A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk for anti-D antibodies, placing the fetus at risk for hemolytic disease of the fetus and newborn (HDFN). If undiagnosed and/or untreated, HDFN carries significant risk for perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk for maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk for fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 137) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimesters calculated a sensitivity of 99.3% and a specificity of 98.4%.⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Continue to: STUDY SUMMARY

Test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 µg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and nine false-negative results. In the nine false negatives, six were due to a lack of fetal DNA in the sample and three were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

Continue to: WHAT'S NEW

Accurate test, potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

CAVEATS

Different results by ethnicity?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D immunoglobulin prophylaxis would be different in the United States than in other countries.

Also, in this study, polymerase chain reaction for two RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[5]: 306, 308, 319).

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk for anti-D antibodies, placing the fetus at risk for hemolytic disease of the fetus and newborn (HDFN). If undiagnosed and/or untreated, HDFN carries significant risk for perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk for maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk for fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 137) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimesters calculated a sensitivity of 99.3% and a specificity of 98.4%.⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Continue to: STUDY SUMMARY

Test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 µg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and nine false-negative results. In the nine false negatives, six were due to a lack of fetal DNA in the sample and three were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

Continue to: WHAT'S NEW

Accurate test, potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

CAVEATS

Different results by ethnicity?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D immunoglobulin prophylaxis would be different in the United States than in other countries.

Also, in this study, polymerase chain reaction for two RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[5]: 306, 308, 319).

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk for anti-D antibodies, placing the fetus at risk for hemolytic disease of the fetus and newborn (HDFN). If undiagnosed and/or untreated, HDFN carries significant risk for perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk for maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk for fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 137) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimesters calculated a sensitivity of 99.3% and a specificity of 98.4%.⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Continue to: STUDY SUMMARY

Test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 µg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and nine false-negative results. In the nine false negatives, six were due to a lack of fetal DNA in the sample and three were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

Continue to: WHAT'S NEW

Accurate test, potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

CAVEATS

Different results by ethnicity?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D immunoglobulin prophylaxis would be different in the United States than in other countries.

Also, in this study, polymerase chain reaction for two RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[5]: 306, 308, 319).

Adding electrocardiography screening to standard cardiovascular disease assessment is not necessary for asymptomatic, low-risk adults, according to final recommendations from the U.S. Preventive Services Task Force.

In the statement published June 12 in JAMA, the USPSTF gave a D recommendation against using ECG screening to evaluate cardiovascular disease risk in asymptomatic, low-risk individuals and issued a statement that current evidence is inadequate (I statement) to evaluate the harms versus benefits of additional ECG for asymptomatic individuals who may be at medium to high risk for future cardiovascular events.

hepatus/iStockphoto

SOURCES: Jonas D et al. JAMA. 2018 Jun 12;319(22):2315-28; Curry S et al. JAMA. 2018 Jun 12;319(22):2308-14.

Adding electrocardiography screening to standard cardiovascular disease assessment is not necessary for asymptomatic, low-risk adults, according to final recommendations from the U.S. Preventive Services Task Force.

In the statement published June 12 in JAMA, the USPSTF gave a D recommendation against using ECG screening to evaluate cardiovascular disease risk in asymptomatic, low-risk individuals and issued a statement that current evidence is inadequate (I statement) to evaluate the harms versus benefits of additional ECG for asymptomatic individuals who may be at medium to high risk for future cardiovascular events.

hepatus/iStockphoto

SOURCES: Jonas D et al. JAMA. 2018 Jun 12;319(22):2315-28; Curry S et al. JAMA. 2018 Jun 12;319(22):2308-14.

Adding electrocardiography screening to standard cardiovascular disease assessment is not necessary for asymptomatic, low-risk adults, according to final recommendations from the U.S. Preventive Services Task Force.

In the statement published June 12 in JAMA, the USPSTF gave a D recommendation against using ECG screening to evaluate cardiovascular disease risk in asymptomatic, low-risk individuals and issued a statement that current evidence is inadequate (I statement) to evaluate the harms versus benefits of additional ECG for asymptomatic individuals who may be at medium to high risk for future cardiovascular events.

hepatus/iStockphoto

SOURCES: Jonas D et al. JAMA. 2018 Jun 12;319(22):2315-28; Curry S et al. JAMA. 2018 Jun 12;319(22):2308-14.

BOSTON – Charting a healthy path for patients after bariatric surgery can be complicated and addressing bone health is an important part of the endocrinologist’s role in keeping patients safe from postsurgical fractures, according to John Bilezikian, MD.

“Abnormal bone metabolism is a feature of both obesity and gastric bypass surgery,” said Dr. Bilezikian, speaking during a bariatric surgery–focused session at the annual scientific & clinical congress of the American Academy of Clinical Endocrinologists.

It’s not easy to assess bone health, even before surgery, said Dr. Bilezikian. Even objective measures of bone density, such as dual-energy x-ray absorptiometry (DXA), may be skewed: very high fat mass causes artifact that interferes with accurate measurement of bone density, and DXA can’t distinguish between cortical and trabecular bone. The latter is a particular issue in high body mass index patients, since obesity is known to be associated with a more fragile bone microarchitecture, said Dr. Bilezikian, the Dorothy L. and Daniel H. Silberberg Professor of Medicine and director of the metabolic bone diseases unit at Columbia University, New York.

With these caveats in mind, Dr. Bilezikian said, there are some lessons to be learned from existing research to better manage bone health in bariatric patients.

After Roux-en-Y gastric bypass surgery (RYGB), bone turnover soon increases, with bone resorption markers increasing by up to 200% in the first 12-18 months after surgery. Bone formation markers also are elevated but to a lesser extent, said Dr. Bilezikian. Over time, the weight loss from RYGB is associated with a significant drop in bone mineral density (BMD) at weight-bearing sites. Weight loss was associated with bone loss at the total hip (r = 0.70; P less than .0003) and femoral neck (r = 0.47; P = .03 (J Clin Endocrinol Metab. 2013 Feb;98[2] 541-9).

A newer-technology, high-resolution peripheral quantitative CT (HR-pQCT) offers a noninvasive look not just at bone size and density but also at microarchitecture, including cortical thickness and details of trabecular structure. This technology “can help elucidate the structural basis for fragility,” said Dr. Bilezikian.

HR-pQCT was used in a recent study (J Bone Min Res. 2017 Dec. 27. doi: 10.1002/jbmr.3371) that followed 48 patients for 1 year after RYGB. Using HR-pQCT, DXA, and serum markers of bone turnover, the researchers found significant decrease in BMD and estimated decrease in bone strength after RYGB. Bone cortex became increasingly porous as well. Taken together, these changes may indicate an increased fracture risk, concluded the investigators.

A longer study that followed RYGB recipients for 2 years and used similar imaging and serum parameters also found that participants had decreased BMD. Tellingly, these investigators saw more marked increase in cortical porosity in the second year after bypass. Estimated bone strength continued to decline during the study period, even after weight loss had stopped.

All of these findings, said Dr. Bilezikian, point to a pathogenetic process other than weight loss that promotes the deteriorating bone microarchitecture seen years after RYGB. “Loss of bone mass and skeletal deterioration after gastric bypass surgery cannot be explained by weight loss alone,” said Dr. Bilezikian.

Another recent study was able to follow a small cohort of patients for a full 5 years, using DXA, lumbar CT, and Hr-pQCT. Though weight loss stabilized after 2 years and 25-OH D and calcium levels were unchanged from presurgical baseline, bone density continued to drop, and bone microarchitecture further deteriorated, said Dr. Bilezikian (Greenblatt L et al. ASBMR 2017, Abstract 1125).

Initially, post–bariatric surgery weight loss may induce bone changes because of skeletal unloading; further down the road, estrogen production by adipose tissue is decreased with ongoing fat loss, and sarcopenia may have an adverse effect on bone microarchitecture. Postsurgical malabsorption may also be an early mechanism of bone loss.

Other hormonal changes can include secondary hyperparathyroidism. Leptin, adiponectin, and peptide YY levels also may be altered.

Do these changes in BMD and bone architecture result in increased fracture risk? This question is difficult to answer, for the same reasons that other bariatric surgery research can be challenging, said Dr. Bilezikian. There is heterogeneity of procedures and supplement regimens, sample sizes can be small, follow-up times short, and adherence often is not tracked.

However, there are some clues that RYGB may be associated with an increased risk of all fractures and of fragility fractures, with appendicular fractures seen most frequently (Osteoporos Int. 2014 Jan; 25[1]:151-8). A larger study that tracked 12,676 patients receiving bariatric surgery, 38,028 patients with obesity, and 126,760 nonobese participants found that the bariatric patients had a 4.1% risk of fracture at 4 years post surgery, compared with 2.7% and 2.4% fracture rates in the participants with and without obesity, respectively (BMJ. 2016;354:i3794).

Other retrospective studies have found “a time-dependent increase in nonvertebral fractures with Roux-en-Y gastric bypass compared to gastric banding,” said Dr. Bilezikian.

How can these risks be managed after gastric bypass surgery? “Strive for nutritional adequacy” as the first step, said Dr. Bilezikian, meaning that calcium and vitamin D should be prescribed – and adherence encouraged – as indicated. Levels of 25-OH D should be checked regularly, with supplementation managed to keep levels over 30 ng/mL, he said.

All patients should be encouraged to develop and maintain an appropriate exercise regimen, and BMD should be followed over time. Those caring for post–gastric bypass patients can still use a bisphosphonate or other bone-health medication, if indicated using standard parameters. However, “You probably shouldn’t use an oral bisphosphonate in this population,” said Dr. Bilezikian.

Dr. Bilezikian reported that he has consulting or advisory relationships with Amgen, Radius Pharmaceuticals, Shire Pharmaceuticals, and Ultragenyx, and serves on a data safety monitoring board for Regeneron.

[email protected]

BOSTON – Charting a healthy path for patients after bariatric surgery can be complicated and addressing bone health is an important part of the endocrinologist’s role in keeping patients safe from postsurgical fractures, according to John Bilezikian, MD.

“Abnormal bone metabolism is a feature of both obesity and gastric bypass surgery,” said Dr. Bilezikian, speaking during a bariatric surgery–focused session at the annual scientific & clinical congress of the American Academy of Clinical Endocrinologists.

It’s not easy to assess bone health, even before surgery, said Dr. Bilezikian. Even objective measures of bone density, such as dual-energy x-ray absorptiometry (DXA), may be skewed: very high fat mass causes artifact that interferes with accurate measurement of bone density, and DXA can’t distinguish between cortical and trabecular bone. The latter is a particular issue in high body mass index patients, since obesity is known to be associated with a more fragile bone microarchitecture, said Dr. Bilezikian, the Dorothy L. and Daniel H. Silberberg Professor of Medicine and director of the metabolic bone diseases unit at Columbia University, New York.

With these caveats in mind, Dr. Bilezikian said, there are some lessons to be learned from existing research to better manage bone health in bariatric patients.

After Roux-en-Y gastric bypass surgery (RYGB), bone turnover soon increases, with bone resorption markers increasing by up to 200% in the first 12-18 months after surgery. Bone formation markers also are elevated but to a lesser extent, said Dr. Bilezikian. Over time, the weight loss from RYGB is associated with a significant drop in bone mineral density (BMD) at weight-bearing sites. Weight loss was associated with bone loss at the total hip (r = 0.70; P less than .0003) and femoral neck (r = 0.47; P = .03 (J Clin Endocrinol Metab. 2013 Feb;98[2] 541-9).

A newer-technology, high-resolution peripheral quantitative CT (HR-pQCT) offers a noninvasive look not just at bone size and density but also at microarchitecture, including cortical thickness and details of trabecular structure. This technology “can help elucidate the structural basis for fragility,” said Dr. Bilezikian.

HR-pQCT was used in a recent study (J Bone Min Res. 2017 Dec. 27. doi: 10.1002/jbmr.3371) that followed 48 patients for 1 year after RYGB. Using HR-pQCT, DXA, and serum markers of bone turnover, the researchers found significant decrease in BMD and estimated decrease in bone strength after RYGB. Bone cortex became increasingly porous as well. Taken together, these changes may indicate an increased fracture risk, concluded the investigators.

A longer study that followed RYGB recipients for 2 years and used similar imaging and serum parameters also found that participants had decreased BMD. Tellingly, these investigators saw more marked increase in cortical porosity in the second year after bypass. Estimated bone strength continued to decline during the study period, even after weight loss had stopped.

All of these findings, said Dr. Bilezikian, point to a pathogenetic process other than weight loss that promotes the deteriorating bone microarchitecture seen years after RYGB. “Loss of bone mass and skeletal deterioration after gastric bypass surgery cannot be explained by weight loss alone,” said Dr. Bilezikian.

Another recent study was able to follow a small cohort of patients for a full 5 years, using DXA, lumbar CT, and Hr-pQCT. Though weight loss stabilized after 2 years and 25-OH D and calcium levels were unchanged from presurgical baseline, bone density continued to drop, and bone microarchitecture further deteriorated, said Dr. Bilezikian (Greenblatt L et al. ASBMR 2017, Abstract 1125).

Initially, post–bariatric surgery weight loss may induce bone changes because of skeletal unloading; further down the road, estrogen production by adipose tissue is decreased with ongoing fat loss, and sarcopenia may have an adverse effect on bone microarchitecture. Postsurgical malabsorption may also be an early mechanism of bone loss.

Other hormonal changes can include secondary hyperparathyroidism. Leptin, adiponectin, and peptide YY levels also may be altered.

Do these changes in BMD and bone architecture result in increased fracture risk? This question is difficult to answer, for the same reasons that other bariatric surgery research can be challenging, said Dr. Bilezikian. There is heterogeneity of procedures and supplement regimens, sample sizes can be small, follow-up times short, and adherence often is not tracked.

However, there are some clues that RYGB may be associated with an increased risk of all fractures and of fragility fractures, with appendicular fractures seen most frequently (Osteoporos Int. 2014 Jan; 25[1]:151-8). A larger study that tracked 12,676 patients receiving bariatric surgery, 38,028 patients with obesity, and 126,760 nonobese participants found that the bariatric patients had a 4.1% risk of fracture at 4 years post surgery, compared with 2.7% and 2.4% fracture rates in the participants with and without obesity, respectively (BMJ. 2016;354:i3794).

Other retrospective studies have found “a time-dependent increase in nonvertebral fractures with Roux-en-Y gastric bypass compared to gastric banding,” said Dr. Bilezikian.

How can these risks be managed after gastric bypass surgery? “Strive for nutritional adequacy” as the first step, said Dr. Bilezikian, meaning that calcium and vitamin D should be prescribed – and adherence encouraged – as indicated. Levels of 25-OH D should be checked regularly, with supplementation managed to keep levels over 30 ng/mL, he said.

All patients should be encouraged to develop and maintain an appropriate exercise regimen, and BMD should be followed over time. Those caring for post–gastric bypass patients can still use a bisphosphonate or other bone-health medication, if indicated using standard parameters. However, “You probably shouldn’t use an oral bisphosphonate in this population,” said Dr. Bilezikian.

Dr. Bilezikian reported that he has consulting or advisory relationships with Amgen, Radius Pharmaceuticals, Shire Pharmaceuticals, and Ultragenyx, and serves on a data safety monitoring board for Regeneron.

[email protected]

BOSTON – Charting a healthy path for patients after bariatric surgery can be complicated and addressing bone health is an important part of the endocrinologist’s role in keeping patients safe from postsurgical fractures, according to John Bilezikian, MD.

