or clinical seizures, and, at the 4-year mark, they are showing fewer neurodevelopmental issues than previous cohorts of untreated neonates.

"I think one thing that is very concerning is emerging evidence that the seizures themselves cause secondary brain injury," she said.

Dr. Naim and Dr. Pigula reported having no financial disclosures.

TORONTO – Routine EEG monitoring after surgery with cardiopulmonary bypass in neonates revealed a seizure incidence of 8% in a recent study. In most cases (85%), seizure activity was detectable only on EEG and would not have been identified or treated without EEG monitoring, reported Dr. Maryam Y. Naim, of Children’s Hospital of Philadelphia, during the AATS Annual Meeting.

Of concern, status epilepticus was noted in 62% of neonates with seizures, and mortality was higher in babies with seizures versus those without (38% vs. 3%; P less than .01). "Postoperative seizures are associated with worse neurological outcomes," said Dr. Naim. In addition to being a biomarker of underlying brain injury, there is some evidence that the seizures themselves may cause secondary brain injury.

A total of 161 neonates had 48-hours of EEG monitoring begun within 6 hours of cardiac surgery with CPB. The median gestational age of the cohort was 39 weeks, 16% were premature, and 13% had identified genetic defects. The median age at surgery was 5 days. Deep hypothermic circulatory arrest was used in 48% of surgeries (median time, 48 minutes), 16% had open chest with delayed sternal closure, and 9% had a cardiac arrest.

Seizures were detected in 13 (8%), with a median onset of 20 hours after return to the cardiac ICU (CICU) from surgery. Seizures were subclinical, or EEG only, in 11 patients (85%), electroclinical in the other 2 (15%), and status epilepticus was seen in 8 (62%). When seizures occurred, the patient was treated with antiseizure medications. Abnormal vital signs or movements suggestive of seizure activity were noted at the bedside; although such events were recorded in 32 patients (22%), none had EEG correlates consistent with seizure activity.

"Neonates with all types of heart disease had seizures ... " said Dr. Naim. " ... with a highest percentage occurring in those with single ventricles and arch obstruction."

Neuroimaging studies were reviewed by a neurologist to determine any association between injury and seizure location. Although neonates with and without seizures had similar CICU lengths of stay, mortality was higher in those with seizures (38% vs. 3%; P less than .01). No predictors of seizures were identified on multivariable analysis.

"Based on these data, we are continuing routine postoperative EEG monitoring in all neonates following surgery with CPB," she said.

While not discredited in any way, Dr. Naim’s data were met with a fair amount of pushback from the gathered group of pediatric cardiothoracic surgical experts. An informal poll of the audience showed that 80%-90% do not routinely monitor neonates for seizures post-CPB despite ACNS recommendations, and several of the comments questioned the technical and financial feasibility of routine EEG monitoring.

Said the invited discussant, Dr. Frank Pigula, a cardiac surgeon from Boston Children’s Hospital, "In all the groups that have studied this, in all patients who have had a seizure, there were documented brain abnormalities. So, the ways I picture these data are that a seizure is a sign of an underlying brain injury, much like a fever is a sign of an underlying infection.

"And you’ve made a good case for the routine postoperative surveillance for seizures; I’m sure everyone would agree that treating seizures is a good thing, but is there any evidence showing us that the early identification and treatment of seizures improves outcomes, either developmental delays or mortality?

In response, Dr. Naim noted that all the CHOP seizure sufferers were treated, whether they had EEG only or clinical seizures, and, at the 4-year mark, they are showing fewer neurodevelopmental issues than previous cohorts of untreated neonates.

"I think one thing that is very concerning is emerging evidence that the seizures themselves cause secondary brain injury," she said.

Dr. Naim and Dr. Pigula reported having no financial disclosures.

The Breathe2Relax app is centered around the basic concept that breathing into the belly—diaphragmatic breathing—provides deeper relaxation than does breathing into the chest. Designed for use by individuals with PTSD and TBI, the app helps with mood stabilization, anger control, and anxiety management. It is a portable stress management tool with breathing exercises documented to decrease the body’s “fight-or-flight” stress response.

Setup

Although you can jump right into the guided breathing exercises, you may find a richer experience by exploring the setup menu of the app before beginning. (TIP: Skip the Personalize button and go straight to Setup.) Setting up the app to your personal preferences will reduce the chances of growing agitated when you begin the breathing exercises.

Almost every element you encounter while using the app can be modified: scenery (eg, mountain meadows or the cosmos), background music (mostly instrumental and earth sounds, plus a choice for no music at all), inhale and exhale lengths set to tenths of a second, whether a breathing metronome and visual prompts will display during the exercise, and whether a voice will prompt breathing instructions. Additional modifications include how many cycles of inhalations/exhalations will be provided, whether you want to track your stress levels (these can be graphed later and tracked over time), and, importantly, whether you want this data to be saved and transmitted to T2 for survey data (there is a choice to remain anonymous) or to disenroll from the study and delete all stored information.

Breathe

Once all of your preferences are set, they will remain saved in the app until you change them. If you already know how to breathe diaphragmatically, click “Breathe” to begin a breathing session. If you are uncertain or need a refresher, click “Show Me How” to watch a 2-minute instructional video. As noted during this instruction, “Be patient. Although breathing sounds like it should be easy to do, diaphragmatic breathing takes practice.” It is recommended that this practice be done every day for maximum benefit, and it is okay to practice when you’re already feeling relaxed.

When you are ready to work through the breathing session, begin by rating your stress level. If you want to skip this step, go ahead and hit “Skip.” If you never want to enter this information when you enter the breathing session portion of the app, click the box that reads “Do Not Show Again” or return to the Setup menu and select “OFF” under Stress Tracking Information. However, by taking just a moment to note stress levels before (and after), you will see over time how you are performing and whether or not this is a beneficial exercise for you. Oftentimes, we don’t accurately perceive our own emotions and reactions, so graphing this output can help limit personal bias.

If you are following the breathing metronome, you will see it rise and fall with each breath until the session is complete. You will then be prompted to record your ending stress level and can click “Finish” to return to the home screen.

Results

The benefit of tracking stress levels during breathing sessions is revealed in a simple line graph. A thin line is produced using starting stress levels and a thick line is produced using ending stress levels. Sometimes the breathing session will result in a dramatic shift in stress level reduction, sometimes an insignificant reduction, and sometimes it may seemingly increase stress levels. If the latter happens, it is possible you were unable to focus on the exercise enough to properly engage in diaphragmatic breathing, or maybe one of the app settings has agitated you and it’s time to update your settings in the Setup menu.

Learning

Read about or watch information on stress by selecting 1 of 3 topics. “Biology of Stress” covers what happens in the body during stress, the consequences of stress on the body, how breathing can help control the stress response, and the resilience of the mind and body after handling a stressful episode. “Diaphragmatic Breathing” explains what the diaphragm is, the difference in oxygen levels supplied to the body during chest breathing and diaphragmatic breathing, and how to determine what kind of a breather you are. Access the Body Scanner under “Effects of Stress on the Body” to learn about the effects of stress on 10 different areas of the body.

Wellness Tips

On the home screen is a button called “Tip.” Tucked away in this little, unsuspecting corner of the app are wellness tips, such as “If you’re feeling guilty about something, remember that self-forgiveness means recognizing mistakes and accepting shortcomings” and “Don’t believe everything you think: Challenge your negative thoughts. Is there evidence to support the way you perceive the situation?” These tips don’t rotate frequently, but it’s a nice surprise when a new one displays.

Final Thoughts

This app can be used in several different ways, serving as a stand-alone stress management tool or in tandem with clinical care directed by a health care provider. As is noted by T2, “Due to its portability, this guided exercise is easily accessible when it is needed most.” And although the app was designed for individuals with PTSD and TBI, anybody who wants to feel more relaxed can access this free tool and reap the many benefits provided through diaphragmatic breathing.

The Breathe2Relax app is centered around the basic concept that breathing into the belly—diaphragmatic breathing—provides deeper relaxation than does breathing into the chest. Designed for use by individuals with PTSD and TBI, the app helps with mood stabilization, anger control, and anxiety management. It is a portable stress management tool with breathing exercises documented to decrease the body’s “fight-or-flight” stress response.

Setup

Although you can jump right into the guided breathing exercises, you may find a richer experience by exploring the setup menu of the app before beginning. (TIP: Skip the Personalize button and go straight to Setup.) Setting up the app to your personal preferences will reduce the chances of growing agitated when you begin the breathing exercises.

Almost every element you encounter while using the app can be modified: scenery (eg, mountain meadows or the cosmos), background music (mostly instrumental and earth sounds, plus a choice for no music at all), inhale and exhale lengths set to tenths of a second, whether a breathing metronome and visual prompts will display during the exercise, and whether a voice will prompt breathing instructions. Additional modifications include how many cycles of inhalations/exhalations will be provided, whether you want to track your stress levels (these can be graphed later and tracked over time), and, importantly, whether you want this data to be saved and transmitted to T2 for survey data (there is a choice to remain anonymous) or to disenroll from the study and delete all stored information.

Breathe

Once all of your preferences are set, they will remain saved in the app until you change them. If you already know how to breathe diaphragmatically, click “Breathe” to begin a breathing session. If you are uncertain or need a refresher, click “Show Me How” to watch a 2-minute instructional video. As noted during this instruction, “Be patient. Although breathing sounds like it should be easy to do, diaphragmatic breathing takes practice.” It is recommended that this practice be done every day for maximum benefit, and it is okay to practice when you’re already feeling relaxed.

When you are ready to work through the breathing session, begin by rating your stress level. If you want to skip this step, go ahead and hit “Skip.” If you never want to enter this information when you enter the breathing session portion of the app, click the box that reads “Do Not Show Again” or return to the Setup menu and select “OFF” under Stress Tracking Information. However, by taking just a moment to note stress levels before (and after), you will see over time how you are performing and whether or not this is a beneficial exercise for you. Oftentimes, we don’t accurately perceive our own emotions and reactions, so graphing this output can help limit personal bias.

If you are following the breathing metronome, you will see it rise and fall with each breath until the session is complete. You will then be prompted to record your ending stress level and can click “Finish” to return to the home screen.

Results

The benefit of tracking stress levels during breathing sessions is revealed in a simple line graph. A thin line is produced using starting stress levels and a thick line is produced using ending stress levels. Sometimes the breathing session will result in a dramatic shift in stress level reduction, sometimes an insignificant reduction, and sometimes it may seemingly increase stress levels. If the latter happens, it is possible you were unable to focus on the exercise enough to properly engage in diaphragmatic breathing, or maybe one of the app settings has agitated you and it’s time to update your settings in the Setup menu.

Learning

Read about or watch information on stress by selecting 1 of 3 topics. “Biology of Stress” covers what happens in the body during stress, the consequences of stress on the body, how breathing can help control the stress response, and the resilience of the mind and body after handling a stressful episode. “Diaphragmatic Breathing” explains what the diaphragm is, the difference in oxygen levels supplied to the body during chest breathing and diaphragmatic breathing, and how to determine what kind of a breather you are. Access the Body Scanner under “Effects of Stress on the Body” to learn about the effects of stress on 10 different areas of the body.

Wellness Tips

On the home screen is a button called “Tip.” Tucked away in this little, unsuspecting corner of the app are wellness tips, such as “If you’re feeling guilty about something, remember that self-forgiveness means recognizing mistakes and accepting shortcomings” and “Don’t believe everything you think: Challenge your negative thoughts. Is there evidence to support the way you perceive the situation?” These tips don’t rotate frequently, but it’s a nice surprise when a new one displays.

Final Thoughts

This app can be used in several different ways, serving as a stand-alone stress management tool or in tandem with clinical care directed by a health care provider. As is noted by T2, “Due to its portability, this guided exercise is easily accessible when it is needed most.” And although the app was designed for individuals with PTSD and TBI, anybody who wants to feel more relaxed can access this free tool and reap the many benefits provided through diaphragmatic breathing.

The Breathe2Relax app is centered around the basic concept that breathing into the belly—diaphragmatic breathing—provides deeper relaxation than does breathing into the chest. Designed for use by individuals with PTSD and TBI, the app helps with mood stabilization, anger control, and anxiety management. It is a portable stress management tool with breathing exercises documented to decrease the body’s “fight-or-flight” stress response.

Setup

Although you can jump right into the guided breathing exercises, you may find a richer experience by exploring the setup menu of the app before beginning. (TIP: Skip the Personalize button and go straight to Setup.) Setting up the app to your personal preferences will reduce the chances of growing agitated when you begin the breathing exercises.

Almost every element you encounter while using the app can be modified: scenery (eg, mountain meadows or the cosmos), background music (mostly instrumental and earth sounds, plus a choice for no music at all), inhale and exhale lengths set to tenths of a second, whether a breathing metronome and visual prompts will display during the exercise, and whether a voice will prompt breathing instructions. Additional modifications include how many cycles of inhalations/exhalations will be provided, whether you want to track your stress levels (these can be graphed later and tracked over time), and, importantly, whether you want this data to be saved and transmitted to T2 for survey data (there is a choice to remain anonymous) or to disenroll from the study and delete all stored information.

