A new toolkit provides coping strategies for people who are anxious about climate change. These strategies include volunteering, building a community, discussing emotions with others, practicing mindfulness, and seeking therapy.

The toolkit, which was developed by nursing experts at the University of British Columbia in Vancouver, also offers reflection questions and a film with diverse voices for people to examine their values, emotions, and behaviors in relation to the environment.

“Many people have a hard time understanding the relationship between climate change and mental health and are experiencing high levels of stress about climate change,” Natania Abebe, MSN/MPH, RN, a registered nurse and graduate student at UBC who developed the toolkit, told this news organization.

“Youth, in particular, appear to have higher levels of consciousness regarding climate change because they’re the ones who are going to inherit the planet,” she said. “A big part of why they have mental health issues is that they feel trapped in sociopolitical structures that they didn’t agree to and didn’t necessarily create.”

The toolkit was published online on April 20.

Empowering agents for change

Ms. Abebe was inspired to create the toolkit after giving guest lectures on climate change and mental health as part of UBC’s Nursing 290 course. Her faculty advisor, Raluca Radu, MSN, a lecturer in the School of Nursing at UBC, developed the course in 2020 to teach students about the broad impacts of climate change on communities.

As the course has grown during the past 2 years, Ms. Abebe wanted to create a coping framework and engaging film for health educators to use with students, as well as for everyday people.

The toolkit includes contributions from three Canadian climate change experts, as well as six students from different backgrounds who have taken the course.

“I wanted to center the voices of youth and empower them to think they can be agents for change,” Ms. Abebe said. “I also wanted to highlight diverse voices and take a collaborative approach because climate change is such a big problem that we have to come together to address it.”

Ms. Abebe and Ms. Radu also noticed an increase in climate anxiety in recent years because of the pandemic, worldwide food and energy shortages, and extreme weather events that hit close to home, such as wildfires and floods in British Columbia.

“With the pandemic, people have been spending more time online and thinking about our world at large,” Ms. Abebe said. “At the same time that they’re thinking about it, climate change events are happening simultaneously – not in the future, but right now.”

Economic, social, and political shifts during the past 2 years have also prompted people to question standard practices and institutions, which has created an opportunity to discuss change, Ms. Radu told this news organization.

“It’s a pivotal time to question our values and highly consumerist society,” she said. “We’re at a point in time where, if we don’t take action, the planetary health will be in an irreversible state, and we won’t be able to turn back time and make changes.”

Our psyches and nature

The toolkit includes three main sections that feature video clips and reflective questions around eco-anxiety, eco-paralysis, and ecological grief.

In the first section, eco-anxiety is defined as a “chronic fear of environmental doom,” which could include anxiousness around the likelihood of a severe weather event because of ongoing news coverage and social media. The reflective questions prompt readers to discuss eco-anxiety in their life, work through their emotions, understand their beliefs and values, and determine how to use them to address climate change anxiety.

The second section defines eco-paralysis as the powerlessness that people may feel when they don’t believe they can do anything meaningful on an individual level to address climate change. Paralysis can look like apathy, complacency, or disengagement. The questions prompt readers to observe how paralysis may show up in their lives, explore the tension between individual versus collective responsibility, and consider ways to address their sense of helplessness about climate change.

In the third section, ecological grief centers around “experienced or anticipated ecological losses,” which could include the loss of species, ecosystems, and landscapes because of short- or long-term environmental change. The questions prompt readers to explore their feelings, beliefs, and values and feel empowered to address their ecological grief over climate change.

The toolkit also includes recommendations for books, journal articles, websites, podcasts, and meditations around mental health and climate change, as well as ways to get involved with others. For instance, health care practitioners can register with PaRx, a program in British Columbia that allows providers to prescribe time in nature to improve a client’s health. The program is being adopted across Canada, and people with a prescription can visit local and national parks, historic sites, and marine conservation areas for free.

“This is about recognizing that there is a connection between our psyches and nature, and by talking about it, we can name what we’re feeling,” Ms. Abebe said. “We can take action not only to handle our emotions, but also to live kinder and more sustainable lifestyles.”

Future work will need to focus on population-level approaches to climate change and mental health as well, including policy and financial support to address environmental changes directly.

“We need to start thinking beyond individualized approaches and focus on how to create supportive and resilient communities to respond to climate change,” Kiffer Card, PhD, executive director of the Mental Health and Climate Change Alliance and an assistant professor of health sciences at Simon Fraser University, Burnaby, B.C., told this news organization.

Dr. Card, who wasn’t involved in developing the toolkit, has researched recent trends around climate change anxiety in Canada and fielded questions from health care practitioners and mental health professionals who are looking for ways to help their patients.

“Communities need to be ready to stand up and respond to acute emergency disasters, and government leaders need to take this seriously,” he said. “Those who are experiencing climate anxiety now are the canaries in the coal mine for the severe weather events and consequences to come.”

The toolkit was developed with funding from the Alma Mater Society of the University of British Columbia, Vancouver. Ms. Abebe, Ms. Radu, and Dr. Card reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

 A new toolkit provides coping strategies for people who are anxious about climate change. These strategies include volunteering, building a community, discussing emotions with others, practicing mindfulness, and seeking therapy.

The toolkit, which was developed by nursing experts at the University of British Columbia in Vancouver, also offers reflection questions and a film with diverse voices for people to examine their values, emotions, and behaviors in relation to the environment.

“Many people have a hard time understanding the relationship between climate change and mental health and are experiencing high levels of stress about climate change,” Natania Abebe, MSN/MPH, RN, a registered nurse and graduate student at UBC who developed the toolkit, told this news organization.

“Youth, in particular, appear to have higher levels of consciousness regarding climate change because they’re the ones who are going to inherit the planet,” she said. “A big part of why they have mental health issues is that they feel trapped in sociopolitical structures that they didn’t agree to and didn’t necessarily create.”

The toolkit was published online on April 20.

Empowering agents for change

Ms. Abebe was inspired to create the toolkit after giving guest lectures on climate change and mental health as part of UBC’s Nursing 290 course. Her faculty advisor, Raluca Radu, MSN, a lecturer in the School of Nursing at UBC, developed the course in 2020 to teach students about the broad impacts of climate change on communities.

As the course has grown during the past 2 years, Ms. Abebe wanted to create a coping framework and engaging film for health educators to use with students, as well as for everyday people.

The toolkit includes contributions from three Canadian climate change experts, as well as six students from different backgrounds who have taken the course.

“I wanted to center the voices of youth and empower them to think they can be agents for change,” Ms. Abebe said. “I also wanted to highlight diverse voices and take a collaborative approach because climate change is such a big problem that we have to come together to address it.”

Ms. Abebe and Ms. Radu also noticed an increase in climate anxiety in recent years because of the pandemic, worldwide food and energy shortages, and extreme weather events that hit close to home, such as wildfires and floods in British Columbia.

“With the pandemic, people have been spending more time online and thinking about our world at large,” Ms. Abebe said. “At the same time that they’re thinking about it, climate change events are happening simultaneously – not in the future, but right now.”

Economic, social, and political shifts during the past 2 years have also prompted people to question standard practices and institutions, which has created an opportunity to discuss change, Ms. Radu told this news organization.

“It’s a pivotal time to question our values and highly consumerist society,” she said. “We’re at a point in time where, if we don’t take action, the planetary health will be in an irreversible state, and we won’t be able to turn back time and make changes.”

Our psyches and nature

The toolkit includes three main sections that feature video clips and reflective questions around eco-anxiety, eco-paralysis, and ecological grief.

In the first section, eco-anxiety is defined as a “chronic fear of environmental doom,” which could include anxiousness around the likelihood of a severe weather event because of ongoing news coverage and social media. The reflective questions prompt readers to discuss eco-anxiety in their life, work through their emotions, understand their beliefs and values, and determine how to use them to address climate change anxiety.

The second section defines eco-paralysis as the powerlessness that people may feel when they don’t believe they can do anything meaningful on an individual level to address climate change. Paralysis can look like apathy, complacency, or disengagement. The questions prompt readers to observe how paralysis may show up in their lives, explore the tension between individual versus collective responsibility, and consider ways to address their sense of helplessness about climate change.

In the third section, ecological grief centers around “experienced or anticipated ecological losses,” which could include the loss of species, ecosystems, and landscapes because of short- or long-term environmental change. The questions prompt readers to explore their feelings, beliefs, and values and feel empowered to address their ecological grief over climate change.

The toolkit also includes recommendations for books, journal articles, websites, podcasts, and meditations around mental health and climate change, as well as ways to get involved with others. For instance, health care practitioners can register with PaRx, a program in British Columbia that allows providers to prescribe time in nature to improve a client’s health. The program is being adopted across Canada, and people with a prescription can visit local and national parks, historic sites, and marine conservation areas for free.

“This is about recognizing that there is a connection between our psyches and nature, and by talking about it, we can name what we’re feeling,” Ms. Abebe said. “We can take action not only to handle our emotions, but also to live kinder and more sustainable lifestyles.”

Future work will need to focus on population-level approaches to climate change and mental health as well, including policy and financial support to address environmental changes directly.

“We need to start thinking beyond individualized approaches and focus on how to create supportive and resilient communities to respond to climate change,” Kiffer Card, PhD, executive director of the Mental Health and Climate Change Alliance and an assistant professor of health sciences at Simon Fraser University, Burnaby, B.C., told this news organization.

Dr. Card, who wasn’t involved in developing the toolkit, has researched recent trends around climate change anxiety in Canada and fielded questions from health care practitioners and mental health professionals who are looking for ways to help their patients.

“Communities need to be ready to stand up and respond to acute emergency disasters, and government leaders need to take this seriously,” he said. “Those who are experiencing climate anxiety now are the canaries in the coal mine for the severe weather events and consequences to come.”

The toolkit was developed with funding from the Alma Mater Society of the University of British Columbia, Vancouver. Ms. Abebe, Ms. Radu, and Dr. Card reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

 A new toolkit provides coping strategies for people who are anxious about climate change. These strategies include volunteering, building a community, discussing emotions with others, practicing mindfulness, and seeking therapy.

The toolkit, which was developed by nursing experts at the University of British Columbia in Vancouver, also offers reflection questions and a film with diverse voices for people to examine their values, emotions, and behaviors in relation to the environment.

“Many people have a hard time understanding the relationship between climate change and mental health and are experiencing high levels of stress about climate change,” Natania Abebe, MSN/MPH, RN, a registered nurse and graduate student at UBC who developed the toolkit, told this news organization.

“Youth, in particular, appear to have higher levels of consciousness regarding climate change because they’re the ones who are going to inherit the planet,” she said. “A big part of why they have mental health issues is that they feel trapped in sociopolitical structures that they didn’t agree to and didn’t necessarily create.”

The toolkit was published online on April 20.

Empowering agents for change

Ms. Abebe was inspired to create the toolkit after giving guest lectures on climate change and mental health as part of UBC’s Nursing 290 course. Her faculty advisor, Raluca Radu, MSN, a lecturer in the School of Nursing at UBC, developed the course in 2020 to teach students about the broad impacts of climate change on communities.

As the course has grown during the past 2 years, Ms. Abebe wanted to create a coping framework and engaging film for health educators to use with students, as well as for everyday people.

The toolkit includes contributions from three Canadian climate change experts, as well as six students from different backgrounds who have taken the course.

“I wanted to center the voices of youth and empower them to think they can be agents for change,” Ms. Abebe said. “I also wanted to highlight diverse voices and take a collaborative approach because climate change is such a big problem that we have to come together to address it.”

Ms. Abebe and Ms. Radu also noticed an increase in climate anxiety in recent years because of the pandemic, worldwide food and energy shortages, and extreme weather events that hit close to home, such as wildfires and floods in British Columbia.

“With the pandemic, people have been spending more time online and thinking about our world at large,” Ms. Abebe said. “At the same time that they’re thinking about it, climate change events are happening simultaneously – not in the future, but right now.”

Economic, social, and political shifts during the past 2 years have also prompted people to question standard practices and institutions, which has created an opportunity to discuss change, Ms. Radu told this news organization.

“It’s a pivotal time to question our values and highly consumerist society,” she said. “We’re at a point in time where, if we don’t take action, the planetary health will be in an irreversible state, and we won’t be able to turn back time and make changes.”

Our psyches and nature

The toolkit includes three main sections that feature video clips and reflective questions around eco-anxiety, eco-paralysis, and ecological grief.

In the first section, eco-anxiety is defined as a “chronic fear of environmental doom,” which could include anxiousness around the likelihood of a severe weather event because of ongoing news coverage and social media. The reflective questions prompt readers to discuss eco-anxiety in their life, work through their emotions, understand their beliefs and values, and determine how to use them to address climate change anxiety.

The second section defines eco-paralysis as the powerlessness that people may feel when they don’t believe they can do anything meaningful on an individual level to address climate change. Paralysis can look like apathy, complacency, or disengagement. The questions prompt readers to observe how paralysis may show up in their lives, explore the tension between individual versus collective responsibility, and consider ways to address their sense of helplessness about climate change.

In the third section, ecological grief centers around “experienced or anticipated ecological losses,” which could include the loss of species, ecosystems, and landscapes because of short- or long-term environmental change. The questions prompt readers to explore their feelings, beliefs, and values and feel empowered to address their ecological grief over climate change.

The toolkit also includes recommendations for books, journal articles, websites, podcasts, and meditations around mental health and climate change, as well as ways to get involved with others. For instance, health care practitioners can register with PaRx, a program in British Columbia that allows providers to prescribe time in nature to improve a client’s health. The program is being adopted across Canada, and people with a prescription can visit local and national parks, historic sites, and marine conservation areas for free.

“This is about recognizing that there is a connection between our psyches and nature, and by talking about it, we can name what we’re feeling,” Ms. Abebe said. “We can take action not only to handle our emotions, but also to live kinder and more sustainable lifestyles.”

Future work will need to focus on population-level approaches to climate change and mental health as well, including policy and financial support to address environmental changes directly.

“We need to start thinking beyond individualized approaches and focus on how to create supportive and resilient communities to respond to climate change,” Kiffer Card, PhD, executive director of the Mental Health and Climate Change Alliance and an assistant professor of health sciences at Simon Fraser University, Burnaby, B.C., told this news organization.

Dr. Card, who wasn’t involved in developing the toolkit, has researched recent trends around climate change anxiety in Canada and fielded questions from health care practitioners and mental health professionals who are looking for ways to help their patients.

“Communities need to be ready to stand up and respond to acute emergency disasters, and government leaders need to take this seriously,” he said. “Those who are experiencing climate anxiety now are the canaries in the coal mine for the severe weather events and consequences to come.”

The toolkit was developed with funding from the Alma Mater Society of the University of British Columbia, Vancouver. Ms. Abebe, Ms. Radu, and Dr. Card reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved two vonoprazan-based treatments for Helicobacter pylori infection: Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), both from Phathom Pharmaceuticals.

Vonoprazan is an oral potassium-competitive acid blocker and “the first innovative acid suppressant from a new drug class approved in the United States in over 30 years,” the company said in a news release announcing the approval.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved two vonoprazan-based treatments for Helicobacter pylori infection: Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), both from Phathom Pharmaceuticals.

