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Bimekizumab shows promise for palmoplantar pustular psoriasis
.
PPP is a type of pustular psoriasis that remains a treatment challenge, and available treatments for palmoplantar plaque psoriasis with pustules also “remain unsatisfactory,” according to Thierry Passeron, MD, PhD, of the dermatology service at Centre Hospitalier Universitaire de Nice (France), and colleagues. Bimekizumab, an anti-interleukin (IL)-17A and anti-IL-17F antibody therapy, has been used for psoriasis and psoriatic arthritis (PsA), but its effectiveness for PPP has not been studied, they said. In the United States, bimekizumab (Bimzelx), administered subcutaneously, was recently approved for treating moderate to severe plaque psoriasis in adults; in the European Union, it is approved for treating psoriasis, in addition to psoriatic arthritis, axial spondyloarthritis and ankylosing spondylitis.
In the case series published in JAMA Dermatology, Dr. Passeron and coinvestigators identified 11 adults with PPP and 10 with palmoplantar plaque psoriasis with pustules who were treated at one of seven tertiary dermatology centers in France from September 2022 through June 2023. PPP also has been associated with bone and joint inflammation in SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.
All patients received bimekizumab for at least 3 months. The patients — 19 women and 2 men — ranged in age from 24 to 68 years (mean age, 46 years). The primary outcome was complete clearance, defined as an Investigator Global Assessment (IGA) score of 0.
A total of 17 patients achieved an IGA score of zero in 1-4 months. Over 3-6 months, three patients achieved an IGA score of 1 (almost clear), and one patient achieved an IGA score of 2 (mild).
Three patients with PPP also had acrodermatitis continua of Hallopeau; in these patients, nail involvement improved by 50%-70% after 4-6 months of bimekizumab use. Two patients with SAPHO experienced complete clearance of skin lesions associated with improvement in joint pain.
Four patients developed oral and genital candidiasis during treatment, but all were treated successfully with antifungals. None of the patients discontinued bimekizumab because of adverse events. “All patients are still receiving treatment, and their psoriatic lesions remain controlled,” the authors wrote.
“The rapid and consistent improvement observed in the present case series supports the effectiveness of bimekizumab therapy in managing PPP, palmoplantar plaque psoriasis with pustules, and SAPHO syndrome,” they said in their discussion.
The study findings were limited by several factors including the small sample size and short follow-up period, and by the inclusion of only patients with severe disease; and prospective, placebo-controlled studies are needed to confirm the results, the researchers noted.
However, the results suggest that bimekizumab could be a treatment approach for PPP, palmoplantar plaque psoriasis with pustules, and SAPHO syndrome, and warrant a prospective, randomized, placebo-controlled, randomized clinical trial to confirm the findings, they concluded.
Dr. Passeron disclosed fees from AbbVie, ACM Pharma, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Galderma, Genzyme/Sanofi, GlaxoSmithKline, Incyte, Janssen, LEO Pharma, Eli Lilly, Novartis, Roivant Sciences, Sun Pharmaceuticals, and VYNE Therapeutics outside the current study; he is a cofounder of Yukin Therapeutics. Three authors disclosed receiving personal fees from UCB, manufacturer of bimekizumab, outside of the submitted work, another author disclosed receiving personal fees from UCB during the conduct of the study, and another reported receiving grants from UCB and several other companies, outside the submitted work.
The study findings were also presented at a meeting, Les Journées Dermatologiques de Paris 2023, on December 6, in Paris.
.
PPP is a type of pustular psoriasis that remains a treatment challenge, and available treatments for palmoplantar plaque psoriasis with pustules also “remain unsatisfactory,” according to Thierry Passeron, MD, PhD, of the dermatology service at Centre Hospitalier Universitaire de Nice (France), and colleagues. Bimekizumab, an anti-interleukin (IL)-17A and anti-IL-17F antibody therapy, has been used for psoriasis and psoriatic arthritis (PsA), but its effectiveness for PPP has not been studied, they said. In the United States, bimekizumab (Bimzelx), administered subcutaneously, was recently approved for treating moderate to severe plaque psoriasis in adults; in the European Union, it is approved for treating psoriasis, in addition to psoriatic arthritis, axial spondyloarthritis and ankylosing spondylitis.
In the case series published in JAMA Dermatology, Dr. Passeron and coinvestigators identified 11 adults with PPP and 10 with palmoplantar plaque psoriasis with pustules who were treated at one of seven tertiary dermatology centers in France from September 2022 through June 2023. PPP also has been associated with bone and joint inflammation in SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.
All patients received bimekizumab for at least 3 months. The patients — 19 women and 2 men — ranged in age from 24 to 68 years (mean age, 46 years). The primary outcome was complete clearance, defined as an Investigator Global Assessment (IGA) score of 0.
A total of 17 patients achieved an IGA score of zero in 1-4 months. Over 3-6 months, three patients achieved an IGA score of 1 (almost clear), and one patient achieved an IGA score of 2 (mild).
Three patients with PPP also had acrodermatitis continua of Hallopeau; in these patients, nail involvement improved by 50%-70% after 4-6 months of bimekizumab use. Two patients with SAPHO experienced complete clearance of skin lesions associated with improvement in joint pain.
Four patients developed oral and genital candidiasis during treatment, but all were treated successfully with antifungals. None of the patients discontinued bimekizumab because of adverse events. “All patients are still receiving treatment, and their psoriatic lesions remain controlled,” the authors wrote.
“The rapid and consistent improvement observed in the present case series supports the effectiveness of bimekizumab therapy in managing PPP, palmoplantar plaque psoriasis with pustules, and SAPHO syndrome,” they said in their discussion.
The study findings were limited by several factors including the small sample size and short follow-up period, and by the inclusion of only patients with severe disease; and prospective, placebo-controlled studies are needed to confirm the results, the researchers noted.
However, the results suggest that bimekizumab could be a treatment approach for PPP, palmoplantar plaque psoriasis with pustules, and SAPHO syndrome, and warrant a prospective, randomized, placebo-controlled, randomized clinical trial to confirm the findings, they concluded.
Dr. Passeron disclosed fees from AbbVie, ACM Pharma, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Galderma, Genzyme/Sanofi, GlaxoSmithKline, Incyte, Janssen, LEO Pharma, Eli Lilly, Novartis, Roivant Sciences, Sun Pharmaceuticals, and VYNE Therapeutics outside the current study; he is a cofounder of Yukin Therapeutics. Three authors disclosed receiving personal fees from UCB, manufacturer of bimekizumab, outside of the submitted work, another author disclosed receiving personal fees from UCB during the conduct of the study, and another reported receiving grants from UCB and several other companies, outside the submitted work.
The study findings were also presented at a meeting, Les Journées Dermatologiques de Paris 2023, on December 6, in Paris.
.
PPP is a type of pustular psoriasis that remains a treatment challenge, and available treatments for palmoplantar plaque psoriasis with pustules also “remain unsatisfactory,” according to Thierry Passeron, MD, PhD, of the dermatology service at Centre Hospitalier Universitaire de Nice (France), and colleagues. Bimekizumab, an anti-interleukin (IL)-17A and anti-IL-17F antibody therapy, has been used for psoriasis and psoriatic arthritis (PsA), but its effectiveness for PPP has not been studied, they said. In the United States, bimekizumab (Bimzelx), administered subcutaneously, was recently approved for treating moderate to severe plaque psoriasis in adults; in the European Union, it is approved for treating psoriasis, in addition to psoriatic arthritis, axial spondyloarthritis and ankylosing spondylitis.
In the case series published in JAMA Dermatology, Dr. Passeron and coinvestigators identified 11 adults with PPP and 10 with palmoplantar plaque psoriasis with pustules who were treated at one of seven tertiary dermatology centers in France from September 2022 through June 2023. PPP also has been associated with bone and joint inflammation in SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.
All patients received bimekizumab for at least 3 months. The patients — 19 women and 2 men — ranged in age from 24 to 68 years (mean age, 46 years). The primary outcome was complete clearance, defined as an Investigator Global Assessment (IGA) score of 0.
A total of 17 patients achieved an IGA score of zero in 1-4 months. Over 3-6 months, three patients achieved an IGA score of 1 (almost clear), and one patient achieved an IGA score of 2 (mild).
Three patients with PPP also had acrodermatitis continua of Hallopeau; in these patients, nail involvement improved by 50%-70% after 4-6 months of bimekizumab use. Two patients with SAPHO experienced complete clearance of skin lesions associated with improvement in joint pain.
Four patients developed oral and genital candidiasis during treatment, but all were treated successfully with antifungals. None of the patients discontinued bimekizumab because of adverse events. “All patients are still receiving treatment, and their psoriatic lesions remain controlled,” the authors wrote.
“The rapid and consistent improvement observed in the present case series supports the effectiveness of bimekizumab therapy in managing PPP, palmoplantar plaque psoriasis with pustules, and SAPHO syndrome,” they said in their discussion.
The study findings were limited by several factors including the small sample size and short follow-up period, and by the inclusion of only patients with severe disease; and prospective, placebo-controlled studies are needed to confirm the results, the researchers noted.
However, the results suggest that bimekizumab could be a treatment approach for PPP, palmoplantar plaque psoriasis with pustules, and SAPHO syndrome, and warrant a prospective, randomized, placebo-controlled, randomized clinical trial to confirm the findings, they concluded.
Dr. Passeron disclosed fees from AbbVie, ACM Pharma, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Galderma, Genzyme/Sanofi, GlaxoSmithKline, Incyte, Janssen, LEO Pharma, Eli Lilly, Novartis, Roivant Sciences, Sun Pharmaceuticals, and VYNE Therapeutics outside the current study; he is a cofounder of Yukin Therapeutics. Three authors disclosed receiving personal fees from UCB, manufacturer of bimekizumab, outside of the submitted work, another author disclosed receiving personal fees from UCB during the conduct of the study, and another reported receiving grants from UCB and several other companies, outside the submitted work.
The study findings were also presented at a meeting, Les Journées Dermatologiques de Paris 2023, on December 6, in Paris.
FROM JAMA DERMATOLOGY
Tape strips detect hidradenitis suppurativa biomarkers, novel study shows
, results from a novel study showed.
“Tape strips can provide important clues to when and which drugs to use in HS in patients with both early and late disease, which can change clinical practice,” corresponding study author Emma Guttman-Yassky, MD, PhD, professor and chair of dermatology at the Icahn School of Medicine at Mount Sinai in New York City, said in an interview. “It is noninvasive and nonscarring,” she added.
Tape stripping has been validated in atopic dermatitis, psoriasis, and other dermatologic conditions in recent years. For the current study, which was published online in the Journal of the American Academy of Dermatology, and is believed to be the first of its kind, Dr. Guttman-Yassky and colleagues performed RNA sequencing from large D-Squame tape strips collected from lesional and nonlesional skin of 22 patients with HS and from 21 age- and sex-matched healthy controls. They correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies. The mean age of patients with HS was 43 years, while the mean age of healthy controls was 35. The average International Hidradenitis Suppurativa Severity Score System (IHS4) score of the HS cohort was 36.
Consistent with published studies, the researchers found that tape strips identified an overall higher inflammatory burden in HS. Specifically, they observed an upregulation of known cytokines within the following pathways: Th1 (such as IFNG, CXCL9/10/11, and CCR5); Th17 (such as interleukin [IL]-17A/F, IL12B, IL23A, CAMP, and CCL20); Th2 (such as IL4R, IL13/IL31/IL10, CCR4, CCL7/CCL13/CCL24, TNFSF4/OX40L, and TNFRSF4/OX40); and Th22 (such as IL22 and IL32).
The researchers also found that the expression of Th17 and tumor necrosis factor (TNF)–alpha pathways were highly correlated between tape strips and biopsies and that HS clinical severity was significantly associated with expression of biomarkers, such as TNF-alpha, IL17A/F, OX40, JAK1-3, and IL4R in HS lesional and/or nonlesional skin.
“It was quite unexpected that we are able to identify, using a minimally invasive approach that samples only the upper layers of the epidermis, products and processes that are considered to be deeper-situated, such as IL-17, and other immune markers,” Dr. Guttman-Yassky said in the interview. “We were also surprised to see how well the tape-stripped–derived skin molecular profile correlated with that of biopsies, as well as how well it correlated with the clinical disease severity of HS.”
Also surprising, she added, was that the biomarkers in nonlesional tape-stripped skin, such as IL-17 and TNF alpha, “show high correlations with disease severity and provide clues to early disease.”
If using tape strips in HS is validated in larger cohort studies, the potential cost implications of using this approach in practice remain unclear, Dr. Guttman-Yassky said. “It is currently not cheap, but we are hoping that one day, we can provide a means to diagnose the disease and treat it early, and appropriately, utilizing this approach,” she commented. “We are excited about the applicability of this study to the early treatment and longitudinal follow up of HS with drugs that are targeting specific immune molecules and pathways,” she said, adding that it will also be useful for helping determine which drug should be used for which patient.
She and her co-authors acknowledged certain limitations of the study, including its small sample size and the fact that tape stripping is limited to the epidermis.
Asked to comment on the study, Jennifer L. Hsiao, MD, a dermatologist who directs the HS clinic at the University of Southern California, Los Angeles, said the findings “have important potential implications for our ability to one day personalize treatments for a patient with early HS in a minimally invasive way.”
As the study authors point out, she added, “tape strips only allow sampling of the epidermis, which is limiting in a disease like HS where much of the disruption is in the dermis with deep nodules and dermal tunnels. However, our overall goal should be to catch patients in the early stages of their disease before the occurrence of irreversible tissue damage such as dermal tunnels. Thus, the ongoing campaign for early diagnosis and early intervention by various stakeholders in the field of HS can help mitigate the impact of this inherent limitation of tape strips. It will be exciting to see larger studies that investigate tape strip results in relation to clinical phenotypes, disease progression, and therapeutic responses.”
The study was funded by an International Dermatology Outcome Measures Hidradenitis Suppurativa Grant. Dr. Guttman-Yassky disclosed that she has been a consultant to, an adviser for, and has received research grants from many pharmaceutical companies. Of the remaining authors, 2 also had multiple disclosures and 11 had no disclosures. Dr. Hsiao disclosed that she is a member of the board of directors for the Hidradenitis Suppurativa Foundation. She has also served as a consultant for AbbVie, Aclaris, Boehringer Ingelheim, Incyte, Novartis, and UCB; as a speaker for AbbVie; and as an investigator for Amgen, Boehringer Ingelheim, and Incyte.
, results from a novel study showed.
“Tape strips can provide important clues to when and which drugs to use in HS in patients with both early and late disease, which can change clinical practice,” corresponding study author Emma Guttman-Yassky, MD, PhD, professor and chair of dermatology at the Icahn School of Medicine at Mount Sinai in New York City, said in an interview. “It is noninvasive and nonscarring,” she added.
Tape stripping has been validated in atopic dermatitis, psoriasis, and other dermatologic conditions in recent years. For the current study, which was published online in the Journal of the American Academy of Dermatology, and is believed to be the first of its kind, Dr. Guttman-Yassky and colleagues performed RNA sequencing from large D-Squame tape strips collected from lesional and nonlesional skin of 22 patients with HS and from 21 age- and sex-matched healthy controls. They correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies. The mean age of patients with HS was 43 years, while the mean age of healthy controls was 35. The average International Hidradenitis Suppurativa Severity Score System (IHS4) score of the HS cohort was 36.
Consistent with published studies, the researchers found that tape strips identified an overall higher inflammatory burden in HS. Specifically, they observed an upregulation of known cytokines within the following pathways: Th1 (such as IFNG, CXCL9/10/11, and CCR5); Th17 (such as interleukin [IL]-17A/F, IL12B, IL23A, CAMP, and CCL20); Th2 (such as IL4R, IL13/IL31/IL10, CCR4, CCL7/CCL13/CCL24, TNFSF4/OX40L, and TNFRSF4/OX40); and Th22 (such as IL22 and IL32).
The researchers also found that the expression of Th17 and tumor necrosis factor (TNF)–alpha pathways were highly correlated between tape strips and biopsies and that HS clinical severity was significantly associated with expression of biomarkers, such as TNF-alpha, IL17A/F, OX40, JAK1-3, and IL4R in HS lesional and/or nonlesional skin.
“It was quite unexpected that we are able to identify, using a minimally invasive approach that samples only the upper layers of the epidermis, products and processes that are considered to be deeper-situated, such as IL-17, and other immune markers,” Dr. Guttman-Yassky said in the interview. “We were also surprised to see how well the tape-stripped–derived skin molecular profile correlated with that of biopsies, as well as how well it correlated with the clinical disease severity of HS.”