“Abnormal bone metabolism is a feature of both obesity and gastric bypass surgery,” said Dr. Bilezikian, speaking during a bariatric surgery–focused session at the annual scientific & clinical congress of the American Academy of Clinical Endocrinologists.

It’s not easy to assess bone health, even before surgery, said Dr. Bilezikian. Even objective measures of bone density, such as dual-energy x-ray absorptiometry (DXA), may be skewed: very high fat mass causes artifact that interferes with accurate measurement of bone density, and DXA can’t distinguish between cortical and trabecular bone. The latter is a particular issue in high body mass index patients, since obesity is known to be associated with a more fragile bone microarchitecture, said Dr. Bilezikian, the Dorothy L. and Daniel H. Silberberg Professor of Medicine and director of the metabolic bone diseases unit at Columbia University, New York.

With these caveats in mind, Dr. Bilezikian said, there are some lessons to be learned from existing research to better manage bone health in bariatric patients.

After Roux-en-Y gastric bypass surgery (RYGB), bone turnover soon increases, with bone resorption markers increasing by up to 200% in the first 12-18 months after surgery. Bone formation markers also are elevated but to a lesser extent, said Dr. Bilezikian. Over time, the weight loss from RYGB is associated with a significant drop in bone mineral density (BMD) at weight-bearing sites. Weight loss was associated with bone loss at the total hip (r = 0.70; P less than .0003) and femoral neck (r = 0.47; P = .03 (J Clin Endocrinol Metab. 2013 Feb;98[2] 541-9).

A newer-technology, high-resolution peripheral quantitative CT (HR-pQCT) offers a noninvasive look not just at bone size and density but also at microarchitecture, including cortical thickness and details of trabecular structure. This technology “can help elucidate the structural basis for fragility,” said Dr. Bilezikian.

HR-pQCT was used in a recent study (J Bone Min Res. 2017 Dec. 27. doi: 10.1002/jbmr.3371) that followed 48 patients for 1 year after RYGB. Using HR-pQCT, DXA, and serum markers of bone turnover, the researchers found significant decrease in BMD and estimated decrease in bone strength after RYGB. Bone cortex became increasingly porous as well. Taken together, these changes may indicate an increased fracture risk, concluded the investigators.

A longer study that followed RYGB recipients for 2 years and used similar imaging and serum parameters also found that participants had decreased BMD. Tellingly, these investigators saw more marked increase in cortical porosity in the second year after bypass. Estimated bone strength continued to decline during the study period, even after weight loss had stopped.

All of these findings, said Dr. Bilezikian, point to a pathogenetic process other than weight loss that promotes the deteriorating bone microarchitecture seen years after RYGB. “Loss of bone mass and skeletal deterioration after gastric bypass surgery cannot be explained by weight loss alone,” said Dr. Bilezikian.

Another recent study was able to follow a small cohort of patients for a full 5 years, using DXA, lumbar CT, and Hr-pQCT. Though weight loss stabilized after 2 years and 25-OH D and calcium levels were unchanged from presurgical baseline, bone density continued to drop, and bone microarchitecture further deteriorated, said Dr. Bilezikian (Greenblatt L et al. ASBMR 2017, Abstract 1125).

Initially, post–bariatric surgery weight loss may induce bone changes because of skeletal unloading; further down the road, estrogen production by adipose tissue is decreased with ongoing fat loss, and sarcopenia may have an adverse effect on bone microarchitecture. Postsurgical malabsorption may also be an early mechanism of bone loss.

Other hormonal changes can include secondary hyperparathyroidism. Leptin, adiponectin, and peptide YY levels also may be altered.

Do these changes in BMD and bone architecture result in increased fracture risk? This question is difficult to answer, for the same reasons that other bariatric surgery research can be challenging, said Dr. Bilezikian. There is heterogeneity of procedures and supplement regimens, sample sizes can be small, follow-up times short, and adherence often is not tracked.

However, there are some clues that RYGB may be associated with an increased risk of all fractures and of fragility fractures, with appendicular fractures seen most frequently (Osteoporos Int. 2014 Jan; 25[1]:151-8). A larger study that tracked 12,676 patients receiving bariatric surgery, 38,028 patients with obesity, and 126,760 nonobese participants found that the bariatric patients had a 4.1% risk of fracture at 4 years post surgery, compared with 2.7% and 2.4% fracture rates in the participants with and without obesity, respectively (BMJ. 2016;354:i3794).

Other retrospective studies have found “a time-dependent increase in nonvertebral fractures with Roux-en-Y gastric bypass compared to gastric banding,” said Dr. Bilezikian.

How can these risks be managed after gastric bypass surgery? “Strive for nutritional adequacy” as the first step, said Dr. Bilezikian, meaning that calcium and vitamin D should be prescribed – and adherence encouraged – as indicated. Levels of 25-OH D should be checked regularly, with supplementation managed to keep levels over 30 ng/mL, he said.

All patients should be encouraged to develop and maintain an appropriate exercise regimen, and BMD should be followed over time. Those caring for post–gastric bypass patients can still use a bisphosphonate or other bone-health medication, if indicated using standard parameters. However, “You probably shouldn’t use an oral bisphosphonate in this population,” said Dr. Bilezikian.

Dr. Bilezikian reported that he has consulting or advisory relationships with Amgen, Radius Pharmaceuticals, Shire Pharmaceuticals, and Ultragenyx, and serves on a data safety monitoring board for Regeneron.

[email protected]

WASHINGTON – Using hemostatic clips to close colonic mucosal defects following endoscopic removal of larger polyps cut the rate of delayed, severe bleeding episodes in half in a multicenter, randomized trial with 918 patients.

“The benefit appears limited to proximal polyps,” Heiko Pohl, MD, said at the annual Digestive Disease Week^®. In that prespecified subgroup, which included two-thirds of enrolled patients, placement of hemostatic clips on defects left after removing polyps 20 mm in diameter or larger cut the rate of delayed, severe bleeding by two-thirds, compared with patients with large defects not treated with clips. This result represented a number needed to treat with clips of 15 patients with large proximal polyps to prevent one episode of delayed severe bleeding, said Dr. Pohl, a gastroenterologist at the VA Medical Center in White River Junction, Vt.

Mitchel L. Zoler/MDedge News

Although the results that Dr. Pohl reported came from a trial that originally had been designed to generate data for Food and Drug Administration approval for using the clips to close defects following large polyp removal, the clips received approval for this indication from the agency in 2016 while the study was still in progress.

But Dr. Pohl maintained that the new evidence for efficacy that he reported will provide further impetus for gastroenterologists to use clips when they remove larger polyps in proximal locations. “I think this study will help standardize treatment of mucosal resections and change clip use,” he said in an interview.

“This was a terrific study, and one that needed to be done,” commented John R. Saltzman, MD, professor of medicine at Harvard Medical School and director of endoscopy at Brigham and Women’s Hospital in Boston. But Dr. Saltzman, who spoke from the floor during discussion of Dr. Pohl’s report, added that data on the average number of clips required to close defects were needed to assess the cost-effectiveness of the treatment, data that Dr. Pohl said were available but still being analyzed.

“We have to know how many clips to use and how to close the polyp,” Dr. Saltzman said. Dr. Pohl estimated that roughly four or five clips had been used per defect, but he cautioned that this estimate was preliminary pending his complete analysis of the data.

The CLIP (Clip Closure After Endoscopic Resection of Large Polyps) study enrolled patients with at least one nonpedunculated colonic polyp that was at least 20 mm in diameter at 16 U.S. centers, as well as one center in Montreal and one in Barcelona. The patients averaged 65 years of age, and 6%-7% of patients had more than one large polyp removed during their procedure. Randomization produced one important imbalance in assignment: 25% of the 454 patients in the clipped arm were on an antithrombotic drug (either an anticoagulant or antiplatelet drug) at the time of their endoscopy, compared with 33% of the 464 patients in the control arm.

The study’s primary endpoint was the incidence of “severe” bleeding within 30 days after the procedure. The study defined severe bleeding as an event that required hospitalization, need for repeat endoscopy, need for a blood transfusion, or need for any other major intervention, explained Dr. Pohl, who is also on the staff of Dartmouth-Hitchcock Medical Center in Lebanon, N.H.

Such events occurred in 3.5% of the patients who underwent clipping and in 7.3% of control patients who received no clipping, a statistically significant difference (P = .01). Among patients with proximal polyps, the bleeding rates were 3.3% among clipped patients and 9.9% among controls, also a statistically significant difference. Among patients with distal polyps the bleeding rates were 4.0% among clipped patients and 1.4% among controls, a difference that was not statistically significant.

Dr. Pohl and his associates ran three other prespecified, secondary analyses that divided the enrolled patients into subgroups. These analyses showed no significant effect on outcome by polyp size when comparing 20-39 mm polyps with polyps 40 mm or larger, treatment with an antithrombotic drug, or method of cauterization. The median time to severe bleeding was 1 day among the controls and 7 days among the clipped patients.

Aside from the difference in rates of delayed bleeding, the two study arms showed no significant differences in the incidence of any other serious postprocedure events. The rates of these nonbleeding events were 1.3% among clipped patients and 2.4% among the controls.

The researchers ran all these analyses based on the intention-to-treat assignment of patients. However, during the study, 9% of patients assigned to the control arm crossed over ended up receiving clips during their procedure after all, a rate that Dr. Pohl called “surprisingly high,” whereas 14% of patients assigned to the clip arm never received clips. A per-protocol analysis that censored patients who did not receive their assigned treatment showed that, among the remaining patients who underwent their assigned treatment, the rate of delayed, severe bleeds was 2.3% among the 390 patients actually treated with clips and 7.2% among the 419 controls who never received clips, a statistically significant difference, he reported.

Dr. Pohl also noted that it was “somewhat surprising” that clipping appeared to result in complete closure in “only” 68% of patients who underwent clipping and that it produced partial closure in an additional 20% of patients, with the remaining patients having mucosal defects that were not considered closed by clipping.

The study was funded by Boston Scientific, the company that markets the hemostatic clip (Resolution 360) tested in the study. Dr. Pohl had no additional disclosures. Dr. Saltzman had no disclosures.

[email protected]

SOURCE: Pohl H et al. Digestive Disease Week, Presentation 886.

WASHINGTON – Using hemostatic clips to close colonic mucosal defects following endoscopic removal of larger polyps cut the rate of delayed, severe bleeding episodes in half in a multicenter, randomized trial with 918 patients.

“The benefit appears limited to proximal polyps,” Heiko Pohl, MD, said at the annual Digestive Disease Week^®. In that prespecified subgroup, which included two-thirds of enrolled patients, placement of hemostatic clips on defects left after removing polyps 20 mm in diameter or larger cut the rate of delayed, severe bleeding by two-thirds, compared with patients with large defects not treated with clips. This result represented a number needed to treat with clips of 15 patients with large proximal polyps to prevent one episode of delayed severe bleeding, said Dr. Pohl, a gastroenterologist at the VA Medical Center in White River Junction, Vt.

Mitchel L. Zoler/MDedge News

Although the results that Dr. Pohl reported came from a trial that originally had been designed to generate data for Food and Drug Administration approval for using the clips to close defects following large polyp removal, the clips received approval for this indication from the agency in 2016 while the study was still in progress.

But Dr. Pohl maintained that the new evidence for efficacy that he reported will provide further impetus for gastroenterologists to use clips when they remove larger polyps in proximal locations. “I think this study will help standardize treatment of mucosal resections and change clip use,” he said in an interview.

“This was a terrific study, and one that needed to be done,” commented John R. Saltzman, MD, professor of medicine at Harvard Medical School and director of endoscopy at Brigham and Women’s Hospital in Boston. But Dr. Saltzman, who spoke from the floor during discussion of Dr. Pohl’s report, added that data on the average number of clips required to close defects were needed to assess the cost-effectiveness of the treatment, data that Dr. Pohl said were available but still being analyzed.

“We have to know how many clips to use and how to close the polyp,” Dr. Saltzman said. Dr. Pohl estimated that roughly four or five clips had been used per defect, but he cautioned that this estimate was preliminary pending his complete analysis of the data.

The CLIP (Clip Closure After Endoscopic Resection of Large Polyps) study enrolled patients with at least one nonpedunculated colonic polyp that was at least 20 mm in diameter at 16 U.S. centers, as well as one center in Montreal and one in Barcelona. The patients averaged 65 years of age, and 6%-7% of patients had more than one large polyp removed during their procedure. Randomization produced one important imbalance in assignment: 25% of the 454 patients in the clipped arm were on an antithrombotic drug (either an anticoagulant or antiplatelet drug) at the time of their endoscopy, compared with 33% of the 464 patients in the control arm.

The study’s primary endpoint was the incidence of “severe” bleeding within 30 days after the procedure. The study defined severe bleeding as an event that required hospitalization, need for repeat endoscopy, need for a blood transfusion, or need for any other major intervention, explained Dr. Pohl, who is also on the staff of Dartmouth-Hitchcock Medical Center in Lebanon, N.H.

Such events occurred in 3.5% of the patients who underwent clipping and in 7.3% of control patients who received no clipping, a statistically significant difference (P = .01). Among patients with proximal polyps, the bleeding rates were 3.3% among clipped patients and 9.9% among controls, also a statistically significant difference. Among patients with distal polyps the bleeding rates were 4.0% among clipped patients and 1.4% among controls, a difference that was not statistically significant.

Dr. Pohl and his associates ran three other prespecified, secondary analyses that divided the enrolled patients into subgroups. These analyses showed no significant effect on outcome by polyp size when comparing 20-39 mm polyps with polyps 40 mm or larger, treatment with an antithrombotic drug, or method of cauterization. The median time to severe bleeding was 1 day among the controls and 7 days among the clipped patients.

Aside from the difference in rates of delayed bleeding, the two study arms showed no significant differences in the incidence of any other serious postprocedure events. The rates of these nonbleeding events were 1.3% among clipped patients and 2.4% among the controls.

The researchers ran all these analyses based on the intention-to-treat assignment of patients. However, during the study, 9% of patients assigned to the control arm crossed over ended up receiving clips during their procedure after all, a rate that Dr. Pohl called “surprisingly high,” whereas 14% of patients assigned to the clip arm never received clips. A per-protocol analysis that censored patients who did not receive their assigned treatment showed that, among the remaining patients who underwent their assigned treatment, the rate of delayed, severe bleeds was 2.3% among the 390 patients actually treated with clips and 7.2% among the 419 controls who never received clips, a statistically significant difference, he reported.

Dr. Pohl also noted that it was “somewhat surprising” that clipping appeared to result in complete closure in “only” 68% of patients who underwent clipping and that it produced partial closure in an additional 20% of patients, with the remaining patients having mucosal defects that were not considered closed by clipping.

The study was funded by Boston Scientific, the company that markets the hemostatic clip (Resolution 360) tested in the study. Dr. Pohl had no additional disclosures. Dr. Saltzman had no disclosures.

[email protected]

SOURCE: Pohl H et al. Digestive Disease Week, Presentation 886.

WASHINGTON – Using hemostatic clips to close colonic mucosal defects following endoscopic removal of larger polyps cut the rate of delayed, severe bleeding episodes in half in a multicenter, randomized trial with 918 patients.

“The benefit appears limited to proximal polyps,” Heiko Pohl, MD, said at the annual Digestive Disease Week^®. In that prespecified subgroup, which included two-thirds of enrolled patients, placement of hemostatic clips on defects left after removing polyps 20 mm in diameter or larger cut the rate of delayed, severe bleeding by two-thirds, compared with patients with large defects not treated with clips. This result represented a number needed to treat with clips of 15 patients with large proximal polyps to prevent one episode of delayed severe bleeding, said Dr. Pohl, a gastroenterologist at the VA Medical Center in White River Junction, Vt.