Vonoprazan is an oral potassium-competitive acid blocker and “the first innovative acid suppressant from a new drug class approved in the United States in over 30 years,” the company said in a news release announcing the approval.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved two vonoprazan-based treatments for Helicobacter pylori infection: Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), both from Phathom Pharmaceuticals.

Vonoprazan is an oral potassium-competitive acid blocker and “the first innovative acid suppressant from a new drug class approved in the United States in over 30 years,” the company said in a news release announcing the approval.

A version of this article first appeared on Medscape.com.

Tuberculosis cases are increasing in Washington, which has put public health officials on “heightened alert,” according to a recent announcement from the Washington State Department of Health.

Widespread disruptions in health care and missed tuberculosis diagnoses during the COVID-19 pandemic have likely added to the increase – both locally and globally.

“It’s been 20 years since we saw a cluster of TB cases like this,” Tao Sheng Kwan-Gett, MD, the state’s chief science officer, said in the announcement.

“The pandemic has likely contributed to the rise in cases and the outbreak in at least one correctional facility,” he said. “Increased access to TB testing and treatment in the community is going to be key to getting TB under control.”

Case numbers appeared to fall in Washington during the first year of the pandemic, possibly because of less reporting and missed diagnoses. But in 2021, cases rose quickly. The state reported 199 cases, marking a 22% increase from 2020.

So far this year, 70 cases have been reported, including 17 new cases that all have connections with each other and several state prisons.

The state’s Department of Corrections, Department of Health, and the Centers for Disease Control and Prevention are working together on testing and decreasing spread, MaryAnn Curl, MD, the chief medical officer for the Department of Corrections, said in the statement.

Tuberculosis cases are increasing worldwide. For the first time in more than a decade, TB deaths increased to about 1.5 million, according to the World Health Organization’s 2021 Global Tuberculosis Report.

Across the U.S., the number of reported TB cases significantly declined at the beginning of the pandemic in 2020 but increased again in 2021, according to a recent CDC study.

The Kansas Department of Health also reported an outbreak of TB cases in March, according to USA Today.

At the beginning of the pandemic, some people with TB may have been diagnosed with COVID-19 because both are infectious diseases that attack the lungs and have similar symptoms, the Washington Health Department said.

Like COVID-19, tuberculosis can spread through the air when an infected person coughs or sneezes. But unlike COVID-19, TB typically requires that you have prolonged exposure to become infected.

Symptoms of tuberculosis can include chest pain and coughing, with or without blood, as well as fever, night sweats, weight loss, and fatigue.

Tuberculosis is preventable, treatable, and curable, the Washington Health Department said. Those who travel to countries where TB is more common face higher risks for exposure, as well as those who live or work in settings where TB may spread, such as homeless shelters, prisons, jails, and nursing homes.

People can develop inactive TB, also called latent TB, which doesn’t have any symptoms and isn’t contagious. If people with inactive TB don’t get quick diagnosis or treatment, the infection can become active TB and cause symptoms. State health officials estimated that about 200,000 people in Washington have inactive TB.

Tuberculosis treatment can take a minimum of 6 months, and if it’s not followed carefully, symptoms can become more severe, the Health Department said. Incomplete treatment can also contribute to the spread of antibiotic-resistant strains of tuberculosis.

A version of this article first appeared on WebMD.com.

Tuberculosis cases are increasing in Washington, which has put public health officials on “heightened alert,” according to a recent announcement from the Washington State Department of Health.

Widespread disruptions in health care and missed tuberculosis diagnoses during the COVID-19 pandemic have likely added to the increase – both locally and globally.

“It’s been 20 years since we saw a cluster of TB cases like this,” Tao Sheng Kwan-Gett, MD, the state’s chief science officer, said in the announcement.

“The pandemic has likely contributed to the rise in cases and the outbreak in at least one correctional facility,” he said. “Increased access to TB testing and treatment in the community is going to be key to getting TB under control.”

Case numbers appeared to fall in Washington during the first year of the pandemic, possibly because of less reporting and missed diagnoses. But in 2021, cases rose quickly. The state reported 199 cases, marking a 22% increase from 2020.

So far this year, 70 cases have been reported, including 17 new cases that all have connections with each other and several state prisons.

The state’s Department of Corrections, Department of Health, and the Centers for Disease Control and Prevention are working together on testing and decreasing spread, MaryAnn Curl, MD, the chief medical officer for the Department of Corrections, said in the statement.

Tuberculosis cases are increasing worldwide. For the first time in more than a decade, TB deaths increased to about 1.5 million, according to the World Health Organization’s 2021 Global Tuberculosis Report.

Across the U.S., the number of reported TB cases significantly declined at the beginning of the pandemic in 2020 but increased again in 2021, according to a recent CDC study.

The Kansas Department of Health also reported an outbreak of TB cases in March, according to USA Today.

At the beginning of the pandemic, some people with TB may have been diagnosed with COVID-19 because both are infectious diseases that attack the lungs and have similar symptoms, the Washington Health Department said.

Like COVID-19, tuberculosis can spread through the air when an infected person coughs or sneezes. But unlike COVID-19, TB typically requires that you have prolonged exposure to become infected.

Symptoms of tuberculosis can include chest pain and coughing, with or without blood, as well as fever, night sweats, weight loss, and fatigue.

Tuberculosis is preventable, treatable, and curable, the Washington Health Department said. Those who travel to countries where TB is more common face higher risks for exposure, as well as those who live or work in settings where TB may spread, such as homeless shelters, prisons, jails, and nursing homes.

People can develop inactive TB, also called latent TB, which doesn’t have any symptoms and isn’t contagious. If people with inactive TB don’t get quick diagnosis or treatment, the infection can become active TB and cause symptoms. State health officials estimated that about 200,000 people in Washington have inactive TB.

Tuberculosis treatment can take a minimum of 6 months, and if it’s not followed carefully, symptoms can become more severe, the Health Department said. Incomplete treatment can also contribute to the spread of antibiotic-resistant strains of tuberculosis.

A version of this article first appeared on WebMD.com.

Tuberculosis cases are increasing in Washington, which has put public health officials on “heightened alert,” according to a recent announcement from the Washington State Department of Health.

Widespread disruptions in health care and missed tuberculosis diagnoses during the COVID-19 pandemic have likely added to the increase – both locally and globally.

“It’s been 20 years since we saw a cluster of TB cases like this,” Tao Sheng Kwan-Gett, MD, the state’s chief science officer, said in the announcement.

“The pandemic has likely contributed to the rise in cases and the outbreak in at least one correctional facility,” he said. “Increased access to TB testing and treatment in the community is going to be key to getting TB under control.”

Case numbers appeared to fall in Washington during the first year of the pandemic, possibly because of less reporting and missed diagnoses. But in 2021, cases rose quickly. The state reported 199 cases, marking a 22% increase from 2020.

So far this year, 70 cases have been reported, including 17 new cases that all have connections with each other and several state prisons.

The state’s Department of Corrections, Department of Health, and the Centers for Disease Control and Prevention are working together on testing and decreasing spread, MaryAnn Curl, MD, the chief medical officer for the Department of Corrections, said in the statement.

Tuberculosis cases are increasing worldwide. For the first time in more than a decade, TB deaths increased to about 1.5 million, according to the World Health Organization’s 2021 Global Tuberculosis Report.

Across the U.S., the number of reported TB cases significantly declined at the beginning of the pandemic in 2020 but increased again in 2021, according to a recent CDC study.

The Kansas Department of Health also reported an outbreak of TB cases in March, according to USA Today.

At the beginning of the pandemic, some people with TB may have been diagnosed with COVID-19 because both are infectious diseases that attack the lungs and have similar symptoms, the Washington Health Department said.

Like COVID-19, tuberculosis can spread through the air when an infected person coughs or sneezes. But unlike COVID-19, TB typically requires that you have prolonged exposure to become infected.

Symptoms of tuberculosis can include chest pain and coughing, with or without blood, as well as fever, night sweats, weight loss, and fatigue.

Tuberculosis is preventable, treatable, and curable, the Washington Health Department said. Those who travel to countries where TB is more common face higher risks for exposure, as well as those who live or work in settings where TB may spread, such as homeless shelters, prisons, jails, and nursing homes.

People can develop inactive TB, also called latent TB, which doesn’t have any symptoms and isn’t contagious. If people with inactive TB don’t get quick diagnosis or treatment, the infection can become active TB and cause symptoms. State health officials estimated that about 200,000 people in Washington have inactive TB.

Tuberculosis treatment can take a minimum of 6 months, and if it’s not followed carefully, symptoms can become more severe, the Health Department said. Incomplete treatment can also contribute to the spread of antibiotic-resistant strains of tuberculosis.

A version of this article first appeared on WebMD.com.

Children who have greater acute appendicitis pain may be less likely to improve if they’re treated with antibiotics alone, according to a secondary analysis of a nonrandomized clinical trial.

“While approximately 35% of families chose nonoperative management, a high pain score between 7-10 on a 10-point scale nearly doubled in-hospital treatment failure,” Rebecca M. Rentea, MD, a pediatric surgeon and the director of the Comprehensive Colorectal Center at Children’s Mercy Kansas City, Mo., told this news organization in an email.

“Even if nonoperative management of pediatric appendicitis did not work – resulting in the need to remove the appendix in 34% of cases – families were happy with their decisions 1 year later,” added Dr. Rentea, who coauthored an invited commentary about the study.

Lead study author Peter C. Minneci, MD, MHSc, a pediatric surgeon at Nationwide Children’s Hospital, Columbus, Ohio, and colleagues analyzed a subgroup of patients from a larger study in 10 tertiary children’s hospitals in the Midwest Pediatric Surgery Consortium.

As they reported in JAMA Network Open, the larger prospective, nonrandomized clinical trial enrolled 1,068 children between 2015 and 2018. The children ranged in age from 7 to 17 years, and they had imaging-confirmed appendicitis with an appendix diameter of 1.1 cm or less, no abscess, no appendicolith, and no phlegmon. White blood cell count was between 5,000 and 18,000 cells/μL, and abdominal pain began less than 48 hours before they received antibiotic therapy.

Caregivers chose either surgery or nonoperative antibiotic management. Patients who were treated first with antibiotics alone and who did not undergo appendectomy within 1 year were considered to have successfully completed nonoperative treatment.

The secondary analysis included the 370 children enrolled in the nonoperative group. Of these, 229 were boys, and the median age was 12.3 years. In this subgroup, the researchers compared outcomes after nonoperative, antibiotic management vs. surgery.

At 1 year, treatment failure had occurred in 125 patients, with 53 having undergone appendectomy during their first hospitalization, and 72 having experienced delayed treatment failure after being discharged.

• Higher patient-reported pain at presentation was linked to higher risk for in-hospital treatment failure (relative risk, 2.1; 95% confidence interval, 1.0-4.4) but not for delayed treatment failure (RR, 1.3; 95% CI, 0.7-2.3) or overall treatment failure at 1 year (RR, 1.5; 95% CI, 1.0-2.2).
• Pain lasting longer than 24 hours was linked to lower risk for delayed treatment failure (RR, 0.3; 95% CI, 0.1-1.0) but not for in-hospital treatment failure (RR, 1.2; 95% CI, 0.5-2.7) or treatment failure at 1 year (RR, 0.7; 95% CI, 0.4-1.2).
• Satisfaction with the decision was higher with successful nonoperative management at 30 days (28.0 vs. 27.0; difference, 1.0; 95% CI, 0.01-2.0) and at 1 year (28.1 vs 27.0; difference, 1.1; 95% CI, 0.2-2.0).

The researchers found no increased risk for treatment failure based on age, sex, race, ethnicity, white blood cell count, primary language, insurance status, transfer status, presentation symptoms, or imaging results.

Antibiotics-only is a safe option for children

“This study suggests that pediatric patients with uncomplicated acute appendicitis should be offered treatment options, including nonoperative management,” the authors write. “Treatment with antibiotics alone is a safe and equitable option for children, with no increased risk of treatment failure based on sociodemographic or objective clinical characteristics at presentation.”

But, the authors advise: “Families need to be made aware that treatment failure is not uncommon, and they should be provided with anticipatory guidance on how to proceed should symptoms recur.”

The investigators acknowledged limitations to the study, including the nonrandomized design that may have introduced bias, the loss to follow-up, and the study population being U.S. Midwest children, who may differ from children elsewhere in the country.

Shawn D. St Peter, MD, a pediatric surgeon, medical chair, and a senior vice president at Children’s Mercy Kansas City told this news organization in an email that having a nonoperative alternative to surgical appendectomy is important.

“Antibiotics are the initial treatment for appendicitis and can be the definitive treatment,” he said.

“Surprisingly, no sociodemographic or clinical characteristics were associated with an increased risk of nonoperative appendicitis treatment failure,” added Dr. St Peter, who coauthored the commentary with Dr. Rentea.

Howard C. Jen, MD, a pediatric surgeon at University of California, Los Angeles, Mattel Children’s Hospital, was not surprised by the findings.

“Nonoperative management for acute noncomplicated appendicitis in children continues to be safe and effective in highly selected patients,” he said in an email. “This alternative to surgery should be offered routinely to patients with early acute appendicitis.” 

Dr. Jen, who was not involved with the current study, noted that it did not address the impact and costs to families of nonoperative management vs. surgery.

“For the most vulnerable children who had difficulties accessing medical care, what is the best treatment option? What factors are important to the families when making this decision?” he asked.

All study and editorial authors report no relevant financial relationships. The study was funded by the Patient-Centered Outcomes Research Institute and the National Center for Advancing Translational Sciences.

A version of this article first appeared on Medscape.com.

Children who have greater acute appendicitis pain may be less likely to improve if they’re treated with antibiotics alone, according to a secondary analysis of a nonrandomized clinical trial.

“While approximately 35% of families chose nonoperative management, a high pain score between 7-10 on a 10-point scale nearly doubled in-hospital treatment failure,” Rebecca M. Rentea, MD, a pediatric surgeon and the director of the Comprehensive Colorectal Center at Children’s Mercy Kansas City, Mo., told this news organization in an email.

“Even if nonoperative management of pediatric appendicitis did not work – resulting in the need to remove the appendix in 34% of cases – families were happy with their decisions 1 year later,” added Dr. Rentea, who coauthored an invited commentary about the study.

Lead study author Peter C. Minneci, MD, MHSc, a pediatric surgeon at Nationwide Children’s Hospital, Columbus, Ohio, and colleagues analyzed a subgroup of patients from a larger study in 10 tertiary children’s hospitals in the Midwest Pediatric Surgery Consortium.

As they reported in JAMA Network Open, the larger prospective, nonrandomized clinical trial enrolled 1,068 children between 2015 and 2018. The children ranged in age from 7 to 17 years, and they had imaging-confirmed appendicitis with an appendix diameter of 1.1 cm or less, no abscess, no appendicolith, and no phlegmon. White blood cell count was between 5,000 and 18,000 cells/μL, and abdominal pain began less than 48 hours before they received antibiotic therapy.

Caregivers chose either surgery or nonoperative antibiotic management. Patients who were treated first with antibiotics alone and who did not undergo appendectomy within 1 year were considered to have successfully completed nonoperative treatment.

The secondary analysis included the 370 children enrolled in the nonoperative group. Of these, 229 were boys, and the median age was 12.3 years. In this subgroup, the researchers compared outcomes after nonoperative, antibiotic management vs. surgery.