Breathe

Once all of your preferences are set, they will remain saved in the app until you change them. If you already know how to breathe diaphragmatically, click “Breathe” to begin a breathing session. If you are uncertain or need a refresher, click “Show Me How” to watch a 2-minute instructional video. As noted during this instruction, “Be patient. Although breathing sounds like it should be easy to do, diaphragmatic breathing takes practice.” It is recommended that this practice be done every day for maximum benefit, and it is okay to practice when you’re already feeling relaxed.

When you are ready to work through the breathing session, begin by rating your stress level. If you want to skip this step, go ahead and hit “Skip.” If you never want to enter this information when you enter the breathing session portion of the app, click the box that reads “Do Not Show Again” or return to the Setup menu and select “OFF” under Stress Tracking Information. However, by taking just a moment to note stress levels before (and after), you will see over time how you are performing and whether or not this is a beneficial exercise for you. Oftentimes, we don’t accurately perceive our own emotions and reactions, so graphing this output can help limit personal bias.

If you are following the breathing metronome, you will see it rise and fall with each breath until the session is complete. You will then be prompted to record your ending stress level and can click “Finish” to return to the home screen.

Results

The benefit of tracking stress levels during breathing sessions is revealed in a simple line graph. A thin line is produced using starting stress levels and a thick line is produced using ending stress levels. Sometimes the breathing session will result in a dramatic shift in stress level reduction, sometimes an insignificant reduction, and sometimes it may seemingly increase stress levels. If the latter happens, it is possible you were unable to focus on the exercise enough to properly engage in diaphragmatic breathing, or maybe one of the app settings has agitated you and it’s time to update your settings in the Setup menu.

Learning

Read about or watch information on stress by selecting 1 of 3 topics. “Biology of Stress” covers what happens in the body during stress, the consequences of stress on the body, how breathing can help control the stress response, and the resilience of the mind and body after handling a stressful episode. “Diaphragmatic Breathing” explains what the diaphragm is, the difference in oxygen levels supplied to the body during chest breathing and diaphragmatic breathing, and how to determine what kind of a breather you are. Access the Body Scanner under “Effects of Stress on the Body” to learn about the effects of stress on 10 different areas of the body.

Wellness Tips

On the home screen is a button called “Tip.” Tucked away in this little, unsuspecting corner of the app are wellness tips, such as “If you’re feeling guilty about something, remember that self-forgiveness means recognizing mistakes and accepting shortcomings” and “Don’t believe everything you think: Challenge your negative thoughts. Is there evidence to support the way you perceive the situation?” These tips don’t rotate frequently, but it’s a nice surprise when a new one displays.

Final Thoughts

This app can be used in several different ways, serving as a stand-alone stress management tool or in tandem with clinical care directed by a health care provider. As is noted by T2, “Due to its portability, this guided exercise is easily accessible when it is needed most.” And although the app was designed for individuals with PTSD and TBI, anybody who wants to feel more relaxed can access this free tool and reap the many benefits provided through diaphragmatic breathing.

Nadia Carlesso, MD, PhD

Credit: Indiana University

Preclinical research has revealed a cascade of molecular events in the bone marrow that produce high levels of inflammation, disrupt hematopoiesis, and lead to the development of myeloproliferative neoplasms (MPNs).

The discovery points the way to potential new strategies for treating MPNs and leukemias and further illuminates the relationship between inflammation and cancer, according to Nadia Carlesso, MD, PhD, of the Indiana University School of Medicine in Indianapolis.

Dr Carlesso and her colleagues described the discovery in Cell Stem Cell.

The team used a mouse model to elucidate the role of Notch in hematopoiesis. And they found that loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.

“Some of these inflammatory molecules are cytokines that induce uncontrolled proliferation of myeloid cells and lead to myeloproliferative disorders,” Dr Carlesso said. “[However,] loss of Notch has to occur in specific cells of the bone marrow microenvironment, like endothelial cells, to really be capable to trigger such a high inflammatory status.”

Specifically, Dr Carlesso and her colleagues showed that Notch signaling represses expression of the microRNA miR-155 by promoting binding of RBPJ, a nonredundant downstream effector of the canonical Notch signaling cascade, to the miR-155 promoter.

Loss of Notch/RBPJ signaling upregulates miR-155 in bone marrow endothelial cells. And this leads to miR-155-mediated targeting of the NF-kB inhibitor kB-Ras1, NF-kB activation, increased proinflammatory cytokine production, and the development of an MPN-like disorder.

But when the researchers deleted miR-155 in the stroma of RBPJ^_/_ mice, they were able to prevent cytokine induction and the MPN-like disease.

The team also discovered elevated levels of miR-155 in samples from humans with MPNs. This suggests that developing drugs to target the inflammatory reaction at key points could be a promising strategy to limit the development of MPNs in humans.

Dr Carlesso noted that a key finding of this research was that the molecular cascade leading to inflammation was not occurring directly in hematopoietic stem cells but in cells of the bone marrow microenvironment.

“This work indicates that we need to target not only the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation,” she said. “We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias.”

Dr Carlesso also pointed out that, because Notch is an oncogene, it is often targeted by therapies for other types of cancer. But this research suggests targeting Notch can have adverse effects on hematopoiesis, and clinicians should be aware of this risk.

Nadia Carlesso, MD, PhD

Credit: Indiana University

Preclinical research has revealed a cascade of molecular events in the bone marrow that produce high levels of inflammation, disrupt hematopoiesis, and lead to the development of myeloproliferative neoplasms (MPNs).

The discovery points the way to potential new strategies for treating MPNs and leukemias and further illuminates the relationship between inflammation and cancer, according to Nadia Carlesso, MD, PhD, of the Indiana University School of Medicine in Indianapolis.

Dr Carlesso and her colleagues described the discovery in Cell Stem Cell.

The team used a mouse model to elucidate the role of Notch in hematopoiesis. And they found that loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.

“Some of these inflammatory molecules are cytokines that induce uncontrolled proliferation of myeloid cells and lead to myeloproliferative disorders,” Dr Carlesso said. “[However,] loss of Notch has to occur in specific cells of the bone marrow microenvironment, like endothelial cells, to really be capable to trigger such a high inflammatory status.”

Specifically, Dr Carlesso and her colleagues showed that Notch signaling represses expression of the microRNA miR-155 by promoting binding of RBPJ, a nonredundant downstream effector of the canonical Notch signaling cascade, to the miR-155 promoter.

Loss of Notch/RBPJ signaling upregulates miR-155 in bone marrow endothelial cells. And this leads to miR-155-mediated targeting of the NF-kB inhibitor kB-Ras1, NF-kB activation, increased proinflammatory cytokine production, and the development of an MPN-like disorder.

But when the researchers deleted miR-155 in the stroma of RBPJ^_/_ mice, they were able to prevent cytokine induction and the MPN-like disease.

The team also discovered elevated levels of miR-155 in samples from humans with MPNs. This suggests that developing drugs to target the inflammatory reaction at key points could be a promising strategy to limit the development of MPNs in humans.

Dr Carlesso noted that a key finding of this research was that the molecular cascade leading to inflammation was not occurring directly in hematopoietic stem cells but in cells of the bone marrow microenvironment.

“This work indicates that we need to target not only the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation,” she said. “We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias.”

Dr Carlesso also pointed out that, because Notch is an oncogene, it is often targeted by therapies for other types of cancer. But this research suggests targeting Notch can have adverse effects on hematopoiesis, and clinicians should be aware of this risk.

Nadia Carlesso, MD, PhD

Credit: Indiana University

Preclinical research has revealed a cascade of molecular events in the bone marrow that produce high levels of inflammation, disrupt hematopoiesis, and lead to the development of myeloproliferative neoplasms (MPNs).

The discovery points the way to potential new strategies for treating MPNs and leukemias and further illuminates the relationship between inflammation and cancer, according to Nadia Carlesso, MD, PhD, of the Indiana University School of Medicine in Indianapolis.

Dr Carlesso and her colleagues described the discovery in Cell Stem Cell.

The team used a mouse model to elucidate the role of Notch in hematopoiesis. And they found that loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.

“Some of these inflammatory molecules are cytokines that induce uncontrolled proliferation of myeloid cells and lead to myeloproliferative disorders,” Dr Carlesso said. “[However,] loss of Notch has to occur in specific cells of the bone marrow microenvironment, like endothelial cells, to really be capable to trigger such a high inflammatory status.”

Specifically, Dr Carlesso and her colleagues showed that Notch signaling represses expression of the microRNA miR-155 by promoting binding of RBPJ, a nonredundant downstream effector of the canonical Notch signaling cascade, to the miR-155 promoter.

Loss of Notch/RBPJ signaling upregulates miR-155 in bone marrow endothelial cells. And this leads to miR-155-mediated targeting of the NF-kB inhibitor kB-Ras1, NF-kB activation, increased proinflammatory cytokine production, and the development of an MPN-like disorder.

But when the researchers deleted miR-155 in the stroma of RBPJ^_/_ mice, they were able to prevent cytokine induction and the MPN-like disease.

The team also discovered elevated levels of miR-155 in samples from humans with MPNs. This suggests that developing drugs to target the inflammatory reaction at key points could be a promising strategy to limit the development of MPNs in humans.

Dr Carlesso noted that a key finding of this research was that the molecular cascade leading to inflammation was not occurring directly in hematopoietic stem cells but in cells of the bone marrow microenvironment.

“This work indicates that we need to target not only the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation,” she said. “We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias.”

Dr Carlesso also pointed out that, because Notch is an oncogene, it is often targeted by therapies for other types of cancer. But this research suggests targeting Notch can have adverse effects on hematopoiesis, and clinicians should be aware of this risk.

Adipose tissue

A new study indicates that adipose-derived stem cells (ASCs) are highly resistant to the chemotherapy drug methotrexate (MTX).

Cultured ASCs and tissue samples that included ASCs were able to withstand exposure to MTX quite well. The drug had little or no effect on ASC viability, division, senescence, or differentiation.

The researchers believe these findings could prove significant for cancer patients, particularly children with acute lymphoblastic leukemia.

“Kids undergo chemotherapy at such an important time, when they should be growing, but, instead, they are introduced to this very harsh environment where bone cells are damaged with these drugs,” said study author Olivia Beane, a graduate student at Brown University in Providence, Rhode Island.

“That leads to major long-term side effects, including osteoporosis and bone defects. If we found a stem cell that was resistant to the chemotherapeutic agent and could promote bone growth by becoming bone itself, then maybe they wouldn’t have these issues.”

Beane’s work, which appears in Experimental Cell Research, grew out of more basic research. She was originally looking for chemicals that could help purify ASCs from mixed cell cultures to encourage their proliferation.

Among other things, she tried chemotherapy drugs, speculating that ASCs might withstand a drug that other cells could not. The idea that this could help cancer patients did not come until later.

To explore potential cancer applications, Beane and her colleagues exposed pure human ASC cultures, stromal vascular fraction (SVF) tissue samples (which include ASCs and several other cell types), and cultures of human fibroblast cells to medically relevant concentrations of chemotherapy drugs for 24 hours.

The researchers then measured how those cell populations fared over the next 10 days. They also measured the ability of MTX-exposed ASCs, both alone and in SVF, to proliferate and differentiate.

In contrast to the fibroblast controls, the ASCs withstood a variety of MTX doses. The drug had little or no effect on ASC viability, cell division, senescence, or differentiation. ASCs also resisted vincristine to an extent, but they could not withstand exposure to cytarabine or etoposide.

The SVF tissue samples withstood MTX doses well too. That is significant, according to the researchers, because the tissue would be clinically useful if an ASC-based therapy were ever developed for cancer patients. Hypothetically, fresh SVF could be harvested from the fat of a donor and injected into bone tissue, delivering ASCs to the site.

To understand why ASCs resist MTX, the researchers conducted further tests. MTX shuts down DNA biosynthesis by binding the protein dihydrofolate reductase so it is unavailable to assist in that essential task.

The testing showed that ASCs ramped up dihydrofolate reductase levels upon exposure to the drug. They produced enough to overcome a clinically relevant dose of MTX.

Now, the researchers are eager to see if they can translate these findings to deliver a medical benefit for cancer patients. To that end, the team is planning several more experiments.

One is to test ASC survival and performance after 48- and 72-hour exposures to MTX. Another is to begin examining how the cells fare in mouse models of chemotherapy. The researchers plan to directly compare ASCs and bone marrow-derived stem cells exposed to various chemotherapies.

Adipose tissue

A new study indicates that adipose-derived stem cells (ASCs) are highly resistant to the chemotherapy drug methotrexate (MTX).

Cultured ASCs and tissue samples that included ASCs were able to withstand exposure to MTX quite well. The drug had little or no effect on ASC viability, division, senescence, or differentiation.

The researchers believe these findings could prove significant for cancer patients, particularly children with acute lymphoblastic leukemia.

“Kids undergo chemotherapy at such an important time, when they should be growing, but, instead, they are introduced to this very harsh environment where bone cells are damaged with these drugs,” said study author Olivia Beane, a graduate student at Brown University in Providence, Rhode Island.

“That leads to major long-term side effects, including osteoporosis and bone defects. If we found a stem cell that was resistant to the chemotherapeutic agent and could promote bone growth by becoming bone itself, then maybe they wouldn’t have these issues.”