Also surprising, she added, was that the biomarkers in nonlesional tape-stripped skin, such as IL-17 and TNF alpha, “show high correlations with disease severity and provide clues to early disease.”
If using tape strips in HS is validated in larger cohort studies, the potential cost implications of using this approach in practice remain unclear, Dr. Guttman-Yassky said. “It is currently not cheap, but we are hoping that one day, we can provide a means to diagnose the disease and treat it early, and appropriately, utilizing this approach,” she commented. “We are excited about the applicability of this study to the early treatment and longitudinal follow up of HS with drugs that are targeting specific immune molecules and pathways,” she said, adding that it will also be useful for helping determine which drug should be used for which patient.
She and her co-authors acknowledged certain limitations of the study, including its small sample size and the fact that tape stripping is limited to the epidermis.
Asked to comment on the study, Jennifer L. Hsiao, MD, a dermatologist who directs the HS clinic at the University of Southern California, Los Angeles, said the findings “have important potential implications for our ability to one day personalize treatments for a patient with early HS in a minimally invasive way.”
As the study authors point out, she added, “tape strips only allow sampling of the epidermis, which is limiting in a disease like HS where much of the disruption is in the dermis with deep nodules and dermal tunnels. However, our overall goal should be to catch patients in the early stages of their disease before the occurrence of irreversible tissue damage such as dermal tunnels. Thus, the ongoing campaign for early diagnosis and early intervention by various stakeholders in the field of HS can help mitigate the impact of this inherent limitation of tape strips. It will be exciting to see larger studies that investigate tape strip results in relation to clinical phenotypes, disease progression, and therapeutic responses.”
The study was funded by an International Dermatology Outcome Measures Hidradenitis Suppurativa Grant. Dr. Guttman-Yassky disclosed that she has been a consultant to, an adviser for, and has received research grants from many pharmaceutical companies. Of the remaining authors, 2 also had multiple disclosures and 11 had no disclosures. Dr. Hsiao disclosed that she is a member of the board of directors for the Hidradenitis Suppurativa Foundation. She has also served as a consultant for AbbVie, Aclaris, Boehringer Ingelheim, Incyte, Novartis, and UCB; as a speaker for AbbVie; and as an investigator for Amgen, Boehringer Ingelheim, and Incyte.
, results from a novel study showed.
“Tape strips can provide important clues to when and which drugs to use in HS in patients with both early and late disease, which can change clinical practice,” corresponding study author Emma Guttman-Yassky, MD, PhD, professor and chair of dermatology at the Icahn School of Medicine at Mount Sinai in New York City, said in an interview. “It is noninvasive and nonscarring,” she added.
Tape stripping has been validated in atopic dermatitis, psoriasis, and other dermatologic conditions in recent years. For the current study, which was published online in the Journal of the American Academy of Dermatology, and is believed to be the first of its kind, Dr. Guttman-Yassky and colleagues performed RNA sequencing from large D-Squame tape strips collected from lesional and nonlesional skin of 22 patients with HS and from 21 age- and sex-matched healthy controls. They correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies. The mean age of patients with HS was 43 years, while the mean age of healthy controls was 35. The average International Hidradenitis Suppurativa Severity Score System (IHS4) score of the HS cohort was 36.
Consistent with published studies, the researchers found that tape strips identified an overall higher inflammatory burden in HS. Specifically, they observed an upregulation of known cytokines within the following pathways: Th1 (such as IFNG, CXCL9/10/11, and CCR5); Th17 (such as interleukin [IL]-17A/F, IL12B, IL23A, CAMP, and CCL20); Th2 (such as IL4R, IL13/IL31/IL10, CCR4, CCL7/CCL13/CCL24, TNFSF4/OX40L, and TNFRSF4/OX40); and Th22 (such as IL22 and IL32).
The researchers also found that the expression of Th17 and tumor necrosis factor (TNF)–alpha pathways were highly correlated between tape strips and biopsies and that HS clinical severity was significantly associated with expression of biomarkers, such as TNF-alpha, IL17A/F, OX40, JAK1-3, and IL4R in HS lesional and/or nonlesional skin.
“It was quite unexpected that we are able to identify, using a minimally invasive approach that samples only the upper layers of the epidermis, products and processes that are considered to be deeper-situated, such as IL-17, and other immune markers,” Dr. Guttman-Yassky said in the interview. “We were also surprised to see how well the tape-stripped–derived skin molecular profile correlated with that of biopsies, as well as how well it correlated with the clinical disease severity of HS.”
Also surprising, she added, was that the biomarkers in nonlesional tape-stripped skin, such as IL-17 and TNF alpha, “show high correlations with disease severity and provide clues to early disease.”
If using tape strips in HS is validated in larger cohort studies, the potential cost implications of using this approach in practice remain unclear, Dr. Guttman-Yassky said. “It is currently not cheap, but we are hoping that one day, we can provide a means to diagnose the disease and treat it early, and appropriately, utilizing this approach,” she commented. “We are excited about the applicability of this study to the early treatment and longitudinal follow up of HS with drugs that are targeting specific immune molecules and pathways,” she said, adding that it will also be useful for helping determine which drug should be used for which patient.
She and her co-authors acknowledged certain limitations of the study, including its small sample size and the fact that tape stripping is limited to the epidermis.
Asked to comment on the study, Jennifer L. Hsiao, MD, a dermatologist who directs the HS clinic at the University of Southern California, Los Angeles, said the findings “have important potential implications for our ability to one day personalize treatments for a patient with early HS in a minimally invasive way.”
As the study authors point out, she added, “tape strips only allow sampling of the epidermis, which is limiting in a disease like HS where much of the disruption is in the dermis with deep nodules and dermal tunnels. However, our overall goal should be to catch patients in the early stages of their disease before the occurrence of irreversible tissue damage such as dermal tunnels. Thus, the ongoing campaign for early diagnosis and early intervention by various stakeholders in the field of HS can help mitigate the impact of this inherent limitation of tape strips. It will be exciting to see larger studies that investigate tape strip results in relation to clinical phenotypes, disease progression, and therapeutic responses.”
The study was funded by an International Dermatology Outcome Measures Hidradenitis Suppurativa Grant. Dr. Guttman-Yassky disclosed that she has been a consultant to, an adviser for, and has received research grants from many pharmaceutical companies. Of the remaining authors, 2 also had multiple disclosures and 11 had no disclosures. Dr. Hsiao disclosed that she is a member of the board of directors for the Hidradenitis Suppurativa Foundation. She has also served as a consultant for AbbVie, Aclaris, Boehringer Ingelheim, Incyte, Novartis, and UCB; as a speaker for AbbVie; and as an investigator for Amgen, Boehringer Ingelheim, and Incyte.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
New COVID variant JN.1 could disrupt holiday plans
No one planning holiday gatherings or travel wants to hear this, but the rise of a new COVID-19 variant, JN.1, is concerning experts, who say it may threaten those good times.
The good news is recent research suggests the 2023-2024 COVID-19 vaccine appears to work against this newest variant. But so few people have gotten the latest vaccine — less than 16% of U.S. adults — that some experts suggest it’s time for the CDC to urge the public who haven’t it to do so now, so the antibodies can kick in before the festivities.
“A significant wave [of JN.1] has started here and could be blunted with a high booster rate and mitigation measures,” said Eric Topol, MD, professor and executive vice president of Scripps Research in La Jolla, CA, and editor-in-chief of Medscape, a sister site of this news organization.
COVID metrics, meanwhile, have started to climb again. Nearly 10,000 people were hospitalized for COVID in the U.S. for the week ending Nov. 25, the CDC said, a 10% increase over the previous week.
Who’s Who in the Family Tree
JN.1, an Omicron subvariant, was first detected in the U.S. in September and is termed “a notable descendent lineage” of Omicron subvariant BA.2.86 by the World Health Organization. When BA.2.86, also known as Pirola, was first identified in August, it appeared very different from other variants, the CDC said. That triggered concerns it might be more infectious than previous ones, even for people with immunity from vaccination and previous infections.
“JN.1 is Pirola’s kid,” said Rajendram Rajnarayanan, PhD, assistant dean of research and associate professor at the New York Institute of Technology at Arkansas State University, who maintains a COVID-19 variant database. The variant BA.2.86 and offspring are worrisome due to the mutations, he said.
How Widespread Is JN.1?
As of Nov. 27, the CDC says, BA.2.86 is projected to comprise 5%-15% of circulating variants in the U.S. “The expected public health risk of this variant, including its offshoot JN.1, is low,” the agency said.
Currently, JN.1 is reported more often in Europe, Dr. Rajnarayanan said, but some countries have better reporting data than others. “It has probably spread to every country tracking COVID,’’ he said, due to the mutations in the spike protein that make it easier for it to bind and infect.
Wastewater data suggest the variant’s rise is helping to fuel a wave, Dr. Topol said.
Vaccine Effectiveness Against JN.1, Other New Variants
The new XBB.1.5 monovalent vaccine, protects against XBB.1.5, another Omicron subvariant, but also JN.1 and other “emergent” viruses, a team of researchers reported Nov. 26 in a study on bioRxiv that has not yet been certified by peer review.
The updated vaccine, when given to uninfected people, boosted antibodies about 27-fold against XBB.1.5 and about 13- to 27-fold against JN.1 and other emergent viruses, the researchers reported.
While even primary doses of the COVID vaccine will likely help protect against the new JN.1 subvariant, “if you got the XBB.1.5 booster, it is going to be protecting you better against this new variant,” Dr. Rajnarayanan said.
2023-2024 Vaccine Uptake Low
In November, the CDC posted the first detailed estimates of who did. As of Nov. 18, less than 16% of U.S. adults had, with nearly 15% saying they planned to get it.
Coverage among children is lower, with just 6.3% of children up to date on the newest vaccine and 19% of parents saying they planned to get the 2023-2024 vaccine for their children.
Predictions, Mitigation
While some experts say a peak due to JN.1 is expected in the weeks ahead, Dr. Topol said it’s impossible to predict exactly how JN.1 will play out.
“It’s not going to be a repeat of November 2021,” when Omicron surfaced, Dr. Rajnarayanan predicted. Within 4 weeks of the World Health Organization declaring Omicron as a virus of concern, it spread around the world.
Mitigation measures can help, Dr. Rajnarayanan said. He suggested:
Get the new vaccine, and especially encourage vulnerable family and friends to do so.
If you are gathering inside for holiday festivities, improve circulation in the house, if possible.
Wear masks in airports and on planes and other public transportation.
A version of this article appeared on WebMD.com.
No one planning holiday gatherings or travel wants to hear this, but the rise of a new COVID-19 variant, JN.1, is concerning experts, who say it may threaten those good times.
The good news is recent research suggests the 2023-2024 COVID-19 vaccine appears to work against this newest variant. But so few people have gotten the latest vaccine — less than 16% of U.S. adults — that some experts suggest it’s time for the CDC to urge the public who haven’t it to do so now, so the antibodies can kick in before the festivities.
“A significant wave [of JN.1] has started here and could be blunted with a high booster rate and mitigation measures,” said Eric Topol, MD, professor and executive vice president of Scripps Research in La Jolla, CA, and editor-in-chief of Medscape, a sister site of this news organization.
COVID metrics, meanwhile, have started to climb again. Nearly 10,000 people were hospitalized for COVID in the U.S. for the week ending Nov. 25, the CDC said, a 10% increase over the previous week.
Who’s Who in the Family Tree
JN.1, an Omicron subvariant, was first detected in the U.S. in September and is termed “a notable descendent lineage” of Omicron subvariant BA.2.86 by the World Health Organization. When BA.2.86, also known as Pirola, was first identified in August, it appeared very different from other variants, the CDC said. That triggered concerns it might be more infectious than previous ones, even for people with immunity from vaccination and previous infections.
“JN.1 is Pirola’s kid,” said Rajendram Rajnarayanan, PhD, assistant dean of research and associate professor at the New York Institute of Technology at Arkansas State University, who maintains a COVID-19 variant database. The variant BA.2.86 and offspring are worrisome due to the mutations, he said.
How Widespread Is JN.1?
As of Nov. 27, the CDC says, BA.2.86 is projected to comprise 5%-15% of circulating variants in the U.S. “The expected public health risk of this variant, including its offshoot JN.1, is low,” the agency said.
Currently, JN.1 is reported more often in Europe, Dr. Rajnarayanan said, but some countries have better reporting data than others. “It has probably spread to every country tracking COVID,’’ he said, due to the mutations in the spike protein that make it easier for it to bind and infect.
Wastewater data suggest the variant’s rise is helping to fuel a wave, Dr. Topol said.
Vaccine Effectiveness Against JN.1, Other New Variants
The new XBB.1.5 monovalent vaccine, protects against XBB.1.5, another Omicron subvariant, but also JN.1 and other “emergent” viruses, a team of researchers reported Nov. 26 in a study on bioRxiv that has not yet been certified by peer review.
The updated vaccine, when given to uninfected people, boosted antibodies about 27-fold against XBB.1.5 and about 13- to 27-fold against JN.1 and other emergent viruses, the researchers reported.
While even primary doses of the COVID vaccine will likely help protect against the new JN.1 subvariant, “if you got the XBB.1.5 booster, it is going to be protecting you better against this new variant,” Dr. Rajnarayanan said.
2023-2024 Vaccine Uptake Low
In November, the CDC posted the first detailed estimates of who did. As of Nov. 18, less than 16% of U.S. adults had, with nearly 15% saying they planned to get it.
Coverage among children is lower, with just 6.3% of children up to date on the newest vaccine and 19% of parents saying they planned to get the 2023-2024 vaccine for their children.
Predictions, Mitigation
While some experts say a peak due to JN.1 is expected in the weeks ahead, Dr. Topol said it’s impossible to predict exactly how JN.1 will play out.
“It’s not going to be a repeat of November 2021,” when Omicron surfaced, Dr. Rajnarayanan predicted. Within 4 weeks of the World Health Organization declaring Omicron as a virus of concern, it spread around the world.
Mitigation measures can help, Dr. Rajnarayanan said. He suggested:
Get the new vaccine, and especially encourage vulnerable family and friends to do so.
If you are gathering inside for holiday festivities, improve circulation in the house, if possible.
Wear masks in airports and on planes and other public transportation.
A version of this article appeared on WebMD.com.
No one planning holiday gatherings or travel wants to hear this, but the rise of a new COVID-19 variant, JN.1, is concerning experts, who say it may threaten those good times.
The good news is recent research suggests the 2023-2024 COVID-19 vaccine appears to work against this newest variant. But so few people have gotten the latest vaccine — less than 16% of U.S. adults — that some experts suggest it’s time for the CDC to urge the public who haven’t it to do so now, so the antibodies can kick in before the festivities.
“A significant wave [of JN.1] has started here and could be blunted with a high booster rate and mitigation measures,” said Eric Topol, MD, professor and executive vice president of Scripps Research in La Jolla, CA, and editor-in-chief of Medscape, a sister site of this news organization.
COVID metrics, meanwhile, have started to climb again. Nearly 10,000 people were hospitalized for COVID in the U.S. for the week ending Nov. 25, the CDC said, a 10% increase over the previous week.
Who’s Who in the Family Tree
JN.1, an Omicron subvariant, was first detected in the U.S. in September and is termed “a notable descendent lineage” of Omicron subvariant BA.2.86 by the World Health Organization. When BA.2.86, also known as Pirola, was first identified in August, it appeared very different from other variants, the CDC said. That triggered concerns it might be more infectious than previous ones, even for people with immunity from vaccination and previous infections.
“JN.1 is Pirola’s kid,” said Rajendram Rajnarayanan, PhD, assistant dean of research and associate professor at the New York Institute of Technology at Arkansas State University, who maintains a COVID-19 variant database. The variant BA.2.86 and offspring are worrisome due to the mutations, he said.
How Widespread Is JN.1?
As of Nov. 27, the CDC says, BA.2.86 is projected to comprise 5%-15% of circulating variants in the U.S. “The expected public health risk of this variant, including its offshoot JN.1, is low,” the agency said.
Currently, JN.1 is reported more often in Europe, Dr. Rajnarayanan said, but some countries have better reporting data than others. “It has probably spread to every country tracking COVID,’’ he said, due to the mutations in the spike protein that make it easier for it to bind and infect.
Wastewater data suggest the variant’s rise is helping to fuel a wave, Dr. Topol said.
Vaccine Effectiveness Against JN.1, Other New Variants
The new XBB.1.5 monovalent vaccine, protects against XBB.1.5, another Omicron subvariant, but also JN.1 and other “emergent” viruses, a team of researchers reported Nov. 26 in a study on bioRxiv that has not yet been certified by peer review.
