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Second Ustekinumab Biosimilar Gets FDA Approval
The US Food and Drug Administration (FDA) has approved the biosimilar ustekinumab-aekn (Selarsdi) for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in adults and pediatric patients aged 6 years or older.
This is the second ustekinumab biosimilar approved by the regulatory agency and is the second biosimilar approval in the United States for the Icelandic pharmaceutical company Alvotech in partnership with Teva Pharmaceuticals.
Ustekinumab (Stelara) is a human monoclonal antibody targeting interleukin (IL)–12 and IL-23. The drug, manufactured by Johnson & Johnson, totaled nearly $7 billion in sales in 2023 alone, according a press release.
“Bringing Selarsdi to market in the US early next year presents a significant opportunity to improve patient access to a vital biologic in inflammatory disease and contribute to the reduction of inflationary pressure in healthcare costs,” the chairman and CEO of Alvotech said in the release.
The first ustekinumab biosimilar, ustekinumab-auub (Wezlana), was approved by the FDA in on October 31, 2023 and is interchangeable with the reference product. This allows pharmacists to substitute the biosimilar for the reference product without involving the prescribing clinician (according to state law). Besides psoriasis and psoriatic arthritis, ustekinumab-auub was also approved for treating moderate to severely active Crohn’s disease and ulcerative colitis. Ustekinumab-aekn does not have an interchangeability designation and was not approved for Crohn’s disease or ulcerative colitis.
The approval of ustekinumab-aekn was based on two clinical studies. A randomized, double blind, multicenter, 52-week study of 581 patients with moderate to severe plaque psoriasis demonstrated that the biosimilar was as effective as the reference product, with equivalent safety and immunogenicity profiles. A phase 1, randomized, double-blind, single-dose, parallel-group, three-arm study also compared the pharmacokinetic profile of the biosimilar to ustekinumab in 294 healthy adults.
Ustekinumab-aekn is expected to be marketed in the United States on or after February 21, 2025 per a settlement and license agreement with Johnson & Johnson.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved the biosimilar ustekinumab-aekn (Selarsdi) for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in adults and pediatric patients aged 6 years or older.
This is the second ustekinumab biosimilar approved by the regulatory agency and is the second biosimilar approval in the United States for the Icelandic pharmaceutical company Alvotech in partnership with Teva Pharmaceuticals.
Ustekinumab (Stelara) is a human monoclonal antibody targeting interleukin (IL)–12 and IL-23. The drug, manufactured by Johnson & Johnson, totaled nearly $7 billion in sales in 2023 alone, according a press release.
“Bringing Selarsdi to market in the US early next year presents a significant opportunity to improve patient access to a vital biologic in inflammatory disease and contribute to the reduction of inflationary pressure in healthcare costs,” the chairman and CEO of Alvotech said in the release.
The first ustekinumab biosimilar, ustekinumab-auub (Wezlana), was approved by the FDA in on October 31, 2023 and is interchangeable with the reference product. This allows pharmacists to substitute the biosimilar for the reference product without involving the prescribing clinician (according to state law). Besides psoriasis and psoriatic arthritis, ustekinumab-auub was also approved for treating moderate to severely active Crohn’s disease and ulcerative colitis. Ustekinumab-aekn does not have an interchangeability designation and was not approved for Crohn’s disease or ulcerative colitis.
The approval of ustekinumab-aekn was based on two clinical studies. A randomized, double blind, multicenter, 52-week study of 581 patients with moderate to severe plaque psoriasis demonstrated that the biosimilar was as effective as the reference product, with equivalent safety and immunogenicity profiles. A phase 1, randomized, double-blind, single-dose, parallel-group, three-arm study also compared the pharmacokinetic profile of the biosimilar to ustekinumab in 294 healthy adults.
Ustekinumab-aekn is expected to be marketed in the United States on or after February 21, 2025 per a settlement and license agreement with Johnson & Johnson.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved the biosimilar ustekinumab-aekn (Selarsdi) for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in adults and pediatric patients aged 6 years or older.
This is the second ustekinumab biosimilar approved by the regulatory agency and is the second biosimilar approval in the United States for the Icelandic pharmaceutical company Alvotech in partnership with Teva Pharmaceuticals.
Ustekinumab (Stelara) is a human monoclonal antibody targeting interleukin (IL)–12 and IL-23. The drug, manufactured by Johnson & Johnson, totaled nearly $7 billion in sales in 2023 alone, according a press release.
“Bringing Selarsdi to market in the US early next year presents a significant opportunity to improve patient access to a vital biologic in inflammatory disease and contribute to the reduction of inflationary pressure in healthcare costs,” the chairman and CEO of Alvotech said in the release.
The first ustekinumab biosimilar, ustekinumab-auub (Wezlana), was approved by the FDA in on October 31, 2023 and is interchangeable with the reference product. This allows pharmacists to substitute the biosimilar for the reference product without involving the prescribing clinician (according to state law). Besides psoriasis and psoriatic arthritis, ustekinumab-auub was also approved for treating moderate to severely active Crohn’s disease and ulcerative colitis. Ustekinumab-aekn does not have an interchangeability designation and was not approved for Crohn’s disease or ulcerative colitis.
The approval of ustekinumab-aekn was based on two clinical studies. A randomized, double blind, multicenter, 52-week study of 581 patients with moderate to severe plaque psoriasis demonstrated that the biosimilar was as effective as the reference product, with equivalent safety and immunogenicity profiles. A phase 1, randomized, double-blind, single-dose, parallel-group, three-arm study also compared the pharmacokinetic profile of the biosimilar to ustekinumab in 294 healthy adults.
Ustekinumab-aekn is expected to be marketed in the United States on or after February 21, 2025 per a settlement and license agreement with Johnson & Johnson.
A version of this article appeared on Medscape.com.
What’s Driving the Higher Breast Cancer Death Rate in Black Women?
More women today are surviving breast cancer if it’s caught early, largely because of better screening and more effective and targeted treatments.
However, not everyone has benefited equitably from this progress. Critical gaps in breast cancer outcomes and survival remain for women in racial and ethnic minority groups.
Black women for instance, have a 41% higher death rate from breast cancer compared with White patients. They also have a greater incidence of aggressive disease like triple-negative breast cancer. Native American and Hispanic women, meanwhile, are more likely to be diagnosed with breast cancer at an earlier age than White women and experience more aggressive breast cancers.
In 2023, Farhad Islami, MD, PhD, and his team published an updated analysis of racial/ethnic and socioeconomic disparities in cancer trends based on data from 2014 to 2020. The analysis found that Black women in particular, were the least likely to have an early-stage diagnosis of breast cancer. Localized‐stage breast cancer was diagnosed in 57% of Black women versus 68% of White women.
“Despite substantial progress in cancer prevention, early detection, and treatments, the burden of cancer remains greater among populations that have been historically marginalized, including people of color, people with lower socioeconomic status, and people living in nonmetropolitan areas,” said Dr. Islami, who is senior scientific director of cancer disparity research in the Surveillance & Health Equity Science Department at the American Cancer Society.
The reasons behind outcomes disparities in breast cancer are complex, making solutions challenging, say experts researching racial differences in cancer outcomes.
Among the findings of this research is that breast cancer tests may be contributing to the disparities and misguiding care for some patients of color.
SDH and Screening Rates Differences By Race
A range of factors contribute to racial and ethnic disparities in breast cancer outcomes, said Pamela Ganschow, MD, an associate professor in the Department of Internal Medicine at the University of Illinois Cancer Center in Chicago and part of the university’s Cancer Prevention and Control research program. These include socioeconomic status, access to timely and high-quality care across the cancer control continuum, cultural beliefs, differences in genetic makeup and tumor biology, as well as system biases, such as implicit biases and systemic racism, Dr. Ganschow said.
Dr. Islami adds that gaps in access to cancer prevention, early detection, and treatment are largely rooted in fundamental inequities in social determinants of health (SDH), such as whether a patient has safe housing, transportation, education, job opportunities, income, access to nutritious foods, and language and literacy skills, among others.
Dr. Islami’s analysis, for example, shows that people of color are generally more likely to have lower educational attainment and to experience poverty, food insecurity, and housing insecurity compared with White people. Among people aged 18-64 years, the age-adjusted proportion of individuals with no health insurance in 2021 was also higher among Black (13.7%), American Indian/Alaskan Native (18.7%), and Hispanic (28.7%) patients than among White (7.8%) or Asian (5.9%) people, according to the report.
Competing needs can also get in the way of prioritizing cancer screenings, especially for patients in lower socio-economic populations, Dr. Ganschow said.
“You’ve got people who are working a job or three jobs, just to make ends meet for their family and can’t necessarily take time off to get that done,” she said. “Nor is it prioritized in their head because they’ve got to put a meal on the table.”
But the racial disparities between Black and White women, at least, are not clearly explained by differences between the screening rates..
Of patients who received mammograms 76% were White and 79% were Black, according to another recent study coauthored by Dr. Islami. While Black women appear to have the highest breast cancer screening rates, some data suggest such rates are being overreported.
Lower screening rates were seen in American Indian/Alaska Native (59%), Asian (67%), and Hispanic women (74%).
Biological Differences, Bad Testing Recommendations May Contribute to Poor Outcomes
Differences in biology may be one overlooked internal driver of lower breast cancer survival in Black women.
Researchers at Sanford Burnham Prebys in La Jolla, California, recently analyzed the breast cells of White and Black women, finding significant molecular differences that may be contributing to higher breast cancer mortality rates in Black women.
Investigators analyzed both healthy tissue and tumor tissue from 185 Black women and compared the samples to that of White women. They discovered differences among Black and White women in the way their DNA repair genes are expressed, both in healthy breast tissue and in tumors positive for estrogen receptor breast cancer. Molecular differences were also present in the cellular signals that control how fast cells, including cancer cells, grow.
DNA repair is part of normal cellular function and helps cells recover from damage that can occur during DNA replication or in response to external factors, such as stress.
“One of the first lines of defense, to prevent the cell from becoming a tumor are DNA damage repair pathways,” said Svasti Haricharan, PhD, a coauthor of the study and an assistant professor at Sanford Burnham Prebys. “We know there are many different DNA damage repair pathways that respond to different types of DNA damage. What we didn’t know was that, even in our normal cells, based on your race and ethnicity, you have different levels of DNA repair proteins.”
The study found that many of the proteins associated with endocrine resistance and poor outcomes in breast cancer patients are differently regulated in Black women compared with White woman. These differences contribute to resistance to standard endocrine therapy, Dr. Haricharan said.
“Because we never studied the biology in Black woman, it was just assumed that across all demographics, it must be the same,” she said. “We are not even accounting for the possibility there are likely intrinsic differences for how you will respond to an endocrine treatment.”
Testing and treatment may also be playing a role in worse breast cancer outcomes for Black women.
In an analysis of 73,363 women with early-stage, estrogen receptor–positive breast cancer, investigators found that a common test used to decide the treatment course for patients may be leading to bad recommendations for Black women.
The test, known as the 21-gene breast recurrence score, is the most commonly ordered biomarker test used to guide doctor’s recommendations for patients with estrogen receptor–positive breast cancer, the most common form of cancer in Black women, representing about 70%-80% of cases.
The test helps physicians identify which patients are good candidates for chemo, but the test may underestimate the benefit of chemo for Black women. It ranks some Black women as unlikely to benefit from chemo, when they actually would have benefited, according to the January 2024 study, published in the Journal of the National Comprehensive Cancer Network.
The test gives a score of zero to 100, explains Kent Hoskins, MD, oncology service line medical director at the University of Illinois (UI) Health and director of the Familial Breast Cancer Clinic at UI Health, both in Chicago. The higher the score, the higher the risk and the greater the benefit of chemotherapy. A patient is either above the cut-off score and receives chemo, or is below the cut-off score and does not. In the analysis, investigators found that Black women start improving with chemo at a lower score than White women do.
Dr. Hoskins said the results raise questions about whether the biomarker test should be modified to be more applicable to Black women, whether other tests should be used, or if physicians should judge cut-off scores differently, depending on race.
How Neighborhood Impacts Breast Cancer, Death Rates
Living in a disadvantaged neighborhood also lowers breast cancer survival, according to new research. A disadvantaged neighborhood is generally defined as a location associated with higher concentrations of poverty, higher rates of unemployment, and less access to health care, quality housing, food, and community resources, according to the Centers for Disease Control and Prevention.
Authors of a study published in JAMA Network Open on April 18 identified 350,824 patients with breast cancer. Of these, 41,519 (11.8%) were Hispanic, 39,631 (11.3%) were non-Hispanic Black, and 234,698 (66.9%) were non-Hispanic White. Investigators divided the patients into five groups representing the lowest to highest neighborhood socioeconomic indices using the Yost Index. (The Yost Index is used by the National Cancer Institute for cancer surveillance and is based on variables such as household income, home value, median rent, percentage below 150% of the poverty line, education, and unemployment.)
Of the Black and Hispanic patients in the study, the highest proportions of both demographics lived in the most disadvantaged neighborhoods. (16,141 Black patients [30.9%]) and 10,168 Hispanic patients [19.5%]). Although 45% of White patients also fell into that same category, the highest proportion of White patients in the study lived in the most advantaged neighborhoods (66,529 patients [76.2%]).
Findings showed patients in the most disadvantaged neighborhoods had the highest proportion of triple-negative breast cancer. Patients in this group also had the lowest proportion of patients who completed surgery and radiation, and the highest proportion of patients who received chemotherapy, compared with all other neighborhood groups. The most advantaged neighborhoods group had higher proportions of localized-stage cancer, a higher proportion of patients who underwent surgery and radiation, and the lowest proportion of patients receiving chemotherapy treatment.
Patients in the most disadvantaged neighborhoods also had the highest risk of mortality (hazard ratio [HR,] 1.53; 95% CI, 1.48-1.59; P less than .001) compared with patients living in the most advantaged neighborhoods. Non-Hispanic Black patients in particular, had the highest risk of mortality, compared with non-Hispanic White patients (HR, 1.16; 95% CI, 1.13-1.20; P less than .001).
Authors wrote that the findings suggest neighborhood disadvantage is independently associated with shorter survival in patients with breast cancer, even after controlling for individual-level factors, tumor characteristics, and treatment.
“To address these residual disparities associated with neighborhood disadvantage, research must focus on which components of the built environment influence outcomes,” the authors said.
Another recent study also found correlations among where breast cancer patients lived and how they fared with the disease.
Jasmine M. Miller-Kleinhenz, PhD, an assistant professor at University of Mississippi Medical Center in Jackson, studied how historical redlining impacts breast cancer development and outcomes in her research published in JAMA Network Open, earlier this year. Redlining refers to the practice of denying people access to credit because of where they live. Historically, mortgage lenders widely redlined neighborhoods with predominantly Black residents. The 1968 Fair Housing Act outlawed racially motivated redlining, but consequences from historical redlining still exist.
Dr. Miller-Kleinhenz and her colleagues analyzed a cohort of 1764 women diagnosed with breast cancer between January 2010 and December 2017, who were followed up through December 2019. Investigators accessed the cohort based on three exposures: historic redlining (HRL), contemporary mortgage discrimination (CMD), and persistent mortgage discrimination (PMD). Contemporary mortgage discrimination refers to current-day discriminatory mortgage practices and persistent mortgage discrimination refers to neighborhoods that have experienced both HRL and CMD.
Findings showed that Black women living in historical redlined areas had increased odds of being diagnosed with aggressive forms of breast cancer, while White women in redlined areas had increased odds of late-stage diagnosis.
White women exposed to persistent mortgage discrimination were twice as likely to die of breast cancer, compared with their White counterparts living in areas without historical redlining or contemporary mortgage discrimination, the study found.
That is not to say that Black women did not have an increased risk of breast cancer mortality, Dr. Miller-Kleinhenz explained. Black women had a more than threefold elevated risk of breast cancer mortality compared with White women no matter where they lived, according to the findings.
“These results were surprising because it is showing that while neighborhood conditions might be a major driver of breast cancer mortality in White women, there are factors beyond the neighborhood that are additional drivers that are contributing to poor outcomes in Black women,” she said.
Hope for Improved Outcomes, Higher Survival Rates
Investigators hope the findings of all of this new research lead to better, more targeted treatments and, in turn, improved outcomes.
Dr. Haricharan is optimistic about the improvement of breast cancer outcomes as more is learned about the biology of Black patients and other non-White patients.
There is a growing effort to include more data from minoritized populations in breast cancer research studies, Dr. Haricharan said, and she foresees associated changes to clinical protocols in the future. Her own team is working on creating larger data sets that are more representative of non-White patients to further analyze the differences found in their prior study.
“I think there’s this understanding that, until we have data sets that are more representative, we really are catering to [only one] population in terms of our diagnostic and therapeutic technological advances,” she said.
The American Cancer Society meanwhile, is launching a new initiative in May that aims to collect more health data from Black women to ultimately develop more effective cancer interventions. VOICES of Black Women will focus on collecting and studying health data from Black women through online surveys. The society’s goal is to enroll at least 100,000 Black women in the United States between ages 25 and 55.
Dr. Miller-Kleinhenz called the initiative “an important step to starting to research and answer some of these lingering questions about why there continue to be breast cancer disparities.”
More women today are surviving breast cancer if it’s caught early, largely because of better screening and more effective and targeted treatments.
However, not everyone has benefited equitably from this progress. Critical gaps in breast cancer outcomes and survival remain for women in racial and ethnic minority groups.
Black women for instance, have a 41% higher death rate from breast cancer compared with White patients. They also have a greater incidence of aggressive disease like triple-negative breast cancer. Native American and Hispanic women, meanwhile, are more likely to be diagnosed with breast cancer at an earlier age than White women and experience more aggressive breast cancers.
In 2023, Farhad Islami, MD, PhD, and his team published an updated analysis of racial/ethnic and socioeconomic disparities in cancer trends based on data from 2014 to 2020. The analysis found that Black women in particular, were the least likely to have an early-stage diagnosis of breast cancer. Localized‐stage breast cancer was diagnosed in 57% of Black women versus 68% of White women.
“Despite substantial progress in cancer prevention, early detection, and treatments, the burden of cancer remains greater among populations that have been historically marginalized, including people of color, people with lower socioeconomic status, and people living in nonmetropolitan areas,” said Dr. Islami, who is senior scientific director of cancer disparity research in the Surveillance & Health Equity Science Department at the American Cancer Society.
The reasons behind outcomes disparities in breast cancer are complex, making solutions challenging, say experts researching racial differences in cancer outcomes.