Beane’s work, which appears in Experimental Cell Research, grew out of more basic research. She was originally looking for chemicals that could help purify ASCs from mixed cell cultures to encourage their proliferation.

Among other things, she tried chemotherapy drugs, speculating that ASCs might withstand a drug that other cells could not. The idea that this could help cancer patients did not come until later.

To explore potential cancer applications, Beane and her colleagues exposed pure human ASC cultures, stromal vascular fraction (SVF) tissue samples (which include ASCs and several other cell types), and cultures of human fibroblast cells to medically relevant concentrations of chemotherapy drugs for 24 hours.

The researchers then measured how those cell populations fared over the next 10 days. They also measured the ability of MTX-exposed ASCs, both alone and in SVF, to proliferate and differentiate.

In contrast to the fibroblast controls, the ASCs withstood a variety of MTX doses. The drug had little or no effect on ASC viability, cell division, senescence, or differentiation. ASCs also resisted vincristine to an extent, but they could not withstand exposure to cytarabine or etoposide.

The SVF tissue samples withstood MTX doses well too. That is significant, according to the researchers, because the tissue would be clinically useful if an ASC-based therapy were ever developed for cancer patients. Hypothetically, fresh SVF could be harvested from the fat of a donor and injected into bone tissue, delivering ASCs to the site.

To understand why ASCs resist MTX, the researchers conducted further tests. MTX shuts down DNA biosynthesis by binding the protein dihydrofolate reductase so it is unavailable to assist in that essential task.

The testing showed that ASCs ramped up dihydrofolate reductase levels upon exposure to the drug. They produced enough to overcome a clinically relevant dose of MTX.

Now, the researchers are eager to see if they can translate these findings to deliver a medical benefit for cancer patients. To that end, the team is planning several more experiments.

One is to test ASC survival and performance after 48- and 72-hour exposures to MTX. Another is to begin examining how the cells fare in mouse models of chemotherapy. The researchers plan to directly compare ASCs and bone marrow-derived stem cells exposed to various chemotherapies.

Adipose tissue

A new study indicates that adipose-derived stem cells (ASCs) are highly resistant to the chemotherapy drug methotrexate (MTX).

Cultured ASCs and tissue samples that included ASCs were able to withstand exposure to MTX quite well. The drug had little or no effect on ASC viability, division, senescence, or differentiation.

The researchers believe these findings could prove significant for cancer patients, particularly children with acute lymphoblastic leukemia.

“Kids undergo chemotherapy at such an important time, when they should be growing, but, instead, they are introduced to this very harsh environment where bone cells are damaged with these drugs,” said study author Olivia Beane, a graduate student at Brown University in Providence, Rhode Island.

“That leads to major long-term side effects, including osteoporosis and bone defects. If we found a stem cell that was resistant to the chemotherapeutic agent and could promote bone growth by becoming bone itself, then maybe they wouldn’t have these issues.”

Beane’s work, which appears in Experimental Cell Research, grew out of more basic research. She was originally looking for chemicals that could help purify ASCs from mixed cell cultures to encourage their proliferation.

Among other things, she tried chemotherapy drugs, speculating that ASCs might withstand a drug that other cells could not. The idea that this could help cancer patients did not come until later.

To explore potential cancer applications, Beane and her colleagues exposed pure human ASC cultures, stromal vascular fraction (SVF) tissue samples (which include ASCs and several other cell types), and cultures of human fibroblast cells to medically relevant concentrations of chemotherapy drugs for 24 hours.

The researchers then measured how those cell populations fared over the next 10 days. They also measured the ability of MTX-exposed ASCs, both alone and in SVF, to proliferate and differentiate.

In contrast to the fibroblast controls, the ASCs withstood a variety of MTX doses. The drug had little or no effect on ASC viability, cell division, senescence, or differentiation. ASCs also resisted vincristine to an extent, but they could not withstand exposure to cytarabine or etoposide.

The SVF tissue samples withstood MTX doses well too. That is significant, according to the researchers, because the tissue would be clinically useful if an ASC-based therapy were ever developed for cancer patients. Hypothetically, fresh SVF could be harvested from the fat of a donor and injected into bone tissue, delivering ASCs to the site.

To understand why ASCs resist MTX, the researchers conducted further tests. MTX shuts down DNA biosynthesis by binding the protein dihydrofolate reductase so it is unavailable to assist in that essential task.

The testing showed that ASCs ramped up dihydrofolate reductase levels upon exposure to the drug. They produced enough to overcome a clinically relevant dose of MTX.

Now, the researchers are eager to see if they can translate these findings to deliver a medical benefit for cancer patients. To that end, the team is planning several more experiments.

One is to test ASC survival and performance after 48- and 72-hour exposures to MTX. Another is to begin examining how the cells fare in mouse models of chemotherapy. The researchers plan to directly compare ASCs and bone marrow-derived stem cells exposed to various chemotherapies.

Thrombus

Credit: Kevin MacKenzie

The activity of transglutaminase factor XIII is critical for retaining red blood cells in a thrombus and therefore affects the clot’s size, investigators have reported in the Journal of Clinical Investigation.

The team showed that mice deficient in factor XIII had smaller thrombi containing fewer red blood cells than wild-type mice. And the same phenomenon occurred in humans.

According to the researchers, this discovery could aid the development of a safer alternative to anticoagulants.

“If we can develop a treatment that exploits this discovery to reduce the size of blood clots, it would represent a whole new approach to treating thrombosis that’s different from anything else on the market,” said study author Alisa Wolberg, PhD, of the University of North Carolina at Chapel Hill.

“We think reducing factor XIII activity could be helpful to a large number of people, perhaps including some who cannot take existing blood-thinning medications.”

Dr Wolberg and her colleagues examined the role of factor XIII in clot formation, first in mice and then in human samples. To their surprise, the team found that mice incapable of producing factor XIII formed thrombi that were half the size of the clots produced by wild-type mice.

“That difference in itself was extremely striking,” said study author Maria Aleman, PhD, also of the University of North Carolina at Chapel Hill.

“Then, the second surprise was discovering that the size difference was actually due to a reduced number of red blood cells in the clot. Since no previous studies had suggested that it was possible to manipulate the number of red blood cells, we knew we had found something new.”

Factor XIII appears to play a crucial role in helping the fibrin matrix keep its integrity during thrombus formation. Normally, the fibrin matrix forms a strong mesh in and around the clot, trapping red blood cells within. Without factor XIII, some red blood cells are squeezed out, resulting in a much smaller clot.

Unlike existing drugs that reduce the formation of fibrin, a drug that reduces factor XIII could potentially cut the body’s ability to produce large, dangerous thrombi without sacrificing the ability to produce small, beneficial clots.

“What’s needed is a drug that reduces the risk of forming large clots but still allows you to form a clot when you need one to stanch bleeding,” Dr Wolberg said. “The biological pathway we’ve discovered may make it possible to strike that balance.”

Thrombus

Credit: Kevin MacKenzie

The activity of transglutaminase factor XIII is critical for retaining red blood cells in a thrombus and therefore affects the clot’s size, investigators have reported in the Journal of Clinical Investigation.

The team showed that mice deficient in factor XIII had smaller thrombi containing fewer red blood cells than wild-type mice. And the same phenomenon occurred in humans.

According to the researchers, this discovery could aid the development of a safer alternative to anticoagulants.

“If we can develop a treatment that exploits this discovery to reduce the size of blood clots, it would represent a whole new approach to treating thrombosis that’s different from anything else on the market,” said study author Alisa Wolberg, PhD, of the University of North Carolina at Chapel Hill.

“We think reducing factor XIII activity could be helpful to a large number of people, perhaps including some who cannot take existing blood-thinning medications.”

Dr Wolberg and her colleagues examined the role of factor XIII in clot formation, first in mice and then in human samples. To their surprise, the team found that mice incapable of producing factor XIII formed thrombi that were half the size of the clots produced by wild-type mice.

“That difference in itself was extremely striking,” said study author Maria Aleman, PhD, also of the University of North Carolina at Chapel Hill.

“Then, the second surprise was discovering that the size difference was actually due to a reduced number of red blood cells in the clot. Since no previous studies had suggested that it was possible to manipulate the number of red blood cells, we knew we had found something new.”

Factor XIII appears to play a crucial role in helping the fibrin matrix keep its integrity during thrombus formation. Normally, the fibrin matrix forms a strong mesh in and around the clot, trapping red blood cells within. Without factor XIII, some red blood cells are squeezed out, resulting in a much smaller clot.

Unlike existing drugs that reduce the formation of fibrin, a drug that reduces factor XIII could potentially cut the body’s ability to produce large, dangerous thrombi without sacrificing the ability to produce small, beneficial clots.

“What’s needed is a drug that reduces the risk of forming large clots but still allows you to form a clot when you need one to stanch bleeding,” Dr Wolberg said. “The biological pathway we’ve discovered may make it possible to strike that balance.”

Thrombus

Credit: Kevin MacKenzie

The activity of transglutaminase factor XIII is critical for retaining red blood cells in a thrombus and therefore affects the clot’s size, investigators have reported in the Journal of Clinical Investigation.

The team showed that mice deficient in factor XIII had smaller thrombi containing fewer red blood cells than wild-type mice. And the same phenomenon occurred in humans.

According to the researchers, this discovery could aid the development of a safer alternative to anticoagulants.

“If we can develop a treatment that exploits this discovery to reduce the size of blood clots, it would represent a whole new approach to treating thrombosis that’s different from anything else on the market,” said study author Alisa Wolberg, PhD, of the University of North Carolina at Chapel Hill.

“We think reducing factor XIII activity could be helpful to a large number of people, perhaps including some who cannot take existing blood-thinning medications.”

Dr Wolberg and her colleagues examined the role of factor XIII in clot formation, first in mice and then in human samples. To their surprise, the team found that mice incapable of producing factor XIII formed thrombi that were half the size of the clots produced by wild-type mice.

“That difference in itself was extremely striking,” said study author Maria Aleman, PhD, also of the University of North Carolina at Chapel Hill.

“Then, the second surprise was discovering that the size difference was actually due to a reduced number of red blood cells in the clot. Since no previous studies had suggested that it was possible to manipulate the number of red blood cells, we knew we had found something new.”

Factor XIII appears to play a crucial role in helping the fibrin matrix keep its integrity during thrombus formation. Normally, the fibrin matrix forms a strong mesh in and around the clot, trapping red blood cells within. Without factor XIII, some red blood cells are squeezed out, resulting in a much smaller clot.

Unlike existing drugs that reduce the formation of fibrin, a drug that reduces factor XIII could potentially cut the body’s ability to produce large, dangerous thrombi without sacrificing the ability to produce small, beneficial clots.

“What’s needed is a drug that reduces the risk of forming large clots but still allows you to form a clot when you need one to stanch bleeding,” Dr Wolberg said. “The biological pathway we’ve discovered may make it possible to strike that balance.”

Monoclonal antibodies

Credit: Linda Bartlett

The European Commission (EC) has expanded the indication for the anti-CD20 monoclonal antibody ofatumumab (Arzerra).

The EC granted conditional approval for ofatumumab in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.

In 2010, the EC granted ofatumumab conditional approval to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. Ofatumumab will not receive full approval until the drug’s developers, GlaxoSmithKline and GenMab, submit results of additional research to the EC.

Trial results

The EC’s new approval of ofatumumab, for previously untreated CLL patients, is based on results from 2 trials, COMPLEMENT 1 and OMB115991.

The phase 3 COMPLEMENT 1 trial was a comparison of ofatumumab plus chlorambucil (n=221) with chlorambucil alone (n=226) in CLL patients for whom fludarabine-based treatment was considered inappropriate.

In this study, ofatumumab plus chlorambucil improved progression-free survival compared to chlorambucil alone. The median times were 22.4 months and 13.1 months, respectively, and the hazard ratio was 0.57 (P<0.001).

In the phase 2 trial known as OMB115991, researchers evaluated ofatumumab in combination with bendamustine in 44 patients with previously untreated CLL for whom fludarabine-based treatment was considered inappropriate.

The combination elicited an overall response rate of 95% and a complete response rate of 43%.

The overall safety profile of ofatumumab in CLL (previously untreated and relapsed/refractory) is based on data from 511 patients in clinical trials.

This includes 250 patients with relapsed/refractory CLL who were treated with ofatumumab alone and 261 patients with previously untreated CLL who were treated in combination with an alkylating agent.

The most common adverse effects associated with ofatumumab were infusion reactions, neutropenia, anemia, febrile neutropenia, thrombocytopenia, leukopenia, lower respiratory tract infection (including pneumonia), upper respiratory tract infection, sepsis (including neutropenic sepsis and septic shock), herpes virus infection, and urinary tract infection.

Monoclonal antibodies

Credit: Linda Bartlett

The European Commission (EC) has expanded the indication for the anti-CD20 monoclonal antibody ofatumumab (Arzerra).

The EC granted conditional approval for ofatumumab in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.

In 2010, the EC granted ofatumumab conditional approval to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. Ofatumumab will not receive full approval until the drug’s developers, GlaxoSmithKline and GenMab, submit results of additional research to the EC.

Trial results

The EC’s new approval of ofatumumab, for previously untreated CLL patients, is based on results from 2 trials, COMPLEMENT 1 and OMB115991.