The updated vaccine, when given to uninfected people, boosted antibodies about 27-fold against XBB.1.5 and about 13- to 27-fold against JN.1 and other emergent viruses, the researchers reported.
While even primary doses of the COVID vaccine will likely help protect against the new JN.1 subvariant, “if you got the XBB.1.5 booster, it is going to be protecting you better against this new variant,” Dr. Rajnarayanan said.
2023-2024 Vaccine Uptake Low
In November, the CDC posted the first detailed estimates of who did. As of Nov. 18, less than 16% of U.S. adults had, with nearly 15% saying they planned to get it.
Coverage among children is lower, with just 6.3% of children up to date on the newest vaccine and 19% of parents saying they planned to get the 2023-2024 vaccine for their children.
Predictions, Mitigation
While some experts say a peak due to JN.1 is expected in the weeks ahead, Dr. Topol said it’s impossible to predict exactly how JN.1 will play out.
“It’s not going to be a repeat of November 2021,” when Omicron surfaced, Dr. Rajnarayanan predicted. Within 4 weeks of the World Health Organization declaring Omicron as a virus of concern, it spread around the world.
Mitigation measures can help, Dr. Rajnarayanan said. He suggested:
Get the new vaccine, and especially encourage vulnerable family and friends to do so.
If you are gathering inside for holiday festivities, improve circulation in the house, if possible.
Wear masks in airports and on planes and other public transportation.
A version of this article appeared on WebMD.com.
FDA approves first 2 gene-editing therapies for sickle cell
These “milestone treatments” mark the first cell-based gene therapies for this debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the United States.
The two therapies are exagamglogene autotemcel, or exa-cel (Casgevy; Vertex Pharmaceuticals and Crispr Therapeutics), and lovotibeglogene autotemcel, or lovo-cel (Lyfgenia; bluebird bio).
“The approval of the first gene therapies for [sickle cell disease] represents a tremendous step forward for the [sickle cell] community, which has been historically overlooked and underfunded,” said Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, in a statement from the American Society of Hematology, following the approval.
“We are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease, by approving two cell-based gene therapies today,” Nicole Verdun, MD, of the FDA’s Center for Biologics Evaluation and Research, added in an agency press release.
Sickle cell disease involves a mutation in hemoglobin, a protein in red blood cells that provides oxygen to tissues. The mutation leads red blood cells to develop a crescent or sickle shape, which can restrict blood flow and cause severe pain and organ damage, known as vaso-occlusive events or crises.
Treatment options prior to these approvals primarily included red blood transfusions and hydroxyurea alongside pain management. The only potential curative option has been allogeneic hematopoietic stem cell transplantation, but that comes with significant risks and most patients don’t have an appropriate donor.
Exa-cel
Exa-cel uses CRISPR gene-editing technology. Before the infusion, patients undergo myeloablative conditioning, which removes cells from the bone marrow. These cells are genetically modified to produce fetal hemoglobin. Patients then receive an infusion of the edited cells, which can help restore normal hemoglobin production.
The FDA approval was based on data from the pivotal CLIMB SCD-121 trial. In an October advisory committee meeting, the FDA highlighted trial data demonstrating that 29 of 31 patients reached the trial’s primary endpoint: freedom from severe vaso-occlusive crises over a 12-month period. In addition, 28 of these patients remained free of vaso-occlusive crises for almost 2 years.
The committee noted that one of the 31 patients died about 9 months after receiving an exa-cel infusion.
The cell-based gene therapy also increased both fetal and total hemoglobin, with total hemoglobin levels increasing to > 11 g/dL by month 3 and remaining at that level afterward. No patients experienced graft failure or rejection.
The most common side effects included low platelets and white blood cell counts, mouth sores, nausea, musculoskeletal pain, vomiting, and febrile neutropenia.
Exa-cel could “provide a one-time functional cure” for patients with severe sickle cell disease, according to Franco Locatelli, MD, of Sapienza University of Rome, who presented initial findings last year.
While the current approval is for patients with infusion-dependent sickle cell disease, exa-cel is also being evaluated in patients with another blood disorder, beta-thalassemia.
Lovo-cel
Lovo-cel, a cell-based gene therapy, uses a different technology — a lentiviral vector, or gene delivery vehicle — that can also genetically modify a patient’s blood stem cells.
Like exa-cel, lovo-cel is a one-time, single-dose infusion that contains the patient’s modified cells. Before the infusion, patients undergo myeloablative conditioning. The patient’s stem cells are then genetically modified to allow them to produce the most common form of hemoglobin, HbA
This approval was based on data from a single-arm, 24-month study in patients aged 12-50 years who had sickle cell disease and a history of vaso-occlusive events.
Overall, 88% of patients (28 of 32) achieved complete resolution of vaso-occlusive events 6-18 months after the infusion.
The most common side effects included stomatitis; febrile neutropenia; and low platelet, white blood cell, and red blood cell counts.
The FDA noted that hematologic cancer has occurred in patients treated with lovo-cel, and the label includes a black-box warning about the risk.
Dr. Brodsky noted, however, that “while these new gene therapies are potentially life-changing for individuals living with [sickle cell disease], they must be accessible to be effective.”
Access is a potential concern. Exa-cel and lovo-cel could cost about $2 million.
A version of this article appeared on Medscape.com.
These “milestone treatments” mark the first cell-based gene therapies for this debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the United States.
The two therapies are exagamglogene autotemcel, or exa-cel (Casgevy; Vertex Pharmaceuticals and Crispr Therapeutics), and lovotibeglogene autotemcel, or lovo-cel (Lyfgenia; bluebird bio).
“The approval of the first gene therapies for [sickle cell disease] represents a tremendous step forward for the [sickle cell] community, which has been historically overlooked and underfunded,” said Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, in a statement from the American Society of Hematology, following the approval.
“We are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease, by approving two cell-based gene therapies today,” Nicole Verdun, MD, of the FDA’s Center for Biologics Evaluation and Research, added in an agency press release.
Sickle cell disease involves a mutation in hemoglobin, a protein in red blood cells that provides oxygen to tissues. The mutation leads red blood cells to develop a crescent or sickle shape, which can restrict blood flow and cause severe pain and organ damage, known as vaso-occlusive events or crises.
Treatment options prior to these approvals primarily included red blood transfusions and hydroxyurea alongside pain management. The only potential curative option has been allogeneic hematopoietic stem cell transplantation, but that comes with significant risks and most patients don’t have an appropriate donor.
Exa-cel
Exa-cel uses CRISPR gene-editing technology. Before the infusion, patients undergo myeloablative conditioning, which removes cells from the bone marrow. These cells are genetically modified to produce fetal hemoglobin. Patients then receive an infusion of the edited cells, which can help restore normal hemoglobin production.
The FDA approval was based on data from the pivotal CLIMB SCD-121 trial. In an October advisory committee meeting, the FDA highlighted trial data demonstrating that 29 of 31 patients reached the trial’s primary endpoint: freedom from severe vaso-occlusive crises over a 12-month period. In addition, 28 of these patients remained free of vaso-occlusive crises for almost 2 years.
The committee noted that one of the 31 patients died about 9 months after receiving an exa-cel infusion.
The cell-based gene therapy also increased both fetal and total hemoglobin, with total hemoglobin levels increasing to > 11 g/dL by month 3 and remaining at that level afterward. No patients experienced graft failure or rejection.
The most common side effects included low platelets and white blood cell counts, mouth sores, nausea, musculoskeletal pain, vomiting, and febrile neutropenia.
Exa-cel could “provide a one-time functional cure” for patients with severe sickle cell disease, according to Franco Locatelli, MD, of Sapienza University of Rome, who presented initial findings last year.
While the current approval is for patients with infusion-dependent sickle cell disease, exa-cel is also being evaluated in patients with another blood disorder, beta-thalassemia.
Lovo-cel
Lovo-cel, a cell-based gene therapy, uses a different technology — a lentiviral vector, or gene delivery vehicle — that can also genetically modify a patient’s blood stem cells.
Like exa-cel, lovo-cel is a one-time, single-dose infusion that contains the patient’s modified cells. Before the infusion, patients undergo myeloablative conditioning. The patient’s stem cells are then genetically modified to allow them to produce the most common form of hemoglobin, HbA
This approval was based on data from a single-arm, 24-month study in patients aged 12-50 years who had sickle cell disease and a history of vaso-occlusive events.
Overall, 88% of patients (28 of 32) achieved complete resolution of vaso-occlusive events 6-18 months after the infusion.
The most common side effects included stomatitis; febrile neutropenia; and low platelet, white blood cell, and red blood cell counts.
The FDA noted that hematologic cancer has occurred in patients treated with lovo-cel, and the label includes a black-box warning about the risk.
Dr. Brodsky noted, however, that “while these new gene therapies are potentially life-changing for individuals living with [sickle cell disease], they must be accessible to be effective.”
Access is a potential concern. Exa-cel and lovo-cel could cost about $2 million.
A version of this article appeared on Medscape.com.
These “milestone treatments” mark the first cell-based gene therapies for this debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the United States.
The two therapies are exagamglogene autotemcel, or exa-cel (Casgevy; Vertex Pharmaceuticals and Crispr Therapeutics), and lovotibeglogene autotemcel, or lovo-cel (Lyfgenia; bluebird bio).
“The approval of the first gene therapies for [sickle cell disease] represents a tremendous step forward for the [sickle cell] community, which has been historically overlooked and underfunded,” said Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, in a statement from the American Society of Hematology, following the approval.
“We are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease, by approving two cell-based gene therapies today,” Nicole Verdun, MD, of the FDA’s Center for Biologics Evaluation and Research, added in an agency press release.
Sickle cell disease involves a mutation in hemoglobin, a protein in red blood cells that provides oxygen to tissues. The mutation leads red blood cells to develop a crescent or sickle shape, which can restrict blood flow and cause severe pain and organ damage, known as vaso-occlusive events or crises.
Treatment options prior to these approvals primarily included red blood transfusions and hydroxyurea alongside pain management. The only potential curative option has been allogeneic hematopoietic stem cell transplantation, but that comes with significant risks and most patients don’t have an appropriate donor.
Exa-cel
Exa-cel uses CRISPR gene-editing technology. Before the infusion, patients undergo myeloablative conditioning, which removes cells from the bone marrow. These cells are genetically modified to produce fetal hemoglobin. Patients then receive an infusion of the edited cells, which can help restore normal hemoglobin production.
The FDA approval was based on data from the pivotal CLIMB SCD-121 trial. In an October advisory committee meeting, the FDA highlighted trial data demonstrating that 29 of 31 patients reached the trial’s primary endpoint: freedom from severe vaso-occlusive crises over a 12-month period. In addition, 28 of these patients remained free of vaso-occlusive crises for almost 2 years.
The committee noted that one of the 31 patients died about 9 months after receiving an exa-cel infusion.
The cell-based gene therapy also increased both fetal and total hemoglobin, with total hemoglobin levels increasing to > 11 g/dL by month 3 and remaining at that level afterward. No patients experienced graft failure or rejection.
The most common side effects included low platelets and white blood cell counts, mouth sores, nausea, musculoskeletal pain, vomiting, and febrile neutropenia.
Exa-cel could “provide a one-time functional cure” for patients with severe sickle cell disease, according to Franco Locatelli, MD, of Sapienza University of Rome, who presented initial findings last year.
While the current approval is for patients with infusion-dependent sickle cell disease, exa-cel is also being evaluated in patients with another blood disorder, beta-thalassemia.
Lovo-cel
Lovo-cel, a cell-based gene therapy, uses a different technology — a lentiviral vector, or gene delivery vehicle — that can also genetically modify a patient’s blood stem cells.
Like exa-cel, lovo-cel is a one-time, single-dose infusion that contains the patient’s modified cells. Before the infusion, patients undergo myeloablative conditioning. The patient’s stem cells are then genetically modified to allow them to produce the most common form of hemoglobin, HbA
This approval was based on data from a single-arm, 24-month study in patients aged 12-50 years who had sickle cell disease and a history of vaso-occlusive events.
Overall, 88% of patients (28 of 32) achieved complete resolution of vaso-occlusive events 6-18 months after the infusion.
The most common side effects included stomatitis; febrile neutropenia; and low platelet, white blood cell, and red blood cell counts.
The FDA noted that hematologic cancer has occurred in patients treated with lovo-cel, and the label includes a black-box warning about the risk.
Dr. Brodsky noted, however, that “while these new gene therapies are potentially life-changing for individuals living with [sickle cell disease], they must be accessible to be effective.”
Access is a potential concern. Exa-cel and lovo-cel could cost about $2 million.
A version of this article appeared on Medscape.com.
Blurred vision and shortness of breath
Given her symptomatology, imaging, and laboratory study results, this patient is diagnosed with small cell lung cancer (SCLC) and brain metastases. The pulmonologist shares the findings with the patient, and over the next several days, a multidisciplinary team, which includes oncology and radiology, forms to guide the patient through staging and treatment options.
SCLC is a neuroendocrine carcinoma, which is an aggressive form of lung cancer associated with rapid growth and early spread to distant sites and frequent association with distinct paraneoplastic syndromes. Approximately 13% of newly diagnosed lung cancers are SCLC. Clinical presentation is often advanced stage and includes shortness of breath, cough, bone pain, weight loss, fatigue, and neurologic dysfunction, including blurred vision, dizziness, and headaches that disturb sleep. Typically, symptom onset is quick, with the duration of symptoms lasting between 8 and 12 weeks before presentation.
According to CHEST guidelines, when clinical and radiographic findings suggest SCLC, diagnosis should be confirmed using the least invasive technique possible on the basis of presentation. Fine-needle aspiration or biopsy is recommended to assess a suspicious singular extrathoracic site for metastasis. If that approach is not feasible, guidelines recommend diagnosing the primary lung lesion. If there is an accessible pleural effusion, ultrasound-guided thoracentesis is recommended for diagnosis. If the result of pleural fluid cytology is negative, pleural biopsy using image-guided pleural biopsy, medical, or surgical thoracoscopy is recommended next. Common mutations associated with SCLC include RB1 and TP53 gene mutations.
Nearly all patients with SCLC (98%) have a history of tobacco use. Uranium or radon exposure has also been linked to SCLC. Pathogenesis occurs in the peribronchial region of the respiratory system and moves into the bronchial submucosa. Widespread metastases can appear early during SCLC and generally affect mediastinal lymph nodes, bones, brain, liver, and adrenal glands.
Patient education should include information about clinical trials, available treatment options, and associated adverse events. Smoking cessation is encouraged for current smokers with SCLC.
For patients with extensive-stage metastatic SCLC, the new standard of care combines the immunotherapy atezolizumab, a humanized monoclonal anti–programmed death–ligand 1 (PD-L1) antibody, with chemotherapy (cisplatin-etoposide). When used in the first-line setting, this combination has been shown to improve survival outcomes. Of course, clinical trials are ongoing; other treatments in development include additional classes of immunotherapies (programmed cell death protein1 [PD-1] inhibitor antibody, anti-PD1 antibody, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor antibody) and targeted therapies (delta-like protein 3 antibody-drug conjugate).
Karl J. D'Silva, MD, Clinical Assistant Professor, Department of Medicine, Tufts University School of Medicine, Boston; Medical Director, Department of Oncology and Hematology, Lahey Hospital and Medical Center, Peabody, Massachusetts.
Karl J. D'Silva, MD, has disclosed no relevant financial relationships.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
Given her symptomatology, imaging, and laboratory study results, this patient is diagnosed with small cell lung cancer (SCLC) and brain metastases. The pulmonologist shares the findings with the patient, and over the next several days, a multidisciplinary team, which includes oncology and radiology, forms to guide the patient through staging and treatment options.
SCLC is a neuroendocrine carcinoma, which is an aggressive form of lung cancer associated with rapid growth and early spread to distant sites and frequent association with distinct paraneoplastic syndromes. Approximately 13% of newly diagnosed lung cancers are SCLC. Clinical presentation is often advanced stage and includes shortness of breath, cough, bone pain, weight loss, fatigue, and neurologic dysfunction, including blurred vision, dizziness, and headaches that disturb sleep. Typically, symptom onset is quick, with the duration of symptoms lasting between 8 and 12 weeks before presentation.
According to CHEST guidelines, when clinical and radiographic findings suggest SCLC, diagnosis should be confirmed using the least invasive technique possible on the basis of presentation. Fine-needle aspiration or biopsy is recommended to assess a suspicious singular extrathoracic site for metastasis. If that approach is not feasible, guidelines recommend diagnosing the primary lung lesion. If there is an accessible pleural effusion, ultrasound-guided thoracentesis is recommended for diagnosis. If the result of pleural fluid cytology is negative, pleural biopsy using image-guided pleural biopsy, medical, or surgical thoracoscopy is recommended next. Common mutations associated with SCLC include RB1 and TP53 gene mutations.
