Conference Coverage

SAN DIEGO — Transmasculine patients with acne require unique care that not only is sensitive but also reflects an understanding about factors that can affect their skin such as hormone therapy, a dermatologist told colleagues in a session at the American Academy of Dermatology annual meeting.

In these patients, treatment of acne is crucial, said Howa Yeung, MD, MSc, assistant professor of dermatology, Emory University, Atlanta. “These are patients who are suffering and reporting that they’re having mental health impacts” related to acne.

In transmasculine patients — those who were biologically female at birth but identify as masculine — testosterone therapy greatly boosts the risk for acne, even in adults who are long past adolescence, Dr. Yeung said. Data suggest that acne appears within the first 6 months after testosterone therapy begins, he said, “and the maximal and complete effect occurs within 1-2 years.”

A 2021 study tracked 988 transgender patients receiving testosterone at Fenway Health in Boston and found that 31% had a diagnosis of acne, up from 6.3% prior to taking hormones. And 2 years following the start of therapy, 25.1% had acne, with cases especially common among those aged 18-20.75 years (29.6%). Even among those aged 28.25-66.5 years, 17.1% had acne.

Transmasculine patients may develop acne in areas across the body “in places that you normally won’t see by just looking at the patient,” Dr. Yeung said. Excoriation in addition to comedones, papules, pustules, and nodules can be common, he added.

Dr. Yeung highlighted a 2019 study of transgender men that linked higher levels of acne to higher levels of serum testosterone, higher body mass index, and current smoking. And in a 2014 study, 6% of 50 transmasculine patients had moderate to severe acne after an average of 10 years on testosterone therapy.

A 2020 study of 696 transgender adults surveyed in California and Georgia found that 14% of transmasculine patients had moderate to severe acne — two thirds attributed it to hormone therapy — vs 1% of transfeminine patients, said Dr. Yeung, the lead author of the study. However, transmasculine patients were less likely to have seen a dermatologist.

Dr. Yeung also highlighted a 2021 study he coauthored that linked current moderate to severe acne in transmasculine patients taking testosterone to higher levels of depression and anxiety vs counterparts who had never had those forms of acne.

Another factor affecting acne in transmasculine patients is the use of chest binders to reduce breast size. “Wearing a chest binder is really helpful for a lot of our patients and is associated with improved self-esteem, mood, mental health, and safety in public,” Dr. Yeung said. However, the binders can contribute to skin problems.

Dr. Yeung said he and his colleagues emphasize the importance of breathable material in binders and suggest to patients that they not wear them when they’re in “safe spaces.”

Isotretinoin, Contraception Considerations

As for treatment of acne in transgender patients, Dr. Yeung cautioned colleagues to not automatically reject isotretinoin as an option for transgender patients who have a history of depression. Dermatologists may be tempted to avoid the drug in these patients because of its link to suicide, he said. (This apparent association has long been debated.) But, Dr. Yeung said, it’s important to consider that many of these patients suffered from anxiety and depression because of the lack of access to proper gender-reassignment treatment.

When using isotretinoin, he emphasized, it’s crucial to consider whether transmasculine patients could become pregnant while on this therapy. Consider whether the patient has the organs needed to become pregnant and ask questions about the potential that they could be impregnated.

“Remember that sexual behavior is different from gender identity,” Dr. Yeung said. A transmasculine person with a uterus and vagina, for example, may still have vaginal intercourse with males and potentially become pregnant. “So, we need to assess what kind of sexual behavior our patients are taking part in.”

Contraceptives such as intrauterine devices, implants, and injectable options may be helpful for transmasculine patients because they can reduce menstrual symptoms like spotting that can be distressing to them, he said. By helping a patient take a contraceptive, “you may actually be helping with their gender dysphoria and helping them get on isotretinoin.”

Dr. Yeung disclosed fees from JAMA and American Academy of Dermatology; grants/research funding from the American Acne & Rosacea Society, Dermatology Foundation, Department of Veterans Affairs, National Eczema Association, and National Institutes of Health; and speaker/faculty education honoraria from Dermatology Digest.

A version of this article appeared on Medscape.com.

SAN DIEGO — Transmasculine patients with acne require unique care that not only is sensitive but also reflects an understanding about factors that can affect their skin such as hormone therapy, a dermatologist told colleagues in a session at the American Academy of Dermatology annual meeting.

In these patients, treatment of acne is crucial, said Howa Yeung, MD, MSc, assistant professor of dermatology, Emory University, Atlanta. “These are patients who are suffering and reporting that they’re having mental health impacts” related to acne.

In transmasculine patients — those who were biologically female at birth but identify as masculine — testosterone therapy greatly boosts the risk for acne, even in adults who are long past adolescence, Dr. Yeung said. Data suggest that acne appears within the first 6 months after testosterone therapy begins, he said, “and the maximal and complete effect occurs within 1-2 years.”

A 2021 study tracked 988 transgender patients receiving testosterone at Fenway Health in Boston and found that 31% had a diagnosis of acne, up from 6.3% prior to taking hormones. And 2 years following the start of therapy, 25.1% had acne, with cases especially common among those aged 18-20.75 years (29.6%). Even among those aged 28.25-66.5 years, 17.1% had acne.

Transmasculine patients may develop acne in areas across the body “in places that you normally won’t see by just looking at the patient,” Dr. Yeung said. Excoriation in addition to comedones, papules, pustules, and nodules can be common, he added.

Dr. Yeung highlighted a 2019 study of transgender men that linked higher levels of acne to higher levels of serum testosterone, higher body mass index, and current smoking. And in a 2014 study, 6% of 50 transmasculine patients had moderate to severe acne after an average of 10 years on testosterone therapy.

A 2020 study of 696 transgender adults surveyed in California and Georgia found that 14% of transmasculine patients had moderate to severe acne — two thirds attributed it to hormone therapy — vs 1% of transfeminine patients, said Dr. Yeung, the lead author of the study. However, transmasculine patients were less likely to have seen a dermatologist.

Dr. Yeung also highlighted a 2021 study he coauthored that linked current moderate to severe acne in transmasculine patients taking testosterone to higher levels of depression and anxiety vs counterparts who had never had those forms of acne.

Another factor affecting acne in transmasculine patients is the use of chest binders to reduce breast size. “Wearing a chest binder is really helpful for a lot of our patients and is associated with improved self-esteem, mood, mental health, and safety in public,” Dr. Yeung said. However, the binders can contribute to skin problems.

Dr. Yeung said he and his colleagues emphasize the importance of breathable material in binders and suggest to patients that they not wear them when they’re in “safe spaces.”

Isotretinoin, Contraception Considerations

As for treatment of acne in transgender patients, Dr. Yeung cautioned colleagues to not automatically reject isotretinoin as an option for transgender patients who have a history of depression. Dermatologists may be tempted to avoid the drug in these patients because of its link to suicide, he said. (This apparent association has long been debated.) But, Dr. Yeung said, it’s important to consider that many of these patients suffered from anxiety and depression because of the lack of access to proper gender-reassignment treatment.

When using isotretinoin, he emphasized, it’s crucial to consider whether transmasculine patients could become pregnant while on this therapy. Consider whether the patient has the organs needed to become pregnant and ask questions about the potential that they could be impregnated.

“Remember that sexual behavior is different from gender identity,” Dr. Yeung said. A transmasculine person with a uterus and vagina, for example, may still have vaginal intercourse with males and potentially become pregnant. “So, we need to assess what kind of sexual behavior our patients are taking part in.”

Contraceptives such as intrauterine devices, implants, and injectable options may be helpful for transmasculine patients because they can reduce menstrual symptoms like spotting that can be distressing to them, he said. By helping a patient take a contraceptive, “you may actually be helping with their gender dysphoria and helping them get on isotretinoin.”

Dr. Yeung disclosed fees from JAMA and American Academy of Dermatology; grants/research funding from the American Acne & Rosacea Society, Dermatology Foundation, Department of Veterans Affairs, National Eczema Association, and National Institutes of Health; and speaker/faculty education honoraria from Dermatology Digest.

A version of this article appeared on Medscape.com.

SAN DIEGO — Transmasculine patients with acne require unique care that not only is sensitive but also reflects an understanding about factors that can affect their skin such as hormone therapy, a dermatologist told colleagues in a session at the American Academy of Dermatology annual meeting.

In these patients, treatment of acne is crucial, said Howa Yeung, MD, MSc, assistant professor of dermatology, Emory University, Atlanta. “These are patients who are suffering and reporting that they’re having mental health impacts” related to acne.

In transmasculine patients — those who were biologically female at birth but identify as masculine — testosterone therapy greatly boosts the risk for acne, even in adults who are long past adolescence, Dr. Yeung said. Data suggest that acne appears within the first 6 months after testosterone therapy begins, he said, “and the maximal and complete effect occurs within 1-2 years.”

A 2021 study tracked 988 transgender patients receiving testosterone at Fenway Health in Boston and found that 31% had a diagnosis of acne, up from 6.3% prior to taking hormones. And 2 years following the start of therapy, 25.1% had acne, with cases especially common among those aged 18-20.75 years (29.6%). Even among those aged 28.25-66.5 years, 17.1% had acne.

Transmasculine patients may develop acne in areas across the body “in places that you normally won’t see by just looking at the patient,” Dr. Yeung said. Excoriation in addition to comedones, papules, pustules, and nodules can be common, he added.

Dr. Yeung highlighted a 2019 study of transgender men that linked higher levels of acne to higher levels of serum testosterone, higher body mass index, and current smoking. And in a 2014 study, 6% of 50 transmasculine patients had moderate to severe acne after an average of 10 years on testosterone therapy.

A 2020 study of 696 transgender adults surveyed in California and Georgia found that 14% of transmasculine patients had moderate to severe acne — two thirds attributed it to hormone therapy — vs 1% of transfeminine patients, said Dr. Yeung, the lead author of the study. However, transmasculine patients were less likely to have seen a dermatologist.

Dr. Yeung also highlighted a 2021 study he coauthored that linked current moderate to severe acne in transmasculine patients taking testosterone to higher levels of depression and anxiety vs counterparts who had never had those forms of acne.

Another factor affecting acne in transmasculine patients is the use of chest binders to reduce breast size. “Wearing a chest binder is really helpful for a lot of our patients and is associated with improved self-esteem, mood, mental health, and safety in public,” Dr. Yeung said. However, the binders can contribute to skin problems.

Dr. Yeung said he and his colleagues emphasize the importance of breathable material in binders and suggest to patients that they not wear them when they’re in “safe spaces.”

Isotretinoin, Contraception Considerations

As for treatment of acne in transgender patients, Dr. Yeung cautioned colleagues to not automatically reject isotretinoin as an option for transgender patients who have a history of depression. Dermatologists may be tempted to avoid the drug in these patients because of its link to suicide, he said. (This apparent association has long been debated.) But, Dr. Yeung said, it’s important to consider that many of these patients suffered from anxiety and depression because of the lack of access to proper gender-reassignment treatment.

When using isotretinoin, he emphasized, it’s crucial to consider whether transmasculine patients could become pregnant while on this therapy. Consider whether the patient has the organs needed to become pregnant and ask questions about the potential that they could be impregnated.

“Remember that sexual behavior is different from gender identity,” Dr. Yeung said. A transmasculine person with a uterus and vagina, for example, may still have vaginal intercourse with males and potentially become pregnant. “So, we need to assess what kind of sexual behavior our patients are taking part in.”

Contraceptives such as intrauterine devices, implants, and injectable options may be helpful for transmasculine patients because they can reduce menstrual symptoms like spotting that can be distressing to them, he said. By helping a patient take a contraceptive, “you may actually be helping with their gender dysphoria and helping them get on isotretinoin.”

Dr. Yeung disclosed fees from JAMA and American Academy of Dermatology; grants/research funding from the American Acne & Rosacea Society, Dermatology Foundation, Department of Veterans Affairs, National Eczema Association, and National Institutes of Health; and speaker/faculty education honoraria from Dermatology Digest.

A version of this article appeared on Medscape.com.

SAN DIEGO — After 24 weeks of treatment with subcutaneously administered sonelokimab 120 mg, about 43% of patients with moderate to severe hidradenitis suppurativa (HS) achieved a Hidradenitis Suppurativa Clinical Response (HiSCR75), defined as at least a 75% reduction in total abscess and inflammatory nodule (AN) count with no increase in abscess or draining tunnel count relative to baseline, results from a randomized clinical trial showed.

Sonelokimab is a novel humanized nanobody that selectively binds to interleukin (IL)-17A and IL-17F, presenting author Brian Kirby, MD, a dermatologist at St. Vincent’s Private Hospital, Dublin, Ireland, said during a late-breaking abstract session at the annual meeting of the American Academy of Dermatology. Sonelokimab is smaller than traditional monoclonal antibodies, he said, “which means it may be able to penetrate tissues better and stay there longer.” It is being developed by MoonLake Immunotherapeutics, based in Zug, Switzerland

Ted Bosworth/MDedge News

According to a press release from the company, nanobodies represent a new generation of targeted therapies derived from antibodies. They consist of one or more domains based on the small antigen-binding variable regions of heavy-chain-only antibodies.

In a phase 2 study known as the MIRA trial, researchers recruited 234 patients with moderate to severe HS to evaluate two different doses of sonelokimab (120 mg and 240 mg every 2 weeks) with a placebo control arm and adalimumab as an active reference arm. The primary endpoint of was the percentage of participants who achieved a HiSCR75. The study population included adults with Hurley Stage II or III HS who had HS lesions in 2 or more anatomical areas and a total abscess and inflammatory nodule (AN) count of 5 or more lesions; and had been treated with 2 or fewer biologics.

Dr. Kirby reported results from 67 patients in the sonelokimab 120 mg arm, 66 in the sonelokimab 240 mg arm, and 39 in the placebo arm. “It’s worth noting that the baseline AN count ranged between 12 and nearly 15, the mean draining tunnel count ranged between 2.9 and 3.7, and between 7% and 13% of patients were on concomitant antibiotics,” he said.

At 24 weeks, 43.3% of patients in the sonelokimab 120 mg arm achieved a HiSCR 75, compared with 34.8% of those in the sonelokimab 240 mg arm and 14.7% of those in the placebo arm, he reported. Meanwhile, 65.7% of patients in the sonelokimab 120 mg arm achieved an HiSCR 75, compared with 53% of those in the sonelokimab 240 mg arm and 27.9% of those in the placebo arm. Discontinuation rates were low and similar between treatment arms, with fewer than 10% of patients failing to complete week 24 of treatment.

In other findings, 69% of patients in the 120 mg arm achieved a HiSCR 50 at week 24 compared with 60.3% in the 240 mg arm; 56.9% in the 120 mg arm achieved a HiSCR 75 compared with 37.9% in the 240 mg arm; and 37.9% in the 120 mg arm achieved a HiSCR 75 compared with 27.6% in the 240 mg arm.

In addition, complete inflammatory remission as defined by the International HS Severity Score System (IHS4-100) continued to increase to week 24, with 24.1% of patients in the 120 mg arm achieving complete remission, compared with 15.5% of those in the 240 mg arm. Meaningful improvements in quality of life, skin pain, and HS symptoms reported by patients treated with sonelokimab were maintained or increased to week 24. Specifically, more than 60% of patients had a meaningful clinical improvement in their Dermatology Life Quality Index, over 45% had a minimum of a 30% increase in the Numerical Rating Scale **30, and more than 41% of patients reported absent or minimal symptoms on the Patient’s Global Impression of their Disease Severity, “which is a high bar to achieve in HS,” Dr. Kirby said.
 

No Serious Safety Signals Noted

There were no unexpected safety signals to week 24. The incidence of treatment-related adverse events was low, and there were no cases of inflammatory bowel disease. There were no serious infections, no major adverse cardiovascular event (MACE) reports, and no significant abnormalities on liver function tests. “There were also no safety signals on suicidal behavior, attempted suicides, or completed suicides,” he said.

“As you would expect with in IL-17 inhibitor, there was a signal for candidiasis, but all cases were judged to be mild or moderate, and no cases led to discontinuation of treatment from the trial because of candidal infection.”

Based on these data, Dr. Kirby said that larger and longer-term phase 3 trials are planned to further examine the safety and efficacy of sonelokimab at the 120 mg dose for the treatment of moderate-to-severe HS.

One of the session moderators, Joel M. Gelfand, MD, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, asked Dr. Kirby why he thought the lower dose resulted in generally better outcomes compared with the higher dose.

“There were no statistically significant differences between the two groups,” Dr. Kirby responded. “The 120 mg dose we know is highly effective in psoriasis, so there may be a ceiling effect. This may also be due to population variability, but the bottom line is that the 120 mg dose performs extremely well.”

Dr. Kirby disclosed that he has received research support from/has been a principal investigator for several pharmaceutical companies, including MoonLake Immunotherapeutics. Dr. Gelfand reported that he has been a consultant to and/or a member of the data safety monitoring board member for several pharmaceutical companies, including MoonLake.

SAN DIEGO — After 24 weeks of treatment with subcutaneously administered sonelokimab 120 mg, about 43% of patients with moderate to severe hidradenitis suppurativa (HS) achieved a Hidradenitis Suppurativa Clinical Response (HiSCR75), defined as at least a 75% reduction in total abscess and inflammatory nodule (AN) count with no increase in abscess or draining tunnel count relative to baseline, results from a randomized clinical trial showed.

Sonelokimab is a novel humanized nanobody that selectively binds to interleukin (IL)-17A and IL-17F, presenting author Brian Kirby, MD, a dermatologist at St. Vincent’s Private Hospital, Dublin, Ireland, said during a late-breaking abstract session at the annual meeting of the American Academy of Dermatology. Sonelokimab is smaller than traditional monoclonal antibodies, he said, “which means it may be able to penetrate tissues better and stay there longer.” It is being developed by MoonLake Immunotherapeutics, based in Zug, Switzerland

Ted Bosworth/MDedge News

According to a press release from the company, nanobodies represent a new generation of targeted therapies derived from antibodies. They consist of one or more domains based on the small antigen-binding variable regions of heavy-chain-only antibodies.

