SAN DIEGO – A new retrospective analysis of patients with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) indicates that treatment with immunotherapy is associated with a lower risk of relapse. The authors note that many MOGAD patients never experience a relapse and it is difficult to predict which ones will.

MOGAD can cause optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis (ADEM). It was first described in 2007, and the best approaches to therapy are not yet understood. The new study is at least a starting point for understanding treatment outcomes, according to Philippe Bilodeau, MD, who presented the study during a poster session at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Predicting which patients will relapse

“I think one of the biggest unanswered clinical questions in MOGAD is trying to determine who’s going to go on to have relapsing MOGAD. About 30% to 40% of patients with MOGAD will never have a second attack. So one of the big questions is: How can we identify patients who would benefit from immunotherapy, and how can we identify patients who will have a more benign disease course and may not need to be started on a treatment,” said Dr. Bilodeau, a neurology resident at Massachusetts General Hospital/Brigham and Women’s Hospital, Boston.

The researchers analyzed data from 143 patients seen at Massachusetts General or Brigham and Women’s Hospital who had presented with their first attack. Over a follow-up period of 5 years, the relapse rate was 61.8%. The researchers examined various factors, including age of onset, high MOG titer, attack type, and male sex, and found that only the latter came close to predicting relapse, though it fell short of clinical significance (hazard ratio [HR], 0.61; P = .07).

However, treatment with mycophenolate, azathioprine, intravenous immunoglobulins (IVIG), rituximab, or tocilizumab strongly predicted a lower probability of relapse (HR, 0.25; P < .0001).
 

The most effective treatment for relapsing MOGAD

In a separate poster, his team examined a subset of the cohort of 88 patients who were treated with mycophenolate mofetil, B-cell depletion, rituximab, or IV immunoglobulins (IVIG) during a first or second relapse, as well as an analysis of every relapse experienced by any patient during the course of their disease. “Using a negative binomial regression, we looked at the annualized relapse rates and incidence rate ratios between the different treatments. No matter how you looked at the data – even if you looked at total time on IVIG, if you looked at time on monotherapy, excluding if they were on prednisone at the same time if they were on both IVIG and rituximab, if you only consider patients that were on high dose IVIG – IVIG was by far the best treatment and rituximab was always the least effective, and mycophenolate was always between IVIG and rituximab. So I think in that cohort, we can say with some confidence that IVIG is the most effective treatment for relapsing MOGAD,” said Dr. Bilodeau.

Other studies had suggested efficacy of individual treatments, but “I think what hadn’t been done is taking one cohort and comparing those treatments head to head, so that’s what we were trying to do,” said Dr. Bilodeau.

Both studies have the usual caveats of a retrospective study and so cannot prove causality. “We need to find more covariates to make sure that there’s no confounding (factor) explaining this and to make sure that there aren’t other demographic or clinical factors that explain the association. But as it stands, I think at this time starting treatment with immunotherapy is the only thing that we know will reduce the risk of having a future relapse. There’s a lot of further analysis that we need to do,” said Dr. Bilodeau.

He said that the study also provided some preliminary insight into treatment of pediatric disease. “We have interesting data from that analysis that pediatric-onset MOGAD actually had a particularly good response to [mycophenolate], more so than in adults,” he said.

“At this point, I think a rational approach if you have someone coming in with a first relapse is, you have to assess their risk tolerance. If they’re a very risk-averse patient, I think it’s reasonable to start them on treatment. I think it’s reasonable to monitor their titer. There’s some data that if they seroconvert to negative, you might be able to stop immunotherapy. If someone has established relapsing disease, and they have adult onset [disease], IVIG should be the first-line treatment. If they’re pediatric onset, either [mycophenolate] or IVIG are probably good first line treatments,” he said.
 

‘A good beginning’

The studies are a good beginning to getting a better understanding of MOGAD treatment, according to Michael Cossoy, MD, who attended the poster session and was asked to comment on the study.

“It’s interesting because MOG antibody-associated disease is so relatively new that we don’t have a great idea yet about who needs to be treated. Should we put them on some immunosuppressive therapy or should we wait? At the moment this is a bit of a tautology. You know that if you put people on therapy from the very first event, some of those people are not going to have a second event. And some of the people are, but you’ve decreased the risk of them having that second (event) if your treatment is effective. So that’s what they’ve shown, which is great. But the question is, can you predict who’s going to have a second event and know who to put on treatment and not put on treatment? It’s too early to know, but this is a good start,” said Dr. Cossoy, assistant professor of ophthalmology at the University of Manitoba.

Dr. Bilodeau and Dr. Cossoy have no relevant financial disclosures.

SAN DIEGO – A new retrospective analysis of patients with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) indicates that treatment with immunotherapy is associated with a lower risk of relapse. The authors note that many MOGAD patients never experience a relapse and it is difficult to predict which ones will.

MOGAD can cause optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis (ADEM). It was first described in 2007, and the best approaches to therapy are not yet understood. The new study is at least a starting point for understanding treatment outcomes, according to Philippe Bilodeau, MD, who presented the study during a poster session at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Predicting which patients will relapse

“I think one of the biggest unanswered clinical questions in MOGAD is trying to determine who’s going to go on to have relapsing MOGAD. About 30% to 40% of patients with MOGAD will never have a second attack. So one of the big questions is: How can we identify patients who would benefit from immunotherapy, and how can we identify patients who will have a more benign disease course and may not need to be started on a treatment,” said Dr. Bilodeau, a neurology resident at Massachusetts General Hospital/Brigham and Women’s Hospital, Boston.

The researchers analyzed data from 143 patients seen at Massachusetts General or Brigham and Women’s Hospital who had presented with their first attack. Over a follow-up period of 5 years, the relapse rate was 61.8%. The researchers examined various factors, including age of onset, high MOG titer, attack type, and male sex, and found that only the latter came close to predicting relapse, though it fell short of clinical significance (hazard ratio [HR], 0.61; P = .07).

However, treatment with mycophenolate, azathioprine, intravenous immunoglobulins (IVIG), rituximab, or tocilizumab strongly predicted a lower probability of relapse (HR, 0.25; P < .0001).
 

The most effective treatment for relapsing MOGAD

In a separate poster, his team examined a subset of the cohort of 88 patients who were treated with mycophenolate mofetil, B-cell depletion, rituximab, or IV immunoglobulins (IVIG) during a first or second relapse, as well as an analysis of every relapse experienced by any patient during the course of their disease. “Using a negative binomial regression, we looked at the annualized relapse rates and incidence rate ratios between the different treatments. No matter how you looked at the data – even if you looked at total time on IVIG, if you looked at time on monotherapy, excluding if they were on prednisone at the same time if they were on both IVIG and rituximab, if you only consider patients that were on high dose IVIG – IVIG was by far the best treatment and rituximab was always the least effective, and mycophenolate was always between IVIG and rituximab. So I think in that cohort, we can say with some confidence that IVIG is the most effective treatment for relapsing MOGAD,” said Dr. Bilodeau.

Other studies had suggested efficacy of individual treatments, but “I think what hadn’t been done is taking one cohort and comparing those treatments head to head, so that’s what we were trying to do,” said Dr. Bilodeau.

Both studies have the usual caveats of a retrospective study and so cannot prove causality. “We need to find more covariates to make sure that there’s no confounding (factor) explaining this and to make sure that there aren’t other demographic or clinical factors that explain the association. But as it stands, I think at this time starting treatment with immunotherapy is the only thing that we know will reduce the risk of having a future relapse. There’s a lot of further analysis that we need to do,” said Dr. Bilodeau.

He said that the study also provided some preliminary insight into treatment of pediatric disease. “We have interesting data from that analysis that pediatric-onset MOGAD actually had a particularly good response to [mycophenolate], more so than in adults,” he said.

“At this point, I think a rational approach if you have someone coming in with a first relapse is, you have to assess their risk tolerance. If they’re a very risk-averse patient, I think it’s reasonable to start them on treatment. I think it’s reasonable to monitor their titer. There’s some data that if they seroconvert to negative, you might be able to stop immunotherapy. If someone has established relapsing disease, and they have adult onset [disease], IVIG should be the first-line treatment. If they’re pediatric onset, either [mycophenolate] or IVIG are probably good first line treatments,” he said.
 

‘A good beginning’

The studies are a good beginning to getting a better understanding of MOGAD treatment, according to Michael Cossoy, MD, who attended the poster session and was asked to comment on the study.

“It’s interesting because MOG antibody-associated disease is so relatively new that we don’t have a great idea yet about who needs to be treated. Should we put them on some immunosuppressive therapy or should we wait? At the moment this is a bit of a tautology. You know that if you put people on therapy from the very first event, some of those people are not going to have a second event. And some of the people are, but you’ve decreased the risk of them having that second (event) if your treatment is effective. So that’s what they’ve shown, which is great. But the question is, can you predict who’s going to have a second event and know who to put on treatment and not put on treatment? It’s too early to know, but this is a good start,” said Dr. Cossoy, assistant professor of ophthalmology at the University of Manitoba.

Dr. Bilodeau and Dr. Cossoy have no relevant financial disclosures.

SAN DIEGO – A new retrospective analysis of patients with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) indicates that treatment with immunotherapy is associated with a lower risk of relapse. The authors note that many MOGAD patients never experience a relapse and it is difficult to predict which ones will.

MOGAD can cause optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis (ADEM). It was first described in 2007, and the best approaches to therapy are not yet understood. The new study is at least a starting point for understanding treatment outcomes, according to Philippe Bilodeau, MD, who presented the study during a poster session at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Predicting which patients will relapse

“I think one of the biggest unanswered clinical questions in MOGAD is trying to determine who’s going to go on to have relapsing MOGAD. About 30% to 40% of patients with MOGAD will never have a second attack. So one of the big questions is: How can we identify patients who would benefit from immunotherapy, and how can we identify patients who will have a more benign disease course and may not need to be started on a treatment,” said Dr. Bilodeau, a neurology resident at Massachusetts General Hospital/Brigham and Women’s Hospital, Boston.

The researchers analyzed data from 143 patients seen at Massachusetts General or Brigham and Women’s Hospital who had presented with their first attack. Over a follow-up period of 5 years, the relapse rate was 61.8%. The researchers examined various factors, including age of onset, high MOG titer, attack type, and male sex, and found that only the latter came close to predicting relapse, though it fell short of clinical significance (hazard ratio [HR], 0.61; P = .07).

However, treatment with mycophenolate, azathioprine, intravenous immunoglobulins (IVIG), rituximab, or tocilizumab strongly predicted a lower probability of relapse (HR, 0.25; P < .0001).
 

The most effective treatment for relapsing MOGAD

In a separate poster, his team examined a subset of the cohort of 88 patients who were treated with mycophenolate mofetil, B-cell depletion, rituximab, or IV immunoglobulins (IVIG) during a first or second relapse, as well as an analysis of every relapse experienced by any patient during the course of their disease. “Using a negative binomial regression, we looked at the annualized relapse rates and incidence rate ratios between the different treatments. No matter how you looked at the data – even if you looked at total time on IVIG, if you looked at time on monotherapy, excluding if they were on prednisone at the same time if they were on both IVIG and rituximab, if you only consider patients that were on high dose IVIG – IVIG was by far the best treatment and rituximab was always the least effective, and mycophenolate was always between IVIG and rituximab. So I think in that cohort, we can say with some confidence that IVIG is the most effective treatment for relapsing MOGAD,” said Dr. Bilodeau.

Other studies had suggested efficacy of individual treatments, but “I think what hadn’t been done is taking one cohort and comparing those treatments head to head, so that’s what we were trying to do,” said Dr. Bilodeau.

Both studies have the usual caveats of a retrospective study and so cannot prove causality. “We need to find more covariates to make sure that there’s no confounding (factor) explaining this and to make sure that there aren’t other demographic or clinical factors that explain the association. But as it stands, I think at this time starting treatment with immunotherapy is the only thing that we know will reduce the risk of having a future relapse. There’s a lot of further analysis that we need to do,” said Dr. Bilodeau.

He said that the study also provided some preliminary insight into treatment of pediatric disease. “We have interesting data from that analysis that pediatric-onset MOGAD actually had a particularly good response to [mycophenolate], more so than in adults,” he said.

“At this point, I think a rational approach if you have someone coming in with a first relapse is, you have to assess their risk tolerance. If they’re a very risk-averse patient, I think it’s reasonable to start them on treatment. I think it’s reasonable to monitor their titer. There’s some data that if they seroconvert to negative, you might be able to stop immunotherapy. If someone has established relapsing disease, and they have adult onset [disease], IVIG should be the first-line treatment. If they’re pediatric onset, either [mycophenolate] or IVIG are probably good first line treatments,” he said.
 

‘A good beginning’

The studies are a good beginning to getting a better understanding of MOGAD treatment, according to Michael Cossoy, MD, who attended the poster session and was asked to comment on the study.

“It’s interesting because MOG antibody-associated disease is so relatively new that we don’t have a great idea yet about who needs to be treated. Should we put them on some immunosuppressive therapy or should we wait? At the moment this is a bit of a tautology. You know that if you put people on therapy from the very first event, some of those people are not going to have a second event. And some of the people are, but you’ve decreased the risk of them having that second (event) if your treatment is effective. So that’s what they’ve shown, which is great. But the question is, can you predict who’s going to have a second event and know who to put on treatment and not put on treatment? It’s too early to know, but this is a good start,” said Dr. Cossoy, assistant professor of ophthalmology at the University of Manitoba.

Dr. Bilodeau and Dr. Cossoy have no relevant financial disclosures.

Emergencies happen anywhere, anytime, and sometimes medical professionals find themselves in situations where they are the only ones who can help. Is There a Doctor in the House? is a series telling these stories.

In December 2017, I was a second-year urology resident at Cleveland Clinic. I’d gone to New Delhi to attend my best friend’s wedding. My flight back was New Delhi to Paris to JFK via Air France. I didn’t sleep on the first flight. So, on the second, I wanted to get some rest, because I had to go back to work the next day. I put on a movie and tried to snooze. As the saying goes in residency, you sleep when you can.

About 3 hours later, a flight attendant made an announcement in French, but I didn’t really hear it. Then they announced in English that they needed a physician. I noticed some flight attendants walking frantically around the economy cabin asking, “Is there a doctor on the plane?” Turns out there were two – the woman sitting next to me happened to be a pediatrician with Doctors Without Borders. I volunteered.

The flight attendant told me a woman was having abdominal pain. I thought it would be something straightforward. Usually, medical emergencies on planes involve chest pain or a panic attack or a vasovagal syncopal episode. Well, I was in for a ride that day.

The woman in pain was traveling from Nigeria. She told me about the abdominal pain. Then she lifted her blanket – she was pregnant. She said she was 37 or 38 weeks in. I said, “Okay, if you’re having this significant abdominal pain, then I need to examine you.” So we decided to move her to the first-class cabin, which was empty (I never did ask why – but it was good we had room to work).

Next step, I went back to my seat and asked the pediatrician if she could assist. My plan was to simply get the passenger through the flight, and as soon as we landed, she would go to the hospital.

There was room to lie down in first class. The pediatrician and I examined her, and she appeared fine. She was traveling with her 4-year-old daughter, and the flight attendants were taking care of her. Everything was okay.

The pilot came back and asked if we would need an emergency landing. I asked him how far it was to JFK – 4 hours. He said the closest place to land would be the Azores Islands, which is Portuguese territory, 2 hours away.