The phase 3 COMPLEMENT 1 trial was a comparison of ofatumumab plus chlorambucil (n=221) with chlorambucil alone (n=226) in CLL patients for whom fludarabine-based treatment was considered inappropriate.

In this study, ofatumumab plus chlorambucil improved progression-free survival compared to chlorambucil alone. The median times were 22.4 months and 13.1 months, respectively, and the hazard ratio was 0.57 (P<0.001).

In the phase 2 trial known as OMB115991, researchers evaluated ofatumumab in combination with bendamustine in 44 patients with previously untreated CLL for whom fludarabine-based treatment was considered inappropriate.

The combination elicited an overall response rate of 95% and a complete response rate of 43%.

The overall safety profile of ofatumumab in CLL (previously untreated and relapsed/refractory) is based on data from 511 patients in clinical trials.

This includes 250 patients with relapsed/refractory CLL who were treated with ofatumumab alone and 261 patients with previously untreated CLL who were treated in combination with an alkylating agent.

The most common adverse effects associated with ofatumumab were infusion reactions, neutropenia, anemia, febrile neutropenia, thrombocytopenia, leukopenia, lower respiratory tract infection (including pneumonia), upper respiratory tract infection, sepsis (including neutropenic sepsis and septic shock), herpes virus infection, and urinary tract infection.

Monoclonal antibodies

Credit: Linda Bartlett

The European Commission (EC) has expanded the indication for the anti-CD20 monoclonal antibody ofatumumab (Arzerra).

The EC granted conditional approval for ofatumumab in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.

In 2010, the EC granted ofatumumab conditional approval to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. Ofatumumab will not receive full approval until the drug’s developers, GlaxoSmithKline and GenMab, submit results of additional research to the EC.

Trial results

The EC’s new approval of ofatumumab, for previously untreated CLL patients, is based on results from 2 trials, COMPLEMENT 1 and OMB115991.

The phase 3 COMPLEMENT 1 trial was a comparison of ofatumumab plus chlorambucil (n=221) with chlorambucil alone (n=226) in CLL patients for whom fludarabine-based treatment was considered inappropriate.

In this study, ofatumumab plus chlorambucil improved progression-free survival compared to chlorambucil alone. The median times were 22.4 months and 13.1 months, respectively, and the hazard ratio was 0.57 (P<0.001).

In the phase 2 trial known as OMB115991, researchers evaluated ofatumumab in combination with bendamustine in 44 patients with previously untreated CLL for whom fludarabine-based treatment was considered inappropriate.

The combination elicited an overall response rate of 95% and a complete response rate of 43%.

The overall safety profile of ofatumumab in CLL (previously untreated and relapsed/refractory) is based on data from 511 patients in clinical trials.

This includes 250 patients with relapsed/refractory CLL who were treated with ofatumumab alone and 261 patients with previously untreated CLL who were treated in combination with an alkylating agent.

The most common adverse effects associated with ofatumumab were infusion reactions, neutropenia, anemia, febrile neutropenia, thrombocytopenia, leukopenia, lower respiratory tract infection (including pneumonia), upper respiratory tract infection, sepsis (including neutropenic sepsis and septic shock), herpes virus infection, and urinary tract infection.

Asymptomatic adults in the general population who have no history of stroke, transient ischemic attack, or neurologic signs or symptoms should not be screened for carotid artery stenosis, according to a U.S. Preventive Services Task Force recommendation published online July 7 in Annals of Internal Medicine.

All screening strategies, even a noninvasive one that has minimal harmful effects such as ultrasonography, are insufficiently sensitive for detecting the condition. And all of them can lead to unnecessary treatment or can themselves induce serious harms including death, stroke, and myocardial infarction. Therefore, at this time, "the harms of screening for asymptomatic carotid artery stenosis outweigh the benefits," said Dr. Michael L. LeFevre of the University of Missouri, Columbia, and his associates with the USPSTF.

The recommendation is an update of the previous one issued in 2007, which also concluded that screening the general population for carotid stenosis was unwarranted. For this update, the USPSTF performed an exhaustive review and meta-analysis of the data that have accrued since that time, which addressed advances in screening tests, risk stratification tools, both screening and treatment using carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAAS), and optimal medical therapies.

Dr. LeFevre, a cochair of USPSTF, and his colleagues reviewed recent randomized controlled trials, meta-analyses, and cohort studies of these topics. They found that the prevalence of carotid artery stenosis is only 0.5%-1% in the general population of adults. The most feasible screen for the condition is duplex ultrasonography; but in real-world practice, even this screen yields many false-positive results in such patients, and so exposes them to harm.

There also is no evidence that another noninvasive screen for carotid artery stenosis – auscultation of the neck to detect carotid bruits – is accurate or provides any benefit. Only four studies examined this strategy; none of them used angiography as a gold standard for diagnosis, and only two involved patients from the general population.

Moreover, even when screening of asymptomatic patients leads to detection and early intervention, "the magnitude of benefit is small to none." In particular, adding medications to current optimal medical management does not appear to convey any benefit, Dr. LeFevre and his associates said.

On the other side of the benefit-to-harm scale, carotid endarterectomy is associated with a 30-day rate of stroke or mortality of approximately 2.4% overall. However, the rates are as high as 5% in low-volume medical centers and 6% in certain states. The 30-day rate of stroke or mortality associated with CAAS is 3.1%-3.8%. Those risks are far too high to counterbalance the small benefit of screening, the USPSTF reviewers noted.

Other important harms after CEA or CAAS include myocardial infarction, surgical complications, cranial nerve injury, lung embolism, pneumonia, and local hematoma requiring further surgery.

The review and meta-analysis were hampered by a dearth of high-quality data. Specifically, much more data are needed comparing patient outcomes after CEA or CAAS with those after optimal medical therapy. The planned CREST-2 (Carotid Revascularization Endarterectomy vs Stenting Trial 2) will include a comparator group on medical management alone, and should provide important findings in this regard, Dr. LeFevre and his associates said.

They added that the USPSTF recommendation against screening the general population for carotid stenosis agrees with recommendations from the American Heart Association, American Stroke Association, American College of Cardiology, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Society for Vascular Surgery, Society for Vascular Medicine, and the American Academy of Family Physicians.

More information on this recommendation – as well as recommendations for the related issues of hypertension, dyslipidemia, CHD, and diet – is available at the USPSTF website.

The USPSTF is an independent group that makes recommendations about the effectiveness of specific preventive care services and is funded by the Agency for Healthcare Research and Quality.

Asymptomatic adults in the general population who have no history of stroke, transient ischemic attack, or neurologic signs or symptoms should not be screened for carotid artery stenosis, according to a U.S. Preventive Services Task Force recommendation published online July 7 in Annals of Internal Medicine.

All screening strategies, even a noninvasive one that has minimal harmful effects such as ultrasonography, are insufficiently sensitive for detecting the condition. And all of them can lead to unnecessary treatment or can themselves induce serious harms including death, stroke, and myocardial infarction. Therefore, at this time, "the harms of screening for asymptomatic carotid artery stenosis outweigh the benefits," said Dr. Michael L. LeFevre of the University of Missouri, Columbia, and his associates with the USPSTF.

The recommendation is an update of the previous one issued in 2007, which also concluded that screening the general population for carotid stenosis was unwarranted. For this update, the USPSTF performed an exhaustive review and meta-analysis of the data that have accrued since that time, which addressed advances in screening tests, risk stratification tools, both screening and treatment using carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAAS), and optimal medical therapies.

Dr. LeFevre, a cochair of USPSTF, and his colleagues reviewed recent randomized controlled trials, meta-analyses, and cohort studies of these topics. They found that the prevalence of carotid artery stenosis is only 0.5%-1% in the general population of adults. The most feasible screen for the condition is duplex ultrasonography; but in real-world practice, even this screen yields many false-positive results in such patients, and so exposes them to harm.

There also is no evidence that another noninvasive screen for carotid artery stenosis – auscultation of the neck to detect carotid bruits – is accurate or provides any benefit. Only four studies examined this strategy; none of them used angiography as a gold standard for diagnosis, and only two involved patients from the general population.

Moreover, even when screening of asymptomatic patients leads to detection and early intervention, "the magnitude of benefit is small to none." In particular, adding medications to current optimal medical management does not appear to convey any benefit, Dr. LeFevre and his associates said.

On the other side of the benefit-to-harm scale, carotid endarterectomy is associated with a 30-day rate of stroke or mortality of approximately 2.4% overall. However, the rates are as high as 5% in low-volume medical centers and 6% in certain states. The 30-day rate of stroke or mortality associated with CAAS is 3.1%-3.8%. Those risks are far too high to counterbalance the small benefit of screening, the USPSTF reviewers noted.

Other important harms after CEA or CAAS include myocardial infarction, surgical complications, cranial nerve injury, lung embolism, pneumonia, and local hematoma requiring further surgery.

The review and meta-analysis were hampered by a dearth of high-quality data. Specifically, much more data are needed comparing patient outcomes after CEA or CAAS with those after optimal medical therapy. The planned CREST-2 (Carotid Revascularization Endarterectomy vs Stenting Trial 2) will include a comparator group on medical management alone, and should provide important findings in this regard, Dr. LeFevre and his associates said.

They added that the USPSTF recommendation against screening the general population for carotid stenosis agrees with recommendations from the American Heart Association, American Stroke Association, American College of Cardiology, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Society for Vascular Surgery, Society for Vascular Medicine, and the American Academy of Family Physicians.

More information on this recommendation – as well as recommendations for the related issues of hypertension, dyslipidemia, CHD, and diet – is available at the USPSTF website.

The USPSTF is an independent group that makes recommendations about the effectiveness of specific preventive care services and is funded by the Agency for Healthcare Research and Quality.

Asymptomatic adults in the general population who have no history of stroke, transient ischemic attack, or neurologic signs or symptoms should not be screened for carotid artery stenosis, according to a U.S. Preventive Services Task Force recommendation published online July 7 in Annals of Internal Medicine.

All screening strategies, even a noninvasive one that has minimal harmful effects such as ultrasonography, are insufficiently sensitive for detecting the condition. And all of them can lead to unnecessary treatment or can themselves induce serious harms including death, stroke, and myocardial infarction. Therefore, at this time, "the harms of screening for asymptomatic carotid artery stenosis outweigh the benefits," said Dr. Michael L. LeFevre of the University of Missouri, Columbia, and his associates with the USPSTF.

The recommendation is an update of the previous one issued in 2007, which also concluded that screening the general population for carotid stenosis was unwarranted. For this update, the USPSTF performed an exhaustive review and meta-analysis of the data that have accrued since that time, which addressed advances in screening tests, risk stratification tools, both screening and treatment using carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAAS), and optimal medical therapies.

Dr. LeFevre, a cochair of USPSTF, and his colleagues reviewed recent randomized controlled trials, meta-analyses, and cohort studies of these topics. They found that the prevalence of carotid artery stenosis is only 0.5%-1% in the general population of adults. The most feasible screen for the condition is duplex ultrasonography; but in real-world practice, even this screen yields many false-positive results in such patients, and so exposes them to harm.

There also is no evidence that another noninvasive screen for carotid artery stenosis – auscultation of the neck to detect carotid bruits – is accurate or provides any benefit. Only four studies examined this strategy; none of them used angiography as a gold standard for diagnosis, and only two involved patients from the general population.

Moreover, even when screening of asymptomatic patients leads to detection and early intervention, "the magnitude of benefit is small to none." In particular, adding medications to current optimal medical management does not appear to convey any benefit, Dr. LeFevre and his associates said.

On the other side of the benefit-to-harm scale, carotid endarterectomy is associated with a 30-day rate of stroke or mortality of approximately 2.4% overall. However, the rates are as high as 5% in low-volume medical centers and 6% in certain states. The 30-day rate of stroke or mortality associated with CAAS is 3.1%-3.8%. Those risks are far too high to counterbalance the small benefit of screening, the USPSTF reviewers noted.

Other important harms after CEA or CAAS include myocardial infarction, surgical complications, cranial nerve injury, lung embolism, pneumonia, and local hematoma requiring further surgery.

The review and meta-analysis were hampered by a dearth of high-quality data. Specifically, much more data are needed comparing patient outcomes after CEA or CAAS with those after optimal medical therapy. The planned CREST-2 (Carotid Revascularization Endarterectomy vs Stenting Trial 2) will include a comparator group on medical management alone, and should provide important findings in this regard, Dr. LeFevre and his associates said.

They added that the USPSTF recommendation against screening the general population for carotid stenosis agrees with recommendations from the American Heart Association, American Stroke Association, American College of Cardiology, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Society for Vascular Surgery, Society for Vascular Medicine, and the American Academy of Family Physicians.

More information on this recommendation – as well as recommendations for the related issues of hypertension, dyslipidemia, CHD, and diet – is available at the USPSTF website.

The USPSTF is an independent group that makes recommendations about the effectiveness of specific preventive care services and is funded by the Agency for Healthcare Research and Quality.

In previous studies on patients under 6 months of age undergoing a wide range of congenital cardiac operations, Dr. Meena Nathan and her colleagues at Boston Children’s Hospital found that immediate revisions of procedures intraoperatively that resulted in adequate anatomic correction of residual defects did not affect outcomes, but that delayed revisions of residual lesions resulted in worse patient outcomes.

