User login
Intermittent fasting tied to positive physiological effects
PHILADELPHIA – Intermittent fasting may help improve weight status and metabolic health, but it is very challenging to adhere to and is possibly associated with certain risks, a physician with expertise in obesity and nutrition said during a presentation.
“I do not necessarily recommend intermittent fasting to my patients, but I do have a lot of patients that will come to me asking about intermittent fasting,” said Fatima Cody Stanford, MD, MPH, of Massachusetts General Hospital Weight Center and Harvard Medical School, both in Boston, at the annual meeting of the American College of Physicians.
Intermittent fasting, which can take several forms including partial-day fasting, every-other-day fasting, or fasting two days per week, has been associated with positive physiological effects in an increasing number of recent studies, Dr. Stanford said.
Those physiological effects, reported in animals or humans, have included a potentially increased lifespan, decreased mortality related to cancers or cardiovascular disease, an improved insulin sensitivity, and reduced oxidative stress and inflammation, she said.
Additionally, weight loss and improvement in other health indicators, including insulin resistance, have been demonstrated in some studies of intermittent fasting that included normal weight or overweight human subjects.
In one systematic review and meta-analysis, intermittent fasting was found to be comparable with continuous energy restriction in overweight and obese adults for short-term weight loss.
Compared with no treatment, intermittent energy restriction was associated with a 4.14-kg drop in weight (95% confidence interval, 6.30-1.99; P less than or equal to 0.001), according to that meta-analysis.
In patients with type 2 diabetes, 12 months of intermittent energy restriction resulted in glycemic control comparable with continuous energy restriction, according to results of a randomized, 137-patient, noninferiority trial.
On the flip side, intermittent fasting has been associated with possible health risks, including having “a deleterious impact on fertility” and “a negative impact on bone health,” according to Dr. Stanford.
“These are things that I bring up with my patients,” she told her audience.
Lean mass may also be in jeopardy in intermittent fasters, according to authors of one systematic review and meta-analysis of randomized controlled trials published in the International Journal of Obesity.
Those investigators found that lean mass was decreased in intermittent dieters as compared with continuous dieters in the 9 trials they included. The mean difference was –0.86 kg (95% CI, –1.62 to –0.10; P = 0.03).
Even if intermittent fasting is comparable with continuous energy restriction in weight loss, getting to that point may be more difficult because of increased hunger, at least according to researchers in one randomized 1-year trial, Dr. Sanford noted.
Subjective hunger scores were higher at 4.7 for intermittent fasters versus 3.6 for continuous restriction participants (P = 0.002), results of that trial showed.
“It’s very difficult for most of us to sustain this,” Dr. Stanford said.
Dr. Stanford reported no relevant disclosures.
PHILADELPHIA – Intermittent fasting may help improve weight status and metabolic health, but it is very challenging to adhere to and is possibly associated with certain risks, a physician with expertise in obesity and nutrition said during a presentation.
“I do not necessarily recommend intermittent fasting to my patients, but I do have a lot of patients that will come to me asking about intermittent fasting,” said Fatima Cody Stanford, MD, MPH, of Massachusetts General Hospital Weight Center and Harvard Medical School, both in Boston, at the annual meeting of the American College of Physicians.
Intermittent fasting, which can take several forms including partial-day fasting, every-other-day fasting, or fasting two days per week, has been associated with positive physiological effects in an increasing number of recent studies, Dr. Stanford said.
Those physiological effects, reported in animals or humans, have included a potentially increased lifespan, decreased mortality related to cancers or cardiovascular disease, an improved insulin sensitivity, and reduced oxidative stress and inflammation, she said.
Additionally, weight loss and improvement in other health indicators, including insulin resistance, have been demonstrated in some studies of intermittent fasting that included normal weight or overweight human subjects.
In one systematic review and meta-analysis, intermittent fasting was found to be comparable with continuous energy restriction in overweight and obese adults for short-term weight loss.
Compared with no treatment, intermittent energy restriction was associated with a 4.14-kg drop in weight (95% confidence interval, 6.30-1.99; P less than or equal to 0.001), according to that meta-analysis.
In patients with type 2 diabetes, 12 months of intermittent energy restriction resulted in glycemic control comparable with continuous energy restriction, according to results of a randomized, 137-patient, noninferiority trial.
On the flip side, intermittent fasting has been associated with possible health risks, including having “a deleterious impact on fertility” and “a negative impact on bone health,” according to Dr. Stanford.
“These are things that I bring up with my patients,” she told her audience.
Lean mass may also be in jeopardy in intermittent fasters, according to authors of one systematic review and meta-analysis of randomized controlled trials published in the International Journal of Obesity.
Those investigators found that lean mass was decreased in intermittent dieters as compared with continuous dieters in the 9 trials they included. The mean difference was –0.86 kg (95% CI, –1.62 to –0.10; P = 0.03).
Even if intermittent fasting is comparable with continuous energy restriction in weight loss, getting to that point may be more difficult because of increased hunger, at least according to researchers in one randomized 1-year trial, Dr. Sanford noted.
Subjective hunger scores were higher at 4.7 for intermittent fasters versus 3.6 for continuous restriction participants (P = 0.002), results of that trial showed.
“It’s very difficult for most of us to sustain this,” Dr. Stanford said.
Dr. Stanford reported no relevant disclosures.
PHILADELPHIA – Intermittent fasting may help improve weight status and metabolic health, but it is very challenging to adhere to and is possibly associated with certain risks, a physician with expertise in obesity and nutrition said during a presentation.
“I do not necessarily recommend intermittent fasting to my patients, but I do have a lot of patients that will come to me asking about intermittent fasting,” said Fatima Cody Stanford, MD, MPH, of Massachusetts General Hospital Weight Center and Harvard Medical School, both in Boston, at the annual meeting of the American College of Physicians.
Intermittent fasting, which can take several forms including partial-day fasting, every-other-day fasting, or fasting two days per week, has been associated with positive physiological effects in an increasing number of recent studies, Dr. Stanford said.
Those physiological effects, reported in animals or humans, have included a potentially increased lifespan, decreased mortality related to cancers or cardiovascular disease, an improved insulin sensitivity, and reduced oxidative stress and inflammation, she said.
Additionally, weight loss and improvement in other health indicators, including insulin resistance, have been demonstrated in some studies of intermittent fasting that included normal weight or overweight human subjects.
In one systematic review and meta-analysis, intermittent fasting was found to be comparable with continuous energy restriction in overweight and obese adults for short-term weight loss.
Compared with no treatment, intermittent energy restriction was associated with a 4.14-kg drop in weight (95% confidence interval, 6.30-1.99; P less than or equal to 0.001), according to that meta-analysis.
In patients with type 2 diabetes, 12 months of intermittent energy restriction resulted in glycemic control comparable with continuous energy restriction, according to results of a randomized, 137-patient, noninferiority trial.
On the flip side, intermittent fasting has been associated with possible health risks, including having “a deleterious impact on fertility” and “a negative impact on bone health,” according to Dr. Stanford.
“These are things that I bring up with my patients,” she told her audience.
Lean mass may also be in jeopardy in intermittent fasters, according to authors of one systematic review and meta-analysis of randomized controlled trials published in the International Journal of Obesity.
Those investigators found that lean mass was decreased in intermittent dieters as compared with continuous dieters in the 9 trials they included. The mean difference was –0.86 kg (95% CI, –1.62 to –0.10; P = 0.03).
Even if intermittent fasting is comparable with continuous energy restriction in weight loss, getting to that point may be more difficult because of increased hunger, at least according to researchers in one randomized 1-year trial, Dr. Sanford noted.
Subjective hunger scores were higher at 4.7 for intermittent fasters versus 3.6 for continuous restriction participants (P = 0.002), results of that trial showed.
“It’s very difficult for most of us to sustain this,” Dr. Stanford said.
Dr. Stanford reported no relevant disclosures.
EXPERT ANALYSIS FROM INTERNAL MEDICINE 2019
Teen e-cigarette use: A public health crisis
After 2 decades of steady decline in adolescent and young adult use of tobacco products, e-cigarettes have dramatically altered the landscape of substance use in youth. E-cigarette use among teens has been on the rise for years but the recent exponential increase is unprecedented. From 2017 to 2018, adolescent e-cigarette use had the largest year-to-year increase (78%, from 12% to 21%) of any individual substance or class of substances at any time during the past 2 decades of nationwide monitoring.1 This has appropriately caught the nation’s attention. In 2016, Surgeon General Vivek H. Murthy, MD, commissioned an extensive report about electronic cigarettes, and in 2018 Surgeon General Jerome Adams, MD, MPH, issued an advisory declaring e-cigarettes a public health crisis for adolescents.2
E-cigarettes have received attention as a possible boon to adult cigarette smokers seeking a less hazardous product. We can consider the use of tobacco products along a continuum from smoked tobacco, dual use (both smoked tobacco and electronic nicotine delivery), electronic nicotine delivery only, and finally, nonuse. For some adults, transitioning from smoked tobacco products to electronic delivery systems has been a step toward less overall harm from substance use, with a small minority of that population going on to achieve abstinence from all nicotine products.3 For youth and teens, the story has been the opposite. With the rapid rise of e-cigarettes, adolescents overwhelmingly have been moving in the wrong direction at each potential step along this continuum.4 Less than 8% of teens who use e-cigarettes indicated that smoking cessation is a factor in their use.5 An estimated 1.3 million U.S. teens now are dependent or at high risk for dependence upon nicotine because of e-cigarette use. Furthermore, these teens are at a fourfold higher risk of progression to cigarette use, compared with their peers.6
One product in particular gives us information as to why this trend has accelerated so rapidly. Juul, now the sales leader among electronic nicotine delivery systems, rose from approximately 25% to a dominant 75% of market share in just over 1 fiscal year after a social media campaign targeted toward youth and young adults. The device is shaped like an elongated flash drive, is marketed as “sleek,” “looking cool,” and being “super easy” to use. This product touts its use of nicotine salts that can deliver higher concentrations of nicotine more rapidly to mimic the experience of smoking a cigarette as closely as possible. The fruity flavors in Juul “pods” and many other devices also appeal to teens. Many youth are left misinformed, thinking they are using a relatively harmless alternative to cigarettes.
E-cigarette use in youth carries many risks. Among the physical risks is exposure to harmful chemicals (even if less numerous than smoked tobacco products) such as diacetyl (a known cause of bronchiolitis obliterans, or “popcorn lung”), formaldehyde, acrolein, benzene, and metals such as nickel, tin and lead.7 “Safer than cigarettes” is a low bar indeed. Cognitive and emotional risks of early nicotine exposure include poor focus and attention, permanent lowering of impulse control, and a higher risk of mood and anxiety disorders.
Furthermore, nicotine is a gateway drug, with a clearly understood molecular basis for how it can potentiate the effects of later used substances, especially stimulants such as cocaine.8 The gateway and priming effect is compounded for youth because of ongoing brain development and plasticity during teen years. E-cigarette use also is associated with other risk behaviors including a manyfold higher likelihood of binge drinking, having multiple sexual partners in a short period of time, and using other substances such as cannabis, cocaine, methamphetamine, and heroin or nonprescribed opioids.9 An electronic system for vaporization also presents a risk for use of other substances. In just 1 year from 2017 to 2018, marijuana “vaping” increased by more than 50% among all ages surveyed.10
Pediatric health care providers are essential educators for both teens and parents regarding the risks of e-cigarette use. Many youth don’t know what they’re using; 66% of youth reported that the vapors they were inhaling contained only flavoring. Only 13% reported they were inhaling nicotine.10 In stark contrast to these self-reports, all Juul “pods” contain nicotine. As has been a pattern with nationwide surveys of substance use for decades, adolescent use is inversely correlated with perception of risk; 70% of 8th-12th graders do not foresee great harm in regular e-cigarette use. In addition, adolescents use substances less often when they know their parents disapprove. Parents also must be taught about the risks of e-cigarette use and can be provided with resources and taught effective strategies if they have difficulty communicating their disapproval to their children.
Age-appropriate screening in primary care settings must include specific language regarding the use of electronic cigarettes, with questions about “vaping” and “juuling.” Discussions with teens may be more effective with emphasis on issues that resonate with youth such as the financial cost, loss of freedom when dependence develops, and the fact that their generation is once again being targeted by the tobacco industry. Referral for further treatment, including individual and group therapy as well as family-focused interventions, should be considered for teens who use daily, use other substances regularly, or could benefit from treatment for co-occurring mental health disorders.
Electronic cigarette use should not be recommended as a smoking cessation strategy for teens.11 Pediatric health care providers must advocate for regulation of these products, including increasing the legal age of purchase and banning flavoring in e-cigarettes products, Internet sales, and advertisements targeted to youth.
The rapid rise in e-cigarette use among teens is of great concern. As with all classes of substances, early initiation of nicotine drastically increases the risk of developing a substance use disorder and portends a prolonged course and greater accumulation of adverse consequences. There is an urgent need for education, prevention, and early identification of e-cigarette use to protect the current and future well-being of children and adolescents.
Dr. Jackson is assistant professor of psychiatry at the University of Vermont, Burlington. He said he had no relevant financial disclosures. Email Dr. Jackson at [email protected].
References
1. MMWR Morb Mortal Wkly Rep. 2018;67:1276-7.
2. e-cigarettes.surgeongeneral.gov
3. N Engl J Med 2019;380:629-37.
4. Pediatrics. 2018 Dec; 142(6):e20180486.
5. MMWR Morb Mortal Wkly Rep 2018;67:196-200.
6. JAMA Pediatr. 2017 Aug 1;171(8):788-97.
7. “Public health consequences of e-cigarettes” (Washington, DC: National Academies Press, January 2018).
8. N Engl J Med 2014;371:932-43.
9. N Engl J Med 2019;380:689-90.
10. MMWR Morb Mortal Wkly Rep. 2016 Jan 8;64(52):1403-8.
11. Pediatrics. 2019 Feb;143(2). pii: e20183652.
After 2 decades of steady decline in adolescent and young adult use of tobacco products, e-cigarettes have dramatically altered the landscape of substance use in youth. E-cigarette use among teens has been on the rise for years but the recent exponential increase is unprecedented. From 2017 to 2018, adolescent e-cigarette use had the largest year-to-year increase (78%, from 12% to 21%) of any individual substance or class of substances at any time during the past 2 decades of nationwide monitoring.1 This has appropriately caught the nation’s attention. In 2016, Surgeon General Vivek H. Murthy, MD, commissioned an extensive report about electronic cigarettes, and in 2018 Surgeon General Jerome Adams, MD, MPH, issued an advisory declaring e-cigarettes a public health crisis for adolescents.2
E-cigarettes have received attention as a possible boon to adult cigarette smokers seeking a less hazardous product. We can consider the use of tobacco products along a continuum from smoked tobacco, dual use (both smoked tobacco and electronic nicotine delivery), electronic nicotine delivery only, and finally, nonuse. For some adults, transitioning from smoked tobacco products to electronic delivery systems has been a step toward less overall harm from substance use, with a small minority of that population going on to achieve abstinence from all nicotine products.3 For youth and teens, the story has been the opposite. With the rapid rise of e-cigarettes, adolescents overwhelmingly have been moving in the wrong direction at each potential step along this continuum.4 Less than 8% of teens who use e-cigarettes indicated that smoking cessation is a factor in their use.5 An estimated 1.3 million U.S. teens now are dependent or at high risk for dependence upon nicotine because of e-cigarette use. Furthermore, these teens are at a fourfold higher risk of progression to cigarette use, compared with their peers.6
One product in particular gives us information as to why this trend has accelerated so rapidly. Juul, now the sales leader among electronic nicotine delivery systems, rose from approximately 25% to a dominant 75% of market share in just over 1 fiscal year after a social media campaign targeted toward youth and young adults. The device is shaped like an elongated flash drive, is marketed as “sleek,” “looking cool,” and being “super easy” to use. This product touts its use of nicotine salts that can deliver higher concentrations of nicotine more rapidly to mimic the experience of smoking a cigarette as closely as possible. The fruity flavors in Juul “pods” and many other devices also appeal to teens. Many youth are left misinformed, thinking they are using a relatively harmless alternative to cigarettes.
E-cigarette use in youth carries many risks. Among the physical risks is exposure to harmful chemicals (even if less numerous than smoked tobacco products) such as diacetyl (a known cause of bronchiolitis obliterans, or “popcorn lung”), formaldehyde, acrolein, benzene, and metals such as nickel, tin and lead.7 “Safer than cigarettes” is a low bar indeed. Cognitive and emotional risks of early nicotine exposure include poor focus and attention, permanent lowering of impulse control, and a higher risk of mood and anxiety disorders.