The problem: Even if we made it to the Azores, the hospital there was a very basic facility with no obstetric care available. And by the time the ambulance picked her up and got her there, it would still be 2 or 3 hours total. I said, “No, let’s just observe and continue our course.” Inside my head, I was hoping and praying to God that was the right decision.

Within an hour, everything changed.

The woman’s pain got worse, and she started having contractions. Then her water broke.

Things progressed quickly from there. The contractions progressively got worse and worse. The interval between them got smaller and smaller. The next time we examined her, we could see the baby’s head beginning to crown.

At that point, we had to decide – are we going to deliver? We were in the middle of the North Atlantic Ocean. There was nothing around us. We were 35,000 feet in the air, surrounded by blue.

The crew wanted us to sign a Good Samaritan agreement. So, we did that. And then I said, “Okay, let’s just go for it.”

We got the plane’s medical kit. They had IV fluids, so I started an IV. I was able to monitor the woman’s blood pressure. They had the usual drugs for doing ACLS [advanced cardiac life support], running the code, and things like that. But they didn’t have a suturing kit or a laceration kit. They didn’t have a scalpel. There was nothing else.

Honestly, there was a lot of panic going through my head. I started thinking about what could go wrong. I’d done an ob.gyn. rotation in medical school and delivered seven babies before it was over. But a plane – even the first-class cabin – is in no way, shape, or form like a delivery room. I was really scared she would hemorrhage out or something.

So, internally, I was having a meltdown. Sij, you have to keep it together right now, because there’s no one else that’s going to do this. Just give it your best shot. And that’s what I did.

I asked the pilot to go to an altitude that would minimize any turbulence, and we were very lucky that the notorious North Atlantic air wasn’t choppy.

More luck: This was the passenger’s second baby, and I was counting on second deliveries being easier. The pediatrician, the flight attendants, and I came together as a team. Two flight attendants had given birth before, so they held the patient’s hand and guided her to push. I was “downstairs” waiting to catch.

She was in some pain. At this point, usually people get an epidural. I kept thinking about what drugs were safe in pregnancy, but I wasn’t sure. I don’t know if they even had morphine or anything on the plane. We gave her some Tylenol.

It didn’t take long. After about 30 minutes, the baby’s head emerged. I was able to navigate it out, avoiding any shoulder dystocia. There’s a certain technique that you learn in medical school, which thankfully came back to me. I caught it – it was a boy born right there in a first-class seat.

I gave him to the pediatrician, and she did the Apgar score, calculating his breathing and appearance. Then my job was to make sure there were no postpartum complications.

I ended up using a piece of string in the kit to tie around the umbilical cord, and then I cut it with scissors. After that, the woman was able to deliver the placenta. She did have some vaginal bleeding, but that resolved by just holding pressure.

The baby was fine. Mom was doing great. No complications. It was a miracle. I was the right person at the right place at the right time. I just think it was something from God.

The pilot made an announcement, “We’re en route to JFK, and there’s an additional passenger on this plane now.”

When we landed, I had very little time because I had to catch my flight to Cleveland. I didn’t even process what had happened.

A few days later, I got this package from Air France with a very expensive bottle of champagne along with a travel voucher. I heard from the mom by email – she and baby were doing fine.

Eventually, the media relations people at Cleveland Clinic heard about the incident, and it became a story that went viral. That was very weird, because I’m usually someone who’s private. All through my residency, people would introduce me with, “Remember that guy who delivered a baby on a plane? That’s him.”

I’m so thankful for everyone who was on that team. It was very beautiful because it was people from different cultures, backgrounds, and faiths who came together to achieve something so miraculous. The patient was Nigerian. The flight attendants were French. The pediatrician and I were American.

That just shows you the power of teamwork and how humanity can come together. Medicine, surgery – everything, in fact – is a team sport.

Sij Hemal, MD, graduated from urology residency at the Cleveland Clinic and is currently a robotic urologic oncology and minimally invasive surgery fellow at the University of Southern California, Los Angeles.

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

Emergencies happen anywhere, anytime, and sometimes medical professionals find themselves in situations where they are the only ones who can help. Is There a Doctor in the House? is a series telling these stories.

In December 2017, I was a second-year urology resident at Cleveland Clinic. I’d gone to New Delhi to attend my best friend’s wedding. My flight back was New Delhi to Paris to JFK via Air France. I didn’t sleep on the first flight. So, on the second, I wanted to get some rest, because I had to go back to work the next day. I put on a movie and tried to snooze. As the saying goes in residency, you sleep when you can.

About 3 hours later, a flight attendant made an announcement in French, but I didn’t really hear it. Then they announced in English that they needed a physician. I noticed some flight attendants walking frantically around the economy cabin asking, “Is there a doctor on the plane?” Turns out there were two – the woman sitting next to me happened to be a pediatrician with Doctors Without Borders. I volunteered.

The flight attendant told me a woman was having abdominal pain. I thought it would be something straightforward. Usually, medical emergencies on planes involve chest pain or a panic attack or a vasovagal syncopal episode. Well, I was in for a ride that day.

The woman in pain was traveling from Nigeria. She told me about the abdominal pain. Then she lifted her blanket – she was pregnant. She said she was 37 or 38 weeks in. I said, “Okay, if you’re having this significant abdominal pain, then I need to examine you.” So we decided to move her to the first-class cabin, which was empty (I never did ask why – but it was good we had room to work).

Next step, I went back to my seat and asked the pediatrician if she could assist. My plan was to simply get the passenger through the flight, and as soon as we landed, she would go to the hospital.

There was room to lie down in first class. The pediatrician and I examined her, and she appeared fine. She was traveling with her 4-year-old daughter, and the flight attendants were taking care of her. Everything was okay.

The pilot came back and asked if we would need an emergency landing. I asked him how far it was to JFK – 4 hours. He said the closest place to land would be the Azores Islands, which is Portuguese territory, 2 hours away.

The problem: Even if we made it to the Azores, the hospital there was a very basic facility with no obstetric care available. And by the time the ambulance picked her up and got her there, it would still be 2 or 3 hours total. I said, “No, let’s just observe and continue our course.” Inside my head, I was hoping and praying to God that was the right decision.

Within an hour, everything changed.

The woman’s pain got worse, and she started having contractions. Then her water broke.

Things progressed quickly from there. The contractions progressively got worse and worse. The interval between them got smaller and smaller. The next time we examined her, we could see the baby’s head beginning to crown.

At that point, we had to decide – are we going to deliver? We were in the middle of the North Atlantic Ocean. There was nothing around us. We were 35,000 feet in the air, surrounded by blue.

The crew wanted us to sign a Good Samaritan agreement. So, we did that. And then I said, “Okay, let’s just go for it.”

We got the plane’s medical kit. They had IV fluids, so I started an IV. I was able to monitor the woman’s blood pressure. They had the usual drugs for doing ACLS [advanced cardiac life support], running the code, and things like that. But they didn’t have a suturing kit or a laceration kit. They didn’t have a scalpel. There was nothing else.

Honestly, there was a lot of panic going through my head. I started thinking about what could go wrong. I’d done an ob.gyn. rotation in medical school and delivered seven babies before it was over. But a plane – even the first-class cabin – is in no way, shape, or form like a delivery room. I was really scared she would hemorrhage out or something.

So, internally, I was having a meltdown. Sij, you have to keep it together right now, because there’s no one else that’s going to do this. Just give it your best shot. And that’s what I did.

I asked the pilot to go to an altitude that would minimize any turbulence, and we were very lucky that the notorious North Atlantic air wasn’t choppy.

More luck: This was the passenger’s second baby, and I was counting on second deliveries being easier. The pediatrician, the flight attendants, and I came together as a team. Two flight attendants had given birth before, so they held the patient’s hand and guided her to push. I was “downstairs” waiting to catch.

She was in some pain. At this point, usually people get an epidural. I kept thinking about what drugs were safe in pregnancy, but I wasn’t sure. I don’t know if they even had morphine or anything on the plane. We gave her some Tylenol.

It didn’t take long. After about 30 minutes, the baby’s head emerged. I was able to navigate it out, avoiding any shoulder dystocia. There’s a certain technique that you learn in medical school, which thankfully came back to me. I caught it – it was a boy born right there in a first-class seat.

I gave him to the pediatrician, and she did the Apgar score, calculating his breathing and appearance. Then my job was to make sure there were no postpartum complications.

I ended up using a piece of string in the kit to tie around the umbilical cord, and then I cut it with scissors. After that, the woman was able to deliver the placenta. She did have some vaginal bleeding, but that resolved by just holding pressure.

The baby was fine. Mom was doing great. No complications. It was a miracle. I was the right person at the right place at the right time. I just think it was something from God.

The pilot made an announcement, “We’re en route to JFK, and there’s an additional passenger on this plane now.”

When we landed, I had very little time because I had to catch my flight to Cleveland. I didn’t even process what had happened.

A few days later, I got this package from Air France with a very expensive bottle of champagne along with a travel voucher. I heard from the mom by email – she and baby were doing fine.

Eventually, the media relations people at Cleveland Clinic heard about the incident, and it became a story that went viral. That was very weird, because I’m usually someone who’s private. All through my residency, people would introduce me with, “Remember that guy who delivered a baby on a plane? That’s him.”

I’m so thankful for everyone who was on that team. It was very beautiful because it was people from different cultures, backgrounds, and faiths who came together to achieve something so miraculous. The patient was Nigerian. The flight attendants were French. The pediatrician and I were American.

That just shows you the power of teamwork and how humanity can come together. Medicine, surgery – everything, in fact – is a team sport.

Sij Hemal, MD, graduated from urology residency at the Cleveland Clinic and is currently a robotic urologic oncology and minimally invasive surgery fellow at the University of Southern California, Los Angeles.

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

Emergencies happen anywhere, anytime, and sometimes medical professionals find themselves in situations where they are the only ones who can help. Is There a Doctor in the House? is a series telling these stories.

In December 2017, I was a second-year urology resident at Cleveland Clinic. I’d gone to New Delhi to attend my best friend’s wedding. My flight back was New Delhi to Paris to JFK via Air France. I didn’t sleep on the first flight. So, on the second, I wanted to get some rest, because I had to go back to work the next day. I put on a movie and tried to snooze. As the saying goes in residency, you sleep when you can.

About 3 hours later, a flight attendant made an announcement in French, but I didn’t really hear it. Then they announced in English that they needed a physician. I noticed some flight attendants walking frantically around the economy cabin asking, “Is there a doctor on the plane?” Turns out there were two – the woman sitting next to me happened to be a pediatrician with Doctors Without Borders. I volunteered.

The flight attendant told me a woman was having abdominal pain. I thought it would be something straightforward. Usually, medical emergencies on planes involve chest pain or a panic attack or a vasovagal syncopal episode. Well, I was in for a ride that day.

The woman in pain was traveling from Nigeria. She told me about the abdominal pain. Then she lifted her blanket – she was pregnant. She said she was 37 or 38 weeks in. I said, “Okay, if you’re having this significant abdominal pain, then I need to examine you.” So we decided to move her to the first-class cabin, which was empty (I never did ask why – but it was good we had room to work).

Next step, I went back to my seat and asked the pediatrician if she could assist. My plan was to simply get the passenger through the flight, and as soon as we landed, she would go to the hospital.

There was room to lie down in first class. The pediatrician and I examined her, and she appeared fine. She was traveling with her 4-year-old daughter, and the flight attendants were taking care of her. Everything was okay.

The pilot came back and asked if we would need an emergency landing. I asked him how far it was to JFK – 4 hours. He said the closest place to land would be the Azores Islands, which is Portuguese territory, 2 hours away.

The problem: Even if we made it to the Azores, the hospital there was a very basic facility with no obstetric care available. And by the time the ambulance picked her up and got her there, it would still be 2 or 3 hours total. I said, “No, let’s just observe and continue our course.” Inside my head, I was hoping and praying to God that was the right decision.

Within an hour, everything changed.

The woman’s pain got worse, and she started having contractions. Then her water broke.

Things progressed quickly from there. The contractions progressively got worse and worse. The interval between them got smaller and smaller. The next time we examined her, we could see the baby’s head beginning to crown.

At that point, we had to decide – are we going to deliver? We were in the middle of the North Atlantic Ocean. There was nothing around us. We were 35,000 feet in the air, surrounded by blue.

The crew wanted us to sign a Good Samaritan agreement. So, we did that. And then I said, “Okay, let’s just go for it.”

We got the plane’s medical kit. They had IV fluids, so I started an IV. I was able to monitor the woman’s blood pressure. They had the usual drugs for doing ACLS [advanced cardiac life support], running the code, and things like that. But they didn’t have a suturing kit or a laceration kit. They didn’t have a scalpel. There was nothing else.

Honestly, there was a lot of panic going through my head. I started thinking about what could go wrong. I’d done an ob.gyn. rotation in medical school and delivered seven babies before it was over. But a plane – even the first-class cabin – is in no way, shape, or form like a delivery room. I was really scared she would hemorrhage out or something.

So, internally, I was having a meltdown. Sij, you have to keep it together right now, because there’s no one else that’s going to do this. Just give it your best shot. And that’s what I did.

I asked the pilot to go to an altitude that would minimize any turbulence, and we were very lucky that the notorious North Atlantic air wasn’t choppy.

More luck: This was the passenger’s second baby, and I was counting on second deliveries being easier. The pediatrician, the flight attendants, and I came together as a team. Two flight attendants had given birth before, so they held the patient’s hand and guided her to push. I was “downstairs” waiting to catch.

She was in some pain. At this point, usually people get an epidural. I kept thinking about what drugs were safe in pregnancy, but I wasn’t sure. I don’t know if they even had morphine or anything on the plane. We gave her some Tylenol.

It didn’t take long. After about 30 minutes, the baby’s head emerged. I was able to navigate it out, avoiding any shoulder dystocia. There’s a certain technique that you learn in medical school, which thankfully came back to me. I caught it – it was a boy born right there in a first-class seat.

I gave him to the pediatrician, and she did the Apgar score, calculating his breathing and appearance. Then my job was to make sure there were no postpartum complications.

I ended up using a piece of string in the kit to tie around the umbilical cord, and then I cut it with scissors. After that, the woman was able to deliver the placenta. She did have some vaginal bleeding, but that resolved by just holding pressure.

The baby was fine. Mom was doing great. No complications. It was a miracle. I was the right person at the right place at the right time. I just think it was something from God.

The pilot made an announcement, “We’re en route to JFK, and there’s an additional passenger on this plane now.”

When we landed, I had very little time because I had to catch my flight to Cleveland. I didn’t even process what had happened.

A few days later, I got this package from Air France with a very expensive bottle of champagne along with a travel voucher. I heard from the mom by email – she and baby were doing fine.

Eventually, the media relations people at Cleveland Clinic heard about the incident, and it became a story that went viral. That was very weird, because I’m usually someone who’s private. All through my residency, people would introduce me with, “Remember that guy who delivered a baby on a plane? That’s him.”

I’m so thankful for everyone who was on that team. It was very beautiful because it was people from different cultures, backgrounds, and faiths who came together to achieve something so miraculous. The patient was Nigerian. The flight attendants were French. The pediatrician and I were American.

That just shows you the power of teamwork and how humanity can come together. Medicine, surgery – everything, in fact – is a team sport.

Sij Hemal, MD, graduated from urology residency at the Cleveland Clinic and is currently a robotic urologic oncology and minimally invasive surgery fellow at the University of Southern California, Los Angeles.