Dr. Nathan presented the results of a larger prospective cohort of patients that she and her colleagues studied who were followed from index surgery to discharge from January 2011 to September 2013.

Patients were divided into four groups: a) intraoperative revisions of residual lesion, b) delayed postoperative revision of residual lesions during the same hospital stay, c) both intraoperative and delayed (BOTH) revision of residual lesions, d) and no revisions (neither intraoperative nor postoperative revision), Dr. Nathan said at the annual meeting of the American Association for Thoracic Surgery.

They used linear and logistic regression to compare the outcomes mortality, complications (excluding unplanned postoperative reinterventions) and postoperative hospital length of stay across the four groups (using patients who had intraoperative revisions only as reference group).

"We adjusted for baseline patient risk including age, prematurity, presence of extracardiac anomalies, and RACHS-1 risk category, each of which could contribute to the difference in outcomes," according to Dr. Nathan.

"In addition, to allow inclusion of all patients in the risk-adjusted analyses, we added two additional categories to the RACHS-1 categories: all patients less than 18 years of age with non–RACHS-1 categorizable procedures, and adults greater than 18 years who are not eligible for RACHS-1 risk adjustment," Dr. Nathan added.

A total of 2,427 patients were discharged after congenital cardiac operations during the time period studied.

As might be expected, on multivariable modeling, adjusting for other significant patient factors, the no-revisions group fared better than the other three groups. The intraoperative revision group had significantly lower postoperative length of stay and complication rates when compared to the delayed postoperative revision and the BOTH group, but they showed no significant differences in mortality compared to these two groups.

On subgroup analysis of the intraoperative revision group, 86% left the hospital with an optimal or adequate repair on discharge echocardiogram, Dr. Nathan added.

"We found that the intraoperative correction of residual lesions results in a shorter length of stay and lower complications when compared to those patients who underwent delayed postoperative revision of residual lesion," she concluded.

Dr. Nathan reported that she had no relevant disclosures.

[email protected]

In previous studies on patients under 6 months of age undergoing a wide range of congenital cardiac operations, Dr. Meena Nathan and her colleagues at Boston Children’s Hospital found that immediate revisions of procedures intraoperatively that resulted in adequate anatomic correction of residual defects did not affect outcomes, but that delayed revisions of residual lesions resulted in worse patient outcomes.

Dr. Nathan presented the results of a larger prospective cohort of patients that she and her colleagues studied who were followed from index surgery to discharge from January 2011 to September 2013.

Patients were divided into four groups: a) intraoperative revisions of residual lesion, b) delayed postoperative revision of residual lesions during the same hospital stay, c) both intraoperative and delayed (BOTH) revision of residual lesions, d) and no revisions (neither intraoperative nor postoperative revision), Dr. Nathan said at the annual meeting of the American Association for Thoracic Surgery.

They used linear and logistic regression to compare the outcomes mortality, complications (excluding unplanned postoperative reinterventions) and postoperative hospital length of stay across the four groups (using patients who had intraoperative revisions only as reference group).

"We adjusted for baseline patient risk including age, prematurity, presence of extracardiac anomalies, and RACHS-1 risk category, each of which could contribute to the difference in outcomes," according to Dr. Nathan.

"In addition, to allow inclusion of all patients in the risk-adjusted analyses, we added two additional categories to the RACHS-1 categories: all patients less than 18 years of age with non–RACHS-1 categorizable procedures, and adults greater than 18 years who are not eligible for RACHS-1 risk adjustment," Dr. Nathan added.

A total of 2,427 patients were discharged after congenital cardiac operations during the time period studied.

As might be expected, on multivariable modeling, adjusting for other significant patient factors, the no-revisions group fared better than the other three groups. The intraoperative revision group had significantly lower postoperative length of stay and complication rates when compared to the delayed postoperative revision and the BOTH group, but they showed no significant differences in mortality compared to these two groups.

On subgroup analysis of the intraoperative revision group, 86% left the hospital with an optimal or adequate repair on discharge echocardiogram, Dr. Nathan added.

"We found that the intraoperative correction of residual lesions results in a shorter length of stay and lower complications when compared to those patients who underwent delayed postoperative revision of residual lesion," she concluded.

Dr. Nathan reported that she had no relevant disclosures.

[email protected]

In previous studies on patients under 6 months of age undergoing a wide range of congenital cardiac operations, Dr. Meena Nathan and her colleagues at Boston Children’s Hospital found that immediate revisions of procedures intraoperatively that resulted in adequate anatomic correction of residual defects did not affect outcomes, but that delayed revisions of residual lesions resulted in worse patient outcomes.

Dr. Nathan presented the results of a larger prospective cohort of patients that she and her colleagues studied who were followed from index surgery to discharge from January 2011 to September 2013.

Patients were divided into four groups: a) intraoperative revisions of residual lesion, b) delayed postoperative revision of residual lesions during the same hospital stay, c) both intraoperative and delayed (BOTH) revision of residual lesions, d) and no revisions (neither intraoperative nor postoperative revision), Dr. Nathan said at the annual meeting of the American Association for Thoracic Surgery.

They used linear and logistic regression to compare the outcomes mortality, complications (excluding unplanned postoperative reinterventions) and postoperative hospital length of stay across the four groups (using patients who had intraoperative revisions only as reference group).

"We adjusted for baseline patient risk including age, prematurity, presence of extracardiac anomalies, and RACHS-1 risk category, each of which could contribute to the difference in outcomes," according to Dr. Nathan.

"In addition, to allow inclusion of all patients in the risk-adjusted analyses, we added two additional categories to the RACHS-1 categories: all patients less than 18 years of age with non–RACHS-1 categorizable procedures, and adults greater than 18 years who are not eligible for RACHS-1 risk adjustment," Dr. Nathan added.

A total of 2,427 patients were discharged after congenital cardiac operations during the time period studied.

As might be expected, on multivariable modeling, adjusting for other significant patient factors, the no-revisions group fared better than the other three groups. The intraoperative revision group had significantly lower postoperative length of stay and complication rates when compared to the delayed postoperative revision and the BOTH group, but they showed no significant differences in mortality compared to these two groups.

On subgroup analysis of the intraoperative revision group, 86% left the hospital with an optimal or adequate repair on discharge echocardiogram, Dr. Nathan added.

"We found that the intraoperative correction of residual lesions results in a shorter length of stay and lower complications when compared to those patients who underwent delayed postoperative revision of residual lesion," she concluded.

Dr. Nathan reported that she had no relevant disclosures.

[email protected]

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy and myomectomy has been in the limelight in 2014—particularly morcellation performed in an “open” fashion (without use of a protective bag). Concerns about the dispersion of tissue throughout the peritoneal cavity—including the risk of disseminating tissue from leiomyosarcoma, a rare but deadly cancer—have drawn statements from the American College of Obstetricians and Gynecologists (ACOG), the AAGL, the US Food and Drug Administration (FDA), and others, cautioning against the use of open power morcellation in women with a known or suspected malignancy.

In February 2014, Robert L. Barbieri, MD, chair of obstetrics and gynecology at Brigham and Women’s Hospital, wrote about this concern for OBG Management in his capacity as editor in chief of the journal.

“When used to treat tumors presumed to be fibroids, open power morcellation is associated with an increased risk of dispersing benign myoma tissue and occult malignant leiomyosarcoma tissue throughout the abdominal cavity,” he wrote.¹ “Dispersion of benign myoma tissue may result in the growth of fibroids on the peritoneal surface, omentum, and bowel, causing abdominal and pelvic pain and necessitating reoperation. Dispersion of leiomyosarcoma tissue throughout the abdominal cavity may result in a Stage I cancer being upstaged to a Stage IV malignancy, requiring additional surgery and chemotherapy. In cases in which open power morcellation causes the upstaging of a leiomyosarcoma, the death rate is increased.”¹

Not surprisingly, the numerous statements and warnings since then have led to some confusion in the specialty about the safest course of action for tissue extraction during hysterectomy and myomectomy in women with a large uterus.

To explore the options more deeply and address the future of minimally invasive surgery (MIS) in women’s health, OBG Management invited two experts to comment: Ray A. Wertheim, MD, Director of the AAGL Center of Excellence Minimally Invasive Gynecology Program at Inova Fair Oaks Hospital in Fairfax, Virginia, and Harry Reich, MD, widely known as the first surgeon to perform laparoscopic hysterectomy, among other achievements. Both Dr. Wertheim and Dr. Reich were members of the AAGL Tissue Extraction Task Force.

In this Q&A, Dr. Wertheim and Dr. Reich discuss:

• options for tissue extraction going forward
• the importance of continuing to offer minimally invasive surgical approaches to patients
• the need to educate surgeons about the safest approaches to tissue extraction.

Both surgeons believe that power morcellation should remain an option for selected cases, though neither performs the technique himself. Both surgeons also believe that minimally invasive approaches to hysterectomy and myomectomy are here to stay and should continue to be utilized whenever possible.

AAGL convened an impartial expert panel
OBG Management: Dr. Wertheim, could you tell us a little about the AAGL position statement on the use of power morcellation for uterine tissue extraction at hysterectomy or myomectomy, since you were on the task force that researched and wrote it?² How does it compare with the ACOG and FDA statements on the use of power morcellation?

Dr. Wertheim: AAGL convened its task force to conduct a critical appraisal of the existing evidence related to the practice of uterine extraction in the setting of hysterectomy and myomectomy. Areas in need of further investigation also were identified.

The task force consisted of experts who had no conflicts, were not allowed to discuss or review findings with anyone, and were not reimbursed for their time. I’ve been practicing for almost 40 years in academic and private settings, and I found this group to be the brightest, most caring and compassionate group with whom I’ve ever worked. Our review is the most complete report to date, more comprehensive than the reports from the FDA, ACOG, the Society of Gynecologic Oncology (SGO), and the American Urogynecologic Society (AUGS).

Interestingly, AAGL, ACOG, SGO, and AUGS all reached the same conclusion: All existing methods of tissue extraction have benefits and risks that must be balanced.

OBG Management: How did the AAGL task force assess the evidence?

Dr. Wertheim: The quality of evidence and strength of recommendations were assessed using US Preventive Services Task Force guidelines. One of the problems we encountered was that there are very few good data on the issue of power morcellation for uterine tissue extraction, especially in regard to leiomyosarcoma. One needs to be careful making recommendations without good data.

At this time, we do not believe there is a single method of tissue extraction that can protect all patients. Therefore, all current methods should remain available. We believe that an understanding of the issues will allow surgeons, hospitals, and patients to make the appropriate informed choices regarding tissue extraction in individual patients undergoing uterine surgery.

How to manage tissue extraction going forward
OBG Management: The FDA will convene another meeting on power morcellation July 10 and 11. Regardless of its final decision, what should the gynecologic specialty be doing to avoid disseminating uterine tissue in the peritoneal cavity, particularly leiomyosarcoma?

Dr. Wertheim: Yes, AAGL will be at the FDA’s July hearing because we are the experts. MIS is a wonderful advancement in women’s health care. All surgical specialties are moving toward MIS. Our challenge is to perform it as safely as possible, given the current data and instrumentation available.

In regard to leiomyosarcoma, because we lack the ability to accurately make the diagnosis preoperatively, we’ve identified risk factors that should be taken into consideration. Risk factors include advanced age, history of radiation or tamoxifen use, black race, hereditary leiomyomatosis, renal cell carcinoma syndrome, and survival of childhood retinoblastoma.

At this time, we have specimen-retrieval bags that can be used with power morcellation. However, it takes skill to be able to place a large specimen inside a bag without injuring surrounding organs due to limited visibility.

OBG Management: How should we go about educating surgeons about MIS alternatives to open power morcellation?

Education, at the hospital and national level, is in the works
Dr. Wertheim: In my hospital, we are mentoring surgeons to help them gain the new skills needed. In addition, Dr. Reich and I, along with Albert Steren, MD, a minimally invasive surgeon from Rockville, Maryland, are hosting an educational dinner meeting on tissue extraction on July 24 in northern Virginia. I plan to give a grand rounds presentation on tissue extraction for hospitals in northern Virginia and also would like to offer a course in the near future. I’m also hoping that we’ll be able to offer courses around the country before the annual AAGL meeting this November, since this is such a pressing issue.

At the annual AAGL meeting, the subject will be discussed at length, with an emphasis on identifying risk factors and conducting appropriate preoperative testing, with workshops likely to teach the skills needed to perform these surgeries as safely as possible.

Why a return to reliance on laparotomy would be unwise
OBG Management: Given all the concerns expressed recently about open power morcellation, do you think some surgeons will revert to abdominal hysterectomy rather than rely on MIS? Would such a move be safer than power morcellation?

Dr. Wertheim: That would be a disaster for women. Very reliable data have shown that MIS is safer than open surgery, with much quicker recovery. Almost all of my patients are discharged within 3 hours after surgery, and most no longer require pain medications other than nonsteroidal anti-inflammatory drugs (NSAIDs) by postoperative day 2. They’re usually back to work within 2 weeks.

We have worked long and hard to develop skills and instrumentation required to perform MIS safely—but nothing replaces good judgment. In some cases, laparotomy or conversion to a laparotomy may be indicated.