Furthermore, nicotine is a gateway drug, with a clearly understood molecular basis for how it can potentiate the effects of later used substances, especially stimulants such as cocaine.8 The gateway and priming effect is compounded for youth because of ongoing brain development and plasticity during teen years. E-cigarette use also is associated with other risk behaviors including a manyfold higher likelihood of binge drinking, having multiple sexual partners in a short period of time, and using other substances such as cannabis, cocaine, methamphetamine, and heroin or nonprescribed opioids.9 An electronic system for vaporization also presents a risk for use of other substances. In just 1 year from 2017 to 2018, marijuana “vaping” increased by more than 50% among all ages surveyed.10
Pediatric health care providers are essential educators for both teens and parents regarding the risks of e-cigarette use. Many youth don’t know what they’re using; 66% of youth reported that the vapors they were inhaling contained only flavoring. Only 13% reported they were inhaling nicotine.10 In stark contrast to these self-reports, all Juul “pods” contain nicotine. As has been a pattern with nationwide surveys of substance use for decades, adolescent use is inversely correlated with perception of risk; 70% of 8th-12th graders do not foresee great harm in regular e-cigarette use. In addition, adolescents use substances less often when they know their parents disapprove. Parents also must be taught about the risks of e-cigarette use and can be provided with resources and taught effective strategies if they have difficulty communicating their disapproval to their children.
Age-appropriate screening in primary care settings must include specific language regarding the use of electronic cigarettes, with questions about “vaping” and “juuling.” Discussions with teens may be more effective with emphasis on issues that resonate with youth such as the financial cost, loss of freedom when dependence develops, and the fact that their generation is once again being targeted by the tobacco industry. Referral for further treatment, including individual and group therapy as well as family-focused interventions, should be considered for teens who use daily, use other substances regularly, or could benefit from treatment for co-occurring mental health disorders.
Electronic cigarette use should not be recommended as a smoking cessation strategy for teens.11 Pediatric health care providers must advocate for regulation of these products, including increasing the legal age of purchase and banning flavoring in e-cigarettes products, Internet sales, and advertisements targeted to youth.
The rapid rise in e-cigarette use among teens is of great concern. As with all classes of substances, early initiation of nicotine drastically increases the risk of developing a substance use disorder and portends a prolonged course and greater accumulation of adverse consequences. There is an urgent need for education, prevention, and early identification of e-cigarette use to protect the current and future well-being of children and adolescents.
Dr. Jackson is assistant professor of psychiatry at the University of Vermont, Burlington. He said he had no relevant financial disclosures. Email Dr. Jackson at [email protected].
References
1. MMWR Morb Mortal Wkly Rep. 2018;67:1276-7.
2. e-cigarettes.surgeongeneral.gov
3. N Engl J Med 2019;380:629-37.
4. Pediatrics. 2018 Dec; 142(6):e20180486.
5. MMWR Morb Mortal Wkly Rep 2018;67:196-200.
6. JAMA Pediatr. 2017 Aug 1;171(8):788-97.
7. “Public health consequences of e-cigarettes” (Washington, DC: National Academies Press, January 2018).
8. N Engl J Med 2014;371:932-43.
9. N Engl J Med 2019;380:689-90.
10. MMWR Morb Mortal Wkly Rep. 2016 Jan 8;64(52):1403-8.
11. Pediatrics. 2019 Feb;143(2). pii: e20183652.
After 2 decades of steady decline in adolescent and young adult use of tobacco products, e-cigarettes have dramatically altered the landscape of substance use in youth. E-cigarette use among teens has been on the rise for years but the recent exponential increase is unprecedented. From 2017 to 2018, adolescent e-cigarette use had the largest year-to-year increase (78%, from 12% to 21%) of any individual substance or class of substances at any time during the past 2 decades of nationwide monitoring.1 This has appropriately caught the nation’s attention. In 2016, Surgeon General Vivek H. Murthy, MD, commissioned an extensive report about electronic cigarettes, and in 2018 Surgeon General Jerome Adams, MD, MPH, issued an advisory declaring e-cigarettes a public health crisis for adolescents.2
E-cigarettes have received attention as a possible boon to adult cigarette smokers seeking a less hazardous product. We can consider the use of tobacco products along a continuum from smoked tobacco, dual use (both smoked tobacco and electronic nicotine delivery), electronic nicotine delivery only, and finally, nonuse. For some adults, transitioning from smoked tobacco products to electronic delivery systems has been a step toward less overall harm from substance use, with a small minority of that population going on to achieve abstinence from all nicotine products.3 For youth and teens, the story has been the opposite. With the rapid rise of e-cigarettes, adolescents overwhelmingly have been moving in the wrong direction at each potential step along this continuum.4 Less than 8% of teens who use e-cigarettes indicated that smoking cessation is a factor in their use.5 An estimated 1.3 million U.S. teens now are dependent or at high risk for dependence upon nicotine because of e-cigarette use. Furthermore, these teens are at a fourfold higher risk of progression to cigarette use, compared with their peers.6
One product in particular gives us information as to why this trend has accelerated so rapidly. Juul, now the sales leader among electronic nicotine delivery systems, rose from approximately 25% to a dominant 75% of market share in just over 1 fiscal year after a social media campaign targeted toward youth and young adults. The device is shaped like an elongated flash drive, is marketed as “sleek,” “looking cool,” and being “super easy” to use. This product touts its use of nicotine salts that can deliver higher concentrations of nicotine more rapidly to mimic the experience of smoking a cigarette as closely as possible. The fruity flavors in Juul “pods” and many other devices also appeal to teens. Many youth are left misinformed, thinking they are using a relatively harmless alternative to cigarettes.
E-cigarette use in youth carries many risks. Among the physical risks is exposure to harmful chemicals (even if less numerous than smoked tobacco products) such as diacetyl (a known cause of bronchiolitis obliterans, or “popcorn lung”), formaldehyde, acrolein, benzene, and metals such as nickel, tin and lead.7 “Safer than cigarettes” is a low bar indeed. Cognitive and emotional risks of early nicotine exposure include poor focus and attention, permanent lowering of impulse control, and a higher risk of mood and anxiety disorders.
Furthermore, nicotine is a gateway drug, with a clearly understood molecular basis for how it can potentiate the effects of later used substances, especially stimulants such as cocaine.8 The gateway and priming effect is compounded for youth because of ongoing brain development and plasticity during teen years. E-cigarette use also is associated with other risk behaviors including a manyfold higher likelihood of binge drinking, having multiple sexual partners in a short period of time, and using other substances such as cannabis, cocaine, methamphetamine, and heroin or nonprescribed opioids.9 An electronic system for vaporization also presents a risk for use of other substances. In just 1 year from 2017 to 2018, marijuana “vaping” increased by more than 50% among all ages surveyed.10
Pediatric health care providers are essential educators for both teens and parents regarding the risks of e-cigarette use. Many youth don’t know what they’re using; 66% of youth reported that the vapors they were inhaling contained only flavoring. Only 13% reported they were inhaling nicotine.10 In stark contrast to these self-reports, all Juul “pods” contain nicotine. As has been a pattern with nationwide surveys of substance use for decades, adolescent use is inversely correlated with perception of risk; 70% of 8th-12th graders do not foresee great harm in regular e-cigarette use. In addition, adolescents use substances less often when they know their parents disapprove. Parents also must be taught about the risks of e-cigarette use and can be provided with resources and taught effective strategies if they have difficulty communicating their disapproval to their children.
Age-appropriate screening in primary care settings must include specific language regarding the use of electronic cigarettes, with questions about “vaping” and “juuling.” Discussions with teens may be more effective with emphasis on issues that resonate with youth such as the financial cost, loss of freedom when dependence develops, and the fact that their generation is once again being targeted by the tobacco industry. Referral for further treatment, including individual and group therapy as well as family-focused interventions, should be considered for teens who use daily, use other substances regularly, or could benefit from treatment for co-occurring mental health disorders.
Electronic cigarette use should not be recommended as a smoking cessation strategy for teens.11 Pediatric health care providers must advocate for regulation of these products, including increasing the legal age of purchase and banning flavoring in e-cigarettes products, Internet sales, and advertisements targeted to youth.
The rapid rise in e-cigarette use among teens is of great concern. As with all classes of substances, early initiation of nicotine drastically increases the risk of developing a substance use disorder and portends a prolonged course and greater accumulation of adverse consequences. There is an urgent need for education, prevention, and early identification of e-cigarette use to protect the current and future well-being of children and adolescents.
Dr. Jackson is assistant professor of psychiatry at the University of Vermont, Burlington. He said he had no relevant financial disclosures. Email Dr. Jackson at [email protected].
References
1. MMWR Morb Mortal Wkly Rep. 2018;67:1276-7.
2. e-cigarettes.surgeongeneral.gov
3. N Engl J Med 2019;380:629-37.
4. Pediatrics. 2018 Dec; 142(6):e20180486.
5. MMWR Morb Mortal Wkly Rep 2018;67:196-200.
6. JAMA Pediatr. 2017 Aug 1;171(8):788-97.
7. “Public health consequences of e-cigarettes” (Washington, DC: National Academies Press, January 2018).
8. N Engl J Med 2014;371:932-43.
9. N Engl J Med 2019;380:689-90.
10. MMWR Morb Mortal Wkly Rep. 2016 Jan 8;64(52):1403-8.
11. Pediatrics. 2019 Feb;143(2). pii: e20183652.
Hip T scores can guide duration of osteoporosis therapy
according to Serge Ferrari, MD, and his colleagues.
Using 10 years of follow-up data from 1,343 women who took denosumab in the FREEDOM trial, Dr. Ferrari and his colleagues determined that a T score of at least –2.5 would be an appropriate target for this decision.
“A T-score unit increase of 1.0 was associated with a significant reduction in fracture risk for T scores up to, but no greater than, –2.0, suggesting that a T-score threshold of at least –2.0 would be an appropriate target for therapy to maximize treatment,” said Dr. Ferrari of the University of Geneva and his colleagues. “Further improvements in bone mineral density were not associated with major additional changes in 1-year nonvertebral fracture incidence.”
The findings “highlight the importance of the relationship between hip T score and fracture risk, which is maintained during long-term therapy with denosumab. Regular monitoring of bone mineral density during therapy may be useful to determine when fracture risk has reached a minimal threshold; treatment could therefore be suspended and/or consolidated, as in the case of a reversible therapy such as denosumab.”
SOURCE: Ferrari S et al. J Bone Miner Res. 2019 Mar 28. doi: 10.1002/jbmr.3722.
according to Serge Ferrari, MD, and his colleagues.
Using 10 years of follow-up data from 1,343 women who took denosumab in the FREEDOM trial, Dr. Ferrari and his colleagues determined that a T score of at least –2.5 would be an appropriate target for this decision.
“A T-score unit increase of 1.0 was associated with a significant reduction in fracture risk for T scores up to, but no greater than, –2.0, suggesting that a T-score threshold of at least –2.0 would be an appropriate target for therapy to maximize treatment,” said Dr. Ferrari of the University of Geneva and his colleagues. “Further improvements in bone mineral density were not associated with major additional changes in 1-year nonvertebral fracture incidence.”
The findings “highlight the importance of the relationship between hip T score and fracture risk, which is maintained during long-term therapy with denosumab. Regular monitoring of bone mineral density during therapy may be useful to determine when fracture risk has reached a minimal threshold; treatment could therefore be suspended and/or consolidated, as in the case of a reversible therapy such as denosumab.”
SOURCE: Ferrari S et al. J Bone Miner Res. 2019 Mar 28. doi: 10.1002/jbmr.3722.
according to Serge Ferrari, MD, and his colleagues.
Using 10 years of follow-up data from 1,343 women who took denosumab in the FREEDOM trial, Dr. Ferrari and his colleagues determined that a T score of at least –2.5 would be an appropriate target for this decision.
“A T-score unit increase of 1.0 was associated with a significant reduction in fracture risk for T scores up to, but no greater than, –2.0, suggesting that a T-score threshold of at least –2.0 would be an appropriate target for therapy to maximize treatment,” said Dr. Ferrari of the University of Geneva and his colleagues. “Further improvements in bone mineral density were not associated with major additional changes in 1-year nonvertebral fracture incidence.”
The findings “highlight the importance of the relationship between hip T score and fracture risk, which is maintained during long-term therapy with denosumab. Regular monitoring of bone mineral density during therapy may be useful to determine when fracture risk has reached a minimal threshold; treatment could therefore be suspended and/or consolidated, as in the case of a reversible therapy such as denosumab.”
SOURCE: Ferrari S et al. J Bone Miner Res. 2019 Mar 28. doi: 10.1002/jbmr.3722.
FROM THE JOURNAL OF BONE AND MINERAL RESEARCH
The genesis of vaginal anomalies
According to our guest author Marc R. Laufer, MD, the “development of the female genital tract is a complex process that is dependent upon a series of events involving cellular differentiation, migration, fusion, and canalization. Failure of any one of these processes results in a congenital anomaly.”1
In 1933, A.K. Koff coined the terms sinovaginal bulb and vaginal plate. He proposed that the upper 80% of the vagina is derived from Müllerian epithelium and the lower 20% derived from urogenital sinus epithelium.2 In 1957, D. Bulmer proposed that vaginal epithelium derives solely from urogenital sinus epithelium.3 And in 2017, Robboy et al. supported Bulmer’s proposal that human vaginal epithelium derives solely from urogenital sinus epithelium and differs from mouse vaginal development.4
Beginning at 3 weeks of embryogenesis and continuing into the second trimester of pregnancy, development of the female genital tract takes place. The sinovaginal bulbs originate in the urogenital sinus at the distal aspect of the Müllerian tubercle. At approximately 13 weeks, these two solid evaginations grow out of the pelvic part of the urogenital sinus and proliferate into the caudal end of the uterovaginal canal to become a solid vaginal plate. Degeneration of the central cells of this vaginal plate, which occur in a cephalad direction, enables creation of the lower vagina. Canalization is generally completed by 20 weeks’ gestation.
Agenesis or absence of the lower vagina is usually associated with normal development of the upper vagina, cervix, uterus, and ovaries. It is the result of abnormal development of the sinovaginal bulbs and vaginal plate.
The hymenal membrane separates the vaginal lumen from the urogenital sinus. Secondary to degeneration of the central epithelial cells, the hymen typically ruptures, leaving a thin fold of mucous membrane around the vaginal introitus. Hymenal anatomic variants include microperforate, septate, or cribriform. They occur secondary to incomplete degeneration of the central portion of the hymen.
Dr. Laufer is chief of the division of gynecology, codirector of the Center for Young Women’s Health, and director of the Boston Center for Endometriosis, all at Boston Children’s Hospital. He also is professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston. Dr. Laufer is an acclaimed physician, surgeon, clinical researcher, author, and teacher, and it is truly my pleasure to welcome him to this edition of the Master Class in Gynecologic Surgery.
Dr. Miller is a clinical associate professor at the University of Illinois at Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He reported no disclosures relevant to this Master Class. Email him at [email protected].
References
1. Laufer M. Congenital anomalies of the hymen and vagina. Uptodate (accessed April 2019).
2. Contrib Embryol. 1933 Sep;24(140):59-91.
3. J Anat. 1957 Oct;91(4):490-509.
4. Differentiation. 2017 Sep-Oct;97:9-22.
According to our guest author Marc R. Laufer, MD, the “development of the female genital tract is a complex process that is dependent upon a series of events involving cellular differentiation, migration, fusion, and canalization. Failure of any one of these processes results in a congenital anomaly.”1
In 1933, A.K. Koff coined the terms sinovaginal bulb and vaginal plate. He proposed that the upper 80% of the vagina is derived from Müllerian epithelium and the lower 20% derived from urogenital sinus epithelium.2 In 1957, D. Bulmer proposed that vaginal epithelium derives solely from urogenital sinus epithelium.3 And in 2017, Robboy et al. supported Bulmer’s proposal that human vaginal epithelium derives solely from urogenital sinus epithelium and differs from mouse vaginal development.4
Beginning at 3 weeks of embryogenesis and continuing into the second trimester of pregnancy, development of the female genital tract takes place. The sinovaginal bulbs originate in the urogenital sinus at the distal aspect of the Müllerian tubercle. At approximately 13 weeks, these two solid evaginations grow out of the pelvic part of the urogenital sinus and proliferate into the caudal end of the uterovaginal canal to become a solid vaginal plate. Degeneration of the central cells of this vaginal plate, which occur in a cephalad direction, enables creation of the lower vagina. Canalization is generally completed by 20 weeks’ gestation.
Agenesis or absence of the lower vagina is usually associated with normal development of the upper vagina, cervix, uterus, and ovaries. It is the result of abnormal development of the sinovaginal bulbs and vaginal plate.
The hymenal membrane separates the vaginal lumen from the urogenital sinus. Secondary to degeneration of the central epithelial cells, the hymen typically ruptures, leaving a thin fold of mucous membrane around the vaginal introitus. Hymenal anatomic variants include microperforate, septate, or cribriform. They occur secondary to incomplete degeneration of the central portion of the hymen.
Dr. Laufer is chief of the division of gynecology, codirector of the Center for Young Women’s Health, and director of the Boston Center for Endometriosis, all at Boston Children’s Hospital. He also is professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston. Dr. Laufer is an acclaimed physician, surgeon, clinical researcher, author, and teacher, and it is truly my pleasure to welcome him to this edition of the Master Class in Gynecologic Surgery.
Dr. Miller is a clinical associate professor at the University of Illinois at Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He reported no disclosures relevant to this Master Class. Email him at [email protected].
