Kate Johnson

MONTREAL – A 66-year-old U.S. man has become the world’s fourth known HIV patient to show complete clearance of the virus after being treated for acute myelogenous leukemia with an allogeneic hematopoietic stem cell transplantation from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.

The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.

Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.

She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.

Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.

“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”

“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.

“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.

Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.

The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.

Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.

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

MONTREAL – A 66-year-old U.S. man has become the world’s fourth known HIV patient to show complete clearance of the virus after being treated for acute myelogenous leukemia with an allogeneic hematopoietic stem cell transplantation from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.

The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.

Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.

She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.

Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.

“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”

“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.

“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.

Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.

The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.

Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.

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

MONTREAL – A 66-year-old U.S. man has become the world’s fourth known HIV patient to show complete clearance of the virus after being treated for acute myelogenous leukemia with an allogeneic hematopoietic stem cell transplantation from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.

The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.

Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.

She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.

Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.

“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”

“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.

“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.

Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.

The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.

Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.

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

Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.

Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.

“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”

The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.

Dr. Grupp said that he is, at last, starting to use the “cure” word.

“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’

“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
 

First patient with ALL

Emily was the first patient with ALL to receive the novel treatment, and also the first child.

There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.

But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.

But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”

Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.

Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
 

The ‘magic formula’

CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.

Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.

“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.

Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.

“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
 

Cytokine storm

The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.

The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.

But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.

“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.

“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”

“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
 

On the fly

It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”

They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.

“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.

“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”

Emily woke up from a 14-day medically induced coma on her seventh birthday.

Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.

She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
 

Talking about ‘cure’

Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.

Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.

“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].

“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
 

Hearing whispers

Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.

As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”

Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.

Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
 

Enduring effect

The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.

“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”

While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.

“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.

“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”

As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.

Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.

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

Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.

Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.

“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”

The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.

Dr. Grupp said that he is, at last, starting to use the “cure” word.

“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’

“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
 

First patient with ALL

Emily was the first patient with ALL to receive the novel treatment, and also the first child.

There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.

But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.

But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”

Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.

Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
 

The ‘magic formula’

CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.

Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.

“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.

Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.

“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
 

Cytokine storm

The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.

The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.

But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.

“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.

“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”

“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
 

On the fly

It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”

They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.

“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.

“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”

Emily woke up from a 14-day medically induced coma on her seventh birthday.

Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.

She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
 

Talking about ‘cure’

Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.

Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.

“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].

“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
 

Hearing whispers

Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.

As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”

Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.

Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
 

Enduring effect

The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.

“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”

While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.

“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.

“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”

As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.

Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.

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

Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.

Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.

“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”

The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.

Dr. Grupp said that he is, at last, starting to use the “cure” word.

“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’

“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
 

First patient with ALL

Emily was the first patient with ALL to receive the novel treatment, and also the first child.

There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.

But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.

But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”

Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.

Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
 

The ‘magic formula’

CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.

Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.

“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.

Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.

“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
 

Cytokine storm

The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.

The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.

But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.

“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.

“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”

“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
 

On the fly

It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”

They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.

“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.

“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”

Emily woke up from a 14-day medically induced coma on her seventh birthday.

Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.

She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
 

Talking about ‘cure’

Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.

Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.

“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].

“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
 

Hearing whispers

Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.

As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”

Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.

Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
 

Enduring effect

The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.

“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”

While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.

“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.

“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”

As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.

Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.

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

An open-label extension of Biogen’s phase 3 VALOR study shows statistically significant benefits for the company’s novel antisense oligonucleotide (ASO), tofersen, in patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations.

The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.

“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”

Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
 

One-year VALOR study results

The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.

For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.

There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.

“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”

Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.

Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).

Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).

Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
 

The bigger picture

While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.

“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
 

What lies ahead?

Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug.  I would like to be able to offer it to them.  But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.

“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”

Dr. Miller added that these results “highlight how difficult ALS drug development still is.  Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”

The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.

An open-label extension of Biogen’s phase 3 VALOR study shows statistically significant benefits for the company’s novel antisense oligonucleotide (ASO), tofersen, in patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations.

The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.

“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”

Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
 

One-year VALOR study results

The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.

For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.

There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.

“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”

Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.

Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).

Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).

Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
 

The bigger picture

While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.

“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
 

What lies ahead?

Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug.  I would like to be able to offer it to them.  But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.

“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”

Dr. Miller added that these results “highlight how difficult ALS drug development still is.  Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”

The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.

An open-label extension of Biogen’s phase 3 VALOR study shows statistically significant benefits for the company’s novel antisense oligonucleotide (ASO), tofersen, in patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations.

The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.

“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”

Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
 

One-year VALOR study results

The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.

For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.

There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.

“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”

Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.

Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).

Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).

Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
 

The bigger picture

While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.

“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
 

What lies ahead?

Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug.  I would like to be able to offer it to them.  But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.

“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”

Dr. Miller added that these results “highlight how difficult ALS drug development still is.  Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”

The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.

People who are not vaccinated against a respiratory virus such as SARS-CoV-2 present a disproportionate infectious risk to those who are vaccinated, according to a mathematical modeling study.

The study, which simulated patterns of infection among vaccinated and unvaccinated populations, showed that, as the populations mixed less, attack rates decreased among vaccinated people (from 15% to 10%) and increased among unvaccinated people (from 62% to 79%). The unvaccinated increasingly became the source of infection, however.

“When the vaccinated and unvaccinated mix, indirect protection is conferred upon the unvaccinated by the buffering effect of vaccinated individuals, and by contrast, risk in the vaccinated goes up,” lead author David Fisman, MD, professor of epidemiology at the University of Toronto, told this news organization.

As the groups mix less and less, the size of the epidemic increases among the unvaccinated and decreases among the vaccinated. “But the impact of the unvaccinated on risk in the vaccinated is disproportionate to the numbers of contacts between the two groups,” said Dr. Fisman.

The study was published online in the Canadian Medical Association Journal.


 

Relative contributions to risk

The researchers used a model of a respiratory viral disease “similar to SARS-CoV-2 infection with Delta variant.” They included reproduction values to capture the dynamics of the Omicron variant, which was emerging at the time. In the study, vaccines ranged in effectiveness from 40% to 80%. The study incorporated various levels of mixing between a partially vaccinated and an unvaccinated population. The mixing ranged from random mixing to like-with-like mixing (“assortativity”). There were three possible “compartments” of people in the model: those considered susceptible to infection, those considered infected and infectious, and those considered immune because of recovery.

The model showed that, as mixing between the vaccinated and the unvaccinated populations increased, case numbers rose, “with cases in the unvaccinated subpopulation accounting for a substantial proportion of infections.” However, as mixing between the populations decreased, the final attack rate decreased among vaccinated people, but the relative “contribution of risk to vaccinated people caused by infection acquired from contact with unvaccinated people ... increased.”

When the vaccination rate was increased in the model, case numbers among the vaccinated declined “as expected, owing to indirect protective effects,” the researchers noted. But this also “further increased the relative contribution to risk in vaccinated people by those who were unvaccinated.”
 

Self-regarding risk?

The findings show that “choices made by people who forgo vaccination contribute disproportionately to risk among those who do get vaccinated,” the researchers wrote. “Although risk associated with avoiding vaccination during a virulent pandemic accrues chiefly to those who are unvaccinated, the choice of some individuals to refuse vaccination is likely to affect the health and safety of vaccinated people in a manner disproportionate to the fraction of unvaccinated people in the population.”

The fact that like-with-like mixing cannot mitigate the risk to vaccinated people “undermines the assertion that vaccine choice is best left to the individual and supports strong public actions aimed at enhancing vaccine uptake and limiting access to public spaces for unvaccinated people,” they wrote.
 

Mandates and passports

“Our model provides support for vaccine mandates and passports during epidemics, such that vaccination is required for people to take part in nonessential activities,” said Dr. Fisman. The choice to not be vaccinated against COVID-19 should not be considered “self-regarding,” he added. “Risk is self-regarding when it only impacts the person engaging in the activity. Something like smoking cigarettes (alone, without others around) creates a lot of risk over time, but if nobody is breathing your secondhand smoke, you’re only creating risk for yourself. By contrast, we regulate, in Ontario, your right to smoke in public indoor spaces such as restaurants, because once other people are around, the risk isn’t self-regarding anymore. You’re creating risk for others.”

The authors also noted that the risks created by the unvaccinated extend beyond those of infection by “creating a risk that those around them may not be able to obtain the care they need.” They recommended that considerations of equity and justice for people who do choose to be vaccinated, as well as those who choose not to be, need to be included in formulating vaccination policy.
 

Illuminating the discussion

Asked to comment on the study, Matthew Oughton, MD, assistant professor of medicine at McGill University, Montreal, said: “It is easy to dismiss a mathematical model as a series of assumptions that leads to an implausible conclusion. ... However, they can serve to illustrate and, to an extent, quantify the results of complex interactions, and this study does just that.” Dr. Oughton was not involved in the research.

During the past 2 years, the scientific press and the general press have often discussed the individual and collective effects of disease-prevention methods, including nonpharmaceutical interventions. “Models like this can help illuminate those discussions by highlighting important consequences of preventive measures,” said Dr. Oughton, who also works in the division of infectious diseases at the Jewish General Hospital, Montreal.

It’s worth noting that the authors modeled vaccine effectiveness against all infection, “rather than the generally greater and more durable effects we have seen for vaccines in prevention of severe infection,” said Dr. Oughton. He added that the authors did not include the effect of vaccination in reducing forward transmission. “Inclusion of this effect would presumably have reduced overall infectious burden in mixed populations and increased the difference between groups at lower levels of mixing between populations.”

The research was supported by a grant from the Canadian Institutes of Health Research. Dr. Fisman has served on advisory boards related to influenza and SARS-CoV-2 vaccines for Seqirus, Pfizer, AstraZeneca, and Sanofi-Pasteur Vaccines and has served as a legal expert on issues related to COVID-19 epidemiology for the Elementary Teachers Federation of Ontario and the Registered Nurses Association of Ontario. Dr. Oughton disclosed no relevant financial relationships.

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

People who are not vaccinated against a respiratory virus such as SARS-CoV-2 present a disproportionate infectious risk to those who are vaccinated, according to a mathematical modeling study.

The study, which simulated patterns of infection among vaccinated and unvaccinated populations, showed that, as the populations mixed less, attack rates decreased among vaccinated people (from 15% to 10%) and increased among unvaccinated people (from 62% to 79%). The unvaccinated increasingly became the source of infection, however.

“When the vaccinated and unvaccinated mix, indirect protection is conferred upon the unvaccinated by the buffering effect of vaccinated individuals, and by contrast, risk in the vaccinated goes up,” lead author David Fisman, MD, professor of epidemiology at the University of Toronto, told this news organization.

As the groups mix less and less, the size of the epidemic increases among the unvaccinated and decreases among the vaccinated. “But the impact of the unvaccinated on risk in the vaccinated is disproportionate to the numbers of contacts between the two groups,” said Dr. Fisman.

The study was published online in the Canadian Medical Association Journal.


 

Relative contributions to risk

The researchers used a model of a respiratory viral disease “similar to SARS-CoV-2 infection with Delta variant.” They included reproduction values to capture the dynamics of the Omicron variant, which was emerging at the time. In the study, vaccines ranged in effectiveness from 40% to 80%. The study incorporated various levels of mixing between a partially vaccinated and an unvaccinated population. The mixing ranged from random mixing to like-with-like mixing (“assortativity”). There were three possible “compartments” of people in the model: those considered susceptible to infection, those considered infected and infectious, and those considered immune because of recovery.