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

A post hoc analysis of the ShortHER trial, including 784 patients with hormone-positive (HR+) and human epidermal growth factor receptor 2–positive (HER2+) early breast cancer who received adjuvant trastuzumab plus chemotherapy, showed that adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) was associated with better outcomes than tamoxifen (TAM) or TAM and AI (TAM-AI) in this population. Disease-free survival rates at 8 years were 86.4% for AI vs 79.7% for the TAM/TAM-AI groups, with an absolute difference of 6.7% (log-rank P = .013). This effect was seen independently of menopausal status in a multivariate analysis.

In the exploratory analysis focusing on the premenopausal patients, the addition of gonadotropin-releasing hormone to ET was associated with a significantly better disease-free survival. This was also noted in an exploratory subgroup analysis of the SOFT trial,^[1] which showed greater benefit from the addition of ovarian suppression to TAM, as compared with TAM alone, among women with HER2+ disease (hazard ratio 0.41; 95% CI 0.22-0.75).

It is important to note that not all patients in the ShortHER trial received the standard-of-care duration of adjuvant trastuzumab; half of them received only 9-week treatment as opposed to the standard 12 months of adjuvant therapy. It is unclear whether this difference in adjuvant therapy could have affected the results, although the disease-free survival multivariate analysis showed no significant effect of the treatment arm on the role of ET. More studies are needed to verify the optimal adjuvant ET for patients with HR+/HER2+ breast cancer, especially in premenopausal patients.

Contralateral Prophylactic Mastectomy Offers No Survival Advantage in Triple-Negative Breast Cancer

There is insufficient evidence that contralateral prophylactic mastectomy (CPM) improves survival in patients with unilateral triple-negative breast cancer (TNBC). A multi-institutional database study, including 796 patients with TNBC, of which 15.5% underwent CPM, showed that CPM did not offer survival benefit to patients with unilateral TNBC. Women who underwent CPM were more likely to be White (P < .001), younger (P < .001), and had had genetic testing performed (P < .001). While there was a borderline improvement in 5-year unadjusted overall survival for patients undergoing CPM compared with no CPM overall (95.1% vs 85.0%; P = .05), no significant improvement was observed for local recurrence-free survival (P = .40) or distant recurrence-free survival (P = .37). Very few (n = 15/673, 2.2%) of the no-CPM patients developed a new primary breast cancer; 3 of the 15 patients were known BRCA1 or BRCA2 mutation carriers. Among the genetic mutation carriers, 5-year overall survival was 97.2% for CPM vs 84.1% for no CPM (P = .35). This study did not demonstrate any statistically significant survival difference between CPM compared with no CPM, regardless of the presence of a BRCA mutation, although prior studies have shown improved outcomes for CPM in BRCA mutation carriers.^[2] Larger prospective studies are needed to evaluate the potential benefit of CPM among patients with TNBC, especially patients with BRCA1/2 mutations.

Adding Endocrine Therapy to Dual Anti-HER2 Targeted Therapy Beneficial in HER2+/HR+ Metastatic Breast Cancer

The current first-line standard of care for HER2+ metastatic breast cancer is dual anti-HER2 targeted therapy plus chemotherapy, with consideration for maintenance treatment with anti-HER2 therapy and ET for patients with HR+ and HER2+ metastatic breast cancer. The potential benefit of adding ET for patients with HR+/HER2+ metastatic breast cancer has been reported previously, but data overall are limited. This study analyzed the real-world data of 147 patients with HR+/HER2+ metastatic breast cancer from a prospective registry and who received first-line chemotherapy plus trastuzumab and pertuzumab with (n = 91) or without (n = 56) concurrent ET. The findings showed that adding ET resulted in a significant improvement in 5-year progression-free survival (PFS) (hazard ratio 0.59; P = .031) and overall survival (hazard ratio 0.52; P = .018) compared with not adding ET. No new safety concerns were identified when combining HER2+ targeted therapy and ET. While this is a small retrospective analysis, results are certainly encouraging and support the addition of ET to dual anti-HER2 therapy as maintenance therapy post chemotherapy in this subset of patients.

High PD-L2 Levels May Predict Worse Clinical Outcomes in ER+ Breast Cancer

Programmed cell death-1 ligand-2 (PD-L2) is a second ligand for programmed cell death-1 (PD-1) and inhibits T-cell activation. A retrospective study including patients with estrogen receptor–positive (ER+) breast cancer looked at PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, locoregional ER+ breast cancer in the main study cohort (n = 684) and in an independent validation cohort (n = 273), and correlated findings with PFS. High levels of PD-L2 protein were present in up to one third (33%) of ER+ tumors and were associated with shorter PFS in the entire cohort of patients with ER+ breast cancer (hazard ratio 2.0; P < .001) and in the subgroup of patients treated with adjuvant chemotherapy (hazard ratio 3.4; P < .001). A multivariable analysis showed that high levels of PD-L2 were an independent prognostic marker in ER+ patients. These findings suggest that high PD-L2 is associated with unfavorable prognosis in ER+ breast cancer and may be a potential biomarker of response to checkpoint inhibitors.

Additional References

1. Francis PA, Pagani O, Fleming GF, et al for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137. Doi: 10.1056/NEJMoa1803164
2. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res. 2016;22:3971-3981. Doi: 10.1158/1078-0432.CCR-15-1465

A post hoc analysis of the ShortHER trial, including 784 patients with hormone-positive (HR+) and human epidermal growth factor receptor 2–positive (HER2+) early breast cancer who received adjuvant trastuzumab plus chemotherapy, showed that adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) was associated with better outcomes than tamoxifen (TAM) or TAM and AI (TAM-AI) in this population. Disease-free survival rates at 8 years were 86.4% for AI vs 79.7% for the TAM/TAM-AI groups, with an absolute difference of 6.7% (log-rank P = .013). This effect was seen independently of menopausal status in a multivariate analysis.

In the exploratory analysis focusing on the premenopausal patients, the addition of gonadotropin-releasing hormone to ET was associated with a significantly better disease-free survival. This was also noted in an exploratory subgroup analysis of the SOFT trial,^[1] which showed greater benefit from the addition of ovarian suppression to TAM, as compared with TAM alone, among women with HER2+ disease (hazard ratio 0.41; 95% CI 0.22-0.75).

It is important to note that not all patients in the ShortHER trial received the standard-of-care duration of adjuvant trastuzumab; half of them received only 9-week treatment as opposed to the standard 12 months of adjuvant therapy. It is unclear whether this difference in adjuvant therapy could have affected the results, although the disease-free survival multivariate analysis showed no significant effect of the treatment arm on the role of ET. More studies are needed to verify the optimal adjuvant ET for patients with HR+/HER2+ breast cancer, especially in premenopausal patients.

Contralateral Prophylactic Mastectomy Offers No Survival Advantage in Triple-Negative Breast Cancer

There is insufficient evidence that contralateral prophylactic mastectomy (CPM) improves survival in patients with unilateral triple-negative breast cancer (TNBC). A multi-institutional database study, including 796 patients with TNBC, of which 15.5% underwent CPM, showed that CPM did not offer survival benefit to patients with unilateral TNBC. Women who underwent CPM were more likely to be White (P < .001), younger (P < .001), and had had genetic testing performed (P < .001). While there was a borderline improvement in 5-year unadjusted overall survival for patients undergoing CPM compared with no CPM overall (95.1% vs 85.0%; P = .05), no significant improvement was observed for local recurrence-free survival (P = .40) or distant recurrence-free survival (P = .37). Very few (n = 15/673, 2.2%) of the no-CPM patients developed a new primary breast cancer; 3 of the 15 patients were known BRCA1 or BRCA2 mutation carriers. Among the genetic mutation carriers, 5-year overall survival was 97.2% for CPM vs 84.1% for no CPM (P = .35). This study did not demonstrate any statistically significant survival difference between CPM compared with no CPM, regardless of the presence of a BRCA mutation, although prior studies have shown improved outcomes for CPM in BRCA mutation carriers.^[2] Larger prospective studies are needed to evaluate the potential benefit of CPM among patients with TNBC, especially patients with BRCA1/2 mutations.

Adding Endocrine Therapy to Dual Anti-HER2 Targeted Therapy Beneficial in HER2+/HR+ Metastatic Breast Cancer

The current first-line standard of care for HER2+ metastatic breast cancer is dual anti-HER2 targeted therapy plus chemotherapy, with consideration for maintenance treatment with anti-HER2 therapy and ET for patients with HR+ and HER2+ metastatic breast cancer. The potential benefit of adding ET for patients with HR+/HER2+ metastatic breast cancer has been reported previously, but data overall are limited. This study analyzed the real-world data of 147 patients with HR+/HER2+ metastatic breast cancer from a prospective registry and who received first-line chemotherapy plus trastuzumab and pertuzumab with (n = 91) or without (n = 56) concurrent ET. The findings showed that adding ET resulted in a significant improvement in 5-year progression-free survival (PFS) (hazard ratio 0.59; P = .031) and overall survival (hazard ratio 0.52; P = .018) compared with not adding ET. No new safety concerns were identified when combining HER2+ targeted therapy and ET. While this is a small retrospective analysis, results are certainly encouraging and support the addition of ET to dual anti-HER2 therapy as maintenance therapy post chemotherapy in this subset of patients.

High PD-L2 Levels May Predict Worse Clinical Outcomes in ER+ Breast Cancer

Programmed cell death-1 ligand-2 (PD-L2) is a second ligand for programmed cell death-1 (PD-1) and inhibits T-cell activation. A retrospective study including patients with estrogen receptor–positive (ER+) breast cancer looked at PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, locoregional ER+ breast cancer in the main study cohort (n = 684) and in an independent validation cohort (n = 273), and correlated findings with PFS. High levels of PD-L2 protein were present in up to one third (33%) of ER+ tumors and were associated with shorter PFS in the entire cohort of patients with ER+ breast cancer (hazard ratio 2.0; P < .001) and in the subgroup of patients treated with adjuvant chemotherapy (hazard ratio 3.4; P < .001). A multivariable analysis showed that high levels of PD-L2 were an independent prognostic marker in ER+ patients. These findings suggest that high PD-L2 is associated with unfavorable prognosis in ER+ breast cancer and may be a potential biomarker of response to checkpoint inhibitors.

Additional References

1. Francis PA, Pagani O, Fleming GF, et al for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137. Doi: 10.1056/NEJMoa1803164
2. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res. 2016;22:3971-3981. Doi: 10.1158/1078-0432.CCR-15-1465

A post hoc analysis of the ShortHER trial, including 784 patients with hormone-positive (HR+) and human epidermal growth factor receptor 2–positive (HER2+) early breast cancer who received adjuvant trastuzumab plus chemotherapy, showed that adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) was associated with better outcomes than tamoxifen (TAM) or TAM and AI (TAM-AI) in this population. Disease-free survival rates at 8 years were 86.4% for AI vs 79.7% for the TAM/TAM-AI groups, with an absolute difference of 6.7% (log-rank P = .013). This effect was seen independently of menopausal status in a multivariate analysis.

In the exploratory analysis focusing on the premenopausal patients, the addition of gonadotropin-releasing hormone to ET was associated with a significantly better disease-free survival. This was also noted in an exploratory subgroup analysis of the SOFT trial,^[1] which showed greater benefit from the addition of ovarian suppression to TAM, as compared with TAM alone, among women with HER2+ disease (hazard ratio 0.41; 95% CI 0.22-0.75).

It is important to note that not all patients in the ShortHER trial received the standard-of-care duration of adjuvant trastuzumab; half of them received only 9-week treatment as opposed to the standard 12 months of adjuvant therapy. It is unclear whether this difference in adjuvant therapy could have affected the results, although the disease-free survival multivariate analysis showed no significant effect of the treatment arm on the role of ET. More studies are needed to verify the optimal adjuvant ET for patients with HR+/HER2+ breast cancer, especially in premenopausal patients.

Contralateral Prophylactic Mastectomy Offers No Survival Advantage in Triple-Negative Breast Cancer

There is insufficient evidence that contralateral prophylactic mastectomy (CPM) improves survival in patients with unilateral triple-negative breast cancer (TNBC). A multi-institutional database study, including 796 patients with TNBC, of which 15.5% underwent CPM, showed that CPM did not offer survival benefit to patients with unilateral TNBC. Women who underwent CPM were more likely to be White (P < .001), younger (P < .001), and had had genetic testing performed (P < .001). While there was a borderline improvement in 5-year unadjusted overall survival for patients undergoing CPM compared with no CPM overall (95.1% vs 85.0%; P = .05), no significant improvement was observed for local recurrence-free survival (P = .40) or distant recurrence-free survival (P = .37). Very few (n = 15/673, 2.2%) of the no-CPM patients developed a new primary breast cancer; 3 of the 15 patients were known BRCA1 or BRCA2 mutation carriers. Among the genetic mutation carriers, 5-year overall survival was 97.2% for CPM vs 84.1% for no CPM (P = .35). This study did not demonstrate any statistically significant survival difference between CPM compared with no CPM, regardless of the presence of a BRCA mutation, although prior studies have shown improved outcomes for CPM in BRCA mutation carriers.^[2] Larger prospective studies are needed to evaluate the potential benefit of CPM among patients with TNBC, especially patients with BRCA1/2 mutations.

Adding Endocrine Therapy to Dual Anti-HER2 Targeted Therapy Beneficial in HER2+/HR+ Metastatic Breast Cancer

The current first-line standard of care for HER2+ metastatic breast cancer is dual anti-HER2 targeted therapy plus chemotherapy, with consideration for maintenance treatment with anti-HER2 therapy and ET for patients with HR+ and HER2+ metastatic breast cancer. The potential benefit of adding ET for patients with HR+/HER2+ metastatic breast cancer has been reported previously, but data overall are limited. This study analyzed the real-world data of 147 patients with HR+/HER2+ metastatic breast cancer from a prospective registry and who received first-line chemotherapy plus trastuzumab and pertuzumab with (n = 91) or without (n = 56) concurrent ET. The findings showed that adding ET resulted in a significant improvement in 5-year progression-free survival (PFS) (hazard ratio 0.59; P = .031) and overall survival (hazard ratio 0.52; P = .018) compared with not adding ET. No new safety concerns were identified when combining HER2+ targeted therapy and ET. While this is a small retrospective analysis, results are certainly encouraging and support the addition of ET to dual anti-HER2 therapy as maintenance therapy post chemotherapy in this subset of patients.

High PD-L2 Levels May Predict Worse Clinical Outcomes in ER+ Breast Cancer

Programmed cell death-1 ligand-2 (PD-L2) is a second ligand for programmed cell death-1 (PD-1) and inhibits T-cell activation. A retrospective study including patients with estrogen receptor–positive (ER+) breast cancer looked at PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, locoregional ER+ breast cancer in the main study cohort (n = 684) and in an independent validation cohort (n = 273), and correlated findings with PFS. High levels of PD-L2 protein were present in up to one third (33%) of ER+ tumors and were associated with shorter PFS in the entire cohort of patients with ER+ breast cancer (hazard ratio 2.0; P < .001) and in the subgroup of patients treated with adjuvant chemotherapy (hazard ratio 3.4; P < .001). A multivariable analysis showed that high levels of PD-L2 were an independent prognostic marker in ER+ patients. These findings suggest that high PD-L2 is associated with unfavorable prognosis in ER+ breast cancer and may be a potential biomarker of response to checkpoint inhibitors.