Mitchel L. Zoler/MDedge News

Although the results that Dr. Pohl reported came from a trial that originally had been designed to generate data for Food and Drug Administration approval for using the clips to close defects following large polyp removal, the clips received approval for this indication from the agency in 2016 while the study was still in progress.

But Dr. Pohl maintained that the new evidence for efficacy that he reported will provide further impetus for gastroenterologists to use clips when they remove larger polyps in proximal locations. “I think this study will help standardize treatment of mucosal resections and change clip use,” he said in an interview.

“This was a terrific study, and one that needed to be done,” commented John R. Saltzman, MD, professor of medicine at Harvard Medical School and director of endoscopy at Brigham and Women’s Hospital in Boston. But Dr. Saltzman, who spoke from the floor during discussion of Dr. Pohl’s report, added that data on the average number of clips required to close defects were needed to assess the cost-effectiveness of the treatment, data that Dr. Pohl said were available but still being analyzed.

“We have to know how many clips to use and how to close the polyp,” Dr. Saltzman said. Dr. Pohl estimated that roughly four or five clips had been used per defect, but he cautioned that this estimate was preliminary pending his complete analysis of the data.

The CLIP (Clip Closure After Endoscopic Resection of Large Polyps) study enrolled patients with at least one nonpedunculated colonic polyp that was at least 20 mm in diameter at 16 U.S. centers, as well as one center in Montreal and one in Barcelona. The patients averaged 65 years of age, and 6%-7% of patients had more than one large polyp removed during their procedure. Randomization produced one important imbalance in assignment: 25% of the 454 patients in the clipped arm were on an antithrombotic drug (either an anticoagulant or antiplatelet drug) at the time of their endoscopy, compared with 33% of the 464 patients in the control arm.

The study’s primary endpoint was the incidence of “severe” bleeding within 30 days after the procedure. The study defined severe bleeding as an event that required hospitalization, need for repeat endoscopy, need for a blood transfusion, or need for any other major intervention, explained Dr. Pohl, who is also on the staff of Dartmouth-Hitchcock Medical Center in Lebanon, N.H.

Such events occurred in 3.5% of the patients who underwent clipping and in 7.3% of control patients who received no clipping, a statistically significant difference (P = .01). Among patients with proximal polyps, the bleeding rates were 3.3% among clipped patients and 9.9% among controls, also a statistically significant difference. Among patients with distal polyps the bleeding rates were 4.0% among clipped patients and 1.4% among controls, a difference that was not statistically significant.

Dr. Pohl and his associates ran three other prespecified, secondary analyses that divided the enrolled patients into subgroups. These analyses showed no significant effect on outcome by polyp size when comparing 20-39 mm polyps with polyps 40 mm or larger, treatment with an antithrombotic drug, or method of cauterization. The median time to severe bleeding was 1 day among the controls and 7 days among the clipped patients.

Aside from the difference in rates of delayed bleeding, the two study arms showed no significant differences in the incidence of any other serious postprocedure events. The rates of these nonbleeding events were 1.3% among clipped patients and 2.4% among the controls.

The researchers ran all these analyses based on the intention-to-treat assignment of patients. However, during the study, 9% of patients assigned to the control arm crossed over ended up receiving clips during their procedure after all, a rate that Dr. Pohl called “surprisingly high,” whereas 14% of patients assigned to the clip arm never received clips. A per-protocol analysis that censored patients who did not receive their assigned treatment showed that, among the remaining patients who underwent their assigned treatment, the rate of delayed, severe bleeds was 2.3% among the 390 patients actually treated with clips and 7.2% among the 419 controls who never received clips, a statistically significant difference, he reported.

Dr. Pohl also noted that it was “somewhat surprising” that clipping appeared to result in complete closure in “only” 68% of patients who underwent clipping and that it produced partial closure in an additional 20% of patients, with the remaining patients having mucosal defects that were not considered closed by clipping.

The study was funded by Boston Scientific, the company that markets the hemostatic clip (Resolution 360) tested in the study. Dr. Pohl had no additional disclosures. Dr. Saltzman had no disclosures.

[email protected]

SOURCE: Pohl H et al. Digestive Disease Week, Presentation 886.

We classify endometrial cancer so that we can communicate and define each patient’s disease status, the potential for harm, and the likelihood that adjuvant therapies might provide help. Traditional forms of classification have clearly fallen short in achieving this aim, as we all know of patients with apparent low-risk disease (such as stage IA grade 1 endometrioid carcinoma) who have had recurrences and died from their disease, and we know that many patients have been subjected to overtreatment for their cancer and have acquired lifelong toxicities of therapy. This column will explore the newer, more sophisticated molecular-based classifications that are being validated for endometrial cancer, and the ways in which this promises to personalize the treatment of endometrial cancer.

What is the Cancer Genome Atlas?

In 2006 the National Institutes of Health announced an initiative to coordinate work between the National Cancer Institute and the National Human Genome Research Institute taking information about the human genome and analyzing it for key genomic alterations found in 33 common cancers. These data were combined with clinical information (such as survival) to classify the behaviors of those cancers with respect to their individual genomic alternations, in order to look for patterns in mutations and behaviors. The goal of this analysis was to shift the paradigm of cancer classification from being centered around primary organ site toward tumors’ shared genomic patterns.

In 2013 the Cancer Genome Atlas published their results of complete gene sequencing in endometrial cancer.³ The authors identified four discrete subgroups of endometrial cancer with distinct molecular mutational profiles and distinct clinical outcomes: polymerase epsilon (POLE, pronounced “pole-ee”) ultramutated, microsatellite instability (MSI) high, copy number high, and copy number low.
 

POLE ultramutated

An important subgroup identified in the Cancer Genome Atlas was a group of patients with a POLE ultramutated state. POLE encodes for a subunit of DNA polymerase, the enzyme responsible for replicating the leading DNA strand. Nonfunctioning POLE results in proofreading errors and a subsequent ultramutated cellular state with a predominance of single nucleotide variants. POLE proofreading domain mutations in endometrial cancer and colon cancer are associated with excellent prognosis, likely secondary to the immune response that is elicited by this ultramutated state from creation of “antigenic neoepitopes” that stimulate T-cell response. Effectively, the very mutated cell is seen as “more foreign” to the body’s immune system.

Approximately 10% of patients with endometrial cancer have a POLE ultramutated state, and, as stated above, prognosis is excellent, even if coexisting with a histologic cell type (such as serous) that is normally associated with adverse outcomes. These women tend to be younger, with a lower body mass index, higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and low stage.
 

MSI high

MSI (microsatellite instability) is a result of epigenetic/hypermethylations or loss of expression in mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2). These genes code for proteins critical in the repair of mismatches in short repeated sequences of DNA. Loss of their function results in an accumulation of errors in these sequences: MSI. It is a feature of the Lynch syndrome inherited state, but is also found sporadically in endometrial tumors. These tumors accumulate a number of mutations during cell replication that, as in POLE hypermutated tumors, are associated with eliciting an immune response.

These tumors tend to be associated with a higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and an advanced stage. Patients with tumors that have been described as MSI high are candidates for “immune therapy” with the PDL1 inhibitor pembrolizumab because of their proinflammatory state and observed favorable responses in clinical trials.⁴
 

Copy number high/low

Copy number (CN) high and low refers to the results of microarrays in which hierarchical clustering was applied to identify reoccurring amplification or deletion regions. The CN-high group was associated with the poorest outcomes (recurrence and survival). There is significant overlap with mutations in TP53. Most serous carcinomas were CN high; however, 25% of patients with high-grade endometrioid cell type shared the CN-high classification. These tumors shared great molecular similarity to high-grade serous ovarian cancers and basal-like breast cancer.

Those patients who did not possess mutations that classified them as POLE hypermutated, MSI high, or CN high were classified as CN low. This group included predominantly grades 1 and 2 endometrioid adenocarcinomas of an early stage and had a favorable prognostic profile, though less favorable than those with a POLE ultramutated state, which appears to be somewhat protective.
 

Molecular/metabolic interactions

While molecular data are clearly important in driving a cancer cell’s behavior, other clinical and metabolic factors influence cancer behavior. For example, body mass index, adiposity, glucose, and lipid metabolism have been shown to be important drivers of cellular behavior and responsiveness to targeted therapies.^5,6 Additionally age, race, and other metabolic states contribute to oncologic behavior. Future classifications of endometrial cancer are unlikely to use molecular profiles in isolation but will need to incorporate these additional patient-specific data to better predict and prognosticate outcomes.

Clinical applications

If researchers can better define and describe a patient’s endometrial cancer from the time of their biopsy, important clinical decisions might be able to be tackled. For example, in a premenopausal patient with an endometrial cancer who is considering fertility-sparing treatments, preoperative knowledge of a POLE ultramutated state (and therefore an anticipated good prognosis) might favor fertility preservation or avoid comprehensive staging which may be of limited value. Similarly, if an MSI-high profile is identified leading to a Lynch syndrome diagnosis, she may be more inclined to undergo a hysterectomy with bilateral salpingo-oophorectomy and staging as she is at known increased risk for a more advanced endometrial cancer, as well as the potential for ovarian cancer.

Postoperative incorporation of molecular data promises to be particularly helpful in guiding adjuvant therapies and sparing some women from unnecessary treatments. For example, women with high-grade endometrioid tumors who are CN high were historically treated with radiotherapy but might do better treated with systemic adjuvant therapies traditionally reserved for nonendometrioid carcinomas. Costly therapies such as immunotherapy can be directed toward those with MSI-high tumors, and the rare patient with a POLE ultramutated state who has a recurrence or advanced disease. Clinical trials will be able to cluster enrollment of patients with CN-high, serouslike cancers with those with serous cancers, rather than combining them with patients whose cancers predictably behave much differently.

Much work is still needed to validate this molecular profiling in endometrial cancer and define the algorithms associated with treatment decisions; however, it is likely that the way we describe endometrial cancer in the near future will be quite different.
 

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures.

References

1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10-7.

2. Clarke BA et al. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63(5):410-5.

3. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.

4. Ott PA et al. Pembrolizumab in advanced endometrial cancer: Preliminary results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2016;34(suppl):Abstract 5581.

5. Roque DR et al. Association between differential gene expression and body mass index among endometrial cancers from the Cancer Genome Atlas Project. Gynecol Oncol. 2016;142(2):317-22.

6. Talhouk A et al. New classification of endometrial cancers: The development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016 Dec;3:14.

We classify endometrial cancer so that we can communicate and define each patient’s disease status, the potential for harm, and the likelihood that adjuvant therapies might provide help. Traditional forms of classification have clearly fallen short in achieving this aim, as we all know of patients with apparent low-risk disease (such as stage IA grade 1 endometrioid carcinoma) who have had recurrences and died from their disease, and we know that many patients have been subjected to overtreatment for their cancer and have acquired lifelong toxicities of therapy. This column will explore the newer, more sophisticated molecular-based classifications that are being validated for endometrial cancer, and the ways in which this promises to personalize the treatment of endometrial cancer.

What is the Cancer Genome Atlas?

In 2006 the National Institutes of Health announced an initiative to coordinate work between the National Cancer Institute and the National Human Genome Research Institute taking information about the human genome and analyzing it for key genomic alterations found in 33 common cancers. These data were combined with clinical information (such as survival) to classify the behaviors of those cancers with respect to their individual genomic alternations, in order to look for patterns in mutations and behaviors. The goal of this analysis was to shift the paradigm of cancer classification from being centered around primary organ site toward tumors’ shared genomic patterns.

In 2013 the Cancer Genome Atlas published their results of complete gene sequencing in endometrial cancer.³ The authors identified four discrete subgroups of endometrial cancer with distinct molecular mutational profiles and distinct clinical outcomes: polymerase epsilon (POLE, pronounced “pole-ee”) ultramutated, microsatellite instability (MSI) high, copy number high, and copy number low.
 

POLE ultramutated

An important subgroup identified in the Cancer Genome Atlas was a group of patients with a POLE ultramutated state. POLE encodes for a subunit of DNA polymerase, the enzyme responsible for replicating the leading DNA strand. Nonfunctioning POLE results in proofreading errors and a subsequent ultramutated cellular state with a predominance of single nucleotide variants. POLE proofreading domain mutations in endometrial cancer and colon cancer are associated with excellent prognosis, likely secondary to the immune response that is elicited by this ultramutated state from creation of “antigenic neoepitopes” that stimulate T-cell response. Effectively, the very mutated cell is seen as “more foreign” to the body’s immune system.

Approximately 10% of patients with endometrial cancer have a POLE ultramutated state, and, as stated above, prognosis is excellent, even if coexisting with a histologic cell type (such as serous) that is normally associated with adverse outcomes. These women tend to be younger, with a lower body mass index, higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and low stage.
 

MSI high

MSI (microsatellite instability) is a result of epigenetic/hypermethylations or loss of expression in mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2). These genes code for proteins critical in the repair of mismatches in short repeated sequences of DNA. Loss of their function results in an accumulation of errors in these sequences: MSI. It is a feature of the Lynch syndrome inherited state, but is also found sporadically in endometrial tumors. These tumors accumulate a number of mutations during cell replication that, as in POLE hypermutated tumors, are associated with eliciting an immune response.

These tumors tend to be associated with a higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and an advanced stage. Patients with tumors that have been described as MSI high are candidates for “immune therapy” with the PDL1 inhibitor pembrolizumab because of their proinflammatory state and observed favorable responses in clinical trials.⁴
 

Copy number high/low

Copy number (CN) high and low refers to the results of microarrays in which hierarchical clustering was applied to identify reoccurring amplification or deletion regions. The CN-high group was associated with the poorest outcomes (recurrence and survival). There is significant overlap with mutations in TP53. Most serous carcinomas were CN high; however, 25% of patients with high-grade endometrioid cell type shared the CN-high classification. These tumors shared great molecular similarity to high-grade serous ovarian cancers and basal-like breast cancer.

Those patients who did not possess mutations that classified them as POLE hypermutated, MSI high, or CN high were classified as CN low. This group included predominantly grades 1 and 2 endometrioid adenocarcinomas of an early stage and had a favorable prognostic profile, though less favorable than those with a POLE ultramutated state, which appears to be somewhat protective.
 

Molecular/metabolic interactions

While molecular data are clearly important in driving a cancer cell’s behavior, other clinical and metabolic factors influence cancer behavior. For example, body mass index, adiposity, glucose, and lipid metabolism have been shown to be important drivers of cellular behavior and responsiveness to targeted therapies.^5,6 Additionally age, race, and other metabolic states contribute to oncologic behavior. Future classifications of endometrial cancer are unlikely to use molecular profiles in isolation but will need to incorporate these additional patient-specific data to better predict and prognosticate outcomes.

Clinical applications

If researchers can better define and describe a patient’s endometrial cancer from the time of their biopsy, important clinical decisions might be able to be tackled. For example, in a premenopausal patient with an endometrial cancer who is considering fertility-sparing treatments, preoperative knowledge of a POLE ultramutated state (and therefore an anticipated good prognosis) might favor fertility preservation or avoid comprehensive staging which may be of limited value. Similarly, if an MSI-high profile is identified leading to a Lynch syndrome diagnosis, she may be more inclined to undergo a hysterectomy with bilateral salpingo-oophorectomy and staging as she is at known increased risk for a more advanced endometrial cancer, as well as the potential for ovarian cancer.