Nearly all patients with SCLC (98%) have a history of tobacco use. Uranium or radon exposure has also been linked to SCLC. Pathogenesis occurs in the peribronchial region of the respiratory system and moves into the bronchial submucosa. Widespread metastases can appear early during SCLC and generally affect mediastinal lymph nodes, bones, brain, liver, and adrenal glands.
Patient education should include information about clinical trials, available treatment options, and associated adverse events. Smoking cessation is encouraged for current smokers with SCLC.
For patients with extensive-stage metastatic SCLC, the new standard of care combines the immunotherapy atezolizumab, a humanized monoclonal anti–programmed death–ligand 1 (PD-L1) antibody, with chemotherapy (cisplatin-etoposide). When used in the first-line setting, this combination has been shown to improve survival outcomes. Of course, clinical trials are ongoing; other treatments in development include additional classes of immunotherapies (programmed cell death protein1 [PD-1] inhibitor antibody, anti-PD1 antibody, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor antibody) and targeted therapies (delta-like protein 3 antibody-drug conjugate).
Karl J. D'Silva, MD, Clinical Assistant Professor, Department of Medicine, Tufts University School of Medicine, Boston; Medical Director, Department of Oncology and Hematology, Lahey Hospital and Medical Center, Peabody, Massachusetts.
Karl J. D'Silva, MD, has disclosed no relevant financial relationships.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
Given her symptomatology, imaging, and laboratory study results, this patient is diagnosed with small cell lung cancer (SCLC) and brain metastases. The pulmonologist shares the findings with the patient, and over the next several days, a multidisciplinary team, which includes oncology and radiology, forms to guide the patient through staging and treatment options.
SCLC is a neuroendocrine carcinoma, which is an aggressive form of lung cancer associated with rapid growth and early spread to distant sites and frequent association with distinct paraneoplastic syndromes. Approximately 13% of newly diagnosed lung cancers are SCLC. Clinical presentation is often advanced stage and includes shortness of breath, cough, bone pain, weight loss, fatigue, and neurologic dysfunction, including blurred vision, dizziness, and headaches that disturb sleep. Typically, symptom onset is quick, with the duration of symptoms lasting between 8 and 12 weeks before presentation.
According to CHEST guidelines, when clinical and radiographic findings suggest SCLC, diagnosis should be confirmed using the least invasive technique possible on the basis of presentation. Fine-needle aspiration or biopsy is recommended to assess a suspicious singular extrathoracic site for metastasis. If that approach is not feasible, guidelines recommend diagnosing the primary lung lesion. If there is an accessible pleural effusion, ultrasound-guided thoracentesis is recommended for diagnosis. If the result of pleural fluid cytology is negative, pleural biopsy using image-guided pleural biopsy, medical, or surgical thoracoscopy is recommended next. Common mutations associated with SCLC include RB1 and TP53 gene mutations.
Nearly all patients with SCLC (98%) have a history of tobacco use. Uranium or radon exposure has also been linked to SCLC. Pathogenesis occurs in the peribronchial region of the respiratory system and moves into the bronchial submucosa. Widespread metastases can appear early during SCLC and generally affect mediastinal lymph nodes, bones, brain, liver, and adrenal glands.
Patient education should include information about clinical trials, available treatment options, and associated adverse events. Smoking cessation is encouraged for current smokers with SCLC.
For patients with extensive-stage metastatic SCLC, the new standard of care combines the immunotherapy atezolizumab, a humanized monoclonal anti–programmed death–ligand 1 (PD-L1) antibody, with chemotherapy (cisplatin-etoposide). When used in the first-line setting, this combination has been shown to improve survival outcomes. Of course, clinical trials are ongoing; other treatments in development include additional classes of immunotherapies (programmed cell death protein1 [PD-1] inhibitor antibody, anti-PD1 antibody, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor antibody) and targeted therapies (delta-like protein 3 antibody-drug conjugate).
Karl J. D'Silva, MD, Clinical Assistant Professor, Department of Medicine, Tufts University School of Medicine, Boston; Medical Director, Department of Oncology and Hematology, Lahey Hospital and Medical Center, Peabody, Massachusetts.
Karl J. D'Silva, MD, has disclosed no relevant financial relationships.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
A 66-year-old woman who is a former smoker presents to her primary care physician with a recent history of dizziness, blurred vision, shortness of breath, and headaches that wake her up in the morning. The patient reports significant weight loss, persistent cough, and fatigue over the past 2 months. The patient owns and runs a local French bakery and reports difficulty keeping up with routine productivity. In addition, she has had to skip several days of work lately and rely more on her staff, which increases business costs, because of the severity of her symptoms. Her height is 5 ft 6 in and weight is 176 lb; her BMI is 28.4.
On physical examination, her physician detects enlarged axillary lymph nodes and dullness to percussion and decreased breath sounds in the central right lung. Fundoscopy reveals increased intracranial pressure, and a neurologic exam shows abnormalities in cerebellar function. The physician orders a CT from the base of the skull to mid-thigh as well as a brain MRI. Results show tumors in the right ipsilateral hemithorax and contralateral lung and metastases in the brain. The patient is referred to pulmonology, where she undergoes a fine needle aspiration of the suspected axillary lymph nodes; cytology reveals metastatic cancer. Thereafter, the patient undergoes a bronchoscopy and transbronchial biopsy. Comprehensive genomic profiling of the tumor sample reveals TP53 and RB1 gene mutations.
Trop-2 drug conjugate may trump chemo in HR+, HER2- breast cancer
SAN ANTONIO — In endocrine-resistant, HR+/HER2- metastatic breast cancer, the antibody-drug conjugate (ADC) datopotamab deruxtecan (dato-DXd, Daiichi Sankyo/AstraZeneca) has greater efficacy and a better safety profile than investigator-chosen chemotherapy, according to the latest results from the TROPION-Breast01 clinical trial.
If approved, the ADC would join sacituzumab govitecan (Trodelvy, Gilead) as agents that target trophoblast cell-surface antigen-2 (Trop-2), which is universally expressed in breast cancer, according to Aditya Bardia, MD, who presented the new results at the San Antonio Breast Cancer Symposium.
“ If this drug gets approved, we need more work in terms of biomarkers of response and resistance to understand how to select these agents and how to sequence these different agents,” Dr. Bardia said in an interview. He is associate professor of medicine at Harvard Medical School and Massachusetts General Hospital Cancer Center.
Dato-DXd has a proprietary linker technology that makes it more stable in plasma and more selective for tumor cells, where overexpressed enzymes cleave it and lead to release of the drug. This reduces off-target toxicity, said Dr. Bardia.
The primary results from TROPION-Breast01, presented at ESMO 2023, showed statistically significant improvement in progression-free survival compared to investigator’s choice of chemotherapy (hazard ratio, [HR], 0.63; P < .0001) and a higher overall response rate (36.4% versus 22.9%).
At SABCS, Dr. Bardia presented additional PFS sub-analyses and safety data.
TROPION-Breast01 included 732 patients who had failed or were ineligible for endocrine therapy, and who had received 1-2 lines of chemotherapy in the metastatic or inoperable setting. They were randomized to dato-DXd or chemotherapy.
The median PFS as determined by blinded independent central review was longer in the dato-DXd group (6.9 versus 4.5 months; P < .0001). Time to first subsequent therapy was also longer (median 8.2 versus 5.0 months; HR, 0.53; 95% CI, 0.45-0.64).
PFS benefit was similar regardless of duration of previous CDK4/6 inhibitor treatment. There was no significant difference in median PFS among patients with brain metastases at baseline (HR, 0.73; 95% CI, 0.39-1.42).
Grade 3 or higher treatment-related adverse events were less common in the dato-DXd group (21% versus 45%), as were the incidences of dose interruption (12% versus 25%), treatment-related neutropenia (11% versus 42%), grade 3 or higher treatment-related neutropenia (1% versus 31%), neutropenia-related dose interruption (0% versus 17%), and neutropenia-related dose reduction (0.3% versus 13%). G-CSF usage was lower in the dato-DXd group during treatment (3% versus 22%) and after treatment (0.3% versus 8%).
Stomatitis was more common in the dato-DXd group (50% versus 13%), including grade 3 (6% versus 3%). Dose reduction due to stomatitis was also more common (12% versus 1%), and discontinuation occurred in just 1 patient (0.3%) in the dato-DXd group.
The median time to confirmed deterioration, as measured by the Global Health Status/Quality of Life scale, was longer in the dato-DXd group (9.0 versus 4.8 months; HR, 0.76; 95% CI, 0.58-0.98).
During the Q & A period after the talk, Marc E. Lippman, MD, professor of oncology and director of the breast cancer program at Georgetown University’s Lombardi Comprehensive Cancer Center, questioned the assumption that Trop-2 is universally expressed in breast cancer, and asked if there were any data on outcomes associated with its expression. “That’s a very good question,” said Dr. Bardia. He said that the team is working on the problem, including identifying the best tool to measure Trop-2 expression, but also addressing whether expression changes over time. Finally, the team hopes to determine if treatment response might relate to levels of expression.
Trop-2 expression was studied in the ASCENT trial that examined sacituzumab govitecan in metastatic triple-negative breast cancer, and there was no apparent link. “In general, we don’t see a very strong correlation between Trop-2 expression and outcomes. In the ASCENT trial, even in patients who had low expression of Trop-2, the outcomes with Trop-2 antibody drug conjugates [were] superior to standard chemotherapy,” replied Dr. Bardia.
Ron Bose, MD, PhD, also asked if there would be broader biomarker analyses of responders versus nonresponders to dato-dxd. “I think it’s very important to know, what are the biomarkers that predict efficacy for dato-dxd. The median progression free survival improvement was only about two months, maybe a little bit more, so knowing which patients are going to get the most benefit will be very important,” Dr. Bose said in an interview. Dr. Bose is associate professor of oncology at the Washington University School of Medicine in St. Louis.
Overall, he was impressed by the results. “The median progression free survival benefit is moderate, but the safety I think is really particularly strong, and when I’m thinking about this for my patients, the fact that there is a progression free survival benefit, plus a safety benefit [compared to chemotherapy] makes it very appealing,” he said.
Dr. Bose has consulted for Genentech. Dr. Bardia has been on advisory boards for Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, and Foundation Medicine. He has received research grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Natera, and Eli Lilly.
SAN ANTONIO — In endocrine-resistant, HR+/HER2- metastatic breast cancer, the antibody-drug conjugate (ADC) datopotamab deruxtecan (dato-DXd, Daiichi Sankyo/AstraZeneca) has greater efficacy and a better safety profile than investigator-chosen chemotherapy, according to the latest results from the TROPION-Breast01 clinical trial.
If approved, the ADC would join sacituzumab govitecan (Trodelvy, Gilead) as agents that target trophoblast cell-surface antigen-2 (Trop-2), which is universally expressed in breast cancer, according to Aditya Bardia, MD, who presented the new results at the San Antonio Breast Cancer Symposium.
“ If this drug gets approved, we need more work in terms of biomarkers of response and resistance to understand how to select these agents and how to sequence these different agents,” Dr. Bardia said in an interview. He is associate professor of medicine at Harvard Medical School and Massachusetts General Hospital Cancer Center.
Dato-DXd has a proprietary linker technology that makes it more stable in plasma and more selective for tumor cells, where overexpressed enzymes cleave it and lead to release of the drug. This reduces off-target toxicity, said Dr. Bardia.
The primary results from TROPION-Breast01, presented at ESMO 2023, showed statistically significant improvement in progression-free survival compared to investigator’s choice of chemotherapy (hazard ratio, [HR], 0.63; P < .0001) and a higher overall response rate (36.4% versus 22.9%).
At SABCS, Dr. Bardia presented additional PFS sub-analyses and safety data.
TROPION-Breast01 included 732 patients who had failed or were ineligible for endocrine therapy, and who had received 1-2 lines of chemotherapy in the metastatic or inoperable setting. They were randomized to dato-DXd or chemotherapy.
The median PFS as determined by blinded independent central review was longer in the dato-DXd group (6.9 versus 4.5 months; P < .0001). Time to first subsequent therapy was also longer (median 8.2 versus 5.0 months; HR, 0.53; 95% CI, 0.45-0.64).
PFS benefit was similar regardless of duration of previous CDK4/6 inhibitor treatment. There was no significant difference in median PFS among patients with brain metastases at baseline (HR, 0.73; 95% CI, 0.39-1.42).
Grade 3 or higher treatment-related adverse events were less common in the dato-DXd group (21% versus 45%), as were the incidences of dose interruption (12% versus 25%), treatment-related neutropenia (11% versus 42%), grade 3 or higher treatment-related neutropenia (1% versus 31%), neutropenia-related dose interruption (0% versus 17%), and neutropenia-related dose reduction (0.3% versus 13%). G-CSF usage was lower in the dato-DXd group during treatment (3% versus 22%) and after treatment (0.3% versus 8%).
Stomatitis was more common in the dato-DXd group (50% versus 13%), including grade 3 (6% versus 3%). Dose reduction due to stomatitis was also more common (12% versus 1%), and discontinuation occurred in just 1 patient (0.3%) in the dato-DXd group.
The median time to confirmed deterioration, as measured by the Global Health Status/Quality of Life scale, was longer in the dato-DXd group (9.0 versus 4.8 months; HR, 0.76; 95% CI, 0.58-0.98).
During the Q & A period after the talk, Marc E. Lippman, MD, professor of oncology and director of the breast cancer program at Georgetown University’s Lombardi Comprehensive Cancer Center, questioned the assumption that Trop-2 is universally expressed in breast cancer, and asked if there were any data on outcomes associated with its expression. “That’s a very good question,” said Dr. Bardia. He said that the team is working on the problem, including identifying the best tool to measure Trop-2 expression, but also addressing whether expression changes over time. Finally, the team hopes to determine if treatment response might relate to levels of expression.
Trop-2 expression was studied in the ASCENT trial that examined sacituzumab govitecan in metastatic triple-negative breast cancer, and there was no apparent link. “In general, we don’t see a very strong correlation between Trop-2 expression and outcomes. In the ASCENT trial, even in patients who had low expression of Trop-2, the outcomes with Trop-2 antibody drug conjugates [were] superior to standard chemotherapy,” replied Dr. Bardia.
Ron Bose, MD, PhD, also asked if there would be broader biomarker analyses of responders versus nonresponders to dato-dxd. “I think it’s very important to know, what are the biomarkers that predict efficacy for dato-dxd. The median progression free survival improvement was only about two months, maybe a little bit more, so knowing which patients are going to get the most benefit will be very important,” Dr. Bose said in an interview. Dr. Bose is associate professor of oncology at the Washington University School of Medicine in St. Louis.
Overall, he was impressed by the results. “The median progression free survival benefit is moderate, but the safety I think is really particularly strong, and when I’m thinking about this for my patients, the fact that there is a progression free survival benefit, plus a safety benefit [compared to chemotherapy] makes it very appealing,” he said.
Dr. Bose has consulted for Genentech. Dr. Bardia has been on advisory boards for Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, and Foundation Medicine. He has received research grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Natera, and Eli Lilly.
SAN ANTONIO — In endocrine-resistant, HR+/HER2- metastatic breast cancer, the antibody-drug conjugate (ADC) datopotamab deruxtecan (dato-DXd, Daiichi Sankyo/AstraZeneca) has greater efficacy and a better safety profile than investigator-chosen chemotherapy, according to the latest results from the TROPION-Breast01 clinical trial.
If approved, the ADC would join sacituzumab govitecan (Trodelvy, Gilead) as agents that target trophoblast cell-surface antigen-2 (Trop-2), which is universally expressed in breast cancer, according to Aditya Bardia, MD, who presented the new results at the San Antonio Breast Cancer Symposium.
“ If this drug gets approved, we need more work in terms of biomarkers of response and resistance to understand how to select these agents and how to sequence these different agents,” Dr. Bardia said in an interview. He is associate professor of medicine at Harvard Medical School and Massachusetts General Hospital Cancer Center.
Dato-DXd has a proprietary linker technology that makes it more stable in plasma and more selective for tumor cells, where overexpressed enzymes cleave it and lead to release of the drug. This reduces off-target toxicity, said Dr. Bardia.
The primary results from TROPION-Breast01, presented at ESMO 2023, showed statistically significant improvement in progression-free survival compared to investigator’s choice of chemotherapy (hazard ratio, [HR], 0.63; P < .0001) and a higher overall response rate (36.4% versus 22.9%).
At SABCS, Dr. Bardia presented additional PFS sub-analyses and safety data.