The model showed that, as mixing between the vaccinated and the unvaccinated populations increased, case numbers rose, “with cases in the unvaccinated subpopulation accounting for a substantial proportion of infections.” However, as mixing between the populations decreased, the final attack rate decreased among vaccinated people, but the relative “contribution of risk to vaccinated people caused by infection acquired from contact with unvaccinated people ... increased.”

When the vaccination rate was increased in the model, case numbers among the vaccinated declined “as expected, owing to indirect protective effects,” the researchers noted. But this also “further increased the relative contribution to risk in vaccinated people by those who were unvaccinated.”
 

Self-regarding risk?

The findings show that “choices made by people who forgo vaccination contribute disproportionately to risk among those who do get vaccinated,” the researchers wrote. “Although risk associated with avoiding vaccination during a virulent pandemic accrues chiefly to those who are unvaccinated, the choice of some individuals to refuse vaccination is likely to affect the health and safety of vaccinated people in a manner disproportionate to the fraction of unvaccinated people in the population.”

The fact that like-with-like mixing cannot mitigate the risk to vaccinated people “undermines the assertion that vaccine choice is best left to the individual and supports strong public actions aimed at enhancing vaccine uptake and limiting access to public spaces for unvaccinated people,” they wrote.
 

Mandates and passports

“Our model provides support for vaccine mandates and passports during epidemics, such that vaccination is required for people to take part in nonessential activities,” said Dr. Fisman. The choice to not be vaccinated against COVID-19 should not be considered “self-regarding,” he added. “Risk is self-regarding when it only impacts the person engaging in the activity. Something like smoking cigarettes (alone, without others around) creates a lot of risk over time, but if nobody is breathing your secondhand smoke, you’re only creating risk for yourself. By contrast, we regulate, in Ontario, your right to smoke in public indoor spaces such as restaurants, because once other people are around, the risk isn’t self-regarding anymore. You’re creating risk for others.”

The authors also noted that the risks created by the unvaccinated extend beyond those of infection by “creating a risk that those around them may not be able to obtain the care they need.” They recommended that considerations of equity and justice for people who do choose to be vaccinated, as well as those who choose not to be, need to be included in formulating vaccination policy.
 

Illuminating the discussion

Asked to comment on the study, Matthew Oughton, MD, assistant professor of medicine at McGill University, Montreal, said: “It is easy to dismiss a mathematical model as a series of assumptions that leads to an implausible conclusion. ... However, they can serve to illustrate and, to an extent, quantify the results of complex interactions, and this study does just that.” Dr. Oughton was not involved in the research.

During the past 2 years, the scientific press and the general press have often discussed the individual and collective effects of disease-prevention methods, including nonpharmaceutical interventions. “Models like this can help illuminate those discussions by highlighting important consequences of preventive measures,” said Dr. Oughton, who also works in the division of infectious diseases at the Jewish General Hospital, Montreal.

It’s worth noting that the authors modeled vaccine effectiveness against all infection, “rather than the generally greater and more durable effects we have seen for vaccines in prevention of severe infection,” said Dr. Oughton. He added that the authors did not include the effect of vaccination in reducing forward transmission. “Inclusion of this effect would presumably have reduced overall infectious burden in mixed populations and increased the difference between groups at lower levels of mixing between populations.”

The research was supported by a grant from the Canadian Institutes of Health Research. Dr. Fisman has served on advisory boards related to influenza and SARS-CoV-2 vaccines for Seqirus, Pfizer, AstraZeneca, and Sanofi-Pasteur Vaccines and has served as a legal expert on issues related to COVID-19 epidemiology for the Elementary Teachers Federation of Ontario and the Registered Nurses Association of Ontario. Dr. Oughton disclosed no relevant financial relationships.

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

People who are not vaccinated against a respiratory virus such as SARS-CoV-2 present a disproportionate infectious risk to those who are vaccinated, according to a mathematical modeling study.

The study, which simulated patterns of infection among vaccinated and unvaccinated populations, showed that, as the populations mixed less, attack rates decreased among vaccinated people (from 15% to 10%) and increased among unvaccinated people (from 62% to 79%). The unvaccinated increasingly became the source of infection, however.

“When the vaccinated and unvaccinated mix, indirect protection is conferred upon the unvaccinated by the buffering effect of vaccinated individuals, and by contrast, risk in the vaccinated goes up,” lead author David Fisman, MD, professor of epidemiology at the University of Toronto, told this news organization.

As the groups mix less and less, the size of the epidemic increases among the unvaccinated and decreases among the vaccinated. “But the impact of the unvaccinated on risk in the vaccinated is disproportionate to the numbers of contacts between the two groups,” said Dr. Fisman.

The study was published online in the Canadian Medical Association Journal.


 

Relative contributions to risk

The researchers used a model of a respiratory viral disease “similar to SARS-CoV-2 infection with Delta variant.” They included reproduction values to capture the dynamics of the Omicron variant, which was emerging at the time. In the study, vaccines ranged in effectiveness from 40% to 80%. The study incorporated various levels of mixing between a partially vaccinated and an unvaccinated population. The mixing ranged from random mixing to like-with-like mixing (“assortativity”). There were three possible “compartments” of people in the model: those considered susceptible to infection, those considered infected and infectious, and those considered immune because of recovery.

The model showed that, as mixing between the vaccinated and the unvaccinated populations increased, case numbers rose, “with cases in the unvaccinated subpopulation accounting for a substantial proportion of infections.” However, as mixing between the populations decreased, the final attack rate decreased among vaccinated people, but the relative “contribution of risk to vaccinated people caused by infection acquired from contact with unvaccinated people ... increased.”

When the vaccination rate was increased in the model, case numbers among the vaccinated declined “as expected, owing to indirect protective effects,” the researchers noted. But this also “further increased the relative contribution to risk in vaccinated people by those who were unvaccinated.”
 

Self-regarding risk?

The findings show that “choices made by people who forgo vaccination contribute disproportionately to risk among those who do get vaccinated,” the researchers wrote. “Although risk associated with avoiding vaccination during a virulent pandemic accrues chiefly to those who are unvaccinated, the choice of some individuals to refuse vaccination is likely to affect the health and safety of vaccinated people in a manner disproportionate to the fraction of unvaccinated people in the population.”

The fact that like-with-like mixing cannot mitigate the risk to vaccinated people “undermines the assertion that vaccine choice is best left to the individual and supports strong public actions aimed at enhancing vaccine uptake and limiting access to public spaces for unvaccinated people,” they wrote.
 

Mandates and passports

“Our model provides support for vaccine mandates and passports during epidemics, such that vaccination is required for people to take part in nonessential activities,” said Dr. Fisman. The choice to not be vaccinated against COVID-19 should not be considered “self-regarding,” he added. “Risk is self-regarding when it only impacts the person engaging in the activity. Something like smoking cigarettes (alone, without others around) creates a lot of risk over time, but if nobody is breathing your secondhand smoke, you’re only creating risk for yourself. By contrast, we regulate, in Ontario, your right to smoke in public indoor spaces such as restaurants, because once other people are around, the risk isn’t self-regarding anymore. You’re creating risk for others.”

The authors also noted that the risks created by the unvaccinated extend beyond those of infection by “creating a risk that those around them may not be able to obtain the care they need.” They recommended that considerations of equity and justice for people who do choose to be vaccinated, as well as those who choose not to be, need to be included in formulating vaccination policy.
 

Illuminating the discussion

Asked to comment on the study, Matthew Oughton, MD, assistant professor of medicine at McGill University, Montreal, said: “It is easy to dismiss a mathematical model as a series of assumptions that leads to an implausible conclusion. ... However, they can serve to illustrate and, to an extent, quantify the results of complex interactions, and this study does just that.” Dr. Oughton was not involved in the research.

During the past 2 years, the scientific press and the general press have often discussed the individual and collective effects of disease-prevention methods, including nonpharmaceutical interventions. “Models like this can help illuminate those discussions by highlighting important consequences of preventive measures,” said Dr. Oughton, who also works in the division of infectious diseases at the Jewish General Hospital, Montreal.

It’s worth noting that the authors modeled vaccine effectiveness against all infection, “rather than the generally greater and more durable effects we have seen for vaccines in prevention of severe infection,” said Dr. Oughton. He added that the authors did not include the effect of vaccination in reducing forward transmission. “Inclusion of this effect would presumably have reduced overall infectious burden in mixed populations and increased the difference between groups at lower levels of mixing between populations.”

The research was supported by a grant from the Canadian Institutes of Health Research. Dr. Fisman has served on advisory boards related to influenza and SARS-CoV-2 vaccines for Seqirus, Pfizer, AstraZeneca, and Sanofi-Pasteur Vaccines and has served as a legal expert on issues related to COVID-19 epidemiology for the Elementary Teachers Federation of Ontario and the Registered Nurses Association of Ontario. Dr. Oughton disclosed no relevant financial relationships.

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

A combination of ulipristal acetate (UA) and a cyclo-oxygenase-2 (COX-2) inhibitor holds promise as a pericoital, “on- demand” female oral contraceptive, taken only when needed, according to an exploratory study published in BMJ Sexual & Reproductive Health.

The prospective, open-label, pilot study showed that UA and meloxicam successfully disrupted ovulation at “the peak of luteal surge, when conception risk is highest,” reported lead author Erica P Cahill, MD, of Stanford (Calif.) University, and colleagues.

“There are many people who report being interested in preventing pregnancy who are not using contraception,” Dr. Cahill said in an interview. The ideal is to be able to take a medication to prevent ovulation and know that you wouldn’t ovulate or be able to become pregnant for the next 3-5 days. These would be pericoital contraceptive pills that one could take prior to or immediately after intercourse that would expand the contraceptive options available and meet some of this need, she said.

Dr. Cahill said currently approved emergency contraceptives containing ulipristal acetate or levonorgestrel “work by inhibiting ovulation at the level of the luteal surge, the pituitary signal that starts the ovulation cascade. Because of this mechanism, they are only effective when taken prior to that signal. If they are taken near or after ovulation has occurred, they are not effective.” She said combining meloxicam with UA could address this because meloxicam “has been shown to prevent some of the later steps of ovulation just prior to the egg being released.”

The study included nine healthy women, with a mean age of 31.4 years, and a mean body mass index of 24.5 ± 3.9 kg/m². All subjects had no exposure to hormonal medication, pregnancy, or lactation in the prior 3 months.

Each participant was followed for two cycles: The first without treatment, to establish normal ovulatory function; and the second during treatment with a one-time dose of UA 30 mg and meloxicam 30 mg during the “fertile window.” This window was defined as when the lead ovarian follicle had a mean diameter of 18 mm, and was determined via thrice-weekly ultrasounds, as well as luteinizing hormone (LH) measurements.

The primary outcome of the study was ovulation disruption, defined as unruptured dominant follicle for 5 days, a blunted LH peak, defined as <15 IU/L, and a nonovulatory luteal phase progesterone level, defined as <3 ng/mL.

Ovulation disruption was achieved in six subjects (67.7%), with eight subjects (88.9%) meeting some criteria.

