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Task force advises behavioral intervention for obese adults
The U.S. Preventive Services Task Force advises clinicians to refer or offer intensive behavioral weight-loss interventions to obese adults, according to an updated recommendation statement published in JAMA.
Obesity affects more than one-third of U.S. adults, according to federal statistics. It carries increased risk for comorbidities including heart disease, diabetes, and various cancers, as well as increased risk of death among adults younger than 65 years, noted lead author Susan J. Curry, PhD, of the University of Iowa, Iowa City, and members of the Task Force.
The B recommendation applies to obese adults; obesity was defined as a body mass index of 30 kg/m2 or higher. The evidence review focused on interventions for weight loss and weight maintenance that could be provided in primary care or referred from primary care, such as nutrition counseling, exercise strategies, and goal setting.
The Task Force found adequate evidence that behavior-based weight-loss interventions improved weight, reduced incidence of type 2 diabetes, and helped maintain weight loss after interventions ended.
The Task Force found small to no evidence of harm associated with any of the behavioral weight-loss interventions, which included group sessions, personal sessions, print-based interventions, and technology-based interventions (such as text messages). Although interventions that combined drug therapy with behavioral intervention resulted in greater weight loss over 12-18 months, compared with behavioral interventions alone, the attrition rates were high and data on weight-loss maintenance after discontinuation of the drugs were limited, the Task Force noted.
“As a result, the USPSTF encourages clinicians to promote behavioral interventions as the primary focus of effective interventions for weight loss in adults,” they wrote.
The Task Force acknowledged the need for future research in subgroups and to explore whether factors such as genetics and untreated conditions are barriers to behavior-based weight loss interventions.
In the evidence review published in JAMA, Erin S. LeBlanc, MD, of Kaiser Permanente in Portland, Ore., and her colleagues reviewed data from 122 randomized, controlled trials including more than 62,000 persons and 2 observational studies including more than 209,000 persons.
The researchers found behavioral interventions were associated with greater weight loss and less risk of developing diabetes, compared with control interventions.
Intensive behavioral interventions included counseling patients about healthy eating, encouraging physical activity, setting weight and health goals, and assisting with weight monitoring. The interventions ranged from text messaging to in-person sessions for individuals or groups. The average absolute weight loss in the trials included in the review ranged from –0.5 kg to –9.3 kg (–1.1 lb to –20.5 lb) for intervention patients and from +1.4 kg to –5.6 kg (+3.1 lb to –12.3 lb) in controls.
Limitations of the review included a lack of data on population subgroups and a lack of long-term data on weight and health outcomes, the researchers noted. However, the results support the value of behavior-based therapy for obesity treatment.
The final recommendation is consistent with the 2018 draft recommendation and updates the 2012 final recommendation on obesity management.
The researchers and Task Force members had no relevant financial conflicts to disclose.
SOURCE: U.S. Preventive Services Task Force. JAMA. 2018;320(11):1163-71. doi: 10.1001/jama.2018.13022.
For most primary care clinicians, referring obese patients for more advanced behavioral therapy will be the most practical integration of the recommendation, Susan Z. Yanovski, MD, wrote in an accompanying editorial. Clinicians with training in motivational interviewing or counseling may help assess a patient’s readiness for treatment, but even being familiar with weight-management resources in the community can help patients find the right fit.
“Clinicians can do their patients a great service by showing respect for their patients’ struggles with weight management, screening for obesity-related comorbidities, and providing treatment for identified conditions regardless of the patient’s motivation for, or success with, weight-loss treatment,” she said.
Dr. Yanovski noted that pharmacotherapy options have increased since the 2012 recommendations, when orlistat was the only approved drug for long-term treatment of obesity. Five medications are currently available for this indication.
The USPSTF review was limited in scope for both drug and behavior therapy, noted Dr. Yanovski. “Because the recommendations are meant to apply to adults without diseases for which weight loss is part of disease management, some large and long-term clinical trials conducted among patients with type 2 diabetes or cardiovascular disease were not included.”
Another limitation was the exclusion of surgical treatments as being outside the primary care setting, but bariatric surgery remains a viable option for many patients, especially for prevention or resolution of type 2 diabetes. Primary care clinicians are in a position to identify patients who might benefit and to provide referrals to surgeons if appropriate, she wrote.
Dr. Yanovski agreed with the recommendations but concluded that early strategies to prevent obesity should not be neglected. “Research to develop effective prevention strategies throughout the life course, including infancy and early childhood, could ultimately decrease the number of adults who must confront the difficult challenge of losing excess weight.”
Dr. Yanovski is affiliated with the National Institute of Diabetes and Digestive and Kidney Diseases. She disclosed that her spouse has received research funding from Zafgen and Rhythm Pharmaceuticals for studies of investigational products to treat obesity. Her comments are summarized from an editorial accompanying the articles by Curry SJ et al. and LeBlanc ES et al. (JAMA. 2018;320[11]:1111-3).
For most primary care clinicians, referring obese patients for more advanced behavioral therapy will be the most practical integration of the recommendation, Susan Z. Yanovski, MD, wrote in an accompanying editorial. Clinicians with training in motivational interviewing or counseling may help assess a patient’s readiness for treatment, but even being familiar with weight-management resources in the community can help patients find the right fit.
“Clinicians can do their patients a great service by showing respect for their patients’ struggles with weight management, screening for obesity-related comorbidities, and providing treatment for identified conditions regardless of the patient’s motivation for, or success with, weight-loss treatment,” she said.
Dr. Yanovski noted that pharmacotherapy options have increased since the 2012 recommendations, when orlistat was the only approved drug for long-term treatment of obesity. Five medications are currently available for this indication.
The USPSTF review was limited in scope for both drug and behavior therapy, noted Dr. Yanovski. “Because the recommendations are meant to apply to adults without diseases for which weight loss is part of disease management, some large and long-term clinical trials conducted among patients with type 2 diabetes or cardiovascular disease were not included.”
Another limitation was the exclusion of surgical treatments as being outside the primary care setting, but bariatric surgery remains a viable option for many patients, especially for prevention or resolution of type 2 diabetes. Primary care clinicians are in a position to identify patients who might benefit and to provide referrals to surgeons if appropriate, she wrote.
Dr. Yanovski agreed with the recommendations but concluded that early strategies to prevent obesity should not be neglected. “Research to develop effective prevention strategies throughout the life course, including infancy and early childhood, could ultimately decrease the number of adults who must confront the difficult challenge of losing excess weight.”
Dr. Yanovski is affiliated with the National Institute of Diabetes and Digestive and Kidney Diseases. She disclosed that her spouse has received research funding from Zafgen and Rhythm Pharmaceuticals for studies of investigational products to treat obesity. Her comments are summarized from an editorial accompanying the articles by Curry SJ et al. and LeBlanc ES et al. (JAMA. 2018;320[11]:1111-3).
For most primary care clinicians, referring obese patients for more advanced behavioral therapy will be the most practical integration of the recommendation, Susan Z. Yanovski, MD, wrote in an accompanying editorial. Clinicians with training in motivational interviewing or counseling may help assess a patient’s readiness for treatment, but even being familiar with weight-management resources in the community can help patients find the right fit.
“Clinicians can do their patients a great service by showing respect for their patients’ struggles with weight management, screening for obesity-related comorbidities, and providing treatment for identified conditions regardless of the patient’s motivation for, or success with, weight-loss treatment,” she said.
Dr. Yanovski noted that pharmacotherapy options have increased since the 2012 recommendations, when orlistat was the only approved drug for long-term treatment of obesity. Five medications are currently available for this indication.
The USPSTF review was limited in scope for both drug and behavior therapy, noted Dr. Yanovski. “Because the recommendations are meant to apply to adults without diseases for which weight loss is part of disease management, some large and long-term clinical trials conducted among patients with type 2 diabetes or cardiovascular disease were not included.”
Another limitation was the exclusion of surgical treatments as being outside the primary care setting, but bariatric surgery remains a viable option for many patients, especially for prevention or resolution of type 2 diabetes. Primary care clinicians are in a position to identify patients who might benefit and to provide referrals to surgeons if appropriate, she wrote.
Dr. Yanovski agreed with the recommendations but concluded that early strategies to prevent obesity should not be neglected. “Research to develop effective prevention strategies throughout the life course, including infancy and early childhood, could ultimately decrease the number of adults who must confront the difficult challenge of losing excess weight.”
Dr. Yanovski is affiliated with the National Institute of Diabetes and Digestive and Kidney Diseases. She disclosed that her spouse has received research funding from Zafgen and Rhythm Pharmaceuticals for studies of investigational products to treat obesity. Her comments are summarized from an editorial accompanying the articles by Curry SJ et al. and LeBlanc ES et al. (JAMA. 2018;320[11]:1111-3).
The U.S. Preventive Services Task Force advises clinicians to refer or offer intensive behavioral weight-loss interventions to obese adults, according to an updated recommendation statement published in JAMA.
Obesity affects more than one-third of U.S. adults, according to federal statistics. It carries increased risk for comorbidities including heart disease, diabetes, and various cancers, as well as increased risk of death among adults younger than 65 years, noted lead author Susan J. Curry, PhD, of the University of Iowa, Iowa City, and members of the Task Force.
The B recommendation applies to obese adults; obesity was defined as a body mass index of 30 kg/m2 or higher. The evidence review focused on interventions for weight loss and weight maintenance that could be provided in primary care or referred from primary care, such as nutrition counseling, exercise strategies, and goal setting.
The Task Force found adequate evidence that behavior-based weight-loss interventions improved weight, reduced incidence of type 2 diabetes, and helped maintain weight loss after interventions ended.
The Task Force found small to no evidence of harm associated with any of the behavioral weight-loss interventions, which included group sessions, personal sessions, print-based interventions, and technology-based interventions (such as text messages). Although interventions that combined drug therapy with behavioral intervention resulted in greater weight loss over 12-18 months, compared with behavioral interventions alone, the attrition rates were high and data on weight-loss maintenance after discontinuation of the drugs were limited, the Task Force noted.
“As a result, the USPSTF encourages clinicians to promote behavioral interventions as the primary focus of effective interventions for weight loss in adults,” they wrote.
The Task Force acknowledged the need for future research in subgroups and to explore whether factors such as genetics and untreated conditions are barriers to behavior-based weight loss interventions.
In the evidence review published in JAMA, Erin S. LeBlanc, MD, of Kaiser Permanente in Portland, Ore., and her colleagues reviewed data from 122 randomized, controlled trials including more than 62,000 persons and 2 observational studies including more than 209,000 persons.