Postoperative incorporation of molecular data promises to be particularly helpful in guiding adjuvant therapies and sparing some women from unnecessary treatments. For example, women with high-grade endometrioid tumors who are CN high were historically treated with radiotherapy but might do better treated with systemic adjuvant therapies traditionally reserved for nonendometrioid carcinomas. Costly therapies such as immunotherapy can be directed toward those with MSI-high tumors, and the rare patient with a POLE ultramutated state who has a recurrence or advanced disease. Clinical trials will be able to cluster enrollment of patients with CN-high, serouslike cancers with those with serous cancers, rather than combining them with patients whose cancers predictably behave much differently.

Much work is still needed to validate this molecular profiling in endometrial cancer and define the algorithms associated with treatment decisions; however, it is likely that the way we describe endometrial cancer in the near future will be quite different.
 

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures.

References

1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10-7.

2. Clarke BA et al. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63(5):410-5.

3. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.

4. Ott PA et al. Pembrolizumab in advanced endometrial cancer: Preliminary results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2016;34(suppl):Abstract 5581.

5. Roque DR et al. Association between differential gene expression and body mass index among endometrial cancers from the Cancer Genome Atlas Project. Gynecol Oncol. 2016;142(2):317-22.

6. Talhouk A et al. New classification of endometrial cancers: The development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016 Dec;3:14.

We classify endometrial cancer so that we can communicate and define each patient’s disease status, the potential for harm, and the likelihood that adjuvant therapies might provide help. Traditional forms of classification have clearly fallen short in achieving this aim, as we all know of patients with apparent low-risk disease (such as stage IA grade 1 endometrioid carcinoma) who have had recurrences and died from their disease, and we know that many patients have been subjected to overtreatment for their cancer and have acquired lifelong toxicities of therapy. This column will explore the newer, more sophisticated molecular-based classifications that are being validated for endometrial cancer, and the ways in which this promises to personalize the treatment of endometrial cancer.

What is the Cancer Genome Atlas?

In 2006 the National Institutes of Health announced an initiative to coordinate work between the National Cancer Institute and the National Human Genome Research Institute taking information about the human genome and analyzing it for key genomic alterations found in 33 common cancers. These data were combined with clinical information (such as survival) to classify the behaviors of those cancers with respect to their individual genomic alternations, in order to look for patterns in mutations and behaviors. The goal of this analysis was to shift the paradigm of cancer classification from being centered around primary organ site toward tumors’ shared genomic patterns.

In 2013 the Cancer Genome Atlas published their results of complete gene sequencing in endometrial cancer.³ The authors identified four discrete subgroups of endometrial cancer with distinct molecular mutational profiles and distinct clinical outcomes: polymerase epsilon (POLE, pronounced “pole-ee”) ultramutated, microsatellite instability (MSI) high, copy number high, and copy number low.
 

POLE ultramutated

An important subgroup identified in the Cancer Genome Atlas was a group of patients with a POLE ultramutated state. POLE encodes for a subunit of DNA polymerase, the enzyme responsible for replicating the leading DNA strand. Nonfunctioning POLE results in proofreading errors and a subsequent ultramutated cellular state with a predominance of single nucleotide variants. POLE proofreading domain mutations in endometrial cancer and colon cancer are associated with excellent prognosis, likely secondary to the immune response that is elicited by this ultramutated state from creation of “antigenic neoepitopes” that stimulate T-cell response. Effectively, the very mutated cell is seen as “more foreign” to the body’s immune system.

Approximately 10% of patients with endometrial cancer have a POLE ultramutated state, and, as stated above, prognosis is excellent, even if coexisting with a histologic cell type (such as serous) that is normally associated with adverse outcomes. These women tend to be younger, with a lower body mass index, higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and low stage.
 

MSI high

MSI (microsatellite instability) is a result of epigenetic/hypermethylations or loss of expression in mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2). These genes code for proteins critical in the repair of mismatches in short repeated sequences of DNA. Loss of their function results in an accumulation of errors in these sequences: MSI. It is a feature of the Lynch syndrome inherited state, but is also found sporadically in endometrial tumors. These tumors accumulate a number of mutations during cell replication that, as in POLE hypermutated tumors, are associated with eliciting an immune response.

These tumors tend to be associated with a higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and an advanced stage. Patients with tumors that have been described as MSI high are candidates for “immune therapy” with the PDL1 inhibitor pembrolizumab because of their proinflammatory state and observed favorable responses in clinical trials.⁴
 

Copy number high/low

Copy number (CN) high and low refers to the results of microarrays in which hierarchical clustering was applied to identify reoccurring amplification or deletion regions. The CN-high group was associated with the poorest outcomes (recurrence and survival). There is significant overlap with mutations in TP53. Most serous carcinomas were CN high; however, 25% of patients with high-grade endometrioid cell type shared the CN-high classification. These tumors shared great molecular similarity to high-grade serous ovarian cancers and basal-like breast cancer.

Those patients who did not possess mutations that classified them as POLE hypermutated, MSI high, or CN high were classified as CN low. This group included predominantly grades 1 and 2 endometrioid adenocarcinomas of an early stage and had a favorable prognostic profile, though less favorable than those with a POLE ultramutated state, which appears to be somewhat protective.
 

Molecular/metabolic interactions

While molecular data are clearly important in driving a cancer cell’s behavior, other clinical and metabolic factors influence cancer behavior. For example, body mass index, adiposity, glucose, and lipid metabolism have been shown to be important drivers of cellular behavior and responsiveness to targeted therapies.^5,6 Additionally age, race, and other metabolic states contribute to oncologic behavior. Future classifications of endometrial cancer are unlikely to use molecular profiles in isolation but will need to incorporate these additional patient-specific data to better predict and prognosticate outcomes.

Clinical applications

If researchers can better define and describe a patient’s endometrial cancer from the time of their biopsy, important clinical decisions might be able to be tackled. For example, in a premenopausal patient with an endometrial cancer who is considering fertility-sparing treatments, preoperative knowledge of a POLE ultramutated state (and therefore an anticipated good prognosis) might favor fertility preservation or avoid comprehensive staging which may be of limited value. Similarly, if an MSI-high profile is identified leading to a Lynch syndrome diagnosis, she may be more inclined to undergo a hysterectomy with bilateral salpingo-oophorectomy and staging as she is at known increased risk for a more advanced endometrial cancer, as well as the potential for ovarian cancer.

Postoperative incorporation of molecular data promises to be particularly helpful in guiding adjuvant therapies and sparing some women from unnecessary treatments. For example, women with high-grade endometrioid tumors who are CN high were historically treated with radiotherapy but might do better treated with systemic adjuvant therapies traditionally reserved for nonendometrioid carcinomas. Costly therapies such as immunotherapy can be directed toward those with MSI-high tumors, and the rare patient with a POLE ultramutated state who has a recurrence or advanced disease. Clinical trials will be able to cluster enrollment of patients with CN-high, serouslike cancers with those with serous cancers, rather than combining them with patients whose cancers predictably behave much differently.

Much work is still needed to validate this molecular profiling in endometrial cancer and define the algorithms associated with treatment decisions; however, it is likely that the way we describe endometrial cancer in the near future will be quite different.
 

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures.

References

1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10-7.

2. Clarke BA et al. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63(5):410-5.

3. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.

4. Ott PA et al. Pembrolizumab in advanced endometrial cancer: Preliminary results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2016;34(suppl):Abstract 5581.

5. Roque DR et al. Association between differential gene expression and body mass index among endometrial cancers from the Cancer Genome Atlas Project. Gynecol Oncol. 2016;142(2):317-22.

6. Talhouk A et al. New classification of endometrial cancers: The development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016 Dec;3:14.

I have a friend who owns a large paving and excavating company. He currently is turning away large contracts because he can’t find employees to drive his dump trucks and operate his heavy machinery. The situation is so dire that he has begun to explore the possibility of recruiting employees out of the corrections system.

Like much of the country, Maine is experiencing a low level of unemployment that few of us over the age of 50 years can recall. Coupled with a confused and unwelcoming immigration policy at the federal level many small and large companies are struggling to find employees. The employment opportunities my friend’s company is offering are well above minimum wage, paying in the $30,000-$70,000 range with benefits. While the jobs require some special skills, his company is large enough that it can provide in-house training.

Doug Menuez/thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

I have a friend who owns a large paving and excavating company. He currently is turning away large contracts because he can’t find employees to drive his dump trucks and operate his heavy machinery. The situation is so dire that he has begun to explore the possibility of recruiting employees out of the corrections system.

Like much of the country, Maine is experiencing a low level of unemployment that few of us over the age of 50 years can recall. Coupled with a confused and unwelcoming immigration policy at the federal level many small and large companies are struggling to find employees. The employment opportunities my friend’s company is offering are well above minimum wage, paying in the $30,000-$70,000 range with benefits. While the jobs require some special skills, his company is large enough that it can provide in-house training.

Doug Menuez/thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

I have a friend who owns a large paving and excavating company. He currently is turning away large contracts because he can’t find employees to drive his dump trucks and operate his heavy machinery. The situation is so dire that he has begun to explore the possibility of recruiting employees out of the corrections system.

Like much of the country, Maine is experiencing a low level of unemployment that few of us over the age of 50 years can recall. Coupled with a confused and unwelcoming immigration policy at the federal level many small and large companies are struggling to find employees. The employment opportunities my friend’s company is offering are well above minimum wage, paying in the $30,000-$70,000 range with benefits. While the jobs require some special skills, his company is large enough that it can provide in-house training.

Doug Menuez/thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

ABSTRACT

Fixator-assisted nailing (FAN) and fixator-assisted locked plating (FALP) are 2 techniques that can be used to correct distal femoral valgus deformities. The fixator aids in achieving an accurate adjustable initial reduction, which is then made permanent with either nail or plate insertion. FALP can be performed with the knee held in a neutral extended position, whereas FAN requires 30° to 90° of knee flexion to insert the nail, which may cause some alignment loss. We hypothesized that FAN may yield less accurate correction than FALP. Prospectively collected data of a consecutive cohort of patients who underwent valgus deformity femoral correction with FAN or FALP at a single institution over an 8-year period were retrospectively evaluated. Twenty extremities (18 patients) were treated using FAN (median follow-up, 5 years; range, 1-10 years), and 7 extremities (6 patients) were treated with FALP (median follow-up, 5 years; range, 1-8 years). In the FAN cohort, the mean preoperative and postoperative mechanical lateral distal femoral angles (mLDFAs) were 81° (range, 67°-86°) and 89° (range, 80°-100°), respectively (P = .009). In the FALP cohort, the mean preoperative and postoperative mLDFAs were 80° (range, 71°-87°) and 88° (range, 81°-94°), respectively (P < .001). Although the average mechanical axis deviation correction for the FALP group was greater than for the FAN group (32 mm and 27 mm, respectively), the difference was not significant (P = .66). Both methods of femoral deformity correction can be considered safe and effective. On the basis of our results, FAN and FALP are comparable in accuracy for deformity correction in the distal femur.

Multiple etiologies for distal femoral valgus deformity have been described in the literature.^1-3 These can be congenital, developmental, secondary to lateral compartmental arthritis, or posttraumatic.⁴ If not corrected, femoral deformities alter the axial alignment and orientation of the joints, and may lead to early degenerative joint disease and abnormal leg kinematics.^3,5 After correcting these deformities, the goal of treatment is to obtain anatomic distal femoral angles and neutral mechanical axis deviation (MAD), but without overcorrecting into varus. Numerous techniques to fix these deformities, such as progressive correction with external fixation or acute correction open reduction with internal fixation (ORIF), have been described.⁶ Modern external fixation allows for a gradual, adjustable, and more accurate correction but may produce discomfort and complications for patients.^7-10 In contrast, ORIF may be more tolerable for the patient, but to achieve a precise correction, considerable technical skills and expertise are required.^1,11-14

Two techniques used to correct these valgus femoral deformities in adults are fixator-assisted nailing (FAN) and fixator-assisted locked plating (FALP).¹ FAN and FALP combine the advantage of external fixation (accuracy, adjustability) with the benefits of internal fixation (patient comfort), because the osteotomy and correction are performed with the guidance of a temporary external fixator and then permanently fixated by an intramedullary (IM) nail or a locking plate.^{1,8,11-13,15-18} Both techniques have the possibility to correct varus and valgus deformities, but whenever correcting sagittal plane angulation, the FAN technique may be more challenging. The paucity of studies available involving FAN and FALP do not lead to a conclusive preference of one technique over the other relative to the accuracy and success of correction.^15,19,20

Continue to: In both FAN and FALP

In both FAN and FALP, the external fixator is applied and adjusted after the osteotomy for accurate alignment. In FALP, the plate is added without moving the leg from its straight position. However, in FAN, the knee must be flexed to 30° to 90° for insertion of the retrograde knee nail, and the alignment may be lost if the external fixation is not fully stable. Therefore, we hypothesized that FAN would be less accurate than FALP. Hence, the purposes of this study is to compare the correction achieved with FAN and FALP in patients with distal femoral valgus deformities and to describe the intraoperative complications associated with both techniques.

MATERIALS AND METHODS

After proper Institutional Review Board approval was obtained, a consecutive cohort of 35 patients who underwent femoral deformity correction with either FAN or FALP during an 8-year period (January 2002 to December 2010) was retrospectively reviewed. Eleven patients had to be excluded because of inadequate follow-up (<12 months) or because additional procedures were simultaneously performed. A total of 24 patients (27 femora) who had a mean age of 26 years (range, 14-68 years) were included in the final study cohort. Specifically, 20 femora (18 patients) were corrected using the FAN technique (7 males and 11 females; mean age, 36 years; range, 14-68 years), and 7 femora (6 patients) were fixed using the FALP technique (2 males and 4 females; mean age, 16 years; range, 15-19 years). The median follow-up in the FAN cohort was 5 years (range, 1-10 years), and the median follow-up in the FALP cohort was 5 years (range, 1-8 years) (Table 1).

Abbreviations: FALP, fixator assisted locked plating; FAN, fixator assisted nailing

The specific measurements performed in all patients were MAD, mechanical lateral distal femoral angle (mLDFA), and medial proximal tibia angle (MPTA). These were measured from standing anteroposterior radiographs of the knee that included the femur.²¹ All outcome data were collected from the medical charts, operative reports, and radiographic evaluations. To ensure accuracy, all measurements were performed by 2 authors blinded to each other’s measurements. If a variation of <5% was obtained, the results were averaged and used for further analysis. Whenever a difference of >5% was obtained, the measurement was repeated by both authors for confirmation.

SURGICAL FAN TECHNIQUE

After measuring the deformity (Figure 1A) with the patient under general anesthesia on a radiolucent table, the involved lower limb is prepared and draped. Two half-pins are inserted medially, 1 proximal and 1 distal to the planned osteotomy site (Figure 1B), and then connected loosely with a monolateral external fixator. Special care is taken while placing the half-pins, not to interfere with the insertion path of the IM rod. When performing the preoperative planning, the level of osteotomy is chosen to enable the placement of at least 2 interlocking screws distal to the osteotomy. Then, a percutaneous osteotomy is performed from a lateral approach, and the bone ends are manipulated (translation and then angulation) to achieve the desired deformity correction. The external fixator is then stabilized and locked in the exact position (Figure 1C). Subsequently, retrograde reaming, nail insertion, and placement of proximal and distal locking screws are performed (Figure 1D). Blocking screws may give additional stability. The removal of the external fixator is the final step (Figure 1E).²⁰

Continue to: When using the FAN technique...