In a phase 2 study known as the MIRA trial, researchers recruited 234 patients with moderate to severe HS to evaluate two different doses of sonelokimab (120 mg and 240 mg every 2 weeks) with a placebo control arm and adalimumab as an active reference arm. The primary endpoint of was the percentage of participants who achieved a HiSCR75. The study population included adults with Hurley Stage II or III HS who had HS lesions in 2 or more anatomical areas and a total abscess and inflammatory nodule (AN) count of 5 or more lesions; and had been treated with 2 or fewer biologics.

Dr. Kirby reported results from 67 patients in the sonelokimab 120 mg arm, 66 in the sonelokimab 240 mg arm, and 39 in the placebo arm. “It’s worth noting that the baseline AN count ranged between 12 and nearly 15, the mean draining tunnel count ranged between 2.9 and 3.7, and between 7% and 13% of patients were on concomitant antibiotics,” he said.

At 24 weeks, 43.3% of patients in the sonelokimab 120 mg arm achieved a HiSCR 75, compared with 34.8% of those in the sonelokimab 240 mg arm and 14.7% of those in the placebo arm, he reported. Meanwhile, 65.7% of patients in the sonelokimab 120 mg arm achieved an HiSCR 75, compared with 53% of those in the sonelokimab 240 mg arm and 27.9% of those in the placebo arm. Discontinuation rates were low and similar between treatment arms, with fewer than 10% of patients failing to complete week 24 of treatment.

In other findings, 69% of patients in the 120 mg arm achieved a HiSCR 50 at week 24 compared with 60.3% in the 240 mg arm; 56.9% in the 120 mg arm achieved a HiSCR 75 compared with 37.9% in the 240 mg arm; and 37.9% in the 120 mg arm achieved a HiSCR 75 compared with 27.6% in the 240 mg arm.

In addition, complete inflammatory remission as defined by the International HS Severity Score System (IHS4-100) continued to increase to week 24, with 24.1% of patients in the 120 mg arm achieving complete remission, compared with 15.5% of those in the 240 mg arm. Meaningful improvements in quality of life, skin pain, and HS symptoms reported by patients treated with sonelokimab were maintained or increased to week 24. Specifically, more than 60% of patients had a meaningful clinical improvement in their Dermatology Life Quality Index, over 45% had a minimum of a 30% increase in the Numerical Rating Scale **30, and more than 41% of patients reported absent or minimal symptoms on the Patient’s Global Impression of their Disease Severity, “which is a high bar to achieve in HS,” Dr. Kirby said.
 

No Serious Safety Signals Noted

There were no unexpected safety signals to week 24. The incidence of treatment-related adverse events was low, and there were no cases of inflammatory bowel disease. There were no serious infections, no major adverse cardiovascular event (MACE) reports, and no significant abnormalities on liver function tests. “There were also no safety signals on suicidal behavior, attempted suicides, or completed suicides,” he said.

“As you would expect with in IL-17 inhibitor, there was a signal for candidiasis, but all cases were judged to be mild or moderate, and no cases led to discontinuation of treatment from the trial because of candidal infection.”

Based on these data, Dr. Kirby said that larger and longer-term phase 3 trials are planned to further examine the safety and efficacy of sonelokimab at the 120 mg dose for the treatment of moderate-to-severe HS.

One of the session moderators, Joel M. Gelfand, MD, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, asked Dr. Kirby why he thought the lower dose resulted in generally better outcomes compared with the higher dose.

“There were no statistically significant differences between the two groups,” Dr. Kirby responded. “The 120 mg dose we know is highly effective in psoriasis, so there may be a ceiling effect. This may also be due to population variability, but the bottom line is that the 120 mg dose performs extremely well.”

Dr. Kirby disclosed that he has received research support from/has been a principal investigator for several pharmaceutical companies, including MoonLake Immunotherapeutics. Dr. Gelfand reported that he has been a consultant to and/or a member of the data safety monitoring board member for several pharmaceutical companies, including MoonLake.

SAN DIEGO — After 24 weeks of treatment with subcutaneously administered sonelokimab 120 mg, about 43% of patients with moderate to severe hidradenitis suppurativa (HS) achieved a Hidradenitis Suppurativa Clinical Response (HiSCR75), defined as at least a 75% reduction in total abscess and inflammatory nodule (AN) count with no increase in abscess or draining tunnel count relative to baseline, results from a randomized clinical trial showed.

Sonelokimab is a novel humanized nanobody that selectively binds to interleukin (IL)-17A and IL-17F, presenting author Brian Kirby, MD, a dermatologist at St. Vincent’s Private Hospital, Dublin, Ireland, said during a late-breaking abstract session at the annual meeting of the American Academy of Dermatology. Sonelokimab is smaller than traditional monoclonal antibodies, he said, “which means it may be able to penetrate tissues better and stay there longer.” It is being developed by MoonLake Immunotherapeutics, based in Zug, Switzerland

Ted Bosworth/MDedge News

According to a press release from the company, nanobodies represent a new generation of targeted therapies derived from antibodies. They consist of one or more domains based on the small antigen-binding variable regions of heavy-chain-only antibodies.

In a phase 2 study known as the MIRA trial, researchers recruited 234 patients with moderate to severe HS to evaluate two different doses of sonelokimab (120 mg and 240 mg every 2 weeks) with a placebo control arm and adalimumab as an active reference arm. The primary endpoint of was the percentage of participants who achieved a HiSCR75. The study population included adults with Hurley Stage II or III HS who had HS lesions in 2 or more anatomical areas and a total abscess and inflammatory nodule (AN) count of 5 or more lesions; and had been treated with 2 or fewer biologics.

Dr. Kirby reported results from 67 patients in the sonelokimab 120 mg arm, 66 in the sonelokimab 240 mg arm, and 39 in the placebo arm. “It’s worth noting that the baseline AN count ranged between 12 and nearly 15, the mean draining tunnel count ranged between 2.9 and 3.7, and between 7% and 13% of patients were on concomitant antibiotics,” he said.

At 24 weeks, 43.3% of patients in the sonelokimab 120 mg arm achieved a HiSCR 75, compared with 34.8% of those in the sonelokimab 240 mg arm and 14.7% of those in the placebo arm, he reported. Meanwhile, 65.7% of patients in the sonelokimab 120 mg arm achieved an HiSCR 75, compared with 53% of those in the sonelokimab 240 mg arm and 27.9% of those in the placebo arm. Discontinuation rates were low and similar between treatment arms, with fewer than 10% of patients failing to complete week 24 of treatment.

In other findings, 69% of patients in the 120 mg arm achieved a HiSCR 50 at week 24 compared with 60.3% in the 240 mg arm; 56.9% in the 120 mg arm achieved a HiSCR 75 compared with 37.9% in the 240 mg arm; and 37.9% in the 120 mg arm achieved a HiSCR 75 compared with 27.6% in the 240 mg arm.

In addition, complete inflammatory remission as defined by the International HS Severity Score System (IHS4-100) continued to increase to week 24, with 24.1% of patients in the 120 mg arm achieving complete remission, compared with 15.5% of those in the 240 mg arm. Meaningful improvements in quality of life, skin pain, and HS symptoms reported by patients treated with sonelokimab were maintained or increased to week 24. Specifically, more than 60% of patients had a meaningful clinical improvement in their Dermatology Life Quality Index, over 45% had a minimum of a 30% increase in the Numerical Rating Scale **30, and more than 41% of patients reported absent or minimal symptoms on the Patient’s Global Impression of their Disease Severity, “which is a high bar to achieve in HS,” Dr. Kirby said.
 

No Serious Safety Signals Noted

There were no unexpected safety signals to week 24. The incidence of treatment-related adverse events was low, and there were no cases of inflammatory bowel disease. There were no serious infections, no major adverse cardiovascular event (MACE) reports, and no significant abnormalities on liver function tests. “There were also no safety signals on suicidal behavior, attempted suicides, or completed suicides,” he said.

“As you would expect with in IL-17 inhibitor, there was a signal for candidiasis, but all cases were judged to be mild or moderate, and no cases led to discontinuation of treatment from the trial because of candidal infection.”

Based on these data, Dr. Kirby said that larger and longer-term phase 3 trials are planned to further examine the safety and efficacy of sonelokimab at the 120 mg dose for the treatment of moderate-to-severe HS.

One of the session moderators, Joel M. Gelfand, MD, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, asked Dr. Kirby why he thought the lower dose resulted in generally better outcomes compared with the higher dose.

“There were no statistically significant differences between the two groups,” Dr. Kirby responded. “The 120 mg dose we know is highly effective in psoriasis, so there may be a ceiling effect. This may also be due to population variability, but the bottom line is that the 120 mg dose performs extremely well.”

Dr. Kirby disclosed that he has received research support from/has been a principal investigator for several pharmaceutical companies, including MoonLake Immunotherapeutics. Dr. Gelfand reported that he has been a consultant to and/or a member of the data safety monitoring board member for several pharmaceutical companies, including MoonLake.

For early-stage cervical cancer, non-radical surgery (simple hysterectomy or cone biopsy plus pelvic lymphadenectomy) appears safe with no lasting negative impact on quality of life, according to results of the GOG-278 trial.

In fact, patients’ quality of life was improved after surgery in both groups, and their concerns about cancer recurrence decreased, especially for those undergoing simple hysterectomy, said Allan Covens, MD, in his late-breaking abstract presentation at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer. 

“Cone biopsy patients reported less concerns about reproductive fertility after surgery and over time compared to preop assessments,” he added.

Due to screening in developed countries, a large proportion of cervical cancers are discovered at an early stage. Treatment of these cancers with radical surgery is associated with high cure rates but significant adverse effects on quality of life, said Dr. Covens, who is with the University of Toronto, Toronto, Ontario, Canada.

He and his colleagues wanted to see if non-radical surgery could be safely used instead. “Multiple case series have indicated that non-radical surgery is associated with less morbidity and improved quality of life,” he explained. “If this can be proven in a prospective evaluation, it will change future practice.”

GOG-278 was a prospective cohort study of women with stage IA1 (lymph-vascular space invasion+) and IA2-IB1 (≤ 2 cm) carcinoma of the cervix who underwent non-radical surgery (simple hysterectomy or fertility-preserving cone biopsy) and pelvic lymphadenectomy. Criteria included ≤ 10 mm stromal invasion and negative margins on the final cone biopsy.

The primary objectives were to assess changes in functional outcomes of quality of life (bladder/bowel function, sexual function, cancer worry, and reproductive concerns), using validated instruments. Findings were based on 55 patients who underwent cone biopsy and 113 who underwent simple hysterectomy.

Both simple hysterectomy and cone biopsy were associated with “small” declines in sexual function and bladder/bowel function at 4-6 weeks after surgery, but function “quickly” recovered to baseline by 6 months, Dr. Covens reported.

Twelve patients reported a diagnosis of lymphedema, with a Gynecologic Cancer Lymphedema Questionnaire score change of 4 or higher on at least two consecutive evaluations from baseline. This occurred in six cone biopsy and six simple hysterectomy patients.

In a separate presentation, Dr. Covens reported secondary oncologic outcomes from GOG-278, which suggest that non-radical surgery for early-stage cervical cancer is safe, with low perioperative morbidity, although longer follow-up is needed.

He also reported 16 pregnancies in 15 patients who had undergone cone biopsies; 12 of these were successful, and there were four early pregnancy losses.
 

‘Impressive’ Data

Study discussant Kristin Bixel, MD, with The Ohio State University, Columbus, Ohio, said the data are “impressive” and clearly show that non-radical surgery has “minimal impact on bladder/bowel function, with no long-term differences from baseline.”

She added that the incidence of lymphedema was “honestly significantly lower than what I typically counsel patients about” and wondered if the percentage of patients with lymphedema would increase over time.

Dr. Bixel particularly noted the decrease in cancer worry scores after surgery, as sometimes patients who have less radical procedures fear that this comes with an increased risk for recurrence.

The “growing body of data suggests that less radical surgery is safe and effective for early-stage low-risk cervical cancer and highlights the potential reproductive success,” she concluded.

Funding for the study was provided by grants from NRG Oncology. Dr. Covens had no disclosures. Dr. Bixel has received research funding from the Intuitive Foundation.

A version of this article appeared on Medscape.com.

For early-stage cervical cancer, non-radical surgery (simple hysterectomy or cone biopsy plus pelvic lymphadenectomy) appears safe with no lasting negative impact on quality of life, according to results of the GOG-278 trial.

In fact, patients’ quality of life was improved after surgery in both groups, and their concerns about cancer recurrence decreased, especially for those undergoing simple hysterectomy, said Allan Covens, MD, in his late-breaking abstract presentation at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer. 

“Cone biopsy patients reported less concerns about reproductive fertility after surgery and over time compared to preop assessments,” he added.

Due to screening in developed countries, a large proportion of cervical cancers are discovered at an early stage. Treatment of these cancers with radical surgery is associated with high cure rates but significant adverse effects on quality of life, said Dr. Covens, who is with the University of Toronto, Toronto, Ontario, Canada.

He and his colleagues wanted to see if non-radical surgery could be safely used instead. “Multiple case series have indicated that non-radical surgery is associated with less morbidity and improved quality of life,” he explained. “If this can be proven in a prospective evaluation, it will change future practice.”

GOG-278 was a prospective cohort study of women with stage IA1 (lymph-vascular space invasion+) and IA2-IB1 (≤ 2 cm) carcinoma of the cervix who underwent non-radical surgery (simple hysterectomy or fertility-preserving cone biopsy) and pelvic lymphadenectomy. Criteria included ≤ 10 mm stromal invasion and negative margins on the final cone biopsy.

The primary objectives were to assess changes in functional outcomes of quality of life (bladder/bowel function, sexual function, cancer worry, and reproductive concerns), using validated instruments. Findings were based on 55 patients who underwent cone biopsy and 113 who underwent simple hysterectomy.

Both simple hysterectomy and cone biopsy were associated with “small” declines in sexual function and bladder/bowel function at 4-6 weeks after surgery, but function “quickly” recovered to baseline by 6 months, Dr. Covens reported.

Twelve patients reported a diagnosis of lymphedema, with a Gynecologic Cancer Lymphedema Questionnaire score change of 4 or higher on at least two consecutive evaluations from baseline. This occurred in six cone biopsy and six simple hysterectomy patients.

In a separate presentation, Dr. Covens reported secondary oncologic outcomes from GOG-278, which suggest that non-radical surgery for early-stage cervical cancer is safe, with low perioperative morbidity, although longer follow-up is needed.

He also reported 16 pregnancies in 15 patients who had undergone cone biopsies; 12 of these were successful, and there were four early pregnancy losses.
 

‘Impressive’ Data

Study discussant Kristin Bixel, MD, with The Ohio State University, Columbus, Ohio, said the data are “impressive” and clearly show that non-radical surgery has “minimal impact on bladder/bowel function, with no long-term differences from baseline.”

She added that the incidence of lymphedema was “honestly significantly lower than what I typically counsel patients about” and wondered if the percentage of patients with lymphedema would increase over time.

Dr. Bixel particularly noted the decrease in cancer worry scores after surgery, as sometimes patients who have less radical procedures fear that this comes with an increased risk for recurrence.

The “growing body of data suggests that less radical surgery is safe and effective for early-stage low-risk cervical cancer and highlights the potential reproductive success,” she concluded.

Funding for the study was provided by grants from NRG Oncology. Dr. Covens had no disclosures. Dr. Bixel has received research funding from the Intuitive Foundation.

A version of this article appeared on Medscape.com.

For early-stage cervical cancer, non-radical surgery (simple hysterectomy or cone biopsy plus pelvic lymphadenectomy) appears safe with no lasting negative impact on quality of life, according to results of the GOG-278 trial.

In fact, patients’ quality of life was improved after surgery in both groups, and their concerns about cancer recurrence decreased, especially for those undergoing simple hysterectomy, said Allan Covens, MD, in his late-breaking abstract presentation at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer. 

“Cone biopsy patients reported less concerns about reproductive fertility after surgery and over time compared to preop assessments,” he added.

Due to screening in developed countries, a large proportion of cervical cancers are discovered at an early stage. Treatment of these cancers with radical surgery is associated with high cure rates but significant adverse effects on quality of life, said Dr. Covens, who is with the University of Toronto, Toronto, Ontario, Canada.

He and his colleagues wanted to see if non-radical surgery could be safely used instead. “Multiple case series have indicated that non-radical surgery is associated with less morbidity and improved quality of life,” he explained. “If this can be proven in a prospective evaluation, it will change future practice.”

GOG-278 was a prospective cohort study of women with stage IA1 (lymph-vascular space invasion+) and IA2-IB1 (≤ 2 cm) carcinoma of the cervix who underwent non-radical surgery (simple hysterectomy or fertility-preserving cone biopsy) and pelvic lymphadenectomy. Criteria included ≤ 10 mm stromal invasion and negative margins on the final cone biopsy.

The primary objectives were to assess changes in functional outcomes of quality of life (bladder/bowel function, sexual function, cancer worry, and reproductive concerns), using validated instruments. Findings were based on 55 patients who underwent cone biopsy and 113 who underwent simple hysterectomy.

Both simple hysterectomy and cone biopsy were associated with “small” declines in sexual function and bladder/bowel function at 4-6 weeks after surgery, but function “quickly” recovered to baseline by 6 months, Dr. Covens reported.

Twelve patients reported a diagnosis of lymphedema, with a Gynecologic Cancer Lymphedema Questionnaire score change of 4 or higher on at least two consecutive evaluations from baseline. This occurred in six cone biopsy and six simple hysterectomy patients.

In a separate presentation, Dr. Covens reported secondary oncologic outcomes from GOG-278, which suggest that non-radical surgery for early-stage cervical cancer is safe, with low perioperative morbidity, although longer follow-up is needed.

He also reported 16 pregnancies in 15 patients who had undergone cone biopsies; 12 of these were successful, and there were four early pregnancy losses.
 