“When we compare ovulation disruption rates in our study with the previous studies on which our protocol is based, the combination of UA and meloxicam disrupted ovulation at each phase of the fertile window more than any other medication previously studied,” the researchers wrote. “This medication combination is an important candidate to evaluate as oral pericoital contraception.”

When comparing subjects’ baseline cycles with their treatment cycles, the latter were approximately 3 days longer, although there was no difference in endometrial stripe thickness or irregular bleeding.

“Cycle length changes are an important parameter as people interested in oral, on-demand contraception may also be using fertility awareness methods which can be affected by cycle length changes.”

The authors noted that measures of full efficacy and side effects were beyond the scope of the study and would require repeat dosing. Similarly, liver enzymes were not measured, because there was only one dose of study medication, but “given the potential impact of repeat UA on liver enzymes, this measurement is critical for future studies.”

Asked to comment on the study, Eve Espey, MD, said that although it was limited in size and the use of an “intermediate outcome” of ovulation disruption, “the combination does show some promise as a focus of future research.” However, Dr. Espey, distinguished professor and chair in the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, said it is too early to determine the significance of the findings. “But it does point the way to further research,” she noted. “Compared with existing emergency contraception, this study shows that the UA-meloxicam combination disrupts ovulation over a broader mid-cycle time period – [an] extended duration of action [that] could theoretically translate into increased effectiveness as a contraceptive.”

The study was supported by the Society for Family Planning Research Fund. None of the authors, or Dr. Espey, declared competing interests.

A combination of ulipristal acetate (UA) and a cyclo-oxygenase-2 (COX-2) inhibitor holds promise as a pericoital, “on- demand” female oral contraceptive, taken only when needed, according to an exploratory study published in BMJ Sexual & Reproductive Health.

The prospective, open-label, pilot study showed that UA and meloxicam successfully disrupted ovulation at “the peak of luteal surge, when conception risk is highest,” reported lead author Erica P Cahill, MD, of Stanford (Calif.) University, and colleagues.

“There are many people who report being interested in preventing pregnancy who are not using contraception,” Dr. Cahill said in an interview. The ideal is to be able to take a medication to prevent ovulation and know that you wouldn’t ovulate or be able to become pregnant for the next 3-5 days. These would be pericoital contraceptive pills that one could take prior to or immediately after intercourse that would expand the contraceptive options available and meet some of this need, she said.

Dr. Cahill said currently approved emergency contraceptives containing ulipristal acetate or levonorgestrel “work by inhibiting ovulation at the level of the luteal surge, the pituitary signal that starts the ovulation cascade. Because of this mechanism, they are only effective when taken prior to that signal. If they are taken near or after ovulation has occurred, they are not effective.” She said combining meloxicam with UA could address this because meloxicam “has been shown to prevent some of the later steps of ovulation just prior to the egg being released.”

The study included nine healthy women, with a mean age of 31.4 years, and a mean body mass index of 24.5 ± 3.9 kg/m². All subjects had no exposure to hormonal medication, pregnancy, or lactation in the prior 3 months.

Each participant was followed for two cycles: The first without treatment, to establish normal ovulatory function; and the second during treatment with a one-time dose of UA 30 mg and meloxicam 30 mg during the “fertile window.” This window was defined as when the lead ovarian follicle had a mean diameter of 18 mm, and was determined via thrice-weekly ultrasounds, as well as luteinizing hormone (LH) measurements.

The primary outcome of the study was ovulation disruption, defined as unruptured dominant follicle for 5 days, a blunted LH peak, defined as <15 IU/L, and a nonovulatory luteal phase progesterone level, defined as <3 ng/mL.

Ovulation disruption was achieved in six subjects (67.7%), with eight subjects (88.9%) meeting some criteria.

“When we compare ovulation disruption rates in our study with the previous studies on which our protocol is based, the combination of UA and meloxicam disrupted ovulation at each phase of the fertile window more than any other medication previously studied,” the researchers wrote. “This medication combination is an important candidate to evaluate as oral pericoital contraception.”

When comparing subjects’ baseline cycles with their treatment cycles, the latter were approximately 3 days longer, although there was no difference in endometrial stripe thickness or irregular bleeding.

“Cycle length changes are an important parameter as people interested in oral, on-demand contraception may also be using fertility awareness methods which can be affected by cycle length changes.”

The authors noted that measures of full efficacy and side effects were beyond the scope of the study and would require repeat dosing. Similarly, liver enzymes were not measured, because there was only one dose of study medication, but “given the potential impact of repeat UA on liver enzymes, this measurement is critical for future studies.”

Asked to comment on the study, Eve Espey, MD, said that although it was limited in size and the use of an “intermediate outcome” of ovulation disruption, “the combination does show some promise as a focus of future research.” However, Dr. Espey, distinguished professor and chair in the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, said it is too early to determine the significance of the findings. “But it does point the way to further research,” she noted. “Compared with existing emergency contraception, this study shows that the UA-meloxicam combination disrupts ovulation over a broader mid-cycle time period – [an] extended duration of action [that] could theoretically translate into increased effectiveness as a contraceptive.”

The study was supported by the Society for Family Planning Research Fund. None of the authors, or Dr. Espey, declared competing interests.

A combination of ulipristal acetate (UA) and a cyclo-oxygenase-2 (COX-2) inhibitor holds promise as a pericoital, “on- demand” female oral contraceptive, taken only when needed, according to an exploratory study published in BMJ Sexual & Reproductive Health.

The prospective, open-label, pilot study showed that UA and meloxicam successfully disrupted ovulation at “the peak of luteal surge, when conception risk is highest,” reported lead author Erica P Cahill, MD, of Stanford (Calif.) University, and colleagues.

“There are many people who report being interested in preventing pregnancy who are not using contraception,” Dr. Cahill said in an interview. The ideal is to be able to take a medication to prevent ovulation and know that you wouldn’t ovulate or be able to become pregnant for the next 3-5 days. These would be pericoital contraceptive pills that one could take prior to or immediately after intercourse that would expand the contraceptive options available and meet some of this need, she said.

Dr. Cahill said currently approved emergency contraceptives containing ulipristal acetate or levonorgestrel “work by inhibiting ovulation at the level of the luteal surge, the pituitary signal that starts the ovulation cascade. Because of this mechanism, they are only effective when taken prior to that signal. If they are taken near or after ovulation has occurred, they are not effective.” She said combining meloxicam with UA could address this because meloxicam “has been shown to prevent some of the later steps of ovulation just prior to the egg being released.”

The study included nine healthy women, with a mean age of 31.4 years, and a mean body mass index of 24.5 ± 3.9 kg/m². All subjects had no exposure to hormonal medication, pregnancy, or lactation in the prior 3 months.

Each participant was followed for two cycles: The first without treatment, to establish normal ovulatory function; and the second during treatment with a one-time dose of UA 30 mg and meloxicam 30 mg during the “fertile window.” This window was defined as when the lead ovarian follicle had a mean diameter of 18 mm, and was determined via thrice-weekly ultrasounds, as well as luteinizing hormone (LH) measurements.

The primary outcome of the study was ovulation disruption, defined as unruptured dominant follicle for 5 days, a blunted LH peak, defined as <15 IU/L, and a nonovulatory luteal phase progesterone level, defined as <3 ng/mL.

Ovulation disruption was achieved in six subjects (67.7%), with eight subjects (88.9%) meeting some criteria.

“When we compare ovulation disruption rates in our study with the previous studies on which our protocol is based, the combination of UA and meloxicam disrupted ovulation at each phase of the fertile window more than any other medication previously studied,” the researchers wrote. “This medication combination is an important candidate to evaluate as oral pericoital contraception.”

When comparing subjects’ baseline cycles with their treatment cycles, the latter were approximately 3 days longer, although there was no difference in endometrial stripe thickness or irregular bleeding.

“Cycle length changes are an important parameter as people interested in oral, on-demand contraception may also be using fertility awareness methods which can be affected by cycle length changes.”

The authors noted that measures of full efficacy and side effects were beyond the scope of the study and would require repeat dosing. Similarly, liver enzymes were not measured, because there was only one dose of study medication, but “given the potential impact of repeat UA on liver enzymes, this measurement is critical for future studies.”

Asked to comment on the study, Eve Espey, MD, said that although it was limited in size and the use of an “intermediate outcome” of ovulation disruption, “the combination does show some promise as a focus of future research.” However, Dr. Espey, distinguished professor and chair in the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, said it is too early to determine the significance of the findings. “But it does point the way to further research,” she noted. “Compared with existing emergency contraception, this study shows that the UA-meloxicam combination disrupts ovulation over a broader mid-cycle time period – [an] extended duration of action [that] could theoretically translate into increased effectiveness as a contraceptive.”

The study was supported by the Society for Family Planning Research Fund. None of the authors, or Dr. Espey, declared competing interests.

Moderate to severe anxiety, depression, and shortness of breath indicate increased risk for nonfatal self-injury (NFSI) among patients newly diagnosed with cancer, according to a Canadian study.

In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.

“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.

Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”

The study was published online in JAMA Oncology.
 

Nine common symptoms

The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).

The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
 

Toward tailored intervention

A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).

“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”

In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.

“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
 

Self-injury vs. suicidality

Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.

“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”

The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.

“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.

The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.

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

Moderate to severe anxiety, depression, and shortness of breath indicate increased risk for nonfatal self-injury (NFSI) among patients newly diagnosed with cancer, according to a Canadian study.

In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.

“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.

Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”

The study was published online in JAMA Oncology.
 

Nine common symptoms

The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).

The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
 

Toward tailored intervention

A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).

“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”

In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.

“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
 

Self-injury vs. suicidality

Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.

“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”

The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.

“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.

The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.

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

Moderate to severe anxiety, depression, and shortness of breath indicate increased risk for nonfatal self-injury (NFSI) among patients newly diagnosed with cancer, according to a Canadian study.

In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.

“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.

Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”

The study was published online in JAMA Oncology.
 

Nine common symptoms

The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).

The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
 

Toward tailored intervention

A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).

“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”

In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.

“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
 

Self-injury vs. suicidality

Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.

“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”

The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.

“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.

The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.

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

Older age and higher ferritin levels at hospital admission predict severe illness in COVID-related multisystem inflammatory syndrome in children (MIS-C), according to a Canadian multicenter cohort study.

The adjusted absolute risk for admission to an intensive care unit was 43.6% among children aged 6 years and older and 46.2% in children aged 13 to 17 years, compared with 18.4% in children aged 5 years or younger.

“We do not understand why teens get more severe MIS-C than younger children,” senior author Joan Robinson, MD, of the University of Alberta, Edmonton, told this news organization. “It is possible that more exposures to other coronaviruses in the past result in them having a more robust immune response to SARS-CoV-2, which results in more inflammation.”

The data were published  in the Canadian Medical Association Journal.
 

A multinational study

The study included data on 232 children admitted with probable or confirmed MIS-C at 15 hospitals in Canada, Iran, and Costa Rica between March 1, 2020, and March 7, 2021. The median age of the children was 5.8 years, 56.0% were boys, and 21.6% had comorbidities.

Although cardiac involvement was common (58.6%), and almost one-third of the cohort (31.5%) was admitted to an ICU, “recovery was typically rapid, with 85% of patients discharged within 10 days,” said Dr. Robinson, for the Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC).
 

Older age as a risk

The results suggest that older age is associated with increased risk of severe MIS-C. “However, one would then predict that adults would be at even higher risk than teens, whereas the same syndrome in adults (MIS-A) is very, very rare,” said Dr. Robinson.