TROPION-Breast01 included 732 patients who had failed or were ineligible for endocrine therapy, and who had received 1-2 lines of chemotherapy in the metastatic or inoperable setting. They were randomized to dato-DXd or chemotherapy.
The median PFS as determined by blinded independent central review was longer in the dato-DXd group (6.9 versus 4.5 months; P < .0001). Time to first subsequent therapy was also longer (median 8.2 versus 5.0 months; HR, 0.53; 95% CI, 0.45-0.64).
PFS benefit was similar regardless of duration of previous CDK4/6 inhibitor treatment. There was no significant difference in median PFS among patients with brain metastases at baseline (HR, 0.73; 95% CI, 0.39-1.42).
Grade 3 or higher treatment-related adverse events were less common in the dato-DXd group (21% versus 45%), as were the incidences of dose interruption (12% versus 25%), treatment-related neutropenia (11% versus 42%), grade 3 or higher treatment-related neutropenia (1% versus 31%), neutropenia-related dose interruption (0% versus 17%), and neutropenia-related dose reduction (0.3% versus 13%). G-CSF usage was lower in the dato-DXd group during treatment (3% versus 22%) and after treatment (0.3% versus 8%).
Stomatitis was more common in the dato-DXd group (50% versus 13%), including grade 3 (6% versus 3%). Dose reduction due to stomatitis was also more common (12% versus 1%), and discontinuation occurred in just 1 patient (0.3%) in the dato-DXd group.
The median time to confirmed deterioration, as measured by the Global Health Status/Quality of Life scale, was longer in the dato-DXd group (9.0 versus 4.8 months; HR, 0.76; 95% CI, 0.58-0.98).
During the Q & A period after the talk, Marc E. Lippman, MD, professor of oncology and director of the breast cancer program at Georgetown University’s Lombardi Comprehensive Cancer Center, questioned the assumption that Trop-2 is universally expressed in breast cancer, and asked if there were any data on outcomes associated with its expression. “That’s a very good question,” said Dr. Bardia. He said that the team is working on the problem, including identifying the best tool to measure Trop-2 expression, but also addressing whether expression changes over time. Finally, the team hopes to determine if treatment response might relate to levels of expression.
Trop-2 expression was studied in the ASCENT trial that examined sacituzumab govitecan in metastatic triple-negative breast cancer, and there was no apparent link. “In general, we don’t see a very strong correlation between Trop-2 expression and outcomes. In the ASCENT trial, even in patients who had low expression of Trop-2, the outcomes with Trop-2 antibody drug conjugates [were] superior to standard chemotherapy,” replied Dr. Bardia.
Ron Bose, MD, PhD, also asked if there would be broader biomarker analyses of responders versus nonresponders to dato-dxd. “I think it’s very important to know, what are the biomarkers that predict efficacy for dato-dxd. The median progression free survival improvement was only about two months, maybe a little bit more, so knowing which patients are going to get the most benefit will be very important,” Dr. Bose said in an interview. Dr. Bose is associate professor of oncology at the Washington University School of Medicine in St. Louis.
Overall, he was impressed by the results. “The median progression free survival benefit is moderate, but the safety I think is really particularly strong, and when I’m thinking about this for my patients, the fact that there is a progression free survival benefit, plus a safety benefit [compared to chemotherapy] makes it very appealing,” he said.
Dr. Bose has consulted for Genentech. Dr. Bardia has been on advisory boards for Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, and Foundation Medicine. He has received research grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Natera, and Eli Lilly.
AT SABCS 2023
Just gas? New study on colic suggests some longer-term implications
Pediatricians commonly are asked to see infants presenting with symptoms of colic. The frequent and intense crying associated with colic is understandably quite distressing to parents, who often worry about a serious underlying medical cause. There also is the stress of trying to soothe an irritable infant who often does not seem to respond to the typical interventions.
Conventional wisdom about colic has been that the behaviors are the result of some gastrointestinal problem that, while not perfectly understood, tends to be mercifully self-limited and not predictive of future medical or mental health problems. This perspective then leads to pediatricians typically offering mainly sympathy and reassurance at these visits.
A new study,1 however, challenges some of this traditional thinking. The data come from a remarkable longitudinal study called the Generation R Study (R being Rotterdam in the Netherlands) that has prospectively studied a group of nearly 5,000 children from before birth into adolescence. Colic symptoms were briefly assessed when infants were about 3 months old and emotional-behavioral problems have been prospectively measured at multiple time points subsequently using well-validated rating scales.
The main finding of the study was and, to a lesser extent, in adolescence. This held for both internalizing problems (like anxiety and depressive symptoms) and externalizing problems (like defiance and aggressive behavior). At age 10, participants also underwent an MRI scan and those who were excessive criers as infants were found to have a smaller amygdala, a region known for being important in regulating emotions.
The authors concluded that colicky behavior in infancy may reflect some underlying temperamental vulnerabilities and may have more predictive value than previously thought. The connection between excessive crying and a measurable brain region difference later in life is also interesting, although these kinds of brain imaging findings have been notoriously difficult to interpret clinically.
Overall, this is a solid study that deserves to be considered. Colic may reflect a bit more than most of us have been taught and shouldn’t necessarily be “shrugged off,” as the authors state in their discussion.
At the same time, however, it is important not to overinterpret the findings. The magnitude of the effects were on the small side (about 0.2 of a standard deviation) and most children with excessive crying in early infancy did not manifest high levels of mental health problems later in life. The mothers of high crying infants also had slightly higher levels of mental health problems themselves so there could be other mechanisms at work here, such as genetic differences between the two groups.
So how could a pediatrician best use this new information without taking things too far? Regardless of the question of whether the excessive crying infancy is a true risk factor for later behavior problems (in the causal sense) or whether it represents more of a marker for something else, its presence so early in life offers an opportunity. Primary care clinicians would still likely want to provide the reassurance that has typically been given in these visits but perhaps with the caveat that some of these kids go on to struggle a bit more with mental health and that they might benefit from some additional support. We are not talking about prophylactic medications here, but something like additional parenting skills. Especially if you, as the pediatrician, suspect that the parents might benefit from expanding their parenting toolkit already, here is a nice opportunity to invite them to learn some new approaches and skills — framed in a way that focuses on the temperament of the child rather than any “deficits” you perceive in the parents. Some parents may be more receptive and less defensive to the idea of participating in parent training under the framework that they are doing this because they have a temperamentally more challenging child (rather than feeling that they are deficient in basic parenting skills).
It’s always a good idea to know about what resources are available in the community when it comes to teaching parenting skills. In addition to scientifically supported books and podcasts, there has been a steady increase in reliable websites, apps, and other digital platforms related to parenting, as well as standard in-person groups and classes. This could also be a great use of an integrated behavioral health professional for practices fortunate enough to have one.
In summary, there is some new evidence that colic can represent a little more than “just gas,” and while we shouldn’t take this one study to the extreme, there may be some good opportunities here to discuss and support good parenting practices in general.
Dr. Rettew is a child and adolescent psychiatrist with Lane County Behavioral Health in Eugene, Ore., and Oregon Health & Science University, Portland. His latest book is “Parenting Made Complicated: What Science Really Knows about the Greatest Debates of Early Childhood.” You can follow him on Twitter and Facebook @PediPsych.
Reference
1. Sammallahti S et al. Excessive crying, behavior problems, and amygdala volume: A study from infancy to adolescence. J Am Acad Child Adolesc Psychiatry. 2023 Jun;62(6):675-83. doi: 10.1016/j.jaac.2023.01.014.
Pediatricians commonly are asked to see infants presenting with symptoms of colic. The frequent and intense crying associated with colic is understandably quite distressing to parents, who often worry about a serious underlying medical cause. There also is the stress of trying to soothe an irritable infant who often does not seem to respond to the typical interventions.
Conventional wisdom about colic has been that the behaviors are the result of some gastrointestinal problem that, while not perfectly understood, tends to be mercifully self-limited and not predictive of future medical or mental health problems. This perspective then leads to pediatricians typically offering mainly sympathy and reassurance at these visits.
A new study,1 however, challenges some of this traditional thinking. The data come from a remarkable longitudinal study called the Generation R Study (R being Rotterdam in the Netherlands) that has prospectively studied a group of nearly 5,000 children from before birth into adolescence. Colic symptoms were briefly assessed when infants were about 3 months old and emotional-behavioral problems have been prospectively measured at multiple time points subsequently using well-validated rating scales.
The main finding of the study was and, to a lesser extent, in adolescence. This held for both internalizing problems (like anxiety and depressive symptoms) and externalizing problems (like defiance and aggressive behavior). At age 10, participants also underwent an MRI scan and those who were excessive criers as infants were found to have a smaller amygdala, a region known for being important in regulating emotions.
The authors concluded that colicky behavior in infancy may reflect some underlying temperamental vulnerabilities and may have more predictive value than previously thought. The connection between excessive crying and a measurable brain region difference later in life is also interesting, although these kinds of brain imaging findings have been notoriously difficult to interpret clinically.
Overall, this is a solid study that deserves to be considered. Colic may reflect a bit more than most of us have been taught and shouldn’t necessarily be “shrugged off,” as the authors state in their discussion.
At the same time, however, it is important not to overinterpret the findings. The magnitude of the effects were on the small side (about 0.2 of a standard deviation) and most children with excessive crying in early infancy did not manifest high levels of mental health problems later in life. The mothers of high crying infants also had slightly higher levels of mental health problems themselves so there could be other mechanisms at work here, such as genetic differences between the two groups.
So how could a pediatrician best use this new information without taking things too far? Regardless of the question of whether the excessive crying infancy is a true risk factor for later behavior problems (in the causal sense) or whether it represents more of a marker for something else, its presence so early in life offers an opportunity. Primary care clinicians would still likely want to provide the reassurance that has typically been given in these visits but perhaps with the caveat that some of these kids go on to struggle a bit more with mental health and that they might benefit from some additional support. We are not talking about prophylactic medications here, but something like additional parenting skills. Especially if you, as the pediatrician, suspect that the parents might benefit from expanding their parenting toolkit already, here is a nice opportunity to invite them to learn some new approaches and skills — framed in a way that focuses on the temperament of the child rather than any “deficits” you perceive in the parents. Some parents may be more receptive and less defensive to the idea of participating in parent training under the framework that they are doing this because they have a temperamentally more challenging child (rather than feeling that they are deficient in basic parenting skills).
It’s always a good idea to know about what resources are available in the community when it comes to teaching parenting skills. In addition to scientifically supported books and podcasts, there has been a steady increase in reliable websites, apps, and other digital platforms related to parenting, as well as standard in-person groups and classes. This could also be a great use of an integrated behavioral health professional for practices fortunate enough to have one.
In summary, there is some new evidence that colic can represent a little more than “just gas,” and while we shouldn’t take this one study to the extreme, there may be some good opportunities here to discuss and support good parenting practices in general.
Dr. Rettew is a child and adolescent psychiatrist with Lane County Behavioral Health in Eugene, Ore., and Oregon Health & Science University, Portland. His latest book is “Parenting Made Complicated: What Science Really Knows about the Greatest Debates of Early Childhood.” You can follow him on Twitter and Facebook @PediPsych.
Reference
1. Sammallahti S et al. Excessive crying, behavior problems, and amygdala volume: A study from infancy to adolescence. J Am Acad Child Adolesc Psychiatry. 2023 Jun;62(6):675-83. doi: 10.1016/j.jaac.2023.01.014.
Pediatricians commonly are asked to see infants presenting with symptoms of colic. The frequent and intense crying associated with colic is understandably quite distressing to parents, who often worry about a serious underlying medical cause. There also is the stress of trying to soothe an irritable infant who often does not seem to respond to the typical interventions.
Conventional wisdom about colic has been that the behaviors are the result of some gastrointestinal problem that, while not perfectly understood, tends to be mercifully self-limited and not predictive of future medical or mental health problems. This perspective then leads to pediatricians typically offering mainly sympathy and reassurance at these visits.
A new study,1 however, challenges some of this traditional thinking. The data come from a remarkable longitudinal study called the Generation R Study (R being Rotterdam in the Netherlands) that has prospectively studied a group of nearly 5,000 children from before birth into adolescence. Colic symptoms were briefly assessed when infants were about 3 months old and emotional-behavioral problems have been prospectively measured at multiple time points subsequently using well-validated rating scales.
The main finding of the study was and, to a lesser extent, in adolescence. This held for both internalizing problems (like anxiety and depressive symptoms) and externalizing problems (like defiance and aggressive behavior). At age 10, participants also underwent an MRI scan and those who were excessive criers as infants were found to have a smaller amygdala, a region known for being important in regulating emotions.
The authors concluded that colicky behavior in infancy may reflect some underlying temperamental vulnerabilities and may have more predictive value than previously thought. The connection between excessive crying and a measurable brain region difference later in life is also interesting, although these kinds of brain imaging findings have been notoriously difficult to interpret clinically.
Overall, this is a solid study that deserves to be considered. Colic may reflect a bit more than most of us have been taught and shouldn’t necessarily be “shrugged off,” as the authors state in their discussion.
At the same time, however, it is important not to overinterpret the findings. The magnitude of the effects were on the small side (about 0.2 of a standard deviation) and most children with excessive crying in early infancy did not manifest high levels of mental health problems later in life. The mothers of high crying infants also had slightly higher levels of mental health problems themselves so there could be other mechanisms at work here, such as genetic differences between the two groups.
So how could a pediatrician best use this new information without taking things too far? Regardless of the question of whether the excessive crying infancy is a true risk factor for later behavior problems (in the causal sense) or whether it represents more of a marker for something else, its presence so early in life offers an opportunity. Primary care clinicians would still likely want to provide the reassurance that has typically been given in these visits but perhaps with the caveat that some of these kids go on to struggle a bit more with mental health and that they might benefit from some additional support. We are not talking about prophylactic medications here, but something like additional parenting skills. Especially if you, as the pediatrician, suspect that the parents might benefit from expanding their parenting toolkit already, here is a nice opportunity to invite them to learn some new approaches and skills — framed in a way that focuses on the temperament of the child rather than any “deficits” you perceive in the parents. Some parents may be more receptive and less defensive to the idea of participating in parent training under the framework that they are doing this because they have a temperamentally more challenging child (rather than feeling that they are deficient in basic parenting skills).
It’s always a good idea to know about what resources are available in the community when it comes to teaching parenting skills. In addition to scientifically supported books and podcasts, there has been a steady increase in reliable websites, apps, and other digital platforms related to parenting, as well as standard in-person groups and classes. This could also be a great use of an integrated behavioral health professional for practices fortunate enough to have one.
In summary, there is some new evidence that colic can represent a little more than “just gas,” and while we shouldn’t take this one study to the extreme, there may be some good opportunities here to discuss and support good parenting practices in general.
Dr. Rettew is a child and adolescent psychiatrist with Lane County Behavioral Health in Eugene, Ore., and Oregon Health & Science University, Portland. His latest book is “Parenting Made Complicated: What Science Really Knows about the Greatest Debates of Early Childhood.” You can follow him on Twitter and Facebook @PediPsych.
Reference
1. Sammallahti S et al. Excessive crying, behavior problems, and amygdala volume: A study from infancy to adolescence. J Am Acad Child Adolesc Psychiatry. 2023 Jun;62(6):675-83. doi: 10.1016/j.jaac.2023.01.014.
Link between vitamin D deficiency and obesity unclear
MADRID — The role of vitamin D in the risk for overweight and obesity has been the subject of multiple studies. Though there’s still not enough evidence to reach a decisive conclusion, several ongoing debates are setting the stage for future research.
Irene Bretón, MD, PhD, discussed these debates in a presentation titled “Vitamin D Deficiency and Obesity: Cause or Consequence?” delivered at the 64th Congress of the Spanish Society of Endocrinology and Nutrition (SEEN). Dr. Bretón is president of the Foundation of the Spanish Society of Endocrinology and Nutrition.
“Vitamin D deficiency can arise from different causes. The percentage that can be attributed to solar radiation is extremely variable. Some studies put it at 80%, while others suggest lower figures. Many diseases have also been associated with vitamin D deficiency or with low vitamin D levels (which are not always at the level of deficiency). Nonetheless, we still have a lot to learn about these associations,” she said.
Dr. Bretón pointed out that many of these studies overlook parathyroid hormone testing. “I also think it’s more appropriate to discuss nutritional status of vitamin D as opposed to serum levels, because these data can be misleading. It would be interesting to focus more on vitamin D metabolism and not just plasma levels.”
Vitamin Deficiency
To answer whether obesity and its complications could be related to low vitamin D levels, Dr. Bretón pointed to this vitamin’s profile in various regions of the world and called attention to the fact that none of the studies on this topic include populations with roughly adequate levels of this vitamin.