‘Impressive’ Data

Study discussant Kristin Bixel, MD, with The Ohio State University, Columbus, Ohio, said the data are “impressive” and clearly show that non-radical surgery has “minimal impact on bladder/bowel function, with no long-term differences from baseline.”

She added that the incidence of lymphedema was “honestly significantly lower than what I typically counsel patients about” and wondered if the percentage of patients with lymphedema would increase over time.

Dr. Bixel particularly noted the decrease in cancer worry scores after surgery, as sometimes patients who have less radical procedures fear that this comes with an increased risk for recurrence.

The “growing body of data suggests that less radical surgery is safe and effective for early-stage low-risk cervical cancer and highlights the potential reproductive success,” she concluded.

Funding for the study was provided by grants from NRG Oncology. Dr. Covens had no disclosures. Dr. Bixel has received research funding from the Intuitive Foundation.

A version of this article appeared on Medscape.com.

Among adolescents with moderate to severe obesity, a nutritionally balanced, very low-calorie diet with the monitoring of a dietitian shows high adherence and safety, with significant weight loss over the course of a month and common, but mild side effects.

More research is needed to understand which patients are best suited for the diet; “however, given the associated rapid weight loss, the use of [very low-energy diets] should be emphasized in clinical practice guidelines for the treatment of severe obesity and obesity-related complications in adolescents, especially before pharmacological or surgical intervention,” first author Megan Gow, PhD, of Children’s Hospital Westmead Clinical School, The University of Sydney, Westmead, Australia, said in a press statement. 

The study will be presented in May at the upcoming European Congress on Obesity, in Venice, Italy.

While very low-calorie diets have been shown to promote rapid weight loss in adolescents, research is lacking on general side effects and acceptability of the regimens. Data is also lacking on important issues including the diet’s effect on growth, heart health, and psychological wellbeing. 

To investigate, Dr. Gow and colleagues conducted a subanalysis of the 52-week Fast Track to Health study evaluating the acceptability of different dietary plans for adolescents with obesity.

The analysis included 141 adolescents between the ages of 13 and 17 years with moderate to severe obesity (average body mass index, 35 kg/m²) and at least one obesity-related complication, such as high blood pressure or insulin resistance.

The participants were placed on a nutritionally balanced very low-energy diet consisting of 800 calories per day. 

The diet involved one of two regimens — either four Optifast-formulated meal replacement products per day, including shakes, soups, bars, and/or dessert, along with low carbohydrate vegetables, such as broccoli, celery, capsicum, mushrooms, and tomatoes, with one teaspoon of vegetable oil, or a regimen of three Optifast-formulated meal replacements and one meal consisting of 100-150 g lean cooked meat, low-carbohydrate vegetables, and one teaspoon of vegetable oil.

Participants, about half of whom were women, also received dietitian support at least weekly. 

After 4 weeks, most of the adolescents, ie, 134 of the 141, with an average age of 14.9 years, completed the diet, with an average weight loss of 5.5 kg or 12 pounds (P < .001).

Most patients (95%) experienced at least one side effect, and 70% reported at least 3 of the side effects, with the most common side effects including hunger, fatigue, headache, irritability, loose stools, constipation, nausea, and a lack of concentration.

Viral infections occurred in seven participants.

While most side effects occurred at the end of week 1, the development of side effects earlier, at day 3-4, was associated with higher levels of weight loss at the 4-week cut-off, which the authors noted could suggest a greater adherence to the diet at that stage.

One adverse event occurred, consisting of a single fainting episode determined to be potentially related to the dietary intervention.

In surveys, the adolescents gave the intervention an acceptability rating of 61 on a scale of 100, the score was 53 of 100 in terms of being “enjoyable to follow.”

The most-liked aspects of the intervention were losing weight (described by 34% of participants) and the prescriptive structure (listed by 28% of participants).

The least-liked aspects included the diet’s restrictive nature, described by 45% of participants, and the taste of meal replacement products, listed by 20% of participants.
 

Alternative to Weight Loss Drugs?

While weight loss drugs are transforming the obesity treatment and semaglutide is now approved for adolescents as young as age 12 years, “access to these medications is limited, and not all families want to commence on medication for their child›s obesity,” Dr. Gow said.

As an alternative, a very low-energy diet, with the interaction of a dietitian, can enable adolescents “to develop a healthier relationship with food, including encouraging the consumption of more fruits and vegetables in their diet, not only to assist in weight loss but for good health,” she said.
 

Very Low-Calorie Diet Concerns for Adolescents Addressed

Early studies suggested concerns of health effects from very low-calorie diets in adolescents, including potential cardiac effects; however, subsequent studies, including a systematic review published by Dr. Gow and her team, have shown that such results were likely the result of nutritional deficiencies in the diets, which can be overcome with careful food selection and dietary counseling.

Another key concern has been a potential effect on growth, but Dr. Gow noted that “in our short-term study we saw small increase in height (0.1 cm), and other more recent studies suggest that a short-term very low-energy diet does not impact growth.”

And in an earlier pilot study, the authors also found an association between the very low-calorie diet and an improvement in the quality of life for youth with type 2 diabetes.

A key caveat with the findings is that participants in the study all received supervision and monitoring from a trained dietitian, and Gow noted that that element is essential.

“We therefore do not recommend adolescents in the community undertake this type of diet without appropriate support,” she said.

“Close monitoring of adolescents by a health professional following a very low-energy diet is essential to ensure that the very low-energy diet is leading to holistic health benefits for the individual.”

Following the 4-week regimen, participants were randomized to transition to interventions of either continuous energy restriction or intermittent energy restriction over the 52 weeks, and further findings from the study will be presented at the obesity meeting in May.

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

Among adolescents with moderate to severe obesity, a nutritionally balanced, very low-calorie diet with the monitoring of a dietitian shows high adherence and safety, with significant weight loss over the course of a month and common, but mild side effects.

More research is needed to understand which patients are best suited for the diet; “however, given the associated rapid weight loss, the use of [very low-energy diets] should be emphasized in clinical practice guidelines for the treatment of severe obesity and obesity-related complications in adolescents, especially before pharmacological or surgical intervention,” first author Megan Gow, PhD, of Children’s Hospital Westmead Clinical School, The University of Sydney, Westmead, Australia, said in a press statement. 

The study will be presented in May at the upcoming European Congress on Obesity, in Venice, Italy.

While very low-calorie diets have been shown to promote rapid weight loss in adolescents, research is lacking on general side effects and acceptability of the regimens. Data is also lacking on important issues including the diet’s effect on growth, heart health, and psychological wellbeing. 

To investigate, Dr. Gow and colleagues conducted a subanalysis of the 52-week Fast Track to Health study evaluating the acceptability of different dietary plans for adolescents with obesity.

The analysis included 141 adolescents between the ages of 13 and 17 years with moderate to severe obesity (average body mass index, 35 kg/m²) and at least one obesity-related complication, such as high blood pressure or insulin resistance.

The participants were placed on a nutritionally balanced very low-energy diet consisting of 800 calories per day. 

The diet involved one of two regimens — either four Optifast-formulated meal replacement products per day, including shakes, soups, bars, and/or dessert, along with low carbohydrate vegetables, such as broccoli, celery, capsicum, mushrooms, and tomatoes, with one teaspoon of vegetable oil, or a regimen of three Optifast-formulated meal replacements and one meal consisting of 100-150 g lean cooked meat, low-carbohydrate vegetables, and one teaspoon of vegetable oil.

Participants, about half of whom were women, also received dietitian support at least weekly. 

After 4 weeks, most of the adolescents, ie, 134 of the 141, with an average age of 14.9 years, completed the diet, with an average weight loss of 5.5 kg or 12 pounds (P < .001).

Most patients (95%) experienced at least one side effect, and 70% reported at least 3 of the side effects, with the most common side effects including hunger, fatigue, headache, irritability, loose stools, constipation, nausea, and a lack of concentration.

Viral infections occurred in seven participants.

While most side effects occurred at the end of week 1, the development of side effects earlier, at day 3-4, was associated with higher levels of weight loss at the 4-week cut-off, which the authors noted could suggest a greater adherence to the diet at that stage.

One adverse event occurred, consisting of a single fainting episode determined to be potentially related to the dietary intervention.

In surveys, the adolescents gave the intervention an acceptability rating of 61 on a scale of 100, the score was 53 of 100 in terms of being “enjoyable to follow.”

The most-liked aspects of the intervention were losing weight (described by 34% of participants) and the prescriptive structure (listed by 28% of participants).

The least-liked aspects included the diet’s restrictive nature, described by 45% of participants, and the taste of meal replacement products, listed by 20% of participants.
 

Alternative to Weight Loss Drugs?

While weight loss drugs are transforming the obesity treatment and semaglutide is now approved for adolescents as young as age 12 years, “access to these medications is limited, and not all families want to commence on medication for their child›s obesity,” Dr. Gow said.

As an alternative, a very low-energy diet, with the interaction of a dietitian, can enable adolescents “to develop a healthier relationship with food, including encouraging the consumption of more fruits and vegetables in their diet, not only to assist in weight loss but for good health,” she said.
 

Very Low-Calorie Diet Concerns for Adolescents Addressed

Early studies suggested concerns of health effects from very low-calorie diets in adolescents, including potential cardiac effects; however, subsequent studies, including a systematic review published by Dr. Gow and her team, have shown that such results were likely the result of nutritional deficiencies in the diets, which can be overcome with careful food selection and dietary counseling.

Another key concern has been a potential effect on growth, but Dr. Gow noted that “in our short-term study we saw small increase in height (0.1 cm), and other more recent studies suggest that a short-term very low-energy diet does not impact growth.”

And in an earlier pilot study, the authors also found an association between the very low-calorie diet and an improvement in the quality of life for youth with type 2 diabetes.

A key caveat with the findings is that participants in the study all received supervision and monitoring from a trained dietitian, and Gow noted that that element is essential.

“We therefore do not recommend adolescents in the community undertake this type of diet without appropriate support,” she said.

“Close monitoring of adolescents by a health professional following a very low-energy diet is essential to ensure that the very low-energy diet is leading to holistic health benefits for the individual.”

Following the 4-week regimen, participants were randomized to transition to interventions of either continuous energy restriction or intermittent energy restriction over the 52 weeks, and further findings from the study will be presented at the obesity meeting in May.

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

Among adolescents with moderate to severe obesity, a nutritionally balanced, very low-calorie diet with the monitoring of a dietitian shows high adherence and safety, with significant weight loss over the course of a month and common, but mild side effects.

More research is needed to understand which patients are best suited for the diet; “however, given the associated rapid weight loss, the use of [very low-energy diets] should be emphasized in clinical practice guidelines for the treatment of severe obesity and obesity-related complications in adolescents, especially before pharmacological or surgical intervention,” first author Megan Gow, PhD, of Children’s Hospital Westmead Clinical School, The University of Sydney, Westmead, Australia, said in a press statement. 

The study will be presented in May at the upcoming European Congress on Obesity, in Venice, Italy.

While very low-calorie diets have been shown to promote rapid weight loss in adolescents, research is lacking on general side effects and acceptability of the regimens. Data is also lacking on important issues including the diet’s effect on growth, heart health, and psychological wellbeing. 

To investigate, Dr. Gow and colleagues conducted a subanalysis of the 52-week Fast Track to Health study evaluating the acceptability of different dietary plans for adolescents with obesity.

The analysis included 141 adolescents between the ages of 13 and 17 years with moderate to severe obesity (average body mass index, 35 kg/m²) and at least one obesity-related complication, such as high blood pressure or insulin resistance.

The participants were placed on a nutritionally balanced very low-energy diet consisting of 800 calories per day. 

The diet involved one of two regimens — either four Optifast-formulated meal replacement products per day, including shakes, soups, bars, and/or dessert, along with low carbohydrate vegetables, such as broccoli, celery, capsicum, mushrooms, and tomatoes, with one teaspoon of vegetable oil, or a regimen of three Optifast-formulated meal replacements and one meal consisting of 100-150 g lean cooked meat, low-carbohydrate vegetables, and one teaspoon of vegetable oil.

Participants, about half of whom were women, also received dietitian support at least weekly. 

After 4 weeks, most of the adolescents, ie, 134 of the 141, with an average age of 14.9 years, completed the diet, with an average weight loss of 5.5 kg or 12 pounds (P < .001).

Most patients (95%) experienced at least one side effect, and 70% reported at least 3 of the side effects, with the most common side effects including hunger, fatigue, headache, irritability, loose stools, constipation, nausea, and a lack of concentration.

Viral infections occurred in seven participants.

While most side effects occurred at the end of week 1, the development of side effects earlier, at day 3-4, was associated with higher levels of weight loss at the 4-week cut-off, which the authors noted could suggest a greater adherence to the diet at that stage.

One adverse event occurred, consisting of a single fainting episode determined to be potentially related to the dietary intervention.

In surveys, the adolescents gave the intervention an acceptability rating of 61 on a scale of 100, the score was 53 of 100 in terms of being “enjoyable to follow.”

The most-liked aspects of the intervention were losing weight (described by 34% of participants) and the prescriptive structure (listed by 28% of participants).

The least-liked aspects included the diet’s restrictive nature, described by 45% of participants, and the taste of meal replacement products, listed by 20% of participants.
 

Alternative to Weight Loss Drugs?

While weight loss drugs are transforming the obesity treatment and semaglutide is now approved for adolescents as young as age 12 years, “access to these medications is limited, and not all families want to commence on medication for their child›s obesity,” Dr. Gow said.

As an alternative, a very low-energy diet, with the interaction of a dietitian, can enable adolescents “to develop a healthier relationship with food, including encouraging the consumption of more fruits and vegetables in their diet, not only to assist in weight loss but for good health,” she said.
 

Very Low-Calorie Diet Concerns for Adolescents Addressed

Early studies suggested concerns of health effects from very low-calorie diets in adolescents, including potential cardiac effects; however, subsequent studies, including a systematic review published by Dr. Gow and her team, have shown that such results were likely the result of nutritional deficiencies in the diets, which can be overcome with careful food selection and dietary counseling.

Another key concern has been a potential effect on growth, but Dr. Gow noted that “in our short-term study we saw small increase in height (0.1 cm), and other more recent studies suggest that a short-term very low-energy diet does not impact growth.”

And in an earlier pilot study, the authors also found an association between the very low-calorie diet and an improvement in the quality of life for youth with type 2 diabetes.

A key caveat with the findings is that participants in the study all received supervision and monitoring from a trained dietitian, and Gow noted that that element is essential.

“We therefore do not recommend adolescents in the community undertake this type of diet without appropriate support,” she said.

“Close monitoring of adolescents by a health professional following a very low-energy diet is essential to ensure that the very low-energy diet is leading to holistic health benefits for the individual.”

Following the 4-week regimen, participants were randomized to transition to interventions of either continuous energy restriction or intermittent energy restriction over the 52 weeks, and further findings from the study will be presented at the obesity meeting in May.

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

SAN DIEGO — In the clinical experience of Mio Nakamura, MD, MS, providing dermatologic care to patients with personality disorders requires a certain level of flexibility and adaptability. 

“You want to recognize the personality disorder, understand that there are underlying conflicts and needs, and adjust accordingly,” Dr. Nakamura, clinical assistant professor of dermatology at the University of Michigan, Ann Arbor, said at the annual meeting of the American Academy of Dermatology. 

Dr. Nakamura

Personality disorders, which she defined as enduring patterns of maladaptive thinking and behavior that deviate from the cultural norm, affect up to 15% of the general population and can be difficult “if not impossible to treat, which can be frustrating.” She shared her approach to providing dermatologic care for individuals with these three conditions: 

Borderline personality disorder (BPD). This condition is marked by instability in interpersonal relationships, self-image, and emotions. Affected individuals are usually impulsive and often demonstrate self-injurious conduct such as risky sexual behaviors, cutting, or suicide attempts. “They often express feelings of emptiness, a fear of abandonment, and they are labile and sensitive to environmental circumstances,” Dr. Nakamura said. “They can be needy and display inappropriate, intense anger.”

In her clinical experience, a patient’s presenting dermatologic complaint is often a “screen” to hide a real, inner psychological problem, “a need to fill the emptiness,” she explained. “They’re kind of lonely, and there is a fear of abandonment. Rejection is frequently perceived as abandonment, creating intense anger and other negative emotions such as splitting.”

She advises against providing tests, treatments, or procedures for individuals with BPD that are not clinically indicated. “If the test is negative, such patients may ask for further testing,” she said. “Especially for cosmetic procedures, the patient may be more dissatisfied with the outcome of a procedure compared to before. Don’t let the patient’s emotions cloud your judgment. Trying to reason with the patient is often ineffective.”

To avoid saying “no” to such patients, Dr. Nakamura recommended discussing other treatment options so that they don’t feel abandoned. “Show that you care,” she said. “Meet the patient’s emotional needs, which may be the real agenda, and schedule regular follow-ups.”

Obsessive-compulsive personality disorder (OCPD). This condition is characterized by a preoccupation with orderliness, perfectionism, and control. “OCPD individuals are excessively concerned with details, rules, and organization to the extent that the major point of the activity is often lost,” Dr. Nakamura said. “They can be over-conscientious with excessive regard for morality and ethics.”

Such patients often fear losing control, she continued, which can lead to anxiety, depression, and sometimes anger. During office visits with patients with OCPD, she recommends that dermatologists “focus on facts and knowledge to replace or subdue emotions. Knowledge and information give a sense of control over illness.” Her approach involves professional, structured encounters that include detailed explanations and plans. “Provide step-by-step written instructions and give specific reasons for the prescribed treatment,” Dr. Nakamura advised. “Schedule regular follow-up appointments.”

Narcissistic personality disorder (NPD). This condition is characterized by a grandiose sense of self-importance, in which the person believes that they are special, unique, and superior to others. These individuals have a sense of entitlement, fantasize about unlimited success or power, display a lack of empathy toward others, and show a constant need for admiration. “The patient’s personality traits are often a ‘screen’ to hide a real, inner psychological problem such as unrecognized low self-esteem or insecurity,” Dr. Nakamura said. “These patients need praise and a sense of power.”