References
1. Laufer M. Congenital anomalies of the hymen and vagina. Uptodate (accessed April 2019).
2. Contrib Embryol. 1933 Sep;24(140):59-91.
3. J Anat. 1957 Oct;91(4):490-509.
4. Differentiation. 2017 Sep-Oct;97:9-22.
According to our guest author Marc R. Laufer, MD, the “development of the female genital tract is a complex process that is dependent upon a series of events involving cellular differentiation, migration, fusion, and canalization. Failure of any one of these processes results in a congenital anomaly.”1
In 1933, A.K. Koff coined the terms sinovaginal bulb and vaginal plate. He proposed that the upper 80% of the vagina is derived from Müllerian epithelium and the lower 20% derived from urogenital sinus epithelium.2 In 1957, D. Bulmer proposed that vaginal epithelium derives solely from urogenital sinus epithelium.3 And in 2017, Robboy et al. supported Bulmer’s proposal that human vaginal epithelium derives solely from urogenital sinus epithelium and differs from mouse vaginal development.4
Beginning at 3 weeks of embryogenesis and continuing into the second trimester of pregnancy, development of the female genital tract takes place. The sinovaginal bulbs originate in the urogenital sinus at the distal aspect of the Müllerian tubercle. At approximately 13 weeks, these two solid evaginations grow out of the pelvic part of the urogenital sinus and proliferate into the caudal end of the uterovaginal canal to become a solid vaginal plate. Degeneration of the central cells of this vaginal plate, which occur in a cephalad direction, enables creation of the lower vagina. Canalization is generally completed by 20 weeks’ gestation.
Agenesis or absence of the lower vagina is usually associated with normal development of the upper vagina, cervix, uterus, and ovaries. It is the result of abnormal development of the sinovaginal bulbs and vaginal plate.
The hymenal membrane separates the vaginal lumen from the urogenital sinus. Secondary to degeneration of the central epithelial cells, the hymen typically ruptures, leaving a thin fold of mucous membrane around the vaginal introitus. Hymenal anatomic variants include microperforate, septate, or cribriform. They occur secondary to incomplete degeneration of the central portion of the hymen.
Dr. Laufer is chief of the division of gynecology, codirector of the Center for Young Women’s Health, and director of the Boston Center for Endometriosis, all at Boston Children’s Hospital. He also is professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston. Dr. Laufer is an acclaimed physician, surgeon, clinical researcher, author, and teacher, and it is truly my pleasure to welcome him to this edition of the Master Class in Gynecologic Surgery.
Dr. Miller is a clinical associate professor at the University of Illinois at Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He reported no disclosures relevant to this Master Class. Email him at [email protected].
References
1. Laufer M. Congenital anomalies of the hymen and vagina. Uptodate (accessed April 2019).
2. Contrib Embryol. 1933 Sep;24(140):59-91.
3. J Anat. 1957 Oct;91(4):490-509.
4. Differentiation. 2017 Sep-Oct;97:9-22.
Vaginal anomalies and their surgical correction
Congenital obstructive anomalies of the vagina are unusual and can be challenging to diagnose and manage. Two of the most challenging are obstructive hemivagina with ipsilateral renal agenesis (Figure 1a) and agenesis of the lower vagina (Figure 1b), the latter of which must be differentiated most commonly from imperforate hymen (Figure 1c). Evaluation and treatment of these anomalies is dependent upon the age of the patient, as well as the symptoms, and the timing of treatment should be individualized.
Agenesis of the lower vagina
Agenesis of the lower vagina and imperforate hymen may present either in the newborn period as a bulging introitus caused by mucocolpos from vaginal secretions stimulated by maternal estradiol or during adolescence at the time of menarche. In neonates, it often is best not to intervene when obstructive anomalies are suspected as long as there is no fever; pain; or compromise of respiration, urinary and bowel function, and other functionality. It will be easier to differentiate agenesis of the lower vagina and imperforate hymen – the latter of which is one of the most common obstructive lesions of the female genital tract – later on. And if the hymen remains imperforate, the mucus will be reabsorbed and the patient usually will remain asymptomatic until menarche.
In the adolescent time period, both anomalies often are identified when the patient presents with pelvic pain – usually cyclic pelvic pain with primary amenorrhea. Because the onset of menses typically occurs 2-3 years after the onset of estrogenization and breast development, evaluating breast development can help us to determine the timing of expected menarche. An obstructive anomaly should be suspected in an adolescent who presents with pain during this time period, after evaluation for an acute abdomen (Figure 2a).
When a vaginal orifice is visualized upon evaluation of the external genitalia and separation of the labia, a higher anomaly such as a transverse vaginal septum should be suspected. When an introitus cannot be visualized, evaluation for an imperforate hymen or agenesis of the lower vagina is necessary (Figure 1b and 1c).
The simplest way to differentiate imperforate hymen from agenesis of the lower vagina is with visualization of the obstructing tissue on exam and usage of transperitoneal ultrasound. With the transducer placed on the vulva, we can evaluate the distance from the normal location of an introitus to the level of the obstruction. If the distance is in millimeters, then typically there is an imperforate hymen. If the distance is larger – more than several millimeters – then the differential diagnosis typically is agenesis of the lower vagina, an anomaly that results from abnormal development of the sinovaginal bulbs and vaginal plate.
The distance as measured by transperitoneal ultrasound also will indicate whether or not pull-through vaginoplasty (Figure 2b) – our standard treatment for lower vaginal agenesis – is possible using native vaginal mucosa from the upper vagina. Most commonly, the distance is less than 5 cm and we are able to make a transverse incision where the hymenal ring should be located, carry the dissection to the upper vagina, drain the obstruction, and mobilize the upper vaginal mucosa, suturing it to the newly created introitus to formulate a patent vaginal tract.
A rectoabdominal examination similarly can be helpful in making the diagnosis of lower vaginal agenesis and in determining whether there is enough tissue available for a pull-through procedure (Figures 2a and 2b). Because patients with this anomaly generally have normal cyclic pituitary-ovarian-endometrial function at menarche, the upper vagina will distend with blood products and secretions that can be palpated on the rectoabdominal exam. If the obstructed vaginal tissue is not felt with the rectal finger at midline, the obstructed agenesis of the vagina probably is too high for a straightforward pull-through procedure. Alternatively, the patient may have a unicornuate system with agenesis of the lower vagina; in this case, the obstructed upper vaginal tissue will not be in the midline but off to one side. MRI also may be helpful for defining the pelvic anatomy.
The optimal timing for a pull-through vaginoplasty (Figure 2b) is when a large hematocolpos (Figure 2a) is present, as the blood acts as a natural expander of the native vaginal tissue, increasing the amount of tissue available for a primary reanastomosis. This emphasizes the importance of an accurate initial diagnosis. Too often, obstructions that are actually lower vaginal agenesis are presumed to be imperforate hymen, and the hematocolpos is subsequently evacuated after a transverse incision and dissection of excess tissue, causing the upper vagina to retract and shrink. This mistake can result in the formation of a fistulous tract from the previously obstructed upper vagina to the level of the introitus.
The vaginoplasty is carried out with the patient in the dorsal lithotomy position. A Foley catheter is placed into the bladder to avoid an inadvertent anterior entry into the posterior wall of the bladder, and the labia are grasped and pulled down and out.
The hymenal tissue should be visible. A transverse incision is made, with electrocautery, where the introitus should be located, and a dissection is carried out to reach the obstructed upper vaginal tissue. Care is needed to keep the dissection in the midline and avoid the bladder above and the rectum below. In cases in which it is difficult to identify the area of obstruction, intraoperative ultrasound can be helpful. A spinal needle with a 10-cc syringe also can be used to identify a track through which to access the fluid.
The linear incision then is made with electrocautery and the obstructed hemivagina is entered. Allis clamps are used to grasp the vaginal mucosa from the previously obstructed upper vagina to help identify the tissue that needs to be mobilized. The tissue then is further dissected to free the upper vagina, and the edges are pulled down to the level of the introitus with Allis clamps. “Relaxing” incisions are made at 1, 5,7, and 11 o’clock to avoid a circumferential scar. The upper vaginal mucosa is sewn to the newly created introitus with a 2-0 vicryl suture on a UR6 (a smaller curved urology needle).
When the distance from normal introitus location to obstruction is greater than 5 cm, we sometimes use vaginal dilators to lessen the distance and reach the obstruction for a pull-through procedure. Alternatively, the upper vagina may be mobilized from above either robotically or laparoscopically so that the upper vaginal mucosa may be pulled down without entering the bladder. Occasionally, with greater distances over 5 cm, the vaginoplasty may require utilization of a buccal mucosal graft or a bowel segment.
Intraoperative ultrasound can be especially helpful for locating the obstructed vagina in women with a unicornuate system because the upper vagina will not be in the midline and ultrasound can help determine the appropriate angle for dissection.
Prophylactic antibiotics initiated postoperatively are important with pull-through vaginoplasty, because the uterus and fallopian tubes may contain blood (an excellent growth media) and because there is a risk of bacteria ascending into what becomes an open system.
Postoperatively, we guide patients on the use of flexible Milex dilators (CooperSurgical) to ensure that the vagina heals without restenosis. The length of postoperative dilation therapy can vary from 2-12 months, depending on healing. The dilator is worn 24 hours a day, 7 days a week, and is removed only for urination, defecation, and cleaning. With adequate postoperative dilation, patients will have normal sexual and reproductive function, and vaginal delivery should be possible.
Obstructed hemivagina
An obstructed hemivagina, an uncommon Müllerian duct anomaly, occurs most often with ipsilateral renal agenesis and is commonly referred to as OHVIRA. Because the formation of the reproductive system is closely associated with the development of the urinary system, it is not unusual for renal anomalies to occur alongside Müllerian anomalies and vaginal anomalies. There should be a high index of suspicion for a reproductive tract anomaly in any patient known to have a horseshoe kidney, duplex collecting system, unilateral renal agenesis, or other renal anomaly.
Patients with obstructed hemivagina typically present in adolescence with pelvic pain or dysmenorrhea, and commonly are misdiagnosed as having endometriomas or vaginal cysts. On vaginal examination, the obstructed hemivagina may be visualized as a bulge coming from the lateral vaginal sidewall. While only one cervix is appreciated on a vaginal exam, an ultrasound examination often will show two uteri and two cervices. MRI also is helpful for diagnosis.
Obstructed hemivagina requires surgical correction to open the obstruction, excise the excess vaginal tissue, and create one vagina with access to the second cervix. Great care must be taken to avoid not only the bladder and rectum but the cervices. It is not unusual for the two cervices to be at different levels, with one cervix sharing medial aspects of the vaginal wall of the second vagina (Figure 1a). The tissue between the two cervices should be left in place to avoid compromising their blood supply.
We manage this anomaly primarily through a single-stage vaginoplasty. For the nonobstructed side to be visualized, a longitudinal incision into the obstructed hemivagina should be made at the point at which it is most easily palpated. As with agenesis of the lower vagina, the fluid to be drained tends to be old menstrual blood that is thick and dark brown. It is useful to set up two suction units at the time of surgery because tubing can become clogged.
The use of vaginal side wall retractors helps with visualization. Alternatively, I tend to use malleable abdominal wall retractors vaginally, as they can be bent to conform to the angle needed and come in different widths. When it is difficult to identify the area of obstruction, a spinal needle with a 10-cc syringe again can be used to identify a track for accessing the fluid. The linear incision then is made with electrocautery, and the obstructed hemivagina is entered.
Allis clamps are used to grasp the vaginal mucosa from the previously obstructed hemivagina to help identify the tissue that needs to be excised. Once the fluid is evacuated, a finger also can be placed into the obstructed vagina is help identify excess tissue. This three-dimensional elliptical area is similar to a septum but becomes the obstructed hemivagina as it attaches to the vaginal wall (Figure 1a).
Retrograde menses and endometriosis occur commonly with obstructive anomalies like obstructed hemivagina and agenesis of the lower vagina, but laparoscopy with the goal of treating endometriosis is not indicated. We discourage its use at the time of repair because there is evidence that almost all endometriosis will completely resorb on its own once the anomalies are corrected.1,2
As with repair of lower vagina agenesis, antibiotics to prevent an ascending infection should be taken after surgical correction of obstructed hemivagina. Patients with obstructed hemivagina can have a vaginal delivery if there are no other contraindications. Women with obstructed hemivagina and ipsilateral renal anomaly have essentially two unicornuate systems and thus are at risk of breech presentation and preterm delivery.
Dr. Laufer is chief of the division of gynecology, codirector of the Center for Young Women’s Health, and director of the Boston Center for Endometriosis, all at Boston Children’s Hospital. He also is professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston.
References
1. Am J Obstet Gynecol. 1986;154:39.
2. J Pediatr Adolesc Gynecol. 2010;23(2):e89.
Congenital obstructive anomalies of the vagina are unusual and can be challenging to diagnose and manage. Two of the most challenging are obstructive hemivagina with ipsilateral renal agenesis (Figure 1a) and agenesis of the lower vagina (Figure 1b), the latter of which must be differentiated most commonly from imperforate hymen (Figure 1c). Evaluation and treatment of these anomalies is dependent upon the age of the patient, as well as the symptoms, and the timing of treatment should be individualized.
Agenesis of the lower vagina
Agenesis of the lower vagina and imperforate hymen may present either in the newborn period as a bulging introitus caused by mucocolpos from vaginal secretions stimulated by maternal estradiol or during adolescence at the time of menarche. In neonates, it often is best not to intervene when obstructive anomalies are suspected as long as there is no fever; pain; or compromise of respiration, urinary and bowel function, and other functionality. It will be easier to differentiate agenesis of the lower vagina and imperforate hymen – the latter of which is one of the most common obstructive lesions of the female genital tract – later on. And if the hymen remains imperforate, the mucus will be reabsorbed and the patient usually will remain asymptomatic until menarche.
In the adolescent time period, both anomalies often are identified when the patient presents with pelvic pain – usually cyclic pelvic pain with primary amenorrhea. Because the onset of menses typically occurs 2-3 years after the onset of estrogenization and breast development, evaluating breast development can help us to determine the timing of expected menarche. An obstructive anomaly should be suspected in an adolescent who presents with pain during this time period, after evaluation for an acute abdomen (Figure 2a).
When a vaginal orifice is visualized upon evaluation of the external genitalia and separation of the labia, a higher anomaly such as a transverse vaginal septum should be suspected. When an introitus cannot be visualized, evaluation for an imperforate hymen or agenesis of the lower vagina is necessary (Figure 1b and 1c).
The simplest way to differentiate imperforate hymen from agenesis of the lower vagina is with visualization of the obstructing tissue on exam and usage of transperitoneal ultrasound. With the transducer placed on the vulva, we can evaluate the distance from the normal location of an introitus to the level of the obstruction. If the distance is in millimeters, then typically there is an imperforate hymen. If the distance is larger – more than several millimeters – then the differential diagnosis typically is agenesis of the lower vagina, an anomaly that results from abnormal development of the sinovaginal bulbs and vaginal plate.
The distance as measured by transperitoneal ultrasound also will indicate whether or not pull-through vaginoplasty (Figure 2b) – our standard treatment for lower vaginal agenesis – is possible using native vaginal mucosa from the upper vagina. Most commonly, the distance is less than 5 cm and we are able to make a transverse incision where the hymenal ring should be located, carry the dissection to the upper vagina, drain the obstruction, and mobilize the upper vaginal mucosa, suturing it to the newly created introitus to formulate a patent vaginal tract.
A rectoabdominal examination similarly can be helpful in making the diagnosis of lower vaginal agenesis and in determining whether there is enough tissue available for a pull-through procedure (Figures 2a and 2b). Because patients with this anomaly generally have normal cyclic pituitary-ovarian-endometrial function at menarche, the upper vagina will distend with blood products and secretions that can be palpated on the rectoabdominal exam. If the obstructed vaginal tissue is not felt with the rectal finger at midline, the obstructed agenesis of the vagina probably is too high for a straightforward pull-through procedure. Alternatively, the patient may have a unicornuate system with agenesis of the lower vagina; in this case, the obstructed upper vaginal tissue will not be in the midline but off to one side. MRI also may be helpful for defining the pelvic anatomy.
The optimal timing for a pull-through vaginoplasty (Figure 2b) is when a large hematocolpos (Figure 2a) is present, as the blood acts as a natural expander of the native vaginal tissue, increasing the amount of tissue available for a primary reanastomosis. This emphasizes the importance of an accurate initial diagnosis. Too often, obstructions that are actually lower vaginal agenesis are presumed to be imperforate hymen, and the hematocolpos is subsequently evacuated after a transverse incision and dissection of excess tissue, causing the upper vagina to retract and shrink. This mistake can result in the formation of a fistulous tract from the previously obstructed upper vagina to the level of the introitus.
The vaginoplasty is carried out with the patient in the dorsal lithotomy position. A Foley catheter is placed into the bladder to avoid an inadvertent anterior entry into the posterior wall of the bladder, and the labia are grasped and pulled down and out.
The hymenal tissue should be visible. A transverse incision is made, with electrocautery, where the introitus should be located, and a dissection is carried out to reach the obstructed upper vaginal tissue. Care is needed to keep the dissection in the midline and avoid the bladder above and the rectum below. In cases in which it is difficult to identify the area of obstruction, intraoperative ultrasound can be helpful. A spinal needle with a 10-cc syringe also can be used to identify a track through which to access the fluid.