The researchers found behavioral interventions were associated with greater weight loss and less risk of developing diabetes, compared with control interventions.
Intensive behavioral interventions included counseling patients about healthy eating, encouraging physical activity, setting weight and health goals, and assisting with weight monitoring. The interventions ranged from text messaging to in-person sessions for individuals or groups. The average absolute weight loss in the trials included in the review ranged from –0.5 kg to –9.3 kg (–1.1 lb to –20.5 lb) for intervention patients and from +1.4 kg to –5.6 kg (+3.1 lb to –12.3 lb) in controls.
Limitations of the review included a lack of data on population subgroups and a lack of long-term data on weight and health outcomes, the researchers noted. However, the results support the value of behavior-based therapy for obesity treatment.
The final recommendation is consistent with the 2018 draft recommendation and updates the 2012 final recommendation on obesity management.
The researchers and Task Force members had no relevant financial conflicts to disclose.
SOURCE: U.S. Preventive Services Task Force. JAMA. 2018;320(11):1163-71. doi: 10.1001/jama.2018.13022.
The U.S. Preventive Services Task Force advises clinicians to refer or offer intensive behavioral weight-loss interventions to obese adults, according to an updated recommendation statement published in JAMA.
Obesity affects more than one-third of U.S. adults, according to federal statistics. It carries increased risk for comorbidities including heart disease, diabetes, and various cancers, as well as increased risk of death among adults younger than 65 years, noted lead author Susan J. Curry, PhD, of the University of Iowa, Iowa City, and members of the Task Force.
The B recommendation applies to obese adults; obesity was defined as a body mass index of 30 kg/m2 or higher. The evidence review focused on interventions for weight loss and weight maintenance that could be provided in primary care or referred from primary care, such as nutrition counseling, exercise strategies, and goal setting.
The Task Force found adequate evidence that behavior-based weight-loss interventions improved weight, reduced incidence of type 2 diabetes, and helped maintain weight loss after interventions ended.
The Task Force found small to no evidence of harm associated with any of the behavioral weight-loss interventions, which included group sessions, personal sessions, print-based interventions, and technology-based interventions (such as text messages). Although interventions that combined drug therapy with behavioral intervention resulted in greater weight loss over 12-18 months, compared with behavioral interventions alone, the attrition rates were high and data on weight-loss maintenance after discontinuation of the drugs were limited, the Task Force noted.
“As a result, the USPSTF encourages clinicians to promote behavioral interventions as the primary focus of effective interventions for weight loss in adults,” they wrote.
The Task Force acknowledged the need for future research in subgroups and to explore whether factors such as genetics and untreated conditions are barriers to behavior-based weight loss interventions.
In the evidence review published in JAMA, Erin S. LeBlanc, MD, of Kaiser Permanente in Portland, Ore., and her colleagues reviewed data from 122 randomized, controlled trials including more than 62,000 persons and 2 observational studies including more than 209,000 persons.
The researchers found behavioral interventions were associated with greater weight loss and less risk of developing diabetes, compared with control interventions.
Intensive behavioral interventions included counseling patients about healthy eating, encouraging physical activity, setting weight and health goals, and assisting with weight monitoring. The interventions ranged from text messaging to in-person sessions for individuals or groups. The average absolute weight loss in the trials included in the review ranged from –0.5 kg to –9.3 kg (–1.1 lb to –20.5 lb) for intervention patients and from +1.4 kg to –5.6 kg (+3.1 lb to –12.3 lb) in controls.
Limitations of the review included a lack of data on population subgroups and a lack of long-term data on weight and health outcomes, the researchers noted. However, the results support the value of behavior-based therapy for obesity treatment.
The final recommendation is consistent with the 2018 draft recommendation and updates the 2012 final recommendation on obesity management.
The researchers and Task Force members had no relevant financial conflicts to disclose.
SOURCE: U.S. Preventive Services Task Force. JAMA. 2018;320(11):1163-71. doi: 10.1001/jama.2018.13022.
FROM JAMA
UN aims to eradicate TB by 2030
A concerted a lethal disease affecting one-quarter of the world’s population by the year 2030.
On September 26 the United Nations General Assembly will convene a high-level meeting of global stakeholders to solidify the eradication plan, addressing the global crisis of tuberculosis (TB), the world’s most deadly infectious disease.
“We must seize the moment,” said Tereza Kasaeva, MD, director of the World Health Organization’s global TB program, speaking at a telebriefing and press conference accompanying the release of the World Health Organization’s annual global tuberculosis report. “It’s unacceptable in the 21st century that millions lose their lives to this preventable and curable disease.”
TB caused 1.6 million deaths globally in 2017, and the World Health Organization (WHO) estimates that of the 10 million new cases of TB last year, 558,000 are multi-drug resistant (MDR) infections.
Though death rates and new cases are falling globally each year, significantly more resources are needed to boost access to preventive treatment for latent TB infection; “Most people needing it are not yet accessing care,” according to the press briefing accompanying the report.
A review and commentary on TB incubation and latency published in BMJ (2018;362:k2738 doi: 10.1136/bmj.k2738; e-pub 23 Aug 2018) has called into question the focus preventive treatment of latent cases at the expense of reaching those most likely to die from TB (e.g., HIV patients, children of individuals living with active TB). The authors state that “latent” TB is identified by indirect evidence of present or past infection with Mycobacterium tuberculosis as inferred by a detectable adaptive immune response to M tuberculosis antigens. Active TB infection is overwhelmingly the result of a primary infection and almost always occurs within two years.
In order to meet the ambitious goal of TB eradication by the year 2030, treatment coverage must rise to 90% globally from the current 64%, according to the report.
Progress in southern Africa and in the Russian Federation, where efforts have led to a 30% reduction in TB mortality and a decrease in incidence of 5% per year, show that steep reductions in TB are possible when resources are brought to bear on the problem, said Dr. Kasaeva. “We should acknowledge that actions in some countries and regions show that progress can accelerate,” she said. Still, she noted, “Four thousand lives per day are lost to TB. Tuberculosis is the leading killer of people living with HIV, and the major cause of deaths related to antimicrobial resistance” at a global level.
Two thirds of all TB cases occur in eight countries, with India, China, and Indonesia leading this group. About half of the cases of MDR TB occur in India, China, and Russia, said Dr. Kasaeva, and globally only one in four individuals with MDR TB who need access to treatment have received it. “We need to urgently tackle the multidrug resistant TB public health crisis,” she said.
Major impediments to successful public health efforts against TB are underdiagnosis and underreporting: It is estimated that 3.6 million of 2017’s 10 million new cases were not officially recorded or reported. Countries where these problems are most serious include India, Indonesia, and Nigeria. Fewer than half of the children with TB are reported globally, according to the report.
People living with HIV/AIDS who are also infected with TB number nearly 1,000,000, but only about half of these were officially reported in 2017.
In terms of prevention priorities, WHO has recommended targeting treatment of latent TB in two groups: People living with HIV/AIDS, and children under the age of 5 years who live in households with TB-infected individuals.
“To enable these actions,” said Dr. Kasaeva, “we need strengthened commitments not just for TB care, but for overall health services. So the aim for universal coverage is real.” Underreporting is particularly prevalent in lower income countries with large unregulated private sectors, she said, though India and Indonesia have taken corrective steps to increase reporting.
A meaningful global initiative will not come cheap: The current annual shortfall in funding for TB prevention, diagnosis, and treatment is about $3.5 billion. By the year 2022, the gap between funding and what’s needed to stay on track for the 2030 target will be over $6 billion, said Dr. Kasaeva.
The best use of increased resources for TB eradication will be in locally focused efforts, said Irene Koek, MD, the United States Agency for International Development’s deputy administrator for global health. “It is likely that each region requires a tailored response.” Further, “to improve quality of care we need to ensure that services are patient centered,” she said at the press conference.
To that end, Dr. Koek expects that at the upcoming high-level meeting, the United Nations member states will be called on to develop an open framework, with clear accountability for monitoring and reviewing progress. The road forward should “celebrate accomplishments and acknowledge shortcomings,” she said. Some recent studies have shown that treatment success rates above 80% for patients with MDR TB can be achieved.
“Lessons learned from these experiences should be documented and shared in order to replicate success globally,” said Dr. Koek.
The United States, said Dr. Koek, is the leading global investor in TB research and treatment. “We welcome increased partnerships, especially with countries with the highest burden, to end global suffering from this disease.”
Eric Goosby, MD, the United Nations special envoy on TB, used his speaking time to lend some perspective to the social framework around TB’s longtime lethality.
There are aspects of TB infection that differentiate it from HIV/AIDS, said Dr. Goosby, who has spent most of his clinical and public health career on HIV/AIDS treatment and prevention. In contrast to an infection that at present requires a lifetime of treatment, TB can ordinarily be treated in 6 months, making it an unpleasant episode that an individual may be eager to move past. Additionally, the fact that TB has had a “hold on the world since the time of the ancient Egyptians” may paradoxically have served to lessen urgency in research and treatment efforts, he noted.
Dr. Goosby also spoke of the stigma surrounding TB, whose sufferers are likely to be facing dire poverty, malnutrition, and other infectious disease burdens. Civil society concerned with TB, he said, has spoken up “for those without a voice, for those who have difficulty advocating for themselves.”
Dr. Kasaeva agreed, noting that TB “affects the poorest of the poor, which makes it extraordinarily difficult for activism to come from that population.”
However, others have spoken for those affected, said Dr. Goosby. “The TB civil society has put its heart and soul this last year into gathering political will from leaders around the world…. It’s not a passive effort; it involves a lot of work.” During the past year of concerted effort, he said, “All of us have known the difficulty of pushing a political leader up that learning curve.”
As the upcoming high-level meeting approaches, those who have been working on the effort can feel the momentum, said Dr. Goosby. Still, he noted, “While there’s a significant step forward, this is not the time for a victory dance. This is really the time for a reflection...Do we understand the burden in our respective countries, and has the response been adequate?”
The goal for the meeting is to have leaders “step up to commit, not for one day, or for one meeting, but for the duration of the effort,” said Dr. Goosby. “We must make sure that the words that we hear next week from our leaders translate into action...Next week the world will say, ‘No more. No longer. No one is immune to TB. Tuberculosis is preventable; tuberculosis is treatable; tuberculosis is curable.’”
The BMJ commentary, by Marcel A. Behr, MD, of McGill International TB Centre, Infectious Diseases and Immunity in Global Health Program, McGill University Health Centre Research Institute, and his colleagues, recommend caution when building a prevention strategy around treating many millions of individuals with “latent” TB. They wrote, “Immunoreactivity to TB does not necessarily indicate the presence of live bacteria, as reactivity can persist after infection has been cleared. Classifying two billion people with evidence of immunoreactivity as having latent TB infection may divert fundamental research and public health interventions away from transmissible active TB disease and newly infected people at highest risk of progression to disease.”