Among the findings of this research is that breast cancer tests may be contributing to the disparities and misguiding care for some patients of color.
SDH and Screening Rates Differences By Race
A range of factors contribute to racial and ethnic disparities in breast cancer outcomes, said Pamela Ganschow, MD, an associate professor in the Department of Internal Medicine at the University of Illinois Cancer Center in Chicago and part of the university’s Cancer Prevention and Control research program. These include socioeconomic status, access to timely and high-quality care across the cancer control continuum, cultural beliefs, differences in genetic makeup and tumor biology, as well as system biases, such as implicit biases and systemic racism, Dr. Ganschow said.
Dr. Islami adds that gaps in access to cancer prevention, early detection, and treatment are largely rooted in fundamental inequities in social determinants of health (SDH), such as whether a patient has safe housing, transportation, education, job opportunities, income, access to nutritious foods, and language and literacy skills, among others.
Dr. Islami’s analysis, for example, shows that people of color are generally more likely to have lower educational attainment and to experience poverty, food insecurity, and housing insecurity compared with White people. Among people aged 18-64 years, the age-adjusted proportion of individuals with no health insurance in 2021 was also higher among Black (13.7%), American Indian/Alaskan Native (18.7%), and Hispanic (28.7%) patients than among White (7.8%) or Asian (5.9%) people, according to the report.
Competing needs can also get in the way of prioritizing cancer screenings, especially for patients in lower socio-economic populations, Dr. Ganschow said.
“You’ve got people who are working a job or three jobs, just to make ends meet for their family and can’t necessarily take time off to get that done,” she said. “Nor is it prioritized in their head because they’ve got to put a meal on the table.”
But the racial disparities between Black and White women, at least, are not clearly explained by differences between the screening rates..
Of patients who received mammograms 76% were White and 79% were Black, according to another recent study coauthored by Dr. Islami. While Black women appear to have the highest breast cancer screening rates, some data suggest such rates are being overreported.
Lower screening rates were seen in American Indian/Alaska Native (59%), Asian (67%), and Hispanic women (74%).
Biological Differences, Bad Testing Recommendations May Contribute to Poor Outcomes
Differences in biology may be one overlooked internal driver of lower breast cancer survival in Black women.
Researchers at Sanford Burnham Prebys in La Jolla, California, recently analyzed the breast cells of White and Black women, finding significant molecular differences that may be contributing to higher breast cancer mortality rates in Black women.
Investigators analyzed both healthy tissue and tumor tissue from 185 Black women and compared the samples to that of White women. They discovered differences among Black and White women in the way their DNA repair genes are expressed, both in healthy breast tissue and in tumors positive for estrogen receptor breast cancer. Molecular differences were also present in the cellular signals that control how fast cells, including cancer cells, grow.
DNA repair is part of normal cellular function and helps cells recover from damage that can occur during DNA replication or in response to external factors, such as stress.
“One of the first lines of defense, to prevent the cell from becoming a tumor are DNA damage repair pathways,” said Svasti Haricharan, PhD, a coauthor of the study and an assistant professor at Sanford Burnham Prebys. “We know there are many different DNA damage repair pathways that respond to different types of DNA damage. What we didn’t know was that, even in our normal cells, based on your race and ethnicity, you have different levels of DNA repair proteins.”
The study found that many of the proteins associated with endocrine resistance and poor outcomes in breast cancer patients are differently regulated in Black women compared with White woman. These differences contribute to resistance to standard endocrine therapy, Dr. Haricharan said.
“Because we never studied the biology in Black woman, it was just assumed that across all demographics, it must be the same,” she said. “We are not even accounting for the possibility there are likely intrinsic differences for how you will respond to an endocrine treatment.”
Testing and treatment may also be playing a role in worse breast cancer outcomes for Black women.
In an analysis of 73,363 women with early-stage, estrogen receptor–positive breast cancer, investigators found that a common test used to decide the treatment course for patients may be leading to bad recommendations for Black women.
The test, known as the 21-gene breast recurrence score, is the most commonly ordered biomarker test used to guide doctor’s recommendations for patients with estrogen receptor–positive breast cancer, the most common form of cancer in Black women, representing about 70%-80% of cases.
The test helps physicians identify which patients are good candidates for chemo, but the test may underestimate the benefit of chemo for Black women. It ranks some Black women as unlikely to benefit from chemo, when they actually would have benefited, according to the January 2024 study, published in the Journal of the National Comprehensive Cancer Network.
The test gives a score of zero to 100, explains Kent Hoskins, MD, oncology service line medical director at the University of Illinois (UI) Health and director of the Familial Breast Cancer Clinic at UI Health, both in Chicago. The higher the score, the higher the risk and the greater the benefit of chemotherapy. A patient is either above the cut-off score and receives chemo, or is below the cut-off score and does not. In the analysis, investigators found that Black women start improving with chemo at a lower score than White women do.
Dr. Hoskins said the results raise questions about whether the biomarker test should be modified to be more applicable to Black women, whether other tests should be used, or if physicians should judge cut-off scores differently, depending on race.
How Neighborhood Impacts Breast Cancer, Death Rates
Living in a disadvantaged neighborhood also lowers breast cancer survival, according to new research. A disadvantaged neighborhood is generally defined as a location associated with higher concentrations of poverty, higher rates of unemployment, and less access to health care, quality housing, food, and community resources, according to the Centers for Disease Control and Prevention.
Authors of a study published in JAMA Network Open on April 18 identified 350,824 patients with breast cancer. Of these, 41,519 (11.8%) were Hispanic, 39,631 (11.3%) were non-Hispanic Black, and 234,698 (66.9%) were non-Hispanic White. Investigators divided the patients into five groups representing the lowest to highest neighborhood socioeconomic indices using the Yost Index. (The Yost Index is used by the National Cancer Institute for cancer surveillance and is based on variables such as household income, home value, median rent, percentage below 150% of the poverty line, education, and unemployment.)
Of the Black and Hispanic patients in the study, the highest proportions of both demographics lived in the most disadvantaged neighborhoods. (16,141 Black patients [30.9%]) and 10,168 Hispanic patients [19.5%]). Although 45% of White patients also fell into that same category, the highest proportion of White patients in the study lived in the most advantaged neighborhoods (66,529 patients [76.2%]).
Findings showed patients in the most disadvantaged neighborhoods had the highest proportion of triple-negative breast cancer. Patients in this group also had the lowest proportion of patients who completed surgery and radiation, and the highest proportion of patients who received chemotherapy, compared with all other neighborhood groups. The most advantaged neighborhoods group had higher proportions of localized-stage cancer, a higher proportion of patients who underwent surgery and radiation, and the lowest proportion of patients receiving chemotherapy treatment.
Patients in the most disadvantaged neighborhoods also had the highest risk of mortality (hazard ratio [HR,] 1.53; 95% CI, 1.48-1.59; P less than .001) compared with patients living in the most advantaged neighborhoods. Non-Hispanic Black patients in particular, had the highest risk of mortality, compared with non-Hispanic White patients (HR, 1.16; 95% CI, 1.13-1.20; P less than .001).
Authors wrote that the findings suggest neighborhood disadvantage is independently associated with shorter survival in patients with breast cancer, even after controlling for individual-level factors, tumor characteristics, and treatment.
“To address these residual disparities associated with neighborhood disadvantage, research must focus on which components of the built environment influence outcomes,” the authors said.
Another recent study also found correlations among where breast cancer patients lived and how they fared with the disease.
Jasmine M. Miller-Kleinhenz, PhD, an assistant professor at University of Mississippi Medical Center in Jackson, studied how historical redlining impacts breast cancer development and outcomes in her research published in JAMA Network Open, earlier this year. Redlining refers to the practice of denying people access to credit because of where they live. Historically, mortgage lenders widely redlined neighborhoods with predominantly Black residents. The 1968 Fair Housing Act outlawed racially motivated redlining, but consequences from historical redlining still exist.
Dr. Miller-Kleinhenz and her colleagues analyzed a cohort of 1764 women diagnosed with breast cancer between January 2010 and December 2017, who were followed up through December 2019. Investigators accessed the cohort based on three exposures: historic redlining (HRL), contemporary mortgage discrimination (CMD), and persistent mortgage discrimination (PMD). Contemporary mortgage discrimination refers to current-day discriminatory mortgage practices and persistent mortgage discrimination refers to neighborhoods that have experienced both HRL and CMD.
Findings showed that Black women living in historical redlined areas had increased odds of being diagnosed with aggressive forms of breast cancer, while White women in redlined areas had increased odds of late-stage diagnosis.
White women exposed to persistent mortgage discrimination were twice as likely to die of breast cancer, compared with their White counterparts living in areas without historical redlining or contemporary mortgage discrimination, the study found.
That is not to say that Black women did not have an increased risk of breast cancer mortality, Dr. Miller-Kleinhenz explained. Black women had a more than threefold elevated risk of breast cancer mortality compared with White women no matter where they lived, according to the findings.
“These results were surprising because it is showing that while neighborhood conditions might be a major driver of breast cancer mortality in White women, there are factors beyond the neighborhood that are additional drivers that are contributing to poor outcomes in Black women,” she said.
Hope for Improved Outcomes, Higher Survival Rates
Investigators hope the findings of all of this new research lead to better, more targeted treatments and, in turn, improved outcomes.
Dr. Haricharan is optimistic about the improvement of breast cancer outcomes as more is learned about the biology of Black patients and other non-White patients.
There is a growing effort to include more data from minoritized populations in breast cancer research studies, Dr. Haricharan said, and she foresees associated changes to clinical protocols in the future. Her own team is working on creating larger data sets that are more representative of non-White patients to further analyze the differences found in their prior study.
“I think there’s this understanding that, until we have data sets that are more representative, we really are catering to [only one] population in terms of our diagnostic and therapeutic technological advances,” she said.
The American Cancer Society meanwhile, is launching a new initiative in May that aims to collect more health data from Black women to ultimately develop more effective cancer interventions. VOICES of Black Women will focus on collecting and studying health data from Black women through online surveys. The society’s goal is to enroll at least 100,000 Black women in the United States between ages 25 and 55.
Dr. Miller-Kleinhenz called the initiative “an important step to starting to research and answer some of these lingering questions about why there continue to be breast cancer disparities.”
More women today are surviving breast cancer if it’s caught early, largely because of better screening and more effective and targeted treatments.
However, not everyone has benefited equitably from this progress. Critical gaps in breast cancer outcomes and survival remain for women in racial and ethnic minority groups.
Black women for instance, have a 41% higher death rate from breast cancer compared with White patients. They also have a greater incidence of aggressive disease like triple-negative breast cancer. Native American and Hispanic women, meanwhile, are more likely to be diagnosed with breast cancer at an earlier age than White women and experience more aggressive breast cancers.
In 2023, Farhad Islami, MD, PhD, and his team published an updated analysis of racial/ethnic and socioeconomic disparities in cancer trends based on data from 2014 to 2020. The analysis found that Black women in particular, were the least likely to have an early-stage diagnosis of breast cancer. Localized‐stage breast cancer was diagnosed in 57% of Black women versus 68% of White women.
“Despite substantial progress in cancer prevention, early detection, and treatments, the burden of cancer remains greater among populations that have been historically marginalized, including people of color, people with lower socioeconomic status, and people living in nonmetropolitan areas,” said Dr. Islami, who is senior scientific director of cancer disparity research in the Surveillance & Health Equity Science Department at the American Cancer Society.
The reasons behind outcomes disparities in breast cancer are complex, making solutions challenging, say experts researching racial differences in cancer outcomes.
Among the findings of this research is that breast cancer tests may be contributing to the disparities and misguiding care for some patients of color.
SDH and Screening Rates Differences By Race
A range of factors contribute to racial and ethnic disparities in breast cancer outcomes, said Pamela Ganschow, MD, an associate professor in the Department of Internal Medicine at the University of Illinois Cancer Center in Chicago and part of the university’s Cancer Prevention and Control research program. These include socioeconomic status, access to timely and high-quality care across the cancer control continuum, cultural beliefs, differences in genetic makeup and tumor biology, as well as system biases, such as implicit biases and systemic racism, Dr. Ganschow said.
Dr. Islami adds that gaps in access to cancer prevention, early detection, and treatment are largely rooted in fundamental inequities in social determinants of health (SDH), such as whether a patient has safe housing, transportation, education, job opportunities, income, access to nutritious foods, and language and literacy skills, among others.
Dr. Islami’s analysis, for example, shows that people of color are generally more likely to have lower educational attainment and to experience poverty, food insecurity, and housing insecurity compared with White people. Among people aged 18-64 years, the age-adjusted proportion of individuals with no health insurance in 2021 was also higher among Black (13.7%), American Indian/Alaskan Native (18.7%), and Hispanic (28.7%) patients than among White (7.8%) or Asian (5.9%) people, according to the report.
Competing needs can also get in the way of prioritizing cancer screenings, especially for patients in lower socio-economic populations, Dr. Ganschow said.
“You’ve got people who are working a job or three jobs, just to make ends meet for their family and can’t necessarily take time off to get that done,” she said. “Nor is it prioritized in their head because they’ve got to put a meal on the table.”
But the racial disparities between Black and White women, at least, are not clearly explained by differences between the screening rates..
Of patients who received mammograms 76% were White and 79% were Black, according to another recent study coauthored by Dr. Islami. While Black women appear to have the highest breast cancer screening rates, some data suggest such rates are being overreported.
Lower screening rates were seen in American Indian/Alaska Native (59%), Asian (67%), and Hispanic women (74%).
Biological Differences, Bad Testing Recommendations May Contribute to Poor Outcomes
Differences in biology may be one overlooked internal driver of lower breast cancer survival in Black women.
Researchers at Sanford Burnham Prebys in La Jolla, California, recently analyzed the breast cells of White and Black women, finding significant molecular differences that may be contributing to higher breast cancer mortality rates in Black women.
Investigators analyzed both healthy tissue and tumor tissue from 185 Black women and compared the samples to that of White women. They discovered differences among Black and White women in the way their DNA repair genes are expressed, both in healthy breast tissue and in tumors positive for estrogen receptor breast cancer. Molecular differences were also present in the cellular signals that control how fast cells, including cancer cells, grow.
DNA repair is part of normal cellular function and helps cells recover from damage that can occur during DNA replication or in response to external factors, such as stress.
“One of the first lines of defense, to prevent the cell from becoming a tumor are DNA damage repair pathways,” said Svasti Haricharan, PhD, a coauthor of the study and an assistant professor at Sanford Burnham Prebys. “We know there are many different DNA damage repair pathways that respond to different types of DNA damage. What we didn’t know was that, even in our normal cells, based on your race and ethnicity, you have different levels of DNA repair proteins.”
The study found that many of the proteins associated with endocrine resistance and poor outcomes in breast cancer patients are differently regulated in Black women compared with White woman. These differences contribute to resistance to standard endocrine therapy, Dr. Haricharan said.
“Because we never studied the biology in Black woman, it was just assumed that across all demographics, it must be the same,” she said. “We are not even accounting for the possibility there are likely intrinsic differences for how you will respond to an endocrine treatment.”
Testing and treatment may also be playing a role in worse breast cancer outcomes for Black women.
In an analysis of 73,363 women with early-stage, estrogen receptor–positive breast cancer, investigators found that a common test used to decide the treatment course for patients may be leading to bad recommendations for Black women.
The test, known as the 21-gene breast recurrence score, is the most commonly ordered biomarker test used to guide doctor’s recommendations for patients with estrogen receptor–positive breast cancer, the most common form of cancer in Black women, representing about 70%-80% of cases.
The test helps physicians identify which patients are good candidates for chemo, but the test may underestimate the benefit of chemo for Black women. It ranks some Black women as unlikely to benefit from chemo, when they actually would have benefited, according to the January 2024 study, published in the Journal of the National Comprehensive Cancer Network.
The test gives a score of zero to 100, explains Kent Hoskins, MD, oncology service line medical director at the University of Illinois (UI) Health and director of the Familial Breast Cancer Clinic at UI Health, both in Chicago. The higher the score, the higher the risk and the greater the benefit of chemotherapy. A patient is either above the cut-off score and receives chemo, or is below the cut-off score and does not. In the analysis, investigators found that Black women start improving with chemo at a lower score than White women do.
Dr. Hoskins said the results raise questions about whether the biomarker test should be modified to be more applicable to Black women, whether other tests should be used, or if physicians should judge cut-off scores differently, depending on race.
How Neighborhood Impacts Breast Cancer, Death Rates
Living in a disadvantaged neighborhood also lowers breast cancer survival, according to new research. A disadvantaged neighborhood is generally defined as a location associated with higher concentrations of poverty, higher rates of unemployment, and less access to health care, quality housing, food, and community resources, according to the Centers for Disease Control and Prevention.
Authors of a study published in JAMA Network Open on April 18 identified 350,824 patients with breast cancer. Of these, 41,519 (11.8%) were Hispanic, 39,631 (11.3%) were non-Hispanic Black, and 234,698 (66.9%) were non-Hispanic White. Investigators divided the patients into five groups representing the lowest to highest neighborhood socioeconomic indices using the Yost Index. (The Yost Index is used by the National Cancer Institute for cancer surveillance and is based on variables such as household income, home value, median rent, percentage below 150% of the poverty line, education, and unemployment.)
Of the Black and Hispanic patients in the study, the highest proportions of both demographics lived in the most disadvantaged neighborhoods. (16,141 Black patients [30.9%]) and 10,168 Hispanic patients [19.5%]). Although 45% of White patients also fell into that same category, the highest proportion of White patients in the study lived in the most advantaged neighborhoods (66,529 patients [76.2%]).
Findings showed patients in the most disadvantaged neighborhoods had the highest proportion of triple-negative breast cancer. Patients in this group also had the lowest proportion of patients who completed surgery and radiation, and the highest proportion of patients who received chemotherapy, compared with all other neighborhood groups. The most advantaged neighborhoods group had higher proportions of localized-stage cancer, a higher proportion of patients who underwent surgery and radiation, and the lowest proportion of patients receiving chemotherapy treatment.
Patients in the most disadvantaged neighborhoods also had the highest risk of mortality (hazard ratio [HR,] 1.53; 95% CI, 1.48-1.59; P less than .001) compared with patients living in the most advantaged neighborhoods. Non-Hispanic Black patients in particular, had the highest risk of mortality, compared with non-Hispanic White patients (HR, 1.16; 95% CI, 1.13-1.20; P less than .001).