At 1 year, treatment failure had occurred in 125 patients, with 53 having undergone appendectomy during their first hospitalization, and 72 having experienced delayed treatment failure after being discharged.

• Higher patient-reported pain at presentation was linked to higher risk for in-hospital treatment failure (relative risk, 2.1; 95% confidence interval, 1.0-4.4) but not for delayed treatment failure (RR, 1.3; 95% CI, 0.7-2.3) or overall treatment failure at 1 year (RR, 1.5; 95% CI, 1.0-2.2).
• Pain lasting longer than 24 hours was linked to lower risk for delayed treatment failure (RR, 0.3; 95% CI, 0.1-1.0) but not for in-hospital treatment failure (RR, 1.2; 95% CI, 0.5-2.7) or treatment failure at 1 year (RR, 0.7; 95% CI, 0.4-1.2).
• Satisfaction with the decision was higher with successful nonoperative management at 30 days (28.0 vs. 27.0; difference, 1.0; 95% CI, 0.01-2.0) and at 1 year (28.1 vs 27.0; difference, 1.1; 95% CI, 0.2-2.0).

The researchers found no increased risk for treatment failure based on age, sex, race, ethnicity, white blood cell count, primary language, insurance status, transfer status, presentation symptoms, or imaging results.

Antibiotics-only is a safe option for children

“This study suggests that pediatric patients with uncomplicated acute appendicitis should be offered treatment options, including nonoperative management,” the authors write. “Treatment with antibiotics alone is a safe and equitable option for children, with no increased risk of treatment failure based on sociodemographic or objective clinical characteristics at presentation.”

But, the authors advise: “Families need to be made aware that treatment failure is not uncommon, and they should be provided with anticipatory guidance on how to proceed should symptoms recur.”

The investigators acknowledged limitations to the study, including the nonrandomized design that may have introduced bias, the loss to follow-up, and the study population being U.S. Midwest children, who may differ from children elsewhere in the country.

Shawn D. St Peter, MD, a pediatric surgeon, medical chair, and a senior vice president at Children’s Mercy Kansas City told this news organization in an email that having a nonoperative alternative to surgical appendectomy is important.

“Antibiotics are the initial treatment for appendicitis and can be the definitive treatment,” he said.

“Surprisingly, no sociodemographic or clinical characteristics were associated with an increased risk of nonoperative appendicitis treatment failure,” added Dr. St Peter, who coauthored the commentary with Dr. Rentea.

Howard C. Jen, MD, a pediatric surgeon at University of California, Los Angeles, Mattel Children’s Hospital, was not surprised by the findings.

“Nonoperative management for acute noncomplicated appendicitis in children continues to be safe and effective in highly selected patients,” he said in an email. “This alternative to surgery should be offered routinely to patients with early acute appendicitis.” 

Dr. Jen, who was not involved with the current study, noted that it did not address the impact and costs to families of nonoperative management vs. surgery.

“For the most vulnerable children who had difficulties accessing medical care, what is the best treatment option? What factors are important to the families when making this decision?” he asked.

All study and editorial authors report no relevant financial relationships. The study was funded by the Patient-Centered Outcomes Research Institute and the National Center for Advancing Translational Sciences.

A version of this article first appeared on Medscape.com.

Children who have greater acute appendicitis pain may be less likely to improve if they’re treated with antibiotics alone, according to a secondary analysis of a nonrandomized clinical trial.

“While approximately 35% of families chose nonoperative management, a high pain score between 7-10 on a 10-point scale nearly doubled in-hospital treatment failure,” Rebecca M. Rentea, MD, a pediatric surgeon and the director of the Comprehensive Colorectal Center at Children’s Mercy Kansas City, Mo., told this news organization in an email.

“Even if nonoperative management of pediatric appendicitis did not work – resulting in the need to remove the appendix in 34% of cases – families were happy with their decisions 1 year later,” added Dr. Rentea, who coauthored an invited commentary about the study.

Lead study author Peter C. Minneci, MD, MHSc, a pediatric surgeon at Nationwide Children’s Hospital, Columbus, Ohio, and colleagues analyzed a subgroup of patients from a larger study in 10 tertiary children’s hospitals in the Midwest Pediatric Surgery Consortium.

As they reported in JAMA Network Open, the larger prospective, nonrandomized clinical trial enrolled 1,068 children between 2015 and 2018. The children ranged in age from 7 to 17 years, and they had imaging-confirmed appendicitis with an appendix diameter of 1.1 cm or less, no abscess, no appendicolith, and no phlegmon. White blood cell count was between 5,000 and 18,000 cells/μL, and abdominal pain began less than 48 hours before they received antibiotic therapy.

Caregivers chose either surgery or nonoperative antibiotic management. Patients who were treated first with antibiotics alone and who did not undergo appendectomy within 1 year were considered to have successfully completed nonoperative treatment.

The secondary analysis included the 370 children enrolled in the nonoperative group. Of these, 229 were boys, and the median age was 12.3 years. In this subgroup, the researchers compared outcomes after nonoperative, antibiotic management vs. surgery.

At 1 year, treatment failure had occurred in 125 patients, with 53 having undergone appendectomy during their first hospitalization, and 72 having experienced delayed treatment failure after being discharged.

• Higher patient-reported pain at presentation was linked to higher risk for in-hospital treatment failure (relative risk, 2.1; 95% confidence interval, 1.0-4.4) but not for delayed treatment failure (RR, 1.3; 95% CI, 0.7-2.3) or overall treatment failure at 1 year (RR, 1.5; 95% CI, 1.0-2.2).
• Pain lasting longer than 24 hours was linked to lower risk for delayed treatment failure (RR, 0.3; 95% CI, 0.1-1.0) but not for in-hospital treatment failure (RR, 1.2; 95% CI, 0.5-2.7) or treatment failure at 1 year (RR, 0.7; 95% CI, 0.4-1.2).
• Satisfaction with the decision was higher with successful nonoperative management at 30 days (28.0 vs. 27.0; difference, 1.0; 95% CI, 0.01-2.0) and at 1 year (28.1 vs 27.0; difference, 1.1; 95% CI, 0.2-2.0).

The researchers found no increased risk for treatment failure based on age, sex, race, ethnicity, white blood cell count, primary language, insurance status, transfer status, presentation symptoms, or imaging results.

Antibiotics-only is a safe option for children

“This study suggests that pediatric patients with uncomplicated acute appendicitis should be offered treatment options, including nonoperative management,” the authors write. “Treatment with antibiotics alone is a safe and equitable option for children, with no increased risk of treatment failure based on sociodemographic or objective clinical characteristics at presentation.”

But, the authors advise: “Families need to be made aware that treatment failure is not uncommon, and they should be provided with anticipatory guidance on how to proceed should symptoms recur.”

The investigators acknowledged limitations to the study, including the nonrandomized design that may have introduced bias, the loss to follow-up, and the study population being U.S. Midwest children, who may differ from children elsewhere in the country.

Shawn D. St Peter, MD, a pediatric surgeon, medical chair, and a senior vice president at Children’s Mercy Kansas City told this news organization in an email that having a nonoperative alternative to surgical appendectomy is important.

“Antibiotics are the initial treatment for appendicitis and can be the definitive treatment,” he said.

“Surprisingly, no sociodemographic or clinical characteristics were associated with an increased risk of nonoperative appendicitis treatment failure,” added Dr. St Peter, who coauthored the commentary with Dr. Rentea.

Howard C. Jen, MD, a pediatric surgeon at University of California, Los Angeles, Mattel Children’s Hospital, was not surprised by the findings.

“Nonoperative management for acute noncomplicated appendicitis in children continues to be safe and effective in highly selected patients,” he said in an email. “This alternative to surgery should be offered routinely to patients with early acute appendicitis.” 

Dr. Jen, who was not involved with the current study, noted that it did not address the impact and costs to families of nonoperative management vs. surgery.

“For the most vulnerable children who had difficulties accessing medical care, what is the best treatment option? What factors are important to the families when making this decision?” he asked.

All study and editorial authors report no relevant financial relationships. The study was funded by the Patient-Centered Outcomes Research Institute and the National Center for Advancing Translational Sciences.

A version of this article first appeared on Medscape.com.

Version 11.0 of the 2021 revised European AIDS Clinical Society (EACS) Guidelines updates all aspects of HIV care and adds recommendations on COVID-19 and antiretroviral treatment (ART) in children and adolescents, the guidelines authors reported in HIV Medicine.

“Conducting a systematic and timely annual revision of all guidelines recommendations is an EACS cornerstone,” EACS Guidelines coordinator Lene Ryom, MD, PhD, DMSc, a researcher at the University of Copenhagen, said in an interview. “These revisions ensure that the EACS Guidelines remain clinically relevant, are updated with the latest scientific evidence, and that they cover all key aspects related to HIV management.”

Key revisions in this update include:
 

Antiretroviral therapy (ART)

• Six recommended treatment options for first-line regimens for ART-naive adults include triple-drug regimens consisting of tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) with either lamivudine or emtricitabine plus dolutegravir, raltegravir, bictegravir, or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with emtricitabine plus dolutegravir. These drug combinations are recommended in single-tablet form if available.
• Alternatives consisting of triple-drug tenofovir-based regimens along with efavirenz, rilpivirine, or boosted darunavir, are advised when no recommended regimens are feasible.
• Bimonthly injections with long-acting cabotegravir plus rilpivirine are now advised as a switch option for people who are virologically suppressed.
• Pre-exposure prophylaxis on demand is advised for cisgender men, and PrEP may be continued during pregnancy and breastfeeding for people at risk of acquiring HIV.

Drug-drug interactions (DDIs) and other prescribing issues

• Four new DDI tables cover antituberculosis drugs, anxiolytics, hormone therapy, and COVID-19 therapies.

Comorbidities

• This update acknowledged the impact of the COVID-19 pandemic on routine health care, provides recommendations, and highlights the role of shared care and consultation for anxiety and other mental health disorders.
• Treatments involving diabetes, hypertension, cardiovascular disease, heart failure, chronic kidney disease, hypercholesterolemia, obesity, cancer, and sexual health have been updated, with new information about elderly and frail patients, women’s sexual health, and special considerations for transgender people.

Viral hepatitis coinfection

Immediate treatment of recently acquired hepatitis C is recommended for people living with HIV and ongoing risk behavior. Bulevirtide is added as a treatment option for hepatitis Delta virus.

Opportunistic infections and COVID-19

• The revision adds new guidance on management of HIV and COVID-19, covering epidemiology, risk factors for severe COVID-19, COVID-19 management, HIV care during a pandemic, HIV management during COVID-19 treatment, and management of long-term COVID-19 symptoms and prophylaxis.
• It includes guidance on management of tuberculosis meningitis, cryptococcosis, Pneumocystis jirovecii pneumonia, and drug-resistant tuberculosis.

Pediatric HIV infection treatments

• This new section, developed with the European pediatric research organization Penta, updates guidance for the use of preferred and alternative first-line drugs from birth to adolescence. Combinations include new child-friendly formulations of dolutegravir as early as 4 weeks of age and 3 kg (6.6 lb) of weight as well as an increased emphasis on dolutegravir as first-line preferred agent for all children except newborns. Abacavir is recommended for children younger than 3 months.
• ART regimens for children with infectious hepatitis or tuberculosis are also provided.

Laura Jane Waters, MD, a genitourinary consultant and HIV and hepatitis lead at Central and North West London National Health Service Mortimer Market Centre, and chair of the British HIV Association (BHIVA), shared her perspective on the revision. She was not involved with the EACS Guidelines revision.

“The addition of a section on COVID-19 in people with HIV, including management, drug interactions, and vaccination, is welcomed, as is the inclusion of key references and, for selected references, the key findings,” Dr. Waters said in an interview.

“Finally, for the first time, EACS covers pediatric HIV treatment by integrating with the Penta guidelines,” she added. “This is an important evolution, considering there are still cases of vertical HIV transmission in Europe, not to mention children living with HIV who have immigrated. Ensuring high and equitable standards of HIV treatment for young people is crucial.”

“This update to the always-pragmatic EACS guidelines further diverges from the United States Department of Health & Human Services guidelines,” Dr. Waters explained. “For 6 months, both guidelines preferred the same ... regimens for first-line therapy, but since DHSS removed raltegravir-based ART in June 2021 and EACS added doravirine-based regimens in October 2021, we’re back in the more familiar territory of EACS offering a broader range of preferred choices.”

Dr. Ryom noted that modern HIV care needs to consider managing coinfections, opportunistic diseases, comorbidities, aging, addictions, and mental health.

“Ensuring an integrated and personalized approach to HIV management is becoming increasingly important in an aging population living with HIV with the potential for complex needs,” she said.

The guidelines are available in several formats: as a free smartphone app, an interactive web version, and an online PDF.

Funding information was not provided. Dr. Ryom and several coauthors disclosed no relevant financial relationships. Most of the guideline coauthors declared financial relationships with pharmaceutical companies “outside the submitted work.” Dr. Waters provided no information on conflicts of interest.

A version of this article first appeared on Medscape.com.

Version 11.0 of the 2021 revised European AIDS Clinical Society (EACS) Guidelines updates all aspects of HIV care and adds recommendations on COVID-19 and antiretroviral treatment (ART) in children and adolescents, the guidelines authors reported in HIV Medicine.

“Conducting a systematic and timely annual revision of all guidelines recommendations is an EACS cornerstone,” EACS Guidelines coordinator Lene Ryom, MD, PhD, DMSc, a researcher at the University of Copenhagen, said in an interview. “These revisions ensure that the EACS Guidelines remain clinically relevant, are updated with the latest scientific evidence, and that they cover all key aspects related to HIV management.”

Key revisions in this update include:
 

Antiretroviral therapy (ART)

• Six recommended treatment options for first-line regimens for ART-naive adults include triple-drug regimens consisting of tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) with either lamivudine or emtricitabine plus dolutegravir, raltegravir, bictegravir, or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with emtricitabine plus dolutegravir. These drug combinations are recommended in single-tablet form if available.
• Alternatives consisting of triple-drug tenofovir-based regimens along with efavirenz, rilpivirine, or boosted darunavir, are advised when no recommended regimens are feasible.
• Bimonthly injections with long-acting cabotegravir plus rilpivirine are now advised as a switch option for people who are virologically suppressed.
• Pre-exposure prophylaxis on demand is advised for cisgender men, and PrEP may be continued during pregnancy and breastfeeding for people at risk of acquiring HIV.

Drug-drug interactions (DDIs) and other prescribing issues

• Four new DDI tables cover antituberculosis drugs, anxiolytics, hormone therapy, and COVID-19 therapies.

Comorbidities

• This update acknowledged the impact of the COVID-19 pandemic on routine health care, provides recommendations, and highlights the role of shared care and consultation for anxiety and other mental health disorders.
• Treatments involving diabetes, hypertension, cardiovascular disease, heart failure, chronic kidney disease, hypercholesterolemia, obesity, cancer, and sexual health have been updated, with new information about elderly and frail patients, women’s sexual health, and special considerations for transgender people.

Viral hepatitis coinfection

Immediate treatment of recently acquired hepatitis C is recommended for people living with HIV and ongoing risk behavior. Bulevirtide is added as a treatment option for hepatitis Delta virus.