This story was updated on 09/24/2018
A concerted a lethal disease affecting one-quarter of the world’s population by the year 2030.
On September 26 the United Nations General Assembly will convene a high-level meeting of global stakeholders to solidify the eradication plan, addressing the global crisis of tuberculosis (TB), the world’s most deadly infectious disease.
“We must seize the moment,” said Tereza Kasaeva, MD, director of the World Health Organization’s global TB program, speaking at a telebriefing and press conference accompanying the release of the World Health Organization’s annual global tuberculosis report. “It’s unacceptable in the 21st century that millions lose their lives to this preventable and curable disease.”
TB caused 1.6 million deaths globally in 2017, and the World Health Organization (WHO) estimates that of the 10 million new cases of TB last year, 558,000 are multi-drug resistant (MDR) infections.
Though death rates and new cases are falling globally each year, significantly more resources are needed to boost access to preventive treatment for latent TB infection; “Most people needing it are not yet accessing care,” according to the press briefing accompanying the report.
A review and commentary on TB incubation and latency published in BMJ (2018;362:k2738 doi: 10.1136/bmj.k2738; e-pub 23 Aug 2018) has called into question the focus preventive treatment of latent cases at the expense of reaching those most likely to die from TB (e.g., HIV patients, children of individuals living with active TB). The authors state that “latent” TB is identified by indirect evidence of present or past infection with Mycobacterium tuberculosis as inferred by a detectable adaptive immune response to M tuberculosis antigens. Active TB infection is overwhelmingly the result of a primary infection and almost always occurs within two years.
In order to meet the ambitious goal of TB eradication by the year 2030, treatment coverage must rise to 90% globally from the current 64%, according to the report.
Progress in southern Africa and in the Russian Federation, where efforts have led to a 30% reduction in TB mortality and a decrease in incidence of 5% per year, show that steep reductions in TB are possible when resources are brought to bear on the problem, said Dr. Kasaeva. “We should acknowledge that actions in some countries and regions show that progress can accelerate,” she said. Still, she noted, “Four thousand lives per day are lost to TB. Tuberculosis is the leading killer of people living with HIV, and the major cause of deaths related to antimicrobial resistance” at a global level.
Two thirds of all TB cases occur in eight countries, with India, China, and Indonesia leading this group. About half of the cases of MDR TB occur in India, China, and Russia, said Dr. Kasaeva, and globally only one in four individuals with MDR TB who need access to treatment have received it. “We need to urgently tackle the multidrug resistant TB public health crisis,” she said.
Major impediments to successful public health efforts against TB are underdiagnosis and underreporting: It is estimated that 3.6 million of 2017’s 10 million new cases were not officially recorded or reported. Countries where these problems are most serious include India, Indonesia, and Nigeria. Fewer than half of the children with TB are reported globally, according to the report.
People living with HIV/AIDS who are also infected with TB number nearly 1,000,000, but only about half of these were officially reported in 2017.
In terms of prevention priorities, WHO has recommended targeting treatment of latent TB in two groups: People living with HIV/AIDS, and children under the age of 5 years who live in households with TB-infected individuals.
“To enable these actions,” said Dr. Kasaeva, “we need strengthened commitments not just for TB care, but for overall health services. So the aim for universal coverage is real.” Underreporting is particularly prevalent in lower income countries with large unregulated private sectors, she said, though India and Indonesia have taken corrective steps to increase reporting.
A meaningful global initiative will not come cheap: The current annual shortfall in funding for TB prevention, diagnosis, and treatment is about $3.5 billion. By the year 2022, the gap between funding and what’s needed to stay on track for the 2030 target will be over $6 billion, said Dr. Kasaeva.
The best use of increased resources for TB eradication will be in locally focused efforts, said Irene Koek, MD, the United States Agency for International Development’s deputy administrator for global health. “It is likely that each region requires a tailored response.” Further, “to improve quality of care we need to ensure that services are patient centered,” she said at the press conference.
To that end, Dr. Koek expects that at the upcoming high-level meeting, the United Nations member states will be called on to develop an open framework, with clear accountability for monitoring and reviewing progress. The road forward should “celebrate accomplishments and acknowledge shortcomings,” she said. Some recent studies have shown that treatment success rates above 80% for patients with MDR TB can be achieved.
“Lessons learned from these experiences should be documented and shared in order to replicate success globally,” said Dr. Koek.
The United States, said Dr. Koek, is the leading global investor in TB research and treatment. “We welcome increased partnerships, especially with countries with the highest burden, to end global suffering from this disease.”
Eric Goosby, MD, the United Nations special envoy on TB, used his speaking time to lend some perspective to the social framework around TB’s longtime lethality.
There are aspects of TB infection that differentiate it from HIV/AIDS, said Dr. Goosby, who has spent most of his clinical and public health career on HIV/AIDS treatment and prevention. In contrast to an infection that at present requires a lifetime of treatment, TB can ordinarily be treated in 6 months, making it an unpleasant episode that an individual may be eager to move past. Additionally, the fact that TB has had a “hold on the world since the time of the ancient Egyptians” may paradoxically have served to lessen urgency in research and treatment efforts, he noted.
Dr. Goosby also spoke of the stigma surrounding TB, whose sufferers are likely to be facing dire poverty, malnutrition, and other infectious disease burdens. Civil society concerned with TB, he said, has spoken up “for those without a voice, for those who have difficulty advocating for themselves.”
Dr. Kasaeva agreed, noting that TB “affects the poorest of the poor, which makes it extraordinarily difficult for activism to come from that population.”
However, others have spoken for those affected, said Dr. Goosby. “The TB civil society has put its heart and soul this last year into gathering political will from leaders around the world…. It’s not a passive effort; it involves a lot of work.” During the past year of concerted effort, he said, “All of us have known the difficulty of pushing a political leader up that learning curve.”
As the upcoming high-level meeting approaches, those who have been working on the effort can feel the momentum, said Dr. Goosby. Still, he noted, “While there’s a significant step forward, this is not the time for a victory dance. This is really the time for a reflection...Do we understand the burden in our respective countries, and has the response been adequate?”
The goal for the meeting is to have leaders “step up to commit, not for one day, or for one meeting, but for the duration of the effort,” said Dr. Goosby. “We must make sure that the words that we hear next week from our leaders translate into action...Next week the world will say, ‘No more. No longer. No one is immune to TB. Tuberculosis is preventable; tuberculosis is treatable; tuberculosis is curable.’”
The BMJ commentary, by Marcel A. Behr, MD, of McGill International TB Centre, Infectious Diseases and Immunity in Global Health Program, McGill University Health Centre Research Institute, and his colleagues, recommend caution when building a prevention strategy around treating many millions of individuals with “latent” TB. They wrote, “Immunoreactivity to TB does not necessarily indicate the presence of live bacteria, as reactivity can persist after infection has been cleared. Classifying two billion people with evidence of immunoreactivity as having latent TB infection may divert fundamental research and public health interventions away from transmissible active TB disease and newly infected people at highest risk of progression to disease.”
This story was updated on 09/24/2018
A concerted a lethal disease affecting one-quarter of the world’s population by the year 2030.
On September 26 the United Nations General Assembly will convene a high-level meeting of global stakeholders to solidify the eradication plan, addressing the global crisis of tuberculosis (TB), the world’s most deadly infectious disease.
“We must seize the moment,” said Tereza Kasaeva, MD, director of the World Health Organization’s global TB program, speaking at a telebriefing and press conference accompanying the release of the World Health Organization’s annual global tuberculosis report. “It’s unacceptable in the 21st century that millions lose their lives to this preventable and curable disease.”
TB caused 1.6 million deaths globally in 2017, and the World Health Organization (WHO) estimates that of the 10 million new cases of TB last year, 558,000 are multi-drug resistant (MDR) infections.
Though death rates and new cases are falling globally each year, significantly more resources are needed to boost access to preventive treatment for latent TB infection; “Most people needing it are not yet accessing care,” according to the press briefing accompanying the report.
A review and commentary on TB incubation and latency published in BMJ (2018;362:k2738 doi: 10.1136/bmj.k2738; e-pub 23 Aug 2018) has called into question the focus preventive treatment of latent cases at the expense of reaching those most likely to die from TB (e.g., HIV patients, children of individuals living with active TB). The authors state that “latent” TB is identified by indirect evidence of present or past infection with Mycobacterium tuberculosis as inferred by a detectable adaptive immune response to M tuberculosis antigens. Active TB infection is overwhelmingly the result of a primary infection and almost always occurs within two years.
In order to meet the ambitious goal of TB eradication by the year 2030, treatment coverage must rise to 90% globally from the current 64%, according to the report.
Progress in southern Africa and in the Russian Federation, where efforts have led to a 30% reduction in TB mortality and a decrease in incidence of 5% per year, show that steep reductions in TB are possible when resources are brought to bear on the problem, said Dr. Kasaeva. “We should acknowledge that actions in some countries and regions show that progress can accelerate,” she said. Still, she noted, “Four thousand lives per day are lost to TB. Tuberculosis is the leading killer of people living with HIV, and the major cause of deaths related to antimicrobial resistance” at a global level.
Two thirds of all TB cases occur in eight countries, with India, China, and Indonesia leading this group. About half of the cases of MDR TB occur in India, China, and Russia, said Dr. Kasaeva, and globally only one in four individuals with MDR TB who need access to treatment have received it. “We need to urgently tackle the multidrug resistant TB public health crisis,” she said.
Major impediments to successful public health efforts against TB are underdiagnosis and underreporting: It is estimated that 3.6 million of 2017’s 10 million new cases were not officially recorded or reported. Countries where these problems are most serious include India, Indonesia, and Nigeria. Fewer than half of the children with TB are reported globally, according to the report.
People living with HIV/AIDS who are also infected with TB number nearly 1,000,000, but only about half of these were officially reported in 2017.
In terms of prevention priorities, WHO has recommended targeting treatment of latent TB in two groups: People living with HIV/AIDS, and children under the age of 5 years who live in households with TB-infected individuals.
“To enable these actions,” said Dr. Kasaeva, “we need strengthened commitments not just for TB care, but for overall health services. So the aim for universal coverage is real.” Underreporting is particularly prevalent in lower income countries with large unregulated private sectors, she said, though India and Indonesia have taken corrective steps to increase reporting.