The study also found that children admitted with ferritin levels greater than 500 μg/L, signaling greater inflammation, also had an increased risk for ICU admission, compared with those with lower levels (adjusted risk difference, 18.4%; relative risk, 1.69). “This is presumably because the more inflammation that the child has, the more likely they are to have inflammation of the heart, which can lead to low blood pressure,” said Dr. Robinson.
 

Features of MIS-C

Among all patients with MIS-C, gastrointestinal involvement was common (89.2%), as were mucocutaneous findings (84.5%). Children with MIS-C had fever for a median duration of 6 days. “Clinicians who see children in their practice commonly have to determine why a child is febrile. Our study shows that one mainly has to consider MIS-C if febrile children have a rash and one or more of vomiting, diarrhea, or abdominal pain,” said Dr. Robinson. 

The study also found that patients with MIS-C who were admitted to the hospital in the latter part of the study period (Nov. 1, 2020, to March 7, 2021) were slightly more likely to require ICU admission, compared with those admitted between March 1 and Oct. 31, 2020. “We cannot provide a clear explanation [for this],” the authors noted. “The features of severe MIS-C were widely publicized by May 2020, so it seems unlikely that severe cases were missed early in the study period. SARS-CoV-2 variants of concern have replaced the wild-type virus. It is possible that the immune response to circulating variants alters the severity of COVID-19 and MIS-C, when compared with wild-type virus.”

Despite initial concerns that pediatric COVID-19 vaccines might cause MIS-C, Dr. Robinson says data suggest this is rarely, if ever, the case, and that vaccines actually prevent the syndrome. She says further studies will be needed to assess MIS-C risk following reinfection with SARS-CoV-2. “I am an optimistic person, and it is my hope that MIS-C following reinfection is rare,” she said. “If this is the case, perhaps we will see very few cases once almost all children have been immunized and/or had SARS-CoV-2 infection.”  
 

‘Differences across countries’

Adrienne Randolph, MD, a pediatrician at Harvard Medical School, Boston, and senior author of a large case series of patients with MIS-C, said that the Canadian study is valuable because it includes children from three countries. “It’s very interesting that there are differences across countries,” she said. “The patients in Iran had the highest percentage (58.7%) going into the ICU, whereas Costa Rica had the lowest percentage (9.2%), and the percentage going to the ICU in Canada (34.7%) was less than the percentages we see in the U.S. – which is pretty consistently about 60% to 70% of MIS-C patients going into the ICU.” Dr. Randolph was not involved in the current study.

Reasons for differences in the rates of ICU visits will be important to explore in the effort to standardize diagnostic criteria, stratification of severity, and recommendations for treatment of MIS-C, said Dr. Randolph.

“What is consistent is that the younger kids, zero to 5 years, in general are less ill,” she said. “That’s been consistent across multiple countries.” It’s unclear whether the cause of this difference is that parents observe younger patients more closely than they do teenagers, or whether other aspects of adolescence, such as prevalence of obesity and attendant inflammation, are at work, said Dr. Randolph.

What is also unclear is why hospitalized patients with MIS-C had higher percentages of ICU admission in the latter part of the study period, compared with the earlier period. “Did the patients change, or did practice change as we got to understand the disease process?” asked Dr. Randolph. “It could be that they got better at the diagnosis and were weeding out some of the patients who they realized didn’t need to be hospitalized. At the very beginning, we had a very low threshold to admit patients, because we didn’t know, and then, over time, people understood what was going on and felt more comfortable monitoring them as outpatients.”

This study was partially funded by a Janeway Foundation Research Grant to support data collection. Dr. Robinson disclosed no conflicts of interest. Dr. Randolph reported receiving royalties from UpToDate and personal fees from the La Jolla Pharmaceutical Company.

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

Older age and higher ferritin levels at hospital admission predict severe illness in COVID-related multisystem inflammatory syndrome in children (MIS-C), according to a Canadian multicenter cohort study.

The adjusted absolute risk for admission to an intensive care unit was 43.6% among children aged 6 years and older and 46.2% in children aged 13 to 17 years, compared with 18.4% in children aged 5 years or younger.

“We do not understand why teens get more severe MIS-C than younger children,” senior author Joan Robinson, MD, of the University of Alberta, Edmonton, told this news organization. “It is possible that more exposures to other coronaviruses in the past result in them having a more robust immune response to SARS-CoV-2, which results in more inflammation.”

The data were published  in the Canadian Medical Association Journal.
 

A multinational study

The study included data on 232 children admitted with probable or confirmed MIS-C at 15 hospitals in Canada, Iran, and Costa Rica between March 1, 2020, and March 7, 2021. The median age of the children was 5.8 years, 56.0% were boys, and 21.6% had comorbidities.

Although cardiac involvement was common (58.6%), and almost one-third of the cohort (31.5%) was admitted to an ICU, “recovery was typically rapid, with 85% of patients discharged within 10 days,” said Dr. Robinson, for the Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC).
 

Older age as a risk

The results suggest that older age is associated with increased risk of severe MIS-C. “However, one would then predict that adults would be at even higher risk than teens, whereas the same syndrome in adults (MIS-A) is very, very rare,” said Dr. Robinson.

The study also found that children admitted with ferritin levels greater than 500 μg/L, signaling greater inflammation, also had an increased risk for ICU admission, compared with those with lower levels (adjusted risk difference, 18.4%; relative risk, 1.69). “This is presumably because the more inflammation that the child has, the more likely they are to have inflammation of the heart, which can lead to low blood pressure,” said Dr. Robinson.
 

Features of MIS-C

Among all patients with MIS-C, gastrointestinal involvement was common (89.2%), as were mucocutaneous findings (84.5%). Children with MIS-C had fever for a median duration of 6 days. “Clinicians who see children in their practice commonly have to determine why a child is febrile. Our study shows that one mainly has to consider MIS-C if febrile children have a rash and one or more of vomiting, diarrhea, or abdominal pain,” said Dr. Robinson. 

The study also found that patients with MIS-C who were admitted to the hospital in the latter part of the study period (Nov. 1, 2020, to March 7, 2021) were slightly more likely to require ICU admission, compared with those admitted between March 1 and Oct. 31, 2020. “We cannot provide a clear explanation [for this],” the authors noted. “The features of severe MIS-C were widely publicized by May 2020, so it seems unlikely that severe cases were missed early in the study period. SARS-CoV-2 variants of concern have replaced the wild-type virus. It is possible that the immune response to circulating variants alters the severity of COVID-19 and MIS-C, when compared with wild-type virus.”

Despite initial concerns that pediatric COVID-19 vaccines might cause MIS-C, Dr. Robinson says data suggest this is rarely, if ever, the case, and that vaccines actually prevent the syndrome. She says further studies will be needed to assess MIS-C risk following reinfection with SARS-CoV-2. “I am an optimistic person, and it is my hope that MIS-C following reinfection is rare,” she said. “If this is the case, perhaps we will see very few cases once almost all children have been immunized and/or had SARS-CoV-2 infection.”  
 

‘Differences across countries’

Adrienne Randolph, MD, a pediatrician at Harvard Medical School, Boston, and senior author of a large case series of patients with MIS-C, said that the Canadian study is valuable because it includes children from three countries. “It’s very interesting that there are differences across countries,” she said. “The patients in Iran had the highest percentage (58.7%) going into the ICU, whereas Costa Rica had the lowest percentage (9.2%), and the percentage going to the ICU in Canada (34.7%) was less than the percentages we see in the U.S. – which is pretty consistently about 60% to 70% of MIS-C patients going into the ICU.” Dr. Randolph was not involved in the current study.

Reasons for differences in the rates of ICU visits will be important to explore in the effort to standardize diagnostic criteria, stratification of severity, and recommendations for treatment of MIS-C, said Dr. Randolph.

“What is consistent is that the younger kids, zero to 5 years, in general are less ill,” she said. “That’s been consistent across multiple countries.” It’s unclear whether the cause of this difference is that parents observe younger patients more closely than they do teenagers, or whether other aspects of adolescence, such as prevalence of obesity and attendant inflammation, are at work, said Dr. Randolph.

What is also unclear is why hospitalized patients with MIS-C had higher percentages of ICU admission in the latter part of the study period, compared with the earlier period. “Did the patients change, or did practice change as we got to understand the disease process?” asked Dr. Randolph. “It could be that they got better at the diagnosis and were weeding out some of the patients who they realized didn’t need to be hospitalized. At the very beginning, we had a very low threshold to admit patients, because we didn’t know, and then, over time, people understood what was going on and felt more comfortable monitoring them as outpatients.”

This study was partially funded by a Janeway Foundation Research Grant to support data collection. Dr. Robinson disclosed no conflicts of interest. Dr. Randolph reported receiving royalties from UpToDate and personal fees from the La Jolla Pharmaceutical Company.

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

Older age and higher ferritin levels at hospital admission predict severe illness in COVID-related multisystem inflammatory syndrome in children (MIS-C), according to a Canadian multicenter cohort study.

The adjusted absolute risk for admission to an intensive care unit was 43.6% among children aged 6 years and older and 46.2% in children aged 13 to 17 years, compared with 18.4% in children aged 5 years or younger.

“We do not understand why teens get more severe MIS-C than younger children,” senior author Joan Robinson, MD, of the University of Alberta, Edmonton, told this news organization. “It is possible that more exposures to other coronaviruses in the past result in them having a more robust immune response to SARS-CoV-2, which results in more inflammation.”

The data were published  in the Canadian Medical Association Journal.
 

A multinational study

The study included data on 232 children admitted with probable or confirmed MIS-C at 15 hospitals in Canada, Iran, and Costa Rica between March 1, 2020, and March 7, 2021. The median age of the children was 5.8 years, 56.0% were boys, and 21.6% had comorbidities.

Although cardiac involvement was common (58.6%), and almost one-third of the cohort (31.5%) was admitted to an ICU, “recovery was typically rapid, with 85% of patients discharged within 10 days,” said Dr. Robinson, for the Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC).
 

Older age as a risk

The results suggest that older age is associated with increased risk of severe MIS-C. “However, one would then predict that adults would be at even higher risk than teens, whereas the same syndrome in adults (MIS-A) is very, very rare,” said Dr. Robinson.

The study also found that children admitted with ferritin levels greater than 500 μg/L, signaling greater inflammation, also had an increased risk for ICU admission, compared with those with lower levels (adjusted risk difference, 18.4%; relative risk, 1.69). “This is presumably because the more inflammation that the child has, the more likely they are to have inflammation of the heart, which can lead to low blood pressure,” said Dr. Robinson.
 

Features of MIS-C

Among all patients with MIS-C, gastrointestinal involvement was common (89.2%), as were mucocutaneous findings (84.5%). Children with MIS-C had fever for a median duration of 6 days. “Clinicians who see children in their practice commonly have to determine why a child is febrile. Our study shows that one mainly has to consider MIS-C if febrile children have a rash and one or more of vomiting, diarrhea, or abdominal pain,” said Dr. Robinson. 