SURGICAL FALP TECHNIQUE

Preoperatively, a decision concerning the planned osteotomy and the correct locking plate size is made. In addition, the outline of the plate is marked on the skin. Under general anesthesia, the patients are prepared and draped. A tourniquet is elevated around the upper thigh. Then, 2 half-pins are medially inserted, 1 proximal and 1 distal to the planned osteotomy site, and are then connected loosely with a monolateral external fixator (Figure 2A). A lateral approach to the distal femur is done, preserving the periosteum, except at the level of the osteotomy. After the osteotomy is performed (through an open lateral incision), both segments are translated (Figure 2B) and then the distal segment is angulated to achieve the desired deformity correction, and the desired position is then stabilized by tightening the external fixator connectors (Figure 2C). Subsequently, a locking plate is inserted in the submuscular-extraperiostal plane. The plate does not require being in full contact (flush) with the bone. At least 3 screws are placed on both sides of the osteotomy through a long lateral incision (Figure 2D). Bone graft may be added to the osteotomy site to encourage healing. Then, the external fixator is removed, and all incisions are closed (Figure 2E).^15,19 

During each of the procedures, we aimed at having “perfect alignment” with a MAD of 0 mm, in which a Bovie cord is used and passed through the center of the femoral head, knee, and ankle. However, to confirm that the surgery was successful, the actual measurements were performed on standing long-leg films. These films were obtained preoperatively and at latest follow-up. They were performed with the patella aiming forward, the toes straight ahead, feet separated enough for good balance, knees fully extended, and weight equally distributed on the feet. Postoperatively, in both cohorts, partial weight-bearing was encouraged immediately with crutches; physical therapy was instituted daily for knee range of motion. Radiographs were scheduled every 4 weeks to monitor callus formation. Full weight-bearing was allowed when at least 3 cortices were consolidated.^{1,15,19,20,25,26}

All statistical analyses were performed with the aid of the SPSS statistical software package (SPSS). Average values and standard error of the mean were assigned to each variable. A nonparametric Mann-Whitney U test was used, and a 2-tailed P < .05 was considered significant. Correlation of continuous variables was determined by Spearman’s correlation coefficient. Also, multivariate Cox regression analyses after adjustment for age, sex, and deformity correction were used to detect associations within the study population. To evaluate whether our data were normally distributed, Shapiro-Wilk tests were performed.

Continue to: Results...

RESULTS

The mLDFA significantly improved in the FAN cohort from a mean of 81° to a mean of 89° (ranges, 67°-86° and 80°-100°; respectively; P = .001) (Figures 3A, 3B). 

Abbreviations: FALP, fixator assisted locked plating; FAN, fixator assisted nailing; mLDFA, mechanical lateral distal femoral angle

After evaluating the MPTA, in the FAN cohort, we found that the mean pre- and postoperative MPTAs were not modified. These patients had a mean preoperative angle of 88° (range, 62°-100°), which was kept postoperatively to a mean of 88° (range, 78°-96°). In the FALP cohort, a slight change from 90° to 88° was observed (ranges, 82°-97° and 83°-94°, respectively). None of these changes in MPTA were significant (P > .05).

When evaluating correction of the MAD, we observed that the FAN cohort changed from a preoperative MAD of 32 mm (range, 6-64 mm) to a postoperative mean of 10 mm (range, 0-22 mm), and this correction was statistically significant. (P = .001). The FALP cohort changed from a mean of 34 mm (range, 17-62 mm) preoperatively to 4 mm (range, 0-11 mm) postoperatively, and this was also statistically significant (P = .002). The mean MAD correction for the FAN group vs FALP group was 27 mm vs 32 mm, respectively (Table 2).

In patients with valgus femoral deformity, the MAD is usually lateralized; however, in the FAN cohort, we included 3 patients with medial MADs (10 mm, 13 mm, and 40 mm). This is justified in these patients because a complex deformity of the distal femur and the proximal tibia was present. In the extreme case of a 40-mm medial MAD, the presurgery mLDFA was 76°, and the presurgery MPTA was 62°. The amount of deformity correction in this patient was 16°.

During the follow-up period, 2 complications occurred in the FAN group. One patient developed gait disturbance that resolved with physical therapy. Another had an infection at the osteotomy site. This was addressed with intravenous antibiotic therapy, surgical irrigation and débridement, hardware removal, and antegrade insertion of an antibiotic-coated nail. In the FALP group, 1 patient developed a persistent incomplete peroneal nerve palsy attributed to a 17° correction from valgus to varus, despite prophylactic peroneal nerve decompression. Nonetheless, the patient was satisfied with the result, recovered partial nerve function, and returned for correction of the contralateral leg deformity. When comparing the complications between both cohorts, no significant differences were found: 2 of 18 cases (11%) in the FAN group vs 1 of 6 cases (17%) in the FALP group (P = .78).

Continue to: The goal of this study...

DISCUSSION

The goal of this study was to compare the accuracy of deformity corrections achieved with either FAN or FALP. A number of authors have described results after deformity correction with several plating and nailing techniques; however, the information derived from comparing these 2 techniques is limited. We hypothesized that FALP would be more accurate, because less mobilization during fixation is required. However, we found no significant differences between these 2 techniques.

This study has several limitations. First, the small size of our cohort had to be further reduced owing to limited data; nevertheless, this pathology and the treatment methods used are not commonly performed, which make this cohort 1 of the largest of its type described in the literature. Also, the procedures were performed by multiple surgeons in a population with a wide age range, creating multiple additional variables that complicate the comparison of the sole differences between FAN and FALP. However, owing to these variables, the generalizability of this study may be increased, and similar outcomes can potentially be obtained by other institutions/surgeons. In addition, the variability of our follow-up period is another limitation; however, these patients were all assessed until bony union after skeletal maturity was achieved. Hence, the development of additional deformity is not expected. The lack of clinical outcome with a standardized questionnaire may also be seen as a limitation. However, because the purpose of our study was to assess both surgeries in terms of their ability to achieve angular correction, the addition of patient-reported outcomes may have increased the variability of our data.

The foremost objective in valgus deformity correction is to establish joint orientation angles within anatomic range to prevent overloading of the lateral joint and thereby prevent lateral compartmental osteoarthritis.^2,20,27-29 There are 2 categories of fixation: internal and external. With FAN and FALP, we strive to have the adjustability and accuracy of external fixation with the comfort (for the patient) of internal fixation. Accurate osteotomy correction requires an accurate preoperative analysis and osteotomy close to the apex of the deformity.^16,21,30-33 The most commonly used osteotomy techniques are drill-hole,³¹ focal dome,³⁴ rotation, and open- or closed-wedge osteotomies.^35,36 After the osteotomy, the resultant correction has to be stabilized. In recent years, the popularity of plates instead of an IM nail for internal fixation has been driven by the rapid development of low contact locking plates.^{16,19,26,30,37-40}

There are certain advantages of using FAN over FALP. In older patients who may require a subsequent total knee arthroplasty (TKA), the midline incision used for retrograde FAN technique is identical to that made for TKA. In contrast, in a younger and more active population, with a longer life expectancy, the extra-articular FALP approach has the advantage of not violating the knee joint. In addition, locking plates may achieve a more rigid fixation than IM nails; however, the stability of IM nails can be augmented with blocking screws.

Continue to: In 20 patients, including children...

In their comparative study, Seah and colleagues¹¹ described monolateral frame vs FALP deformity correction in a series of 34 extremities (26 patients) that required distal femoral osteotomy. No differences related to knee range of motion or the ability to correct the deformity between internal and external fixation were reported (P > .05). Similarly, Eidelman and colleagues¹ evaluated the outcomes of 6 patients (7 procedures) who underwent surgery performed with the FALP technique for distal femoral valgus deformity. They concluded that this technique is minimally invasive and can provide a precise deformity correction with minimal morbidity.

Other methods of fixation while performing FAN have been described by Jasiewicz and colleagues,²² who evaluated possible differences between the classic Ilizarov device and monolateral fixators in 19 femoral lengthening procedures. The authors concluded that there is no difference between concerning complication rate and treatment time. The use of FAN has also been described in patients with metabolic disease who required deformity correction. In this regard, Kocaoglu and colleagues¹² described the use of a monolateral external fixator in combination with an IM nail in a series of 17 patients with metabolic bone disease. The authors concluded that the use of the IM nail prevented recurrence of deformity and refracture.¹² Kocaoglu and colleagues¹⁴ also published a series of 25 patients treated with the FAN and LON (lengthening over a nail) technique for lengthening and deformity correction. The mean MAD improved from 33.9 mm to11.3 mm (range, 0-30 mm). In contrast, Erlap and colleagues¹³ compared FAN with circular external fixator for bone realignment of the lower extremity for deformities in patients with rickets. Although no significant difference was found between both groups, FAN was shown to be accurate and to provide great comfort to patients, and it also shortened the total treatment time.¹³ Finally, the advent of newer technologies could also provide alternatives for correcting valgus deformities. For example, Saragaglia and Chedal-Bornu⁶ performed 29 computer-assisted valgus knees osteotomies (27 patients) and reported that the goal hip-knee angle was achieved in 86% of patients and that the goal MPTA was achieved in 100% of patients.⁶

CONCLUSION

Both the FALP and FAN methods of femoral deformity correction are safe and effective surgical techniques. In our opinion, the advantages of the FALP technique result from the easy lateral surgical approach under medial external fixation and stabilization of the osteotomy without bending the knee. Ultimately, the decision to use FAN may be influenced by the surgeon’s perception of the potential need for future TKA. In such cases, a midline anterior approach with nailing is very compatible with subsequent TKA. The surgeon’s experience and preference, while keeping in mind the patient’s predilection, will play an important role in the decision-making process. Larger prospective clinical trials with larger cohorts have to be conducted to confirm our findings.

ABSTRACT

Fixator-assisted nailing (FAN) and fixator-assisted locked plating (FALP) are 2 techniques that can be used to correct distal femoral valgus deformities. The fixator aids in achieving an accurate adjustable initial reduction, which is then made permanent with either nail or plate insertion. FALP can be performed with the knee held in a neutral extended position, whereas FAN requires 30° to 90° of knee flexion to insert the nail, which may cause some alignment loss. We hypothesized that FAN may yield less accurate correction than FALP. Prospectively collected data of a consecutive cohort of patients who underwent valgus deformity femoral correction with FAN or FALP at a single institution over an 8-year period were retrospectively evaluated. Twenty extremities (18 patients) were treated using FAN (median follow-up, 5 years; range, 1-10 years), and 7 extremities (6 patients) were treated with FALP (median follow-up, 5 years; range, 1-8 years). In the FAN cohort, the mean preoperative and postoperative mechanical lateral distal femoral angles (mLDFAs) were 81° (range, 67°-86°) and 89° (range, 80°-100°), respectively (P = .009). In the FALP cohort, the mean preoperative and postoperative mLDFAs were 80° (range, 71°-87°) and 88° (range, 81°-94°), respectively (P < .001). Although the average mechanical axis deviation correction for the FALP group was greater than for the FAN group (32 mm and 27 mm, respectively), the difference was not significant (P = .66). Both methods of femoral deformity correction can be considered safe and effective. On the basis of our results, FAN and FALP are comparable in accuracy for deformity correction in the distal femur.

Multiple etiologies for distal femoral valgus deformity have been described in the literature.^1-3 These can be congenital, developmental, secondary to lateral compartmental arthritis, or posttraumatic.⁴ If not corrected, femoral deformities alter the axial alignment and orientation of the joints, and may lead to early degenerative joint disease and abnormal leg kinematics.^3,5 After correcting these deformities, the goal of treatment is to obtain anatomic distal femoral angles and neutral mechanical axis deviation (MAD), but without overcorrecting into varus. Numerous techniques to fix these deformities, such as progressive correction with external fixation or acute correction open reduction with internal fixation (ORIF), have been described.⁶ Modern external fixation allows for a gradual, adjustable, and more accurate correction but may produce discomfort and complications for patients.^7-10 In contrast, ORIF may be more tolerable for the patient, but to achieve a precise correction, considerable technical skills and expertise are required.^1,11-14

Two techniques used to correct these valgus femoral deformities in adults are fixator-assisted nailing (FAN) and fixator-assisted locked plating (FALP).¹ FAN and FALP combine the advantage of external fixation (accuracy, adjustability) with the benefits of internal fixation (patient comfort), because the osteotomy and correction are performed with the guidance of a temporary external fixator and then permanently fixated by an intramedullary (IM) nail or a locking plate.^{1,8,11-13,15-18} Both techniques have the possibility to correct varus and valgus deformities, but whenever correcting sagittal plane angulation, the FAN technique may be more challenging. The paucity of studies available involving FAN and FALP do not lead to a conclusive preference of one technique over the other relative to the accuracy and success of correction.^15,19,20

Continue to: In both FAN and FALP

In both FAN and FALP, the external fixator is applied and adjusted after the osteotomy for accurate alignment. In FALP, the plate is added without moving the leg from its straight position. However, in FAN, the knee must be flexed to 30° to 90° for insertion of the retrograde knee nail, and the alignment may be lost if the external fixation is not fully stable. Therefore, we hypothesized that FAN would be less accurate than FALP. Hence, the purposes of this study is to compare the correction achieved with FAN and FALP in patients with distal femoral valgus deformities and to describe the intraoperative complications associated with both techniques.

MATERIALS AND METHODS

After proper Institutional Review Board approval was obtained, a consecutive cohort of 35 patients who underwent femoral deformity correction with either FAN or FALP during an 8-year period (January 2002 to December 2010) was retrospectively reviewed. Eleven patients had to be excluded because of inadequate follow-up (<12 months) or because additional procedures were simultaneously performed. A total of 24 patients (27 femora) who had a mean age of 26 years (range, 14-68 years) were included in the final study cohort. Specifically, 20 femora (18 patients) were corrected using the FAN technique (7 males and 11 females; mean age, 36 years; range, 14-68 years), and 7 femora (6 patients) were fixed using the FALP technique (2 males and 4 females; mean age, 16 years; range, 15-19 years). The median follow-up in the FAN cohort was 5 years (range, 1-10 years), and the median follow-up in the FALP cohort was 5 years (range, 1-8 years) (Table 1).

Abbreviations: FALP, fixator assisted locked plating; FAN, fixator assisted nailing

The specific measurements performed in all patients were MAD, mechanical lateral distal femoral angle (mLDFA), and medial proximal tibia angle (MPTA). These were measured from standing anteroposterior radiographs of the knee that included the femur.²¹ All outcome data were collected from the medical charts, operative reports, and radiographic evaluations. To ensure accuracy, all measurements were performed by 2 authors blinded to each other’s measurements. If a variation of <5% was obtained, the results were averaged and used for further analysis. Whenever a difference of >5% was obtained, the measurement was repeated by both authors for confirmation.

SURGICAL FAN TECHNIQUE

After measuring the deformity (Figure 1A) with the patient under general anesthesia on a radiolucent table, the involved lower limb is prepared and draped. Two half-pins are inserted medially, 1 proximal and 1 distal to the planned osteotomy site (Figure 1B), and then connected loosely with a monolateral external fixator. Special care is taken while placing the half-pins, not to interfere with the insertion path of the IM rod. When performing the preoperative planning, the level of osteotomy is chosen to enable the placement of at least 2 interlocking screws distal to the osteotomy. Then, a percutaneous osteotomy is performed from a lateral approach, and the bone ends are manipulated (translation and then angulation) to achieve the desired deformity correction. The external fixator is then stabilized and locked in the exact position (Figure 1C). Subsequently, retrograde reaming, nail insertion, and placement of proximal and distal locking screws are performed (Figure 1D). Blocking screws may give additional stability. The removal of the external fixator is the final step (Figure 1E).²⁰

Continue to: When using the FAN technique...