Opportunistic infections and COVID-19

• The revision adds new guidance on management of HIV and COVID-19, covering epidemiology, risk factors for severe COVID-19, COVID-19 management, HIV care during a pandemic, HIV management during COVID-19 treatment, and management of long-term COVID-19 symptoms and prophylaxis.
• It includes guidance on management of tuberculosis meningitis, cryptococcosis, Pneumocystis jirovecii pneumonia, and drug-resistant tuberculosis.

Pediatric HIV infection treatments

• This new section, developed with the European pediatric research organization Penta, updates guidance for the use of preferred and alternative first-line drugs from birth to adolescence. Combinations include new child-friendly formulations of dolutegravir as early as 4 weeks of age and 3 kg (6.6 lb) of weight as well as an increased emphasis on dolutegravir as first-line preferred agent for all children except newborns. Abacavir is recommended for children younger than 3 months.
• ART regimens for children with infectious hepatitis or tuberculosis are also provided.

Laura Jane Waters, MD, a genitourinary consultant and HIV and hepatitis lead at Central and North West London National Health Service Mortimer Market Centre, and chair of the British HIV Association (BHIVA), shared her perspective on the revision. She was not involved with the EACS Guidelines revision.

“The addition of a section on COVID-19 in people with HIV, including management, drug interactions, and vaccination, is welcomed, as is the inclusion of key references and, for selected references, the key findings,” Dr. Waters said in an interview.

“Finally, for the first time, EACS covers pediatric HIV treatment by integrating with the Penta guidelines,” she added. “This is an important evolution, considering there are still cases of vertical HIV transmission in Europe, not to mention children living with HIV who have immigrated. Ensuring high and equitable standards of HIV treatment for young people is crucial.”

“This update to the always-pragmatic EACS guidelines further diverges from the United States Department of Health & Human Services guidelines,” Dr. Waters explained. “For 6 months, both guidelines preferred the same ... regimens for first-line therapy, but since DHSS removed raltegravir-based ART in June 2021 and EACS added doravirine-based regimens in October 2021, we’re back in the more familiar territory of EACS offering a broader range of preferred choices.”

Dr. Ryom noted that modern HIV care needs to consider managing coinfections, opportunistic diseases, comorbidities, aging, addictions, and mental health.

“Ensuring an integrated and personalized approach to HIV management is becoming increasingly important in an aging population living with HIV with the potential for complex needs,” she said.

The guidelines are available in several formats: as a free smartphone app, an interactive web version, and an online PDF.

Funding information was not provided. Dr. Ryom and several coauthors disclosed no relevant financial relationships. Most of the guideline coauthors declared financial relationships with pharmaceutical companies “outside the submitted work.” Dr. Waters provided no information on conflicts of interest.

A version of this article first appeared on Medscape.com.

Version 11.0 of the 2021 revised European AIDS Clinical Society (EACS) Guidelines updates all aspects of HIV care and adds recommendations on COVID-19 and antiretroviral treatment (ART) in children and adolescents, the guidelines authors reported in HIV Medicine.

“Conducting a systematic and timely annual revision of all guidelines recommendations is an EACS cornerstone,” EACS Guidelines coordinator Lene Ryom, MD, PhD, DMSc, a researcher at the University of Copenhagen, said in an interview. “These revisions ensure that the EACS Guidelines remain clinically relevant, are updated with the latest scientific evidence, and that they cover all key aspects related to HIV management.”

Key revisions in this update include:
 

Antiretroviral therapy (ART)

• Six recommended treatment options for first-line regimens for ART-naive adults include triple-drug regimens consisting of tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) with either lamivudine or emtricitabine plus dolutegravir, raltegravir, bictegravir, or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with emtricitabine plus dolutegravir. These drug combinations are recommended in single-tablet form if available.
• Alternatives consisting of triple-drug tenofovir-based regimens along with efavirenz, rilpivirine, or boosted darunavir, are advised when no recommended regimens are feasible.
• Bimonthly injections with long-acting cabotegravir plus rilpivirine are now advised as a switch option for people who are virologically suppressed.
• Pre-exposure prophylaxis on demand is advised for cisgender men, and PrEP may be continued during pregnancy and breastfeeding for people at risk of acquiring HIV.

Drug-drug interactions (DDIs) and other prescribing issues

• Four new DDI tables cover antituberculosis drugs, anxiolytics, hormone therapy, and COVID-19 therapies.

Comorbidities

• This update acknowledged the impact of the COVID-19 pandemic on routine health care, provides recommendations, and highlights the role of shared care and consultation for anxiety and other mental health disorders.
• Treatments involving diabetes, hypertension, cardiovascular disease, heart failure, chronic kidney disease, hypercholesterolemia, obesity, cancer, and sexual health have been updated, with new information about elderly and frail patients, women’s sexual health, and special considerations for transgender people.

Viral hepatitis coinfection

Immediate treatment of recently acquired hepatitis C is recommended for people living with HIV and ongoing risk behavior. Bulevirtide is added as a treatment option for hepatitis Delta virus.

Opportunistic infections and COVID-19

• The revision adds new guidance on management of HIV and COVID-19, covering epidemiology, risk factors for severe COVID-19, COVID-19 management, HIV care during a pandemic, HIV management during COVID-19 treatment, and management of long-term COVID-19 symptoms and prophylaxis.
• It includes guidance on management of tuberculosis meningitis, cryptococcosis, Pneumocystis jirovecii pneumonia, and drug-resistant tuberculosis.

Pediatric HIV infection treatments

• This new section, developed with the European pediatric research organization Penta, updates guidance for the use of preferred and alternative first-line drugs from birth to adolescence. Combinations include new child-friendly formulations of dolutegravir as early as 4 weeks of age and 3 kg (6.6 lb) of weight as well as an increased emphasis on dolutegravir as first-line preferred agent for all children except newborns. Abacavir is recommended for children younger than 3 months.
• ART regimens for children with infectious hepatitis or tuberculosis are also provided.

Laura Jane Waters, MD, a genitourinary consultant and HIV and hepatitis lead at Central and North West London National Health Service Mortimer Market Centre, and chair of the British HIV Association (BHIVA), shared her perspective on the revision. She was not involved with the EACS Guidelines revision.

“The addition of a section on COVID-19 in people with HIV, including management, drug interactions, and vaccination, is welcomed, as is the inclusion of key references and, for selected references, the key findings,” Dr. Waters said in an interview.

“Finally, for the first time, EACS covers pediatric HIV treatment by integrating with the Penta guidelines,” she added. “This is an important evolution, considering there are still cases of vertical HIV transmission in Europe, not to mention children living with HIV who have immigrated. Ensuring high and equitable standards of HIV treatment for young people is crucial.”

“This update to the always-pragmatic EACS guidelines further diverges from the United States Department of Health & Human Services guidelines,” Dr. Waters explained. “For 6 months, both guidelines preferred the same ... regimens for first-line therapy, but since DHSS removed raltegravir-based ART in June 2021 and EACS added doravirine-based regimens in October 2021, we’re back in the more familiar territory of EACS offering a broader range of preferred choices.”

Dr. Ryom noted that modern HIV care needs to consider managing coinfections, opportunistic diseases, comorbidities, aging, addictions, and mental health.

“Ensuring an integrated and personalized approach to HIV management is becoming increasingly important in an aging population living with HIV with the potential for complex needs,” she said.

The guidelines are available in several formats: as a free smartphone app, an interactive web version, and an online PDF.

Funding information was not provided. Dr. Ryom and several coauthors disclosed no relevant financial relationships. Most of the guideline coauthors declared financial relationships with pharmaceutical companies “outside the submitted work.” Dr. Waters provided no information on conflicts of interest.

A version of this article first appeared on Medscape.com.

Higher levels of specific carotenoid antioxidants in blood may help guard against age-related dementia, new research suggests.

Investigators found that individuals with the highest serum levels of lutein + zeaxanthin and beta-cryptoxanthin at baseline were less likely to have dementia decades later than were their peers with lower levels of these antioxidants.

Lutein and zeaxanthin are found in green leafy vegetables such as kale, spinach, broccoli, and peas. Beta-cryptoxanthin is found in fruits such as oranges, papaya, tangerines, and persimmons.

“Antioxidants may help protect the brain from oxidative stress, which can cause cell damage,” first author May A. Beydoun, PhD, with the National Institute on Aging (NIA), said in a news release. 

“This is the first nationally representative study to analyze blood levels of antioxidants in relation to dementia risk,” NIA scientific director Luigi Ferrucci, MD, said in an interview.

“Blood test results may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume,” Dr. Ferrucci added.

The study was published online in Neurology.
 

Reduced dementia risk

The researchers tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s disease (AD) and all-cause dementia.

They analyzed data from 7,283 participants in the Third National Health and Nutrition Examination Survey (NHANES III) who were at least 45 years old at baseline and followed for an average of 16-17 years.

They found serum levels of lutein + zeaxanthin were associated with reduced risk of all-cause dementia among people aged 65 and older in models adjusted for lifestyle.

For lutein + zeaxanthin, every standard deviation (SD) increase (roughly 15.4 µmol/liter) was associated with a 7% decrease in risk for dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.87-0.99, P = .037). This association was attenuated somewhat after adjustment for socioeconomic status.

Serum levels of beta-cryptoxanthin showed a “strong” inverse relationship with all-cause dementia in age- and sex-adjusted models.

For beta-cryptoxanthin, every SD increase (roughly 8.6 µmol/liter) was associated with a 14% reduced risk for dementia in people aged 45 and older (HR, 0.86; 95% CI, 0.80-0.93, P < .001) and 65 and older (HR, 0.86; 95% CI, 0.80-0.93, P = .001).

This relationship remained strong in models adjusted for sociodemographic and socioeconomic factors but attenuated in subsequent models.

No associations were found for lycopene, alpha-carotene, beta-carotene, or vitamins A, C, or E in the fully adjusted models.

Antagonistic interactions were observed for vitamin A and alpha-carotene, vitamin A and beta-carotene, vitamin E and lycopene, and lycopene and beta-carotene, suggesting putative protective effects of one antioxidant at lower levels of the other, the researchers noted.

“This analysis of an observational study found that the most important carotenoids in potentially protecting the brain may be lutein + zeaxanthin and beta-cryptoxanthin. However, randomized controlled trials are needed to prove causality,” said Dr. Ferrucci.

“Experts do not yet know the daily level of antioxidant intake to promote healthy aging of the brain. More research is needed to establish the necessary level of antioxidant intake – through the diet and/or supplements – to promote brain health and healthy aging,” he added.
 

An important step forward

In an accompanying editorial, Babak Hooshmand, MD, PhD, and Miia Kivipelto, MD, PhD, with Karolinska Institute, Stockholm, noted that while nutrition and dietary components are “potential targets” for dementia risk reduction, observational studies to date have reported “inconsistent findings.”

This study is “an important step towards exploring the complex relationship between antioxidants and dementia because it accounts for factors that could possibly influence the associations and considers interactions between different components,” they wrote.

The findings are “challenging,” they added, because they may lead to the hypothesis that inhibition of oxidative damage by antioxidants might have beneficial effects on preventing dementia.

However, clinical trials of antioxidant supplementation have been mainly “disappointing” and a recent Cochrane review found a lack of evidence for supplement use to preserve cognitive function or prevent dementia, Dr. Hooshmand and Dr. Kivipelto noted.

They added that the study contributes to the belief that antioxidants don’t act independently of each other or other factors, including socioeconomic status and lifestyle, in the mediation of dementia risk.

“A careful examination of the evidence is required to learn how antioxidants influence the complex pathology of dementia, because it appears to be more to it than meets the eye,”they concluded.

The research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute on Aging. Dr. Beydoun, Dr. Ferrucci, and Dr. Hooshmand report no relevant disclosures. Dr. Kivipelto has supported advisory boards for Combinostics, Roche, and Biogen.

A version of this article first appeared on Medscape.com.

Higher levels of specific carotenoid antioxidants in blood may help guard against age-related dementia, new research suggests.

Investigators found that individuals with the highest serum levels of lutein + zeaxanthin and beta-cryptoxanthin at baseline were less likely to have dementia decades later than were their peers with lower levels of these antioxidants.

Lutein and zeaxanthin are found in green leafy vegetables such as kale, spinach, broccoli, and peas. Beta-cryptoxanthin is found in fruits such as oranges, papaya, tangerines, and persimmons.

“Antioxidants may help protect the brain from oxidative stress, which can cause cell damage,” first author May A. Beydoun, PhD, with the National Institute on Aging (NIA), said in a news release. 

“This is the first nationally representative study to analyze blood levels of antioxidants in relation to dementia risk,” NIA scientific director Luigi Ferrucci, MD, said in an interview.

“Blood test results may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume,” Dr. Ferrucci added.

The study was published online in Neurology.
 

Reduced dementia risk

The researchers tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s disease (AD) and all-cause dementia.

They analyzed data from 7,283 participants in the Third National Health and Nutrition Examination Survey (NHANES III) who were at least 45 years old at baseline and followed for an average of 16-17 years.

They found serum levels of lutein + zeaxanthin were associated with reduced risk of all-cause dementia among people aged 65 and older in models adjusted for lifestyle.

For lutein + zeaxanthin, every standard deviation (SD) increase (roughly 15.4 µmol/liter) was associated with a 7% decrease in risk for dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.87-0.99, P = .037). This association was attenuated somewhat after adjustment for socioeconomic status.

Serum levels of beta-cryptoxanthin showed a “strong” inverse relationship with all-cause dementia in age- and sex-adjusted models.

For beta-cryptoxanthin, every SD increase (roughly 8.6 µmol/liter) was associated with a 14% reduced risk for dementia in people aged 45 and older (HR, 0.86; 95% CI, 0.80-0.93, P < .001) and 65 and older (HR, 0.86; 95% CI, 0.80-0.93, P = .001).

This relationship remained strong in models adjusted for sociodemographic and socioeconomic factors but attenuated in subsequent models.

No associations were found for lycopene, alpha-carotene, beta-carotene, or vitamins A, C, or E in the fully adjusted models.

Antagonistic interactions were observed for vitamin A and alpha-carotene, vitamin A and beta-carotene, vitamin E and lycopene, and lycopene and beta-carotene, suggesting putative protective effects of one antioxidant at lower levels of the other, the researchers noted.

“This analysis of an observational study found that the most important carotenoids in potentially protecting the brain may be lutein + zeaxanthin and beta-cryptoxanthin. However, randomized controlled trials are needed to prove causality,” said Dr. Ferrucci.

“Experts do not yet know the daily level of antioxidant intake to promote healthy aging of the brain. More research is needed to establish the necessary level of antioxidant intake – through the diet and/or supplements – to promote brain health and healthy aging,” he added.
 

An important step forward

In an accompanying editorial, Babak Hooshmand, MD, PhD, and Miia Kivipelto, MD, PhD, with Karolinska Institute, Stockholm, noted that while nutrition and dietary components are “potential targets” for dementia risk reduction, observational studies to date have reported “inconsistent findings.”

This study is “an important step towards exploring the complex relationship between antioxidants and dementia because it accounts for factors that could possibly influence the associations and considers interactions between different components,” they wrote.

The findings are “challenging,” they added, because they may lead to the hypothesis that inhibition of oxidative damage by antioxidants might have beneficial effects on preventing dementia.