A meaningful global initiative will not come cheap: The current annual shortfall in funding for TB prevention, diagnosis, and treatment is about $3.5 billion. By the year 2022, the gap between funding and what’s needed to stay on track for the 2030 target will be over $6 billion, said Dr. Kasaeva.
The best use of increased resources for TB eradication will be in locally focused efforts, said Irene Koek, MD, the United States Agency for International Development’s deputy administrator for global health. “It is likely that each region requires a tailored response.” Further, “to improve quality of care we need to ensure that services are patient centered,” she said at the press conference.
To that end, Dr. Koek expects that at the upcoming high-level meeting, the United Nations member states will be called on to develop an open framework, with clear accountability for monitoring and reviewing progress. The road forward should “celebrate accomplishments and acknowledge shortcomings,” she said. Some recent studies have shown that treatment success rates above 80% for patients with MDR TB can be achieved.
“Lessons learned from these experiences should be documented and shared in order to replicate success globally,” said Dr. Koek.
The United States, said Dr. Koek, is the leading global investor in TB research and treatment. “We welcome increased partnerships, especially with countries with the highest burden, to end global suffering from this disease.”
Eric Goosby, MD, the United Nations special envoy on TB, used his speaking time to lend some perspective to the social framework around TB’s longtime lethality.
There are aspects of TB infection that differentiate it from HIV/AIDS, said Dr. Goosby, who has spent most of his clinical and public health career on HIV/AIDS treatment and prevention. In contrast to an infection that at present requires a lifetime of treatment, TB can ordinarily be treated in 6 months, making it an unpleasant episode that an individual may be eager to move past. Additionally, the fact that TB has had a “hold on the world since the time of the ancient Egyptians” may paradoxically have served to lessen urgency in research and treatment efforts, he noted.
Dr. Goosby also spoke of the stigma surrounding TB, whose sufferers are likely to be facing dire poverty, malnutrition, and other infectious disease burdens. Civil society concerned with TB, he said, has spoken up “for those without a voice, for those who have difficulty advocating for themselves.”
Dr. Kasaeva agreed, noting that TB “affects the poorest of the poor, which makes it extraordinarily difficult for activism to come from that population.”
However, others have spoken for those affected, said Dr. Goosby. “The TB civil society has put its heart and soul this last year into gathering political will from leaders around the world…. It’s not a passive effort; it involves a lot of work.” During the past year of concerted effort, he said, “All of us have known the difficulty of pushing a political leader up that learning curve.”
As the upcoming high-level meeting approaches, those who have been working on the effort can feel the momentum, said Dr. Goosby. Still, he noted, “While there’s a significant step forward, this is not the time for a victory dance. This is really the time for a reflection...Do we understand the burden in our respective countries, and has the response been adequate?”
The goal for the meeting is to have leaders “step up to commit, not for one day, or for one meeting, but for the duration of the effort,” said Dr. Goosby. “We must make sure that the words that we hear next week from our leaders translate into action...Next week the world will say, ‘No more. No longer. No one is immune to TB. Tuberculosis is preventable; tuberculosis is treatable; tuberculosis is curable.’”
The BMJ commentary, by Marcel A. Behr, MD, of McGill International TB Centre, Infectious Diseases and Immunity in Global Health Program, McGill University Health Centre Research Institute, and his colleagues, recommend caution when building a prevention strategy around treating many millions of individuals with “latent” TB. They wrote, “Immunoreactivity to TB does not necessarily indicate the presence of live bacteria, as reactivity can persist after infection has been cleared. Classifying two billion people with evidence of immunoreactivity as having latent TB infection may divert fundamental research and public health interventions away from transmissible active TB disease and newly infected people at highest risk of progression to disease.”
This story was updated on 09/24/2018
FROM A WORLD HEALTH ORGANIZATION PRESS CONFERENCE
White coats and provider attire: Does it matter to patients?
What is appropriate “ward garb”?
The question of appropriate ward garb is a problem for the ages. Compared with photo stills and films from the 1960s, the doctors of today appear like vagabonds. No ties, no lab coats, and scrub tops have become the norm for a number (a majority?) of hospital-based docs – and even more so on the surgical wards and in the ER.
Past studies have addressed patient preferences for provider dress, but none like the results of a recent survey.
From the University of Michigan, Ann Arbor, comes a physician attire survey of a convenience sample of 4,000 patients at 10 U.S. academic medical centers. It included both inpatients and outpatients, and used the design of many previous studies, showing patients the same doctor dressed seven different ways. After viewing the photographs, the patients received surveys as to their preference of physician based on attire, as well as being asked to rate the physician in the areas of knowledge, trust, care, approachability, and comfort.
You can see the domains: casual, scrubs, and formal, each with and without a lab coat. The seventh category is business attire (future C-suite wannabes – you know who you are).
Over half of the participants indicated that how a physician dresses was important to them, with more than one in three stating that this influenced how happy they were with care received. Overall, respondents indicated that formal attire with white coats was the most preferred form of physician dress.
I found the discussion in the study worthwhile, along with the strengths and weaknesses of the author’s outline. They went to great lengths to design a nonbiased questionnaire and used a consistent approach to shooting their photos. They also discussed lab coats, long sleeves, and hygiene.
But what to draw from the findings? Does patient satisfaction matter or just clinical outcomes? Is patient happiness a means to an end or an end unto itself? Can I even get you exercised about a score of 6 versus 8 (a 25% difference)? For instance, imagine the worst-dressed doc – say shorts and flip-flops. Is that a 5.8 or a 2.3? The anchor matters, and it helps to put the ratings in context.
Read the full post at hospitalleader.org.
Dr. Flansbaum works for Geisinger Health System in Danville, Pa., in both the divisions of hospital medicine and population health. He is a founding member of the Society of Hospital Medicine and served as a board member and officer.
Also in The Hospital Leader
•Hospitalists Can Improve Patient Trust…in Their Colleagues by Chris Moriates, MD, SFHM
•Treatment of Type II MIs by Brad Flansbaum, MD, MPH, MHM
•The $64,000 Question: How Can Hospitalists Improve Their HCAHPS Scores? by Leslie Flores, MHA, SFHM
What is appropriate “ward garb”?
What is appropriate “ward garb”?
The question of appropriate ward garb is a problem for the ages. Compared with photo stills and films from the 1960s, the doctors of today appear like vagabonds. No ties, no lab coats, and scrub tops have become the norm for a number (a majority?) of hospital-based docs – and even more so on the surgical wards and in the ER.
Past studies have addressed patient preferences for provider dress, but none like the results of a recent survey.
From the University of Michigan, Ann Arbor, comes a physician attire survey of a convenience sample of 4,000 patients at 10 U.S. academic medical centers. It included both inpatients and outpatients, and used the design of many previous studies, showing patients the same doctor dressed seven different ways. After viewing the photographs, the patients received surveys as to their preference of physician based on attire, as well as being asked to rate the physician in the areas of knowledge, trust, care, approachability, and comfort.
You can see the domains: casual, scrubs, and formal, each with and without a lab coat. The seventh category is business attire (future C-suite wannabes – you know who you are).
Over half of the participants indicated that how a physician dresses was important to them, with more than one in three stating that this influenced how happy they were with care received. Overall, respondents indicated that formal attire with white coats was the most preferred form of physician dress.
I found the discussion in the study worthwhile, along with the strengths and weaknesses of the author’s outline. They went to great lengths to design a nonbiased questionnaire and used a consistent approach to shooting their photos. They also discussed lab coats, long sleeves, and hygiene.
But what to draw from the findings? Does patient satisfaction matter or just clinical outcomes? Is patient happiness a means to an end or an end unto itself? Can I even get you exercised about a score of 6 versus 8 (a 25% difference)? For instance, imagine the worst-dressed doc – say shorts and flip-flops. Is that a 5.8 or a 2.3? The anchor matters, and it helps to put the ratings in context.
Read the full post at hospitalleader.org.
Dr. Flansbaum works for Geisinger Health System in Danville, Pa., in both the divisions of hospital medicine and population health. He is a founding member of the Society of Hospital Medicine and served as a board member and officer.
Also in The Hospital Leader
•Hospitalists Can Improve Patient Trust…in Their Colleagues by Chris Moriates, MD, SFHM
•Treatment of Type II MIs by Brad Flansbaum, MD, MPH, MHM
•The $64,000 Question: How Can Hospitalists Improve Their HCAHPS Scores? by Leslie Flores, MHA, SFHM
The question of appropriate ward garb is a problem for the ages. Compared with photo stills and films from the 1960s, the doctors of today appear like vagabonds. No ties, no lab coats, and scrub tops have become the norm for a number (a majority?) of hospital-based docs – and even more so on the surgical wards and in the ER.
Past studies have addressed patient preferences for provider dress, but none like the results of a recent survey.
From the University of Michigan, Ann Arbor, comes a physician attire survey of a convenience sample of 4,000 patients at 10 U.S. academic medical centers. It included both inpatients and outpatients, and used the design of many previous studies, showing patients the same doctor dressed seven different ways. After viewing the photographs, the patients received surveys as to their preference of physician based on attire, as well as being asked to rate the physician in the areas of knowledge, trust, care, approachability, and comfort.
You can see the domains: casual, scrubs, and formal, each with and without a lab coat. The seventh category is business attire (future C-suite wannabes – you know who you are).
Over half of the participants indicated that how a physician dresses was important to them, with more than one in three stating that this influenced how happy they were with care received. Overall, respondents indicated that formal attire with white coats was the most preferred form of physician dress.
I found the discussion in the study worthwhile, along with the strengths and weaknesses of the author’s outline. They went to great lengths to design a nonbiased questionnaire and used a consistent approach to shooting their photos. They also discussed lab coats, long sleeves, and hygiene.
But what to draw from the findings? Does patient satisfaction matter or just clinical outcomes? Is patient happiness a means to an end or an end unto itself? Can I even get you exercised about a score of 6 versus 8 (a 25% difference)? For instance, imagine the worst-dressed doc – say shorts and flip-flops. Is that a 5.8 or a 2.3? The anchor matters, and it helps to put the ratings in context.
Read the full post at hospitalleader.org.
Dr. Flansbaum works for Geisinger Health System in Danville, Pa., in both the divisions of hospital medicine and population health. He is a founding member of the Society of Hospital Medicine and served as a board member and officer.
Also in The Hospital Leader
•Hospitalists Can Improve Patient Trust…in Their Colleagues by Chris Moriates, MD, SFHM
•Treatment of Type II MIs by Brad Flansbaum, MD, MPH, MHM
•The $64,000 Question: How Can Hospitalists Improve Their HCAHPS Scores? by Leslie Flores, MHA, SFHM
PARP inhibitor plus trabectedin shows promise for sarcoma
A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.