Additional References

1. Francis PA, Pagani O, Fleming GF, et al for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137. Doi: 10.1056/NEJMoa1803164
2. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res. 2016;22:3971-3981. Doi: 10.1158/1078-0432.CCR-15-1465

Treatment strategies designed to improve or maintain efficacy while minimizing toxicity are desired by both patients and healthcare providers. Neoadjuvant endocrine therapy (NET) represents a therapeutic option for certain patients with luminal breast cancers who may not be candidates for chemotherapy because of comorbidities or preferences to avoid certain treatments. Furthermore, studies have demonstrated tumor or nodal downstaging with NET, as well as the ability of genomic assays to predict clinical response to NET and its association with breast-conserving therapy (BCT).^[4,5] The phase 2 ACOSOG Z1031 trial reported outcomes among 509 women with clinical stage II or III estrogen receptor (ER)–positive breast cancer who received an aromatase inhibitor (AI; exemestane, letrozole, or anastrozole) for 16-18 weeks before surgery. A total of 67.2% of patients had BCT, and of the patients thought to require mastectomy or have inoperable breast cancer at presentation (N = 226), 50.4% were able to have BCT. The pCR rate was low (1%); however, the 5-year cumulative incidence rate for local-regional recurrence was estimated at 1.53% (Hunt et al). This study supports the consideration of NET for select patients, demonstrating a favorable impact on surgery and local-regional recurrence rates. It is also thought-provoking in terms of identifying predictors of response to NET and other novel therapies that can be combined with endocrine therapy in the neoadjuvant space.

The CLEOPATRA trial has established a regimen of docetaxel/trastuzumab/pertuzumab as standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with superior progression-free survival (PFS) and overall survival (OS) compared with a docetaxel/trastuzumab regimen. Crosstalk between HER2 and ER signaling pathways has been implicated in resistance to anti-HER2 and endocrine therapies. Real-world data have shown that the addition of endocrine therapy to first-line dual anti-HER2-targeted therapy post chemotherapy in HER+/hormone receptor positive (HR+) metastatic breast cancer was associated with benefits in PFS and OS.^[6] The phase 2 PERTAIN trial randomly assigned 258 patients with HER2+/HR+ metastatic breast cancer to receive pertuzumab/trastuzumab plus an AI or trastuzumab/AI, with induction chemotherapy given at the investigator’s discretion. At a median follow-up of > 6 years, the PFS benefit seen with the addition of pertuzumab was maintained (20.6 vs 15.8 months in the trastuzumab/AI arm; stratified hazard ratio 0.67; P = .006). Although there was not a statistically significant difference in median OS (60.2 months in the pertuzumab/trastuzumab/AI arm vs 57.2 months in the trastuzumab/AI arm; stratified hazard ratio 1.05; P = .78), the effect of pertuzumab was potentially amplified in those without induction chemotherapy (26.6 vs 12.5 months) (Arpino et al). These data provide further support for the addition of pertuzumab to trastuzumab in the first-line treatment setting for HER2+ metastatic breast cancer and suggest that some patients may benefit from dual HER2 blockade with endocrine therapy (without chemotherapy).

Additional References

1. Schmid P, Cortes J, Pusztai L, et al, for the KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. Doi: 10.1056/NEJMoa1910549
2. Schmid P, Cortes J, Dent R, et al, for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
3. Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30:1279-1288. Doi: 10.1093/annonc/mdz158
4. Cao L, Sugumar K, Keller E, et al. Neoadjuvant endocrine therapy as an alternative to neoadjuvant chemotherapy among hormone receptor-positive breast cancer patients: Pathologic and surgical outcomes. Ann Surg Oncol. 2021;28:5730-5741. Doi: 10.1245/s10434-021-10459-3
5. Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: The TransNEOS study. Breast Cancer Res Treat. 2019;173:123-133. Doi: 10.1007/s10549-018-4964-y
6. Loft M, Lok SW, De Boer R, et al. Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer. Breast Cancer Res Treat. 2023;198:67-74. Doi: 10.1007/s10549-022-06856-1

Treatment strategies designed to improve or maintain efficacy while minimizing toxicity are desired by both patients and healthcare providers. Neoadjuvant endocrine therapy (NET) represents a therapeutic option for certain patients with luminal breast cancers who may not be candidates for chemotherapy because of comorbidities or preferences to avoid certain treatments. Furthermore, studies have demonstrated tumor or nodal downstaging with NET, as well as the ability of genomic assays to predict clinical response to NET and its association with breast-conserving therapy (BCT).^[4,5] The phase 2 ACOSOG Z1031 trial reported outcomes among 509 women with clinical stage II or III estrogen receptor (ER)–positive breast cancer who received an aromatase inhibitor (AI; exemestane, letrozole, or anastrozole) for 16-18 weeks before surgery. A total of 67.2% of patients had BCT, and of the patients thought to require mastectomy or have inoperable breast cancer at presentation (N = 226), 50.4% were able to have BCT. The pCR rate was low (1%); however, the 5-year cumulative incidence rate for local-regional recurrence was estimated at 1.53% (Hunt et al). This study supports the consideration of NET for select patients, demonstrating a favorable impact on surgery and local-regional recurrence rates. It is also thought-provoking in terms of identifying predictors of response to NET and other novel therapies that can be combined with endocrine therapy in the neoadjuvant space.

The CLEOPATRA trial has established a regimen of docetaxel/trastuzumab/pertuzumab as standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with superior progression-free survival (PFS) and overall survival (OS) compared with a docetaxel/trastuzumab regimen. Crosstalk between HER2 and ER signaling pathways has been implicated in resistance to anti-HER2 and endocrine therapies. Real-world data have shown that the addition of endocrine therapy to first-line dual anti-HER2-targeted therapy post chemotherapy in HER+/hormone receptor positive (HR+) metastatic breast cancer was associated with benefits in PFS and OS.^[6] The phase 2 PERTAIN trial randomly assigned 258 patients with HER2+/HR+ metastatic breast cancer to receive pertuzumab/trastuzumab plus an AI or trastuzumab/AI, with induction chemotherapy given at the investigator’s discretion. At a median follow-up of > 6 years, the PFS benefit seen with the addition of pertuzumab was maintained (20.6 vs 15.8 months in the trastuzumab/AI arm; stratified hazard ratio 0.67; P = .006). Although there was not a statistically significant difference in median OS (60.2 months in the pertuzumab/trastuzumab/AI arm vs 57.2 months in the trastuzumab/AI arm; stratified hazard ratio 1.05; P = .78), the effect of pertuzumab was potentially amplified in those without induction chemotherapy (26.6 vs 12.5 months) (Arpino et al). These data provide further support for the addition of pertuzumab to trastuzumab in the first-line treatment setting for HER2+ metastatic breast cancer and suggest that some patients may benefit from dual HER2 blockade with endocrine therapy (without chemotherapy).

Additional References

1. Schmid P, Cortes J, Pusztai L, et al, for the KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. Doi: 10.1056/NEJMoa1910549
2. Schmid P, Cortes J, Dent R, et al, for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
3. Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30:1279-1288. Doi: 10.1093/annonc/mdz158
4. Cao L, Sugumar K, Keller E, et al. Neoadjuvant endocrine therapy as an alternative to neoadjuvant chemotherapy among hormone receptor-positive breast cancer patients: Pathologic and surgical outcomes. Ann Surg Oncol. 2021;28:5730-5741. Doi: 10.1245/s10434-021-10459-3
5. Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: The TransNEOS study. Breast Cancer Res Treat. 2019;173:123-133. Doi: 10.1007/s10549-018-4964-y
6. Loft M, Lok SW, De Boer R, et al. Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer. Breast Cancer Res Treat. 2023;198:67-74. Doi: 10.1007/s10549-022-06856-1

Treatment strategies designed to improve or maintain efficacy while minimizing toxicity are desired by both patients and healthcare providers. Neoadjuvant endocrine therapy (NET) represents a therapeutic option for certain patients with luminal breast cancers who may not be candidates for chemotherapy because of comorbidities or preferences to avoid certain treatments. Furthermore, studies have demonstrated tumor or nodal downstaging with NET, as well as the ability of genomic assays to predict clinical response to NET and its association with breast-conserving therapy (BCT).^[4,5] The phase 2 ACOSOG Z1031 trial reported outcomes among 509 women with clinical stage II or III estrogen receptor (ER)–positive breast cancer who received an aromatase inhibitor (AI; exemestane, letrozole, or anastrozole) for 16-18 weeks before surgery. A total of 67.2% of patients had BCT, and of the patients thought to require mastectomy or have inoperable breast cancer at presentation (N = 226), 50.4% were able to have BCT. The pCR rate was low (1%); however, the 5-year cumulative incidence rate for local-regional recurrence was estimated at 1.53% (Hunt et al). This study supports the consideration of NET for select patients, demonstrating a favorable impact on surgery and local-regional recurrence rates. It is also thought-provoking in terms of identifying predictors of response to NET and other novel therapies that can be combined with endocrine therapy in the neoadjuvant space.

The CLEOPATRA trial has established a regimen of docetaxel/trastuzumab/pertuzumab as standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with superior progression-free survival (PFS) and overall survival (OS) compared with a docetaxel/trastuzumab regimen. Crosstalk between HER2 and ER signaling pathways has been implicated in resistance to anti-HER2 and endocrine therapies. Real-world data have shown that the addition of endocrine therapy to first-line dual anti-HER2-targeted therapy post chemotherapy in HER+/hormone receptor positive (HR+) metastatic breast cancer was associated with benefits in PFS and OS.^[6] The phase 2 PERTAIN trial randomly assigned 258 patients with HER2+/HR+ metastatic breast cancer to receive pertuzumab/trastuzumab plus an AI or trastuzumab/AI, with induction chemotherapy given at the investigator’s discretion. At a median follow-up of > 6 years, the PFS benefit seen with the addition of pertuzumab was maintained (20.6 vs 15.8 months in the trastuzumab/AI arm; stratified hazard ratio 0.67; P = .006). Although there was not a statistically significant difference in median OS (60.2 months in the pertuzumab/trastuzumab/AI arm vs 57.2 months in the trastuzumab/AI arm; stratified hazard ratio 1.05; P = .78), the effect of pertuzumab was potentially amplified in those without induction chemotherapy (26.6 vs 12.5 months) (Arpino et al). These data provide further support for the addition of pertuzumab to trastuzumab in the first-line treatment setting for HER2+ metastatic breast cancer and suggest that some patients may benefit from dual HER2 blockade with endocrine therapy (without chemotherapy).

Additional References

1. Schmid P, Cortes J, Pusztai L, et al, for the KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. Doi: 10.1056/NEJMoa1910549
2. Schmid P, Cortes J, Dent R, et al, for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
3. Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30:1279-1288. Doi: 10.1093/annonc/mdz158
4. Cao L, Sugumar K, Keller E, et al. Neoadjuvant endocrine therapy as an alternative to neoadjuvant chemotherapy among hormone receptor-positive breast cancer patients: Pathologic and surgical outcomes. Ann Surg Oncol. 2021;28:5730-5741. Doi: 10.1245/s10434-021-10459-3
5. Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: The TransNEOS study. Breast Cancer Res Treat. 2019;173:123-133. Doi: 10.1007/s10549-018-4964-y
6. Loft M, Lok SW, De Boer R, et al. Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer. Breast Cancer Res Treat. 2023;198:67-74. Doi: 10.1007/s10549-022-06856-1

Proinflammatory elements mediated through metabolic pathways related to obesity and increased cellular senescence in CD57 expression in CD8+ T cells are associated with postacute sequelae of COVID-19 (PASC), according to a Mexican study. The researchers followed a Mexican cohort of 102 patients 3 months and 6 months after acute SARS-CoV-2 infection.

The study’s principal investigator was Diana Gómez-Martín, MD, PhD, of the department of immunology and rheumatology at the Salvador Zubirán National Institute of Medical Sciences and Nutrition, Mexico City. She told this news organization that follow-up of the patients began with the objective of understanding the determinative clinical, genetic, metabolic, and immunological factors in the progression of the acute disease. However, clinical aspects associated with PASC developed in the selected cohort. As a result, the study was extended, and the clinical, metabolic, and immunologic conditions in this single-center Mexican cohort were evaluated 3 months 6 months after the onset of infection.

Dr. Gómez-Martín explained that the immune senescence in CD57 of CD8+ T cells is one of the best-known findings of the present study. If it is confirmed in future studies, it could have important implications. “Its main implication is the possibility of better understanding the physiopathology of the clinical aspects associated with postacute sequelae of COVID-19, potentially being used for early detection and to provide follow-up aimed at patients, in addition to eventually developing targeted therapeutic strategies, such as immunometabolism regulation, in certain populations.”
 

Patients with PASC

The study was conducted from August 2020 to August 2021. Investigators recruited 102 patients (median age, 50.5 years; 55% were women) at the Mexico City Temporary Unit with a confirmed diagnosis of SARS-CoV-2. Of the patients, 44% had mild or moderate COVID-19, 30% had severe cases, and 26% of patients had critical cases. The most frequent comorbidities were obesity (44%), hypertension (24%), and type 2 diabetes (24%). The authors used a questionnaire to assess the presence of symptoms during follow-up. They analyzed immunologic variables at the time of recruitment, as well as levels of cytokines, immunoglobulin G against SARS-CoV-2, and neutrophil extracellular traps (NETs) at 1, 3, and 6 months. At 6 months’ follow-up, 12.7% of the cohort had symptoms compatible with PASC, which was defined for the study as the presence and report of three or more symptoms at 6 months’ follow-up.

As in similar studies, the authors found that female gender, remaining in intensive care, and having had more symptoms and greater titers of anti-SARS-CoV-2 antibodies during the acute infection were associated with the development of clinical aspects associated with PASC. Patients who had the disease at 6 months had increased serum levels of interleukin-1 alpha (6.21 pg/mL vs. 2.21 pg/mL), granulocyte colony-stimulating factor (55.08 pg/mL vs. 14.68 pg/mL), and interferon gamma-induced protein 10 (2,309.40 pg/mL vs. 780 pg/mL). Also, there was a trend toward an increase in serum concentration of interleukin-1 beta, interleukin-6, and interferon-gamma.

Patients whose condition met the definition of persistent PASC had increased expression of CD57 in CD8+ T cells (42,714 arbitrary units vs. 28,506) 6 months after the acute infection. The authors reported that there was no association between the persistence of PASC and the baseline amount of NETs, TRIM63, and anticellular antibodies. Nor was there an association between PASC and the titers of anti-SARS-CoV-2 antibodies at baseline and 1 month after COVID-19 diagnosis. Nonetheless, patients with persistent PASC had higher titers of anti-SARS-CoV-2 IgGs 3 months after the onset of COVID-19.

On the basis of previous data, the researchers aimed to construct a preliminary explanatory model to address the clinical and immunologic features associated with persistent PASC 6 months after SARS-CoV-2 infection. In the univariate analysis, the variables associated with the diagnosis of persistent PASC were the serum levels of granulocyte colony-stimulating factor (odds ratio, 1.01), macrophage inflammatory protein-1 alpha (OR, 1.13), interferon gamma-induced protein 10 (OR, 1.00), interleukin-6 (OR, 1.03), the expression of CD57 in CD8+ T cells (OR, 1.00), and the titers of anti-SARS-CoV-2 IgG at 1 month (OR, 1.45).

Patients with a diagnosis of clinical aspects associated with PASC at 6 months were characterized by certain predisposing factors, such as obesity, greater levels of macrophage inflammatory protein-1 alpha and interferon gamma-induced protein 10 in peripheral blood, greater expression of the senescence CD57 marker in CD8+ T lymphocytes, and persistent symptoms at 3 months.