New instrumentation is needed and is being developed. In the meantime, my personal bias is to rule out risk factors for malignancy and continue to morcellate with a scalpel, preferably inside a bag. After all, we know that with open power morcellation, fragments and cells are usually left behind regardless of inspection and irrigation. These fragments may cause leiomyomatosis, endometriosis, bowel obstruction, sepsis, and possible dissemination of tumor fragments. Moreover, morcellation into small fragments complicates the pathologist’s ability to give an accurate report. The use of open power morcellation also subjects the patient to a risk of damage to surrounding organs—usually due to the surgeon’s inexperience.

As I have said before, our challenge is to perform these surgeries using the safest techniques possible, given the current data and instrumentation.

OBG Management: Dr. Reich, you have a unique perspective on this issue, since you pioneered laparoscopic hysterectomy. How has uterine tissue extraction evolved since then? Do you think open power morcellation should remain an option?

Dr. Reich: Uterine tissue extraction has not evolved. The terms “laparoscopic hysterectomy” and “total laparoscopic hysterectomy” imply vaginal extraction using a scalpel, not abdominal extraction using a morcellator. Unfortunately there is no substitute for hard work using a #10 blade on a long handle and special vaginal retraction tools.

In 1983, I made a decision to stop performing laparotomy for all gynecologic procedures, including hysterectomy, myomectomy, urology, oncology, abscesses, extensive adhesions, and rectovaginal endometriosis. I was an accomplished vaginal surgeon at that time, as well as a one-handed laparoscopic surgeon, operating while looking through the scope with one eye.

Interest in a laparoscopic approach to hysterectomy began with my presentations about laparoscopic hysterectomy in January 1988. At that time I had over 10 years of experience doing what is now called laparoscopic-assisted vaginal hysterectomy.

I wrote extensively about specimen removal using a scalpel before electronic power morcellators were available. Since then, I have asked those using power morcellators to stop calling their operation a laparoscopic hysterectomy, as it has more in common with an abdominal-extraction hysterectomy.

I have never advocated removing the uterus using power morcellators, and I still believe that most specimens can be removed vaginally without the spray of pieces of the specimen around the peritoneal cavity that occurs with power morcellation. This goes for hysterectomy involving a large uterus, myomectomy through a culdotomy incision, and removal of the uterine fundus after supracervical hysterectomy. (It is irresponsible to use expensive power morcellation to remove small supracervical hysterectomy specimens.) It is time to get back to learning and teaching vaginal morcellation, although I readily admit it is time consuming.

Nevertheless, I believe power morcellation should remain an option. Recent laparoscopic fellowship trainees know only this technique, which is still better than a return to mutilation by laparotomy.

Gynecology is a frustrating profession—30 years of MIS as a sideshow. General surgery has rapidly adopted a laparoscopic approach to most operations, after gynecologists taught them. Today the majority of gynecologists do not do advanced laparoscopic surgery and would love to get back to open incision laparotomy for their operations. We cannot go back.

OBG Management: Dr. Wertheim and Dr. Reich, do your personal views of the morcellation issue differ at all from the official views of professional societies?

Dr. Wertheim: Yes. However, before I share them, I’d like to emphasize that the views I’m about to express are mine and mine only, not those of the AAGL or its task force.

The issue of uterine extraction is a highly emotional and political issue, about which there are few good data.

Abundant Level 1 data strongly support a vaginal or laparoscopic approach for benign hysterectomy when possible. ACOG and AAGL have issued position papers supporting these approaches for benign hysterectomies. Gynecologic surgeons and other surgical specialists have embraced MIS because it is safer, offers faster recovery, produces less postoperative pain, and has fewer complications than open surgery. However, AAGL has maintained for several years that morcellation is contraindicated in cases where uterine malignancy is either known or suspected.

The dilemma with open power morcellation is that even with our best diagnostic tools, the rare uterine sarcoma cannot always be definitively ruled out preoperatively. Endometrial cancer usually can be diagnosed before surgery. However, rare subtypes such as sarcomas are more difficult to reliably diagnose preoperatively, and risk factors for uterine sarcomas are not nearly as well understood as those for endometrial cancer.

I do agree with the FDA’s cautionary statement, which pointedly prohibits power morcellation for women with suspected precancer or known cancer of the gynecologic organs.³ However, the AAGL task force critically reviewed about 120 articles, including the studies assessed by the FDA. Concerns arose regarding the FDA’s interpretation of the data. Due to a number of deficiencies in these studies, some of the conclusions of the FDA may not be completely accurate. The studies analyzed by the FDA were not stratified by risk factors for sarcoma and were not necessarily performed in a setting of reproductive-aged women with presumed fibroids.

Dr. Reich: Here are my personal views about the sarcoma problem and I am sure they differ from the official views of the professional societies:

• Laparoscopic hysterectomy should always mean vaginal extraction unless a less disfiguring site can be discovered; power morcellation implies minilaparotomy and should be renamed to reflect that fact.
• Power morcellation must be differentiated from vaginal and minilaparotomy scalpel morcellation, especially in the media. Vaginal hysterectomy has entailed vaginal scalpel morcellation with successful outcomes for more than 100 years.
• Remember that most gynecologic cancers are approached using the laparoscope today. This certainly includes cervical and endometrial cancer and some ovarian cancers. (For example, one of my neighbors is a 25-year survivor of laparoscopically treated bilateral ovarian cancer who refused laparotomy!)
• I have removed sarcomas by vaginal morcellation during laparoscopic hysterectomy and laparoscopic myomectomy with no late sequelae. In fact, most cervical cancer surgery is done by laparoscopic surgery today. And even an open laparotomy hysterectomy can spread a sarcoma.
• The current morcellation debate arose when a single case of disseminated leiomyosarcoma became highly publicized. It involved a prominent physician whose leiomyosarcoma was unknown to her initial surgeon, and the malignancy was upstaged after the use of power morcellation during hysterectomy. After this case was covered in the media, other cases began to be reported in the lay press as well, some of which predated the publicized case. The truth is, regrettably, that sarcomas carry poor prognoses even when specimens are removed intact. And we don’t know much about the sarcoma that started this debate. Was it mild or aggressive? How many mitotic figures were there per high-powered field? And what was found macroscopically and microscopically at the subsequent laparotomy? We on the AAGL task force do not know the answers to these questions, although at least some of these variables are reported in other published cases. And because this case is likely to have a powerful effect on MIS in our country and the rest of the world, it is my opinion that we need to know these details.

What is your preferred surgical approach?
OBG Management: Do you perform open power morcellation in selected patients?

Dr. Wertheim: Even though I have performed morcellation with a scalpel ­transvaginally or through a mini-laparotomy incision for many years, I have never used open power morcellation because of the risk of leaving behind benign or malignant tissue fragments. Morcellation with a scalpel is easily learned and can be performed as quickly as power morcellation. Morcellation with a scalpel produces much larger pieces than with power morcellation. This probably markedly decreases the loss of fragments. I cannot make a definitive statement regarding cell loss, however. Until we have improved instrumentation and are better able to make a preoperative diagnosis of sarcoma, I’m going to rule out risk factors identified by the AAGL task force, do the appropriate work-up, and continue to morcellate with a scalpel, placing the specimen in a bag, if technically possible.

Dr. Reich: As I mentioned, I am a vaginal scalpel morcellator. I tried power morcellation when it first was developed but was never a fan. The same techniques used for vaginal extraction using a coring maneuver can be used abdominally through the umbilicus or a 1- or 2-cm trocar site.

What should the FDA’s next move be?
OBG Management: Care to make any predictions about the FDA’s final decision?

Dr. Wertheim: This has become a highly emotional and controversial issue with little good existing data. During the preoperative visit, this issue should be discussed with the patient using clear, lay-friendly language. Having said that, I also do not believe we should hide behind informed consent. The FDA has a responsibility to keep the public safe. If open power morcellation is allowed to continue, there will be another morcellated sarcoma or complications from retained benign tissue fragments. I doubt the FDA can live with this. I believe the risk factors identified by the AAGL task force should be ruled out, the appropriate workup done and then, if power morcellation is performed, it should be done inside a bag. In addition, I think the FDA should require that complications be reported and recorded in a registry.

Dr. Reich: I disagree. The FDA has to back off. It’s important to note that this is an American problem, as the rest of the world cannot afford power morcellators. The data are not in yet. The decision about what kind of hysterectomy is performed will be made by the “informed” patient, who undoubtedly will be very afraid to have MIS because of the surrounding negative publicity. We must do a better job of promoting the advantages of a minimally invasive approach.

OBG Management: Thank you both for your time and expertise.

Dr. Wertheim: Thank you for giving us the opportunity to express our opinions regarding this highly emotional and controversial issue.

Tell us what you think!
Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Share your thoughts by sending a letter to [email protected]. Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy and myomectomy has been in the limelight in 2014—particularly morcellation performed in an “open” fashion (without use of a protective bag). Concerns about the dispersion of tissue throughout the peritoneal cavity—including the risk of disseminating tissue from leiomyosarcoma, a rare but deadly cancer—have drawn statements from the American College of Obstetricians and Gynecologists (ACOG), the AAGL, the US Food and Drug Administration (FDA), and others, cautioning against the use of open power morcellation in women with a known or suspected malignancy.

In February 2014, Robert L. Barbieri, MD, chair of obstetrics and gynecology at Brigham and Women’s Hospital, wrote about this concern for OBG Management in his capacity as editor in chief of the journal.

“When used to treat tumors presumed to be fibroids, open power morcellation is associated with an increased risk of dispersing benign myoma tissue and occult malignant leiomyosarcoma tissue throughout the abdominal cavity,” he wrote.¹ “Dispersion of benign myoma tissue may result in the growth of fibroids on the peritoneal surface, omentum, and bowel, causing abdominal and pelvic pain and necessitating reoperation. Dispersion of leiomyosarcoma tissue throughout the abdominal cavity may result in a Stage I cancer being upstaged to a Stage IV malignancy, requiring additional surgery and chemotherapy. In cases in which open power morcellation causes the upstaging of a leiomyosarcoma, the death rate is increased.”¹

Not surprisingly, the numerous statements and warnings since then have led to some confusion in the specialty about the safest course of action for tissue extraction during hysterectomy and myomectomy in women with a large uterus.

To explore the options more deeply and address the future of minimally invasive surgery (MIS) in women’s health, OBG Management invited two experts to comment: Ray A. Wertheim, MD, Director of the AAGL Center of Excellence Minimally Invasive Gynecology Program at Inova Fair Oaks Hospital in Fairfax, Virginia, and Harry Reich, MD, widely known as the first surgeon to perform laparoscopic hysterectomy, among other achievements. Both Dr. Wertheim and Dr. Reich were members of the AAGL Tissue Extraction Task Force.

In this Q&A, Dr. Wertheim and Dr. Reich discuss:

• options for tissue extraction going forward
• the importance of continuing to offer minimally invasive surgical approaches to patients
• the need to educate surgeons about the safest approaches to tissue extraction.

Both surgeons believe that power morcellation should remain an option for selected cases, though neither performs the technique himself. Both surgeons also believe that minimally invasive approaches to hysterectomy and myomectomy are here to stay and should continue to be utilized whenever possible.

AAGL convened an impartial expert panel
OBG Management: Dr. Wertheim, could you tell us a little about the AAGL position statement on the use of power morcellation for uterine tissue extraction at hysterectomy or myomectomy, since you were on the task force that researched and wrote it?² How does it compare with the ACOG and FDA statements on the use of power morcellation?

Dr. Wertheim: AAGL convened its task force to conduct a critical appraisal of the existing evidence related to the practice of uterine extraction in the setting of hysterectomy and myomectomy. Areas in need of further investigation also were identified.

The task force consisted of experts who had no conflicts, were not allowed to discuss or review findings with anyone, and were not reimbursed for their time. I’ve been practicing for almost 40 years in academic and private settings, and I found this group to be the brightest, most caring and compassionate group with whom I’ve ever worked. Our review is the most complete report to date, more comprehensive than the reports from the FDA, ACOG, the Society of Gynecologic Oncology (SGO), and the American Urogynecologic Society (AUGS).

Interestingly, AAGL, ACOG, SGO, and AUGS all reached the same conclusion: All existing methods of tissue extraction have benefits and risks that must be balanced.

OBG Management: How did the AAGL task force assess the evidence?

Dr. Wertheim: The quality of evidence and strength of recommendations were assessed using US Preventive Services Task Force guidelines. One of the problems we encountered was that there are very few good data on the issue of power morcellation for uterine tissue extraction, especially in regard to leiomyosarcoma. One needs to be careful making recommendations without good data.

At this time, we do not believe there is a single method of tissue extraction that can protect all patients. Therefore, all current methods should remain available. We believe that an understanding of the issues will allow surgeons, hospitals, and patients to make the appropriate informed choices regarding tissue extraction in individual patients undergoing uterine surgery.

How to manage tissue extraction going forward
OBG Management: The FDA will convene another meeting on power morcellation July 10 and 11. Regardless of its final decision, what should the gynecologic specialty be doing to avoid disseminating uterine tissue in the peritoneal cavity, particularly leiomyosarcoma?