SURGICAL FALP TECHNIQUE

Preoperatively, a decision concerning the planned osteotomy and the correct locking plate size is made. In addition, the outline of the plate is marked on the skin. Under general anesthesia, the patients are prepared and draped. A tourniquet is elevated around the upper thigh. Then, 2 half-pins are medially inserted, 1 proximal and 1 distal to the planned osteotomy site, and are then connected loosely with a monolateral external fixator (Figure 2A). A lateral approach to the distal femur is done, preserving the periosteum, except at the level of the osteotomy. After the osteotomy is performed (through an open lateral incision), both segments are translated (Figure 2B) and then the distal segment is angulated to achieve the desired deformity correction, and the desired position is then stabilized by tightening the external fixator connectors (Figure 2C). Subsequently, a locking plate is inserted in the submuscular-extraperiostal plane. The plate does not require being in full contact (flush) with the bone. At least 3 screws are placed on both sides of the osteotomy through a long lateral incision (Figure 2D). Bone graft may be added to the osteotomy site to encourage healing. Then, the external fixator is removed, and all incisions are closed (Figure 2E).^15,19 

During each of the procedures, we aimed at having “perfect alignment” with a MAD of 0 mm, in which a Bovie cord is used and passed through the center of the femoral head, knee, and ankle. However, to confirm that the surgery was successful, the actual measurements were performed on standing long-leg films. These films were obtained preoperatively and at latest follow-up. They were performed with the patella aiming forward, the toes straight ahead, feet separated enough for good balance, knees fully extended, and weight equally distributed on the feet. Postoperatively, in both cohorts, partial weight-bearing was encouraged immediately with crutches; physical therapy was instituted daily for knee range of motion. Radiographs were scheduled every 4 weeks to monitor callus formation. Full weight-bearing was allowed when at least 3 cortices were consolidated.^{1,15,19,20,25,26}

All statistical analyses were performed with the aid of the SPSS statistical software package (SPSS). Average values and standard error of the mean were assigned to each variable. A nonparametric Mann-Whitney U test was used, and a 2-tailed P < .05 was considered significant. Correlation of continuous variables was determined by Spearman’s correlation coefficient. Also, multivariate Cox regression analyses after adjustment for age, sex, and deformity correction were used to detect associations within the study population. To evaluate whether our data were normally distributed, Shapiro-Wilk tests were performed.

Continue to: Results...

RESULTS

The mLDFA significantly improved in the FAN cohort from a mean of 81° to a mean of 89° (ranges, 67°-86° and 80°-100°; respectively; P = .001) (Figures 3A, 3B). 

Abbreviations: FALP, fixator assisted locked plating; FAN, fixator assisted nailing; mLDFA, mechanical lateral distal femoral angle

After evaluating the MPTA, in the FAN cohort, we found that the mean pre- and postoperative MPTAs were not modified. These patients had a mean preoperative angle of 88° (range, 62°-100°), which was kept postoperatively to a mean of 88° (range, 78°-96°). In the FALP cohort, a slight change from 90° to 88° was observed (ranges, 82°-97° and 83°-94°, respectively). None of these changes in MPTA were significant (P > .05).

When evaluating correction of the MAD, we observed that the FAN cohort changed from a preoperative MAD of 32 mm (range, 6-64 mm) to a postoperative mean of 10 mm (range, 0-22 mm), and this correction was statistically significant. (P = .001). The FALP cohort changed from a mean of 34 mm (range, 17-62 mm) preoperatively to 4 mm (range, 0-11 mm) postoperatively, and this was also statistically significant (P = .002). The mean MAD correction for the FAN group vs FALP group was 27 mm vs 32 mm, respectively (Table 2).

In patients with valgus femoral deformity, the MAD is usually lateralized; however, in the FAN cohort, we included 3 patients with medial MADs (10 mm, 13 mm, and 40 mm). This is justified in these patients because a complex deformity of the distal femur and the proximal tibia was present. In the extreme case of a 40-mm medial MAD, the presurgery mLDFA was 76°, and the presurgery MPTA was 62°. The amount of deformity correction in this patient was 16°.

During the follow-up period, 2 complications occurred in the FAN group. One patient developed gait disturbance that resolved with physical therapy. Another had an infection at the osteotomy site. This was addressed with intravenous antibiotic therapy, surgical irrigation and débridement, hardware removal, and antegrade insertion of an antibiotic-coated nail. In the FALP group, 1 patient developed a persistent incomplete peroneal nerve palsy attributed to a 17° correction from valgus to varus, despite prophylactic peroneal nerve decompression. Nonetheless, the patient was satisfied with the result, recovered partial nerve function, and returned for correction of the contralateral leg deformity. When comparing the complications between both cohorts, no significant differences were found: 2 of 18 cases (11%) in the FAN group vs 1 of 6 cases (17%) in the FALP group (P = .78).

Continue to: The goal of this study...

DISCUSSION

The goal of this study was to compare the accuracy of deformity corrections achieved with either FAN or FALP. A number of authors have described results after deformity correction with several plating and nailing techniques; however, the information derived from comparing these 2 techniques is limited. We hypothesized that FALP would be more accurate, because less mobilization during fixation is required. However, we found no significant differences between these 2 techniques.

This study has several limitations. First, the small size of our cohort had to be further reduced owing to limited data; nevertheless, this pathology and the treatment methods used are not commonly performed, which make this cohort 1 of the largest of its type described in the literature. Also, the procedures were performed by multiple surgeons in a population with a wide age range, creating multiple additional variables that complicate the comparison of the sole differences between FAN and FALP. However, owing to these variables, the generalizability of this study may be increased, and similar outcomes can potentially be obtained by other institutions/surgeons. In addition, the variability of our follow-up period is another limitation; however, these patients were all assessed until bony union after skeletal maturity was achieved. Hence, the development of additional deformity is not expected. The lack of clinical outcome with a standardized questionnaire may also be seen as a limitation. However, because the purpose of our study was to assess both surgeries in terms of their ability to achieve angular correction, the addition of patient-reported outcomes may have increased the variability of our data.

The foremost objective in valgus deformity correction is to establish joint orientation angles within anatomic range to prevent overloading of the lateral joint and thereby prevent lateral compartmental osteoarthritis.^2,20,27-29 There are 2 categories of fixation: internal and external. With FAN and FALP, we strive to have the adjustability and accuracy of external fixation with the comfort (for the patient) of internal fixation. Accurate osteotomy correction requires an accurate preoperative analysis and osteotomy close to the apex of the deformity.^16,21,30-33 The most commonly used osteotomy techniques are drill-hole,³¹ focal dome,³⁴ rotation, and open- or closed-wedge osteotomies.^35,36 After the osteotomy, the resultant correction has to be stabilized. In recent years, the popularity of plates instead of an IM nail for internal fixation has been driven by the rapid development of low contact locking plates.^{16,19,26,30,37-40}

There are certain advantages of using FAN over FALP. In older patients who may require a subsequent total knee arthroplasty (TKA), the midline incision used for retrograde FAN technique is identical to that made for TKA. In contrast, in a younger and more active population, with a longer life expectancy, the extra-articular FALP approach has the advantage of not violating the knee joint. In addition, locking plates may achieve a more rigid fixation than IM nails; however, the stability of IM nails can be augmented with blocking screws.

Continue to: In 20 patients, including children...

In their comparative study, Seah and colleagues¹¹ described monolateral frame vs FALP deformity correction in a series of 34 extremities (26 patients) that required distal femoral osteotomy. No differences related to knee range of motion or the ability to correct the deformity between internal and external fixation were reported (P > .05). Similarly, Eidelman and colleagues¹ evaluated the outcomes of 6 patients (7 procedures) who underwent surgery performed with the FALP technique for distal femoral valgus deformity. They concluded that this technique is minimally invasive and can provide a precise deformity correction with minimal morbidity.

Other methods of fixation while performing FAN have been described by Jasiewicz and colleagues,²² who evaluated possible differences between the classic Ilizarov device and monolateral fixators in 19 femoral lengthening procedures. The authors concluded that there is no difference between concerning complication rate and treatment time. The use of FAN has also been described in patients with metabolic disease who required deformity correction. In this regard, Kocaoglu and colleagues¹² described the use of a monolateral external fixator in combination with an IM nail in a series of 17 patients with metabolic bone disease. The authors concluded that the use of the IM nail prevented recurrence of deformity and refracture.¹² Kocaoglu and colleagues¹⁴ also published a series of 25 patients treated with the FAN and LON (lengthening over a nail) technique for lengthening and deformity correction. The mean MAD improved from 33.9 mm to11.3 mm (range, 0-30 mm). In contrast, Erlap and colleagues¹³ compared FAN with circular external fixator for bone realignment of the lower extremity for deformities in patients with rickets. Although no significant difference was found between both groups, FAN was shown to be accurate and to provide great comfort to patients, and it also shortened the total treatment time.¹³ Finally, the advent of newer technologies could also provide alternatives for correcting valgus deformities. For example, Saragaglia and Chedal-Bornu⁶ performed 29 computer-assisted valgus knees osteotomies (27 patients) and reported that the goal hip-knee angle was achieved in 86% of patients and that the goal MPTA was achieved in 100% of patients.⁶

CONCLUSION

Both the FALP and FAN methods of femoral deformity correction are safe and effective surgical techniques. In our opinion, the advantages of the FALP technique result from the easy lateral surgical approach under medial external fixation and stabilization of the osteotomy without bending the knee. Ultimately, the decision to use FAN may be influenced by the surgeon’s perception of the potential need for future TKA. In such cases, a midline anterior approach with nailing is very compatible with subsequent TKA. The surgeon’s experience and preference, while keeping in mind the patient’s predilection, will play an important role in the decision-making process. Larger prospective clinical trials with larger cohorts have to be conducted to confirm our findings.

ABSTRACT

Fixator-assisted nailing (FAN) and fixator-assisted locked plating (FALP) are 2 techniques that can be used to correct distal femoral valgus deformities. The fixator aids in achieving an accurate adjustable initial reduction, which is then made permanent with either nail or plate insertion. FALP can be performed with the knee held in a neutral extended position, whereas FAN requires 30° to 90° of knee flexion to insert the nail, which may cause some alignment loss. We hypothesized that FAN may yield less accurate correction than FALP. Prospectively collected data of a consecutive cohort of patients who underwent valgus deformity femoral correction with FAN or FALP at a single institution over an 8-year period were retrospectively evaluated. Twenty extremities (18 patients) were treated using FAN (median follow-up, 5 years; range, 1-10 years), and 7 extremities (6 patients) were treated with FALP (median follow-up, 5 years; range, 1-8 years). In the FAN cohort, the mean preoperative and postoperative mechanical lateral distal femoral angles (mLDFAs) were 81° (range, 67°-86°) and 89° (range, 80°-100°), respectively (P = .009). In the FALP cohort, the mean preoperative and postoperative mLDFAs were 80° (range, 71°-87°) and 88° (range, 81°-94°), respectively (P < .001). Although the average mechanical axis deviation correction for the FALP group was greater than for the FAN group (32 mm and 27 mm, respectively), the difference was not significant (P = .66). Both methods of femoral deformity correction can be considered safe and effective. On the basis of our results, FAN and FALP are comparable in accuracy for deformity correction in the distal femur.

Multiple etiologies for distal femoral valgus deformity have been described in the literature.^1-3 These can be congenital, developmental, secondary to lateral compartmental arthritis, or posttraumatic.⁴ If not corrected, femoral deformities alter the axial alignment and orientation of the joints, and may lead to early degenerative joint disease and abnormal leg kinematics.^3,5 After correcting these deformities, the goal of treatment is to obtain anatomic distal femoral angles and neutral mechanical axis deviation (MAD), but without overcorrecting into varus. Numerous techniques to fix these deformities, such as progressive correction with external fixation or acute correction open reduction with internal fixation (ORIF), have been described.⁶ Modern external fixation allows for a gradual, adjustable, and more accurate correction but may produce discomfort and complications for patients.^7-10 In contrast, ORIF may be more tolerable for the patient, but to achieve a precise correction, considerable technical skills and expertise are required.^1,11-14

Two techniques used to correct these valgus femoral deformities in adults are fixator-assisted nailing (FAN) and fixator-assisted locked plating (FALP).¹ FAN and FALP combine the advantage of external fixation (accuracy, adjustability) with the benefits of internal fixation (patient comfort), because the osteotomy and correction are performed with the guidance of a temporary external fixator and then permanently fixated by an intramedullary (IM) nail or a locking plate.^{1,8,11-13,15-18} Both techniques have the possibility to correct varus and valgus deformities, but whenever correcting sagittal plane angulation, the FAN technique may be more challenging. The paucity of studies available involving FAN and FALP do not lead to a conclusive preference of one technique over the other relative to the accuracy and success of correction.^15,19,20

Continue to: In both FAN and FALP

In both FAN and FALP, the external fixator is applied and adjusted after the osteotomy for accurate alignment. In FALP, the plate is added without moving the leg from its straight position. However, in FAN, the knee must be flexed to 30° to 90° for insertion of the retrograde knee nail, and the alignment may be lost if the external fixation is not fully stable. Therefore, we hypothesized that FAN would be less accurate than FALP. Hence, the purposes of this study is to compare the correction achieved with FAN and FALP in patients with distal femoral valgus deformities and to describe the intraoperative complications associated with both techniques.

MATERIALS AND METHODS

After proper Institutional Review Board approval was obtained, a consecutive cohort of 35 patients who underwent femoral deformity correction with either FAN or FALP during an 8-year period (January 2002 to December 2010) was retrospectively reviewed. Eleven patients had to be excluded because of inadequate follow-up (<12 months) or because additional procedures were simultaneously performed. A total of 24 patients (27 femora) who had a mean age of 26 years (range, 14-68 years) were included in the final study cohort. Specifically, 20 femora (18 patients) were corrected using the FAN technique (7 males and 11 females; mean age, 36 years; range, 14-68 years), and 7 femora (6 patients) were fixed using the FALP technique (2 males and 4 females; mean age, 16 years; range, 15-19 years). The median follow-up in the FAN cohort was 5 years (range, 1-10 years), and the median follow-up in the FALP cohort was 5 years (range, 1-8 years) (Table 1).

Abbreviations: FALP, fixator assisted locked plating; FAN, fixator assisted nailing

The specific measurements performed in all patients were MAD, mechanical lateral distal femoral angle (mLDFA), and medial proximal tibia angle (MPTA). These were measured from standing anteroposterior radiographs of the knee that included the femur.²¹ All outcome data were collected from the medical charts, operative reports, and radiographic evaluations. To ensure accuracy, all measurements were performed by 2 authors blinded to each other’s measurements. If a variation of <5% was obtained, the results were averaged and used for further analysis. Whenever a difference of >5% was obtained, the measurement was repeated by both authors for confirmation.

SURGICAL FAN TECHNIQUE

After measuring the deformity (Figure 1A) with the patient under general anesthesia on a radiolucent table, the involved lower limb is prepared and draped. Two half-pins are inserted medially, 1 proximal and 1 distal to the planned osteotomy site (Figure 1B), and then connected loosely with a monolateral external fixator. Special care is taken while placing the half-pins, not to interfere with the insertion path of the IM rod. When performing the preoperative planning, the level of osteotomy is chosen to enable the placement of at least 2 interlocking screws distal to the osteotomy. Then, a percutaneous osteotomy is performed from a lateral approach, and the bone ends are manipulated (translation and then angulation) to achieve the desired deformity correction. The external fixator is then stabilized and locked in the exact position (Figure 1C). Subsequently, retrograde reaming, nail insertion, and placement of proximal and distal locking screws are performed (Figure 1D). Blocking screws may give additional stability. The removal of the external fixator is the final step (Figure 1E).²⁰

Continue to: When using the FAN technique...