Authors wrote that the findings suggest neighborhood disadvantage is independently associated with shorter survival in patients with breast cancer, even after controlling for individual-level factors, tumor characteristics, and treatment.
“To address these residual disparities associated with neighborhood disadvantage, research must focus on which components of the built environment influence outcomes,” the authors said.
Another recent study also found correlations among where breast cancer patients lived and how they fared with the disease.
Jasmine M. Miller-Kleinhenz, PhD, an assistant professor at University of Mississippi Medical Center in Jackson, studied how historical redlining impacts breast cancer development and outcomes in her research published in JAMA Network Open, earlier this year. Redlining refers to the practice of denying people access to credit because of where they live. Historically, mortgage lenders widely redlined neighborhoods with predominantly Black residents. The 1968 Fair Housing Act outlawed racially motivated redlining, but consequences from historical redlining still exist.
Dr. Miller-Kleinhenz and her colleagues analyzed a cohort of 1764 women diagnosed with breast cancer between January 2010 and December 2017, who were followed up through December 2019. Investigators accessed the cohort based on three exposures: historic redlining (HRL), contemporary mortgage discrimination (CMD), and persistent mortgage discrimination (PMD). Contemporary mortgage discrimination refers to current-day discriminatory mortgage practices and persistent mortgage discrimination refers to neighborhoods that have experienced both HRL and CMD.
Findings showed that Black women living in historical redlined areas had increased odds of being diagnosed with aggressive forms of breast cancer, while White women in redlined areas had increased odds of late-stage diagnosis.
White women exposed to persistent mortgage discrimination were twice as likely to die of breast cancer, compared with their White counterparts living in areas without historical redlining or contemporary mortgage discrimination, the study found.
That is not to say that Black women did not have an increased risk of breast cancer mortality, Dr. Miller-Kleinhenz explained. Black women had a more than threefold elevated risk of breast cancer mortality compared with White women no matter where they lived, according to the findings.
“These results were surprising because it is showing that while neighborhood conditions might be a major driver of breast cancer mortality in White women, there are factors beyond the neighborhood that are additional drivers that are contributing to poor outcomes in Black women,” she said.
Hope for Improved Outcomes, Higher Survival Rates
Investigators hope the findings of all of this new research lead to better, more targeted treatments and, in turn, improved outcomes.
Dr. Haricharan is optimistic about the improvement of breast cancer outcomes as more is learned about the biology of Black patients and other non-White patients.
There is a growing effort to include more data from minoritized populations in breast cancer research studies, Dr. Haricharan said, and she foresees associated changes to clinical protocols in the future. Her own team is working on creating larger data sets that are more representative of non-White patients to further analyze the differences found in their prior study.
“I think there’s this understanding that, until we have data sets that are more representative, we really are catering to [only one] population in terms of our diagnostic and therapeutic technological advances,” she said.
The American Cancer Society meanwhile, is launching a new initiative in May that aims to collect more health data from Black women to ultimately develop more effective cancer interventions. VOICES of Black Women will focus on collecting and studying health data from Black women through online surveys. The society’s goal is to enroll at least 100,000 Black women in the United States between ages 25 and 55.
Dr. Miller-Kleinhenz called the initiative “an important step to starting to research and answer some of these lingering questions about why there continue to be breast cancer disparities.”
FDA Approves AI Diagnostic Tool for Early Sepsis Detection
The US Food and Drug Administration (FDA) has approved a medical device named the Sepsis ImmunoScore, which is an artificial intelligence/machine learning software, to guide rapid diagnosis and prediction of sepsis. The authorization was granted through the FDA’s De Novo pathway.
Sepsis is a complex condition, so diagnosing it early is difficult and has been a decades-long challenge for the US healthcare system.
Using both biomarkers and clinical data with the assistance of AI, the Sepsis ImmunoScore helps assess the risk for the presence of or progression to sepsis within 24 hours of patient evaluation in the emergency department or hospital. By considering 22 diverse parameters, the AI-powered tool provides a comprehensive evaluation of the patient’s biological condition, resulting in a risk score and categorization into four distinct risk levels.
It’s important to note that this system is not an alert mechanism. These risk categories are correlated with the risk for patient deterioration, including length of hospital stay, in-hospital mortality, and the need for escalated care within 24 hours (such as intensive care unit admission, mechanical ventilation, or vasopressor use). The diagnostic software is integrated directly into hospital electronic medical records.
This is the first AI diagnostic tool for sepsis to receive marketing authorization from the FDA.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved a medical device named the Sepsis ImmunoScore, which is an artificial intelligence/machine learning software, to guide rapid diagnosis and prediction of sepsis. The authorization was granted through the FDA’s De Novo pathway.
Sepsis is a complex condition, so diagnosing it early is difficult and has been a decades-long challenge for the US healthcare system.
Using both biomarkers and clinical data with the assistance of AI, the Sepsis ImmunoScore helps assess the risk for the presence of or progression to sepsis within 24 hours of patient evaluation in the emergency department or hospital. By considering 22 diverse parameters, the AI-powered tool provides a comprehensive evaluation of the patient’s biological condition, resulting in a risk score and categorization into four distinct risk levels.
It’s important to note that this system is not an alert mechanism. These risk categories are correlated with the risk for patient deterioration, including length of hospital stay, in-hospital mortality, and the need for escalated care within 24 hours (such as intensive care unit admission, mechanical ventilation, or vasopressor use). The diagnostic software is integrated directly into hospital electronic medical records.
This is the first AI diagnostic tool for sepsis to receive marketing authorization from the FDA.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved a medical device named the Sepsis ImmunoScore, which is an artificial intelligence/machine learning software, to guide rapid diagnosis and prediction of sepsis. The authorization was granted through the FDA’s De Novo pathway.
Sepsis is a complex condition, so diagnosing it early is difficult and has been a decades-long challenge for the US healthcare system.
Using both biomarkers and clinical data with the assistance of AI, the Sepsis ImmunoScore helps assess the risk for the presence of or progression to sepsis within 24 hours of patient evaluation in the emergency department or hospital. By considering 22 diverse parameters, the AI-powered tool provides a comprehensive evaluation of the patient’s biological condition, resulting in a risk score and categorization into four distinct risk levels.
It’s important to note that this system is not an alert mechanism. These risk categories are correlated with the risk for patient deterioration, including length of hospital stay, in-hospital mortality, and the need for escalated care within 24 hours (such as intensive care unit admission, mechanical ventilation, or vasopressor use). The diagnostic software is integrated directly into hospital electronic medical records.
This is the first AI diagnostic tool for sepsis to receive marketing authorization from the FDA.
A version of this article appeared on Medscape.com.
Timing Is Everything: CAR T for Follicular Lymphoma
“CAR T-cells offer patients with relapsed or refractory follicular lymphoma the most durable responses and improved chance of survival beyond all other available therapies. This holds true for a broad range of high-risk disease features in patients with relapsed or refractory FL. Furthermore, it accomplishes this with a single infusion, and a discrete toxicity that is predictable, reversible and manageable,” said Caron Jacobson, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.
Presenting at the Great Debates & Updates Hematologic Malignancies conference, held April 5-6 in New York City, Dr. Jacobson argued that more patients with R/R FL should be treated with CAR T.
She cited follow-up results from the ZUMA-5 study indicating that patients with R/R FL treated with the CAR T axicabtagene ciloleucel (YESCARTA; Kite Pharma) have a median progression free survival (PFS) of 57.3 months and a complete response rate (CR) of 80%. Furthermore, the lymphoma-specific four-year PFS appears to be reaching a plateau, suggesting that some patients treated with the agent may be cured.
The most significant drawback of treatment with axicabtagene ciloleucel is cytokine release syndrome (CRS) and neurotoxicity, which occurred at grade three and higher in 6% and 15%, of ZUMA-5 participants, respectively.
Two newer studies of anti-CD-19 CAR T-cell therapy in R/R FL, tisagenlecleucel in ELARA and lisocabtagene maraleucel in TRANSCEND FL, suggest that other CAR T-cell treatments can be as effective as axicabtagene ciloleucel, but with fewer side effects.
At a median follow up of 29 months, CR among patients in the ELARA study was 68.1%, and the overall response rate (ORR) was 86.2%. Fewer than half of patients had any CRS, and none had grade three or higher. Only 10% of patients had serious neurologic events, with only 1% of these events rated as grade three or higher.
At a median of 18.1 months, patients in the TRANSCEND FL study had a CR of 94% and an ORR of 97%. Over 58% of patients had CRS but it was grade three or higher only 1% of the time (one patient); 15% of patients had neurologic toxicity, but it was grade three or higher only 2% of the time (three patients).
Dr. Jacobson’s opponent in the debate, Peter Martin, MD, of NewYork–Presbyterian Hospital, Weill Cornell Medicine in New York City, acknowledged the strong performance of CAR T in R/R FL patients but argued that they should be used only in a small subset of patients.
“About 20% of patients will experience an early recurrence or progression of diseases within 24 months (PoD-24) which is associated with worse outcomes. About half of those patients experienced transformation, so they have diffuse large B-cell lymphoma, and they’re getting CAR T-cells. In the end, only 10% of patients with follicular lymphoma are relapsed or refractory and should consider getting Car T-cell therapy,” said Dr. Martin, who focused the rest of his presentation on the best options for treating patients with indolent R/R FL who did not have PoD-24.
He said these patients may be able to avoid the side effects of CAR T and perform well when treated with lenalidomide rituximab (R2) or bispecific antibodies. Data from the MAGNIFY trial of patients with R/R FL indicate that patients treated with R2 who did not experience relapse less than 24 months after starting treatment and were not heavily refractory to rituximab achieved a median PFS of over 4 years, with grade 3 or higher adverse events occurring in 5% of patients or less.
Treatment with bispecific antibodies, although inferior in performance to CAR T-cell therapy, may offer durable responses in some R/R CL patients without the risk of side effects associated with CAR T.
Mosunetuzumab, a bispecific antibody that is currently approved for follicular lymphoma, is designed with step-up dosing to reduce cytokine release syndrome and “achieved a complete response rate of 60% and a median PFS that looks like it’s probably about two years,” said Dr. Martin, noting that some patients continue to do well after the 3-year mark and speculated that “there will be some really long-term responders.”
In addition to the possibly durable nature of bispecific antibodies, they induce cytokine release syndrome at a much lower rate than CAR T, and most side effects are manageable in an outpatient setting, “usually just with Tylenol occasionally with a dose of steroids,” said Dr. Martin.
He contrasted this response with CAR T-cell therapy, which requires referral and travel to a specialized center for at least 1 month around the time of therapy.
Despite the differences of opinion between the presenters about whether CAR T should be used more or less in R/R FL, essentially the two specialists were making recommendations for different patient groups.
Dr. Jacobson observed that “Dr. Martin is looking at the 80% of people who do really well with follicular lymphoma." Those are the people who don’t require a third line of therapy. They are the people who don’t have PoD-24. I’m looking at the 20% of people who either do require a third line of therapy or who do have PoD-24, and we’re not treating nearly enough of those patients with follicular lymphoma.
“We’re actually arguing about treatment strategies for different populations of patients. And I think ultimately, we agree more than we disagree in the end,” she concluded.
The notion that CAR T, chemotherapy, and bispecific antibodies all have a place in treating R/R FL patients is supported by Charalambos (Babis) Andreadis, MD, hematologist at the University of California San Francisco’s Helen Diller Family Comprehensive Care Center. “If I had a patient with follicular who relapsed 24 months or later after primary therapy and had active disease that needed treatment, most providers would do a lenalidomide-based or chemo-based regimen. Down the line either bispecific or CAR T would be appropriate in third line,” said Dr. Andreadis.
However, he noted,“for someone who is an early progressor, I would similarly not be able to use either [chemotherapy or bispecific antibodies] in second line [therapy] but would definitely think that early CART would be a good option to consider given the longevity of the observed responses so far.”
Dr. Martin disclosed ties with AbbVie, AstraZeneca, BeiGene, Daiichi Sankyo, Epizyme, Genentech, Janssen, Merck, and PeproMene. Dr. Jacobson reported relationships with AbbVie, Abintus Bio, ADC Therapeutics, Appia Bio, AstraZeneca, BMS/Celgene, Caribou Bio, Daiichi Sankyo, ImmPACT Bio, Ipsen, Janssen, Kite/Gilead, MorphoSys, Novartis, Sana, Synthekine, Kite/Gilead, and Pfizer. Dr. Andreadis had no disclosures.
“CAR T-cells offer patients with relapsed or refractory follicular lymphoma the most durable responses and improved chance of survival beyond all other available therapies. This holds true for a broad range of high-risk disease features in patients with relapsed or refractory FL. Furthermore, it accomplishes this with a single infusion, and a discrete toxicity that is predictable, reversible and manageable,” said Caron Jacobson, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.
Presenting at the Great Debates & Updates Hematologic Malignancies conference, held April 5-6 in New York City, Dr. Jacobson argued that more patients with R/R FL should be treated with CAR T.
She cited follow-up results from the ZUMA-5 study indicating that patients with R/R FL treated with the CAR T axicabtagene ciloleucel (YESCARTA; Kite Pharma) have a median progression free survival (PFS) of 57.3 months and a complete response rate (CR) of 80%. Furthermore, the lymphoma-specific four-year PFS appears to be reaching a plateau, suggesting that some patients treated with the agent may be cured.
The most significant drawback of treatment with axicabtagene ciloleucel is cytokine release syndrome (CRS) and neurotoxicity, which occurred at grade three and higher in 6% and 15%, of ZUMA-5 participants, respectively.
Two newer studies of anti-CD-19 CAR T-cell therapy in R/R FL, tisagenlecleucel in ELARA and lisocabtagene maraleucel in TRANSCEND FL, suggest that other CAR T-cell treatments can be as effective as axicabtagene ciloleucel, but with fewer side effects.
At a median follow up of 29 months, CR among patients in the ELARA study was 68.1%, and the overall response rate (ORR) was 86.2%. Fewer than half of patients had any CRS, and none had grade three or higher. Only 10% of patients had serious neurologic events, with only 1% of these events rated as grade three or higher.
At a median of 18.1 months, patients in the TRANSCEND FL study had a CR of 94% and an ORR of 97%. Over 58% of patients had CRS but it was grade three or higher only 1% of the time (one patient); 15% of patients had neurologic toxicity, but it was grade three or higher only 2% of the time (three patients).
Dr. Jacobson’s opponent in the debate, Peter Martin, MD, of NewYork–Presbyterian Hospital, Weill Cornell Medicine in New York City, acknowledged the strong performance of CAR T in R/R FL patients but argued that they should be used only in a small subset of patients.
“About 20% of patients will experience an early recurrence or progression of diseases within 24 months (PoD-24) which is associated with worse outcomes. About half of those patients experienced transformation, so they have diffuse large B-cell lymphoma, and they’re getting CAR T-cells. In the end, only 10% of patients with follicular lymphoma are relapsed or refractory and should consider getting Car T-cell therapy,” said Dr. Martin, who focused the rest of his presentation on the best options for treating patients with indolent R/R FL who did not have PoD-24.
He said these patients may be able to avoid the side effects of CAR T and perform well when treated with lenalidomide rituximab (R2) or bispecific antibodies. Data from the MAGNIFY trial of patients with R/R FL indicate that patients treated with R2 who did not experience relapse less than 24 months after starting treatment and were not heavily refractory to rituximab achieved a median PFS of over 4 years, with grade 3 or higher adverse events occurring in 5% of patients or less.
Treatment with bispecific antibodies, although inferior in performance to CAR T-cell therapy, may offer durable responses in some R/R CL patients without the risk of side effects associated with CAR T.
Mosunetuzumab, a bispecific antibody that is currently approved for follicular lymphoma, is designed with step-up dosing to reduce cytokine release syndrome and “achieved a complete response rate of 60% and a median PFS that looks like it’s probably about two years,” said Dr. Martin, noting that some patients continue to do well after the 3-year mark and speculated that “there will be some really long-term responders.”
In addition to the possibly durable nature of bispecific antibodies, they induce cytokine release syndrome at a much lower rate than CAR T, and most side effects are manageable in an outpatient setting, “usually just with Tylenol occasionally with a dose of steroids,” said Dr. Martin.
He contrasted this response with CAR T-cell therapy, which requires referral and travel to a specialized center for at least 1 month around the time of therapy.
Despite the differences of opinion between the presenters about whether CAR T should be used more or less in R/R FL, essentially the two specialists were making recommendations for different patient groups.
Dr. Jacobson observed that “Dr. Martin is looking at the 80% of people who do really well with follicular lymphoma." Those are the people who don’t require a third line of therapy. They are the people who don’t have PoD-24. I’m looking at the 20% of people who either do require a third line of therapy or who do have PoD-24, and we’re not treating nearly enough of those patients with follicular lymphoma.
“We’re actually arguing about treatment strategies for different populations of patients. And I think ultimately, we agree more than we disagree in the end,” she concluded.
The notion that CAR T, chemotherapy, and bispecific antibodies all have a place in treating R/R FL patients is supported by Charalambos (Babis) Andreadis, MD, hematologist at the University of California San Francisco’s Helen Diller Family Comprehensive Care Center. “If I had a patient with follicular who relapsed 24 months or later after primary therapy and had active disease that needed treatment, most providers would do a lenalidomide-based or chemo-based regimen. Down the line either bispecific or CAR T would be appropriate in third line,” said Dr. Andreadis.
However, he noted,“for someone who is an early progressor, I would similarly not be able to use either [chemotherapy or bispecific antibodies] in second line [therapy] but would definitely think that early CART would be a good option to consider given the longevity of the observed responses so far.”
Dr. Martin disclosed ties with AbbVie, AstraZeneca, BeiGene, Daiichi Sankyo, Epizyme, Genentech, Janssen, Merck, and PeproMene. Dr. Jacobson reported relationships with AbbVie, Abintus Bio, ADC Therapeutics, Appia Bio, AstraZeneca, BMS/Celgene, Caribou Bio, Daiichi Sankyo, ImmPACT Bio, Ipsen, Janssen, Kite/Gilead, MorphoSys, Novartis, Sana, Synthekine, Kite/Gilead, and Pfizer. Dr. Andreadis had no disclosures.
“CAR T-cells offer patients with relapsed or refractory follicular lymphoma the most durable responses and improved chance of survival beyond all other available therapies. This holds true for a broad range of high-risk disease features in patients with relapsed or refractory FL. Furthermore, it accomplishes this with a single infusion, and a discrete toxicity that is predictable, reversible and manageable,” said Caron Jacobson, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.