To provide patients with NPD with “a sense of uniqueness,” she recommended engaging with them at a medical level as one might with a work colleague. “Such patients often respond better to respect and concern rather than warmth and caring,” she said. Asking them to make decisions about their care can also give them a sense of power: asking them, for example, about which type of topical steroid they might prefer from those in the same class, whether they prefer creams or ointments, and that they can choose to follow up in 4 weeks or 6 weeks. 

“Do not let the patient dictate the encounter [or] get under your skin,” Dr. Nakamura emphasized. “Be careful about rejecting the patient from your practice. Even though that is perfectly within your rights, it could lead to ‘narcissistic injury’ where the patient becomes very angry and wants to get back at you.”

Dr. Nakamura disclosed that she is an investigator for Amgen, argenx, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Regeneron. She is also a member of the advisory board for argenx, Boehringer Ingelheim, and Bristol-Myers Squibb. 

A version of this article appeared on Medscape.com.

SAN DIEGO — In the clinical experience of Mio Nakamura, MD, MS, providing dermatologic care to patients with personality disorders requires a certain level of flexibility and adaptability. 

“You want to recognize the personality disorder, understand that there are underlying conflicts and needs, and adjust accordingly,” Dr. Nakamura, clinical assistant professor of dermatology at the University of Michigan, Ann Arbor, said at the annual meeting of the American Academy of Dermatology. 

Dr. Nakamura

Personality disorders, which she defined as enduring patterns of maladaptive thinking and behavior that deviate from the cultural norm, affect up to 15% of the general population and can be difficult “if not impossible to treat, which can be frustrating.” She shared her approach to providing dermatologic care for individuals with these three conditions: 

Borderline personality disorder (BPD). This condition is marked by instability in interpersonal relationships, self-image, and emotions. Affected individuals are usually impulsive and often demonstrate self-injurious conduct such as risky sexual behaviors, cutting, or suicide attempts. “They often express feelings of emptiness, a fear of abandonment, and they are labile and sensitive to environmental circumstances,” Dr. Nakamura said. “They can be needy and display inappropriate, intense anger.”

In her clinical experience, a patient’s presenting dermatologic complaint is often a “screen” to hide a real, inner psychological problem, “a need to fill the emptiness,” she explained. “They’re kind of lonely, and there is a fear of abandonment. Rejection is frequently perceived as abandonment, creating intense anger and other negative emotions such as splitting.”

She advises against providing tests, treatments, or procedures for individuals with BPD that are not clinically indicated. “If the test is negative, such patients may ask for further testing,” she said. “Especially for cosmetic procedures, the patient may be more dissatisfied with the outcome of a procedure compared to before. Don’t let the patient’s emotions cloud your judgment. Trying to reason with the patient is often ineffective.”

To avoid saying “no” to such patients, Dr. Nakamura recommended discussing other treatment options so that they don’t feel abandoned. “Show that you care,” she said. “Meet the patient’s emotional needs, which may be the real agenda, and schedule regular follow-ups.”

Obsessive-compulsive personality disorder (OCPD). This condition is characterized by a preoccupation with orderliness, perfectionism, and control. “OCPD individuals are excessively concerned with details, rules, and organization to the extent that the major point of the activity is often lost,” Dr. Nakamura said. “They can be over-conscientious with excessive regard for morality and ethics.”

Such patients often fear losing control, she continued, which can lead to anxiety, depression, and sometimes anger. During office visits with patients with OCPD, she recommends that dermatologists “focus on facts and knowledge to replace or subdue emotions. Knowledge and information give a sense of control over illness.” Her approach involves professional, structured encounters that include detailed explanations and plans. “Provide step-by-step written instructions and give specific reasons for the prescribed treatment,” Dr. Nakamura advised. “Schedule regular follow-up appointments.”

Narcissistic personality disorder (NPD). This condition is characterized by a grandiose sense of self-importance, in which the person believes that they are special, unique, and superior to others. These individuals have a sense of entitlement, fantasize about unlimited success or power, display a lack of empathy toward others, and show a constant need for admiration. “The patient’s personality traits are often a ‘screen’ to hide a real, inner psychological problem such as unrecognized low self-esteem or insecurity,” Dr. Nakamura said. “These patients need praise and a sense of power.”

To provide patients with NPD with “a sense of uniqueness,” she recommended engaging with them at a medical level as one might with a work colleague. “Such patients often respond better to respect and concern rather than warmth and caring,” she said. Asking them to make decisions about their care can also give them a sense of power: asking them, for example, about which type of topical steroid they might prefer from those in the same class, whether they prefer creams or ointments, and that they can choose to follow up in 4 weeks or 6 weeks. 

“Do not let the patient dictate the encounter [or] get under your skin,” Dr. Nakamura emphasized. “Be careful about rejecting the patient from your practice. Even though that is perfectly within your rights, it could lead to ‘narcissistic injury’ where the patient becomes very angry and wants to get back at you.”

Dr. Nakamura disclosed that she is an investigator for Amgen, argenx, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Regeneron. She is also a member of the advisory board for argenx, Boehringer Ingelheim, and Bristol-Myers Squibb. 

A version of this article appeared on Medscape.com.

SAN DIEGO — In the clinical experience of Mio Nakamura, MD, MS, providing dermatologic care to patients with personality disorders requires a certain level of flexibility and adaptability. 

“You want to recognize the personality disorder, understand that there are underlying conflicts and needs, and adjust accordingly,” Dr. Nakamura, clinical assistant professor of dermatology at the University of Michigan, Ann Arbor, said at the annual meeting of the American Academy of Dermatology. 

Dr. Nakamura

Personality disorders, which she defined as enduring patterns of maladaptive thinking and behavior that deviate from the cultural norm, affect up to 15% of the general population and can be difficult “if not impossible to treat, which can be frustrating.” She shared her approach to providing dermatologic care for individuals with these three conditions: 

Borderline personality disorder (BPD). This condition is marked by instability in interpersonal relationships, self-image, and emotions. Affected individuals are usually impulsive and often demonstrate self-injurious conduct such as risky sexual behaviors, cutting, or suicide attempts. “They often express feelings of emptiness, a fear of abandonment, and they are labile and sensitive to environmental circumstances,” Dr. Nakamura said. “They can be needy and display inappropriate, intense anger.”

In her clinical experience, a patient’s presenting dermatologic complaint is often a “screen” to hide a real, inner psychological problem, “a need to fill the emptiness,” she explained. “They’re kind of lonely, and there is a fear of abandonment. Rejection is frequently perceived as abandonment, creating intense anger and other negative emotions such as splitting.”

She advises against providing tests, treatments, or procedures for individuals with BPD that are not clinically indicated. “If the test is negative, such patients may ask for further testing,” she said. “Especially for cosmetic procedures, the patient may be more dissatisfied with the outcome of a procedure compared to before. Don’t let the patient’s emotions cloud your judgment. Trying to reason with the patient is often ineffective.”

To avoid saying “no” to such patients, Dr. Nakamura recommended discussing other treatment options so that they don’t feel abandoned. “Show that you care,” she said. “Meet the patient’s emotional needs, which may be the real agenda, and schedule regular follow-ups.”

Obsessive-compulsive personality disorder (OCPD). This condition is characterized by a preoccupation with orderliness, perfectionism, and control. “OCPD individuals are excessively concerned with details, rules, and organization to the extent that the major point of the activity is often lost,” Dr. Nakamura said. “They can be over-conscientious with excessive regard for morality and ethics.”

Such patients often fear losing control, she continued, which can lead to anxiety, depression, and sometimes anger. During office visits with patients with OCPD, she recommends that dermatologists “focus on facts and knowledge to replace or subdue emotions. Knowledge and information give a sense of control over illness.” Her approach involves professional, structured encounters that include detailed explanations and plans. “Provide step-by-step written instructions and give specific reasons for the prescribed treatment,” Dr. Nakamura advised. “Schedule regular follow-up appointments.”

Narcissistic personality disorder (NPD). This condition is characterized by a grandiose sense of self-importance, in which the person believes that they are special, unique, and superior to others. These individuals have a sense of entitlement, fantasize about unlimited success or power, display a lack of empathy toward others, and show a constant need for admiration. “The patient’s personality traits are often a ‘screen’ to hide a real, inner psychological problem such as unrecognized low self-esteem or insecurity,” Dr. Nakamura said. “These patients need praise and a sense of power.”

To provide patients with NPD with “a sense of uniqueness,” she recommended engaging with them at a medical level as one might with a work colleague. “Such patients often respond better to respect and concern rather than warmth and caring,” she said. Asking them to make decisions about their care can also give them a sense of power: asking them, for example, about which type of topical steroid they might prefer from those in the same class, whether they prefer creams or ointments, and that they can choose to follow up in 4 weeks or 6 weeks. 

“Do not let the patient dictate the encounter [or] get under your skin,” Dr. Nakamura emphasized. “Be careful about rejecting the patient from your practice. Even though that is perfectly within your rights, it could lead to ‘narcissistic injury’ where the patient becomes very angry and wants to get back at you.”

Dr. Nakamura disclosed that she is an investigator for Amgen, argenx, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Regeneron. She is also a member of the advisory board for argenx, Boehringer Ingelheim, and Bristol-Myers Squibb. 

A version of this article appeared on Medscape.com.

SAN DIEGO — Treatment with topical roflumilast, 0.05%, approved at a higher concentration for treating psoriasis, showed high levels of improvement in about a quarter of children aged 2-5 years with mild to moderate atopic dermatitis (AD), according to the results of a phase 3 study reported at the annual meeting of the American Academy of Dermatology.

Among patients treated with roflumilast cream, 0.05%, 25.4% reached the primary endpoint of “clear” or “almost clear” plus a two-grade improvement from baseline at week 4 vs 10.7% among those in the vehicle group (P < .0001) in a phase 3 randomized controlled trial of children. The findings were released in a late-breaker session at the meeting.

Roflumilast cream, 0.3% (Zoryve), is approved by the Food and Drug Administration (FDA) for treating psoriasis in patients 6 years and older, and lower doses are being evaluated for AD: 0.15% for adults and children ages 6 and older, and 0.05% for ages 2-5. Roflumilast is a phosphodiesterase-4 inhibitor. In 2023, the FDA accepted a supplemental drug application from the manufacturer, Arcutis, for roflumilast, 0.15%, for treating AD in patients ages 6 and older, based on the results from two recently published phase 3 trials, INTEGUMENT-1 and INTEGUMENT-2.

The study of younger children, INTEGUMENT-PED, recruited 652 patients aged 2-5 with mild to moderate AD, with a Validated Investigator Global Assessment scale for AD (vlGA-AD) score of 2 or 3, a mean body surface area of 22% overall (range, 3%-82%), and an Eczema Area and Severity Index (EASI) score of at least 5. Of the patients enrolled, 437 were assigned to 0.05% roflumilast cream, applied once a day for 4 weeks (mean age, 3.3 years; 51.6% male; 67.4% White; 15.6% Black; 8.5% Asian; 8.5% other or more than one race; 80.5% not Latino/Hispanic). The remaining 215 children were assigned to vehicle cream and had similar characteristics.

About 52% of the patients in both groups had an inadequate response, intolerance, or contraindications to topical corticosteroids (and about 17% for topical calcineurin inhibitors and about 9% for crisaborole).

The proportions of patients who reached “clear” (0) or “almost clear” (1) on the vlGA-AD scale were 35.4% and 14.6%, respectively, at week 4 (P < .0001) for roflumilast and vehicle, respectively, according to the lead author of the study, Lawrence M. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, who presented the results at the meeting. In addition, 39.4% and 20.6% achieved an EASI-75 (a secondary endpoint), respectively (P < .0001), and itch also improved within 24 hours of starting treatment.

With regard to safety, 29.7% of patients taking roflumilast had treatment-emergent adverse effects (including upper respiratory tract infections in 4.1%) vs 21.9% of those in the vehicle arm (including upper respiratory tract infections in 1.4%). Reports of pain at the administration site were low (1.6% for roflumilast vs 1.9% for vehicle). Only one patient, a 2-year-old girl, had a treatment-emergent serious adverse event. The child, who was in the roflumilast group, had cellulitis involving noneczematous skin and was treated with antibiotics in the hospital for 3 days. The event was not attributed to roflumilast, which was stopped for 5 days, according to Dr. Eichenfield.

In an interview, Fairfield, Connecticut–based dermatologist Brittany Craiglow, MD, who was not involved in the study, said topical roflumilast would be an “important” new treatment because there are still few nonsteroidal options for the treatment of AD in children under 12. “The excellent local tolerability combined with early improvements in itch and skin clearance will make this a particularly attractive option, if approved,” she said.

Dr. Eichenfield disclosed multiple relationships with various drugmakers. He and several other study authors are investigators and/or consultants for Arcutis and received grants/research funding and/or honoraria. Two authors are Arcutis employees. Other disclosure information for the authors was not immediately available. Dr. Craiglow had no disclosures.

A version of this article appeared on Medscape.com .

SAN DIEGO — Treatment with topical roflumilast, 0.05%, approved at a higher concentration for treating psoriasis, showed high levels of improvement in about a quarter of children aged 2-5 years with mild to moderate atopic dermatitis (AD), according to the results of a phase 3 study reported at the annual meeting of the American Academy of Dermatology.

Among patients treated with roflumilast cream, 0.05%, 25.4% reached the primary endpoint of “clear” or “almost clear” plus a two-grade improvement from baseline at week 4 vs 10.7% among those in the vehicle group (P < .0001) in a phase 3 randomized controlled trial of children. The findings were released in a late-breaker session at the meeting.

Roflumilast cream, 0.3% (Zoryve), is approved by the Food and Drug Administration (FDA) for treating psoriasis in patients 6 years and older, and lower doses are being evaluated for AD: 0.15% for adults and children ages 6 and older, and 0.05% for ages 2-5. Roflumilast is a phosphodiesterase-4 inhibitor. In 2023, the FDA accepted a supplemental drug application from the manufacturer, Arcutis, for roflumilast, 0.15%, for treating AD in patients ages 6 and older, based on the results from two recently published phase 3 trials, INTEGUMENT-1 and INTEGUMENT-2.

The study of younger children, INTEGUMENT-PED, recruited 652 patients aged 2-5 with mild to moderate AD, with a Validated Investigator Global Assessment scale for AD (vlGA-AD) score of 2 or 3, a mean body surface area of 22% overall (range, 3%-82%), and an Eczema Area and Severity Index (EASI) score of at least 5. Of the patients enrolled, 437 were assigned to 0.05% roflumilast cream, applied once a day for 4 weeks (mean age, 3.3 years; 51.6% male; 67.4% White; 15.6% Black; 8.5% Asian; 8.5% other or more than one race; 80.5% not Latino/Hispanic). The remaining 215 children were assigned to vehicle cream and had similar characteristics.

About 52% of the patients in both groups had an inadequate response, intolerance, or contraindications to topical corticosteroids (and about 17% for topical calcineurin inhibitors and about 9% for crisaborole).

The proportions of patients who reached “clear” (0) or “almost clear” (1) on the vlGA-AD scale were 35.4% and 14.6%, respectively, at week 4 (P < .0001) for roflumilast and vehicle, respectively, according to the lead author of the study, Lawrence M. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, who presented the results at the meeting. In addition, 39.4% and 20.6% achieved an EASI-75 (a secondary endpoint), respectively (P < .0001), and itch also improved within 24 hours of starting treatment.

With regard to safety, 29.7% of patients taking roflumilast had treatment-emergent adverse effects (including upper respiratory tract infections in 4.1%) vs 21.9% of those in the vehicle arm (including upper respiratory tract infections in 1.4%). Reports of pain at the administration site were low (1.6% for roflumilast vs 1.9% for vehicle). Only one patient, a 2-year-old girl, had a treatment-emergent serious adverse event. The child, who was in the roflumilast group, had cellulitis involving noneczematous skin and was treated with antibiotics in the hospital for 3 days. The event was not attributed to roflumilast, which was stopped for 5 days, according to Dr. Eichenfield.

In an interview, Fairfield, Connecticut–based dermatologist Brittany Craiglow, MD, who was not involved in the study, said topical roflumilast would be an “important” new treatment because there are still few nonsteroidal options for the treatment of AD in children under 12. “The excellent local tolerability combined with early improvements in itch and skin clearance will make this a particularly attractive option, if approved,” she said.

Dr. Eichenfield disclosed multiple relationships with various drugmakers. He and several other study authors are investigators and/or consultants for Arcutis and received grants/research funding and/or honoraria. Two authors are Arcutis employees. Other disclosure information for the authors was not immediately available. Dr. Craiglow had no disclosures.

A version of this article appeared on Medscape.com .

SAN DIEGO — Treatment with topical roflumilast, 0.05%, approved at a higher concentration for treating psoriasis, showed high levels of improvement in about a quarter of children aged 2-5 years with mild to moderate atopic dermatitis (AD), according to the results of a phase 3 study reported at the annual meeting of the American Academy of Dermatology.

Among patients treated with roflumilast cream, 0.05%, 25.4% reached the primary endpoint of “clear” or “almost clear” plus a two-grade improvement from baseline at week 4 vs 10.7% among those in the vehicle group (P < .0001) in a phase 3 randomized controlled trial of children. The findings were released in a late-breaker session at the meeting.

Roflumilast cream, 0.3% (Zoryve), is approved by the Food and Drug Administration (FDA) for treating psoriasis in patients 6 years and older, and lower doses are being evaluated for AD: 0.15% for adults and children ages 6 and older, and 0.05% for ages 2-5. Roflumilast is a phosphodiesterase-4 inhibitor. In 2023, the FDA accepted a supplemental drug application from the manufacturer, Arcutis, for roflumilast, 0.15%, for treating AD in patients ages 6 and older, based on the results from two recently published phase 3 trials, INTEGUMENT-1 and INTEGUMENT-2.