However, clinical trials of antioxidant supplementation have been mainly “disappointing” and a recent Cochrane review found a lack of evidence for supplement use to preserve cognitive function or prevent dementia, Dr. Hooshmand and Dr. Kivipelto noted.

They added that the study contributes to the belief that antioxidants don’t act independently of each other or other factors, including socioeconomic status and lifestyle, in the mediation of dementia risk.

“A careful examination of the evidence is required to learn how antioxidants influence the complex pathology of dementia, because it appears to be more to it than meets the eye,”they concluded.

The research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute on Aging. Dr. Beydoun, Dr. Ferrucci, and Dr. Hooshmand report no relevant disclosures. Dr. Kivipelto has supported advisory boards for Combinostics, Roche, and Biogen.

A version of this article first appeared on Medscape.com.

Higher levels of specific carotenoid antioxidants in blood may help guard against age-related dementia, new research suggests.

Investigators found that individuals with the highest serum levels of lutein + zeaxanthin and beta-cryptoxanthin at baseline were less likely to have dementia decades later than were their peers with lower levels of these antioxidants.

Lutein and zeaxanthin are found in green leafy vegetables such as kale, spinach, broccoli, and peas. Beta-cryptoxanthin is found in fruits such as oranges, papaya, tangerines, and persimmons.

“Antioxidants may help protect the brain from oxidative stress, which can cause cell damage,” first author May A. Beydoun, PhD, with the National Institute on Aging (NIA), said in a news release. 

“This is the first nationally representative study to analyze blood levels of antioxidants in relation to dementia risk,” NIA scientific director Luigi Ferrucci, MD, said in an interview.

“Blood test results may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume,” Dr. Ferrucci added.

The study was published online in Neurology.
 

Reduced dementia risk

The researchers tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s disease (AD) and all-cause dementia.

They analyzed data from 7,283 participants in the Third National Health and Nutrition Examination Survey (NHANES III) who were at least 45 years old at baseline and followed for an average of 16-17 years.

They found serum levels of lutein + zeaxanthin were associated with reduced risk of all-cause dementia among people aged 65 and older in models adjusted for lifestyle.

For lutein + zeaxanthin, every standard deviation (SD) increase (roughly 15.4 µmol/liter) was associated with a 7% decrease in risk for dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.87-0.99, P = .037). This association was attenuated somewhat after adjustment for socioeconomic status.

Serum levels of beta-cryptoxanthin showed a “strong” inverse relationship with all-cause dementia in age- and sex-adjusted models.

For beta-cryptoxanthin, every SD increase (roughly 8.6 µmol/liter) was associated with a 14% reduced risk for dementia in people aged 45 and older (HR, 0.86; 95% CI, 0.80-0.93, P < .001) and 65 and older (HR, 0.86; 95% CI, 0.80-0.93, P = .001).

This relationship remained strong in models adjusted for sociodemographic and socioeconomic factors but attenuated in subsequent models.

No associations were found for lycopene, alpha-carotene, beta-carotene, or vitamins A, C, or E in the fully adjusted models.

Antagonistic interactions were observed for vitamin A and alpha-carotene, vitamin A and beta-carotene, vitamin E and lycopene, and lycopene and beta-carotene, suggesting putative protective effects of one antioxidant at lower levels of the other, the researchers noted.

“This analysis of an observational study found that the most important carotenoids in potentially protecting the brain may be lutein + zeaxanthin and beta-cryptoxanthin. However, randomized controlled trials are needed to prove causality,” said Dr. Ferrucci.

“Experts do not yet know the daily level of antioxidant intake to promote healthy aging of the brain. More research is needed to establish the necessary level of antioxidant intake – through the diet and/or supplements – to promote brain health and healthy aging,” he added.
 

An important step forward

In an accompanying editorial, Babak Hooshmand, MD, PhD, and Miia Kivipelto, MD, PhD, with Karolinska Institute, Stockholm, noted that while nutrition and dietary components are “potential targets” for dementia risk reduction, observational studies to date have reported “inconsistent findings.”

This study is “an important step towards exploring the complex relationship between antioxidants and dementia because it accounts for factors that could possibly influence the associations and considers interactions between different components,” they wrote.

The findings are “challenging,” they added, because they may lead to the hypothesis that inhibition of oxidative damage by antioxidants might have beneficial effects on preventing dementia.

However, clinical trials of antioxidant supplementation have been mainly “disappointing” and a recent Cochrane review found a lack of evidence for supplement use to preserve cognitive function or prevent dementia, Dr. Hooshmand and Dr. Kivipelto noted.

They added that the study contributes to the belief that antioxidants don’t act independently of each other or other factors, including socioeconomic status and lifestyle, in the mediation of dementia risk.

“A careful examination of the evidence is required to learn how antioxidants influence the complex pathology of dementia, because it appears to be more to it than meets the eye,”they concluded.

The research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute on Aging. Dr. Beydoun, Dr. Ferrucci, and Dr. Hooshmand report no relevant disclosures. Dr. Kivipelto has supported advisory boards for Combinostics, Roche, and Biogen.

A version of this article first appeared on Medscape.com.

BERLIN – Some breast cancer specialists still have misconceptions about the appropriate use of multigene signatures in making prognostic and treatment decisions in early-stage disease, a European survey suggests.

The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.

Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.

“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.

Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.

Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.

To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.

The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.

In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.

Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.

Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.

Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.

Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.

In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.

No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.

When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.

When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.

In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.

Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.

The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.

The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.

A version of this article first appeared on Medscape.com.

This article was updated 5/9/22.

BERLIN – Some breast cancer specialists still have misconceptions about the appropriate use of multigene signatures in making prognostic and treatment decisions in early-stage disease, a European survey suggests.

The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.

Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.

“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.

Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.

Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.

To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.

The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.

In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.

Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.

Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.

Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.

Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.

In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.

No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.

When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.

When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.

In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.

Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.

The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.

The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.

A version of this article first appeared on Medscape.com.

This article was updated 5/9/22.

BERLIN – Some breast cancer specialists still have misconceptions about the appropriate use of multigene signatures in making prognostic and treatment decisions in early-stage disease, a European survey suggests.

The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.

Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.

“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.

Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.

Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.

To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.

The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.

In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.

Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.

Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.

Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.

Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.

In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.

No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.

When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.

When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.

In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.

Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.

The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.

The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.

A version of this article first appeared on Medscape.com.

This article was updated 5/9/22.

The more boosters the better? Data from Israel show that immune protection in elderly people is strengthened even further after a fourth dose. Karl Lauterbach, MD, German minister of health, recently pleaded for a second booster for those aged 18 years and older, and he pushed for a European Union–wide recommendation. He has not been able to implement this yet.

Just as before, Germany’s Standing Committee on Vaccination (STIKO) is only recommending the second booster for people aged 70 years and older, the European Medicines Agency (EMA) is recommending the fourth vaccination for everyone aged 80 years and older, and the United States has set the general age limit at 50 years.

Specialists remain skeptical about expanding the availability of the second booster. “From an immunologic perspective, people under the age of 70 with a healthy immune system do not need this fourth vaccination,” said Christiane Falk, PhD, head of the Institute for Transplantation Immunology of the Hannover Medical School (Germany) and member of the German Federal Government COVID Expert Panel, at a Science Media Center press briefing.

After the second vaccination, young healthy people are sufficiently protected against a severe course of the disease. Dr. Falk sees the STIKO recommendation as feasible, since it can be worked with. People in nursing facilities or those with additional underlying conditions would be considered for a fourth vaccination, explained Dr. Falk.
 

Complete protection unrealistic

Achieving complete protection against infection through multiple boosters is not realistic, said Christoph Neumann-Haefelin, MD, head of the Working Group for Translational Virus Immunology at the Clinic for Internal Medicine II, University Hospital Freiburg, Germany. Therefore, this should not be pursued when discussing boosters. “The aim of the booster vaccination should be to protect different groups of people against severe courses of the disease,” said Dr. Neumann-Haefelin.

Neutralizing antibodies that are only present in high concentrations for a few weeks after infection or vaccination are sometimes able to prevent the infection on their own. The immunologic memory of B cells and T cells, which ensures long-lasting protection against severe courses of the disease, is at a high level after two doses, and a third dose increases the protection more.

While people with a weak immune system need significantly more vaccinations in a shorter period to receive the same protection, too many booster vaccinations against SARS-CoV-2 are not sensible for young healthy people.
 

Immune saturation effect

A recent study in macaques showed that an adjusted Omicron booster did not lead to higher antibody titers, compared with a usual booster. In January 2022, the EMA warned against frequent consecutive boosters that may no longer produce the desired immune response.

If someone receives a booster too early, a saturation effect can occur, warned Andreas Radbruch, PhD, scientific director of the German Rheumatism Research Center Berlin. “We know this from lots of experimental studies but also from lots of other vaccinations. For example, you cannot be vaccinated against tetanus twice at 3- or 4-week intervals. Nothing at all will happen the second time,” explained Dr. Radbruch.

If the same antigen is applied again and again at the same dose, the immune system is made so active that the antigen is directly intercepted and cannot have any new effect on the immune system. This mechanism has been known for a long time, said Dr. Radbruch.
 

‘Original antigenic sin’

Premature boosting could even be a handicap in the competition between immune response and virus, said Dr. Radbruch. This is due to the principle of “original antigenic sin.” If the immune system has already come into contact with a virus, contact with a new virus variant will cause it to form antibodies predominantly against those epitopes that were already present in the original virus. As a result of this, too many boosters can weaken protection against different variants.

“We have not actually observed this with SARS-CoV-2, however,” said Dr. Radbruch. “Immunity is always extremely broad. With a double or triple vaccination, all previously existing variants are covered by an affinity-matured immune system.”

Dr. Neumann-Haefelin confirmed this and added that all virus mutations, including Omicron, have different epitopes that affect the antibody response, but the T-cell response does not differ.

Dr. Radbruch said that the vaccine protection probably lasts for decades. Following an infection or vaccination, the antibody concentration in the bone marrow is similar to that achieved after a measles or tetanus vaccination. “The vaccination is already extremely efficient. You have protection at the same magnitude as for other infectious diseases or vaccinations, which is expected to last decades,” said Dr. Radbruch.

He clarified that the decrease in antibodies after vaccination and infection is normal and does not indicate a drop in protection. “Quantity and quality must not be confused here. There is simply less mass, but the grade of remaining antibody increases.”

In the competition around the virus antigens (referred to as affinity maturation), antibodies develop that bind 10 to 100 times better and are particularly protective against the virus. The immune system is thereby sustainably effective.
 

For whom and when?

Since the immune response is age dependent, it makes more sense to administer an additional booster to elderly people than to young people. Also included in this group, however, are people whose immune system still does not provide the same level of protection after the second or even third vaccination as that of younger, healthy people.

Dr. Radbruch noted that 4% of people older than 70 years exhibited autoantibodies against interferons. The effects are huge. “That is 20% of patients in an intensive care unit – and they all have a very poor prognosis,” said Dr. Radbruch. These people are extremely threatened by the virus. Multiple vaccinations are sensible for them.

Even people with a weak immune response benefit from multiple vaccinations, confirmed Dr. Neumann-Haefelin. “We are not seeing the antibody responses here that we see in young people with healthy immune systems until the third or fourth vaccination sometimes.”

Although for young healthy people, it is particularly important to ensure a sufficient period between vaccinations so that the affinity maturation is not impaired, those with a weak immune response can be vaccinated again as soon as after 3 months.

The “optimum minimum period of time” for people with healthy immune systems is 6 months, according to Dr. Neumann-Haefelin. “This is true for everyone in whom a proper response is expected.” The vaccine protection probably lasts significantly longer, and therefore, frequent boosting may not be necessary in the future, he said. The time separation also applies for medical personnel, for whom the Robert Koch Institute also recommends a second booster.

A version of this article first appeared on Medscape.com.

The more boosters the better? Data from Israel show that immune protection in elderly people is strengthened even further after a fourth dose. Karl Lauterbach, MD, German minister of health, recently pleaded for a second booster for those aged 18 years and older, and he pushed for a European Union–wide recommendation. He has not been able to implement this yet.

Just as before, Germany’s Standing Committee on Vaccination (STIKO) is only recommending the second booster for people aged 70 years and older, the European Medicines Agency (EMA) is recommending the fourth vaccination for everyone aged 80 years and older, and the United States has set the general age limit at 50 years.

Specialists remain skeptical about expanding the availability of the second booster. “From an immunologic perspective, people under the age of 70 with a healthy immune system do not need this fourth vaccination,” said Christiane Falk, PhD, head of the Institute for Transplantation Immunology of the Hannover Medical School (Germany) and member of the German Federal Government COVID Expert Panel, at a Science Media Center press briefing.

After the second vaccination, young healthy people are sufficiently protected against a severe course of the disease. Dr. Falk sees the STIKO recommendation as feasible, since it can be worked with. People in nursing facilities or those with additional underlying conditions would be considered for a fourth vaccination, explained Dr. Falk.
 

Complete protection unrealistic

Achieving complete protection against infection through multiple boosters is not realistic, said Christoph Neumann-Haefelin, MD, head of the Working Group for Translational Virus Immunology at the Clinic for Internal Medicine II, University Hospital Freiburg, Germany. Therefore, this should not be pursued when discussing boosters. “The aim of the booster vaccination should be to protect different groups of people against severe courses of the disease,” said Dr. Neumann-Haefelin.

Neutralizing antibodies that are only present in high concentrations for a few weeks after infection or vaccination are sometimes able to prevent the infection on their own. The immunologic memory of B cells and T cells, which ensures long-lasting protection against severe courses of the disease, is at a high level after two doses, and a third dose increases the protection more.

While people with a weak immune system need significantly more vaccinations in a shorter period to receive the same protection, too many booster vaccinations against SARS-CoV-2 are not sensible for young healthy people.
 

Immune saturation effect

A recent study in macaques showed that an adjusted Omicron booster did not lead to higher antibody titers, compared with a usual booster. In January 2022, the EMA warned against frequent consecutive boosters that may no longer produce the desired immune response.

If someone receives a booster too early, a saturation effect can occur, warned Andreas Radbruch, PhD, scientific director of the German Rheumatism Research Center Berlin. “We know this from lots of experimental studies but also from lots of other vaccinations. For example, you cannot be vaccinated against tetanus twice at 3- or 4-week intervals. Nothing at all will happen the second time,” explained Dr. Radbruch.

If the same antigen is applied again and again at the same dose, the immune system is made so active that the antigen is directly intercepted and cannot have any new effect on the immune system. This mechanism has been known for a long time, said Dr. Radbruch.
 

‘Original antigenic sin’

Premature boosting could even be a handicap in the competition between immune response and virus, said Dr. Radbruch. This is due to the principle of “original antigenic sin.” If the immune system has already come into contact with a virus, contact with a new virus variant will cause it to form antibodies predominantly against those epitopes that were already present in the original virus. As a result of this, too many boosters can weaken protection against different variants.

“We have not actually observed this with SARS-CoV-2, however,” said Dr. Radbruch. “Immunity is always extremely broad. With a double or triple vaccination, all previously existing variants are covered by an affinity-matured immune system.”

Dr. Neumann-Haefelin confirmed this and added that all virus mutations, including Omicron, have different epitopes that affect the antibody response, but the T-cell response does not differ.