The linear incision then is made with electrocautery and the obstructed hemivagina is entered. Allis clamps are used to grasp the vaginal mucosa from the previously obstructed upper vagina to help identify the tissue that needs to be mobilized. The tissue then is further dissected to free the upper vagina, and the edges are pulled down to the level of the introitus with Allis clamps. “Relaxing” incisions are made at 1, 5,7, and 11 o’clock to avoid a circumferential scar. The upper vaginal mucosa is sewn to the newly created introitus with a 2-0 vicryl suture on a UR6 (a smaller curved urology needle).
When the distance from normal introitus location to obstruction is greater than 5 cm, we sometimes use vaginal dilators to lessen the distance and reach the obstruction for a pull-through procedure. Alternatively, the upper vagina may be mobilized from above either robotically or laparoscopically so that the upper vaginal mucosa may be pulled down without entering the bladder. Occasionally, with greater distances over 5 cm, the vaginoplasty may require utilization of a buccal mucosal graft or a bowel segment.
Intraoperative ultrasound can be especially helpful for locating the obstructed vagina in women with a unicornuate system because the upper vagina will not be in the midline and ultrasound can help determine the appropriate angle for dissection.
Prophylactic antibiotics initiated postoperatively are important with pull-through vaginoplasty, because the uterus and fallopian tubes may contain blood (an excellent growth media) and because there is a risk of bacteria ascending into what becomes an open system.
Postoperatively, we guide patients on the use of flexible Milex dilators (CooperSurgical) to ensure that the vagina heals without restenosis. The length of postoperative dilation therapy can vary from 2-12 months, depending on healing. The dilator is worn 24 hours a day, 7 days a week, and is removed only for urination, defecation, and cleaning. With adequate postoperative dilation, patients will have normal sexual and reproductive function, and vaginal delivery should be possible.
Obstructed hemivagina
An obstructed hemivagina, an uncommon Müllerian duct anomaly, occurs most often with ipsilateral renal agenesis and is commonly referred to as OHVIRA. Because the formation of the reproductive system is closely associated with the development of the urinary system, it is not unusual for renal anomalies to occur alongside Müllerian anomalies and vaginal anomalies. There should be a high index of suspicion for a reproductive tract anomaly in any patient known to have a horseshoe kidney, duplex collecting system, unilateral renal agenesis, or other renal anomaly.
Patients with obstructed hemivagina typically present in adolescence with pelvic pain or dysmenorrhea, and commonly are misdiagnosed as having endometriomas or vaginal cysts. On vaginal examination, the obstructed hemivagina may be visualized as a bulge coming from the lateral vaginal sidewall. While only one cervix is appreciated on a vaginal exam, an ultrasound examination often will show two uteri and two cervices. MRI also is helpful for diagnosis.
Obstructed hemivagina requires surgical correction to open the obstruction, excise the excess vaginal tissue, and create one vagina with access to the second cervix. Great care must be taken to avoid not only the bladder and rectum but the cervices. It is not unusual for the two cervices to be at different levels, with one cervix sharing medial aspects of the vaginal wall of the second vagina (Figure 1a). The tissue between the two cervices should be left in place to avoid compromising their blood supply.
We manage this anomaly primarily through a single-stage vaginoplasty. For the nonobstructed side to be visualized, a longitudinal incision into the obstructed hemivagina should be made at the point at which it is most easily palpated. As with agenesis of the lower vagina, the fluid to be drained tends to be old menstrual blood that is thick and dark brown. It is useful to set up two suction units at the time of surgery because tubing can become clogged.
The use of vaginal side wall retractors helps with visualization. Alternatively, I tend to use malleable abdominal wall retractors vaginally, as they can be bent to conform to the angle needed and come in different widths. When it is difficult to identify the area of obstruction, a spinal needle with a 10-cc syringe again can be used to identify a track for accessing the fluid. The linear incision then is made with electrocautery, and the obstructed hemivagina is entered.
Allis clamps are used to grasp the vaginal mucosa from the previously obstructed hemivagina to help identify the tissue that needs to be excised. Once the fluid is evacuated, a finger also can be placed into the obstructed vagina is help identify excess tissue. This three-dimensional elliptical area is similar to a septum but becomes the obstructed hemivagina as it attaches to the vaginal wall (Figure 1a).
Retrograde menses and endometriosis occur commonly with obstructive anomalies like obstructed hemivagina and agenesis of the lower vagina, but laparoscopy with the goal of treating endometriosis is not indicated. We discourage its use at the time of repair because there is evidence that almost all endometriosis will completely resorb on its own once the anomalies are corrected.1,2
As with repair of lower vagina agenesis, antibiotics to prevent an ascending infection should be taken after surgical correction of obstructed hemivagina. Patients with obstructed hemivagina can have a vaginal delivery if there are no other contraindications. Women with obstructed hemivagina and ipsilateral renal anomaly have essentially two unicornuate systems and thus are at risk of breech presentation and preterm delivery.
Dr. Laufer is chief of the division of gynecology, codirector of the Center for Young Women’s Health, and director of the Boston Center for Endometriosis, all at Boston Children’s Hospital. He also is professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston.
References
1. Am J Obstet Gynecol. 1986;154:39.
2. J Pediatr Adolesc Gynecol. 2010;23(2):e89.
Congenital obstructive anomalies of the vagina are unusual and can be challenging to diagnose and manage. Two of the most challenging are obstructive hemivagina with ipsilateral renal agenesis (Figure 1a) and agenesis of the lower vagina (Figure 1b), the latter of which must be differentiated most commonly from imperforate hymen (Figure 1c). Evaluation and treatment of these anomalies is dependent upon the age of the patient, as well as the symptoms, and the timing of treatment should be individualized.
Agenesis of the lower vagina
Agenesis of the lower vagina and imperforate hymen may present either in the newborn period as a bulging introitus caused by mucocolpos from vaginal secretions stimulated by maternal estradiol or during adolescence at the time of menarche. In neonates, it often is best not to intervene when obstructive anomalies are suspected as long as there is no fever; pain; or compromise of respiration, urinary and bowel function, and other functionality. It will be easier to differentiate agenesis of the lower vagina and imperforate hymen – the latter of which is one of the most common obstructive lesions of the female genital tract – later on. And if the hymen remains imperforate, the mucus will be reabsorbed and the patient usually will remain asymptomatic until menarche.
In the adolescent time period, both anomalies often are identified when the patient presents with pelvic pain – usually cyclic pelvic pain with primary amenorrhea. Because the onset of menses typically occurs 2-3 years after the onset of estrogenization and breast development, evaluating breast development can help us to determine the timing of expected menarche. An obstructive anomaly should be suspected in an adolescent who presents with pain during this time period, after evaluation for an acute abdomen (Figure 2a).
When a vaginal orifice is visualized upon evaluation of the external genitalia and separation of the labia, a higher anomaly such as a transverse vaginal septum should be suspected. When an introitus cannot be visualized, evaluation for an imperforate hymen or agenesis of the lower vagina is necessary (Figure 1b and 1c).
The simplest way to differentiate imperforate hymen from agenesis of the lower vagina is with visualization of the obstructing tissue on exam and usage of transperitoneal ultrasound. With the transducer placed on the vulva, we can evaluate the distance from the normal location of an introitus to the level of the obstruction. If the distance is in millimeters, then typically there is an imperforate hymen. If the distance is larger – more than several millimeters – then the differential diagnosis typically is agenesis of the lower vagina, an anomaly that results from abnormal development of the sinovaginal bulbs and vaginal plate.
The distance as measured by transperitoneal ultrasound also will indicate whether or not pull-through vaginoplasty (Figure 2b) – our standard treatment for lower vaginal agenesis – is possible using native vaginal mucosa from the upper vagina. Most commonly, the distance is less than 5 cm and we are able to make a transverse incision where the hymenal ring should be located, carry the dissection to the upper vagina, drain the obstruction, and mobilize the upper vaginal mucosa, suturing it to the newly created introitus to formulate a patent vaginal tract.
A rectoabdominal examination similarly can be helpful in making the diagnosis of lower vaginal agenesis and in determining whether there is enough tissue available for a pull-through procedure (Figures 2a and 2b). Because patients with this anomaly generally have normal cyclic pituitary-ovarian-endometrial function at menarche, the upper vagina will distend with blood products and secretions that can be palpated on the rectoabdominal exam. If the obstructed vaginal tissue is not felt with the rectal finger at midline, the obstructed agenesis of the vagina probably is too high for a straightforward pull-through procedure. Alternatively, the patient may have a unicornuate system with agenesis of the lower vagina; in this case, the obstructed upper vaginal tissue will not be in the midline but off to one side. MRI also may be helpful for defining the pelvic anatomy.
The optimal timing for a pull-through vaginoplasty (Figure 2b) is when a large hematocolpos (Figure 2a) is present, as the blood acts as a natural expander of the native vaginal tissue, increasing the amount of tissue available for a primary reanastomosis. This emphasizes the importance of an accurate initial diagnosis. Too often, obstructions that are actually lower vaginal agenesis are presumed to be imperforate hymen, and the hematocolpos is subsequently evacuated after a transverse incision and dissection of excess tissue, causing the upper vagina to retract and shrink. This mistake can result in the formation of a fistulous tract from the previously obstructed upper vagina to the level of the introitus.
The vaginoplasty is carried out with the patient in the dorsal lithotomy position. A Foley catheter is placed into the bladder to avoid an inadvertent anterior entry into the posterior wall of the bladder, and the labia are grasped and pulled down and out.
The hymenal tissue should be visible. A transverse incision is made, with electrocautery, where the introitus should be located, and a dissection is carried out to reach the obstructed upper vaginal tissue. Care is needed to keep the dissection in the midline and avoid the bladder above and the rectum below. In cases in which it is difficult to identify the area of obstruction, intraoperative ultrasound can be helpful. A spinal needle with a 10-cc syringe also can be used to identify a track through which to access the fluid.
The linear incision then is made with electrocautery and the obstructed hemivagina is entered. Allis clamps are used to grasp the vaginal mucosa from the previously obstructed upper vagina to help identify the tissue that needs to be mobilized. The tissue then is further dissected to free the upper vagina, and the edges are pulled down to the level of the introitus with Allis clamps. “Relaxing” incisions are made at 1, 5,7, and 11 o’clock to avoid a circumferential scar. The upper vaginal mucosa is sewn to the newly created introitus with a 2-0 vicryl suture on a UR6 (a smaller curved urology needle).
When the distance from normal introitus location to obstruction is greater than 5 cm, we sometimes use vaginal dilators to lessen the distance and reach the obstruction for a pull-through procedure. Alternatively, the upper vagina may be mobilized from above either robotically or laparoscopically so that the upper vaginal mucosa may be pulled down without entering the bladder. Occasionally, with greater distances over 5 cm, the vaginoplasty may require utilization of a buccal mucosal graft or a bowel segment.
Intraoperative ultrasound can be especially helpful for locating the obstructed vagina in women with a unicornuate system because the upper vagina will not be in the midline and ultrasound can help determine the appropriate angle for dissection.
Prophylactic antibiotics initiated postoperatively are important with pull-through vaginoplasty, because the uterus and fallopian tubes may contain blood (an excellent growth media) and because there is a risk of bacteria ascending into what becomes an open system.
Postoperatively, we guide patients on the use of flexible Milex dilators (CooperSurgical) to ensure that the vagina heals without restenosis. The length of postoperative dilation therapy can vary from 2-12 months, depending on healing. The dilator is worn 24 hours a day, 7 days a week, and is removed only for urination, defecation, and cleaning. With adequate postoperative dilation, patients will have normal sexual and reproductive function, and vaginal delivery should be possible.
Obstructed hemivagina
An obstructed hemivagina, an uncommon Müllerian duct anomaly, occurs most often with ipsilateral renal agenesis and is commonly referred to as OHVIRA. Because the formation of the reproductive system is closely associated with the development of the urinary system, it is not unusual for renal anomalies to occur alongside Müllerian anomalies and vaginal anomalies. There should be a high index of suspicion for a reproductive tract anomaly in any patient known to have a horseshoe kidney, duplex collecting system, unilateral renal agenesis, or other renal anomaly.
Patients with obstructed hemivagina typically present in adolescence with pelvic pain or dysmenorrhea, and commonly are misdiagnosed as having endometriomas or vaginal cysts. On vaginal examination, the obstructed hemivagina may be visualized as a bulge coming from the lateral vaginal sidewall. While only one cervix is appreciated on a vaginal exam, an ultrasound examination often will show two uteri and two cervices. MRI also is helpful for diagnosis.
Obstructed hemivagina requires surgical correction to open the obstruction, excise the excess vaginal tissue, and create one vagina with access to the second cervix. Great care must be taken to avoid not only the bladder and rectum but the cervices. It is not unusual for the two cervices to be at different levels, with one cervix sharing medial aspects of the vaginal wall of the second vagina (Figure 1a). The tissue between the two cervices should be left in place to avoid compromising their blood supply.
We manage this anomaly primarily through a single-stage vaginoplasty. For the nonobstructed side to be visualized, a longitudinal incision into the obstructed hemivagina should be made at the point at which it is most easily palpated. As with agenesis of the lower vagina, the fluid to be drained tends to be old menstrual blood that is thick and dark brown. It is useful to set up two suction units at the time of surgery because tubing can become clogged.
The use of vaginal side wall retractors helps with visualization. Alternatively, I tend to use malleable abdominal wall retractors vaginally, as they can be bent to conform to the angle needed and come in different widths. When it is difficult to identify the area of obstruction, a spinal needle with a 10-cc syringe again can be used to identify a track for accessing the fluid. The linear incision then is made with electrocautery, and the obstructed hemivagina is entered.
Allis clamps are used to grasp the vaginal mucosa from the previously obstructed hemivagina to help identify the tissue that needs to be excised. Once the fluid is evacuated, a finger also can be placed into the obstructed vagina is help identify excess tissue. This three-dimensional elliptical area is similar to a septum but becomes the obstructed hemivagina as it attaches to the vaginal wall (Figure 1a).
Retrograde menses and endometriosis occur commonly with obstructive anomalies like obstructed hemivagina and agenesis of the lower vagina, but laparoscopy with the goal of treating endometriosis is not indicated. We discourage its use at the time of repair because there is evidence that almost all endometriosis will completely resorb on its own once the anomalies are corrected.1,2
As with repair of lower vagina agenesis, antibiotics to prevent an ascending infection should be taken after surgical correction of obstructed hemivagina. Patients with obstructed hemivagina can have a vaginal delivery if there are no other contraindications. Women with obstructed hemivagina and ipsilateral renal anomaly have essentially two unicornuate systems and thus are at risk of breech presentation and preterm delivery.
Dr. Laufer is chief of the division of gynecology, codirector of the Center for Young Women’s Health, and director of the Boston Center for Endometriosis, all at Boston Children’s Hospital. He also is professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston.
References
1. Am J Obstet Gynecol. 1986;154:39.
2. J Pediatr Adolesc Gynecol. 2010;23(2):e89.
Survival after squamous recurrence may be unaffected by immune status
Patients who have recurrence of cutaneous squamous cell cancer of the head and neck (cSCC-HN) tend to have poor outcomes regardless of immune status, according to investigators.
Patients with surgically unsalvageable recurrent disease had the worst outcomes, reported lead author Lillian Sun, of the Cleveland Clinic, and her colleagues.
These findings support more intensive upfront therapy for patients with cSCC-HN, the investigators wrote in JAMA Dermatology. They noted that most patients with cSCC have good outcomes, with less than 5% experiencing recurrence or distant metastasis; however, “there is a subset of patients with adverse pathologic features and a more aggressive clinical course,” the investigators pointed out, “with substantially higher rates of locoregional recurrence (13%-41%) and distant metastasis (7%-16%) after surgical resection.”
According to the investigators, previous research has identified several patient factors that predict poor outcomes, such as invasiveness and differentiation, as well as chronic immunosuppression. To build on these data, and, in particular, to determine if immune suppression was linked with poor outcomes, the investigators conducted a retrospective analysis of 205 patients with cSCC-HN.
From this cohort, 72 patients had disease recurrence after surgery and radiotherapy. The average age of the patients was 71 years. About half were immunosuppressed (55.6%). On average, disease recurrence occurred slightly earlier in immunosuppressed patients (9.1 months) than in immunocompetent patients (10.1 months). Most patients had locoregional recurrence first, at rates of 65.6% and 77.5% among immunocompetent and immunosuppressed patients, respectively. Irrespective of immune status, median overall survival was 8.4 months and the 1-year overall survival rate was 43.2%. In contrast with previous findings, immune status was not statistically associated with median overall survival; immunocompetent patients did tend to live longer (12.9 months) than immunosuppressed patients (8.0 months), but this difference carried a P value of .90.
The investigators found that surgical candidacy after recurrence had the strongest impact on survival. Patients with surgically salvageable disease had a median overall survival of 26.1 months, compared with just 4.7 months for those who were not amenable to surgical salvage (P = .01). Among patients with unsalvageable disease, again, immune status did not have a significant impact on outcome.