Dr. Wertheim: Yes, AAGL will be at the FDA’s July hearing because we are the experts. MIS is a wonderful advancement in women’s health care. All surgical specialties are moving toward MIS. Our challenge is to perform it as safely as possible, given the current data and instrumentation available.

In regard to leiomyosarcoma, because we lack the ability to accurately make the diagnosis preoperatively, we’ve identified risk factors that should be taken into consideration. Risk factors include advanced age, history of radiation or tamoxifen use, black race, hereditary leiomyomatosis, renal cell carcinoma syndrome, and survival of childhood retinoblastoma.

At this time, we have specimen-retrieval bags that can be used with power morcellation. However, it takes skill to be able to place a large specimen inside a bag without injuring surrounding organs due to limited visibility.

OBG Management: How should we go about educating surgeons about MIS alternatives to open power morcellation?

Education, at the hospital and national level, is in the works
Dr. Wertheim: In my hospital, we are mentoring surgeons to help them gain the new skills needed. In addition, Dr. Reich and I, along with Albert Steren, MD, a minimally invasive surgeon from Rockville, Maryland, are hosting an educational dinner meeting on tissue extraction on July 24 in northern Virginia. I plan to give a grand rounds presentation on tissue extraction for hospitals in northern Virginia and also would like to offer a course in the near future. I’m also hoping that we’ll be able to offer courses around the country before the annual AAGL meeting this November, since this is such a pressing issue.

At the annual AAGL meeting, the subject will be discussed at length, with an emphasis on identifying risk factors and conducting appropriate preoperative testing, with workshops likely to teach the skills needed to perform these surgeries as safely as possible.

Why a return to reliance on laparotomy would be unwise
OBG Management: Given all the concerns expressed recently about open power morcellation, do you think some surgeons will revert to abdominal hysterectomy rather than rely on MIS? Would such a move be safer than power morcellation?

Dr. Wertheim: That would be a disaster for women. Very reliable data have shown that MIS is safer than open surgery, with much quicker recovery. Almost all of my patients are discharged within 3 hours after surgery, and most no longer require pain medications other than nonsteroidal anti-inflammatory drugs (NSAIDs) by postoperative day 2. They’re usually back to work within 2 weeks.

We have worked long and hard to develop skills and instrumentation required to perform MIS safely—but nothing replaces good judgment. In some cases, laparotomy or conversion to a laparotomy may be indicated.

New instrumentation is needed and is being developed. In the meantime, my personal bias is to rule out risk factors for malignancy and continue to morcellate with a scalpel, preferably inside a bag. After all, we know that with open power morcellation, fragments and cells are usually left behind regardless of inspection and irrigation. These fragments may cause leiomyomatosis, endometriosis, bowel obstruction, sepsis, and possible dissemination of tumor fragments. Moreover, morcellation into small fragments complicates the pathologist’s ability to give an accurate report. The use of open power morcellation also subjects the patient to a risk of damage to surrounding organs—usually due to the surgeon’s inexperience.

As I have said before, our challenge is to perform these surgeries using the safest techniques possible, given the current data and instrumentation.

OBG Management: Dr. Reich, you have a unique perspective on this issue, since you pioneered laparoscopic hysterectomy. How has uterine tissue extraction evolved since then? Do you think open power morcellation should remain an option?

Dr. Reich: Uterine tissue extraction has not evolved. The terms “laparoscopic hysterectomy” and “total laparoscopic hysterectomy” imply vaginal extraction using a scalpel, not abdominal extraction using a morcellator. Unfortunately there is no substitute for hard work using a #10 blade on a long handle and special vaginal retraction tools.

In 1983, I made a decision to stop performing laparotomy for all gynecologic procedures, including hysterectomy, myomectomy, urology, oncology, abscesses, extensive adhesions, and rectovaginal endometriosis. I was an accomplished vaginal surgeon at that time, as well as a one-handed laparoscopic surgeon, operating while looking through the scope with one eye.

Interest in a laparoscopic approach to hysterectomy began with my presentations about laparoscopic hysterectomy in January 1988. At that time I had over 10 years of experience doing what is now called laparoscopic-assisted vaginal hysterectomy.

I wrote extensively about specimen removal using a scalpel before electronic power morcellators were available. Since then, I have asked those using power morcellators to stop calling their operation a laparoscopic hysterectomy, as it has more in common with an abdominal-extraction hysterectomy.

I have never advocated removing the uterus using power morcellators, and I still believe that most specimens can be removed vaginally without the spray of pieces of the specimen around the peritoneal cavity that occurs with power morcellation. This goes for hysterectomy involving a large uterus, myomectomy through a culdotomy incision, and removal of the uterine fundus after supracervical hysterectomy. (It is irresponsible to use expensive power morcellation to remove small supracervical hysterectomy specimens.) It is time to get back to learning and teaching vaginal morcellation, although I readily admit it is time consuming.

Nevertheless, I believe power morcellation should remain an option. Recent laparoscopic fellowship trainees know only this technique, which is still better than a return to mutilation by laparotomy.

Gynecology is a frustrating profession—30 years of MIS as a sideshow. General surgery has rapidly adopted a laparoscopic approach to most operations, after gynecologists taught them. Today the majority of gynecologists do not do advanced laparoscopic surgery and would love to get back to open incision laparotomy for their operations. We cannot go back.

OBG Management: Dr. Wertheim and Dr. Reich, do your personal views of the morcellation issue differ at all from the official views of professional societies?

Dr. Wertheim: Yes. However, before I share them, I’d like to emphasize that the views I’m about to express are mine and mine only, not those of the AAGL or its task force.

The issue of uterine extraction is a highly emotional and political issue, about which there are few good data.

Abundant Level 1 data strongly support a vaginal or laparoscopic approach for benign hysterectomy when possible. ACOG and AAGL have issued position papers supporting these approaches for benign hysterectomies. Gynecologic surgeons and other surgical specialists have embraced MIS because it is safer, offers faster recovery, produces less postoperative pain, and has fewer complications than open surgery. However, AAGL has maintained for several years that morcellation is contraindicated in cases where uterine malignancy is either known or suspected.

The dilemma with open power morcellation is that even with our best diagnostic tools, the rare uterine sarcoma cannot always be definitively ruled out preoperatively. Endometrial cancer usually can be diagnosed before surgery. However, rare subtypes such as sarcomas are more difficult to reliably diagnose preoperatively, and risk factors for uterine sarcomas are not nearly as well understood as those for endometrial cancer.

I do agree with the FDA’s cautionary statement, which pointedly prohibits power morcellation for women with suspected precancer or known cancer of the gynecologic organs.³ However, the AAGL task force critically reviewed about 120 articles, including the studies assessed by the FDA. Concerns arose regarding the FDA’s interpretation of the data. Due to a number of deficiencies in these studies, some of the conclusions of the FDA may not be completely accurate. The studies analyzed by the FDA were not stratified by risk factors for sarcoma and were not necessarily performed in a setting of reproductive-aged women with presumed fibroids.

Dr. Reich: Here are my personal views about the sarcoma problem and I am sure they differ from the official views of the professional societies:

• Laparoscopic hysterectomy should always mean vaginal extraction unless a less disfiguring site can be discovered; power morcellation implies minilaparotomy and should be renamed to reflect that fact.
• Power morcellation must be differentiated from vaginal and minilaparotomy scalpel morcellation, especially in the media. Vaginal hysterectomy has entailed vaginal scalpel morcellation with successful outcomes for more than 100 years.
• Remember that most gynecologic cancers are approached using the laparoscope today. This certainly includes cervical and endometrial cancer and some ovarian cancers. (For example, one of my neighbors is a 25-year survivor of laparoscopically treated bilateral ovarian cancer who refused laparotomy!)
• I have removed sarcomas by vaginal morcellation during laparoscopic hysterectomy and laparoscopic myomectomy with no late sequelae. In fact, most cervical cancer surgery is done by laparoscopic surgery today. And even an open laparotomy hysterectomy can spread a sarcoma.
• The current morcellation debate arose when a single case of disseminated leiomyosarcoma became highly publicized. It involved a prominent physician whose leiomyosarcoma was unknown to her initial surgeon, and the malignancy was upstaged after the use of power morcellation during hysterectomy. After this case was covered in the media, other cases began to be reported in the lay press as well, some of which predated the publicized case. The truth is, regrettably, that sarcomas carry poor prognoses even when specimens are removed intact. And we don’t know much about the sarcoma that started this debate. Was it mild or aggressive? How many mitotic figures were there per high-powered field? And what was found macroscopically and microscopically at the subsequent laparotomy? We on the AAGL task force do not know the answers to these questions, although at least some of these variables are reported in other published cases. And because this case is likely to have a powerful effect on MIS in our country and the rest of the world, it is my opinion that we need to know these details.

What is your preferred surgical approach?
OBG Management: Do you perform open power morcellation in selected patients?

Dr. Wertheim: Even though I have performed morcellation with a scalpel ­transvaginally or through a mini-laparotomy incision for many years, I have never used open power morcellation because of the risk of leaving behind benign or malignant tissue fragments. Morcellation with a scalpel is easily learned and can be performed as quickly as power morcellation. Morcellation with a scalpel produces much larger pieces than with power morcellation. This probably markedly decreases the loss of fragments. I cannot make a definitive statement regarding cell loss, however. Until we have improved instrumentation and are better able to make a preoperative diagnosis of sarcoma, I’m going to rule out risk factors identified by the AAGL task force, do the appropriate work-up, and continue to morcellate with a scalpel, placing the specimen in a bag, if technically possible.

Dr. Reich: As I mentioned, I am a vaginal scalpel morcellator. I tried power morcellation when it first was developed but was never a fan. The same techniques used for vaginal extraction using a coring maneuver can be used abdominally through the umbilicus or a 1- or 2-cm trocar site.

What should the FDA’s next move be?
OBG Management: Care to make any predictions about the FDA’s final decision?

Dr. Wertheim: This has become a highly emotional and controversial issue with little good existing data. During the preoperative visit, this issue should be discussed with the patient using clear, lay-friendly language. Having said that, I also do not believe we should hide behind informed consent. The FDA has a responsibility to keep the public safe. If open power morcellation is allowed to continue, there will be another morcellated sarcoma or complications from retained benign tissue fragments. I doubt the FDA can live with this. I believe the risk factors identified by the AAGL task force should be ruled out, the appropriate workup done and then, if power morcellation is performed, it should be done inside a bag. In addition, I think the FDA should require that complications be reported and recorded in a registry.

Dr. Reich: I disagree. The FDA has to back off. It’s important to note that this is an American problem, as the rest of the world cannot afford power morcellators. The data are not in yet. The decision about what kind of hysterectomy is performed will be made by the “informed” patient, who undoubtedly will be very afraid to have MIS because of the surrounding negative publicity. We must do a better job of promoting the advantages of a minimally invasive approach.

OBG Management: Thank you both for your time and expertise.

Dr. Wertheim: Thank you for giving us the opportunity to express our opinions regarding this highly emotional and controversial issue.

Tell us what you think!
Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Share your thoughts by sending a letter to [email protected]. Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy and myomectomy has been in the limelight in 2014—particularly morcellation performed in an “open” fashion (without use of a protective bag). Concerns about the dispersion of tissue throughout the peritoneal cavity—including the risk of disseminating tissue from leiomyosarcoma, a rare but deadly cancer—have drawn statements from the American College of Obstetricians and Gynecologists (ACOG), the AAGL, the US Food and Drug Administration (FDA), and others, cautioning against the use of open power morcellation in women with a known or suspected malignancy.

In February 2014, Robert L. Barbieri, MD, chair of obstetrics and gynecology at Brigham and Women’s Hospital, wrote about this concern for OBG Management in his capacity as editor in chief of the journal.

“When used to treat tumors presumed to be fibroids, open power morcellation is associated with an increased risk of dispersing benign myoma tissue and occult malignant leiomyosarcoma tissue throughout the abdominal cavity,” he wrote.¹ “Dispersion of benign myoma tissue may result in the growth of fibroids on the peritoneal surface, omentum, and bowel, causing abdominal and pelvic pain and necessitating reoperation. Dispersion of leiomyosarcoma tissue throughout the abdominal cavity may result in a Stage I cancer being upstaged to a Stage IV malignancy, requiring additional surgery and chemotherapy. In cases in which open power morcellation causes the upstaging of a leiomyosarcoma, the death rate is increased.”¹

Not surprisingly, the numerous statements and warnings since then have led to some confusion in the specialty about the safest course of action for tissue extraction during hysterectomy and myomectomy in women with a large uterus.

To explore the options more deeply and address the future of minimally invasive surgery (MIS) in women’s health, OBG Management invited two experts to comment: Ray A. Wertheim, MD, Director of the AAGL Center of Excellence Minimally Invasive Gynecology Program at Inova Fair Oaks Hospital in Fairfax, Virginia, and Harry Reich, MD, widely known as the first surgeon to perform laparoscopic hysterectomy, among other achievements. Both Dr. Wertheim and Dr. Reich were members of the AAGL Tissue Extraction Task Force.

In this Q&A, Dr. Wertheim and Dr. Reich discuss:

• options for tissue extraction going forward
• the importance of continuing to offer minimally invasive surgical approaches to patients
• the need to educate surgeons about the safest approaches to tissue extraction.