Using these parameters to construct a predictive model after 3 months, the authors found a sensitivity of 97.7%, specificity of 53.8%, positive predictive value of 93.5%, and a negative predictive value of 77.7% for the diagnosis of clinical aspects associated with PASC at 6 months.
 

Interpreting CD57

One of the researchers who participated in the study was Luis Martínez-Juárez, MD, MPH, DrPH. He is on the operative solutions team at the Carlos Slim Foundation. Dr. Martínez-Juárez pointed out that one of the contributions of this study was that it specifically examined the Mexican population. He noted that “according to the findings, obesity is not only a comorbidity associated with more severe progressions during acute COVID-19 disease, but also, through inflammation parameters, such as interleukin-6, interferon gamma-induced protein 10, and macrophage inflammatory protein-1 alpha, it’s involved in the development of clinical aspects related to postacute sequelae of COVID-19.”

Dr. Gómez-Martín added that finding proinflammatory and obesity parameters in the patients could potentially support the hypothesis of the persistence of virus fragments in adipose tissue as possibly involved in clinical aspects associated with PASC, as some groups have reported in the medical literature.

Angélica Cuapio, MD, DrMed, an immunologist and senior investigator at the Karolinska Institute, Stockholm, who did not participate in the study, said in an interview that the authors’ findings on the sustained increase of the CD57 marker in CD8+ lymphocytes are of notable interest. They may be associated with senescence states or cellular aging or with a stage of chronic viral infections. Therefore, Dr. Cuapio argued, it would have been valuable to include cellular markers of the innate system, such as natural killer cells, since in various infections, an increase in CD57 in lymphocytes is accompanied by an almost proportional increase of this marker in natural killer cells.

“This information would help to determine more accurately if we are talking about a cellular senescence or more about a chronic infection in persistent COVID-19.” The finding is important, but future research is needed in this developing field.

Dr. Cuapio pointed out that the authors found an interesting elevation in interleukin-1 alpha in patients with clinical aspects associated with PASC in a clinically well-characterized population in Mexico. “It is possible that this is a specific marker either of a specific population or location, or this could be an association with a humoral response. Despite the fact that this finding is new and unclear, it is worth investigating. This study is of great value for the scientific community because it’s one more piece in the complex puzzle of clinical aspects associated with postacute sequelae of COVID-19.”

Dr. Gómez-Martín noted that the main limitations of the study consist of its single-center design and the small patient sample. Dr. Martínez-Juárez added that the study did not consider reinfections. In future studies, it would be ideal to integrate other molecular assessments associated with various hypotheses of the physiopathology of clinical aspects associated with PASC, such as microbiota alteration, coagulation anomalies, endothelial damage, and dysfunctional neurologic signaling.

The study was supported and funded by the Carlos Slim Foundation. Dr. Gómez-Martín, Dr. Martínez-Juárez, and Dr. Cuapio have disclosed no relevant financial relationships.

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

Proinflammatory elements mediated through metabolic pathways related to obesity and increased cellular senescence in CD57 expression in CD8+ T cells are associated with postacute sequelae of COVID-19 (PASC), according to a Mexican study. The researchers followed a Mexican cohort of 102 patients 3 months and 6 months after acute SARS-CoV-2 infection.

The study’s principal investigator was Diana Gómez-Martín, MD, PhD, of the department of immunology and rheumatology at the Salvador Zubirán National Institute of Medical Sciences and Nutrition, Mexico City. She told this news organization that follow-up of the patients began with the objective of understanding the determinative clinical, genetic, metabolic, and immunological factors in the progression of the acute disease. However, clinical aspects associated with PASC developed in the selected cohort. As a result, the study was extended, and the clinical, metabolic, and immunologic conditions in this single-center Mexican cohort were evaluated 3 months 6 months after the onset of infection.

Dr. Gómez-Martín explained that the immune senescence in CD57 of CD8+ T cells is one of the best-known findings of the present study. If it is confirmed in future studies, it could have important implications. “Its main implication is the possibility of better understanding the physiopathology of the clinical aspects associated with postacute sequelae of COVID-19, potentially being used for early detection and to provide follow-up aimed at patients, in addition to eventually developing targeted therapeutic strategies, such as immunometabolism regulation, in certain populations.”
 

Patients with PASC

The study was conducted from August 2020 to August 2021. Investigators recruited 102 patients (median age, 50.5 years; 55% were women) at the Mexico City Temporary Unit with a confirmed diagnosis of SARS-CoV-2. Of the patients, 44% had mild or moderate COVID-19, 30% had severe cases, and 26% of patients had critical cases. The most frequent comorbidities were obesity (44%), hypertension (24%), and type 2 diabetes (24%). The authors used a questionnaire to assess the presence of symptoms during follow-up. They analyzed immunologic variables at the time of recruitment, as well as levels of cytokines, immunoglobulin G against SARS-CoV-2, and neutrophil extracellular traps (NETs) at 1, 3, and 6 months. At 6 months’ follow-up, 12.7% of the cohort had symptoms compatible with PASC, which was defined for the study as the presence and report of three or more symptoms at 6 months’ follow-up.

As in similar studies, the authors found that female gender, remaining in intensive care, and having had more symptoms and greater titers of anti-SARS-CoV-2 antibodies during the acute infection were associated with the development of clinical aspects associated with PASC. Patients who had the disease at 6 months had increased serum levels of interleukin-1 alpha (6.21 pg/mL vs. 2.21 pg/mL), granulocyte colony-stimulating factor (55.08 pg/mL vs. 14.68 pg/mL), and interferon gamma-induced protein 10 (2,309.40 pg/mL vs. 780 pg/mL). Also, there was a trend toward an increase in serum concentration of interleukin-1 beta, interleukin-6, and interferon-gamma.

Patients whose condition met the definition of persistent PASC had increased expression of CD57 in CD8+ T cells (42,714 arbitrary units vs. 28,506) 6 months after the acute infection. The authors reported that there was no association between the persistence of PASC and the baseline amount of NETs, TRIM63, and anticellular antibodies. Nor was there an association between PASC and the titers of anti-SARS-CoV-2 antibodies at baseline and 1 month after COVID-19 diagnosis. Nonetheless, patients with persistent PASC had higher titers of anti-SARS-CoV-2 IgGs 3 months after the onset of COVID-19.

On the basis of previous data, the researchers aimed to construct a preliminary explanatory model to address the clinical and immunologic features associated with persistent PASC 6 months after SARS-CoV-2 infection. In the univariate analysis, the variables associated with the diagnosis of persistent PASC were the serum levels of granulocyte colony-stimulating factor (odds ratio, 1.01), macrophage inflammatory protein-1 alpha (OR, 1.13), interferon gamma-induced protein 10 (OR, 1.00), interleukin-6 (OR, 1.03), the expression of CD57 in CD8+ T cells (OR, 1.00), and the titers of anti-SARS-CoV-2 IgG at 1 month (OR, 1.45).

Patients with a diagnosis of clinical aspects associated with PASC at 6 months were characterized by certain predisposing factors, such as obesity, greater levels of macrophage inflammatory protein-1 alpha and interferon gamma-induced protein 10 in peripheral blood, greater expression of the senescence CD57 marker in CD8+ T lymphocytes, and persistent symptoms at 3 months.

Using these parameters to construct a predictive model after 3 months, the authors found a sensitivity of 97.7%, specificity of 53.8%, positive predictive value of 93.5%, and a negative predictive value of 77.7% for the diagnosis of clinical aspects associated with PASC at 6 months.
 

Interpreting CD57

One of the researchers who participated in the study was Luis Martínez-Juárez, MD, MPH, DrPH. He is on the operative solutions team at the Carlos Slim Foundation. Dr. Martínez-Juárez pointed out that one of the contributions of this study was that it specifically examined the Mexican population. He noted that “according to the findings, obesity is not only a comorbidity associated with more severe progressions during acute COVID-19 disease, but also, through inflammation parameters, such as interleukin-6, interferon gamma-induced protein 10, and macrophage inflammatory protein-1 alpha, it’s involved in the development of clinical aspects related to postacute sequelae of COVID-19.”

Dr. Gómez-Martín added that finding proinflammatory and obesity parameters in the patients could potentially support the hypothesis of the persistence of virus fragments in adipose tissue as possibly involved in clinical aspects associated with PASC, as some groups have reported in the medical literature.

Angélica Cuapio, MD, DrMed, an immunologist and senior investigator at the Karolinska Institute, Stockholm, who did not participate in the study, said in an interview that the authors’ findings on the sustained increase of the CD57 marker in CD8+ lymphocytes are of notable interest. They may be associated with senescence states or cellular aging or with a stage of chronic viral infections. Therefore, Dr. Cuapio argued, it would have been valuable to include cellular markers of the innate system, such as natural killer cells, since in various infections, an increase in CD57 in lymphocytes is accompanied by an almost proportional increase of this marker in natural killer cells.

“This information would help to determine more accurately if we are talking about a cellular senescence or more about a chronic infection in persistent COVID-19.” The finding is important, but future research is needed in this developing field.

Dr. Cuapio pointed out that the authors found an interesting elevation in interleukin-1 alpha in patients with clinical aspects associated with PASC in a clinically well-characterized population in Mexico. “It is possible that this is a specific marker either of a specific population or location, or this could be an association with a humoral response. Despite the fact that this finding is new and unclear, it is worth investigating. This study is of great value for the scientific community because it’s one more piece in the complex puzzle of clinical aspects associated with postacute sequelae of COVID-19.”

Dr. Gómez-Martín noted that the main limitations of the study consist of its single-center design and the small patient sample. Dr. Martínez-Juárez added that the study did not consider reinfections. In future studies, it would be ideal to integrate other molecular assessments associated with various hypotheses of the physiopathology of clinical aspects associated with PASC, such as microbiota alteration, coagulation anomalies, endothelial damage, and dysfunctional neurologic signaling.

The study was supported and funded by the Carlos Slim Foundation. Dr. Gómez-Martín, Dr. Martínez-Juárez, and Dr. Cuapio have disclosed no relevant financial relationships.

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

Proinflammatory elements mediated through metabolic pathways related to obesity and increased cellular senescence in CD57 expression in CD8+ T cells are associated with postacute sequelae of COVID-19 (PASC), according to a Mexican study. The researchers followed a Mexican cohort of 102 patients 3 months and 6 months after acute SARS-CoV-2 infection.

The study’s principal investigator was Diana Gómez-Martín, MD, PhD, of the department of immunology and rheumatology at the Salvador Zubirán National Institute of Medical Sciences and Nutrition, Mexico City. She told this news organization that follow-up of the patients began with the objective of understanding the determinative clinical, genetic, metabolic, and immunological factors in the progression of the acute disease. However, clinical aspects associated with PASC developed in the selected cohort. As a result, the study was extended, and the clinical, metabolic, and immunologic conditions in this single-center Mexican cohort were evaluated 3 months 6 months after the onset of infection.

Dr. Gómez-Martín explained that the immune senescence in CD57 of CD8+ T cells is one of the best-known findings of the present study. If it is confirmed in future studies, it could have important implications. “Its main implication is the possibility of better understanding the physiopathology of the clinical aspects associated with postacute sequelae of COVID-19, potentially being used for early detection and to provide follow-up aimed at patients, in addition to eventually developing targeted therapeutic strategies, such as immunometabolism regulation, in certain populations.”
 

Patients with PASC

The study was conducted from August 2020 to August 2021. Investigators recruited 102 patients (median age, 50.5 years; 55% were women) at the Mexico City Temporary Unit with a confirmed diagnosis of SARS-CoV-2. Of the patients, 44% had mild or moderate COVID-19, 30% had severe cases, and 26% of patients had critical cases. The most frequent comorbidities were obesity (44%), hypertension (24%), and type 2 diabetes (24%). The authors used a questionnaire to assess the presence of symptoms during follow-up. They analyzed immunologic variables at the time of recruitment, as well as levels of cytokines, immunoglobulin G against SARS-CoV-2, and neutrophil extracellular traps (NETs) at 1, 3, and 6 months. At 6 months’ follow-up, 12.7% of the cohort had symptoms compatible with PASC, which was defined for the study as the presence and report of three or more symptoms at 6 months’ follow-up.

As in similar studies, the authors found that female gender, remaining in intensive care, and having had more symptoms and greater titers of anti-SARS-CoV-2 antibodies during the acute infection were associated with the development of clinical aspects associated with PASC. Patients who had the disease at 6 months had increased serum levels of interleukin-1 alpha (6.21 pg/mL vs. 2.21 pg/mL), granulocyte colony-stimulating factor (55.08 pg/mL vs. 14.68 pg/mL), and interferon gamma-induced protein 10 (2,309.40 pg/mL vs. 780 pg/mL). Also, there was a trend toward an increase in serum concentration of interleukin-1 beta, interleukin-6, and interferon-gamma.

Patients whose condition met the definition of persistent PASC had increased expression of CD57 in CD8+ T cells (42,714 arbitrary units vs. 28,506) 6 months after the acute infection. The authors reported that there was no association between the persistence of PASC and the baseline amount of NETs, TRIM63, and anticellular antibodies. Nor was there an association between PASC and the titers of anti-SARS-CoV-2 antibodies at baseline and 1 month after COVID-19 diagnosis. Nonetheless, patients with persistent PASC had higher titers of anti-SARS-CoV-2 IgGs 3 months after the onset of COVID-19.

On the basis of previous data, the researchers aimed to construct a preliminary explanatory model to address the clinical and immunologic features associated with persistent PASC 6 months after SARS-CoV-2 infection. In the univariate analysis, the variables associated with the diagnosis of persistent PASC were the serum levels of granulocyte colony-stimulating factor (odds ratio, 1.01), macrophage inflammatory protein-1 alpha (OR, 1.13), interferon gamma-induced protein 10 (OR, 1.00), interleukin-6 (OR, 1.03), the expression of CD57 in CD8+ T cells (OR, 1.00), and the titers of anti-SARS-CoV-2 IgG at 1 month (OR, 1.45).

Patients with a diagnosis of clinical aspects associated with PASC at 6 months were characterized by certain predisposing factors, such as obesity, greater levels of macrophage inflammatory protein-1 alpha and interferon gamma-induced protein 10 in peripheral blood, greater expression of the senescence CD57 marker in CD8+ T lymphocytes, and persistent symptoms at 3 months.

Using these parameters to construct a predictive model after 3 months, the authors found a sensitivity of 97.7%, specificity of 53.8%, positive predictive value of 93.5%, and a negative predictive value of 77.7% for the diagnosis of clinical aspects associated with PASC at 6 months.
 

Interpreting CD57

One of the researchers who participated in the study was Luis Martínez-Juárez, MD, MPH, DrPH. He is on the operative solutions team at the Carlos Slim Foundation. Dr. Martínez-Juárez pointed out that one of the contributions of this study was that it specifically examined the Mexican population. He noted that “according to the findings, obesity is not only a comorbidity associated with more severe progressions during acute COVID-19 disease, but also, through inflammation parameters, such as interleukin-6, interferon gamma-induced protein 10, and macrophage inflammatory protein-1 alpha, it’s involved in the development of clinical aspects related to postacute sequelae of COVID-19.”

Dr. Gómez-Martín added that finding proinflammatory and obesity parameters in the patients could potentially support the hypothesis of the persistence of virus fragments in adipose tissue as possibly involved in clinical aspects associated with PASC, as some groups have reported in the medical literature.