“This study demonstrates that survival in this population is poor,” the investigators concluded. “Although we hypothesized that immunosuppressed status would be a significant contributor to outcomes in these patients, similar to findings in the upfront treatment setting, the current study suggests that this is not the case.”
The investigators reported clinical trial support from Genentech, Merck, and Bristol-Myers Squibb.
SOURCE: Sun et al. JAMA Derm. 27 Feb 2019. doi: 10.1001/jamadermatol.2018.5453.
Patients who have recurrence of cutaneous squamous cell cancer of the head and neck (cSCC-HN) tend to have poor outcomes regardless of immune status, according to investigators.
Patients with surgically unsalvageable recurrent disease had the worst outcomes, reported lead author Lillian Sun, of the Cleveland Clinic, and her colleagues.
These findings support more intensive upfront therapy for patients with cSCC-HN, the investigators wrote in JAMA Dermatology. They noted that most patients with cSCC have good outcomes, with less than 5% experiencing recurrence or distant metastasis; however, “there is a subset of patients with adverse pathologic features and a more aggressive clinical course,” the investigators pointed out, “with substantially higher rates of locoregional recurrence (13%-41%) and distant metastasis (7%-16%) after surgical resection.”
According to the investigators, previous research has identified several patient factors that predict poor outcomes, such as invasiveness and differentiation, as well as chronic immunosuppression. To build on these data, and, in particular, to determine if immune suppression was linked with poor outcomes, the investigators conducted a retrospective analysis of 205 patients with cSCC-HN.
From this cohort, 72 patients had disease recurrence after surgery and radiotherapy. The average age of the patients was 71 years. About half were immunosuppressed (55.6%). On average, disease recurrence occurred slightly earlier in immunosuppressed patients (9.1 months) than in immunocompetent patients (10.1 months). Most patients had locoregional recurrence first, at rates of 65.6% and 77.5% among immunocompetent and immunosuppressed patients, respectively. Irrespective of immune status, median overall survival was 8.4 months and the 1-year overall survival rate was 43.2%. In contrast with previous findings, immune status was not statistically associated with median overall survival; immunocompetent patients did tend to live longer (12.9 months) than immunosuppressed patients (8.0 months), but this difference carried a P value of .90.
The investigators found that surgical candidacy after recurrence had the strongest impact on survival. Patients with surgically salvageable disease had a median overall survival of 26.1 months, compared with just 4.7 months for those who were not amenable to surgical salvage (P = .01). Among patients with unsalvageable disease, again, immune status did not have a significant impact on outcome.
“This study demonstrates that survival in this population is poor,” the investigators concluded. “Although we hypothesized that immunosuppressed status would be a significant contributor to outcomes in these patients, similar to findings in the upfront treatment setting, the current study suggests that this is not the case.”
The investigators reported clinical trial support from Genentech, Merck, and Bristol-Myers Squibb.
SOURCE: Sun et al. JAMA Derm. 27 Feb 2019. doi: 10.1001/jamadermatol.2018.5453.
Patients who have recurrence of cutaneous squamous cell cancer of the head and neck (cSCC-HN) tend to have poor outcomes regardless of immune status, according to investigators.
Patients with surgically unsalvageable recurrent disease had the worst outcomes, reported lead author Lillian Sun, of the Cleveland Clinic, and her colleagues.
These findings support more intensive upfront therapy for patients with cSCC-HN, the investigators wrote in JAMA Dermatology. They noted that most patients with cSCC have good outcomes, with less than 5% experiencing recurrence or distant metastasis; however, “there is a subset of patients with adverse pathologic features and a more aggressive clinical course,” the investigators pointed out, “with substantially higher rates of locoregional recurrence (13%-41%) and distant metastasis (7%-16%) after surgical resection.”
According to the investigators, previous research has identified several patient factors that predict poor outcomes, such as invasiveness and differentiation, as well as chronic immunosuppression. To build on these data, and, in particular, to determine if immune suppression was linked with poor outcomes, the investigators conducted a retrospective analysis of 205 patients with cSCC-HN.
From this cohort, 72 patients had disease recurrence after surgery and radiotherapy. The average age of the patients was 71 years. About half were immunosuppressed (55.6%). On average, disease recurrence occurred slightly earlier in immunosuppressed patients (9.1 months) than in immunocompetent patients (10.1 months). Most patients had locoregional recurrence first, at rates of 65.6% and 77.5% among immunocompetent and immunosuppressed patients, respectively. Irrespective of immune status, median overall survival was 8.4 months and the 1-year overall survival rate was 43.2%. In contrast with previous findings, immune status was not statistically associated with median overall survival; immunocompetent patients did tend to live longer (12.9 months) than immunosuppressed patients (8.0 months), but this difference carried a P value of .90.
The investigators found that surgical candidacy after recurrence had the strongest impact on survival. Patients with surgically salvageable disease had a median overall survival of 26.1 months, compared with just 4.7 months for those who were not amenable to surgical salvage (P = .01). Among patients with unsalvageable disease, again, immune status did not have a significant impact on outcome.
“This study demonstrates that survival in this population is poor,” the investigators concluded. “Although we hypothesized that immunosuppressed status would be a significant contributor to outcomes in these patients, similar to findings in the upfront treatment setting, the current study suggests that this is not the case.”
The investigators reported clinical trial support from Genentech, Merck, and Bristol-Myers Squibb.
SOURCE: Sun et al. JAMA Derm. 27 Feb 2019. doi: 10.1001/jamadermatol.2018.5453.
FROM JAMA DERMATOLOGY
HAVEN 4: Monthly emicizumab shows value
For many patients with hemophilia A, with or without inhibitors, a monthly emicizumab injection is enough to ensure a high level of bleed control, based on results from the ongoing HAVEN 4 trial.
Most patients reported three or fewer treated bleeds, while slightly more than half had no treated bleeds at all, according to lead author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor, and his colleagues. The investigators noted that results from this trial have already led to approval of a monthly dosing schedule in the United States and several other countries.
“This convenient regimen has the potential to improve the care of patients by decreasing their treatment burden, and increasing uptake and adherence to effective prophylaxis, which is known to decrease the development of debilitating secondary complications,” the investigators wrote. The report is in The Lancet Haematology.
The data were collected at 20 centers in 8 countries. Eligibility required that patients have severe congenital hemophilia A (less than 1% normal FVIII activity), or hemophilia A with FVIII inhibitors and concurrent treatment with bypassing agents or FVIII concentrates.
An initial run-in cohort that included seven patients assessed pharmacokinetics and safety. These patients received 6 mg/kg of emicizumab subcutaneously every 4 weeks for at least 24 weeks. After this group showed good responses, 41 additional patients were enrolled in an expansion cohort, which involved an initial loading phase of weekly doses at 3 mg/kg for the first month, followed by monthly dosing at 6 mg/kg for at least 6 months (24 weeks).
The efficacy endpoint of the study was bleed prevention, as measured by treated target joint bleeds, treated joint bleeds, treated spontaneous bleeds, all bleeds (untreated and treated), and annualized bleed rates for treated bleeds.
In the expansion cohort, the median number of bleeds in the 24-week period preceding enrollment was five. In the same group, five patients (12%) had FVIII inhibitors and 61% of patients exhibited at least one target joint.
After a median treatment of 25.6 weeks, the model-based annualized bleed rate for treated bleeds was 2.4, while the median annualized bleed rate was zero.
Slightly more than half of the patients (56.1%) reported no treated bleeds, 90% of patients reported 0-3 treated bleeds, and 85% of patients did not require treatment for targeted joint bleeds.
When untreated bleeds were included, the model-based annualized bleed rate was 4.5, while the median annualized bleed rate was 2.1. Almost one-third of patients (29%) had no bleeding events of any kind and most (80%) had 0-3 treated or untreated bleeds.
Overall, treatment was well tolerated, with no patients withdrawing from the study, discontinuing treatment, or requiring dose modifications. Laboratory parameters remained stable throughout. The most common treatment-related adverse event was injection-site reaction (22%), followed distantly by pre-syncope, chills, rash, and erythema, each of which occurred in 2% of patients.
“Overall, the results of HAVEN 4 are consistent with the findings of other HAVEN studies,” the investigators wrote. “The option of treatment with emicizumab every 4 weeks broadens the range of administration frequencies and allows clinicians to tailor treatment to each patient’s needs and preferences.”
F. Hoffman-La Roche and Chugai funded the study. The investigators reported financial relationships with the study sponsors and other companies.
SOURCE: Pipe SW et al. Lancet Haem. 2019 Apr 16. doi: 10.1016/S2352-3026(19)30054-7.
For many patients with hemophilia A, with or without inhibitors, a monthly emicizumab injection is enough to ensure a high level of bleed control, based on results from the ongoing HAVEN 4 trial.
Most patients reported three or fewer treated bleeds, while slightly more than half had no treated bleeds at all, according to lead author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor, and his colleagues. The investigators noted that results from this trial have already led to approval of a monthly dosing schedule in the United States and several other countries.
“This convenient regimen has the potential to improve the care of patients by decreasing their treatment burden, and increasing uptake and adherence to effective prophylaxis, which is known to decrease the development of debilitating secondary complications,” the investigators wrote. The report is in The Lancet Haematology.
The data were collected at 20 centers in 8 countries. Eligibility required that patients have severe congenital hemophilia A (less than 1% normal FVIII activity), or hemophilia A with FVIII inhibitors and concurrent treatment with bypassing agents or FVIII concentrates.
An initial run-in cohort that included seven patients assessed pharmacokinetics and safety. These patients received 6 mg/kg of emicizumab subcutaneously every 4 weeks for at least 24 weeks. After this group showed good responses, 41 additional patients were enrolled in an expansion cohort, which involved an initial loading phase of weekly doses at 3 mg/kg for the first month, followed by monthly dosing at 6 mg/kg for at least 6 months (24 weeks).
The efficacy endpoint of the study was bleed prevention, as measured by treated target joint bleeds, treated joint bleeds, treated spontaneous bleeds, all bleeds (untreated and treated), and annualized bleed rates for treated bleeds.
In the expansion cohort, the median number of bleeds in the 24-week period preceding enrollment was five. In the same group, five patients (12%) had FVIII inhibitors and 61% of patients exhibited at least one target joint.
After a median treatment of 25.6 weeks, the model-based annualized bleed rate for treated bleeds was 2.4, while the median annualized bleed rate was zero.
Slightly more than half of the patients (56.1%) reported no treated bleeds, 90% of patients reported 0-3 treated bleeds, and 85% of patients did not require treatment for targeted joint bleeds.
When untreated bleeds were included, the model-based annualized bleed rate was 4.5, while the median annualized bleed rate was 2.1. Almost one-third of patients (29%) had no bleeding events of any kind and most (80%) had 0-3 treated or untreated bleeds.
Overall, treatment was well tolerated, with no patients withdrawing from the study, discontinuing treatment, or requiring dose modifications. Laboratory parameters remained stable throughout. The most common treatment-related adverse event was injection-site reaction (22%), followed distantly by pre-syncope, chills, rash, and erythema, each of which occurred in 2% of patients.
“Overall, the results of HAVEN 4 are consistent with the findings of other HAVEN studies,” the investigators wrote. “The option of treatment with emicizumab every 4 weeks broadens the range of administration frequencies and allows clinicians to tailor treatment to each patient’s needs and preferences.”
F. Hoffman-La Roche and Chugai funded the study. The investigators reported financial relationships with the study sponsors and other companies.
SOURCE: Pipe SW et al. Lancet Haem. 2019 Apr 16. doi: 10.1016/S2352-3026(19)30054-7.
For many patients with hemophilia A, with or without inhibitors, a monthly emicizumab injection is enough to ensure a high level of bleed control, based on results from the ongoing HAVEN 4 trial.
Most patients reported three or fewer treated bleeds, while slightly more than half had no treated bleeds at all, according to lead author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor, and his colleagues. The investigators noted that results from this trial have already led to approval of a monthly dosing schedule in the United States and several other countries.
“This convenient regimen has the potential to improve the care of patients by decreasing their treatment burden, and increasing uptake and adherence to effective prophylaxis, which is known to decrease the development of debilitating secondary complications,” the investigators wrote. The report is in The Lancet Haematology.
The data were collected at 20 centers in 8 countries. Eligibility required that patients have severe congenital hemophilia A (less than 1% normal FVIII activity), or hemophilia A with FVIII inhibitors and concurrent treatment with bypassing agents or FVIII concentrates.
An initial run-in cohort that included seven patients assessed pharmacokinetics and safety. These patients received 6 mg/kg of emicizumab subcutaneously every 4 weeks for at least 24 weeks. After this group showed good responses, 41 additional patients were enrolled in an expansion cohort, which involved an initial loading phase of weekly doses at 3 mg/kg for the first month, followed by monthly dosing at 6 mg/kg for at least 6 months (24 weeks).
The efficacy endpoint of the study was bleed prevention, as measured by treated target joint bleeds, treated joint bleeds, treated spontaneous bleeds, all bleeds (untreated and treated), and annualized bleed rates for treated bleeds.
In the expansion cohort, the median number of bleeds in the 24-week period preceding enrollment was five. In the same group, five patients (12%) had FVIII inhibitors and 61% of patients exhibited at least one target joint.
After a median treatment of 25.6 weeks, the model-based annualized bleed rate for treated bleeds was 2.4, while the median annualized bleed rate was zero.
Slightly more than half of the patients (56.1%) reported no treated bleeds, 90% of patients reported 0-3 treated bleeds, and 85% of patients did not require treatment for targeted joint bleeds.
When untreated bleeds were included, the model-based annualized bleed rate was 4.5, while the median annualized bleed rate was 2.1. Almost one-third of patients (29%) had no bleeding events of any kind and most (80%) had 0-3 treated or untreated bleeds.
Overall, treatment was well tolerated, with no patients withdrawing from the study, discontinuing treatment, or requiring dose modifications. Laboratory parameters remained stable throughout. The most common treatment-related adverse event was injection-site reaction (22%), followed distantly by pre-syncope, chills, rash, and erythema, each of which occurred in 2% of patients.
“Overall, the results of HAVEN 4 are consistent with the findings of other HAVEN studies,” the investigators wrote. “The option of treatment with emicizumab every 4 weeks broadens the range of administration frequencies and allows clinicians to tailor treatment to each patient’s needs and preferences.”
F. Hoffman-La Roche and Chugai funded the study. The investigators reported financial relationships with the study sponsors and other companies.
SOURCE: Pipe SW et al. Lancet Haem. 2019 Apr 16. doi: 10.1016/S2352-3026(19)30054-7.
FROM THE LANCET HAEMATOLOGY
PAP may reduce mortality in patients with obesity and severe OSA
according to the results of a cohort study published in JAMA Otolaryngology–Head & Neck Surgery.
The association becomes evident several years after positive airway pressure (PAP) initiation, according to the researchers. Obstructive sleep apnea (OSA) is among the top 10 modifiable cardiovascular risk factors, and is associated with increased risks of coronary artery disease, stroke, and death. PAP is the most effective treatment for OSA, but this treatment’s effect on all-cause and cardiovascular mortality is uncertain. Randomized trials have yielded inconclusive answers to this question, and evidence from observational studies has been weak.
To investigate the association between PAP prescription and mortality in patients with obesity and severe OSA, Quentin Lisan, MD, of the Paris Cardiovascular Research Center and his colleagues conducted a multicenter, population-based cohort study. The researchers examined data for 392 participants in the Sleep Heart Health Study, in which adult men and women age 40 years or older were recruited from nine population-based studies between 1995 and 1998 and followed for a mean of 11.1 years. With each participant who had been prescribed PAP, the investigators matched as many as four participants who had not been prescribed PAP, on the basis of age, sex, and apnea-hypopnea index. Of this sample, 81 patients were prescribed PAP, and 311 were not.
All participants had a clinic visit and underwent overnight polysomnography at baseline. At 2-3 years, participants had a follow-up visit or phone call, during which they were asked whether their physicians had prescribed PAP. Participants were monitored for cardiovascular and all-cause mortality.
In all, 319 of the 392 participants were men; the population’s mean age was 63 years. Patients who had received a PAP prescription had a higher body mass index and more education, compared with patients who had not received a prescription. Mean follow-up duration was 11.6 years in the PAP-prescribed group and 10.9 years in the nonprescribed group.
A total of 96 deaths occurred during follow-up: 12 in the PAP-prescribed group and 84 in the nonprescribed PAP group. The crude incidence rate of mortality was 24.7 deaths per 1,000 person-years in the nonprescribed group and 12.8 deaths per 1,000 person-years in the PAP-prescribed group. The difference in survival between the prescribed and nonprescribed groups was evident in survival curves after 6-7 years of follow-up. After adjustments for prevalent cardiovascular disease, hypertension, diabetes, body mass index, education level, smoking status, and alcohol consumption, the hazard ratio of all-cause mortality for the prescribed group was 0.38, compared with the nonprescribed group.