High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.
PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.
“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.
The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.
Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.
“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”
Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).
“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.
They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”
The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.
PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.
“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.
In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.
Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.
As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”
“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”
“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”
William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .
The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.
PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.
“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.
In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.
Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.
As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”
“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”
“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”
William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .
The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.
PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.
“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.
In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.
Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.
As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”
“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”
“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”
William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .
A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.
High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.
PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.
“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.
The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.
Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.
“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”
Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).
“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.
They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”
The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.
High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.
PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.
“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.
The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.
Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.
“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”
Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).
“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.
They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”
The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
FROM THE LANCET ONCOLOGY
Key clinical point: A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma.
Major finding: Of those with high PARP1 expression, 59% were progression free 6 months after treatment.
Study details: TOMAS was an open-label phase 1b trial involving 50 patients with sarcoma who had disease progression after standard therapy.
Disclosures: The study was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
Source: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
Researchers propose new acute leukemia subtypes
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
FROM NATURE
Key clinical point:
Major finding: In total, 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL.
Study details: Whole-genome, -exome, and RNA sequencing of 115 samples from pediatric patients with MPAL.
Disclosures: This research was supported by the National Cancer Institute and other organizations. The researchers reported having no competing interests.
Source: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
Vaginal intraepithelial neoplasia: What to do when dysplasia persists after hysterectomy
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
References
1. Gynecol Oncol. 2016 Jun;141(3):507-10.
2. Arch Gynecol Obstet. 2016 Feb;293(2):415-9.
3. Anticancer Res. 2013 Jan;33(1):29-38.
4. Obstet Gynecol. 2017 Dec;130(6):1237-43.
5. Eur J Obstet Gynecol Reprod Biol. 2017 Nov;218:129-36.
6. J Low Genit Tract Dis. 2014 Apr;18(2):115-21.
7. Gynecol Oncol. 2007 Jul;106(1):105-11.
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
References
1. Gynecol Oncol. 2016 Jun;141(3):507-10.
2. Arch Gynecol Obstet. 2016 Feb;293(2):415-9.
3. Anticancer Res. 2013 Jan;33(1):29-38.
4. Obstet Gynecol. 2017 Dec;130(6):1237-43.
5. Eur J Obstet Gynecol Reprod Biol. 2017 Nov;218:129-36.
6. J Low Genit Tract Dis. 2014 Apr;18(2):115-21.
7. Gynecol Oncol. 2007 Jul;106(1):105-11.
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
References
1. Gynecol Oncol. 2016 Jun;141(3):507-10.
2. Arch Gynecol Obstet. 2016 Feb;293(2):415-9.
3. Anticancer Res. 2013 Jan;33(1):29-38.
4. Obstet Gynecol. 2017 Dec;130(6):1237-43.
5. Eur J Obstet Gynecol Reprod Biol. 2017 Nov;218:129-36.
6. J Low Genit Tract Dis. 2014 Apr;18(2):115-21.
7. Gynecol Oncol. 2007 Jul;106(1):105-11.
ASCO addresses financial barriers to cancer clinical trials
The American Society of Clinical Oncology (ASCO) has released a policy statement addressing financial barriers that may prevent cancer patients from participating in clinical trials.
The four main recommendations in ASCO’s policy statement are:
- Payers should create clear, consistent, streamlined, and transparent policies regarding clinical trial coverage.
- Patients should receive easy-to-understand information about potential out-of-pocket costs.
- “Ethically appropriate” financial compensation for out-of-pocket costs should be allowed.
- Researchers should be incentivized to investigate and “better characterize” costs incurred by cancer patients in clinical trials as well as identify ways to “mitigate the risk of trial-associated financial hardship.”
ASCO’s full policy statement, “Addressing Financial Barriers to Patient Participation in Clinical Trials,” is available on the Journal of Clinical Oncology website.
SOURCE: Winkfield KM et al. J Clin Oncol. 2018 Sep 13:JCO1801132. doi: 10.1200/JCO.18.01132.
The American Society of Clinical Oncology (ASCO) has released a policy statement addressing financial barriers that may prevent cancer patients from participating in clinical trials.
The four main recommendations in ASCO’s policy statement are:
- Payers should create clear, consistent, streamlined, and transparent policies regarding clinical trial coverage.
- Patients should receive easy-to-understand information about potential out-of-pocket costs.
- “Ethically appropriate” financial compensation for out-of-pocket costs should be allowed.
- Researchers should be incentivized to investigate and “better characterize” costs incurred by cancer patients in clinical trials as well as identify ways to “mitigate the risk of trial-associated financial hardship.”
ASCO’s full policy statement, “Addressing Financial Barriers to Patient Participation in Clinical Trials,” is available on the Journal of Clinical Oncology website.
SOURCE: Winkfield KM et al. J Clin Oncol. 2018 Sep 13:JCO1801132. doi: 10.1200/JCO.18.01132.
The American Society of Clinical Oncology (ASCO) has released a policy statement addressing financial barriers that may prevent cancer patients from participating in clinical trials.
The four main recommendations in ASCO’s policy statement are:
- Payers should create clear, consistent, streamlined, and transparent policies regarding clinical trial coverage.
- Patients should receive easy-to-understand information about potential out-of-pocket costs.
- “Ethically appropriate” financial compensation for out-of-pocket costs should be allowed.
- Researchers should be incentivized to investigate and “better characterize” costs incurred by cancer patients in clinical trials as well as identify ways to “mitigate the risk of trial-associated financial hardship.”
ASCO’s full policy statement, “Addressing Financial Barriers to Patient Participation in Clinical Trials,” is available on the Journal of Clinical Oncology website.
SOURCE: Winkfield KM et al. J Clin Oncol. 2018 Sep 13:JCO1801132. doi: 10.1200/JCO.18.01132.
FROM JOURNAL OF CLINICAL ONCOLOGY
One-step gestational diabetes screening doesn’t improve outcomes
according to data from a before-and-after cohort study of women in the state of Washington.
The one-step test, a 75-g 2-hour oral glucose tolerance test (OGTT), was recommended for all pregnant women in 2010, although the traditional two-step test – a 50-g screening glucose challenge test followed by a 100-g 3-hour OGTT – remains widely used, wrote Gaia Pocobelli, PhD, of Kaiser Permanente Washington Health Research Institute, Seattle, and her colleagues. “No randomized trial has been published comparing outcomes of the two approaches.”
In a study published in Obstetrics & Gynecology, the researchers compared data from 23,257 women who received prenatal care in Washington State between January 2009 and December 2014, including 8,363 women who received care before the guideline change, 4,103 who received care during a transition period, and 10,791 after the guideline change. Approximately 60% of the women received care from clinicians internal to Kaiser Permanente; 40% received care from external providers. Most (87%) of the internal clinicians switched to the one-step approach, the researchers said. Only 5% of external providers did so.
Overall, adopting the one-step approach was associated with a 41% increase in the diagnosis of GDM without improved maternal or neonatal outcomes, the researchers noted.
The incidence of GDM increased from 7% before the guideline change to 11% afterward for women seen by internal providers. For women seen by external providers, gestational diabetes incidence increased from 10% to 11%.
For women seen by internal providers, the use of insulin increased from 1% before the guideline change to 4% afterward; for women seen by external providers, use of insulin increased from 1.3% to 1.4% (change between the groups P less than .001).
In addition, women seen by internal providers were more likely to undergo induction of labor after the guideline change (25% to 29%), while labor induction decreased for women seen by external providers (31% to 29%) for a relative risk of 1.2.
Neonatal hypoglycemia increased from 1% to 2% among women seen by internal providers, but decreased slightly from 2.4% to 2.1% for women seen by external providers, for a relative risk of 1.77.
There were no significant differences between the women seen by internal and external providers in risk of primary cesarean section, large for gestational age, small for gestational age, or neonatal ICU admission.
The main limitation of the study was the potential confounding variables including maternal diet and exercise, and possible underreporting of risk factors such as smoking, the researchers noted. However, the results were strengthened by the large study population, and the results “do not suggest a benefit of adopting the one-step over the two-step approach.
“Kaiser Permanente Washington has revised [its] guidelines to return to a two-step process. We recommend that any health care system considering switching to the one-step approach incorporate a rigorous evaluation of changes in maternal and neonatal outcomes,” Dr. Pocobelli and her associates added.
Dr. Pocobelli disclosed funding from Jazz Pharmaceuticals for work unrelated to this study. The study was supported in part by a grant from the Group Health Foundation Momentum Fund.
Diabetes is a significant global public health concern, but is especially problematic for women of reproductive age because diabetes in pregnancy can cause significant health complications for the mother and baby. Gestational diabetes mellitus (GDM) affects up to 10% of pregnancies in the United States annually, and is associated with perinatal loss, operative delivery, macrosomia, hypoglycemia, respiratory distress syndrome, and metabolic derangements for the offspring. For the mother, GDM is associated with hypertensive disorders, infections, hydramnios, and increased risk for developing type 2 diabetes later in life. As the incidence of GDM continues to rise, studies examining how to reduce, manage or prevent this condition become increasingly important.
The authors’ conclusions, that adopting the one-step approach increased the number of women with diagnosed GDM but did not significantly improve maternal or neonatal outcomes, are not surprising. Since the initial publication of the Hyperglycemia and Adverse Pregnancy Outcome Study, upon which the International Association of the Diabetes in Pregnancy Study Groups based its recommendations to go to a one-step approach, much debate has ensued about the best method to diagnose GDM. Indeed, the National Institutes of Health convened a consensus panel to review the literature and determine whether the one-step approach should be universally adopted (the panel concluded that more information was needed, and that the current two-step approach should continue to be used).
As the authors concede, studies have shown conflicting results, and no large-scale randomized controlled trial has been conducted to date. However, the literature does not bear out the idea that the one-step approach is truly better. The current study, although including a significant number of women and a reasonable control group, only serves as yet another study to reinforce what has previously been published.
I would agree with the researchers’ conclusions that the one-step approach is not necessarily beneficial. Although the one-step approach may identify a subset of patients who might not otherwise be diagnosed with GDM, it still remains unclear whether the outcomes for these patients will be improved. Furthermore, additional testing, need for insulin or other oral antidiabetic medications, etc., would result in additional stress to the patient and the health care system. Based on the authors’ findings, and results of other studies, it remains to be determined if the effort (diagnosing additional patients with GDM) is justified medically, economically, or otherwise.