Angélica Cuapio, MD, DrMed, an immunologist and senior investigator at the Karolinska Institute, Stockholm, who did not participate in the study, said in an interview that the authors’ findings on the sustained increase of the CD57 marker in CD8+ lymphocytes are of notable interest. They may be associated with senescence states or cellular aging or with a stage of chronic viral infections. Therefore, Dr. Cuapio argued, it would have been valuable to include cellular markers of the innate system, such as natural killer cells, since in various infections, an increase in CD57 in lymphocytes is accompanied by an almost proportional increase of this marker in natural killer cells.

“This information would help to determine more accurately if we are talking about a cellular senescence or more about a chronic infection in persistent COVID-19.” The finding is important, but future research is needed in this developing field.

Dr. Cuapio pointed out that the authors found an interesting elevation in interleukin-1 alpha in patients with clinical aspects associated with PASC in a clinically well-characterized population in Mexico. “It is possible that this is a specific marker either of a specific population or location, or this could be an association with a humoral response. Despite the fact that this finding is new and unclear, it is worth investigating. This study is of great value for the scientific community because it’s one more piece in the complex puzzle of clinical aspects associated with postacute sequelae of COVID-19.”

Dr. Gómez-Martín noted that the main limitations of the study consist of its single-center design and the small patient sample. Dr. Martínez-Juárez added that the study did not consider reinfections. In future studies, it would be ideal to integrate other molecular assessments associated with various hypotheses of the physiopathology of clinical aspects associated with PASC, such as microbiota alteration, coagulation anomalies, endothelial damage, and dysfunctional neurologic signaling.

The study was supported and funded by the Carlos Slim Foundation. Dr. Gómez-Martín, Dr. Martínez-Juárez, and Dr. Cuapio have disclosed no relevant financial relationships.

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

A two-part research study suggests that frequent cannabis is a risk factor for coronary artery disease (CAD).

In the first part, in an observational study, daily cannabis use was associated with 34% higher odds for CAD, compared with never-users, in a large population-based U.S. cohort. Less frequent use was not associated with increased odds for CAD.

In the second part, people with a genetic susceptibility to cannabis use disorder or severe cannabis dependency had an increased risk for CAD, compared with other people.

Ishan Paranjpe, MD, the study’s lead author, reported these results in a press briefing and will present the study at the upcoming joint scientific sessions of the American College of Cardiology and the World Heart Federation 2023.

“A couple of takeaway points are that daily cannabis use, but not less frequent cannabis use, was associated with CAD” in the large population-based cohort, said Dr. Paranjpe, a resident physician at Stanford (Calif.) University, during the press conference.

“This analysis was adjusted for several possible confounders including age, sex at birth, [body mass index (BMI)], race, education, cigarette use, hypertension, high cholesterol, and diabetes,” he noted, and even after accounting for these risk factors, the association with heart disease remained.

“And the next thing, using Mendelian randomization, we sort of implied that there might be a causal relationship between cannabis and heart disease. Importantly this effect is independent of alcohol and cigarette use.

“The notion that cannabis is completely benign is probably wrong, and there might be certain risk of certain cardiovascular effects of cannabis we should be more on the lookout for,” Dr. Paranjpe said in an interview.

“Our main conclusion was that prevalent CAD is associated with cannabis consumption,” he added. “Other mechanistic work published in Cell has also shown that cannabis causes vascular inflammation that may lead to CAD.

“Thus, there is growing evidence from both laboratory and population studies that cannabis consumption may be harmful for cardiovascular health,” he said. “However, we still need more work on whether it affects the risk of incident cardiovascular events (i.e., stroke, heart attack) in patient[s] with existing CAD.”
 

ASCVD risk

Invited to comment, Robert L. Page II, PharmD, chair of the writing group for the American Heart Association’s scientific statement Medical Marijuana, Recreational Cannabis, and Cardiovascular Health, published in 2020, said, “This adds to our hypothesis that if you are using marijuana over a longer period, greater exposure, you’re going to see an increase in the risk” for atherosclerotic cardiovascular disease (ASCVD).

“We’re seeing this increased risk for ASCVD in young adults between ages 18 to 40 – people who think that they’re invincible,” Dr. Page, a professor at the University of Colorado at Denver, Aurora, who was not involved with this research, told this news organization in an interview.

“The bottom line is that the risk that they are seeing is what has also been documented in other observational studies, and it adds fuel to the fire. We need to be paying close attention to this,” he said.

“Primary care [clinicians], cardiologists, need to address this, particularly in younger adults – because that’s where you’re seeing the highest amount of use.”
 

‘All of Us’ observational study

In the first part of the study, the researchers analyzed data from the “All of Us” cohort comprising adults age 18 and older from 340 inpatient and outpatient sites across the United States.

They identified 57,958 individuals who replied to a questionnaire asking about cannabis use (medicinal or recreational and whether it was edible or used by smoking or vaping) over the past 3 months.

There were 39,678 never-users, 8,749 who used it once or twice, 2,075 who used it monthly, 2,720 who used it weekly, and 4,736 who used it daily.

Of these, 3,506 individuals had CAD, based on medical records.

Only daily users had a significantly higher risk for CAD, compared with never-users (odds ratio, 1.34; P = .001) after adjusting for age, sex, hypertension, hyperlipidemia, type 2 diabetes, BMI, education, insurance status, and cigarette use.

The median age for daily users was 41, whereas the median age for never-users was 59.
 

GWAS analyses

The researchers then performed a Mendelian randomization analysis based on genome-wide association studies (GWAS) of cannabis use disorder and of CAD.

“Cannabis use disorder is a psychiatric diagnosis of severe cannabis dependency, equivalent to ‘alcohol use disorder’ for alcohol consumption,” Dr. Paranjpe explained. “The exact definition involves frequent use leading to significant dependence (but does not specify how often it is used).”

The GWAS data for cannabis use disorder came from a recent meta-analysis of three cohorts: the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE.

The GWAS statistics for CAD were obtained from the CARDIoGRAMplusC4D Consortium.

Cannabis use disorder was associated with significantly increased odds for CAD (OR, 1.05; P = .001), which remained after adjusting for both cigarette and alcohol use (OR, 1.04).

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

A two-part research study suggests that frequent cannabis is a risk factor for coronary artery disease (CAD).

In the first part, in an observational study, daily cannabis use was associated with 34% higher odds for CAD, compared with never-users, in a large population-based U.S. cohort. Less frequent use was not associated with increased odds for CAD.

In the second part, people with a genetic susceptibility to cannabis use disorder or severe cannabis dependency had an increased risk for CAD, compared with other people.

Ishan Paranjpe, MD, the study’s lead author, reported these results in a press briefing and will present the study at the upcoming joint scientific sessions of the American College of Cardiology and the World Heart Federation 2023.

“A couple of takeaway points are that daily cannabis use, but not less frequent cannabis use, was associated with CAD” in the large population-based cohort, said Dr. Paranjpe, a resident physician at Stanford (Calif.) University, during the press conference.

“This analysis was adjusted for several possible confounders including age, sex at birth, [body mass index (BMI)], race, education, cigarette use, hypertension, high cholesterol, and diabetes,” he noted, and even after accounting for these risk factors, the association with heart disease remained.

“And the next thing, using Mendelian randomization, we sort of implied that there might be a causal relationship between cannabis and heart disease. Importantly this effect is independent of alcohol and cigarette use.

“The notion that cannabis is completely benign is probably wrong, and there might be certain risk of certain cardiovascular effects of cannabis we should be more on the lookout for,” Dr. Paranjpe said in an interview.

“Our main conclusion was that prevalent CAD is associated with cannabis consumption,” he added. “Other mechanistic work published in Cell has also shown that cannabis causes vascular inflammation that may lead to CAD.

“Thus, there is growing evidence from both laboratory and population studies that cannabis consumption may be harmful for cardiovascular health,” he said. “However, we still need more work on whether it affects the risk of incident cardiovascular events (i.e., stroke, heart attack) in patient[s] with existing CAD.”
 

ASCVD risk

Invited to comment, Robert L. Page II, PharmD, chair of the writing group for the American Heart Association’s scientific statement Medical Marijuana, Recreational Cannabis, and Cardiovascular Health, published in 2020, said, “This adds to our hypothesis that if you are using marijuana over a longer period, greater exposure, you’re going to see an increase in the risk” for atherosclerotic cardiovascular disease (ASCVD).

“We’re seeing this increased risk for ASCVD in young adults between ages 18 to 40 – people who think that they’re invincible,” Dr. Page, a professor at the University of Colorado at Denver, Aurora, who was not involved with this research, told this news organization in an interview.

“The bottom line is that the risk that they are seeing is what has also been documented in other observational studies, and it adds fuel to the fire. We need to be paying close attention to this,” he said.

“Primary care [clinicians], cardiologists, need to address this, particularly in younger adults – because that’s where you’re seeing the highest amount of use.”
 

‘All of Us’ observational study

In the first part of the study, the researchers analyzed data from the “All of Us” cohort comprising adults age 18 and older from 340 inpatient and outpatient sites across the United States.

They identified 57,958 individuals who replied to a questionnaire asking about cannabis use (medicinal or recreational and whether it was edible or used by smoking or vaping) over the past 3 months.

There were 39,678 never-users, 8,749 who used it once or twice, 2,075 who used it monthly, 2,720 who used it weekly, and 4,736 who used it daily.

Of these, 3,506 individuals had CAD, based on medical records.

Only daily users had a significantly higher risk for CAD, compared with never-users (odds ratio, 1.34; P = .001) after adjusting for age, sex, hypertension, hyperlipidemia, type 2 diabetes, BMI, education, insurance status, and cigarette use.

The median age for daily users was 41, whereas the median age for never-users was 59.
 

GWAS analyses

The researchers then performed a Mendelian randomization analysis based on genome-wide association studies (GWAS) of cannabis use disorder and of CAD.

“Cannabis use disorder is a psychiatric diagnosis of severe cannabis dependency, equivalent to ‘alcohol use disorder’ for alcohol consumption,” Dr. Paranjpe explained. “The exact definition involves frequent use leading to significant dependence (but does not specify how often it is used).”

The GWAS data for cannabis use disorder came from a recent meta-analysis of three cohorts: the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE.

The GWAS statistics for CAD were obtained from the CARDIoGRAMplusC4D Consortium.

Cannabis use disorder was associated with significantly increased odds for CAD (OR, 1.05; P = .001), which remained after adjusting for both cigarette and alcohol use (OR, 1.04).

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

A two-part research study suggests that frequent cannabis is a risk factor for coronary artery disease (CAD).

In the first part, in an observational study, daily cannabis use was associated with 34% higher odds for CAD, compared with never-users, in a large population-based U.S. cohort. Less frequent use was not associated with increased odds for CAD.

In the second part, people with a genetic susceptibility to cannabis use disorder or severe cannabis dependency had an increased risk for CAD, compared with other people.

Ishan Paranjpe, MD, the study’s lead author, reported these results in a press briefing and will present the study at the upcoming joint scientific sessions of the American College of Cardiology and the World Heart Federation 2023.

“A couple of takeaway points are that daily cannabis use, but not less frequent cannabis use, was associated with CAD” in the large population-based cohort, said Dr. Paranjpe, a resident physician at Stanford (Calif.) University, during the press conference.

“This analysis was adjusted for several possible confounders including age, sex at birth, [body mass index (BMI)], race, education, cigarette use, hypertension, high cholesterol, and diabetes,” he noted, and even after accounting for these risk factors, the association with heart disease remained.

“And the next thing, using Mendelian randomization, we sort of implied that there might be a causal relationship between cannabis and heart disease. Importantly this effect is independent of alcohol and cigarette use.

“The notion that cannabis is completely benign is probably wrong, and there might be certain risk of certain cardiovascular effects of cannabis we should be more on the lookout for,” Dr. Paranjpe said in an interview.

“Our main conclusion was that prevalent CAD is associated with cannabis consumption,” he added. “Other mechanistic work published in Cell has also shown that cannabis causes vascular inflammation that may lead to CAD.

“Thus, there is growing evidence from both laboratory and population studies that cannabis consumption may be harmful for cardiovascular health,” he said. “However, we still need more work on whether it affects the risk of incident cardiovascular events (i.e., stroke, heart attack) in patient[s] with existing CAD.”
 

ASCVD risk

Invited to comment, Robert L. Page II, PharmD, chair of the writing group for the American Heart Association’s scientific statement Medical Marijuana, Recreational Cannabis, and Cardiovascular Health, published in 2020, said, “This adds to our hypothesis that if you are using marijuana over a longer period, greater exposure, you’re going to see an increase in the risk” for atherosclerotic cardiovascular disease (ASCVD).

“We’re seeing this increased risk for ASCVD in young adults between ages 18 to 40 – people who think that they’re invincible,” Dr. Page, a professor at the University of Colorado at Denver, Aurora, who was not involved with this research, told this news organization in an interview.

“The bottom line is that the risk that they are seeing is what has also been documented in other observational studies, and it adds fuel to the fire. We need to be paying close attention to this,” he said.

“Primary care [clinicians], cardiologists, need to address this, particularly in younger adults – because that’s where you’re seeing the highest amount of use.”
 

‘All of Us’ observational study

In the first part of the study, the researchers analyzed data from the “All of Us” cohort comprising adults age 18 and older from 340 inpatient and outpatient sites across the United States.

They identified 57,958 individuals who replied to a questionnaire asking about cannabis use (medicinal or recreational and whether it was edible or used by smoking or vaping) over the past 3 months.

There were 39,678 never-users, 8,749 who used it once or twice, 2,075 who used it monthly, 2,720 who used it weekly, and 4,736 who used it daily.

Of these, 3,506 individuals had CAD, based on medical records.

Only daily users had a significantly higher risk for CAD, compared with never-users (odds ratio, 1.34; P = .001) after adjusting for age, sex, hypertension, hyperlipidemia, type 2 diabetes, BMI, education, insurance status, and cigarette use.

The median age for daily users was 41, whereas the median age for never-users was 59.
 

GWAS analyses

The researchers then performed a Mendelian randomization analysis based on genome-wide association studies (GWAS) of cannabis use disorder and of CAD.

“Cannabis use disorder is a psychiatric diagnosis of severe cannabis dependency, equivalent to ‘alcohol use disorder’ for alcohol consumption,” Dr. Paranjpe explained. “The exact definition involves frequent use leading to significant dependence (but does not specify how often it is used).”

The GWAS data for cannabis use disorder came from a recent meta-analysis of three cohorts: the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE.

The GWAS statistics for CAD were obtained from the CARDIoGRAMplusC4D Consortium.

Cannabis use disorder was associated with significantly increased odds for CAD (OR, 1.05; P = .001), which remained after adjusting for both cigarette and alcohol use (OR, 1.04).

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

Health officials are warning that an increase in the drug-resistant form of the bacteria Shigella is a “serious public health threat.”

The CDC issued the warning Feb. 24 about the rise in the problematic infections. Most of them have been seen in men who have sex with men, but a small number have also occurred in women and in young children.

The bacteria can be spread in a variety of ways, including changing the diaper of an infected baby, touching your mouth when the bacteria are on your hands, eating or drinking contaminated food or water, or through sexual contact. It’s easily transmitted because just a tiny amount of the bacteria is enough to make someone sick.

Shigella infection causes diarrhea that can be bloody. Other symptoms are a fever, belly cramping, and the feeling that you have to poop but your bowels are already empty. Most people recover on their own with rest and fluids, and severe cases can need antibiotic treatment. But strains of the bacteria that are resistant to treatment are on the rise.