“This highlights the prevalence of vitamin D deficiency worldwide. It affects approximately 50% of the population, has been described in all age groups, and affects both men and women — particularly pregnant women and those in menopause — and older adults,” said Dr. Bretón.
She also cited the figures backing this fact: 88% have 25-hydroxyvitamin D levels < 30 ng/mL, 37% have levels < 20 ng/mL, and 7% have levels < 10 ng/mL.
“These percentages have brought us to consider their potential link to the current obesity epidemic. Studies in humans have observed a relationship between low plasma levels and markers for obesity and adiposity. Free 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are known to be reduced in obesity, and treatments to correct vitamin D deficiency are less effective in people with the disease,” she noted.
Regarding the impact in “the opposite direction,” that is, whether obesity affects the nutritional status of vitamin D, Bretón explained that observational studies have generally found a relationship between overweight and obesity and lower plasma levels of vitamin D. “Data from these studies show that each kg/m2 increase in [body mass index (BMI)] is associated with a 1.15% decrease in 25-hydroxyvitamin D. These studies also show that the prevalence of vitamin D deficiency is 35% higher in patients with obesity and 24% higher in those that are overweight compared with individuals of normal weight. A relationship has been observed between vitamin D deficiency and body fat percentage in men and women and in all age groups,” explained Dr. Bretón.
Dr. Bretón noted that the diseases most closely associated with obesity are type 2 diabetes, hypertension, ischemic heart disease, cancer (colon, breast, prostate, and ovarian), inflammatory liver disease, asthma, and inflammatory diseases.
Mechanisms Involved
“People with obesity may experience less solar exposure (more of their body is covered, or they spend more time indoors), but reduced exposure to the sun is known to have less of an influence on vitamin D levels. Studies where people were given radiation to test how their plasma levels of vitamin D respond have found that there is a smaller effect in people with obesity, and that the effect is inversely correlated with BMI: the higher the BMI, the less vitamin D levels increase under exposure to solar radiation.”
Another mechanism is sequestration in adipose tissue, which is the largest reservoir of vitamin D in the body. Nevertheless, factors such as vitamin D concentration in this tissue, regulation of local metabolism, and vitamin uptake and release are less understood. It is therefore unclear whether this mechanism acts to regulate plasma levels.
“This is why severe vitamin D deficiencies (and deficiencies of other fat-soluble vitamins) that occur after bariatric surgery are often not seen in the first year after surgery but develop much later, when the vitamin that has accumulated in adipose tissue is released as weight is lost,” said Dr. Bretón.
“On the other hand, the volumetric dilution in blood that occurs in relation to total body fat content may explain the variability of plasma levels and the response to treatment. Predictive equations have been described,” she explained.
The Prenatal Stage
Dr. Bretón mentioned that the best setting for studying the impact of vitamin D and preventing future obesity is during the initial stages of life, when adipogenesis and fetal programming are occurring.
“Studies in animals have shown how maternal vitamin D deficiency (due to nongenetic or nonepigenetic mechanisms) leads to changes in adipogenesis and programming of adipose reserves. A fetal or perinatal environment with low vitamin D levels programs all these mechanisms differently, and not just adipogenesis and adipocyte differentiation in utero,” she added.
Various mechanisms involved in vitamin D deficiency as a cause of obesity are currently being studied in the prenatal setting. One such mechanism is the interaction between the vitamin D receptor and 1 alpha–hydroxylase, which are present in the adipose tissue and help modulate lipid metabolism.
“The vitamin D receptor is particularly expressed in the early stages of adipocyte differentiation, but its expression drops off as the differentiation process continues. Vitamin D receptor knockout mice have a slender phenotype and are resistant to diet-induced obesity. They also accumulate less fat with age and a high-fat diet,” explained Dr. Bretón.
“However, vitamin D also influences the production of inflammatory adipokines in these early stages of life. It specifically plays a central role in modulating the inflammatory response in adipose tissue. These anti-inflammatory effects appear to be mediated by inhibition of [NF–kappa B] and MAPK signaling pathways. All of this suggests that vitamin D influences both adipogenesis and how the adipose tissue functions,” she added.
Weight Loss
When considering the link between vitamin D and obesity in the context of weight loss, Dr. Bretón explained that studies in this area suggest that weight loss per se is not sufficient to increase serum 25-hydroxyvitamin D. Rather, increased synthesis by the skin or increased dietary intake are the most relevant factors for the nutritional status of this vitamin.
“A recent systematic review looking at the relationship between vitamin D levels and weight loss via caloric restriction and exercise showed a small but significant effect in the sense that weight loss increases vitamin D levels. However, other meta-analyses have not found significant results in this area,” she said.
“In my opinion, these results depend on how long the intervention is performed. If a lot of weight is lost in a short time frame, vitamin D is released into the adipose tissue, a process that doesn’t have any significant impact on the nutritional status of this vitamin. Generally, the effect of this relationship is small (1.5 ng/mL) and of little clinical relevance. Moreover, many systematic reviews have analyzed this relationship following bariatric surgery and have also come up with inconclusive results,” Dr. Bretón added.
What role do treatments play in correcting vitamin D deficiency? Dr. Bretón explained that studies that have examined how fortified foods affect obesity show that though these foods don’t cause significant weight changes, they do affect fat mass and waist circumference. This finding suggests that fortified foods have some impact, not necessarily on weight but perhaps on adiposity.
“To rightly value all this data, one has to pay special attention to the environment and the context where the research took place (children or adults, baseline vitamin D levels, and so on). If fortified foods are directly supplemented with cholecalciferol, the results are very inconsistent. We therefore cannot say that treatment with vitamin D can reduce body weight and adiposity,” she said.
When it comes to the complications from obesity, studies of vitamin D supplementation, cancer, and cardiovascular disease did not find any beneficial effect on preventing these pathologies.
For obesity’s impact on vitamin D supplementation, it is known that the levels achieved are lower in patients with obesity compared with patients of normal weight. “Compared with other interventions, however, these levels (15.27 ng/mL) are clinically relevant,” she noted.
Future Directions
Dr. Bretón explained that all this evidence has revealed many debates regarding the association of vitamin D levels with obesity. “For example, it appears that obesity could predict low vitamin D levels (not necessarily a deficiency). In turn, these low levels could cause obesity, especially during embryonic development, when programming of adipocyte physiology is taking place.”
Dr. Bretón sees many confounding factors that will need to be elucidated in the future. “One factor is that we aren’t sure whether the patient we’re seeing has vitamin D deficiency or if other factors are in play, like time since weight loss, laboratory technique used to measure vitamin D, nutritional status, geographic location, time of year when the test is performed, et cetera. You also have to assess other factors having to do with obesity, like how adiposity is being measured and whether BMI reflects that adiposity.”
Last, the expert reviewed the major research efforts underway that are based on evidence that vitamin D is associated with insulin resistance. Studies are being performed on pancreatic function, the role of vitamin D levels in ovarian physiology related to insulin resistance (specifically, the role of hyperandrogenism), adipose tissue (vitamin D receptor expression, volumetric dilution), and other components of metabolic syndrome to determine how this vitamin’s status influences the renin-angiotensin system, apoptosis, and cardiovascular risk.
“There is also plenty of research going on surrounding metabolic liver disease, which has a lot to do with the microbiota. So, they’re studying the relationship between vitamin D and dysbiosis, especially regarding local immunomodulation in the gut in relation to the microbiota,” she added.
Another area of research is cancer, focusing primarily on analyzing the nutritional status of vitamin D in relation to the microbiome and how this status may affect the therapeutic effect of chemotherapy and radiation therapy. “It would be interesting to find out whether the effect of immunotherapy varies depending on the patient’s vitamin D status,” concluded Dr. Bretón.
Dr. Bretón’s lecture at the 64th Congress of the SEEN was sponsored by the Foundation for Analysis and Social Studies (FAES).
This article was translated from the Medscape Spanish edition. A version of this article appeared on Medscape.com.
MADRID — The role of vitamin D in the risk for overweight and obesity has been the subject of multiple studies. Though there’s still not enough evidence to reach a decisive conclusion, several ongoing debates are setting the stage for future research.
Irene Bretón, MD, PhD, discussed these debates in a presentation titled “Vitamin D Deficiency and Obesity: Cause or Consequence?” delivered at the 64th Congress of the Spanish Society of Endocrinology and Nutrition (SEEN). Dr. Bretón is president of the Foundation of the Spanish Society of Endocrinology and Nutrition.
“Vitamin D deficiency can arise from different causes. The percentage that can be attributed to solar radiation is extremely variable. Some studies put it at 80%, while others suggest lower figures. Many diseases have also been associated with vitamin D deficiency or with low vitamin D levels (which are not always at the level of deficiency). Nonetheless, we still have a lot to learn about these associations,” she said.
Dr. Bretón pointed out that many of these studies overlook parathyroid hormone testing. “I also think it’s more appropriate to discuss nutritional status of vitamin D as opposed to serum levels, because these data can be misleading. It would be interesting to focus more on vitamin D metabolism and not just plasma levels.”
Vitamin Deficiency
To answer whether obesity and its complications could be related to low vitamin D levels, Dr. Bretón pointed to this vitamin’s profile in various regions of the world and called attention to the fact that none of the studies on this topic include populations with roughly adequate levels of this vitamin.
“This highlights the prevalence of vitamin D deficiency worldwide. It affects approximately 50% of the population, has been described in all age groups, and affects both men and women — particularly pregnant women and those in menopause — and older adults,” said Dr. Bretón.
She also cited the figures backing this fact: 88% have 25-hydroxyvitamin D levels < 30 ng/mL, 37% have levels < 20 ng/mL, and 7% have levels < 10 ng/mL.
“These percentages have brought us to consider their potential link to the current obesity epidemic. Studies in humans have observed a relationship between low plasma levels and markers for obesity and adiposity. Free 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are known to be reduced in obesity, and treatments to correct vitamin D deficiency are less effective in people with the disease,” she noted.
Regarding the impact in “the opposite direction,” that is, whether obesity affects the nutritional status of vitamin D, Bretón explained that observational studies have generally found a relationship between overweight and obesity and lower plasma levels of vitamin D. “Data from these studies show that each kg/m2 increase in [body mass index (BMI)] is associated with a 1.15% decrease in 25-hydroxyvitamin D. These studies also show that the prevalence of vitamin D deficiency is 35% higher in patients with obesity and 24% higher in those that are overweight compared with individuals of normal weight. A relationship has been observed between vitamin D deficiency and body fat percentage in men and women and in all age groups,” explained Dr. Bretón.
Dr. Bretón noted that the diseases most closely associated with obesity are type 2 diabetes, hypertension, ischemic heart disease, cancer (colon, breast, prostate, and ovarian), inflammatory liver disease, asthma, and inflammatory diseases.
Mechanisms Involved
“People with obesity may experience less solar exposure (more of their body is covered, or they spend more time indoors), but reduced exposure to the sun is known to have less of an influence on vitamin D levels. Studies where people were given radiation to test how their plasma levels of vitamin D respond have found that there is a smaller effect in people with obesity, and that the effect is inversely correlated with BMI: the higher the BMI, the less vitamin D levels increase under exposure to solar radiation.”
Another mechanism is sequestration in adipose tissue, which is the largest reservoir of vitamin D in the body. Nevertheless, factors such as vitamin D concentration in this tissue, regulation of local metabolism, and vitamin uptake and release are less understood. It is therefore unclear whether this mechanism acts to regulate plasma levels.
“This is why severe vitamin D deficiencies (and deficiencies of other fat-soluble vitamins) that occur after bariatric surgery are often not seen in the first year after surgery but develop much later, when the vitamin that has accumulated in adipose tissue is released as weight is lost,” said Dr. Bretón.
“On the other hand, the volumetric dilution in blood that occurs in relation to total body fat content may explain the variability of plasma levels and the response to treatment. Predictive equations have been described,” she explained.
The Prenatal Stage
Dr. Bretón mentioned that the best setting for studying the impact of vitamin D and preventing future obesity is during the initial stages of life, when adipogenesis and fetal programming are occurring.
“Studies in animals have shown how maternal vitamin D deficiency (due to nongenetic or nonepigenetic mechanisms) leads to changes in adipogenesis and programming of adipose reserves. A fetal or perinatal environment with low vitamin D levels programs all these mechanisms differently, and not just adipogenesis and adipocyte differentiation in utero,” she added.
Various mechanisms involved in vitamin D deficiency as a cause of obesity are currently being studied in the prenatal setting. One such mechanism is the interaction between the vitamin D receptor and 1 alpha–hydroxylase, which are present in the adipose tissue and help modulate lipid metabolism.
“The vitamin D receptor is particularly expressed in the early stages of adipocyte differentiation, but its expression drops off as the differentiation process continues. Vitamin D receptor knockout mice have a slender phenotype and are resistant to diet-induced obesity. They also accumulate less fat with age and a high-fat diet,” explained Dr. Bretón.
“However, vitamin D also influences the production of inflammatory adipokines in these early stages of life. It specifically plays a central role in modulating the inflammatory response in adipose tissue. These anti-inflammatory effects appear to be mediated by inhibition of [NF–kappa B] and MAPK signaling pathways. All of this suggests that vitamin D influences both adipogenesis and how the adipose tissue functions,” she added.
Weight Loss
When considering the link between vitamin D and obesity in the context of weight loss, Dr. Bretón explained that studies in this area suggest that weight loss per se is not sufficient to increase serum 25-hydroxyvitamin D. Rather, increased synthesis by the skin or increased dietary intake are the most relevant factors for the nutritional status of this vitamin.
“A recent systematic review looking at the relationship between vitamin D levels and weight loss via caloric restriction and exercise showed a small but significant effect in the sense that weight loss increases vitamin D levels. However, other meta-analyses have not found significant results in this area,” she said.
“In my opinion, these results depend on how long the intervention is performed. If a lot of weight is lost in a short time frame, vitamin D is released into the adipose tissue, a process that doesn’t have any significant impact on the nutritional status of this vitamin. Generally, the effect of this relationship is small (1.5 ng/mL) and of little clinical relevance. Moreover, many systematic reviews have analyzed this relationship following bariatric surgery and have also come up with inconclusive results,” Dr. Bretón added.
What role do treatments play in correcting vitamin D deficiency? Dr. Bretón explained that studies that have examined how fortified foods affect obesity show that though these foods don’t cause significant weight changes, they do affect fat mass and waist circumference. This finding suggests that fortified foods have some impact, not necessarily on weight but perhaps on adiposity.
“To rightly value all this data, one has to pay special attention to the environment and the context where the research took place (children or adults, baseline vitamin D levels, and so on). If fortified foods are directly supplemented with cholecalciferol, the results are very inconsistent. We therefore cannot say that treatment with vitamin D can reduce body weight and adiposity,” she said.
When it comes to the complications from obesity, studies of vitamin D supplementation, cancer, and cardiovascular disease did not find any beneficial effect on preventing these pathologies.
For obesity’s impact on vitamin D supplementation, it is known that the levels achieved are lower in patients with obesity compared with patients of normal weight. “Compared with other interventions, however, these levels (15.27 ng/mL) are clinically relevant,” she noted.
Future Directions
Dr. Bretón explained that all this evidence has revealed many debates regarding the association of vitamin D levels with obesity. “For example, it appears that obesity could predict low vitamin D levels (not necessarily a deficiency). In turn, these low levels could cause obesity, especially during embryonic development, when programming of adipocyte physiology is taking place.”
Dr. Bretón sees many confounding factors that will need to be elucidated in the future. “One factor is that we aren’t sure whether the patient we’re seeing has vitamin D deficiency or if other factors are in play, like time since weight loss, laboratory technique used to measure vitamin D, nutritional status, geographic location, time of year when the test is performed, et cetera. You also have to assess other factors having to do with obesity, like how adiposity is being measured and whether BMI reflects that adiposity.”
Last, the expert reviewed the major research efforts underway that are based on evidence that vitamin D is associated with insulin resistance. Studies are being performed on pancreatic function, the role of vitamin D levels in ovarian physiology related to insulin resistance (specifically, the role of hyperandrogenism), adipose tissue (vitamin D receptor expression, volumetric dilution), and other components of metabolic syndrome to determine how this vitamin’s status influences the renin-angiotensin system, apoptosis, and cardiovascular risk.
“There is also plenty of research going on surrounding metabolic liver disease, which has a lot to do with the microbiota. So, they’re studying the relationship between vitamin D and dysbiosis, especially regarding local immunomodulation in the gut in relation to the microbiota,” she added.
Another area of research is cancer, focusing primarily on analyzing the nutritional status of vitamin D in relation to the microbiome and how this status may affect the therapeutic effect of chemotherapy and radiation therapy. “It would be interesting to find out whether the effect of immunotherapy varies depending on the patient’s vitamin D status,” concluded Dr. Bretón.