Dr. Lisan and his colleagues identified 27 deaths of cardiovascular origin, one of which occurred in the prescribed group. After adjusting for prevalent cardiovascular disease, the hazard ratio of cardiovascular mortality for the prescribed group was 0.06, compared with the nonprescribed group.
One reason that the reduction in mortality associated with PAP was not found in previous randomized, controlled trials could be that their mean length of follow-up was not long enough, the researchers wrote. For example, the mean length of follow-up in the SAVE trial was 3.7 years, but the survival benefit was not apparent in the present analysis until 6-7 years after treatment initiation.
These results are exploratory and require confirmation in future research, Dr. Lisan and his colleagues wrote. No information on adherence to PAP was available, and the researchers could not account for initiation and interruption of PAP therapy. Nevertheless, “prescribing PAP in patients with OSA should be pursued and encouraged, given its potential major public health implication,” they concluded.
The Sleep Heart Health Study was supported by grants from the National Institutes of Health.
SOURCE: Lisan Q et al. JAMA Otolaryngol Head Neck Surg. 2019 Apr 11. doi: 10.1001/jamaoto.2019.0281.
Further confirmation of the benefits of positive airway pressure (PAP) on mortality in patients with obstructive sleep apnea (OSA) may follow the results published by Lisan et al., wrote Clete A. Kushida, MD, PhD, in an accompanying editorial. Dr. Kushida is a professor of psychiatry and behavioral sciences at Stanford (Calif.) University. “Of the study limitations described by Lisan et al., a major factor is the participants’ use of PAP therapy: The participants self-reported if they were prescribed PAP therapy, but their PAP adherence data (i.e., duration and frequency of PAP use) were unknown. Discrepancies exist between self-reported versus objective PAP adherence, as well as between patterns of PAP adherence over time, and the lack of adherence data would be expected to limit our understanding of the effects of PAP therapy on mortality.” A further limitation is that the study’s findings are restricted to patients with obesity and severe OSA.
“Even taking into consideration the technological improvement in size, comfort, and convenience of these devices since PAP was first tried on patients with OSA, every knowledgeable sleep specialist has had difficulty in convincing some patients of the need to treat their OSA with these devices, and/or the need to improve their use of the devices once they have been prescribed,” Dr. Kushida continued. “Although at this point experienced sleep specialists cannot say with certainty that use of PAP improves survival, the study by Lisan et al. will undoubtedly make these clinicians’ jobs a little easier by enabling them to present to their patients evidence that PAP may be associated with reduced mortality, particularly in those with severe OSA and comorbid obesity.”
Dr. Kushida receives salary support from a contract between Stanford University and Philips-Respironics for the conduct of a clinical trial. These comments are from an accompanying editorial (JAMA Otolaryngol Head Neck Surg. 2019 April 11. doi: 10.1001/jamaoto.2019.0345).
Further confirmation of the benefits of positive airway pressure (PAP) on mortality in patients with obstructive sleep apnea (OSA) may follow the results published by Lisan et al., wrote Clete A. Kushida, MD, PhD, in an accompanying editorial. Dr. Kushida is a professor of psychiatry and behavioral sciences at Stanford (Calif.) University. “Of the study limitations described by Lisan et al., a major factor is the participants’ use of PAP therapy: The participants self-reported if they were prescribed PAP therapy, but their PAP adherence data (i.e., duration and frequency of PAP use) were unknown. Discrepancies exist between self-reported versus objective PAP adherence, as well as between patterns of PAP adherence over time, and the lack of adherence data would be expected to limit our understanding of the effects of PAP therapy on mortality.” A further limitation is that the study’s findings are restricted to patients with obesity and severe OSA.
“Even taking into consideration the technological improvement in size, comfort, and convenience of these devices since PAP was first tried on patients with OSA, every knowledgeable sleep specialist has had difficulty in convincing some patients of the need to treat their OSA with these devices, and/or the need to improve their use of the devices once they have been prescribed,” Dr. Kushida continued. “Although at this point experienced sleep specialists cannot say with certainty that use of PAP improves survival, the study by Lisan et al. will undoubtedly make these clinicians’ jobs a little easier by enabling them to present to their patients evidence that PAP may be associated with reduced mortality, particularly in those with severe OSA and comorbid obesity.”
Dr. Kushida receives salary support from a contract between Stanford University and Philips-Respironics for the conduct of a clinical trial. These comments are from an accompanying editorial (JAMA Otolaryngol Head Neck Surg. 2019 April 11. doi: 10.1001/jamaoto.2019.0345).
Further confirmation of the benefits of positive airway pressure (PAP) on mortality in patients with obstructive sleep apnea (OSA) may follow the results published by Lisan et al., wrote Clete A. Kushida, MD, PhD, in an accompanying editorial. Dr. Kushida is a professor of psychiatry and behavioral sciences at Stanford (Calif.) University. “Of the study limitations described by Lisan et al., a major factor is the participants’ use of PAP therapy: The participants self-reported if they were prescribed PAP therapy, but their PAP adherence data (i.e., duration and frequency of PAP use) were unknown. Discrepancies exist between self-reported versus objective PAP adherence, as well as between patterns of PAP adherence over time, and the lack of adherence data would be expected to limit our understanding of the effects of PAP therapy on mortality.” A further limitation is that the study’s findings are restricted to patients with obesity and severe OSA.
“Even taking into consideration the technological improvement in size, comfort, and convenience of these devices since PAP was first tried on patients with OSA, every knowledgeable sleep specialist has had difficulty in convincing some patients of the need to treat their OSA with these devices, and/or the need to improve their use of the devices once they have been prescribed,” Dr. Kushida continued. “Although at this point experienced sleep specialists cannot say with certainty that use of PAP improves survival, the study by Lisan et al. will undoubtedly make these clinicians’ jobs a little easier by enabling them to present to their patients evidence that PAP may be associated with reduced mortality, particularly in those with severe OSA and comorbid obesity.”
Dr. Kushida receives salary support from a contract between Stanford University and Philips-Respironics for the conduct of a clinical trial. These comments are from an accompanying editorial (JAMA Otolaryngol Head Neck Surg. 2019 April 11. doi: 10.1001/jamaoto.2019.0345).
according to the results of a cohort study published in JAMA Otolaryngology–Head & Neck Surgery.
The association becomes evident several years after positive airway pressure (PAP) initiation, according to the researchers. Obstructive sleep apnea (OSA) is among the top 10 modifiable cardiovascular risk factors, and is associated with increased risks of coronary artery disease, stroke, and death. PAP is the most effective treatment for OSA, but this treatment’s effect on all-cause and cardiovascular mortality is uncertain. Randomized trials have yielded inconclusive answers to this question, and evidence from observational studies has been weak.
To investigate the association between PAP prescription and mortality in patients with obesity and severe OSA, Quentin Lisan, MD, of the Paris Cardiovascular Research Center and his colleagues conducted a multicenter, population-based cohort study. The researchers examined data for 392 participants in the Sleep Heart Health Study, in which adult men and women age 40 years or older were recruited from nine population-based studies between 1995 and 1998 and followed for a mean of 11.1 years. With each participant who had been prescribed PAP, the investigators matched as many as four participants who had not been prescribed PAP, on the basis of age, sex, and apnea-hypopnea index. Of this sample, 81 patients were prescribed PAP, and 311 were not.
All participants had a clinic visit and underwent overnight polysomnography at baseline. At 2-3 years, participants had a follow-up visit or phone call, during which they were asked whether their physicians had prescribed PAP. Participants were monitored for cardiovascular and all-cause mortality.
In all, 319 of the 392 participants were men; the population’s mean age was 63 years. Patients who had received a PAP prescription had a higher body mass index and more education, compared with patients who had not received a prescription. Mean follow-up duration was 11.6 years in the PAP-prescribed group and 10.9 years in the nonprescribed group.
A total of 96 deaths occurred during follow-up: 12 in the PAP-prescribed group and 84 in the nonprescribed PAP group. The crude incidence rate of mortality was 24.7 deaths per 1,000 person-years in the nonprescribed group and 12.8 deaths per 1,000 person-years in the PAP-prescribed group. The difference in survival between the prescribed and nonprescribed groups was evident in survival curves after 6-7 years of follow-up. After adjustments for prevalent cardiovascular disease, hypertension, diabetes, body mass index, education level, smoking status, and alcohol consumption, the hazard ratio of all-cause mortality for the prescribed group was 0.38, compared with the nonprescribed group.
Dr. Lisan and his colleagues identified 27 deaths of cardiovascular origin, one of which occurred in the prescribed group. After adjusting for prevalent cardiovascular disease, the hazard ratio of cardiovascular mortality for the prescribed group was 0.06, compared with the nonprescribed group.
One reason that the reduction in mortality associated with PAP was not found in previous randomized, controlled trials could be that their mean length of follow-up was not long enough, the researchers wrote. For example, the mean length of follow-up in the SAVE trial was 3.7 years, but the survival benefit was not apparent in the present analysis until 6-7 years after treatment initiation.
These results are exploratory and require confirmation in future research, Dr. Lisan and his colleagues wrote. No information on adherence to PAP was available, and the researchers could not account for initiation and interruption of PAP therapy. Nevertheless, “prescribing PAP in patients with OSA should be pursued and encouraged, given its potential major public health implication,” they concluded.
The Sleep Heart Health Study was supported by grants from the National Institutes of Health.
SOURCE: Lisan Q et al. JAMA Otolaryngol Head Neck Surg. 2019 Apr 11. doi: 10.1001/jamaoto.2019.0281.
according to the results of a cohort study published in JAMA Otolaryngology–Head & Neck Surgery.
The association becomes evident several years after positive airway pressure (PAP) initiation, according to the researchers. Obstructive sleep apnea (OSA) is among the top 10 modifiable cardiovascular risk factors, and is associated with increased risks of coronary artery disease, stroke, and death. PAP is the most effective treatment for OSA, but this treatment’s effect on all-cause and cardiovascular mortality is uncertain. Randomized trials have yielded inconclusive answers to this question, and evidence from observational studies has been weak.
To investigate the association between PAP prescription and mortality in patients with obesity and severe OSA, Quentin Lisan, MD, of the Paris Cardiovascular Research Center and his colleagues conducted a multicenter, population-based cohort study. The researchers examined data for 392 participants in the Sleep Heart Health Study, in which adult men and women age 40 years or older were recruited from nine population-based studies between 1995 and 1998 and followed for a mean of 11.1 years. With each participant who had been prescribed PAP, the investigators matched as many as four participants who had not been prescribed PAP, on the basis of age, sex, and apnea-hypopnea index. Of this sample, 81 patients were prescribed PAP, and 311 were not.
All participants had a clinic visit and underwent overnight polysomnography at baseline. At 2-3 years, participants had a follow-up visit or phone call, during which they were asked whether their physicians had prescribed PAP. Participants were monitored for cardiovascular and all-cause mortality.
In all, 319 of the 392 participants were men; the population’s mean age was 63 years. Patients who had received a PAP prescription had a higher body mass index and more education, compared with patients who had not received a prescription. Mean follow-up duration was 11.6 years in the PAP-prescribed group and 10.9 years in the nonprescribed group.
A total of 96 deaths occurred during follow-up: 12 in the PAP-prescribed group and 84 in the nonprescribed PAP group. The crude incidence rate of mortality was 24.7 deaths per 1,000 person-years in the nonprescribed group and 12.8 deaths per 1,000 person-years in the PAP-prescribed group. The difference in survival between the prescribed and nonprescribed groups was evident in survival curves after 6-7 years of follow-up. After adjustments for prevalent cardiovascular disease, hypertension, diabetes, body mass index, education level, smoking status, and alcohol consumption, the hazard ratio of all-cause mortality for the prescribed group was 0.38, compared with the nonprescribed group.
Dr. Lisan and his colleagues identified 27 deaths of cardiovascular origin, one of which occurred in the prescribed group. After adjusting for prevalent cardiovascular disease, the hazard ratio of cardiovascular mortality for the prescribed group was 0.06, compared with the nonprescribed group.
One reason that the reduction in mortality associated with PAP was not found in previous randomized, controlled trials could be that their mean length of follow-up was not long enough, the researchers wrote. For example, the mean length of follow-up in the SAVE trial was 3.7 years, but the survival benefit was not apparent in the present analysis until 6-7 years after treatment initiation.
These results are exploratory and require confirmation in future research, Dr. Lisan and his colleagues wrote. No information on adherence to PAP was available, and the researchers could not account for initiation and interruption of PAP therapy. Nevertheless, “prescribing PAP in patients with OSA should be pursued and encouraged, given its potential major public health implication,” they concluded.
The Sleep Heart Health Study was supported by grants from the National Institutes of Health.
SOURCE: Lisan Q et al. JAMA Otolaryngol Head Neck Surg. 2019 Apr 11. doi: 10.1001/jamaoto.2019.0281.
FROM JAMA OTOLARYNGOLOGY–HEAD & NECK SURGERY
Beyond disclosure: Industry relationships face renewed scrutiny in oncology
Just as conflict of interest (COI) disclosure has moved center stage in recent months, so too have certain physician-industry relationships. Some cancer centers and academic medical institutions across the country have reinvigorated or renewed discussions about the participation of leaders on outside corporate boards and about how to best navigate an increasingly complex web of individual and institutional relationships with industry.
Memorial Sloan Kettering Cancer Center (MSK), which was thrust into the spotlight last fall with news coverage of a top leader’s disclosure failures and coverage of other leaders’ financial relationships with start-up companies, has decided that its senior executives may no longer serve on boards of directors of for-profit health- or science-related companies.
MSK officials also decided that its board members may not serve on the boards of MSK-affiliated start-up companies or make any direct investments in them.
Other institutions, such as the Fred Hutchinson Cancer Research Center in Seattle, were also reviewing their conflict of interest policies.
Participation of academic medical center leaders on the boards of public companies is one of the “most important topics” of discussion – along with disclosure – among those who oversee and manage COI through institutional research offices and COI committees, said Raed Dweik, MD, MBA, chair of Cleveland Clinic’s Innovation Management and COI Committee.
Discussions cover “whether [participation on outside boards] should be allowed in the first place, how relationships should be managed if they’re allowed, and whether there should be limits on compensation,” said Dr. Dweik, who also chairs the American Association of Medical Colleges’ Forum on Conflict of Interest in Academe, a group of over 600 representatives from academic health centers, medical schools, teaching hospitals, and other hospitals and centers with substantive research programs.
Institutions have been grappling with these issues for years. But “what was reported [about] MSK has brought these topics into hyperfocus in a way,” he said, along with questions concerning the magnitude of compensation and financial interest more broadly.
Institutional approaches
One of the reports on MSK’s financial ties involved a vice president and expert in technology transfer who was appointed to the board of a biotech company, Y-mAbs, in which MSK had an equity stake; the vice president had stock options that soared when the start-up went public. (He later turned over a nearly $1.4 million windfall profit to the hospital.)
In addition to barring appointments of its leaders to boards of MSK start-ups and any direct investments in them, MSK announced that going forward, “any potential equity that could be attained by employees appointed as MSK designees to outside boards will be returned to the institution and dedicated to research.”
A letter to MSK staff also said that “when profits emerge through the monetization of our research, financial payments to MSK-designated board members should be used for the benefit of the institution.”
Broadly speaking, conflict of interest deliberations within institutions center on how financial relationships with industry can potentially compromise the integrity of research (from patient selection to data analysis and the reporting of findings), the safety of research subjects and other patients, and the protection of public trust in physicians and their institutions.
Public trust is important, said Heather Pierce, JD, MPH, senior director of science policy and regulatory counsel for the Association of American Medical Colleges.
“In some cases, institutions may decide,” she said, “that they can control for any potential bias in research, but they can’t control for a perception that a person should not be engaged, or should not be compensated by a company because of appearance.”
Institutions are guided by federal regulations and institutional considerations that deal mainly with “how to evaluate and assess [potential conflicts] and the types of information needed [to do so] – not with specific delineations on what types of relationships are prohibited or not,” said Ms. Pierce. “There are some bright lines, but most things are a lot more complicated.”
Since 2001, the AAMC has recommended the use of a rebuttable presumption framework, in which individuals with a financial interest are prohibited from participating in related research unless “compelling circumstances” justify an exemption. Institutions typically use a “de minimis threshold” to define what financial interests are significant enough for application of the rebuttable presumptions framework.
Cleveland Clinic’s COI Committee considers anything above $20,000 from one company to be significant for the purposes of rebuttable presumption. Compensation between $5,000 and $20,000 (per company per year) triggers a COI management plan that typically focuses on disclosure, but can also include elements such as limits on compensation or the involvement of nonconflicted individuals in data analysis, Dr. Dweik said.
“Anything above $20,000, or equity, we more deeply scrutinize,” he said. “You have to have a really good reason to participate in research related to that company or product. There have to be compelling circumstances.”
Any amount of equity, he emphasized, “is automatically treated as high compensation, because the potential value is high. We are very keenly aware of this in our decisions about what research goes through and what doesn’t.”
Compensation of $5,000 or less is generally considered low at Cleveland Clinic and other institutions (and not in need of COI management), in keeping with U.S. Department of Health and Human Services regulations designed to promote objectivity in research. Thresholds for rebuttable presumption vary from institution to institution, with some being much higher – around $50,000 – than at the Cleveland Clinic, said Dr. Dweik, a pulmonary and critical care medicine specialist who chairs the clinic’s Respiratory Institute.