Presenting at the Great Debates & Updates Hematologic Malignancies conference, held April 5-6 in New York City, Dr. Jacobson argued that more patients with R/R FL should be treated with CAR T.
She cited follow-up results from the ZUMA-5 study indicating that patients with R/R FL treated with the CAR T axicabtagene ciloleucel (YESCARTA; Kite Pharma) have a median progression free survival (PFS) of 57.3 months and a complete response rate (CR) of 80%. Furthermore, the lymphoma-specific four-year PFS appears to be reaching a plateau, suggesting that some patients treated with the agent may be cured.
The most significant drawback of treatment with axicabtagene ciloleucel is cytokine release syndrome (CRS) and neurotoxicity, which occurred at grade three and higher in 6% and 15%, of ZUMA-5 participants, respectively.
Two newer studies of anti-CD-19 CAR T-cell therapy in R/R FL, tisagenlecleucel in ELARA and lisocabtagene maraleucel in TRANSCEND FL, suggest that other CAR T-cell treatments can be as effective as axicabtagene ciloleucel, but with fewer side effects.
At a median follow up of 29 months, CR among patients in the ELARA study was 68.1%, and the overall response rate (ORR) was 86.2%. Fewer than half of patients had any CRS, and none had grade three or higher. Only 10% of patients had serious neurologic events, with only 1% of these events rated as grade three or higher.
At a median of 18.1 months, patients in the TRANSCEND FL study had a CR of 94% and an ORR of 97%. Over 58% of patients had CRS but it was grade three or higher only 1% of the time (one patient); 15% of patients had neurologic toxicity, but it was grade three or higher only 2% of the time (three patients).
Dr. Jacobson’s opponent in the debate, Peter Martin, MD, of NewYork–Presbyterian Hospital, Weill Cornell Medicine in New York City, acknowledged the strong performance of CAR T in R/R FL patients but argued that they should be used only in a small subset of patients.
“About 20% of patients will experience an early recurrence or progression of diseases within 24 months (PoD-24) which is associated with worse outcomes. About half of those patients experienced transformation, so they have diffuse large B-cell lymphoma, and they’re getting CAR T-cells. In the end, only 10% of patients with follicular lymphoma are relapsed or refractory and should consider getting Car T-cell therapy,” said Dr. Martin, who focused the rest of his presentation on the best options for treating patients with indolent R/R FL who did not have PoD-24.
He said these patients may be able to avoid the side effects of CAR T and perform well when treated with lenalidomide rituximab (R2) or bispecific antibodies. Data from the MAGNIFY trial of patients with R/R FL indicate that patients treated with R2 who did not experience relapse less than 24 months after starting treatment and were not heavily refractory to rituximab achieved a median PFS of over 4 years, with grade 3 or higher adverse events occurring in 5% of patients or less.
Treatment with bispecific antibodies, although inferior in performance to CAR T-cell therapy, may offer durable responses in some R/R CL patients without the risk of side effects associated with CAR T.
Mosunetuzumab, a bispecific antibody that is currently approved for follicular lymphoma, is designed with step-up dosing to reduce cytokine release syndrome and “achieved a complete response rate of 60% and a median PFS that looks like it’s probably about two years,” said Dr. Martin, noting that some patients continue to do well after the 3-year mark and speculated that “there will be some really long-term responders.”
In addition to the possibly durable nature of bispecific antibodies, they induce cytokine release syndrome at a much lower rate than CAR T, and most side effects are manageable in an outpatient setting, “usually just with Tylenol occasionally with a dose of steroids,” said Dr. Martin.
He contrasted this response with CAR T-cell therapy, which requires referral and travel to a specialized center for at least 1 month around the time of therapy.
Despite the differences of opinion between the presenters about whether CAR T should be used more or less in R/R FL, essentially the two specialists were making recommendations for different patient groups.
Dr. Jacobson observed that “Dr. Martin is looking at the 80% of people who do really well with follicular lymphoma." Those are the people who don’t require a third line of therapy. They are the people who don’t have PoD-24. I’m looking at the 20% of people who either do require a third line of therapy or who do have PoD-24, and we’re not treating nearly enough of those patients with follicular lymphoma.
“We’re actually arguing about treatment strategies for different populations of patients. And I think ultimately, we agree more than we disagree in the end,” she concluded.
The notion that CAR T, chemotherapy, and bispecific antibodies all have a place in treating R/R FL patients is supported by Charalambos (Babis) Andreadis, MD, hematologist at the University of California San Francisco’s Helen Diller Family Comprehensive Care Center. “If I had a patient with follicular who relapsed 24 months or later after primary therapy and had active disease that needed treatment, most providers would do a lenalidomide-based or chemo-based regimen. Down the line either bispecific or CAR T would be appropriate in third line,” said Dr. Andreadis.
However, he noted,“for someone who is an early progressor, I would similarly not be able to use either [chemotherapy or bispecific antibodies] in second line [therapy] but would definitely think that early CART would be a good option to consider given the longevity of the observed responses so far.”
Dr. Martin disclosed ties with AbbVie, AstraZeneca, BeiGene, Daiichi Sankyo, Epizyme, Genentech, Janssen, Merck, and PeproMene. Dr. Jacobson reported relationships with AbbVie, Abintus Bio, ADC Therapeutics, Appia Bio, AstraZeneca, BMS/Celgene, Caribou Bio, Daiichi Sankyo, ImmPACT Bio, Ipsen, Janssen, Kite/Gilead, MorphoSys, Novartis, Sana, Synthekine, Kite/Gilead, and Pfizer. Dr. Andreadis had no disclosures.
COVID Vaccinations Less Prevalent in Marginalized Patients
Primary care physicians who served marginalized communities had the highest proportion of patients who were unvaccinated against COVID-19, Canadian data suggested.
A study of more than 9000 family physicians in Ontario also found that the physicians with the largest proportion of unvaccinated patients were more likely to be male, to have trained outside Canada, to be older, and to work in an enhanced fee-for-service model than their counterparts who had lower proportions of unvaccinated patients.
“The family physicians with the most unvaccinated patients were also more likely to be solo practitioners and less likely to practice in team-based models, meaning they may have fewer support staff in their clinics,” lead author Jennifer Shuldiner, PhD, a scientist at Women’s College Hospital in Toronto, Ontario, Canada, told this news organization.
The findings were published in CMAJ.
Need vs Resources
Dr. Shuldiner and her team had been working on a project to provide additional support to family physicians with large numbers of patients who had not received their COVID-19 vaccinations. Their goal was to encourage family physicians to support these patients in getting vaccinated.
“As we were designing this project, we wondered how these physicians and their patients might differ. What characteristics might they have that would enable us to design and implement an intervention with high uptake and impact?” she said.
The researchers conducted a cross-sectional, population-based cohort study using linked administrative datasets in Ontario. They calculated the percentage of patients unvaccinated against SARS-CoV-2 who were enrolled with each comprehensive care family physician, ranked physicians according to the proportion of unvaccinated patients, and identified 906 physicians in the top 10% of unvaccinated patients. These physicians were compared with the remaining 90% of family physicians.
The physicians with the highest proportion of unvaccinated patients cared for 259,130 unvaccinated patients as of November 1, 2021. The proportion of patients who received two or more doses of the SARS-CoV-2 vaccine in this group was 74.2%. In comparison, the proportion of patients who received two or more doses of the vaccine was 87.0% in the remaining 90% of physicians.
Physicians with the largest proportion of unvaccinated patients were more likely to be male (64.6% vs 48.1%), to have trained outside Canada (46.9% vs 29.3%), to be older (mean age, 56 years vs 49 years), and to work in an enhanced fee-for-service model (49% vs 28%).
The study also found that patients enrolled with physicians in the most unvaccinated group tended to live in places with more ethnic diversity, higher material deprivation, and lower incomes. The proportion of recent immigrants was higher in this group.
“Clinics or practices with a large number of unvaccinated patients could be viable targets for efforts to coordinate public health and primary care,” said Dr. Shuldiner.
The findings indicate “the ongoing inverse relationship between the need for care and its accessibility and utilization. In other words, the practices with the highest need receive the fewest resources,” she noted.
“We know that relationships with trusted family physicians can positively influence patients’ decisions. Our study highlights the need to create equitable systems and processes that create opportunities for primary care teams to play a crucial role in influencing general and COVID-19-specific vaccine-related decision-making.”
Helping Primary Care Physicians
Commenting on the study for this news organization, Sabrina Wong, RN, PhD, professor of nursing at the University of British Columbia in Vancouver, British Columbia, Canada, said, “They did quite a nice analysis to show this using administrative data, and I think the information they’ve uncovered will be helpful in trying to fill the gaps and provide these practitioners with more support.”
Dr. Wong did not participate in the study. “The information they provide will be useful in helping us to move forward working with underserved, underresourced communities and also hopefully provide the clinicians, family physicians, and nurse practitioners working in these areas with more resources,” she said.
“The authors also point out that there needs to be more collaboration between public health and primary care to support these communities in their efforts to get the vaccines to the people in these communities who need them.”
The study was supported by a Canadian Institutes of Health Research grant. Dr. Shuldiner and Dr. Wong reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Primary care physicians who served marginalized communities had the highest proportion of patients who were unvaccinated against COVID-19, Canadian data suggested.
A study of more than 9000 family physicians in Ontario also found that the physicians with the largest proportion of unvaccinated patients were more likely to be male, to have trained outside Canada, to be older, and to work in an enhanced fee-for-service model than their counterparts who had lower proportions of unvaccinated patients.
“The family physicians with the most unvaccinated patients were also more likely to be solo practitioners and less likely to practice in team-based models, meaning they may have fewer support staff in their clinics,” lead author Jennifer Shuldiner, PhD, a scientist at Women’s College Hospital in Toronto, Ontario, Canada, told this news organization.
The findings were published in CMAJ.
Need vs Resources
Dr. Shuldiner and her team had been working on a project to provide additional support to family physicians with large numbers of patients who had not received their COVID-19 vaccinations. Their goal was to encourage family physicians to support these patients in getting vaccinated.
“As we were designing this project, we wondered how these physicians and their patients might differ. What characteristics might they have that would enable us to design and implement an intervention with high uptake and impact?” she said.
The researchers conducted a cross-sectional, population-based cohort study using linked administrative datasets in Ontario. They calculated the percentage of patients unvaccinated against SARS-CoV-2 who were enrolled with each comprehensive care family physician, ranked physicians according to the proportion of unvaccinated patients, and identified 906 physicians in the top 10% of unvaccinated patients. These physicians were compared with the remaining 90% of family physicians.
The physicians with the highest proportion of unvaccinated patients cared for 259,130 unvaccinated patients as of November 1, 2021. The proportion of patients who received two or more doses of the SARS-CoV-2 vaccine in this group was 74.2%. In comparison, the proportion of patients who received two or more doses of the vaccine was 87.0% in the remaining 90% of physicians.
Physicians with the largest proportion of unvaccinated patients were more likely to be male (64.6% vs 48.1%), to have trained outside Canada (46.9% vs 29.3%), to be older (mean age, 56 years vs 49 years), and to work in an enhanced fee-for-service model (49% vs 28%).
The study also found that patients enrolled with physicians in the most unvaccinated group tended to live in places with more ethnic diversity, higher material deprivation, and lower incomes. The proportion of recent immigrants was higher in this group.
“Clinics or practices with a large number of unvaccinated patients could be viable targets for efforts to coordinate public health and primary care,” said Dr. Shuldiner.
The findings indicate “the ongoing inverse relationship between the need for care and its accessibility and utilization. In other words, the practices with the highest need receive the fewest resources,” she noted.
“We know that relationships with trusted family physicians can positively influence patients’ decisions. Our study highlights the need to create equitable systems and processes that create opportunities for primary care teams to play a crucial role in influencing general and COVID-19-specific vaccine-related decision-making.”
Helping Primary Care Physicians
Commenting on the study for this news organization, Sabrina Wong, RN, PhD, professor of nursing at the University of British Columbia in Vancouver, British Columbia, Canada, said, “They did quite a nice analysis to show this using administrative data, and I think the information they’ve uncovered will be helpful in trying to fill the gaps and provide these practitioners with more support.”
Dr. Wong did not participate in the study. “The information they provide will be useful in helping us to move forward working with underserved, underresourced communities and also hopefully provide the clinicians, family physicians, and nurse practitioners working in these areas with more resources,” she said.
“The authors also point out that there needs to be more collaboration between public health and primary care to support these communities in their efforts to get the vaccines to the people in these communities who need them.”
The study was supported by a Canadian Institutes of Health Research grant. Dr. Shuldiner and Dr. Wong reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Primary care physicians who served marginalized communities had the highest proportion of patients who were unvaccinated against COVID-19, Canadian data suggested.
A study of more than 9000 family physicians in Ontario also found that the physicians with the largest proportion of unvaccinated patients were more likely to be male, to have trained outside Canada, to be older, and to work in an enhanced fee-for-service model than their counterparts who had lower proportions of unvaccinated patients.
“The family physicians with the most unvaccinated patients were also more likely to be solo practitioners and less likely to practice in team-based models, meaning they may have fewer support staff in their clinics,” lead author Jennifer Shuldiner, PhD, a scientist at Women’s College Hospital in Toronto, Ontario, Canada, told this news organization.
The findings were published in CMAJ.
Need vs Resources
Dr. Shuldiner and her team had been working on a project to provide additional support to family physicians with large numbers of patients who had not received their COVID-19 vaccinations. Their goal was to encourage family physicians to support these patients in getting vaccinated.
“As we were designing this project, we wondered how these physicians and their patients might differ. What characteristics might they have that would enable us to design and implement an intervention with high uptake and impact?” she said.
The researchers conducted a cross-sectional, population-based cohort study using linked administrative datasets in Ontario. They calculated the percentage of patients unvaccinated against SARS-CoV-2 who were enrolled with each comprehensive care family physician, ranked physicians according to the proportion of unvaccinated patients, and identified 906 physicians in the top 10% of unvaccinated patients. These physicians were compared with the remaining 90% of family physicians.
The physicians with the highest proportion of unvaccinated patients cared for 259,130 unvaccinated patients as of November 1, 2021. The proportion of patients who received two or more doses of the SARS-CoV-2 vaccine in this group was 74.2%. In comparison, the proportion of patients who received two or more doses of the vaccine was 87.0% in the remaining 90% of physicians.
Physicians with the largest proportion of unvaccinated patients were more likely to be male (64.6% vs 48.1%), to have trained outside Canada (46.9% vs 29.3%), to be older (mean age, 56 years vs 49 years), and to work in an enhanced fee-for-service model (49% vs 28%).
The study also found that patients enrolled with physicians in the most unvaccinated group tended to live in places with more ethnic diversity, higher material deprivation, and lower incomes. The proportion of recent immigrants was higher in this group.
“Clinics or practices with a large number of unvaccinated patients could be viable targets for efforts to coordinate public health and primary care,” said Dr. Shuldiner.
The findings indicate “the ongoing inverse relationship between the need for care and its accessibility and utilization. In other words, the practices with the highest need receive the fewest resources,” she noted.
“We know that relationships with trusted family physicians can positively influence patients’ decisions. Our study highlights the need to create equitable systems and processes that create opportunities for primary care teams to play a crucial role in influencing general and COVID-19-specific vaccine-related decision-making.”
Helping Primary Care Physicians
Commenting on the study for this news organization, Sabrina Wong, RN, PhD, professor of nursing at the University of British Columbia in Vancouver, British Columbia, Canada, said, “They did quite a nice analysis to show this using administrative data, and I think the information they’ve uncovered will be helpful in trying to fill the gaps and provide these practitioners with more support.”
Dr. Wong did not participate in the study. “The information they provide will be useful in helping us to move forward working with underserved, underresourced communities and also hopefully provide the clinicians, family physicians, and nurse practitioners working in these areas with more resources,” she said.
“The authors also point out that there needs to be more collaboration between public health and primary care to support these communities in their efforts to get the vaccines to the people in these communities who need them.”
The study was supported by a Canadian Institutes of Health Research grant. Dr. Shuldiner and Dr. Wong reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CMAJ
Diabetic Foot Ulcers: Life-Threatening Issue in Need of Help
The photo of the patient’s foot, sent from his campsite, included a cheeky note: “I remember you telling me that getting in trouble doing something was better than getting in trouble doing nothing. This lets me get out there and know that I have feedback.”
The “this” was the patient’s “foot selfie,” an approach that allows patients at a risk for diabetic foot ulcers (DFUs) to snap a picture and send it to their healthcare providers for evaluation.
This particular patient had an extensive history of previous wounds. Some had essentially kept him house-bound in the past, as he was afraid to get another one.
This time, however, he got an all-clear to keep on camping, “and we scheduled him in on the following Tuesday [for follow-up],” said the camper’s physician David G. Armstrong, DPM, MD, PhD, professor of surgery and neurological surgery, USC Keck School of Medicine, Los Angeles.
Dr. Armstrong is one of the researchers evaluating the concept of foot selfies. It’s a welcome advance, he and others said, and has been shown to help heal wounds and reverse pre-ulcer lesions. Research on foot selfies continues, but much more is needed to solve the issue of DFUs, diabetic foot infections (DFIs), and the high rates of reinfection, experts know.
Worldwide, about 18.6 million people have a DFU each year, including 1.6 million in the United States. About 50%-60% of ulcers become infected, with 20% of moderate to severe infections requiring amputation of the limb. The 5-year mortality rate for DFUs is 30%, but it climbs to 70% after amputation. While about 40% of ulcers heal within 12 weeks, 42% recur at the 1-year mark, setting up a vicious and costly cycle. Healthcare costs for patients with diabetes and DFUs are five times as high as costs for patients with diabetes but no DFUs. The per capita cost to treat a DFU in America is $17,500.
While the statistics paint a grim picture, progress is being made on several fronts:
- US Food and Drug Administration (FDA) guidance on the development of drugs for DFUs, under evaluation, is forthcoming.
- New treatments are under study.
- A multidisciplinary team approach is known to improve outcomes.
Anatomy of a DFU
When neuropathy develops in those with diabetes, they no longer have what Dr. Armstrong calls the “gift” of pain perception. “They can wear a hole in their foot like you and I wear a hole in our sock or shoe,” he said. “That hole is called a diabetic foot ulcer.”
A DFU is an open wound on the foot, often occurring when bleeding develops beneath a callus and then the callus wears away. Deeper tissues of the foot are then exposed.