Dr. Bretón’s lecture at the 64th Congress of the SEEN was sponsored by the Foundation for Analysis and Social Studies (FAES).
This article was translated from the Medscape Spanish edition. A version of this article appeared on Medscape.com.
MADRID — The role of vitamin D in the risk for overweight and obesity has been the subject of multiple studies. Though there’s still not enough evidence to reach a decisive conclusion, several ongoing debates are setting the stage for future research.
Irene Bretón, MD, PhD, discussed these debates in a presentation titled “Vitamin D Deficiency and Obesity: Cause or Consequence?” delivered at the 64th Congress of the Spanish Society of Endocrinology and Nutrition (SEEN). Dr. Bretón is president of the Foundation of the Spanish Society of Endocrinology and Nutrition.
“Vitamin D deficiency can arise from different causes. The percentage that can be attributed to solar radiation is extremely variable. Some studies put it at 80%, while others suggest lower figures. Many diseases have also been associated with vitamin D deficiency or with low vitamin D levels (which are not always at the level of deficiency). Nonetheless, we still have a lot to learn about these associations,” she said.
Dr. Bretón pointed out that many of these studies overlook parathyroid hormone testing. “I also think it’s more appropriate to discuss nutritional status of vitamin D as opposed to serum levels, because these data can be misleading. It would be interesting to focus more on vitamin D metabolism and not just plasma levels.”
Vitamin Deficiency
To answer whether obesity and its complications could be related to low vitamin D levels, Dr. Bretón pointed to this vitamin’s profile in various regions of the world and called attention to the fact that none of the studies on this topic include populations with roughly adequate levels of this vitamin.
“This highlights the prevalence of vitamin D deficiency worldwide. It affects approximately 50% of the population, has been described in all age groups, and affects both men and women — particularly pregnant women and those in menopause — and older adults,” said Dr. Bretón.
She also cited the figures backing this fact: 88% have 25-hydroxyvitamin D levels < 30 ng/mL, 37% have levels < 20 ng/mL, and 7% have levels < 10 ng/mL.
“These percentages have brought us to consider their potential link to the current obesity epidemic. Studies in humans have observed a relationship between low plasma levels and markers for obesity and adiposity. Free 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are known to be reduced in obesity, and treatments to correct vitamin D deficiency are less effective in people with the disease,” she noted.
Regarding the impact in “the opposite direction,” that is, whether obesity affects the nutritional status of vitamin D, Bretón explained that observational studies have generally found a relationship between overweight and obesity and lower plasma levels of vitamin D. “Data from these studies show that each kg/m2 increase in [body mass index (BMI)] is associated with a 1.15% decrease in 25-hydroxyvitamin D. These studies also show that the prevalence of vitamin D deficiency is 35% higher in patients with obesity and 24% higher in those that are overweight compared with individuals of normal weight. A relationship has been observed between vitamin D deficiency and body fat percentage in men and women and in all age groups,” explained Dr. Bretón.
Dr. Bretón noted that the diseases most closely associated with obesity are type 2 diabetes, hypertension, ischemic heart disease, cancer (colon, breast, prostate, and ovarian), inflammatory liver disease, asthma, and inflammatory diseases.
Mechanisms Involved
“People with obesity may experience less solar exposure (more of their body is covered, or they spend more time indoors), but reduced exposure to the sun is known to have less of an influence on vitamin D levels. Studies where people were given radiation to test how their plasma levels of vitamin D respond have found that there is a smaller effect in people with obesity, and that the effect is inversely correlated with BMI: the higher the BMI, the less vitamin D levels increase under exposure to solar radiation.”
Another mechanism is sequestration in adipose tissue, which is the largest reservoir of vitamin D in the body. Nevertheless, factors such as vitamin D concentration in this tissue, regulation of local metabolism, and vitamin uptake and release are less understood. It is therefore unclear whether this mechanism acts to regulate plasma levels.
“This is why severe vitamin D deficiencies (and deficiencies of other fat-soluble vitamins) that occur after bariatric surgery are often not seen in the first year after surgery but develop much later, when the vitamin that has accumulated in adipose tissue is released as weight is lost,” said Dr. Bretón.
“On the other hand, the volumetric dilution in blood that occurs in relation to total body fat content may explain the variability of plasma levels and the response to treatment. Predictive equations have been described,” she explained.
The Prenatal Stage
Dr. Bretón mentioned that the best setting for studying the impact of vitamin D and preventing future obesity is during the initial stages of life, when adipogenesis and fetal programming are occurring.
“Studies in animals have shown how maternal vitamin D deficiency (due to nongenetic or nonepigenetic mechanisms) leads to changes in adipogenesis and programming of adipose reserves. A fetal or perinatal environment with low vitamin D levels programs all these mechanisms differently, and not just adipogenesis and adipocyte differentiation in utero,” she added.
Various mechanisms involved in vitamin D deficiency as a cause of obesity are currently being studied in the prenatal setting. One such mechanism is the interaction between the vitamin D receptor and 1 alpha–hydroxylase, which are present in the adipose tissue and help modulate lipid metabolism.
“The vitamin D receptor is particularly expressed in the early stages of adipocyte differentiation, but its expression drops off as the differentiation process continues. Vitamin D receptor knockout mice have a slender phenotype and are resistant to diet-induced obesity. They also accumulate less fat with age and a high-fat diet,” explained Dr. Bretón.
“However, vitamin D also influences the production of inflammatory adipokines in these early stages of life. It specifically plays a central role in modulating the inflammatory response in adipose tissue. These anti-inflammatory effects appear to be mediated by inhibition of [NF–kappa B] and MAPK signaling pathways. All of this suggests that vitamin D influences both adipogenesis and how the adipose tissue functions,” she added.
Weight Loss
When considering the link between vitamin D and obesity in the context of weight loss, Dr. Bretón explained that studies in this area suggest that weight loss per se is not sufficient to increase serum 25-hydroxyvitamin D. Rather, increased synthesis by the skin or increased dietary intake are the most relevant factors for the nutritional status of this vitamin.
“A recent systematic review looking at the relationship between vitamin D levels and weight loss via caloric restriction and exercise showed a small but significant effect in the sense that weight loss increases vitamin D levels. However, other meta-analyses have not found significant results in this area,” she said.
“In my opinion, these results depend on how long the intervention is performed. If a lot of weight is lost in a short time frame, vitamin D is released into the adipose tissue, a process that doesn’t have any significant impact on the nutritional status of this vitamin. Generally, the effect of this relationship is small (1.5 ng/mL) and of little clinical relevance. Moreover, many systematic reviews have analyzed this relationship following bariatric surgery and have also come up with inconclusive results,” Dr. Bretón added.
What role do treatments play in correcting vitamin D deficiency? Dr. Bretón explained that studies that have examined how fortified foods affect obesity show that though these foods don’t cause significant weight changes, they do affect fat mass and waist circumference. This finding suggests that fortified foods have some impact, not necessarily on weight but perhaps on adiposity.
“To rightly value all this data, one has to pay special attention to the environment and the context where the research took place (children or adults, baseline vitamin D levels, and so on). If fortified foods are directly supplemented with cholecalciferol, the results are very inconsistent. We therefore cannot say that treatment with vitamin D can reduce body weight and adiposity,” she said.
When it comes to the complications from obesity, studies of vitamin D supplementation, cancer, and cardiovascular disease did not find any beneficial effect on preventing these pathologies.
For obesity’s impact on vitamin D supplementation, it is known that the levels achieved are lower in patients with obesity compared with patients of normal weight. “Compared with other interventions, however, these levels (15.27 ng/mL) are clinically relevant,” she noted.
Future Directions
Dr. Bretón explained that all this evidence has revealed many debates regarding the association of vitamin D levels with obesity. “For example, it appears that obesity could predict low vitamin D levels (not necessarily a deficiency). In turn, these low levels could cause obesity, especially during embryonic development, when programming of adipocyte physiology is taking place.”
Dr. Bretón sees many confounding factors that will need to be elucidated in the future. “One factor is that we aren’t sure whether the patient we’re seeing has vitamin D deficiency or if other factors are in play, like time since weight loss, laboratory technique used to measure vitamin D, nutritional status, geographic location, time of year when the test is performed, et cetera. You also have to assess other factors having to do with obesity, like how adiposity is being measured and whether BMI reflects that adiposity.”
Last, the expert reviewed the major research efforts underway that are based on evidence that vitamin D is associated with insulin resistance. Studies are being performed on pancreatic function, the role of vitamin D levels in ovarian physiology related to insulin resistance (specifically, the role of hyperandrogenism), adipose tissue (vitamin D receptor expression, volumetric dilution), and other components of metabolic syndrome to determine how this vitamin’s status influences the renin-angiotensin system, apoptosis, and cardiovascular risk.
“There is also plenty of research going on surrounding metabolic liver disease, which has a lot to do with the microbiota. So, they’re studying the relationship between vitamin D and dysbiosis, especially regarding local immunomodulation in the gut in relation to the microbiota,” she added.
Another area of research is cancer, focusing primarily on analyzing the nutritional status of vitamin D in relation to the microbiome and how this status may affect the therapeutic effect of chemotherapy and radiation therapy. “It would be interesting to find out whether the effect of immunotherapy varies depending on the patient’s vitamin D status,” concluded Dr. Bretón.
Dr. Bretón’s lecture at the 64th Congress of the SEEN was sponsored by the Foundation for Analysis and Social Studies (FAES).
This article was translated from the Medscape Spanish edition. A version of this article appeared on Medscape.com.
Adverse events in childhood alter brain function
In a meta-analysis of 83 functional magnetic resonance imaging (fMRI) studies that included more than 5000 patients, exposure to adversity was associated with higher amygdala reactivity and lower prefrontal cortical reactivity across a range of task domains.
The altered responses were only observed in studies including adult participants and were clearest in participants who had been exposed to severe threat and trauma. Children and adolescents did not show significant adversity-related differences in brain function.
“By integrating the results from 83 previous brain imaging studies, we were able to provide what is arguably the clearest evidence to date that adults who have been exposed to early life trauma have different brain responses to psychological challenges,” senior author Marco Leyton, PhD, professor of psychiatry and director of the Temperament Adversity Biology Lab at McGill University in Montreal, Quebec, Canada, said in a press release. “This includes exaggerated responses in a region that processes emotionally intense information (the amygdala) and reduced responses in a region that helps people regulate emotions and associated behaviors (the frontal cortex).”
The findings were published in JAMA Network Open.
Changes in Reactivity
“One big issue we have in psychology, and especially in neuroscience, is that single-study results are often not reproducible,” lead author Niki Hosseini-Kamkar, PhD, neuroimaging research associate at Atlas Institute for Veterans and Families at Royal Ottawa Hospital, said in an interview.
“It was very important to me to use a meta-analysis to get an overall picture of what brain regions are consistently reported across all these different studies. That is what we did here,” she added. Dr. Hosseini-Kamkar conducted this analysis while she was a postdoctoral research fellow at McGill University in Montreal.
She and her group examined adversity exposure and brain function in the following four domains of task-based fMRI: emotion processing, memory processing, inhibitory control, and reward processing. Their study included 5242 participants. The researchers used multilevel kernel density analyses (MKDA) to analyze the data more accurately.
Adversity exposure was associated with higher amygdala reactivity (P < .001) and lower prefrontal cortical reactivity (P < .001), compared with controls with no adversity exposure.
Threat types of adversity were associated with greater blood-oxygen-level-dependent (BOLD) responses in the superior temporal gyrus and lower prefrontal cortex activity in participants exposed to threat, compared with controls.
Analysis of studies of inhibitory control tasks found greater activity in the claustrum, anterior cingulate cortex, and insula in the adversity-exposed participants, compared with controls.
In addition, studies that administered emotion processing tasks showed greater amygdala reactivity and lower prefrontal cortex (superior frontal gyrus) reactivity in the adversity exposure group, compared with controls.
“The main takeaway is that there’s an exaggerated activity in the amygdala, and diminished prefrontal cortex activity, and together, this might point to a mechanism for how a history of adversity diminishes the ability to cope with later stressors and can therefore heighten susceptibility to mental illness,” said Dr. Hosseini-Kamkar.
‘Important Next Step’
“Overall, the meta-analysis by Dr. Hosseini-Kamkar and colleagues represents an important next step in understanding associations of adversity exposure with brain function while highlighting the importance of considering the role of development,” wrote Dylan G. Gee, PhD, associate professor of psychology at Yale University in New Haven, Connecticut, and Alexis Brieant, PhD, assistant professor of research or creative works at the University of Vermont in Burlington, in an accompanying commentary.
They also applauded the authors for their use of MKDA. They noted that the technique “allows inferences about the consistency and specificity of brain activation across studies and is thought to be more robust to small sample sizes than activation likelihood estimation (ALE) meta-analysis.”
Dr. Gee and Dr. Brieant also observed that a recent ALE meta-analysis failed to find a link between adversity and brain function. “Although it is important to note that the file drawer problem — by which researchers are less likely to publish null results — presents challenges to the inferences that can be drawn in the current work, the current study may provide complementary information to prior ALE meta-analyses.”
Epigenetic Changes?
Commenting on the findings for this article, Victor Fornari, MD, director of child and adolescent psychiatry at Northwell Health in Glen Oaks, New York, said, “Historically, when someone went through a traumatic event, they were told to just get over it, because somehow trauma doesn’t have a lasting impact on the brain.” Dr. Fornari was not involved in the research.
“We have certainly learned so much more over the past decade about early adversity and that it does have a profound impact on the brain and probably even epigenetic changes in our genes,” Dr. Fornari said.
“This is a very important avenue of investigation. People are really trying to understand if there are biological markers that we can actually measure in the brain that will offer us a window to better understand the consequence of adversity, as well as possible avenues of treatment.”
No funding source for this study was reported. Dr. Leyton, Dr. Hosseini-Kamkar, and Dr. Fornari report no relevant financial relationships. Gee reports receiving grants from the National Science Foundation and National Institutes of Health outside the submitted work. Dr. Brieant reports receiving grants from the National Institute of Mental Health outside the submitted work.
A version of this article appeared on Medscape.com.
In a meta-analysis of 83 functional magnetic resonance imaging (fMRI) studies that included more than 5000 patients, exposure to adversity was associated with higher amygdala reactivity and lower prefrontal cortical reactivity across a range of task domains.
The altered responses were only observed in studies including adult participants and were clearest in participants who had been exposed to severe threat and trauma. Children and adolescents did not show significant adversity-related differences in brain function.
“By integrating the results from 83 previous brain imaging studies, we were able to provide what is arguably the clearest evidence to date that adults who have been exposed to early life trauma have different brain responses to psychological challenges,” senior author Marco Leyton, PhD, professor of psychiatry and director of the Temperament Adversity Biology Lab at McGill University in Montreal, Quebec, Canada, said in a press release. “This includes exaggerated responses in a region that processes emotionally intense information (the amygdala) and reduced responses in a region that helps people regulate emotions and associated behaviors (the frontal cortex).”
The findings were published in JAMA Network Open.
Changes in Reactivity
“One big issue we have in psychology, and especially in neuroscience, is that single-study results are often not reproducible,” lead author Niki Hosseini-Kamkar, PhD, neuroimaging research associate at Atlas Institute for Veterans and Families at Royal Ottawa Hospital, said in an interview.
“It was very important to me to use a meta-analysis to get an overall picture of what brain regions are consistently reported across all these different studies. That is what we did here,” she added. Dr. Hosseini-Kamkar conducted this analysis while she was a postdoctoral research fellow at McGill University in Montreal.
She and her group examined adversity exposure and brain function in the following four domains of task-based fMRI: emotion processing, memory processing, inhibitory control, and reward processing. Their study included 5242 participants. The researchers used multilevel kernel density analyses (MKDA) to analyze the data more accurately.
Adversity exposure was associated with higher amygdala reactivity (P < .001) and lower prefrontal cortical reactivity (P < .001), compared with controls with no adversity exposure.
Threat types of adversity were associated with greater blood-oxygen-level-dependent (BOLD) responses in the superior temporal gyrus and lower prefrontal cortex activity in participants exposed to threat, compared with controls.
Analysis of studies of inhibitory control tasks found greater activity in the claustrum, anterior cingulate cortex, and insula in the adversity-exposed participants, compared with controls.
In addition, studies that administered emotion processing tasks showed greater amygdala reactivity and lower prefrontal cortex (superior frontal gyrus) reactivity in the adversity exposure group, compared with controls.