The study of younger children, INTEGUMENT-PED, recruited 652 patients aged 2-5 with mild to moderate AD, with a Validated Investigator Global Assessment scale for AD (vlGA-AD) score of 2 or 3, a mean body surface area of 22% overall (range, 3%-82%), and an Eczema Area and Severity Index (EASI) score of at least 5. Of the patients enrolled, 437 were assigned to 0.05% roflumilast cream, applied once a day for 4 weeks (mean age, 3.3 years; 51.6% male; 67.4% White; 15.6% Black; 8.5% Asian; 8.5% other or more than one race; 80.5% not Latino/Hispanic). The remaining 215 children were assigned to vehicle cream and had similar characteristics.

About 52% of the patients in both groups had an inadequate response, intolerance, or contraindications to topical corticosteroids (and about 17% for topical calcineurin inhibitors and about 9% for crisaborole).

The proportions of patients who reached “clear” (0) or “almost clear” (1) on the vlGA-AD scale were 35.4% and 14.6%, respectively, at week 4 (P < .0001) for roflumilast and vehicle, respectively, according to the lead author of the study, Lawrence M. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, who presented the results at the meeting. In addition, 39.4% and 20.6% achieved an EASI-75 (a secondary endpoint), respectively (P < .0001), and itch also improved within 24 hours of starting treatment.

With regard to safety, 29.7% of patients taking roflumilast had treatment-emergent adverse effects (including upper respiratory tract infections in 4.1%) vs 21.9% of those in the vehicle arm (including upper respiratory tract infections in 1.4%). Reports of pain at the administration site were low (1.6% for roflumilast vs 1.9% for vehicle). Only one patient, a 2-year-old girl, had a treatment-emergent serious adverse event. The child, who was in the roflumilast group, had cellulitis involving noneczematous skin and was treated with antibiotics in the hospital for 3 days. The event was not attributed to roflumilast, which was stopped for 5 days, according to Dr. Eichenfield.

In an interview, Fairfield, Connecticut–based dermatologist Brittany Craiglow, MD, who was not involved in the study, said topical roflumilast would be an “important” new treatment because there are still few nonsteroidal options for the treatment of AD in children under 12. “The excellent local tolerability combined with early improvements in itch and skin clearance will make this a particularly attractive option, if approved,” she said.

Dr. Eichenfield disclosed multiple relationships with various drugmakers. He and several other study authors are investigators and/or consultants for Arcutis and received grants/research funding and/or honoraria. Two authors are Arcutis employees. Other disclosure information for the authors was not immediately available. Dr. Craiglow had no disclosures.

A version of this article appeared on Medscape.com .

FAIRFAX, VIRGINIA — Nearly 30 years ago, in a 1995 paper, the British physician-epidemiologist David Barker, MD, PhD, wrote about his fetal origins hypothesis — the idea that programs to address fetal undernutrition and low birth weight produced later coronary heart disease (BMJ 1995;311:171-4).

His hypothesis and subsequent research led to the concept of adult diseases of fetal origins, which today extends beyond low birth weight and implicates the in utero environment as a significant determinant of risk for adverse childhood and adult metabolic outcomes and for major chronic diseases, including diabetes and obesity. Studies have shown that the offspring of pregnant mothers with diabetes have a higher risk of developing obesity and diabetes themselves.

“It’s a whole discipline [of research],” E. Albert Reece, MD, PhD, MBA, of the University of Maryland School of Medicine (UMSOM), said in an interview. “But what we’ve never quite understood is the ‘how’ and ‘why’? What are the mechanisms driving the fetal origins of such adverse outcomes in offspring?

At the biennial meeting of the Diabetes in Pregnancy Study Group of North America (DPSG), investigators described studies underway that are digging deeper into the associations between the intrauterine milieu and longer-term offspring health — and that are searching for biological and molecular processes that may be involved.

The studies are like “branches of the Barker hypothesis,” said Dr. Reece, former dean of UMSOM and current director of the UMSOM Center for Advanced Research Training and Innovation, who co-organized the DPSG meeting. “They’re taking the hypothesis and dissecting it by asking, for instance, it is possible that transgenerational obesity may align with the Barker hypothesis? Is it possible that it involves epigenetics regulation? Could we find biomarkers?”

The need for a better understanding of the fetal origins framework — and its subsequent transgenerational impact — is urgent. From 2000 to 2018, the prevalence of childhood obesity increased from 14.7% to 19.2% (a 31% increase) and the prevalence of severe childhood obesity rose from 3.9% to 6.1% (a 56% increase), according to data from the U.S. National Health and Nutrition Examination Survey (Obes Facts. 2022;15[4]:560-9).

Children aged 2-5 years have had an especially sharp increase in obesity (Pediatrics 2018;141[3]:e20173459), Christine Wey Hockett, PhD, of the University of South Dakota School of Medicine, said at the DPSG meeting (Figure 1).

Deeper Dives Into Associations, Potential Mechanisms

The EPOCH prospective cohort study with which Dr. Hockett was involved gave her a front-seat view of the transgenerational adverse effects of in utero exposure to hyperglycemia. The study recruited ethnically diverse maternal/child dyads from the Kaiser Permanente of Colorado perinatal database from 1992 to 2002 and assessed 418 offspring at two points — a mean age of 10.5 years and 16.5 years — for fasting blood glucose, adiposity, and diet and physical activity. The second visit also involved an oral glucose tolerance test.

The 77 offspring who had been exposed in utero to GDM had a homeostatic model assessment of insulin resistance (HOMA-IR) that was 18% higher, a 19% lower Matsuda index, and a 9% greater HOMA of β-cell function (HOMA-β) than the 341 offspring whose mothers did not have diabetes. Each 5-kg/m² increase in prepregnancy body mass index predicted increased insulin resistance, but there was no combined effect of both maternal obesity and diabetes in utero.

Exposed offspring had a higher BMI and increased adiposity, but when BMI was controlled for in the analysis of metabolic outcomes, maternal diabetes was still associated with 12% higher HOMA-IR and a 17% lower Matsuda index. “So [the metabolic outcomes] are a direct effect of maternal diabetes,” Dr. Hockett said at the DPSG meeting, noting the fetal overnutrition hypothesis in which maternal glucose, but not maternal insulin, freely passes through the placenta, promoting growth and adiposity in the fetus.

[The EPOCH results on metabolic outcomes and offspring adiposity were published in 2017 and 2019, respectively (Diabet Med. 2017;34:1392-9; Diabetologia. 2019;62:2017-24). In 2020, EPOCH researchers reported sex-specific effects on cardiovascular outcomes, with GDM exposure associated with higher total and LDL cholesterol in girls and higher systolic blood pressure in boys (Pediatr Obes. 2020;15[5]:e12611).]

Now, a new longitudinal cohort study underway in Phoenix, is taking a deeper dive, trying to pinpoint what exactly influences childhood obesity and metabolic risk by following Hispanic and American Indian maternal/child dyads from pregnancy until 18 years postpartum. Researchers are looking not only at associations between maternal risk factors (pregnancy BMI, gestational weight gain, and diabetes in pregnancy) and offspring BMI, adiposity, and growth patterns, but also how various factors during pregnancy — clinical, genetic, lifestyle, biochemical — ”may mediate the associations,” said lead investigator Madhumita Sinha, MD.

“We need a better understanding at the molecular level of the biological processes that lead to obesity in children and that cause metabolic dysfunction,” said Dr. Sinha, who heads the Diabetes Epidemiology and Clinical Research Section of the of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch in Phoenix.

The populations being enrolled in the ETCHED study (for Early Tracking of Childhood Health Determinants) are at especially high risk of childhood obesity and metabolic dysfunction. Research conducted decades ago by the NIDDK in Phoenix showed that approximately 50% of Pima Indian children from diabetic pregnancies develop type 2 diabetes by age 25 (N Engl J Med. 1983;308:242-5). Years later, to tease out possible genetic factors, researchers compared siblings born before and after their mother was found to have type 2 diabetes, and found significantly higher rates of diabetes in those born after the mother’s diagnosis, affirming the role of in utero toxicity (Diabetes 2000;49:2208-11).

In the new study, the researchers will look at adipokines and inflammatory biomarkers in the mothers and offspring in addition to traditional anthropometric and glycemic measures. They’ll analyze placental tissue, breast milk, and the gut microbiome longitudinally, and they’ll lean heavily on genomics/epigenomics, proteomics, and metabolomics. “There’s potential,” Dr. Sinha said, “to develop a more accurate predictive and prognostic model of childhood obesity.”

The researchers also will study the role of family, socioeconomics, and environmental factors in influencing child growth patterns and they’ll look at neurodevelopment in infancy and childhood. As of October 2023, almost 80 pregnant women, most with obesity and almost one-third with type 2 diabetes, had enrolled in the study. Over the next several years, the study aims to enroll 750 dyads.
 

The Timing of In Utero Exposure

Shelley Ehrlich, MD, ScD, MPH, of the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, is aiming, meanwhile, to learn how the timing of in utero exposure to hyperglycemia predicts specific metabolic and cardiovascular morbidities in the adult offspring of diabetic mothers.

“While we know that exposure to maternal diabetes, regardless of type, increases the risk of obesity, insulin resistance, diabetes, renal compromise, and cardiovascular disease in the offspring, there is little known about the level and timing of hyperglycemic exposure during fetal development that triggers these adverse outcomes,” said Dr. Ehrlich. A goal, she said, is to identify gestational profiles that predict phenotypes of offspring at risk for morbidity in later life.

She and other investigators with the TEAM (Transgenerational Effect on Adult Morbidity) study have recruited over 170 offspring of mothers who participated in the Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati Medical Center from 1978 to 1995 — a landmark study that demonstrated the effect of strict glucose control in reducing major congenital malformations.

The women in the PPG study had frequent glucose monitoring (up to 6-8 times a day) throughout their pregnancies, and now, their recruited offspring, who are up to 43 years of age, are being assessed for obesity, diabetes/metabolic health, cardiovascular disease/cardiac and peripheral vascular structure and function, and other outcomes including those that may be amenable to secondary prevention (J Diabetes Res. Nov 1;2021:6590431).

Preliminary findings from over 170 offspring recruited between 2017 and 2022 suggest that in utero exposure to dysglycemia (as measured by standard deviations of glycohemoglobin) in the third trimester appears to increase the risk of morbid obesity in adulthood, while exposure to dysglycemia in the first trimester increases the risk of impaired glucose tolerance. The risk of B-cell dysfunction, meanwhile, appears to be linked to dysglycemia in the first and third trimesters — particularly the first — Dr. Ehrlich reported.

Cognitive outcomes in offspring have also been assessed and here it appears that dysglycemia in the third trimester is linked to worse scores on the Wechsler Abbreviated Scale of Intelligence (WASI-II), said Katherine Bowers, PhD, MPH, a TEAM study coinvestigator, also of Cincinnati Children’s Hospital Medical Center.

“We’ve already observed [an association between] diabetes in pregnancy and cognition in early childhood and through adolescence, but [the question has been] does this association persist into adulthood?” she said.

Preliminary analyses of 104 offspring show no statistically significant associations between maternal dysglycemia in the first or second trimesters and offspring cognition, but “consistent inverse associations between maternal glycohemoglobin in the third trimester across two [WASI-II] subscales and composite measures of cognition,” Dr. Bowers said.

Their analysis adjusted for a variety of factors, including maternal age, prepregnancy and first trimester BMI, race, family history of diabetes, and diabetes severity/macrovascular complications.
 

Back In The Laboratory

At the other end of the research spectrum, basic research scientists are also investigating the mechanisms and sequelae of in utero hyperglycemia and other injuries, including congenital malformations, placental adaptive responses and fetal programming. Researchers are asking, for instance, what does placental metabolic reprogramming entail? What role do placental extracellular vesicles play in GDM? Can we alter the in utero environment and thus improve the short and long-term fetal/infant outcomes?

Animal research done at the UMSOM Center for Birth Defects Research, led by Dr. Reece and Peixin Yang, PhD, suggests that “a good portion of in utero injury is due to epigenetics,” Dr. Reece said in the interview. “We’ve shown that under conditions of hyperglycemia, for example, genetic regulation and genetic function can be altered.”

Through in vivo research, they have also shown that antioxidants or membrane stabilizers such as arachidonic acid or myo-inositol, or experimental inhibitors to certain pro-apoptotic intermediates, can individually or collectively result in reduced malformations. “It is highly likely that understanding the biological impact of various altered in utero environments, and then modifying or reversing those environments, will result in short and long-term outcome improvements similar to those shown with congenital malformations,” Dr. Reece said.

FAIRFAX, VIRGINIA — Nearly 30 years ago, in a 1995 paper, the British physician-epidemiologist David Barker, MD, PhD, wrote about his fetal origins hypothesis — the idea that programs to address fetal undernutrition and low birth weight produced later coronary heart disease (BMJ 1995;311:171-4).

His hypothesis and subsequent research led to the concept of adult diseases of fetal origins, which today extends beyond low birth weight and implicates the in utero environment as a significant determinant of risk for adverse childhood and adult metabolic outcomes and for major chronic diseases, including diabetes and obesity. Studies have shown that the offspring of pregnant mothers with diabetes have a higher risk of developing obesity and diabetes themselves.

“It’s a whole discipline [of research],” E. Albert Reece, MD, PhD, MBA, of the University of Maryland School of Medicine (UMSOM), said in an interview. “But what we’ve never quite understood is the ‘how’ and ‘why’? What are the mechanisms driving the fetal origins of such adverse outcomes in offspring?

At the biennial meeting of the Diabetes in Pregnancy Study Group of North America (DPSG), investigators described studies underway that are digging deeper into the associations between the intrauterine milieu and longer-term offspring health — and that are searching for biological and molecular processes that may be involved.

The studies are like “branches of the Barker hypothesis,” said Dr. Reece, former dean of UMSOM and current director of the UMSOM Center for Advanced Research Training and Innovation, who co-organized the DPSG meeting. “They’re taking the hypothesis and dissecting it by asking, for instance, it is possible that transgenerational obesity may align with the Barker hypothesis? Is it possible that it involves epigenetics regulation? Could we find biomarkers?”

The need for a better understanding of the fetal origins framework — and its subsequent transgenerational impact — is urgent. From 2000 to 2018, the prevalence of childhood obesity increased from 14.7% to 19.2% (a 31% increase) and the prevalence of severe childhood obesity rose from 3.9% to 6.1% (a 56% increase), according to data from the U.S. National Health and Nutrition Examination Survey (Obes Facts. 2022;15[4]:560-9).

Children aged 2-5 years have had an especially sharp increase in obesity (Pediatrics 2018;141[3]:e20173459), Christine Wey Hockett, PhD, of the University of South Dakota School of Medicine, said at the DPSG meeting (Figure 1).

Deeper Dives Into Associations, Potential Mechanisms

The EPOCH prospective cohort study with which Dr. Hockett was involved gave her a front-seat view of the transgenerational adverse effects of in utero exposure to hyperglycemia. The study recruited ethnically diverse maternal/child dyads from the Kaiser Permanente of Colorado perinatal database from 1992 to 2002 and assessed 418 offspring at two points — a mean age of 10.5 years and 16.5 years — for fasting blood glucose, adiposity, and diet and physical activity. The second visit also involved an oral glucose tolerance test.

The 77 offspring who had been exposed in utero to GDM had a homeostatic model assessment of insulin resistance (HOMA-IR) that was 18% higher, a 19% lower Matsuda index, and a 9% greater HOMA of β-cell function (HOMA-β) than the 341 offspring whose mothers did not have diabetes. Each 5-kg/m² increase in prepregnancy body mass index predicted increased insulin resistance, but there was no combined effect of both maternal obesity and diabetes in utero.

Exposed offspring had a higher BMI and increased adiposity, but when BMI was controlled for in the analysis of metabolic outcomes, maternal diabetes was still associated with 12% higher HOMA-IR and a 17% lower Matsuda index. “So [the metabolic outcomes] are a direct effect of maternal diabetes,” Dr. Hockett said at the DPSG meeting, noting the fetal overnutrition hypothesis in which maternal glucose, but not maternal insulin, freely passes through the placenta, promoting growth and adiposity in the fetus.

[The EPOCH results on metabolic outcomes and offspring adiposity were published in 2017 and 2019, respectively (Diabet Med. 2017;34:1392-9; Diabetologia. 2019;62:2017-24). In 2020, EPOCH researchers reported sex-specific effects on cardiovascular outcomes, with GDM exposure associated with higher total and LDL cholesterol in girls and higher systolic blood pressure in boys (Pediatr Obes. 2020;15[5]:e12611).]

Now, a new longitudinal cohort study underway in Phoenix, is taking a deeper dive, trying to pinpoint what exactly influences childhood obesity and metabolic risk by following Hispanic and American Indian maternal/child dyads from pregnancy until 18 years postpartum. Researchers are looking not only at associations between maternal risk factors (pregnancy BMI, gestational weight gain, and diabetes in pregnancy) and offspring BMI, adiposity, and growth patterns, but also how various factors during pregnancy — clinical, genetic, lifestyle, biochemical — ”may mediate the associations,” said lead investigator Madhumita Sinha, MD.

“We need a better understanding at the molecular level of the biological processes that lead to obesity in children and that cause metabolic dysfunction,” said Dr. Sinha, who heads the Diabetes Epidemiology and Clinical Research Section of the of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch in Phoenix.

The populations being enrolled in the ETCHED study (for Early Tracking of Childhood Health Determinants) are at especially high risk of childhood obesity and metabolic dysfunction. Research conducted decades ago by the NIDDK in Phoenix showed that approximately 50% of Pima Indian children from diabetic pregnancies develop type 2 diabetes by age 25 (N Engl J Med. 1983;308:242-5). Years later, to tease out possible genetic factors, researchers compared siblings born before and after their mother was found to have type 2 diabetes, and found significantly higher rates of diabetes in those born after the mother’s diagnosis, affirming the role of in utero toxicity (Diabetes 2000;49:2208-11).

In the new study, the researchers will look at adipokines and inflammatory biomarkers in the mothers and offspring in addition to traditional anthropometric and glycemic measures. They’ll analyze placental tissue, breast milk, and the gut microbiome longitudinally, and they’ll lean heavily on genomics/epigenomics, proteomics, and metabolomics. “There’s potential,” Dr. Sinha said, “to develop a more accurate predictive and prognostic model of childhood obesity.”