About half of the DFUs get infected, hence the FDA guidance, said Dr. Armstrong, who is also founding president of the American Limb Preservation Society, which aims to eliminate preventable amputations within the next generation. Every 20 seconds, Dr. Armstrong said, someone in the world loses a leg due to diabetes.
FDA Guidance on Drug Development for DFIs
In October, the FDA issued draft guidance for industry to articulate the design of clinical trials for developing antibacterial drugs to treat DFIs without concomitant bone and joint involvement. Comments closed on December 18. Among the points in the guidance, which is nonbinding, are to include DFIs of varying depths and extent in phase 3 trials and ideally to include only those patients who have not had prior antibacterial treatment for the current DFI.
According to an FDA spokesperson, “The agency is working to finalize the guidance. However, a timeline for its release has not yet been established.”
The good news about the upcoming FDA guidance, Dr. Armstrong said, is that the agency has realized the importance of treating the infections. Fully one third of direct costs of care for diabetes are spent on the lower extremities, he said. Keeping patients out of the hospital, uninfected, and “keeping legs on bodies” are all important goals, he said.
Pharmaceutical firms need to understand that “you aren’t dealing with a normal ulcer,” said Andrew J.M. Boulton, MD, professor of medicine at the University of Manchester and physician consultant at the Manchester Royal Infirmary, Manchester, England, and a visiting professor at the University of Miami. For research, “the most important thing is to take account of off-loading the ulcers,” he said. “Most ulcers will heal if put in a boot.”
Dr. Boulton, like Dr. Armstrong, a long-time expert in the field, contended that pharma has not understood this concept and has wasted millions over the last three decades doing studies that were poorly designed and controlled.
Treatments: Current, Under Study
Currently, DFIs are treated with antimicrobial therapy, without or without debridement, along with a clinical assessment for ischemia. If ischemia is found, care progresses to wound care and off-loading devices, such as healing sandals. Clinicians then assess the likelihood of improved outcomes with revascularization based on operative risks and distribution of lower extremity artery disease and proceed depending on the likelihood. If osteomyelitis testing shows it is present, providers proceed to wound debridement, limb-sparing amputation, and prolonged antimicrobials, as needed.
More options are needed, Dr. Armstrong said.
Among the many approaches under study:
- DFUs can be accurately detected by applying artificial intelligence to the “foot selfie” images taken by patients on smartphones, research by Dr. and has found.
- After a phase 3 study of for DFUs originally intending to enroll 300 subjects was discontinued because of slow patient recruitment, an interim analysis was conducted on 44 participants. It showed a positive trend toward wound closure in the group receiving the injected gene therapy, VM202 (ENGENSIS), in their calf muscles. VM202 is a plasmid DNA-encoding human hepatocyte growth factor. While those in both the intervention and placebo groups showed wound-closing effects at month 6, in 23 patients with neuro-ischemic ulcers, the percentage of those reaching complete closure of the DFU was significantly higher in the treated group at months 3, 4, and 5 (P = .0391, .0391, and .0361, respectively). After excluding two outliers, the difference in months 3-6 became more significant (P = .03).
- An closed more DFUs than standard care after 12 weeks — 70% vs 34% (P = .00032). Of the 100 participants randomized, 50 per group, 42% of the treatment group and 56% of the control group experienced adverse events, with eight withdrawn due to serious adverse events (such as osteomyelitis).
- A closed more refractory DFUs over a 16-week study than standard sharp debridement, with 65% of water-treated ulcers healed but just 42% of the standard care group (P = .021, unadjusted).
- Researchers from UC Davis and VA Northern California Healthcare are evaluating timolol, a beta adrenergic receptor blocker already approved for topical administration for glaucoma, as a way to heal chronic DFUs faster. After demonstrating that the medication worked in animal models, researchers then launched a study to use it off-label for DFUs. While data are still being analyzed, researcher Roslyn (Rivkah) Isseroff, MD, of UC Davis and VA, said that data so far demonstrate that the timolol reduced transepidermal water loss in the healed wounds, and that is linked with a decrease in re-ulceration.
The Power of a Team
Multidisciplinary approaches to treatment are effective in reducing amputation, with one review of 33 studies finding the approach worked to decrease amputation in 94% of them. “The American Limb Preservation Society (ALPS) lists 30 programs,” said Dr. Armstrong, the founding president of the organization. “There may be as many as 100.”
Team compositions vary but usually include at least one medical specialty clinician, such as infectious disease, primary care, or endocrinology, and two or more specialty clinicians, such as vascular, podiatric, orthopedic, or plastic surgery. A shoe specialist is needed to prescribe and manage footwear. Other important team members include nutrition experts and behavioral health professionals to deal with associated depression.
Johns Hopkins’ Multidisciplinary Diabetic Foot and Wound Service launched in 2012 and includes vascular surgeons, surgical podiatrists, endocrinologists, wound care nurses, advanced practice staff, board-certified wound care specialists, orthopedic surgeons, infection disease experts, physical therapists, and certified orthotists.
“This interdisciplinary care model has been repeatedly validated by research as superior for limb salvage and wound healing,” said Nestoras Mathioudakis, MD, codirector of the service. “For instance, endocrinologists and diabetes educators are crucial for managing uncontrolled diabetes — a key factor in infection and delayed wound healing. Similarly, vascular surgeons play a vital role in addressing peripheral arterial disease to improve blood flow to the affected area.”
“Diabetic foot ulcers might require prolonged periods of specialized care, including meticulous wound management and off-loading, overseen by surgical podiatrists and wound care experts,” he said. “In cases where infection is present, particularly with multidrug resistant organisms or when standard antibiotics are contraindicated, the insight of an infectious disease specialist is invaluable.”
While the makeup of teams varies from location to location, he said “the hallmark of effective teams is their ability to comprehensively manage glycemic control, foot wounds, vascular disease, and infections.”
The power of teams, Dr. Armstrong said, is very much evident after his weekly “foot selfie rounds” conducted Mondays at 7 AM, with an “all feet on deck” approach. “Not a week goes by when we don’t stop a hospitalization,” he said of the team evaluating the photos, due to detecting issues early, while still in the manageable state.
Teams can trump technology, Dr. Armstrong said. A team of just a primary care doctor and a podiatrist can make a significant reduction in amputations, he said, just by a “Knock your socks off” approach. He reminds primary care doctors that observing the feet of their patients with diabetes can go a long way to reducing DFUs and the hospitalizations and amputations that can result.
Dr. Mathioudakis and Dr. Isseroff reported no disclosures. Dr. Boulton consults for Urgo Medical, Nevro Corporation, and AOT, Inc. Dr. Armstrong reported receiving consulting fees from Podimetrics; Molnlycke; Cardiovascular Systems, Inc.; Endo Pharmaceuticals; and Averitas Pharma (GRT US).
A version of this article first appeared on Medscape.com.
The photo of the patient’s foot, sent from his campsite, included a cheeky note: “I remember you telling me that getting in trouble doing something was better than getting in trouble doing nothing. This lets me get out there and know that I have feedback.”
The “this” was the patient’s “foot selfie,” an approach that allows patients at a risk for diabetic foot ulcers (DFUs) to snap a picture and send it to their healthcare providers for evaluation.
This particular patient had an extensive history of previous wounds. Some had essentially kept him house-bound in the past, as he was afraid to get another one.
This time, however, he got an all-clear to keep on camping, “and we scheduled him in on the following Tuesday [for follow-up],” said the camper’s physician David G. Armstrong, DPM, MD, PhD, professor of surgery and neurological surgery, USC Keck School of Medicine, Los Angeles.
Dr. Armstrong is one of the researchers evaluating the concept of foot selfies. It’s a welcome advance, he and others said, and has been shown to help heal wounds and reverse pre-ulcer lesions. Research on foot selfies continues, but much more is needed to solve the issue of DFUs, diabetic foot infections (DFIs), and the high rates of reinfection, experts know.
Worldwide, about 18.6 million people have a DFU each year, including 1.6 million in the United States. About 50%-60% of ulcers become infected, with 20% of moderate to severe infections requiring amputation of the limb. The 5-year mortality rate for DFUs is 30%, but it climbs to 70% after amputation. While about 40% of ulcers heal within 12 weeks, 42% recur at the 1-year mark, setting up a vicious and costly cycle. Healthcare costs for patients with diabetes and DFUs are five times as high as costs for patients with diabetes but no DFUs. The per capita cost to treat a DFU in America is $17,500.
While the statistics paint a grim picture, progress is being made on several fronts:
- US Food and Drug Administration (FDA) guidance on the development of drugs for DFUs, under evaluation, is forthcoming.
- New treatments are under study.
- A multidisciplinary team approach is known to improve outcomes.
Anatomy of a DFU
When neuropathy develops in those with diabetes, they no longer have what Dr. Armstrong calls the “gift” of pain perception. “They can wear a hole in their foot like you and I wear a hole in our sock or shoe,” he said. “That hole is called a diabetic foot ulcer.”
A DFU is an open wound on the foot, often occurring when bleeding develops beneath a callus and then the callus wears away. Deeper tissues of the foot are then exposed.
About half of the DFUs get infected, hence the FDA guidance, said Dr. Armstrong, who is also founding president of the American Limb Preservation Society, which aims to eliminate preventable amputations within the next generation. Every 20 seconds, Dr. Armstrong said, someone in the world loses a leg due to diabetes.
FDA Guidance on Drug Development for DFIs
In October, the FDA issued draft guidance for industry to articulate the design of clinical trials for developing antibacterial drugs to treat DFIs without concomitant bone and joint involvement. Comments closed on December 18. Among the points in the guidance, which is nonbinding, are to include DFIs of varying depths and extent in phase 3 trials and ideally to include only those patients who have not had prior antibacterial treatment for the current DFI.
According to an FDA spokesperson, “The agency is working to finalize the guidance. However, a timeline for its release has not yet been established.”
The good news about the upcoming FDA guidance, Dr. Armstrong said, is that the agency has realized the importance of treating the infections. Fully one third of direct costs of care for diabetes are spent on the lower extremities, he said. Keeping patients out of the hospital, uninfected, and “keeping legs on bodies” are all important goals, he said.
Pharmaceutical firms need to understand that “you aren’t dealing with a normal ulcer,” said Andrew J.M. Boulton, MD, professor of medicine at the University of Manchester and physician consultant at the Manchester Royal Infirmary, Manchester, England, and a visiting professor at the University of Miami. For research, “the most important thing is to take account of off-loading the ulcers,” he said. “Most ulcers will heal if put in a boot.”
Dr. Boulton, like Dr. Armstrong, a long-time expert in the field, contended that pharma has not understood this concept and has wasted millions over the last three decades doing studies that were poorly designed and controlled.
Treatments: Current, Under Study
Currently, DFIs are treated with antimicrobial therapy, without or without debridement, along with a clinical assessment for ischemia. If ischemia is found, care progresses to wound care and off-loading devices, such as healing sandals. Clinicians then assess the likelihood of improved outcomes with revascularization based on operative risks and distribution of lower extremity artery disease and proceed depending on the likelihood. If osteomyelitis testing shows it is present, providers proceed to wound debridement, limb-sparing amputation, and prolonged antimicrobials, as needed.
More options are needed, Dr. Armstrong said.
Among the many approaches under study:
- DFUs can be accurately detected by applying artificial intelligence to the “foot selfie” images taken by patients on smartphones, research by Dr. and has found.
- After a phase 3 study of for DFUs originally intending to enroll 300 subjects was discontinued because of slow patient recruitment, an interim analysis was conducted on 44 participants. It showed a positive trend toward wound closure in the group receiving the injected gene therapy, VM202 (ENGENSIS), in their calf muscles. VM202 is a plasmid DNA-encoding human hepatocyte growth factor. While those in both the intervention and placebo groups showed wound-closing effects at month 6, in 23 patients with neuro-ischemic ulcers, the percentage of those reaching complete closure of the DFU was significantly higher in the treated group at months 3, 4, and 5 (P = .0391, .0391, and .0361, respectively). After excluding two outliers, the difference in months 3-6 became more significant (P = .03).
- An closed more DFUs than standard care after 12 weeks — 70% vs 34% (P = .00032). Of the 100 participants randomized, 50 per group, 42% of the treatment group and 56% of the control group experienced adverse events, with eight withdrawn due to serious adverse events (such as osteomyelitis).
- A closed more refractory DFUs over a 16-week study than standard sharp debridement, with 65% of water-treated ulcers healed but just 42% of the standard care group (P = .021, unadjusted).
- Researchers from UC Davis and VA Northern California Healthcare are evaluating timolol, a beta adrenergic receptor blocker already approved for topical administration for glaucoma, as a way to heal chronic DFUs faster. After demonstrating that the medication worked in animal models, researchers then launched a study to use it off-label for DFUs. While data are still being analyzed, researcher Roslyn (Rivkah) Isseroff, MD, of UC Davis and VA, said that data so far demonstrate that the timolol reduced transepidermal water loss in the healed wounds, and that is linked with a decrease in re-ulceration.
The Power of a Team
Multidisciplinary approaches to treatment are effective in reducing amputation, with one review of 33 studies finding the approach worked to decrease amputation in 94% of them. “The American Limb Preservation Society (ALPS) lists 30 programs,” said Dr. Armstrong, the founding president of the organization. “There may be as many as 100.”
Team compositions vary but usually include at least one medical specialty clinician, such as infectious disease, primary care, or endocrinology, and two or more specialty clinicians, such as vascular, podiatric, orthopedic, or plastic surgery. A shoe specialist is needed to prescribe and manage footwear. Other important team members include nutrition experts and behavioral health professionals to deal with associated depression.
Johns Hopkins’ Multidisciplinary Diabetic Foot and Wound Service launched in 2012 and includes vascular surgeons, surgical podiatrists, endocrinologists, wound care nurses, advanced practice staff, board-certified wound care specialists, orthopedic surgeons, infection disease experts, physical therapists, and certified orthotists.
“This interdisciplinary care model has been repeatedly validated by research as superior for limb salvage and wound healing,” said Nestoras Mathioudakis, MD, codirector of the service. “For instance, endocrinologists and diabetes educators are crucial for managing uncontrolled diabetes — a key factor in infection and delayed wound healing. Similarly, vascular surgeons play a vital role in addressing peripheral arterial disease to improve blood flow to the affected area.”
“Diabetic foot ulcers might require prolonged periods of specialized care, including meticulous wound management and off-loading, overseen by surgical podiatrists and wound care experts,” he said. “In cases where infection is present, particularly with multidrug resistant organisms or when standard antibiotics are contraindicated, the insight of an infectious disease specialist is invaluable.”
While the makeup of teams varies from location to location, he said “the hallmark of effective teams is their ability to comprehensively manage glycemic control, foot wounds, vascular disease, and infections.”
The power of teams, Dr. Armstrong said, is very much evident after his weekly “foot selfie rounds” conducted Mondays at 7 AM, with an “all feet on deck” approach. “Not a week goes by when we don’t stop a hospitalization,” he said of the team evaluating the photos, due to detecting issues early, while still in the manageable state.
Teams can trump technology, Dr. Armstrong said. A team of just a primary care doctor and a podiatrist can make a significant reduction in amputations, he said, just by a “Knock your socks off” approach. He reminds primary care doctors that observing the feet of their patients with diabetes can go a long way to reducing DFUs and the hospitalizations and amputations that can result.
Dr. Mathioudakis and Dr. Isseroff reported no disclosures. Dr. Boulton consults for Urgo Medical, Nevro Corporation, and AOT, Inc. Dr. Armstrong reported receiving consulting fees from Podimetrics; Molnlycke; Cardiovascular Systems, Inc.; Endo Pharmaceuticals; and Averitas Pharma (GRT US).
A version of this article first appeared on Medscape.com.
The photo of the patient’s foot, sent from his campsite, included a cheeky note: “I remember you telling me that getting in trouble doing something was better than getting in trouble doing nothing. This lets me get out there and know that I have feedback.”
The “this” was the patient’s “foot selfie,” an approach that allows patients at a risk for diabetic foot ulcers (DFUs) to snap a picture and send it to their healthcare providers for evaluation.
This particular patient had an extensive history of previous wounds. Some had essentially kept him house-bound in the past, as he was afraid to get another one.
This time, however, he got an all-clear to keep on camping, “and we scheduled him in on the following Tuesday [for follow-up],” said the camper’s physician David G. Armstrong, DPM, MD, PhD, professor of surgery and neurological surgery, USC Keck School of Medicine, Los Angeles.
Dr. Armstrong is one of the researchers evaluating the concept of foot selfies. It’s a welcome advance, he and others said, and has been shown to help heal wounds and reverse pre-ulcer lesions. Research on foot selfies continues, but much more is needed to solve the issue of DFUs, diabetic foot infections (DFIs), and the high rates of reinfection, experts know.
Worldwide, about 18.6 million people have a DFU each year, including 1.6 million in the United States. About 50%-60% of ulcers become infected, with 20% of moderate to severe infections requiring amputation of the limb. The 5-year mortality rate for DFUs is 30%, but it climbs to 70% after amputation. While about 40% of ulcers heal within 12 weeks, 42% recur at the 1-year mark, setting up a vicious and costly cycle. Healthcare costs for patients with diabetes and DFUs are five times as high as costs for patients with diabetes but no DFUs. The per capita cost to treat a DFU in America is $17,500.
While the statistics paint a grim picture, progress is being made on several fronts:
- US Food and Drug Administration (FDA) guidance on the development of drugs for DFUs, under evaluation, is forthcoming.
- New treatments are under study.
- A multidisciplinary team approach is known to improve outcomes.
Anatomy of a DFU
When neuropathy develops in those with diabetes, they no longer have what Dr. Armstrong calls the “gift” of pain perception. “They can wear a hole in their foot like you and I wear a hole in our sock or shoe,” he said. “That hole is called a diabetic foot ulcer.”
A DFU is an open wound on the foot, often occurring when bleeding develops beneath a callus and then the callus wears away. Deeper tissues of the foot are then exposed.
About half of the DFUs get infected, hence the FDA guidance, said Dr. Armstrong, who is also founding president of the American Limb Preservation Society, which aims to eliminate preventable amputations within the next generation. Every 20 seconds, Dr. Armstrong said, someone in the world loses a leg due to diabetes.