SURGICAL FALP TECHNIQUE

Preoperatively, a decision concerning the planned osteotomy and the correct locking plate size is made. In addition, the outline of the plate is marked on the skin. Under general anesthesia, the patients are prepared and draped. A tourniquet is elevated around the upper thigh. Then, 2 half-pins are medially inserted, 1 proximal and 1 distal to the planned osteotomy site, and are then connected loosely with a monolateral external fixator (Figure 2A). A lateral approach to the distal femur is done, preserving the periosteum, except at the level of the osteotomy. After the osteotomy is performed (through an open lateral incision), both segments are translated (Figure 2B) and then the distal segment is angulated to achieve the desired deformity correction, and the desired position is then stabilized by tightening the external fixator connectors (Figure 2C). Subsequently, a locking plate is inserted in the submuscular-extraperiostal plane. The plate does not require being in full contact (flush) with the bone. At least 3 screws are placed on both sides of the osteotomy through a long lateral incision (Figure 2D). Bone graft may be added to the osteotomy site to encourage healing. Then, the external fixator is removed, and all incisions are closed (Figure 2E).^15,19 

During each of the procedures, we aimed at having “perfect alignment” with a MAD of 0 mm, in which a Bovie cord is used and passed through the center of the femoral head, knee, and ankle. However, to confirm that the surgery was successful, the actual measurements were performed on standing long-leg films. These films were obtained preoperatively and at latest follow-up. They were performed with the patella aiming forward, the toes straight ahead, feet separated enough for good balance, knees fully extended, and weight equally distributed on the feet. Postoperatively, in both cohorts, partial weight-bearing was encouraged immediately with crutches; physical therapy was instituted daily for knee range of motion. Radiographs were scheduled every 4 weeks to monitor callus formation. Full weight-bearing was allowed when at least 3 cortices were consolidated.^{1,15,19,20,25,26}

All statistical analyses were performed with the aid of the SPSS statistical software package (SPSS). Average values and standard error of the mean were assigned to each variable. A nonparametric Mann-Whitney U test was used, and a 2-tailed P < .05 was considered significant. Correlation of continuous variables was determined by Spearman’s correlation coefficient. Also, multivariate Cox regression analyses after adjustment for age, sex, and deformity correction were used to detect associations within the study population. To evaluate whether our data were normally distributed, Shapiro-Wilk tests were performed.

Continue to: Results...

RESULTS

The mLDFA significantly improved in the FAN cohort from a mean of 81° to a mean of 89° (ranges, 67°-86° and 80°-100°; respectively; P = .001) (Figures 3A, 3B). 

Abbreviations: FALP, fixator assisted locked plating; FAN, fixator assisted nailing; mLDFA, mechanical lateral distal femoral angle

After evaluating the MPTA, in the FAN cohort, we found that the mean pre- and postoperative MPTAs were not modified. These patients had a mean preoperative angle of 88° (range, 62°-100°), which was kept postoperatively to a mean of 88° (range, 78°-96°). In the FALP cohort, a slight change from 90° to 88° was observed (ranges, 82°-97° and 83°-94°, respectively). None of these changes in MPTA were significant (P > .05).

When evaluating correction of the MAD, we observed that the FAN cohort changed from a preoperative MAD of 32 mm (range, 6-64 mm) to a postoperative mean of 10 mm (range, 0-22 mm), and this correction was statistically significant. (P = .001). The FALP cohort changed from a mean of 34 mm (range, 17-62 mm) preoperatively to 4 mm (range, 0-11 mm) postoperatively, and this was also statistically significant (P = .002). The mean MAD correction for the FAN group vs FALP group was 27 mm vs 32 mm, respectively (Table 2).

In patients with valgus femoral deformity, the MAD is usually lateralized; however, in the FAN cohort, we included 3 patients with medial MADs (10 mm, 13 mm, and 40 mm). This is justified in these patients because a complex deformity of the distal femur and the proximal tibia was present. In the extreme case of a 40-mm medial MAD, the presurgery mLDFA was 76°, and the presurgery MPTA was 62°. The amount of deformity correction in this patient was 16°.

During the follow-up period, 2 complications occurred in the FAN group. One patient developed gait disturbance that resolved with physical therapy. Another had an infection at the osteotomy site. This was addressed with intravenous antibiotic therapy, surgical irrigation and débridement, hardware removal, and antegrade insertion of an antibiotic-coated nail. In the FALP group, 1 patient developed a persistent incomplete peroneal nerve palsy attributed to a 17° correction from valgus to varus, despite prophylactic peroneal nerve decompression. Nonetheless, the patient was satisfied with the result, recovered partial nerve function, and returned for correction of the contralateral leg deformity. When comparing the complications between both cohorts, no significant differences were found: 2 of 18 cases (11%) in the FAN group vs 1 of 6 cases (17%) in the FALP group (P = .78).

Continue to: The goal of this study...

DISCUSSION

The goal of this study was to compare the accuracy of deformity corrections achieved with either FAN or FALP. A number of authors have described results after deformity correction with several plating and nailing techniques; however, the information derived from comparing these 2 techniques is limited. We hypothesized that FALP would be more accurate, because less mobilization during fixation is required. However, we found no significant differences between these 2 techniques.

This study has several limitations. First, the small size of our cohort had to be further reduced owing to limited data; nevertheless, this pathology and the treatment methods used are not commonly performed, which make this cohort 1 of the largest of its type described in the literature. Also, the procedures were performed by multiple surgeons in a population with a wide age range, creating multiple additional variables that complicate the comparison of the sole differences between FAN and FALP. However, owing to these variables, the generalizability of this study may be increased, and similar outcomes can potentially be obtained by other institutions/surgeons. In addition, the variability of our follow-up period is another limitation; however, these patients were all assessed until bony union after skeletal maturity was achieved. Hence, the development of additional deformity is not expected. The lack of clinical outcome with a standardized questionnaire may also be seen as a limitation. However, because the purpose of our study was to assess both surgeries in terms of their ability to achieve angular correction, the addition of patient-reported outcomes may have increased the variability of our data.

The foremost objective in valgus deformity correction is to establish joint orientation angles within anatomic range to prevent overloading of the lateral joint and thereby prevent lateral compartmental osteoarthritis.^2,20,27-29 There are 2 categories of fixation: internal and external. With FAN and FALP, we strive to have the adjustability and accuracy of external fixation with the comfort (for the patient) of internal fixation. Accurate osteotomy correction requires an accurate preoperative analysis and osteotomy close to the apex of the deformity.^16,21,30-33 The most commonly used osteotomy techniques are drill-hole,³¹ focal dome,³⁴ rotation, and open- or closed-wedge osteotomies.^35,36 After the osteotomy, the resultant correction has to be stabilized. In recent years, the popularity of plates instead of an IM nail for internal fixation has been driven by the rapid development of low contact locking plates.^{16,19,26,30,37-40}

There are certain advantages of using FAN over FALP. In older patients who may require a subsequent total knee arthroplasty (TKA), the midline incision used for retrograde FAN technique is identical to that made for TKA. In contrast, in a younger and more active population, with a longer life expectancy, the extra-articular FALP approach has the advantage of not violating the knee joint. In addition, locking plates may achieve a more rigid fixation than IM nails; however, the stability of IM nails can be augmented with blocking screws.

Continue to: In 20 patients, including children...

In their comparative study, Seah and colleagues¹¹ described monolateral frame vs FALP deformity correction in a series of 34 extremities (26 patients) that required distal femoral osteotomy. No differences related to knee range of motion or the ability to correct the deformity between internal and external fixation were reported (P > .05). Similarly, Eidelman and colleagues¹ evaluated the outcomes of 6 patients (7 procedures) who underwent surgery performed with the FALP technique for distal femoral valgus deformity. They concluded that this technique is minimally invasive and can provide a precise deformity correction with minimal morbidity.

Other methods of fixation while performing FAN have been described by Jasiewicz and colleagues,²² who evaluated possible differences between the classic Ilizarov device and monolateral fixators in 19 femoral lengthening procedures. The authors concluded that there is no difference between concerning complication rate and treatment time. The use of FAN has also been described in patients with metabolic disease who required deformity correction. In this regard, Kocaoglu and colleagues¹² described the use of a monolateral external fixator in combination with an IM nail in a series of 17 patients with metabolic bone disease. The authors concluded that the use of the IM nail prevented recurrence of deformity and refracture.¹² Kocaoglu and colleagues¹⁴ also published a series of 25 patients treated with the FAN and LON (lengthening over a nail) technique for lengthening and deformity correction. The mean MAD improved from 33.9 mm to11.3 mm (range, 0-30 mm). In contrast, Erlap and colleagues¹³ compared FAN with circular external fixator for bone realignment of the lower extremity for deformities in patients with rickets. Although no significant difference was found between both groups, FAN was shown to be accurate and to provide great comfort to patients, and it also shortened the total treatment time.¹³ Finally, the advent of newer technologies could also provide alternatives for correcting valgus deformities. For example, Saragaglia and Chedal-Bornu⁶ performed 29 computer-assisted valgus knees osteotomies (27 patients) and reported that the goal hip-knee angle was achieved in 86% of patients and that the goal MPTA was achieved in 100% of patients.⁶

CONCLUSION

Both the FALP and FAN methods of femoral deformity correction are safe and effective surgical techniques. In our opinion, the advantages of the FALP technique result from the easy lateral surgical approach under medial external fixation and stabilization of the osteotomy without bending the knee. Ultimately, the decision to use FAN may be influenced by the surgeon’s perception of the potential need for future TKA. In such cases, a midline anterior approach with nailing is very compatible with subsequent TKA. The surgeon’s experience and preference, while keeping in mind the patient’s predilection, will play an important role in the decision-making process. Larger prospective clinical trials with larger cohorts have to be conducted to confirm our findings.

Most prescribers of buprenorphine view diversion or misappropriation of the drug as a concern, and most assess their patients for diversion, according to Lewei (Allison) Lin, MD, and her associates.

In a survey of 1,174 buprenorphine prescribers conducted from July 2014 to January 2017, 79% of the prescribers reported assessing all their patients for diversion of the drug, and 79.1% reported conducting urine tests for the presence of buprenorphine. In addition, 85% of prescribers viewed diversion as a problem in their community, and 80.3% of prescribers were willing to terminate treatment because of diversion, reported Dr. Lin of the department of psychiatry at the University of Michigan, Ann Arbor, and her associates in Drug and Alcohol Dependence.

Diversion was defined as “unauthorized rerouting or misappropriation of prescribed buprenorphine to someone other than the person for whom it was intended.”

Dr. Lin and her associates found that prescribers were more likely to assess all of their patients for diversion if they viewed diversion as a problem in their community, had fewer years of experience, or were white. Urine testing was more likely if prescribers viewed diversion as a problem in their community, had more patients, had less experience, had a 100-patient waiver, or were nonpsychiatrists. Treatment termination was more likely for prescribers who had a greater percentages of patients with medication counts, viewed diversion as a problem in their community, or practiced in nonaddiction/nonpsychiatric specialties.

“Although we did not include detailed questions about termination, the high proportion of prescribers who would terminate patients for diversion is important to note,” wrote Dr. Lin, also a research investigator at the VA Center for Clinical Management Research, Ann Arbor, and her associates. Addiction medicine specialists and psychiatrists were less likely to terminate patients because of concerns about diversion – which suggests that additional training in addiction might make clinicians more comfortable managing patients with high-risk behaviors, the investigators said.

They cited several limitations. For example, the survey’s cross-sectional design makes causal inferences difficult. In addition, when the survey was conducted, physicians were the only buprenorphine prescribers. It is therefore unclear whether the study results are generalizable to physician assistants or nurse practitioners, who now are able to prescribe buprenorphine after meeting certain requirements.

Still, the study uncovered new information about the steps that prescribers take to mitigate diversion. “Addressing diversion is a complex clinical dilemma and contextual factors, including availability of services, may need to be explored in the future alongside provider practices addressing diversion,” the investigators wrote.

[email protected]

SOURCE: LA Lin et al. Drug Alcohol Depend. 2018 May 1. doi: 10.1016/j.drugalcdep.2018.01.015.

Most prescribers of buprenorphine view diversion or misappropriation of the drug as a concern, and most assess their patients for diversion, according to Lewei (Allison) Lin, MD, and her associates.

In a survey of 1,174 buprenorphine prescribers conducted from July 2014 to January 2017, 79% of the prescribers reported assessing all their patients for diversion of the drug, and 79.1% reported conducting urine tests for the presence of buprenorphine. In addition, 85% of prescribers viewed diversion as a problem in their community, and 80.3% of prescribers were willing to terminate treatment because of diversion, reported Dr. Lin of the department of psychiatry at the University of Michigan, Ann Arbor, and her associates in Drug and Alcohol Dependence.

Diversion was defined as “unauthorized rerouting or misappropriation of prescribed buprenorphine to someone other than the person for whom it was intended.”

Dr. Lin and her associates found that prescribers were more likely to assess all of their patients for diversion if they viewed diversion as a problem in their community, had fewer years of experience, or were white. Urine testing was more likely if prescribers viewed diversion as a problem in their community, had more patients, had less experience, had a 100-patient waiver, or were nonpsychiatrists. Treatment termination was more likely for prescribers who had a greater percentages of patients with medication counts, viewed diversion as a problem in their community, or practiced in nonaddiction/nonpsychiatric specialties.

“Although we did not include detailed questions about termination, the high proportion of prescribers who would terminate patients for diversion is important to note,” wrote Dr. Lin, also a research investigator at the VA Center for Clinical Management Research, Ann Arbor, and her associates. Addiction medicine specialists and psychiatrists were less likely to terminate patients because of concerns about diversion – which suggests that additional training in addiction might make clinicians more comfortable managing patients with high-risk behaviors, the investigators said.

They cited several limitations. For example, the survey’s cross-sectional design makes causal inferences difficult. In addition, when the survey was conducted, physicians were the only buprenorphine prescribers. It is therefore unclear whether the study results are generalizable to physician assistants or nurse practitioners, who now are able to prescribe buprenorphine after meeting certain requirements.

Still, the study uncovered new information about the steps that prescribers take to mitigate diversion. “Addressing diversion is a complex clinical dilemma and contextual factors, including availability of services, may need to be explored in the future alongside provider practices addressing diversion,” the investigators wrote.

[email protected]

SOURCE: LA Lin et al. Drug Alcohol Depend. 2018 May 1. doi: 10.1016/j.drugalcdep.2018.01.015.

Most prescribers of buprenorphine view diversion or misappropriation of the drug as a concern, and most assess their patients for diversion, according to Lewei (Allison) Lin, MD, and her associates.

In a survey of 1,174 buprenorphine prescribers conducted from July 2014 to January 2017, 79% of the prescribers reported assessing all their patients for diversion of the drug, and 79.1% reported conducting urine tests for the presence of buprenorphine. In addition, 85% of prescribers viewed diversion as a problem in their community, and 80.3% of prescribers were willing to terminate treatment because of diversion, reported Dr. Lin of the department of psychiatry at the University of Michigan, Ann Arbor, and her associates in Drug and Alcohol Dependence.

Diversion was defined as “unauthorized rerouting or misappropriation of prescribed buprenorphine to someone other than the person for whom it was intended.”