The researchers also will study the role of family, socioeconomics, and environmental factors in influencing child growth patterns and they’ll look at neurodevelopment in infancy and childhood. As of October 2023, almost 80 pregnant women, most with obesity and almost one-third with type 2 diabetes, had enrolled in the study. Over the next several years, the study aims to enroll 750 dyads.
 

The Timing of In Utero Exposure

Shelley Ehrlich, MD, ScD, MPH, of the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, is aiming, meanwhile, to learn how the timing of in utero exposure to hyperglycemia predicts specific metabolic and cardiovascular morbidities in the adult offspring of diabetic mothers.

“While we know that exposure to maternal diabetes, regardless of type, increases the risk of obesity, insulin resistance, diabetes, renal compromise, and cardiovascular disease in the offspring, there is little known about the level and timing of hyperglycemic exposure during fetal development that triggers these adverse outcomes,” said Dr. Ehrlich. A goal, she said, is to identify gestational profiles that predict phenotypes of offspring at risk for morbidity in later life.

She and other investigators with the TEAM (Transgenerational Effect on Adult Morbidity) study have recruited over 170 offspring of mothers who participated in the Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati Medical Center from 1978 to 1995 — a landmark study that demonstrated the effect of strict glucose control in reducing major congenital malformations.

The women in the PPG study had frequent glucose monitoring (up to 6-8 times a day) throughout their pregnancies, and now, their recruited offspring, who are up to 43 years of age, are being assessed for obesity, diabetes/metabolic health, cardiovascular disease/cardiac and peripheral vascular structure and function, and other outcomes including those that may be amenable to secondary prevention (J Diabetes Res. Nov 1;2021:6590431).

Preliminary findings from over 170 offspring recruited between 2017 and 2022 suggest that in utero exposure to dysglycemia (as measured by standard deviations of glycohemoglobin) in the third trimester appears to increase the risk of morbid obesity in adulthood, while exposure to dysglycemia in the first trimester increases the risk of impaired glucose tolerance. The risk of B-cell dysfunction, meanwhile, appears to be linked to dysglycemia in the first and third trimesters — particularly the first — Dr. Ehrlich reported.

Cognitive outcomes in offspring have also been assessed and here it appears that dysglycemia in the third trimester is linked to worse scores on the Wechsler Abbreviated Scale of Intelligence (WASI-II), said Katherine Bowers, PhD, MPH, a TEAM study coinvestigator, also of Cincinnati Children’s Hospital Medical Center.

“We’ve already observed [an association between] diabetes in pregnancy and cognition in early childhood and through adolescence, but [the question has been] does this association persist into adulthood?” she said.

Preliminary analyses of 104 offspring show no statistically significant associations between maternal dysglycemia in the first or second trimesters and offspring cognition, but “consistent inverse associations between maternal glycohemoglobin in the third trimester across two [WASI-II] subscales and composite measures of cognition,” Dr. Bowers said.

Their analysis adjusted for a variety of factors, including maternal age, prepregnancy and first trimester BMI, race, family history of diabetes, and diabetes severity/macrovascular complications.
 

Back In The Laboratory

At the other end of the research spectrum, basic research scientists are also investigating the mechanisms and sequelae of in utero hyperglycemia and other injuries, including congenital malformations, placental adaptive responses and fetal programming. Researchers are asking, for instance, what does placental metabolic reprogramming entail? What role do placental extracellular vesicles play in GDM? Can we alter the in utero environment and thus improve the short and long-term fetal/infant outcomes?

Animal research done at the UMSOM Center for Birth Defects Research, led by Dr. Reece and Peixin Yang, PhD, suggests that “a good portion of in utero injury is due to epigenetics,” Dr. Reece said in the interview. “We’ve shown that under conditions of hyperglycemia, for example, genetic regulation and genetic function can be altered.”

Through in vivo research, they have also shown that antioxidants or membrane stabilizers such as arachidonic acid or myo-inositol, or experimental inhibitors to certain pro-apoptotic intermediates, can individually or collectively result in reduced malformations. “It is highly likely that understanding the biological impact of various altered in utero environments, and then modifying or reversing those environments, will result in short and long-term outcome improvements similar to those shown with congenital malformations,” Dr. Reece said.

FAIRFAX, VIRGINIA — Nearly 30 years ago, in a 1995 paper, the British physician-epidemiologist David Barker, MD, PhD, wrote about his fetal origins hypothesis — the idea that programs to address fetal undernutrition and low birth weight produced later coronary heart disease (BMJ 1995;311:171-4).

His hypothesis and subsequent research led to the concept of adult diseases of fetal origins, which today extends beyond low birth weight and implicates the in utero environment as a significant determinant of risk for adverse childhood and adult metabolic outcomes and for major chronic diseases, including diabetes and obesity. Studies have shown that the offspring of pregnant mothers with diabetes have a higher risk of developing obesity and diabetes themselves.

“It’s a whole discipline [of research],” E. Albert Reece, MD, PhD, MBA, of the University of Maryland School of Medicine (UMSOM), said in an interview. “But what we’ve never quite understood is the ‘how’ and ‘why’? What are the mechanisms driving the fetal origins of such adverse outcomes in offspring?

At the biennial meeting of the Diabetes in Pregnancy Study Group of North America (DPSG), investigators described studies underway that are digging deeper into the associations between the intrauterine milieu and longer-term offspring health — and that are searching for biological and molecular processes that may be involved.

The studies are like “branches of the Barker hypothesis,” said Dr. Reece, former dean of UMSOM and current director of the UMSOM Center for Advanced Research Training and Innovation, who co-organized the DPSG meeting. “They’re taking the hypothesis and dissecting it by asking, for instance, it is possible that transgenerational obesity may align with the Barker hypothesis? Is it possible that it involves epigenetics regulation? Could we find biomarkers?”

The need for a better understanding of the fetal origins framework — and its subsequent transgenerational impact — is urgent. From 2000 to 2018, the prevalence of childhood obesity increased from 14.7% to 19.2% (a 31% increase) and the prevalence of severe childhood obesity rose from 3.9% to 6.1% (a 56% increase), according to data from the U.S. National Health and Nutrition Examination Survey (Obes Facts. 2022;15[4]:560-9).

Children aged 2-5 years have had an especially sharp increase in obesity (Pediatrics 2018;141[3]:e20173459), Christine Wey Hockett, PhD, of the University of South Dakota School of Medicine, said at the DPSG meeting (Figure 1).

Deeper Dives Into Associations, Potential Mechanisms

The EPOCH prospective cohort study with which Dr. Hockett was involved gave her a front-seat view of the transgenerational adverse effects of in utero exposure to hyperglycemia. The study recruited ethnically diverse maternal/child dyads from the Kaiser Permanente of Colorado perinatal database from 1992 to 2002 and assessed 418 offspring at two points — a mean age of 10.5 years and 16.5 years — for fasting blood glucose, adiposity, and diet and physical activity. The second visit also involved an oral glucose tolerance test.

The 77 offspring who had been exposed in utero to GDM had a homeostatic model assessment of insulin resistance (HOMA-IR) that was 18% higher, a 19% lower Matsuda index, and a 9% greater HOMA of β-cell function (HOMA-β) than the 341 offspring whose mothers did not have diabetes. Each 5-kg/m² increase in prepregnancy body mass index predicted increased insulin resistance, but there was no combined effect of both maternal obesity and diabetes in utero.

Exposed offspring had a higher BMI and increased adiposity, but when BMI was controlled for in the analysis of metabolic outcomes, maternal diabetes was still associated with 12% higher HOMA-IR and a 17% lower Matsuda index. “So [the metabolic outcomes] are a direct effect of maternal diabetes,” Dr. Hockett said at the DPSG meeting, noting the fetal overnutrition hypothesis in which maternal glucose, but not maternal insulin, freely passes through the placenta, promoting growth and adiposity in the fetus.

[The EPOCH results on metabolic outcomes and offspring adiposity were published in 2017 and 2019, respectively (Diabet Med. 2017;34:1392-9; Diabetologia. 2019;62:2017-24). In 2020, EPOCH researchers reported sex-specific effects on cardiovascular outcomes, with GDM exposure associated with higher total and LDL cholesterol in girls and higher systolic blood pressure in boys (Pediatr Obes. 2020;15[5]:e12611).]

Now, a new longitudinal cohort study underway in Phoenix, is taking a deeper dive, trying to pinpoint what exactly influences childhood obesity and metabolic risk by following Hispanic and American Indian maternal/child dyads from pregnancy until 18 years postpartum. Researchers are looking not only at associations between maternal risk factors (pregnancy BMI, gestational weight gain, and diabetes in pregnancy) and offspring BMI, adiposity, and growth patterns, but also how various factors during pregnancy — clinical, genetic, lifestyle, biochemical — ”may mediate the associations,” said lead investigator Madhumita Sinha, MD.

“We need a better understanding at the molecular level of the biological processes that lead to obesity in children and that cause metabolic dysfunction,” said Dr. Sinha, who heads the Diabetes Epidemiology and Clinical Research Section of the of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch in Phoenix.

The populations being enrolled in the ETCHED study (for Early Tracking of Childhood Health Determinants) are at especially high risk of childhood obesity and metabolic dysfunction. Research conducted decades ago by the NIDDK in Phoenix showed that approximately 50% of Pima Indian children from diabetic pregnancies develop type 2 diabetes by age 25 (N Engl J Med. 1983;308:242-5). Years later, to tease out possible genetic factors, researchers compared siblings born before and after their mother was found to have type 2 diabetes, and found significantly higher rates of diabetes in those born after the mother’s diagnosis, affirming the role of in utero toxicity (Diabetes 2000;49:2208-11).

In the new study, the researchers will look at adipokines and inflammatory biomarkers in the mothers and offspring in addition to traditional anthropometric and glycemic measures. They’ll analyze placental tissue, breast milk, and the gut microbiome longitudinally, and they’ll lean heavily on genomics/epigenomics, proteomics, and metabolomics. “There’s potential,” Dr. Sinha said, “to develop a more accurate predictive and prognostic model of childhood obesity.”

The researchers also will study the role of family, socioeconomics, and environmental factors in influencing child growth patterns and they’ll look at neurodevelopment in infancy and childhood. As of October 2023, almost 80 pregnant women, most with obesity and almost one-third with type 2 diabetes, had enrolled in the study. Over the next several years, the study aims to enroll 750 dyads.
 

The Timing of In Utero Exposure

Shelley Ehrlich, MD, ScD, MPH, of the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, is aiming, meanwhile, to learn how the timing of in utero exposure to hyperglycemia predicts specific metabolic and cardiovascular morbidities in the adult offspring of diabetic mothers.

“While we know that exposure to maternal diabetes, regardless of type, increases the risk of obesity, insulin resistance, diabetes, renal compromise, and cardiovascular disease in the offspring, there is little known about the level and timing of hyperglycemic exposure during fetal development that triggers these adverse outcomes,” said Dr. Ehrlich. A goal, she said, is to identify gestational profiles that predict phenotypes of offspring at risk for morbidity in later life.

She and other investigators with the TEAM (Transgenerational Effect on Adult Morbidity) study have recruited over 170 offspring of mothers who participated in the Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati Medical Center from 1978 to 1995 — a landmark study that demonstrated the effect of strict glucose control in reducing major congenital malformations.

The women in the PPG study had frequent glucose monitoring (up to 6-8 times a day) throughout their pregnancies, and now, their recruited offspring, who are up to 43 years of age, are being assessed for obesity, diabetes/metabolic health, cardiovascular disease/cardiac and peripheral vascular structure and function, and other outcomes including those that may be amenable to secondary prevention (J Diabetes Res. Nov 1;2021:6590431).

Preliminary findings from over 170 offspring recruited between 2017 and 2022 suggest that in utero exposure to dysglycemia (as measured by standard deviations of glycohemoglobin) in the third trimester appears to increase the risk of morbid obesity in adulthood, while exposure to dysglycemia in the first trimester increases the risk of impaired glucose tolerance. The risk of B-cell dysfunction, meanwhile, appears to be linked to dysglycemia in the first and third trimesters — particularly the first — Dr. Ehrlich reported.

Cognitive outcomes in offspring have also been assessed and here it appears that dysglycemia in the third trimester is linked to worse scores on the Wechsler Abbreviated Scale of Intelligence (WASI-II), said Katherine Bowers, PhD, MPH, a TEAM study coinvestigator, also of Cincinnati Children’s Hospital Medical Center.

“We’ve already observed [an association between] diabetes in pregnancy and cognition in early childhood and through adolescence, but [the question has been] does this association persist into adulthood?” she said.

Preliminary analyses of 104 offspring show no statistically significant associations between maternal dysglycemia in the first or second trimesters and offspring cognition, but “consistent inverse associations between maternal glycohemoglobin in the third trimester across two [WASI-II] subscales and composite measures of cognition,” Dr. Bowers said.

Their analysis adjusted for a variety of factors, including maternal age, prepregnancy and first trimester BMI, race, family history of diabetes, and diabetes severity/macrovascular complications.
 

Back In The Laboratory

At the other end of the research spectrum, basic research scientists are also investigating the mechanisms and sequelae of in utero hyperglycemia and other injuries, including congenital malformations, placental adaptive responses and fetal programming. Researchers are asking, for instance, what does placental metabolic reprogramming entail? What role do placental extracellular vesicles play in GDM? Can we alter the in utero environment and thus improve the short and long-term fetal/infant outcomes?

Animal research done at the UMSOM Center for Birth Defects Research, led by Dr. Reece and Peixin Yang, PhD, suggests that “a good portion of in utero injury is due to epigenetics,” Dr. Reece said in the interview. “We’ve shown that under conditions of hyperglycemia, for example, genetic regulation and genetic function can be altered.”

Through in vivo research, they have also shown that antioxidants or membrane stabilizers such as arachidonic acid or myo-inositol, or experimental inhibitors to certain pro-apoptotic intermediates, can individually or collectively result in reduced malformations. “It is highly likely that understanding the biological impact of various altered in utero environments, and then modifying or reversing those environments, will result in short and long-term outcome improvements similar to those shown with congenital malformations,” Dr. Reece said.

Adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancer does not harm quality of life, according to patient-reported outcome analyses from the KEYNOTE-A18 trial.

Progression-free survival data from the trial, reported at the 2023 meeting of the European Society for Medical Oncology, showed a 30% reduction in the risk for progression (P =.002) with the addition of pembrolizumab vs placebo, as well as favorable overall survival trends, reported Leslie Randall, MD, with VCU Health in Richmond, Virginia. Now the new analyses bring the “voices of the patients from this large phase 3 study.”

“I think the data can put us at ease and give patients a measure of comfort because there was no detriment in the quality of life,” said Dr. Randall, who presented the data on March 17 at the Society of Gynecologic Oncology (SGO) 2024 conference.

The phase 3 KEYNOTE-A18 trial enrolled 1060 patients new to treatment who had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease. They were randomly allocated to receive pembrolizumab or placebo plus concurrent chemoradiotherapy.

Patient-reported outcome instruments used in the study were the European Organization for Research and Treatment of Cancer (EORTC) 30-item quality-of-life (QOL) core questionnaire (QLQ-C30), the EORTC cervical cancer–specific module (QLQ-CX24), and the EuroQol EQ-5D-5L visual analog scale (VAS). 

Prespecified secondary study endpoints were changes from baseline to week 36 in QLQ-C30 global health status/QOL (GHS/QOL) and physical functioning, and the QLQ-CX24 symptom-experience scale.

At baseline, patient-reported outcome scores were similar between treatment groups. Patients in both treatment groups had an initial decrease in QLQ-C30 GHS/QOL and physical functioning subscale and EQ-5D-5L VAS scores at weeks 3 and 6, but these improved relative to baseline at week 12 and subsequent weeks. 

A similar number of patients in the pembrolizumab and placebo groups had improved or stable scores for QLQ-C30 GHS/QOL (76% vs 75%), QLQ-C30 physical functioning (77% vs 77%), QLQ-CX24 symptom experience (85% vs 85%) and EQ-5D-5L VAS (73% vs 76%). 

Across all QOL instruments evaluated, there were no meaningful differences in patient-reported outcomes among patients who received pembrolizumab compared with those who received placebo, said Dr. Randall.

The improvement in progression-free survival, coupled with the patient-reported outcomes showing no additional harms to quality of life, support pembrolizumab plus concurrent chemoradiotherapy as a “new standard of care” for patients with high-risk locally advanced cervical cancer, she told attendees. 

“We have had stunning success in cervical cancer treatments over the past 10-15 years, and now we see that the addition of pembrolizumab to standard chemotherapy not only improves outcome but very importantly does not significantly impact the quality of life in our patients,” said study discussant R. Wendel Naumann, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Funding for KEYNOTE-A18 was provided by Merck. Dr. Randall has disclosed relationships with Seagen/Genmab, Merck, GSK, ImmunoGen, AstraZeneca, and On Target Laboratories. Dr. Naumann has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancer does not harm quality of life, according to patient-reported outcome analyses from the KEYNOTE-A18 trial.

Progression-free survival data from the trial, reported at the 2023 meeting of the European Society for Medical Oncology, showed a 30% reduction in the risk for progression (P =.002) with the addition of pembrolizumab vs placebo, as well as favorable overall survival trends, reported Leslie Randall, MD, with VCU Health in Richmond, Virginia. Now the new analyses bring the “voices of the patients from this large phase 3 study.”

“I think the data can put us at ease and give patients a measure of comfort because there was no detriment in the quality of life,” said Dr. Randall, who presented the data on March 17 at the Society of Gynecologic Oncology (SGO) 2024 conference.

The phase 3 KEYNOTE-A18 trial enrolled 1060 patients new to treatment who had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease. They were randomly allocated to receive pembrolizumab or placebo plus concurrent chemoradiotherapy.