As ob.gyns., we must continually ask ourselves: “By not doing something, are we causing harm to our patients?” If we change the diagnostic criteria for GDM, thereby increasing the number of women with the condition who would then require additional care, medications, and, potentially, more complex decisions around timing and mode of delivery, we need to be certain that we are not doing harm. This, and other studies examining the use of the one- versus two-step approach have yet to demonstrate, unequivocally, that changing the criteria reduces harm, and, perhaps, might – unintentionally – cause more.
As the study authors and the NIH consensus panel concluded, more rigorous evaluation is needed; that is, a large, multicenter randomized controlled trial that examines not only the benefits during pregnancy but also the long-term benefits to women and their children.
E. Albert Reece, MD, PhD, MBA, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He provided commentary on the study by Pocobelli et al. Dr. Reece said he had no relevant financial disclosures.
Diabetes is a significant global public health concern, but is especially problematic for women of reproductive age because diabetes in pregnancy can cause significant health complications for the mother and baby. Gestational diabetes mellitus (GDM) affects up to 10% of pregnancies in the United States annually, and is associated with perinatal loss, operative delivery, macrosomia, hypoglycemia, respiratory distress syndrome, and metabolic derangements for the offspring. For the mother, GDM is associated with hypertensive disorders, infections, hydramnios, and increased risk for developing type 2 diabetes later in life. As the incidence of GDM continues to rise, studies examining how to reduce, manage or prevent this condition become increasingly important.
The authors’ conclusions, that adopting the one-step approach increased the number of women with diagnosed GDM but did not significantly improve maternal or neonatal outcomes, are not surprising. Since the initial publication of the Hyperglycemia and Adverse Pregnancy Outcome Study, upon which the International Association of the Diabetes in Pregnancy Study Groups based its recommendations to go to a one-step approach, much debate has ensued about the best method to diagnose GDM. Indeed, the National Institutes of Health convened a consensus panel to review the literature and determine whether the one-step approach should be universally adopted (the panel concluded that more information was needed, and that the current two-step approach should continue to be used).
As the authors concede, studies have shown conflicting results, and no large-scale randomized controlled trial has been conducted to date. However, the literature does not bear out the idea that the one-step approach is truly better. The current study, although including a significant number of women and a reasonable control group, only serves as yet another study to reinforce what has previously been published.
I would agree with the researchers’ conclusions that the one-step approach is not necessarily beneficial. Although the one-step approach may identify a subset of patients who might not otherwise be diagnosed with GDM, it still remains unclear whether the outcomes for these patients will be improved. Furthermore, additional testing, need for insulin or other oral antidiabetic medications, etc., would result in additional stress to the patient and the health care system. Based on the authors’ findings, and results of other studies, it remains to be determined if the effort (diagnosing additional patients with GDM) is justified medically, economically, or otherwise.
As ob.gyns., we must continually ask ourselves: “By not doing something, are we causing harm to our patients?” If we change the diagnostic criteria for GDM, thereby increasing the number of women with the condition who would then require additional care, medications, and, potentially, more complex decisions around timing and mode of delivery, we need to be certain that we are not doing harm. This, and other studies examining the use of the one- versus two-step approach have yet to demonstrate, unequivocally, that changing the criteria reduces harm, and, perhaps, might – unintentionally – cause more.
As the study authors and the NIH consensus panel concluded, more rigorous evaluation is needed; that is, a large, multicenter randomized controlled trial that examines not only the benefits during pregnancy but also the long-term benefits to women and their children.
E. Albert Reece, MD, PhD, MBA, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He provided commentary on the study by Pocobelli et al. Dr. Reece said he had no relevant financial disclosures.
Diabetes is a significant global public health concern, but is especially problematic for women of reproductive age because diabetes in pregnancy can cause significant health complications for the mother and baby. Gestational diabetes mellitus (GDM) affects up to 10% of pregnancies in the United States annually, and is associated with perinatal loss, operative delivery, macrosomia, hypoglycemia, respiratory distress syndrome, and metabolic derangements for the offspring. For the mother, GDM is associated with hypertensive disorders, infections, hydramnios, and increased risk for developing type 2 diabetes later in life. As the incidence of GDM continues to rise, studies examining how to reduce, manage or prevent this condition become increasingly important.
The authors’ conclusions, that adopting the one-step approach increased the number of women with diagnosed GDM but did not significantly improve maternal or neonatal outcomes, are not surprising. Since the initial publication of the Hyperglycemia and Adverse Pregnancy Outcome Study, upon which the International Association of the Diabetes in Pregnancy Study Groups based its recommendations to go to a one-step approach, much debate has ensued about the best method to diagnose GDM. Indeed, the National Institutes of Health convened a consensus panel to review the literature and determine whether the one-step approach should be universally adopted (the panel concluded that more information was needed, and that the current two-step approach should continue to be used).
As the authors concede, studies have shown conflicting results, and no large-scale randomized controlled trial has been conducted to date. However, the literature does not bear out the idea that the one-step approach is truly better. The current study, although including a significant number of women and a reasonable control group, only serves as yet another study to reinforce what has previously been published.
I would agree with the researchers’ conclusions that the one-step approach is not necessarily beneficial. Although the one-step approach may identify a subset of patients who might not otherwise be diagnosed with GDM, it still remains unclear whether the outcomes for these patients will be improved. Furthermore, additional testing, need for insulin or other oral antidiabetic medications, etc., would result in additional stress to the patient and the health care system. Based on the authors’ findings, and results of other studies, it remains to be determined if the effort (diagnosing additional patients with GDM) is justified medically, economically, or otherwise.
As ob.gyns., we must continually ask ourselves: “By not doing something, are we causing harm to our patients?” If we change the diagnostic criteria for GDM, thereby increasing the number of women with the condition who would then require additional care, medications, and, potentially, more complex decisions around timing and mode of delivery, we need to be certain that we are not doing harm. This, and other studies examining the use of the one- versus two-step approach have yet to demonstrate, unequivocally, that changing the criteria reduces harm, and, perhaps, might – unintentionally – cause more.
As the study authors and the NIH consensus panel concluded, more rigorous evaluation is needed; that is, a large, multicenter randomized controlled trial that examines not only the benefits during pregnancy but also the long-term benefits to women and their children.
E. Albert Reece, MD, PhD, MBA, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He provided commentary on the study by Pocobelli et al. Dr. Reece said he had no relevant financial disclosures.
according to data from a before-and-after cohort study of women in the state of Washington.
The one-step test, a 75-g 2-hour oral glucose tolerance test (OGTT), was recommended for all pregnant women in 2010, although the traditional two-step test – a 50-g screening glucose challenge test followed by a 100-g 3-hour OGTT – remains widely used, wrote Gaia Pocobelli, PhD, of Kaiser Permanente Washington Health Research Institute, Seattle, and her colleagues. “No randomized trial has been published comparing outcomes of the two approaches.”
In a study published in Obstetrics & Gynecology, the researchers compared data from 23,257 women who received prenatal care in Washington State between January 2009 and December 2014, including 8,363 women who received care before the guideline change, 4,103 who received care during a transition period, and 10,791 after the guideline change. Approximately 60% of the women received care from clinicians internal to Kaiser Permanente; 40% received care from external providers. Most (87%) of the internal clinicians switched to the one-step approach, the researchers said. Only 5% of external providers did so.
Overall, adopting the one-step approach was associated with a 41% increase in the diagnosis of GDM without improved maternal or neonatal outcomes, the researchers noted.
The incidence of GDM increased from 7% before the guideline change to 11% afterward for women seen by internal providers. For women seen by external providers, gestational diabetes incidence increased from 10% to 11%.
For women seen by internal providers, the use of insulin increased from 1% before the guideline change to 4% afterward; for women seen by external providers, use of insulin increased from 1.3% to 1.4% (change between the groups P less than .001).
In addition, women seen by internal providers were more likely to undergo induction of labor after the guideline change (25% to 29%), while labor induction decreased for women seen by external providers (31% to 29%) for a relative risk of 1.2.
Neonatal hypoglycemia increased from 1% to 2% among women seen by internal providers, but decreased slightly from 2.4% to 2.1% for women seen by external providers, for a relative risk of 1.77.
There were no significant differences between the women seen by internal and external providers in risk of primary cesarean section, large for gestational age, small for gestational age, or neonatal ICU admission.
The main limitation of the study was the potential confounding variables including maternal diet and exercise, and possible underreporting of risk factors such as smoking, the researchers noted. However, the results were strengthened by the large study population, and the results “do not suggest a benefit of adopting the one-step over the two-step approach.
“Kaiser Permanente Washington has revised [its] guidelines to return to a two-step process. We recommend that any health care system considering switching to the one-step approach incorporate a rigorous evaluation of changes in maternal and neonatal outcomes,” Dr. Pocobelli and her associates added.
Dr. Pocobelli disclosed funding from Jazz Pharmaceuticals for work unrelated to this study. The study was supported in part by a grant from the Group Health Foundation Momentum Fund.
according to data from a before-and-after cohort study of women in the state of Washington.
The one-step test, a 75-g 2-hour oral glucose tolerance test (OGTT), was recommended for all pregnant women in 2010, although the traditional two-step test – a 50-g screening glucose challenge test followed by a 100-g 3-hour OGTT – remains widely used, wrote Gaia Pocobelli, PhD, of Kaiser Permanente Washington Health Research Institute, Seattle, and her colleagues. “No randomized trial has been published comparing outcomes of the two approaches.”
In a study published in Obstetrics & Gynecology, the researchers compared data from 23,257 women who received prenatal care in Washington State between January 2009 and December 2014, including 8,363 women who received care before the guideline change, 4,103 who received care during a transition period, and 10,791 after the guideline change. Approximately 60% of the women received care from clinicians internal to Kaiser Permanente; 40% received care from external providers. Most (87%) of the internal clinicians switched to the one-step approach, the researchers said. Only 5% of external providers did so.
Overall, adopting the one-step approach was associated with a 41% increase in the diagnosis of GDM without improved maternal or neonatal outcomes, the researchers noted.
The incidence of GDM increased from 7% before the guideline change to 11% afterward for women seen by internal providers. For women seen by external providers, gestational diabetes incidence increased from 10% to 11%.
For women seen by internal providers, the use of insulin increased from 1% before the guideline change to 4% afterward; for women seen by external providers, use of insulin increased from 1.3% to 1.4% (change between the groups P less than .001).
In addition, women seen by internal providers were more likely to undergo induction of labor after the guideline change (25% to 29%), while labor induction decreased for women seen by external providers (31% to 29%) for a relative risk of 1.2.