Dr. Radbruch said that the vaccine protection probably lasts for decades. Following an infection or vaccination, the antibody concentration in the bone marrow is similar to that achieved after a measles or tetanus vaccination. “The vaccination is already extremely efficient. You have protection at the same magnitude as for other infectious diseases or vaccinations, which is expected to last decades,” said Dr. Radbruch.

He clarified that the decrease in antibodies after vaccination and infection is normal and does not indicate a drop in protection. “Quantity and quality must not be confused here. There is simply less mass, but the grade of remaining antibody increases.”

In the competition around the virus antigens (referred to as affinity maturation), antibodies develop that bind 10 to 100 times better and are particularly protective against the virus. The immune system is thereby sustainably effective.
 

For whom and when?

Since the immune response is age dependent, it makes more sense to administer an additional booster to elderly people than to young people. Also included in this group, however, are people whose immune system still does not provide the same level of protection after the second or even third vaccination as that of younger, healthy people.

Dr. Radbruch noted that 4% of people older than 70 years exhibited autoantibodies against interferons. The effects are huge. “That is 20% of patients in an intensive care unit – and they all have a very poor prognosis,” said Dr. Radbruch. These people are extremely threatened by the virus. Multiple vaccinations are sensible for them.

Even people with a weak immune response benefit from multiple vaccinations, confirmed Dr. Neumann-Haefelin. “We are not seeing the antibody responses here that we see in young people with healthy immune systems until the third or fourth vaccination sometimes.”

Although for young healthy people, it is particularly important to ensure a sufficient period between vaccinations so that the affinity maturation is not impaired, those with a weak immune response can be vaccinated again as soon as after 3 months.

The “optimum minimum period of time” for people with healthy immune systems is 6 months, according to Dr. Neumann-Haefelin. “This is true for everyone in whom a proper response is expected.” The vaccine protection probably lasts significantly longer, and therefore, frequent boosting may not be necessary in the future, he said. The time separation also applies for medical personnel, for whom the Robert Koch Institute also recommends a second booster.

A version of this article first appeared on Medscape.com.

The more boosters the better? Data from Israel show that immune protection in elderly people is strengthened even further after a fourth dose. Karl Lauterbach, MD, German minister of health, recently pleaded for a second booster for those aged 18 years and older, and he pushed for a European Union–wide recommendation. He has not been able to implement this yet.

Just as before, Germany’s Standing Committee on Vaccination (STIKO) is only recommending the second booster for people aged 70 years and older, the European Medicines Agency (EMA) is recommending the fourth vaccination for everyone aged 80 years and older, and the United States has set the general age limit at 50 years.

Specialists remain skeptical about expanding the availability of the second booster. “From an immunologic perspective, people under the age of 70 with a healthy immune system do not need this fourth vaccination,” said Christiane Falk, PhD, head of the Institute for Transplantation Immunology of the Hannover Medical School (Germany) and member of the German Federal Government COVID Expert Panel, at a Science Media Center press briefing.

After the second vaccination, young healthy people are sufficiently protected against a severe course of the disease. Dr. Falk sees the STIKO recommendation as feasible, since it can be worked with. People in nursing facilities or those with additional underlying conditions would be considered for a fourth vaccination, explained Dr. Falk.
 

Complete protection unrealistic

Achieving complete protection against infection through multiple boosters is not realistic, said Christoph Neumann-Haefelin, MD, head of the Working Group for Translational Virus Immunology at the Clinic for Internal Medicine II, University Hospital Freiburg, Germany. Therefore, this should not be pursued when discussing boosters. “The aim of the booster vaccination should be to protect different groups of people against severe courses of the disease,” said Dr. Neumann-Haefelin.

Neutralizing antibodies that are only present in high concentrations for a few weeks after infection or vaccination are sometimes able to prevent the infection on their own. The immunologic memory of B cells and T cells, which ensures long-lasting protection against severe courses of the disease, is at a high level after two doses, and a third dose increases the protection more.

While people with a weak immune system need significantly more vaccinations in a shorter period to receive the same protection, too many booster vaccinations against SARS-CoV-2 are not sensible for young healthy people.
 

Immune saturation effect

A recent study in macaques showed that an adjusted Omicron booster did not lead to higher antibody titers, compared with a usual booster. In January 2022, the EMA warned against frequent consecutive boosters that may no longer produce the desired immune response.

If someone receives a booster too early, a saturation effect can occur, warned Andreas Radbruch, PhD, scientific director of the German Rheumatism Research Center Berlin. “We know this from lots of experimental studies but also from lots of other vaccinations. For example, you cannot be vaccinated against tetanus twice at 3- or 4-week intervals. Nothing at all will happen the second time,” explained Dr. Radbruch.

If the same antigen is applied again and again at the same dose, the immune system is made so active that the antigen is directly intercepted and cannot have any new effect on the immune system. This mechanism has been known for a long time, said Dr. Radbruch.
 

‘Original antigenic sin’

Premature boosting could even be a handicap in the competition between immune response and virus, said Dr. Radbruch. This is due to the principle of “original antigenic sin.” If the immune system has already come into contact with a virus, contact with a new virus variant will cause it to form antibodies predominantly against those epitopes that were already present in the original virus. As a result of this, too many boosters can weaken protection against different variants.

“We have not actually observed this with SARS-CoV-2, however,” said Dr. Radbruch. “Immunity is always extremely broad. With a double or triple vaccination, all previously existing variants are covered by an affinity-matured immune system.”

Dr. Neumann-Haefelin confirmed this and added that all virus mutations, including Omicron, have different epitopes that affect the antibody response, but the T-cell response does not differ.

Dr. Radbruch said that the vaccine protection probably lasts for decades. Following an infection or vaccination, the antibody concentration in the bone marrow is similar to that achieved after a measles or tetanus vaccination. “The vaccination is already extremely efficient. You have protection at the same magnitude as for other infectious diseases or vaccinations, which is expected to last decades,” said Dr. Radbruch.

He clarified that the decrease in antibodies after vaccination and infection is normal and does not indicate a drop in protection. “Quantity and quality must not be confused here. There is simply less mass, but the grade of remaining antibody increases.”

In the competition around the virus antigens (referred to as affinity maturation), antibodies develop that bind 10 to 100 times better and are particularly protective against the virus. The immune system is thereby sustainably effective.
 

For whom and when?

Since the immune response is age dependent, it makes more sense to administer an additional booster to elderly people than to young people. Also included in this group, however, are people whose immune system still does not provide the same level of protection after the second or even third vaccination as that of younger, healthy people.

Dr. Radbruch noted that 4% of people older than 70 years exhibited autoantibodies against interferons. The effects are huge. “That is 20% of patients in an intensive care unit – and they all have a very poor prognosis,” said Dr. Radbruch. These people are extremely threatened by the virus. Multiple vaccinations are sensible for them.

Even people with a weak immune response benefit from multiple vaccinations, confirmed Dr. Neumann-Haefelin. “We are not seeing the antibody responses here that we see in young people with healthy immune systems until the third or fourth vaccination sometimes.”

Although for young healthy people, it is particularly important to ensure a sufficient period between vaccinations so that the affinity maturation is not impaired, those with a weak immune response can be vaccinated again as soon as after 3 months.

The “optimum minimum period of time” for people with healthy immune systems is 6 months, according to Dr. Neumann-Haefelin. “This is true for everyone in whom a proper response is expected.” The vaccine protection probably lasts significantly longer, and therefore, frequent boosting may not be necessary in the future, he said. The time separation also applies for medical personnel, for whom the Robert Koch Institute also recommends a second booster.

A version of this article first appeared on Medscape.com.

Standard therapies for depression are antidepressants and psychotherapy. In particularly severe cases, electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) may also be indicated. VNS is an approved, effective, well-tolerated, long-term therapy for chronic and therapy-resistant depression, wrote Christine Reif-Leonhardt, MD, and associates from the University Hospital Frankfurt am Main (Germany), in a recent journal article. In contrast to more common treatments, such as ECT, VNS is little known in the general population and among specialists. The cost of VNS is covered by health insurance funds in Germany.

Available since 1994

As the authors reported, invasive VNS was approved in the European Union in 1994 and in the United States in 1997 for the treatment of children with medicinal therapy–refractory epilepsy. Because positive and lasting effects on mood could be seen in adults after around 3 months of VNS, irrespective of the effectiveness of anticonvulsive medication, “a genuinely antidepressant effect of VNS [was] postulated,” and therefore it was further developed as an antidepressant therapy.

A VNS system first received a CE certification in 2001 in the European Union for the treatment of patients with chronic or relapsing depression who had therapy-resistant depression or who were intolerant of the current depression therapy. In 2005, VNS was approved in the United States for the treatment of patients aged 18 years or older with therapy-resistant major depression for which at least four antidepressant therapies had not helped sufficiently.
 

Few sham-controlled studies

According to Dr. Reif-Leonhardt and colleagues, there have been multiple studies and case series on VNS in patients with therapy-resistant depression in the past 20 years. Many of the studies highlighted the additional benefits of VNS as an adjuvant procedure, but they were observational studies. Sham-controlled studies are in short supply because of methodologic difficulties and ethical problems.

The largest long-term study is a registry study in which 494 patients with therapy-resistant depression received the combination of the usual antidepressant therapy and VNS. The study lasted 5 years; 301 patients served as a control group and received the usual therapy. The cumulative response to the therapy (68% vs. 41%) and the remission rate (43% vs. 26%) were significantly greater in the group that received VNS, according to the authors. Patients who underwent at least one ECT series of at least seven sessions responded particularly well to VNS. The combined therapy was also more effective in ECT nonresponders than the usual therapy alone.

To date, only one sham-controlled study of VNS treatment for therapy-resistant depression has been conducted. In it, VNS was not significantly superior to a sham stimulation over an observation period of 10 weeks. However, observational studies have provided evidence that the antidepressant effect of VNS only develops after at least 12 months of treatment. According to Dr. Reif-Leonhardt and colleagues, the data indicate that differences in response rate and therapy effect can only be observed in the longer term after 3-12 months and that as the therapy duration increases, so do the effects of VNS. From this, it can be assumed “that the VNS mechanism of action can be attributed to neuroplastic and adaptive phenomena.”

The typical, common side effects of surgery are pain and paresthesia. Through irritation of the nerve, approximately every third patient experiences postoperative hoarseness and a voice change. Serious side effects and complications, such as temporary swallowing disorders, are rare. By reducing the stimulation intensity or lowering the stimulation frequency or impulse width, the side effects associated with stimulation can be alleviated or even eliminated. A second small surgical intervention may become necessary to replace broken cables or the battery (life span, 3-8 years).
 

Criteria for VNS therapy

When should VNS be considered? The authors specified the following criteria:

• An insufficient response to at least two antidepressants from different substance classes (ideally including one tricyclic) at a sufficient dosage and duration, as well as to two augmentation agents (such as lithium and quetiapine) in combination with guideline psychotherapy
• Intolerable side effects from pharmacotherapy or contraindications to medicinal therapy
• For patients who respond to ECT, the occurrence of relapses or residual symptoms after cessation of (maintenance) ECT, intolerable ECT side effects, or the need for maintenance ECT
• Repeated or long hospital treatments because of depression

This article is a translation of an article from Univadis Germany and first appeared on Medscape.com.

Standard therapies for depression are antidepressants and psychotherapy. In particularly severe cases, electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) may also be indicated. VNS is an approved, effective, well-tolerated, long-term therapy for chronic and therapy-resistant depression, wrote Christine Reif-Leonhardt, MD, and associates from the University Hospital Frankfurt am Main (Germany), in a recent journal article. In contrast to more common treatments, such as ECT, VNS is little known in the general population and among specialists. The cost of VNS is covered by health insurance funds in Germany.

Available since 1994

As the authors reported, invasive VNS was approved in the European Union in 1994 and in the United States in 1997 for the treatment of children with medicinal therapy–refractory epilepsy. Because positive and lasting effects on mood could be seen in adults after around 3 months of VNS, irrespective of the effectiveness of anticonvulsive medication, “a genuinely antidepressant effect of VNS [was] postulated,” and therefore it was further developed as an antidepressant therapy.

A VNS system first received a CE certification in 2001 in the European Union for the treatment of patients with chronic or relapsing depression who had therapy-resistant depression or who were intolerant of the current depression therapy. In 2005, VNS was approved in the United States for the treatment of patients aged 18 years or older with therapy-resistant major depression for which at least four antidepressant therapies had not helped sufficiently.
 

Few sham-controlled studies

According to Dr. Reif-Leonhardt and colleagues, there have been multiple studies and case series on VNS in patients with therapy-resistant depression in the past 20 years. Many of the studies highlighted the additional benefits of VNS as an adjuvant procedure, but they were observational studies. Sham-controlled studies are in short supply because of methodologic difficulties and ethical problems.

The largest long-term study is a registry study in which 494 patients with therapy-resistant depression received the combination of the usual antidepressant therapy and VNS. The study lasted 5 years; 301 patients served as a control group and received the usual therapy. The cumulative response to the therapy (68% vs. 41%) and the remission rate (43% vs. 26%) were significantly greater in the group that received VNS, according to the authors. Patients who underwent at least one ECT series of at least seven sessions responded particularly well to VNS. The combined therapy was also more effective in ECT nonresponders than the usual therapy alone.

To date, only one sham-controlled study of VNS treatment for therapy-resistant depression has been conducted. In it, VNS was not significantly superior to a sham stimulation over an observation period of 10 weeks. However, observational studies have provided evidence that the antidepressant effect of VNS only develops after at least 12 months of treatment. According to Dr. Reif-Leonhardt and colleagues, the data indicate that differences in response rate and therapy effect can only be observed in the longer term after 3-12 months and that as the therapy duration increases, so do the effects of VNS. From this, it can be assumed “that the VNS mechanism of action can be attributed to neuroplastic and adaptive phenomena.”

The typical, common side effects of surgery are pain and paresthesia. Through irritation of the nerve, approximately every third patient experiences postoperative hoarseness and a voice change. Serious side effects and complications, such as temporary swallowing disorders, are rare. By reducing the stimulation intensity or lowering the stimulation frequency or impulse width, the side effects associated with stimulation can be alleviated or even eliminated. A second small surgical intervention may become necessary to replace broken cables or the battery (life span, 3-8 years).
 

Criteria for VNS therapy

When should VNS be considered? The authors specified the following criteria:

• An insufficient response to at least two antidepressants from different substance classes (ideally including one tricyclic) at a sufficient dosage and duration, as well as to two augmentation agents (such as lithium and quetiapine) in combination with guideline psychotherapy
• Intolerable side effects from pharmacotherapy or contraindications to medicinal therapy
• For patients who respond to ECT, the occurrence of relapses or residual symptoms after cessation of (maintenance) ECT, intolerable ECT side effects, or the need for maintenance ECT
• Repeated or long hospital treatments because of depression

This article is a translation of an article from Univadis Germany and first appeared on Medscape.com.

Standard therapies for depression are antidepressants and psychotherapy. In particularly severe cases, electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) may also be indicated. VNS is an approved, effective, well-tolerated, long-term therapy for chronic and therapy-resistant depression, wrote Christine Reif-Leonhardt, MD, and associates from the University Hospital Frankfurt am Main (Germany), in a recent journal article. In contrast to more common treatments, such as ECT, VNS is little known in the general population and among specialists. The cost of VNS is covered by health insurance funds in Germany.