Patient-reported outcome instruments used in the study were the European Organization for Research and Treatment of Cancer (EORTC) 30-item quality-of-life (QOL) core questionnaire (QLQ-C30), the EORTC cervical cancer–specific module (QLQ-CX24), and the EuroQol EQ-5D-5L visual analog scale (VAS). 

Prespecified secondary study endpoints were changes from baseline to week 36 in QLQ-C30 global health status/QOL (GHS/QOL) and physical functioning, and the QLQ-CX24 symptom-experience scale.

At baseline, patient-reported outcome scores were similar between treatment groups. Patients in both treatment groups had an initial decrease in QLQ-C30 GHS/QOL and physical functioning subscale and EQ-5D-5L VAS scores at weeks 3 and 6, but these improved relative to baseline at week 12 and subsequent weeks. 

A similar number of patients in the pembrolizumab and placebo groups had improved or stable scores for QLQ-C30 GHS/QOL (76% vs 75%), QLQ-C30 physical functioning (77% vs 77%), QLQ-CX24 symptom experience (85% vs 85%) and EQ-5D-5L VAS (73% vs 76%). 

Across all QOL instruments evaluated, there were no meaningful differences in patient-reported outcomes among patients who received pembrolizumab compared with those who received placebo, said Dr. Randall.

The improvement in progression-free survival, coupled with the patient-reported outcomes showing no additional harms to quality of life, support pembrolizumab plus concurrent chemoradiotherapy as a “new standard of care” for patients with high-risk locally advanced cervical cancer, she told attendees. 

“We have had stunning success in cervical cancer treatments over the past 10-15 years, and now we see that the addition of pembrolizumab to standard chemotherapy not only improves outcome but very importantly does not significantly impact the quality of life in our patients,” said study discussant R. Wendel Naumann, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Funding for KEYNOTE-A18 was provided by Merck. Dr. Randall has disclosed relationships with Seagen/Genmab, Merck, GSK, ImmunoGen, AstraZeneca, and On Target Laboratories. Dr. Naumann has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancer does not harm quality of life, according to patient-reported outcome analyses from the KEYNOTE-A18 trial.

Progression-free survival data from the trial, reported at the 2023 meeting of the European Society for Medical Oncology, showed a 30% reduction in the risk for progression (P =.002) with the addition of pembrolizumab vs placebo, as well as favorable overall survival trends, reported Leslie Randall, MD, with VCU Health in Richmond, Virginia. Now the new analyses bring the “voices of the patients from this large phase 3 study.”

“I think the data can put us at ease and give patients a measure of comfort because there was no detriment in the quality of life,” said Dr. Randall, who presented the data on March 17 at the Society of Gynecologic Oncology (SGO) 2024 conference.

The phase 3 KEYNOTE-A18 trial enrolled 1060 patients new to treatment who had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease. They were randomly allocated to receive pembrolizumab or placebo plus concurrent chemoradiotherapy.

Patient-reported outcome instruments used in the study were the European Organization for Research and Treatment of Cancer (EORTC) 30-item quality-of-life (QOL) core questionnaire (QLQ-C30), the EORTC cervical cancer–specific module (QLQ-CX24), and the EuroQol EQ-5D-5L visual analog scale (VAS). 

Prespecified secondary study endpoints were changes from baseline to week 36 in QLQ-C30 global health status/QOL (GHS/QOL) and physical functioning, and the QLQ-CX24 symptom-experience scale.

At baseline, patient-reported outcome scores were similar between treatment groups. Patients in both treatment groups had an initial decrease in QLQ-C30 GHS/QOL and physical functioning subscale and EQ-5D-5L VAS scores at weeks 3 and 6, but these improved relative to baseline at week 12 and subsequent weeks. 

A similar number of patients in the pembrolizumab and placebo groups had improved or stable scores for QLQ-C30 GHS/QOL (76% vs 75%), QLQ-C30 physical functioning (77% vs 77%), QLQ-CX24 symptom experience (85% vs 85%) and EQ-5D-5L VAS (73% vs 76%). 

Across all QOL instruments evaluated, there were no meaningful differences in patient-reported outcomes among patients who received pembrolizumab compared with those who received placebo, said Dr. Randall.

The improvement in progression-free survival, coupled with the patient-reported outcomes showing no additional harms to quality of life, support pembrolizumab plus concurrent chemoradiotherapy as a “new standard of care” for patients with high-risk locally advanced cervical cancer, she told attendees. 

“We have had stunning success in cervical cancer treatments over the past 10-15 years, and now we see that the addition of pembrolizumab to standard chemotherapy not only improves outcome but very importantly does not significantly impact the quality of life in our patients,” said study discussant R. Wendel Naumann, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Funding for KEYNOTE-A18 was provided by Merck. Dr. Randall has disclosed relationships with Seagen/Genmab, Merck, GSK, ImmunoGen, AstraZeneca, and On Target Laboratories. Dr. Naumann has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Stefan Bornstein, MD, PhD, professor, made it clear during a press conference at the 67th Congress of the German Society of Endocrinology (DGE) that there is more than one interaction between them. Nowadays, one can almost speak of an “endocrine virology and even of the virome as an additional, hormonally metabolically active gland,” said Dr. Bornstein, who will receive the Berthold Medal from the DGE in 2024.

Many questions remain unanswered: “We need a better understanding of the interaction of hormone systems with infectious agents — from basics to therapeutic applications,” emphasized the director of the Medical Clinic and Polyclinic III and the Center for Internal Medicine at the Carl Gustav Carus University Hospital, Dresden, Germany.

If infectious diseases could trigger diabetes and other metabolic diseases, this means that “through vaccination programs, we may be able to prevent the occurrence of common metabolic diseases such as diabetes,” said Dr. Bornstein. He highlighted that many people who experienced severe COVID-19 during the pandemic, or died from it, exhibited diabetes or a pre-metabolic syndrome.

“SARS-CoV-2 has utilized an endocrine signaling pathway to invade our cells and cause damage in the organ systems and inflammation,” said Dr. Bornstein. Conversely, it is now known that infections with coronaviruses or other infectious agents like influenza can significantly worsen metabolic status, diabetes, and other endocrine diseases.
 

SARS-CoV-2 Infects the Beta Cells

Data from the COVID-19 pandemic showed that the likelihood of developing type 1 diabetes significantly increases with a SARS-CoV-2 infection. Researchers led by Dr. Bornstein demonstrated in 2021 that SARS-CoV-2 can infect the insulin-producing cells of the organ. They examined pancreatic tissue from 20 patients who died from COVID-19 using immunofluorescence, immunohistochemistry, RNA in situ hybridization, and electron microscopy.

They found viral SARS-CoV-2 infiltration of the beta cells in all patients. In 11 patients with COVID-19, the expression of ACE2, TMPRSS, and other receptors and factors like DPP4, HMBG1, and NRP1 that can facilitate virus entry was examined. They found that even in the absence of manifest newly onset diabetes, necroptotic cell death, immune cell infiltration, and SARS-CoV-2 infection of the pancreas beta cells can contribute to varying degrees of metabolic disturbance in patients with COVID-19.

In a report published in October 2020, Tim Hollstein, MD, from the Institute for Diabetology and Clinical Metabolic Research at UKSH in Kiel, Germany, and colleagues described the case of a 19-year-old man who developed symptoms of insulin-dependent diabetes after a SARS-CoV-2 infection, without the presence of autoantibodies typical for type 1 diabetes.

The man presented to the emergency department with diabetic ketoacidosis, a C-peptide level of 0.62 µg/L, a blood glucose concentration of 30.6 mmol/L (552 mg/dL), and an A1c level of 16.8%. The patient’s history revealed a probable SARS-CoV-2 infection 5-7 weeks before admission, based on a positive antibody test against SARS-CoV-2.
 

Some Viruses Produce Insulin-Like Proteins

Recent studies have shown that some viruses can produce insulin-like proteins or hormones that interfere with the metabolism of the affected organism, reported Dr. Bornstein. In addition to metabolic regulation, these “viral hormones” also seem to influence cell turnover and cell death.

Dr. Bornstein pointed out that antiviral medications can delay the onset of type 1 diabetes by preserving the function of insulin-producing beta cells. It has also been shown that conventional medications used to treat hormonal disorders can reduce the susceptibility of the organism to infections — such as antidiabetic preparations like DPP-4 inhibitors or metformin.

In a review published in 2023, Nikolaos Perakakis, MD, professor, research group leader at the Paul Langerhans Institute Dresden, Dresden, Germany, Dr. Bornstein, and colleagues discussed scientific evidence for a close mutual dependence between various virus infections and metabolic diseases. They discussed how viruses can lead to the development or progression of metabolic diseases and vice versa and how metabolic diseases can increase the severity of a virus infection.
 

Viruses Favor Metabolic Diseases...

Viruses can favor metabolic diseases by, for example, influencing the regulation of cell survival and specific signaling pathways relevant for cell death, proliferation, or dedifferentiation in important endocrine and metabolic organs. Viruses are also capable of controlling cellular glucose metabolism by modulating glucose transporters, altering glucose uptake, regulating signaling pathways, and stimulating glycolysis in infected cells.

Due to the destruction of beta cells, enteroviruses, but also the mumps virus, parainfluenza virus, or human herpes virus 6, are associated with the development of diabetes. The timing of infection often precedes or coincides with the peak of development of islet autoantibodies. The fact that only a small proportion of patients actually develop type 1 diabetes suggests that genetic background, and likely the timing of infection, play an important role.
 

...And Metabolic Diseases Influence the Course of Infection

Infection with hepatitis C virus (HCV), on the other hand, is associated with an increased risk for type 2 diabetes, with the risk being higher for older individuals with a family history of diabetes. The negative effects of HCV on glucose balance are mainly attributed to increased insulin resistance in the liver. HCV reduces hepatic glucose uptake by downregulating the expression of glucose transporters and additionally impairs insulin signal transduction by inhibiting the PI3K/Akt signaling pathway.

People with obesity, diabetes, or insulin resistance show significant changes in the innate and adaptive functions of the immune system. Regarding the innate immune system, impaired chemotaxis and phagocytosis of neutrophils have been observed in patients with type 2 diabetes.

In the case of obesity, the number of natural killer T cells in adipose tissue decreases, whereas B cells accumulate in adipose tissue and secrete more proinflammatory cytokines. Longitudinal multiomics analyses of various biopsies from individuals with insulin resistance showed a delayed immune response to respiratory virus infections compared with individuals with normal insulin sensitivity.

This story was translated from Medscape Germany using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Stefan Bornstein, MD, PhD, professor, made it clear during a press conference at the 67th Congress of the German Society of Endocrinology (DGE) that there is more than one interaction between them. Nowadays, one can almost speak of an “endocrine virology and even of the virome as an additional, hormonally metabolically active gland,” said Dr. Bornstein, who will receive the Berthold Medal from the DGE in 2024.

Many questions remain unanswered: “We need a better understanding of the interaction of hormone systems with infectious agents — from basics to therapeutic applications,” emphasized the director of the Medical Clinic and Polyclinic III and the Center for Internal Medicine at the Carl Gustav Carus University Hospital, Dresden, Germany.

If infectious diseases could trigger diabetes and other metabolic diseases, this means that “through vaccination programs, we may be able to prevent the occurrence of common metabolic diseases such as diabetes,” said Dr. Bornstein. He highlighted that many people who experienced severe COVID-19 during the pandemic, or died from it, exhibited diabetes or a pre-metabolic syndrome.

“SARS-CoV-2 has utilized an endocrine signaling pathway to invade our cells and cause damage in the organ systems and inflammation,” said Dr. Bornstein. Conversely, it is now known that infections with coronaviruses or other infectious agents like influenza can significantly worsen metabolic status, diabetes, and other endocrine diseases.
 

SARS-CoV-2 Infects the Beta Cells

Data from the COVID-19 pandemic showed that the likelihood of developing type 1 diabetes significantly increases with a SARS-CoV-2 infection. Researchers led by Dr. Bornstein demonstrated in 2021 that SARS-CoV-2 can infect the insulin-producing cells of the organ. They examined pancreatic tissue from 20 patients who died from COVID-19 using immunofluorescence, immunohistochemistry, RNA in situ hybridization, and electron microscopy.

They found viral SARS-CoV-2 infiltration of the beta cells in all patients. In 11 patients with COVID-19, the expression of ACE2, TMPRSS, and other receptors and factors like DPP4, HMBG1, and NRP1 that can facilitate virus entry was examined. They found that even in the absence of manifest newly onset diabetes, necroptotic cell death, immune cell infiltration, and SARS-CoV-2 infection of the pancreas beta cells can contribute to varying degrees of metabolic disturbance in patients with COVID-19.

In a report published in October 2020, Tim Hollstein, MD, from the Institute for Diabetology and Clinical Metabolic Research at UKSH in Kiel, Germany, and colleagues described the case of a 19-year-old man who developed symptoms of insulin-dependent diabetes after a SARS-CoV-2 infection, without the presence of autoantibodies typical for type 1 diabetes.

The man presented to the emergency department with diabetic ketoacidosis, a C-peptide level of 0.62 µg/L, a blood glucose concentration of 30.6 mmol/L (552 mg/dL), and an A1c level of 16.8%. The patient’s history revealed a probable SARS-CoV-2 infection 5-7 weeks before admission, based on a positive antibody test against SARS-CoV-2.
 

Some Viruses Produce Insulin-Like Proteins

Recent studies have shown that some viruses can produce insulin-like proteins or hormones that interfere with the metabolism of the affected organism, reported Dr. Bornstein. In addition to metabolic regulation, these “viral hormones” also seem to influence cell turnover and cell death.

Dr. Bornstein pointed out that antiviral medications can delay the onset of type 1 diabetes by preserving the function of insulin-producing beta cells. It has also been shown that conventional medications used to treat hormonal disorders can reduce the susceptibility of the organism to infections — such as antidiabetic preparations like DPP-4 inhibitors or metformin.

In a review published in 2023, Nikolaos Perakakis, MD, professor, research group leader at the Paul Langerhans Institute Dresden, Dresden, Germany, Dr. Bornstein, and colleagues discussed scientific evidence for a close mutual dependence between various virus infections and metabolic diseases. They discussed how viruses can lead to the development or progression of metabolic diseases and vice versa and how metabolic diseases can increase the severity of a virus infection.
 

Viruses Favor Metabolic Diseases...

Viruses can favor metabolic diseases by, for example, influencing the regulation of cell survival and specific signaling pathways relevant for cell death, proliferation, or dedifferentiation in important endocrine and metabolic organs. Viruses are also capable of controlling cellular glucose metabolism by modulating glucose transporters, altering glucose uptake, regulating signaling pathways, and stimulating glycolysis in infected cells.

Due to the destruction of beta cells, enteroviruses, but also the mumps virus, parainfluenza virus, or human herpes virus 6, are associated with the development of diabetes. The timing of infection often precedes or coincides with the peak of development of islet autoantibodies. The fact that only a small proportion of patients actually develop type 1 diabetes suggests that genetic background, and likely the timing of infection, play an important role.
 

...And Metabolic Diseases Influence the Course of Infection

Infection with hepatitis C virus (HCV), on the other hand, is associated with an increased risk for type 2 diabetes, with the risk being higher for older individuals with a family history of diabetes. The negative effects of HCV on glucose balance are mainly attributed to increased insulin resistance in the liver. HCV reduces hepatic glucose uptake by downregulating the expression of glucose transporters and additionally impairs insulin signal transduction by inhibiting the PI3K/Akt signaling pathway.

People with obesity, diabetes, or insulin resistance show significant changes in the innate and adaptive functions of the immune system. Regarding the innate immune system, impaired chemotaxis and phagocytosis of neutrophils have been observed in patients with type 2 diabetes.

In the case of obesity, the number of natural killer T cells in adipose tissue decreases, whereas B cells accumulate in adipose tissue and secrete more proinflammatory cytokines. Longitudinal multiomics analyses of various biopsies from individuals with insulin resistance showed a delayed immune response to respiratory virus infections compared with individuals with normal insulin sensitivity.

This story was translated from Medscape Germany using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Stefan Bornstein, MD, PhD, professor, made it clear during a press conference at the 67th Congress of the German Society of Endocrinology (DGE) that there is more than one interaction between them. Nowadays, one can almost speak of an “endocrine virology and even of the virome as an additional, hormonally metabolically active gland,” said Dr. Bornstein, who will receive the Berthold Medal from the DGE in 2024.

Many questions remain unanswered: “We need a better understanding of the interaction of hormone systems with infectious agents — from basics to therapeutic applications,” emphasized the director of the Medical Clinic and Polyclinic III and the Center for Internal Medicine at the Carl Gustav Carus University Hospital, Dresden, Germany.

If infectious diseases could trigger diabetes and other metabolic diseases, this means that “through vaccination programs, we may be able to prevent the occurrence of common metabolic diseases such as diabetes,” said Dr. Bornstein. He highlighted that many people who experienced severe COVID-19 during the pandemic, or died from it, exhibited diabetes or a pre-metabolic syndrome.

“SARS-CoV-2 has utilized an endocrine signaling pathway to invade our cells and cause damage in the organ systems and inflammation,” said Dr. Bornstein. Conversely, it is now known that infections with coronaviruses or other infectious agents like influenza can significantly worsen metabolic status, diabetes, and other endocrine diseases.
 

SARS-CoV-2 Infects the Beta Cells

Data from the COVID-19 pandemic showed that the likelihood of developing type 1 diabetes significantly increases with a SARS-CoV-2 infection. Researchers led by Dr. Bornstein demonstrated in 2021 that SARS-CoV-2 can infect the insulin-producing cells of the organ. They examined pancreatic tissue from 20 patients who died from COVID-19 using immunofluorescence, immunohistochemistry, RNA in situ hybridization, and electron microscopy.

They found viral SARS-CoV-2 infiltration of the beta cells in all patients. In 11 patients with COVID-19, the expression of ACE2, TMPRSS, and other receptors and factors like DPP4, HMBG1, and NRP1 that can facilitate virus entry was examined. They found that even in the absence of manifest newly onset diabetes, necroptotic cell death, immune cell infiltration, and SARS-CoV-2 infection of the pancreas beta cells can contribute to varying degrees of metabolic disturbance in patients with COVID-19.