Neonatal hypoglycemia increased from 1% to 2% among women seen by internal providers, but decreased slightly from 2.4% to 2.1% for women seen by external providers, for a relative risk of 1.77.
There were no significant differences between the women seen by internal and external providers in risk of primary cesarean section, large for gestational age, small for gestational age, or neonatal ICU admission.
The main limitation of the study was the potential confounding variables including maternal diet and exercise, and possible underreporting of risk factors such as smoking, the researchers noted. However, the results were strengthened by the large study population, and the results “do not suggest a benefit of adopting the one-step over the two-step approach.
“Kaiser Permanente Washington has revised [its] guidelines to return to a two-step process. We recommend that any health care system considering switching to the one-step approach incorporate a rigorous evaluation of changes in maternal and neonatal outcomes,” Dr. Pocobelli and her associates added.
Dr. Pocobelli disclosed funding from Jazz Pharmaceuticals for work unrelated to this study. The study was supported in part by a grant from the Group Health Foundation Momentum Fund.
FROM OBSTETRICS & GYNECOLOGY
Key clinical point: Increased diagnoses of gestational diabetes did not significantly improve maternal or fetal outcomes.
Major finding: Adoption of a one-step screening process for gestational diabetes increased diagnoses by 41%.
Study details: The data come from a before-and-after cohort study with a population of 23,257 women.
Disclosures: Dr. Pocobelli disclosed funding from Jazz Pharmaceuticals for work unrelated to this study. The study was supported in part by a grant from the Group Health Foundation Momentum Fund.
Source: Pocobelli G et al. Obstet Gynecol. 2018;132:859-67.
Tau PET tracer distinguishes Alzheimer’s from other disorders
PET imaging with an investigational tau tracer, 18F-flortaucipir, distinguished Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy in a multicenter study.
PET with 18F-flortaucipir also outperformed structural MRI markers for Alzheimer’s disease (AD), and when compared against amyloid-beta (Abeta) biomarkers, showed higher specificity for an AD dementia diagnosis, researchers wrote in a report published online Sept. 18 in JAMA.
“The accuracy and potential utility of this test in patient care require further research in clinically more representative populations,” they wrote.
The study included 719 participants recruited from memory disorder clinics in Sweden, Korea, and California. That cohort included 179 patients with AD dementia, 254 who had non-AD neurodegenerative diseases, 126 with mild cognitive impairment (MCI), and 160 controls who were cognitively normal. All participants underwent 18F-flortaucipir PET between June 2014 and November 2017.
They found that 18F-flortaucipir showed “high accuracy” for distinguishing AD dementia from non-AD neurodegenerative disorders across all five regions of interest (ROI) evaluated in the study.
For example, 18F-flortaucipir PET had 90.3% accuracy, 89.9% sensitivity, and 90.6% specificity in the temporal meta-ROI, they reported.
By contrast, the accuracy of 18F-flortaucipir was lower for distinguishing MCI caused by AD versus non-AD neurodegenerative conditions. In the temporal meta-ROI, that translated into an 83.4% accuracy, 61.5% sensitivity, and 90.6% specificity, according to the report.
The 18F-flortaucipir tracer outperformed state-of-the-art MRI measures for distinguishing AD dementia from non-AD neurodegenerative disorders, including hippocampal volumes, AD-signature thickness, and whole-brain cortical thickness, Dr. Ossenkoppele and his colleagues found in a secondary analysis.
Likewise, certain analyses showed that specificity for AD dementia versus non-AD neurodegenerative disorders was higher with 18F-flortaucipir than with Abeta status.
While both MRI measures and Abeta status are increasingly used to evaluate cognitive impairment adjunctively in a clinical setting, the utility of 18F-flortaucipir PET as a diagnostic biomarker still must be determined, the investigators wrote in a discussion of their results.
“An intended clinical use of 18F-flortaucipir PET might be to improve the diagnostic work-up as an add-on test to Abeta biomarkers in patients with early-onset dementia and possibly as a triage or even replacement test in patients with late-onset dementia in whom incidental Abeta pathology is common,” they wrote.
The study was sponsored by different sources at each of the clinic sites. Many authors disclosed relationships with companies that are marketing and/or developing PET imaging tracers, including Avid Radiopharmaceuticals/Eli Lilly, GE Healthcare, and Piramal, as well as other pharmaceutical companies.
SOURCE: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.
PET imaging with an investigational tau tracer, 18F-flortaucipir, distinguished Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy in a multicenter study.
PET with 18F-flortaucipir also outperformed structural MRI markers for Alzheimer’s disease (AD), and when compared against amyloid-beta (Abeta) biomarkers, showed higher specificity for an AD dementia diagnosis, researchers wrote in a report published online Sept. 18 in JAMA.
“The accuracy and potential utility of this test in patient care require further research in clinically more representative populations,” they wrote.
The study included 719 participants recruited from memory disorder clinics in Sweden, Korea, and California. That cohort included 179 patients with AD dementia, 254 who had non-AD neurodegenerative diseases, 126 with mild cognitive impairment (MCI), and 160 controls who were cognitively normal. All participants underwent 18F-flortaucipir PET between June 2014 and November 2017.
They found that 18F-flortaucipir showed “high accuracy” for distinguishing AD dementia from non-AD neurodegenerative disorders across all five regions of interest (ROI) evaluated in the study.
For example, 18F-flortaucipir PET had 90.3% accuracy, 89.9% sensitivity, and 90.6% specificity in the temporal meta-ROI, they reported.
By contrast, the accuracy of 18F-flortaucipir was lower for distinguishing MCI caused by AD versus non-AD neurodegenerative conditions. In the temporal meta-ROI, that translated into an 83.4% accuracy, 61.5% sensitivity, and 90.6% specificity, according to the report.
The 18F-flortaucipir tracer outperformed state-of-the-art MRI measures for distinguishing AD dementia from non-AD neurodegenerative disorders, including hippocampal volumes, AD-signature thickness, and whole-brain cortical thickness, Dr. Ossenkoppele and his colleagues found in a secondary analysis.
Likewise, certain analyses showed that specificity for AD dementia versus non-AD neurodegenerative disorders was higher with 18F-flortaucipir than with Abeta status.
While both MRI measures and Abeta status are increasingly used to evaluate cognitive impairment adjunctively in a clinical setting, the utility of 18F-flortaucipir PET as a diagnostic biomarker still must be determined, the investigators wrote in a discussion of their results.
“An intended clinical use of 18F-flortaucipir PET might be to improve the diagnostic work-up as an add-on test to Abeta biomarkers in patients with early-onset dementia and possibly as a triage or even replacement test in patients with late-onset dementia in whom incidental Abeta pathology is common,” they wrote.
The study was sponsored by different sources at each of the clinic sites. Many authors disclosed relationships with companies that are marketing and/or developing PET imaging tracers, including Avid Radiopharmaceuticals/Eli Lilly, GE Healthcare, and Piramal, as well as other pharmaceutical companies.
SOURCE: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.
PET imaging with an investigational tau tracer, 18F-flortaucipir, distinguished Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy in a multicenter study.
PET with 18F-flortaucipir also outperformed structural MRI markers for Alzheimer’s disease (AD), and when compared against amyloid-beta (Abeta) biomarkers, showed higher specificity for an AD dementia diagnosis, researchers wrote in a report published online Sept. 18 in JAMA.
“The accuracy and potential utility of this test in patient care require further research in clinically more representative populations,” they wrote.
The study included 719 participants recruited from memory disorder clinics in Sweden, Korea, and California. That cohort included 179 patients with AD dementia, 254 who had non-AD neurodegenerative diseases, 126 with mild cognitive impairment (MCI), and 160 controls who were cognitively normal. All participants underwent 18F-flortaucipir PET between June 2014 and November 2017.
They found that 18F-flortaucipir showed “high accuracy” for distinguishing AD dementia from non-AD neurodegenerative disorders across all five regions of interest (ROI) evaluated in the study.
For example, 18F-flortaucipir PET had 90.3% accuracy, 89.9% sensitivity, and 90.6% specificity in the temporal meta-ROI, they reported.
By contrast, the accuracy of 18F-flortaucipir was lower for distinguishing MCI caused by AD versus non-AD neurodegenerative conditions. In the temporal meta-ROI, that translated into an 83.4% accuracy, 61.5% sensitivity, and 90.6% specificity, according to the report.
The 18F-flortaucipir tracer outperformed state-of-the-art MRI measures for distinguishing AD dementia from non-AD neurodegenerative disorders, including hippocampal volumes, AD-signature thickness, and whole-brain cortical thickness, Dr. Ossenkoppele and his colleagues found in a secondary analysis.
Likewise, certain analyses showed that specificity for AD dementia versus non-AD neurodegenerative disorders was higher with 18F-flortaucipir than with Abeta status.
While both MRI measures and Abeta status are increasingly used to evaluate cognitive impairment adjunctively in a clinical setting, the utility of 18F-flortaucipir PET as a diagnostic biomarker still must be determined, the investigators wrote in a discussion of their results.
“An intended clinical use of 18F-flortaucipir PET might be to improve the diagnostic work-up as an add-on test to Abeta biomarkers in patients with early-onset dementia and possibly as a triage or even replacement test in patients with late-onset dementia in whom incidental Abeta pathology is common,” they wrote.
The study was sponsored by different sources at each of the clinic sites. Many authors disclosed relationships with companies that are marketing and/or developing PET imaging tracers, including Avid Radiopharmaceuticals/Eli Lilly, GE Healthcare, and Piramal, as well as other pharmaceutical companies.
SOURCE: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.
FROM JAMA
Key clinical point:
Major finding: PET with 18F-flortaucipir PET had 90.3% accuracy, 89.9% sensitivity, and 90.6% specificity in the temporal metaregion of interest.
Study details: A multicenter, cross-sectional study including 719 participants recruited from memory disorder clinics in Sweden, Korea, and California.
Disclosures: The study was sponsored by different sources at each of the clinic sites. Many authors disclosed relationships with companies marketing and/or developing PET imaging tracers, including Avid Radiopharmaceuticals/Eli Lilly, GE Healthcare, and Piramal, as well as other pharmaceutical companies.
Source: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.
Amantadine-Induced Livedo Reticularis in a Child Treated Off Label for Neurobehavioral Disorders
Livedo reticularis (LR) is a common dermatologic finding consisting of diffuse, reticulated, violaceous patches. It often is a benign physical finding known as cutis marmorata; however, LR can be associated with other medical conditions as well as with the use of some medications.1,2 Amantadine is a common cause of LR in Parkinson disease patients.3,4 We present a rare case of amantadine-induced LR in a pediatric patient and highlight the off-label use of this medication in children.