Between 2015 and 2022, cases of antibiotic-resistant Shigella infection rose from 0% to 5% of all Shigella cases in the United States. One analysis showed that 82% of cases were in men, 13% in women, and 5% in children. A small sample of affected people provided information about their sexual activity, and 88% of them reported male-to-male sexual contact.

People at increased risk of infections are young children, people who are homeless, international travelers, people who have weakened immune systems, people living with HIV, and men who have sex with men.

The CDC asked health care workers to be on the lookout for these infections and report them.

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

Health officials are warning that an increase in the drug-resistant form of the bacteria Shigella is a “serious public health threat.”

The CDC issued the warning Feb. 24 about the rise in the problematic infections. Most of them have been seen in men who have sex with men, but a small number have also occurred in women and in young children.

The bacteria can be spread in a variety of ways, including changing the diaper of an infected baby, touching your mouth when the bacteria are on your hands, eating or drinking contaminated food or water, or through sexual contact. It’s easily transmitted because just a tiny amount of the bacteria is enough to make someone sick.

Shigella infection causes diarrhea that can be bloody. Other symptoms are a fever, belly cramping, and the feeling that you have to poop but your bowels are already empty. Most people recover on their own with rest and fluids, and severe cases can need antibiotic treatment. But strains of the bacteria that are resistant to treatment are on the rise.

Between 2015 and 2022, cases of antibiotic-resistant Shigella infection rose from 0% to 5% of all Shigella cases in the United States. One analysis showed that 82% of cases were in men, 13% in women, and 5% in children. A small sample of affected people provided information about their sexual activity, and 88% of them reported male-to-male sexual contact.

People at increased risk of infections are young children, people who are homeless, international travelers, people who have weakened immune systems, people living with HIV, and men who have sex with men.

The CDC asked health care workers to be on the lookout for these infections and report them.

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

Health officials are warning that an increase in the drug-resistant form of the bacteria Shigella is a “serious public health threat.”

The CDC issued the warning Feb. 24 about the rise in the problematic infections. Most of them have been seen in men who have sex with men, but a small number have also occurred in women and in young children.

The bacteria can be spread in a variety of ways, including changing the diaper of an infected baby, touching your mouth when the bacteria are on your hands, eating or drinking contaminated food or water, or through sexual contact. It’s easily transmitted because just a tiny amount of the bacteria is enough to make someone sick.

Shigella infection causes diarrhea that can be bloody. Other symptoms are a fever, belly cramping, and the feeling that you have to poop but your bowels are already empty. Most people recover on their own with rest and fluids, and severe cases can need antibiotic treatment. But strains of the bacteria that are resistant to treatment are on the rise.

Between 2015 and 2022, cases of antibiotic-resistant Shigella infection rose from 0% to 5% of all Shigella cases in the United States. One analysis showed that 82% of cases were in men, 13% in women, and 5% in children. A small sample of affected people provided information about their sexual activity, and 88% of them reported male-to-male sexual contact.

People at increased risk of infections are young children, people who are homeless, international travelers, people who have weakened immune systems, people living with HIV, and men who have sex with men.

The CDC asked health care workers to be on the lookout for these infections and report them.

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

Considered fringe just a few years ago, oral immunotherapy (OIT) has entered mainstream conversation about treating food allergies – particularly in younger children.

The buzz surrounding OIT – which involves ingesting daily doses of the culprit food to raise the threshold that would trigger a reaction – grew with the approval, by the U.S. Food and Drug Administration of Palforzia, of the peanut OIT pill in January 2020. Yet many allergists remained wary about the treatment, a monthslong regimen that can itself trigger allergic reactions.

Now, accumulating research points to “a possible window of opportunity early in life, less than 3 years of age, for more successful disease remission,” Justin Schwartz, MD, PhD, an allergist at Cincinnati Children’s Hospital, told a crowd at the annual meeting of the American Academy of Allergy, Asthma, & Immunology.

His presentation about OIT in toddlers kicked off a 3-hour clinical practice course, one of several dozen conference offerings highlighting this emerging approach.

Several AAAAI posters add to prior studies (for example, DEVIL and IMPACT) suggesting that OIT proceeds more smoothly and faster during a child’s earliest years – a season fraught with accidental exposures and reactions.

One poster described a retrospective study of 73 children younger than 4 years who underwent OIT at the Cleveland Clinic Food Allergy Center. Sixty-four were treated for peanut allergies, and seven patients received OIT for multiple foods, including tree nuts, milk, wheat, and sesame.

Of the 80 total OIT courses, 76 (95%) reached maintenance – meaning the child tolerated a small amount (for example, 1-2 peanuts) without reacting – in a median of 104 days (~3.4 months).

That is “quite impressive,” said allergist Hugh Windom, MD, whose clinic in Sarasota, Fla., has offered OIT since 2012.

Older children typically have 80%-90% success and take longer (6-8 months) to reach maintenance because of busier schedules and reactions that slow them down, he said. In his clinic’s larger retrospective analysis of preschool-aged OIT patients, presented at the 2022 AAAAI meeting, 89% of patients with peanut allergies and 72% of children with multiple food allergies achieved maintenance.

In the Cleveland Clinic study, children with favorable lab test results after receiving the maintenance dose for 6 months were offered an oral food challenge. Of 24 patients who completed the challenge, 75% “passed with a normal serving size of the treated food (for example, two tablespoons of peanut butter),” Sarah Johnson, MD, lead author and Cleveland Clinic allergy/immunology fellow, said in an interview.

Plus, OIT seemed safer for toddlers. Although 41% of the children had reactions during clinic updosing and 48% had reactions at home, only ~3% of toddler OIT courses required epinephrine. By comparison, ~11% of treatments required epinephrine in a large OIT study of older children.

When a child reacts, “you might keep them on the dose or go a little slower,” said Johnson, who worked with allergist Jaclyn Bjelac, MD, on the study. These setbacks occurred less frequently in toddlers, allowing their OIT to “go a lot faster” than in older children. And so far, Dr. Johnson said, none of the toddlers have shown signs of eosinophilic esophagitis, a rare complication that can develop during OIT.

A smaller analysis of real-world outcomes in an academic clinical setting also found that OIT was well tolerated at very young ages. Since 2020, this ongoing study at UVA Children’s Hospital in Charlottesville has enrolled 22 peanut-allergic children (aged 6 months to 3 years) for OIT. Three patients have dropped out, four are in the buildup phrase, and 15 have reached maintenance dosing. None have reported having to use epinephrine.

Three patients have completed 1 year of maintenance therapy, and another patient accidentally consumed ~3,000 mg of peanut protein (equivalent to ~10 peanuts) after 5 months of maintenance. All four “now incorporate peanut into their diets ad lib,” according to lead author and allergist Jonathan Hemler, MD, who directs the UVA pediatric food allergy program.

These findings are “really reassuring – because even if you may not offer OIT, you’re still going to get questions about it,” said Ama Alexis, MD, an allergist/immunologist in private practice in New York and a clinical assistant professor at NYU Grossmann School of Medicine, commenting on the Cleveland Clinic study.

“It’s great that we’re hearing and seeing so much about OIT,” she added. While training as an allergy/immunology fellow 15 years ago, many saw the treatment as dangerous – “an absolute no-no,” she said.

The AAAAI still considers OIT “investigational,” yet this year’s annual meeting featured 22 posters – plus a course, workshop, seminar, and oral abstract session – on the approach.

The “thought process has shifted,” Dr. Alexis said. “It’s good to see all these numbers, these results. I think once you’re comfortable, you should embrace new therapies.”

Dr. Schwartz has consulted for Shire/Takeda and has received research funding from Knopp Biosciences. Dr. Alexis consults for AbbVie, serves on advisory boards for Jansen and Eli Lilli, and is a member of Pfizer’s advisory board and speaker’s bureau. Dr. Johnson, Dr. Windom, and Dr. Hemler report no relevant financial relationships.

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

Considered fringe just a few years ago, oral immunotherapy (OIT) has entered mainstream conversation about treating food allergies – particularly in younger children.

The buzz surrounding OIT – which involves ingesting daily doses of the culprit food to raise the threshold that would trigger a reaction – grew with the approval, by the U.S. Food and Drug Administration of Palforzia, of the peanut OIT pill in January 2020. Yet many allergists remained wary about the treatment, a monthslong regimen that can itself trigger allergic reactions.

Now, accumulating research points to “a possible window of opportunity early in life, less than 3 years of age, for more successful disease remission,” Justin Schwartz, MD, PhD, an allergist at Cincinnati Children’s Hospital, told a crowd at the annual meeting of the American Academy of Allergy, Asthma, & Immunology.

His presentation about OIT in toddlers kicked off a 3-hour clinical practice course, one of several dozen conference offerings highlighting this emerging approach.

Several AAAAI posters add to prior studies (for example, DEVIL and IMPACT) suggesting that OIT proceeds more smoothly and faster during a child’s earliest years – a season fraught with accidental exposures and reactions.

One poster described a retrospective study of 73 children younger than 4 years who underwent OIT at the Cleveland Clinic Food Allergy Center. Sixty-four were treated for peanut allergies, and seven patients received OIT for multiple foods, including tree nuts, milk, wheat, and sesame.

Of the 80 total OIT courses, 76 (95%) reached maintenance – meaning the child tolerated a small amount (for example, 1-2 peanuts) without reacting – in a median of 104 days (~3.4 months).

That is “quite impressive,” said allergist Hugh Windom, MD, whose clinic in Sarasota, Fla., has offered OIT since 2012.

Older children typically have 80%-90% success and take longer (6-8 months) to reach maintenance because of busier schedules and reactions that slow them down, he said. In his clinic’s larger retrospective analysis of preschool-aged OIT patients, presented at the 2022 AAAAI meeting, 89% of patients with peanut allergies and 72% of children with multiple food allergies achieved maintenance.

In the Cleveland Clinic study, children with favorable lab test results after receiving the maintenance dose for 6 months were offered an oral food challenge. Of 24 patients who completed the challenge, 75% “passed with a normal serving size of the treated food (for example, two tablespoons of peanut butter),” Sarah Johnson, MD, lead author and Cleveland Clinic allergy/immunology fellow, said in an interview.

Plus, OIT seemed safer for toddlers. Although 41% of the children had reactions during clinic updosing and 48% had reactions at home, only ~3% of toddler OIT courses required epinephrine. By comparison, ~11% of treatments required epinephrine in a large OIT study of older children.

When a child reacts, “you might keep them on the dose or go a little slower,” said Johnson, who worked with allergist Jaclyn Bjelac, MD, on the study. These setbacks occurred less frequently in toddlers, allowing their OIT to “go a lot faster” than in older children. And so far, Dr. Johnson said, none of the toddlers have shown signs of eosinophilic esophagitis, a rare complication that can develop during OIT.

A smaller analysis of real-world outcomes in an academic clinical setting also found that OIT was well tolerated at very young ages. Since 2020, this ongoing study at UVA Children’s Hospital in Charlottesville has enrolled 22 peanut-allergic children (aged 6 months to 3 years) for OIT. Three patients have dropped out, four are in the buildup phrase, and 15 have reached maintenance dosing. None have reported having to use epinephrine.

Three patients have completed 1 year of maintenance therapy, and another patient accidentally consumed ~3,000 mg of peanut protein (equivalent to ~10 peanuts) after 5 months of maintenance. All four “now incorporate peanut into their diets ad lib,” according to lead author and allergist Jonathan Hemler, MD, who directs the UVA pediatric food allergy program.

These findings are “really reassuring – because even if you may not offer OIT, you’re still going to get questions about it,” said Ama Alexis, MD, an allergist/immunologist in private practice in New York and a clinical assistant professor at NYU Grossmann School of Medicine, commenting on the Cleveland Clinic study.

“It’s great that we’re hearing and seeing so much about OIT,” she added. While training as an allergy/immunology fellow 15 years ago, many saw the treatment as dangerous – “an absolute no-no,” she said.

The AAAAI still considers OIT “investigational,” yet this year’s annual meeting featured 22 posters – plus a course, workshop, seminar, and oral abstract session – on the approach.

The “thought process has shifted,” Dr. Alexis said. “It’s good to see all these numbers, these results. I think once you’re comfortable, you should embrace new therapies.”

Dr. Schwartz has consulted for Shire/Takeda and has received research funding from Knopp Biosciences. Dr. Alexis consults for AbbVie, serves on advisory boards for Jansen and Eli Lilli, and is a member of Pfizer’s advisory board and speaker’s bureau. Dr. Johnson, Dr. Windom, and Dr. Hemler report no relevant financial relationships.

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

Considered fringe just a few years ago, oral immunotherapy (OIT) has entered mainstream conversation about treating food allergies – particularly in younger children.

The buzz surrounding OIT – which involves ingesting daily doses of the culprit food to raise the threshold that would trigger a reaction – grew with the approval, by the U.S. Food and Drug Administration of Palforzia, of the peanut OIT pill in January 2020. Yet many allergists remained wary about the treatment, a monthslong regimen that can itself trigger allergic reactions.

Now, accumulating research points to “a possible window of opportunity early in life, less than 3 years of age, for more successful disease remission,” Justin Schwartz, MD, PhD, an allergist at Cincinnati Children’s Hospital, told a crowd at the annual meeting of the American Academy of Allergy, Asthma, & Immunology.

His presentation about OIT in toddlers kicked off a 3-hour clinical practice course, one of several dozen conference offerings highlighting this emerging approach.

Several AAAAI posters add to prior studies (for example, DEVIL and IMPACT) suggesting that OIT proceeds more smoothly and faster during a child’s earliest years – a season fraught with accidental exposures and reactions.

One poster described a retrospective study of 73 children younger than 4 years who underwent OIT at the Cleveland Clinic Food Allergy Center. Sixty-four were treated for peanut allergies, and seven patients received OIT for multiple foods, including tree nuts, milk, wheat, and sesame.

Of the 80 total OIT courses, 76 (95%) reached maintenance – meaning the child tolerated a small amount (for example, 1-2 peanuts) without reacting – in a median of 104 days (~3.4 months).

That is “quite impressive,” said allergist Hugh Windom, MD, whose clinic in Sarasota, Fla., has offered OIT since 2012.

Older children typically have 80%-90% success and take longer (6-8 months) to reach maintenance because of busier schedules and reactions that slow them down, he said. In his clinic’s larger retrospective analysis of preschool-aged OIT patients, presented at the 2022 AAAAI meeting, 89% of patients with peanut allergies and 72% of children with multiple food allergies achieved maintenance.

In the Cleveland Clinic study, children with favorable lab test results after receiving the maintenance dose for 6 months were offered an oral food challenge. Of 24 patients who completed the challenge, 75% “passed with a normal serving size of the treated food (for example, two tablespoons of peanut butter),” Sarah Johnson, MD, lead author and Cleveland Clinic allergy/immunology fellow, said in an interview.

Plus, OIT seemed safer for toddlers. Although 41% of the children had reactions during clinic updosing and 48% had reactions at home, only ~3% of toddler OIT courses required epinephrine. By comparison, ~11% of treatments required epinephrine in a large OIT study of older children.

When a child reacts, “you might keep them on the dose or go a little slower,” said Johnson, who worked with allergist Jaclyn Bjelac, MD, on the study. These setbacks occurred less frequently in toddlers, allowing their OIT to “go a lot faster” than in older children. And so far, Dr. Johnson said, none of the toddlers have shown signs of eosinophilic esophagitis, a rare complication that can develop during OIT.