The big challenge with industry ties involving key executives and leaders – chief medical officers, deans, department chairs, and division chiefs – is that these ties involve institutional COI (not only individual COI) since an individual’s conflicts can be imputed to the institution.
Institutional COI issues generally are much “trickier” for the AAMC’s COI forum to discuss and guide because institutions have different structures and cultures, Dr. Dweik said. Institutional start-ups, moreover, have no standard structure.
“Some institutions, once a company is spun off, will build a firewall between the institution and the company,” he said. “Some institutions will keep the company embedded within the inventor’s lab, or provide infrastructure. And there’s a lot in between.”
Regarding the participation of academic medical center leaders on outside boards, it appears “that institutions are all over the map” in how they regard and evaluate such relationships, Dr. Dweik said. Some institutions address these relationships in their COI policies, while others don’t. And “some are more liberal,” he said. “Others are stricter.”
The magnitude of personal financial interest among MSK leaders (both in institutional start-ups and other companies) is “way outside the norm,” Dr. Dweik said.
Still, board participation can be quite lucrative. One study described in a research letter in JAMA 2014;311[13]:1353-5 5 years ago reported that the mean financial compensation of pharmaceutical company board members who held academic medical center leadership positions was more than $300,000 corporate board participation is “one of the most egregious examples of conflict of interest,” said Vinay Prasad, MD, MPH , a hematologist-oncologist and associate professor of medicine at Oregon Health & Science University, who researches COI and bias. “You have a fiduciary duty to the company’s best interest. … so there will inevitably be a tension between that oath and your other duties,” from responsibilities for institutional oversight to one’s individual research and clinical practices, he said. Physicians at academic medical centers and cancer centers “need to interact with industry,” he said. “But it’s about creating independence.”
A muddied field
S. Vincent Rajkumar, MD, a hematologist-oncologist and active researcher at the Mayo Clinic in Rochester, agrees. “Being on the board of directors of a pharmaceutical company, particularly by institutional leaders, is one of the genuine COIs” amid a field of COI that’s become increasingly muddied with the shift toward more comprehensive, general disclosure practices.
“It’s important that we don’t lose sight of clarity in what types of financial ties and relationships we’re really concerned about,” he said. “The ties that are really concerning – the significant conflicts of interest – are serving on boards of companies or getting large personal payments for participating in speakers’ bureaus or single, company-sponsored CME lectures, for instance, or having stocks, investments, or significant royalties or large payments to your lab or research program [outside of clinical trial funding].”
Other financial transactions such as “reasonable” payments for participation in data-monitoring committees and steering committees are financial ties that should be disclosed, but generally aren’t concerning, Dr. Rajkumar said.
Dr. Rajkumar serves as an editor-in-chief of the Blood Cancer Journal and is an author of several UptoDate chapters. Because of these roles and in keeping with his own views on COI, he has worked deliberately over the past decade to be free of industry payments.
This has become increasingly difficult given the breadth of payments attributed to individual physicians on the federal Open Payments website – some of which are “not truly personal financial ties.” He cited industry payments to support multicompany-sponsored meetings or to institutions for clinical trials.
“It’s nearly impossible to have zero dollars against your name unless you do no clinical trials,” Dr. Rajkumar said.
Still, he said, transparency and disclosure programs like Open Payments are important. “I do think bias arising from COI is very real. There are people with significant conflicts of interest who are writing influential reviews, speaking at influential meetings, and writing influential guidelines – and you can sense the bias pretty quickly,” he said, with endpoints that aren’t appropriate for the trial at hand, for instance, or with overly rosy assessments and the exclusion of negative results.
Collaboration benefits
But Thomas Stossel, MD, American Cancer Society Professor of Medicine Emeritus at Harvard Medical School and founder and chief science advisor at BioAegis Therapeutics, worries that the benefit of physician-industry collaboration is being drowned out with all the attention paid to COI.
His experience on a scientific advisory board in the late 1980s was a “transforming experience that opened my eyes to [the complexities] of product development. … and [later] enabled me to turn my basic research into a potentially life-saving product,” he said.
The “conflict-of-interest narrative” falsely maintains that collaboration causes corruption, he said, and the resultant “hand wringing over [assumed risks]” has slowed innovation by preventing or delaying research and development projects. “It’s like death by a thousand cuts,” said Dr. Stossel, who wrote a book, Pharmacophobia – How the Conflict-of-Interest Myth Undermines American Medical Innovation, to document his concerns.
Dr. Dweik said he has seen the “field move in a good direction” with most academic institutions now deeming physician participation in drug company speakers’ bureaus as “no longer acceptable,” unless physicians discuss drugs in balanced, “disease-specific, not drug-specific” presentations. At this point, it’s unclear exactly how the needle will move on other types of relationships.
“I wouldn’t be surprised if over the next couple of years there is more consistency, more standardization” on issues of participation on outside boards. “The [academic medical center] community is certainly trying to get a better handle on this,” Dr. Dweik said.
Future institutional changes will come, said Ms. Pierce of the AAMC, “but in more subtle ways than we’ve seen in the past, given [progress] already made” through major reports, guidance, and laws and regulations relating to COI. Today, she said, “technology transfer is incrementally more complicated, relationships are more complicated, and corporate structures are more complicated. This makes teasing apart what the issues are a little bit harder.”
Just as conflict of interest (COI) disclosure has moved center stage in recent months, so too have certain physician-industry relationships. Some cancer centers and academic medical institutions across the country have reinvigorated or renewed discussions about the participation of leaders on outside corporate boards and about how to best navigate an increasingly complex web of individual and institutional relationships with industry.
Memorial Sloan Kettering Cancer Center (MSK), which was thrust into the spotlight last fall with news coverage of a top leader’s disclosure failures and coverage of other leaders’ financial relationships with start-up companies, has decided that its senior executives may no longer serve on boards of directors of for-profit health- or science-related companies.
MSK officials also decided that its board members may not serve on the boards of MSK-affiliated start-up companies or make any direct investments in them.
Other institutions, such as the Fred Hutchinson Cancer Research Center in Seattle, were also reviewing their conflict of interest policies.
Participation of academic medical center leaders on the boards of public companies is one of the “most important topics” of discussion – along with disclosure – among those who oversee and manage COI through institutional research offices and COI committees, said Raed Dweik, MD, MBA, chair of Cleveland Clinic’s Innovation Management and COI Committee.
Discussions cover “whether [participation on outside boards] should be allowed in the first place, how relationships should be managed if they’re allowed, and whether there should be limits on compensation,” said Dr. Dweik, who also chairs the American Association of Medical Colleges’ Forum on Conflict of Interest in Academe, a group of over 600 representatives from academic health centers, medical schools, teaching hospitals, and other hospitals and centers with substantive research programs.
Institutions have been grappling with these issues for years. But “what was reported [about] MSK has brought these topics into hyperfocus in a way,” he said, along with questions concerning the magnitude of compensation and financial interest more broadly.
Institutional approaches
One of the reports on MSK’s financial ties involved a vice president and expert in technology transfer who was appointed to the board of a biotech company, Y-mAbs, in which MSK had an equity stake; the vice president had stock options that soared when the start-up went public. (He later turned over a nearly $1.4 million windfall profit to the hospital.)
In addition to barring appointments of its leaders to boards of MSK start-ups and any direct investments in them, MSK announced that going forward, “any potential equity that could be attained by employees appointed as MSK designees to outside boards will be returned to the institution and dedicated to research.”
A letter to MSK staff also said that “when profits emerge through the monetization of our research, financial payments to MSK-designated board members should be used for the benefit of the institution.”
Broadly speaking, conflict of interest deliberations within institutions center on how financial relationships with industry can potentially compromise the integrity of research (from patient selection to data analysis and the reporting of findings), the safety of research subjects and other patients, and the protection of public trust in physicians and their institutions.
Public trust is important, said Heather Pierce, JD, MPH, senior director of science policy and regulatory counsel for the Association of American Medical Colleges.
“In some cases, institutions may decide,” she said, “that they can control for any potential bias in research, but they can’t control for a perception that a person should not be engaged, or should not be compensated by a company because of appearance.”
Institutions are guided by federal regulations and institutional considerations that deal mainly with “how to evaluate and assess [potential conflicts] and the types of information needed [to do so] – not with specific delineations on what types of relationships are prohibited or not,” said Ms. Pierce. “There are some bright lines, but most things are a lot more complicated.”
Since 2001, the AAMC has recommended the use of a rebuttable presumption framework, in which individuals with a financial interest are prohibited from participating in related research unless “compelling circumstances” justify an exemption. Institutions typically use a “de minimis threshold” to define what financial interests are significant enough for application of the rebuttable presumptions framework.
Cleveland Clinic’s COI Committee considers anything above $20,000 from one company to be significant for the purposes of rebuttable presumption. Compensation between $5,000 and $20,000 (per company per year) triggers a COI management plan that typically focuses on disclosure, but can also include elements such as limits on compensation or the involvement of nonconflicted individuals in data analysis, Dr. Dweik said.
“Anything above $20,000, or equity, we more deeply scrutinize,” he said. “You have to have a really good reason to participate in research related to that company or product. There have to be compelling circumstances.”
Any amount of equity, he emphasized, “is automatically treated as high compensation, because the potential value is high. We are very keenly aware of this in our decisions about what research goes through and what doesn’t.”
Compensation of $5,000 or less is generally considered low at Cleveland Clinic and other institutions (and not in need of COI management), in keeping with U.S. Department of Health and Human Services regulations designed to promote objectivity in research. Thresholds for rebuttable presumption vary from institution to institution, with some being much higher – around $50,000 – than at the Cleveland Clinic, said Dr. Dweik, a pulmonary and critical care medicine specialist who chairs the clinic’s Respiratory Institute.
The big challenge with industry ties involving key executives and leaders – chief medical officers, deans, department chairs, and division chiefs – is that these ties involve institutional COI (not only individual COI) since an individual’s conflicts can be imputed to the institution.
Institutional COI issues generally are much “trickier” for the AAMC’s COI forum to discuss and guide because institutions have different structures and cultures, Dr. Dweik said. Institutional start-ups, moreover, have no standard structure.
“Some institutions, once a company is spun off, will build a firewall between the institution and the company,” he said. “Some institutions will keep the company embedded within the inventor’s lab, or provide infrastructure. And there’s a lot in between.”
Regarding the participation of academic medical center leaders on outside boards, it appears “that institutions are all over the map” in how they regard and evaluate such relationships, Dr. Dweik said. Some institutions address these relationships in their COI policies, while others don’t. And “some are more liberal,” he said. “Others are stricter.”
The magnitude of personal financial interest among MSK leaders (both in institutional start-ups and other companies) is “way outside the norm,” Dr. Dweik said.
Still, board participation can be quite lucrative. One study described in a research letter in JAMA 2014;311[13]:1353-5 5 years ago reported that the mean financial compensation of pharmaceutical company board members who held academic medical center leadership positions was more than $300,000 corporate board participation is “one of the most egregious examples of conflict of interest,” said Vinay Prasad, MD, MPH , a hematologist-oncologist and associate professor of medicine at Oregon Health & Science University, who researches COI and bias. “You have a fiduciary duty to the company’s best interest. … so there will inevitably be a tension between that oath and your other duties,” from responsibilities for institutional oversight to one’s individual research and clinical practices, he said. Physicians at academic medical centers and cancer centers “need to interact with industry,” he said. “But it’s about creating independence.”
A muddied field
S. Vincent Rajkumar, MD, a hematologist-oncologist and active researcher at the Mayo Clinic in Rochester, agrees. “Being on the board of directors of a pharmaceutical company, particularly by institutional leaders, is one of the genuine COIs” amid a field of COI that’s become increasingly muddied with the shift toward more comprehensive, general disclosure practices.
“It’s important that we don’t lose sight of clarity in what types of financial ties and relationships we’re really concerned about,” he said. “The ties that are really concerning – the significant conflicts of interest – are serving on boards of companies or getting large personal payments for participating in speakers’ bureaus or single, company-sponsored CME lectures, for instance, or having stocks, investments, or significant royalties or large payments to your lab or research program [outside of clinical trial funding].”
Other financial transactions such as “reasonable” payments for participation in data-monitoring committees and steering committees are financial ties that should be disclosed, but generally aren’t concerning, Dr. Rajkumar said.
Dr. Rajkumar serves as an editor-in-chief of the Blood Cancer Journal and is an author of several UptoDate chapters. Because of these roles and in keeping with his own views on COI, he has worked deliberately over the past decade to be free of industry payments.
This has become increasingly difficult given the breadth of payments attributed to individual physicians on the federal Open Payments website – some of which are “not truly personal financial ties.” He cited industry payments to support multicompany-sponsored meetings or to institutions for clinical trials.
“It’s nearly impossible to have zero dollars against your name unless you do no clinical trials,” Dr. Rajkumar said.
Still, he said, transparency and disclosure programs like Open Payments are important. “I do think bias arising from COI is very real. There are people with significant conflicts of interest who are writing influential reviews, speaking at influential meetings, and writing influential guidelines – and you can sense the bias pretty quickly,” he said, with endpoints that aren’t appropriate for the trial at hand, for instance, or with overly rosy assessments and the exclusion of negative results.
Collaboration benefits
But Thomas Stossel, MD, American Cancer Society Professor of Medicine Emeritus at Harvard Medical School and founder and chief science advisor at BioAegis Therapeutics, worries that the benefit of physician-industry collaboration is being drowned out with all the attention paid to COI.
His experience on a scientific advisory board in the late 1980s was a “transforming experience that opened my eyes to [the complexities] of product development. … and [later] enabled me to turn my basic research into a potentially life-saving product,” he said.
The “conflict-of-interest narrative” falsely maintains that collaboration causes corruption, he said, and the resultant “hand wringing over [assumed risks]” has slowed innovation by preventing or delaying research and development projects. “It’s like death by a thousand cuts,” said Dr. Stossel, who wrote a book, Pharmacophobia – How the Conflict-of-Interest Myth Undermines American Medical Innovation, to document his concerns.
Dr. Dweik said he has seen the “field move in a good direction” with most academic institutions now deeming physician participation in drug company speakers’ bureaus as “no longer acceptable,” unless physicians discuss drugs in balanced, “disease-specific, not drug-specific” presentations. At this point, it’s unclear exactly how the needle will move on other types of relationships.
“I wouldn’t be surprised if over the next couple of years there is more consistency, more standardization” on issues of participation on outside boards. “The [academic medical center] community is certainly trying to get a better handle on this,” Dr. Dweik said.
Future institutional changes will come, said Ms. Pierce of the AAMC, “but in more subtle ways than we’ve seen in the past, given [progress] already made” through major reports, guidance, and laws and regulations relating to COI. Today, she said, “technology transfer is incrementally more complicated, relationships are more complicated, and corporate structures are more complicated. This makes teasing apart what the issues are a little bit harder.”
Just as conflict of interest (COI) disclosure has moved center stage in recent months, so too have certain physician-industry relationships. Some cancer centers and academic medical institutions across the country have reinvigorated or renewed discussions about the participation of leaders on outside corporate boards and about how to best navigate an increasingly complex web of individual and institutional relationships with industry.
Memorial Sloan Kettering Cancer Center (MSK), which was thrust into the spotlight last fall with news coverage of a top leader’s disclosure failures and coverage of other leaders’ financial relationships with start-up companies, has decided that its senior executives may no longer serve on boards of directors of for-profit health- or science-related companies.
MSK officials also decided that its board members may not serve on the boards of MSK-affiliated start-up companies or make any direct investments in them.
Other institutions, such as the Fred Hutchinson Cancer Research Center in Seattle, were also reviewing their conflict of interest policies.
Participation of academic medical center leaders on the boards of public companies is one of the “most important topics” of discussion – along with disclosure – among those who oversee and manage COI through institutional research offices and COI committees, said Raed Dweik, MD, MBA, chair of Cleveland Clinic’s Innovation Management and COI Committee.
Discussions cover “whether [participation on outside boards] should be allowed in the first place, how relationships should be managed if they’re allowed, and whether there should be limits on compensation,” said Dr. Dweik, who also chairs the American Association of Medical Colleges’ Forum on Conflict of Interest in Academe, a group of over 600 representatives from academic health centers, medical schools, teaching hospitals, and other hospitals and centers with substantive research programs.
Institutions have been grappling with these issues for years. But “what was reported [about] MSK has brought these topics into hyperfocus in a way,” he said, along with questions concerning the magnitude of compensation and financial interest more broadly.
Institutional approaches
One of the reports on MSK’s financial ties involved a vice president and expert in technology transfer who was appointed to the board of a biotech company, Y-mAbs, in which MSK had an equity stake; the vice president had stock options that soared when the start-up went public. (He later turned over a nearly $1.4 million windfall profit to the hospital.)
In addition to barring appointments of its leaders to boards of MSK start-ups and any direct investments in them, MSK announced that going forward, “any potential equity that could be attained by employees appointed as MSK designees to outside boards will be returned to the institution and dedicated to research.”