The study also found that patients with MIS-C who were admitted to the hospital in the latter part of the study period (Nov. 1, 2020, to March 7, 2021) were slightly more likely to require ICU admission, compared with those admitted between March 1 and Oct. 31, 2020. “We cannot provide a clear explanation [for this],” the authors noted. “The features of severe MIS-C were widely publicized by May 2020, so it seems unlikely that severe cases were missed early in the study period. SARS-CoV-2 variants of concern have replaced the wild-type virus. It is possible that the immune response to circulating variants alters the severity of COVID-19 and MIS-C, when compared with wild-type virus.”

Despite initial concerns that pediatric COVID-19 vaccines might cause MIS-C, Dr. Robinson says data suggest this is rarely, if ever, the case, and that vaccines actually prevent the syndrome. She says further studies will be needed to assess MIS-C risk following reinfection with SARS-CoV-2. “I am an optimistic person, and it is my hope that MIS-C following reinfection is rare,” she said. “If this is the case, perhaps we will see very few cases once almost all children have been immunized and/or had SARS-CoV-2 infection.”  
 

‘Differences across countries’

Adrienne Randolph, MD, a pediatrician at Harvard Medical School, Boston, and senior author of a large case series of patients with MIS-C, said that the Canadian study is valuable because it includes children from three countries. “It’s very interesting that there are differences across countries,” she said. “The patients in Iran had the highest percentage (58.7%) going into the ICU, whereas Costa Rica had the lowest percentage (9.2%), and the percentage going to the ICU in Canada (34.7%) was less than the percentages we see in the U.S. – which is pretty consistently about 60% to 70% of MIS-C patients going into the ICU.” Dr. Randolph was not involved in the current study.

Reasons for differences in the rates of ICU visits will be important to explore in the effort to standardize diagnostic criteria, stratification of severity, and recommendations for treatment of MIS-C, said Dr. Randolph.

“What is consistent is that the younger kids, zero to 5 years, in general are less ill,” she said. “That’s been consistent across multiple countries.” It’s unclear whether the cause of this difference is that parents observe younger patients more closely than they do teenagers, or whether other aspects of adolescence, such as prevalence of obesity and attendant inflammation, are at work, said Dr. Randolph.

What is also unclear is why hospitalized patients with MIS-C had higher percentages of ICU admission in the latter part of the study period, compared with the earlier period. “Did the patients change, or did practice change as we got to understand the disease process?” asked Dr. Randolph. “It could be that they got better at the diagnosis and were weeding out some of the patients who they realized didn’t need to be hospitalized. At the very beginning, we had a very low threshold to admit patients, because we didn’t know, and then, over time, people understood what was going on and felt more comfortable monitoring them as outpatients.”

This study was partially funded by a Janeway Foundation Research Grant to support data collection. Dr. Robinson disclosed no conflicts of interest. Dr. Randolph reported receiving royalties from UpToDate and personal fees from the La Jolla Pharmaceutical Company.

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

In a deep dive into obscure Chinese language transplant journals, a pair of researchers from Australia and Israel have added a new layer of horror to what’s already known about forced organ harvesting in China.

Searching for documentation that vital organs are being harvested from nonconsenting executed prisoners, a practice that the China Tribunal confirmed “beyond any reasonable doubt” in 2020, Jacob Lavee, MD, an Israeli heart transplant surgeon, and Matthew Roberston, a PhD student at Australian National University, uncovered something even more shocking: that vital organs are being explanted from patients who are still alive.

“We have shown for the first time that the transplant surgeons are the executioners – that the mode of execution is organ procurement. These are self-admissions of executing the patient,” Dr. Lavee told this news organization. “Up until now, there has been what we call circumstantial evidence of this, but our paper is what you’d call the smoking gun, because it’s in the words of the physicians themselves that they are doing it. In the words of these surgeons, intubation was done only after the beginning of surgery, which means the patients were breathing spontaneously up until the moment the operation started ... meaning they were not brain dead.”

The research, published in the American Journal of Transplantation, involved intricate analysis of thousands of Chinese language transplant articles and identified 71 articles in which transplant surgeons describe starting organ procurement surgery before declaring their patients brain dead.

“What we found were improper, illegitimate, nonexistent, or false declarations of brain death,” Mr. Robertson said in an interview. He explained that this violates what’s known as the dead donor rule, which is fundamental in transplant ethics. “The surgeons wrote that the donor was brain dead, but according to everything we know about medical science, they could not possibly have been brain dead because there was no apnea test performed. Brain death is not just something you say, there’s this whole battery of tests, and the key is the apnea test, [in which] the patient is already intubated and ventilated, they turn the machine off, and they’re looking for carbon dioxide in the blood above a certain level.”

Mr. Robertson and Dr. Lavee have painstakingly documented “incriminating sentences” in each of the 71 articles proving that brain death had not occurred before the organ explantation procedure began. “There were two criteria by which we claimed a problematic brain death declaration,” said Mr. Robertson, who translated the Chinese. “One was where the patient was not ventilated and was only intubated after they were declared brain dead; the other was that the intubation took place immediately prior to the surgery beginning.”

“It was mind-boggling,” said Dr. Lavee, from Tel Aviv University. “When I first started reading, my initial reaction is, ‘This can’t be.’ I read it once, and again, and I insisted that Matt get another independent translation of the Chinese just to be sure. I told him, ‘There’s no way a physician, a surgeon could write this – it doesn’t make sense.’ But the more of these papers we read, we saw it was a pattern – and they didn’t come out of a single medical center, they are spread all over China.”

For the analysis, Mr. Robertson wrote code and customized an algorithm to examine 124,770 medical articles from official Chinese databases between 1980 and 2020. The 71 articles revealing cases involving problematic brain death came from 56 hospitals (of which 12 were military) in 33 cities across 15 provinces, they report. In total, 348 surgeons, nurses, anesthesiologists, and other medical workers or researchers were listed as authors of these publications.

Why would these medical personnel write such self-incriminating evidence? The researchers say it’s unclear. “They don’t think anyone’s reading this stuff,” Mr. Robertson suggests. “Sometimes it’s revealed in just five or six characters in a paper of eight pages.” Dr. Lavee wonders if it’s also ignorance. “If this has been a practice for 20 or 30 years in China, I guess nobody at that time was aware they were doing something wrong, although how to declare brain death is something that is known in China. They’ve published a lot about it.”

The article is “evidence that this barbarity continues and is a very valuable contribution that continues to bring attention to an enormous human rights violation,” said Arthur Caplan, PhD, head of the Division of Medical Ethics at New York University’s Grossman School of Medicine. “What they’ve reported has been going on for many, many years, the data are very clear that China’s doing many more transplants than they have cadaver organ donors,” he said, adding that the country’s well-documented and lucrative involvement in transplant tourism “means you have to have a donor ready when the would-be recipient appears; you have to have a matched organ available, and that’s hard to do waiting on a cadaver donor.”

Although the researchers found no incriminating publications after 2015, they speculate that this is likely due to growing awareness among Chinese surgeons that publishing the information would attract international condemnation. “We think these practices are continuing to go on,” said Dr. Lavee. He acknowledged that a voluntary organ donation program is slowly developing in parallel to this. He said, given China’s place as the world’s second largest transplant country behind the U.S., as well as its low rate of voluntary donation, it’s reasonable to conclude that the main source of organs remains prisoners on death row.

Dr. Caplan and the researchers have called for academic institutions and medical journals to resume their previous boycotts of Chinese transplant publications and speakers, but as long as China denies the practices, economic and political leaders will turn a blind eye. “In the past, I don’t think the question of China’s medical professional involvement in the execution of donors has been taken as seriously as it should have,” said Mr. Robertson. “I certainly hope that with the publication of this paper in the leading journal in the field, this will change.”

The study was supported by the Google Cloud Research Credits program, the Australian Government Research Training Program Scholarship, and the Victims of Communism Memorial Foundation. Mr. Robertson, Dr. Lavee, and Dr. Caplan have disclosed no relevant financial relationships.

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

In a deep dive into obscure Chinese language transplant journals, a pair of researchers from Australia and Israel have added a new layer of horror to what’s already known about forced organ harvesting in China.

Searching for documentation that vital organs are being harvested from nonconsenting executed prisoners, a practice that the China Tribunal confirmed “beyond any reasonable doubt” in 2020, Jacob Lavee, MD, an Israeli heart transplant surgeon, and Matthew Roberston, a PhD student at Australian National University, uncovered something even more shocking: that vital organs are being explanted from patients who are still alive.

“We have shown for the first time that the transplant surgeons are the executioners – that the mode of execution is organ procurement. These are self-admissions of executing the patient,” Dr. Lavee told this news organization. “Up until now, there has been what we call circumstantial evidence of this, but our paper is what you’d call the smoking gun, because it’s in the words of the physicians themselves that they are doing it. In the words of these surgeons, intubation was done only after the beginning of surgery, which means the patients were breathing spontaneously up until the moment the operation started ... meaning they were not brain dead.”

The research, published in the American Journal of Transplantation, involved intricate analysis of thousands of Chinese language transplant articles and identified 71 articles in which transplant surgeons describe starting organ procurement surgery before declaring their patients brain dead.

“What we found were improper, illegitimate, nonexistent, or false declarations of brain death,” Mr. Robertson said in an interview. He explained that this violates what’s known as the dead donor rule, which is fundamental in transplant ethics. “The surgeons wrote that the donor was brain dead, but according to everything we know about medical science, they could not possibly have been brain dead because there was no apnea test performed. Brain death is not just something you say, there’s this whole battery of tests, and the key is the apnea test, [in which] the patient is already intubated and ventilated, they turn the machine off, and they’re looking for carbon dioxide in the blood above a certain level.”

Mr. Robertson and Dr. Lavee have painstakingly documented “incriminating sentences” in each of the 71 articles proving that brain death had not occurred before the organ explantation procedure began. “There were two criteria by which we claimed a problematic brain death declaration,” said Mr. Robertson, who translated the Chinese. “One was where the patient was not ventilated and was only intubated after they were declared brain dead; the other was that the intubation took place immediately prior to the surgery beginning.”

“It was mind-boggling,” said Dr. Lavee, from Tel Aviv University. “When I first started reading, my initial reaction is, ‘This can’t be.’ I read it once, and again, and I insisted that Matt get another independent translation of the Chinese just to be sure. I told him, ‘There’s no way a physician, a surgeon could write this – it doesn’t make sense.’ But the more of these papers we read, we saw it was a pattern – and they didn’t come out of a single medical center, they are spread all over China.”

For the analysis, Mr. Robertson wrote code and customized an algorithm to examine 124,770 medical articles from official Chinese databases between 1980 and 2020. The 71 articles revealing cases involving problematic brain death came from 56 hospitals (of which 12 were military) in 33 cities across 15 provinces, they report. In total, 348 surgeons, nurses, anesthesiologists, and other medical workers or researchers were listed as authors of these publications.

Why would these medical personnel write such self-incriminating evidence? The researchers say it’s unclear. “They don’t think anyone’s reading this stuff,” Mr. Robertson suggests. “Sometimes it’s revealed in just five or six characters in a paper of eight pages.” Dr. Lavee wonders if it’s also ignorance. “If this has been a practice for 20 or 30 years in China, I guess nobody at that time was aware they were doing something wrong, although how to declare brain death is something that is known in China. They’ve published a lot about it.”