FDA Guidance on Drug Development for DFIs
In October, the FDA issued draft guidance for industry to articulate the design of clinical trials for developing antibacterial drugs to treat DFIs without concomitant bone and joint involvement. Comments closed on December 18. Among the points in the guidance, which is nonbinding, are to include DFIs of varying depths and extent in phase 3 trials and ideally to include only those patients who have not had prior antibacterial treatment for the current DFI.
According to an FDA spokesperson, “The agency is working to finalize the guidance. However, a timeline for its release has not yet been established.”
The good news about the upcoming FDA guidance, Dr. Armstrong said, is that the agency has realized the importance of treating the infections. Fully one third of direct costs of care for diabetes are spent on the lower extremities, he said. Keeping patients out of the hospital, uninfected, and “keeping legs on bodies” are all important goals, he said.
Pharmaceutical firms need to understand that “you aren’t dealing with a normal ulcer,” said Andrew J.M. Boulton, MD, professor of medicine at the University of Manchester and physician consultant at the Manchester Royal Infirmary, Manchester, England, and a visiting professor at the University of Miami. For research, “the most important thing is to take account of off-loading the ulcers,” he said. “Most ulcers will heal if put in a boot.”
Dr. Boulton, like Dr. Armstrong, a long-time expert in the field, contended that pharma has not understood this concept and has wasted millions over the last three decades doing studies that were poorly designed and controlled.
Treatments: Current, Under Study
Currently, DFIs are treated with antimicrobial therapy, without or without debridement, along with a clinical assessment for ischemia. If ischemia is found, care progresses to wound care and off-loading devices, such as healing sandals. Clinicians then assess the likelihood of improved outcomes with revascularization based on operative risks and distribution of lower extremity artery disease and proceed depending on the likelihood. If osteomyelitis testing shows it is present, providers proceed to wound debridement, limb-sparing amputation, and prolonged antimicrobials, as needed.
More options are needed, Dr. Armstrong said.
Among the many approaches under study:
- DFUs can be accurately detected by applying artificial intelligence to the “foot selfie” images taken by patients on smartphones, research by Dr. and has found.
- After a phase 3 study of for DFUs originally intending to enroll 300 subjects was discontinued because of slow patient recruitment, an interim analysis was conducted on 44 participants. It showed a positive trend toward wound closure in the group receiving the injected gene therapy, VM202 (ENGENSIS), in their calf muscles. VM202 is a plasmid DNA-encoding human hepatocyte growth factor. While those in both the intervention and placebo groups showed wound-closing effects at month 6, in 23 patients with neuro-ischemic ulcers, the percentage of those reaching complete closure of the DFU was significantly higher in the treated group at months 3, 4, and 5 (P = .0391, .0391, and .0361, respectively). After excluding two outliers, the difference in months 3-6 became more significant (P = .03).
- An closed more DFUs than standard care after 12 weeks — 70% vs 34% (P = .00032). Of the 100 participants randomized, 50 per group, 42% of the treatment group and 56% of the control group experienced adverse events, with eight withdrawn due to serious adverse events (such as osteomyelitis).
- A closed more refractory DFUs over a 16-week study than standard sharp debridement, with 65% of water-treated ulcers healed but just 42% of the standard care group (P = .021, unadjusted).
- Researchers from UC Davis and VA Northern California Healthcare are evaluating timolol, a beta adrenergic receptor blocker already approved for topical administration for glaucoma, as a way to heal chronic DFUs faster. After demonstrating that the medication worked in animal models, researchers then launched a study to use it off-label for DFUs. While data are still being analyzed, researcher Roslyn (Rivkah) Isseroff, MD, of UC Davis and VA, said that data so far demonstrate that the timolol reduced transepidermal water loss in the healed wounds, and that is linked with a decrease in re-ulceration.
The Power of a Team
Multidisciplinary approaches to treatment are effective in reducing amputation, with one review of 33 studies finding the approach worked to decrease amputation in 94% of them. “The American Limb Preservation Society (ALPS) lists 30 programs,” said Dr. Armstrong, the founding president of the organization. “There may be as many as 100.”
Team compositions vary but usually include at least one medical specialty clinician, such as infectious disease, primary care, or endocrinology, and two or more specialty clinicians, such as vascular, podiatric, orthopedic, or plastic surgery. A shoe specialist is needed to prescribe and manage footwear. Other important team members include nutrition experts and behavioral health professionals to deal with associated depression.
Johns Hopkins’ Multidisciplinary Diabetic Foot and Wound Service launched in 2012 and includes vascular surgeons, surgical podiatrists, endocrinologists, wound care nurses, advanced practice staff, board-certified wound care specialists, orthopedic surgeons, infection disease experts, physical therapists, and certified orthotists.
“This interdisciplinary care model has been repeatedly validated by research as superior for limb salvage and wound healing,” said Nestoras Mathioudakis, MD, codirector of the service. “For instance, endocrinologists and diabetes educators are crucial for managing uncontrolled diabetes — a key factor in infection and delayed wound healing. Similarly, vascular surgeons play a vital role in addressing peripheral arterial disease to improve blood flow to the affected area.”
“Diabetic foot ulcers might require prolonged periods of specialized care, including meticulous wound management and off-loading, overseen by surgical podiatrists and wound care experts,” he said. “In cases where infection is present, particularly with multidrug resistant organisms or when standard antibiotics are contraindicated, the insight of an infectious disease specialist is invaluable.”
While the makeup of teams varies from location to location, he said “the hallmark of effective teams is their ability to comprehensively manage glycemic control, foot wounds, vascular disease, and infections.”
The power of teams, Dr. Armstrong said, is very much evident after his weekly “foot selfie rounds” conducted Mondays at 7 AM, with an “all feet on deck” approach. “Not a week goes by when we don’t stop a hospitalization,” he said of the team evaluating the photos, due to detecting issues early, while still in the manageable state.
Teams can trump technology, Dr. Armstrong said. A team of just a primary care doctor and a podiatrist can make a significant reduction in amputations, he said, just by a “Knock your socks off” approach. He reminds primary care doctors that observing the feet of their patients with diabetes can go a long way to reducing DFUs and the hospitalizations and amputations that can result.
Dr. Mathioudakis and Dr. Isseroff reported no disclosures. Dr. Boulton consults for Urgo Medical, Nevro Corporation, and AOT, Inc. Dr. Armstrong reported receiving consulting fees from Podimetrics; Molnlycke; Cardiovascular Systems, Inc.; Endo Pharmaceuticals; and Averitas Pharma (GRT US).
A version of this article first appeared on Medscape.com.
IV Ketamine Promising for Severe Refractory Headache in Children
DENVER — , new research suggests. In a retrospective chart review, IV ketamine led to in a 50% reduction in pain at discharge, with “nearly two-thirds” of patients having no recurrence within 30 days, noted lead investigator Scott Rosenthal, MD, from the University of Colorado Anschutz Medical Campus, Aurora.
Dr. Rosenthal reported the findings at the 2024 annual meeting of the American Academy of Neurology.
Statistically Significant Pain Relief
“IV ketamine has shown benefit in nonheadache chronic pain syndromes and refractory mood disorders. Patients with refractory status migraines are often left with ongoing pain and dysfunction after failing typical interventions,” Dr. Rosenthal said.
“Ketamine has emerged as a potential treatment option in this population. However, there’s very little research on the efficacy and tolerability of it in general as well as the pediatric population,” he noted.
Dr. Rosenthal and colleagues took a look back at patients admitted to Children’s Hospital Colorado between 2019 and 2022 for treatment of severe refractory headache who were treated with continuous IV ketamine.
They analyzed 68 encounters of 41 unique patients aged 5-21 years (median age 16 years; 85% girls). Chronic migraine without aura made up 79% of cases.
On presentation, most patients had an exacerbation or ongoing worsening of pain for about 10 days, and all but two were taking a preventive medication. Nearly 70% had a comorbid psychiatric diagnosis such as anxiety or depression, and 60% had a comorbid chronic pain diagnosis separate from their headache diagnosis.
The primary outcome was percent pain reduction at discharge and headache recurrence within 72 hours, with headache recurrence defined as receipt of neurology care via phone, clinic, or hospital encounter.
Patients received IV ketamine at a median dose of 0.25 mg/kg/hr for a median of 3 days.
Overall, the treatment was “safe and well tolerated,” Dr. Rosenthal said.
There were no serious adverse events and no cardiac side effects; 7% (five out of 68) stopped treatment due to side effects. The most common side effects were dizziness (23%), nausea (16%), blurred vision (12%), hallucinations (19%), cognitive fog (7%), vomiting (6%) and dysphoria (4%), worsening headache (4%), and paresthesia and cramping (1.5%).
‘Exciting Starting Point’
At baseline, pain scores were 8 (on a scale of 0-10) and progressively fell (improved) during treatment. Pain scores were 6 on day 1 and were 5 on day 2, with a slight rebound to 5 at discharge, although the pain reduction at discharge (vs baseline) remained statistically significant (P < .001).
“The median percent pain reduction after 3 days of ketamine was about 40%,” Dr. Rosenthal said.
He noted that on the first day of treatment, 16% of patients responded to treatment (with a > 50% reduction in their initial pain); this doubled to 33% on day 2 and increased to 44% at discharge.
In terms of recurrence, 38% had a recurrence within 1 month, “meaning two thirds did not,” Dr. Rosenthal noted. Median time to recurrence was 7 days. There were no recurrences within 72 hours.
The researchers also tried to tease out which patients might respond best to ketamine.
“Surprisingly,” there wasn’t a strong effect of most demographic variables such as age, sex, gender identity, chronic pain, psychiatric comorbidities, duration of headache, or prior interventions, Dr. Rosenthal noted.
“Interestingly,” he said, patients who were on two or more preventive medications had a 50% reduction in their pain at discharge compared with a 33% reduction in patients taking one or no preventive medication. It’s possible that more preventative medications may “prime” a patient’s response to ketamine, Dr. Rosenthal said.
She added that future randomized studies are needed to further assess IV ketamine for refractory headache in children, but these results are “an exciting starting point.”
‘Still an Unknown’
Seniha Nur Ozudogru, MD, assistant professor of clinical neurology at Penn Medicine in Philadelphia, echoed the need for further study.
The role of IV ketamine in refractory pediatric headache is “still an unknown,” said Dr. Ozudogru, who was not involved in the study.
She noted that currently, there is “no standard protocol for ketamine infusion, even for adults. Every institution has their own protocols, which makes it difficult.”
Dr. Ozudogru also wonders how “doable” in-hospital IV infusions over 3 days may be for children.
“Especially for chronic migraine patients, it can be really tricky to manage expectations in that even if they don’t respond and the headache doesn’t go away, they still may have to be discharged. That requires a specific approach and discussion with the patients,” Dr. Ozudogru said.
Intranasal ketamine is another potential option, she said, with a recent study suggesting that intranasal ketamine is an effective treatment for children hospitalized with refractory migraine.
“However, there is some concern about the potential of addiction and the side effects of hallucinations and what the main protocol will be, so this not a standard treatment and has to be studied further,” she said.
The study had no specific funding. Dr. Rosenthal and Dr. Ozudogru have no relevant disclosures.
A version of this article appeared on Medscape.com.
DENVER — , new research suggests. In a retrospective chart review, IV ketamine led to in a 50% reduction in pain at discharge, with “nearly two-thirds” of patients having no recurrence within 30 days, noted lead investigator Scott Rosenthal, MD, from the University of Colorado Anschutz Medical Campus, Aurora.
Dr. Rosenthal reported the findings at the 2024 annual meeting of the American Academy of Neurology.
Statistically Significant Pain Relief
“IV ketamine has shown benefit in nonheadache chronic pain syndromes and refractory mood disorders. Patients with refractory status migraines are often left with ongoing pain and dysfunction after failing typical interventions,” Dr. Rosenthal said.
“Ketamine has emerged as a potential treatment option in this population. However, there’s very little research on the efficacy and tolerability of it in general as well as the pediatric population,” he noted.
Dr. Rosenthal and colleagues took a look back at patients admitted to Children’s Hospital Colorado between 2019 and 2022 for treatment of severe refractory headache who were treated with continuous IV ketamine.
They analyzed 68 encounters of 41 unique patients aged 5-21 years (median age 16 years; 85% girls). Chronic migraine without aura made up 79% of cases.
On presentation, most patients had an exacerbation or ongoing worsening of pain for about 10 days, and all but two were taking a preventive medication. Nearly 70% had a comorbid psychiatric diagnosis such as anxiety or depression, and 60% had a comorbid chronic pain diagnosis separate from their headache diagnosis.
The primary outcome was percent pain reduction at discharge and headache recurrence within 72 hours, with headache recurrence defined as receipt of neurology care via phone, clinic, or hospital encounter.
Patients received IV ketamine at a median dose of 0.25 mg/kg/hr for a median of 3 days.
Overall, the treatment was “safe and well tolerated,” Dr. Rosenthal said.
There were no serious adverse events and no cardiac side effects; 7% (five out of 68) stopped treatment due to side effects. The most common side effects were dizziness (23%), nausea (16%), blurred vision (12%), hallucinations (19%), cognitive fog (7%), vomiting (6%) and dysphoria (4%), worsening headache (4%), and paresthesia and cramping (1.5%).
‘Exciting Starting Point’
At baseline, pain scores were 8 (on a scale of 0-10) and progressively fell (improved) during treatment. Pain scores were 6 on day 1 and were 5 on day 2, with a slight rebound to 5 at discharge, although the pain reduction at discharge (vs baseline) remained statistically significant (P < .001).
“The median percent pain reduction after 3 days of ketamine was about 40%,” Dr. Rosenthal said.
He noted that on the first day of treatment, 16% of patients responded to treatment (with a > 50% reduction in their initial pain); this doubled to 33% on day 2 and increased to 44% at discharge.
In terms of recurrence, 38% had a recurrence within 1 month, “meaning two thirds did not,” Dr. Rosenthal noted. Median time to recurrence was 7 days. There were no recurrences within 72 hours.
The researchers also tried to tease out which patients might respond best to ketamine.
“Surprisingly,” there wasn’t a strong effect of most demographic variables such as age, sex, gender identity, chronic pain, psychiatric comorbidities, duration of headache, or prior interventions, Dr. Rosenthal noted.
“Interestingly,” he said, patients who were on two or more preventive medications had a 50% reduction in their pain at discharge compared with a 33% reduction in patients taking one or no preventive medication. It’s possible that more preventative medications may “prime” a patient’s response to ketamine, Dr. Rosenthal said.
She added that future randomized studies are needed to further assess IV ketamine for refractory headache in children, but these results are “an exciting starting point.”
‘Still an Unknown’
Seniha Nur Ozudogru, MD, assistant professor of clinical neurology at Penn Medicine in Philadelphia, echoed the need for further study.
The role of IV ketamine in refractory pediatric headache is “still an unknown,” said Dr. Ozudogru, who was not involved in the study.
She noted that currently, there is “no standard protocol for ketamine infusion, even for adults. Every institution has their own protocols, which makes it difficult.”
Dr. Ozudogru also wonders how “doable” in-hospital IV infusions over 3 days may be for children.
“Especially for chronic migraine patients, it can be really tricky to manage expectations in that even if they don’t respond and the headache doesn’t go away, they still may have to be discharged. That requires a specific approach and discussion with the patients,” Dr. Ozudogru said.
Intranasal ketamine is another potential option, she said, with a recent study suggesting that intranasal ketamine is an effective treatment for children hospitalized with refractory migraine.
“However, there is some concern about the potential of addiction and the side effects of hallucinations and what the main protocol will be, so this not a standard treatment and has to be studied further,” she said.
The study had no specific funding. Dr. Rosenthal and Dr. Ozudogru have no relevant disclosures.
A version of this article appeared on Medscape.com.
DENVER — , new research suggests. In a retrospective chart review, IV ketamine led to in a 50% reduction in pain at discharge, with “nearly two-thirds” of patients having no recurrence within 30 days, noted lead investigator Scott Rosenthal, MD, from the University of Colorado Anschutz Medical Campus, Aurora.
Dr. Rosenthal reported the findings at the 2024 annual meeting of the American Academy of Neurology.
Statistically Significant Pain Relief
“IV ketamine has shown benefit in nonheadache chronic pain syndromes and refractory mood disorders. Patients with refractory status migraines are often left with ongoing pain and dysfunction after failing typical interventions,” Dr. Rosenthal said.
“Ketamine has emerged as a potential treatment option in this population. However, there’s very little research on the efficacy and tolerability of it in general as well as the pediatric population,” he noted.
Dr. Rosenthal and colleagues took a look back at patients admitted to Children’s Hospital Colorado between 2019 and 2022 for treatment of severe refractory headache who were treated with continuous IV ketamine.
They analyzed 68 encounters of 41 unique patients aged 5-21 years (median age 16 years; 85% girls). Chronic migraine without aura made up 79% of cases.
On presentation, most patients had an exacerbation or ongoing worsening of pain for about 10 days, and all but two were taking a preventive medication. Nearly 70% had a comorbid psychiatric diagnosis such as anxiety or depression, and 60% had a comorbid chronic pain diagnosis separate from their headache diagnosis.
The primary outcome was percent pain reduction at discharge and headache recurrence within 72 hours, with headache recurrence defined as receipt of neurology care via phone, clinic, or hospital encounter.
Patients received IV ketamine at a median dose of 0.25 mg/kg/hr for a median of 3 days.
Overall, the treatment was “safe and well tolerated,” Dr. Rosenthal said.
There were no serious adverse events and no cardiac side effects; 7% (five out of 68) stopped treatment due to side effects. The most common side effects were dizziness (23%), nausea (16%), blurred vision (12%), hallucinations (19%), cognitive fog (7%), vomiting (6%) and dysphoria (4%), worsening headache (4%), and paresthesia and cramping (1.5%).
‘Exciting Starting Point’
At baseline, pain scores were 8 (on a scale of 0-10) and progressively fell (improved) during treatment. Pain scores were 6 on day 1 and were 5 on day 2, with a slight rebound to 5 at discharge, although the pain reduction at discharge (vs baseline) remained statistically significant (P < .001).
“The median percent pain reduction after 3 days of ketamine was about 40%,” Dr. Rosenthal said.
He noted that on the first day of treatment, 16% of patients responded to treatment (with a > 50% reduction in their initial pain); this doubled to 33% on day 2 and increased to 44% at discharge.
In terms of recurrence, 38% had a recurrence within 1 month, “meaning two thirds did not,” Dr. Rosenthal noted. Median time to recurrence was 7 days. There were no recurrences within 72 hours.
The researchers also tried to tease out which patients might respond best to ketamine.