Available since 1994

As the authors reported, invasive VNS was approved in the European Union in 1994 and in the United States in 1997 for the treatment of children with medicinal therapy–refractory epilepsy. Because positive and lasting effects on mood could be seen in adults after around 3 months of VNS, irrespective of the effectiveness of anticonvulsive medication, “a genuinely antidepressant effect of VNS [was] postulated,” and therefore it was further developed as an antidepressant therapy.

A VNS system first received a CE certification in 2001 in the European Union for the treatment of patients with chronic or relapsing depression who had therapy-resistant depression or who were intolerant of the current depression therapy. In 2005, VNS was approved in the United States for the treatment of patients aged 18 years or older with therapy-resistant major depression for which at least four antidepressant therapies had not helped sufficiently.
 

Few sham-controlled studies

According to Dr. Reif-Leonhardt and colleagues, there have been multiple studies and case series on VNS in patients with therapy-resistant depression in the past 20 years. Many of the studies highlighted the additional benefits of VNS as an adjuvant procedure, but they were observational studies. Sham-controlled studies are in short supply because of methodologic difficulties and ethical problems.

The largest long-term study is a registry study in which 494 patients with therapy-resistant depression received the combination of the usual antidepressant therapy and VNS. The study lasted 5 years; 301 patients served as a control group and received the usual therapy. The cumulative response to the therapy (68% vs. 41%) and the remission rate (43% vs. 26%) were significantly greater in the group that received VNS, according to the authors. Patients who underwent at least one ECT series of at least seven sessions responded particularly well to VNS. The combined therapy was also more effective in ECT nonresponders than the usual therapy alone.

To date, only one sham-controlled study of VNS treatment for therapy-resistant depression has been conducted. In it, VNS was not significantly superior to a sham stimulation over an observation period of 10 weeks. However, observational studies have provided evidence that the antidepressant effect of VNS only develops after at least 12 months of treatment. According to Dr. Reif-Leonhardt and colleagues, the data indicate that differences in response rate and therapy effect can only be observed in the longer term after 3-12 months and that as the therapy duration increases, so do the effects of VNS. From this, it can be assumed “that the VNS mechanism of action can be attributed to neuroplastic and adaptive phenomena.”

The typical, common side effects of surgery are pain and paresthesia. Through irritation of the nerve, approximately every third patient experiences postoperative hoarseness and a voice change. Serious side effects and complications, such as temporary swallowing disorders, are rare. By reducing the stimulation intensity or lowering the stimulation frequency or impulse width, the side effects associated with stimulation can be alleviated or even eliminated. A second small surgical intervention may become necessary to replace broken cables or the battery (life span, 3-8 years).
 

Criteria for VNS therapy

When should VNS be considered? The authors specified the following criteria:

• An insufficient response to at least two antidepressants from different substance classes (ideally including one tricyclic) at a sufficient dosage and duration, as well as to two augmentation agents (such as lithium and quetiapine) in combination with guideline psychotherapy
• Intolerable side effects from pharmacotherapy or contraindications to medicinal therapy
• For patients who respond to ECT, the occurrence of relapses or residual symptoms after cessation of (maintenance) ECT, intolerable ECT side effects, or the need for maintenance ECT
• Repeated or long hospital treatments because of depression

This article is a translation of an article from Univadis Germany and first appeared on Medscape.com.

Approximately 50% of melanomas contain BRAF mutations, which occur in a greater proportion of melanomas found on sites of intermittent sun exposure.¹BRAF-mutated melanomas have been associated with high levels of early-life ambient UV exposure, especially between ages 0 and 20 years.² In addition, studies have shown that BRAF-mutated melanomas commonly are found on the trunk and extremities.^1-3BRAF mutations also have been associated with younger age, superficial spreading subtype and low tumor thickness, absence of dermal melanocyte mitosis, low Ki-67 score, low phospho-histone H3 score, pigmented melanoma, advanced melanoma stage, and conjunctival melanoma.^4-7BRAF mutations are found more frequently in metastatic melanoma lesions than primary melanomas, suggesting that BRAF mutations may be acquired during metastasis.⁸ Studies have shown different conclusions on the effect of BRAF mutation on melanoma-related death.^5,9,10

The aim of this study was to identify trends in BRAF V600E–mutated melanoma according to age, sex, and melanoma-specific survival among Olmsted County, Minnesota, residents with a first diagnosis of melanoma at 18 to 60 years of age.

Methods

In total, 638 patients aged 18 to 60 years who resided in Olmsted County and had a first lifetime diagnosis of cutaneous melanoma between 1970 and 2009 were retrospectively identified as a part of the Rochester Epidemiology Project (REP). The REP is a health records linkage system that encompasses almost all sources of medical care available to the local population of Olmsted County.¹¹ This study was approved by the Mayo Clinic Institutional Review Board (Rochester, Minnesota).

Of the 638 individuals identified in the REP, 536 had been seen at Mayo Clinic and thus potentially had tissue blocks available for the study of BRAF mutation expression. Of these 536 patients, 156 did not have sufficient residual tissue available. As a result, 380 (60%) of the original 638 patients had available blocks with sufficient tissue for immunohistochemical analysis of BRAF expression. Only primary cutaneous melanomas were included in the present study.

All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) for appropriateness of inclusion, which involved confirmation of the diagnosis of melanoma, histologic type of melanoma, and presence of sufficient residual tissue for immunohistochemical stains.

All specimens were originally diagnosed as malignant melanoma at the time of clinical care by at least 2 board-certified dermatopathologists. For the purposes of this study, all specimens were rereviewed for diagnostic accuracy. We required that specimens exhibit severe cytologic and architectural atypia as well as other features favoring melanoma, such as consumption of rete pegs, pagetosis, confluence of junctional melanocytes, evidence of regression, lack of maturation of melanocytes with descent into the dermis, or mitotic figures among the dermal melanocyte population.

The available tissue blocks were retrieved, sectioned, confirmed as melanoma, and stained with a mouse antihuman BRAF V600E monoclonal antibody (clone VE1; Spring Bioscience) to determine the presence of a BRAF V600E mutation. BRAF staining was evaluated in conjunction with a review of the associated slides stained with hematoxylin and eosin. Cytoplasmic staining of melanocytes for BRAF was graded as negative, focal or partial positive (<50% of tumor), or diffuse positive (>50% of tumor)(Figure 1). When a melanoma arose in association with a nevus, we considered only the melanoma component for BRAF staining. We categorized the histologic type as superficial spreading, nodular, or lentigo maligna, and the location as head and neck, trunk, or extremities.

Results

Clinical and Tumor Characteristics—Of the 380 tissue specimens that underwent BRAF V600E analysis, 247 had negative staining; 106 had diffuse strong staining; and 27 had focal or partial staining. In total, 133 (35%) were positive, either partially or diffusely. The median age for patients who had negative staining was 45 years; for those with positive staining, it was 41 years (P=.07).

The patients who met inclusion criteria (n=380) were compared with those who were excluded (n=258)(eTable 1). The groups were similar on the basis of sex; age; and melanoma location, stage, and histologic subtype. However, some evidence showed that patients included in the study received the diagnosis of melanoma more recently (1970-1989, 13.2%; 1990-1999, 28.7%; 2000-2009, 58.2%) than those who were excluded (1970-1989, 24.7%; 1990-1999, 23.5%; 2000-2009, 51.8%)(P=.02).

BRAF V600E expression was more commonly found in superficial spreading (37.7%) and nodular melanomas (35.0%) than in situ melanomas (17.1%)(P=.01). Other characteristics of BRAF V600E expression are described in eTable 2. Overall, invasive and advanced melanomas were significantly more likely to harbor BRAF V600E expression than noninvasive melanomas (39.6% and 37.9%, respectively, vs 17.9%; P=.003). However, advanced melanomas more commonly expressed BRAF positivity among women, and invasive melanomas more commonly expressed BRAF positivity among men (eTable 2).

Survival—Survival analyses were limited to 297 patients with confirmed invasive or advanced disease. Of these, 180 (61%) had no BRAF V600E staining; 25 (8%) had partial staining; and 92 (31%) had diffuse positive staining. In total, 117 patients (39%) had a BRAF-mutated melanoma.

Among the patients still alive, the median (interquartile range [IQR]) duration of follow-up was 10.2 (7.0-16.8) years. Thirty-nine patients with invasive or advanced disease had died of any cause at a median (IQR) of 3.0 (1.3-10.2) years after diagnosis. In total, 26 patients died of melanoma at a median (IQR) follow-up of 2.5 (1.3-7.4) years after diagnosis. Eight women and 18 men died of malignant melanoma. Five deaths occurred because of malignant melanoma among patients aged 18 to 39 years, and 21 occurred among patients aged 40 to 60 years. In the 18- to 39-year-old group, all 5 deaths were among patients with a BRAF-positive melanoma. Estimated disease-specific survival rate (95% CI; number still at risk) at 5, 10, 15, and 20 years after diagnosis was 94% (91%-97%; 243), 91% (87%-95%; 142), 89% (85%-94%; 87), and 88% (83%-93%; 45), respectively.

Comment

We found that melanomas with BRAF mutations were more likely in advanced and invasive melanoma. The frequency of BRAF mutations among melanomas that were considered advanced was higher in women than men. Although the number of deaths was limited, women with a melanoma with BRAF expression were more likely to die of melanoma, young adults with a BRAF-mutated melanoma had an almost 10-fold increased risk of dying from any cause, and middle-aged adults showed no increased risk of death. These findings suggest that young adults who are genetically prone to a BRAF-mutated melanoma could be at a disadvantage for all-cause mortality. Although this finding was significant, the 95% CI was large, and further studies would be warranted before sound conclusions could be made.

Melanoma has been increasing in incidence across all age groups in Olmsted County over the last 4 decades.^12-14 However, our results show that the percentage of BRAF-mutated melanomas in this population has been stable over time, with no statistically significant difference by age or sex. Other confounding factors may have an influence, such as increased rates of early detection and diagnosis of melanoma in contemporary times. Our data suggest that patients included in the BRAF-mutation analysis study had received the diagnosis of melanoma more recently than those who were excluded from the study, which could be due to older melanomas being less likely to have adequate tissue specimens available for immunohistochemical staining/evaluation.

Prior research has shown that BRAF-mutated melanomas typically occur on the trunk and are more likely in individuals with more than 14 nevi on the back.² In the present cohort, BRAF-positive melanomas had a predisposition toward the trunk but also were found on the head, neck, and extremities—areas that are more likely to have long-term sun damage. One suggestion is that 2 distinct pathways for melanoma development exist: one associated with a large number of melanocytic nevi (that is more prone to genetic mutations in melanocytes) and the other associated with long-term sun exposure.^15,16 The combination of these hypotheses suggests that individuals who are prone to the development of large numbers of nevi may require sun exposure for the initial insult, but the development of melanoma may be carried out by other factors after this initial sun exposure insult, whereas individuals without large numbers of nevi who may have less genetic risk may require continued long-term sun exposure for melanoma to develop.¹⁷

Our study had limitations, including the small numbers of deaths overall and cause-specific deaths of metastatic melanoma, which limited our ability to conduct more extensive multivariable modeling. Also, the retrospective nature and time frame of looking back 4 decades did not allow us to have information sufficient to categorize some patients as having dysplastic nevus syndrome or not, which would be a potentially interesting variable to include in the analysis. Because the number of deaths in the 18- to 39-year-old cohort was only 5, further statistical comparison regarding tumor type and other variables pertaining to BRAF positivity were not possible. In addition, our data were collected from patients residing in a single geographic county (Olmsted County, Minnesota), which may limit generalizability. Lastly, BRAF V600E mutations were identified through immunostaining only, not molecular data, so it is possible some patients had false-negative immunohistochemistry findings and thus were not identified.

Conclusion

BRAF-mutated melanomas were found in 35% of our cohort, with no significant change in the percentage of melanomas with BRAF V600E mutations over the last 4 decades in this population. In addition, no differences or significant trends existed according to sex and BRAF-mutated melanoma development. Women with BRAF-mutated melanomas were more likely to die of metastatic melanoma than men, and young adults with BRAF-mutated melanomas had a higher all-cause mortality risk. Further research is needed to decipher what effect BRAF-mutated melanomas have on metastasis and cause-specific death in women as well as all-cause mortality in young adults.

Acknowledgment—The authors are indebted to Scientific Publications, Mayo Clinic (Rochester, Minnesota).

Approximately 50% of melanomas contain BRAF mutations, which occur in a greater proportion of melanomas found on sites of intermittent sun exposure.¹BRAF-mutated melanomas have been associated with high levels of early-life ambient UV exposure, especially between ages 0 and 20 years.² In addition, studies have shown that BRAF-mutated melanomas commonly are found on the trunk and extremities.^1-3BRAF mutations also have been associated with younger age, superficial spreading subtype and low tumor thickness, absence of dermal melanocyte mitosis, low Ki-67 score, low phospho-histone H3 score, pigmented melanoma, advanced melanoma stage, and conjunctival melanoma.^4-7BRAF mutations are found more frequently in metastatic melanoma lesions than primary melanomas, suggesting that BRAF mutations may be acquired during metastasis.⁸ Studies have shown different conclusions on the effect of BRAF mutation on melanoma-related death.^5,9,10

The aim of this study was to identify trends in BRAF V600E–mutated melanoma according to age, sex, and melanoma-specific survival among Olmsted County, Minnesota, residents with a first diagnosis of melanoma at 18 to 60 years of age.

Methods

In total, 638 patients aged 18 to 60 years who resided in Olmsted County and had a first lifetime diagnosis of cutaneous melanoma between 1970 and 2009 were retrospectively identified as a part of the Rochester Epidemiology Project (REP). The REP is a health records linkage system that encompasses almost all sources of medical care available to the local population of Olmsted County.¹¹ This study was approved by the Mayo Clinic Institutional Review Board (Rochester, Minnesota).

Of the 638 individuals identified in the REP, 536 had been seen at Mayo Clinic and thus potentially had tissue blocks available for the study of BRAF mutation expression. Of these 536 patients, 156 did not have sufficient residual tissue available. As a result, 380 (60%) of the original 638 patients had available blocks with sufficient tissue for immunohistochemical analysis of BRAF expression. Only primary cutaneous melanomas were included in the present study.

All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) for appropriateness of inclusion, which involved confirmation of the diagnosis of melanoma, histologic type of melanoma, and presence of sufficient residual tissue for immunohistochemical stains.

All specimens were originally diagnosed as malignant melanoma at the time of clinical care by at least 2 board-certified dermatopathologists. For the purposes of this study, all specimens were rereviewed for diagnostic accuracy. We required that specimens exhibit severe cytologic and architectural atypia as well as other features favoring melanoma, such as consumption of rete pegs, pagetosis, confluence of junctional melanocytes, evidence of regression, lack of maturation of melanocytes with descent into the dermis, or mitotic figures among the dermal melanocyte population.

The available tissue blocks were retrieved, sectioned, confirmed as melanoma, and stained with a mouse antihuman BRAF V600E monoclonal antibody (clone VE1; Spring Bioscience) to determine the presence of a BRAF V600E mutation. BRAF staining was evaluated in conjunction with a review of the associated slides stained with hematoxylin and eosin. Cytoplasmic staining of melanocytes for BRAF was graded as negative, focal or partial positive (<50% of tumor), or diffuse positive (>50% of tumor)(Figure 1). When a melanoma arose in association with a nevus, we considered only the melanoma component for BRAF staining. We categorized the histologic type as superficial spreading, nodular, or lentigo maligna, and the location as head and neck, trunk, or extremities.