A letter to MSK staff also said that “when profits emerge through the monetization of our research, financial payments to MSK-designated board members should be used for the benefit of the institution.”
Broadly speaking, conflict of interest deliberations within institutions center on how financial relationships with industry can potentially compromise the integrity of research (from patient selection to data analysis and the reporting of findings), the safety of research subjects and other patients, and the protection of public trust in physicians and their institutions.
Public trust is important, said Heather Pierce, JD, MPH, senior director of science policy and regulatory counsel for the Association of American Medical Colleges.
“In some cases, institutions may decide,” she said, “that they can control for any potential bias in research, but they can’t control for a perception that a person should not be engaged, or should not be compensated by a company because of appearance.”
Institutions are guided by federal regulations and institutional considerations that deal mainly with “how to evaluate and assess [potential conflicts] and the types of information needed [to do so] – not with specific delineations on what types of relationships are prohibited or not,” said Ms. Pierce. “There are some bright lines, but most things are a lot more complicated.”
Since 2001, the AAMC has recommended the use of a rebuttable presumption framework, in which individuals with a financial interest are prohibited from participating in related research unless “compelling circumstances” justify an exemption. Institutions typically use a “de minimis threshold” to define what financial interests are significant enough for application of the rebuttable presumptions framework.
Cleveland Clinic’s COI Committee considers anything above $20,000 from one company to be significant for the purposes of rebuttable presumption. Compensation between $5,000 and $20,000 (per company per year) triggers a COI management plan that typically focuses on disclosure, but can also include elements such as limits on compensation or the involvement of nonconflicted individuals in data analysis, Dr. Dweik said.
“Anything above $20,000, or equity, we more deeply scrutinize,” he said. “You have to have a really good reason to participate in research related to that company or product. There have to be compelling circumstances.”
Any amount of equity, he emphasized, “is automatically treated as high compensation, because the potential value is high. We are very keenly aware of this in our decisions about what research goes through and what doesn’t.”
Compensation of $5,000 or less is generally considered low at Cleveland Clinic and other institutions (and not in need of COI management), in keeping with U.S. Department of Health and Human Services regulations designed to promote objectivity in research. Thresholds for rebuttable presumption vary from institution to institution, with some being much higher – around $50,000 – than at the Cleveland Clinic, said Dr. Dweik, a pulmonary and critical care medicine specialist who chairs the clinic’s Respiratory Institute.
The big challenge with industry ties involving key executives and leaders – chief medical officers, deans, department chairs, and division chiefs – is that these ties involve institutional COI (not only individual COI) since an individual’s conflicts can be imputed to the institution.
Institutional COI issues generally are much “trickier” for the AAMC’s COI forum to discuss and guide because institutions have different structures and cultures, Dr. Dweik said. Institutional start-ups, moreover, have no standard structure.
“Some institutions, once a company is spun off, will build a firewall between the institution and the company,” he said. “Some institutions will keep the company embedded within the inventor’s lab, or provide infrastructure. And there’s a lot in between.”
Regarding the participation of academic medical center leaders on outside boards, it appears “that institutions are all over the map” in how they regard and evaluate such relationships, Dr. Dweik said. Some institutions address these relationships in their COI policies, while others don’t. And “some are more liberal,” he said. “Others are stricter.”
The magnitude of personal financial interest among MSK leaders (both in institutional start-ups and other companies) is “way outside the norm,” Dr. Dweik said.
Still, board participation can be quite lucrative. One study described in a research letter in JAMA 2014;311[13]:1353-5 5 years ago reported that the mean financial compensation of pharmaceutical company board members who held academic medical center leadership positions was more than $300,000 corporate board participation is “one of the most egregious examples of conflict of interest,” said Vinay Prasad, MD, MPH , a hematologist-oncologist and associate professor of medicine at Oregon Health & Science University, who researches COI and bias. “You have a fiduciary duty to the company’s best interest. … so there will inevitably be a tension between that oath and your other duties,” from responsibilities for institutional oversight to one’s individual research and clinical practices, he said. Physicians at academic medical centers and cancer centers “need to interact with industry,” he said. “But it’s about creating independence.”
A muddied field
S. Vincent Rajkumar, MD, a hematologist-oncologist and active researcher at the Mayo Clinic in Rochester, agrees. “Being on the board of directors of a pharmaceutical company, particularly by institutional leaders, is one of the genuine COIs” amid a field of COI that’s become increasingly muddied with the shift toward more comprehensive, general disclosure practices.
“It’s important that we don’t lose sight of clarity in what types of financial ties and relationships we’re really concerned about,” he said. “The ties that are really concerning – the significant conflicts of interest – are serving on boards of companies or getting large personal payments for participating in speakers’ bureaus or single, company-sponsored CME lectures, for instance, or having stocks, investments, or significant royalties or large payments to your lab or research program [outside of clinical trial funding].”
Other financial transactions such as “reasonable” payments for participation in data-monitoring committees and steering committees are financial ties that should be disclosed, but generally aren’t concerning, Dr. Rajkumar said.
Dr. Rajkumar serves as an editor-in-chief of the Blood Cancer Journal and is an author of several UptoDate chapters. Because of these roles and in keeping with his own views on COI, he has worked deliberately over the past decade to be free of industry payments.
This has become increasingly difficult given the breadth of payments attributed to individual physicians on the federal Open Payments website – some of which are “not truly personal financial ties.” He cited industry payments to support multicompany-sponsored meetings or to institutions for clinical trials.
“It’s nearly impossible to have zero dollars against your name unless you do no clinical trials,” Dr. Rajkumar said.
Still, he said, transparency and disclosure programs like Open Payments are important. “I do think bias arising from COI is very real. There are people with significant conflicts of interest who are writing influential reviews, speaking at influential meetings, and writing influential guidelines – and you can sense the bias pretty quickly,” he said, with endpoints that aren’t appropriate for the trial at hand, for instance, or with overly rosy assessments and the exclusion of negative results.
Collaboration benefits
But Thomas Stossel, MD, American Cancer Society Professor of Medicine Emeritus at Harvard Medical School and founder and chief science advisor at BioAegis Therapeutics, worries that the benefit of physician-industry collaboration is being drowned out with all the attention paid to COI.
His experience on a scientific advisory board in the late 1980s was a “transforming experience that opened my eyes to [the complexities] of product development. … and [later] enabled me to turn my basic research into a potentially life-saving product,” he said.
The “conflict-of-interest narrative” falsely maintains that collaboration causes corruption, he said, and the resultant “hand wringing over [assumed risks]” has slowed innovation by preventing or delaying research and development projects. “It’s like death by a thousand cuts,” said Dr. Stossel, who wrote a book, Pharmacophobia – How the Conflict-of-Interest Myth Undermines American Medical Innovation, to document his concerns.
Dr. Dweik said he has seen the “field move in a good direction” with most academic institutions now deeming physician participation in drug company speakers’ bureaus as “no longer acceptable,” unless physicians discuss drugs in balanced, “disease-specific, not drug-specific” presentations. At this point, it’s unclear exactly how the needle will move on other types of relationships.
“I wouldn’t be surprised if over the next couple of years there is more consistency, more standardization” on issues of participation on outside boards. “The [academic medical center] community is certainly trying to get a better handle on this,” Dr. Dweik said.
Future institutional changes will come, said Ms. Pierce of the AAMC, “but in more subtle ways than we’ve seen in the past, given [progress] already made” through major reports, guidance, and laws and regulations relating to COI. Today, she said, “technology transfer is incrementally more complicated, relationships are more complicated, and corporate structures are more complicated. This makes teasing apart what the issues are a little bit harder.”
VA Weighs Improvements to Disability Determination Process
The severity of traumatic brain injury (TBI) is typically defined at the time of the initial injury, but a diagnosis may not come for months or even years later. Given the complexities of diagnosing what might be a slowly revealed condition, with signs and symptoms that may manifest over time; the need for self-report of symptoms; and the time that might have elapsed since the original injury, a diagnostician needs not only to have experience with TBI but to stay abreast of the state of the science.
As of now, only health care professionals in 4 specialties—neurologist, neurosurgeon, physiatrist, or psychiatrist—are allowed to diagnose TBI in the VA’s disability compensation process. A new congressionally mandated report by the National Academies of Sciences, Engineering, and Medicine, though, is advising that it’s training and experience that count, not necessarily the specialty.
In Evaluation of the Disability Determination Process for Traumatic Brain Injury in Veterans, a committee of experts in emergency medicine, neurology, neurosurgery, psychiatry, psychology, physical medicine and rehabilitation, and epidemiology and biostatistics review the process and current literature on TBI. The committee advises that any health care professional with “pertinent and ongoing brain injury training and experience” and up-to-date knowledge about TBI should be included in the diagnostic process.
The disability compensation is a tax-free benefit paid to veterans with disabilities resulting from disease or injury incurred or aggravated during active military service. The amount is determined in a 6-step process beginning when the veteran (or a proxy) files a claim. An approved clinician typically must diagnose and evaluate the degree of impairment, functional limitation, and disability.
Between 2000 and 2018, an estimated 384,000 incidents of TBI occurred in the military. That increasing prevalence means more medical specialties now include TBI training in their curriculum. The committee notes that at least 18 brain injury programs are accredited by the Accreditation Council for Graduate Medical Education to train physicians in many specialties to diagnose, treat, and rehabilitate patients with brain injury.
Among other recommendations, the committee advised that the VA take specific actions to increase transparency at both individual and systemwide levels, such as providing veterans full access to the details of their examinations, allowing veterans to rate the quality of their evaluations, and providing public access to detailed systemwide data on the outcomes of evaluations and outcome quality. Those changes will represent a “fundamental enhancement” in the quality of disability evaluations, the committee says, which added that shifting from a focus on the consistency of the process and practitioner qualifications to a focus on the accuracy of the outcome of the evaluation will help identify steps or components in the process that warrant improvement.
It also suggested regularly updating the Veteran Affairs Schedule for Rating Disabilities and the Disability Benefits Questionnaires (DBQs) for residuals of TBI to “better reflect the current state of medical knowledge.” The committee found that 3 important residuals of TBI are not adequately covered by any of the existing DBQs: insomnia, vestibular dysfunction, and near-vision dysfunction. Although 4 DBQs (mental disorder, chronic fatigue syndrome, PTSD, and sleep apnea) contain isolated questions related to insomnia and sleep disruption, no single DBQ, the committee says, combines them all “in a way that captures the full extent of disability associated with post-TBI sleep disruption.” Similarly, no single DBQ captures the full extent of disability associated with post-TBI vestibular dysfunction or the disability associated with near-vision dysfunction.
The committee sums up: “[B]y adopting an explicit learning structure in which the reliability and validity of disability determinations are directly assessed, the VA will be able to devote its resources to those modifications and enhancements … that will have the greatest impact in improving the service provided to injured veterans.”
The severity of traumatic brain injury (TBI) is typically defined at the time of the initial injury, but a diagnosis may not come for months or even years later. Given the complexities of diagnosing what might be a slowly revealed condition, with signs and symptoms that may manifest over time; the need for self-report of symptoms; and the time that might have elapsed since the original injury, a diagnostician needs not only to have experience with TBI but to stay abreast of the state of the science.
As of now, only health care professionals in 4 specialties—neurologist, neurosurgeon, physiatrist, or psychiatrist—are allowed to diagnose TBI in the VA’s disability compensation process. A new congressionally mandated report by the National Academies of Sciences, Engineering, and Medicine, though, is advising that it’s training and experience that count, not necessarily the specialty.
In Evaluation of the Disability Determination Process for Traumatic Brain Injury in Veterans, a committee of experts in emergency medicine, neurology, neurosurgery, psychiatry, psychology, physical medicine and rehabilitation, and epidemiology and biostatistics review the process and current literature on TBI. The committee advises that any health care professional with “pertinent and ongoing brain injury training and experience” and up-to-date knowledge about TBI should be included in the diagnostic process.
The disability compensation is a tax-free benefit paid to veterans with disabilities resulting from disease or injury incurred or aggravated during active military service. The amount is determined in a 6-step process beginning when the veteran (or a proxy) files a claim. An approved clinician typically must diagnose and evaluate the degree of impairment, functional limitation, and disability.
Between 2000 and 2018, an estimated 384,000 incidents of TBI occurred in the military. That increasing prevalence means more medical specialties now include TBI training in their curriculum. The committee notes that at least 18 brain injury programs are accredited by the Accreditation Council for Graduate Medical Education to train physicians in many specialties to diagnose, treat, and rehabilitate patients with brain injury.
Among other recommendations, the committee advised that the VA take specific actions to increase transparency at both individual and systemwide levels, such as providing veterans full access to the details of their examinations, allowing veterans to rate the quality of their evaluations, and providing public access to detailed systemwide data on the outcomes of evaluations and outcome quality. Those changes will represent a “fundamental enhancement” in the quality of disability evaluations, the committee says, which added that shifting from a focus on the consistency of the process and practitioner qualifications to a focus on the accuracy of the outcome of the evaluation will help identify steps or components in the process that warrant improvement.
It also suggested regularly updating the Veteran Affairs Schedule for Rating Disabilities and the Disability Benefits Questionnaires (DBQs) for residuals of TBI to “better reflect the current state of medical knowledge.” The committee found that 3 important residuals of TBI are not adequately covered by any of the existing DBQs: insomnia, vestibular dysfunction, and near-vision dysfunction. Although 4 DBQs (mental disorder, chronic fatigue syndrome, PTSD, and sleep apnea) contain isolated questions related to insomnia and sleep disruption, no single DBQ, the committee says, combines them all “in a way that captures the full extent of disability associated with post-TBI sleep disruption.” Similarly, no single DBQ captures the full extent of disability associated with post-TBI vestibular dysfunction or the disability associated with near-vision dysfunction.
The committee sums up: “[B]y adopting an explicit learning structure in which the reliability and validity of disability determinations are directly assessed, the VA will be able to devote its resources to those modifications and enhancements … that will have the greatest impact in improving the service provided to injured veterans.”
The severity of traumatic brain injury (TBI) is typically defined at the time of the initial injury, but a diagnosis may not come for months or even years later. Given the complexities of diagnosing what might be a slowly revealed condition, with signs and symptoms that may manifest over time; the need for self-report of symptoms; and the time that might have elapsed since the original injury, a diagnostician needs not only to have experience with TBI but to stay abreast of the state of the science.
As of now, only health care professionals in 4 specialties—neurologist, neurosurgeon, physiatrist, or psychiatrist—are allowed to diagnose TBI in the VA’s disability compensation process. A new congressionally mandated report by the National Academies of Sciences, Engineering, and Medicine, though, is advising that it’s training and experience that count, not necessarily the specialty.
In Evaluation of the Disability Determination Process for Traumatic Brain Injury in Veterans, a committee of experts in emergency medicine, neurology, neurosurgery, psychiatry, psychology, physical medicine and rehabilitation, and epidemiology and biostatistics review the process and current literature on TBI. The committee advises that any health care professional with “pertinent and ongoing brain injury training and experience” and up-to-date knowledge about TBI should be included in the diagnostic process.
The disability compensation is a tax-free benefit paid to veterans with disabilities resulting from disease or injury incurred or aggravated during active military service. The amount is determined in a 6-step process beginning when the veteran (or a proxy) files a claim. An approved clinician typically must diagnose and evaluate the degree of impairment, functional limitation, and disability.
Between 2000 and 2018, an estimated 384,000 incidents of TBI occurred in the military. That increasing prevalence means more medical specialties now include TBI training in their curriculum. The committee notes that at least 18 brain injury programs are accredited by the Accreditation Council for Graduate Medical Education to train physicians in many specialties to diagnose, treat, and rehabilitate patients with brain injury.
Among other recommendations, the committee advised that the VA take specific actions to increase transparency at both individual and systemwide levels, such as providing veterans full access to the details of their examinations, allowing veterans to rate the quality of their evaluations, and providing public access to detailed systemwide data on the outcomes of evaluations and outcome quality. Those changes will represent a “fundamental enhancement” in the quality of disability evaluations, the committee says, which added that shifting from a focus on the consistency of the process and practitioner qualifications to a focus on the accuracy of the outcome of the evaluation will help identify steps or components in the process that warrant improvement.
It also suggested regularly updating the Veteran Affairs Schedule for Rating Disabilities and the Disability Benefits Questionnaires (DBQs) for residuals of TBI to “better reflect the current state of medical knowledge.” The committee found that 3 important residuals of TBI are not adequately covered by any of the existing DBQs: insomnia, vestibular dysfunction, and near-vision dysfunction. Although 4 DBQs (mental disorder, chronic fatigue syndrome, PTSD, and sleep apnea) contain isolated questions related to insomnia and sleep disruption, no single DBQ, the committee says, combines them all “in a way that captures the full extent of disability associated with post-TBI sleep disruption.” Similarly, no single DBQ captures the full extent of disability associated with post-TBI vestibular dysfunction or the disability associated with near-vision dysfunction.
The committee sums up: “[B]y adopting an explicit learning structure in which the reliability and validity of disability determinations are directly assessed, the VA will be able to devote its resources to those modifications and enhancements … that will have the greatest impact in improving the service provided to injured veterans.”