Case Report
An 8-year-old boy presented with a diffuse rash on the trunk, arms, and legs of 9 months’ duration. The patient denied any associated symptoms as well as alleviating or exacerbating factors. He also denied any changes with temperature. He had no recent international travel and no prior drug allergies. His medical history was remarkable for attention deficit hyperactivity disorder (ADHD), bipolar disorder, and autism spectrum disorder. His previously prescribed medications included atomoxetine, quetiapine, and valproic acid. The only new medication that had been started within the last year was amantadine. Physical examination revealed a diffuse, reticulated, erythematous to violaceous, blanching rash that was most notable on the legs (Figure 1A) but also was present on the trunk (Figure 1B) and arms (Figure 1C). The clinical examination was consistent with LR, which was presumed to be secondary to amantadine use. Given the multiple psychiatric diagnoses and medication history in this young patient, a consultation with child psychiatry was facilitated. His medications and diagnosis were reviewed, and amantadine was discontinued. At a follow-up visit 5 months later, the patient’s LR had improved (Figure 2).
Comment
Amantadine has a well-documented association with LR in patients with Parkinson disease,3,4 which has been reported in up to 40% of those taking amantadine.2 More recently, amantadine has been used off label to treat neurobehavioral disorders in children due to beneficial effects including improvement in attention and concentration, distractibility, and fatigue.5 Our patient was being treated off label with amantadine for ADHD and bipolar disorder. Amantadine acts as a noncompetitive antagonist of the N-methyl-D-aspartate receptor, enhancing dopamine release to reduce symptoms of ADHD.5,6 Additionally, amantadine can cause a depletion of catecholamines in the peripheral nerve terminals, which may lead to dilatation of dermal vessels.4,6 This sequence of events has been proposed as a possible mechanism contributing to amantadine-induced LR, though the pathophysiology is not fully understood.1,3,4
Our case of LR likely was induced by amantadine given the temporal relationship between initiation of the medication, onset of the rash, and the considerable improvement of the rash upon discontinuation of amantadine. Barrera and Browning6 reported another case of amantadine-induced LR in a pediatric patient. Because amantadine is increasingly being used off label to treat childhood neurobehavioral disorders, amantadine-induced LR may become more prevalent in patients who do not have Parkinson disease; therefore, physicians who treat pediatric patients must be aware of this side effect.5
- Quaresma MV, Gomes-Dias AC, Serruya A, et al. Amantadine-induced livedo reticularis: a case report. An Bras Dermatol. 2015;90:745-747.
- Gibbs MB, English JC, Zirwas MJ. Livedo reticularis: an update. J Am Acad Dermatol. 2005;52:1009-1019.
- Silva SB, Miot HA. Case for diagnosis. amantadine-induced livedo reticularis. An Bras Dermatol. 2012;87:319-321.
- Vollum DI, Parkes JD, Doyle D. Livedo reticularis during amantadine treatment. Br Med J. 1971;2:627-628.
- Hosenbocus S, Chahal R. Amantadine: a review of use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry. 2013;22:55-60.
- Barrera F, Browning JC. Likely amantadine-induced livedo reticularis in a child. Pediatr Dermatol. 2012;29:329-330.
Livedo reticularis (LR) is a common dermatologic finding consisting of diffuse, reticulated, violaceous patches. It often is a benign physical finding known as cutis marmorata; however, LR can be associated with other medical conditions as well as with the use of some medications.1,2 Amantadine is a common cause of LR in Parkinson disease patients.3,4 We present a rare case of amantadine-induced LR in a pediatric patient and highlight the off-label use of this medication in children.
Case Report
An 8-year-old boy presented with a diffuse rash on the trunk, arms, and legs of 9 months’ duration. The patient denied any associated symptoms as well as alleviating or exacerbating factors. He also denied any changes with temperature. He had no recent international travel and no prior drug allergies. His medical history was remarkable for attention deficit hyperactivity disorder (ADHD), bipolar disorder, and autism spectrum disorder. His previously prescribed medications included atomoxetine, quetiapine, and valproic acid. The only new medication that had been started within the last year was amantadine. Physical examination revealed a diffuse, reticulated, erythematous to violaceous, blanching rash that was most notable on the legs (Figure 1A) but also was present on the trunk (Figure 1B) and arms (Figure 1C). The clinical examination was consistent with LR, which was presumed to be secondary to amantadine use. Given the multiple psychiatric diagnoses and medication history in this young patient, a consultation with child psychiatry was facilitated. His medications and diagnosis were reviewed, and amantadine was discontinued. At a follow-up visit 5 months later, the patient’s LR had improved (Figure 2).
Comment
Amantadine has a well-documented association with LR in patients with Parkinson disease,3,4 which has been reported in up to 40% of those taking amantadine.2 More recently, amantadine has been used off label to treat neurobehavioral disorders in children due to beneficial effects including improvement in attention and concentration, distractibility, and fatigue.5 Our patient was being treated off label with amantadine for ADHD and bipolar disorder. Amantadine acts as a noncompetitive antagonist of the N-methyl-D-aspartate receptor, enhancing dopamine release to reduce symptoms of ADHD.5,6 Additionally, amantadine can cause a depletion of catecholamines in the peripheral nerve terminals, which may lead to dilatation of dermal vessels.4,6 This sequence of events has been proposed as a possible mechanism contributing to amantadine-induced LR, though the pathophysiology is not fully understood.1,3,4
Our case of LR likely was induced by amantadine given the temporal relationship between initiation of the medication, onset of the rash, and the considerable improvement of the rash upon discontinuation of amantadine. Barrera and Browning6 reported another case of amantadine-induced LR in a pediatric patient. Because amantadine is increasingly being used off label to treat childhood neurobehavioral disorders, amantadine-induced LR may become more prevalent in patients who do not have Parkinson disease; therefore, physicians who treat pediatric patients must be aware of this side effect.5
Livedo reticularis (LR) is a common dermatologic finding consisting of diffuse, reticulated, violaceous patches. It often is a benign physical finding known as cutis marmorata; however, LR can be associated with other medical conditions as well as with the use of some medications.1,2 Amantadine is a common cause of LR in Parkinson disease patients.3,4 We present a rare case of amantadine-induced LR in a pediatric patient and highlight the off-label use of this medication in children.
Case Report
An 8-year-old boy presented with a diffuse rash on the trunk, arms, and legs of 9 months’ duration. The patient denied any associated symptoms as well as alleviating or exacerbating factors. He also denied any changes with temperature. He had no recent international travel and no prior drug allergies. His medical history was remarkable for attention deficit hyperactivity disorder (ADHD), bipolar disorder, and autism spectrum disorder. His previously prescribed medications included atomoxetine, quetiapine, and valproic acid. The only new medication that had been started within the last year was amantadine. Physical examination revealed a diffuse, reticulated, erythematous to violaceous, blanching rash that was most notable on the legs (Figure 1A) but also was present on the trunk (Figure 1B) and arms (Figure 1C). The clinical examination was consistent with LR, which was presumed to be secondary to amantadine use. Given the multiple psychiatric diagnoses and medication history in this young patient, a consultation with child psychiatry was facilitated. His medications and diagnosis were reviewed, and amantadine was discontinued. At a follow-up visit 5 months later, the patient’s LR had improved (Figure 2).
Comment
Amantadine has a well-documented association with LR in patients with Parkinson disease,3,4 which has been reported in up to 40% of those taking amantadine.2 More recently, amantadine has been used off label to treat neurobehavioral disorders in children due to beneficial effects including improvement in attention and concentration, distractibility, and fatigue.5 Our patient was being treated off label with amantadine for ADHD and bipolar disorder. Amantadine acts as a noncompetitive antagonist of the N-methyl-D-aspartate receptor, enhancing dopamine release to reduce symptoms of ADHD.5,6 Additionally, amantadine can cause a depletion of catecholamines in the peripheral nerve terminals, which may lead to dilatation of dermal vessels.4,6 This sequence of events has been proposed as a possible mechanism contributing to amantadine-induced LR, though the pathophysiology is not fully understood.1,3,4
Our case of LR likely was induced by amantadine given the temporal relationship between initiation of the medication, onset of the rash, and the considerable improvement of the rash upon discontinuation of amantadine. Barrera and Browning6 reported another case of amantadine-induced LR in a pediatric patient. Because amantadine is increasingly being used off label to treat childhood neurobehavioral disorders, amantadine-induced LR may become more prevalent in patients who do not have Parkinson disease; therefore, physicians who treat pediatric patients must be aware of this side effect.5
- Quaresma MV, Gomes-Dias AC, Serruya A, et al. Amantadine-induced livedo reticularis: a case report. An Bras Dermatol. 2015;90:745-747.
- Gibbs MB, English JC, Zirwas MJ. Livedo reticularis: an update. J Am Acad Dermatol. 2005;52:1009-1019.
- Silva SB, Miot HA. Case for diagnosis. amantadine-induced livedo reticularis. An Bras Dermatol. 2012;87:319-321.
- Vollum DI, Parkes JD, Doyle D. Livedo reticularis during amantadine treatment. Br Med J. 1971;2:627-628.
- Hosenbocus S, Chahal R. Amantadine: a review of use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry. 2013;22:55-60.
- Barrera F, Browning JC. Likely amantadine-induced livedo reticularis in a child. Pediatr Dermatol. 2012;29:329-330.
- Quaresma MV, Gomes-Dias AC, Serruya A, et al. Amantadine-induced livedo reticularis: a case report. An Bras Dermatol. 2015;90:745-747.
- Gibbs MB, English JC, Zirwas MJ. Livedo reticularis: an update. J Am Acad Dermatol. 2005;52:1009-1019.
- Silva SB, Miot HA. Case for diagnosis. amantadine-induced livedo reticularis. An Bras Dermatol. 2012;87:319-321.
- Vollum DI, Parkes JD, Doyle D. Livedo reticularis during amantadine treatment. Br Med J. 1971;2:627-628.
- Hosenbocus S, Chahal R. Amantadine: a review of use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry. 2013;22:55-60.
- Barrera F, Browning JC. Likely amantadine-induced livedo reticularis in a child. Pediatr Dermatol. 2012;29:329-330.
Practice Points
- Amantadine is a generally well-tolerated medication that is more commonly used for off-label treatment of several pediatric neurobehavioral conditions such as attention deficit hyperactivity disorder, autism spectrum disorders, obsessive compulsive disorder, depression, and others.
- Livedo reticularis has known associations with several medications and diseases; however, the most common presentation is cutis marmorata, a benign condition that typically affects newborns.