“Surprisingly,” there wasn’t a strong effect of most demographic variables such as age, sex, gender identity, chronic pain, psychiatric comorbidities, duration of headache, or prior interventions, Dr. Rosenthal noted.
“Interestingly,” he said, patients who were on two or more preventive medications had a 50% reduction in their pain at discharge compared with a 33% reduction in patients taking one or no preventive medication. It’s possible that more preventative medications may “prime” a patient’s response to ketamine, Dr. Rosenthal said.
She added that future randomized studies are needed to further assess IV ketamine for refractory headache in children, but these results are “an exciting starting point.”
‘Still an Unknown’
Seniha Nur Ozudogru, MD, assistant professor of clinical neurology at Penn Medicine in Philadelphia, echoed the need for further study.
The role of IV ketamine in refractory pediatric headache is “still an unknown,” said Dr. Ozudogru, who was not involved in the study.
She noted that currently, there is “no standard protocol for ketamine infusion, even for adults. Every institution has their own protocols, which makes it difficult.”
Dr. Ozudogru also wonders how “doable” in-hospital IV infusions over 3 days may be for children.
“Especially for chronic migraine patients, it can be really tricky to manage expectations in that even if they don’t respond and the headache doesn’t go away, they still may have to be discharged. That requires a specific approach and discussion with the patients,” Dr. Ozudogru said.
Intranasal ketamine is another potential option, she said, with a recent study suggesting that intranasal ketamine is an effective treatment for children hospitalized with refractory migraine.
“However, there is some concern about the potential of addiction and the side effects of hallucinations and what the main protocol will be, so this not a standard treatment and has to be studied further,” she said.
The study had no specific funding. Dr. Rosenthal and Dr. Ozudogru have no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM AAN 2024
4 Years In, a Sobering Look at Long COVID Progress
Four years ago in the spring of 2020, physicians and patients coined the term “long COVID” to describe a form of the viral infection from which recovery seemed impossible. (And the old nickname “long-haulers” seems so quaint now.)
What started as a pandemic that killed nearly 3 million people globally in 2020 alone would turn into a chronic disease causing a long list of symptoms — from extreme fatigue, to brain fog, tremors, nausea, headaches, rapid heartbeat, and more.
Today, 6.4% of Americans report symptoms of long COVID, and many have never recovered.
Still, we’ve come a long way, although there’s much we don’t understand about the condition. At the very least, physicians have a greater understanding that long COVID exists and can cause serious long-term symptoms.
While physicians may not have a blanket diagnostic tool that works for all patients with long COVID, they have refined existing tests for more accurate results, said Nisha Viswanathan, MD, director of the University of California Los Angeles Long COVID Program at UCLA Health.
Also, a range of new treatments, now undergoing clinical trials, have emerged that have proved effective in managing long COVID symptoms.
Catecholamine testing, for example, is now commonly used to diagnose long COVID, particularly in those who have dysautonomia, a condition caused by dysfunction of the autonomic nervous system and marked by dizziness, low blood pressure, nausea, and brain fog.
Very high levels of the neurotransmitter, for example, were shown to indicate long COVID in a January 2021 study published in the journal Clinical Medicine.
Certain biomarkers have also been shown indicative of the condition, including low serotonin levels. A study published this year in Cell found lower serotonin levels in patients with long COVID driven by low levels of circulating SARS-CoV-2, the virus that causes the condition.
Still, said Dr. Viswanathan, long COVID is a disease diagnosed by figuring out what a patient does not have — by ruling out other causes — rather than what they do. “It’s still a moving target,” she said, meaning that the disease is always changing based on the variant of acute COVID.
Promising Treatments Have Emerged
Dysautonomia, and especially the associated brain fog, fatigue, and dizziness, are now common conditions. As a result, physicians have gotten better at treating them. The vagus nerve is the main nerve of the parasympathetic nervous system that controls everything from digestion to mental health. A February 2022 pilot study suggested a link between vagus nerve dysfunction and some long COVID symptoms.
Vagus nerve stimulation is one form of treatment which involves using a device to stimulate the vagus nerve with electrical impulses. Dr. Viswanathan has been using the treatment in patients with fatigue, brain fog, anxiety, and depression — results, she contends, have been positive.
“This is something tangible that we can offer to patients,” she said.
Curative treatments for long COVID remain elusive, but doctors have many more tools for symptom management than before, said Ziyad Al-Aly, MD, a global expert on long COVID and chief of research and development at the Veterans Affairs St. Louis Health Care System.
For example, physicians are using beta-blockers to treat postural tachycardia syndrome (POTS), a symptom of long COVID that happens when the heart rate increases rapidly after someone stands up or lies down. Beta-blockers, such as the off-label medication ivabradine, have been used clinically to control heart rate, according to a March 2022 study published in the journal HeartRhythm Case Reports.
“It’s not a cure, but beta-blockers can help patients manage their symptoms,” said Dr. Al-Aly.
Additionally, some patients respond well to low-dose naltrexone for the treatment of extreme fatigue associated with long COVID. A January 2024 article in the journal Clinical Therapeutics found that fatigue symptoms improved in patients taking the medication.
Dr. Al-Aly said doctors treating patients with long COVID are getting better at pinpointing the phenotype or manifestation of the condition and diagnosing a treatment accordingly. Treating long COVID fatigue is not the same as treating POTS or symptoms of headache and joint pain.
It’s still all about the management of symptoms and doctors lack any US Food and Drug Administration–approved medications specifically for the condition.
Clinical Trials Exploring New Therapies
Still, a number of large clinical trials currently underway may change that, said David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City.
Two clinical trials headed by Dr. Putrino’s lab are looking into repurposing two HIV antivirals to see whether they affect the levels of circulating SARS-CoV-2 virus in the body that may cause long COVID. The hope is that the antivirals Truvada and maraviroc can reduce the «reactivation of latent virus» that, said Dr. Putrino, causes lingering long COVID symptoms.
Ongoing trials are looking into the promise of SARS-CoV-2 monoclonal antibodies, produced from cells made by cloning a unique white blood cell, as a treatment option. The trials are investigating whether these antibodies may similarly target viral reservoirs that are causing persistence of symptoms in some patients.
Other trials are underway through the National Institutes of Health (NIH) RECOVER initiative in which more than 17,000 patients are enrolled, the largest study of its kind, said Grace McComsey, MD.
Dr. McComsey, who leads the study at University Hospitals Health System in Cleveland, said that after following patients for up to 4 years researchers have gathered “a massive repository of information” they hope will help scientists crack the code of this very complex disease.
She and other RECOVER researchers have recently published studies on a variety of findings, reporting in February, for example, that COVID infections may trigger other autoimmune diseases such as rheumatoid arthritis and type 2 diabetes. Another recent finding showed that people with HIV are at a higher risk for complications due to acute COVID-19.
Lack of Urgency Holds Back Progress
Still, others like Dr. Al-Aly and Dr. Putrino felt that the initiative isn’t moving fast enough. Dr. Al-Aly said that the NIH needs to “get its act together” and do more for long COVID. In the future, he said that we need to double down on our efforts to expand funding and increase urgency to better understand the mechanism of disease, risk factors, and treatments, as well as societal and economic implications.
“We did trials for COVID-19 vaccines at warp speed, but we’re doing trials for long COVID at a snail’s pace,” he said.
Dr. Al-Aly is concerned about the chronic nature of the disease and how it affects patients down the line. His large-scale study published last month in the journal Science looked specifically at chronic fatigue syndrome triggered by the infection and its long-term impact on patients.
He’s concerned about the practical implications for people who are weighted down with symptoms for multiple years.
“Being fatigued and ill for a few months is one thing, but being at home for 5 years is a totally different ballgame.”
A version of this article first appeared on Medscape.com.
Four years ago in the spring of 2020, physicians and patients coined the term “long COVID” to describe a form of the viral infection from which recovery seemed impossible. (And the old nickname “long-haulers” seems so quaint now.)
What started as a pandemic that killed nearly 3 million people globally in 2020 alone would turn into a chronic disease causing a long list of symptoms — from extreme fatigue, to brain fog, tremors, nausea, headaches, rapid heartbeat, and more.
Today, 6.4% of Americans report symptoms of long COVID, and many have never recovered.
Still, we’ve come a long way, although there’s much we don’t understand about the condition. At the very least, physicians have a greater understanding that long COVID exists and can cause serious long-term symptoms.
While physicians may not have a blanket diagnostic tool that works for all patients with long COVID, they have refined existing tests for more accurate results, said Nisha Viswanathan, MD, director of the University of California Los Angeles Long COVID Program at UCLA Health.
Also, a range of new treatments, now undergoing clinical trials, have emerged that have proved effective in managing long COVID symptoms.
Catecholamine testing, for example, is now commonly used to diagnose long COVID, particularly in those who have dysautonomia, a condition caused by dysfunction of the autonomic nervous system and marked by dizziness, low blood pressure, nausea, and brain fog.
Very high levels of the neurotransmitter, for example, were shown to indicate long COVID in a January 2021 study published in the journal Clinical Medicine.
Certain biomarkers have also been shown indicative of the condition, including low serotonin levels. A study published this year in Cell found lower serotonin levels in patients with long COVID driven by low levels of circulating SARS-CoV-2, the virus that causes the condition.
Still, said Dr. Viswanathan, long COVID is a disease diagnosed by figuring out what a patient does not have — by ruling out other causes — rather than what they do. “It’s still a moving target,” she said, meaning that the disease is always changing based on the variant of acute COVID.
Promising Treatments Have Emerged
Dysautonomia, and especially the associated brain fog, fatigue, and dizziness, are now common conditions. As a result, physicians have gotten better at treating them. The vagus nerve is the main nerve of the parasympathetic nervous system that controls everything from digestion to mental health. A February 2022 pilot study suggested a link between vagus nerve dysfunction and some long COVID symptoms.
Vagus nerve stimulation is one form of treatment which involves using a device to stimulate the vagus nerve with electrical impulses. Dr. Viswanathan has been using the treatment in patients with fatigue, brain fog, anxiety, and depression — results, she contends, have been positive.
“This is something tangible that we can offer to patients,” she said.
Curative treatments for long COVID remain elusive, but doctors have many more tools for symptom management than before, said Ziyad Al-Aly, MD, a global expert on long COVID and chief of research and development at the Veterans Affairs St. Louis Health Care System.
For example, physicians are using beta-blockers to treat postural tachycardia syndrome (POTS), a symptom of long COVID that happens when the heart rate increases rapidly after someone stands up or lies down. Beta-blockers, such as the off-label medication ivabradine, have been used clinically to control heart rate, according to a March 2022 study published in the journal HeartRhythm Case Reports.
“It’s not a cure, but beta-blockers can help patients manage their symptoms,” said Dr. Al-Aly.
Additionally, some patients respond well to low-dose naltrexone for the treatment of extreme fatigue associated with long COVID. A January 2024 article in the journal Clinical Therapeutics found that fatigue symptoms improved in patients taking the medication.
Dr. Al-Aly said doctors treating patients with long COVID are getting better at pinpointing the phenotype or manifestation of the condition and diagnosing a treatment accordingly. Treating long COVID fatigue is not the same as treating POTS or symptoms of headache and joint pain.
It’s still all about the management of symptoms and doctors lack any US Food and Drug Administration–approved medications specifically for the condition.
Clinical Trials Exploring New Therapies
Still, a number of large clinical trials currently underway may change that, said David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City.
Two clinical trials headed by Dr. Putrino’s lab are looking into repurposing two HIV antivirals to see whether they affect the levels of circulating SARS-CoV-2 virus in the body that may cause long COVID. The hope is that the antivirals Truvada and maraviroc can reduce the «reactivation of latent virus» that, said Dr. Putrino, causes lingering long COVID symptoms.
Ongoing trials are looking into the promise of SARS-CoV-2 monoclonal antibodies, produced from cells made by cloning a unique white blood cell, as a treatment option. The trials are investigating whether these antibodies may similarly target viral reservoirs that are causing persistence of symptoms in some patients.
Other trials are underway through the National Institutes of Health (NIH) RECOVER initiative in which more than 17,000 patients are enrolled, the largest study of its kind, said Grace McComsey, MD.
Dr. McComsey, who leads the study at University Hospitals Health System in Cleveland, said that after following patients for up to 4 years researchers have gathered “a massive repository of information” they hope will help scientists crack the code of this very complex disease.
She and other RECOVER researchers have recently published studies on a variety of findings, reporting in February, for example, that COVID infections may trigger other autoimmune diseases such as rheumatoid arthritis and type 2 diabetes. Another recent finding showed that people with HIV are at a higher risk for complications due to acute COVID-19.
Lack of Urgency Holds Back Progress
Still, others like Dr. Al-Aly and Dr. Putrino felt that the initiative isn’t moving fast enough. Dr. Al-Aly said that the NIH needs to “get its act together” and do more for long COVID. In the future, he said that we need to double down on our efforts to expand funding and increase urgency to better understand the mechanism of disease, risk factors, and treatments, as well as societal and economic implications.
“We did trials for COVID-19 vaccines at warp speed, but we’re doing trials for long COVID at a snail’s pace,” he said.
Dr. Al-Aly is concerned about the chronic nature of the disease and how it affects patients down the line. His large-scale study published last month in the journal Science looked specifically at chronic fatigue syndrome triggered by the infection and its long-term impact on patients.
He’s concerned about the practical implications for people who are weighted down with symptoms for multiple years.
“Being fatigued and ill for a few months is one thing, but being at home for 5 years is a totally different ballgame.”
A version of this article first appeared on Medscape.com.
Four years ago in the spring of 2020, physicians and patients coined the term “long COVID” to describe a form of the viral infection from which recovery seemed impossible. (And the old nickname “long-haulers” seems so quaint now.)
What started as a pandemic that killed nearly 3 million people globally in 2020 alone would turn into a chronic disease causing a long list of symptoms — from extreme fatigue, to brain fog, tremors, nausea, headaches, rapid heartbeat, and more.
Today, 6.4% of Americans report symptoms of long COVID, and many have never recovered.
Still, we’ve come a long way, although there’s much we don’t understand about the condition. At the very least, physicians have a greater understanding that long COVID exists and can cause serious long-term symptoms.
While physicians may not have a blanket diagnostic tool that works for all patients with long COVID, they have refined existing tests for more accurate results, said Nisha Viswanathan, MD, director of the University of California Los Angeles Long COVID Program at UCLA Health.
Also, a range of new treatments, now undergoing clinical trials, have emerged that have proved effective in managing long COVID symptoms.
Catecholamine testing, for example, is now commonly used to diagnose long COVID, particularly in those who have dysautonomia, a condition caused by dysfunction of the autonomic nervous system and marked by dizziness, low blood pressure, nausea, and brain fog.
Very high levels of the neurotransmitter, for example, were shown to indicate long COVID in a January 2021 study published in the journal Clinical Medicine.
Certain biomarkers have also been shown indicative of the condition, including low serotonin levels. A study published this year in Cell found lower serotonin levels in patients with long COVID driven by low levels of circulating SARS-CoV-2, the virus that causes the condition.
Still, said Dr. Viswanathan, long COVID is a disease diagnosed by figuring out what a patient does not have — by ruling out other causes — rather than what they do. “It’s still a moving target,” she said, meaning that the disease is always changing based on the variant of acute COVID.
Promising Treatments Have Emerged
Dysautonomia, and especially the associated brain fog, fatigue, and dizziness, are now common conditions. As a result, physicians have gotten better at treating them. The vagus nerve is the main nerve of the parasympathetic nervous system that controls everything from digestion to mental health. A February 2022 pilot study suggested a link between vagus nerve dysfunction and some long COVID symptoms.
Vagus nerve stimulation is one form of treatment which involves using a device to stimulate the vagus nerve with electrical impulses. Dr. Viswanathan has been using the treatment in patients with fatigue, brain fog, anxiety, and depression — results, she contends, have been positive.
“This is something tangible that we can offer to patients,” she said.
Curative treatments for long COVID remain elusive, but doctors have many more tools for symptom management than before, said Ziyad Al-Aly, MD, a global expert on long COVID and chief of research and development at the Veterans Affairs St. Louis Health Care System.
For example, physicians are using beta-blockers to treat postural tachycardia syndrome (POTS), a symptom of long COVID that happens when the heart rate increases rapidly after someone stands up or lies down. Beta-blockers, such as the off-label medication ivabradine, have been used clinically to control heart rate, according to a March 2022 study published in the journal HeartRhythm Case Reports.
“It’s not a cure, but beta-blockers can help patients manage their symptoms,” said Dr. Al-Aly.
Additionally, some patients respond well to low-dose naltrexone for the treatment of extreme fatigue associated with long COVID. A January 2024 article in the journal Clinical Therapeutics found that fatigue symptoms improved in patients taking the medication.
Dr. Al-Aly said doctors treating patients with long COVID are getting better at pinpointing the phenotype or manifestation of the condition and diagnosing a treatment accordingly. Treating long COVID fatigue is not the same as treating POTS or symptoms of headache and joint pain.
It’s still all about the management of symptoms and doctors lack any US Food and Drug Administration–approved medications specifically for the condition.
Clinical Trials Exploring New Therapies
Still, a number of large clinical trials currently underway may change that, said David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City.
Two clinical trials headed by Dr. Putrino’s lab are looking into repurposing two HIV antivirals to see whether they affect the levels of circulating SARS-CoV-2 virus in the body that may cause long COVID. The hope is that the antivirals Truvada and maraviroc can reduce the «reactivation of latent virus» that, said Dr. Putrino, causes lingering long COVID symptoms.
Ongoing trials are looking into the promise of SARS-CoV-2 monoclonal antibodies, produced from cells made by cloning a unique white blood cell, as a treatment option. The trials are investigating whether these antibodies may similarly target viral reservoirs that are causing persistence of symptoms in some patients.
Other trials are underway through the National Institutes of Health (NIH) RECOVER initiative in which more than 17,000 patients are enrolled, the largest study of its kind, said Grace McComsey, MD.
Dr. McComsey, who leads the study at University Hospitals Health System in Cleveland, said that after following patients for up to 4 years researchers have gathered “a massive repository of information” they hope will help scientists crack the code of this very complex disease.
She and other RECOVER researchers have recently published studies on a variety of findings, reporting in February, for example, that COVID infections may trigger other autoimmune diseases such as rheumatoid arthritis and type 2 diabetes. Another recent finding showed that people with HIV are at a higher risk for complications due to acute COVID-19.