A smaller analysis of real-world outcomes in an academic clinical setting also found that OIT was well tolerated at very young ages. Since 2020, this ongoing study at UVA Children’s Hospital in Charlottesville has enrolled 22 peanut-allergic children (aged 6 months to 3 years) for OIT. Three patients have dropped out, four are in the buildup phrase, and 15 have reached maintenance dosing. None have reported having to use epinephrine.

Three patients have completed 1 year of maintenance therapy, and another patient accidentally consumed ~3,000 mg of peanut protein (equivalent to ~10 peanuts) after 5 months of maintenance. All four “now incorporate peanut into their diets ad lib,” according to lead author and allergist Jonathan Hemler, MD, who directs the UVA pediatric food allergy program.

These findings are “really reassuring – because even if you may not offer OIT, you’re still going to get questions about it,” said Ama Alexis, MD, an allergist/immunologist in private practice in New York and a clinical assistant professor at NYU Grossmann School of Medicine, commenting on the Cleveland Clinic study.

“It’s great that we’re hearing and seeing so much about OIT,” she added. While training as an allergy/immunology fellow 15 years ago, many saw the treatment as dangerous – “an absolute no-no,” she said.

The AAAAI still considers OIT “investigational,” yet this year’s annual meeting featured 22 posters – plus a course, workshop, seminar, and oral abstract session – on the approach.

The “thought process has shifted,” Dr. Alexis said. “It’s good to see all these numbers, these results. I think once you’re comfortable, you should embrace new therapies.”

Dr. Schwartz has consulted for Shire/Takeda and has received research funding from Knopp Biosciences. Dr. Alexis consults for AbbVie, serves on advisory boards for Jansen and Eli Lilli, and is a member of Pfizer’s advisory board and speaker’s bureau. Dr. Johnson, Dr. Windom, and Dr. Hemler report no relevant financial relationships.

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

SAN FRANCISCO – For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a gonadotropin-releasing hormone (GnRH) agonist with salvage radiation therapy (SRT), as established by the GETUG-AFU 16 trial.

A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.

This approach did not provide a significant improvement in progression-free survival (PFS) or metastasis-free survival (MFS) in the overall study population.

However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.

“Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival,” said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston, and professor of radiation oncology at Harvard Medical School.

“This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a preplanned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival,” he said. “Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy.”

The study results were presented at the ASCO Genitourinary Cancers Symposium.
 

Benefit in subset

The FORMULA-509 trial included 305 patients with PSA ≥ 0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative margins, persistent PSA, gross local/regional disease).

“This was a pretty high-risk population,” Dr. Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.

All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1,000 mg/5 mg + apalutamide 240 mg daily.

At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs. 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs. 87.2%, respectively (HR, 0.57; P = .05).

In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs. 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs. 66.1% (HR, 0.32; P = .02).

Adverse events were consistent with the known safety profiles of the agents being studied, Dr. Nguyen noted. The most common toxicities for AAP-apalutamide vs. controls were hypertension (21.8% vs. 13.3%), maculopapular rash (11.5% vs. 0.6%), diarrhea (8.5% vs. 4.8%), and fatigue (7.9% vs. 6.1%).

Dr. Nguyen noted that even though “we’re not supposed to compare clinical trials,” the results of this study appeared to compare favorably with those of another trial, RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.

However, Dr. Nguyen emphasized that it would have to be formally tested, to see if “FORMULA-509 is performing in the ballpark of what 24 months of ADT would do.

“And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark,” he said. “So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months.”

He added that this concept would be formally tested in the upcoming PROSTATE IQ study.
 

Strong evidence, standardization needed

In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, said that “escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1,500 men with 10 years of  follow-up and a clear statistically significant result.

“Intensification for 6 months is a very compelling concept, as most patients are not getting 2 years of androgen deprivation therapy at this point post prostatectomy,” he continued. “While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide.”

Another expert weighed in on the data. Approached by this news organization for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, and president of the American Society of Radiation Oncology, noted a few issues in the study.

He said that standards had changed since this study was first approved and had begun accrual several years ago. “In context of today’s era, the current standard is to do a PET scan if patients have a chemical failure after surgery,” he said. “The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level.”

Dr. Michalski also pointed out the number of patients getting radiation was less than the number who had node-positive disease. “This shows that patients had received suboptimal therapy late in the disease,” he said.

Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. “A recent study of almost 1,800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation,” he said. “Because it wasn’t mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit.”

The reasons for not giving pelvic radiation to these men is unclear. “Treatment was left at the discretion of the physician and this could create bias,” Dr. Michalski said. “It could drive one arm more than another.”

The study also wasn’t controlled for pelvic radiation. “Most of the nodal positive patients received it, but the other patients were undertreated,” he noted.

Dr. Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.

The trial was supported by Janssen Oncology. Dr. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Dr. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.

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

SAN FRANCISCO – For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a gonadotropin-releasing hormone (GnRH) agonist with salvage radiation therapy (SRT), as established by the GETUG-AFU 16 trial.

A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.

This approach did not provide a significant improvement in progression-free survival (PFS) or metastasis-free survival (MFS) in the overall study population.

However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.

“Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival,” said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston, and professor of radiation oncology at Harvard Medical School.

“This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a preplanned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival,” he said. “Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy.”

The study results were presented at the ASCO Genitourinary Cancers Symposium.
 

Benefit in subset

The FORMULA-509 trial included 305 patients with PSA ≥ 0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative margins, persistent PSA, gross local/regional disease).

“This was a pretty high-risk population,” Dr. Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.

All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1,000 mg/5 mg + apalutamide 240 mg daily.

At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs. 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs. 87.2%, respectively (HR, 0.57; P = .05).

In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs. 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs. 66.1% (HR, 0.32; P = .02).

Adverse events were consistent with the known safety profiles of the agents being studied, Dr. Nguyen noted. The most common toxicities for AAP-apalutamide vs. controls were hypertension (21.8% vs. 13.3%), maculopapular rash (11.5% vs. 0.6%), diarrhea (8.5% vs. 4.8%), and fatigue (7.9% vs. 6.1%).

Dr. Nguyen noted that even though “we’re not supposed to compare clinical trials,” the results of this study appeared to compare favorably with those of another trial, RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.

However, Dr. Nguyen emphasized that it would have to be formally tested, to see if “FORMULA-509 is performing in the ballpark of what 24 months of ADT would do.

“And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark,” he said. “So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months.”

He added that this concept would be formally tested in the upcoming PROSTATE IQ study.
 

Strong evidence, standardization needed

In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, said that “escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1,500 men with 10 years of  follow-up and a clear statistically significant result.

“Intensification for 6 months is a very compelling concept, as most patients are not getting 2 years of androgen deprivation therapy at this point post prostatectomy,” he continued. “While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide.”

Another expert weighed in on the data. Approached by this news organization for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, and president of the American Society of Radiation Oncology, noted a few issues in the study.

He said that standards had changed since this study was first approved and had begun accrual several years ago. “In context of today’s era, the current standard is to do a PET scan if patients have a chemical failure after surgery,” he said. “The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level.”

Dr. Michalski also pointed out the number of patients getting radiation was less than the number who had node-positive disease. “This shows that patients had received suboptimal therapy late in the disease,” he said.

Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. “A recent study of almost 1,800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation,” he said. “Because it wasn’t mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit.”

The reasons for not giving pelvic radiation to these men is unclear. “Treatment was left at the discretion of the physician and this could create bias,” Dr. Michalski said. “It could drive one arm more than another.”

The study also wasn’t controlled for pelvic radiation. “Most of the nodal positive patients received it, but the other patients were undertreated,” he noted.

Dr. Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.

The trial was supported by Janssen Oncology. Dr. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Dr. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.

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

SAN FRANCISCO – For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a gonadotropin-releasing hormone (GnRH) agonist with salvage radiation therapy (SRT), as established by the GETUG-AFU 16 trial.

A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.

This approach did not provide a significant improvement in progression-free survival (PFS) or metastasis-free survival (MFS) in the overall study population.

However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.

“Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival,” said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston, and professor of radiation oncology at Harvard Medical School.

“This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a preplanned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival,” he said. “Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy.”

The study results were presented at the ASCO Genitourinary Cancers Symposium.
 

Benefit in subset

The FORMULA-509 trial included 305 patients with PSA ≥ 0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative margins, persistent PSA, gross local/regional disease).

“This was a pretty high-risk population,” Dr. Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.

All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1,000 mg/5 mg + apalutamide 240 mg daily.

At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs. 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs. 87.2%, respectively (HR, 0.57; P = .05).

In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs. 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs. 66.1% (HR, 0.32; P = .02).

Adverse events were consistent with the known safety profiles of the agents being studied, Dr. Nguyen noted. The most common toxicities for AAP-apalutamide vs. controls were hypertension (21.8% vs. 13.3%), maculopapular rash (11.5% vs. 0.6%), diarrhea (8.5% vs. 4.8%), and fatigue (7.9% vs. 6.1%).

Dr. Nguyen noted that even though “we’re not supposed to compare clinical trials,” the results of this study appeared to compare favorably with those of another trial, RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.

However, Dr. Nguyen emphasized that it would have to be formally tested, to see if “FORMULA-509 is performing in the ballpark of what 24 months of ADT would do.

“And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark,” he said. “So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months.”

He added that this concept would be formally tested in the upcoming PROSTATE IQ study.
 

Strong evidence, standardization needed

In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, said that “escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1,500 men with 10 years of  follow-up and a clear statistically significant result.

“Intensification for 6 months is a very compelling concept, as most patients are not getting 2 years of androgen deprivation therapy at this point post prostatectomy,” he continued. “While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide.”

Another expert weighed in on the data. Approached by this news organization for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, and president of the American Society of Radiation Oncology, noted a few issues in the study.

He said that standards had changed since this study was first approved and had begun accrual several years ago. “In context of today’s era, the current standard is to do a PET scan if patients have a chemical failure after surgery,” he said. “The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level.”

Dr. Michalski also pointed out the number of patients getting radiation was less than the number who had node-positive disease. “This shows that patients had received suboptimal therapy late in the disease,” he said.

Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. “A recent study of almost 1,800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation,” he said. “Because it wasn’t mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit.”

The reasons for not giving pelvic radiation to these men is unclear. “Treatment was left at the discretion of the physician and this could create bias,” Dr. Michalski said. “It could drive one arm more than another.”

The study also wasn’t controlled for pelvic radiation. “Most of the nodal positive patients received it, but the other patients were undertreated,” he noted.

Dr. Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.

The trial was supported by Janssen Oncology. Dr. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Dr. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.

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

HONOLULU – Nearly every day, Candrice R. Heath, MD, spends time during office visits dispelling myths about hair care practices in patients with skin of color. One myth is the idea that not washing hair helps it to grow.

“This is false,” Dr. Heath, director of pediatric dermatology at Temple University, Philadelphia, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! With little manipulation, length may be retained, since tightly coiled hair has a higher likelihood of breakage, she said. “But washing the scalp and hair is recommended for tightly coiled hair weekly or every other week. Exclusively co-washing – a technique where hair conditioner is used instead of shampooing – is also not advised due to scalp build-up.”

JGI/Jamie Grill/Getty Images

Other myths she addressed include the following:

“I have a weak spot (or stress spot) on the top of my scalp.” These terms may be used to describe hair on a spot that goes through cycles of breaking off and re-growing. This is false. “If someone were to say that, and we see short hairs on the top of a patient’s scalp, with or without tenderness, pruritus, or pain, we want to recognize that as possibly an early sign of central centrifugal cicatricial alopecia [CCCA],” she said. “We want to pick up cases of CCCA forme fruste [central hair breakage] early.”

Medicated shampoos are helpful for all patients with seborrheic dermatitis. This notion is more complicated. “In theory, medicated shampoos like ketoconazole should be helpful, but if the shampoos are too drying for the hair and they cause further hair breakage, that’s going to be a problem as well,” explained Dr. Heath, who was the senior author of an article on how to address common conditions affecting pediatric and adolescent patients with skin of color. For patients with tightly coiled hair, she recommends applying antifungal shampoos to the scalp only, waiting 5-10 minutes, rinsing, and shampooing the scalp and hair with a moisturizing shampoo and rinsing. They can then condition with a moisturizing conditioner and style their hair as desired.

HONOLULU – Nearly every day, Candrice R. Heath, MD, spends time during office visits dispelling myths about hair care practices in patients with skin of color. One myth is the idea that not washing hair helps it to grow.

“This is false,” Dr. Heath, director of pediatric dermatology at Temple University, Philadelphia, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! With little manipulation, length may be retained, since tightly coiled hair has a higher likelihood of breakage, she said. “But washing the scalp and hair is recommended for tightly coiled hair weekly or every other week. Exclusively co-washing – a technique where hair conditioner is used instead of shampooing – is also not advised due to scalp build-up.”

JGI/Jamie Grill/Getty Images

Other myths she addressed include the following:

“I have a weak spot (or stress spot) on the top of my scalp.” These terms may be used to describe hair on a spot that goes through cycles of breaking off and re-growing. This is false. “If someone were to say that, and we see short hairs on the top of a patient’s scalp, with or without tenderness, pruritus, or pain, we want to recognize that as possibly an early sign of central centrifugal cicatricial alopecia [CCCA],” she said. “We want to pick up cases of CCCA forme fruste [central hair breakage] early.”

Medicated shampoos are helpful for all patients with seborrheic dermatitis. This notion is more complicated. “In theory, medicated shampoos like ketoconazole should be helpful, but if the shampoos are too drying for the hair and they cause further hair breakage, that’s going to be a problem as well,” explained Dr. Heath, who was the senior author of an article on how to address common conditions affecting pediatric and adolescent patients with skin of color. For patients with tightly coiled hair, she recommends applying antifungal shampoos to the scalp only, waiting 5-10 minutes, rinsing, and shampooing the scalp and hair with a moisturizing shampoo and rinsing. They can then condition with a moisturizing conditioner and style their hair as desired.

HONOLULU – Nearly every day, Candrice R. Heath, MD, spends time during office visits dispelling myths about hair care practices in patients with skin of color. One myth is the idea that not washing hair helps it to grow.

“This is false,” Dr. Heath, director of pediatric dermatology at Temple University, Philadelphia, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! With little manipulation, length may be retained, since tightly coiled hair has a higher likelihood of breakage, she said. “But washing the scalp and hair is recommended for tightly coiled hair weekly or every other week. Exclusively co-washing – a technique where hair conditioner is used instead of shampooing – is also not advised due to scalp build-up.”

JGI/Jamie Grill/Getty Images

Other myths she addressed include the following:

“I have a weak spot (or stress spot) on the top of my scalp.” These terms may be used to describe hair on a spot that goes through cycles of breaking off and re-growing. This is false. “If someone were to say that, and we see short hairs on the top of a patient’s scalp, with or without tenderness, pruritus, or pain, we want to recognize that as possibly an early sign of central centrifugal cicatricial alopecia [CCCA],” she said. “We want to pick up cases of CCCA forme fruste [central hair breakage] early.”

Medicated shampoos are helpful for all patients with seborrheic dermatitis. This notion is more complicated. “In theory, medicated shampoos like ketoconazole should be helpful, but if the shampoos are too drying for the hair and they cause further hair breakage, that’s going to be a problem as well,” explained Dr. Heath, who was the senior author of an article on how to address common conditions affecting pediatric and adolescent patients with skin of color. For patients with tightly coiled hair, she recommends applying antifungal shampoos to the scalp only, waiting 5-10 minutes, rinsing, and shampooing the scalp and hair with a moisturizing shampoo and rinsing. They can then condition with a moisturizing conditioner and style their hair as desired.