In a report published in October 2020, Tim Hollstein, MD, from the Institute for Diabetology and Clinical Metabolic Research at UKSH in Kiel, Germany, and colleagues described the case of a 19-year-old man who developed symptoms of insulin-dependent diabetes after a SARS-CoV-2 infection, without the presence of autoantibodies typical for type 1 diabetes.

The man presented to the emergency department with diabetic ketoacidosis, a C-peptide level of 0.62 µg/L, a blood glucose concentration of 30.6 mmol/L (552 mg/dL), and an A1c level of 16.8%. The patient’s history revealed a probable SARS-CoV-2 infection 5-7 weeks before admission, based on a positive antibody test against SARS-CoV-2.
 

Some Viruses Produce Insulin-Like Proteins

Recent studies have shown that some viruses can produce insulin-like proteins or hormones that interfere with the metabolism of the affected organism, reported Dr. Bornstein. In addition to metabolic regulation, these “viral hormones” also seem to influence cell turnover and cell death.

Dr. Bornstein pointed out that antiviral medications can delay the onset of type 1 diabetes by preserving the function of insulin-producing beta cells. It has also been shown that conventional medications used to treat hormonal disorders can reduce the susceptibility of the organism to infections — such as antidiabetic preparations like DPP-4 inhibitors or metformin.

In a review published in 2023, Nikolaos Perakakis, MD, professor, research group leader at the Paul Langerhans Institute Dresden, Dresden, Germany, Dr. Bornstein, and colleagues discussed scientific evidence for a close mutual dependence between various virus infections and metabolic diseases. They discussed how viruses can lead to the development or progression of metabolic diseases and vice versa and how metabolic diseases can increase the severity of a virus infection.
 

Viruses Favor Metabolic Diseases...

Viruses can favor metabolic diseases by, for example, influencing the regulation of cell survival and specific signaling pathways relevant for cell death, proliferation, or dedifferentiation in important endocrine and metabolic organs. Viruses are also capable of controlling cellular glucose metabolism by modulating glucose transporters, altering glucose uptake, regulating signaling pathways, and stimulating glycolysis in infected cells.

Due to the destruction of beta cells, enteroviruses, but also the mumps virus, parainfluenza virus, or human herpes virus 6, are associated with the development of diabetes. The timing of infection often precedes or coincides with the peak of development of islet autoantibodies. The fact that only a small proportion of patients actually develop type 1 diabetes suggests that genetic background, and likely the timing of infection, play an important role.
 

...And Metabolic Diseases Influence the Course of Infection

Infection with hepatitis C virus (HCV), on the other hand, is associated with an increased risk for type 2 diabetes, with the risk being higher for older individuals with a family history of diabetes. The negative effects of HCV on glucose balance are mainly attributed to increased insulin resistance in the liver. HCV reduces hepatic glucose uptake by downregulating the expression of glucose transporters and additionally impairs insulin signal transduction by inhibiting the PI3K/Akt signaling pathway.

People with obesity, diabetes, or insulin resistance show significant changes in the innate and adaptive functions of the immune system. Regarding the innate immune system, impaired chemotaxis and phagocytosis of neutrophils have been observed in patients with type 2 diabetes.

In the case of obesity, the number of natural killer T cells in adipose tissue decreases, whereas B cells accumulate in adipose tissue and secrete more proinflammatory cytokines. Longitudinal multiomics analyses of various biopsies from individuals with insulin resistance showed a delayed immune response to respiratory virus infections compared with individuals with normal insulin sensitivity.

This story was translated from Medscape Germany using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Adding an immune checkpoint inhibitor to platinum-based chemotherapy resulted in a more than 1-year gain in median overall survival for women with primary advanced or recurrent endometrial cancer.

The benefit of the combination of the programmed death protein 1 (PD-1) inhibitor dostarlimab (Jemperli) and chemotherapy was even more pronounced among patients with DNA mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) tumors.

These results, from the second interim analysis of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial, were cheered by audience members when they were reported at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer, held in San Diego, California.

“Overall survival benefit to the addition of PD-1 inhibitor to chemotherapy upfront for patients with advanced and recurrent MSI-high endometrial cancer: SOLD!” said invited discussant Gini Fleming, medical director of gynecologic oncology at the University of Chicago.

“I think this is a huge win for our patients. It’s something that none of us have seen before over many years of working with endometrial cancer and should be incorporated into everybody’s practice as of yesterday,” she said.

Continued Improvement

Results from the first interim analysis of the trial showed that dostarlimab and chemotherapy significantly improved progression-free survival (PFS) in the dMMR/MSI-H population, and there was an early trend toward improved overall survival, compared with chemotherapy plus placebo.

As Matthew A. Powell, MD from Washington University School of Medicine in Saint Louis, Missouri reported at SGO 2024, that early trend has become an undeniable survival advantage.

At a median follow-up of 37.2 months, the median overall survival was 44.6 months for patients randomized to the combination, compared with 28.2 months for those assigned to chemotherapy plus placebo.

The respective 3-year overall survival (OS) rates were 54.9% and 42.9%, translating into a hazard ratio (HR) for death with dostarlimab/chemotherapy of 0.69 (P = .002).

Among the subset of patients with dMMR/MSI-H tumors the survival benefit conferred by the combination was even greater, with median OS not reached in the dostarlimab group vs 31.4 months in the chemotherapy-alone arm, with respective 3-year OS rates of 78% and 46%. This difference translated into a HR for death with the combination of 0.32 (P = .0002) for patients with deficient mismatch-repair cancers.

“Dostarlimab plus carboplatin-paclitaxel chemotherapy demonstrated statistically significant and clinically meaningful overall survival improvements in the overall population, a substantial unprecedented overall survival benefit in patients with defective mismatch-repair tumors, and a clinically meaningful; 7-month improvement in the OS difference in patients with proficient mismatch-repair tumors,” Dr. Powell said.

RUBY Details

The trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m² of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or dostarlimab placebo every 6 weeks for up to 3 years.

Within the cohort, 118 patients (23.9%) had dMMR/MSI-H tumors.

At the time of the first interim analysis the estimated progression-free survival at 24 months in the dMMR–MSI-H subgroup was 61.4% in the dostarlimab group vs 15.7 in the placebo group (HR for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < .001).

A prespecified exploratory analysis of progression-free survival in proficient MMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.

Overall survival at that time also favored dostarlimab, although it was only mature for 33% of the population. But at 24 months, OS rates were 71.3% vs 56.0% among placebo recipients; this difference approached but did not reach statistical significance.

The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR/MSS population.

The most common adverse events observed were nausea, alopecia, and fatigue. Grade 3 and higher adverse events at the most recent follow-up were more frequent in the dostarlimab group than in the placebo group (72.2% vs 60.2%).

“Importantly, safety was maintained” at the second interim analysis, Dr. Powell said.

“No new safety signals were noted, no new deaths related to therapy were noted with the subsequent 1-year additional analysis time,” he said.

What’s Next?

Dr. Fleming reviewed potential strategies for further improving care of patients with advanced or recurrent endometrial cancer during her discussion.

“What are the next directions for patients with MSI-high disease? Well, obviously could we use immune checkpoint inhibitors without chemotherapy and not compromise results? There are two ongoing trials or trials that we’re awaiting results of that have compared single-agent immune checkpoint inhibitor to just chemotherapy in mismatch repair-deficient advanced disease, and hopefully we can extrapolate from these trials to determine if this might be a more patient-friendly and equally effective strategy, but we don’t yet know,” she said.

Dr. Fleming also noted that ongoing or planned clinical trials will address questions about potential options for patients with MSI-H tumors whose disease progresses on frontline chemotherapy and immunotherapy. Other trials are assessing whether combining radiotherapy with checkpoint inhibitors will be effective in treating patients with earlier-stage tumors, or whether the addition of a PARP inhibitor might offer additional benefit for these patients.

“Immune checkpoint inhibitor should be given first line to patients with advanced/recurrent microsatellite [instability] endometrial cancer, and they should be considered as front line in patients with microsatellite stable disease. At this point, unfortunately, we have no reasonable predictive factors to know which of those patients with microsatellite stable disease will truly benefit. Multiple other agents are being tested in this setting, and will hopefully prove useful in subgroups,” she said.

The study is funded by GlaxoSmithKline. Dr. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. Dr. Fleming reports serving as an institutional principal investigator for trials sponsored by multiple companies, not including GSK.

Adding an immune checkpoint inhibitor to platinum-based chemotherapy resulted in a more than 1-year gain in median overall survival for women with primary advanced or recurrent endometrial cancer.

The benefit of the combination of the programmed death protein 1 (PD-1) inhibitor dostarlimab (Jemperli) and chemotherapy was even more pronounced among patients with DNA mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) tumors.

These results, from the second interim analysis of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial, were cheered by audience members when they were reported at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer, held in San Diego, California.

“Overall survival benefit to the addition of PD-1 inhibitor to chemotherapy upfront for patients with advanced and recurrent MSI-high endometrial cancer: SOLD!” said invited discussant Gini Fleming, medical director of gynecologic oncology at the University of Chicago.

“I think this is a huge win for our patients. It’s something that none of us have seen before over many years of working with endometrial cancer and should be incorporated into everybody’s practice as of yesterday,” she said.

Continued Improvement

Results from the first interim analysis of the trial showed that dostarlimab and chemotherapy significantly improved progression-free survival (PFS) in the dMMR/MSI-H population, and there was an early trend toward improved overall survival, compared with chemotherapy plus placebo.

As Matthew A. Powell, MD from Washington University School of Medicine in Saint Louis, Missouri reported at SGO 2024, that early trend has become an undeniable survival advantage.

At a median follow-up of 37.2 months, the median overall survival was 44.6 months for patients randomized to the combination, compared with 28.2 months for those assigned to chemotherapy plus placebo.

The respective 3-year overall survival (OS) rates were 54.9% and 42.9%, translating into a hazard ratio (HR) for death with dostarlimab/chemotherapy of 0.69 (P = .002).

Among the subset of patients with dMMR/MSI-H tumors the survival benefit conferred by the combination was even greater, with median OS not reached in the dostarlimab group vs 31.4 months in the chemotherapy-alone arm, with respective 3-year OS rates of 78% and 46%. This difference translated into a HR for death with the combination of 0.32 (P = .0002) for patients with deficient mismatch-repair cancers.

“Dostarlimab plus carboplatin-paclitaxel chemotherapy demonstrated statistically significant and clinically meaningful overall survival improvements in the overall population, a substantial unprecedented overall survival benefit in patients with defective mismatch-repair tumors, and a clinically meaningful; 7-month improvement in the OS difference in patients with proficient mismatch-repair tumors,” Dr. Powell said.

RUBY Details

The trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m² of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or dostarlimab placebo every 6 weeks for up to 3 years.

Within the cohort, 118 patients (23.9%) had dMMR/MSI-H tumors.

At the time of the first interim analysis the estimated progression-free survival at 24 months in the dMMR–MSI-H subgroup was 61.4% in the dostarlimab group vs 15.7 in the placebo group (HR for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < .001).

A prespecified exploratory analysis of progression-free survival in proficient MMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.

Overall survival at that time also favored dostarlimab, although it was only mature for 33% of the population. But at 24 months, OS rates were 71.3% vs 56.0% among placebo recipients; this difference approached but did not reach statistical significance.

The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR/MSS population.

The most common adverse events observed were nausea, alopecia, and fatigue. Grade 3 and higher adverse events at the most recent follow-up were more frequent in the dostarlimab group than in the placebo group (72.2% vs 60.2%).

“Importantly, safety was maintained” at the second interim analysis, Dr. Powell said.

“No new safety signals were noted, no new deaths related to therapy were noted with the subsequent 1-year additional analysis time,” he said.

What’s Next?

Dr. Fleming reviewed potential strategies for further improving care of patients with advanced or recurrent endometrial cancer during her discussion.

“What are the next directions for patients with MSI-high disease? Well, obviously could we use immune checkpoint inhibitors without chemotherapy and not compromise results? There are two ongoing trials or trials that we’re awaiting results of that have compared single-agent immune checkpoint inhibitor to just chemotherapy in mismatch repair-deficient advanced disease, and hopefully we can extrapolate from these trials to determine if this might be a more patient-friendly and equally effective strategy, but we don’t yet know,” she said.

Dr. Fleming also noted that ongoing or planned clinical trials will address questions about potential options for patients with MSI-H tumors whose disease progresses on frontline chemotherapy and immunotherapy. Other trials are assessing whether combining radiotherapy with checkpoint inhibitors will be effective in treating patients with earlier-stage tumors, or whether the addition of a PARP inhibitor might offer additional benefit for these patients.

“Immune checkpoint inhibitor should be given first line to patients with advanced/recurrent microsatellite [instability] endometrial cancer, and they should be considered as front line in patients with microsatellite stable disease. At this point, unfortunately, we have no reasonable predictive factors to know which of those patients with microsatellite stable disease will truly benefit. Multiple other agents are being tested in this setting, and will hopefully prove useful in subgroups,” she said.

The study is funded by GlaxoSmithKline. Dr. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. Dr. Fleming reports serving as an institutional principal investigator for trials sponsored by multiple companies, not including GSK.

Adding an immune checkpoint inhibitor to platinum-based chemotherapy resulted in a more than 1-year gain in median overall survival for women with primary advanced or recurrent endometrial cancer.

The benefit of the combination of the programmed death protein 1 (PD-1) inhibitor dostarlimab (Jemperli) and chemotherapy was even more pronounced among patients with DNA mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) tumors.

These results, from the second interim analysis of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial, were cheered by audience members when they were reported at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer, held in San Diego, California.

“Overall survival benefit to the addition of PD-1 inhibitor to chemotherapy upfront for patients with advanced and recurrent MSI-high endometrial cancer: SOLD!” said invited discussant Gini Fleming, medical director of gynecologic oncology at the University of Chicago.

“I think this is a huge win for our patients. It’s something that none of us have seen before over many years of working with endometrial cancer and should be incorporated into everybody’s practice as of yesterday,” she said.

Continued Improvement

Results from the first interim analysis of the trial showed that dostarlimab and chemotherapy significantly improved progression-free survival (PFS) in the dMMR/MSI-H population, and there was an early trend toward improved overall survival, compared with chemotherapy plus placebo.

As Matthew A. Powell, MD from Washington University School of Medicine in Saint Louis, Missouri reported at SGO 2024, that early trend has become an undeniable survival advantage.

At a median follow-up of 37.2 months, the median overall survival was 44.6 months for patients randomized to the combination, compared with 28.2 months for those assigned to chemotherapy plus placebo.

The respective 3-year overall survival (OS) rates were 54.9% and 42.9%, translating into a hazard ratio (HR) for death with dostarlimab/chemotherapy of 0.69 (P = .002).

Among the subset of patients with dMMR/MSI-H tumors the survival benefit conferred by the combination was even greater, with median OS not reached in the dostarlimab group vs 31.4 months in the chemotherapy-alone arm, with respective 3-year OS rates of 78% and 46%. This difference translated into a HR for death with the combination of 0.32 (P = .0002) for patients with deficient mismatch-repair cancers.

“Dostarlimab plus carboplatin-paclitaxel chemotherapy demonstrated statistically significant and clinically meaningful overall survival improvements in the overall population, a substantial unprecedented overall survival benefit in patients with defective mismatch-repair tumors, and a clinically meaningful; 7-month improvement in the OS difference in patients with proficient mismatch-repair tumors,” Dr. Powell said.

RUBY Details

The trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m² of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or dostarlimab placebo every 6 weeks for up to 3 years.

Within the cohort, 118 patients (23.9%) had dMMR/MSI-H tumors.

At the time of the first interim analysis the estimated progression-free survival at 24 months in the dMMR–MSI-H subgroup was 61.4% in the dostarlimab group vs 15.7 in the placebo group (HR for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < .001).

A prespecified exploratory analysis of progression-free survival in proficient MMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.

Overall survival at that time also favored dostarlimab, although it was only mature for 33% of the population. But at 24 months, OS rates were 71.3% vs 56.0% among placebo recipients; this difference approached but did not reach statistical significance.

The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR/MSS population.

The most common adverse events observed were nausea, alopecia, and fatigue. Grade 3 and higher adverse events at the most recent follow-up were more frequent in the dostarlimab group than in the placebo group (72.2% vs 60.2%).

“Importantly, safety was maintained” at the second interim analysis, Dr. Powell said.

“No new safety signals were noted, no new deaths related to therapy were noted with the subsequent 1-year additional analysis time,” he said.

What’s Next?

Dr. Fleming reviewed potential strategies for further improving care of patients with advanced or recurrent endometrial cancer during her discussion.

“What are the next directions for patients with MSI-high disease? Well, obviously could we use immune checkpoint inhibitors without chemotherapy and not compromise results? There are two ongoing trials or trials that we’re awaiting results of that have compared single-agent immune checkpoint inhibitor to just chemotherapy in mismatch repair-deficient advanced disease, and hopefully we can extrapolate from these trials to determine if this might be a more patient-friendly and equally effective strategy, but we don’t yet know,” she said.

Dr. Fleming also noted that ongoing or planned clinical trials will address questions about potential options for patients with MSI-H tumors whose disease progresses on frontline chemotherapy and immunotherapy. Other trials are assessing whether combining radiotherapy with checkpoint inhibitors will be effective in treating patients with earlier-stage tumors, or whether the addition of a PARP inhibitor might offer additional benefit for these patients.

“Immune checkpoint inhibitor should be given first line to patients with advanced/recurrent microsatellite [instability] endometrial cancer, and they should be considered as front line in patients with microsatellite stable disease. At this point, unfortunately, we have no reasonable predictive factors to know which of those patients with microsatellite stable disease will truly benefit. Multiple other agents are being tested in this setting, and will hopefully prove useful in subgroups,” she said.

The study is funded by GlaxoSmithKline. Dr. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. Dr. Fleming reports serving as an institutional principal investigator for trials sponsored by multiple companies, not including GSK.