The article is “evidence that this barbarity continues and is a very valuable contribution that continues to bring attention to an enormous human rights violation,” said Arthur Caplan, PhD, head of the Division of Medical Ethics at New York University’s Grossman School of Medicine. “What they’ve reported has been going on for many, many years, the data are very clear that China’s doing many more transplants than they have cadaver organ donors,” he said, adding that the country’s well-documented and lucrative involvement in transplant tourism “means you have to have a donor ready when the would-be recipient appears; you have to have a matched organ available, and that’s hard to do waiting on a cadaver donor.”

Although the researchers found no incriminating publications after 2015, they speculate that this is likely due to growing awareness among Chinese surgeons that publishing the information would attract international condemnation. “We think these practices are continuing to go on,” said Dr. Lavee. He acknowledged that a voluntary organ donation program is slowly developing in parallel to this. He said, given China’s place as the world’s second largest transplant country behind the U.S., as well as its low rate of voluntary donation, it’s reasonable to conclude that the main source of organs remains prisoners on death row.

Dr. Caplan and the researchers have called for academic institutions and medical journals to resume their previous boycotts of Chinese transplant publications and speakers, but as long as China denies the practices, economic and political leaders will turn a blind eye. “In the past, I don’t think the question of China’s medical professional involvement in the execution of donors has been taken as seriously as it should have,” said Mr. Robertson. “I certainly hope that with the publication of this paper in the leading journal in the field, this will change.”

The study was supported by the Google Cloud Research Credits program, the Australian Government Research Training Program Scholarship, and the Victims of Communism Memorial Foundation. Mr. Robertson, Dr. Lavee, and Dr. Caplan have disclosed no relevant financial relationships.

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

In a deep dive into obscure Chinese language transplant journals, a pair of researchers from Australia and Israel have added a new layer of horror to what’s already known about forced organ harvesting in China.

Searching for documentation that vital organs are being harvested from nonconsenting executed prisoners, a practice that the China Tribunal confirmed “beyond any reasonable doubt” in 2020, Jacob Lavee, MD, an Israeli heart transplant surgeon, and Matthew Roberston, a PhD student at Australian National University, uncovered something even more shocking: that vital organs are being explanted from patients who are still alive.

“We have shown for the first time that the transplant surgeons are the executioners – that the mode of execution is organ procurement. These are self-admissions of executing the patient,” Dr. Lavee told this news organization. “Up until now, there has been what we call circumstantial evidence of this, but our paper is what you’d call the smoking gun, because it’s in the words of the physicians themselves that they are doing it. In the words of these surgeons, intubation was done only after the beginning of surgery, which means the patients were breathing spontaneously up until the moment the operation started ... meaning they were not brain dead.”

The research, published in the American Journal of Transplantation, involved intricate analysis of thousands of Chinese language transplant articles and identified 71 articles in which transplant surgeons describe starting organ procurement surgery before declaring their patients brain dead.

“What we found were improper, illegitimate, nonexistent, or false declarations of brain death,” Mr. Robertson said in an interview. He explained that this violates what’s known as the dead donor rule, which is fundamental in transplant ethics. “The surgeons wrote that the donor was brain dead, but according to everything we know about medical science, they could not possibly have been brain dead because there was no apnea test performed. Brain death is not just something you say, there’s this whole battery of tests, and the key is the apnea test, [in which] the patient is already intubated and ventilated, they turn the machine off, and they’re looking for carbon dioxide in the blood above a certain level.”

Mr. Robertson and Dr. Lavee have painstakingly documented “incriminating sentences” in each of the 71 articles proving that brain death had not occurred before the organ explantation procedure began. “There were two criteria by which we claimed a problematic brain death declaration,” said Mr. Robertson, who translated the Chinese. “One was where the patient was not ventilated and was only intubated after they were declared brain dead; the other was that the intubation took place immediately prior to the surgery beginning.”

“It was mind-boggling,” said Dr. Lavee, from Tel Aviv University. “When I first started reading, my initial reaction is, ‘This can’t be.’ I read it once, and again, and I insisted that Matt get another independent translation of the Chinese just to be sure. I told him, ‘There’s no way a physician, a surgeon could write this – it doesn’t make sense.’ But the more of these papers we read, we saw it was a pattern – and they didn’t come out of a single medical center, they are spread all over China.”

For the analysis, Mr. Robertson wrote code and customized an algorithm to examine 124,770 medical articles from official Chinese databases between 1980 and 2020. The 71 articles revealing cases involving problematic brain death came from 56 hospitals (of which 12 were military) in 33 cities across 15 provinces, they report. In total, 348 surgeons, nurses, anesthesiologists, and other medical workers or researchers were listed as authors of these publications.

Why would these medical personnel write such self-incriminating evidence? The researchers say it’s unclear. “They don’t think anyone’s reading this stuff,” Mr. Robertson suggests. “Sometimes it’s revealed in just five or six characters in a paper of eight pages.” Dr. Lavee wonders if it’s also ignorance. “If this has been a practice for 20 or 30 years in China, I guess nobody at that time was aware they were doing something wrong, although how to declare brain death is something that is known in China. They’ve published a lot about it.”

The article is “evidence that this barbarity continues and is a very valuable contribution that continues to bring attention to an enormous human rights violation,” said Arthur Caplan, PhD, head of the Division of Medical Ethics at New York University’s Grossman School of Medicine. “What they’ve reported has been going on for many, many years, the data are very clear that China’s doing many more transplants than they have cadaver organ donors,” he said, adding that the country’s well-documented and lucrative involvement in transplant tourism “means you have to have a donor ready when the would-be recipient appears; you have to have a matched organ available, and that’s hard to do waiting on a cadaver donor.”

Although the researchers found no incriminating publications after 2015, they speculate that this is likely due to growing awareness among Chinese surgeons that publishing the information would attract international condemnation. “We think these practices are continuing to go on,” said Dr. Lavee. He acknowledged that a voluntary organ donation program is slowly developing in parallel to this. He said, given China’s place as the world’s second largest transplant country behind the U.S., as well as its low rate of voluntary donation, it’s reasonable to conclude that the main source of organs remains prisoners on death row.

Dr. Caplan and the researchers have called for academic institutions and medical journals to resume their previous boycotts of Chinese transplant publications and speakers, but as long as China denies the practices, economic and political leaders will turn a blind eye. “In the past, I don’t think the question of China’s medical professional involvement in the execution of donors has been taken as seriously as it should have,” said Mr. Robertson. “I certainly hope that with the publication of this paper in the leading journal in the field, this will change.”

The study was supported by the Google Cloud Research Credits program, the Australian Government Research Training Program Scholarship, and the Victims of Communism Memorial Foundation. Mr. Robertson, Dr. Lavee, and Dr. Caplan have disclosed no relevant financial relationships.

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

Breast cancer screening modality has less effect on the probability of false-positive results than screening interval, patient age, and breast density according to a new study comparing digital breast tomosynthesis (DBT) with digital mammography.

Although DBT was associated with a modest improvement in recalls for false-positive results compared with mammography, about half of women in both groups received at least one false-positive result over a 10-year period of annual screening, reported senior author Diana L. Miglioretti, PhD, from the University of California, Davis, and colleagues.

By contrast, the authors reported “substantial reductions” in false-positive recalls with biennial screening. Specifically, while annual mammography and DBT resulted in cumulative 10-year false-positive recall rates of 56.3% and 49.6% respectively, biennial rates were 38.1% and 35.7%.

The comparative effectiveness study, published in JAMA Network Open, included 903,495 women who underwent 10 years of breast cancer screening at 126 radiology facilities in the Breast Cancer Surveillance Consortium. The mean age of participants was 57.6 years, and 46% of them had dense breasts. A total of 2,969,055 screening exams were performed (15% DBT), with each woman receiving a mean of 3.3 exams over 10 years. Most participants (71.8%) had annual exams, while 16.8% had biennial, with the remainder being performed at intervals of 3 years or more.

Investigators looked at the cumulative rate of three kinds of false-positive results over 10 years: false-positive recalls for further imaging, false-positive short-interval follow-up recommendations, and false-positive biopsy recommendations. A result was considered false positive if there was no diagnosis of invasive carcinoma or ductal carcinoma in situ within 1 year of the screening examination and before the next screening examination.

Overall, across all screening intervals, and after adjusting for age and breast density, the percentage of false-positive results was slightly lower for DBT vs. mammography: 7.6% vs. 9.0%, respectively, for false-positive recalls; 1.8% vs. 2.1%, respectively, for false-positive short-interval follow-up recommendations; and 1.1% vs. 1.2% for false-positive biopsy recommendations. “We did not observe consistent clinically meaningful differences in the cumulative probabilities of false-positive short-interval follow-up or biopsy recommendation by screening modality,” they noted, adding that, although DBT provided “modest” reductions in false-positive recalls, compared with mammography (2.4% less for biennial screening and 6.7% less for annual screening), “nonetheless, this percentage equates to many thousands of individuals in absolute numbers, especially for annual screening, which is the dominant practice in the U.S.”

The authors also noted that, regardless of screening modality, all three types of false-positive results were substantially lower for biennial versus annual mammograph, and depended on age and breast density. The highest cumulative rates of false-positive results occurred in women aged 40-49 years (68.0% with annual digital mammography and 60.8% with annual DBT). Women with extremely dense breasts had the highest probability of all three types of false positive, which “may be due to the lack of interspersed fat within dense fibroglandular tissue, with the contrast between the fat and tissue being a requirement for more accurate detection of suspicious features by interpreting radiologists.”

The study findings “offer new information about the potential harms of repeated screening, which may be used to inform screening guidelines and decision-making between individuals and their physicians. However, it is important to weigh these and other potential harms with potential benefits of earlier diagnosis. … Women at high risk of an advanced cancer under biennial screening, including some women with dense breasts, may reduce their risk with annual screening,” they suggested.

Although DBT is now widely used in the United States, amid growing optimism about its superiority over digital mammography, this study reminds clinicians to counsel patients appropriately, according to Lydia E. Pace, MD, from Brigham and Women’s Hospital in Boston. “Unfortunately, the growing availability of DBT does not substantially change the likelihood that women will experience a false-positive result over years of regular mammograms,” she wrote in an invited commentary published with the study. She noted that, although many women tolerate false-positive results, “they are associated with at least transient anxiety as well as time, inconvenience, and expense. More information is needed to understand the association of DBT with overdiagnosis, which is the more clinically important harm of screening.”

The study was funded by the National Cancer Institute. Dr. Miglioretti and Dr. Pace reported no conflicts of interest. One coauthor of the study is an unpaid consultant for Grail, for the STRIVE study, and another coauthor receives personal fees from Grail for work on a data safety monitoring board. No other disclosures were reported.

Breast cancer screening modality has less effect on the probability of false-positive results than screening interval, patient age, and breast density according to a new study comparing digital breast tomosynthesis (DBT) with digital mammography.

Although DBT was associated with a modest improvement in recalls for false-positive results compared with mammography, about half of women in both groups received at least one false-positive result over a 10-year period of annual screening, reported senior author Diana L. Miglioretti, PhD, from the University of California, Davis, and colleagues.

By contrast, the authors reported “substantial reductions” in false-positive recalls with biennial screening. Specifically, while annual mammography and DBT resulted in cumulative 10-year false-positive recall rates of 56.3% and 49.6% respectively, biennial rates were 38.1% and 35.7%.