“The main takeaway is that there’s an exaggerated activity in the amygdala, and diminished prefrontal cortex activity, and together, this might point to a mechanism for how a history of adversity diminishes the ability to cope with later stressors and can therefore heighten susceptibility to mental illness,” said Dr. Hosseini-Kamkar.
‘Important Next Step’
“Overall, the meta-analysis by Dr. Hosseini-Kamkar and colleagues represents an important next step in understanding associations of adversity exposure with brain function while highlighting the importance of considering the role of development,” wrote Dylan G. Gee, PhD, associate professor of psychology at Yale University in New Haven, Connecticut, and Alexis Brieant, PhD, assistant professor of research or creative works at the University of Vermont in Burlington, in an accompanying commentary.
They also applauded the authors for their use of MKDA. They noted that the technique “allows inferences about the consistency and specificity of brain activation across studies and is thought to be more robust to small sample sizes than activation likelihood estimation (ALE) meta-analysis.”
Dr. Gee and Dr. Brieant also observed that a recent ALE meta-analysis failed to find a link between adversity and brain function. “Although it is important to note that the file drawer problem — by which researchers are less likely to publish null results — presents challenges to the inferences that can be drawn in the current work, the current study may provide complementary information to prior ALE meta-analyses.”
Epigenetic Changes?
Commenting on the findings for this article, Victor Fornari, MD, director of child and adolescent psychiatry at Northwell Health in Glen Oaks, New York, said, “Historically, when someone went through a traumatic event, they were told to just get over it, because somehow trauma doesn’t have a lasting impact on the brain.” Dr. Fornari was not involved in the research.
“We have certainly learned so much more over the past decade about early adversity and that it does have a profound impact on the brain and probably even epigenetic changes in our genes,” Dr. Fornari said.
“This is a very important avenue of investigation. People are really trying to understand if there are biological markers that we can actually measure in the brain that will offer us a window to better understand the consequence of adversity, as well as possible avenues of treatment.”
No funding source for this study was reported. Dr. Leyton, Dr. Hosseini-Kamkar, and Dr. Fornari report no relevant financial relationships. Gee reports receiving grants from the National Science Foundation and National Institutes of Health outside the submitted work. Dr. Brieant reports receiving grants from the National Institute of Mental Health outside the submitted work.
A version of this article appeared on Medscape.com.
In a meta-analysis of 83 functional magnetic resonance imaging (fMRI) studies that included more than 5000 patients, exposure to adversity was associated with higher amygdala reactivity and lower prefrontal cortical reactivity across a range of task domains.
The altered responses were only observed in studies including adult participants and were clearest in participants who had been exposed to severe threat and trauma. Children and adolescents did not show significant adversity-related differences in brain function.
“By integrating the results from 83 previous brain imaging studies, we were able to provide what is arguably the clearest evidence to date that adults who have been exposed to early life trauma have different brain responses to psychological challenges,” senior author Marco Leyton, PhD, professor of psychiatry and director of the Temperament Adversity Biology Lab at McGill University in Montreal, Quebec, Canada, said in a press release. “This includes exaggerated responses in a region that processes emotionally intense information (the amygdala) and reduced responses in a region that helps people regulate emotions and associated behaviors (the frontal cortex).”
The findings were published in JAMA Network Open.
Changes in Reactivity
“One big issue we have in psychology, and especially in neuroscience, is that single-study results are often not reproducible,” lead author Niki Hosseini-Kamkar, PhD, neuroimaging research associate at Atlas Institute for Veterans and Families at Royal Ottawa Hospital, said in an interview.
“It was very important to me to use a meta-analysis to get an overall picture of what brain regions are consistently reported across all these different studies. That is what we did here,” she added. Dr. Hosseini-Kamkar conducted this analysis while she was a postdoctoral research fellow at McGill University in Montreal.
She and her group examined adversity exposure and brain function in the following four domains of task-based fMRI: emotion processing, memory processing, inhibitory control, and reward processing. Their study included 5242 participants. The researchers used multilevel kernel density analyses (MKDA) to analyze the data more accurately.
Adversity exposure was associated with higher amygdala reactivity (P < .001) and lower prefrontal cortical reactivity (P < .001), compared with controls with no adversity exposure.
Threat types of adversity were associated with greater blood-oxygen-level-dependent (BOLD) responses in the superior temporal gyrus and lower prefrontal cortex activity in participants exposed to threat, compared with controls.
Analysis of studies of inhibitory control tasks found greater activity in the claustrum, anterior cingulate cortex, and insula in the adversity-exposed participants, compared with controls.
In addition, studies that administered emotion processing tasks showed greater amygdala reactivity and lower prefrontal cortex (superior frontal gyrus) reactivity in the adversity exposure group, compared with controls.
“The main takeaway is that there’s an exaggerated activity in the amygdala, and diminished prefrontal cortex activity, and together, this might point to a mechanism for how a history of adversity diminishes the ability to cope with later stressors and can therefore heighten susceptibility to mental illness,” said Dr. Hosseini-Kamkar.
‘Important Next Step’
“Overall, the meta-analysis by Dr. Hosseini-Kamkar and colleagues represents an important next step in understanding associations of adversity exposure with brain function while highlighting the importance of considering the role of development,” wrote Dylan G. Gee, PhD, associate professor of psychology at Yale University in New Haven, Connecticut, and Alexis Brieant, PhD, assistant professor of research or creative works at the University of Vermont in Burlington, in an accompanying commentary.
They also applauded the authors for their use of MKDA. They noted that the technique “allows inferences about the consistency and specificity of brain activation across studies and is thought to be more robust to small sample sizes than activation likelihood estimation (ALE) meta-analysis.”
Dr. Gee and Dr. Brieant also observed that a recent ALE meta-analysis failed to find a link between adversity and brain function. “Although it is important to note that the file drawer problem — by which researchers are less likely to publish null results — presents challenges to the inferences that can be drawn in the current work, the current study may provide complementary information to prior ALE meta-analyses.”
Epigenetic Changes?
Commenting on the findings for this article, Victor Fornari, MD, director of child and adolescent psychiatry at Northwell Health in Glen Oaks, New York, said, “Historically, when someone went through a traumatic event, they were told to just get over it, because somehow trauma doesn’t have a lasting impact on the brain.” Dr. Fornari was not involved in the research.
“We have certainly learned so much more over the past decade about early adversity and that it does have a profound impact on the brain and probably even epigenetic changes in our genes,” Dr. Fornari said.
“This is a very important avenue of investigation. People are really trying to understand if there are biological markers that we can actually measure in the brain that will offer us a window to better understand the consequence of adversity, as well as possible avenues of treatment.”
No funding source for this study was reported. Dr. Leyton, Dr. Hosseini-Kamkar, and Dr. Fornari report no relevant financial relationships. Gee reports receiving grants from the National Science Foundation and National Institutes of Health outside the submitted work. Dr. Brieant reports receiving grants from the National Institute of Mental Health outside the submitted work.
A version of this article appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Can younger postmenopausal women with low-risk BC skip radiation?
SAN ANTONIO — Women 65-70 years old are often offered the option of skipping radiation after lumpectomy for hormone receptor–positive early-stage breast cancer and moving straight to endocrine therapy.
The recurrence rate with and without radiation is well known so women can be counseled accurately about their options.
Omitting radiation for older postmenopausal women is “very reasonable to offer so long as they are willing to accept the risk,” said Reshma Jagsi, MD, chief of radiation oncology at Emory University, Atlanta.
The option, however, isn’t generally offered to postmenopausal women younger than 65 years old because their risk from skipping adjuvant radiation isn’t known, but that’s about to change.
Several teams are investigating the issue, including one led by Dr. Jagsi, who presented her and her colleagues’ latest results at the San Antonio Breast Cancer Symposium.
In the single-arm IDEA [Individualized Decisions for Endocrine therapy Alone] study, 200 women 50-69 years old with pT1N0 unifocal hormone receptor–positive, HER2-negative invasive breast cancer agreed to the approach when it was offered to them following lumpectomy with sentinel lymph node biopsy. The mean tumor size was 10 mm with margins of at least 2 mm.
The women were at low risk for recurrence, with recurrence risk scores no higher than 18 points on the Oncotype DX 21-gene assay; the mean score was 11 points.
Radiation would have been the usual next step after lumpectomy, but instead the patients went directly to endocrine therapy for 5 years, with adherence above 80%.
At 5 years, the results are “promising,” Dr. Jagsi said at the meeting. Overall and breast cancer–specific survival were both 100%, and the recurrence rate was just 1%, with two recurrences before the 5-year point. The women were a mean of 62 years old.
A similar single-arm trial, LUMINA, recently reported comparable results.
Dr. Jagsi called the findings of the studies “reassuring,” but cautioned that it will be a while before younger postmenopausal women can be offered radiation-free treatment like their older peers.
Even though the results suggest “that this might well be a really good idea,” longer follow-up and randomized data are needed “before we change the standard of care,” she said.
Of concern, for instance, is that there were six additional recurrences in the IDEA study past the 5-year mark, for a total of three recurrences among the 60 women 50-59 years old (5%) and five among the 140 women 60-69 years old (3.6%). Five of the recurrent cases were adherent to endocrine therapy.
Also, so few women in IDEA have passed the 5-year mark that “we can’t [conclude] anything” about long-term relapse risks, Dr. Jagsi said. Besides that, skipping radiation for such women at this point is “not reasonable,” Dr. Jagsi added.
Carlos Arteaga, MD, director of the UT Southwestern Simmons Cancer Center, Dallas, agreed.
“I think we have to wait. We have randomized studies that will test this in a formal way. Be that as it may, this provides the basis for a conversation physicians can have with patients because this could be an option” at some point, said Dr. Arteaga, who moderated Dr. Jagsi’s presentation.
“This is a big step in trying not to do too much for patients who don’t need it,” Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, said in an interview.
IDEA was published in the Journal of Clinical Oncology to coincide with Dr. Jagsi’s presentation.
The study was funded by the Susan G. Komen Breast Cancer Foundation and the University of Michigan Rogel Cancer Center. Dr. Jagsi has stock in Equity Quotient and research support form Genentech. Disclosure information for Arteaga was not available. Dr. Kaklamani has extensive industry ties, including being a speaker for Pfizer, Genentech, Novartis, and AstraZeneca.
SAN ANTONIO — Women 65-70 years old are often offered the option of skipping radiation after lumpectomy for hormone receptor–positive early-stage breast cancer and moving straight to endocrine therapy.
The recurrence rate with and without radiation is well known so women can be counseled accurately about their options.
Omitting radiation for older postmenopausal women is “very reasonable to offer so long as they are willing to accept the risk,” said Reshma Jagsi, MD, chief of radiation oncology at Emory University, Atlanta.
The option, however, isn’t generally offered to postmenopausal women younger than 65 years old because their risk from skipping adjuvant radiation isn’t known, but that’s about to change.
Several teams are investigating the issue, including one led by Dr. Jagsi, who presented her and her colleagues’ latest results at the San Antonio Breast Cancer Symposium.
In the single-arm IDEA [Individualized Decisions for Endocrine therapy Alone] study, 200 women 50-69 years old with pT1N0 unifocal hormone receptor–positive, HER2-negative invasive breast cancer agreed to the approach when it was offered to them following lumpectomy with sentinel lymph node biopsy. The mean tumor size was 10 mm with margins of at least 2 mm.
The women were at low risk for recurrence, with recurrence risk scores no higher than 18 points on the Oncotype DX 21-gene assay; the mean score was 11 points.
Radiation would have been the usual next step after lumpectomy, but instead the patients went directly to endocrine therapy for 5 years, with adherence above 80%.
At 5 years, the results are “promising,” Dr. Jagsi said at the meeting. Overall and breast cancer–specific survival were both 100%, and the recurrence rate was just 1%, with two recurrences before the 5-year point. The women were a mean of 62 years old.
A similar single-arm trial, LUMINA, recently reported comparable results.
Dr. Jagsi called the findings of the studies “reassuring,” but cautioned that it will be a while before younger postmenopausal women can be offered radiation-free treatment like their older peers.
Even though the results suggest “that this might well be a really good idea,” longer follow-up and randomized data are needed “before we change the standard of care,” she said.
Of concern, for instance, is that there were six additional recurrences in the IDEA study past the 5-year mark, for a total of three recurrences among the 60 women 50-59 years old (5%) and five among the 140 women 60-69 years old (3.6%). Five of the recurrent cases were adherent to endocrine therapy.
Also, so few women in IDEA have passed the 5-year mark that “we can’t [conclude] anything” about long-term relapse risks, Dr. Jagsi said. Besides that, skipping radiation for such women at this point is “not reasonable,” Dr. Jagsi added.
Carlos Arteaga, MD, director of the UT Southwestern Simmons Cancer Center, Dallas, agreed.
“I think we have to wait. We have randomized studies that will test this in a formal way. Be that as it may, this provides the basis for a conversation physicians can have with patients because this could be an option” at some point, said Dr. Arteaga, who moderated Dr. Jagsi’s presentation.
“This is a big step in trying not to do too much for patients who don’t need it,” Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, said in an interview.
IDEA was published in the Journal of Clinical Oncology to coincide with Dr. Jagsi’s presentation.
The study was funded by the Susan G. Komen Breast Cancer Foundation and the University of Michigan Rogel Cancer Center. Dr. Jagsi has stock in Equity Quotient and research support form Genentech. Disclosure information for Arteaga was not available. Dr. Kaklamani has extensive industry ties, including being a speaker for Pfizer, Genentech, Novartis, and AstraZeneca.
SAN ANTONIO — Women 65-70 years old are often offered the option of skipping radiation after lumpectomy for hormone receptor–positive early-stage breast cancer and moving straight to endocrine therapy.
The recurrence rate with and without radiation is well known so women can be counseled accurately about their options.
Omitting radiation for older postmenopausal women is “very reasonable to offer so long as they are willing to accept the risk,” said Reshma Jagsi, MD, chief of radiation oncology at Emory University, Atlanta.
The option, however, isn’t generally offered to postmenopausal women younger than 65 years old because their risk from skipping adjuvant radiation isn’t known, but that’s about to change.
Several teams are investigating the issue, including one led by Dr. Jagsi, who presented her and her colleagues’ latest results at the San Antonio Breast Cancer Symposium.
In the single-arm IDEA [Individualized Decisions for Endocrine therapy Alone] study, 200 women 50-69 years old with pT1N0 unifocal hormone receptor–positive, HER2-negative invasive breast cancer agreed to the approach when it was offered to them following lumpectomy with sentinel lymph node biopsy. The mean tumor size was 10 mm with margins of at least 2 mm.
The women were at low risk for recurrence, with recurrence risk scores no higher than 18 points on the Oncotype DX 21-gene assay; the mean score was 11 points.
Radiation would have been the usual next step after lumpectomy, but instead the patients went directly to endocrine therapy for 5 years, with adherence above 80%.
At 5 years, the results are “promising,” Dr. Jagsi said at the meeting. Overall and breast cancer–specific survival were both 100%, and the recurrence rate was just 1%, with two recurrences before the 5-year point. The women were a mean of 62 years old.
A similar single-arm trial, LUMINA, recently reported comparable results.
Dr. Jagsi called the findings of the studies “reassuring,” but cautioned that it will be a while before younger postmenopausal women can be offered radiation-free treatment like their older peers.
Even though the results suggest “that this might well be a really good idea,” longer follow-up and randomized data are needed “before we change the standard of care,” she said.
Of concern, for instance, is that there were six additional recurrences in the IDEA study past the 5-year mark, for a total of three recurrences among the 60 women 50-59 years old (5%) and five among the 140 women 60-69 years old (3.6%). Five of the recurrent cases were adherent to endocrine therapy.
Also, so few women in IDEA have passed the 5-year mark that “we can’t [conclude] anything” about long-term relapse risks, Dr. Jagsi said. Besides that, skipping radiation for such women at this point is “not reasonable,” Dr. Jagsi added.
Carlos Arteaga, MD, director of the UT Southwestern Simmons Cancer Center, Dallas, agreed.
“I think we have to wait. We have randomized studies that will test this in a formal way. Be that as it may, this provides the basis for a conversation physicians can have with patients because this could be an option” at some point, said Dr. Arteaga, who moderated Dr. Jagsi’s presentation.
“This is a big step in trying not to do too much for patients who don’t need it,” Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, said in an interview.
IDEA was published in the Journal of Clinical Oncology to coincide with Dr. Jagsi’s presentation.
The study was funded by the Susan G. Komen Breast Cancer Foundation and the University of Michigan Rogel Cancer Center. Dr. Jagsi has stock in Equity Quotient and research support form Genentech. Disclosure information for Arteaga was not available. Dr. Kaklamani has extensive industry ties, including being a speaker for Pfizer, Genentech, Novartis, and AstraZeneca.
FROM SABCS 2023