Lack of Urgency Holds Back Progress
Still, others like Dr. Al-Aly and Dr. Putrino felt that the initiative isn’t moving fast enough. Dr. Al-Aly said that the NIH needs to “get its act together” and do more for long COVID. In the future, he said that we need to double down on our efforts to expand funding and increase urgency to better understand the mechanism of disease, risk factors, and treatments, as well as societal and economic implications.
“We did trials for COVID-19 vaccines at warp speed, but we’re doing trials for long COVID at a snail’s pace,” he said.
Dr. Al-Aly is concerned about the chronic nature of the disease and how it affects patients down the line. His large-scale study published last month in the journal Science looked specifically at chronic fatigue syndrome triggered by the infection and its long-term impact on patients.
He’s concerned about the practical implications for people who are weighted down with symptoms for multiple years.
“Being fatigued and ill for a few months is one thing, but being at home for 5 years is a totally different ballgame.”
A version of this article first appeared on Medscape.com.
Microbial Signature of KRAS-Mutated Colorectal Cancer Identified
Their findings suggest that the gut microbes may serve as noninvasive biomarkers to help identify subtypes of CRC and guide personalized treatment recommendations.
“Our new work contributes to the growing body of evidence highlighting the significance of microbiota-driven mechanisms in cancer pathogenesis,” lead investigator Weizhong Tang, MD, with Guangxi Medical University Cancer Hospital in Nanning, China, said in a statement.
The research was recently published online in Microbiology Spectrum.
The onset and growth of CRC has been linked both to imbalances in the gut microbiome and to mutations in the KRAS gene — about 40% of people with CRC have a KRAS mutation. Yet, the interplay between gut dysbiosis and KRAS mutations in CRC remains unclear.
To investigate further, Dr. Tang and colleagues used 16s rRNA sequencing to analyze stool samples from 94 patients with CRC, including 24 with KRAS-mutated CRC and 70 with KRAS wild-type (nonmutated) CRC.
The researchers identified 26 distinct types of gut microbiota with statistically significant differences in abundance between the KRAS mutant and KRAS wild-type CRC patients.
At the genus level, Fusobacterium, Clostridium, and Shewanella were all abundant in the KRAS mutant group.
Fusobacterium is a Gram-negative microbe found in the gastrointestinal tract and the oral cavity. Recent studies have established a strong link between Fusobacterium and CRC development. Other work found elevated levels of Fusobacterium nucleatum were not only closely associated with KRAS mutation but also correlated with chemoresistance in CRC.
Clostridium produces metabolites in the large intestine, which are known to cause DNA damage and trigger inflammatory responses, thereby increasing the risk of CRC development.
Similarly, Shewanella has been proven to be a contributor to CRC development.
The researchers say it’s “plausible” to consider all three as potential noninvasive biomarkers for identifying KRAS mutation in CRC patients.
In contrast, Bifidobacterium and Akkermansia were abundant in the KRAS wild-type group.
Bifidobacterium is a probiotic with antitumor activity and Akkermansia is a Gram-negative anaerobic bacterium abundant in the gut and currently recognized as a potential probiotic.
The researchers speculated that CRC patients may have a reduced likelihood of developing KRAS mutation in the presence of Bifidobacterium and Akkermansia.
Analyses of biological pathways of gut microbiota associated with KRAS mutation status in CRC revealed a significantly higher abundance of the isoflavonoid biosynthesis pathway in the KRAS wild-type group compared with the KRAS mutant group.
“In comparison to KRAS mutant CRC, it is postulated that KRAS wild-type CRC may be less aggressive due to the upregulation of the isoflavonoid biosynthesis pathway, which may inhibit CRC development and progression,” the authors wrote.
Promising Predictive Model
Dr. Tang and colleagues also developed a machine learning model to predict KRAS mutation status in CRC patients based on the gut microbiota signature in KRAS mutant CRC.
The initial results underscore the model’s predictive efficacy and suggest that it has “considerable potential for clinical application, offering a novel dimension in the prediction of KRAS mutation status among CRC patients in a clinical setting,” the authors wrote.
They caution that the model requires data from a larger cohort to improve its efficacy, and they plan to do larger studies to validate the findings.
The study had no commercial funding. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Their findings suggest that the gut microbes may serve as noninvasive biomarkers to help identify subtypes of CRC and guide personalized treatment recommendations.
“Our new work contributes to the growing body of evidence highlighting the significance of microbiota-driven mechanisms in cancer pathogenesis,” lead investigator Weizhong Tang, MD, with Guangxi Medical University Cancer Hospital in Nanning, China, said in a statement.
The research was recently published online in Microbiology Spectrum.
The onset and growth of CRC has been linked both to imbalances in the gut microbiome and to mutations in the KRAS gene — about 40% of people with CRC have a KRAS mutation. Yet, the interplay between gut dysbiosis and KRAS mutations in CRC remains unclear.
To investigate further, Dr. Tang and colleagues used 16s rRNA sequencing to analyze stool samples from 94 patients with CRC, including 24 with KRAS-mutated CRC and 70 with KRAS wild-type (nonmutated) CRC.
The researchers identified 26 distinct types of gut microbiota with statistically significant differences in abundance between the KRAS mutant and KRAS wild-type CRC patients.
At the genus level, Fusobacterium, Clostridium, and Shewanella were all abundant in the KRAS mutant group.
Fusobacterium is a Gram-negative microbe found in the gastrointestinal tract and the oral cavity. Recent studies have established a strong link between Fusobacterium and CRC development. Other work found elevated levels of Fusobacterium nucleatum were not only closely associated with KRAS mutation but also correlated with chemoresistance in CRC.
Clostridium produces metabolites in the large intestine, which are known to cause DNA damage and trigger inflammatory responses, thereby increasing the risk of CRC development.
Similarly, Shewanella has been proven to be a contributor to CRC development.
The researchers say it’s “plausible” to consider all three as potential noninvasive biomarkers for identifying KRAS mutation in CRC patients.
In contrast, Bifidobacterium and Akkermansia were abundant in the KRAS wild-type group.
Bifidobacterium is a probiotic with antitumor activity and Akkermansia is a Gram-negative anaerobic bacterium abundant in the gut and currently recognized as a potential probiotic.
The researchers speculated that CRC patients may have a reduced likelihood of developing KRAS mutation in the presence of Bifidobacterium and Akkermansia.
Analyses of biological pathways of gut microbiota associated with KRAS mutation status in CRC revealed a significantly higher abundance of the isoflavonoid biosynthesis pathway in the KRAS wild-type group compared with the KRAS mutant group.
“In comparison to KRAS mutant CRC, it is postulated that KRAS wild-type CRC may be less aggressive due to the upregulation of the isoflavonoid biosynthesis pathway, which may inhibit CRC development and progression,” the authors wrote.
Promising Predictive Model
Dr. Tang and colleagues also developed a machine learning model to predict KRAS mutation status in CRC patients based on the gut microbiota signature in KRAS mutant CRC.
The initial results underscore the model’s predictive efficacy and suggest that it has “considerable potential for clinical application, offering a novel dimension in the prediction of KRAS mutation status among CRC patients in a clinical setting,” the authors wrote.
They caution that the model requires data from a larger cohort to improve its efficacy, and they plan to do larger studies to validate the findings.
The study had no commercial funding. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Their findings suggest that the gut microbes may serve as noninvasive biomarkers to help identify subtypes of CRC and guide personalized treatment recommendations.
“Our new work contributes to the growing body of evidence highlighting the significance of microbiota-driven mechanisms in cancer pathogenesis,” lead investigator Weizhong Tang, MD, with Guangxi Medical University Cancer Hospital in Nanning, China, said in a statement.
The research was recently published online in Microbiology Spectrum.
The onset and growth of CRC has been linked both to imbalances in the gut microbiome and to mutations in the KRAS gene — about 40% of people with CRC have a KRAS mutation. Yet, the interplay between gut dysbiosis and KRAS mutations in CRC remains unclear.
To investigate further, Dr. Tang and colleagues used 16s rRNA sequencing to analyze stool samples from 94 patients with CRC, including 24 with KRAS-mutated CRC and 70 with KRAS wild-type (nonmutated) CRC.
The researchers identified 26 distinct types of gut microbiota with statistically significant differences in abundance between the KRAS mutant and KRAS wild-type CRC patients.
At the genus level, Fusobacterium, Clostridium, and Shewanella were all abundant in the KRAS mutant group.
Fusobacterium is a Gram-negative microbe found in the gastrointestinal tract and the oral cavity. Recent studies have established a strong link between Fusobacterium and CRC development. Other work found elevated levels of Fusobacterium nucleatum were not only closely associated with KRAS mutation but also correlated with chemoresistance in CRC.
Clostridium produces metabolites in the large intestine, which are known to cause DNA damage and trigger inflammatory responses, thereby increasing the risk of CRC development.
Similarly, Shewanella has been proven to be a contributor to CRC development.
The researchers say it’s “plausible” to consider all three as potential noninvasive biomarkers for identifying KRAS mutation in CRC patients.
In contrast, Bifidobacterium and Akkermansia were abundant in the KRAS wild-type group.
Bifidobacterium is a probiotic with antitumor activity and Akkermansia is a Gram-negative anaerobic bacterium abundant in the gut and currently recognized as a potential probiotic.
The researchers speculated that CRC patients may have a reduced likelihood of developing KRAS mutation in the presence of Bifidobacterium and Akkermansia.
Analyses of biological pathways of gut microbiota associated with KRAS mutation status in CRC revealed a significantly higher abundance of the isoflavonoid biosynthesis pathway in the KRAS wild-type group compared with the KRAS mutant group.
“In comparison to KRAS mutant CRC, it is postulated that KRAS wild-type CRC may be less aggressive due to the upregulation of the isoflavonoid biosynthesis pathway, which may inhibit CRC development and progression,” the authors wrote.
Promising Predictive Model
Dr. Tang and colleagues also developed a machine learning model to predict KRAS mutation status in CRC patients based on the gut microbiota signature in KRAS mutant CRC.
The initial results underscore the model’s predictive efficacy and suggest that it has “considerable potential for clinical application, offering a novel dimension in the prediction of KRAS mutation status among CRC patients in a clinical setting,” the authors wrote.
They caution that the model requires data from a larger cohort to improve its efficacy, and they plan to do larger studies to validate the findings.
The study had no commercial funding. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Too Little Sleep Raises Health Risks for Teens With T1D
TOPLINE:
METHODOLOGY:
- Sleep is recognized as an important factor in diabetes assessment and treatment by the 2023 American Diabetes Association’s Standards of Medical Care in Diabetes, but it is unclear whether sleep may improve health outcomes across the lifespan in patients with T1D.
- This secondary analysis of the BCQR-T1D crossover trial investigated the link between sleep and cardiometabolic health in 42 adults (age, 19-60 years) and 42 adolescents (age, 12-18 years) with T1D.
- Participants had T1D duration greater than 9 months and received bromocriptine quick-release (BCQR) therapy or placebo for 4 weeks and then switched between the treatments in a separate 4-week period.
- They underwent laboratory testing and anthropometric measurements. Also, continuous glucose monitoring data were collected for a week during each treatment phase along with an accompanying insulin dosing diary.
- Participants were required to wear an actigraphy monitor on the wrist of their nondominant hand for 7 days during each treatment phase to estimate sleep duration.
TAKEAWAY:
- Most adolescents (62%) and adults (74%) with T1D reported less than 7 hours of sleep at baseline.
- Participants with insufficient sleep versus those without insufficient sleep (< 7 vs > 7 hours) had a larger waist circumference and higher mean body mass index, systolic blood pressure, and pulse pressure, as well as lower estimated insulin sensitivity and brachial artery distensibility (P < .05 for all).
- When stratified by age, only adolescents with T1D with insufficient sleep had significant differences in most health outcomes by sleep duration status, except that adults with less than 7 hours of sleep had higher pulse pressure than those with more than 7 hours of sleep.
- Compared with placebo, BCQR slightly improved sleeping parameters in adolescents by delaying their time of waking up and prolonging their time in bed.
IN PRACTICE:
“Sleep may be an important and novel target for improving health in individuals with T1D, particularly when initiated in adolescence or early in diabetes,” the authors wrote.
SOURCE:
Stacey L. Simon, PhD, and Janet K. Snell-Bergeon, PhD, University of Colorado Anschutz Medical Campus, Aurora, led this study, which was published online in Diabetes, Obesity and Metabolism.
LIMITATIONS:
The study lacked polysomnography or melatonin assessment to quantify circadian rhythms and subjective sleep quality ratings. It also had no objective measurement of the timing of the daily pills of BCQR, which, when taken in the morning, are hypothesized to reset the circadian rhythm for hypothalamic dopamine and serotonin. The recommended sleep duration of 8 hours for adolescents was not used as the cutoff value due to too few participants who qualified. Also, this study›s findings may be affected by the fact that participants were recruited throughout the year, while adolescents show different sleeping patterns during the academic year compared with school breaks.
DISCLOSURES:
This work was supported by a JDRF grant. Two authors declared receiving equipment, honoraria for lectures, and support for conference travel, which were all unrelated to this study.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Sleep is recognized as an important factor in diabetes assessment and treatment by the 2023 American Diabetes Association’s Standards of Medical Care in Diabetes, but it is unclear whether sleep may improve health outcomes across the lifespan in patients with T1D.
- This secondary analysis of the BCQR-T1D crossover trial investigated the link between sleep and cardiometabolic health in 42 adults (age, 19-60 years) and 42 adolescents (age, 12-18 years) with T1D.
- Participants had T1D duration greater than 9 months and received bromocriptine quick-release (BCQR) therapy or placebo for 4 weeks and then switched between the treatments in a separate 4-week period.
- They underwent laboratory testing and anthropometric measurements. Also, continuous glucose monitoring data were collected for a week during each treatment phase along with an accompanying insulin dosing diary.
- Participants were required to wear an actigraphy monitor on the wrist of their nondominant hand for 7 days during each treatment phase to estimate sleep duration.
TAKEAWAY:
- Most adolescents (62%) and adults (74%) with T1D reported less than 7 hours of sleep at baseline.
- Participants with insufficient sleep versus those without insufficient sleep (< 7 vs > 7 hours) had a larger waist circumference and higher mean body mass index, systolic blood pressure, and pulse pressure, as well as lower estimated insulin sensitivity and brachial artery distensibility (P < .05 for all).
- When stratified by age, only adolescents with T1D with insufficient sleep had significant differences in most health outcomes by sleep duration status, except that adults with less than 7 hours of sleep had higher pulse pressure than those with more than 7 hours of sleep.
- Compared with placebo, BCQR slightly improved sleeping parameters in adolescents by delaying their time of waking up and prolonging their time in bed.
IN PRACTICE:
“Sleep may be an important and novel target for improving health in individuals with T1D, particularly when initiated in adolescence or early in diabetes,” the authors wrote.
SOURCE:
Stacey L. Simon, PhD, and Janet K. Snell-Bergeon, PhD, University of Colorado Anschutz Medical Campus, Aurora, led this study, which was published online in Diabetes, Obesity and Metabolism.
LIMITATIONS:
The study lacked polysomnography or melatonin assessment to quantify circadian rhythms and subjective sleep quality ratings. It also had no objective measurement of the timing of the daily pills of BCQR, which, when taken in the morning, are hypothesized to reset the circadian rhythm for hypothalamic dopamine and serotonin. The recommended sleep duration of 8 hours for adolescents was not used as the cutoff value due to too few participants who qualified. Also, this study›s findings may be affected by the fact that participants were recruited throughout the year, while adolescents show different sleeping patterns during the academic year compared with school breaks.
DISCLOSURES:
This work was supported by a JDRF grant. Two authors declared receiving equipment, honoraria for lectures, and support for conference travel, which were all unrelated to this study.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Sleep is recognized as an important factor in diabetes assessment and treatment by the 2023 American Diabetes Association’s Standards of Medical Care in Diabetes, but it is unclear whether sleep may improve health outcomes across the lifespan in patients with T1D.
- This secondary analysis of the BCQR-T1D crossover trial investigated the link between sleep and cardiometabolic health in 42 adults (age, 19-60 years) and 42 adolescents (age, 12-18 years) with T1D.
- Participants had T1D duration greater than 9 months and received bromocriptine quick-release (BCQR) therapy or placebo for 4 weeks and then switched between the treatments in a separate 4-week period.
- They underwent laboratory testing and anthropometric measurements. Also, continuous glucose monitoring data were collected for a week during each treatment phase along with an accompanying insulin dosing diary.
- Participants were required to wear an actigraphy monitor on the wrist of their nondominant hand for 7 days during each treatment phase to estimate sleep duration.
TAKEAWAY:
- Most adolescents (62%) and adults (74%) with T1D reported less than 7 hours of sleep at baseline.
- Participants with insufficient sleep versus those without insufficient sleep (< 7 vs > 7 hours) had a larger waist circumference and higher mean body mass index, systolic blood pressure, and pulse pressure, as well as lower estimated insulin sensitivity and brachial artery distensibility (P < .05 for all).
- When stratified by age, only adolescents with T1D with insufficient sleep had significant differences in most health outcomes by sleep duration status, except that adults with less than 7 hours of sleep had higher pulse pressure than those with more than 7 hours of sleep.
- Compared with placebo, BCQR slightly improved sleeping parameters in adolescents by delaying their time of waking up and prolonging their time in bed.
IN PRACTICE:
“Sleep may be an important and novel target for improving health in individuals with T1D, particularly when initiated in adolescence or early in diabetes,” the authors wrote.
SOURCE:
Stacey L. Simon, PhD, and Janet K. Snell-Bergeon, PhD, University of Colorado Anschutz Medical Campus, Aurora, led this study, which was published online in Diabetes, Obesity and Metabolism.
LIMITATIONS:
The study lacked polysomnography or melatonin assessment to quantify circadian rhythms and subjective sleep quality ratings. It also had no objective measurement of the timing of the daily pills of BCQR, which, when taken in the morning, are hypothesized to reset the circadian rhythm for hypothalamic dopamine and serotonin. The recommended sleep duration of 8 hours for adolescents was not used as the cutoff value due to too few participants who qualified. Also, this study›s findings may be affected by the fact that participants were recruited throughout the year, while adolescents show different sleeping patterns during the academic year compared with school breaks.
DISCLOSURES:
This work was supported by a JDRF grant. Two authors declared receiving equipment, honoraria for lectures, and support for conference travel, which were all unrelated to this study.
A version of this article appeared on Medscape.com.