The comparative effectiveness study, published in JAMA Network Open, included 903,495 women who underwent 10 years of breast cancer screening at 126 radiology facilities in the Breast Cancer Surveillance Consortium. The mean age of participants was 57.6 years, and 46% of them had dense breasts. A total of 2,969,055 screening exams were performed (15% DBT), with each woman receiving a mean of 3.3 exams over 10 years. Most participants (71.8%) had annual exams, while 16.8% had biennial, with the remainder being performed at intervals of 3 years or more.

Investigators looked at the cumulative rate of three kinds of false-positive results over 10 years: false-positive recalls for further imaging, false-positive short-interval follow-up recommendations, and false-positive biopsy recommendations. A result was considered false positive if there was no diagnosis of invasive carcinoma or ductal carcinoma in situ within 1 year of the screening examination and before the next screening examination.

Overall, across all screening intervals, and after adjusting for age and breast density, the percentage of false-positive results was slightly lower for DBT vs. mammography: 7.6% vs. 9.0%, respectively, for false-positive recalls; 1.8% vs. 2.1%, respectively, for false-positive short-interval follow-up recommendations; and 1.1% vs. 1.2% for false-positive biopsy recommendations. “We did not observe consistent clinically meaningful differences in the cumulative probabilities of false-positive short-interval follow-up or biopsy recommendation by screening modality,” they noted, adding that, although DBT provided “modest” reductions in false-positive recalls, compared with mammography (2.4% less for biennial screening and 6.7% less for annual screening), “nonetheless, this percentage equates to many thousands of individuals in absolute numbers, especially for annual screening, which is the dominant practice in the U.S.”

The authors also noted that, regardless of screening modality, all three types of false-positive results were substantially lower for biennial versus annual mammograph, and depended on age and breast density. The highest cumulative rates of false-positive results occurred in women aged 40-49 years (68.0% with annual digital mammography and 60.8% with annual DBT). Women with extremely dense breasts had the highest probability of all three types of false positive, which “may be due to the lack of interspersed fat within dense fibroglandular tissue, with the contrast between the fat and tissue being a requirement for more accurate detection of suspicious features by interpreting radiologists.”

The study findings “offer new information about the potential harms of repeated screening, which may be used to inform screening guidelines and decision-making between individuals and their physicians. However, it is important to weigh these and other potential harms with potential benefits of earlier diagnosis. … Women at high risk of an advanced cancer under biennial screening, including some women with dense breasts, may reduce their risk with annual screening,” they suggested.

Although DBT is now widely used in the United States, amid growing optimism about its superiority over digital mammography, this study reminds clinicians to counsel patients appropriately, according to Lydia E. Pace, MD, from Brigham and Women’s Hospital in Boston. “Unfortunately, the growing availability of DBT does not substantially change the likelihood that women will experience a false-positive result over years of regular mammograms,” she wrote in an invited commentary published with the study. She noted that, although many women tolerate false-positive results, “they are associated with at least transient anxiety as well as time, inconvenience, and expense. More information is needed to understand the association of DBT with overdiagnosis, which is the more clinically important harm of screening.”

The study was funded by the National Cancer Institute. Dr. Miglioretti and Dr. Pace reported no conflicts of interest. One coauthor of the study is an unpaid consultant for Grail, for the STRIVE study, and another coauthor receives personal fees from Grail for work on a data safety monitoring board. No other disclosures were reported.

Breast cancer screening modality has less effect on the probability of false-positive results than screening interval, patient age, and breast density according to a new study comparing digital breast tomosynthesis (DBT) with digital mammography.

Although DBT was associated with a modest improvement in recalls for false-positive results compared with mammography, about half of women in both groups received at least one false-positive result over a 10-year period of annual screening, reported senior author Diana L. Miglioretti, PhD, from the University of California, Davis, and colleagues.

By contrast, the authors reported “substantial reductions” in false-positive recalls with biennial screening. Specifically, while annual mammography and DBT resulted in cumulative 10-year false-positive recall rates of 56.3% and 49.6% respectively, biennial rates were 38.1% and 35.7%.

The comparative effectiveness study, published in JAMA Network Open, included 903,495 women who underwent 10 years of breast cancer screening at 126 radiology facilities in the Breast Cancer Surveillance Consortium. The mean age of participants was 57.6 years, and 46% of them had dense breasts. A total of 2,969,055 screening exams were performed (15% DBT), with each woman receiving a mean of 3.3 exams over 10 years. Most participants (71.8%) had annual exams, while 16.8% had biennial, with the remainder being performed at intervals of 3 years or more.

Investigators looked at the cumulative rate of three kinds of false-positive results over 10 years: false-positive recalls for further imaging, false-positive short-interval follow-up recommendations, and false-positive biopsy recommendations. A result was considered false positive if there was no diagnosis of invasive carcinoma or ductal carcinoma in situ within 1 year of the screening examination and before the next screening examination.

Overall, across all screening intervals, and after adjusting for age and breast density, the percentage of false-positive results was slightly lower for DBT vs. mammography: 7.6% vs. 9.0%, respectively, for false-positive recalls; 1.8% vs. 2.1%, respectively, for false-positive short-interval follow-up recommendations; and 1.1% vs. 1.2% for false-positive biopsy recommendations. “We did not observe consistent clinically meaningful differences in the cumulative probabilities of false-positive short-interval follow-up or biopsy recommendation by screening modality,” they noted, adding that, although DBT provided “modest” reductions in false-positive recalls, compared with mammography (2.4% less for biennial screening and 6.7% less for annual screening), “nonetheless, this percentage equates to many thousands of individuals in absolute numbers, especially for annual screening, which is the dominant practice in the U.S.”

The authors also noted that, regardless of screening modality, all three types of false-positive results were substantially lower for biennial versus annual mammograph, and depended on age and breast density. The highest cumulative rates of false-positive results occurred in women aged 40-49 years (68.0% with annual digital mammography and 60.8% with annual DBT). Women with extremely dense breasts had the highest probability of all three types of false positive, which “may be due to the lack of interspersed fat within dense fibroglandular tissue, with the contrast between the fat and tissue being a requirement for more accurate detection of suspicious features by interpreting radiologists.”

The study findings “offer new information about the potential harms of repeated screening, which may be used to inform screening guidelines and decision-making between individuals and their physicians. However, it is important to weigh these and other potential harms with potential benefits of earlier diagnosis. … Women at high risk of an advanced cancer under biennial screening, including some women with dense breasts, may reduce their risk with annual screening,” they suggested.

Although DBT is now widely used in the United States, amid growing optimism about its superiority over digital mammography, this study reminds clinicians to counsel patients appropriately, according to Lydia E. Pace, MD, from Brigham and Women’s Hospital in Boston. “Unfortunately, the growing availability of DBT does not substantially change the likelihood that women will experience a false-positive result over years of regular mammograms,” she wrote in an invited commentary published with the study. She noted that, although many women tolerate false-positive results, “they are associated with at least transient anxiety as well as time, inconvenience, and expense. More information is needed to understand the association of DBT with overdiagnosis, which is the more clinically important harm of screening.”

The study was funded by the National Cancer Institute. Dr. Miglioretti and Dr. Pace reported no conflicts of interest. One coauthor of the study is an unpaid consultant for Grail, for the STRIVE study, and another coauthor receives personal fees from Grail for work on a data safety monitoring board. No other disclosures were reported.

Cancer care is not a top priority for the United Nations agency that is helping Ukrainian refugees across the border into neighboring countries, which makes the role of oncology groups vitally important.

“They’re trying to deal with an extremely vulnerable and traumatized population – children who’ve lost their families, elderly who are confused and potentially abandoned,” commented Richard Sullivan, MD, PhD.

“The triage that’s happening on the border is not focusing on noncommunicable diseases,” he continued. “We know from previous crises that many cancer patients are lost; they simply do not present with their symptoms once they become refugees, and that’s going to become a really big issue.”

Oncology groups are needed to “provide the navigation, the treatment, and also the intelligence to ensure we deliver excellent cancer care where it’s needed for our Ukrainian friends,” he added. Dr. Sullivan is a member of the World Health Organization’s Emergency Committee and is director of the Institute of Cancer Policy at King’s College London.

He was speaking at a virtual briefing organized by the American Society of Clinical Oncology (ASCO) and the European Cancer Organisation (ECO), which have joined forces to centralize cancer care efforts.

With an estimated 3.3 million refugees having already crossed Ukraine’s borders, neighboring countries are experiencing an approximately 5% increase in their overall populations, making increased demand for cancer care inevitable, said Dr. Sullivan.

“Suggestions are that with 4 million refugees, you’re going to be looking at an increase of 13,000-16,000 cancer patients per month. ... But it will take time for the issue to evolve. At the moment, people are not being overwhelmed ... but there’s no doubt cancer care capacity for host countries is going to be an issue in the future.”

So far, about 2 million refugees are in Poland, where cancer centers have experienced a 10% increase in new patients since the war started, said Piotr Rutkowski, MD, PhD, professor of surgical oncology at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw.

“Of course, our resources are limited,” he said, adding that efforts are underway to accredit Ukrainian health care workers to work in Poland. “It’s unpredictable how the health care system in Europe can overcome these difficulties.”

“Until now, I don’t think any cancer patients have not received care, so still, we are in a positive situation, but the waiting list can enlarge in the near future,” Dr. Rutkowsli commented.

Indeed, the anticipated increase will “likely exceed the possibilities of the Polish health system” soon, warned Jacek Jassem, MD, PhD, professor of clinical oncology and radiotherapy and the head of the department of oncology and radiotherapy at the Medical University of Gdansk, Poland.

Although there is an EU international agreement for a more widespread allocation of cancer patients, “when they come to Poland, many of them want to be treated in Poland, because they have family here, the language is more familiar.”

Dr. Jassem suggests the best way to avoid overwhelming host cancer centers is to triage patients directly from Ukraine. “Some therapies shouldn’t be interrupted. So, for example, radiotherapy started in Ukraine should be continued there, but otherwise, chemotherapy can be continued elsewhere, surgery may be postponed and done elsewhere. These are the decisions that should be considered in Ukraine, and then patients who are selected for particular therapies should be reallocated to other countries,” he suggested.

Romania has seen an influx of about 400,000 refugees, including cancer patients seeking systemic therapy, radiotherapy, or follow-up, said Nicoleta Antone, MD, a medical oncologist at the Cancer Institute of Ion Chiricuta in Cluj-Napoca, Romania. “We have seen patients mainly with breast cancer because most of the refugees [with cancer] are women looking for systemic therapy, but also all the other tumor types, both solid and hematologic tumors.”

Dr. Sullivan says attempts by EU member states to address cancer needs are complicated by the fact that many refugees are still on the move. They have been passing through their initial host countries and moving on to Greece, Slovenia, Austria, Germany, Italy, and Turkey, “making the therapeutic geographies at any potential time quite challenging to keep an eye on.” Other countries, such as Moldova, are not part of the EU, “so we dealing with some really quite complex political and financial issues.”

The situation calls for a broader approach to refugees generally, he added. “We’re talking free cancer care for Ukrainian patients, but there’s also, of course, this dialogue of ensuring there’s free care for all refugees. Europe already has a large refugee contingent from other countries, so there’s no doubt this is an opportunity to talk more broadly about cancer care for refugees and also progressive universalism.

“You can’t have rules for one set of patients and a different set of rules for another set of patients, so there’s going to be a real issue around fairness and equity which Europe is going to have to address,” he said.