Results

Clinical and Tumor Characteristics—Of the 380 tissue specimens that underwent BRAF V600E analysis, 247 had negative staining; 106 had diffuse strong staining; and 27 had focal or partial staining. In total, 133 (35%) were positive, either partially or diffusely. The median age for patients who had negative staining was 45 years; for those with positive staining, it was 41 years (P=.07).

The patients who met inclusion criteria (n=380) were compared with those who were excluded (n=258)(eTable 1). The groups were similar on the basis of sex; age; and melanoma location, stage, and histologic subtype. However, some evidence showed that patients included in the study received the diagnosis of melanoma more recently (1970-1989, 13.2%; 1990-1999, 28.7%; 2000-2009, 58.2%) than those who were excluded (1970-1989, 24.7%; 1990-1999, 23.5%; 2000-2009, 51.8%)(P=.02).

BRAF V600E expression was more commonly found in superficial spreading (37.7%) and nodular melanomas (35.0%) than in situ melanomas (17.1%)(P=.01). Other characteristics of BRAF V600E expression are described in eTable 2. Overall, invasive and advanced melanomas were significantly more likely to harbor BRAF V600E expression than noninvasive melanomas (39.6% and 37.9%, respectively, vs 17.9%; P=.003). However, advanced melanomas more commonly expressed BRAF positivity among women, and invasive melanomas more commonly expressed BRAF positivity among men (eTable 2).

Survival—Survival analyses were limited to 297 patients with confirmed invasive or advanced disease. Of these, 180 (61%) had no BRAF V600E staining; 25 (8%) had partial staining; and 92 (31%) had diffuse positive staining. In total, 117 patients (39%) had a BRAF-mutated melanoma.

Among the patients still alive, the median (interquartile range [IQR]) duration of follow-up was 10.2 (7.0-16.8) years. Thirty-nine patients with invasive or advanced disease had died of any cause at a median (IQR) of 3.0 (1.3-10.2) years after diagnosis. In total, 26 patients died of melanoma at a median (IQR) follow-up of 2.5 (1.3-7.4) years after diagnosis. Eight women and 18 men died of malignant melanoma. Five deaths occurred because of malignant melanoma among patients aged 18 to 39 years, and 21 occurred among patients aged 40 to 60 years. In the 18- to 39-year-old group, all 5 deaths were among patients with a BRAF-positive melanoma. Estimated disease-specific survival rate (95% CI; number still at risk) at 5, 10, 15, and 20 years after diagnosis was 94% (91%-97%; 243), 91% (87%-95%; 142), 89% (85%-94%; 87), and 88% (83%-93%; 45), respectively.

Comment

We found that melanomas with BRAF mutations were more likely in advanced and invasive melanoma. The frequency of BRAF mutations among melanomas that were considered advanced was higher in women than men. Although the number of deaths was limited, women with a melanoma with BRAF expression were more likely to die of melanoma, young adults with a BRAF-mutated melanoma had an almost 10-fold increased risk of dying from any cause, and middle-aged adults showed no increased risk of death. These findings suggest that young adults who are genetically prone to a BRAF-mutated melanoma could be at a disadvantage for all-cause mortality. Although this finding was significant, the 95% CI was large, and further studies would be warranted before sound conclusions could be made.

Melanoma has been increasing in incidence across all age groups in Olmsted County over the last 4 decades.^12-14 However, our results show that the percentage of BRAF-mutated melanomas in this population has been stable over time, with no statistically significant difference by age or sex. Other confounding factors may have an influence, such as increased rates of early detection and diagnosis of melanoma in contemporary times. Our data suggest that patients included in the BRAF-mutation analysis study had received the diagnosis of melanoma more recently than those who were excluded from the study, which could be due to older melanomas being less likely to have adequate tissue specimens available for immunohistochemical staining/evaluation.

Prior research has shown that BRAF-mutated melanomas typically occur on the trunk and are more likely in individuals with more than 14 nevi on the back.² In the present cohort, BRAF-positive melanomas had a predisposition toward the trunk but also were found on the head, neck, and extremities—areas that are more likely to have long-term sun damage. One suggestion is that 2 distinct pathways for melanoma development exist: one associated with a large number of melanocytic nevi (that is more prone to genetic mutations in melanocytes) and the other associated with long-term sun exposure.^15,16 The combination of these hypotheses suggests that individuals who are prone to the development of large numbers of nevi may require sun exposure for the initial insult, but the development of melanoma may be carried out by other factors after this initial sun exposure insult, whereas individuals without large numbers of nevi who may have less genetic risk may require continued long-term sun exposure for melanoma to develop.¹⁷

Our study had limitations, including the small numbers of deaths overall and cause-specific deaths of metastatic melanoma, which limited our ability to conduct more extensive multivariable modeling. Also, the retrospective nature and time frame of looking back 4 decades did not allow us to have information sufficient to categorize some patients as having dysplastic nevus syndrome or not, which would be a potentially interesting variable to include in the analysis. Because the number of deaths in the 18- to 39-year-old cohort was only 5, further statistical comparison regarding tumor type and other variables pertaining to BRAF positivity were not possible. In addition, our data were collected from patients residing in a single geographic county (Olmsted County, Minnesota), which may limit generalizability. Lastly, BRAF V600E mutations were identified through immunostaining only, not molecular data, so it is possible some patients had false-negative immunohistochemistry findings and thus were not identified.

Conclusion

BRAF-mutated melanomas were found in 35% of our cohort, with no significant change in the percentage of melanomas with BRAF V600E mutations over the last 4 decades in this population. In addition, no differences or significant trends existed according to sex and BRAF-mutated melanoma development. Women with BRAF-mutated melanomas were more likely to die of metastatic melanoma than men, and young adults with BRAF-mutated melanomas had a higher all-cause mortality risk. Further research is needed to decipher what effect BRAF-mutated melanomas have on metastasis and cause-specific death in women as well as all-cause mortality in young adults.

Acknowledgment—The authors are indebted to Scientific Publications, Mayo Clinic (Rochester, Minnesota).

Approximately 50% of melanomas contain BRAF mutations, which occur in a greater proportion of melanomas found on sites of intermittent sun exposure.¹BRAF-mutated melanomas have been associated with high levels of early-life ambient UV exposure, especially between ages 0 and 20 years.² In addition, studies have shown that BRAF-mutated melanomas commonly are found on the trunk and extremities.^1-3BRAF mutations also have been associated with younger age, superficial spreading subtype and low tumor thickness, absence of dermal melanocyte mitosis, low Ki-67 score, low phospho-histone H3 score, pigmented melanoma, advanced melanoma stage, and conjunctival melanoma.^4-7BRAF mutations are found more frequently in metastatic melanoma lesions than primary melanomas, suggesting that BRAF mutations may be acquired during metastasis.⁸ Studies have shown different conclusions on the effect of BRAF mutation on melanoma-related death.^5,9,10

The aim of this study was to identify trends in BRAF V600E–mutated melanoma according to age, sex, and melanoma-specific survival among Olmsted County, Minnesota, residents with a first diagnosis of melanoma at 18 to 60 years of age.

Methods

In total, 638 patients aged 18 to 60 years who resided in Olmsted County and had a first lifetime diagnosis of cutaneous melanoma between 1970 and 2009 were retrospectively identified as a part of the Rochester Epidemiology Project (REP). The REP is a health records linkage system that encompasses almost all sources of medical care available to the local population of Olmsted County.¹¹ This study was approved by the Mayo Clinic Institutional Review Board (Rochester, Minnesota).

Of the 638 individuals identified in the REP, 536 had been seen at Mayo Clinic and thus potentially had tissue blocks available for the study of BRAF mutation expression. Of these 536 patients, 156 did not have sufficient residual tissue available. As a result, 380 (60%) of the original 638 patients had available blocks with sufficient tissue for immunohistochemical analysis of BRAF expression. Only primary cutaneous melanomas were included in the present study.

All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) for appropriateness of inclusion, which involved confirmation of the diagnosis of melanoma, histologic type of melanoma, and presence of sufficient residual tissue for immunohistochemical stains.

All specimens were originally diagnosed as malignant melanoma at the time of clinical care by at least 2 board-certified dermatopathologists. For the purposes of this study, all specimens were rereviewed for diagnostic accuracy. We required that specimens exhibit severe cytologic and architectural atypia as well as other features favoring melanoma, such as consumption of rete pegs, pagetosis, confluence of junctional melanocytes, evidence of regression, lack of maturation of melanocytes with descent into the dermis, or mitotic figures among the dermal melanocyte population.

The available tissue blocks were retrieved, sectioned, confirmed as melanoma, and stained with a mouse antihuman BRAF V600E monoclonal antibody (clone VE1; Spring Bioscience) to determine the presence of a BRAF V600E mutation. BRAF staining was evaluated in conjunction with a review of the associated slides stained with hematoxylin and eosin. Cytoplasmic staining of melanocytes for BRAF was graded as negative, focal or partial positive (<50% of tumor), or diffuse positive (>50% of tumor)(Figure 1). When a melanoma arose in association with a nevus, we considered only the melanoma component for BRAF staining. We categorized the histologic type as superficial spreading, nodular, or lentigo maligna, and the location as head and neck, trunk, or extremities.

Results

Clinical and Tumor Characteristics—Of the 380 tissue specimens that underwent BRAF V600E analysis, 247 had negative staining; 106 had diffuse strong staining; and 27 had focal or partial staining. In total, 133 (35%) were positive, either partially or diffusely. The median age for patients who had negative staining was 45 years; for those with positive staining, it was 41 years (P=.07).

The patients who met inclusion criteria (n=380) were compared with those who were excluded (n=258)(eTable 1). The groups were similar on the basis of sex; age; and melanoma location, stage, and histologic subtype. However, some evidence showed that patients included in the study received the diagnosis of melanoma more recently (1970-1989, 13.2%; 1990-1999, 28.7%; 2000-2009, 58.2%) than those who were excluded (1970-1989, 24.7%; 1990-1999, 23.5%; 2000-2009, 51.8%)(P=.02).

BRAF V600E expression was more commonly found in superficial spreading (37.7%) and nodular melanomas (35.0%) than in situ melanomas (17.1%)(P=.01). Other characteristics of BRAF V600E expression are described in eTable 2. Overall, invasive and advanced melanomas were significantly more likely to harbor BRAF V600E expression than noninvasive melanomas (39.6% and 37.9%, respectively, vs 17.9%; P=.003). However, advanced melanomas more commonly expressed BRAF positivity among women, and invasive melanomas more commonly expressed BRAF positivity among men (eTable 2).

Survival—Survival analyses were limited to 297 patients with confirmed invasive or advanced disease. Of these, 180 (61%) had no BRAF V600E staining; 25 (8%) had partial staining; and 92 (31%) had diffuse positive staining. In total, 117 patients (39%) had a BRAF-mutated melanoma.

Among the patients still alive, the median (interquartile range [IQR]) duration of follow-up was 10.2 (7.0-16.8) years. Thirty-nine patients with invasive or advanced disease had died of any cause at a median (IQR) of 3.0 (1.3-10.2) years after diagnosis. In total, 26 patients died of melanoma at a median (IQR) follow-up of 2.5 (1.3-7.4) years after diagnosis. Eight women and 18 men died of malignant melanoma. Five deaths occurred because of malignant melanoma among patients aged 18 to 39 years, and 21 occurred among patients aged 40 to 60 years. In the 18- to 39-year-old group, all 5 deaths were among patients with a BRAF-positive melanoma. Estimated disease-specific survival rate (95% CI; number still at risk) at 5, 10, 15, and 20 years after diagnosis was 94% (91%-97%; 243), 91% (87%-95%; 142), 89% (85%-94%; 87), and 88% (83%-93%; 45), respectively.

Comment

We found that melanomas with BRAF mutations were more likely in advanced and invasive melanoma. The frequency of BRAF mutations among melanomas that were considered advanced was higher in women than men. Although the number of deaths was limited, women with a melanoma with BRAF expression were more likely to die of melanoma, young adults with a BRAF-mutated melanoma had an almost 10-fold increased risk of dying from any cause, and middle-aged adults showed no increased risk of death. These findings suggest that young adults who are genetically prone to a BRAF-mutated melanoma could be at a disadvantage for all-cause mortality. Although this finding was significant, the 95% CI was large, and further studies would be warranted before sound conclusions could be made.

Melanoma has been increasing in incidence across all age groups in Olmsted County over the last 4 decades.^12-14 However, our results show that the percentage of BRAF-mutated melanomas in this population has been stable over time, with no statistically significant difference by age or sex. Other confounding factors may have an influence, such as increased rates of early detection and diagnosis of melanoma in contemporary times. Our data suggest that patients included in the BRAF-mutation analysis study had received the diagnosis of melanoma more recently than those who were excluded from the study, which could be due to older melanomas being less likely to have adequate tissue specimens available for immunohistochemical staining/evaluation.

Prior research has shown that BRAF-mutated melanomas typically occur on the trunk and are more likely in individuals with more than 14 nevi on the back.² In the present cohort, BRAF-positive melanomas had a predisposition toward the trunk but also were found on the head, neck, and extremities—areas that are more likely to have long-term sun damage. One suggestion is that 2 distinct pathways for melanoma development exist: one associated with a large number of melanocytic nevi (that is more prone to genetic mutations in melanocytes) and the other associated with long-term sun exposure.^15,16 The combination of these hypotheses suggests that individuals who are prone to the development of large numbers of nevi may require sun exposure for the initial insult, but the development of melanoma may be carried out by other factors after this initial sun exposure insult, whereas individuals without large numbers of nevi who may have less genetic risk may require continued long-term sun exposure for melanoma to develop.¹⁷

Our study had limitations, including the small numbers of deaths overall and cause-specific deaths of metastatic melanoma, which limited our ability to conduct more extensive multivariable modeling. Also, the retrospective nature and time frame of looking back 4 decades did not allow us to have information sufficient to categorize some patients as having dysplastic nevus syndrome or not, which would be a potentially interesting variable to include in the analysis. Because the number of deaths in the 18- to 39-year-old cohort was only 5, further statistical comparison regarding tumor type and other variables pertaining to BRAF positivity were not possible. In addition, our data were collected from patients residing in a single geographic county (Olmsted County, Minnesota), which may limit generalizability. Lastly, BRAF V600E mutations were identified through immunostaining only, not molecular data, so it is possible some patients had false-negative immunohistochemistry findings and thus were not identified.

Conclusion

BRAF-mutated melanomas were found in 35% of our cohort, with no significant change in the percentage of melanomas with BRAF V600E mutations over the last 4 decades in this population. In addition, no differences or significant trends existed according to sex and BRAF-mutated melanoma development. Women with BRAF-mutated melanomas were more likely to die of metastatic melanoma than men, and young adults with BRAF-mutated melanomas had a higher all-cause mortality risk. Further research is needed to decipher what effect BRAF-mutated melanomas have on metastasis and cause-specific death in women as well as all-cause mortality in young adults.

Acknowledgment—The authors are indebted to Scientific Publications, Mayo Clinic (Rochester, Minnesota).