Dr. Lin and her associates found that prescribers were more likely to assess all of their patients for diversion if they viewed diversion as a problem in their community, had fewer years of experience, or were white. Urine testing was more likely if prescribers viewed diversion as a problem in their community, had more patients, had less experience, had a 100-patient waiver, or were nonpsychiatrists. Treatment termination was more likely for prescribers who had a greater percentages of patients with medication counts, viewed diversion as a problem in their community, or practiced in nonaddiction/nonpsychiatric specialties.

“Although we did not include detailed questions about termination, the high proportion of prescribers who would terminate patients for diversion is important to note,” wrote Dr. Lin, also a research investigator at the VA Center for Clinical Management Research, Ann Arbor, and her associates. Addiction medicine specialists and psychiatrists were less likely to terminate patients because of concerns about diversion – which suggests that additional training in addiction might make clinicians more comfortable managing patients with high-risk behaviors, the investigators said.

They cited several limitations. For example, the survey’s cross-sectional design makes causal inferences difficult. In addition, when the survey was conducted, physicians were the only buprenorphine prescribers. It is therefore unclear whether the study results are generalizable to physician assistants or nurse practitioners, who now are able to prescribe buprenorphine after meeting certain requirements.

Still, the study uncovered new information about the steps that prescribers take to mitigate diversion. “Addressing diversion is a complex clinical dilemma and contextual factors, including availability of services, may need to be explored in the future alongside provider practices addressing diversion,” the investigators wrote.

[email protected]

SOURCE: LA Lin et al. Drug Alcohol Depend. 2018 May 1. doi: 10.1016/j.drugalcdep.2018.01.015.

To the Editor:

A 13-year-old white adolescent girl presented with asymptomatic discrete hyperpigmented papules on the chest, back, arms, and upper legs of 7 months’ duration. The patient otherwise was in good health; her weight and height were on the 40th percentile on growth curves and she had no history of any medications. Treatments for the skin condition prescribed by outside dermatologists included minocycline 75 mg twice daily for 2 months, lactic acid lotion 12% daily, and ketoconazole 400 mg administered twice 1 week apart.

Physical examination revealed more than 50 scattered hyperpigmented papules on the chest, back, arms, and upper legs ranging in size from 2 to 3.5 cm (Figure 1). Stroking of lesions failed to elicit Darier sign. A potassium hydroxide preparation and fungal culture were negative for pathogenic fungal organisms. The plasma insulin level was within reference range. A punch biopsy from the abdomen was obtained and sent for histopathologic examination. Histopathology showed mild hyperkeratosis, subtle papillomatosis, and interanastomosing acanthosis comprising squamoid cells with mild basilar hyperpigmentation (Figure 2). Sparse superficial perivascular lymphocytic infiltrate and increased pigmentation was seen in the basal layer. The dermis showed a few scattered dermal melanophages. A periodic acid–Schiff with diastase stain was negative. Giemsa and Leder stains highlighted a normal number and distribution of mast cells. Based on the histologic findings, the patient was diagnosed with idiopathic eruptive macular pigmentation (IEMP).

Idiopathic eruptive macular pigmentation is a rare condition that was described in 1978 by Degos et al.¹ Sanz de Galdeano et al² established the following diagnostic criteria: (1) eruption of brownish black, nonconfluent, asymptomatic macules involving the trunk, neck, and proximal arms and legs in children or adolescents; (2) absence of preceding inflammatory lesions; (3) no prior drug exposure; (4) basal cell layer hyperpigmentation of the epidermis and prominent dermal melanophages without visible basal layer damage or lichenoid inflammatory infiltrate; and (5) normal mast cell count.

Idiopathic eruptive macular pigmentation with papillomatosis (IEMPwP) is a variant of IEMP.³ It is undecided if IEMP and IEMPwP are variants of the same entity or distinct conditions. Until a clear etiology of these entities is established, we prefer to separate them on purely morphologic grounds. Marcoux et al⁴ labeled IEMPwP as a variant of acanthosis nigricans. Although morphologically the 2 conditions appear similar, our patient’s plasma insulin level essentially ruled out acanthosis nigricans.

Idiopathic eruptive macular pigmentation is a rare condition with the majority of cases reported in the Asian population with some reports in white, Hispanic, and black individuals.⁵ Idiopathic eruptive macular pigmentation with papillomatosis was reported by Joshi³ in 2007 in 9 Indian children with the classic findings of IEMP along with a velvety rash that correlated with papillomatosis. Diagnosis of IEMPwP is important, as the disease generally is self-limited and resolves over the course of a few weeks to a few years.

To the Editor:

A 13-year-old white adolescent girl presented with asymptomatic discrete hyperpigmented papules on the chest, back, arms, and upper legs of 7 months’ duration. The patient otherwise was in good health; her weight and height were on the 40th percentile on growth curves and she had no history of any medications. Treatments for the skin condition prescribed by outside dermatologists included minocycline 75 mg twice daily for 2 months, lactic acid lotion 12% daily, and ketoconazole 400 mg administered twice 1 week apart.

Physical examination revealed more than 50 scattered hyperpigmented papules on the chest, back, arms, and upper legs ranging in size from 2 to 3.5 cm (Figure 1). Stroking of lesions failed to elicit Darier sign. A potassium hydroxide preparation and fungal culture were negative for pathogenic fungal organisms. The plasma insulin level was within reference range. A punch biopsy from the abdomen was obtained and sent for histopathologic examination. Histopathology showed mild hyperkeratosis, subtle papillomatosis, and interanastomosing acanthosis comprising squamoid cells with mild basilar hyperpigmentation (Figure 2). Sparse superficial perivascular lymphocytic infiltrate and increased pigmentation was seen in the basal layer. The dermis showed a few scattered dermal melanophages. A periodic acid–Schiff with diastase stain was negative. Giemsa and Leder stains highlighted a normal number and distribution of mast cells. Based on the histologic findings, the patient was diagnosed with idiopathic eruptive macular pigmentation (IEMP).

Idiopathic eruptive macular pigmentation is a rare condition that was described in 1978 by Degos et al.¹ Sanz de Galdeano et al² established the following diagnostic criteria: (1) eruption of brownish black, nonconfluent, asymptomatic macules involving the trunk, neck, and proximal arms and legs in children or adolescents; (2) absence of preceding inflammatory lesions; (3) no prior drug exposure; (4) basal cell layer hyperpigmentation of the epidermis and prominent dermal melanophages without visible basal layer damage or lichenoid inflammatory infiltrate; and (5) normal mast cell count.

Idiopathic eruptive macular pigmentation with papillomatosis (IEMPwP) is a variant of IEMP.³ It is undecided if IEMP and IEMPwP are variants of the same entity or distinct conditions. Until a clear etiology of these entities is established, we prefer to separate them on purely morphologic grounds. Marcoux et al⁴ labeled IEMPwP as a variant of acanthosis nigricans. Although morphologically the 2 conditions appear similar, our patient’s plasma insulin level essentially ruled out acanthosis nigricans.

Idiopathic eruptive macular pigmentation is a rare condition with the majority of cases reported in the Asian population with some reports in white, Hispanic, and black individuals.⁵ Idiopathic eruptive macular pigmentation with papillomatosis was reported by Joshi³ in 2007 in 9 Indian children with the classic findings of IEMP along with a velvety rash that correlated with papillomatosis. Diagnosis of IEMPwP is important, as the disease generally is self-limited and resolves over the course of a few weeks to a few years.

To the Editor:

A 13-year-old white adolescent girl presented with asymptomatic discrete hyperpigmented papules on the chest, back, arms, and upper legs of 7 months’ duration. The patient otherwise was in good health; her weight and height were on the 40th percentile on growth curves and she had no history of any medications. Treatments for the skin condition prescribed by outside dermatologists included minocycline 75 mg twice daily for 2 months, lactic acid lotion 12% daily, and ketoconazole 400 mg administered twice 1 week apart.

Physical examination revealed more than 50 scattered hyperpigmented papules on the chest, back, arms, and upper legs ranging in size from 2 to 3.5 cm (Figure 1). Stroking of lesions failed to elicit Darier sign. A potassium hydroxide preparation and fungal culture were negative for pathogenic fungal organisms. The plasma insulin level was within reference range. A punch biopsy from the abdomen was obtained and sent for histopathologic examination. Histopathology showed mild hyperkeratosis, subtle papillomatosis, and interanastomosing acanthosis comprising squamoid cells with mild basilar hyperpigmentation (Figure 2). Sparse superficial perivascular lymphocytic infiltrate and increased pigmentation was seen in the basal layer. The dermis showed a few scattered dermal melanophages. A periodic acid–Schiff with diastase stain was negative. Giemsa and Leder stains highlighted a normal number and distribution of mast cells. Based on the histologic findings, the patient was diagnosed with idiopathic eruptive macular pigmentation (IEMP).

Idiopathic eruptive macular pigmentation is a rare condition that was described in 1978 by Degos et al.¹ Sanz de Galdeano et al² established the following diagnostic criteria: (1) eruption of brownish black, nonconfluent, asymptomatic macules involving the trunk, neck, and proximal arms and legs in children or adolescents; (2) absence of preceding inflammatory lesions; (3) no prior drug exposure; (4) basal cell layer hyperpigmentation of the epidermis and prominent dermal melanophages without visible basal layer damage or lichenoid inflammatory infiltrate; and (5) normal mast cell count.

Idiopathic eruptive macular pigmentation with papillomatosis (IEMPwP) is a variant of IEMP.³ It is undecided if IEMP and IEMPwP are variants of the same entity or distinct conditions. Until a clear etiology of these entities is established, we prefer to separate them on purely morphologic grounds. Marcoux et al⁴ labeled IEMPwP as a variant of acanthosis nigricans. Although morphologically the 2 conditions appear similar, our patient’s plasma insulin level essentially ruled out acanthosis nigricans.

Idiopathic eruptive macular pigmentation is a rare condition with the majority of cases reported in the Asian population with some reports in white, Hispanic, and black individuals.⁵ Idiopathic eruptive macular pigmentation with papillomatosis was reported by Joshi³ in 2007 in 9 Indian children with the classic findings of IEMP along with a velvety rash that correlated with papillomatosis. Diagnosis of IEMPwP is important, as the disease generally is self-limited and resolves over the course of a few weeks to a few years.

BOSTON – The direct acting oral anticoagulants boost patient adherence compared with warfarin anticoagulation, but when patients did not adhere to their regimens, those prescribed a new, direct-acting oral anticoagulant had worse outcomes than did patients on warfarin – even patients poorly adherent with warfarin – based on data from more than 80,000 U.S. patients.

Among low-adherence patients, defined as those with adherence rates of 40%-80% based on prescriptions filled, patients with nonvalvular atrial fibrillation and a CHA₂DS₂-VASc score of at least 2 and treated with warfarin had a 3.37/100 patient-years rate of thromboembolic events–driven hospitalizations or emergency department visits, compared with a 4.05/100 patient-years rate among low-adherence patients receiving a direct-acting oral anticoagulant (DOAC), Dhanunjaya Lakkireddy, MD, said at the annual scientific sessions of the Heart Rhythm Society. The incidence of strokes of any kind was also lower in the low-adherence warfarin patients compared with the low-adherence DOAC patients, although the relationship flipped for hemorrhagic strokes and bleeds, which were more common in the warfarin patients.

In contrast, when patients were adherent, taking more than 80% of their prescribed drug, the performance of the DOACs generally surpassed that of warfarin. In an analysis adjusted for several demographic and clinical confounders, and when compared with patients adherent to a warfarin regimen, those adherent to a DOAC had a 7% lower rate of thromboembolic events, a 36% lower rate of hemorrhagic strokes, an 8% lower rate of any stroke, and a 10% lower rate of bleeds (excluding hemorrhagic strokes), all statistically significant differences, reported Dr. Lakkireddy, medical director of the Kansas City Heart Rhythm Institute in Overland Park, Kan.

The message from this analysis is the importance of maximizing patient adherence, Dr. Lakkireddy said.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

[email protected]

SOURCE: Lakkireddy D et al. Heart Rhythm 2018, Abstract B-LBCT02-03.

BOSTON – The direct acting oral anticoagulants boost patient adherence compared with warfarin anticoagulation, but when patients did not adhere to their regimens, those prescribed a new, direct-acting oral anticoagulant had worse outcomes than did patients on warfarin – even patients poorly adherent with warfarin – based on data from more than 80,000 U.S. patients.

Among low-adherence patients, defined as those with adherence rates of 40%-80% based on prescriptions filled, patients with nonvalvular atrial fibrillation and a CHA₂DS₂-VASc score of at least 2 and treated with warfarin had a 3.37/100 patient-years rate of thromboembolic events–driven hospitalizations or emergency department visits, compared with a 4.05/100 patient-years rate among low-adherence patients receiving a direct-acting oral anticoagulant (DOAC), Dhanunjaya Lakkireddy, MD, said at the annual scientific sessions of the Heart Rhythm Society. The incidence of strokes of any kind was also lower in the low-adherence warfarin patients compared with the low-adherence DOAC patients, although the relationship flipped for hemorrhagic strokes and bleeds, which were more common in the warfarin patients.

In contrast, when patients were adherent, taking more than 80% of their prescribed drug, the performance of the DOACs generally surpassed that of warfarin. In an analysis adjusted for several demographic and clinical confounders, and when compared with patients adherent to a warfarin regimen, those adherent to a DOAC had a 7% lower rate of thromboembolic events, a 36% lower rate of hemorrhagic strokes, an 8% lower rate of any stroke, and a 10% lower rate of bleeds (excluding hemorrhagic strokes), all statistically significant differences, reported Dr. Lakkireddy, medical director of the Kansas City Heart Rhythm Institute in Overland Park, Kan.

The message from this analysis is the importance of maximizing patient adherence, Dr. Lakkireddy said.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

[email protected]

SOURCE: Lakkireddy D et al. Heart Rhythm 2018, Abstract B-LBCT02-03.

BOSTON – The direct acting oral anticoagulants boost patient adherence compared with warfarin anticoagulation, but when patients did not adhere to their regimens, those prescribed a new, direct-acting oral anticoagulant had worse outcomes than did patients on warfarin – even patients poorly adherent with warfarin – based on data from more than 80,000 U.S. patients.

Among low-adherence patients, defined as those with adherence rates of 40%-80% based on prescriptions filled, patients with nonvalvular atrial fibrillation and a CHA₂DS₂-VASc score of at least 2 and treated with warfarin had a 3.37/100 patient-years rate of thromboembolic events–driven hospitalizations or emergency department visits, compared with a 4.05/100 patient-years rate among low-adherence patients receiving a direct-acting oral anticoagulant (DOAC), Dhanunjaya Lakkireddy, MD, said at the annual scientific sessions of the Heart Rhythm Society. The incidence of strokes of any kind was also lower in the low-adherence warfarin patients compared with the low-adherence DOAC patients, although the relationship flipped for hemorrhagic strokes and bleeds, which were more common in the warfarin patients.

In contrast, when patients were adherent, taking more than 80% of their prescribed drug, the performance of the DOACs generally surpassed that of warfarin. In an analysis adjusted for several demographic and clinical confounders, and when compared with patients adherent to a warfarin regimen, those adherent to a DOAC had a 7% lower rate of thromboembolic events, a 36% lower rate of hemorrhagic strokes, an 8% lower rate of any stroke, and a 10% lower rate of bleeds (excluding hemorrhagic strokes), all statistically significant differences, reported Dr. Lakkireddy, medical director of the Kansas City Heart Rhythm Institute in Overland Park, Kan.

The message from this analysis is the importance of maximizing patient adherence, Dr. Lakkireddy said.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

[email protected]

SOURCE: Lakkireddy D et al. Heart Rhythm 2018, Abstract B-LBCT02-03.