In an attempt, ASCO and ECO have joined forces in a special network, noted Julie Gralow, MD, chief medical officer at ASCO.

“The ECO/ASCO Special Network is all about collaboration and coordination across professional societies, across cancer patient groups, across academic and other clinical centers. We’re providing information in the various national languages and trying to amplify the work that each of us is doing. ... We’re sharing intelligence, regular reports from the field, information, experience, and most of all, contacts. We’re all being approached individually about people who need help or people who want to help, and we’re trying to bring this all together in a focused way.”

Separately, there is also an ASCO resource page, as well as an ECO resource page.

The American Cancer Society also has patient resources on their site, including a 24-hour international call center in multiple languages and a Volunteer Corp of Clinicians, which currently has 123 active volunteers (and another 300 applicants) available to answer questions.

Europe and other countries must consider both a medium and a long-term commitment to refugees with cancer, said Dr. Sullivan. “Because even if the war stopped tomorrow, it’s going to take between a year and a year and a half to rebuild cancer care in Ukraine.”

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

Cancer care is not a top priority for the United Nations agency that is helping Ukrainian refugees across the border into neighboring countries, which makes the role of oncology groups vitally important.

“They’re trying to deal with an extremely vulnerable and traumatized population – children who’ve lost their families, elderly who are confused and potentially abandoned,” commented Richard Sullivan, MD, PhD.

“The triage that’s happening on the border is not focusing on noncommunicable diseases,” he continued. “We know from previous crises that many cancer patients are lost; they simply do not present with their symptoms once they become refugees, and that’s going to become a really big issue.”

Oncology groups are needed to “provide the navigation, the treatment, and also the intelligence to ensure we deliver excellent cancer care where it’s needed for our Ukrainian friends,” he added. Dr. Sullivan is a member of the World Health Organization’s Emergency Committee and is director of the Institute of Cancer Policy at King’s College London.

He was speaking at a virtual briefing organized by the American Society of Clinical Oncology (ASCO) and the European Cancer Organisation (ECO), which have joined forces to centralize cancer care efforts.

With an estimated 3.3 million refugees having already crossed Ukraine’s borders, neighboring countries are experiencing an approximately 5% increase in their overall populations, making increased demand for cancer care inevitable, said Dr. Sullivan.

“Suggestions are that with 4 million refugees, you’re going to be looking at an increase of 13,000-16,000 cancer patients per month. ... But it will take time for the issue to evolve. At the moment, people are not being overwhelmed ... but there’s no doubt cancer care capacity for host countries is going to be an issue in the future.”

So far, about 2 million refugees are in Poland, where cancer centers have experienced a 10% increase in new patients since the war started, said Piotr Rutkowski, MD, PhD, professor of surgical oncology at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw.

“Of course, our resources are limited,” he said, adding that efforts are underway to accredit Ukrainian health care workers to work in Poland. “It’s unpredictable how the health care system in Europe can overcome these difficulties.”

“Until now, I don’t think any cancer patients have not received care, so still, we are in a positive situation, but the waiting list can enlarge in the near future,” Dr. Rutkowsli commented.

Indeed, the anticipated increase will “likely exceed the possibilities of the Polish health system” soon, warned Jacek Jassem, MD, PhD, professor of clinical oncology and radiotherapy and the head of the department of oncology and radiotherapy at the Medical University of Gdansk, Poland.

Although there is an EU international agreement for a more widespread allocation of cancer patients, “when they come to Poland, many of them want to be treated in Poland, because they have family here, the language is more familiar.”

Dr. Jassem suggests the best way to avoid overwhelming host cancer centers is to triage patients directly from Ukraine. “Some therapies shouldn’t be interrupted. So, for example, radiotherapy started in Ukraine should be continued there, but otherwise, chemotherapy can be continued elsewhere, surgery may be postponed and done elsewhere. These are the decisions that should be considered in Ukraine, and then patients who are selected for particular therapies should be reallocated to other countries,” he suggested.

Romania has seen an influx of about 400,000 refugees, including cancer patients seeking systemic therapy, radiotherapy, or follow-up, said Nicoleta Antone, MD, a medical oncologist at the Cancer Institute of Ion Chiricuta in Cluj-Napoca, Romania. “We have seen patients mainly with breast cancer because most of the refugees [with cancer] are women looking for systemic therapy, but also all the other tumor types, both solid and hematologic tumors.”

Dr. Sullivan says attempts by EU member states to address cancer needs are complicated by the fact that many refugees are still on the move. They have been passing through their initial host countries and moving on to Greece, Slovenia, Austria, Germany, Italy, and Turkey, “making the therapeutic geographies at any potential time quite challenging to keep an eye on.” Other countries, such as Moldova, are not part of the EU, “so we dealing with some really quite complex political and financial issues.”

The situation calls for a broader approach to refugees generally, he added. “We’re talking free cancer care for Ukrainian patients, but there’s also, of course, this dialogue of ensuring there’s free care for all refugees. Europe already has a large refugee contingent from other countries, so there’s no doubt this is an opportunity to talk more broadly about cancer care for refugees and also progressive universalism.

“You can’t have rules for one set of patients and a different set of rules for another set of patients, so there’s going to be a real issue around fairness and equity which Europe is going to have to address,” he said.

In an attempt, ASCO and ECO have joined forces in a special network, noted Julie Gralow, MD, chief medical officer at ASCO.

“The ECO/ASCO Special Network is all about collaboration and coordination across professional societies, across cancer patient groups, across academic and other clinical centers. We’re providing information in the various national languages and trying to amplify the work that each of us is doing. ... We’re sharing intelligence, regular reports from the field, information, experience, and most of all, contacts. We’re all being approached individually about people who need help or people who want to help, and we’re trying to bring this all together in a focused way.”

Separately, there is also an ASCO resource page, as well as an ECO resource page.

The American Cancer Society also has patient resources on their site, including a 24-hour international call center in multiple languages and a Volunteer Corp of Clinicians, which currently has 123 active volunteers (and another 300 applicants) available to answer questions.

Europe and other countries must consider both a medium and a long-term commitment to refugees with cancer, said Dr. Sullivan. “Because even if the war stopped tomorrow, it’s going to take between a year and a year and a half to rebuild cancer care in Ukraine.”

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

Cancer care is not a top priority for the United Nations agency that is helping Ukrainian refugees across the border into neighboring countries, which makes the role of oncology groups vitally important.

“They’re trying to deal with an extremely vulnerable and traumatized population – children who’ve lost their families, elderly who are confused and potentially abandoned,” commented Richard Sullivan, MD, PhD.

“The triage that’s happening on the border is not focusing on noncommunicable diseases,” he continued. “We know from previous crises that many cancer patients are lost; they simply do not present with their symptoms once they become refugees, and that’s going to become a really big issue.”

Oncology groups are needed to “provide the navigation, the treatment, and also the intelligence to ensure we deliver excellent cancer care where it’s needed for our Ukrainian friends,” he added. Dr. Sullivan is a member of the World Health Organization’s Emergency Committee and is director of the Institute of Cancer Policy at King’s College London.

He was speaking at a virtual briefing organized by the American Society of Clinical Oncology (ASCO) and the European Cancer Organisation (ECO), which have joined forces to centralize cancer care efforts.

With an estimated 3.3 million refugees having already crossed Ukraine’s borders, neighboring countries are experiencing an approximately 5% increase in their overall populations, making increased demand for cancer care inevitable, said Dr. Sullivan.

“Suggestions are that with 4 million refugees, you’re going to be looking at an increase of 13,000-16,000 cancer patients per month. ... But it will take time for the issue to evolve. At the moment, people are not being overwhelmed ... but there’s no doubt cancer care capacity for host countries is going to be an issue in the future.”

So far, about 2 million refugees are in Poland, where cancer centers have experienced a 10% increase in new patients since the war started, said Piotr Rutkowski, MD, PhD, professor of surgical oncology at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw.

“Of course, our resources are limited,” he said, adding that efforts are underway to accredit Ukrainian health care workers to work in Poland. “It’s unpredictable how the health care system in Europe can overcome these difficulties.”

“Until now, I don’t think any cancer patients have not received care, so still, we are in a positive situation, but the waiting list can enlarge in the near future,” Dr. Rutkowsli commented.

Indeed, the anticipated increase will “likely exceed the possibilities of the Polish health system” soon, warned Jacek Jassem, MD, PhD, professor of clinical oncology and radiotherapy and the head of the department of oncology and radiotherapy at the Medical University of Gdansk, Poland.

Although there is an EU international agreement for a more widespread allocation of cancer patients, “when they come to Poland, many of them want to be treated in Poland, because they have family here, the language is more familiar.”

Dr. Jassem suggests the best way to avoid overwhelming host cancer centers is to triage patients directly from Ukraine. “Some therapies shouldn’t be interrupted. So, for example, radiotherapy started in Ukraine should be continued there, but otherwise, chemotherapy can be continued elsewhere, surgery may be postponed and done elsewhere. These are the decisions that should be considered in Ukraine, and then patients who are selected for particular therapies should be reallocated to other countries,” he suggested.

Romania has seen an influx of about 400,000 refugees, including cancer patients seeking systemic therapy, radiotherapy, or follow-up, said Nicoleta Antone, MD, a medical oncologist at the Cancer Institute of Ion Chiricuta in Cluj-Napoca, Romania. “We have seen patients mainly with breast cancer because most of the refugees [with cancer] are women looking for systemic therapy, but also all the other tumor types, both solid and hematologic tumors.”

Dr. Sullivan says attempts by EU member states to address cancer needs are complicated by the fact that many refugees are still on the move. They have been passing through their initial host countries and moving on to Greece, Slovenia, Austria, Germany, Italy, and Turkey, “making the therapeutic geographies at any potential time quite challenging to keep an eye on.” Other countries, such as Moldova, are not part of the EU, “so we dealing with some really quite complex political and financial issues.”

The situation calls for a broader approach to refugees generally, he added. “We’re talking free cancer care for Ukrainian patients, but there’s also, of course, this dialogue of ensuring there’s free care for all refugees. Europe already has a large refugee contingent from other countries, so there’s no doubt this is an opportunity to talk more broadly about cancer care for refugees and also progressive universalism.

“You can’t have rules for one set of patients and a different set of rules for another set of patients, so there’s going to be a real issue around fairness and equity which Europe is going to have to address,” he said.

In an attempt, ASCO and ECO have joined forces in a special network, noted Julie Gralow, MD, chief medical officer at ASCO.

“The ECO/ASCO Special Network is all about collaboration and coordination across professional societies, across cancer patient groups, across academic and other clinical centers. We’re providing information in the various national languages and trying to amplify the work that each of us is doing. ... We’re sharing intelligence, regular reports from the field, information, experience, and most of all, contacts. We’re all being approached individually about people who need help or people who want to help, and we’re trying to bring this all together in a focused way.”

Separately, there is also an ASCO resource page, as well as an ECO resource page.

The American Cancer Society also has patient resources on their site, including a 24-hour international call center in multiple languages and a Volunteer Corp of Clinicians, which currently has 123 active volunteers (and another 300 applicants) available to answer questions.

Europe and other countries must consider both a medium and a long-term commitment to refugees with cancer, said Dr. Sullivan. “Because even if the war stopped tomorrow, it’s going to take between a year and a year and a half to rebuild cancer care in Ukraine.”

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