Both surgeons believe that power morcellation should remain an option for selected cases, though neither performs the technique himself. Both surgeons also believe that minimally invasive approaches to hysterectomy and myomectomy are here to stay and should continue to be utilized whenever possible.

AAGL convened an impartial expert panel
OBG Management: Dr. Wertheim, could you tell us a little about the AAGL position statement on the use of power morcellation for uterine tissue extraction at hysterectomy or myomectomy, since you were on the task force that researched and wrote it?² How does it compare with the ACOG and FDA statements on the use of power morcellation?

Dr. Wertheim: AAGL convened its task force to conduct a critical appraisal of the existing evidence related to the practice of uterine extraction in the setting of hysterectomy and myomectomy. Areas in need of further investigation also were identified.

The task force consisted of experts who had no conflicts, were not allowed to discuss or review findings with anyone, and were not reimbursed for their time. I’ve been practicing for almost 40 years in academic and private settings, and I found this group to be the brightest, most caring and compassionate group with whom I’ve ever worked. Our review is the most complete report to date, more comprehensive than the reports from the FDA, ACOG, the Society of Gynecologic Oncology (SGO), and the American Urogynecologic Society (AUGS).

Interestingly, AAGL, ACOG, SGO, and AUGS all reached the same conclusion: All existing methods of tissue extraction have benefits and risks that must be balanced.

OBG Management: How did the AAGL task force assess the evidence?

Dr. Wertheim: The quality of evidence and strength of recommendations were assessed using US Preventive Services Task Force guidelines. One of the problems we encountered was that there are very few good data on the issue of power morcellation for uterine tissue extraction, especially in regard to leiomyosarcoma. One needs to be careful making recommendations without good data.

At this time, we do not believe there is a single method of tissue extraction that can protect all patients. Therefore, all current methods should remain available. We believe that an understanding of the issues will allow surgeons, hospitals, and patients to make the appropriate informed choices regarding tissue extraction in individual patients undergoing uterine surgery.

How to manage tissue extraction going forward
OBG Management: The FDA will convene another meeting on power morcellation July 10 and 11. Regardless of its final decision, what should the gynecologic specialty be doing to avoid disseminating uterine tissue in the peritoneal cavity, particularly leiomyosarcoma?

Dr. Wertheim: Yes, AAGL will be at the FDA’s July hearing because we are the experts. MIS is a wonderful advancement in women’s health care. All surgical specialties are moving toward MIS. Our challenge is to perform it as safely as possible, given the current data and instrumentation available.

In regard to leiomyosarcoma, because we lack the ability to accurately make the diagnosis preoperatively, we’ve identified risk factors that should be taken into consideration. Risk factors include advanced age, history of radiation or tamoxifen use, black race, hereditary leiomyomatosis, renal cell carcinoma syndrome, and survival of childhood retinoblastoma.

At this time, we have specimen-retrieval bags that can be used with power morcellation. However, it takes skill to be able to place a large specimen inside a bag without injuring surrounding organs due to limited visibility.

OBG Management: How should we go about educating surgeons about MIS alternatives to open power morcellation?

Education, at the hospital and national level, is in the works
Dr. Wertheim: In my hospital, we are mentoring surgeons to help them gain the new skills needed. In addition, Dr. Reich and I, along with Albert Steren, MD, a minimally invasive surgeon from Rockville, Maryland, are hosting an educational dinner meeting on tissue extraction on July 24 in northern Virginia. I plan to give a grand rounds presentation on tissue extraction for hospitals in northern Virginia and also would like to offer a course in the near future. I’m also hoping that we’ll be able to offer courses around the country before the annual AAGL meeting this November, since this is such a pressing issue.

At the annual AAGL meeting, the subject will be discussed at length, with an emphasis on identifying risk factors and conducting appropriate preoperative testing, with workshops likely to teach the skills needed to perform these surgeries as safely as possible.

Why a return to reliance on laparotomy would be unwise
OBG Management: Given all the concerns expressed recently about open power morcellation, do you think some surgeons will revert to abdominal hysterectomy rather than rely on MIS? Would such a move be safer than power morcellation?

Dr. Wertheim: That would be a disaster for women. Very reliable data have shown that MIS is safer than open surgery, with much quicker recovery. Almost all of my patients are discharged within 3 hours after surgery, and most no longer require pain medications other than nonsteroidal anti-inflammatory drugs (NSAIDs) by postoperative day 2. They’re usually back to work within 2 weeks.

We have worked long and hard to develop skills and instrumentation required to perform MIS safely—but nothing replaces good judgment. In some cases, laparotomy or conversion to a laparotomy may be indicated.

New instrumentation is needed and is being developed. In the meantime, my personal bias is to rule out risk factors for malignancy and continue to morcellate with a scalpel, preferably inside a bag. After all, we know that with open power morcellation, fragments and cells are usually left behind regardless of inspection and irrigation. These fragments may cause leiomyomatosis, endometriosis, bowel obstruction, sepsis, and possible dissemination of tumor fragments. Moreover, morcellation into small fragments complicates the pathologist’s ability to give an accurate report. The use of open power morcellation also subjects the patient to a risk of damage to surrounding organs—usually due to the surgeon’s inexperience.

As I have said before, our challenge is to perform these surgeries using the safest techniques possible, given the current data and instrumentation.

OBG Management: Dr. Reich, you have a unique perspective on this issue, since you pioneered laparoscopic hysterectomy. How has uterine tissue extraction evolved since then? Do you think open power morcellation should remain an option?

Dr. Reich: Uterine tissue extraction has not evolved. The terms “laparoscopic hysterectomy” and “total laparoscopic hysterectomy” imply vaginal extraction using a scalpel, not abdominal extraction using a morcellator. Unfortunately there is no substitute for hard work using a #10 blade on a long handle and special vaginal retraction tools.

In 1983, I made a decision to stop performing laparotomy for all gynecologic procedures, including hysterectomy, myomectomy, urology, oncology, abscesses, extensive adhesions, and rectovaginal endometriosis. I was an accomplished vaginal surgeon at that time, as well as a one-handed laparoscopic surgeon, operating while looking through the scope with one eye.

Interest in a laparoscopic approach to hysterectomy began with my presentations about laparoscopic hysterectomy in January 1988. At that time I had over 10 years of experience doing what is now called laparoscopic-assisted vaginal hysterectomy.

I wrote extensively about specimen removal using a scalpel before electronic power morcellators were available. Since then, I have asked those using power morcellators to stop calling their operation a laparoscopic hysterectomy, as it has more in common with an abdominal-extraction hysterectomy.

I have never advocated removing the uterus using power morcellators, and I still believe that most specimens can be removed vaginally without the spray of pieces of the specimen around the peritoneal cavity that occurs with power morcellation. This goes for hysterectomy involving a large uterus, myomectomy through a culdotomy incision, and removal of the uterine fundus after supracervical hysterectomy. (It is irresponsible to use expensive power morcellation to remove small supracervical hysterectomy specimens.) It is time to get back to learning and teaching vaginal morcellation, although I readily admit it is time consuming.

Nevertheless, I believe power morcellation should remain an option. Recent laparoscopic fellowship trainees know only this technique, which is still better than a return to mutilation by laparotomy.

Gynecology is a frustrating profession—30 years of MIS as a sideshow. General surgery has rapidly adopted a laparoscopic approach to most operations, after gynecologists taught them. Today the majority of gynecologists do not do advanced laparoscopic surgery and would love to get back to open incision laparotomy for their operations. We cannot go back.

OBG Management: Dr. Wertheim and Dr. Reich, do your personal views of the morcellation issue differ at all from the official views of professional societies?

Dr. Wertheim: Yes. However, before I share them, I’d like to emphasize that the views I’m about to express are mine and mine only, not those of the AAGL or its task force.

The issue of uterine extraction is a highly emotional and political issue, about which there are few good data.

Abundant Level 1 data strongly support a vaginal or laparoscopic approach for benign hysterectomy when possible. ACOG and AAGL have issued position papers supporting these approaches for benign hysterectomies. Gynecologic surgeons and other surgical specialists have embraced MIS because it is safer, offers faster recovery, produces less postoperative pain, and has fewer complications than open surgery. However, AAGL has maintained for several years that morcellation is contraindicated in cases where uterine malignancy is either known or suspected.

The dilemma with open power morcellation is that even with our best diagnostic tools, the rare uterine sarcoma cannot always be definitively ruled out preoperatively. Endometrial cancer usually can be diagnosed before surgery. However, rare subtypes such as sarcomas are more difficult to reliably diagnose preoperatively, and risk factors for uterine sarcomas are not nearly as well understood as those for endometrial cancer.

I do agree with the FDA’s cautionary statement, which pointedly prohibits power morcellation for women with suspected precancer or known cancer of the gynecologic organs.³ However, the AAGL task force critically reviewed about 120 articles, including the studies assessed by the FDA. Concerns arose regarding the FDA’s interpretation of the data. Due to a number of deficiencies in these studies, some of the conclusions of the FDA may not be completely accurate. The studies analyzed by the FDA were not stratified by risk factors for sarcoma and were not necessarily performed in a setting of reproductive-aged women with presumed fibroids.

Dr. Reich: Here are my personal views about the sarcoma problem and I am sure they differ from the official views of the professional societies:

• Laparoscopic hysterectomy should always mean vaginal extraction unless a less disfiguring site can be discovered; power morcellation implies minilaparotomy and should be renamed to reflect that fact.
• Power morcellation must be differentiated from vaginal and minilaparotomy scalpel morcellation, especially in the media. Vaginal hysterectomy has entailed vaginal scalpel morcellation with successful outcomes for more than 100 years.
• Remember that most gynecologic cancers are approached using the laparoscope today. This certainly includes cervical and endometrial cancer and some ovarian cancers. (For example, one of my neighbors is a 25-year survivor of laparoscopically treated bilateral ovarian cancer who refused laparotomy!)
• I have removed sarcomas by vaginal morcellation during laparoscopic hysterectomy and laparoscopic myomectomy with no late sequelae. In fact, most cervical cancer surgery is done by laparoscopic surgery today. And even an open laparotomy hysterectomy can spread a sarcoma.
• The current morcellation debate arose when a single case of disseminated leiomyosarcoma became highly publicized. It involved a prominent physician whose leiomyosarcoma was unknown to her initial surgeon, and the malignancy was upstaged after the use of power morcellation during hysterectomy. After this case was covered in the media, other cases began to be reported in the lay press as well, some of which predated the publicized case. The truth is, regrettably, that sarcomas carry poor prognoses even when specimens are removed intact. And we don’t know much about the sarcoma that started this debate. Was it mild or aggressive? How many mitotic figures were there per high-powered field? And what was found macroscopically and microscopically at the subsequent laparotomy? We on the AAGL task force do not know the answers to these questions, although at least some of these variables are reported in other published cases. And because this case is likely to have a powerful effect on MIS in our country and the rest of the world, it is my opinion that we need to know these details.

What is your preferred surgical approach?
OBG Management: Do you perform open power morcellation in selected patients?

Dr. Wertheim: Even though I have performed morcellation with a scalpel ­transvaginally or through a mini-laparotomy incision for many years, I have never used open power morcellation because of the risk of leaving behind benign or malignant tissue fragments. Morcellation with a scalpel is easily learned and can be performed as quickly as power morcellation. Morcellation with a scalpel produces much larger pieces than with power morcellation. This probably markedly decreases the loss of fragments. I cannot make a definitive statement regarding cell loss, however. Until we have improved instrumentation and are better able to make a preoperative diagnosis of sarcoma, I’m going to rule out risk factors identified by the AAGL task force, do the appropriate work-up, and continue to morcellate with a scalpel, placing the specimen in a bag, if technically possible.

Dr. Reich: As I mentioned, I am a vaginal scalpel morcellator. I tried power morcellation when it first was developed but was never a fan. The same techniques used for vaginal extraction using a coring maneuver can be used abdominally through the umbilicus or a 1- or 2-cm trocar site.

What should the FDA’s next move be?
OBG Management: Care to make any predictions about the FDA’s final decision?

Dr. Wertheim: This has become a highly emotional and controversial issue with little good existing data. During the preoperative visit, this issue should be discussed with the patient using clear, lay-friendly language. Having said that, I also do not believe we should hide behind informed consent. The FDA has a responsibility to keep the public safe. If open power morcellation is allowed to continue, there will be another morcellated sarcoma or complications from retained benign tissue fragments. I doubt the FDA can live with this. I believe the risk factors identified by the AAGL task force should be ruled out, the appropriate workup done and then, if power morcellation is performed, it should be done inside a bag. In addition, I think the FDA should require that complications be reported and recorded in a registry.

Dr. Reich: I disagree. The FDA has to back off. It’s important to note that this is an American problem, as the rest of the world cannot afford power morcellators. The data are not in yet. The decision about what kind of hysterectomy is performed will be made by the “informed” patient, who undoubtedly will be very afraid to have MIS because of the surrounding negative publicity. We must do a better job of promoting the advantages of a minimally invasive approach.

OBG Management: Thank you both for your time and expertise.

Dr. Wertheim: Thank you for giving us the opportunity to express our opinions regarding this highly emotional and controversial issue.

Tell us what you think!
Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Share your thoughts by sending a letter to [email protected]. Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!